Besides cancer cells, how many cell types are there in tumors? What are the “good” cells and “bad” cells?

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Are certain cells within tumors really good or bad? Aren’t cells just cells, neither good nor bad? Engendering a distorted view of biology, conceptual landscapes that assign cells such non-scientific labels commit them to unnatural pre-ordained, immutable fates. Obscuring rather than illuminating, such cartoon landscapes are populated by static dummy stand-ins that bear little or no resemblance to their real counterparts, which are actually much more dynamic. Such labels also restrict consideration of what and how to examine and why.

Thus, rather than ask whether a tumor-associated cell is good or bad, examining the role of each cell type over the course of tumor progression and comparing a given cell type across tumors is more fruitful. Doing so reveals that most non-cancerous cell types within cancers are capable of both promoting and inhibiting tumor growth. Examining tumor-dwelling cells in this fashion is more fruitful because it helps alter the approach from the scorched earth one that sees them as either inherently ‘good’ or ‘bad’ to one that considers them amenable to manipulations, i.e., future therapies, that could alter their fates to inhibit tumor growth.

Apart from cancer cells themselves, solid tumors usually contain CAFs (cancer-associated fibroblasts), MDSC (Myeloid-derived suppressor cell – Wikipedia), TAMs (Tumor-associated macrophage – Wikipedia), TANs (Tumor-Associated Neutrophils), TILs (Tumor-infiltrating lymphocytes – Wikipedia), and blood vessel-associated cells.

This answer shares brief summaries of some of these various tumor-associated cells, highlighting the inherent ambiguity in determining what they augur for various cancer outcomes.

CAFs (Cancer-Associated Fibroblasts)

Key cells in wound healing, that fibroblasts from different tissues are quite different is itself a fairly recent realization (1).

CAF OTOH usually differ from their normal counterparts through increased rate of proliferation, and altered expression of extracellular matrix (ECM) and growth factors (2).

CAF are hypothesized to remodel the ECM in tumor tissue and provide tumor cells with growth factors (3).

While there are plenty of in vitro and mouse model (4, 5, 6) and even human (7) studies with data suggesting CAF promote tumor growth and invasion, at least one in vitro and mouse model study (8) also showed that high levels of estrogen receptor alpha- expressing CAF inhibited infiltration of TAM, an outcome that in turn suppressed prostate cancer invasion.

TAMs (Tumor-associated macrophage – Wikipedia)

Meta-analyses (9, 10) of TAM studies in most human solid tumors conclude they could be either pro- or anti-tumorigenic, specifically that their presence is associated with worse overall survival in gastric, urogenital, and head and neck cancer, and better overall survival in colorectal cancer.

TANs (Tumor-Associated Neutrophils)

TANs epitomize the Janus – Wikipedia face of non-cancerous tumor-associated cells (11). At least one mouse model study (12) chose to examine TAN phenotype and effects at different points of time during tumor progression in mouse lung and mesothelioma models. Doing so showed TANS are tumor-killing (cytotoxic) in early tumors but tumorigenic in established tumors. Such an answer wouldn’t be possible if researchers pursued their studies stuck on the notion that TANs are inherently ‘bad’, i.e., tumor-promoting.

Obviously such tumor progression studies are far less feasible in humans. Instead TAN snapshots of well-established human tumors suggest they’re associated with poor prognosis in renal cell carcinoma, melanoma, colorectal cancer, and many others (13). Of course, this still leaves their role in human tumor initiation open-ended.

TILs (Tumor-infiltrating lymphocytes – Wikipedia)

For the most part, heavy tumor infiltration by CD8+ CTLs (Cytotoxic T cell – Wikipedia) (14) augurs well for cancer patients except in the case of renal cell carcinoma (15).

Situation is even more confusing and ambiguous with prognoses ranging from poor to no effect to good across T helper cell – Wikipedia phenotypes and tumor types (14). Prevailing norm of forcing CD4 T cells into artificial bins/buckets of phenotypes such as Th1, Th2, Th17, Treg, etc., is a major source of such confusion (16), classic example of missing the forest for the trees.

Bibliography

1. Rinn, John L., et al. “Anatomic demarcation by positional variation in fibroblast gene expression programs.” PLoS Genet 2.7 (2006): e119. http://journals.plos.org/plosgen…

2. Kalluri, Raghu, and Michael Zeisberg. “Fibroblasts in cancer.” Nature Reviews Cancer 6.5 (2006): 392-401. http://s3.amazonaws.com/academia…

3. Bhowmick, Neil A., Eric G. Neilson, and Harold L. Moses. “Stromal fibroblasts in cancer initiation and progression.” Nature 432.7015 (2004): 332-337. https://www.ncbi.nlm.nih.gov/pmc…

4. Franco, Omar E., et al. “Cancer associated fibroblasts in cancer pathogenesis.” Seminars in cell & developmental biology. Vol. 21. No. 1. Academic Press, 2010. https://www.researchgate.net/pro…

5. Chiarugi, Paola. “Cancer-associated fibroblasts and macrophages: Friendly conspirators for malignancy.” Oncoimmunology 2.9 (2013): e25563. http://www.tandfonline.com/doi/p…

6. Shiga, Kazuyoshi, et al. “Cancer-associated fibroblasts: their characteristics and their roles in tumor growth.” Cancers 7.4 (2015): 2443-2458. http://www.mdpi.com/2072-6694/7/…

7. Erez, Neta, et al. “Cancer associated fibroblasts express pro-inflammatory factors in human breast and ovarian tumors.” Biochemical and biophysical research communications 437.3 (2013): 397-402.

8. Yeh, Chiuan-Ren, et al. “Estrogen receptor α in cancer associated fibroblasts suppresses prostate cancer invasion via reducing CCL5, IL6 and macrophage infiltration in the tumor microenvironment.” Molecular cancer 15.1 (2016): 7. https://pdfs.semanticscholar.org…

9. Zhang, Qiong-wen, et al. “Prognostic significance of tumor-associated macrophages in solid tumor: a meta-analysis of the literature.” PloS one 7.12 (2012): e50946. http://journals.plos.org/plosone…

10. Kim, Jaehong, and Jong-Sup Bae. “Tumor-associated macrophages and neutrophils in tumor microenvironment.” Mediators of inflammation 2016 (2016). http://downloads.hindawi.com/jou…

11. Gregory, Alyssa D., and A. McGarry Houghton. “Tumor-associated neutrophils: new targets for cancer therapy.” Cancer research 71.7 (2011): 2411-2416. http://cancerres.aacrjournals.or…

12. Mishalian, Inbal, et al. “Tumor-associated neutrophils (TAN) develop pro-tumorigenic properties during tumor progression.” Cancer Immunology, Immunotherapy 62.11 (2013): 1745-1756.

13. Donskov, Frede. “Immunomonitoring and prognostic relevance of neutrophils in clinical trials.” Seminars in cancer biology. Vol. 23. No. 3. Academic Press, 2013. https://www.researchgate.net/pro…

14. Fridman, Wolf Herman, et al. “The immune contexture in human tumours: impact on clinical outcome.” Nature Reviews Cancer 12.4 (2012): 298-306. https://www.researchgate.net/pro…

15. Nakano, Osamu, et al. “Proliferative activity of intratumoral CD8+ T-lymphocytes as a prognostic factor in human renal cell carcinoma.” Cancer research 61.13 (2001): 5132-5136. http://cancerres.aacrjournals.or…

16. Tirumalai Kamala’s answer to What’s the difference between Th1 and Th2 helper T-cell subsets?

https://www.quora.com/Besides-cancer-cells-how-many-cell-types-are-there-in-tumors-What-are-the-good-cells-and-bad-cells/answer/Tirumalai-Kamala

Why do some studies use CMV recall assays to check in vitro functional activity of checkpoint inhibitors?

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Short answer: CMV (Cytomegalovirus – Wikipedia) infects most human beings at some point in their life. Human anti-CMV T cell responses are thus a convenient in vitro antigen-specific tool to assess checkpoint inhibitor mAb (monoclonal antibody) functional capability, specifically, whether they function as they should and thus by extension, could reverse human cancer antigen-specific T cell inhibition.

Slightly longer answer

Brief Explanation For Rationale Of Checkpoint Inhibitors

Activated T cells express the PD-1 molecule on their surface. T cell PD-1 binding to PD-L1 expressed by other cells sends an inhibitory signal into the T cell. Such T cells stop proliferating and secreting cytokines, meaning PD-1-PD-L1 binding essentially inhibits T cell effector function.

Many cancer cells highly express PD-L1. Checkpoint inhibitor mAbs that selectively target PD-1 (Nivolumab – Wikipedia and Pembrolizumab – Wikipedia) and PD-L1 (Atezolizumab – Wikipedia) molecules prevent PD-1-PD-L1 interaction. This is akin to releasing the brakes off of previously activated and presently inhibited T cells.

Checkpoint inhibitors used in Cancer immunotherapy – Wikipedia imply cancer antigen-specific T cells exist but are inhibited by molecules such as PD-1 and CTLA-4 and that blocking them releases the full tumor-killing potential of such T cells. Checkpoint inhibitors unblock other T cells as well, meaning autoimmunity and other tissue pathologies are also possible.

CMV Recall Assay To Assess Functional Capability Of Checkpoint Inhibitor mAbs

A checkpoint inhibitor mAb such as anti-PD-1 Nivolumab can bind PD-1 expressed by any T cell. How to assess if such binding did indeed lift the brakes off of that T cell as it should? Knowing a T cell’s antigenic specificity makes it a piece of cake to assess changes in its responsiveness. For example, in basic immunology, often experiments are done with genetically engineered TCR – Wikipedia transgenic mice having T cells with a single known, i.e., monoclonal, antigenic specificity. The antigenic peptide specificity of all the T cells in such a mouse is the same. Just culture such T cells with APCs (Antigen-presenting cell – Wikipedia) pulsed with the antigenic peptide they’re specific for in the presence or absence of a checkpoint inhibitor mAb.

Obviously, this is far from feasible for assessing human T cell responses. What type of antigen could then be used to assess functional alterations in human T cell responsiveness? This is especially an issue when using checkpoint inhibitor mAbs in cancer immunotherapy, where cancer-specific T cell antigens often remain unknown. How to confirm functional capability of checkpoint inhibitor mAbs, confirm that a new batch can lift the brakes off of previously activated but currently inhibited T cells as it should? That’s where in vitro assays such as the non-antigen-specific MLR (Mixed lymphocyte reaction – Wikipedia), Superantigen – Wikipedia SEB (Enterotoxin type B – Wikipedia) stimulation and the antigen-specific CMV recall assay enter the picture.

CMV

  • Chronically infects most human beings at some point in their life (1).
  • Estimated ~60% and ~90% US prevalence in those >/=6 and >/=80 years of age, respectively, from 1988 to 1994 (2).
  • Elicits strong T cell immune responses and plenty is known about the features of effective human anti-CMV immunity (3).
  • For example, CMV’s pp65 protein is a major target of human CD4 and CD8 T cell responses (4, 5, 6, 7, 8).

Such features make assessing changes in human anti-CMV T cell responses a handy tool to monitor functional capability of checkpoint inhibitor mAbs. See an example of such assessment below from 9.

Bibliography

1. Tirumalai Kamala’s answer to What do we know about the function of viruses in the microbiome?

2. Staras, Stephanie AS, et al. “Seroprevalence of cytomegalovirus infection in the United States, 1988–1994.” Clinical Infectious Diseases 43.9 (2006): 1143-1151. https://www.researchgate.net/pro…

3. Gamadia, Laila E., et al. “Primary immune responses to human CMV: a critical role for IFN-γ–producing CD4+ T cells in protection against CMV disease.” Blood 101.7 (2003): 2686-2692. https://www.researchgate.net/pro…

4. Grefte, J. M. M., et al. “The lower matrix protein pp65 is the principal viral antigen present in peripheral blood leukocytes during an active cytomegalovirus infection.” Journal of general virology 73.11 (1992): 2923-2932.

5. Khattab, Barbara Anna‐Maria, et al. “Three T‐cell epitopes within the C‐terminal 265 amino acids of the matrix protein pp65 of human cytomegalovirus recognized by human lymphocytes.” Journal of medical virology 52.1 (1997): 68-76.

6. Gyulai, Zsofia, et al. “Cytotoxic T lymphocyte (CTL) responses to human cytomegalovirus pp65, IE1-Exon4, gB, pp150, and pp28 in healthy individuals: reevaluation of prevalence of IE1-specific CTLs.” Journal of Infectious Diseases 181.5 (2000): 1537-1546. https://www.researchgate.net/pro…

7. Gibson, Laura, et al. “Human cytomegalovirus proteins pp65 and immediate early protein 1 are common targets for CD8+ T cell responses in children with congenital or postnatal human cytomegalovirus infection.” The Journal of Immunology 172.4 (2004): 2256-2264. https://www.researchgate.net/pro…

8. Sylwester, Andrew W., et al. “Broadly targeted human cytomegalovirus-specific CD4+ and CD8+ T cells dominate the memory compartments of exposed subjects.” Journal of Experimental Medicine 202.5 (2005): 673-685. https://pdfs.semanticscholar.org…

9. Wang, Changyu, et al. “In vitro characterization of the anti-PD-1 antibody nivolumab, BMS-936558, and in vivo toxicology in non-human primates.” Cancer immunology research 2.9 (2014): 846-856. http://cancerimmunolres.aacrjour…

https://www.quora.com/Why-do-some-studies-use-CMV-recall-assays-to-check-in-vitro-functional-activity-of-checkpoint-inhibitors/answer/Tirumalai-Kamala

How might gut bacteria affect the brain function in humans?

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Animal models show gut microflora (bacteria, viruses, fungi, archaea and eukaryotes such as helminths) influence various aspects of physiology including brain function. Though data on their effect on human physiology is sparse, gut-associated pathologies and mental health issues such as depression (1) are strongly linked. Reverse also applies. For example, strong correlations between autism severity and gastrointestinal (GI) symptoms (2, 3).

Physicians have for long recognized the link between ‘melancholia’ and constipation and other GI tract disturbances, and attempted to treat their symptoms with GI tract interventions (4). Though ideas such as autointoxication, the notion that psychiatric symptoms owed their genesis to GI tract disturbances (Colon cleansing – Wikipedia), faded over the 20th century, renewed research interest in gut-microbiota-brain link is helping move an idea that relied more on pseudoscience onto a firmer scientific footing.

Recently the term psychobiotic was coined for, ‘a live organism that, when ingested in adequate amounts, produces a health benefit in patients suffering from psychiatric illness‘ (5). Could such outcomes be engineered reproducibly and if yes, exactly how do they work? Here the story gets much murkier because so far little can be stated unequivocally and even less claimed as a replicable therapeutic approach capable of manipulating human neuropsychiatric outcomes at will (6).

This answer briefly explores

  1. Physical and neurochemical links between gut, gut bacteria and brain: Vagus nerve, Serotonin, other neurochemicals.
  2. Human studies on gut bacteria and brain: too few, poorly done, contradictory results.
  3. Antibiotics could affect brain function: Could harm (insomnia, mood alterations, psychosis, mania, depression, autism) or help (treatment-resistant depression, schizophrenia).

1. Physical & Neurochemical Links Between Gut, Gut Bacteria & Brain

Vagus nerve – Wikipedia

Major nerve of the parasympathetic division of the autonomic nervous system, the vagus nerve physically connects the ~100 million neurons of the enteric (gut) nervous system to the base of the brain at the medulla (7) with projections into many other parts of the brain including the thalamus, hypothalamus, amygdala (8). Gut inflammation and brain are theorized to connect via the vagus nerve, i.e., Inflammatory reflex – Wikipedia (9).

https://en.wikipedia.org/wiki/Se…

  • Influencing brain states from appetite to circadian rhythms to moods, Serotonin is one of the clearest tangible links between gut microflora and brain function. Major target of antidepressants, it’s also the most studied neurotransmitter in psychiatric illnesses. Rather than the brain, the https://en.wikipedia.org/wiki/En… in the gut are the body’s major source of serotonin (14), and mouse gut microbiota were found to play a role in its synthesis (15). Gut being abundant in both microflora and serotonin, the latter in turn playing a major role in brain states, makes this a credible link though how serotonin, densely packed inside platelet granules, makes its way into the brain is still a mystery.

Bacteria As Source Of Other Neurochemicals

Many microbes can not only abundantly secrete neurochemicals such as Acetylcholine, Dopamine, Epinephrine, GABA, Norpeinephrine, Serotonin in culture (16) but also respond to them (17). Sheer quantity of such neurochemicals suggests they may be of physiologic importance.

  • For example, fermented foods such as Japanese funa-sushi (18) and Chinese paocai (19) use lactobacilli in their making and have millimolar levels of GABA in the final product.
  • Bacteria that contaminate fish or shellfish products can secrete such large amounts of the neurotransmitter, histamine, testing is necessary to ensure levels don’t exceed government guidelines for food poisoning (20).
  • Gut bacteria are also an important source of vitamins important for CNS (https://en.wikipedia.org/wiki/Ce…) function. For example, Lactobacillus reuteri, a normal human gut inhabitant, is a rich source of https://en.wikipedia.org/wiki/Vi… (21), whose deficiency is implicated in https://en.wikipedia.org/wiki/Ne… in fetuses (22, 23).

2. Human Studies On Gut Bacteria & Brain

Too many fundamentals yet lack answers. No consensus definition of what constitutes a healthy human gut microbiota. Gut bacteria alone are estimated to be >1000 species. Add how confounding variables such as age, diet, ethnicity, gender, location influence gut microbiota composition and the picture gets fuzzier rather than clearer. While proper understanding of gut microbiota-brain link requires an ecological approach, many studies assess gut microbiota-brain link in reductionist inbred rodent models whose results are hard if not impossible to extrapolate to human brain function.

  • Often studies on effect of probiotics on brain function are poorly done, have few subjects and use questionnaires or scale-based assessments plagued by subjective bias.
  • There are few RCT (https://en.wikipedia.org/wiki/Ra…).
  • No wonder a 2015 systematic review found ‘very limited evidence for the efficacy of probiotic interventions in psychological outcomes‘ (24) while a 2016 meta-analysis of RCTs could only provisionally conclude probiotics might improve CNS function but couldn’t rule out https://en.wikipedia.org/wiki/Pu… towards positive results (25).
  • No surprise that studies so far (26, 27, 28, 29, 30) comparing gut microbiota between MDD (https://en.wikipedia.org/wiki/Ma…) patients and healthy controls yield contradictory data.
  • OTOH, a small study when well-designed and controlled can yield useful pointers for future studies. In one such (31), healthy women were given fermented milk product with probiotic (n=12), non-fermented milk product (n=11), or nothing (n=13) twice daily for 4 weeks. The probiotics included Bifidobacterium animalis subsp lactis, Streptococcus thermophiles, Lactobacillus bulgaricus, Lactobacillus lactis subsp lactis. fMRI (https://en.wikipedia.org/wiki/Fu…) suggested such probiotics might reduce stress responses and enhance cognition in healthy subjects.

3. Antibiotics Could Affect Brain Function

Do antibiotics influence neuropsychiatric symptoms? Since antibiotics wipe out gut bacteria, this offers another avenue to explore gut bacteria-brain link. Case-reports, epidemiological studies, clinical trials, a variety of such studies suggest antibiotics could either harm or help brain function, distinction depending on the antibiotic and kinds of bacteria it targets.

Harm

  • One of the clearest examples is from case reports of antibiotics inducing insomnia, mood alteration (32), psychosis (33, 34, 35), even mania, antibiomania, especially in the elderly (36). Antibiotics most commonly implicated in these unusual behavior changes are clarithromycin, ciprofloxacin and ofloxacin.
  • A retrospective medical records-based study (37) of 202974 patients with depression, 14570 with anxiety, 2690 with psychosis with 803961, 57862 and 10644 matched controls, respectively, concluded recurrent antibiotic Rx increased risk for depression and anxiety but not psychosis.
  • Link between prior heavy antibiotic use and autism is quite strong (38, 39, 40), especially use of trimethoprim/sulfamethoxazole (41).

Help

https://en.wikipedia.org/wiki/Mi…, a semi-synthetic https://en.wikipedia.org/wiki/Br… https://en.wikipedia.org/wiki/Te…, is usually used to treat acne and other skin conditions. It’s been suggested as a possibility for treatment-resistant depression (42) and schizophrenia (43).

  • A small, open-label study found minocycline effective and well-tolerated in treatment-resistant depression (44).
  • A pilot study by King’s College, London, is completed but no results posted yet (45, 46).
  • A couple of clinical trials are underway, one a phase II in Germany (47) and another in Thailand/Australia (48).

Thus, accumulating circumstantial data suggests gut microbiota influence human brain function but little of it is as yet tangible and reproducible.

Bibliography

1. Foster, Jane A., and Karen-Anne McVey Neufeld. “Gut–brain axis: how the microbiome influences anxiety and depression.” Trends in neurosciences 36.5 (2013): 305-312. http://neuroscienceresearch.wust…

2. Adams, James B., et al. “Gastrointestinal flora and gastrointestinal status in children with autism–comparisons to typical children and correlation with autism severity.” BMC gastroenterology 11.1 (2011): 22. http://download.springer.com/sta…

3. de Theije, Caroline GM, et al. “Pathways underlying the gut-to-brain connection in autism spectrum disorders as future targets for disease management.” European journal of pharmacology 668 (2011): S70-S80. https://www.researchgate.net/pro…

4. Phillips, J. George Porter. “The treatment of melancholia by the lactic acid bacillus.” The British Journal of Psychiatry 56.234 (1910): 422-NP.

5. Dinan, Timothy G., Catherine Stanton, and John F. Cryan. “Psychobiotics: a novel class of psychotropic.” Biological psychiatry 74.10 (2013): 720-726.

6. MacQueen, Glenda, Michael Surette, and Paul Moayyedi. “The gut microbiota and psychiatric illness.” J Psychiatry Neurosci 42.2 (2017): 75. http://jpn.ca/wp-content/uploads…

7. Alcock, Joe, Carlo C. Maley, and C. Aktipis. “Is eating behavior manipulated by the gastrointestinal microbiota? Evolutionary pressures and potential mechanisms.” Bioessays 36.10 (2014): 940-949. http://onlinelibrary.wiley.com/d…

8. Kennedy, Paul J., et al. “Microbiome in brain function and mental health.” Trends in Food Science & Technology 57 (2016): 289-301. http://download.xuebalib.com/xue…

9. Tracey, Kevin J. “The inflammatory reflex.” Nature 420.6917 (2002): 853-859. https://www.researchgate.net/pro…

10. Raybould, Helen E. “Gut chemosensing: interactions between gut endocrine cells and visceral afferents.” Autonomic Neuroscience 153.1 (2010): 41-46. https://www.ncbi.nlm.nih.gov/pmc…

11. Strader, April D., and Stephen C. Woods. “Gastrointestinal hormones and food intake.” Gastroenterology 128.1 (2005): 175-191. http://www.siumed.edu/~astrader/…

12. Camilleri, Michael, et al. “Intra-abdominal vagal blocking (VBLOC therapy): clinical results with a new implantable medical device.” Surgery 143.6 (2008): 723-731. https://www.researchgate.net/pro…

13. Sarr, Michael G., et al. “The EMPOWER study: randomized, prospective, double-blind, multicenter trial of vagal blockade to induce weight loss in morbid obesity.” Obesity surgery 22.11 (2012): 1771-1782.

14. Tirumalai Kamala’s answer to How do SSRIs affect the microbiome?

15. Wikoff, William R., et al. “Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites.” Proceedings of the national academy of sciences 106.10 (2009): 3698-3703. https://www.researchgate.net/pro…

16. Lyte, Mark. “Probiotics function mechanistically as delivery vehicles for neuroactive compounds: microbial endocrinology in the design and use of probiotics.” Bioessays 33.8 (2011): 574-581. http://insanemedicine.com/wp-con…

17. Iyer, Lakshminarayan M., et al. “Evolution of cell–cell signaling in animals: did late horizontal gene transfer from bacteria have a role?.” TRENDS in Genetics 20.7 (2004): 292-299. https://www.researchgate.net/pro…

18. Komatsuzaki, Noriko, et al. “Production of γ-aminobutyric acid (GABA) by Lactobacillus paracasei isolated from traditional fermented foods.” Food microbiology 22.6 (2005): 497-504.

19. Li, Haixing, et al. “A high γ-aminobutyric acid-producing Lactobacillus brevis isolated from Chinese traditional paocai.” Annals of Microbiology 58.4 (2008): 649-653.

20. Ieniştea, C. “Bacterial production and destruction of histamine in foods, and food poisoning caused by histamine.” Molecular Nutrition & Food Research 15.1 (1971): 109-113.

21. Santos, Filipe, et al. “High-level folate production in fermented foods by the B12 producer Lactobacillus reuteri JCM1112.” Applied and environmental microbiology 74.10 (2008): 3291-3294. http://library.wur.nl/WebQuery/w…

22. Smithells, R. W., S. Sheppard, and C. J. Schorah. “Vitamin dificiencies and neural tube defects.” Archives of Disease in Childhood 51.12 (1976): 944-950. https://www.ncbi.nlm.nih.gov/pmc…

23. Dror, Daphna K., and Lindsay H. Allen. “Effect of vitamin B12 deficiency on neurodevelopment in infants: current knowledge and possible mechanisms.” Nutrition reviews 66.5 (2008): 250-255. https://pubag.nal.usda.gov/pubag…

24. Romijn, Amy R., and Julia J. Rucklidge. “Systematic review of evidence to support the theory of psychobiotics.” Nutrition reviews 73.10 (2015): 675-693. https://www.researchgate.net/pro…

25. Wang, Huiying, et al. “Effect of probiotics on central nervous system functions in animals and humans: A systematic review.” Journal of Neurogastroenterology and Motility 22.4 (2016): 589-605. https://pdfs.semanticscholar.org…

26. Naseribafrouei, A., et al. “Correlation between the human fecal microbiota and depression.” Neurogastroenterology & Motility 26.8 (2014): 1155-1162. https://www.researchgate.net/pro…

27. Jiang, Haiyin, et al. “Altered fecal microbiota composition in patients with major depressive disorder.” Brain, behavior, and immunity 48 (2015): 186-194. https://pdfs.semanticscholar.org…

28. Zheng, P., et al. “Gut microbiome remodeling induces depressive-like behaviors through a pathway mediated by the host’s metabolism.” Molecular psychiatry 21.6 (2016): 786-796.

29. Aizawa, Emiko, et al. “Possible association of Bifidobacterium and Lactobacillus in the gut microbiota of patients with major depressive disorder.” Journal of affective disorders 202 (2016): 254-257. https://www.researchgate.net/pro…

30. Kelly, John R., et al. “Transferring the blues: Depression-associated gut microbiota induces neurobehavioural changes in the rat.” Journal of Psychiatric Research 82 (2016): 109-118.

31. Tillisch, Kirsten, et al. “Consumption of fermented milk product with probiotic modulates brain activity.” Gastroenterology 144.7 (2013): 1394-1401. http://ac.els-cdn.com/S001650851…

32. Sternbach H & State R. (1997). Antibiotics: neuropsychiatric effects and psychotropic interactions. HarvRevPsychiatry 5, 214-226.

33. Mehdi S. (2010). Antibiotic-induced psychosis: a link to D-alanine?. MedHypotheses 75, 676- 677.

34. Bercik, Premysl, and Stephen M. Collins. “The effects of inflammation, infection and antibiotics on the microbiota-gut-brain axis.” microbial endocrinology: the microbiota-gut-brain axis in health and disease. Springer New York, 2014. 279-289.

35. Ly, Duy, and Lynn E. DeLisi. “Can antibiotics cause a psychosis?: Case report and review of the literature.” Schizophrenia Research (2017).

36. Abouesh, A., Stone, C. & Hobbs, W. R. Antimicrobial‐ induced mania (antibiomania): a review of spontaneous reports. J. Clin. Psychopharmacol. 22, 71–81 (2002).

37. Lurie, Ido, et al. “Antibiotic exposure and the risk for depression, anxiety, or psychosis: a nested case-control study.” The Journal of clinical psychiatry 76.11 (2015): 1522.

38. Niehus, Rebecca, and Catherine Lord. “Early medical history of children with autism spectrum disorders.” Journal of Developmental & Behavioral Pediatrics 27.2 (2006): S120-S127.

39. Atladóttir, Hjördis Ósk, et al. “Autism after infection, febrile episodes, and antibiotic use during pregnancy: an exploratory study.” Pediatrics 130.6 (2012): e1447-e1454. http://pediatrics.aappublication…;

40. Mezzelani, Alessandra, et al. “Environment, dysbiosis, immunity and sex-specific susceptibility: a translational hypothesis for regressive autism pathogenesis.” Nutritional neuroscience 18.4 (2015): 145-161. https://pdfs.semanticscholar.org…

41. Finegold, Sydney M., et al. “Gastrointestinal microflora studies in late-onset autism.” Clinical Infectious Diseases 35.Supplement 1 (2002): S6-S16. https://www.researchgate.net/pro…

42. Soczynska, Joanna K., et al. “Novel therapeutic targets in depression: minocycline as a candidate treatment.” Behavioural brain research 235.2 (2012): 302-317. http://www.medicinabiomolecular….

43. Chaudhry, Imran B., et al. “Minocycline benefits negative symptoms in early schizophrenia: a randomised double-blind placebo-controlled clinical trial in patients on standard treatment.” Journal of psychopharmacology 26.9 (2012): 1185-1193. https://www.researchgate.net/pro…

44. Miyaoka, Tsuyoshi, et al. “Minocycline as adjunctive therapy for patients with unipolar psychotic depression: an open-label study.” Progress in Neuro-Psychopharmacology and Biological Psychiatry 37.2 (2012): 222-226.

45. https://clinicaltrials.gov/ct2/s…

46. Husain, Muhammad I., et al. “Minocycline as an adjunct for treatment-resistant depressive symptoms: study protocol for a pilot randomised controlled trial.” Trials 16.1 (2015): 410. http://download.springer.com/sta…

47. https://clinicaltrials.gov/ct2/s…

48. Dean, Olivia May, et al. “Protocol and rationale-the efficacy of minocycline as an adjunctive treatment for major depressive disorder: a double blind, randomised, placebo controlled trial.” Clinical psychopharmacology and neuroscience 12.3 (2014): 180-188. http://www.cpn.or.kr/journal/dow…

https://www.quora.com/How-might-gut-bacteria-affect-the-brain-function-in-humans/answer/Tirumalai-Kamala

What is the evolutionary explanation for blood type antibodies? Blood transfusion is so recent in history, why do we have this ‘defense’ mechanism from the evolutionary perspective?

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Shorter answer

Already by 6 months of age, gut microflora polysaccharides stimulate antibodies capable of binding ABO blood group antigens (1). In particular, anti-histo blood group B antibodies can bind gut microflora (2) while the environmental trigger for anti-histo blood group A still remains undefined (3).

Thus, rather than indicative of defense, Cross-reactivity – Wikipedia as in structural similarity between microbial and histo-blood group antigens explains antibodies against the latter. The 20th century human invention of blood transfusion simply uncovers the scope of such cross-reactivity (4).

A dynamic snapshot of a person’s immunological history, circulating antibodies embody the immunological imprint of past antigenic encounters. However, which antigens specifically induce such circulating antibodies? Grouped under the umbrella term, Natural antibodies – Wikipedia, they’re found in circulation even in absence of explicit infection. In actuality, the term simply signifies unknown antigenic targets triggered such antibodies. Until recently, explicitly looking for such antigens was akin to looking for the proverbial needle in a haystack.

Now though Systems biology – Wikipedia approaches that combine high-throughput computational and Omics – Wikipedia techniques are beginning to trace out the broad overlaps in structure within the universe of antigens, overlaps that antibodies and other receptors of the Adaptive immune system – Wikipedia already so brilliantly glom onto when they bind their antigenic targets so specifically.

Such studies reveal how a contradiction of terms, specificity married to redundancy, could even come to be such a hallmark feature of the adaptive immune system receptors. For example, one study (5) suggests a universal architecture for the human anti-carbohydrate antibody repertoire, universal implying capacity to bind structurally similar Moiety (chemistry) – Wikipedia across living organisms, be they microbes or mammals.

Back in the mid-20th century, Arthur Mourant – Wikipedia proposed that modern-day geographic ABO distributions are the consequence of past epidemics (6). Though severely understudied, research spanning decades has in fact uncovered several examples of antibodies that cross-react on microbial and histo-blood group antigens.

  • Exposure to bacterial antigens stimulates anti-histo blood group antigen antibody titers (7), suggesting the two, bacterial and blood group antigens, are antigenically related.
  • As far back as 1971, researchers discovered that blood group O and A volunteers fed E.coli O86 had spike in anti-blood group B antibody titers (1), clearly indicating antigenic similarity between E.coli O86 and blood group B antigens.
  • Histo-blood group and viral antigen similarities have been reported for SARS Coronavirus – Wikipedia (Severe acute respiratory syndrome – Wikipedia) (8) and Crimean–Congo hemorrhagic fever – Wikipedia virus (9).

Such cross-reactivity can co-exist with immunological tolerance to one’s own histo-blood group antigens since sources of antibodies, the B cell – Wikipedia with receptors capable of binding them would get deleted through the process of developmentally dictated tolerance.

Longer Answer With Some Examples Of Antibodies Cross-Reactive to Histo-Blood Groups & Microbial Antigens

Table below from 10 lists some linkages between disease-causing/associated microbial agents and blood groups.

Malaria

O blood group is associated with resistance to severe malaria (11). As well, high percentage of O blood group individuals in malaria-endemic regions suggests selective advantage of having this blood group (12). Malaria seems to have exerted selective pressure in blood group distribution (13).

Cholera

Anti-Vibrio cholerae antibody response induced by cholera vaccines was lower in blood group O compared to A individuals (14, 15). Epidemiological studies have found O blood group correlates with cholera disease severity (16, 17) fueling the speculation cholera selection pressure may account for the extremely low and high prevalence of histo-blood groups O and B, respectively, among people living in the Gangetic Delta (18, 19).

FUT2 – Wikipedia Lewis Blood Group Antigen: Rotavirus & Norovirus

Rotavirus infectivity appears to be highly dependent on histo-blood groups (7). Non-B and FUT2 – Wikipedia secretor blood groups tend to be more susceptible to norovirus and rotavirus infection-associated gastroenteritis (13, 20, 21). In a test of norovirus vaccine candidates, anti-histo blood group antibody titers in placebo group individuals positively correlated with protection while vaccinees with higher pre-challenge anti-histo blood group antibody titers had lower frequency of severe disease (22). OTOH, FUT2 – Wikipedia secretor phenotype is associated with influenza, respiratory syncytial virus, echovirus (23).

HIV

Anti-histo blood group antibodies could even function to neutralize viruses such as HIV, albeit in a blood group-specific manner. For example, an anti-blood group A monoclonal antibody could neutralize HIV viruses isolated from peripheral blood lymphocytes from blood group A donors but not B or O donors (24, 25).

Vaccines

The biomedical literature is pockmarked with sporadic reports of various vaccines triggering increase in anti-histo blood group antibodies, pneumoccocal vaccine (26) and tetanus and diphtheria toxoids (27) being cases in point. Again antigenic similarity explains the data. Streptococcus pneumoniae‘s polysaccharide capsule and pig stomach pepsin used back then to produce toxoids, both contain an A-like substance (28).

Lifestyle & Diet Influence Anti-Histo Blood Group Antibodies

Some volunteers who took probiotic supplements developed high anti-histo blood group B antibody titers (28). Turned out some bacterial strains in these supplements had antigenic similarity to histo-blood group B antigens.

Children who are fed intravenously for a long time have low to practically non-existent ABO antibodies, especially anti-B (29). Being essentially ‘sterile’, such nutrition alters and reduces gut microflora suggesting major source of triggers for anti-histo blood group antibodies are gut microflora. Interesting then that mean ABO titers have declined dramatically among those on present-day diet of processed, ‘pasteurized’ food compared to historical controls (30).

Bibliography

1. Springer, G. F. “Blood-Group and Forssman Antigenic Determinants Shared between Microbes and Mammalian Cells1.” Progress in Allergy Vol. 15. Karger Publishers, 1971. 9-77.

2. Galili, U., et al. “Interaction between human natural anti-alpha-galactosyl immunoglobulin G and bacteria of the human flora.” Infection and immunity 56.7 (1988): 1730-1737. https://www.ncbi.nlm.nih.gov/pmc…

3. Branch, Donald R. “Anti‐A and anti‐B: what are they and where do they come from?.” Transfusion 55.S2 (2015): S74-S79. https://www.researchgate.net/pro…

4. Blackwell, C. Caroline, et al. “Blood group phenotypes and infectious diseases.” Susceptibility to infectious diseases: the importance of host genetics 4 (2004).

5. Schneider, Christoph, et al. “The human IgG anti-carbohydrate repertoire exhibits a universal architecture and contains specificity for microbial attachment sites.” Science translational medicine 7.269 (2015): 269ra1-269ra1. https://www.ncbi.nlm.nih.gov/pmc…

6. Mourant, Arthur Ernest. “The Distribution of the Human Blood Groups.” The Distribution of the Human Blood Groups. (1954).

7. Cooling, Laura. “Blood groups in infection and host susceptibility.” Clinical microbiology reviews 28.3 (2015): 801-870. Blood Groups in Infection and Host Susceptibility

8. Guillon, Patrice, et al. “Inhibition of the interaction between the SARS-CoV spike protein and its cellular receptor by anti-histo-blood group antibodies.” Glycobiology 18.12 (2008): 1085-1093. https://www.researchgate.net/pro…

9. Güven, Ahmet Sami, et al. “Value of ABO blood group in predicting the severity of children with Crimean-Congo hemorrhagic fever.” International journal of clinical and experimental medicine 7.2 (2014): 416. https://www.ncbi.nlm.nih.gov/pmc…

10. Dotz, Viktoria, and Manfred Wuhrer. “Histo-blood group glycans in the context of personalized medicine.” Biochimica et Biophysica Acta (BBA)-General Subjects 1860.8 (2016): 1596-1607. https://www.researchgate.net/pro…

11. Timmann, Christian, et al. “Genome-wide association study indicates two novel resistance loci for severe malaria.” Nature 489.7416 (2012): 443-446.

12. Anstee, David J. “The relationship between blood groups and disease.” Blood 115.23 (2010): 4635-4643. https://www.researchgate.net/pro…

13. Tirumalai Kamala’s answer to What are the similarities of people having the same blood group?

14. Clemens, John D., et al. “ABO blood groups and cholera: new observations on specificity of risk and modification of vaccine efficacy.” The Journal of infectious diseases 159.4 (1989): 770-773.

15. Qadri, Firdausi, et al. “Peru-15, a live attenuated oral cholera vaccine, is safe and immunogenic in Bangladeshi toddlers and infants.” Vaccine 25.2 (2007): 231-238. https://www.researchgate.net/pro…

16. Barua, D., and A. S. Paguio. “ABO blood groups and cholera.” Annals of human biology 4.5 (1977): 489-492.

17. Glass, Roger I., et al. “Predisposition for cholera of individuals with o blood group possible evolutionary significance.” American journal of epidemiology 121.6 (1985): 791-796.

18. Harris, Jason B., and Regina C. LaRocque. “Cholera and ABO Blood Group: Understanding an Ancient Association.” The American Journal of Tropical Medicine and Hygiene 95.2 (2016): 263-264. https://pdfs.semanticscholar.org…

19. Kuhlmann, F. Matthew, et al. “Blood group O–dependent cellular responses to cholera toxin: parallel clinical and epidemiological links to severe cholera.” The American journal of tropical medicine and hygiene (2016): 16-0161.

20. Tirumalai Kamala’s answer to Why do my American friends get sick by norovirus every Thanksgiving, but I’ve never seen a Russian citizen gotten sick by norovirus in her homeland?

21. Payne, Daniel C., et al. “Epidemiologic association between FUT2 secretor status and severe rotavirus gastroenteritis in children in the United States.” JAMA pediatrics 169.11 (2015): 1040-1045. <i>FUT2</i> Secretor Status and Severe Rotavirus Gastroenteritis

22. Atmar, Robert L., et al. “Serological correlates of protection against a GII. 4 norovirus.” Clinical and Vaccine Immunology 22.8 (2015): 923-929. https://www.researchgate.net/pro…

23. Raza, M. W., et al. “Association between secretor status and respiratory viral illness.” Bmj 303.6806 (1991): 815-818. http://pubmedcentralcanada.ca/pm…

24. Arendrup, Maiken, et al. “Antibody to histo-blood group A antigen neutralizes HIV produced by lymphocytes from blood group A donors but not from blood group B or O donors.” Aids 5.4 (1991): 441-444.

25. Rother, Russell P., et al. “A novel mechanism of retrovirus inactivation in human serum mediated by anti-alpha-galactosyl natural antibody.” Journal of Experimental Medicine 182.5 (1995): 1345-1355. http://europepmc.org/backend/ptp…

26. Boyer, Kenneth M., et al. “Antibody response to group B streptococcus type III and AB blood group antigens induced by pneumococcal vaccine.” The Journal of pediatrics 98.3 (1981): 374-378.

27. Elliott, G. B. “Transiently dangerous universal blood donor.” Canadian Medical Association journal 70.5 (1954): 571. https://www.ncbi.nlm.nih.gov/pmc…

28. Daniel‐Johnson, Jennifer, et al. “Probiotic‐associated high‐titer anti‐B in a group A platelet donor as a cause of severe hemolytic transfusion reactions.” Transfusion 49.9 (2009): 1845-1849. https://www.ncbi.nlm.nih.gov/pmc…

29. Cooling, L. W., et al. “Abo Typing Discrepancies in Children Requiring Long-term Nutritional Support.” Transfusion 47 (2007): 9A-10A.

30. Mazda, T., et al. “Differences in ABO antibody levels among blood donors: a comparison between past and present Japanese, Laotian, and Thai populations.” Immunohematology/American Red Cross 23.1 (2006): 38-41.

https://www.quora.com/What-is-the-evolutionary-explanation-for-blood-type-antibodies/answer/Tirumalai-Kamala

What implications does Thomas Kuhn have for research methodology?

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The main message of The Structure of Scientific Revolutions – Wikipedia (SSR) could be restated as science is self-correcting though individual scientists may not be or science is rational though individual scientists may not be. A facetious one is an abbreviated version of Planck’s principle – Wikipedia, (Max Planck – Wikiquote),

‘Science advances one funeral at a time’

Perspective: Kuhn, The Apple Cart Upsetter

Kuhn’s singular and unprecedented insight came by questioning the then prevailing consensus that being progressive and cumulative constitute the dominant attributes of scientific progress. Progressive and cumulative imply steady, thoughtful, rational, unemotional, and yet the history of scientific progress suggests it has been anything but. There’s an eerie resonance to Kuhn’s synthesis in the The Sleepwalkers – Wikipedia, a 1959 book by Arthur Koestler – Wikipedia,

‘The progress of science is generally regarded as a kind of clean, rational advance along a straight ascending line; in fact it has followed a zigzag course, at times more bewildering than the evolution of political thought.’

Three years later, in 1962 Kuhn wrote (1, p.208, emphasis mine),

‘scientific development as a succession of tradition-bound periods punctuated by non-cumulative breaks

Kuhn’s thesis was a poke in the eye for philosophy titans like Karl Popper (Stanford Encyclopedia of Philosophy) who’d held sway until then with their contention that science was a unique human endeavor where objective pursuit of truth held sway, that scientific progress, i.e., the discovery of new facts, followed from scientists calmly, objectively and rationally incorporating new data and adjusting their mental constructs accordingly in the form of new theories or hypotheses.

Kuhn comes along and says none of such accepted tropes about the scientific process are accurate, that instead

  • Science consists of periods of ‘normal’ science leavened by periods of crisis, with revolutionary science breaking the impasse, overturning and replacing the old paradigm with a new one. Thus, neither necessarily progressive nor cumulative though it could also be both.
  • Scientific education helps inculcate the unquestioning attitude and habits of ‘normal’ science (2).

Though the scientific enterprise may be open-minded, the individual scientist is very often not. Whether his work is predominantly theoretical or experimental, he usually seems to know, before his research project is well under way, all but the most intimate details of the result which that project will achieve. If the result is quickly forthcoming, well and good. If not, he will struggle with his apparatus and with his equations until, if at all possible, they will yield results which conform to the sort of pattern which he has foreseen from the start…a relatively dogmatic initiation into a pre-established problem-solving tradition that the student is neither invited nor equipped to evaluate

  • Criteria and methods scientists use to justify their choice of paradigms are habitually ambiguous and imprecise as well as inconsistent and changing.
  • ‘Normal’ scientists engage in puzzle-solving, using the prevailing paradigm as a road-map to solve remaining puzzles within a given field. Periods of ‘normal’ science thus consist of unquestioning adherence to the prevailing consensus of beliefs and methods, i.e., paradigm, and therefore as well unquestioning use of such methods in routine puzzle-solving until over time, anomalies accumulate, anomalies the prevailing paradigm fails to adequately explain and which thwart these scientists in achieving their puzzle solving goals. Tension over accumulating anomalies then leads that scientific field into a period of crisis, one eventually resolved by a revolution wherein a new theory supplants the older one by being able to adequately or better explain such anomalies. Why would such anomalies accumulate in the first place? According to Kuhn, if the scientific approach operates the way it should then, regardless of scientists, scientism and inherent biases attendant to the two, it should ferret out some undeniable truism, what Popper called verisimilitude (Verisimilitude – Wikipedia). What to do about the truism then becomes the question. Fits with the prevailing paradigm? Accept wholeheartedly. Doesn’t fit? Ignore or minimize and so anomalies accrue with time. Generation gap may also apply as in younger, presumably conceptually uncommitted or less committed, practitioners assessing the same data and the lay of the land with fresh, less biased eyes.
  • Aware of and driven by anomalies within their field, revolutionary scientists pursue answers that could explain them and in the process create revolutionary science (3).

Thus, rather than the Popperian view of science as ‘revolution in permanence‘ (4), Kuhn proposed ‘Periods of stable growth punctuated by revisionary revolutions‘ (5), with both defining scientific progress as the discovery of new facts. Which is more accurate? History of science suggests Kuhn’s.

Self-Inflicted Problem: What Did Kuhn Actually Mean By Paradigm?

Problem is Kuhn’s writing in the book he’s best known for was so ambiguous, it triggered and sustained a furore of criticism led by philosophical luminaries such as Karl Popper, Paul Feyerabend (Stanford Encyclopedia of Philosophy), Imre Lakatos (Stanford Encyclopedia of Philosophy) (4, 6, 7). Unfortunately Kuhn’s ambiguity and vague use of the word paradigm also encouraged popular culture to over-use it to the point of abuse and meaninglessness. A thorny issue fought over ever since is whether Kuhn offered prescriptions or descriptions of the scientific process.

Paul Feyerabend (Stanford Encyclopedia of Philosophy) famously wrote (6, page 198) of SSR,

Whenever I read Kuhn, I am troubled by the following question: are we here presented with methodological prescriptions which tell the scientist how to proceed; or are we given a description, void of any evaluative element, of those activities which are generally called “scientific”? Kuhn’s writings, it seems to me, do not lead to a straightforward answer. They are ambiguous in the sense that they are compatible with, and lend support to, both interpretations’

To which Thomas Kuhn (Stanford Encyclopedia of Philosophy) felt compelled to respond (6, page 237),

‘The answer, of course, is that they should be read in both ways at once. If I have a theory of how and why science works, it must necessarily have implications for the way in which scientists should behave if their enterprise is to flourish…scientists should behave essentially as they do if their concern is to improve scientific knowledge’

Margaret Masterman – Wikipedia from the Cambridge Language Research Unit carefully analyzed SSR and identified 21 different senses in which Kuhn used it, grouping them into 3 categories, metaphysical, sociological and construct. The last includes the nuts and bolts of a practicing scientist’s tool-kit including among others, standard textbooks, methods, reagents, analytical tools (8).

Sustained criticism forced Kuhn to re-analyze his position and clarify what he meant by paradigm (1, page 175, emphasis mine),

‘in much of the book the term ‘paradigm’ is used in two different senses. On the one hand, it stands for the entire constellation of beliefs, values, techniques, and so on shared by the members of a given community. On the other, it denotes one sort of element in that constellation, the concrete puzzle-solutions which, employed as models or examples, can replace explicit rules as a basis for the solution of the remaining puzzles of normal science’

In further revisions, Kuhn eventually divided his use of paradigm into two categories, disciplinary matrix, all the shared commitments of a scientific group, and exemplars as in concrete problem solutions, accepted by the group as, in a quite usual sense, paradigmatic (9). ‘Disciplinary’ as in the common possession of the practitioners of a professional discipline; ‘matrix’ as in being composed of ordered elements of various sorts, each requiring further specification. Obviously disciplinary matrix and exemplar never took off into popular culture the way paradigm did.

Meaning Kuhn intended paradigm to signify a given scientific field’s tacitly agreed upon worldview or mental construct, the corresponding tool-kit and language to define and interrogate it, and the authoritative, supportive examples of how to do science to solve remaining puzzles within that field.

Kuhn’s Prescriptions & Descriptions: How Scientists Do And Ought To Behave Go Hand In Hand

As a historian, sociologist and philosopher of science, to me Thomas Kuhn’s place is akin to that of behavioral scientists.

Classical economists schooled in the manner of Friedrich Hayek – Wikipedia or Milton Friedman – Wikipedia chose to regard individuals as rational actors making rational economic decisions. Behavioral scientists and economists such as Richard Thaler – Wikipedia, Amos Tversky – Wikipedia, Daniel Kahneman – Wikipedia, Dan Ariely – Wikipedia, to name some notables, instead show that economical decision making is beset by cognitive biases that each and every one of us, the supposed rational actors, unwittingly bring to the decision making process, be it about economics or anything else for that matter.

In like manner, Kuhn may be best understood as a counterpoint to philosophers such as Karl Popper and sociologists such as Robert K. Merton – Wikipedia who envisaged scientific development as smooth, cumulative, progressive. Implicit in the latter analysis is the assumption that scientists as the players involved in the system are rational actors making unbiased decisions.

Problem with this notion is at least two-fold.

For one, we now know and understand much better in a way that wasn’t as explicitly understood in the days of Popper and Merton that we each operate within a maze of cognitive biases that constantly attend our every thought and decision. Or at least we more openly acknowledge that this is so.

For another, scientific culture gets established the same way others do, viz., individuals within the group behave and are expected to hew to a set of normative values tacitly assumed to be common to that group.

Habituation of ‘normal’ scientists, those accepting of the prevailing status quo, their habits of thought and thinking processes, their habitual experimental constructs, read-outs, and analyses, their scientific method, create a further, unbridgeable divide such that status quo acceptors and challengers live in ‘different worlds’ and their concepts are also ‘incommensurable’ (Commensurability (philosophy of science) – Wikipedia. Failure to communicate is then a predictable outcome. Language is after all an imperfect tool. Practitioners may use but imply very different meanings to the same terms. Seen in one light, per Kuhn, ‘normal’ scientists behave non-rationally, trying the same approach over and over again even when the outcome doesn’t support the prevailing paradigm. Seen in another light, the ‘revolutionary’ scientists are the non-rational actors, bucking the prevailing norm. Either view threatens the Popperian view of slow, steady, rational, relentless march of scientific progress, and philosophers continue to debate these opposing views.

For Kuhn, criteria and essentials of the scientific process go together as do how scientists do and ought to behave. Contingent on their commitment to improve scientific knowledge, Kuhn’s implications for research methodology is to make no change and to keep doing what scientists have been doing. After all, science has been spectacularly successful so far.

Bibliography

1. The Structure of Scientific Revolutions – Wikipedia, 2nd edition, Thomas S. Kuhn.

2. Kuhn, Thomas S. The function of dogma in scientific research. Na, 1963.

3. Maurice A. Finocchiaro. Essay-Review of Lakatos’ Criticism and the Growth of Knowledge. Studies in History and Philosophy of Science 3(1972 -73): 357-72.

4. Lakatos, Imre. “Criticism and the methodology of scientific research programmes.” Proceedings of the Aristotelian society. Vol. 69. Aristotelian Society, Wiley, 1968. Publications

5. Thomas Kuhn (Stanford Encyclopedia of Philosophy)

6. Musgrave, Alan, ed. Criticism and the Growth of Knowledge: Volume 4: Proceedings of the International Colloquium in the Philosophy of Science, London, 1965. Vol. 4. Cambridge University Press, 1970.

7. Lakatos, Imre. “Falsification and the methodology of scientific research programmes.” Can Theories be Refuted?. Springer Netherlands, 1976. 205-259. http://www.csun.edu/~vcsoc00i/cl…

8. Masterman, M. “The Nature of a Paradigm, w: Lakatos, I., Musgrave A.(eds.), Criticism and the Growth of Knowledge.” (1970).

9. Kuhn, Thomas S. “Second thoughts on paradigms.” The structure of scientific theories 2 (1974): 459-482. http://eu.pravo.hr/_download/rep…

https://www.quora.com/What-implications-does-Thomas-Kuhn-have-for-research-methodology/answer/Tirumalai-Kamala

What side effects does Perjeta have when administered without other chemotherapy drugs?

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Difficult to consider side effects of Perjeta aka Pertuzumab – Wikipedia in isolation because

  • It’s been tested in combination therapies, usually with Herceptin aka Trastuzumab – Wikipedia and also often Docetaxel – Wikipedia. Neutropenia – Wikipedia (low neutrophil count), febrile neutropenia, alopecia, nausea, fatigue, and infusion reactions are already common side effects of docetaxel.
  • Most clinical trial patients have usually been on other Rx previously, some of which may leave long-term adverse effects on various organ systems.

That said, side effects particular to drugs like Perjeta are dictated by expression pattern of their targets. Like Herceptin, Perjeta targets HER2/neu – Wikipedia, an extracellular human EGFR (Epidermal growth factor receptor – Wikipedia). Both used to treat HER2 positive breast cancer, Perjeta and Herceptin have complementary modes of action. Binding HER2’s extracellular domain, Perjeta prevents it from heterodimerzing with EGFR (Epidermal growth factor receptor – Wikipedia). This blocks transmission of proliferative signals into HER2-positive tumor cells.

Though targeting something expressed by some breast cancers, nevertheless Rx such as Perjeta and Herceptin are still non-specific since HER2 is also expressed by other tissue types.

  • Colonic epithelial cells hence diarrhea is possible.
    • Studies (1) have shown HER2 blockade can cause non-life threatening diarrhea, presumably as a result of excess chloride secretion by EGFR blockade on colonic epithelial cells.
    • 40 to 80% of patients who got Perjeta in clinical trials experienced diarrhea (2, 3, 4, 5, 6).
    • Specifically, grades 1 to 3 diarrhea (7, page 20, grades 1 thru’ 3 are milder, grade 4 is life-threatening, grade 5 is death) were a common symptom in 3 breast cancer trials testing Perjeta with other drugs, CLEOPATRA (n=804, 2) for metastatic, and NeoSphere (n=416, 3) and TRYPHAENA (n=223, 4) for early-stage.
    • Highest during the first Perjeta-containing cycle, diarrhea incidence decreased with subsequent cycles.
    • The data suggest diarrhea is more common when Perjeta‘s given since rate was 68% for Docetaxel plus Hercpetin and Perjeta compared to 49% for Docetaxel plus Hercpetin in CLEOPATRA (2).
  • Cardiac myocytes hence heart toxicity is possible (8).
    • However, the way these drugs affect heart function is highly reversible (9).
    • As well, low numbers of patients tend to be affected. For example, 6 of 92 (6.5%) in one trial (10).
  • Keratinocytes so rashes, and skin and nail infections, typically Staphylococcus aureus (11).
    • Detailed meta-analysis suggests Perjeta significantly increased risk of rash (12).

However, these trials and meta-analyses also conclude these side effects are well manageable.

Bibliography

1. Gao, Jennifer, and Sandra M. Swain. “Pertuzumab for the treatment of breast cancer: a safety review.” Expert opinion on drug safety 15.6 (2016): 853-863.

2. Baselga, José, et al. “Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer.” New England Journal of Medicine 366.2 (2012): 109-119. http://www.nejm.org/doi/pdf/10.1…

3. Gianni, Luca, et al. “Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial.” The lancet oncology 13.1 (2012): 25-32. http://www.rits.onc.jhmi.edu/dbb…

4. Schneeweiss, A., et al. “Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA).” Annals of oncology 24.9 (2013): 2278-2284. https://www.researchgate.net/pro…

5. Cortés, Javier, et al. Pertuzumab Monotherapy After Trastuzumab-Based Treatment and Subsequent Reintroduction of Trastuzumab: Activity and Tolerability in Patients With Advanced Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: Journal of Clinical Oncology: Vol 30, No 14

6. Baselga, José, et al. Phase II Trial of Pertuzumab and Trastuzumab in Patients With Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer That Progressed During Prior Trastuzumab Therapy: Journal of Clinical Oncology: Vol 28, No 7

7. https://ctep.cancer.gov/protocol…

8. Valachis, Antonis, et al. “Cardiac toxicity in breast cancer patients treated with dual HER2 blockade.” International journal of cancer 133.9 (2013): 2245-2252. http://onlinelibrary.wiley.com/d…

9. Lenihan, D., et al. “Pooled analysis of cardiac safety in patients with cancer treated with pertuzumab.” Annals of oncology 23.3 (2012): 791-800. https://www.researchgate.net/pro…

10. Portera, Chia C., et al. “Cardiac toxicity and efficacy of trastuzumab combined with pertuzumab in patients with trastuzumab-insensitive human epidermal growth factor receptor 2–positive metastatic breast cancer.” Clinical Cancer Research 14.9 (2008): 2710-2716. https://www.researchgate.net/pro…

11. Mortimer, Joanne E., et al. “Skin, nail, and staphylococcal infections associated with the addition of pertuzumab to trastuzumab-based chemotherapy.” (2015): e11610-e11610.

12. Drucker, Aaron M., et al. “Risk of rash with the anti-HER2 dimerization antibody pertuzumab: a meta-analysis.” Breast cancer research and treatment 135.2 (2012): 347-354.

https://www.quora.com/What-side-effects-does-Perjeta-have-when-administered-without-other-chemotherapy-drugs/answer/Tirumalai-Kamala

Is there an association between inflammation and cancer?

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Inflammation-cancer link is indirect and convoluted. Rather than inflammation per se, failure to resolve it is a common feature of early tumor development. In particular chronic inflammation (1, 2), specifically tumor-promoting inflammation is now considered a tumor-enabling characteristic (3).

This answer

I. Explains inflammation is a process, not an outcome, and why the distinction matters.

II. Explains how the inflammatory process could either help or hinder cancer growth. Dysregulated (unresolved and/or inappropriate) helps while regulated inflammation hinders.

III. Shares some epidemiological data suggesting dysregulated inflammation could increase cancer risk.

IV. Explains how certain types of inflammation could hinder, even eliminate cancers, as William Coley – Wikipedia showed with his Coley’s toxins – Wikipedia.

V. Shares some epidemiological data suggesting certain types of inflammation could reduce cancer risk.

VI. Shares some epidemiological data suggesting reducing inflammation could reduce cancer risk.

I. Inflammation Is A Process, Not An Outcome

Inflammation, a normal physiological process (4), has been dealt a bad rap in popular culture where it’s usually used tacitly as synonymous with bad outcome when it’s actually a fundamental attribute of physiology, a dynamic immunological process that appears designed to

  • Manifest itself in response to homeostatic perturbation in a given tissue,
  • Help resolve such perturbation and help restore the tissue to its former homeostasis, and
  • Itself disappear.

The last clearly indicates inflammation is normally a self-limiting process with a finite end (5, 6, 7). For thousands of years, starting with its first apparent recorded report by the Roman encyclopedist, Aulus Cornelius Celsus – Wikipedia, inflammation was described using its cardinal features, redness (rubor), heat (calor), swelling (tumor) and pain (dolor) until 1852 when Rudolf Virchow – Wikipedia added loss of function (functio laesa, injured function) (8). Given its characteristic features, infections are stereotypical triggers of the inflammatory process.

Mild or severe, short-lived (acute) or prolonged (chronic), it’s a process whose features, course and consequences vary vastly in scope and length, and are contingent on the triggers that initiate it and the constraints of the tissues where it occurs. For example, being encased by the bony skull renders the soft brain tissue particularly ill-suited to effectively deal with some of inflammation’s characteristic consequences such as greater than normal influx of blood-derived cells and fluid, especially when it presents abruptly as an intense and relentless process as happens in Traumatic brain injury – Wikipedia.

Unfortunately, even in biomedicine, the word inflammation is also often misused to describe any number and variety of undesirable or adverse outcomes when it is instead a process. Such distortion of the fundamental framework ends up distorting experimental goals and design so no surprise if confusing results ensue.

Another problem of epidemic proportions plaguing our understanding of inflammation’s role in cancer is blanket over-reliance on pre-clinical mouse models which are increasingly recognized to poorly recapitulate human physiology (9, 10). Too often, such over-reliance dictates what to examine how and when. For example, mouse models did not predict pituitary gland inflammation (hypophysitis) and colitis as common, severe side effects of Ipilimumab – Wikipedia, an anti- CTLA-4 – Wikipedia mAb (monoclonal antibody) approved for use in human metastatic melanoma patients (11, 12) nor did they predict mAbs targeting Programmed cell death protein 1 – Wikipedia and PD-L1 – Wikipedia would be far more effective compared to those targeting CTLA-4.

II. Inflammation Could Either Help Or Hinder Cancer Growth

Disagreement about the role of tumor-infiltrating immunocytes is long-standing, starting from the very genesis of the field of modern immunology. While Rudolph Virchow saw ‘white’ cell, i.e., leukocyte, infiltrates in solid tumors and in 1863 ascribed to them a cancer-promoting role (1), Paul Ehrlich in 1909 proposed the human immune system eliminated nascent tumors (13). However, such opposing views can be reconciled by considering inflammation’s outcome, tumor-promoting or tumor-inhibiting/eradicating, to be inherently context-based. Doing so shifts the spotlight away from outcome to process.

Specifically, dysregulated (unresolved and/or inappropriate) inflammation as tumor-promoting/enabling and regulated inflammation as tumor-inhibiting. In 1972 Alexander Haddow speculated ‘tumor production is a possible overhealing‘ (14). In 1986 Harold F. Dvorak observed inflammation and cancer share some basic developmental features such as angiogenesis and leukocyte infiltration, and suggested tumors were ‘wounds that did not heal‘ (15). Enabling/promoting implies chronic tumor site activation of immunocytes (granulocytes, monocytes, macrophages, mast cells, even eventually lymphocytes) and also fibroblasts (16) that over time get hopelessly compromised and locked into an unproductive tissue repair/wound healing process that ends up promoting tumor growth (see below from 17). Predictably differentiating different types of inflammation locally as well as systemically is very much work in progress.

III. Epidemiological Data Suggesting Dysregulated Inflammation Could Increase Cancer Risk

Albeit indirect, some epidemiological studies estimate infection-driven cancer risk to be considerable.

  • Some infections can directly drive the genetic transformation process necessary for cancer. For example, EBV, HPV and HTLV-1 can directly induce cell transformation.
  • Other infections may lock in an unproductive chronic inflammation process that enables cancer in those predisposed to it. For example, hepatitis viruses drive chronic inflammation in infected tissues. Reasons for such predisposition could be genetic as well as environmental, with diet and lifestyle being the main drivers of the latter.
  • Estimates suggest 15 (18) to ~18% (19) of global cancer are infection-related with agents ranging from Helicobater pylori, HPV (human papilloma virus), hepatitis B and C viruses, EBV (Epstein-Barr virus), HIV and herpes, schistosomes, HTLV, and liver flukes. Tumor-promoting inflammation is suspected to be involved in all of them.
  • Success of prophylactic vaccines in preventing cancers caused by viral infections has led to the estimate that 10 to 20% of all human tumors could be outcomes of such infections (20, 21).
  • 25% of all human cancers are estimated to result from chronic inflammation (2).

IBDs (Inflammatory bowel disease – Wikipedia) such as UC and Crohn’s have 10-fold greater colorectal cancer risk (22, 23).

Abundant infiltration of renal cell carcinoma by CD4+ and CD8+ T cells with specific features is associated with worse prognosis (24, 25, 26).

Age, ethnicity, family history being the major risk factors for prostate cancer would seem to preclude a role for chronic inflammation except its rate rises within one generation of migrating to the US or Western Europe among low-risk Chinese and Japanese men (27). Diet and lifestyle would thus be the prime environmental factors with chronic inflammation linking them to prostate cancer, except the particulars of such inflammation are yet unresolved. This may be why epidemiological data on link between chronic inflammation and prostate cancer is a mixed bag, several supporting (28, 29, 30, 31, 32, 33, 34, 35), some not (36, 37, 38, 39, 40), with strongest supportive data from studies with larger number of subjects and with confirmed diagnosis of Prostatitis – Wikipedia.

Such contradictions emphasize the difficulty inherent to human studies, especially so for solid tumors. Reconstructing an entire process with recourse only to snapshots, be they biopsies or images, can only ever be fraught with uncertainty.

  • Different studies used different size biopsies and may have taken them at different stages of the cancer process.
  • Different studies used different qualitative approaches to categorize inflammation.

IV. Spontaneous Regressions, William Coley and Coley’s Toxins: Mimicking Acute Infections Could Eradicate Tumors

His observation of several cases of spontaneous tumor regressions in the context of acute infections, specifically infections that induced high fevers, drove William Coley – Wikipedia to a life-long endeavor of trying to eliminate tumors using infection-mimics in the form of his artisanal Coley’s toxins – Wikipedia (41). Though Coley’s ideas fell into disfavor and his legacy was ignored through much of the 20th century, the explication of the Adaptive immune system – Wikipedia starting in the 1960s and of the Innate immune system – Wikipedia starting in the 1990s reversed that trend with modern cancer immunotherapy a direct inheritor and beneficiary of his ideas.

V. Epidemiological Data That Certain Types Of Inflammation Could Reduce Cancer Risk

Ectopic lymph node-like structures in solid tissues are considered emblematic of chronic inflammation. However, their presence in lung and colorectal cancers is associated with improved prognosis (42, 43, 44). As well, such studies show up the limitation of terminology. Clearly even chronic inflammation isn’t inherently tumor-enabling. Process, not outcome and more than one type of chronic inflammation.

VI. Epidemiological Data That Reducing Inflammation Reduces Cancer Risk

Daily Aspirin &/Or NSAID Intake Reduces Risk Of Several Cancers

  • Several meta-analyses (55, 56, 57, 58, 59, 60) suggest daily aspirin but not other NSAID intake consistently shows some protection against prostate cancer incidence.
  • Meta-analysis – Wikipedia of cardiovascular trials found low daily dose (75 to 100mg) of aspirin may reduce cancer incidence and cancer mortality for many cancer types (61, 62).
  • Meta-analysis of data from 8 RCTs (Randomized controlled trial – Wikipedia) where patients took daily aspirin to prevent cardiovascular diseases also found lower incidence of cancers, not just colon but also brain, esophageal, lung, pancreatic, prostate and stomach, with the benefit becoming apparent after at least 5 years of daily aspirin while aspirin for >7.5 years reduced 20-year risk of cancer death by 30% for all solid cancers and by 60% for gastrointestinal cancers (63).

However, drawback of prolonged use of aspirin and NSAIDs is side effects such as stomach and brain bleeds.

Used to treat IBD for >50 years, a meta-analysis of 9 observational studies found drugs such as Mesalazine – Wikipedia reduce colitis-associated colorectal cancer risk by 49% (64).

Anti-Diabetic Drug Metformin – Wikipedia Might Reduce Cancer Risk In The Diabetic

  • Meta-analysis (65) of 11 studies including cohort and case-control studies on 4042 cancer cases and 529 cancer deaths found 31% reduction in cancer incidence and mortality risk among metformin takers.
  • Meta-analysis (66) of 47 independent studies including 65540 cancer cases in diabetic patients found metformin reduced overall cancer incidence and mortality by 31 and 34%, respectively, specifically risk for colorectal cancer.
  • Meta-analysis (67) of 24 independent metformin cohort and case-control studies on 386825 subjects found 30% reduced cancer risk for metformin users.

Metformin might inhibit tumor progression by altering tumor metabolism as well as tumor-associated inflammation (68).

Bibliography

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4. I learned from Guido Majno’s definition of Inflammation that a great definition is a work of genius. by Tirumalai Kamala on TK Talk

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10. Seok, Junhee, et al. “Genomic responses in mouse models poorly mimic human inflammatory diseases.” Proceedings of the National Academy of Sciences 110.9 (2013): 3507-3512. http://www.pnas.org/content/110/…

11. Hodi, F. Stephen, et al. “Improved survival with ipilimumab in patients with metastatic melanoma.” N Engl j Med 2010.363 (2010): 711-723. http://www.nejm.org/doi/pdf/10.1…

12. Dranoff, Glenn. “Experimental mouse tumour models: what can be learnt about human cancer immunology?.” Nature Reviews Immunology 12.1 (2012): 61-66.

13. Ehrlich, P. “On the current state of cancer research.” Ned Tijdschr Geneeskd 5 (1909): 273-290.

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15. Dvorak, Harold F. “Tumors: wounds that do not heal.” New England Journal of Medicine 315.26 (1986): 1650-1659.

16. Marsh, Timothy, Kristian Pietras, and Sandra S. McAllister. “Fibroblasts as architects of cancer pathogenesis.” Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease 1832.7 (2013): 1070-1078. Fibroblasts as architects of cancer pathogenesis

17. Kuraishy, Ali, Michael Karin, and Sergei I. Grivennikov. “Tumor promotion via injury-and death-induced inflammation.” Immunity 35.4 (2011): 467-477. http://www.stem-art.com/Library/…

18. Barcellos-Hoff, Mary Helen, David Lyden, and Timothy C. Wang. “The evolution of the cancer niche during multistage carcinogenesis.” Nature Reviews Cancer 13.7 (2013): 511-518. https://eclass.duth.gr/modules/d…

19. Parkin, Donald Maxwell. “The global health burden of infection‐associated cancers in the year 2002.” International journal of cancer 118.12 (2006): 3030-3044. http://onlinelibrary.wiley.com/d…

20. Lollini, Pier-Luigi, et al. “Vaccines and other immunological approaches for cancer immunoprevention.” Current drug targets 12.13 (2011): 1957-1973. http://www.ingentaconnect.com/co…

21. Tuohy, Vincent K., and Ritika Jaini. “Prophylactic cancer vaccination by targeting functional non-self.” Annals of medicine 43.5 (2011): 356-365. https://www.ncbi.nlm.nih.gov/pmc…

22. Seril, Darren N., et al. “Oxidative stress and ulcerative colitis-associated carcinogenesis: studies in humans and animal models.” Carcinogenesis 24.3 (2003): 353-362. https://www.researchgate.net/pro…

23. Itzkowitz, Steven H., and Xianyang Yio. “Inflammation and cancer IV. Colorectal cancer in inflammatory bowel disease: the role of inflammation.” American Journal of Physiology-Gastrointestinal and Liver Physiology 287.1 (2004): G7-G17. http://ajpgi.physiology.org/cont…

24. Nakano, Osamu, et al. “Proliferative activity of intratumoral CD8+ T-lymphocytes as a prognostic factor in human renal cell carcinoma.” Cancer research 61.13 (2001): 5132-5136. http://cancerres.aacrjournals.or…

25. Granier, Clémence, et al. “Tim-3 expression on tumor-infiltrating PD-1+ CD8+ T cells correlates with poor clinical outcome in renal cell carcinoma.” Cancer Research (2016): canres-0274.

26. Giraldo, Nicolas A., et al. “Tumor-Infiltrating and Peripheral Blood T Cell Immunophenotypes Predict Early Relapse in Localized Clear Cell Renal Cell Carcinoma.” Clinical Cancer Research (2017): clincanres-2848.

27. Peto, Julian. “Cancer epidemiology in the last century and the next decade.” Nature 411.6835 (2001): 390-395. http://www.ph.ucla.edu/EPI/facul…

28. Irani, Jacques, et al. “High-grade inflammation in prostate cancer as a prognostic factor for biochemical recurrence after radical prostatectomy.” Urology 54.3 (1999): 467-472.

29. Dennis, Leslie K., Charles F. Lynch, and James C. Torner. “Epidemiologic association between prostatitis and prostate cancer.” Urology 60.1 (2002): 78-83.

30. Roberts, Rosebud O., et al. “Prostatitis as a risk factor for prostate cancer.” Epidemiology 15.1 (2004): 93-99.

31. MacLennan, Gregory T., et al. “The influence of chronic inflammation in prostatic carcinogenesis: a 5-year followup study.” The Journal of urology 176.3 (2006): 1012-1016.

32. Karakiewicz, P. I., et al. “Chronic inflammation is negatively associated with prostate cancer and high‐grade prostatic intraepithelial neoplasia on needle biopsy.” International journal of clinical practice 61.3 (2007): 425-430.

33. Davidsson, Sabina, et al. “Inflammation, focal atrophic lesions, and prostatic intraepithelial neoplasia with respect to risk of lethal prostate cancer.” Cancer Epidemiology and Prevention Biomarkers 20.10 (2011): 2280-2287. http://cebp.aacrjournals.org/con…

34. Jiang, Junyi, et al. “The role of prostatitis in prostate cancer: meta-analysis.” PloS one 8.12 (2013): e85179. http://journals.plos.org/plosone…

35. Gurel, Bora, et al. “Chronic inflammation in benign prostate tissue is associated with high-grade prostate cancer in the placebo arm of the prostate cancer prevention trial.” Cancer Epidemiology and Prevention Biomarkers 23.5 (2014): 847-856. https://www.researchgate.net/pro…

36. Pepe, Pietro, and Francesco Aragona. “Does an inflammatory pattern at primary biopsy suggest a lower risk for prostate cancer at repeated saturation prostate biopsy.” Urologia internationalis 87.2 (2011): 171-174.

37. Vral, Anne, et al. “Topographic and quantitative relationship between prostate inflammation, proliferative inflammatory atrophy and low-grade prostate intraepithelial neoplasia: a biopsy study in chronic prostatitis patients.” International journal of oncology 41.6 (2012): 1950-1958. https://www.researchgate.net/pro…

38. Engelhardt, P. F., et al. “Chronic asymptomatic inflammation of the prostate type IV and carcinoma of the prostate: Is there a correlation?.” Scandinavian journal of urology 47.3 (2013): 230-235.

39. Yli‐Hemminki, Tytti H., et al. “Histological inflammation and risk of subsequent prostate cancer among men with initially elevated serum prostate‐specific antigen (PSA) concentration in the Finnish prostate cancer screening trial.” BJU international 112.6 (2013): 735-741. http://onlinelibrary.wiley.com/d…

40. Moreira, Daniel M., et al. “Baseline prostate inflammation is associated with a reduced risk of prostate cancer in men undergoing repeat prostate biopsy: results from the REDUCE study.” Cancer 120.2 (2014): 190-196. Baseline prostate inflammation is associated with a reduced risk of prostate cancer in men undergoing repeat prostate biopsy: Results from the REDUCE study – Moreira – 2013 – Cancer – Wiley Online Library

41. Tirumalai Kamala’s answer to What is the relationship between tumors and immune tolerance?

42. Dieu-Nosjean, Marie-Caroline, et al. “Long-term survival for patients with non–small-cell lung cancer with intratumoral lymphoid structures.” Journal of Clinical Oncology 26.27 (2008): 4410-4417. Long-Term Survival for Patients With Non-Small-Cell Lung Cancer With Intratumoral Lymphoid Structures

43. de Chaisemartin, Luc, et al. “Characterization of chemokines and adhesion molecules associated with T cell presence in tertiary lymphoid structures in human lung cancer.” Cancer research 71.20 (2011): 6391-6399. http://cancerres.aacrjournals.or…

44. Coppola, Domenico, et al. “Unique ectopic lymph node-like structures present in human primary colorectal carcinoma are identified by immune gene array profiling.” The American journal of pathology 179.1 (2011): 37-45. http://ac.els-cdn.com/S000294401…

45. Naito, Yoshitaka, et al. “CD8+ T cells infiltrated within cancer cell nests as a prognostic factor in human colorectal cancer.” Cancer research 58.16 (1998): 3491-3494. http://cancerres.aacrjournals.or…

46. Galon, Jérôme, et al. “Type, density, and location of immune cells within human colorectal tumors predict clinical outcome.” Science 313.5795 (2006): 1960-1964. https://www.researchgate.net/pro…

47. Laghi, Luigi, et al. “CD3+ cells at the invasive margin of deeply invading (pT3–T4) colorectal cancer and risk of post-surgical metastasis: a longitudinal study.” The lancet oncology 10.9 (2009): 877-884.

48. Loi, Sherene, et al. “Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02-98.” Journal of clinical oncology 31.7 (2013): 860-867. Prognostic and Predictive Value of Tumor-Infiltrating Lymphocytes in a Phase III Randomized Adjuvant Breast Cancer Trial in Node-Positive Breast Cancer Comparing the Addition of Docetaxel to Doxorubicin With Doxorubicin-Based Chemotherapy: BIG 02-98: Journal of Clinical Oncology: Vol 31, No 7

49. Ali, H. R., et al. “Association between CD8+ T-cell infiltration and breast cancer survival in 12 439 patients.” Annals of oncology (2014): mdu191. https://oup.silverchair-cdn.com/…

50. Loi, S., et al. “Tumor infiltrating lymphocytes are prognostic in triple negative breast cancer and predictive for trastuzumab benefit in early breast cancer: results from the FinHER trial.” Annals of oncology 25.8 (2014): 1544-1550. https://www.researchgate.net/pro…

51. Adams, Sylvia, et al. “Prognostic value of tumor-infiltrating lymphocytes in triple-negative breast cancers from two phase III randomized adjuvant breast cancer trials: ECOG 2197 and ECOG 1199.” Journal of clinical oncology 32.27 (2014): 2959-2966. Prognostic Value of Tumor-Infiltrating Lymphocytes in Triple-Negative Breast Cancers From Two Phase III Randomized Adjuvant Breast Cancer Trials: ECOG 2197 and ECOG 1199: Journal of Clinical Oncology: Vol 32, No 27

52. Salgado, Roberto, et al. “Tumor-infiltrating lymphocytes and associations with pathological complete response and event-free survival in HER2-positive early-stage breast cancer treated with lapatinib and trastuzumab: a secondary analysis of the NeoALTTO trial.” JAMA oncology 1.4 (2015): 448-455. https://www.researchgate.net/pro…

53. Pages, F., et al. “Immune infiltration in human tumors: a prognostic factor that should not be ignored.” Oncogene 29.8 (2010): 1093-1102. http://www.nature.com/onc/journa…

54. Nelson, Brad H. “The impact of T‐cell immunity on ovarian cancer outcomes.” Immunological reviews 222.1 (2008): 101-116.

55. Jafari, Siavash, Mahyar Etminan, and Kourosh Afshar. “Nonsteroidal anti-inflammatory drugs and prostate cancer: a systematic review of the literature and meta-analysis.” Can Urol Assoc J 3.4 (2009): 323-330. http://citeseerx.ist.psu.edu/vie…

56. Mahmud, Salaheddin M., Eduardo L. Franco, and Armen G. Aprikian. “Use of nonsteroidal anti‐inflammatory drugs and prostate cancer risk: A meta‐analysis.” International journal of cancer 127.7 (2010): 1680-1691. http://onlinelibrary.wiley.com/d…

57. Bosetti, Cristina, et al. “Aspirin and urologic cancer risk: an update.” Nature Reviews Urology 9.2 (2012): 102-110.

58. Liu, Yanqiong, et al. “Effect of aspirin and other non-steroidal anti-inflammatory drugs on prostate cancer incidence and mortality: a systematic review and meta-analysis.” BMC medicine 12.1 (2014): 55. Effect of aspirin and other non-steroidal anti-inflammatory drugs on prostate cancer incidence and mortality: a systematic review and meta-analysis

59. Huang, Tian-bao, et al. “Aspirin use and the risk of prostate cancer: a meta-analysis of 24 epidemiologic studies.” International urology and nephrology 46.9 (2014): 1715-1728. https://www.researchgate.net/pro…

60. Vidal, Adriana C., et al. “Aspirin, NSAIDs, and risk of prostate cancer: results from the REDUCE study.” Clinical Cancer Research 21.4 (2015): 756-762. http://clincancerres.aacrjournal…

61. Sostres, Carlos, Carla Jerusalen Gargallo, and Angel Lanas. “Aspirin, cyclooxygenase inhibition and colorectal cancer.” World J Gastrointest Pharmacol Ther 5.1 (2014): 40-9. http://www.wjgnet.com/esps/DownL…

62. Thun, Michael J., Eric J. Jacobs, and Carlo Patrono. “The role of aspirin in cancer prevention.” Nature reviews Clinical oncology 9.5 (2012): 259-267. http://vetbiotech.um.ac.ir/param…

63. Rothwell, Peter M., et al. “Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials.” The Lancet 377.9759 (2011): 31-41. https://www.researchgate.net/pro…

64. Velayos, Fernando S., et al. “Predictive and protective factors associated with colorectal cancer in ulcerative colitis: a case-control study.” Gastroenterology 130.7 (2006): 1941-1949.

65. DeCensi, Andrea, et al. “Metformin and cancer risk in diabetic patients: a systematic review and meta-analysis.” Cancer prevention research (2010): 1940-6207. http://cancerpreventionresearch….

66. Gandini, Sara, et al. “Metformin and cancer risk and mortality: a systematic review and meta-analysis taking into account biases and confounders.” Cancer prevention research (2014). http://cancerpreventionresearch….

67. Thakkar, Bindiya, et al. “Metformin and sulfonylureas in relation to cancer risk in type II diabetes patients: a meta-analysis using primary data of published studies.” Metabolism 62.7 (2013): 922-934. http://ac.els-cdn.com/S002604951…

68. Pulito, Claudio, et al. “Metformin: on ongoing journey across diabetes, cancer therapy and prevention.” Metabolites 3.4 (2013): 1051-1075. http://www.mdpi.com/2218-1989/3/…

https://www.quora.com/Is-there-an-association-between-inflammation-and-cancer/answer/Tirumalai-Kamala

What are the various applications of polyclonal antibodies?

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Some definitions first for a general audience

Polyclonal antibodies – Wikipedia: Usually the serum product of an immunized animal. Heterogeneous because they comprise

  • Various antibodies specific for a variety of antigens, some specific for different epitopes of the same antigen,
  • Different antibody classes and sub-classes, i.e., Isotype (immunology) – Wikipedia, and
  • Wide range of antibody concentrations (Antibody titer – Wikipedia) and affinities for their respective antigens.

Monoclonal antibody – Wikipedia (mAbs): Products of a hybridoma clone (Hybridoma technology – Wikipedia), derived from a single antibody-secreting B cell fused to a myeloma cell line. Homogeneous. In essence, product of a cellular factory spewing out that one mAb. Thus, the secreted antibody is mono-specific, with a single affinity to the single epitope it binds on the antigen, and is of a single antibody class (Immunoglobulin class switching – Wikipedia).

Epitope: Site that an antibody binds on an antigen.

Affinity: Strength of antibody binding to antigen.

Avidity: Sum of affinities of multiple antigen-binding sites on an antibody.

Polyclonal antibodies: Pros & Cons

Unlike mAbs, polyclonal antibodies

  • Can be produced faster and more cheaply.
  • Can bind their target antigens under a variety of salt and pH concentrations so are more stable.
  • Comprise antibodies specific for different epitopes of a given antigen. Outcome is higher antibody affinity, i.e., antigen-binding sensitivity.
  • Easier to couple to a variety of labels such as enzymes, Fluorophore – Wikipedia, etc.

Such attributes make polyclonal antibodies a better option in assays

  • For binding proteins sensitive to conformational changes or denaturation, or which are polymorphic.
  • In Immunoprecipitation – Wikipedia (IP) and Chromatin immunoprecipitation – Wikipedia (ChIP) assays.
  • For detecting low concentrations of a given protein.
  • As capture antibody in sandwich ELISA – Wikipedia (Enzyme-Linked Immunosorbent Assay), one of the most widely used assays to detect and quantify antigens. For capture and not for detection. ELISA assays using them for detection are more susceptible to dramatic changes when diluting sera since a polyclonal serum contains varying antigen specificities and affinities at different concentrations (titers). OTOH, diluting mAbs doesn’t affect their affinity/avidity so easier to interpret that a change in reaction results from change in antigen concentration. While mAbs have a single specificity, heterogeneity of polyclonal antibodies means varying affinities even against the same epitope which makes assessing their specificity much more complicated. Unlike polyclonal antibodies, using mAbs for detection in ELISAs allows calibration, and therefore, standardization.

However, major drawbacks of polyclonal antibodies are

  • Batch-to-batch variability since each batch is typically product of one or few immunized animals. OTOH, being products of immortalized cells, practically limitless amounts of mAbs can be produced.
  • Binding multiple epitopes on a given antigen increases scope for cross-reactivity. This necessitates affinity purification (Affinity chromatography – Wikipedia) before using them in assays.
  • Consequence of polyclonal antibodies comprising different antigenic specificities and affinities is higher background signal in various assays, i.e., lower specificity.

Some Therapeutic Applications of Polyclonal antibodies

Polyclonal antibodies are widely used for Immunosuppression – Wikipedia to prevent acute rejection in transplant recipients. In transplants, one of the major logistical problems is severe, chronic shortage of living donors. As a result, criteria have steadily expanded to include organs previously precluded from consideration. These include greater tissue mismatches, and organ and tissue donations after cardiac death. Problem with using expanded criteria organs is higher probability of rejection. This necessitates using more powerful immunosuppressive therapy, often lifelong.

Some polyclonal antibody preparations have become mainstays among immunosuppressive regimens used to prevent early, acute rejection in solid organ transplants. Two main types of polyclonal antibody preparations are widely used, one sourced from rabbits, the other from horses (Anti-thymocyte globulin – Wikipedia). They are (1, 2, 3, 4, 5, 6)

  • Thymoglobulin®, a rabbit anthymocyte globulin (rATG).
  • ATG-Fresenius, a rabbit anthymocyte globulin.
  • ATGAM® or eATG, equine antithymocyte globulin.
  • Lymphoglobulin®, horse ATG.

Thymoglobulin®, a rabbit anthymocyte globulin (rATG)

  • First licensed in April 1984 in Europe and in 1999 in USA (6).
  • Manufactured by Genzyme/Sanofi.
  • Is polyclonal IgG anti-human thymocyte globulin.
  • Rabbits are immunized with human Thymocyte – Wikipedia (developing T cells).
  • Is widely used in solid organ transplants.
  • Was given to ~ half of all new kidney transplant recipients in the US between 2000 and 2009 (7).
  • Initially used in kidney transplants, today it’s used in a variety of solid organ transplants such as liver, heart, lung, pancreas, intestinal as well as hematopoietic stem cell transplantation and aplastic anemia (1, 5).

ATG-Fresenius

  • Manufactured by Neovii Biotech (formerly Fresenius Biotech) (4).
  • Rabbits are immunized with a human Jurkat cells – Wikipedia line.

ATGAM® or eATG, equine antithymocyte globulin (5)

  • Horses are immunized with human T cells and their antibodies harvested from their serum.
  • Developed by Peter Medawar – Wikipedia in the 1950s.
  • Thomas Starzl – Wikipedia started using it in the 1960s.
  • Registered for use in kidney transplantation in the US since 1981.
  • First commercially available ATG in Europe and USA.
  • Manufactured by Pfizer (previously Pharmacia Upjohn).

Lymphoglobulin®, Horse ATG

  • Manufactured by Genzyme/Sanofi.

To avoid early, acute rejection, high-risk transplant recipients, usually defined as glucocorticoid-resistant, are typically given these antibodies starting shortly before the transplant and continuing immediately afterward for a few weeks.

While exact mechanism by which these complex reagents immunosuppress is unknown, ADCC (Antibody-dependent cell-mediated cytotoxicity – Wikipedia) likely causes rapid and widespead lysis of T cells though elimination of other cells such as NK cells is also possible. This Rx also entails serious risks which include Cytokine release syndrome – Wikipedia, Thrombocytopenia – Wikipedia, Leukopenia – Wikipedia, higher infection risk, and many others (2, 3, 4, 5, 8, 9).

Bibliography

1. Gaber, A. Osama, et al. “Rabbit antithymocyte globulin (thymoglobulin): 25 years and new frontiers in solid organ transplantation and haematology.” Drugs 70.6 (2010): 691-732. https://www.researchgate.net/pro…

2. Penninga, Luit. Immunosuppressive Polyclonal and Monoclonal T-cell Antibody Induction Therapy for Solid Organ Transplant Recipients: Systematic Reviews with Meta-analyses and Trial Sequential Analyses of Randomised Clinical Trials: Ph. D. Thesis. Afsnit 7812, Blegdamsvej 9, 2100 Ø, 2014. http://citeseerx.ist.psu.edu/vie…

3. Chen, Huifang, Qian, Shiguang. “Current Immunosuppressive Therapy in Organ Transplantation.” CURRENT IMMUNOSUPPRESSIVE THERAPY IN ORGAN TRANSPLANTATION: 51. https://www.researchgate.net/pro…

4. Nishihori, Taiga, et al. “Antithymocyte globulin in allogeneic hematopoietic cell transplantation: benefits and limitations.” Immunotherapy 8.4 (2016): 435-447.

5. https://www.fda.gov/downloads/Ap…

6. Thymoglobulin

7. Cai, J., and P. I. Terasaki. “The current trend of induction and maintenance treatment in patient of different PRA levels: a report on OPTN/UNOS Kidney Transplant Registry data.” Clinical transplants (2009): 45-52.

8. Bamoulid, Jamal, et al. “Anti-thymocyte globulins in kidney transplantation: focus on current indications and long-term immunological side effects.” Nephrology Dialysis Transplantation (2016): gfw368.)

9. Malvezzi, Paolo, Thomas Jouve, and Lionel Rostaing. “Induction by anti-thymocyte globulins in kidney transplantation: a review of the literature and current usage.” Journal of nephropathology 4.4 (2015): 110. https://www.researchgate.net/pro…

https://www.quora.com/What-are-the-various-applications-of-polyclonal-antibodies/answer/Tirumalai-Kamala

Why are some clinical trials finished, but the results not reported?

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Short answer

  • Too many exemptions. Legal requirements for reporting results of completed clinical trials contain so many exemptions that most trials entered into Home – ClinicalTrials.gov are exempt.
  • Enforcement too lax. The US FDA and NIH are tasked with enforcing these reporting rules but not only do they themselves flout them, they also do little to ensure compliance. For example, a 2015 investigation (1) found not a single researcher or trial sponsor had been fined or penalized since the law came into effect in 2008.

Clinical Trial Results Under-reporting: A Chronic Problem Of Epidemic Proportions

Under-reporting of clinical trial results has long been chronic and widespread for decades (2).

A 2016 analysis (3) of the fate of 5918 abstracts presented at the American Society of Anesthesiologists annual meetings from 2001 to 2004 found

  • 1052 presented results of human RCTs.
  • Only 54%, 568 of 1052, were published within 10 years of the initial presentation.
  • RCTs with positive data (defined as one showing a statistically significant result in favor of the experimental group) were 42% more likely to be published compared to those with negative data.
  • Positive or negative data notwithstanding, most of these studies were small with median 40 to 50 participants, which only adds insult to injury. Not only is scope of false inference already considerable, such inferences would be drawn from tiny, utterly unrepresentative slices of the whole, greatly increasing scope of false positives (4).

A 2016 analysis (5) of drugs and biologics tested in pivotal trials from 1998 to 2008 found

  • 54% of them failed.
  • Trial results were published for only 40% of the ones that failed.

Eventually the epidemic scale of the problem prompted the US government to enact the 2007 US FDA Amendments Act (FDAAA), which (6, emphasis mine)

‘requires that the results from clinical trials of Food and Drug Administration–approved drugs and devices conducted in the United States must be made publicly available at Home – ClinicalTrials.gov within 1 y of the completion of the trial, whether the results are published or not.’

So Much Promised, So Little Achieved: Laws Mean Nothing If They Aren’t Enforced

A 2016 analysis (7) found that of 13327 completed or terminated clinical trials from January 1 2008 until August 31, 2012,

  • 51 top academic and non-profit institutions posted clinical trial results on Home – ClinicalTrials.gov only 13% of the time even two years after they’re finished when the legal requirement is to do so within one year of completion.
  • Researchers published their findings in medical journals within two years only 29% of the time.

A 2017 analysis (8) of breast cancer trials registered at Home – ClinicalTrials.gov from 2000 to 2012 found no improvement in reporting. Rather it found

  • Trials with statistically significant outcome more likely to be published.
  • Under-reporting of clinical trial results.
  • Delay in publication of statistically non-significant results.

Situation is not much different even for posting trial results on the Home – ClinicalTrials.gov webpage. One study (9) examined 17536 studies with results posted at Home – ClinicalTrials.gov, 2823 of which were completed randomized phase II or III trials.

  • 1400 of 2823 completed trials (~50%) reported the treatment effect estimate and/or p value. Of these, 844 (60%) had statistically significant results.
  • 1423 trials only posted data without reporting results, which, however, could be calculated, at least in theory. Calculation was possible for 929 (65%), not for 494 (35%), either due to insufficient reporting, data censoring or repeat measurements. Of these 929, only 342 (37%) had statistically significant results.
  • Key comparison then is the large difference in statistically significant results between those who posted their treatment effect estimate and/or p value (844 of 1400, 60%) versus those who didn’t (342 of 929, 37%).
  • Thus, positive result bias is prevalent not just in publications but even in merely reporting them to Home – ClinicalTrials.gov.
  • Irony is posting results to Home – ClinicalTrials.gov is likely far more valuable to the public
    • Site is freely accessible worldwide unlike scientific journals which are more often hidden behind exorbitantly priced paywalls.
    • A 2013 Plos Medicine analysis (6) found posted Home – ClinicalTrials.gov results for 212 published studies were far more complete, especially in reporting potentially adverse events, information of vital importance to patients.

The American health news web-site Stat (website) – Wikipedia, published results of a 2015 investigation (1) that showed

  • Top flouters weren’t merely prestigious ones like Memorial Sloan Kettering, Stanford, Eli Lilly and GlaxoSmithKline but ironically the enforcers themselves. Yes, even NIH routinely flouted the rule it’s supposed to enforce (see below from 1).
  • Such high-profile exposure caught the attention of the US Senate with one senator chiding the NIH for failing to do its job (10).
  • Even then US Vice-President Joe Biden called for defunding federal grant recipients who didn’t comply with the law.
  • In the short-term, reporting of clinical trials results jumped 25% over the same period the previous years.

Later in 2016, the US government posted new regulations (11) requiring public reporting of many more clinical trials, including some for drugs and devices that never reach the market. Problem is these rules don’t go far enough. There are too many exemptions.

  • Trials entered into Home – ClinicalTrials.gov before 2008 are exempt.
  • So are ‘privately funded studies — including small trials examining just the safety of a new drug, small feasibility studies of medical devices, and behavioral intervention studies‘ (1).
  • Thus the rules only apply to a fraction of registered trials.
  • The 2015 STAT news investigation (1) found they only applied to a mere 4.5%, ~9000 of ~200000 trials.

Rampant Publication bias – Wikipedia, defined as ‘published research which is systematically unrepresentative of the population of completed studies‘ (12), and originally described in 1979 as the file drawer problem (13). The usual suspects of employers (universities, academic institutes, biotech/pharma, hospitals, medical centers, etc), journal editors, peer reviewers, funding agencies, even mass media, seem to continue to strongly prefer positive and novel results. Cost of basing treatments on not the whole picture but on a small, biased slice of it is harm to patients (14, 15, 16, 17). Treatments based on a single RCT could later turn out to be useless or even dangerous (18).

Bibliography

1. STAT, Charles Piller, December 13, 2015. Patients endangered as law is ignored

2. Rotonda, Tavola. “Underreporting research is scientific misconduct.” Jama 263 (1990): 1405-1408.; Antes, Gerd, and Iain Chalmers. “Under-reporting of clinical trials is unethical.” The Lancet 361.9362 (2003): 978-979.

3. Chong, Simon W., et al. “The relationship between study findings and publication outcome in anesthesia research: a retrospective observational study examining publication bias.” Canadian Journal of Anesthesia/Journal canadien d’anesthésie 63.6 (2016): 682-690.

4. Dumas-Mallet, Estelle, et al. “Low statistical power in biomedical science: a review of three human research domains.” Royal Society Open Science 4.2 (2017): 160254. http://rsos.royalsocietypublishi…

5. Hwang, Thomas J., et al. “Failure of investigational drugs in late-stage clinical development and publication of trial results.” JAMA Internal Medicine 176.12 (2016): 1826-1833.

6. Riveros, Carolina, et al. “Timing and completeness of trial results posted at ClinicalTrials. gov and published in journals.” PLoS Med 10.12 (2013): e1001566. http://journals.plos.org/plosmed…

7. Chen, Ruijun, et al. “Publication and reporting of clinical trial results: cross sectional analysis across academic medical centers.” bmj 352 (2016): i637. http://www.bmj.com/content/bmj/3…

8. Song, Seung Yeon, et al. “The significance of the trial outcome was associated with publication rate and time to publication.” Journal of Clinical Epidemiology (2017).

9. Dechartres, Agnes, et al. “Reporting of statistically significant results at ClinicalTrials. gov for completed superiority randomized controlled trials.” BMC medicine 14.1 (2016): 192. Reporting of statistically significant results at ClinicalTrials.gov for completed superiority randomized controlled trials

10. STAT, Charles Piller, February 19, 2016. Senator Charles Grassley urges better clinical trials reporting

11. https://s3.amazonaws.com/public-…

12. Rothstein HR, Sutton AJ, Borenstein M. Publication bias in meta-analysis. In: Rothstein HR, Sutton AJ, Borenstein M (Eds). Publication Bias in Meta-Analysis: Prevention, Assesment and Adjustments. John Wiley & Sons, Inc. 2006.

13. Rosenthal, Robert. “The file drawer problem and tolerance for null results.” Psychological bulletin 86.3 (1979): 638. http://datacolada.org/wp-content…

14. Horton, Richard. “Offline: What is medicine’s 5 sigma?.” The Lancet 385.9976 (2015): 1380. http://www.thelancet.com/pdfs/jo…

15. Smaldino, Paul E., and Richard McElreath. “The natural selection of bad science.” Royal Society Open Science 3.9 (2016): 160384. https://www.researchgate.net/pro…

16. Higginson, Andrew D., and Marcus R. Munafò. “Current incentives for scientists lead to underpowered studies with erroneous conclusions.” PLoS Biology 14.11 (2016): e2000995. http://journals.plos.org/plosbio…

17. Nissen, Silas Boye, et al. “Publication bias and the canonization of false facts.” Elife 5 (2016): e21451. https://elifesciences.org/conten…

18. Prasad, Vinay, et al. “A decade of reversal: an analysis of 146 contradicted medical practices.” Mayo Clinic Proceedings. Vol. 88. No. 8. Elsevier, 2013. https://www.researchgate.net/pro…

https://www.quora.com/Why-are-some-clinical-trials-finished-but-the-results-not-reported/answer/Tirumalai-Kamala

Does processed milk cause multiple sclerosis flare up?

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Brief History Of Nebulous Connection Between Milk & MS (Multiple Sclerosis)

Sparse data on this subject consists of

  • An US epidemiological study that compared 1949 to 1967 MS mortality rates and food consumption data, and found high correlation (0.8 to 0.9) with milk consumption (1).
  • A couple of cross-sectional epidemiological studies from 1976 (2) and 1992 (3) that compared MS prevalence and dairy product consumption. The second one looked across 29 populations in 27 countries and suggested MS progression could be influenced by factors in liquid cow’s milk but not in processed milk.

The story then appeared to lie dormant for the next several years until revived by a 2000 rat EAE (Experimental autoimmune encephalomyelitis – Wikipedia) model study (4). This study mechanistically showed Butyrophilin – Wikipedia, a milk fat globule membrane protein expressed only by the lactating mammary gland,

Similar experiments in a mouse model (5) also showed Butyrophilin could prevent MOG-induced EAE, i.e., that this milk component could protect against EAE.

Problem is though originally developed in the 1950s to supposedly mimic human MS, these rodent (mainly rat and mouse) models simply don’t mimic human MS very well (6), haven’t yielded much insight or practical therapies and yet have taken over basic MS research and remain the mainstay in the field.

Meantime, a couple of small human studies from France (n=44 MS versus 30 controls, 7) and the US (n= 35 MS versus 25 controls, 8) yielded contradictory data

  • The French study (7) found MS patients with higher circulating antibody levels cross-reactive to MOG and Butyrophilin.
  • The US study (8) found MS patients and controls had similar levels of circulating antibodies cross-reactive to MOG and Butyrophilin. However, this US study also compared anti-MOG and -Butyrophilin antibody responses in blood as well as CSF (Cerebrospinal fluid – Wikipedia) of MS patients and found they were specific for different epitopes (parts) of Butyrophilin, the one dominating in the CSF also cross-reacting to a homologous MOG peptide in 34% of MS patients, i.e., possible Molecular mimicry – Wikipedia between MOG and Butyrophilin.

In addition to these two human studies contradicting each other, these purely observational studies examined circulating antibody levels, i.e., B cell – Wikipedia, not T, cell response as the animal model studies did. Apples and oranges.

While Butyrophilin’s plausible role in MS progression lies in its high sequence similarity to MOG (9), i.e., Molecular mimicry – Wikipedia, data from these two small human studies are inconclusive and so far there’s no other data on milk proteins’ role in MS prognosis or disease course (10).

How Milk Or Any Other Factor Might Trigger Or Flare MS (Multiple Sclerosis)

Though there are many suspects, confirmed triggers for MS are still unknown. Most convincing data exist not for dietary factors such as milk but for vitamin D levels and its receptor polymorphisms, history of Epstein-Barr virus infection including Infectious mononucleosis – Wikipedia and smoking (11, 12).

No matter the trigger though, how might MS disease cascade follow? Prime suspect is molecular mimicry, i.e., molecular level similarity between such triggers and the target of autoimmune attack in MS, typically proteins such as MOG expressed on Oligodendrocyte – Wikipedia, myelin sheath cells.

  • However, even this is insufficient. Consider milk for example. Many more people drink milk than get MS. If molecular mimicry alone sufficed, they should all have MS and they don’t.
  • Clearly other factors are also involved. No matter the degree of molecular mimicry, nothing can ensue if a person’s immune system can’t ‘see’ it.
    • An immunologically necessary condition would thus be the HLA (Human leukocyte antigen – Wikipedia) haplotype. However, HLA haplotype alone wouldn’t suffice because far more people share HLA haplotypes than develop MS.
    • Breakdown in T cell tolerance is also necessary. After all, during their development in the thymus, T cells with the capacity to recognize oligodendrocyte proteins should get deleted. Obviously that process seems to fall short in MS patients.
  • Thus target antigen (and molecular mimic)-specific T cells should be present and such target(s) of immune attack should be properly processed and presented to these T cells. However, though appropriate HLA haplotype and CNS (Central nervous system – Wikipedia) protein(s)-specific T cells are the necessary building blocks for MS autoimmune pathology, their presence alone doesn’t suffice either.
  • Context is also necessary, i.e., predisposing and/or conditioning factors necessary to drive the pathological immune response necessary for MS expression. Totality of such factors, sufficient to explain MS in each and every case, still remain undefined.

Bibliography

1. Agranoff, BernardW, and David Goldberg. “Diet and the geographical distribution of multiple sclerosis.” The Lancet 304.7888 (1974): 1061-1066. https://deepblue.lib.umich.edu/b…

2. Butcher, J. “The distribution of multiple sclerosis in relation to the dairy industry and milk consumption.” The New Zealand Medical Journal 83.566 (1976): 427-430)

3. Malosse, D., et al. “Correlation between milk and dairy product consumption and multiple sclerosis prevalence: a worldwide study.” Neuroepidemiology 11.4-6 (1993): 304-312.

4. Stefferl, Andreas, et al. “Butyrophilin, a milk protein, modulates the encephalitogenic T cell response to myelin oligodendrocyte glycoprotein in experimental autoimmune encephalomyelitis.” The Journal of Immunology 165.5 (2000): 2859-2865. http://www.jimmunol.org/content/…

5. Mañá, Paula, et al. “Tolerance induction by molecular mimicry: prevention and suppression of experimental autoimmune encephalomyelitis with the milk protein butyrophilin.” International immunology 16.3 (2004): 489-499. https://www.researchgate.net/pro…

6. Tirumalai Kamala’s answer to Why can chemicals that block the alpha tumour necrosis factor make multiple sclerosis worse? Do inhibiting cytokines make inflammation worse?

7. De March, A. Kennel, et al. “Anti-myelin oligodendrocyte glycoprotein B-cell responses in multiple sclerosis.” Journal of neuroimmunology 135.1 (2003): 117-125.

8. Guggenmos, Johannes, et al. “Antibody cross-reactivity between myelin oligodendrocyte glycoprotein and the milk protein butyrophilin in multiple sclerosis.” The Journal of Immunology 172.1 (2004): 661-668. http://www.jimmunol.org/content/…

9. Vojdani, Aristo. “Molecular mimicry as a mechanism for food immune reactivities and autoimmunity.” Altern Ther Health Med 21.Suppl 1 (2015): 34-45. http://bant.org.uk/wp-content/up…

10. Von Geldern, Gloria, and Ellen M. Mowry. “The influence of nutritional factors on the prognosis of multiple sclerosis.” Nature Reviews Neurology 8.12 (2012): 678-689.

11. Belbasis, Lazaros, et al. “Environmental risk factors and multiple sclerosis: an umbrella review of systematic reviews and meta-analyses.” The Lancet Neurology 14.3 (2015): 263-273.

12. Tirumalai Kamala’s answer to Why does Colorado have the highest rate of multiple sclerosis?

https://www.quora.com/Does-processed-milk-cause-multiple-sclerosis-flare-up/answer/Tirumalai-Kamala