Evidence based science and COVID-19

There is so much of confusing rather conflicting data regarding spread and lethality of COVID19 infection that people are divided about it based on what political ideology they believe in. There are "believers" and then there are "non-believers". Most likely truth lies somewhere in the middle. And given the crumbling economies everywhere in the world, it has become absolutely necessary to find the "truth". To me following questions are important to be asked from government agencies so as the real threat of this virus can be assessed: 

1. In the US alone, lots of people die naturally of "flu" every year, gravity of which can be can be seen in the fact that as many as 61,000 people died from influenza (flu) just in one year (2017-2018). 

So it will be interesting to know as to how many people died of regular "flu" during this pandemic times? Do we have overlap of these two separate "diseases" (flu vs. COVID19) in the number of the patients? 

2. Cardiovascular diseases are the number one killer in the US. 647,000 Americans die from heart disease each year—that's 1 in every 4 deaths. 

Would the agencies release the data from the same period (pandemic period) as to how many people died of cardiovascular diseases during these months? Are these numbers independent from COVID19 patients who died during this time or are they same? More important question is as to how many people died of cardiovascular diseases during this period who did not have COVID19? 

Same question can be asked regarding other major killers such as real number of deaths from stroke (number 2 killer), COPD (number 3 killer), cancer, etc. and some other infectious diseases for lower income countries. 

Get these numbers and measure the overlap between these diseases and COVID19 by subtracting the number of deaths from these diseases from COVID19 related deaths, that will tell the real impact of COVID19. In absence of these numbers, vested interests will continue to manipulate the people's mind to suit their political agenda and millions of people will continue to suffer from non-COVID19 related issues such as unemployment etc.

An example of "believers" vs. "non-believers":

Controversial Lancet study on Hydroxychloroquine retracted

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255293/

In the above paper published on May 22, 2020, investigators concluded that they were unable to confirm a benefit of hydroxychloroquine or chloroquine, when used alone or with a macrolide, on in-hospital outcomes for COVID-19. Each of these drug regimens was associated with decreased in-hospital survival and an increased frequency of ventricular arrhythmias when used for treatment of COVID-19.


Soon after it was published, it was considered as a major finding- Hydroxychloroquine (HCQ) touted by the Mr. Trump as possible COVID-19 treatment looked to be not only ineffective, but downright deadly. This study used hospital records procured by a little-known data analytics company called Surgisphere to conclude that coronavirus patients taking chloroquine or hydroxychloroquine were more likely to show an irregular heart rhythm and were more likely to die in the hospital.


Soon after this paper published others in the field started raising concern regarding the mysterious database company that supplied the content for this whole study. The database belongs to Surgisphere Corporation whose founder and CEO, is Dr. Sapan Desai, who is a lead co-author of the study. The Lancet started its internal investigation in search for the raw data but Dr. Desai refused to disclose the data – for independent confirmatory review. In fact, he refuses to identify the participating hospitals, or even the countries.

https://www.sciencemag.org/news/2020/06/mysterious-company-s-coronavirus-papers-top-medical-journals-may-be-unraveling?fbclid=IwAR3qJmis6GzYBQGq2hho3aRrSxwYxCBDjRRRQxIjHYIHNoT0RK6ka6XCF-4


From my little experience of having analyzed the thought pattern and modus operandi of controversial researchers, I have noticed that most of them would like to go with something that majority of the people in the field already believe in or has been established. In this case, we know that when Trump touted HCQ as probable drug for COVID19, of course based on a flawed French study, naturally biomedical community criticized that vehemently and as it is a human nature (that applies to scientists as well) most of us started developing a bias against HCQ, some of us just because of our adherence to a political ideology which is different from those those that come from Trump camp which is broadly considered as anti-science.


However, in this Lancet study, I consider these authors more guilty because all of them are very senior investigators (Professor level), no resident/trainee/postdoctoral fellow involved so they can not blame junior members of the team.
To me, looks like investigators of this controversial Lancet study sensed that air against HCQ in biomedical community and exploited it by extrapolating probably a smaller observation/trend regarding HCQ's clinical benefit or lack of it under disguise of now a dubious "clinical database company" run by Sapan Desai so that they can publish it in a reputed journal.


I would still give benefit of doubt to authors of this paper (except Dr Sapan Desai) as they simply may have relied on the "database" provided by Dr Desai who is the chief of the database company - Surgisphere. However, they still are accountable for being careless and not doing due diligence in collaborating with Dr. Desai who has a bad reputation of having been sued multiple times for medical malpractice.

I personally do not think that Lancet editorial board can be blamed for this disaster as they rely on peer review. However, reviewers can partially be blamed for not taking red signal when they came across a "database" that has no reputation in the field. This is where our biases come into play, when we see a study submitted from Harvard (Mandeep Mehra) most of us take it at face value and become less critical than same data coming from a smaller center/third world country.


Another thing that I want to note that this paper is a perfect example of how reputation of modern medicine/biomedical research has a greater risk of being tarnished by too much reliance on "big data". I am quite old fashioned in this regard and have personally suffered in my career because of my hesitations regarding the use of "data analytics", "cloud computing", "machine learning", "artificial intelligence" etc which is dominating the field these days. I can not say for clinical sciences, but in the basic biomedical sciences it is getting harder and harder to publish studies that investigate the role of one gene/one protein/one pathway in a disease context. It has become fashion to use big data sets derived from whole genome sequencing which is totally dependent on computer based data analytics and things can be changed/tailored very easily just by tweaking one parameter to favor one's hypothesis. Even in the case of Lancet study, I do not think same thing was possible if they had to go and collect the clinical data old fashioned way from one hospital to another.


I might sound retrogressive in this regard but I think its reminder for all of us in the field to slow down a bit when it comes to making real progress in biomedical sciences, we need a balance between real life scientific observation in lab/clinic and use of cloud based " big databases".

Fast forward, while I was writing this blog, retraction notice came up for this paper: 

https://marlin-prod.literatumonline.com/…/S0140673620313246…

As most of us expected who have faith in science and goodwill of it, 3 authors of the controversial Lancet paper came forward and realized their mistake and asked for retraction of the their research paper on findings. So now we know that the sole culprit of this fraudulent study is only one person - Dr. Sapan Desai.


In brief, it was an observational study on allegedly a large number of COVID19 patient dataset claimed to be in possession of doctor named Dr Sapan Desai. Dr. Desai apparently does not have much reputation in the field but it is strange that he got hold of three eminent doctors/investigators namely Mandeep R Mehra, Frank Ruschitzka, and Amit N Patel from reputed institutes.


Scientific/medical studies always need collaboration, more often multiple teams from multiple institutes with different specialities collaborate and work together to conduct a biomedical study. Trust is everything in a team work and people work together in good faith. To me it appears that these 3 authors of this study were oblivious of the background of this guy Sapan Desai who is a mastermind of the fraudulent study. Read the statement of these 3 authors:

"We all entered this collaboration to contribute in good faith and at a time of great need during the COVID-19 pandemic."


Like any other field we scientists too have our share of evil. There are bad people who sometimes commit wrongdoing intentionally and sometimes it is committed due to their carelessness. Whatever may be the case, scientific fraternity is very self critical. We are taught to doubt our own data, ourselves, so whenever any wrongdoing is caught, community takes its cognizance and corrective measures are taken. So as soon as this study came up, biomedical fraternity started raising concerns and the journal started it's internal investigation.


So retraction of a research paper is not a new things for those of us who are insider, but this episode of wrongdoing by Sapan Desai is certainly very disappointing especially at a time when the whole world is watching us with hope. I am still very upset and would personally hope I am still very upset and would hope that some kind of criminal prosecution be launched against Dr. Sapan Desai.

Moral of the story 

Do your due diligence background check before falling in love with your collaborator/s.  

CD13 - an important protein for cellular migration.

Cell migration is a fundamental process that involves the coordination of complex biochemical and biomechanical signals to modulate cell morphology by dynamically rearranging cytoskeleton filaments and to cause cellular traction. Slight alteration in this tightly regulated process in a cell could result in a wide variety of pathologies including metastasis of cancer cells. More than 200 proteins are known to be involved in this dynamic process. A new study from University of Connecticut identifies crucial role for a novel protein CD13 in cell to extracellular matrix (ECM) adhesion. This study demonstrates that CD13 controls integrin recycling a major protein family responsible for cellular migration.

https://stke.sciencemag.org/content/12/579/eaav5938?utm_campaign=toc_signaling_2019-04-30&et_rid=17082276&et_cid=2793732

Circadian rhythm and cancer !

It has been known for quite some time that disrupting sleep and other elements of humans' circadian rhythm can harm health. The same is true for the circadian clock of individual cells as well. So a a group of Japanese scientists wondered if disturbing the circadian clock of cancer cells could potentially hurt/weaken or even kill these cancer cells. They were right indeed...! What these researchers reported that a molecule named GO289 targets an enzyme casein kinase 2 that controls the cell's circadian rhythm, shows great clinical promise in halting cancer cells' growth by enabling manipulation of clock protein phosphorylation.

http://advances.sciencemag.org/content/5/1/eaau9060

"Trans-differentiation" approach to treat metastasis

It is well established that de-differentiation in cancer cells lead to increased malignancy and cancer-metastatic potential. Therefore, treating cancer by inducing cancer cell differentiation has been long haunted strategy for cancer biologists with little success in clinic, except few successful examples such as use of all-trans retinoic acid as differentiation therapy for acute promyelocytic leukemia. One of the major impediment underlying failure of various differentiation therapies is due to the dynamic nature of epithelial to mesenchymal transition (EMT) and its reverse (MET) of cancer cells during tumor dissemination and metastatic outgrowth which underscores the possible weakness of epithelial re-differentiation strategies. Here is a breakthrough study that demonstrates with strong body of evidences that cancer cell plasticity can directly be targeted and inhibited by a “trans-differentiation approach”, such as forced adipogenesis. Indeed, these findings using a therapeutic approach to target metastatic cancer cell by inducing them to become adipocytes (fat cells) show a great promise at least in pre-clinical studies. hashtag
https://www.cell.com/action/showPdf?pii=S1535-6108%2818%2930573-7

#tumors hashtag#metastasis hashtag#health

"Metastatic cells are preferentially vulnerable to lysosomal inhibition"

A group of cancer researchers at University of Colorado School of Medicine showed in a series of elegant experimental set-up that there is a functional reciprocal relationship between lysosome activity and metastasis that allows chloroquine  and other inhibitors of lysosome function, such as bafilomycin A1, to preferentially kill human metastatic bladder cancer cells by targeting autophagy-independent lysosome functions. They also demonstrated that chloroquine treatment of bladder cancer cells and subsequent acquisition of resistance to this therapy lead to altered gene expression programs that drive a less aggressive and metastatic phenotype via up-regulation of inhibitor of DNA binding 4, also known as ID4. 

This work suggest that there is an intimate reciprocal relationship between metastatic ability and lysosome function and that targeting the lysosome itself, rather than autophagy specifically, may provide an effective therapy in patients with metastasis.

This work also has clinical implications as to how ID4 expression could be used as a predictive and prognostic biomarker for chloroquine sensitivity and metastasis in patients with bladder cancer. 

http://www.pnas.org/content/early/2018/08/15/1706526115

Gallbladder Cancer and Aflatoxin: Do We Have Sufficient Evidence?

My recently published article in Gastroenterology:

https://www.sciencedirect.com/science/article/pii/S001650851736345X?via%3Dihub

"Dear Editors:

Gallbladder carcinoma (GBC) is the most common malignancy of the biliary tract and the third most common gastrointestinal tract malignancy. About 178,100 new cases were diagnosed around the world in 2012, but the number of deaths from the disease was relatively high by comparison at 142,800.1 The incidence of GBC is especially high in South America, affecting 27 per 100,000 people.2 The high rates of GBC in South America and Asia including India, Pakistan, Korea, and Japan have been attributed to high rates of gallstones (GS) and chronic Salmonella infection, both of which are known risk factors for GBC.3 However, other risk factors, including those emanating from environmental exposure and heritable genetic traits and gender predisposition etc, have been focus of researchers for a long time so as to develop preventive strategies.

We read with great interest the recent article on association of aflatoxins with GBC published in Gastroenterology.4 In this case-control study of patients with GBC and GS versus patients with GS without cancer, the authors report an association between exposure to aflatoxin (based on plasma level of AFB1-lysine) with GBC, and based on which they further suggest that reducing aflatoxin exposure may reduce the incidence of GBC. Aflatoxins are secondary metabolites of Aspergillus flavus and Aspergillus parasiticus, and contaminate a variety of staple foods, particularly maize and groundnuts, in low-income countries. However, as per an estimate, approximately 4.5 billion of the world's population is exposed to aflatoxins,5 affecting many tropical countries comprising parts of Africa, Asia, and Latin America, but GBC is not as rampant disease in these geographical areas as compared with hepatocellular carcinoma, which has s more established connection with aflatoxin exposure based on the evidence from epidemiologic studies in exposed populations and mechanistic studies. In fact, GBC is a cancer type for which differences in incidence ratios point to variations in etiology in different populations.1

This study by Koshiol et al4 is based on the premise that GS are the strongest risk factor for GBC and this study allowed them to evaluate whether exposure to aflatoxin is associated with risk of GBC in the context of GS. It is important to note that in Asia, India has highest incidence of GS (10%–22%) as compared with China (5%) and Japan (5%).3 These data4 showing higher levels of aflatoxins adducts in the plasma of Chinese population with GS as a risk factor for GBC raises another pertinent question as to what makes patients with GS in India (another Asian country with higher GBC incidence, at 11,172 and 9450 cases of incidence and mortality in females has been reported just for 2012) less vulnerable for GBC as compared with their Chinese counterparts (27,699 cases of incidence and 22,475 cases of mortality in females), with incidence and mortality almost twice to that of India,6 even though China has lower incidence of GS in its population3 as compared with that of India? Does no association between aflatoxin exposure and patients with GBC in the Indian population as reported earlier in a recent study7 hold the key to the answer of this question?

Interestingly, the incidence of GBC has a specific geographic and ethnic variation in most populations; for example, in India GBC is most prevalent in northern and northeastern states of Uttar Pradesh, Bihar, Orissa, West Bengal, and Assam, with a 10 times lower incidence per 100,000 in South India compared with the North, the age-adjusted incidence rate for females being 0.8 in Chennai in the south and 8.9 in Delhi in the north.3,6 This stark difference in the incidence of GBC within a country where exposure to aflatoxins is almost similar suggests a need for further studies to explore the role of aflatoxins in a disease with as complex an etiology as GBC with more variables to be taken into considerations. Although this study4 explored the role of R249S mutation in the TP53 gene, which has been known to be associated with aflatoxin-related hepatocellular carcinoma, no association between GBC and this mutation was observed indicating the need for discovery of more genetic markers to serve as surrogate for aflatoxins’ exposure in the populations. Further studies in other populations using polymorphic variants of genes and proteins such as glutathione S-transferase and cytochrome-P450, known to be involved in the metabolism of aflatoxins as well as known genetic risk factors associated with GBC,8 are needed to generate more robust datasets after multivariate analyses so as to adjust for confounding factors, if any, which may otherwise distort the apparent exposure–disease relationship.

References

1

Ferlay J, et al. Available from: globocan.iarc.fr.

2

E.C. Lazcano-Ponce, et al.

CA Cancer J Clin, 5 (2001), pp. 349-364

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3

R.K. Sharma, et al.

PLoS One, 11 (2016), p. e0166351

CrossRef

4

J. Koshiol, et al.

Gastroenterology, 153 (2017), pp. 488-494

View Record in Scopus

5

J.H. Williams, et al.

Am J Clin Nutr, 80 (2004), pp. 1106-1122

View Record in Scopus

6

C. Are, et al.

J Surg Oncol, 115 (2017), pp. 580-590

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7

T. Ikoma, et al.

Asian Pac J Cancer Prev, 17 (2016), pp. 3499-3503

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8

K. Srivastava, et al.

Mutat Res, 728 (2011), pp. 67-79

ArticleDownload PDFView Record in Scopus

Conflicts of interest The authors disclose no conflicts."