All posts by shaffins

The Anti-Tumor Potential of Salt

By Megan Leinenbach

While we usually think of salt as just another tasty ingredient found on our kitchen tables, it has actually played a variety of important rolesthroughout human history. In fact, salt used to be a form of currency in the Roman empire, a lucrative trading good in Italy, and its preservative properties led to dramatic improvements in food storage. One could say that salt is a “jack of all trades”, and new research shows that it might also improve cancer treatment. 

A 2019 paper titled “High Salt Inhibits Tumor Growth by Enhancing Anti-tumor Immunity”describes how a high salt diet can limit tumor growth in mice and in human cancer cells. The researchers concluded that high salt concentrations significantly inhibited tumor growth in both mice and human cells by blocking the activity of myeloid-derived suppressor cells (MDSCs). MDSCs are important players in the tumor microenvironment and are a double threat to cancer patients: not only do MDSCs help tumors grow by forming new blood vessels, but they suppress the immune system of patients. More specifically, MDSCs inhibit the function of important immune cells in mice and humans, like T cells and B cells, which attack foreign and self-antigens in the body. 

While MDSCs rule the tumor microenvironment, high salt concentrations could be their weakness, as a high salt diet in mice inactivated MDSCs near the tumor.  Consequently, the mice that were fed a high salt diet saw significantly slower tumor growth than mice that were fed a normal diet. These findings could be important to the treatment of cancer, specifically cancer immunotherapy, a method of treatment that uses the natural abilities of the immune system to fight cancer. In addition to slowing tumor growth in mice, high salt diets were able to inhibit MDSC function in human cancer cells. Indeed, the activity of immunosuppressive MDSC cells was almost entirely blocked in human cancer cells. This data shows that increased sodium concentrations of a high salt diet can make MDSCs less effective, not only slowing tumor growth, but also strengthening the immune system of a cancer patient. This is a significant finding because one of the greatest difficulties associated with cancer immunotherapy is that cancer patients often have weakened immune systems, partially due to the accumulation of MDSCs near the tumor. 

While these results may prove useful for cancer immunotherapy in the future, we should keep in mind that salt has already been associated with health risks. Researchshows that excessive salt intake can lead to cardiovascular disease, chronic kidney disease, osteoporosis, and stomach cancer. Even though this study demonstrated the benefits of a high salt diet in mice and human cells, it is important to keep in mind that increasing sodium intake has negative health effects as well. 

Nonetheless, these results have given medical professionals another tool in their toolbelt when it comes to managing tumor growth: manipulating salt concentrations. While eating a diet high in salt may not be the best way to take advantage of salt’s anti-tumor effects, this mechanism could be used in the future to block MDSC function in cancer immunotherapy.

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Whole-Genome Cancer Sequencing: A Milestone in Cancer Biology

By Zsombor Gal

According to the World Health Organization, cancer is the second leading cause of death worldwide. Estimated at nearly 10 million deaths in 2018, fatalities due to cancer are expected to increasesubstantially in the next few decades due to an aging population. These data warrant the development of new therapeutic approaches and early detection methods for cancer. 

Although oncologists, pharmaceutical companies, and academic researchers have been collectively contributing to the search for cancer treatments and preventative methods, their efforts are lacking in many respects. In this regard, one of the most pressing issues has been a lack of genetic data linking abnormalities in the somatic genome to oncogenesis. Until recently, mutational processes and single-nucleotide polymorphisms (SNPs) associated with cancer have been identified on a mostly individual basis with a lack of information regarding their pan-cancer prevalence. In February of this year, Nature published a groundbreaking articlefrom the Pan-Cancer Analysis of Whole Genomes Consortium (PCAWG), an initiative established by the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA).

The collaborators describe the unified analysis of more than 2,000 whole-cancer genomes received from North American, European, Asian, and Australian organizations. The goal of this work is to identify common SNPs via genome-wide association studies, detect chromosomal aberrations and other genomic abnormalities in cancer cells, and define the evolutionary basis of oncogenesis. This feat, requiring an enormous amount of computational analysis, is now achieved via next-generation sequencing and cloud computing. 

A vast majority of samples contain several driver mutations, which provide a selective advantage to somatic clones. These mutations, some of which are found in tumor suppressor or telomere maintenance genes, allow a cancer cell to outgrow other clones and promote unrestrained proliferation in the presence of tumor cell-targeting immune surveillance. Interestingly, about 5% of samples lack driver mutations, which may suggest the list of known drivers is not complete. The collaborators also investigated mutations in non-coding regions of the genome, which are mostly uncharted territory in cancer genomics.

Other genomic abnormalities, including chromosomal abnormalities, insertions, deletions, and gene duplications, were analyzed and elaborated upon in a collection of paperspublished at the same time. The data suggests chromosomal rearrangements such as chromoplexy and chromothripsis are common and occur early in tumorigenesis, as revealed through the generation of evolutionary timelines from subclones, a defining feature of tumor heterogeneity. This implies that cancer cell populations accumulate genomic aberrations throughout their evolution, emphasizing early detection as an important factor in cancer treatment.

The PCAWG presents crucial information for the pharmaceutical industry, academics, and clinicians alike. The breadth of the data presented in these papers provides potential drug targets, new research avenues, and novel therapeutic considerations. Despite the well-organized genomic analyses the PCAWG has given us, their findings lack clinical dataregarding treatment plans and other interventions. While bearing in mind that patient privacy is a necessity, this information could link genetic findings to patient outcomes. In the context of personalized medicine, this could revolutionize cancer treatment practices and redefine care for future cancer patients.

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To Operate or Not: The Dilemma of Preventative Cardiac Surgery

by Shaffin Siddiqui

While it may be considered a platitude, the objective of medicine – in addition to actually administering hands-on care – is to pursue the path of treatment that minimizes long-term harm. Hence, the role of the doctor is not to simply slice and dice, but also to advise a patient whether to undergo the risky route of an invasive operation in the first place. Should one undergo the arduously invasive procedure of receiving a pacemaker for a heart chronically prone to arrythmia or settle for the less onerous alternative, albeit less bulletproof, alternative of oral treatment? The dilemma is often times acute, yet how often is it that this gradient of risk is assessed with the scruple it deserves…?

This past summer I had the privilege of conducting clinical research in the field of cardiology with Dr. William Roberts M.D[DS1] . at Baylor Scott and White in Dallas, Texas. With his guidance, I investigated replacement of the aorta in patients with congenitally abnormal aortic valves. Most individuals are born with normal three-leaflet (tricuspid) aortic valves which are located at the juncture of the left ventricle and aorta, from which oxygenated blood flows to the rest of the body. However, 1% of the American population is born with two-leaflet (bicuspid) aortic valves. In early cardiology, being born with these valves was strongly associated with aortic dilation (also given the scarier and more provocative label of “aortic aneurysm”) during one’s adult life. While bicuspid patients tend to see highest incidences of aortic dilation, many with normal valves experience idiopathic (i.e. random) dilation as well. Researchers[DS2]  and doctors believed that the more dilated an aorta from its normal size, the more likely it was to crack open (i.e. dissect) or even rupture fully – incidents, both of which, are acutely painful and potentially fatal.

If aortic dilation is detected even in mild amounts, especially in patients with bicuspid aortic valves, surgeons insist that patients preemptively opt for an elective surgery to replace their dilated aorta in order to prevent the incidence of dissection/rupture in the future should it dilate even more. The thought of an aorta slowly expanding and popping, like a balloon, is terrifying to both physician and patient. Even if a surgeon happened to be performing cardiac surgery for another “neighboring” issue and incidentally noticed the patient had aortic dilation, many would subsequently replace the aorta in addition to the initial operation intended.

However, recent clinical data (~2007 onwards) has contested the need to categorically replace dilated aortas. Some aortas are so enlarged that it goes without saying that they deserve the title of aneurysm and need to be replaced. But, even then, rates of aortic dissection across the most frequently occurring sizes of dilation were shown to be exceedingly low. As well, rates of aortic expansion (i.e. how fast an aorta dilates) were shown to be quite low – if not, negligible – reducing the need to panic to preempt disaster. Even more strikingly, patients with bicuspid aortic valves were shown to be equally at risk for dissection/rupture as those with normal valves if given the same degree of dilation. Bicuspid patients, who had their aortas replaced the most frequently, had nothing to fear more than a patient with ordinary valves.

Given the data, one would think surgeons would be more deliberate in their decision to remove dilated aortas, especially with the operational risk associated cardiac surgery and specifically aortic replacement. Yet, my time at Baylor with Dr. Roberts, a cardiac pathologist – who looked at excised cardiac tissue post-operationally – showed me something quite different: countless pieces of functional heart tissue that were excised seemingly needlessly, and the most frequent organ amongst them: mildly dilated aortas. Indeed, the majority of the time the tissue was macroscopically and microscopically normal! As someone who has personally suffered from the tragedy of superfluous invasive operation, I was appalled. What could be behind this? For one, some CT surgeons are just not up to date on the data, and, to their credit, these studies are fairly new. Nonetheless, surgical practices should be in tune with changes in literature, especially when there is so much at stake, as with cardiac surgery.  The bigger catalysts, however, seem to be more pecuniary: cardio-thoracic surgeons are paid by the operation, not by a fixed salary. As such, like it or not, there are incentives to operate on pathologies, even if they are likely benign for the patient. These operations are often elective, meaning the patient can opt out. When physicians, however, throw words like “aneurysm” onto the table, patients have a proclivity to panic. As such, combatting the tendency to needlessly operate requires a fundamental shift in health policy. While fixed salaries may be a somewhat tenable solution, this is an issue in health care that requires more awareness and the serious thought of health-care officials.

The views expressed in this article are mine alone, and do not express the opinion of the Princeton Public Health Review.

Dementia: A Forgotten Crisis

By Chino Kieran Eke

In the United States, there are approximately 5.8 millions Americans living with Alzheimer’s disease. This disease causes the slow loss of mental faculties, including memory, critical thinking, and the ability to carry out simple tasks. While the disease principally affects individuals in their mid-60s, it is projected to impact the lives of 13.8 million Americans by 2050 despite medical advances that have improved the overall quality of life of afflicted patients.

While the treatment for Alzheimer’s disease is largely ineffective in the pharmaceutical realm, complementary therapies have proven to help maintain or improve the quality of life of a person with Alzheimer’s. For example, music therapy has proven to treat the behavioral and psychological symptoms of dementia. It enables people with Alzheimer’s to form meaningful human interactions with the therapist. Although music therapy and other complementary therapies do not provide a cure for the disease, they improve the quality of life for those with Alzheimer’s.

Alzheimer’s is believed to be caused by the buildup tau proteins which form plaques that effectively block the spread of information between neurons. As more plaques form, the information flow between neurons becomes more restricted, impairing a neuron’s ability to function properly. These plaques eventually cause neuronal death which leads to the shrinkage of the brain and the loss of memory, control over reasoning, language and thinking. Ultimately, this disease has devastating effects on those it affects and their loved ones. 

In 1980, a Congressional Hearing was held on the impact of Alzheimer’s disease on America’s elderly in order to help establish public funding for citizens with the disease. During this hearing, Alzheimer’s patients without proper care were described as suffering an “unbearable loss of dignity and self-respect” which undeniably has had a “crushing impact upon their spouses.” This hearing, ultimately, lead to the establishment of public funding for hospice and long-term care through Medicaid which cost the government an approximate “$290 billion for Alzheimer’s or other dementias” in 2019. With a growing number of Americans expected to have Alzheimer’s by 2050, the annual spending is projected to increase to 1.1 trillion. The near quadrupling of the current cost demonstrates how Alzheimer’s and other dementias present a daunting crisis for society. 

Currently, pharmaceuticals such as “cholinesterase inhibitors and memantine only treat the cognitive symptoms of Alzheimer’s disease,” but no medications exist that directly treats or prevents the buildup of tau plaques in the brain. There have been a number of studies performed in the last decade that have led to major advancements in the understanding of the disease, but they have all been quite limited in scope. This is primarily due to “low recruitment and high attrition rates” of research subjects with Alzhermier’s disease or related dementias. The best solution to this research impediment is increasing awareness surrounding the importance of this type of research; perhaps, then, rates of public participation might actually rise and a pharmaceutical treatment that slows or prevents the progression of plaque buildup may become a reality. 

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The First Cancer Vaccine: Design, Barriers, and Importance

By Zsombor Gal

In 2018, the World Health Organization counted nearly 570,000 new cases of cervical cancer in addition to 310,000 deaths worldwide. Roughly 90% of these deaths occurred in low- and middle-income countries, where screening and treatment programs are not as readily available as in developed nations. Though it may be surprising, prevention of cervical cancer through vaccination has only recently been viewed as a comprehensive solution to this global health crisis.

21st century innovation provided the first vaccine specifically approved for the prevention of cancer. In 2006, the U.S. Food and Drug Administration approved a vaccine developed by Merck & Co. to prevent human papillomavirus (HPV) infection. The tetravalent vaccine, known as Gardasil, protects against four HPV strains known to cause cervical, anal, vulvar, vaginal, and penile cancers. More recently, Gardasil 9 was approved to protect against five additional HPV strains associated with cervical cancer. These vaccines contain virus-like particles, which consist of self-assembled HPV capsid proteins, but lack the viral DNA. Thus, the vaccine enables the recipient to produce antibodies against HPV virions while preventing the production of harmful viral proteins that are responsible for disease. HPV is an example of a transforming virus, in that it encodes proteins that inactivate tumor suppressor proteins within human cells. This causes the rapid proliferation of cells, leading to tumor formation. Hence, as HPV is the most common sexually transmitted infection, not only in the United States but globally, it represents a serious threat to human health.

Not everyone infected with HPV will develop cancer. In fact, HPV is typically cleared by the immune system or simply causes precancerous lesions such as skin warts. However, exposure to high-risk HPV strains or long-lasting infectious greatly increases the risk for cancers caused by HPV. Because the risk of death due to these cancers is exceptionally high, it is important that all children and adolescents receive the vaccine prior to becoming sexually active.

However, this has unfortunately not been the case. In 2017, the Centers for Disease Control and Prevention reported that only 49 percent of adolescents in the United States are up to date on HPV vaccination. Many developing nations fall short of this statistic or have only recently introduced countrywide vaccination programs. The reasons for low vaccination rates encompass a variety of factors, including awareness, healthcare accessibility, cost, and misguided parental decisions.

Cancer-causing viruses are not a recent discovery, but public awareness of genital and oropharyngeal cancers caused by HPV is strikingly low. Additionally, because HPV is typically diagnosed in sexually active adults, many pediatricians are either unaware of the cancer risk or unwilling to discuss sex with the parents of younger children. The HPV vaccine may be suffering from an “image problem,” as it is often portrayed as a sexually transmitted disease vaccine, not as a cancer prevention vaccine. This contributes to parental anxieties that receiving the vaccine may encourage sexual promiscuity at a young age.

Poor access to healthcare and infrequent medical check-ups also contribute to low vaccination rates. Citizens of developing nations and minority populations face difficulties in obtaining regular care by a physician at all and thus have lower vaccination rates overall. Further complicating the matter is the fact that the HPV vaccine is rather expensive. Those without health insurance can expect to pay $250 dollars per dose for Gardasil in the United States, which consists of three doses!

The HPV vaccine clearly needs a rebranding. As the world’s first vaccine against cancer, and perhaps the simplest form of cancer prevention aside from lifestyle change, it seems illogical that parents should reject vaccination for their children. Initiatives must be put into place to serve populations without reliable and inexpensive access to healthcare, as well as in developing nations with high incidences of HPV infection. There is hope: leaders in these countries may choose to follow the example of Rwanda, a sub-Saharan nation that has achieved 93% vaccination coverage. Rwandan leaders combined the expertise and influence of state agencies, infectious disease entities, and international vaccine providers to reach a substantial portion of the population within a short period of time. The elimination of preventable cancers such as HPV would be a major milestone in the history of medicine.