Tag: 26/7/21

Categories : Cancer GeneticsTags :

Comprehensive Genome Sequencing Can Improve Cancer Outcomes

On By ModernMedia
Image source: National Cancer Institute

Researchers from St Jude Children’s Research Hospital have demonstrated the feasibility of comprehensive genomic sequencing for all paediatric cancer patients, which maximises the lifesaving potential of precision medicine.

All 309 patients who enrolled in the study were offered whole genome and whole exome sequencing of germline DNA. For the 253 patients for whom adequate tumour samples were available, whole genome, whole exome and RNA sequencing of tumour DNA was carried out.

Overall, 86% of patients had at least one clinically significant variation in tumour or germline DNA. Those included variants related to diagnosis, prognosis, therapy or cancer predisposition. An estimated 1 in 5 patients had clinically relevant mutations that would not have been picked up with standard sequencing methods.

“Some of the most clinically relevant findings were only possible because the study combined whole genome sequencing with whole exome and RNA sequencing,” said Jinghui Zhang, PhD, St Jude Department of Computational Biology chair and co-corresponding author of the study.

While such comprehensive clinical sequencing is not widely available, as the technology becomes less expensive and accessible to more patients, comprehensive sequencing will become an important addition to paediatric cancer care.

“We want to change the thinking in the field,” said David Wheeler, PhD, St Jude Precision Genomics team director and a co-author of the study. “We showed the potential to use genomic data at the patient level. Even in common pediatric cancers, every tumor is unique, every patient is unique.

“This study showed the feasibility of identifying tumour vulnerabilities and learning to exploit them to improve patient care,” he said.

Tumour sequencing resulted in a change in treatment for 12 of the 78 study patients for whom standard of care was unsuccessful. In four of the 12 patients, the treatment changes stabilised disease and extended patient lives. Another patient, one with acute myeloid leukaemia, went into remission and was cured by blood stem cell transplantation.

“Through the comprehensive genomic testing in this study, we were able to clearly identify tumor variations that could be treated with targeted agents, opening doors for how oncologists manage their patients,” said co-corresponding author Kim Nichols, MD, St Jude Cancer Predisposition Division director.

The results of the study were published online in the journal Cancer Discovery.

Source: St. Jude Children’s Research Hospital

Journal information: Newman, S., et al (2021) Genomes for Kids: The scope of pathogenic mutations in pediatric cancer revealed by comprehensive DNA and RNA sequencing. Cancer Discovery. doi.org/10.1158/2159-8290.CD-20-1631.

Categories : CancerTags :

Organ-on-a-chip Enables Rapid Cancer Treatment Evaluation

On By ModernMedia

Researchers at Texas A&M University are advancing organ-on-a-chip devices to new levels, which may change the way clinicians approach cancer treatment, particularly for ovarian cancer.

The research team, led by Abhishek Jain, an assistant professor in the Department of Biomedical Engineering with a joint appointment in the College of Medicine, has developed a device focusing on platelets. The ovarian tumour microenivornment-chip (OTME-Chip) is about the size of a USB and models the properties of a tumour in a laboratory setting. The microdevice is able to recreate events within platelets circulating in the blood as they approach the tumour, making it more potent and metastatic.

“We claim several novelties in technological design as well as biological capabilities that didn’t exist in prior organs-on-chips,” Prof Jain said.

Advances in organ-on-a-chip microdevices allow researchers to discover more about cancer outside the human body. These organs-on-chips serve as a model of the state a cancer patient is in, giving clinicians a chance to find the correct treatment before administering it to the patient.

“We are creating a platform technology using the organ-on-a-chip approach where tumour biology can be advanced, and new drugs can be identified by recreating the platelet-tumor and platelet-tumour-drug interactions under the influence of flow, supporting blood vessels and the extracellular matrix,” Jain said.

Ovarian cancer is one of the leading causes of cancer deaths for women in developed countries. Tumours typically form deep inside a patient’s tissue, and it can be difficult to obtain real-time information of the tumour’s properties and its interaction with blood cells. Ovarian tumours can also rapidly metastasise, meaning that analysis and intervention must be prompt.

The OTME-Chip builds on current understanding of how blood platelets move inside tumour tissue and what triggers them to spread outside the tumour. The actual mechanism behind this process, however, had remained mostly unknown, until now.

“For the first time, we identified a crucial interaction between platelets and the tumor via their surface proteins,” Prof Jain said. “By applying high-resolution imaging, advanced cell and molecular readouts and RNA sequencing methods leveraging the OTME-Chip, we discovered the actual genetic signaling pathways behind the blood cell triggered metastasis of ovarian cancer and a new drug strategy to stop this process.”

Their study was recently published in the journal Science Advances.

Prof Jain said the OTME-Chip has several applications, both in observing cancer cells interactions with vascular and blood cells and testing novel complementary ways to treat cancer.

“This multimodal OTME-Chip is going to provide an ideal platform to the health care researchers to evaluate their anti-cancer, vascular and haematological drugs individually or in combination in an artificially created human-level tumor microenvironment,” Prof Jain said.

Source: Texas A&M University

Journal information: Saha, B., et al. (2021) Human tumor microenvironment chip evaluates the consequences of platelet extravasation and combinatorial antitumor-antiplatelet therapy in ovarian cancer. Science Advances. doi.org/10.1126/sciadv.abg5283.

Categories : Ageing GeneticsTags :

Junk DNA Yields Insights into Ageing and Cancer

On By ModernMedia

Findings from a new study into ‘junk DNA’ have brought scientists one step closer to solving the mysteries of ageing and cancer.

Jiyue Zhu, a professor in the College of Pharmacy and Pharmaceutical Sciences, led a team which recently identified a DNA region known as VNTR2-1 which seems to drive activity of the telomerase gene, which has been shown to prevent ageing in certain types of cells. The study was published in the journal Proceedings of the National Academy of Sciences (PNAS).

The telomerase gene controls the activity of the telomerase enzyme, which helps produce telomeres, the caps at the end of each strand of DNA that protect the chromosomes within our cells and which shorten over time until cells are no longer able to divide.

However, in certain cell types, such as reproductive cells and cancer cells, the telomerase gene’s activity ensures that telomeres are reset to the same length when DNA is copied. This is essentially what restarts the aging clock in new offspring but is also the reason why cancer cells can continue to multiply and form tumors.

Understanding how the telomerase gene is regulated and activated and why it is only active in certain types of cells could someday be the key to understanding how humans age, as well as how to stop the spread of cancer. That is why Prof Zhu has focused the past 20 years of his career as a scientist solely on the study of this gene.

Zhu said that VNTR2-1’s discovery is especially noteworthy due to the type of DNA sequence it represents.

“Almost 50% of our genome consists of repetitive DNA that does not code for protein,” noted Prof Zhu. “These DNA sequences tend to be considered as ‘junk DNA’ or dark matter in our genome, and they are difficult to study. Our study describes that one of those units actually has a function in that it enhances the activity of the telomerase gene.”

In previous work, deleting the DNA sequence from human and mouse cancer cells caused telomeres to shorten, cells to age, and tumours to stop growing. They conducted a subsequent study measuring the length of the sequence in DNA samples taken from Caucasian and African American centenarians and control participants in the Georgia Centenarian Study, a study that followed a group of people aged 100 or above between 1988 and 2008. The researchers found that the length of the sequence ranged from as short as 53 repeats of the DNA to as long as 160 repeats.

“It varies a lot, and our study actually shows that the telomerase gene is more active in people with a longer sequence,” Prof Zhu said.

Since very short sequences were found only in African American participants, they looked more closely at that group and found that there were relatively few centenarians with a short VNTR2-1 sequence as compared to control participants. However, Prof Zhu said that a shorter sequence does not necessarily translate to a shorter lifespan, since the telomerase gene is less active with possibly a shorter telomere length which could reduce cancer risk.

“Our findings are telling us that this VNTR2-1 sequence contributes to the genetic diversity of how we age and how we get cancer,” Prof Zhu said. “We know that oncogenes–or cancer genes–and tumor suppressor genes don’t account for all the reasons why we get cancer. Our research shows that the picture is a lot more complicated than a mutation of an oncogene and makes a strong case for expanding our research to look more closely at this so-called junk DNA.”

Prof Zhu observed that many African Americans in the United States for generations have Caucasian ancestry, which could have added this sequence. So he and his team hope to next be able to study the sequence in an African population.

Source: Washington State University

Journal information: Xu, T., et al. (2021) Polymorphic tandem DNA repeats activate the human telomerase reverse transcriptase gene. PNAS. doi.org/10.1073/pnas.2019043118.

Categories : COVIDTags :

First South African-produced Vaccine Batch Shipped as Lockdown Eases

On By ModernMedia

The day after President Cyril Ramaphosa announced an easing of COVID restrictions to an adjusted Level 3 lockdown, Durban-based pharmaceutical company Aspen stated that it was releasing its first batch of locally-produced COVID vaccines under a licensing deal with the US giant Johnson & Johnson.

The first batch was leaving its manufacturing unit in Gqeberha, to be further distributed throughout South Africa. The company also stated that vaccines from these batches will be made available through the African Vaccine Acquisition Task Team/African Union platform.

In a statement, Aspen’s Group Chief Executive Stephen Saad, said, “Aspen is proud of the role we are playing in producing vaccines for distribution in South Africa, across Africa and the world. Our ability to produce these vaccines on behalf of Johnson & Johnson builds on our strategic vision of delivering high quality, affordable medicines that improve health outcomes for patients in our own country, continent and around the world.  Supply for Africa and South Africa is particularly rewarding, given the current global inequality in accessing vaccines. This represents a big step forward in ensuring that Africa can address its healthcare priorities. The manufacture of the Johnson & Johnson COVID vaccine builds on the global contributions we have already made in fighting the COVID-19 pandemic with both our anaesthetics portfolio and dexamethasone supply.”
Aspen has invested over R3 billion at the Gqeberha sterile manufacturing site, which contains high-technology, state-of-the-art pharmaceutical equipment and systems that will be used to manufacture advanced sterile medicines, including vaccines.

BioNTech and Pfizer last week signed a deal with South African manufacturer Biovac to help produce vaccine doses in Cape Town through what is known as a ‘fill and finish’ process. Once completed, this is expected to produce 100 million doses per year. President Cyril Ramaphosa has been vocal about global inequality in vaccine procurement, and has been pushing for an African source of vaccines to help the continent fend for itself.
With new cases falling in Gauteng, South Africa’s lockdown was lowered to an adjusted Level 3 on Sunday, with the sale of alcohol once again permitted during the week and at bars and restaurants.

Source: Aspen Holdings

Categories : Cardiovascular DiseaseTags :

ARB Has Slight Edge Over ACE Inhibitors for Hypertension Treatment

On By ModernMedia
Photo by Hush Naidoo on Unsplash

A huge multinational study found that while angiotensin-converting enzyme (ACE) inhibitors are just as effective as angiotensin receptor blockers (ARBs) for hypertension treatment, ARBs have slightly fewer side effects.

The study, led by researchers at Columbia University Vagelos College of Physicians and Surgeons and encompassing millions of electronic health records, is the largest to compare the safety and efficacy of these two types of drugs. The findings were published online in Hypertension.

“Physicians in the United States and Europe overwhelmingly prescribe ACE inhibitors, simply because the drugs have been around longer and tend to be less expensive than ARBs,” said senior study author George Hripcsak, MD, the Vivian Beaumont Allen Professor and chair of biomedical informatics at Columbia University Vagelos College of Physicians and Surgeons.

“But our study shows that ARBs are associated with fewer side effects than ACE inhibitors. The study focused on first-time users of these drugs. If you’re just starting drug therapy for hypertension, you might consider trying an ARB first. If you’re already taking an ACE inhibitor and you’re not having any side effects, there is nothing that we found that would indicate a need for a change.”

“U.S. and European hypertension guidelines list 30 medications from five different drug classes as possible choices, yet there are very few head-to-head studies to help physicians determine which ones are better,” Dr Hripcsak said. “In our research, we are trying to fill in this information gap with real-world observational data.”

ACE inhibitors and ARBs are among the choices, and they have a similar mechanism of action. Both reduce the risk of stroke and heart attacks, though it’s known that ACE inhibitors are associated with increased risk of cough and angioedema.

“We wanted to see if there were any surprises–were both drug classes equally effective, and were ARBs producing any unexpected side effects when used in the real world?” Hripcsak says. “We’re unlikely to see head-to-head clinical trials comparing the two since we are reasonably sure that both are effective.”

To tackle the problem, the researchers analysed insurance claims and electronic health records from approximately 3 million patients in Europe, Korea, and the United States who were starting antihypertensive treatment with either an ACE inhibitor or an ARB.

The researchers employed a variety of cutting-edge mathematical techniques to dramatically reduce the bias and deal with information gaps from electronic health records, balancing the two treatment groups as if they had been enrolled in a prospective study.

The researchers tracked four cardiovascular outcomes–heart attack, heart failure, stroke, and sudden cardiac death–and 51 adverse events in patients after they started antihypertensive treatment.

They found that the vast majority of patients–2.3 million–were prescribed an ACE inhibitor, but found no significant difference between the two drug classes in reducing major cardiovascular complications in people with hypertension. As expected, patients taking ACE inhibitors had a higher risk of cough and angioedema, but the risk of pancreatitis and gastrointestinal bleeding was slightly higher as well.

“Our study largely confirmed that both antihypertensive drug classes are similarly effective, though ARBs may be a little safer than ACE inhibitors,” Hripcsak said. “This provides that extra bit of evidence that may make physicians feel more comfortable about prescribing ARBs versus ACE inhibitors when initiating monotherapy for patients with hypertension. And it shows that large-scale observational studies such as this can offer important insight in choosing among different treatment options in the absence of large randomised clinical trials.”

Source: EurekAlert!

Categories : COVID Metabolic DisordersTags :

Is There an Imminent Wave of COVID-caused Diabetes?

On By ModernMedia
Source: Unsplash CC0

A new study found that about half of hospitalised COVID patients at the start of the pandemic developed new cases of hyperglycemia and had poorer outcomes, prompting concerns about waves of COVID-caused diabetes.

“These people were not diabetic before,” said lead author Paolo Fiorina, MD, PhD, who is affiliated with the Division of Nephrology at Boston Children’s Hospital. “But during admission, about 46 percent of the patients were found to have new hyperglycaemia.” About 35 percent of the newly hyperglycaemic patients were still so six months after infection.

New cases of post-COVID diabetes had been observed since the first waves of the COVID pandemic, though the mechanism behind it was not understood at the time.

The study examined 551 people admitted to the hospital in Italy from March to May 2020, with follow-ups up to six months. All patients were fitted with a glucose sensor at admission.

Compared with patients without signs of glucose abnormalities, the hyperglycaemic patients had worse clinical concerns: longer hospitalisations, worse clinical symptoms, and greater need for oxygen, ventilation and intensive care treatment.

“We wanted to understand the mechanism why these patients did poorly compared to those who did not have hyperglycemia,” said Fiorina, who previously authored a paper showing COVID worsened glucometabolic control in diabetics. The current study was published in Nature Metabolism.
Over the course of time, the researchers detected many abnormalities in glucose metabolic control in the hyperglycaemic patients. They also found that hyperglycaemic patients had abnormal hormonal levels: “We discovered they were severely hyperinsulinaemic; they produced too much insulin,” said Fiorina. They also had abnormal levels of pro-insulin and markers of impaired islet beta cell function.
“Basically, the hormonal profile suggests that the endocrine pancreatic function is abnormal in those patients with COVID and it persists long after recovery,” he said.
Hyperglycaemic patients also had severe abnormalities in levels of inflammatory cytokines, including IL-6.

“We thought that blocking IL-6, and potentially even other cytokines, would be a benefit for beta cell function,” added Fiorina, an idea that proved to work. Patients treated with anti-IL-6 therapy (tocilizumab) had greater improvement in glycaemic control compared.

While glucometabolic abnormalities gradually reduced for some (particularly after COVID infection), other issues persisted: many patients had higher post-prandial glucose levels and abnormal pancreatic hormones after COVID.

“This study is one of the first to show that COVID has a direct effect on the pancreas,” said Fiorina. “It indicates that the pancreas is another target of the virus affecting not only the acute phase during hospitalisation but potentially also the long-term health of these patients.”

The study highlights the importance of evaluating pancreatic function in patients hospitalised for COVID. “This goes beyond fasting glucose testing because we observed glucose metabolic abnormalities during the day which were not always present in a normal fasting test,” said Fiorina.  

Questions remain as to whether patients should be treated just with an anti-diabetic drug like an insulin sensitiser, or should anti-inflammatory drugs like tocilizumab and other drugs be used?

“If you keep targeting and blocking insulin, but you have a strong and chronic inflammation, it may lead to chronic damage,” said Dr Fiorina, who suggested that larger studies to test anti-diabetic and anti-inflammatory treatment are needed. “When you consider how many patients have been hospitalised with COVID and continue to be worldwide, we may see a huge increase in the diabetic population.”

Source: Children’s Hospital Boston

Journal information (1): Laura Montefusco et al, Acute and long-term disruption of glycometabolic control after SARS-CoV-2 infection, Nature Metabolism (2021). DOI: 10.1038/s42255-021-00407-6

Journal information (2): Sebastiano Bruno Solerte et al, Sitagliptin Treatment at the Time of Hospitalization Was Associated With Reduced Mortality in Patients With Type 2 Diabetes and COVID-19: A Multicenter, Case-Control, Retrospective, Observational Study, Diabetes Care (2020). DOI: 10.2337/dc20-1521