Day: September 16, 2022

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African Scientists Show How COVID Variants Spread across Africa

On By ModernMedia
Source: Fusion Medical Animation on Unsplash

A major scientific report from Africa is featured in the journal Science today. This scientific report shows how the rapid expansion of genomics surveillance in Africa allowed the continent to describe the introduction and spread of the SARS-CoV-2 variants in African countries in real time during the COVID pandemic.

The scientific report includes over 300 authors from Africa and abroad who worked together to describe and analyse over 100 000 genomes and characterise SARS-CoV-2 variants in real time. This was the largest consortium of African scientists and public health institutions ever to work together to support data-driven COVID response in Africa.

This report shows how the large investment, collaboration and capacity building in genomic surveillance on the African continent enabled real-time public health response. Particularly it describes the setting up of the Africa Centres for Disease Control (CDC) – Africa Pathogen Genomics Initiative (Africa PGI) and the continental network by the Africa CDC and World Health Organisation (WHO) Regional Office for Africa (WHO AFRO) to expand access to sequencing and cover surveillance blind spots, in parallel with the growth of the number of countries that are able to sequence SARS-CoV-2 within their own country.

“The publication highlights that sustained investment for diagnostics and genomic surveillance in Africa was needed to not only combat SARS-CoV-2 on the continent, but establish a platform to address the emerging, re-emerging, endemic infectious disease threats, such as Ebola, HIV/AIDS, TB and Malaria. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century,” said Dr. Yenew Kebede, Head Division of Laboratory Systems and Acting Head: Surveillance and Disease Intelligence at the Africa CDC.

African Scientists receiving training in genomics surveillance at the KwaZulu-Natal Research Innovation and Sequencing Platform (KRISP), South Africa.

This study was led by two labs that setup the network for genomics surveillance in South Africa – the Centre for Epidemic Response and Innovation (CERI) at Stellenbosch University and the KwaZulu Natal Research and Innovation Sequencing Platform (KRISP) at the University of KwaZulu-Natal, in close coordination with the Africa CDC, WHO AFRO and 300 other institutions across the continent.
 
“The enormous leap Africa made in genomic surveillance during the past two years is the silver lining in the COVID pandemic,” said Dr Matshidiso Moeti, WHO Regional Director for Africa. “The continent is now better prepared to face down both old and emerging pathogens. This is a model of how when Africans are in the driving seat we can come up with lasting change and stay a step ahead of dangerous diseases.”
 
“It has been an inspiring experience to continuously share knowledge, support and learn from colleagues all over the continent during the pandemic. We witnessed small countries with no previous genomics experience become empowered in sequencing and bioinformatics methods, and how they started to actively participate in regular pathogen genomic surveillance for SARS-CoV-2. I think it will be a real model of how scientists and public health officials across countries can form a unified front against infectious diseases in the future,” says Houriiyah Tegally, Bioinformatician at KRISP and CERI and first author on this report.
 
The results also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most relevant being the detection of the Beta and various Omicron subvariants. The report highlights that most SARS-CoV-2 variants, which caused  an epidemic in Africa, were introduced from abroad.

The scientists proceeded carefully in analysing genomic and epidemiological data collected in over 50 countries that experienced quite heterogenous epidemics in order to reconstruct transmission dynamics of the virus in the most accurate way. “The phylogeographic methods that we employ to investigate the movement of the SARS-CoV-2 virus and its variants into, out of, and within the African continent account for uneven testing and sampling proportions across countries, arising from the realities of doing genomic sequencing in the middle of a pandemic, often in low resourced settings,” explains Dr Eduan Wilkinson, head of bioinformatics at CERI at Stellenbosch University and senior author on this report.
 
The initial waves of infections in Africa were primarily seeded by multiple introductions of viral lineages from abroad (mainly Europe). The Alpha variant that emerged in Europe at the end of 2020, was responsible for infections in 43 countries with evidence of community transmission in Ghana, Nigeria, Kenya, Gabon and Angola. For the Delta variant, the bulk of introductions were attributed to India (~72%), mainland Europe (~8%), the UK (~5%), and the US (~2.5%). Viral introductions of Delta also occurred between African countries in 7% of inferred introduction. For Omicron, the scientific results indicate more reintroductions of the variant back into Africa, with at least 69 (95% CI: 60 – 78) from Europe and 102 (95% CI: 92 – 112) from North America than from other African countries. This was amplified for Omicron BA.2; the results suggest at least 99 separate introduction or reintroduction events of BA.2 into African countries, ~65% of which are from Europe and ~30% from Asia.
 
“The ironical part of these results is that most of the introductions of variants in Africa were from abroad, but Africa was the most discriminated and penalized continent in the world with travel bans imposed. Instead of unscientific and inappropriate reactions, we should be building on the infrastructure established in Africa so that the continent can rapidly pivot to other epidemics without the fear of being punished,” says Prof Tulio de Oliveira, director of CERI and KRISP, which lead the consortium analysis with the Africa CDC and WHO AFRO.
 
“This study is a testament of the Africa CDC – Africa PGI efforts to expand access to sequencing to member states and create a platform of coordination and collaboration among institutions within and outside of the continent,” said Dr. Ahmed Ogwell, Acting Director of the Africa CDC.

Provided by Stellenbosch University

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Killer T Cells Grab and Twist Cancer Cells Like Expert Warriors

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Killer T cells about to destroy cancer cell
Killer T cells about to destroy cancer cell (centre). Credit: NIH

While killer T cells have long been known to kill cancer cells with a cytotoxic weapon, new research has shown that they deliver the lethal strikes like expert warriors, grabbing and pulling the cancer cell’s membrane to more easily penetrate it like a dagger penetrating armour. The findings are detailed in a paper published in Developmental Cell.

Killer T cells are armed with lytic granules containing two key components for immune attack: a perforin proteins stabs a hole in the cell membrane, and the lethal granzymes which kill the cell.

T cells cosy up to targeted diseased cells in a close junction called the ‘cytotoxic immunological synapse’.

A research team at UNSW Sydney has found that mechanical forces generated by T cells influence how effectively perforin can punch through tumour cell membranes. The researchers describe the cell interactions and the integration of forces at both the front and rear of the cell.

The researchers detected physical forces within T cells that propel lytic granules toward the immunological synapse where their payloads are released. These forces also enable T cells to grab onto regions of the cancer cell membrane where the membranes of both immune and target cells are pulled and manipulated.

“It was very exciting to discover that, in addition to its mechanical tension and biochemical configuration, the shape of the target cell membrane plays an important role in T cell mediated cancer cell killing,” said Dr Daryan Kempe at UNSW Medicine & Health who co-led the research.

By stretching and bending the membranes of tumour cells in a certain direction, T cells made it easier for perforin to punch through, but only if the membranes were bent in the right direction.

Bias towards outwardly curved cell membranes

Using human melanoma cell lines, the researchers demonstrated that perforin preferentially perforated outwardly curved tumour cell membranes, rather than inwardly curved ones – which may help the T cells avoid being harmed by their own attack.

“As the granules arrive, their contents will be emptied at this region of the membrane that is very highly curved. That there was a bias between positively curved and negatively curved membranes was completely unexpected,” said senior Associate Professor Maté Biro at UNSW Medicine & Health.

Source: University of New South Wales

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Specific Drug Sequence for Metastatic Breast Cancer Lowers Costs

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Photo by Andrea Piacquadio on Unsplash

Giving standard chemotherapy drugs in a specific sequence for certain types of metastatic breast cancer can cut costs while preserving quality of life, according to a study in the Journal of Clinical Oncology.

The study, led by researchers from UNC Lineberger Comprehensive Cancer Center and UNC Gillings School of Global Public Health, developed three different computer models to predict how a hypothetical set of 10 000 patients with specific types of metastatic breast cancer would respond to different sequences and types of chemotherapy. For this study, the patient’s cancer was either endocrine resistant or was triple-negative breast cancer.

Many chemotherapy choices are available to treat metastatic breast cancer. While oncologists may prefer certain drugs to use early in treatment, the best order in which to give the drugs is unclear. The researchers consulted oncologists and experts in the field to choose which chemotherapy drugs were preferred choices to include in the study.

Mimicking clinical practice, and based upon existing data, the researchers then assumed that if a person started treatment with one drug, they would change to a second-choice treatment after their cancer stopped responding to the first drug, or if the side effects weren’t tolerable. The purpose of the study was to test whether putting the drugs in one sequence compared to another could keep the patient on treatment for similar times while decreasing their side effect and/or cost burden.

“The cost of cancer drugs in the US has rapidly increased, even for generics. As a society, we urgently need more strategies to reduce cancer drug costs without compromising outcomes, and our analysis provides quantifiable evidence to help providers choose lower priced, but equally effective sequences of drugs,” said Stephanie B. Wheeler, PhD, MPH, professor of health policy & management at UNC Gillings and associate director of community outreach and engagement at UNC Lineberger and corresponding author of the article. “More spending on cancer care does not necessarily confer greater health benefits.”

The costs calculated in this study were inclusive of medical and nonmedical costs borne by patients, including lost productivity. In this simulation, after two years, nearly all women would have completed the first three sets of treatment, but the cancer would cause the death of about one-third of the women. Productivity days lost due to sickness were similar across chemotherapy sequences, so most of the cost difference was due to drug savings. In the simulation, patients were placed in three groups, depending on what treatments they had already received for earlier episodes of breast cancer.

Outcomes in the three groups were:

  • For people who had not previously received the common chemotherapy drug categories, including a taxane (e.g., paclitaxel) or an anthracycline (e.g., capecitabine), treatment with paclitaxel then capecitabine followed by doxorubicin corresponded to the highest expected gains in quality of life and lowest costs.
  • For people who had previously received a taxane and an anthracycline drug, treatment with carboplatin, followed by capecitabine, followed by eribulin, corresponded to the highest expected gains in quality of life and lowest costs.
  • For people who had previously received a taxane but not an anthracycline, treatment sequences beginning with capecitabine or doxorubicin, followed by eribulin, were most cost-effective.

“The drugs we studied are already recommended and reimbursed for the treatment of metastatic breast cancer, but the optimal sequencing of them has been unclear, which has led to considerable variation in physician preference and practice. Our study suggests that treatment sequencing approaches that minimise costs early may improve the value of care,” Wheeler said. “The implications of this study are fairly straightforward for medical oncologists and those developing value-based clinical pathways to implement in practice now.”

Associate professor Katherine E. Reeder-Hayes, one of the study’s authors, said the treatment choices for metastatic breast cancer are constantly changing, and new options for targeted therapy have emerged even since this study was conducted. “Many oncologists and patients find that there aren’t any more targeted therapies that fit the cancer’s molecular profiles, so they are left with the choice of a number of chemotherapy drugs that may feel pretty similar or have an unclear balance of pros and cons.

“In that scenario, I hope our study will help expand the framework that we use to make these decisions from one where we just think about the biologic action of the drug to one where we also consider the bigger picture of what the treatment experience is like for the patient, including their financial burden, investment of time, and side effects,” Reeder-Hayes added. “The most potent drug isn’t always the next best choice depending on what the patient values and wants to accomplish with their treatment.”

Source: UNC Lineberger Comprehensive Cancer Center

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Asthma from Smoke Exposure Can Pass Down the Generations

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Cigarette smoking
Source: Sabine R on Unsplash

Children are more likely to develop asthma if their father was exposed to secondhand smoke when he was a child, according to a study published today in the European Respiratory Journal. The researchers also found that the children have an even higher asthma risk if their father was exposed to secondhand smoke and then also became a smoker.

The researchers say their findings highlight how smoking can cause intergenerational harm, impacting even grandchildren.

The research drew on on data from the Tasmanian Longitudinal Health Study (TAHS). TAHS began in 1968 and is one of the world’s largest and longest ongoing respiratory studies.

For this study, researchers looked at 1689 children who grew up in Tasmania, and their fathers and their paternal grandparents. They compared data on whether the children had developed asthma by age 7 with data on whether the fathers grew up with parents who smoked when they were under age 15. They also included data on whether the fathers were current or former smokers.

First author Mr Jiacheng Liu said, “We found that the risk of non-allergic asthma in children increases by 59% if their fathers were exposed to secondhand smoke in childhood, compared to children whose fathers were not exposed. The risk was even higher, at 72%, if the fathers were exposed to secondhand smoke and went on to smoke themselves.”

Researcher Dr Dinh Bui said, “Our findings show how the damage caused by smoking can have an impact not only on smokers, but also their children and grandchildren. For men who were exposed to secondhand smoke as children, our study suggests that they can still lower the risk they pass on to their own children, if they avoid smoking.”

Senior author Professor Shyamali Dharmage said, “We can’t be certain of how this damage is passed on through generations, but we think it may be to do with epigenetic changes. This is where factors in our environment, such as tobacco smoke, interact with our genes to modify their expression. These changes can be inherited but may be partially reversible for each generation.

“It’s possible that tobacco smoke is creating epigenetic changes in the cells that will go on to produce sperm when boys grow up. These changes can then be passed on to their children.”

The researchers will now investigate if the increased risk of asthma persists into adult life and whether fathers who were exposed to secondhand smoke as children pass on any increase in allergies or other lung diseases to their children.

Source: University of Melbourne

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A New Analytical Technique for Dense Breast Tissue Mammograms

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Source: National Cancer Institute

Researchers have developed a two-pronged approach to imaging breast density in mice, resulted in better detection of changes in breast tissue, including spotting early signs of cancer. If applied in humans, the technology may also help with prognosis of disease as density can be linked to specific patterns of mammary gland growth, including signs of cancer development. The findings appeared in the American Journal of Pathology.

“Having a means to accurately assess mammary gland density in mice, just as is done clinically for women using mammograms, is an important research advance,” said Priscilla A. Furth, MD, professor of oncology and medicine at Georgetown Lombardi Comprehensive Cancer Center, and corresponding author of the study. “This method has the benefit of being applicable across all ages of mice and mammary gland shapes, unlike some methods used in earlier studies.”

While working as an undergraduate in Furth’s lab, Brendan Rooney developed an innovative analytic computer program (C’20), which allowed for sorting of mammary gland tissue to one of two imaging assessments. At first, Rooney looked at younger mouse glands and found that a program that removed background ‘noise’ in those images helped boost detection of abnormalities in what are typically rounder, more lobular tissues. But as aging occurs and the chances of developing cancer increase, lobules diminish and ridges become more apparent, just as falling autumn leaves expose tree branches. The mammary ridges represent ducts that carry milk and other fluids. When the de-noising technique was applied to the images from the older mice, it was found to be less reliable in detecting ridges. Therefore Rooney and the team turned to a different imaging program, which has primarily been used to detect blood vessel changes in the eye’s retina.

“The idea for the analytic program came from routine visual observations of tissue samples and the challenges inherent in observing differences in breast tissue with just a microscope. We found that visual human observations are important but having another read on abnormalities from optimal imaging programs added validity and rigor to our assessments,” says Rooney, the lead author of the study. “Not only does our program result in a high degree of diagnostic accuracy, it is freely available and easy to use.”

Now that the broad strokes of the research have been laid down and proof-of-principle has been established, Rooney has started medical school with a possible eye toward specializing in oncology. Both Furth and Rooney believe that future studies will need to refine and streamline their research approach in mice, including better density measurements that could enable sorting of samples into higher and lower probabilities of cancer.

Source: Georgetown University Medical Center