Publisher Health

Whole Genome Sequencing from a single blood test picks up 31% more cases of rare genetic disorders than standard tests, shortening the ‘diagnostic odyssey’ affected families experience and providing huge opportunities for future research.
Mitochondrial disorders affect around 1 in 4300 people and cause progressive, incurable diseases. They are amongst the most common inherited diseases but are difficult for clinicians to diagnose, not least because they can affect many different organs and resemble many other conditions.
Current genetic testing regimes fail to diagnose around 40% of patients, with major implications for patients, their families and the health services they use.
A new study, published today in the BMJ, offers hope to families with no diagnosis, and endorses plans for the UK to establish a national diagnostic programme based on whole genome sequencing (WGS) to make more diagnoses faster.
While previous studies based on small, highly selected cohorts have suggested that WGS can identify mitochondrial disorders, this is the first to examine its effectiveness in a national healthcare system — the NHS.
The study, led by researchers from the MRC Mitochondrial Biology Unit and Departments of Clinical Neuroscience and Medical Genetics at the University of Cambridge, involved 319 families with suspected mitochondrial disease recruited through the 100,000 Genomes Project which was set up to embed genomic testing in the NHS, discover new disease genes and make genetic diagnosis available for more patients.

New evidence suggests that adding the targeted therapy ibrutinib (Imbruvica) to a standard chemotherapy regimen can improve how long some younger people with a specific form of diffuse large B-cell lymphoma (DLBCL) live. The findings, published November 4, 2021, in Cancer Cell, come from a new analysis by researchers at the National Cancer Institute (NCI), part of the National Institutes of Health, of a previously conducted phase 3 clinical trial.
Initial results from that study, known as the PHOENIX trial, showed that combining ibrutinib with the standard chemotherapy regimen did not help patients with a form of DLBCL called non-GCB DLBCL to live longer overall. However, by analyzing tumor biopsy samples from patients on the trial, NCI researchers and their collaborators have now shown that younger patients with specific genetic subtypes of non-GCB DLBCL, called MCD and N1, had an exceptional response to the treatment combination, with all such patients alive without disease three years after diagnosis.
“People thought the trial didn’t work,” said Louis M. Staudt, M.D., Ph.D., chief of the Lymphoid Malignancies Branch in the Cancer for Cancer Research at NCI. “But there was something interesting going on — if you just considered younger patients under the age of 60, they had a real benefit from ibrutinib, and we now understand why.”
“This new analysis provides a compelling rationale for doctors to consider adding ibrutinib to standard chemotherapy for the initial treatment of younger patients with non-GCB DLBCL,” said Wyndham H. Wilson, M.D., Ph.D., senior investigator in the Lymphoid Malignancies Branch and a co-author of the study.
DLBCL is the most common type of lymphoma, accounting for 40% of lymphoma cases worldwide. This fast-growing cancer affects B cells, a type of white blood cell, and usually starts in the lymph nodes. People with DLBCL are typically treated with a chemotherapy regimen known as R-CHOP that includes cyclophosphamide, doxorubicin, vincristine, prednisone, and the monoclonal antibody rituximab. But R-CHOP is not effective for all people with DLBCL.
In the 2000s, to better understand individual variation in treatment response, researchers analyzed the patterns of gene activity in DLBCL tumors. They discovered that there are three molecular subgroups of DLBCL: germinal center B cell-like (GCB), activated B cell-like (ABC), and unclassified. Researchers later found that these subgroups respond differently to chemotherapy. More recently, researchers showed that the ABC and GCB subgroups can be further divided into seven genetic subtypes that also respond differently to chemotherapy.

According to an open-access Editor’s Choice article in ARRS’ American Journal of Roentgenology (AJR), imaging practice leaders should carefully consider efforts to match interpretation of subspecialty examinations with radiologists’ fellowship training in the acute community setting.
Pointing out that major and minor discrepancy rates were not higher for acute community setting examinations outside of interpreting radiologists’ fellowship training, “discrepancy rates increased for advanced examinations,” acknowledged lead investigators Suzanne Chong from Indiana University in Indianapolis and Tarek Hanna of Emory University in Atlanta, GA.
Using the databank of a large US teleradiology company (Virtual Radiologic), Chong, Hanna, and colleagues’ analysis included 5,883,980 acute examinations performed from 2012 to 2016 that were preliminarily interpreted by 269 teleradiologists with a fellowship of neuroradiology, abdominal radiology, or musculoskeletal radiology. When providing final interpretations, client on-site radiologists voluntarily submitted quality assurance (QA) requests if preliminary and final interpretations were discrepant; the teleradiology company’s own QA committee categorized discrepancies as major (n=8,444) or minor (n=17,208).
Among the preliminary teleradiology interpretations of acute community setting examinations, common examinations’ major and minor discrepancies rates were not different when concordant versus discordant with radiologists’ fellowship training (p >.05). However, advanced examinations’ discrepancy rates were higher when concordant with radiologists’ fellowship (relative risk = 1.45 and 1.17, respectively; p

Researchers have developed a technique whereby they can spontaneously encapsulate microscopic droplets of water and oil emulsion in a tiny sphere made of salt crystals—sort of like a minute, self-constructing origami soccer ball filled with liquid. The process, which they are calling ‘crystal capillary origami,’ could be used in a range of fields from more precise drug delivery to nanoscale medical devices.The technique is described in a paper appearing in the journal Nanoscale on September 21.
Capillary action, or ‘capillarity,’ will be familiar to most people as the way that water or other liquids can move up narrow tubes or other porous materials seemingly in defiance of gravity (for example within the vascular systems of plants, or even more simply, the drawing up of paint between the hairs of a paintbrush). This effect is due to the forces of cohesion (the tendency of a liquid’s molecules to stick together), which results in surface tension, and adhesion (their tendency to stick to the surface of other substances). The strength of the capillarity depends on the chemistry of the liquid, the chemistry of the porous material, and on the other forces acting on them both. For example, a liquid with lower surface tension than water would not be able to hold up a water strider insect. 
Less well known is a related phenomenon, elasto-capillarity, that takes advantage of the relationship between capillarity and the elasticity of a very tiny flat sheet of a solid material. In certain circumstances, the capillary forces can overcome the elastic bending resistance of the sheet. 
This relationship can be exploited to create ‘capillary origami,’ or three-dimensional structures. When a liquid droplet is placed on the flat sheet, the latter can spontaneously encapsulate the former due to surface tension. Capillary origami can take on other forms including wrinkling, buckling, or self-folding into other shapes. The specific geometrical shape that the 3D capillary origami structure ends up taking is determined by both the chemistry of the flat sheet and that of the liquid, and by carefully designing the shape and size of the sheet.
There is one big problem with these small devices, however. “These conventional self-assembled origami structures cannot be completely spherical and will always have discontinuous boundaries, or what you might call ‘edges,’ as a result of the original two-dimensional shape of the sheet,” said Kwangseok Park, a lead researcher on the project. He added, “These edges could turn out to be future defects with the potential for failure in the face of increased stress.” Non-spherical particles are also known to be more disadvantageous than spherical particles in terms of cellular uptake. 
Professor Hyoungsoo Kim from the Department of Mechanical Engineering explained, “This is why researchers have long been on the hunt for substances that could produce a fully spherical capillary origami structure.” 
The authors of the study have demonstrated such an origami sphere for the first time. They showed how instead of a flat sheet, the growth of salt-crystals can perform capillary origami action in a similar manner. What they call ‘crystal capillary origami’ spontaneously constructs a smooth spherical shell capsule from these same surface tension e?ects, but now the spontaneous encapsulation of a liquid is determined by the elasto-capillary conditions of growing crystals.
Here, the term ‘salt’ refers to a compound of one positively charged ion and another negatively charged. Table salt, or sodium chloride, is just one example of a salt. The researchers used four other salts: calcium propionate, sodium salicylate, calcium nitrate tetrahydrate, and sodium bicarbonate to envelop a water-oil emulsion. Normally, a salt such as sodium chloride has a cubical crystal structure, but these four salts form plate-like structures as crystallites or ‘grains’ (the microscopic shape that forms when a crystal first starts to grow) instead. These plates then self-assemble into perfect spheres.
Using scanning electron microscopy and X-ray di?raction analysis, they investigated the mechanism of such formation and concluded that it was ‘Laplace pressure’ that drives the crystallite plates to cover the emulsion surface. Laplace pressure describes the pressure difference between the interior and exterior of a curved surface caused by the surface tension at the interface between the two substances, in this case between the salt water and the oil.
The researchers hope that these self-assembling nanostructures can be used for encapsulation applications in a range of sectors, from the food industry and cosmetics to drug delivery and even tiny medical devices.

A sweat-collecting patch has been developed using the principle based on how the cactus spines attract water.
Sweat is an effective body fluid for analyzing bioanalytes in the body without collecting blood. The sweat sensor can reduce the hassle for diabetic patients who repeatedly have to draw blood, and can also be used in wearable devices for daily healthcare monitoring. However, the practical use of sweat sensors is impeded by irregular and low sweat secretion rates. There is a pressing need to effectively collect these sweat secretions.
To this, a research team led by Professor Kilwon Cho and Ph.D candidate Jonghyun Son of POSTECH’s Department of Chemical Engineering has recently developed a skin-attachable patch that quickly collects sweat by mimicking the principle behind cactus spines.
Cacti, which grow in arid environments, move water droplets that form on the tip of their spines to their base in order to survive. During this process, the fine water droplets move due to the difference in pressure acting on the inside and outside of the curved surface of the water droplet. This phenomenon is called the Laplace pressure.
The patch newly developed by Professor Kilwon Cho’s research team applied this principle of how cactus spines collect water. The researchers mimicked the structure of the cactus spine by using the wedge-shaped wettability patterns with superhydrophobic/superhydrophilic surfaces. Through this, a sweat droplet on the wedge-patterned surface spontaneously moves to the wide end of the wedge pattern because the Laplace pressure difference between the front and back surfaces of the droplet is maximized.
The results confirm that the wedge-patterned channel can collect sweat quickly and spontaneously regardless of the inclination of the microfluidic channels, without the need for additional force. In addition, the wedge-patterned channel shows great sweat-collecting efficiency as it transports nearly all sweat droplets to the sensing area without leaving much behind inside the channel, enabling it to collect sweat much faster than the conventional microfluidic channels. This allows the patch to continuously monitor the bioanalytes in the blood.
“Difficulties in collecting sweat has hindered its use in wearable healthcare devices,” explained Professor Kilwon Cho of POSTECH. He added, “This newly developed patch solves that issue by quickly collecting sweat and facilitating its use in various wearable healthcare devices, including blood sugar monitoring.”
Recently selected as the inside back cover paper of Advanced Materials, this study was supported by a grant from the Center for Advanced Soft Electronics under the Global Frontier Research Program and the National Research Foundation of Korea grant funded by the Ministry of Science and ICT of Korea.
Story Source:
Materials provided by Pohang University of Science & Technology (POSTECH). Note: Content may be edited for style and length.

The damage caused by Covid-19 to the lungs’ smallest blood vessels has been intricately captured using high-energy X-rays emitted by a special type of particle accelerator.
Scientists from UCL and the European Synchrotron Research Facility (ESRF) used a new revolutionary imaging technology called Hierarchical Phase-Contrast Tomography (HiP-CT), to scan donated human organs, including lungs from a Covid-19 donor.
HiP-CT enables 3D mapping across a range of scales, allowing clinicians to view the whole organ as never before by imaging it as a whole and then zooming down to cellular level.
The technique uses X-rays supplied by the European Synchrotron (a particle accelerator) in Grenoble, France, which following its recent Extremely Brilliant Source upgrade (ESRF-EBS), now provides the brightest source of X-rays in the world at 100 billion times brighter than a hospital X-ray.
Due to this intense brilliance, researchers can view blood vessels five microns in diameter (a tenth of the diameter of a hair) in an intact human lung. A clinical CT scan only resolves blood vessels that are about 100 times larger, around 1mm in diameter.
Dr Claire Walsh (UCL Mechanical Engineering) said: “The ability to see organs across scales like this will really be revolutionary for medical imaging. As we start to link our HiP-CT images to clinical images through AI techniques, we will — for the first time — be able to highly accurately validate ambiguous findings in clinical images. For understanding human anatomy this is also a very exciting technique, being able to see tiny organ structures in 3D in their correct spatial context is key to understanding how our bodies are structured and how they therefore function.”
Using HiP-CT, the research team, which includes clinicians in Germany and France, have seen how severe Covid-19 infection ‘shunts’ blood between the two separate systems — the capillaries which oxygenate the blood and those which feed the lung tissue itself. Such cross-linking stops the patient’s blood from being properly oxygenated, which was previously hypothesised but not proven.

An experimental drug enhanced the benefit of an immunotherapy to fight pancreatic cancer in mice by increasing the number of immune cells in the immediate vicinity of the tumor, leading to a reduction in tumor growth, and in some mice, eliminating their cancer. The findings, from researchers at Georgetown Lombardi Comprehensive Cancer Center and BioXcel Therapeutics, Inc., provide early evidence that the drug could jump-start an immune response against pancreatic cancer, a disease that has so far been resistant to immunotherapy.
The data come from experiments of BXCL701, an experimental dipeptidyl peptidase (DPP) inhibitor developed by BioXcel Therapeutics, and appear in the Journal for ImmunoTherapy of Cancer on November 4, 2021.
“This combination treatment not only cured some mice but also demonstrated having instilled an immune-cell memory so that, when the cured mice were injected with cancer cells months later, the immune systems in 10 of 13 mice recognized and killed the cancer cells, leaving the mice cancer-free again,” says Allison Fitzgerald, Ph.D., at Georgetown Lombardi and co-first author. “If this result holds true in humans, it means the therapy may have the potential to offer long-lasting remissions for patients with pancreatic cancer.”
The National Cancer Institute estimates there will be 60,430 new cases of pancreatic cancer diagnosed in 2021 with an estimated 48,220 deaths. Only about 10 percent of pancreatic cancer patients live five years or more, making it one of the deadliest cancers.
The microenvironment surrounding most pancreatic tumors is very effective at blocking immune system attacks, so researchers turned to BXCL701, an experimental oral DPP inhibitor. The drug candidate has been observed to help boost the effectiveness of immunotherapies in some early-phase clinical trials. (Research directed to evaluating the compound’s ability to promote immunotherapy in preclinical models was sponsored by BioXcel Therapeutics, Inc. through a research agreement with Georgetown Lombardi).
“While our success in mice is promising, we hold out additional hope due to the benefits of this DPP inhibitor seen in other types of cancer,” says the study’s corresponding author Louis M. Weiner, MD, director of Georgetown Lombardi and director of the lab where the research was conducted. “What we found to be unique in our study was how this drug candidate seems to enhance the effectiveness of immune response in pancreatic cancer, which is remarkable as standard immunotherapies have been unsuccessful to date.”
Scientists studied two sets of mice that were injected with cells that closely mimic human pancreatic cancer. The mice were then given the immunotherapy, along with BXCL701. The combination of therapies enhanced immunotherapy effectiveness by boosting two key immune system components: T cells and natural killer cells. Investigators found that natural killer cells contributed importantly to longer survival.
Natural killer cells play a key role in an immune defense against cancer in two ways: they recognize and kill cancer cells directly, similar to T cells, but also release small signaling molecules that can influence and regulate other parts of the immune system. Investigators believe that, based on this and other research, many immune cell types work together to keep cancer cells at bay.
“We would like to conduct additional studies in mice to better understand the biology of why this treatment is working so well and how we can make it work even better,” says Fitzgerald. “We are also hoping to develop a clinical trial based on the results of this study to see if this combination treatment works as well in humans as it does in mice.”
Story Source:
Materials provided by Georgetown University Medical Center. Note: Content may be edited for style and length.

Laura Flaherty was diagnosed with cervical cancer after a routine smear test. She then had a hysterectomy at 29 years old. She spoke to BBC Breakfast after the results of a study that showed the human papillomavirus (HPV) vaccine is cutting cervical cancer by nearly 90%. Cancer Research UK described the findings as “historic” and said it showed the vaccine was saving lives.Read more: HPV vaccine cutting cervical cancer by nearly 90%

Whether it’s reporting on conflicts abroad and political divisions at home, or covering the latest style trends and scientific developments, Times Video journalists provide a revealing and unforgettable view of the world.Whether it’s reporting on conflicts abroad and political divisions at home, or covering the latest style trends and scientific developments, Times Video journalists provide a revealing and unforgettable view of the world.