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Using skin biopsy samples, investigators found that patients with severe COVID-19 had clots in small venous and arterial blood vessels in skin that appears normal. This was not seen in the skin of patents with other types of severe infectious lung disease, or in individuals with only mild or moderate COVID-19. Their findings appear in The American Journal of Pathology, published by Elsevier.
The researchers document, for the first time in premortem evidence, that a minimally invasive skin biopsy can help assess tissue damage related to COVID-19 as well as help distinguish this blood vessel pathology from other forms of severe respiratory illnesses. Prior to this study, invasive procedures such as nerve, kidney, or lung biopsy would have been required.
“We were the first group to recognize that the lung disease of acute COVID-19 was different from other severe critical respiratory infections, and that the unusual pathology was systemic,” explained lead investigator Jeffrey Laurence, MD, Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY, USA.
The investigators collected simple 4mm punch biopsy samples of normal-appearing deltoid skin from 15 patients who were in intensive care with COVID-19 and six patients with mild to moderate COVID-19 symptoms, such as fever, chills, cough, or shortness of breath. Biopsy samples from nine hospitalized patients with severe or critical respiratory or kidney disease who died before the COVID-19 era were also included in the study.
Microthrombi were detected in 13 of the 15 patients with severe or critical COVID-19. No microthrombi were detected in the biopsies of patients who had mild to moderate COVID-19 or the pre-COVID-19 era patients with severe respiratory illness or kidney diseases. It is likely that these microvascular changes may be a unique characteristic of COVID-19 respiratory disorder compared to other acute respiratory diseases.
An antiviral protein capable of blocking SARS-CoV-2 growth, MxA, was found in all six mild to moderate COVID-19 patients, indicating that their immune systems were actively fighting the virus, versus only two patients with severe to critical disease.
An interferon-induced inflammatory protein, SIN3A, was prominent in the microvascular of normal-appearing skin from patients with severe or critical COVID-19, but not in similar samples from normal control subjects. Increased SN3A levels in plasma and expression in skin microvasculature were associated with the severity of the patient’s disease and could contribute to the cytokine storm characteristic in such patients.
Dr. Laurence notes that these results have clinical implications. “Although anticoagulants were used in the pre-COVID-19 era in sepsis-associated pneumonias to reduce macrovessel thromboembolism, most randomized trials to date have not found this treatment benefits hospitalized patients who are critically ill with COVID-19 acute respiratory distress syndrome. These drugs may not be capable of reducing the microvessel thrombosis found with SARS-CoV-2 infection.”
The investigators acknowledge that their work is limited by its nonrandomized referral process, and before the clinical significance of these findings as actionable correlates of disease progression can be established, a prospective study using serial biopsy samples of normal-looking skin is required. However, they emphasize that the simple punch skin biopsy allows tissue-based assessment for microvascular thrombosis, complement disposition, and MxA and SN3A levels at different time points.
“If validated in a longitudinal cohort, earlier identification of factors linked to severe COVID-19 using a simple skin biopsy in patients at early stages of SARS-CoV-2 infection may help identify individuals at risk of acute disease progression and long COVID and enable early targeted interventions,” Dr. Laurence said.
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Materials provided by Elsevier. Note: Content may be edited for style and length.

A study led by researchers from Mayo Clinic Comprehensive Cancer Center has found that the addition of brentuximab vedotin to standard chemotherapy treatment improves overall survival in patients with Hodgkin Lymphoma, when compared to the current standard of chemotherapy alone. Results of the research were presented by Stephen Ansell, M.D., Ph.D., at the 2022 American Society of Clinical Oncology Annual Meeting (ASCO) in Chicago and were published today in the New England Journal of Medicine.
Dr. Ansell says that contrary to what was previously thought, research now shows that the selection of an initial therapy that includes brentuximab vedotin, has a positive impact on overall survival in patients with advanced stage Hodgkin lymphoma, regardless of other treatments administered later in the course of care.
“Our randomized study showed that the addition of an antibody drug conjugate, brentuximab vedotin, to standard chemotherapy in patients with advanced stage classical Hodgkin lymphoma improved overall survival for patients with Hodgkin Lymphoma, when compared to patients who received standard chemotherapy alone,” says Dr. Ansell.
“Brentuximab plus AVD chemotherapy was previously reported to improve progression-free survival in patients with classical Hodgkin lymphoma, so its impact on overall survival was not completely surprising,” says Dr. Ansell. However, he says patients who relapse are often successfully treated with additional treatments so previous comparative studies of other drug combinations failed to show an overall survival benefit. “The impact on overall survival with brentuximab vedotin plus AVD chemotherapy is somewhat surprising but it confirms that the use of novel agents in the frontline treatment of patients with Hodgkin lymphoma has a long-term impact,” says Dr. Ansell.
Dr. Ansell and his colleagues also evaluated long-term toxicities of brentuximab vedotin. They found that neuropathy from the addition of the drug to treatment was found to resolve over time. In addition, the number of subsequent pregnancies were not negatively impacted with the addition of the new agent. “Surprisingly, second malignancies including other lymphomas were less frequently seen in the brentuximab vedotin +AVD arm of the trial,” says Dr. Ansell.
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Materials provided by Mayo Clinic. Original written by Joe Dangor. Note: Content may be edited for style and length.

An individualized diet program that empowers users to create their own plan based on targeted levels of protein and fiber shows promise at helping people lose extra pounds and keep them off.
The Individualized Diet Improvement Program is a self-guided approach that involves easy-to-use tools, according to the nutritionists at the University of Illinois Urbana-Champaign who created iDip.
“Our program does not provide or offer a strict diet plan or recipes for participants to follow,” said graduate student Mindy H. Lee, a co-author of the study. “We’re not excluding food groups as low-carbohydrate or low-fat plans do. The primary goal is to empower dieters to make informed choices so they can create their own sustainable weight-management program.”
Diet flexibility is key to making weight loss and maintenance sustainable, said study co-author Manabu T. Nakamura, a professor of nutrition at the university.
“The problem with currently available commercial weight-loss programs and products is that the magnitude of dieters’ weight loss is not great,” he said. “The more serious problem is that people can’t maintain it.
“If they follow the program or consume only the foods they’re told to for four or six months, they lose a certain amount of weight, but when they quit following the program or buying the products the weight comes right back. And that’s very discouraging for them.”
A visual tool developed by the researchers plots dieters’ protein and fiber intake, helping them choose foods that reduce their overall calories without reducing their protein and fiber.

A novel peptide developed at the Universities of Bayreuth and Bristol is eminently suited for the targeted transport of molecules, for example of active substances and dyes, into the cells of mammals. The peptide is characterized by a dual function: It can enter the cell from the outside and interact there with a partner peptide. The partner peptide has to be previously placed inside the cell exactly where the transported molecules are to take effect. The transport system presented in the journal Nature Chemical Biology exemplifies the promising potential of a de novo design of peptides and proteins.
In recent years, biomedicine and pharmacology have developed a large number of active substances that are capable of triggering, enhancing, or inhibiting processes in mammalian cells. However, transporting these substances exactly to where they are required is still a challenge in many cases. The situation is similar when it comes to colour-marking certain structures inside cells for research or diagnostic purposes. It is true that mammalian cells have the ability to incorporate foreign substances through endocytosis. But this by no means guarantees transport to the desired site of action. A new research approach that the Bayreuth biochemist Prof. Dr. Birte Höcker is pursuing with her research group is the rational design of peptides. These should be able to penetrate into the cell interior from the outside and take attached active substances or dye molecules with them. Peptides suitable for this purpose are rather small as they usually consist of less than 30 amino acids.
Until now, however, the problem has been that such peptides — precisely because of their simplicity and small size — do not offer many possible applications. This is because there are only a few areas in the diverse structures of the cell interior where they can dock and deliver the molecules they transport. This disadvantage has been overcome by the peptide developed in Bayreuth and Bristol. It is a basic peptide with a high content of arginine amino acids, and it has two components essential for its functionality. One allows the peptide to enter the cell interior, and the other is able to interact with an acidic partner peptide. This partner peptide is such that it can be placed in very different locations inside the cell using established biochemical methods. Once proteins, larger molecular complexes, or organelles have been labelled with the partner peptide, they can be targeted by the basic peptide that has entered the cell. Like a key in a lock, the basic peptide latches on to the acidic peptide. The targeted placement of the acidic partner peptide is achieved by coupling it with molecules that are in turn introduced into the cell’s DNA by transfection.
The Anglo-German research team designed the two previously unknown de novo peptides using methods of computer-assisted protein design. The basis for this work were peptides with a coiled structure, which were described in a structure database. The peptides designed on the computer were then synthesised in the laboratory. Here, biophysical methods and X-ray crystallography were used to identify the real properties and behaviour of the peptides. Experiments with E. coli bacteria and eukaryotic cells revealed that the new peptide system is even suitable for transporting other peptides and proteins.
“Our investigations exemplify how the computational design of peptides and proteins, their subsequent synthesis and characterisation in the laboratory, as well as testing in living cells can intertwine when innovative solutions for biochemical or biomedical questions are being sought,” says Prof. Dr. Birte Höcker, head of the Protein Design Group at the University of Bayreuth and corresponding author of the new study. “The new peptide system makes it clear that de novo design is a promising research approach in the search for methods that enable drug or dye molecules to be introduced into mammalian cells in a targeted and gentle manner,” adds Dr Guto Rhys, postdoc at the Protein Design research group and one of the three first authors.
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A drug used in the clinical treatment of angina symptoms also has an anti-inflammatory effect and reduces atherosclerotic plaques in blood vessels — thereby reducing the risk of heart attack or stroke. The study, led by MedUni Vienna and including access to data from Harvard Medical School, has now been published in Proceedings of the National Academy of Sciences.
The complications of atherosclerosis — heart attack and stroke — are the leading causes of death in Europe and the United States. In recent years, it has been shown that chronic inflammation in the arteries leads to the formation and progression of atherosclerotic plaques (deposits in the blood vessels). The MedUni Vienna research group led by Walter Speidl (Department of Medicine II, Division of Cardiology) and Philipp Hohensinner (Center for Biomedical Research) has now demonstrated for the first time that a reduction in intracellular sodium concentration inhibits the important inflammatory modulator NF-kappa-B. The drug ranolazine is a long-established drug used to relieve the symptoms of angina pectoris. However, it also inhibits the uptake of sodium into cells.
Johann Wojta, Head of the Cardiology Research Laboratory at the Medical University of Vienna, and co-author of the study explains: “In this publication, we used research involving cell culture, animal models and a large-scale human study to identify a new mechanism for inhibiting inflammation in atherosclerosis. We now have evidence that an established drug not only combats the symptoms of angina but can also reduce the risk of heart attack and stroke.”
Using data provided by Harvard Medical School, this anti-inflammatory effect was demonstrated in 6,500 patients who had suffered myocardial infarction. It was found that treatment with ranolazine results in lower levels of the inflammatory and cardiovascular risk marker “high-sensitivity C-reactive protein” compared to placebo. Max Lenz, lead author of the study says: “We have now been able to show that ranolazine is not only effective against symptoms. It has an anti-inflammatory effect and reduces atherosclerotic plaques in our mouse models. These plaques also become more stable, potentially significantly reducing the risk of heart attack.” Ranolazine is thus a safe drug that has already been approved for patients with coronary heart disease and leads to a reduction in chronic vascular inflammation.
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Materials provided by Medical University of Vienna. Note: Content may be edited for style and length.

Protein function and activity is determined by both their assembly and secondary structure. Abnormalities related to either protein aggregation or secondary structure can lead to neurodegenerative diseases. In a new study, an international research team reveal how fluoride nanoparticles, materials used in in vivo imaging, affect the assembly and structure of the amyloid β protein. Their results present a step towards better treatment and prevention of neurologic disorders like Alzheimer’s disease.
Self-assembly, or the association of individual units of a material into ordered structures or patterns, is a phenomenon of great research interest for materials scientists. One prominent example of self-assembly comes from the self-assembly of proteins in biological systems. The function and activity of proteins are governed by their assembly state. Additionally, the protein’s “secondary structure,” characterized by its folding into structures, such as a β-sheet, also plays a role. In fact, abnormalities in the protein secondary structures or their assembly can lead to various neurodegenerative diseases, including Alzheimer’s disease.
Nanoparticles (NPs) offer a promising route for the treatment and prevention of such diseases by allowing a controlled and targeted drug delivery. Additionally, inorganic NPs, such as fluoride NPs, are used in brain imaging applications. Compared to organic NPs, inorganic NPs are considered a better candidate for developing high functional materials. But, there is much concern regarding their bio-toxicity. While their interactions with bioproteins have been studied, the mechanism underlying these interactions are not well understood.
An international team of scientists from Tokyo University of Science (TUS) in Japan and Nazarbayev University in Kazakhstan has now addressed this issue. In their study, which was made available online on June 2, 2022, and was published in Volume 5, Issue 6 the journal ACS Applied Bio Materials on June 20, 2022, the team investigated a section of the amyloid β peptide (a protein found in the plaques forming in the brains of patients with Alzheimer’s disease) in solution with fluoride ceramic (CeF3) NPs. The study was led by Junior Associate Professor Masakazu Umezawa and included contributions from Mr. Naoya Sakaguchi from TUS and Assistant Professors Mehdi Amouei Torkmahalleh and Dhawal Shah from Nazarbayev University.
The team used a technique called “Fourier transform infrared spectroscopy” (FTIR) to directly monitor the effect of the NP surface on the peptide bonds. “We found that, near the nanoparticle surface, peptides are more likely to form β-sheets. This comes as an effect of hydrophobicity. The parts of the peptide that repelled by the water solution stick to the nanoparticles, and form aggregates more easily,” explains Dr. Umezawa.
In addition, the team investigated the effect of other surrounding ions in the solution. “What we found was very surprising. Even without the nanoparticles, the environment affected the rate of secondary structure formation,” says Dr. Umezawa, “This effect, resulting from a combination of electrostatic interaction and hydrogen bonding, was exaggerated upon adding nanoparticles. With a careful choice of ions and nanoparticles, the β-sheet formation can be either suppressed or promoted. This implies that the process can be controlled and engineered to eradicate adverse effects.”
The experimental results were complemented with molecular dynamics simulations performed by the Nazarbayev University team. This, in turn, helped design and guide the experiments as well as provide insights into the results.
With this deeper understanding of the interaction between proteins and NPs, the study paves the way for controlled protein folding processes. With such control, any protein deformations could be eliminated, and positive interactions and structural changes could be promoted. This could lead to a better prevention and treatment protocol for Alzheimer’s disease and, eventually, to a better quality of life for aged adults.
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Materials provided by Tokyo University of Science. Note: Content may be edited for style and length.

You may think that a good night’s sleep should be uninterrupted. But in fact, the neurotransmitter noradrenaline causes you to wake up more than 100 times a night, new research from the University of Copenhagen concludes. It is perfectly normal and may even indicate that you have slept well.
You wake up. The alarm clock says 02:56.
“Oh no, it is not time to wake up yet,” you think, fearing that you will need lots of coffee to stay awake the following day.
Most people believe that a good night’s sleep should be uninterrupted. That is why it can be extremely annoying to wake up in the middle of the night when all you want to do is sleep.
New research from the University of Copenhagen shows that the stress transmitter noradrenaline causes you to wake up many times a night. But do not worry. It is all part of a normal, good night’s sleep and can even mean that you have slept well.
Noradrenaline
Noradrenaline is a stress hormone and transmitter substance, which i.a. is associated with the body’s fight or flight response. It is related to adrenaline, and levels may increase during stress, but it also helps you stay focussed.

In an analysis of medical information of more than 6,000 American adults with a history of cardiovascular disease (CVD), researchers at Johns Hopkins Medicine conclude that CVD risk “profiles” in secondary prevention have failed to improve over the last two decades.
Secondary prevention refers to prevention of recurrent cardiovascular events such as heart attack or stroke in individuals who already have CVD. Despite recent advancements in safe and effective therapies reflected in guideline recommendations, trends in CVD risk profiles in adults with the condition were not ideal from 1999 through 2018. An ideal risk profile is based on targets that health professionals agree to be considered desirable. The study was published July 4 in the Journal of the American College of Cardiology.
Risk-factor profiles analyzed included blood glucose, blood pressure, cholesterol, body mass index, smoking, physical activity and diet. All factors showed a worsening or unchanged trend, except for cholesterol, which showed a modest improvement. However, only 30% of adults with CVD had an ideal cholesterol profile in 2015-2018.
“We’re not really moving the needle on these risk factors, and that’s leaving a lot of people at risk for recurrent events,” says corresponding author of the study, Seth S. Martin, M.D., M.H.S., associate professor of medicine in the division of cardiology at the Johns Hopkins University School of Medicine. He called for “re-engineering preventive care.”
“Our numbers are disappointing and alarming,” says co-first author of the study Yumin Gao, Sc.M., premedical student and biostatistician at the Johns Hopkins Digital Health Innovation Lab.
“Our study shows that there remains a critical need and opportunity to effectively translate established guidelines into patient care,” says co-first author of the study Nino Isakadze, M.D., M.H.S., Cardiac Electrophysiology Fellow at the Johns Hopkins Hospital. “We have to get innovative about how to reach diverse groups of patients, and to improve secondary prevention in everyone with cardiovascular disease.”
The study also revealed persistent racial and ethnic disparities in heart-related health. Isakadze says access to healthcare, patient education and affordability of medications are likely the main drivers of disparities seen in high-risk populations.

A new technique that can analyse how drug molecules bind to proteins in tissue samples could offer an improved route to drug discovery and development.
Researchers at the University of Birmingham developed the technique in collaboration with global biopharmaceutical company AstraZeneca. It uses mass spectrometry, an analytical tool commonly used for identifying the properties of molecules within a sample.
Part of the early stages of drug discovery takes place in cell cultures, clusters of cells that are grown in the laboratory, outside of their natural environment. Cell cultures enable the effects of different compounds to be tested on specific biological targets involved in various diseases. Although this allows researchers to assess how the compounds act against the target, it does not capture the full effects of the physiological environment.
This new technique, described in a paper published today [14 July 2022] in Angewandte Chemie, enables researchers to use real tissue samples to assess which proteins the drug will bind to in the body and therefore how effective it is likely to be against the target.
Being able to pinpoint the interaction between the drug and the protein can provide valuable insight to guide drug discovery.
Lead researcher Professor Helen Cooper said: “Usually in early-stage drug discovery, measurements are taken outside of the physiological environment, so when researchers move onto testing drugs in tissue, they can fail because they have interactions that were not expected.
“Identifying the drug protein interaction at this early stage, however, is incredibly hard. Using mass spectrometry on proteins is often compared to making an elephant fly. What we’ve done is add an unsecured hat — the drug molecule — to the elephant, and measured the whole process. It’s exciting because it opens up the possibility of being able to follow the route of a drug through the body. By identifying which proteins it interacts with scientists will be able to predict at an earlier stage whether or not it will have the desired therapeutic effect.”
In the study, the researchers used tissue taken from the livers of rats dosed with bezafibrate, a drug commonly used to treat high cholesterol. They used mass spectrometry on thin sections of tissue to detect the drug molecule and the specific fatty acid binding protein to which it attaches to form a complex.
The researchers were also able to measure both the varying amounts of this complex in the liver over time, and how it spreads through the tissue.
AstraZeneca lead Professor Richard Goodwin, Senior Director, Imaging Sciences said: “What is key to delivering such innovative science is sustained collaboration between academic leaders and industry partners. This research builds on a long-standing collaboration between AstraZeneca and the University of Birmingham, and exemplifies what can be done when we combine complementary skills to address significant unmet need. This research will continue to support drug discovery and help accelerate us bringing new medicines to patients.”
Next steps for the research will include improving the sensitivity of the technique, and extending it to other types of drug compounds. Looking further ahead, the team hopes it can be developed for use in human tissue, taken from biopsies. This would yield a greater understanding of why drugs work differently in different patients.
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Researchers have created a liquid biopsy test, which uses two circulating proteins, to test for major liver diseases. The test was found to be highly accurate, sensitive, and specific for both NASH and liver fibrosis. For the first time, a non-invasive test will allow for the determination of staging of both diseases without recurring to invasive liver biopsy.
Non-alcoholic steato-hepatitis (NASH) is the most severe form of non-alcoholic fatty liver disease (NAFLD) and is diagnosed in approximately 60% of NAFLD patients. NASH puts people at risk of progressing to advanced liver diseases such as liver fibrosis, cirrhosis, and liver cancer.
NAFLD affects approximately 52 million people in Europe and 64 million people in the US, costing $138 billion annually to the European and US healthcare systems combined.
Currently, NASH can only be diagnosed with invasive liver biopsy, which is the standard of diagnosis, but is expensive and has co-morbidities and complications. There are also no reliable blood (i.e. liquid biopsy) tests for the diseases because of low sensitivity and specificity. Current blood tests are also unable to reliably predict NASH and fibrosis staging.
Professor Geltrude Mingrone, from King’s College London and Catholic University of Rome, Italy, looked to find a more accurate liquid biopsy test.
The paper, published in leading journal Gut, identified two protein biomarkers, PLIN2 and RAB14, that were used as part of an algorithm to identify people with NASH and/or liver fibrosis. The ability for these proteins to detect NASH was tested in cohorts of people with either biopsy-confirmed NASH or liver fibrosis.
The algorithms, which used A.I., gave impressive results, including a sensitivity of 88-95%, a specificity of 90%-100%, and an overall accuracy of 92-93% for NASH. For fibrosis, they were even better, with a sensitivity of 99%-100%, specificity of 90%-96%, and accuracy of 98%-99%. As well as being much more accurate than all other currently available biomarkers, it is now possible to predict the stages of the diseases without invasive liver biopsy.
Professor Geltrude Mingrone, from King’s College London, said: “This blood test will allow to define the real prevalence of NASH in large and small populations, including children and adolescents, avoiding the need for invasive liver biopsy. Importantly, it will also allow to monitor the efficacy of NASH treatments over time, reducing screen failures and helping generate better drugs.”
These results show that the PLIN2/RAB14-based liquid biopsy can provide rapid and cost-effective testing to combat the growing epidemic of NASH and liver fibrosis. This will be an invaluable tool in diagnosing and monitoring cases of liver diseases, enabling people to receive earlier treatment.
The authors also believe that the testing will allow for the improved capacity for researchers to study NASH and liver fibrosis in the general population, including disease progression, and record the effects of treatment, from lifestyle to surgical and pharmacological interventions.
No NASH drug has been approved by the FDA or EMA due to the lack of an accurate, reliable, and non-invasive test. Between 65-73% of patients that currently enrol in clinical trials for NASH-related therapies are found to be ineligible for the trial due to screen failure. The test — developed in collaboration with Metadeq Corp. — is expected to significantly reduce screen failures in clinical trials and improve the chances of new life-saving drugs reaching the market.
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Materials provided by King’s College London. Note: Content may be edited for style and length.