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Tag: Tokyo Medical and Dental University

  • Tears in Tokyo: Muscle–tendon injuries during Olympic competition can spell heartbreak

    Tears in Tokyo: Muscle–tendon injuries during Olympic competition can spell heartbreak

    Newswise — Tokyo, Japan—In a recent study, researchers reviewed magnetic resonance images (MRI) of muscle injuries experienced by athletes during the Tokyo Olympic Games and found that when muscle injuries were characterized by torn fibers extending to the tendon, athletes were often unable to finish their events. Muscle injuries can derail training and preparation, and when they occur during competition they can prevent athletes from showcasing the best of their abilities. A better understanding of different types of muscle injuries and their likely outcomes may help sports physicians to answer the question that is most prominent in the mind of an injured athlete—will I be able to continue?

    In a study published last month in the British Journal of Sports Medicine, a team that included several researchers from Tokyo Medical and Dental University (TMDU) took a closer look at the circumstances of injuries sustained by athletes during the 2020 Tokyo Olympic Games and examined whether injury characteristics could be linked to whether an athlete was able to finish competing or had to drop out.

    “When a muscle injury is experienced by an elite athlete during training or competition, they (and their medical team) are faced with the ultimate athlete’s dilemma—deciding whether to continue competing and if, in doing so, they risk further harm,” explains senior author Hideyuki Koga. “It is not an easy dilemma given that the chance to compete in the Olympic Games is often a once in a lifetime chance, so the hope is that our findings and those from future studies of sporting competitions will contribute information that can help athletes and their medical teams make informed decisions.”

    With data from a wide range of sports being included in the study the research team was able to uncover useful information towards their research question. Lead author Hiroki Katagiri says, “We found that the proportion of athletes who were unable to finish competing was significantly higher for athletes with muscle tears that extended to the tendon than for athletes with tears in the muscle belly or peripheral part of the injured muscle.”

    Such a wide data pool gives high quality information that helps us understant which types of muscle tears are more likely to prevent athletes from competing and this can be used to improve injury management or even injury prevention.

    So, it seems that there is more one type of photo finish in the Olympic Games. For an athlete who sustains a muscle injury, everything (hopes, dreams, and four years of training) may ride upon a single picture—an MRI.

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    The article, “Epidemiology of MRI-detected muscle injury in athletes participating in the Tokyo 2020 Olympic Games,” was published in the British Journal of Sports Medicine at DOI: 10.1136/bjsports-2022-105827

    Tokyo Medical and Dental University

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  • From grave to cradle: Collagen-induced gut cell reprogramming

    From grave to cradle: Collagen-induced gut cell reprogramming

    Newswise — Tokyo, Japan – Most cells have a pretty normal life: they’re born, they grow, they get old, and they die. But the Benjamin Buttons of the cellular world can go from old to young again in the right context. Now, researchers from Japan have identified a physical cue that sparks this change in cells in the human gut.

    In a study published this month in Inflammation and Regeneration, researchers from Tokyo Medical and Dental University (TMDU) have revealed that the accumulation of a thick, extracellular material called collagen at injured sites in the gut stimulates cellular reprogramming.

    When the intestine is injured, an inflammatory response occurs that is often associated with regeneration of the injured tissues. This process involves converting some mature intestinal cells back into fetal-like cells that can then generate new healthy tissue to repair the injured area.

    “We previously showed that deposition of collagen at the site of intestinal injury promotes the conversion of intestinal/colonic epithelial cells covering the wound bed towards fetal-like progenitors in mice,” says lead author of the study, Sakurako Kobayashi. “However, the detailed mechanism by which this occurs, and whether this process also occurs in humans, remained unclear.”

    To explore these questions, the researchers created collagen spheres, which are tiny balls of epithelial cells grown in purified collagen, from mouse and human intestinal cells. They then assessed gene expression in these spheres to clarify the mechanisms of inflammation-associated reprogramming.

    “The results showed that culturing in collagen induced the expression of inflammation-associated and fetal-like genes in both human and mouse intestinal cells,” explains Shiro Yui, senior author. “As previously reported, the YAP/TAZ-TEAD axis definitely plays a central role in the induction of this distinctive gene expression signature, but this time we identified the cooperative transcriptional activity of Fra1 and RUNX2 in the process, which hammers the gene network centered on Fibronectin.”

    Importantly, the representative genes that were activated in the human collagen spheres were also highly expressed in tissue samples taken from inflamed regions of the gut in patients with ulcerative colitis.

    “Taken together, our findings demonstrate that collagen has a significant influence on inflammation and cellular reprogramming in both mice and humans,” says Kobayashi.

    Given that some of the genes that were upregulated in the collagen spheres are also overexpressed in conditions such as colorectal cancer, it is possible that there is a link between the regenerative cascade and colorectal carcinogenesis. Thus, investigating the mechanisms of cell fate conversion using this model may enhance our understanding not only of how inflammation is influenced by the extracellular environment, but also how other disease processes occur in the gut.

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    The article, “Collagen type I‑mediated mechanotransduction controls epithelial cell fate conversion during intestinal inflammation,” was published in Inflammation and Regeneration at DOI: 10.1186/s41232-022-00237-3

    Tokyo Medical and Dental University

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  • Expanding the arsenal of drugs against COVID-19

    Expanding the arsenal of drugs against COVID-19

    Newswise — Tokyo, Japan – The ongoing COVID-19 pandemic, caused by the SARS-CoV-2 virus, has been devastating the entire world. While the vaccination program is advancing, drug treatments for COVID-19 are still highly important for those who become infected. Now, a team at Tokyo Medical and Dental University (TMDU), National Center for Global Health and Medicine (NCGM), Tohoku University, NCI/NIH, and Kumamoto University has designed and synthesized compounds that have the potential to be novel drugs targeting SARS-CoV-2.

    The SARS-CoV-2 virus contains an enzyme called the “main protease”, or Mpro, that cleaves other proteins encoded in the SARS-CoV-2 genome as part of viral activity and replication. Mpro is an important and appealing target for drugs treating COVID-19 because it is both essential for viral replication and very different from any human molecules, so drugs targeting Mpro are likely to have few side effects and be very effective.

    When testing a panel of compounds known to have inhibitory activity against SARS-CoV, the virus responsible for the 2002 SARS outbreak, the team identified a compound named 5h/YH-53 that showed some activity inhibiting SARS-CoV-2 Mpro, but was inefficient and unstable. Therefore, they used 5h as a starting point to develop other compounds with increased efficiency and stability. “Our strategy involved introducing fluorine atoms into the part of the molecule responsible for inhibiting Mpro to increase its binding affinity, as well as replacing a bond within 5h that is easily broken down by the liver with a different structure to increase biostability,” explains lead author Kohei Tsuji.

    “Of the compounds we developed, compound 3 showed high potency and was able to block SARS-CoV-2 infection in vitro without any viral breakthrough,” explains senior author Hirokazu Tamamura. “Compound 4, a derivative of compound 3 in which an easily broken-down amide bond had been replaced with a stable thioamide bond, also showed remarkable anti-SARS-CoV-2 activity.” Although compound 4 had lower Mpro inhibitory activity than compound 3, the increased stability meant that the overall activity of compound 4 was comparable to that of compound 3.

    When they tested these novel compounds on a variety of strains of SARS-CoV-2, compound 3 was as effective on mutant strains of the virus as on the ancestral Wuhan strain. Additionally, neither compound 3 or 4 showed any toxicity to cultured cells. These data suggest that these compounds show high potential as drug treatments for COVID-19.

    A repertory of drug choice is important for treating disease, and so the development of efficient drugs to target the novel SARS-CoV-2 virus is highly important. This work identifies two compounds as potential drugs, and further development of these compounds continues. It also proves the principle that easily broken-down amide bonds can be replaced with thioamide bonds in drug development to increase the stability of the resulting compounds. Taken together, this is an important advance in both the wider drug development field as well as for drugs to treat COVID-19.

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    The article, “Potent and Biostable Inhibitors of the Main Protease of SARS-CoV-2”, was published in iScience at DOI: 10.1016/j.isci.2022.105365

    Tokyo Medical and Dental University

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  • Remdesivir reduces COVID-19 mortality in a real-world setting

    Remdesivir reduces COVID-19 mortality in a real-world setting

    Newswise — Tokyo, Japan – The COVID-19 pandemic has led to an explosion of clinical research resulting in the development of a variety of vaccines and treatments, although the efficacy of some remains controversial. Now, researchers from Japan report that remdesivir, a drug whose effectiveness has been debated, appears to make a big difference in Japanese patients with COVID-19 who received corticosteroids in the ICU.

    In a study published in September in the Journal of Medical Virology, researchers from Tokyo Medical and Dental University (TMDU) have revealed that remdesivir can reduce mortality in Asian patients if administered shortly after they begin showing COVID-19 symptoms.

    Several studies have already shown that remdesivir can shorten recovery time in patients with COVID-19, although there are conflicting reports on whether the drug prevents patients from dying. In addition, previous trials did not focus on patients who required breathing support while in the ICU.

    “Given the inconsistent evidence regarding the survival benefit it confers, we sought to investigate the effectiveness of remdesivir in patients with COVID-19, who were admitted to an ICU in Japan,” says Mariko Hanafusa, first author of the study. “All of these patients were being treated with corticosteroids for pneumonia, and some were receiving mechanical assistance for breathing.” 

    The researchers analyzed the medical records of 168 patients with COVID-19 admitted to the ICU at TMDU Hospital between April 2020 and November 2021. The patients were divided into groups based on whether or not they were also treated with remdesivir.

    “The results showed a clear difference in patient survival based on when they received treatment with remdesivir,” states Takeo Fujiwara, senior author of the study. “In-hospital mortality rates were significantly lower in ICU patients who received remdesivir and corticosteroids within 9 days of symptom onset than in patients whose treatment with remdesivir started 10 or more days after they first developed symptoms.”

    A small number of patients experienced adverse events such as a rash, requiring them to stop taking remdesivir, while a greater proportion experienced acute kidney injury or liver injury but were able to continue treatment.

    “Our findings suggest that, at least in a largely Japanese patient population with severe to critical COVID-19, early treatment with remdesivir and corticosteroids is associated with decreased mortality,” says Hanafusa.

    Given the survival benefit demonstrated in this study, the time that has elapsed since symptom onset should be considered when using remdesivir to treat patients who are critically ill with COVID-19. The varying effectiveness of remdesivir at different time points may reflect increasing viral load and lung damage over time, and could help explain why the effectiveness of this drug remains controversial.

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    The article, “Effectiveness of remdesivir with corticosteroids for COVID-19 patients in intensive care unit: A hospital-based observational study,” was published in the Journal of Medical Virology at DOI: 10.1002/jmv.28168.

    Tokyo Medical and Dental University

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  • Promotion of cancer progression via extracellular vesicles

    Promotion of cancer progression via extracellular vesicles

    Newswise — Tokyo, Japan – The advent of cell phones, the internet, and various messaging platforms has allowed for faster and broader communication worldwide. But did you know that your body has its own complex communication system in the form of extracellular vesicles (EVs)? These small structures, which contain cellular “cargo” such as protein and nucleic acids, are secreted by cells and can travel throughout the body, influencing a variety of physiological and pathological processes. Recently, researchers in Japan have shed new light on the role of EVs in the progression of cancer.

    In a new study published in Inflammation and Regeneration, researchers led by Tokyo Medical and Dental University (TMDU) examined the effects of oral cancer cell-derived EVs in endothelial-mesenchymal transition (EndoMT). EndoMT is a process in which endothelial cells, or cells that line the blood vessels, lose their characteristics and take on properties of mesenchymal cells.

    While EndoMT occurs normally during embryonic development, it has also been shown to destabilize vascular structures such as blood vessels. In cancer, vascular destabilization may make it easier for cancer cells to enter and exit the bloodstream, thereby promoting metastasis. Previous research has shown that cancer cells release EVs that act to induce a similar process called epithelial-mesenchymal transition (EMT), thereby promoting tumor development. However, the effects of cancer cell EVs on EndoMT in normal vascular endothelial cells have not yet been elucidated. Therefore, the TMDU-led research team set out to characterize EVs released by oral cancer cells and to investigate the effects of these EVs on healthy vascular endothelial cells.

    “A signaling factor known as transforming growth factor-β (TGF-β) has been shown to induce EMT in cancer cells, so we began by investigating charactered changes of human oral cancer cells brought by TGF-β-induced EMT” says lead author Miho Kobayashi. “We found that oral cancer cells exposed to TGF-β released roughly three times as many EVs as those that were not exposed.”

    The research team next incubated human vascular endothelial cells with EVs from TGF-β-exposed cells or EVs from cells that were not exposed to TGF-β. RNA and protein analysis showed increased expression of mesenchymal cell markers and decreased expression of endothelial cell markers in vascular cells exposed to EVs secreted from cancer cells that were exposed to TGF-β.

    “The changes in endothelial and mesenchymal marker expression in the vascular cells indicated that EndoMT was induced by EVs from oral cancer cells in which EMT had occurred,” says lead author Kashio Fujiwara. Furthermore, evaluation of the effects of cancer cell-derived EVs on vascular stability in human vascular endothelial monolayer cultures showed that treatment with the EVs enhanced vascular destabilization.

    This research provides further understanding of the mechanisms involved in EndoMT and vascular instability, which may aid in the development of therapeutic treatments to disrupt cancer progression and metastasis. 

     

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    The article, “Transforming growth factor-β-induced secretion of extracellular vesicles from oral cancer cells evokes endothelial barrier instability via endothelial-mesenchymal transition,” was published in Inflammation and Regeneration at DOI: 10.1186/s41232-022-00225-7

    Tokyo Medical and Dental University

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