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Tag: Hiroshima University

  • Cancer drug combo slows tumor growth

    Cancer drug combo slows tumor growth

    Newswise — An international team of researchers has demonstrated that a combination of inhibitors may suppress tumor growth and prevent relapse in patients with certain cancers, including head and neck squamous cell carcinoma and lung adenocarcinoma. Their findings support the future development of innovative therapeutic approaches targeting these cancers.

    The team’s work is published in the journal Oncogene on August 17, 2023.

    Scientists know that in humans and other mammals, the Hippo signaling pathway plays a key role in the rapid increase of cells that occurs with cancers in the body. Yes-associated protein 1, or YAP, is a protein that is critical in regulating the progression of tumor growth, and it plays an important role in the beginning and spread of a variety of cancers. When the Hippo pathway is dysregulated, it triggers the activation of YAP and this contributes to head and neck squamous cell carcinoma. Both the Hippo pathway and YAP have attracted attention as signaling pathways that regulate cancer cell characteristics.

    Epidermal growth factor receptor, or EGFR, is a protein on cells that contributes to their growth. When a mutation occurs in the gene for EGFR, it can grow too much, leading to cancer. EGFR is frequently amplified and highly overexpressed in head and neck squamous cell carcinoma, and mutated and activated in lung adenocarcinoma. So the EGFR inhibitor, a drug that blocks the cancer’s growth, is used as a targeted therapy in fighting these cancers. 

    In earlier work, the research team clarified the mechanism by which EGFR activates YAP through the Hippo pathway. However, EGFR-targeted monotherapy has shown a low response rate. Based on this evidence, researchers believe that EGFR inhibitors may temporarily inactivate YAP, but when YAP is re-activated, it increases resistance to the EGFR inhibitors used to fight the cancer. Scientists do not yet fully understand how the YAP is re-activated. 

    The team focused their current study on AXL, a receptor-type tyrosine kinase. They set out to clarify the mechanism that causes the cancer cells’ resistance to EGFR inhibitors, specifically focusing on the novel regulatory mechanism of YAP by AXL. Receptor-type tyrosine kinases like AXL play an important role in cell processes. When it is working properly, AXL is mainly expressed in immune cells, and does the work of removing dead cells and controlling the duration of immune responses. But when AXL becomes dysregulated, they can contribute to cancers, including lung adenocarcinoma, acute leukemia, and head and neck squamous cell carcinoma.

    The team used comprehensive transcriptional analysis and in vitro experiments in their study. With this research, the team clarified that AXL stimulates YAP through a novel mechanism when AXL combines with EGFR. This combination activates YAP via the EGFR-LATS1/2 axis. LATS1/2, or large tumor suppressor kinases, are important members of the Hippo pathway. The team determined that the combination of AXL and EGFR inhibitors working together inactivates YAP and suppresses the viability of head and neck squamous cell carcinoma and lung adenocarcinoma cells.

    “The combination therapy targeting both EGFR and AXL or YAP simultaneously may effectively suppress tumor growth and prevent resistance and relapse in patients with EGFR-altered cancers, including head and neck squamous cell carcinoma and lung adenocarcinoma,” said Toshinori Ando, assistant professor at the Center of Clinical Oral Examination, Hiroshima University Hospital. 

    Looking ahead, the team plans to try to generate effective drugs that can target EGFR, AXL, and YAP. “We think that intrinsic YAP activation or acquired re-activation after EGFR-targeted therapy in head and neck squamous cell carcinoma and lung adenocarcinoma has not been clarified yet. We will continue the research,” said J. Silvio Gutkind, distinguished professor, Department of Pharmacology, University of California, San Diego. 

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  • Genetically Edited Eggs: Allergen-Free and Safe

    Genetically Edited Eggs: Allergen-Free and Safe

    Newswise — Researchers have developed a chicken egg that may be safe for people with egg white allergies. Chicken egg allergies are one of the most common allergies in children. Though most children outgrow this allergy by age 16, some will still have an egg allergy into adulthood. Egg white allergies can cause a variety of symptoms, including vomiting, stomach cramps, breathing problems, hives, and swelling and some people with egg white allergies are unable to receive certain flu vaccines.

    Using genome editing technology, researchers have produced an egg without the protein that causes egg white allergies. This protein, called ovomucoid, accounts for approximately 11% of all the protein in egg whites.

    Research detailing the food safety profile of this modified egg, called the OVM-knockout, was detailed in a paper published in Food and Chemical Toxicology in April 2023.

    “To use OVM-knockout chicken eggs as food, it is important to evaluate its safety as food. In this study, we examined the presence or absence of mutant protein expression, vector sequence insertion, and off-target effects in chickens knocked out with OVM by platinum transcription activator-like effector nucleases (TALENs),” said Ryo Ezaki, an assistant professor at the Graduate School of Integrated Sciences for Life at Hiroshima University in Hiroshima, Japan. TALENs are restriction enzymes that recognize specific DNA sequences and break or cut them.

    In order to develop the OVM-knockout eggs, researchers needed to detect and eliminate the ovomucoid protein in the egg whites. TALENs were engineered to target a piece of RNA called exon 1, which codes for specific proteins. The eggs produced from this technique were then tested to ensure there was no ovomucoid protein, mutant ovomucoid protein, or other off-target effects. The eggs had the desired frameshift mutation, which is a mutation created by inserting or deleting nucleotide bases in a gene, and none of them expressed mature ovomucoid proteins. Anti-ovomucoid and anti-mutant ovomucoid antibodies were used to detect any traces of the protein, but there was no evidence of ovomucoid in the eggs. This means that mutant ovomucoids could not create new allergens. This is an important step in determining the safety profile of the eggs.

    Other gene editing tools, such as CRISPR, tend to have off-target mutagenesis effects. This means that new mutations are prompted by the gene editing process. However, whole genome sequencing of the altered egg whites showed mutations, which were possibly off-target effects, were not localized to the protein-coding regions.

    “The eggs laid by homozygous OVM-knockout hens showed no evident abnormalities. The albumen contained neither the mature OVM nor the OVM-truncated variant,” said Ezaki. “The potential TALEN-induced off-target effects in OVM-knockout chickens were localized in the intergenic and intron regions. Plasmid vectors used for genome editing were only transiently present and did not integrate into the genome of edited chickens. These results indicate the importance of safety evaluations and reveal that the eggs laid by this OVM knockout chicken solve the allergy problem in food and vaccines.”

    Looking ahead, researchers will continue to verify the safety profile of the OVM-knockout eggs. Because some people are highly allergic to this specific protein, even small amounts of ovomucoid can cause a reaction. Researchers will need to perform additional immunological and clinical studies to determine the safety of the OVM-knockout eggs. At this time, researchers have determined that OVM-knockout eggs are less allergenic than standard eggs and can be safely used in heat-processed foods that patients with egg allergies can eat. “The next phase of research will be to evaluate the physical properties and processing suitability of OVM-knockout eggs, and to confirm their efficacy through clinical trials,” said Ezaki. “We will continue to conduct further research toward the practical application of allergy-reduced eggs.”

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    Other contributors include Tetsushi Sakuma, Mei Matsuzaki, Takashi Yamamoto, and Hiroyuki Horiuchi of the Graduate School of Integrated Sciences for Life at Hiroshima University and Daisuke Kodama, Ryou Sasahara, and Taichi Shiraogawa from the R&D Division of the Institute of Technology Solution at Kewpie Corporation in Tokyo Japan.

    The Japan Society for the Promotion of Science KAKENHI (19H03107, 19K22286) and JST COI Grant Number JPMJPF 2010 supported this research.

    About Hiroshima University

    Since its foundation in 1949, Hiroshima University has striven to become one of the most prominent and comprehensive universities in Japan for the promotion and development of scholarship and education. Consisting of 12 schools for undergraduate level and 5 graduate schools, ranging from natural sciences to humanities and social sciences, the university has grown into one of the most distinguished comprehensive research universities in Japan. English website: https://www.hiroshima-u.ac.jp/en

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  • Gum infection linked to increased risk of heart arrhythmia

    Gum infection linked to increased risk of heart arrhythmia

    Newswise — Periodontitis, a gum disease, can cause various dental problems such as bad breath, bleeding gums, and tooth loss. Additionally, research suggests it may also be linked to more serious health issues, such as those related to the heart.

    Team found a significant correlation between periodontitis and fibrosis scarring to an appendage of the heart’s left atrium that can lead to an irregular heartbeat called atrial fibrillation in a sample of 76 patients with cardiac disease. 

    “Periodontitis is associated with a long-standing inflammation, and inflammation plays a key role in atrial fibrosis progression and atrial fibrillation pathogenesis. Researcher hypothesized that periodontitis exacerbates atrial fibrosis. This histological study of left atrial appendages aimed to clarify the relationship between clinical periodontitis status and degree of atrial fibrosis.

    The left atrial appendages were surgically removed from the patients, and the researchers analyzed the tissue to establish the correlation between severity of the atrial fibrosis and severity of the gum disease. They found that the worse the periodontitis, the worse the fibrosis, suggesting that the inflammation of gums may intensify inflammation and disease in the heart. 

    Study provides basic evidence that periodontitis can aggravate atrial fibrosis and can be a novel modifiable risk factor for atrial fibrillation. According to researcher,for  improving other risk factors such as weight, activity levels, tobacco and alcohol use, periodontal care could aid in comprehensive atrial fibrillation management. However, she cautioned that this study did not establish a causal relationship, meaning that while gum disease and atrial fibrosis degrees of severity appear connected, researchers have not found that one definitively leads to the other. 

    While research suggests a connection between periodontitis and atrial fibrosis, further evidence is needed to establish a causal relationship and to determine if periodontal care can reduce fibrosis. The goal of the study is to confirm that periodontitis is a modifiable risk factor for atrial fibrillation and to encourage dental specialists to play a role in comprehensive atrial fibrillation management. Periodontitis is an easily modifiable risk factor with lower cost compared to other known atrial fibrillation risk factors, thus the results of this study could have a significant impact on the health of people worldwide.

    Next, the researchers said they hope to conduct future clinical trials to clarify if periodontal intervention reduces atrial fibrillation occurrence and improves patient outcomes. 

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  • Case study proposes framework for analyzing U.S.-China geo-political tensions in Indo-Pacific

    Case study proposes framework for analyzing U.S.-China geo-political tensions in Indo-Pacific

    Newswise — Social sciences and international relations experts at Hiroshima University in Japan have proposed a new framework for studying the immensely complex power dynamics between China and the U.S., and its allies bordering the Pacific Ocean – “hybrid balancing.” The concept evolved out of “hybrid warfare,” which was an outgrowth of the Cold War between the U.S. and the former Soviet Union, when war became more about public perception, trust in governments, and economic leverage than bullets and tanks.

    Since then, and especially since the invasion of Crimea by the Russian Federation in March 2014, hybrid warfare has been popularized to the extent that the concept has become a cornerstone of security studies worldwide, according to Assistant Professor Ryuta Ito of the Graduate School of Humanities and Social Sciences, who wrote and published the case study in peer-reviewed journal International Affairs in early November 2022.

    “Hybrid warfare has recently attracted scholarly attention,” Ito said. “Despite its importance, hybrid warfare research remains underdeveloped, as it sometimes falls into the trap of ‘simplistic hypothesis testing’, which focuses on narrowly defined military factors while downplaying the fundamentals of international politics (e.g. balancing and diplomacy). My recent article fills this gap by constructing a new theoretical concept called ‘hybrid balancing’ by introducing the essence of hybrid warfare into classical realism, based on the scientific realism in the philosophy of science as a meta-theoretical foundation.”

    Political scientists and international relations academics and analysts hope to better understand how China uses its vast social and economic influence across the Indo-Pacific region to maintain favorable trade conditions while also seeking to quell the proliferation of liberal Western cultural ideals. Geographically, the Indo-Pacific region extends from the Indian Ocean to the Pacific Ocean (especially the western Pacific): namely, from the eastern coast of Africa and the environs of Madagascar, through the waters around the Philippines and Indonesia between the two oceans, to the eastern edge of Oceania, Ito wrote in the case study. “Politically, since 2010, it has gradually established itself as a strategic concept in the foreign policy lexicon of some countries, particularly Australia, India, Japan, and the United States.”

    “Rather than being a new form of conflict, hybrid warfare is a strategy that the belligerent uses to advance its political goals on the battlefield by applying military force subversively,” Ito wrote, referencing a 2016 paper in International Affairs.

    The interest and urgency surrounding the study of hybrid warfare are growing in part because of the conflict between Ukraine and the Russian Federation. “As has been widely reported, the war in Ukraine has the potential to demonstrate costs and consequences of a powerful nation attempting to overtake a smaller, yet highly productive and resource-rich state such as Taiwan,” Ito said. “In the case of China and Taiwan, the stakes in an all-out military conflict would be on the orders of magnitude greater than what we’re seeing in Ukraine, so a conventional war is virtually unthinkable. However, hybrid balancing as I’ve described better encapsulates the ebb and flow of power in the Indo-Pacific.”

    What has emerged in the past decade in response to China’s hybrid balancing posturing is the “Free and Open Indo-Pacific (FOIP) Coalition,” which includes pro-democracy nations across the Indo-Pacific and led by economic heavyweights U.S., Japan, and Australia.

    “It is apparent to us that China is engaging in hybrid balancing in this region to counter the liberal democratic coalition advancing the FOIP strategy,” Ito said. “Further study is warranted as tensions across this economically crucial region continue to grow. Cases other than China’s use of hybrid warfare in the Indo-Pacific are needed to verify hybrid balancing more robustly. Since our article’s case-study is a plausibility probe, which aims not to test a theory but merely to illustrate it to show that the argument is sufficiently grounded in evidence to justify further research, the next step may be rigorous case-studies to confirm the logic of hybrid balancing.”

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    About Hiroshima University

    Since its foundation in 1949, Hiroshima University has striven to become one of the most prominent and comprehensive universities in Japan for the promotion and development of scholarship and education. Consisting of 12 schools for undergraduate level and 4 graduate schools, ranging from natural sciences to humanities and social sciences, the university has grown into one of the most distinguished comprehensive research universities in Japan.
    English website: https://www.hiroshima-u.ac.jp/en

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