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Key Outcomes Observed in Three-Year Follow-Up Study Using the Werner Syndrome Registry | Aging-US administrator 9 Views • 2 years ago

Dr. Masaya Koshizaka from the Department of Endocrinology, Hematology, and Gerontology at Chiba University Graduate School of Medicine, details a research paper he co-authored that was published by Aging (Aging-US) in Volume 15, Issue 9, entitled, “Renal dysfunction, malignant neoplasms, atherosclerotic cardiovascular diseases, and sarcopenia as key outcomes observed in a three-year follow-up study using the Werner Syndrome Registry.”
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#aging #research #researchpaper #author #authorinterview #renal #cardiovasculardisease #sarcopenia #study #openaccess #openscience #peerreview #journal #publication

DOI - https://doi.org/10.18632/aging.204681

Corresponding authors - Masaya Koshizaka - overslope@chiba-u.jp, and Koutaro Yokote - kyokote@faculty.chiba-u.jp

Video transcription - https://aging-us.net/2023/06/0....9/behind-the-study-k

Abstract

Werner syndrome is an adult-onset progeria syndrome that results in various complications. This study aimed to clarify the profile and secular variation of the disease. Fifty-one patients were enrolled and registered in the Werner Syndrome Registry. Their data were collected annually following registration. A cross-sectional analysis at registration and a longitudinal analysis between the baseline and each subsequent year was performed. Pearson's chi-squared and Wilcoxon signed-rank tests were used. Malignant neoplasms were observed from the fifth decade of life (mean onset: 49.7 years) and were observed in approximately 30% of patients during the 3-year survey period. Regarding renal function, the mean estimated glomerular filtration rate calculated from serum creatinine (eGFRcre) and eGFRcys, which were calculated from cystatin C in the first year, were 98.3 and 83.2 mL/min/1.73 m2, respectively, and differed depending on the index used. In longitudinal analysis, the average eGFRcre for the first and fourth years was 74.8 and 63.4 mL/min/1.73 m2, showing a rapid decline. Secular changes in Werner syndrome in multiple patients were identified. The prevalence of malignant neoplasms is high, and renal function may decline rapidly. It is, therefore, necessary to carry out active and detailed examinations and pay attention to the type and dose of the drugs used.

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Keywords - aging, disease profile, long-term follow-up, malignant neoplasm, renal function, Werner syndrome

About Aging-US

Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways.

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Gorlin syndrome model with active GLI1 expression and higher sensitivity to SMO inhibitor administrator 5 Views • 2 years ago

Hajime made his first talk in the laboratory meeting in 2016.

Hajime Ikehara, Akihiro Umezawa 20160623091301

This study was published in Laboratory Investigation 2020 as an open access paper.
https://www.nature.com/articles/s41374-019-0346-2

ABSTRUCT
The hedgehog signaling pathway is a vital factor for embryonic development and stem cell maintenance. Dysregulation of its function results in tumor initiation and progression. The aim of this research was to establish a disease model of hedgehog-related tumorigenesis with Gorlin syndrome-derived induced pluripotent stem cells (GS-iPSCs). Induced neural progenitor cells from GS-iPSCs (GS-NPCs) shows constitutive high GLI1 expression and higher sensitivity to smoothened (SMO) inhibition compared to wild-type induced neural progenitor cells (WT-NPCs). The differentiation process from iPSCs to NPCs may have similarity in gene expression to Hedgehog signal related-carcinogenesis. Therefore, GS-NPCs may be useful for screening compounds to find effective drugs to control Hedgehog signaling activity.

INTRODUCTION
The hedgehog (Hh) signaling pathway plays an important role in embryogenesis and stem cell maintenance. Ectopic Hh signal up-regulation causes tumors such as basal cell carcinoma (BCC) and medulloblastoma. Hh signaling is also related to other malignancies such as breast cancer, pancreatic cancer, lung cancer, and prostate cancer. A lot of medications have been under research to establish treatment and prevention of Hh signaling pathway-related tumors. The Hh signaling pathway can be initiated by three ligands: desert hedgehog (DHH), Indian hedgehog(IHH) or sonic hedgehog (SHH). These proteins bind to the 12-pass transmembrane protein receptor PTCH1. Once ligand binding occurs, the PTCH1 receptor relieves its inhibitory action on smoothened (SMO), a 7-pass transmembrane G-protein-coupled signal transduction molecule, which then activates a signaling cascade resulting in the translocation of Gli transcription factors to the nucleus. In the absence of the ligand, SMO is normally localized in vesicles. When the pathway is activated, SMO localizes to the primary cilium on the cell membrane.

Gorlin syndrome (GS) or nevoid basal cell carcinoma syndrome (NBCCS; OMIM 109400) is a rare autosomal dominantly inherited disorder that is characterized by congenital anomalies and development of tumors such as basal cell carcinoma and medulloblastoma. GS is caused by mutations in the PTCH1 gene and is transmitted as an autosomal dominant trait with complete penetrance and variable expressivity. Haploinsufficiency of PTCH1 results in constitutive activation of the Hh signaling pathway. Multiple genes that influence embryogenesis and pluripotency are oncogenes that drive the development of tumors. Additionally, some mechanisms of tumorigenesis are similar to embryonic development. GS patients frequently develop medulloblastoma at a young age compared to patients with sporadic cases, because mutation of PTCH1 causes dysregulation of the Hh signaling pathway during development of the cerebellum, which can lead to medulloblastoma.

Ptch1+/- mice, an animal model of Gorlin syndrome, develop medulloblastoma in early life stages, and have BCC-like tumors in their skin from UV or radiation exposure. However, there are few reports of tumorigenesis models with human cells. Differences between human and other vertebrate hedgehog signaling pathways might make it difficult to precisely predict effects and side effects of a candidate drug to treat hedgehog pathway-related tumors.

Disease models using human induced pluripotent stem cells (iPSCs) have recently been described as a promising tool for the investigation of disease mechanisms and identification of new drugs. Cell functions with human cells and get organs that cannot be taken from live human body can now be analyzed to investigate the efficacy and safety of potential Hh signaling inhibitors. Vismodegib (CDC-044), inhibitor of SMO, is the first oral medicine that disrupts Hh pathway to be approved by the US Food and Drug Administration for treatment of advanced phase basal cell carcinoma in adults. But because of its many side effects, most of patients do not continue treatment27. Safer and more tolerable drugs are necessary.

In this study, we generated GS-iPSCs with a heterozygous mutation of PTCH1, and induced neural progenitor cells (NPCs) from GS-iPSCs. Neural progenitors from GS-iPSCs expressed GLI1, a downstream target gene of Hh signaling and exhibited sensitivity to Vismodegib, an SMO inhibitor. Induced neural progenitor cells from Gorlin syndrome iPSCs may therefore serve a good precancerous model for Hh related tumors.