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BACKGROUND AND AIM: The burden of cirrhosis and other chronic liver diseases has changed in recent years due to shifts in the contributing aetiologies. We estimated the burden of cirrhosis and other chronic liver diseases, including etiological and regional differences, across 204 countries and territories from 2010 to 2021. APPROACH AND RESULTS: We analysed temporal trends in the burden of cirrhosis and other chronic liver diseases utilising data from the Global Burden of Disease Study 2021. We estimated annual frequencies and age-standardised rates (ASRs) of incident cases, deaths and disability-adjusted life-years (DALYs) by sex, country, World Health Organisation region and its contributing aetiologies. In 2021, there were an estimated 58 417 006 incident cases, 1 425 142 deaths and 46 417 777 DALYs related to cirrhosis and other chronic liver diseases. From 2010 to 2021, there was a rise in age-standardised incidence rates (ASIRs) (APC: +0.35%) but age-standardised death rates (ASDRs) (APC: -1.74%) and age-standardised disability-adjusted life-years (ASDALYs) (APC: -1.85%) declined. Cirrhosis related to metabolic dysfunction-associated steatohepatitis (MASH) contributed to 48 310 981 incident cases in 2021 and was largely responsible for the overall increase in ASIRs from 2010 to 2021. Cirrhosis and other chronic liver diseases related to MASH were the only aetiology with a rise in ASIR (APC: +0.86%). Age-standardised deaths related to all aetiologies of cirrhosis and other chronic liver diseases declined during the study period. Age-standardised deaths and DALYs related to MASH increased in the Americas, unlike all other world regions where they declined or remained stable. CONCLUSIONS: Age-adjusted deaths related to cirrhosis and other chronic liver diseases are declining. However, the age-adjusted incidence of cirrhosis and other chronic liver diseases is increasing, driven by increases in the incidence of MASH.

BackgroundThe cause of liver disease is changing, but its impact on liver transplantation (LT) for hepatocellular carcinoma (HCC) in women and men is unclear. We performed a nationwide study to assess the prevalence and posttransplant survival outcomes of the various causes of liver disease in women and men with HCC.MethodsData were obtained from the United Network for Organ Sharing database from 2000 to 2022. Data related to the listing, transplant, waitlist mortality, and posttransplant mortality for HCC were extracted. The proportion of HCC related to the various causes of liver disease among LT candidates and recipients and posttransplant survival were compared between women and men.ResultsA total of 51 721 individuals (39 465 men, 12 256 women) with HCC were included. From 2000 to 2022, nonalcoholic steatohepatitis (NASH) was the fastest-growing cause of liver disease among female LT candidates with HCC (P

Abstract Introduction Granulomatous lesions are commonly encountered abnormalities in pulmonary pathology, and often pose a diagnostic challenge. We report an unusual case of granulomatous lung disease with uncommon characteristics, which developed following Epstein-Barr-virus-induced mononucleosis and new-onset systemic lupus erythematosus. We aim to highlight a diagnostic approach for the condition and to raise awareness of the possibility of it being related to the immunological reaction caused by Epstein-Barr virus infection. Case presentation A 36-year-old Japanese man, who had been diagnosed with Epstein-Barr-virus-induced infectious mononucleosis, new-onset systemic lupus erythematosus, and secondary Sjögren’s syndrome three weeks previously, presented to our facility with fever and diffuse pulmonary infiltrates. A computed tomography scan of the chest revealed multiple small nodules in both lungs. Fiberoptic bronchoscopy with bronchoalveolar lavage revealed lymphocytosis with predominance of T lymphocytes. A histological examination of a lung biopsy taken during video-assisted thoracic surgery showed randomly distributed tiny granulomatous lesions with infiltration of eosinophils. The differential diagnoses included hypersensitivity pneumonitis, sarcoidosis, and pulmonary involvement of Crohn’s disease, systemic lupus erythematosus, and Sjögren’s syndrome, but the clinical and pathological findings were not consistent with any of these. Our patient’s condition did not improve; therefore, prednisolone therapy was started because of the possibility of specific immunological reactions associated with Epstein-Barr virus infection. After steroid treatment, our patient showed radiological and clinical improvement. Conclusions To the best of our knowledge, this is the first case of a patient developing randomly distributed multiple granulomatous lung lesions with eosinophilic infiltrates after Epstein-Barr virus infection and systemic lupus erythematosus. On the basis of our data, we hypothesize that Epstein-Barr virus infection altered the immune response of our predisposed patient and contributed to the pathogenesis of the lung lesions. Our patient’s clinical response to steroid treatment was excellent.

Abstract Background Wee1 kinase plays a critical role in maintaining G2 arrest through its inhibitory phosphorylation of cdc2. In previous reports, a pyridopyrimidine molecule PD0166285 was identified to inhibit Wee1 activity at nanomolar concentrations. This G2 checkpoint abrogation by PD0166285 was demonstrated to kill cancer cells, there at a toxic highest dose of 0.5 μM in some cell lines for exposure periods of no longer than 6 hours. The deregulated cell cycle progression may have ultimately damaged the cancer cells. We herein report one of the mechanism by which PD0166285 leads to cell death in the B16 mouse melanoma cell line. Methods Tumor cell proliferation was determined by counting cell numbers. Cell cycle distribution was determined by flow cytometry. Morphogenesis analysis such as microtubule stabilization, Wee1 distribution, and cyclin B location were observed by immunofluorescence confocal microscopy. An immunoblot analysis of cdc2-Tyr15, cyclin D, E, p16, 21, 27, and Rb. A real-time PCR of the mRNA of cyclin D were completed. Results In our experiment, B16 cells also dramatically abrogated the G2 checkpoint and were found to arrest in the early G1 phase by treatment with 0.5 μM for 4 hours observed by flow cytometry. Cyclin D mRNA decreased within 4 hours observed by Real-time PCR. Rb was dephosphrylated for 24 hours. However, B16 cells did not undergo cell death after 0.5 μM treatment for 24 hours. Immnofluoscence microscopy showed that the cells become round and small in the morphogenesis. More interesting phenomena were that microtubule stabilization was blocked, and Wee1 distribution was restricted after treatment for 4 hours. Conclusion We analyzed the effect of Wee1 inhibitor PD0166285 described first by Wang in the G2 transition in the B16 melanoma cell line. The inhibitor PD0166285 abrogated G2/M checkpoint inducing early cell division. Moreover, we found that the treatment of cells with the inhibitor is related to microtubule stabilization and decrease in cyclin D transcription. These effects together suggest that Wee1 inhibitor may thus be a potentially useful anti-cancer therapy.

Abstract Background Nuclear genes determine the vast range of phenotypes that are responsible for the adaptive abilities of organisms in nature. Nevertheless, the evolutionary processes that generate the structures and functions of nuclear genes are only now be coming understood. The aim of our study is to isolate the alcohol dehydrogenase (Adh) genes in two distantly related legumes, and use these sequences to examine the molecular evolutionary history of this nuclear gene. Results We isolated the expressed Adh genes from two species of legumes, Sophora flavescens Ait. and Wisteria floribunda DC., by a RT-PCR based approach and found a new Adh locus in addition to homologues of the Adh genes found previously in legumes. To examine the evolution of these genes, we compared the species and gene trees and found gene duplication of the Adh loci in the legumes occurred as an ancient event. Conclusion This is the first report revealing that some legume species have at least two Adh gene loci belonging to separate clades. Phylogenetic analyses suggest that these genes resulted from relatively ancient duplication events.

Background: Robot-assisted thoracoscopic surgery has become prevalent as a feasible approach for anterior mediastinal tumor resections, while conventional open surgery, such as a median sternotomy, remains preferred for a combined resection of adjacent organs. However, an additional thoracotomy may be necessary when tumors extend into one hemithorax. This complex approach can cause significant damage to the osseous thoracic cage, increasing the risk of surgical morbidity especially in immunocompromised patients. Case presentation: A 77-year-old man presented with an anterior mediastinal thymoma measuring 71 mm, detected during an annual health check with suspected involvement of the left brachiocephalic vein and upper lobe of the left lung. The patient had a medical history of recurrent surgical site infections and fasciitis panniculitis syndrome requiring immunosuppressive therapy. To minimize any thoracic cage destruction, a multidisciplinary approach combining robotic surgery with open surgery according to vascular or pulmonary invasion was planned. The patient, initially placed in the supine position with the robot docked over the right side, underwent a thymic dissection, revealing a firm adhesion to the left brachiocephalic vein. The robot was then undocked, and a transmanubrial osteomuscular sparing approach was initiated, enabling a tumor dissection under the proximal and distal control of the left brachiocephalic vein. As invasion into the proximal upper pulmonary vein and extensive dorsal adhesions were observed, the patient was repositioned to the right lateral decubitus position, and a thoracoscopic left upper segmentectomy with adhesiolysis was performed, achieving an R0 resection. The patient was extubated on day 1 but required non-invasive ventilation until day 5. Mediastinitis, likely due to a sternal wire infection, developed on day 9, necessitating debridement, sternal wire removal, and negative pressure wound therapy. After 17 days of treatment, the infection subsided, allowing for a sequestrectomy and chest wall reconstruction with a pedicled pectoralis major myocutaneous flap. By avoiding a total sternotomy, the extent of the mediastinitis was localized, allowing for a limited sequestrectomy. Wound healing was satisfactory, with no recurrent infection at 12 months and minimal functional impairment. Conclusions: A multidisciplinary approach offers a feasible option for managing an invasive thymoma to minimize postoperative morbidity, particularly in immunocompromised patients. Preoperative surgical planning is essential for guiding intraoperative decision-making and ensuring optimal outcomes. [ABSTRACT FROM AUTHOR]

Toca 511, a retroviral replicating vector (RRV) encoding the yeast cytosine deaminase (yCD) prodrug activator gene, which mediates conversion of the prodrug 5-fluorocytosine (5-FC) to the anticancer drug 5-fluorouracil (5-FU), is currently being evaluated in Phase II/III clinical trials for glioma, and showing highly promising evidence of therapeutic activity. Here we evaluated RRV-mediated prodrug activator gene therapy as a new therapeutic approach for pancreatic ductal adenocarcinoma (PDAC). RRV spread rapidly and conferred significant cytotoxicity with prodrug in a panel of PDAC cells. Efficient intratumoral replication and complete inhibition of tumor growth upon 5-FC administration were observed in both immunodeficient and immunocompetent subcutaneous PDAC models. Biodistribution of RRV was highly restricted in normal tissues, especially in immunocompetent hosts. Tumor growth inhibition by Toca 511 followed by 5-FC was also confirmed in the orthotopic PDAC model. This study provides the first proof-of-concept for application of Toca 511 and Toca FC (extended release 5-FC) to the treatment of human PDAC, and provided support for inclusion of PDAC in a Phase I study evaluating Toca 511 in various systemic malignancies, (NCT02576665), which has recently been initiated.