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Background and Aims: The common genetic variant rs641738 C>T is a risk factor for metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction-associated steatohepatitis (MASH), including liver fibrosis, and is associated with decreased expression of the phospholipid-remodeling enzyme MBOAT7 (LPIAT1). However, whether restoring MBOAT7 expression in established metabolic dysfunction-associated steatotic liver disease dampens the progression to liver fibrosis and, importantly, the mechanism through which decreased MBOAT7 expression exacerbates MASH fibrosis remain unclear., Approach and Results: We first showed that hepatocyte MBOAT7 restoration in mice with diet-induced steatohepatitis slows the progression to liver fibrosis. Conversely, when hepatocyte-MBOAT7 was silenced in mice with established hepatosteatosis, liver fibrosis but not hepatosteatosis was exacerbated. Mechanistic studies revealed that hepatocyte-MBOAT7 restoration in MASH mice lowered hepatocyte-TAZ (WWTR1), which is known to promote MASH fibrosis. Conversely, hepatocyte-MBOAT7 silencing enhanced TAZ upregulation in MASH. Finally, we discovered that changes in hepatocyte phospholipids due to MBOAT7 loss-of-function promote a cholesterol trafficking pathway that upregulates TAZ and the TAZ-induced profibrotic factor Indian hedgehog (IHH). As evidence for relevance in humans, we found that the livers of individuals with MASH carrying the rs641738-T allele had higher hepatocyte nuclear TAZ, indicating higher TAZ activity and increased IHH mRNA., Conclusions: This study provides evidence for a novel mechanism linking MBOAT7-LoF to MASH fibrosis, adds new insight into an established genetic locus for MASH, and, given the druggability of hepatocyte TAZ for MASH fibrosis, suggests a personalized medicine approach for subjects at increased risk for MASH fibrosis due to inheritance of variants that lower MBOAT7., (Copyright © 2024 American Association for the Study of Liver Diseases.)

The three-drug anesthetic mixture (medetomidine, midazolam and butorphanol), developed as an injectable anesthetic for laboratory animals, has been verified from various perspectives and applied to mice and other laboratory animals. However, the effects of its storage conditions and periods on its efficacy have not yet been studied. This study investigated the mixture's efficacy after storage under various conditions (room temperature, 4°C and -20°C) for 1 and 2 years. Mice in all groups were induced into a stable anesthetic state for at least 15 min after administration. The mice recovered from the anesthetized state 35 min after administration of the antagonist. These findings demonstrate the mixture's stability under different storage conditions and durations, potentially improving laboratory mouse welfare.

Malaria rapid diagnostic tests (mRDTs) that detect histidine-rich protein 2 (HRP2) remain the mainstay of falciparum malaria diagnosis in Sub-Saharan Africa. Understanding their test characteristics when used for surveillance in asymptomatic populations is important. We explored the rate of false-positive and false-negative mRDT results among asymptomatic persons >5 years old screened for malaria at schools and clinics in the rural Bagamoyo District using 18S ribosomal RNA real-time polymerase chain reaction (qPCR) as the reference test. Among 5,966 persons screened using mRDTs, microscopy, and qPCR tests from 2018 to 2021, 14% (832) were mRDT-positive. Twelve percent of these (98/832) were negative by both microscopy and qPCR, with children overrepresented among those with false-positive mRDTs. Among those who were mRDT-negative, 22% (1,136/5,134) tested qPCR-positive, predominantly because of low-density parasitemia (92% had <100 p/µL by qPCR). Among mRDT-negative samples with >100 p/µL, we looked for evidence of hrp2 or histidine-rich protein 3 (hrp3) deletion using two methods, multiplexed qPCR and multiplex bead-based immunoassay. When sufficient parasite material existed for a reliable deletion assessment, 12/34 (35%) had evidence of hrp2/3 deletion by qPCR (nine hrp2-/3+ and three hrp2-/3-), and 20/52 (38%) had evidence of deletion by immunoassay. Only three isolates showed evidence of hrp2 deletion by both assays. In an area of low to moderate transmission in Tanzania, false-positive mRDTs are relatively common (12% of positive tests), and false-negative mRDTs are even more common (22% of negative tests), but hrp2/3 deletion causing false-negative mRDTs remains rare (<1% of negative tests).

Purpose: To analyze the frequency and predictive factors of the development of postoperative pectus excavatum and scoliosis in children who underwent surgery for cystic lung disease., Methods: This study examined patients who underwent surgery for cystic lung disease (open and thoracoscopic) between July 2000 and December 2018 with a > 3-year follow-up period. Lesion size, surgical outcomes, and subsequent musculoskeletal complications were compared between the open surgery and thoracoscopic surgery groups. Univariate and multivariate analyses were performed to identify predictive factors., Results: Overall, 90 patients (19 and 71 patients in the open and thoracoscopic groups, respectively) were included in this study. There was no significant difference in the incidence of pectus excavatum or scoliosis between open and thoracoscopic surgery; however, Haller's index and Cobb angle were significantly higher in the open surgery group. In the univariate analysis, neonatal surgery and lesion size were substantial predictors of musculoskeletal malformations., Conclusion: Postoperative musculoskeletal deformities emerge after surgical treatment for cystic lung disease, with thoracoscopic surgery showing advantages in selected dimensions. Neonatal surgery and lesion size are pivotal prognostic factors for musculoskeletal complications. Further corroborative multicenter studies are imperative to substantiate these findings and foster enhanced patient outcomes., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests., (© 2024. The Author(s).)

Background/aim: The five members of the mammalian muscarinic acetylcholine receptor family are encoded by the cholinergic receptor, muscarinic, 1-5 (CHRM1-5) genes. CHRM genes are incriminated in formation of various cancer types, but their roles in head and neck squamous cell carcinoma (HNSCC) are improperly understood. Aberrant epigenetic modifications of specific tumor-suppressor genes and oncogenes are known to promote cancer development. We aimed to analyze the connection between methylation of CHRM genes and HNSCC recurrence, with specific reference to human papillomavirus (HPV)-positive oropharyngeal carcinoma., Materials and Methods: We investigated the methylation state of CHRM1-CHRM5 genes expressed in 305 samples of primary HNSCCs by quantitative methylation-specific polymerase chain reaction. We explored associations between methylation of these genes and the clinicopathological characteristics of HNSCC (location of the tumor as well as recurrence) Results: We found 1.08±0.94 methylated genes per sample (range=0-5), with promoters of CHRM1-5 genes methylated in 85.9%, 47.5%, 10.2%, 17.7%, and 19.3%, respectively, of the evaluated samples. Methylation levels of CHRM2 were significantly raised in HNSCC samples compared to corresponding normal tissues (p<0.001). Although there was no significance of tumor location, analysis by Kaplan-Meier estimate and multivariate Cox proportional hazard methods showed that methylated CHRM2 was significantly associated with increased recurrence of HNSCC with HPV-positive oropharyngeal cancer., Conclusion: CHRM methylation status is associated with HNSCC pathogenesis., (Copyright © 2025 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)