Calmodulin enhances mTORC1 signaling by preventing TSC2-Rheb binding.

The mechanistic target of rapamycin complex 1 (mTORC1) functions as a master regulator of cell growth and proliferation. We previously demonstrated that intracellular calcium ion (Ca) concentration modulates the mTORC1 pathway via binding of the Ca sensor protein calmodulin (CaM) to tuberous sclerosis complex 2 (TSC2), a critical negative regulator of mTORC1. However, the precise molecular mechanism by which Ca/CaM modulates mTORC1 activity remains unclear.

Examining the NEUROG2-lineage and associated-gene expression in human cortical organoids.

Proneural genes are conserved drivers of neurogenesis across the animal kingdom. How their functions have adapted to guide human-specific neurodevelopmental features is poorly understood. Here, we mined transcriptomic data from human fetal cortices and generated from human embryonic stem cell (hESC)-derived cortical organoids (COs) to show that NEUROG1 and NEUROG2 are most highly expressed in basal neural progenitor cells, with pseudotime trajectory analyses indicating that NEUROG1-derived lineages predominate early and NEUROG2 lineages later.

Optimal dose of tranexamic acid in traumatic brain injury: Systematic review and network meta-analysis of randomized controlled trials.

Background: Tranexamic acid (TXA) has been used to treat traumatic brain injury (TBI); however, no definitive conclusions have been drawn regarding its effectiveness or dosage. This study evaluated the optimal TXA dose for treating TBI using a network meta-analysis (NMA).

Methods: Five databases were searched for peer-reviewed randomized controlled trials (RCTs) published from inception to May 2024.

Neurofilament Light Chain as a Biomarker of Global Cognition in Individuals With Possible Vascular Mild Cognitive Impairment.

Background: Neurofilament Light Chain (NfL) is a biomarker of axonal injury elevated in mild cognitive impairment (MCI) and Alzheimer's disease dementia. Blood NfL also inversely correlates with cognitive performance in those conditions. However, few studies have assessed NfL as a biomarker of global cognition in individuals demonstrating mild cognitive deficits who are at risk for vascular-related cognitive decline.

Association Between Acute Kidney Injury and the Trendelenburg Position Angle During Robot-assisted Radical Prostatectomy.

Background/aim: Robot-assisted radical prostatectomy (RARP) has been widely adopted as the standard treatment for localized prostate cancer. RARP is safer and results in better oncological control than conventional open total prostatectomy. However, it has also been reported that acute kidney injury (AKI) can be caused by the use of carbon dioxide pneumoperitoneum and a steep Trendelenburg position.

Age-dependent final size equation to anticipate mortality impact of COVID-19 in China.

Before reopening society in December 2022, China had not achieved sufficiently high vaccination coverage among people aged 80 years and older, who are vulnerable to severe infection and death owing to COVID-19. Suddenly ending the zero-COVID policy was anticipated to lead to substantial mortality. To investigate the mortality impact of COVID-19, we devised an age-dependent transmission model to derive a final size equation, permitting calculation of the expected cumulative incidence.

Genomic profiling of dedifferentiated endometrial carcinomas arising in the background of high-grade carcinoma: a targeted next-generation sequencing study.

Aims: Our understanding of dedifferentiated endometrial carcinoma (DEC), a rare and aggressive malignancy, mainly reflects undifferentiated carcinomas (UC) arising in the setting of low-grade endometrial cancer (DEC-LG). However, cases of UC arising in the setting of high-grade EC (DEC-HG) have been noted in the literature. Our knowledge of the genomics of DEC-HG is limited.

Host Expression Profiling From Diagnostic Coronavirus Disease 2019 Swabs Associates Upper Respiratory Tract Immune Responses With Radiologic Lung Pathology and Clinical Severity.

Background: COVID-19 presents with a breadth of symptomatology including a spectrum of clinical severity requiring intensive care unit (ICU) admission. We investigated the mucosal host gene response at the time of gold standard COVID-19 diagnosis using clinical surplus RNA from upper respiratory tract swabs.

Methods: Host response was evaluated by RNA-sequencing, and transcriptomic profiles of 44 unvaccinated patients including outpatients and in-patients with varying levels of oxygen supplementation were included.

Combined effect of early diagnosis and treatment on the case fatality risk of COVID-19 in Japan, 2020.

Japanese government initially enforced restrictions on outpatient attendances among febrile individuals suspected of having COVID-19, asking everyone to remain at home for at least 4 days from the onset of fever. This restriction was cancelled on 8 May 2020, and a new antiviral, remdesivir, was approved from 7 May 2020. To investigate how this policy change influenced the prognosis of people with COVID-19, we estimated the case fatality risk as a function of the date of illness onset from April to June 2020.

Mesonephric-like adenocarcinoma of the female genital tract: novel observations and detailed molecular characterisation of mixed tumours and mesonephric-like carcinosarcomas.

Aims: To report novel observations in five mesonephric-like adenocarcinomas (MLAs) of the female genital tract.

Methods And Results: We report two endometrial MLAs in association with endometrioid carcinoma and atypical hyperplasia and three (one endometrial, two ovarian) cases with a sarcomatoid component (mesonephric-like carcinosarcoma). Pathogenic KRAS mutations, which are characteristic of MLA, were identified in all cases although interestingly, in one of the mixed carcinomas, this was confined to the endometrioid component.

Epidemiological Associations between Rabies Vaccination and Dog Owner Characteristics.

Background: The annual rabies vaccination coverage in dogs among 47 prefectures in Japan has been reported to range from 42.3% to 92.4%, and the overall coverage has been steadily declining.

New Insights into the Regulation of mTOR Signaling via Ca-Binding Proteins.

Environmental factors are important regulators of cell growth and proliferation. Mechanistic target of rapamycin (mTOR) is a central kinase that maintains cellular homeostasis in response to a variety of extracellular and intracellular inputs. Dysregulation of mTOR signaling is associated with many diseases, including diabetes and cancer.

Effect of a systematic lung-protective protocol for COVID-19 pneumonia requiring invasive ventilation: A single center retrospective study.

The benefits of introducing a systematic lung-protective protocol for coronavirus disease 2019 (COVID-19) pneumonia requiring invasive ventilation in the intensive care unit (ICU) are unknown. Herein, we aimed to evaluate the clinical effects of introducing such a protocol in terms of mortality, duration of ventilation, and length of ICU stay. In this single-centre, retrospective, quality comparison study, we identified patients with COVID-19 pneumonia who received invasive ventilation in our ICU between February 2020 and October 2021.

PAXgene Fixation for Pancreatic Cancer: Implications for Molecular and Surgical Pathology.

Genomic profiling of pancreatic cancer using small core biopsies has taken an increasingly prominent role in precision medicine. However, if not appropriately preserved, nucleic acids (NA) from pancreatic tissues are known to be susceptible to degradation due to high intrinsic levels of nucleases. PAXgene fixation (PreAnalytix, Switzerland) represents a novel formalin-free tissue preservation method.

Multisite verification of the accuracy of a multi-gene next generation sequencing panel for detection of mutations and copy number alterations in solid tumours.

Molecular variants including single nucleotide variants (SNVs), copy number variants (CNVs) and fusions can be detected in the clinical setting using deep targeted sequencing. These assays support low limits of detection using little genomic input material. They are gaining in popularity in clinical laboratories, where sample volumes are limited, and low variant allele fractions may be present.

Delayed MRI Enhancement of Colorectal Cancer Liver Metastases Is Associated With Metastatic Mutational Profile.

Background/aim: Individual tumor genomics plays a key role in determining patient prognosis, response to chemotherapy and in guiding therapy. In prior studies, it was shown that the degree of late enhancement of colorectal liver metastases (CRCLM) target tumor enhancement (TTE) as seen on magnetic resonance imaging (MRI) was associated with overall survival. In order to better understand the relationship between MRI enhancement and survival, the aim of this study was to characterize genomic profiles of tumors clustered by MRI TTE, and investigate the association between TTE and genetic mutations.

An open-access future for Journal of Synchrotron Radiation - Editorial from the Main Editors and IUCr Journals Editor-in-Chief.

Discussing ’s forthcoming transition to open access.

Amino Acid-Mediated Intracellular Ca Rise Modulates mTORC1 by Regulating the TSC2-Rheb Axis through Ca/Calmodulin.

Mechanistic target of rapamycin complex 1 (mTORC1) is a master growth regulator by controlling protein synthesis and autophagy in response to environmental cues. Amino acids, especially leucine and arginine, are known to be important activators of mTORC1 and to promote lysosomal translocation of mTORC1, where mTORC1 is thought to make contact with its activator Rheb GTPase. Although amino acids are believed to exclusively regulate lysosomal translocation of mTORC1 by Rag GTPases, how amino acids increase mTORC1 activity besides regulation of mTORC1 subcellular localization remains largely unclear.

MiR-139 Induces an Interferon-β Response in Prostate Cancer Cells by Binding to RIG-1.

Background: We previously identified a panel of five miRNAs associated with prostate cancer recurrence and metastasis. Expression of one of the down-regulated miRNAs, miR-139-5p, was significantly associated with a lower incidence of biochemical recurrence and metastasis. Transcriptome profiling of miR-139-expressing prostate cancer cells revealed up-regulation of genes involved in interferon (IFN) stimulation.

MR-guided focused ultrasound liquid biopsy enriches circulating biomarkers in patients with brain tumors.

Background: Liquid biopsy is promising for early detection, monitoring of response, and recurrence of cancer. The blood-brain barrier (BBB) limits the shedding of biomarker, such as cell-free DNA (cfDNA), into the blood from brain tumors, and their detection by conventional assays. Transcranial MR-guided focused ultrasound (MRgFUS) can safely and transiently open the BBB, providing an opportunity for less-invasive access to brain pathology.

Mir-139 Regulates Autophagy in Prostate Cancer Cells Through Beclin-1 and mTOR Signaling Proteins.

Background/aim: We previously identified a panel of five miRNAs (including miR-139) associated with biochemical recurrence and metastasis in prostate cancer patients.

Materials And Methods: We examined miR-139 transfected PC3, DU145 and LNCaP cells by morphology as well as by cell-based assays, confocal microscopy and immunoblotting.

Results: We found that treatment of prostate cancer cells with miR-139 resulted in phenotypic changes characteristic of autophagic cells.

Amino acid-dependent control of mTORC1 signaling: a variety of regulatory modes.

The mechanistic target of rapamycin complex 1 (mTORC1) is an essential regulator of cell growth and metabolism through the modulation of protein and lipid synthesis, lysosome biogenesis, and autophagy. The activity of mTORC1 is dynamically regulated by several environmental cues, including amino acid availability, growth factors, energy levels, and stresses, to coordinate cellular status with environmental conditions. Dysregulation of mTORC1 activity is closely associated with various diseases, including diabetes, cancer, and neurodegenerative disorders.

CTNNB1 Mutations and Aberrant β-Catenin Expression in Ovarian Endometrioid Carcinoma: Correlation With Patient Outcome.

CTNNB1 mutations and aberrant β-catenin expression have adverse prognosis in endometrial endometrioid carcinoma, and recent evidence suggests a prognostic role of β-catenin in ovarian endometrioid carcinoma. Thus, we aimed to determine the prognostic value of the CTNNB1 mutational status, and its correlation with β-catenin expression, in a well-annotated cohort of 51 ovarian endometrioid carcinomas. We performed immunohistochemistry for β-catenin and developed an 11-gene next-generation sequencing panel that included whole exome sequencing of CTNNB1 and TP53.

Differentiated exophytic vulvar intraepithelial lesion: Clinicopathologic and molecular analysis documenting its relationship with verrucous carcinoma of the vulva.

Verruciform proliferations of the vulva unrelated to HPV infection are rare. The term differentiated exophytic vulvar intraepithelial lesion (DEVIL) was recently proposed for these lesions, which harbor recurrent PIK3CA mutations. It is still unclear whether DEVIL is related to verrucous carcinoma, a neoplasm characterized by persistence and local recurrence but nil risk of distant spread.