Safety and efficacy of itacitinib, a selective JAK1 inhibitor, in advanced hepatocellular cancer: Phase 1b trial (JAKAL).

Overactivation of the JAK/STAT pathway is one of the drivers for the pathophysiology of hepatocellular carcinoma (HCC). We propose a Phase Ib study to evaluate the safety and efficacy of itacitinib, a selective JAK1 inhibitor, as a second-line treatment for patients with advanced or metastatic HCC.Twenty-five patients will receive 400 mg itacitinib orally daily, 28-day cycle.

Pediatric residency milestone performance is not predicted by the United States Medical Licensing Examination Step 2 Clinical Knowledge.

Objectives: This study aims to show whether correlation exists between pediatric residency applicants' quantitative scores on the United States Medical Licensing Exam Step 2 Clinical Knowledge examination and their subsequent performance in residency training based on the Accreditation Council for Graduate Medical Education Milestones, which are competency-based assessments that aim to determine residents' ability to work unsupervised after postgraduate training. No previous literature has correlated Step 2 Clinical Knowledge scores with pediatric residency performance assessed by Milestones.

Methods: In this retrospective cohort study, the United States Medical Licensing Exam Step 2 Clinical Knowledge Scores and Milestones data were collected from all 188 residents enrolled in a single categorical pediatric residency program from 2012 - 2017.

Aging disrupts the coordination between mRNA and protein expression in mouse and human midbrain.

Age-related dopamine (DA) neuron loss is a primary feature of Parkinson's disease. However, it remains unclear whether similar biological processes occur during healthy aging, albeit to a lesser degree. We therefore determined whether midbrain DA neurons degenerate during aging in mice and humans.

Adjunctive Brexpiprazole for Patient Life Engagement in Major Depressive Disorder: A Canadian, Phase 4, Open-Label, Interventional Study: Brexpiprazole d'appoint pour l'engagement dans la vie des patients souffrant de trouble dépressif majeur: une étude interventionnelle canadienne ouverte de phase 4.

Objectives: To characterize the effects of adjunctive brexpiprazole on patient life engagement and depressive symptoms in patients with major depressive disorder (MDD) using patient-reported outcomes.

Methods: An 8-week, Phase 4, open-label, interventional study was conducted at 15 Canadian trial sites between April 2021 and May 2022. Adult outpatients with MDD (at least moderately severe) and inadequate response to 1-2 antidepressants continued their current antidepressant and received oral adjunctive brexpiprazole 0.

Study protocol of LANTana: a phase Ib study to investigate epigenetic modification of somatostatin receptor-2 with ASTX727 to improve therapeutic outcome with [177Lu]Lu-DOTA-TATE in patients with metastatic neuroendocrine tumours, UK.

Introduction: Suitability for peptide receptor radionuclide therapy (PRRT) for neuroendocrine neoplasia (NENs) depends on presence of somatostatin receptor-2 (SSTR2) determined by [68Ga]Ga-DOTA-peptide-positron emission tomography (PET). Some patients have low or no uptake on [68Ga]Ga-DOTA-peptide-PET, precluding PRRT. The upstream promoter region of SSRT2 is methylated, with percentage of methylation correlating with SSTR2 expression.

Drosha-dependent microRNAs modulate FUS-mediated neurodegeneration in vivo.

Mutations in the Fused in Sarcoma (FUS) gene cause the familial and progressive form of amyotrophic lateral sclerosis (ALS). FUS is a nuclear RNA-binding protein involved in RNA processing and the biogenesis of a specific set of microRNAs. Here we report that Drosha and two previously uncharacterized Drosha-dependent miRNAs are strong modulators of FUS expression and prevent the cytoplasmic segregation of insoluble mutant FUS in vivo.

Population Pharmacokinetic Analysis of Brexpiprazole to Support its Indication and Dose Selection in Adolescents With Schizophrenia.

Due to the customary delay between medication approvals in adult and adolescent populations, adolescents with schizophrenia may receive off-label antipsychotic treatment, without empirically justified dosing recommendations. In order to accelerate pediatric drug development, the US Food and Drug Administration (FDA) released a general advice letter to sponsors permitting the effectiveness of atypical antipsychotics for the treatment of schizophrenia in adults to be extrapolated to adolescents based on a pharmacokinetic (PK) analysis to support dose selection, plus a safety study. The aim of the present article is to describe the population PK analysis that was submitted to the FDA to inform brexpiprazole dose selection in adolescents with schizophrenia.

SMN regulates GEMIN5 expression and acts as a modifier of GEMIN5-mediated neurodegeneration.

GEMIN5 is essential for core assembly of small nuclear Ribonucleoproteins (snRNPs), the building blocks of spliceosome formation. Loss-of-function mutations in GEMIN5 lead to a neurodevelopmental syndrome among patients presenting with developmental delay, motor dysfunction, and cerebellar atrophy by perturbing SMN complex protein expression and assembly. Currently, molecular determinants of GEMIN5-mediated disease have yet to be explored.

Signaling pathways driving ocular malignancies and their targeting by bioactive phytochemicals.

Ocular cancers represent a rare pathology. The American Cancer Society estimates that 3,360 cases of ocular cancer occur annually in the United States. The major types of cancers of the eye include ocular melanoma (also known as uveal melanoma), ocular lymphoma, retinoblastoma, and squamous cell carcinoma.

Assessing the Efficacy of Imiquimod Use in Patients With Persistent Locally Advanced Melanoma In Situ.

Background: The standard of care when treating melanoma in situ (MMIS) is an excision with at least 5 mm surgical margins.1 Some studies have suggested up to 9 mm margins to maximize local recurrence-free survival.2 This retrospective review aims to assess the efficacy of imiquimod as a topical treatment for persistently positive MMIS at the margins of prior excisions or where surgery is not an option.

PETAL protocol: a phase Ib study of pembrolizumab after transarterial chemoembolization in hepatocellular carcinoma.

Transarterial chemoembolization (TACE) is the treatment of choice for intermediate-stage hepatocellular carcinoma (HCC). Recent data suggest that TACE may boost the efficacy of anti-PD-1 immunotherapy. The authors present the trial protocol for PETAL, a phase Ib study, which will assess the safety and bioactivity of pembrolizumab, an anti-PD-1 antibody, following TACE in HCC.

Discriminatory Changes in Circulating Metabolites as a Predictor of Hepatocellular Cancer in Patients with Metabolic (Dysfunction) Associated Fatty Liver Disease.

Introduction: The burden of metabolic (dysfunction) associated fatty liver disease (MAFLD) is rising mirrored by an increase in hepatocellular cancer (HCC). MAFLD and its sequelae are characterized by perturbations in lipid handling, inflammation, and mitochondrial damage. The profile of circulating lipid and small molecule metabolites with the development of HCC is poorly characterized in MAFLD and could be used in future studies as a biomarker for HCC.

Rare Presentation of Umbilical Condyloma.

Syphilis is associated with 3 stages of infection-primary, secondary, and tertiary-each with their own associated clinical findings. Secondary syphilis manifests with condyloma lata and other cutaneous findings, and typically occurs several months after the initial infection. Condyloma lata are primarily found in the genital area, but may also be found in other locations such as the umbilicus, axilla, and neck.

ArTisaN trial protocol: a single Centre, open-label, phase II trial of the safety and efficacy of TheraSphere selective internal radiation therapy (SIRT) in the treatment of inoperable metastatic (liver) neuroendocrine neoplasia (NENs).

Background: Neuroendocrine neoplasias (NENs) are a rare type of malignancy that arise from the cells of the neuroendocrine system. Most patients present with advanced, unresectable disease, typically with metastases to the liver. The presence of liver metastases dictates prognosis and there has been a number of studies investigating therapies that reduce the burden of liver disease.

DDX17 is involved in DNA damage repair and modifies FUS toxicity in an RGG-domain dependent manner.

Mutations in the RNA binding protein, Fused in Sarcoma (FUS), lead to amyotrophic lateral sclerosis (ALS), the most frequent form of motor neuron disease. Cytoplasmic aggregation and defective DNA repair machinery are etiologically linked to mutant FUS-associated ALS. Although FUS is involved in numerous aspects of RNA processing, little is understood about the pathophysiological mechanisms of mutant FUS.

Learning needs, preferred learning methods and learning challenges of first five general practitioners in NHS Scotland: a qualitative study.

Objectives: To identify the learning needs and preferred learning methods of First5 general practitioners (GPs) in National Health Service (NHS) Scotland.

Design: Qualitative research study using grounded theory methods. First5 GPs were interviewed in small focus groups or individual interviews in-person, or over the telephone depending on their preference.

Loss of function mutations in GEMIN5 cause a neurodevelopmental disorder.

GEMIN5, an RNA-binding protein is essential for assembly of the survival motor neuron (SMN) protein complex and facilitates the formation of small nuclear ribonucleoproteins (snRNPs), the building blocks of spliceosomes. Here, we have identified 30 affected individuals from 22 unrelated families presenting with developmental delay, hypotonia, and cerebellar ataxia harboring biallelic variants in the GEMIN5 gene. Mutations in GEMIN5 perturb the subcellular distribution, stability, and expression of GEMIN5 protein and its interacting partners in patient iPSC-derived neurons, suggesting a potential loss-of-function mechanism.

PRIME-HCC: phase Ib study of neoadjuvant ipilimumab and nivolumab prior to liver resection for hepatocellular carcinoma.

Background: After liver resection (LR), patients with hepatocellular cancer (HCC) are at high risk of recurrence. There are no approved anti-cancer therapies known to affect such risk, highlighting the acute need for novel systemic therapies to control the probability of disease relapse. Immunotherapy is expanding as a novel treatment option for HCC.

Smallholder perceptions of land restoration activities: rewetting tropical peatland oil palm areas in Sumatra, Indonesia.

Unlabelled: The Indonesian government committed to restoring over 2 million ha of degraded peatland by the end of 2020, mainly to reduce peat fires and greenhouse gas emissions. Although it is unlikely the government will meet this target, restoration projects are still underway. One restoration strategy involves blocking peatland drainage canals, but the consequences of this for smallholder farmers whose livelihoods are dependent on agriculture are unclear.

Older Adult Productive Activity Participation Using the National Health and Aging Trends Study.

This study aims to characterize factors related to productive activity participation among community-dwelling older adults. Cross-sectional analyses using data from the National Health and Aging Trends Study were used to calculate weighted frequencies representative of the U.S.

How to transition to reduced-meat diets that benefit people and the planet.

Overwhelming evidence shows that overconsumption of meat is bad for human and environmental health and that moving towards a more plant-based diet is more sustainable. For instance, replacing beef with beans in the US could free up 42% of US cropland and reduce greenhouse gas emissions by 334 mmt, accomplishing 75% of the 2020 carbon reduction target. We summarise the evidence on how overconsumption of meat affects social, environmental and economic sustainability.