Current Strategies and Future Dimensions in the Development of KRAS Inhibitors for Targeted Anticancer Therapy.

KRAS is a proto-oncogene that is found to be mutated in 15% of all metastatic cancers with high prevalence in pancreatic, lung, and colorectal cancers. Additionally, patients harboring KRAS mutations respond poorly to standard cancer therapy. As a result, KRAS is seen as an attractive target for targeted anticancer therapy.

Granting Permission: Toward Embracing Grief.

Grief, unavoidable and often excruciating, is rarely sufficiently acknowledged or supported in Western society. It is not granted to exist without barriers. By considering and evaluating grief experiences through the lens of their access to , clinicians can collectively imagine and promote inclusivity in grief.

Enhanced recovery after surgery (ERAS) in stoma reversal surgery: a systematic review and meta-analysis.

Stoma reversal surgery is known for relatively high complication rates. While Enhanced Recovery After Surgery (ERAS) protocols are extensively validated for colorectal surgery, their use in stoma reversal remains underexplored. This systematic review and meta-analysis evaluates clinical outcomes of stoma reversal surgery under ERAS protocols compared to standard care (SC) practices.

Negative Symptoms in Schizophrenia: An Update on Research Assessment and the Current and Upcoming Treatment Landscape.

The negative symptoms of schizophrenia include diminished emotional expression, avolition, alogia, anhedonia, and asociality, and due to their low responsiveness to available treatments, are a primary driver of functional disability in schizophrenia. This narrative review has the aim of providing a comprehensive overview of the current research developments in the treatment of negative symptoms in schizophrenia, and begins by introducing the concepts of primary, secondary, prominent, predominant, and broadly defined negative symptoms. We then compare and contrast commonly used research assessment scales for negative symptoms and review the evidence for the specific utility of widely available off-label and investigational treatments that have been studied for negative symptoms.

Kinetically-derived maximal dose (KMD) confirms lack of human relevance for high-dose effects of octamethylcyclotetrasiloxane (D4).

The kinetically-derived maximal dose (KMD) is defined as the maximum external dose at which kinetics are unchanged relative to lower doses, e.g., doses at which kinetic processes are not saturated.

PhyloMix: Enhancing microbiome-trait association prediction through phylogeny-mixing augmentation.

Motivation: Understanding the associations between traits and microbial composition is a fundamental objective in microbiome research. Recently, researchers have turned to machine learning (ML) models to achieve this goal with promising results. However, the effectiveness of advanced ML models is often limited by the unique characteristics of microbiome data, which are typically high-dimensional, compositional, and imbalanced.

Sex Differences in Melanoma Survival-a GEM study.

Sex differences in melanoma are prominent, with females having a significant survival advantage. However, it is unclear why we see this survival advantage. Here we investigate the relationship between sex, clinicopathologic variables, and melanoma specific survival in 1,753 single primary melanomas from patients in the GEM study.

Making the Case for an International Childhood Cancer Data Partnership.

Childhood cancers are a heterogeneous group of rare diseases, accounting for less than 2% of all cancers diagnosed worldwide. Most countries, therefore, do not have enough cases to provide robust information on epidemiology, treatment, and late effects, especially for rarer types of cancer. Thus, only through a concerted effort to share data internationally will we be able to answer research questions that could not otherwise be answered.

Identification of significant SNPs for yield-related salt tolerant traits in rice through genome-wide association analysis.

Rice salt tolerance is highly anticipated to meet global demand in response to decreasing farmland and soil salinization. Therefore, dissecting the genetic loci controlling salt tolerance in rice for improving productivity is of utmost importance. Here, we evaluated six salt-tolerance-related traits of a biparental mapping population comprising 280 F2 rice individuals (Oryza sativa L.

Preliminary Evidence for Perturbation-Based tACS-EEG Biomarkers of Gamma Activity in Alzheimer's Disease.

Background: Alzheimer's disease (AD) is characterized by impaired inhibitory circuitry and GABAergic dysfunction, which is associated with reduced fast brain oscillations in the gamma band (γ, 30-90 Hz) in several animal models. Investigating such activity in human patients could lead to the identification of novel biomarkers of diagnostic and prognostic value. The current study aimed to test a multimodal "Perturbation-based" transcranial Alternating Current Stimulation-Electroencephalography (tACS)-EEG protocol to detect how responses to tACS in AD patients correlate with patients' clinical phenotype.

Crosslinked Versus Non-Crosslinked Resorbable Collagen Membranes for Periodontal Regeneration: A Multicenter, Randomized, Double-Blind, Non-Inferiority Clinical Trial.

Aim: This study aimed to evaluate and compare the results of combination therapy involving bone grafting and two different resorbable collagen membranes in 1-, 2- and 3-wall infrabony defects.

Methods: A total of 174 patients with infrabony defects (≥ 7 mm periodontal probing depth) were randomized to receive deproteinized bovine bone mineral (DBBM) with either a native porcine non-crosslinked collagen membrane (N-CM, control, n = 87) or a novel porcine crosslinked collagen membrane (C-CM, test, n = 87). Clinical parameters, including periodontal probing depth (PPD), clinical attachment level (CAL), and gingival recession (GR), were recorded at baseline, 12 weeks, and 24 weeks.

Insomnia Prevalence and Correlates in Cancer Patients Undergoing Treatment.

Background: Insomnia is the most common sleep disturbance among cancer patients undergoing active treatment. If untreated, it is associated with significant physical and psychological health consequences. Prior efforts to determine insomnia prevalence and correlates have primarily assessed patients in clinical trials, in limited disease groups, and excluding important patient subgroups.

High-Frequency Ultrasound for Detecting Periodontal Inflammation: A Preclinical Diagnostic Accuracy Study.

Aim: Ultrasonography (US) has shown accuracy in imaging healthy periodontium. This study aims to evaluate the feasibility and accuracy of US for estimating dimensions of inflamed periodontium induced by ligature and bacteria.

Methods: Periodontal tissues of maxillary as well as mandibular premolars and molars in six female mini pigs were treated with ligature and three strains of bacteria for 4-10 weeks.

5-FU Weakens Defensive Functions of the Junctional Epithelium.

Aim: To investigate additional factors contributing to the pathophysiology of chemotherapy-induced oral mucositis and periodontitis beyond the systemic immune suppression caused by the chemotherapeutic agent 5-Fluorouracil (5-FU).

Methods: 5-Fluorouracil was topically delivered to the non-keratinized, rapidly proliferating junctional epithelium (JE) surrounding the dentition, and acts as an immunologic and functional barrier to bacterial ingression. Various techniques, including EdU incorporation, quantitative immunohistochemistry (qIHC), histology, enzymatic activity assays, and micro-computed tomographic (μCT) imaging, were employed to analyze the JE at multiple time points following topical 5-FU treatment.

Multiclass Steroid Profiling in Short-Finned Pilot Whale Blubber Using Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS).

Rationale: Wildlife scientists are quantifying steroid hormones in a growing number of tissues and employing novel methods that must undergo validation before application. This study tested the accuracy and precision of liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods for use on blubber samples from short-finned pilot whales (Globicephala macrorhynchus). We expanded upon a method for corticosteroid quantification by adding analytes and optimizing internal standard (IS) application.

Measuring the impact of a catchment area surveillance tool on cancer center adopters.

Background: The University of Kentucky Markey Cancer Center developed the data gathering and visualization platform Cancer InFocus (CIF) as a solution for cancer center catchment area surveillance. CIF was released in June 2022 and made available for use to other institutions through a no-cost licensing agreement. The purpose of this study was to evaluate the impact CIF has had on cancer centers since its release.

Biomechanical Properties of Meniscal Repair Versus Meniscectomy for Horizontal Meniscal Tears: A Systematic Review.

Background: Limited biomechanical evidence exists describing how horizontal meniscus tears (HMTs), meniscal repair (MR), and meniscectomy alter the knee's biomechanical environment.

Purpose: To evaluate changes in knee contact mechanics following HMTs, MR, and meniscectomy.

Study Design: Systematic review; Level of evidence, 5.

The Continuous Fragility Index of Statistically Significant Findings in Studies Based on High Levels of Evidence Comparing Interventions for Femoroacetabular Impingement Syndrome.

Background: Critical analysis of studies with high level of evidence has relied on the significance set by the reported values. However, this strategy steers readers toward categorical interpretation of the data; therefore, a more comprehensive approach of data analysis is warranted. The continuous fragility index (CFI) allows for frailty interpretation of any given study's continuous outcome results.

A Drosophila cardiac myosin increases jump muscle stretch activation and shortening deactivation.

Stretch activation (SA), a delayed increase in force production following rapid muscle lengthening, is critical to the function of vertebrate cardiac muscle and insect asynchronous indirect flight muscle (IFM). SA enables or increases power generation in muscle types used in a cyclical manner. Recently, myosin isoform expression has been implicated as a mechanism for varying the amplitude of SA in some muscle types.

Intersection of rare pathogenic variants from TCGA in the All of Us Research Program v6.

Using rare cancer predisposition alleles derived from The Cancer Genome Atlas (TCGA) and high cancer prevalence (14% of participants) in All of Us (version 6), we assessed the impact of these rare alleles on cancer occurrence in six broad groups of genetic similarity provided by All of Us: African/African American (AFR), Admixed American/Latino (AMR), East Asian (EAS), European (EUR), Middle Eastern (MID), or South Asian (SAS). We observed that germline susceptibility to cancer consistently replicates in EUR-like participants but less so in other participants. We found that All of Us participants from the EUR (p = 1.

Characterization of a novel conditional knockout mouse model to assess efficacy of mRNA therapy in the context of severe ornithine transcarbamylase deficiency.

Ornithine transcarbamylase deficiency (OTCD) is the most common urea cycle disorder, characterized by hyperammonemia and accompanied by a high unmet patient need. mRNA therapies have been shown to be efficacious in hypomorphic Sparse-fur abnormal skin and hair (Spf-ash) mice, a model of late-onset disease. However, studying the efficacy of ornithine transcarbamylase (OTC) mRNA therapy in traditional knockout mice, a model for severe early-onset OTCD, is hampered by the rapid lethality of the model, and poor lipid nanoparticle (LNP) uptake into neonatal mouse liver.

Efficient Gene Delivery Admitted by small Metabolites Specifically Targeting Astrocytes in the Mouse Brain.

The development of efficient and targeted methods for delivering DNA in vivo has long been a major focus of research. In this study, we introduce a gene Delivery approach Admitted by small Metabolites, named gDAM, for the efficient and targeted delivery of naked DNA into astrocytes in the adult brains of mice. gDAM utilizes a straightforward combination of DNA and small metabolites, including glycine, L-proline, L-serine, L-histidine, D-alanine, Gly-Gly, and Gly-Gly-Gly, to achieve astrocyte-specific delivery of naked DNA, resulting in transient and robust gene expression in these cells.

Artificial enforcement of the unfolded protein response (UPR) reduces disease features in multiple preclinical models of ALS/FTD.

Amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia (FTD) are part of a spectrum of diseases that share several causative genes, resulting in a combinatory of motor and cognitive symptoms and abnormal protein aggregation. Multiple unbiased studies have revealed that proteostasis impairment at the level of the endoplasmic reticulum (ER) is a transversal pathogenic feature of ALS/FTD. The transcription factor XBP1s is a master regulator of the unfolded protein response (UPR), the main adaptive pathway to cope with ER stress.

Psychotic-Spectrum Disorders With Comorbid Anxiety are Predisposing Factors for Parkinson's Disease in a Case-Control Study.

Background: Multiple studies have demonstrated associations between psychiatric conditions and Parkinson's disease (PD) development; fewer have examined psychotic-spectrum disorders and PD development.

Objective: The objective was to assess the prevalence of psychotic-spectrum disorders with and without depression and anxiety preceding a PD diagnosis.

Methods: In this retrospective, case-control study of adults > 60 years of age, cases were identified by PD diagnosis and controls were identified in a 3:1 ratio by ambulatory encounter from 2015 to 2020.