A temporal model of tumor-immune dynamics during the metastatic progression of high-grade serous ovarian cancer.

Patients with high-grade serous ovarian cancer (HGSOC) typically present with widespread metastasis, obscuring a temporal understanding of tumor-immune dynamics. To address this, we perform multi-site global proteomics alongside matched immunohistochemistry (IHC) for CD4⁺ and CD8⁺ tumor-infiltrating lymphocytes (TILs) in patient samples. We order the protein expression profiles using an unbiased pseudotime analysis, recapitulating clinical observations of metastatic progression, and providing a framework to explore tumor-immune dynamics from localized to metastatic disease.

Quantitative Protein Expression of Antibody-Drug Conjugate Targets in EGFR Mutated and Wild-type Non-Small Cell Lung Cancer.

Purpose: Antibody-drug conjugates (ADC) are a promising approach for the management of patients with non-small cell lung cancer (NSCLC). However, only a small subset of patients derive benefit from these therapies.

Experimental Design: We used quantitative immunofluorescence assays to measure the levels of four ADC target proteins (HER2, TROP2, HER3, and EGFR) in three NSCLC tissue microarray cohorts stratified according to EGFR mutation [EGFR mutated (n = 83), EGFR wild-type (n = 128), and EGFR unknown (n = 232)].

Discovery of VU0467319: an M Positive Allosteric Modulator Candidate That Advanced into Clinical Trials.

Herein we detail the of VU0467319 (VU319), an M Positive Allosteric Modulator (PAM) clinical candidate that successfully completed a Phase I Single Ascending Dose (SAD) clinical trial. VU319 () is a moderately potent M PAM (M PAM EC = 492 nM ± 2.9 nM, 71.

Enhancing the natural absorbing capacity of rivers to restore their resilience.

Resilience, which can also be described as absorbing capacity, describes the amount of change that a system can undergo in response to disturbance and maintain a characteristic, self-sustaining regime of functions, processes, or sets of feedback loops. Rivers exhibit varying levels of resilience, but the net effect of industrialized anthropogenic alteration has been to suppress river resilience. As changing climate alters the inputs to rivers and human modification alters the morphology and connectivity of rivers, restoration increasingly considers how to enhance resilience.

Fusobacterium nucleatum infection modulates the transcriptome and epigenome of HCT116 colorectal cancer cells in an oxygen-dependent manner.

Fusobacterium nucleatum, a gram-negative oral bacterium, has been consistently validated as a strong contributor to the progression of several types of cancer, including colorectal (CRC) and pancreatic cancer. While previous in vitro studies have shown that intracellular F. nucleatum enhances malignant phenotypes such as cell migration, the dependence of this regulation on features of the tumor microenvironment (TME) such as oxygen levels are wholly uncharacterized.

The Rising Tide of Point-of-Care Ultrasound (POCUS) in Medical Education: An Essential Skillset for Undergraduate and Graduate Medical Education.

As point-of-care ultrasound (POCUS) becomes an integral component of healthcare, both undergraduate and graduate medical POCUS education is urgently necessary in curricula. Despite the apparent need of POCUS curricula, there remains a lingering question: Are there evidence-based benefits to POCUS training in undergraduate and/or graduate medical education settings? Qualitative review of research was conducted to identify common themes for benefits of POCUS and the requirements and/or characteristics for effective POCUS educational curricula. Results for undergraduate medical education were separated into preclinical and clinical education.

Anatomical Considerations for Gallbladder Sonography: A Cross-Sectional Study of CT Imaging by BMI Group.

Objective The purpose of this study was to establish an association between the body mass index (BMI) group and anatomical gallbladder position to aid novices in gallbladder sonography. Methods This was a cross-sectional, Strengthening the Reporting of Observational Studies in Epidemiology (STROBE)-compliant study that examined the association between gender and the BMI group with quantitative gallbladder position measurements from computed tomography (CT) scans. Results A quantitative analysis determined that the gallbladder was positioned relatively higher and oriented more horizontally within the abdomen of individuals with obese BMI than those with normal BMI (p < 0.

Targeted Quantitative Mass Spectrometry Analysis of Protein Biomarkers From Previously Stained Single Formalin-Fixed Paraffin-Embedded Tissue Sections.

Formalin-fixed, paraffin-embedded tissues represent a majority of all biopsy specimens commonly analyzed by histologic or immunohistochemical staining with adhesive coverslips attached. Mass spectrometry (MS) has recently been used to precisely quantify proteins in samples consisting of multiple unstained formalin-fixed, paraffin-embedded sections. Here, we report an MS method to analyze proteins from a single coverslipped 4-μm section previously stained with hematoxylin and eosin, Masson trichrome, or 3,3'-diaminobenzidine-based immunohistochemical staining.

Open-Source Ultrasound Trainer for Healthcare Professionals: A Pilot Randomized Control Trial.

Introduction: This technical report describes the development of a high-fidelity, open-source ultrasound trainer and showcases its abilities through a proof-of-concept, pilot randomized control trial. The open-source ultrasound trainer (OSUT) aims to enhance anatomical visualization during ultrasound education. The OSUT can attach to any ultrasound transducer, uses minimal hardware, and is able to be used during live patient ultrasound examinations.

Diastereo- and enantioselective synthesis of compounds with a trifluoromethyl- and fluoro-substituted carbon centre.

Molecules that contain one or more fluorine atoms are crucial to drug discovery. There are protocols available for the selective synthesis of different organofluorine compounds, including those with a fluoro-substituted or a trifluoromethyl-substituted stereogenic carbon centre. However, approaches for synthesizing compounds with a trifluoromethyl- and fluoro-substituent stereogenic carbon centre are far less common.

Contrast-Enhanced Ultrasound Tumor Therapy With Abdominal Imaging Transducer.

A diagnostic ultrasound machine add-on module (AOM) was created to enable an off-the-shelf abdominal imaging transducer to perform contrast-enhanced therapeutic ultrasound. The AOM creates plane-wave ultrasound through an abdominal imaging transducer targeting intravascular microbubbles within tumors. This therapeutic antivascular ultrasound (AVUS) causes heating and cavitation effects that destroy tumor vasculature and starves it of nutrients.

Mapping hydrologic alteration and ecological consequences in stream reaches of the conterminous United States.

Environmental flows are critical for balancing societal water needs with that of riverine ecosystems; however, data limitations often hinder the development of predictive relationships between anthropogenic modifications to streamflow regimes and ecological responses - these relationships are the basis for setting regional water policy standards for rivers. Herein, we present and describe a comprehensive dataset of modeled hydrologic alteration and consequences for native fish biodiversity, both mapped at the stream-reach resolution for the conterminous U.S.

A river ran through it: Floodplains as America's newest relict landform.

Artificial levees are a major human modification of river corridors, but we still do not have a clear understanding of how artificial levees affect floodplain extent at regional and larger scales. We estimated changes in river-floodplain connectivity due to artificial levees in the contiguous United States (CONUS) using a combination of artificial levee databases, delineations of floodplain areas, and deletion of artificial levees from topography. Our results indicate that artificial levees do not only decrease floodplain extent but also alter locations of floodplain connectivity.

Levees don't protect, they disconnect: A critical review of how artificial levees impact floodplain functions.

Despite the recognition of floodplain importance in the scientific community, floodplains are not afforded the same legal protection as river channels. In the United States alone, flood-related economic losses were much higher in the second half of the 20th century than the first half despite the expenditure of billions of dollars on flood defenses. Partially to blame are the low appraisal and understanding of human impacts to floodplain functions.

Biogeomorphic influences on river corridor resilience to wildfire disturbances in a mountain stream of the Southern Rockies, USA.

We examine a 9.4-km-long portion of a montane river corridor in the Southern Rockies, the upper 8 km of which burned in 2020. We focus on sediment storage in logjam backwaters and how spatial heterogeneity in the river corridor attenuates downstream fluxes of material following the wildfire.

3-D modeling applications in ultrasound education: a systematic review.

Ultrasound offers a real-time 2-D view of structures within the human body. While many medical education programs have already dedicated a portion of their curriculum to ultrasound, others are concerned about cost, accessibility and limits to student practice. Student benefit may be affected by cognitive errors, which are in part owing to the mental heuristics required to visualize a 3-D structure by interpreting a 2-D image.

Proteomic characterisations of ulcerative colitis endoscopic biopsies associate with clinically relevant histological measurements of disease severity.

Aims And Methods: Accurate protein measurements using formalin-fixed biopsies are needed to improve disease characterisation. This feasibility study used targeted and global mass spectrometry (MS) to interrogate a spectrum of disease severities using 19 ulcerative colitis (UC) biopsies.

Results: Targeted assays for CD8, CD19, CD132 (interleukin-2 receptor subunit gamma/common cytokine receptor gamma chain), FOXP3 (forkhead box P3) and IL17RA (interleukin 17 receptor A) were successful; however, assays for IL17A (interleukin 17A), IL23 (p19) (interleukin 23, alpha subunit p19) and IL23R (interleukin 23 receptor) did not permit target detection.

Analysis of Immune Checkpoint Drug Targets and Tumor Proteotypes in Non-Small Cell Lung Cancer.

New therapeutics targeting immune checkpoint proteins have significantly advanced treatment of non-small cell lung cancer (NSCLC), but protein level quantitation of drug targets presents a critical problem. We used multiplexed, targeted mass spectrometry (MS) to quantify immunotherapy target proteins PD-1, PD-L1, PD-L2, IDO1, LAG3, TIM3, ICOSLG, VISTA, GITR, and CD40 in formalin-fixed, paraffin-embedded (FFPE) NSCLC specimens. Immunohistochemistry (IHC) and MS measurements for PD-L1 were weakly correlated, but IHC did not distinguish protein abundance differences detected by MS.

Regio- and Enantioselective Synthesis of Trifluoromethyl-Substituted Homoallylic α-Tertiary NH -Amines by Reactions Facilitated by a Threonine-Based Boron-Containing Catalyst.

A method for catalytic regio- and enantioselective synthesis of trifluoromethyl-substituted and aryl-, heteroaryl-, alkenyl-, and alkynyl-substituted homoallylic α-tertiary NH -amines is introduced. Easy-to-synthesize and robust N-silyl ketimines are converted to NH-ketimines in situ, which then react with a Z-allyl boronate. Transformations are promoted by a readily accessible l-threonine-derived aminophenol-based boryl catalyst, affording the desired products in up to 91 % yield, >98:2 α:γ selectivity, >98:2 Z:E selectivity, and >99:1 enantiomeric ratio.

Accelerated instability testing reveals quantitative mass spectrometry overcomes specimen storage limitations associated with PD-L1 immunohistochemistry.

Immunohistochemistry (IHC) using formalin-fixed, paraffin embedded (FFPE) tissue is limited by epitope masking, posttranslational modification and immunoreactivity loss that occurs in stored tissue by poorly characterized mechanisms. Conformational epitopes recognized by many programmed-death-ligand-1 (PD-L1) IHC assays are particularly susceptible to degradation and provide an ideal model for understanding signal loss in stored FFPE tissue. Here we assessed 1206 tissue sections to evaluate environmental factors impacting immunoreactivity loss.

A Catalytic Approach for Enantioselective Synthesis of Homoallylic Alcohols Bearing a -Alkenyl Chloride or Trifluoromethyl Group. A Concise and Protecting Group-Free Synthesis of Mycothiazole.

A protecting group-free strategy is presented for diastereo- and enantioselective routes that can be used to prepare a wide variety of -homoallylic alcohols with significantly higher efficiency than is otherwise feasible. The approach entails the merger of several catalytic processes and is expected to facilitate the preparation of bioactive organic molecules. More specifically, chloro-substituted allylic pinacolatoboronate is first obtained through stereoretentive cross-metathesis between -crotyl-B(pin) (pin = pinacolato) and -dichloroethene, both of which are commercially available.

Bioanalytical Assessment of Plasma Concentrations of Angiotensin-Converting Enzyme II Inhibitors and Angiotensin Receptor Blockers: A Pilot Study Among Patients Hospitalized With Acute Heart Failure.

Background: Although angiotensin-converting enzyme II inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) improve chronic heart failure (HF) outcomes, their potential harms and benefits in acute HF (AHF) is less clear.

Study Question: We explored the relationship between ACEI or ARB plasma concentrations among patients with AHF with in-hospital change in estimated glomerular filtration rate (eGFR).

Data Sources And Study Design: From August 2016-June 2017, patients with AHF prescribed an outpatient ACEI or ARB were enrolled before AHF treatment.

Supratherapeutic Psychotropic Drug Levels in the Emergency Department and Their Association with Delirium Duration: A Preliminary Study.

Objectives: Polypharmacy is associated with delirium, but the mechanisms for this connection are unclear. Our goal was to determine the frequency of supratherapeutic psychotropic drug levels (SPDLs) in older hospitalized patients and if it is associated with the duration of emergency department (ED) delirium.

Design: Secondary analysis of a prospective cohort study.

The effect of the EP3 antagonist DG-041 on male mice with diet-induced obesity.

Background/aims: The prostaglandin E (PGE) EP3 receptor has a multifaceted role in metabolism. Drugs targeting EP3 have been proposed as therapeutics for diabetes; however, studies utilizing global EP3 knockout mice suggest that EP3 blockade increases obesity and insulin resistance. The present studies attempt to determine the effect of acute EP3 antagonist treatment on the diabetic phenotype.