MoA Studies of the TEAD P-Site Binding Ligand MSC-4106 and Its Optimization to TEAD1-Selective Amide M3686.

Taking the structural information into account, we were able to tune the TEAD selectivity for a specific chemotype. However, different TEAD selectivity profiles did not affect the compound potency or efficacy in the NCI-H226 viability assay. Amides based on or analogues showed improved viability efficacy compared with the corresponding acids.

2024 ACLP Recommendations for Training Residents in Consultation-Liaison Psychiatry.

Background: Despite rapid shifts in consultation-liaison psychiatry (CLP) training in residency, including increasing general residency training requirements from the Accreditation Council for Graduate Medical Education, greater utilization of advanced practice providers, and effects of the coronavirus-2019 pandemic, the Academy of Consultation-Liaison Psychiatry has not updated recommendations for residency training in CLP since 2014. A national survey of residency program directors in 2021 suggested many changes to the structure of CLP rotations at individual programs over the past decade.

Objective: These recommendations are intended to guide residency program directors toward optimizing CLP training for all residents, including those who will eventually pursue CLP fellowship.

Discovery of reversible and covalent TEAD 1 selective inhibitors MSC-1254 and MSC-5046 based on one scaffold.

The Transcriptional Enhanced Associated Domain (TEAD) family of transcription factors are key components of the Hippo signalling family which play a crucial role in the regulation of cell proliferation, differentiation and apoptosis. The identification of inhibitors of the TEAD transcription factors are an attractive strategy for the development of novel anticancer therapies. A HTS campaign identified hit 1, which was optimised using structure-based drug design, to deliver potent TEAD1 selective inhibitors with both a reversible and covalent mode of inhibition.

Implementation of an Evidence-Based Treatment Protocol and Order Set for Alcohol Withdrawal Syndrome.

Background: Alcohol withdrawal syndrome (AWS) is highly prevalent in hospital inpatients. Recent evidence supports use of phenobarbital and gabapentin in certain patients, and screening tools for severe withdrawal risk can be used to guide care. Inpatients with AWS should also be considered for evidence-based treatment for alcohol use disorder (AUD).

Discovery of YAP1/TAZ pathway inhibitors through phenotypic screening with potent anti-tumor activity via blockade of Rho-GTPase signaling.

This study describes the identification and target deconvolution of small molecule inhibitors of oncogenic Yes-associated protein (YAP1)/TAZ activity with potent anti-tumor activity in vivo. A high-throughput screen (HTS) of 3.8 million compounds was conducted using a cellular YAP1/TAZ reporter assay.

Requesting That Delirium Achieve Parity With Acute Encephalopathy in the MS-DRG System.

Since 2007, the Medicare Severity Diagnosis Related Groups classification system has favored billing codes for acute encephalopathy over delirium codes in determining hospital reimbursement and several quality-of-care value metrics, despite broad overlap between these sets of diagnostic codes. Toxic and metabolic encephalopathy codes are designated as major complication or comorbidity, whereas causally specified delirium codes are designated as complication or comorbidity and thus associated with a lower reimbursement and lesser impact on value metrics. The authors led a submission to the U.

Which foreign vaccine should the government purchase in a pandemic? Evidence from a survey experiment in the United States.

Background: For many countries confronting a future pandemic, the initial vaccines available will come from abroad. Public hesitancy to receive these foreign vaccines is important, as it may create an incentive for governments to forego procuring them for public use. We investigate the influence of the vaccine's country of origin on public support for government procurement during the early stages of a pandemic and examine whether endorsements from the WHO can mitigate such biases.

Association Between COVID-19 and Delirium Development in the General Medical Units at an Academic Medical Center.

Introduction: Evidence suggests that inpatients who develop delirium experience worse outcomes. Although there is reason to believe that COVID-positive patients may be at a higher risk for developing delirium, little is known about the association between COVID-19 and delirium among hospitalized patients outside the intensive care unit (ICU). This study aimed to examine (1) the independent association between COVID-19 infection and the development of delirium among all non-ICU patients and (2) the risk factors associated with developing delirium among patients admitted with COVID-19, with a special focus on presenting symptoms.

Novel Methionine Aminopeptidase 2 Inhibitor M8891 Synergizes with VEGF Receptor Inhibitors to Inhibit Tumor Growth of Renal Cell Carcinoma Models.

N-terminal processing by methionine aminopeptidases (MetAP) is a crucial step in the maturation of proteins during protein biosynthesis. Small-molecule inhibitors of MetAP2 have antiangiogenic and antitumoral activity. Herein, we characterize the structurally novel MetAP2 inhibitor M8891.

Extract2Chip-Bypassing Protein Purification in Drug Discovery Using Surface Plasmon Resonance.

Modern drug discovery relies on combinatorial screening campaigns to find drug molecules targeting specific disease-associated proteins. The success of such campaigns often relies on functional and structural information of the selected therapeutic target, only achievable once its purification is mastered. With the aim of bypassing the protein purification process to gain insights on the druggability, ligand binding, and/or characterization of protein-protein interactions, herein, we describe the Extract2Chip method.

MCT4 blockade increases the efficacy of immune checkpoint blockade.

Background & Aims: Intratumoral lactate accumulation and acidosis impair T-cell function and antitumor immunity. Interestingly, expression of the lactate transporter monocarboxylate transporter (MCT) 4, but not MCT1, turned out to be prognostic for the survival of patients with rectal cancer, indicating that single MCT4 blockade might be a promising strategy to overcome glycolysis-related therapy resistance.

Methods: To determine whether blockade of MCT4 alone is sufficient to improve the efficacy of immune checkpoint blockade (ICB) therapy, we examined the effects of the selective MCT1 inhibitor AZD3965 and a novel MCT4 inhibitor in a colorectal carcinoma (CRC) tumor spheroid model co-cultured with blood leukocytes in vitro and the MC38 murine CRC model in vivo in combination with an antibody against programmed cell death ligand-1(PD-L1).

Diagnostic genome sequencing improves diagnostic yield: a prospective single-centre study in 1000 patients with inherited eye diseases.

Purpose: Genome sequencing (GS) is expected to reduce the diagnostic gap in rare disease genetics. We aimed to evaluate a scalable framework for genome-based analyses 'beyond the exome' in regular care of patients with inherited retinal degeneration (IRD) or inherited optic neuropathy (ION).

Methods: PCR-free short-read GS was performed on 1000 consecutive probands with IRD/ION in routine diagnostics.

Best-response dynamics, playing sequences, and convergence to equilibrium in random games.

We analyze the performance of the best-response dynamic across all normal-form games using a random games approach. The playing sequence-the order in which players update their actions-is essentially irrelevant in determining whether the dynamic converges to a Nash equilibrium in certain classes of games (e.g.

DNA-Binding Magnetic Nanoreactor Beads for Digital PCR Analysis.

Digital PCR (dPCR) is based on the separation of target amplification reactions into many compartments with randomly distributed template molecules. Here, we present a novel digital PCR format based on DNA binding magnetic nanoreactor beads (mNRBs). Our approach relies on the binding of all nucleic acids present in a sample to the mNRBs, which both provide a high-capacity binding matrix for capturing nucleic acids from a sample and define the space available for PCR amplification by the internal volume of their hydrogel core.

Comparative analysis of YAP/TEAD inhibitors in 2D and 3D cultures of primary human hepatocytes reveals a novel non-canonical mechanism of CYP induction.

Induction of cytochrome P450 (CYP) genes constitutes an important cause of drug-drug interactions and preclinical evaluation of induction liability is mandatory for novel drug candidates. YAP/TEAD signaling has emerged as an attractive target for various oncological indications and multiple chemically distinct YAP/TEAD inhibitors are rapidly progressing towards clinical stages. Here, we tested the liability for CYP induction of a diverse set of YAP/TEAD inhibitors with different modes of action and TEAD isoform selectivity profiles in monolayers and 3D spheroids of primary human hepatocytes (PHH).

A 10-Year Follow-up Survey of Psychiatry Resident Education in Consultation-Liaison Psychiatry.

Background: In 2010, the Academy of Consultation-Liaison (then Academy of Psychosomatic Medicine) surveyed US residency programs to understand training in consultation-liaison (CL) psychiatry, leading to recommendations in 2014. Since then, residency training in CL has evolved in the context of competing training demands, increased prioritization of electives, and reactions to coronavirus 2019.

Objective: To determine the current state of residency training in CL across the United States, including the structure of core and elective resident rotations in CL, attending physician staffing, presence of fellows and other trainees, didactic curriculum, and impact of coronavirus 2019.

MSC-1186, a Highly Selective Pan-SRPK Inhibitor Based on an Exceptionally Decorated Benzimidazole-Pyrimidine Core.

The highly conserved catalytic sites in protein kinases make it difficult to identify ATP competitive inhibitors with kinome-wide selectivity. Serendipitously, during a dedicated fragment campaign for the focal adhesion kinase (FAK), a scaffold that had lost its initial FAK affinity showed remarkable potency and selectivity for serine-arginine-protein kinases 1-3 (SRPK1-3). Non-conserved interactions with the uniquely structured hinge region of the SRPK family were the key drivers of the exclusive selectivity of the discovered fragment hit.

Bridging vascular physiology to vascular medicine: an integrative laboratory class.

Vascular diseases of the legs are highly prevalent and constitute an important part of medical curricula. The understanding of these diseases relies on strongly interwoven aspects of vascular physiology and vascular medicine. We aimed to connect these within a horizontally integrated laboratory class on vascular physiology of the leg that was designed in cooperation between the departments of physiology and vascular surgery.

Body image disturbance and associated eating disorder and body dysmorphic disorder pathology in gay and heterosexual men: A systematic analyses of cognitive, affective, behavioral und perceptual aspects.

Objective: This study contributes to the quantitatively large, yet narrow in scope research on body image in gay men by assessing whether gay and heterosexual men systematically differ on various dimensions of body image disturbance and associated pathology, i.e., eating disorder and body dysmorphic disorder symptoms.

Investigating how historical legacies of militarized violence can motivate COVID-19 vaccine hesitancy: Evidence from global dyadic survey.

Background: In almost all countries, COVID-19 vaccines available for public use are produced outside of that country. Consistent with recent social science research, we hypothesize that legacies of violent conflict from vaccine-producing against vaccine-consuming countries may motivate vaccine hesitancy among people in targeted countries that purchase vaccines produced by the erstwhile aggressor.

Methods: Our analyses draw on data from the Correlates of War project and a large, representative survey of 18,291 adults that asked respondents in 16 countries to self-report their attitudes toward COVID-19 vaccines originating from 12 potential vaccine-producing countries in December 2020 (184 country-pairs, 208,422 ratings).

Synthesis and crystal structure of -2-(1,3-dioxo-isoindolin-2-yl)ethyl 4-methyl--phenyl-'-(tri-iso-propyl-sil-yl)benzene-sulfondiimidoate: the first member of a new substance class.

The title compound {systematic name: -2-[7-methyl-4-(4-methylphenyl)-4-(phenylimino)-6,6-bis(propan-2-yl)-3-oxa-4λ-thia-5-aza-6-silaoct-4-en-1-yl]-2,3-dihydro-1-isoindole-1,3-dione}, CHNOSSi, was synthesized by desoxychlorination of 4-methyl--phenyl-'-(triisopropyl-sil-yl)benzene-sul-fon-imid-am-ide and subsequent reaction with 2-(2-hy-droxy-eth-yl)isoindoline-1,3-dione. The racemic compound was crystallized from isopropanol. The structural characterization by single-crystal X-ray diffraction revealed two double-bonded nitro-gen atoms to the central sulfur atom and an overall crystal packing driven by its aromatic inter-actions.

The baroreceptor reflex brought to life outside the classroom - an e-learning based asynchronous laboratory class using a non-supervised modified Active Standing Test.

Background: E-learning based laboratory classes can replace or enhance in-classroom laboratories. They typically offer temporal flexibility, self-determined learning speed, repeatability and do not require supervision or face-to-face contact. The aim of this feasibility study was to investigate whether the established in-classroom laboratory class on the baroreceptor reflex (BRR) can be transformed into a new e-learning based asynchronous laboratory class for untrained, non-supervised students without medical equipment.

Optimization of TEAD P-Site Binding Fragment Hit into In Vivo Active Lead .

The dysregulated Hippo pathway and, consequently, hyperactivity of the transcriptional YAP/TAZ-TEAD complexes is associated with diseases such as cancer. Prevention of YAP/TAZ-TEAD triggered gene transcription is an attractive strategy for therapeutic intervention. The deeply buried and conserved lipidation pocket (P-site) of the TEAD transcription factors is druggable.