Fatty Acid Derivatization and Cyclization of the Immunomodulatory Peptide RP-182 Targeting CD206high Macrophages Improve Antitumor Activity.

As tumor-associated macrophages (TAM) exercise a plethora of protumor and immune evasive functions, novel strategies targeting TAMs to inhibit tumor progression have emerged within the current arena of cancer immunotherapy. Activation of the mannose receptor 1 (CD206) is a recent approach that recognizes immunosuppressive CD206high M2-like TAMs as a drug target. Ligation of CD206 both induces reprogramming of CD206high TAMs toward a proinflammatory phenotype and selectively triggers apoptosis in these cells.

The effectiveness of coronary computed tomography angiography and functional testing for the diagnosis of obstructive coronary artery disease: results from the individual patient data Collaborative Meta-Analysis of Cardiac CT (COME-CCT).

Aim: To determine the effectiveness of functional stress testing and computed tomography angiography (CTA) for diagnosis of obstructive coronary artery disease (CAD).

Methods And Results: Two-thousand nine-hundred twenty symptomatic stable chest pain patients were included in the international Collaborative Meta-Analysis of Cardiac CT consortium to compare CTA with exercise electrocardiography (exercise-ECG) and single-photon emission computed tomography (SPECT) for diagnosis of CAD defined as ≥ 50% diameter stenosis by invasive coronary angiography (ICA) as reference standard. Generalised linear mixed models were used for calculating the diagnostic accuracy of each diagnostic test including non-diagnostic results as dependent variables in a logistic regression model with random intercepts and slopes.

Rescue in vitro maturation using ovarian support cells of human oocytes from conventional stimulation cycles yields oocytes with improved nuclear maturation and transcriptomic resemblance to in vivo matured oocytes.

Purpose: Determine if the gene expression profiles of ovarian support cells (OSCs) and cumulus-free oocytes are bidirectionally influenced by co-culture during in vitro maturation (IVM).

Methods: Fertility patients aged 25 to 45 years old undergoing conventional ovarian stimulation donated denuded immature oocytes for research. Oocytes were randomly allocated to either OSC-IVM culture (intervention) or Media-IVM culture (control) for 24-28 h.

A CD38-directed, single-chain T-cell engager targets leukemia stem cells through IFN-γ-induced CD38 expression.

Treatment resistance of leukemia stem cells (LSCs) and suppression of the autologous immune system represent major challenges to achieve a cure in acute myeloid leukemia (AML). Although AML blasts generally retain high levels of surface CD38 (CD38pos), LSCs are frequently enriched in the CD34posCD38neg blast fraction. Here, we report that interferon gamma (IFN-γ) reduces LSCs clonogenic activity and induces CD38 upregulation in both CD38pos and CD38neg LSC-enriched blasts.

BAY-9835: Discovery of the First Orally Bioavailable ADAMTS7 Inhibitor.

The matrix metalloprotease ADAMTS7 has been identified by multiple genome-wide association studies as being involved in the development of coronary artery disease. Subsequent research revealed the proteolytic function of the enzyme to be relevant for atherogenesis and restenosis after vessel injury. Based on a publicly known dual ADAMTS4/ADAMTS5 inhibitor, we have in silico designed an ADAMTS7 inhibitor of the catalytic domain, which served as a starting point for an optimization campaign.

A tale of two cities: Policing and firearm homicides in Boston and Philadelphia.

Background: Recent political movements have raised questions about the effectiveness of police funding, but the impact of law enforcement budgets on firearm violence is unknown. We hypothesized that department funding and measures of police activity would be associated with decreased shootings and firearm homicides (FHs) in two major cities with different police funding patterns.

Methods: We collected data from the following sources: district attorney's offices, police departments, Federal Bureau of Investigation Uniform Crime Reporting program, the Centers for Disease Control, the Annual Survey of Public Employment and Payroll, and the American Community Survey.

Feasibility of redo-TAVI in self-expanding Evolut valves: a CT analysis from the Evolut Low Risk Trial substudy.

Background: Transcatheter aortic valve implantation in an existing transcatheter valve (redo-TAVI) pins the index valve leaflets in the open position (neoskirt), which can cause coronary flow compromise and limit access. Whether anatomy may preclude redo-TAVI in self-expanding Evolut valves is unknown.

Aims: We aimed to evaluate the anatomical feasibility of redo-TAVI by simulating implantation of a balloon-expandable SAPIEN 3 (S3) within an Evolut or an Evolut within an Evolut.

Funding the war in America: A look in the mirror.

Background: Health care political action committees (HPACs) historically contribute more to candidates opposing firearm restrictions (FRs), clashing with their affiliated medical societies. These societies have increasingly emphasized the prevention of firearm violence and it is not known if recent contributions by their HPACs have aligned with their stated goals. We hypothesized that such HPACs still contribute similar amounts toward legislators up for reelection opposing FR.

Phytochemical Characterization and In Vitro and In Silico Biological Studies from Ferns of Genus (Blechnaceae, Polypodiales).

The genus represents one of the most ecologically and therapeutically important groups of ferns that grow in tropical, subtropical and temperate regions. In this work, the chemical fingerprint of lyophilized extracts of and species, the determination of their antioxidant activity through ORAC, FRAP and DPPH assays and inhibition of cholinesterase enzymes (AChE and BChE), and an in silico analysis of selected majority compounds on cholinesterase enzymes were identified. Nineteen compounds were recorded for , nine in seventeen in and seventeen in by liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry (UHPLC-ESI-QTOF-MS).

Validation of a suite of ERP and QEEG biomarkers in a pre-competitive, industry-led study in subjects with schizophrenia and healthy volunteers.

Objective: Complexity and lack of standardization have mostly limited the use of event-related potentials (ERPs) and quantitative EEG (QEEG) biomarkers in drug development to small early phase trials. We present results from a clinical study on healthy volunteers (HV) and patients with schizophrenia (SZ) that assessed test-retest, group differences, variance, and correlation with functional assessments for ERP and QEEG measures collected at clinical and commercial trial sites with standardized instrumentation and methods, and analyzed through an automated data analysis pipeline.

Methods: 81 HV and 80 SZ were tested at one of four study sites.

Urban policy interventions to reduce traffic-related emissions and air pollution: A systematic evidence map.

Background: Urban areas are hot spots for human exposure to air pollution, which originates in large part from traffic. As the urban population continues to grow, a greater number of people risk exposure to traffic-related air pollution (TRAP) and its adverse, costly health effects. In many cities, there is a need and scope for air quality improvements through targeted policy interventions, which continue to grow including rapidly changing technologies.

Coincident Regulation of PLC Signaling by Gq-Coupled and -Opioid Receptors Opposes Opioid-Mediated Antinociception.

Pain management is an important problem worldwide. The current frontline approach for pain management is the use of opioid analgesics. The primary analgesic target of opioids is the -opioid receptor (MOR).

Real-Time Cellular Thermal Shift Assay to Monitor Target Engagement.

Determining a molecule's mechanism of action is paramount during chemical probe development and drug discovery. The cellular thermal shift assay (CETSA) is a valuable tool to confirm target engagement in cells for a small molecule that demonstrates a pharmacological effect. CETSA directly detects biophysical interactions between ligands and protein targets, which can alter a protein's unfolding and aggregation properties in response to thermal challenge.

Quiescent cancer cells resist T cell attack by forming an immunosuppressive niche.

Immunotherapy is a promising treatment for triple-negative breast cancer (TNBC), but patients relapse, highlighting the need to understand the mechanisms of resistance. We discovered that in primary breast cancer, tumor cells that resist T cell attack are quiescent. Quiescent cancer cells (QCCs) form clusters with reduced immune infiltration.

Identification of a Distinct miRNA Regulatory Network in the Tumor Microenvironment of Transformed Mycosis Fungoides.

Large cell transformation of mycosis fungoides (LCT-MF) occurs in 20-50% of advanced MF and is generally associated with poor response and dismal prognosis. Although different mechanisms have been proposed to explain the pathogenesis, little is known about the role of microRNAs (miRs) in transcriptional regulation of LCT-MF. Here, we investigated the miR and mRNA expression profile in lesional skin samples of patients with LCT-MF and non-LCT MF using RNA-seq analysis.

Risk for Recurrent Venous Thromboembolism in Patients With Subsegmental Pulmonary Embolism Managed Without Anticoagulation : A Multicenter Prospective Cohort Study.

Background: The incidence of pulmonary embolism has been increasing, but its case-fatality rate is decreasing, suggesting a lesser severity of illness. The clinical importance of patients with pulmonary embolism isolated to the subsegmental vessels is unknown.

Objective: To determine the rate of recurrent venous thromboembolism in patients with subsegmental pulmonary embolism managed without anticoagulation.

The Impact of Age on Mortality in Chronic Haemodialysis Popu-Lation with COVID-19.

Age and chronic kidney disease have been described as mortality risk factors for coronavirus disease 2019 (COVID-19). Currently, an important percentage of patients in haemodialysis are elderly. Herein, we investigated the impact of age on mortality among haemodialysis patients with COVID-19.

1q21.1 distal copy number variants are associated with cerebral and cognitive alterations in humans.

Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively.

Two Randomized Trials of Neutralizing Antibodies to Prevent HIV-1 Acquisition.

Background: Whether a broadly neutralizing antibody (bnAb) can be used to prevent human immunodeficiency virus type 1 (HIV-1) acquisition is unclear.

Methods: We enrolled at-risk cisgender men and transgender persons in the Americas and Europe in the HVTN 704/HPTN 085 trial and at-risk women in sub-Saharan Africa in the HVTN 703/HPTN 081 trial. Participants were randomly assigned to receive, every 8 weeks, infusions of a bnAb (VRC01) at a dose of either 10 or 30 mg per kilogram (low-dose group and high-dose group, respectively) or placebo, for 10 infusions in total.