Mechanistic insights into a heterobifunctional degrader-induced PTPN2/N1 complex.

PTPN2 (protein tyrosine phosphatase non-receptor type 2, or TC-PTP) and PTPN1 are attractive immuno-oncology targets, with the deletion of Ptpn1 and Ptpn2 improving response to immunotherapy in disease models. Targeted protein degradation has emerged as a promising approach to drug challenging targets including phosphatases. We developed potent PTPN2/N1 dual heterobifunctional degraders (Cmpd-1 and Cmpd-2) which facilitate efficient complex assembly with E3 ubiquitin ligase CRL4, and mediate potent PTPN2/N1 degradation in cells and mice.

Mixed-methods feasibility cluster randomised controlled trial of a paramedic-administered breathlessness management intervention for acute-on-chronic breathlessness (BREATHE): study findings.

Introduction: One-fifth of emergency department presentations by ambulance are due to acute-on-chronic breathlessness. We explored the feasibility of an evaluation-phase, cluster randomised controlled trial (cRCT) of the effectiveness and cost-effectiveness of a paramedic-administered, non-pharmacological breathlessness intervention for people with acute-on-chronic breathlessness at ambulance call-out (BREATHE) regarding breathlessness intensity and conveyance to hospital.

Methods: This mixed-methods, feasibility cRCT (ISRCTN80330546) randomised paramedics to usual care or intervention plus usual care.

Trends, variations and prediction of staff sickness absence rates among NHS ambulance services in England: a time series study.

Objectives: Our aim was to measure ambulance sickness absence rates over time, comparing ambulance services and investigate the predictability of rates for future forecasting.

Setting: All English ambulance services, UK.

Design: We used a time series design analysing published monthly National Health Service staff sickness rates by gender, age, job role and region, comparing the 10 regional ambulance services in England between 2009 and 2018.

A feasibility cluster randomised controlled trial of a paramedic-administered breathlessness management intervention for acute-on-chronic breathlessness (BREATHE).

Chronic breathlessness, persistent and disabling despite optimal treatment of underlying causes, is a prevalent and frightening symptom and is associated with many emergency presentations and admission to hospital. Breathlessness management techniques used by paramedics may reduce the need for conveyance to hospital. The Breathlessness RElief AT HomE study (BREATHE) aims to explore the feasibility of conducting a definitive cluster randomised controlled trial (cRCT) for people with acute-on-chronic breathlessness who have called an ambulance, to evaluate the effectiveness and cost-effectiveness of a paramedic-administered non-pharmacological breathlessness intervention.

Discovery of AZD4573, a Potent and Selective Inhibitor of CDK9 That Enables Short Duration of Target Engagement for the Treatment of Hematological Malignancies.

A CDK9 inhibitor having short target engagement would enable a reduction of Mcl-1 activity, resulting in apoptosis in cancer cells dependent on Mcl-1 for survival. We report the optimization of a series of amidopyridines (from compound ), focusing on properties suitable for achieving short target engagement after intravenous administration. By increasing potency and human metabolic clearance, we identified compound , a potent and selective CDK9 inhibitor with suitable predicted human pharmacokinetic properties to deliver transient inhibition of CDK9.

The achromatic locus: effect of navigation direction in color space.

An achromatic stimulus is defined as a patch of light that is devoid of any hue. This is usually achieved by asking observers to adjust the stimulus such that it looks neither red nor green and at the same time neither yellow nor blue. Despite the theoretical and practical importance of the achromatic locus, little is known about the variability in these settings.

Influenza vaccination for immunocompromised patients: summary of a systematic review and meta-analysis.

Vaccination of immunocompromised patients is recommended in many national guidelines to protect against severe or complicated influenza infection. However, due to uncertainties over the evidence base, implementation is frequently patchy and dependent on individual clinical discretion. We conducted a systematic review and meta-analysis to assess the evidence for influenza vaccination in this patient group.

Production and characterization of a trehalolipid biosurfactant produced by the novel marine bacterium Rhodococcus sp., strain PML026.

Aims: The aim of this study was to evaluate biosurfactant production by a novel marine Rhodococcus sp., strain PML026 and characterize the chemical nature and properties of the biosurfactant.

Methods And Results: A novel marine bacterium (Rhodococcus species; strain PML026) was shown to produce biosurfactant in the presence of hydrophobic substrate (sunflower oil).

Influenza vaccination for immunocompromised patients: systematic review and meta-analysis from a public health policy perspective.

Background: Immunocompromised patients are vulnerable to severe or complicated influenza infection. Vaccination is widely recommended for this group. This systematic review and meta-analysis assesses influenza vaccination for immunocompromised patients in terms of preventing influenza-like illness and laboratory confirmed influenza, serological response and adverse events.

A study of in vivo immune complex formation and clearance in man.

C and CR1 have been shown to participate in the clearance of injected, preformed, immune complexes in humans and in non-human primates. Their role in the physiologic disposal of immune complexes formed in vivo in humans was investigated in three patients receiving radioimmunotherapy for ovarian carcinoma. On day 0 each patient received, by intraperitoneal injection, 10 mg of 131I-mouse anti-tumor mAb (10 mCi/mg).

Clearance of 131I-labeled murine monoclonal antibody from patients' blood by intravenous human anti-murine immunoglobulin antibody.

Five patients treated with intraperitoneal 131I-labeled mouse monoclonal antibody for ovarian cancer also received i.v. exogenous polyclonal human anti-murine immunoglobulin antibody.

Use of an rRNA probe and restriction endonuclease analysis to fingerprint Pasteurella multocida isolated from turkeys and wildlife.

Twenty-five isolates of the bacterium Pasteurella multocida were characterized (fingerprinted) phenotypically and genotypically in order to compare the abilities of various techniques to differentiate strains for epidemiologic studies of fowl cholera. Isolates were obtained over a 16-month period from turkeys dying from fowl cholera (six outbreak flocks) and from wildlife captured on premises with a history of the disease. The characteristics compared included (i) serotype, (ii) subspecies, (iii) antibiogram, (iv) presence of plasmid DNA, (v) restriction endonuclease analysis patterns of whole-cell DNA, and (vi) ribotype.

Intraperitoneal 131I- and 90Y-labelled monoclonal antibodies for ovarian cancer: pharmacokinetics and normal tissue dosimetry.

The pharmacokinetics of intraperitoneal (i.p.) radiolabelled monoclonal antibody (MAb) was studied in 35 patients receiving 40 i.