Efficacy and Safety of Intravenous Secukinumab for the Treatment of Active Psoriatic Arthritis: Results From a Randomized, Placebo-Controlled Phase 3 Study.

Objective: The aim of this study was to evaluate the efficacy and safety of intravenous (IV) secukinumab in patients with active psoriatic arthritis (PsA).

Methods: INVIGORATE-2 (NCT04209205) was a randomized, placebo-controlled, phase 3 trial. Patients with active PsA were randomized 1:1 to receive IV secukinumab (6 mg/kg at baseline followed by 3 mg/kg every four weeks [q4w]) or placebo.

Control of ENaC ubiquitination.

Ubiquitination influences the expression of the epithelial Na channel (ENaC). We assessed the mechanisms of selective ubiquitination of the mature, cleaved form of γENaC in both native rodent kidneys and Fisher rat thyroid (FRT) cells expressing the channel heterologously. In both models, singly cleaved and fully cleaved γENaCs were strongly ubiquitinated, implying that the second cleavage releasing an inhibitory peptide was not essential for the process.

alternative splicing in mouse kidney: regulation during development and by dietary K intake.

The pore-forming α-subunit of the large-conductance K (BK) channel is encoded by a single gene, BK channel-mediated K secretion in the kidney is crucial for overall renal K homeostasis in both physiological and pathological conditions. BK channels achieve phenotypic diversity by various mechanisms, including substantial exon rearrangements at seven major alternative splicing sites. However, alternative splicing in the kidney has not been characterized.

Role of paraoxonase 3 in regulating ENaC-mediated Na transport in the distal nephron.

Paraoxonase 3 (PON3) is expressed in the aldosterone-sensitive distal nephron, where filtered Na is reabsorbed mainly via the epithelial Na channel (ENaC) and Na -coupled co-transporters. We previously showed that PON3 negatively regulates ENaC through a chaperone mechanism. The present study aimed to determine the physiological role of PON3 in renal Na and K homeostasis.

Hyperstable Synthetic Mini-Proteins as Effective Ligand Scaffolds.

Small, single-domain protein scaffolds are compelling sources of molecular binding ligands with the potential for efficient physiological transport, modularity, and manufacturing. Yet, mini-proteins require a balance between biophysical robustness and diversity to enable new functions. We tested the developability and evolvability of millions of variants of 43 designed libraries of synthetic 40-amino acid βαββ proteins with diversified sheet, loop, or helix paratopes.

BRAF-mutated serrated colorectal neoplasia drives transcriptional activation of cholesterol metabolism.

BRAF mutations occur early in serrated colorectal cancers, but their long-term influence on tissue homeostasis is poorly characterized. We investigated the impact of short-term (3 days) and long-term (6 months) expression of Braf in the intestinal tissue of an inducible mouse model. We show that Braf perturbs the homeostasis of intestinal epithelial cells, with impaired differentiation of enterocytes emerging after prolonged expression of the oncogene.

Secukinumab in enthesitis-related arthritis and juvenile psoriatic arthritis: a randomised, double-blind, placebo-controlled, treatment withdrawal, phase 3 trial.

Background: Treatment options in patients with enthesitis-related arthritis (ERA) and juvenile psoriatic arthritis (JPsA) are currently limited. This trial aimed to demonstrate the efficacy and safety of secukinumab in patients with active ERA and JPsA with inadequate response to conventional therapy.

Methods: In this randomised, double-blind, placebo-controlled, treatment-withdrawal, phase 3 trial, biologic-naïve patients (aged 2 to <18 years) with active disease were treated with open-label subcutaneous secukinumab (75/150 mg in patients <50/≥50 kg) in treatment period (TP) 1 up to week 12, and juvenile idiopathic arthritis (JIA) American College of Rheumatology 30 responders at week 12 were randomised 1:1 to secukinumab or placebo up to 100 weeks.

Similar Clinical Outcomes in Patients with Systemic Juvenile Idiopathic Arthritis and Adult-Onset Still's Disease Treated with Canakinumab: Bayesian and Population Model-Based Analyses.

Introduction: Systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still's disease (AOSD) represent pediatric and adult variants of the Still's disease continuum. To determine whether clinical outcomes between patients with sJIA and AOSD were similar, Bayesian and population model-based analyses were conducted on endpoints from studies of canakinumab in both patient populations. The objective was to further support the efficacy of canakinumab in patients with AOSD.

Effect of Canakinumab vs Placebo on Survival Without Invasive Mechanical Ventilation in Patients Hospitalized With Severe COVID-19: A Randomized Clinical Trial.

Importance: Effective treatments for patients with severe COVID-19 are needed.

Objective: To evaluate the efficacy of canakinumab, an anti-interleukin-1β antibody, in patients hospitalized with severe COVID-19.

Design, Setting, And Participants: This randomized, double-blind, placebo-controlled phase 3 trial was conducted at 39 hospitals in Europe and the United States.

COM902, a novel therapeutic antibody targeting TIGIT augments anti-tumor T cell function in combination with PVRIG or PD-1 pathway blockade.

Immune checkpoint inhibitors (ICIs) have emerged as promising therapies for the treatment of cancer. However, existing ICIs, namely PD-(L)1 and CTLA-4 inhibitors, generate durable responses only in a subset of patients. TIGIT is a co-inhibitory receptor and member of the DNAM-1 family of immune modulating proteins.

Therapeutic Targeting of Checkpoint Receptors within the DNAM1 Axis.

Therapeutic antibodies targeting the CTLA4/PD-1 pathways have revolutionized cancer immunotherapy by eliciting durable remission in patients with cancer. However, relapse following early response, attributable to primary and adaptive resistance, is frequently observed. Additional immunomodulatory pathways are being studied in patients with primary or acquired resistance to CTLA4 or PD-1 blockade.

PVRIG is a novel natural killer cell immune checkpoint receptor in acute myeloid leukemia.

This study explored the novel immune checkpoint poliovirus receptor-related immunoglobulin domain-containing (PVRIG) in acute myeloid leukemia (AML). We showed that AML patient blasts consistently expressed the PVRIG ligand (poliovirus receptor-related 2, PVRL2). Furthermore, PVRIG blockade significantly enhanced NK cell killing of PVRL2+, poliovirus receptor (PVR)lo AML cell lines, and significantly increased NK cell activation and degranulation in the context of patient primary AML blasts.

Improvement in health status with once-daily indacaterol/glycopyrronium 110/50 μg in COPD patients: real-world evidence from an observational study in Ireland.

Aims: Indacaterol/glycopyrronium (IND/GLY) 110/50 μg is a once-daily (o.d.) fixed-dose combination of long-acting β-agonist/long-acting muscarinic antagonist approved in over 90 countries, including Ireland, for the management of COPD.

PVRIG and PVRL2 Are Induced in Cancer and Inhibit CD8 T-cell Function.

Although checkpoint inhibitors that block CTLA-4 and PD-1 have improved cancer immunotherapies, targeting additional checkpoint receptors may be required to broaden patient response to immunotherapy. PVRIG is a coinhibitory receptor of the DNAM/TIGIT/CD96 nectin family that binds to PVRL2. We report that antagonism of PVRIG and TIGIT, but not CD96, increased CD8 T-cell cytokine production and cytotoxic activity.

Tissue-resident Eomes(hi) T-bet(lo) CD56(bright) NK cells with reduced proinflammatory potential are enriched in the adult human liver.

The adult human liver is enriched with natural killer (NK) cells, accounting for 30-50% of hepatic lymphocytes, which include tissue-resident hepatic NK-cell subpopulations, distinct from peripheral blood NK cells. In murine liver, a subset of liver-resident hepatic NK cells have altered expression of the two highly related T-box transcription factors, T-bet and eomesodermin (Eomes). Here, we investigate the heterogeneity of T-bet and Eomes expression in NK cells from healthy adult human liver with a view to identifying human liver-resident populations.

Myeloid Engraftment in Humanized Mice: Impact of Granulocyte-Colony Stimulating Factor Treatment and Transgenic Mouse Strain.

Poor myeloid engraftment remains a barrier to experimental use of humanized mice. Focusing primarily on peripheral blood cells, we compared the engraftment profile of NOD-scid-IL2Rγc(-/-) (NSG) mice with that of NSG mice transgenic for human membrane stem cell factor (hu-mSCF mice), NSG mice transgenic for human interleukin (IL)-3, granulocyte-macrophage-colony stimulating factor (GM-CSF), and stem cell factor (SGM3 mice). hu-mSCF and SGM3 mice showed enhanced engraftment of human leukocytes compared to NSG mice, and this was reflected in the number of human neutrophils and monocytes present in these strains.

Midwife shortage is at its most acute in inner cities.

Further to Christian Duffin's interview with Cathy Warwick, general secretary of the Royal College of Midwives (career development September 8), I fear for the future of maternity services.

Purified chicken intestinal mucin attenuates Campylobacter jejuni pathogenicity in vitro.

Campylobacter jejuni is a major causative agent of diarrhoeal disease worldwide in the human population. In contrast, heavy colonization of poultry typically does not lead to disease and colonized chickens are a major source of Campylobacter infections in humans. Previously, we have shown that chicken (but not human) intestinal mucus inhibits C.