Superior preclinical efficacy of co-treatment with BRG1/BRM and FLT3 inhibitor against AML cells with FLT3 mutations.

Although treatment with standard frontline therapies, including a FLT3 inhibitor (FLT3i) reduces AML burden and achieves clinical remissions, most patients with AML with FLT3 mutation relapse due to therapy-resistant stem/progenitor cells. The core ATPases, BRG1 (SMARCA4) and BRM (SMARCA2) of the canonical (c) BAF (BRG1/BRM-associated factor) complex is a dependency in AML cells, including those harboring FLT3 mutations. We have previously reported that treatment with FHD-286, a BRG1/BRM ATPases inhibitor, induces differentiation and loss of viability of AML stem/progenitor cells.

COSMIN systematic review and meta-analysis of the measurement properties of the PANSS-6.

The Positive and Negative Syndrome Scale (PANSS-30) is the standard instrument for assessing symptoms of schizophrenia and related psychotic disorders. However, its long administration time and structural issues have prompted the development of shorter versions. The PANSS-6, derived through Item Response Theory and Rasch analysis of the PANSS-8, emerged as a potential alternative.

Quantifying and improving rheumatoid arthritis algorithm performance in biobank settings.

Objective: To quantify and improve the performance of standard rheumatoid arthritis (RA) algorithms in a biobank setting.

Methods: This retrospective cohort study within the Mayo Clinic (MC) Biobank and MC Tapestry Study identified RA cases by presence of at least two RA codes OR positive anti-cyclic citrullinated peptide antibodies (CCP) plus disease-modifying anti-rheumatic drug (DMARD) prescription as of 7/18/2022. Rheumatology physicians manually verified all RA cases using RA criteria and/or rheumatology physician diagnosis plus DMARD use.

Efficacy of clozapine versus second-generation antipsychotics in people with treatment-resistant schizophrenia: a systematic review and individual patient data meta-analysis.

Background: Clozapine is recommended by national and international guidelines for people with treatment-resistant schizophrenia. However, available meta-analyses of randomised controlled trials have not shown superior efficacy of clozapine when compared with other second-generation antipsychotics, with heterogeneity identified between the original studies. We aimed to use individual patient data (IPD) to account for potential reasons of variability and to synthesise an adjusted estimate for the difference in efficacy between clozapine and other second-generation antipsychotics for treatment-resistant schizophrenia.

Efficacy and safety of fasinumab in an NSAID-controlled study in patients with pain due to osteoarthritis of the knee or hip.

Objective: Osteoarthritis (OA) causes significant musculoskeletal pain. This study assessed the efficacy and safety of fasinumab, an investigational nerve growth factor inhibitor, in patients with moderate-to-severe OA pain of the knee/hip.

Methods: In this Phase 3, randomized, double-blind, placebo- and non-steroidal anti-inflammatory drug (NSAID)-controlled study, patients with OA (Kellgren-Lawrence grade ≥ 2; Western Ontario and McMaster Universities Arthritis Index [WOMAC] pain score ≥ 4) received (2:1:1:1) fasinumab 1 mg every 4 weeks, diclofenac 75 mg twice daily, celecoxib 200 mg daily, or placebo for 24 weeks.

Is it Possible To Identify Patients After Their First Hospitalization for a Psychotic Disorder Who Do Not Use Anti-Psychotics and are Not Later Rehospitalized?

Background: Guidelines issued by professional organizations recommend that all patients with psychotic disorders who have had several psychotic relapses, continue maintenance anti-psychotic treatment. However, some patients discontinue anti-psychotics and do not later relapse. This study attempted to characterize those patients with psychotic disorders early in their disease not taking maintenance antipsychotics, who were not later hospitalized.

Exploring Completion Rates of the SNOT-22 Questionnaire.

Background: The 22-item Sinonasal Outcome Test (SNOT-22) is a widely used patient-reported outcome measure (PROM) for assessing chronic rhinosinusitis (CRS). However, incomplete surveys may impact its predictive utility.

Aims: This study explores SNOT-22 completion rates, response trends, and potential factors influencing survey omissions aiming to optimize its predictive utility and practical application.

Sex-dependent increases in oxytocin levels in response to intravenous kisspeptin in humans.

Background: A clinically significant oxytocin-deficient state (OXT-D) has been established in adults with arginine vasopressin deficiency, and there is a need to develop diagnostic testing. Kisspeptin (KP) is a candidate for such a test, as KP receptors are found on oxytocinergic neurons, and KP administration increases plasma OXT in animals. We hypothesized that intravenous KP administration would increase peripheral OXT levels post-injection in healthy adults.

Uncovering specific genetic-respiratory disease endotypes for rheumatoid arthritis risk.

Objective: We aimed to identify specific genetic-respiratory disease endotypes for rheumatoid arthritis (RA) risk.

Methods: This case-control study used the Mass General Brigham (MGB) and Mayo Clinic (MC) Biobanks for discovery and replication, respectively. We matched criteria-confirmed incident RA cases to four non-RA controls on age, sex and health record history.

Effects of transcranial alternating current stimulation on measures of cognition and symptom scores in Chinese patients with schizophrenia.

Transcranial alternating current stimulation (tACS) may have effects on cognition and symptoms in psychiatric illness but there have been few randomized controlled studies in people with schizophrenia. We conducted a randomized sham-controlled double-blind study of 40 Hz tACS on measures of cognition and symptoms scores in 50 patients diagnosed with DSM-5 schizophrenia. tACS was delivered in 10 sessions (20 min each) over a 2-week period.

Efficacy and Safety of Sulforaphane Added to Antipsychotics for the Treatment of Negative Symptoms of Schizophrenia: A Randomized Controlled Trial.

There are few established treatments for negative symptoms in schizophrenia, which persist in many patients after positive symptoms are reduced. Oxidative stress, inflammation, and epigenetic modifications involving histone deacetylase (HDAC) have been implicated in the pathophysiology of schizophrenia. Sulforaphane has antioxidant properties and is an HDAC inhibitor.

Structural Dynamics of the Ubiquitin Specific Protease USP30 in Complex with a Cyanopyrrolidine-Containing Covalent Inhibitor.

Inhibition of the mitochondrial deubiquitinating (DUB) enzyme USP30 is neuroprotective and presents therapeutic opportunities for the treatment of idiopathic Parkinson's disease and mitophagy-related disorders. We integrated structural and quantitative proteomics with biochemical assays to decipher the mode of action of covalent USP30 inhibition by a small-molecule containing a cyanopyrrolidine reactive group, . The inhibitor demonstrated high potency and selectivity for endogenous USP30 in neuroblastoma cells.

Associations of Fire Smoke and Other Pollutants With Incident Rheumatoid Arthritis and Rheumatoid Arthritis-Associated Interstitial Lung Disease.

Objective: The aim of this study was to determine whether pollutants such as fire smoke-related particulate matter <2.5 μm (PM) are associated with incident rheumatoid arthritis (RA) and RA-associated interstitial lung disease (RA-ILD).

Methods: This patient-control study used Veterans Affairs (VA) data from October 1, 2009, to December 31, 2018.

QSP modeling of a transiently inactivating antibody-drug conjugate highlights benefit of short antibody half life.

Antibody drug conjugates (ADC) are a promising class of oncology therapeutics consisting of an antibody conjugated to a payload via a linker. DYP688 is a novel ADC comprising of a signaling protein inhibitor payload (FR900359) that undergoes unique on-antibody inactivation in plasma, resulting in complex pharmacology. To assess the impact of FR inactivation on DYP688 pharmacology and clinical developability, we performed translational modeling of preclinical PK and tumor growth inhibition (TGI) data, accompanied by mechanistic Krogh cylinder tumor modeling.

Translational findings support regimen selection for first-in-human study of ubamatamab (MUC16 × CD3 bispecific antibody) in patients with recurrent ovarian cancer.

Ubamatamab, a Mucin 16 (MUC16) × cluster of differentiation 3 (CD3) bispecific antibody that promotes T-cell-mediated cytotoxicity of MUC16-expressing cells, is being investigated for the treatment of ovarian cancer. Intravenous administration of ubamatamab, with or without the anti-programmed cell death-1 inhibitor cemiplimab, is being evaluated in a first-in-human study in patients with recurrent ovarian cancer. In vitro cytotoxicity and cytokine data and projected ubamatamab human pharmacokinetic (PK) profiles scaled with monkey PK parameters enabled starting-dose selection in humans.

Immunogenicity of dupilumab in adult and pediatric patients with atopic dermatitis.

Background: Development of anti-drug antibodies (ADAs) and neutralizing antibodies (NAbs) to monoclonal antibodies may adversely impact pharmacokinetics, efficacy, and/or safety.

Objective: To describe incidence, titer, and persistence of dupilumab ADAs and NAbs, and their effects on pharmacokinetics, efficacy, and safety in patients with atopic dermatitis (AD).

Methods: This analysis included seven phase 3 randomized, placebo-controlled (N=2,992) and two long-term open-label extension (N=2,287) trials of subcutaneous dupilumab in adults and pediatric patients with moderate-to-severe AD.

Luteal fibroblasts produce prostaglandins in response to IL1β in a MAPK-mediated manner.

The corpus luteum is a temporary endocrine gland that is crucial for pregnancy, as it produces the progesterone needed to maintain optimal uterine conditions for implantation. In the absence of a conceptus, the corpus luteum becomes non-functional and undergoes rapid tissue remodeling to regress into a fibrotic corpus albicans. Early luteal regression is characterized by increased cytokine release.

Preclinical efficacy of CDK7 inhibitor-based combinations against myeloproliferative neoplasms transformed to AML.

Rising blast percentage or secondary acute myeloid leukemia (sAML) transformation in myeloproliferative neoplasms (MPNs) leads to JAK1/2 inhibitor (JAKi) therapy resistance and poor survival. Here, we demonstrate that treatment with the CDK7 inhibitor (CDK7i) SY-5609 depletes phenotypically characterized post-MPN sAML stem/progenitor cells. In cultured post-MPN sAML SET2, HEL and patient-derived (PD) post-MPN sAML cells, SY-5609 treatment inhibited growth and induced lethality while sparing normal cells.

A phase III study to evaluate the long-term safety and efficacy of fasinumab in patients with pain due to osteoarthritis of the knee or hip.

Background: Pain associated with osteoarthritis (OA) is frequently disabling; treatments are often ineffective or intolerable. Fasinumab selectively inhibits nerve-growth factor and has shown efficacy for the management of OA pain.

Methods: In this randomized, double-blind, phase III safety study, patients with moderate-to-severe OA pain and history of inadequate pain relief received placebo or fasinumab (at 1, 3, 6, and 9 ​mg every 4 weeks [Q4W] and 1 and 6 ​mg every 8 weeks [Q8W] for 52 weeks).