Autogene cevumeran with or without atezolizumab in advanced solid tumors: a phase 1 trial.

Effective targeting of somatic cancer mutations to enhance the efficacy of cancer immunotherapy requires an individualized approach. Autogene cevumeran is a uridine messenger RNA lipoplex-based individualized neoantigen-specific immunotherapy designed from tumor-specific somatic mutation data obtained from tumor tissue of each individual patient to stimulate T cell responses against up to 20 neoantigens. This ongoing phase 1 study evaluated autogene cevumeran as monotherapy (n = 30) and in combination with atezolizumab (n = 183) in pretreated patients with advanced solid tumors.

Systemic Neutrophil Gelatinase-Associated Lipocalin Alterations in Chronic Pancreatitis: A Multicenter, Cross-Sectional Study.

Introduction: Chronic pancreatitis (CP) is a progressive fibroinflammatory disorder lacking therapies and biomarkers. Neutrophil gelatinase-associated lipocalin (NGAL) is a proinflammatory cytokine elevated during inflammation that binds fatty acids (FAs) such as linoleic acid. We hypothesized that systemic NGAL could serve as a biomarker for CP and, with FAs, provide insights into inflammatory and metabolic alterations.

Transport Strategy in Patients With Suspected Acute Large Vessel Occlusion Stroke: TRIAGE-STROKE, a Randomized Clinical Trial.

Background: When patients with acute ischemic stroke present with suspected large vessel occlusion in the catchment area of a primary stroke center (PSC), the benefit of direct transport to a comprehensive stroke center (CSC) has been suggested. Equipoise remains between transport strategies and the best transport strategy is not well established.

Methods: We conducted a national investigator-driven, multicenter, randomized, assessor-blinded clinical trial.

A Novel Risk Score to Predict Hungry Bone Syndrome After Parathyroidectomy for Renal Hyperparathyroidism.

Objective: Hungry bone syndrome (HBS) is a known complication of parathyroidectomy. Patients with renal hyperparathyroidism are particularly vulnerable to HBS because of their prolonged exposure to electrolyte abnormalities and elevated parathyroid hormone (PTH). However, in-depth characterization of predictive factors for HBS in these patients is lacking.

Activation priming and cytokine polyfunctionality modulate the enhanced functionality of low-affinity CD19 CAR T cells.

We recently described a low-affinity second-generation CD19 chimeric antigen receptor (CAR) CAT that showed enhanced expansion, cytotoxicity, and antitumor efficacy compared with the high-affinity (FMC63-based) CAR used in tisagenlecleucel, in preclinical models. Furthermore, CAT demonstrated an excellent toxicity profile, enhanced in vivo expansion, and long-term persistence in a phase 1 clinical study. To understand the molecular mechanisms behind these properties of CAT CAR T cells, we performed a systematic in vitro characterization of the transcriptomic (RNA sequencing) and protein (cytometry by time of flight) changes occurring in T cells expressing low-affinity vs high-affinity CD19 CARs following stimulation with CD19-expressing cells.

Sotigalimab and/or nivolumab with chemotherapy in first-line metastatic pancreatic cancer: clinical and immunologic analyses from the randomized phase 2 PRINCE trial.

Chemotherapy combined with immunotherapy has improved the treatment of certain solid tumors, but effective regimens remain elusive for pancreatic ductal adenocarcinoma (PDAC). We conducted a randomized phase 2 trial evaluating the efficacy of nivolumab (nivo; anti-PD-1) and/or sotigalimab (sotiga; CD40 agonistic antibody) with gemcitabine/nab-paclitaxel (chemotherapy) in patients with first-line metastatic PDAC ( NCT03214250 ). In 105 patients analyzed for efficacy, the primary endpoint of 1-year overall survival (OS) was met for nivo/chemo (57.

Clinical Trial Design Principles and Outcomes Definitions for Device-Based Therapies for Hypertension: A Consensus Document From the Hypertension Academic Research Consortium.

The clinical implications of hypertension in addition to a high prevalence of both uncontrolled blood pressure and medication nonadherence promote interest in developing device-based approaches to hypertension treatment. The expansion of device-based therapies and ongoing clinical trials underscores the need for consistency in trial design, conduct, and definitions of clinical study elements to permit trial comparability and data poolability. Standardizing methods of blood pressure assessment, effectiveness measures beyond blood pressure alone, and safety outcomes are paramount.

Tasimelteon safely and effectively improves sleep in Smith-Magenis syndrome: a double-blind randomized trial followed by an open-label extension.

Purpose: To assess the efficacy of tasimelteon to improve sleep in Smith-Magenis syndrome (SMS).

Methods: A 9-week, double-blind, randomized, two-period crossover study was conducted at four US clinical centers. Genetically confirmed patients with SMS, aged 3 to 39, with sleep complaints participated in the study.

Impact of Patient Adherence to Stool-Based Colorectal Cancer Screening and Colonoscopy Following a Positive Test on Clinical Outcomes.

Colorectal cancer-screening models commonly assume 100% adherence, which is inconsistent with real-world experience. The influence of adherence to initial stool-based screening [fecal immunochemical test (FIT), multitarget stool DNA (mt-sDNA)] and follow-up colonoscopy (after a positive stool test) on colorectal cancer outcomes was modeled using the Colorectal Cancer and Adenoma Incidence and Mortality Microsimulation Model. Average-risk individuals without diagnosed colorectal cancer at age 40 undergoing annual FIT or triennial mt-sDNA screening from ages 50 to 75 were simulated.

A Phase 2 Randomized Placebo-Controlled Adjuvant Trial of GI-4000, a Recombinant Yeast Expressing Mutated RAS Proteins in Patients with Resected Pancreas Cancer.

GI-4000, a series of recombinant yeast expressing four different mutated RAS proteins, was evaluated in subjects with resected -mutated pancreas cancer. Subjects ( = 176) received GI-4000 or placebo plus gemcitabine. Subjects' tumors were genotyped to identify which matched GI-4000 product to administer.

Impact of screening and follow-up colonoscopy adenoma sensitivity on colorectal cancer screening outcomes in the CRC-AIM microsimulation model.

Background: Real-world data for patients with positive colorectal cancer (CRC) screening stool-tests demonstrate that adenoma detection rates are lower when endoscopists are blinded to the stool-test results. This suggests adenoma sensitivity may be lower for screening colonoscopy than for follow-up to a known positive stool-based test. Previous CRC microsimulation models assume identical sensitivities between screening and follow-up colonoscopies after positive stool-tests.

Biased M receptor-positive allosteric modulators reveal role of phospholipase D in M-dependent rodent cortical plasticity.

Highly selective, positive allosteric modulators (PAMs) of the M subtype of muscarinic acetylcholine receptor have emerged as an exciting new approach to potentially improve cognitive function in patients suffering from Alzheimer's disease and schizophrenia. Discovery programs have produced a structurally diverse range of M receptor PAMs with distinct pharmacological properties, including different extents of agonist activity and differences in signal bias. This includes biased M receptor PAMs that can potentiate coupling of the receptor to activation of phospholipase C (PLC) but not phospholipase D (PLD).

Microvascular Outcomes in Patients With Diabetes After Bariatric Surgery Versus Usual Care: A Matched Cohort Study.

Background: Bariatric surgery improves glycemic control in patients with type 2 diabetes mellitus (T2DM), but less is known about microvascular outcomes.

Objective: To investigate the relationship between bariatric surgery and incident microvascular complications of T2DM.

Design: Retrospective matched cohort study from 2005 to 2011 with follow-up through September 2015.

Fundamental constructs in food parenting practices: a content map to guide future research.

Although research shows that "food parenting practices" can impact children's diet and eating habits, current understanding of the impact of specific practices has been limited by inconsistencies in terminology and definitions. This article represents a critical appraisal of food parenting practices, including clear terminology and definitions, by a working group of content experts. The result of this effort was the development of a content map for future research that presents 3 overarching, higher-order food parenting constructs--coercive control, structure, and autonomy support--as well as specific practice subconstructs.

Translating slow-binding inhibition kinetics into cellular and in vivo effects.

Many drug candidates fail in clinical trials owing to a lack of efficacy from limited target engagement or an insufficient therapeutic index. Minimizing off-target effects while retaining the desired pharmacodynamic (PD) response can be achieved by reduced exposure for drugs that display kinetic selectivity in which the drug-target complex has a longer half-life than off-target-drug complexes. However, though slow-binding inhibition kinetics are a key feature of many marketed drugs, prospective tools that integrate drug-target residence time into predictions of drug efficacy are lacking, hindering the integration of drug-target kinetics into the drug discovery cascade.

Autologous transplantation as consolidation for aggressive non-Hodgkin's lymphoma.

Background: The efficacy of autologous stem-cell transplantation during the first remission in patients with diffuse, aggressive non-Hodgkin's lymphoma classified as high-intermediate risk or high risk on the International Prognostic Index remains controversial and is untested in the rituximab era.

Methods: We treated 397 patients who had disease with an age-adjusted classification of high risk or high-intermediate risk with five cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or CHOP plus rituximab. Patients with a response were randomly assigned to receive three additional cycles of induction chemotherapy (control group) or one additional cycle of induction chemotherapy followed by autologous stem-cell transplantation (transplantation group).

A cross-sectional investigation of trait disinhibition and its association with mindfulness and impulsivity.

Two online surveys were conducted to assess the relationship between trait disinhibition, impulsivity, mindfulness and adverse psychological symptoms. In study 1 adult females (n=196; mean age=21 yrs) completed the Three-Factor Eating Questionnaire (TEFQ-R21), the Hospital Anxiety and Depression Scale and a measure of dispositional mindfulness. In study 2 adult females (n=190; mean age=26 yrs) completed the same measures as in study 1 with the addition of the Barratt Impulsivity Scale.