Design of Potent Menin-KMT2A Interaction Inhibitors with Improved ADME Properties and Reduced hERG Affinity.

Inhibitors of the interaction of menin (MEN1) with lysine methyltransferase 2A (KMT2A) have emerged as novel therapeutic options in the treatment of genetically defined acute leukemias. Herein, we describe the structure-based design, synthesis, and biological evaluation of novel inhibitors of the menin-KMT2A interaction. Our structure-activity relationship campaign focused on achieving high antiproliferative cellular activity while mitigating risks associated with CYP3A4-dependent metabolism and hERG inhibition, which were characterized in some early clinical candidates.

Interpersonal Continuity of Care May Help Delay Progression to Type 2 Diabetes.

Background: The association between interpersonal continuity of care (CoC) and progression from the prediabetic state to Type 2 Diabetes (T2D) remains unknown.

Aim: To evaluate the association between interpersonal CoC and the progression to T2D among persons with prediabetes.

Design And Setting: A retrospective cohort study using electronic health record (EHR) data from 6620 patients at Geisinger, a large rural health care system in Danville, PA.

Home environment factors associated with child BMI changes during COVID-19 pandemic.

Background: The influence of home obesogenic environments, as assessed by the validated Family Nutrition and Physical Activity (FNPA) tool, and child obesity during the COVID pandemic were evaluated using electronic health records in this retrospective cohort study.

Methods: Historical data on BMI and the FNPA screening tool were obtained from annual well-child visits within the Geisinger Health System. The study examined youth ages 2-17 that had a BMI record and an FNPA assessment prior to the pandemic (BMI 3/1/19-2/29/20), 1 BMI record 3 months into the pandemic (6/1/20-12/31/20) and 1 BMI in the second year of the pandemic (1/1/21-12/31/21).

An S1-Approach to Cross-Coupling: Deoxygenative Arylation Facilitated by the β-Silicon Effect.

We report a dual metal-catalyzed method for the cross-coupling of unprotected alcohols by exploiting the β-Si effect. This deoxygenative Suzuki-Miyaura reaction tolerates a range of primary, secondary, and tertiary alcohol substrates along with diverse functional groups and heterocycles. Mechanistic experiments including KIE, VTNA, and Eyring analyses suggest the existence of a carbocation intermediate on the reaction pathway, consistent with a rare S1 pathway for the activation of an electrophile in cross-coupling reactions.

Alcohols as Substrates in Transition-Metal-Catalyzed Arylation, Alkylation, and Related Reactions.

Alcohols are abundant and attractive feedstock molecules for organic synthesis. Many methods for their functionalization require them to first be converted into a more activated derivative, while recent years have seen a vast increase in the number of complexity-building transformations that directly harness unprotected alcohols. This Review discusses how transition metal catalysis can be used toward this goal.

Discovery of 5-Azaquinoxaline Derivatives as Potent and Orally Bioavailable Allosteric SHP2 Inhibitors.

SHP2 has emerged as an important target for oncology small-molecule drug discovery. As a nonreceptor tyrosine phosphatase within the MAPK pathway, it has been shown to control cell growth, differentiation, and oncogenic transformation. We used structure-based design to find a novel class of potent and orally bioavailable SHP2 inhibitors.

Free-Form Liquid Crystal Elastomers via Embedded 4D Printing.

Liquid crystal elastomers (LCEs) are a class of active materials that can generate rapid, reversible mechanical actuation in response to external stimuli. Fabrication methods for LCEs have remained a topic of intense research interest in recent years. One promising approach, termed 4D printing, combines the advantages of 3D printing with responsive materials, such as LCEs, to generate smart structures that not only possess user-defined static shapes but also can change their shape over time.

SHP2 Inhibition Sensitizes Diverse Oncogene-Addicted Solid Tumors to Re-treatment with Targeted Therapy.

Unlabelled: Rationally targeted therapies have transformed cancer treatment, but many patients develop resistance through bypass signaling pathway activation. PF-07284892 (ARRY-558) is an allosteric SHP2 inhibitor designed to overcome bypass-signaling-mediated resistance when combined with inhibitors of various oncogenic drivers. Activity in this setting was confirmed in diverse tumor models.

Reductive Cleavage of C(sp)-CF Bonds in Trifluoromethylpyridines.

A reductive detrifluoromethylation protocol has been developed making use of an earth-abundant alkoxide base and silicon hydride species. A variety of pyridine and quinoline substrates bearing alkyl, aryl, and amino functional groups are reduced in moderate to high yields. The reaction is chemoselective for C(sp)-CF groups located at the 2-position on the pyridine ring, leaving trifluoromethyl groups located elsewhere on the molecule intact.

3D Printing of Ridged FeS Cathodes for Improved Rate Capability and Custom-Form Lithium Batteries.

Additive manufacturing can enable the fabrication of batteries in nonconventional form factors, enabling higher practical energy density due to improved material packing efficiency of power sources in devices. Furthermore, energy density can be improved by transitioning from conventional Li-ion battery materials to lithium metal anodes and conversion cathodes. Iron disulfide (FeS) is a prominent conversion cathode of commercial interest; however, the direct-ink-write (DIW) printing of FeS inks for custom-form battery applications has yet to be demonstrated or optimized.

Framework From a Multidisciplinary Approach for Transitioning Variants of Unknown Significance From Clinical Genetic Testing in Kidney Disease to a Definitive Classification.

Introduction: Monogenic causes in over 300 kidney-associated genes account for approximately 12% of end stage kidney disease (ESKD) cases. Advances in sequencing and large customized panels enable the noninvasive diagnosis of monogenic kidney disease at relatively low cost, thereby allowing for more precise management for patients and their families. A major challenge is interpreting rare variants, many of which are classified as variants of unknown significance (VUS).

Family-Based Telehealth Initiative to Improve Nutrition and Physical Activity for Children With Obesity and Its Utility During COVID-19: A Mixed Methods Evaluation.

Guidelines recommend primary care providers refer children with obesity to behavioral interventions, but given limited program availability, access, and parental engagement, referrals remain rare. We developed telehealth coaching interventions for families whose children received care at a health system in Pennsylvania, United States in 2019-2020. Intervention referrals were facilitated by the pediatrician and/or project team for 6-12-year-old children with obesity following well-child visits.

Cancer in deceased adults with intellectual disabilities: English population-based study using linked data from three sources.

Objective: To improve our understanding of cancer in adults with intellectual disabilities.

Design: Population-based study using linked data about deceased adults from the Learning (Intellectual) Disabilities Mortality Review (LeDeR) programme, the national cancer registry and NHS Digital.

Setting: England.

Continuous Additive Manufacturing using Olefin Metathesis.

The development of chemistry is reported to implement selective dual-wavelength olefin metathesis polymerization for continuous additive manufacturing (AM). A resin formulation based on dicyclopentadiene is produced using a latent olefin metathesis catalyst, various photosensitizers (PSs) and photobase generators (PBGs) to achieve efficient initiation at one wavelength (e.g.

Effects of sustained weight loss on outcomes associated with obesity comorbidities and healthcare resource utilization.

Objective: Determine the impact of long-term non-surgical weight loss maintenance on clinical relevance for osteoarthritis, cancer, opioid use, and depression/anxiety and healthcare resource utilization.

Methods: A cohort of adults receiving primary care within Geisinger Health System between 2001-2017 was retrospectively studied. Patients with ≥3 weight measurements in the two-year index period and obesity at baseline (BMI ≥30 kg/m2) were categorized: Obesity Maintainers (reference group) maintained weight within +/-3%; Weight Loss Rebounders lost ≥5% body weight in year one, regaining ≥20% of weight loss in year two; Weight Loss Maintainers lost ≥5% body weight in year one, maintaining ≥80% of weight loss.

Impact of Sustained Weight Loss on Cardiometabolic Outcomes.

Obesity increases the risk of developing type 2 diabetes, hypertension, and hyperlipidemia. We sought to determine the impact of obesity maintenance, weight regain, weight loss maintenance, and magnitudes of weight loss on future risk and time to developing these cardiometabolic conditions. This was a retrospective cohort study of adults receiving primary care at Geisinger Health System between 2001 and 2017.

Association of varicose veins with rare protein-truncating variants in PIEZO1 identified by exome sequencing of a large clinical population.

Objective: The present study sought to determine whether protein-truncating variants (PTVs) in PIEZO1 and CASZ1 genes, previously shown to be associated with varicose veins, were associated with an altered risk of varicose veins.

Methods: An exome sequence database of 131,918 participants from the Geisinger MyCode Community Health Initiative was used to identify individuals with genetic variants in the PIEZO1 or CASZ1 gene. Clinical phenotypes, including varicose vein diagnoses, were determined by analysis of the electronic health record data.

Reaction screening in multiwell plates: high-throughput optimization of a Buchwald-Hartwig amination.

Chemical space is vast, and chemical reactions involve the complex interplay of multiple variables. As a consequence, reactions can fail for subtle reasons, necessitating screening of conditions. High-throughput experimentation (HTE) techniques enable a more comprehensive array of data to be obtained in a relatively short amount of time.

Advanced Health Information Technologies to Engage Parents, Clinicians, and Community Nutritionists in Coordinating Responsive Parenting Care: Descriptive Case Series of the Women, Infants, and Children Enhancements to Early Healthy Lifestyles for Baby (WEE Baby) Care Randomized Controlled Trial.

Background: Socioeconomically disadvantaged newborns receive care from primary care providers (PCPs) and Women, Infants, and Children (WIC) nutritionists. However, care is not coordinated between these settings, which can result in conflicting messages. Stakeholders support an integrated approach that coordinates services between settings with care tailored to patient-centered needs.

Communicating personalized risk of diabetes and offering weight reduction program choice: Recruitment, participation, and outcomes.

Objective: Low patient recruitment into diabetes prevention programs is a challenge. The primary aim of this study was to demonstrate that an increased recruitment rate can be achieved by communicating personalized risk of progression to type 2 diabetes, estimating risk reduction with weight loss, and offering program choice. Secondary aims included program participation rate, weight loss, and short-term decreased diabetes risk.

Exhaustive Reduction of Esters Enabled by Nickel Catalysis.

We report a one-step procedure to directly reduce unactivated aryl esters into their corresponding tolyl derivatives. This is achieved by an organosilane-mediated ester hydrosilylation reaction and subsequent Ni/NHC-catalyzed hydrogenolysis. The resulting conditions provide a direct and efficient alternative to multi-step procedures for this transformation that often require the use of hazardous metal hydrides.