A Phase 1b study of the OxPhos inhibitor ME-344 with bevacizumab in refractory metastatic colorectal cancer.

Antiangiogenic drugs may cause vascular normalization and correct hypoxia in tumors, shifting cells to mitochondrial respiration as the primary source of energy. In turn, the addition of an inhibitor of mitochondrial respiration to antiangiogenic therapy holds potential to induce synthetic lethality. This study evaluated the mitochondrial inhibitor ME-344 in combination with bevacizumab in patients with refractory metastatic colorectal cancer (mCRC).

A phase 1 study of the CDK9 inhibitor voruciclib in relapsed/refractory acute myeloid leukemia and B-cell malignancies.

The anti-apoptotic protein myeloid cell leukemia-1 (Mcl-1) contributes to the pathophysiology of acute myeloid leukemia (AML) and certain B-cell malignancies. Tumor dependence on Mcl-1 is associated with resistance to venetoclax. Voruciclib, an oral cyclin-dependent kinase (CDK) inhibitor targeting CDK9, indirectly decreases Mcl-1 protein expression and synergizes with venetoclax in preclinical models.

Executive functioning and nonverbal cognitive factors associated with response to technology-assisted language intervention.

Objective: To explore potential differences in the relationship between executive function (EF) skills and language development when integrating augmentative and alternative communication technology into speech-language therapy for deaf/hard of hearing (DHH) children.

Method: Randomized trial data were analysed to investigate this relationship among children who participated in a Technology-Assisted Language Intervention (TALI) compared to treatment as usual (TAU). Language samples were assessed for pre-post-intervention changes, including mean length of utterance in morphemes (MLU), mean turn length (MTL), and number of different words spoken (NDW).

"My Aim Is True": An Attribution-Identity Model of Ally Sincerity.

Academic Abstract: Advantaged group allies have multiple motives for supporting equality, raising questions about their sincerity. We draw upon the covariation model of attributions to explain how disadvantaged group members make attributions about whether advantaged group "allies" are sincerely motivated to empower the disadvantaged group. We propose an Attribution-Identity Model of Sincerity (AIMS) which posits that disadvantaged group members view advantaged group members as sincere allies when they support equality in the presence of inhibitory causes and in the absence of facilitative causes, exceed expectations for the advantaged group, and provide support across time and contexts.

Hearing Loss and Autism Spectrum Disorder.

Gretta is a 3.5-year-old girl with a history of congenital cytomegalovirus, congenital bilateral profound sensorineural hearing loss (SNHL), and bilateral vestibular dysfunction, resulting in frequent falls. She underwent cochlear implantation at 12 months of age and was diagnosed with autism spectrum disorder at 2.

Concerns about the deportation of friends or family members shape U.S.-born Latines' feelings about U.S. immigration policy with implications for collective action for immigrants' rights.

Objectives: As citizens by birth, U.S.-born Latines are not subject to deportation.

An alcove at the acetyl-CoA synthase nickel active site is required for productive substrate CO binding and anaerobic carbon fixation.

One of the seven natural CO fixation pathways, the anaerobic Wood-Ljungdahl pathway (WLP) is unique in generating CO as a metabolic intermediate, operating through organometallic intermediates, and in conserving (versus utilizing) net ATP. The key enzyme in the WLP is acetyl-CoA synthase (ACS), which uses an active site [2Ni-4Fe-4S] cluster (A-cluster), a CO tunnel, and an organometallic (Ni-CO, Ni-methyl, and Ni-acetyl) reaction sequence to generate acetyl-CoA. Here, we reveal that an alcove, which interfaces the tunnel and the A-cluster, is essential for CO fixation and autotrophic growth by the WLP.

A Randomized Controlled Trial of Povidone-Iodine Versus Chlorhexidine Gluconate With Isopropyl Alcohol for Preoperative Vaginal Antisepsis.

Many surgeons request use of 10% povidone-iodine (PI) for vaginal antisepsis; however, when PI is contraindicated, some surgeons request use of chlorhexidine gluconate (CHG) instead. The purpose of this randomized controlled trial was to determine any significant differences in self-reported symptoms associated with vaginal antisepsis with either 10% PI scrub or 4% CHG with 4% isopropyl alcohol. The control group comprised 62 participants who underwent vaginal antisepsis with the PI product, and the intervention group comprised 58 participants who underwent vaginal antisepsis with the CHG product.

Rapid-reaction kinetics of the bifurcating NAD-dependent NADPH:ferredoxin oxidoreductase NfnI from Pyrococcus furiosus.

We have investigated the kinetics of NAD-dependent NADPH:ferredoxin oxidoreductase (NfnI), a bifurcating transhydrogenase that takes two electron pairs from NADPH to reduce two ferredoxins and one NAD through successive bifurcation events. NADPH reduction takes place at the bifurcating FAD of NfnI's large subunit, with high-potential electrons transferred to the [2Fe-2S] cluster and S-FADH of the small subunit, ultimately on to NAD; low-potential electrons are transferred to two [4Fe-4S] clusters of the large subunit and on to ferredoxin. Reduction of NfnI by NADPH goes to completion only at higher pH, with a limiting k of 36 ± 1.

Enhancing anti-AML activity of venetoclax by isoflavone ME-344 through suppression of OXPHOS and/or purine biosynthesis in vitro.

Venetoclax (VEN), in combination with low dose cytarabine (AraC) or a hypomethylating agent, is FDA approved to treat acute myeloid leukemia (AML) in patients who are over the age of 75 or cannot tolerate standard chemotherapy. Despite high response rates to these therapies, most patients succumb to the disease due to relapse and/or drug resistance, providing an unmet clinical need for novel therapies to improve AML patient survival. ME-344 is a potent isoflavone with demonstrated inhibitory activity toward oxidative phosphorylation (OXPHOS) and clinical activity in solid tumors.

The Association Between Family Resources and Language Among Young Children Who are Deaf and Hard of Hearing.

Objective: Our study (1) examined demographic factors in families with children with bilateral hearing loss and how they relate to Family Resource Scale (FRS) questionnaire data and (2) examined correlations between FRS data and measures of language.

Methods: Children aged 6 months to 10 years with bilateral hearing loss were enrolled. Parents completed the FRS questionnaire to assess their access to socioeconomic resources at the first language measurement visit.

Characterization of Methyl- and Acetyl-Ni Intermediates in Acetyl CoA Synthase Formed during Anaerobic CO and CO Fixation.

The Wood-Ljungdahl Pathway is a unique biological mechanism of carbon dioxide and carbon monoxide fixation proposed to operate through nickel-based organometallic intermediates. The most unusual steps in this metabolic cycle involve a complex of two distinct nickel-iron-sulfur proteins: CO dehydrogenase and acetyl-CoA synthase (CODH/ACS). Here, we describe the nickel-methyl and nickel-acetyl intermediates in ACS completing the characterization of all its proposed organometallic intermediates.

Psychometric properties of inhibitory control measures among youth with Down syndrome.

Background: Inhibitory control measures have been commonly used when assessing individuals with Down syndrome. However, minimal attention has been devoted to evaluating the appropriateness of specific assessments for use in this population, potentially leading to erroneous conclusions. This study aimed to examine the psychometric properties of measures of inhibitory control among youth with Down syndrome.

Enhancing anti-AML activity of venetoclax by isoflavone ME-344 through suppression of OXPHOS and/or purine biosynthesis.

Venetoclax (VEN), in combination with low dose cytarabine (AraC) or a hypomethylating agent, is FDA approved to treat acute myeloid leukemia (AML) in patients who are over the age of 75 or cannot tolerate standard chemotherapy. Despite high response rates to these combination therapies, most patients succumb to the disease due to relapse and/or drug resistance, providing an unmet clinical need for novel therapies to improve AML patient survival. ME-344 is a potent isoflavone with demonstrated inhibitory activity toward oxidative phosphorylation (OXPHOS) and clinical activity in solid tumors.

Evaluating Processing Speed and Reaction Time Outcome Measures in Children and Adolescents with Down Syndrome.

Reliable and valid cognitive outcome measures, including examiner-administered and computer-facilitated assessments of processing speed and reaction time, are necessary for future clinical trials that include individuals with Down syndrome (DS). The current study evaluated the score distributions and psychometric properties of four examiner-administered and three computerized processing speed and reaction time measures. Participants included 97 individuals with DS, aged 6 to 17 (M = 12.

Dual inhibition of HSF1 and DYRK2 impedes cancer progression.

Preserving proteostasis is a major survival mechanism for cancer. Dual specificity tyrosine phosphorylation-regulated kinase 2 (DYRK2) is a key oncogenic kinase that directly activates the transcription factor heat-shock factor 1 (HSF1) and the 26S proteasome. Targeting DYRK2 has proven to be a tractable strategy to target cancers sensitive to proteotoxic stress; however, the development of HSF1 inhibitors remains in its infancy.

GPCR Signaling Measurement and Drug Profiling with an Automated Live-Cell Microscopy System.

A major limitation of time-lapse microscopy combined with fluorescent biosensors, a powerful tool for quantifying spatiotemporal dynamics of signaling in single living cells, is low-experimental throughput. To overcome this limitation, we created a highly customizable, MATLAB-based platform: flexible automated liquid-handling combined microscope (FALCOscope) that coordinates an OpenTrons liquid handler and a fluorescence microscope to automate drug treatments, fluorescence imaging, and single-cell analysis. To test the feasibility of the FALCOscope, we quantified G protein-coupled receptor (GPCR)-stimulated Protein Kinase A activity and cAMP responses to GPCR agonists and antagonists.

Understanding decision-making and educational need in the management of pediatric patients with moderate-to-severe asthma: analysis of a US-based clinician survey.

Asthma creates a substantial burden on the pediatric healthcare system, particularly by those with moderate-to-severe disease. As few studies have been published specific to clinician evaluation and management of this population, this analysis serves to begin to identify educational needs and potential clinical impact. We conducted a case-based survey of US general pediatric ( = 227), allergy ( = 158), and pediatric pulmonology ( = 70) clinicians to understand the current approach to management of pediatric patients with moderate-to-severe asthma.

Evaluating Verbal Fluency Outcome Measures in Children With Down Syndrome.

This study evaluates the psychometric properties of a verbal fluency task for potential use as an outcome measure in future clinical trials involving children with Down syndrome. Eighty-five participants attempted a modified version of the Neuropsychological Assessment of Children, Second Edition Word Generation Task at two time points. In the full sample, the measure fell below a priori reliability and feasibility criteria, though feasibility of the semantic trials were higher than feasibility of the phonemic trials.

Time-Resolved Infrared Spectroscopy Reveals the pH-Independence of the First Electron Transfer Step in the [FeFe] Hydrogenase Catalytic Cycle.

[FeFe] hydrogenases are highly active catalysts for hydrogen conversion. Their active site has two components: a [4Fe-4S] electron relay covalently attached to the H binding site and a diiron cluster ligated by CO, CN, and 2-azapropane-1,3-dithiolate (ADT) ligands. Reduction of the [4Fe-4S] site was proposed to be coupled with protonation of one of its cysteine ligands.

The Importance of Accessible Language for Development in Deaf and Hard of Hearing Children.

Brady is a 5-year-old boy who was seen in a multidisciplinary clinic for evaluation of deaf and hard of hearing children. Brady was born full-term after an uncomplicated pregnancy. He was referred for audiological evaluation after his newborn hearing screen and was diagnosed with a severe-to-profound bilateral sensorineural hearing difference at age 6 months.

Factors Associated with Early Intervention Intensity for Children Who Are Deaf or Hard of Hearing.

We quantified the intensity of early intervention (EI) services allocated to 1262 children who were deaf or hard of hearing (DHH) within a state program and identified factors associated with intervention intensity. Child specific data were collected on children born between 2008 and 2014. Data from Individualized Family Service Plans of children enrolled in Part C EI programming were evaluated for the type and duration of services during their EI enrollment.

Down syndrome and the autonomic nervous system, an educational review for the anesthesiologist.

Approximately one in every 700 babies in the United States is born with Down syndrome, or 0.14%. Children with Down syndrome have cognitive impairment and congenital malformations necessitating frequent occurrences of general anesthesia and surgery.