Bimolecular collision outcomes on multidimensional potential energy surfaces: infrared spectroscopy and activation of NO-alkane collision complexes.

In bimolecular collisions between open-shell radicals and increasingly-larger alkanes, the relative impact configurations open the possibility of reactive and nonreactive outcomes that are isomer specific. To model the interaction potential between molecular scattering partners, observables are needed from experiments that can quantify both the initial molecular orientations and internal energies on multidimensional potential energy surfaces. Recent work by our group demonstrated that upon infrared (IR) excitation, the dynamics of the nitric oxide-methane collision complex (NO-CH4) are dependent on the initial monomer geometries, as small changes in configuration substantially affect the energies, electronic couplings, and predissociation pathways due to the Jahn-Teller effect. This study focuses on the isomer-specific scattering mechanisms between NO and ethane (C2H6), encoded in the spectroscopic and dynamical signatures of the NO-C2H6 collision complex. IR action spectroscopy with 1 + 1 resonance-enhanced multiphoton ionization of NO products was employed to characterize the fundamental CH stretch transitions of NO-C2H6, as well as to initiate the nonreactive decay mechanisms of the complex. Furthermore, velocity map imaging (VMI) was utilized to explore the dynamics prior to and following IR excitation of NO-C2H6, imprinted on the NO photoproducts. This work compares the dynamics from NO-C2H6 and NO-CH4 vibrational predissociation, in which substantial differences are observed in the energy exchange mechanisms during the evolution of the collision complexes to products.

Expert Perspectives on Controversies in Castration-Sensitive Prostate Cancer Management: Narrative Review and Report of the First US Prostate Cancer Conference Part 1.

Purpose: Castration-sensitive prostate cancer (CSPC) is a complex and heterogeneous condition encompassing a range of clinical presentations. As new approaches have expanded management options, clinicians are left with myriad questions and controversies regarding the optimal individualized management of CSPC. Materials and Methods: The US Prostate Cancer Conference (USPCC) multidisciplinary panel was assembled to address the challenges of prostate cancer management. The first annual USPCC meeting included experts in urology, medical oncology, radiation oncology, and nuclear medicine. USPCC co-chairs and session moderators identified key areas of controversy and uncertainty in prostate cancer management and organized the sessions with multidisciplinary presentations and discussion. Throughout the meeting, experts responded to questions prepared by chairs and moderators to identify areas of agreement and controversy. Results: The USPCC panel discussion and question responses for CSPC-related topics are presented. Key advances in CSPC management endorsed by USPCC experts included the development and clinical utilization of gene expression classifiers and artificial intelligence (AI) models for risk stratification and treatment selection in specific patient populations, the use of advanced imaging modalities in patients with clinically localized unfavorable intermediate or high-risk disease and those with biochemical recurrence, recommendations of doublet or triplet therapy for metastatic CSPC (mCSPC), and consideration of prostate and/or metastasis-directed radiation therapy in select patients with mCSPC. Conclusions: CSPC is a diverse disease with many therapeutic options and the potential for adverse outcomes associated with either undertreatment or overtreatment. Future studies are needed to validate and clinically integrate novel technologies, including genomics, AI, and advanced imaging, to optimize outcomes among patients with CSPC.

Expert Perspectives on Controversies in Metastatic Castration-Resistant Prostate Cancer Management: Narrative Review and Report of the First US Prostate Cancer Conference Part 2.

Background: Management strategies for metastatic castration-resistant prostate cancer (mCRPC) have rapidly shifted in recent years. As novel imaging and therapeutic approaches have made their way to the clinic, providers are encountering increasingly challenging clinical scenarios, with limited guidance from the current literature. Materials and Methods: The US Prostate Cancer Conference (USPCC) is a multidisciplinary meeting of prostate cancer experts intended to address the many challenges of prostate cancer management. At the first annual USPCC meeting, areas of controversy and consensus were identified during a 2-day meeting that included expert presentations, full-panel discussions, and postdiscussion responses to questions developed by the USPCC cochairs and session moderators. Results: This narrative review covers the USPCC expert discussion and perspectives relevant to mCRPC, including neuroendocrine/aggressive-variant prostate cancer (NEPC/AVPC). Areas of broad agreement identified among USPCC experts include the benefits of poly (ADP-ribose) polymerase (PARP) inhibitors for patients with BRCA1/2 mutations, the use of radioligand therapy in patients with prostate-specific membrane antigen (PSMA)-positive mCRPC, and the need for clinical trials that address real-world clinical questions, including the performance of novel therapies when compared with modern standard-of-care treatment. Ongoing areas of controversy and uncertainty included the appropriateness of PARP inhibitors in patients with non-BRCA1/2 mutations, the optimal definition of PSMA positivity, and systemic therapies for patients with NEPC/AVPC after progression on platinum-based therapies. Conclusions: The first annual USPCC meeting identified several areas of controversy in the management of mCRPC, highlighting the urgent need for clinical trials designed to facilitate treatment selection and sequencing in this heterogeneous disease state.

Are Gait Patterns during In-Lab Running Representative of Gait Patterns during Real-World Training? An Experimental Study.

Biomechanical assessments of running typically take place inside motion capture laboratories. However, it is unclear whether data from these in-lab gait assessments are representative of gait during real-world running. This study sought to test how well real-world gait patterns are represented by in-lab gait data in two cohorts of runners equipped with consumer-grade wearable sensors measuring speed, step length, vertical oscillation, stance time, and leg stiffness. Cohort 1 (N = 49) completed an in-lab treadmill run plus five real-world runs of self-selected distances on self-selected courses. Cohort 2 (N = 19) completed a 2.4 km outdoor run on a known course plus five real-world runs of self-selected distances on self-selected courses. The degree to which in-lab gait reflected real-world gait was quantified using univariate overlap and multivariate depth overlap statistics, both for all real-world running and for real-world running on flat, straight segments only. When comparing in-lab and real-world data from the same subject, univariate overlap ranged from 65.7% (leg stiffness) to 95.2% (speed). When considering all gait metrics together, only 32.5% of real-world data were well-represented by in-lab data from the same subject. Pooling in-lab gait data across multiple subjects led to greater distributional overlap between in-lab and real-world data (depth overlap 89.3-90.3%) due to the broader variability in gait seen across (as opposed to within) subjects. Stratifying real-world running to only include flat, straight segments did not meaningfully increase the overlap between in-lab and real-world running (changes of <1%). Individual gait patterns during real-world running, as characterized by consumer-grade wearable sensors, are not well-represented by the same runner's in-lab data. Researchers and clinicians should consider "borrowing" information from a pool of many runners to predict individual gait behavior when using biomechanical data to make clinical or sports performance decisions.

Sexual and gender minority content in undergraduate medical education in the United States and Canada: current state and changes since 2011.

PURPOSE: To characterize current lesbian, gay, bisexual, transgender, queer, and intersex (LGBTQI +) health-related undergraduate medical education (UME) curricular content and associated changes since a 2011 study and to determine the frequency and extent of institutional instruction in 17 LGBTQI + health-related topics, strategies for increasing LGBTQI + health-related content, and faculty development opportunities. METHOD: Deans of medical education (or equivalent) at 214 allopathic or osteopathic medical schools in Canada and the United States were invited to complete a 36-question, Web-based questionnaire between June 2021 and September 2022. The main outcome measured was reported hours of LGBTQI + health-related curricular content. RESULTS: Of 214 schools, 100 (46.7%) responded, of which 85 (85.0%) fully completed the questionnaire. Compared to 5 median hours dedicated to LGBTQI + health-related in a 2011 study, the 2022 median reported time was 11 h (interquartile range [IQR], 6-16 h, p < 0.0001). Two UME institutions (2.4%; 95% CI, 0.0%-5.8%) reported 0 h during the pre-clerkship phase; 21 institutions (24.7%; CI, 15.5%-33.9%) reported 0 h during the clerkship phase; and 1 institution (1.2%; CI, 0%-3.5%) reported 0 h across the curriculum. Median US allopathic clerkship hours were significantly different from US osteopathic clerkship hours (4 h [IQR, 1-6 h] versus 0 h [IQR, 0-0 h]; p = 0.01). Suggested strategies to increase content included more curricular material focusing on LGBTQI + health and health disparities at 55 schools (64.7%; CI, 54.6%-74.9%), more faculty willing and able to teach LGBTQI + -related content at 49 schools (57.7%; CI, 47.1%-68.2%), and more evidence-based research on LGBTQI + health and health disparities at 24 schools (28.2%; CI, 18.7%-37.8%). CONCLUSION: Compared to a 2011 study, the median reported time dedicated to LGBTQI + health-related topics in 2022 increased across US and Canadian UME institutions, but the breadth, efficacy, or quality of instruction continued to vary substantially. Despite the increased hours, this still falls short of the number of hours based on recommended LGBTQI + health competencies from the Association of American Medical Colleges. While most deans of medical education reported their institutions' coverage of LGBTQI + health as 'fair,' 'good,' or 'very good,' there continues to be a call from UME leadership to increase curricular content. This requires dedicated training for faculty and students.

Severe PTSD is marked by reduced oxytocin and elevated vasopressin.

Neuroendocrine analyses of posttraumatic stress disorder (PTSD) have generally focused on hypothalamic-pituitary-adrenal (HPA) axis alterations. In the present analyses, we examine two additional neuroendocrine factors that have been previously implicated in biological stress responses: oxytocin (OT) and arginine vasopressin (AVP). Here we examined basal neuropeptide status in military veterans clinically diagnosed with PTSD (n = 29) and in two non-traumatized comparison groups with previous stress exposure (n = 11 SWAT trainees and n = 21 ultramarathon runners). PTSD patients showed low levels of plasma OT and high levels of AVP. The ratio of AVP/OT robustly related to PTSD status, and emerged as a statistically plausible mediator of relationships between the number of personal traumatic experiences and subsequent PTSD symptom burden. Over the course of behavioral therapy for PTSD, measures of OT showed a significant but modest normalization. Plasma cortisol levels were not statistically different among the three groups. This study suggests that AVP/OT ratios may represent a neuroendocrine predictor of severe PTSD, as well as a potential treatment response biomarker.

Surface State Dissipation in Confined

We have studied the power dependence of superfluid Helmholtz resonators in flat (750 and 1800 nm) rectangular channels. In the A phase of superfluid ^{3}He, we observe a nonlinear response for velocities larger than a critical value. The small size of the channels stabilizes a static uniform texture that eliminates dissipative processes produced by changes in the texture. For such a static texture, the lowest velocity dissipative process is due to the pumping of surface bound states into the bulk liquid. We show that the temperature dependence of the critical velocity observed in our devices is consistent with this surface-state dissipation. Characterization of the force-velocity curves of our devices may provide a platform for studying the physics of exotic surface bound states in superfluid ^{3}He.

Positive association between dehydroepiandrosterone (DHEA) and gene expression of the gamma-aminobutyric acid (GABA-A) receptor δ subunit.

Gamma-aminobutyric acid A (GABA-A) receptors in the cells of the immune system enhance anti-inflammatory responses by regulating cytokine secretion, cytotoxic responses, and cell activation. In the CNS, the formation of GABA-A subunits into a pentameric structure has been extensively studied; however, no such study has been conducted in the immune system. The objective of the present study was to examine associations between the levels of steroid hormones and GABA-A receptor δ subunit expression in the immune system. We focused on this subunit because GABA-A receptors that contain it become significantly more sensitive to steroid hormones. We collected 80 blood samples from reproductive age women for the purpose of analyzing dehydroepiandrosterone (DHEA), 17ß-estradiol, progesterone, and allopregnanolone using liquid chromatography-mass spectrometry (LC-MS). Furthermore, we extracted peripheral blood mononuclear cells (PBMCs) for determining mRNA expression levels of GABA-A receptor genes encoding the δ and ε subunits. We constructed linear mixed effect models for each GABA-A receptor subunit with all 4 steroid hormones, age, and age of menarche as predictors. Whereas DHEA was significantly associated with δ subunit expression (t-value = 2.981; p = 0.003), in line with our hypothesis, none of the steroid hormones were significantly associated with the expression of the ε subunit. Results of this study indicate that significant interactions between hormones from the steroid hormone biosynthesis pathway and GABAergic machinery from the immune cells may be utilized to expand models examining the molecular basis of inflammatory conditions.

Visuospatial Function in Women with Premenstrual Dysphoric Disorder.

Background/Objectives: Premenstrual dysphoric disorder (PMDD) is an understudied psychiatric condition affecting reproductive-age women who experience negative mood in the luteal phase of the menstrual cycle. Cognitive functions in PMDD are not well understood as patients have been tested in the luteal phase. This may confound study results due to noted emotional interferences, as well as the potential opposing effects of the sex hormones estradiol and progesterone. In the present study, we evaluated visuospatial function in the follicular phase in women with PMDD and healthy controls, and further examined the effect of estradiol as research into the hormonal mediation of visuospatial function in reproductive-age women has produced mixed results. Methods: To this end, we analyzed estradiol concentrations using the gold standard mass spectrometry. Serum samples were collected in the early follicular and mid/late follicular subphases when estradiol is low and high, respectively, while progesterone is low and steady. We assessed visuospatial function using the classic mental rotation task. Results: Women with PMDD had a higher mental rotation total score (t = 2.17; p < 0.05). The addition of six demographic, biological, and anthropomorphic variables in a hierarchical fashion accounted for 45.3% of the total variance in the final model with diagnosis remaining statistically significant (t = 4.36; p < 0.001). Estradiol did not mediate the group difference and was not significantly associated with visuospatial function. Conclusions: The present results provide support for new research directions into the potential biological mechanisms that underlie the pathophysiology of PMDD, represented as enhanced visuospatial ability in women with PMDD in the follicular phase. We review the theory that PMDD is a disorder of the enhanced excitation-to-inhibition ratio, with a focus on findings to date from brain imaging research.

An environmentally relevant mixture of Perfluoroalkyl Substances (PFAS) impacts proliferation, steroid hormone synthesis, and gene transcription in primary human granulosa cells.

Perfluoroalkyl substances (PFAS) are a group of synthetic chemicals that are resistant to biodegradation and are environmentally persistent. PFAS are found in many consumer products and are a major source of water and soil contamination. This study investigated the effects of an environmentally relevant PFAS mixture [perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), perfluorohexanesulfonic acid (PFHxS)] on the transcriptome and function of human granulosa cells (hGCs). Primary hGCs were harvested from follicular aspirates of healthy, reproductive-age women who were undergoing oocyte retrieval for in vitro fertilization. LC/MS-MS was performed to identify PFAS compounds in pure follicular fluid. Cells were cultured with vehicle control or a PFAS mixture (2 nM PFHxS, 7 nM PFOA, 10 nM PFOS) for 96h. Analyses of cell proliferation/apoptosis, steroidogenesis, and gene expression were measured via MTT assays/immunofluorescence, ELISA/western blotting, and RNA sequencing/bioinformatics, respectively. PFOA, PFOS, and PFHxS were detected in 100% of follicle fluid samples. Increased cell proliferation was observed in hGCs treated with the PFAS mixture with no impacts on cellular apoptosis. The PFAS mixture also altered steroid hormone synthesis, increasing both FSH-stimulated and basal progesterone secretion and concomitant upregulation of STAR protein. RNA sequencing revealed inherent differences in transcriptomic profiles in hGCs after PFAS exposure. This study demonstrates functional and transcriptomic changes in hGCs after exposure to a PFAS mixture, improving our knowledge about the impacts of PFAS exposures and female reproductive health. These findings suggest that PFAS compounds can disrupt normal granulosa cell function with possible long-term consequences on overall reproductive health.

Pharmacokinetics and pharmacodynamics of mibavademab (a leptin receptor agonist): Results from a first-in-human phase I study.

Mibavademab (previously known as REGN4461), a fully human monoclonal antibody, is being investigated for the treatment of conditions associated with leptin deficiency. Here, we report pharmacokinetics (PKs), pharmacodynamics, and immunogenicity from a phase I study in healthy participants (NCT03530514). In part A, lean or overweight healthy participants were randomized to single-ascending-dose cohorts of 0.3, 1.0, 3.0, 10, and 30 mg/kg intravenous (i.v.), or 300 and 600 mg subcutaneous doses of mibavademab or placebo. In part B, overweight or obese participants were randomized to receive multiple doses of mibavademab (15 mg/kg i.v. loading dose and 10 mg/kg i.v. at weeks 3, 6, and 9) or placebo, stratified by body mass index and baseline leptin levels: low leptin (<5 ng/mL) or relatively low leptin (5-8 ng/mL in men and 5-24 ng/mL in women). Fifty-six and 55 participants completed the single-ascending-dose and multiple-dose parts, respectively. In the single-ascending-dose cohorts, mibavademab PKs were nonlinear with target-mediated elimination, greater than dose-proportional increases in exposure, and there were no dose-dependent differences in total soluble leptin receptor (sLEPR) levels in serum over time. Following multiple-dose administration of mibavademab in participants with leptin <8 ng/mL, lower mean mibavademab concentrations, higher mean total sLEPR concentrations, and larger mean decreases in body weight than in the relatively low leptin cohorts were observed. Baseline leptin was correlated with mibavademab PKs and pharmacodynamics. No treatment-emergent anti-mibavademab antibodies were observed in any mibavademab-treated participant. Results from this study collectively inform further development of mibavademab to treat conditions associated with leptin deficiency.

Neuroactive steroid hormone trajectories across the menstrual cycle in premenstrual dysphoric disorder (PMDD): the PHASE study.

It is presently not known whether endogenous neuroactive steroid hormone trajectories across the menstrual cycle are distinguishable in women with premenstrual dysphoric disorder (PMDD). To improve the rigor in this area of research, we implemented a validated study methodology, involving blood sample collection at 8 key menstrual cycle timepoints, following which the study data is realigned so that all women are compared at the same biological window (i.e., menstrual cycle subphase). Using liquid chromatography-mass spectrometry (LC-MS), we analyzed serum levels of nine steroid hormones previously implicated in the etiology of PMDD, including allopregnanolone. Other than progesterone (p ≤ 0.001), none of the steroid hormones displayed significant changes across menstrual cycle subphases when comparing participants with PMDD to the healthy controls. A thorough investigation of the progesterone trajectory showed that its left shift in the luteal phase (e.g., earlier rise in progesterone) exposes women with PMDD to a higher periovulatory progesterone and a more acute withdrawal in the late luteal subphase. Results of the present study indicate that the largely overlooked brief periovulatory subphase should be thoroughly examined in PMDD and agree with prior conclusions that rapid progesterone withdrawal associates with the development of negative affect.

Efficacy, acceptability and side-effects of oral versus long-acting- injectables antipsychotics: Systematic review and network meta-analysis.

Long-acting injectable antipsychotics (LAIs) are primarily used for relapse prevention, but in some settings and situations, they may also be useful for acute treatment of schizophrenia. We conducted a systematic review and frequentist network meta-analysis of randomized-controlled trials (RCTs), focusing on adult patients in the acute phase of schizophrenia. Interventions were risperidone, paliperidone, aripiprazole, olanzapine, and placebo, administered either orally or as LAI. We synthesized data on overall symptoms, complemented by 17 other efficacy and tolerability outcomes. Confidence in the evidence was assessed with the Confidence-in-Network-Meta-Analysis-framework (CINeMA). We included 115 RCTs with 25,550 participants. All drugs were significantly more efficacious than placebo with the following standardized mean differences and their 95 % confidence intervals: olanzapine LAI -0.66 [-1.00; -0.33], risperidone LAI -0.59[-0.73;-0.46], olanzapine oral -0.55[-0.62;-0.48], aripiprazole LAI -0.54[-0.71; -0.37], risperidone oral -0.48[-0.55;-0.41], paliperidone oral -0.47[-0.58;-0.37], paliperidone LAI -0.45[-0.57;-0.33], aripiprazole oral -0.40[-0.50; -0.31]. There were no significant efficacy differences between LAIs and oral formulations. Sensitivity analyses of the primary outcome overall symptoms largely confirmed these findings. Moreover, some side effects were less frequent under LAIs than under their oral counterparts. Confidence in the evidence was moderate for most comparisons. LAIs are efficacious for acute schizophrenia and may have some benefits compared to oral formulations in terms of side effects. These findings assist clinicians with insights to weigh the risks and benefits between oral and injectable agents when treating patients in the acute phase.

Blunted Cortisol Response to Acute Psychosocial Stress in Women With Premenstrual Dysphoric Disorder.

BACKGROUND: Despite being considered a stress-related condition, it is not known whether the hypothalamic-pituitary-adrenal (HPA) axis is dysfunctional in response to acute psychosocial stress in premenstrual dysphoric disorder (PMDD). This is problematic because many women with PMDD report that they are not able to control their stress levels, and a blunted cortisol output has been identified in women with related psychiatric conditions, such as anxiety and depression. The present study is a part of the Premenstrual Hormonal and Affective State Evaluation (PHASE) project, and it aimed to characterize the cortisol trajectory in response to an acute psychosocial stress challenge. METHODS: Women with PMDD and healthy controls with confirmed ovulatory cycles underwent the Trier Social Stress Test (TSST) procedure in the mid-late luteal phase of the menstrual cycle, throughout which we collected serum samples of cortisol that we analyzed using ultra-performance liquid chromatography tandem mass spectrometry. RESULTS: The linear mixed model analysis indicated a significant time*diagnosis interaction (P = .008) such that women with PMDD displayed significantly lower serum cortisol levels at +40 through +90 minutes from the time of stress induction. CONCLUSION: This is the first study to show that women with PMDD have a blunted cortisol response to psychosocial stress. Combined with our earlier finding showing a greater parasympathetic nervous system withdrawal on heart oscillations in PMDD during acute stress, these and other results show that the dysregulated processing of stress in PMDD may be captured using objective study measures.

Neddylation inhibition affects early embryonic development by disrupting maternal-to-zygotic transition and mitochondrial function in mice.

Post-translational modifications (PTMs) are critical for early development in mice because early cleavage-stage embryos are characterized by transcriptional inactivity. Neddylation is an important ubiquitin-like PTM that regulates multiple biophysical processes. However, the exact roles of neddylation in regulating early embryonic development remain largely unknown. In the present study, we found that inhibition of neddylation by specific inhibitor MLN4924 led to severe arrest of early embryonic development. Transcriptomic analysis showed that neddylation inhibition changed the expression of 3959 genes at the 2-cell stage. Importantly, neddylation inhibition blocked zygotic genome activation and maternal mRNA degradation, thus disrupting the maternal-to-zygotic transition. Moreover, inhibition of neddylation induced mitochondrial dysfunction including aberrant mitochondrial distribution, decreased mitochondrial membrane potential, and reduced ATP content. Further analysis showed that inhibition of neddylation resulted in the accumulation of reactive oxygen species and superoxide anion, thereby resulting in oxidative stress and severe DNA damage at the 2-cell stage. Overall, this study demonstrates that neddylation is vital for early embryonic development in mice. Our findings suggest that proper neddylation regulation is essential for the timely inter-stage transition during early embryonic development.

Integrative Molecular Analyses of the MD Anderson Prostate Cancer Patient-derived Xenograft (MDA PCa PDX) Series.

PURPOSE: Develop and deploy a robust discovery platform that encompasses heterogeneity, clinical annotation, and molecular characterization and overcomes the limited availability of prostate cancer models. This initiative builds on the rich MD Anderson (MDA) prostate cancer (PCa) patient-derived xenograft (PDX) resource to complement existing publicly available databases by addressing gaps in clinically annotated models reflecting the heterogeneity of potentially lethal and lethal prostate cancer. EXPERIMENTAL DESIGN: We performed whole-genome, targeted, and RNA sequencing in representative samples of the same tumor from 44 PDXs derived from 38 patients linked to donor tumor metadata and corresponding organoids. The cohort includes models derived from different morphologic groups, disease states, and involved organ sites (including circulating tumor cells), as well as paired samples representing heterogeneity or stages before and after therapy. RESULTS: The cohort recapitulates clinically reported alterations in prostate cancer genes, providing a data resource for clinical and molecular interrogation of suitable experimental models. Paired samples displayed conserved molecular alteration profiles, suggesting the relevance of other regulatory mechanisms (e.g., epigenomic) influenced by the microenvironment and/or treatment. Transcriptomically, models were grouped on the basis of morphologic classification. DNA damage response-associated mechanisms emerged as differentially regulated between adenocarcinoma and neuroendocrine prostate cancer in a cross-interrogation of PDX/patient datasets. CONCLUSIONS: We addressed the gap in clinically relevant prostate cancer models through comprehensive molecular characterization of MDA PCa PDXs, providing a discovery platform that integrates with patient data and benchmarked to therapeutically relevant consensus clinical groupings. This unique resource supports robust hypothesis generation and testing from basic, translational, and clinical perspectives.

BRG1/BRM inhibitor targets AML stem cells and exerts superior preclinical efficacy combined with BET or menin inhibitor.

ABSTRACT: BRG1 (SMARCA4) and BRM (SMARCA2) are the mutually exclusive core ATPases of the chromatin remodeling BAF (BRG1/BRM-associated factor) complexes. They enable transcription factors/cofactors to access enhancers/promoter and modulate gene expressions responsible for cell growth and differentiation of acute myeloid leukemia (AML) stem/progenitor cells. In AML with MLL1 rearrangement (MLL1r) or mutant NPM1 (mtNPM1), although menin inhibitor (MI) treatment induces clinical remissions, most patients either fail to respond or relapse, some harboring menin mutations. FHD-286 is an orally bioavailable, selective inhibitor of BRG1/BRM under clinical development in AML. Present studies show that FHD-286 induces differentiation and lethality in AML cells with MLL1r or mtNPM1, concomitantly causing perturbed chromatin accessibility and repression of c-Myc, PU.1, and CDK4/6. Cotreatment with FHD-286 and decitabine, BET inhibitor (BETi) or MI, or venetoclax synergistically induced in vitro lethality in AML cells with MLL1r or mtNPM1. In models of xenografts derived from patients with AML with MLL1r or mtNPM1, FHD-286 treatment reduced AML burden, improved survival, and attenuated AML-initiating potential of stem-progenitor cells. Compared with each drug, cotreatment with FHD-286 and BETi, MI, decitabine, or venetoclax significantly reduced AML burden and improved survival, without inducing significant toxicity. These findings highlight the FHD-286-based combinations as a promising therapy for AML with MLL1r or mtNPM1.

Assembly and analysis of the genome of Notholithocarpus densiflorus.

Tanoak (Notholithocarpus densiflorus) is an evergreen tree in the Fagaceae family found in California and southern Oregon. Historically, tanoak acorns were an important food source for Native American tribes, and the bark was used extensively in the leather tanning process. Long considered a disjunct relictual element of the Asian stone oaks (Lithocarpus spp.), phylogenetic analysis has determined that the tanoak is an example of convergent evolution. Tanoaks are deeply divergent from oaks (Quercus) of the Pacific Northwest and comprise a new genus with a single species. These trees are highly susceptible to "sudden oak death" (SOD), a plant pathogen (Phytophthora ramorum) that has caused widespread deaths of tanoaks. In this study, we set out to assemble the genome and perform comparative studies among a number of individuals that demonstrated varying levels of susceptibility to SOD. First, we sequenced and de novo assembled a draft reference genome of N. densiflorus using cobarcoded library processing methods and an MGI DNBSEQ-G400 sequencer. To increase the contiguity of the final assembly, we also sequenced Oxford Nanopore long reads to 30× coverage. To our knowledge, the draft genome reported here is one of the more contiguous and complete genomes of a tree species published to date, with a contig N50 of ∼1.2 Mb, a scaffold N50 of ∼2.1 Mb, and a complete gene score of 95.5% through BUSCO analysis. In addition, we sequenced 11 genetically distinct individuals and mapped these onto the draft reference genome, enabling the discovery of almost 25 million single nucleotide polymorphisms and ∼4.4 million small insertions and deletions. Finally, using cobarcoded data, we were able to generate a complete haplotype coverage of all 11 genomes.

Developing and Implementing a Web-Based Branching Logic Survey to Support Psychiatric Crisis Evaluations of Individuals With Developmental Disabilities: Qualitative Study and Evaluation of Validity.

BACKGROUND: Individuals with developmental disabilities (DD) experience increased rates of emotional and behavioral crises that necessitate assessment and intervention. Psychiatric disorders can contribute to crises; however, screening measures developed for the general population are inadequate for those with DD. Medical conditions can exacerbate crises and merit evaluation. Screening tools using checklist formats, even when designed for DD, are too limited in depth and scope for crisis assessments. The Sources of Distress survey implements a web-based branching logic format to screen for common psychiatric and medical conditions experienced by individuals with DD by querying caregiver knowledge and observations. OBJECTIVE: This paper aims to (1) describe the initial survey development, (2) report on focus group and expert review processes and findings, and (3) present results from the survey's clinical implementation and evaluation of validity. METHODS: Sources of Distress was reviewed by focus groups and clinical experts; this feedback informed survey revisions. The survey was subsequently implemented in clinical settings to augment providers' psychiatric and medical history taking. Informal and formal consults followed the completion of Sources of Distress for a subset of individuals. A records review was performed to identify working diagnoses established during these consults. RESULTS: Focus group members (n=17) expressed positive feedback overall about the survey's content and provided specific recommendations to add categories and items. The survey was completed for 231 individuals with DD in the clinical setting (n=161, 69.7% men and boys; mean age 17.7, SD 10.3; range 2-65 years). Consults were performed for 149 individuals (n=102, 68.5% men and boys; mean age 18.9, SD 10.9 years), generating working diagnoses to compare survey screening results. Sources of Distress accuracy rates were 91% (95% CI 85%-95%) for posttraumatic stress disorder, 87% (95% CI 81%-92%) for anxiety, 87% (95% CI 81%-92%) for episodic expansive mood and bipolar disorder, 82% (95% CI 75%-87%) for psychotic disorder, 79% (95% CI 71%-85%) for unipolar depression, and 76% (95% CI 69%-82%) for attention-deficit/hyperactivity disorder. While no specific survey items or screening algorithm existed for unspecified mood disorder and disruptive mood dysregulation disorder, these conditions were caregiver-reported and working diagnoses for 11.7% (27/231) and 16.8% (25/149) of individuals, respectively. CONCLUSIONS: Caregivers described Sources of Distress as an acceptable tool for sharing their knowledge and insights about individuals with DD who present in crisis. As a screening tool, this survey demonstrates good accuracy. However, better differentiation among mood disorders is needed, including the addition of items and screening algorithm for unspecified mood disorder and disruptive mood dysregulation disorder. Additional validation efforts are necessary to include a more geographically diverse population and reevaluate mood disorder differentiation. Future study is merited to investigate the survey's impact on the psychiatric and medical management of distress in individuals with DD.