A Benzarone Derivative Inhibits EYA to Suppress Tumor Growth in SHH Medulloblastoma.

Medulloblastoma is one of the most common malignant brain tumors of children, and 30% of medulloblastomas are driven by gain-of-function genetic lesions in the Sonic Hedgehog (SHH) signaling pathway. EYA1, a haloacid dehalogenase phosphatase and transcription factor, is critical for tumorigenesis and proliferation of SHH medulloblastoma (SHH-MB). Benzarone and benzbromarone have been identified as allosteric inhibitors of EYA proteins. Using benzarone as a point of departure, we developed a panel of 35 derivatives and tested them in SHH-MB. Among these compounds, DS-1-38 functioned as an EYA antagonist and opposed SHH signaling. DS-1-38 inhibited SHH-MB growth in vitro and in vivo, showed excellent brain penetrance, and increased the lifespan of genetically engineered mice predisposed to fatal SHH-MB. These data suggest that EYA inhibitors represent promising therapies for pediatric SHH-MB. SIGNIFICANCE: Development of a benzarone derivative that inhibits EYA1 and impedes the growth of SHH medulloblastoma provides an avenue for improving treatment of this malignant pediatric brain cancer.

Transcranial Low-Intensity Focused Ultrasound Stimulation of the Visual Thalamus Produces Long-Term Depression of Thalamocortical Synapses in the Adult Visual Cortex.

Transcranial focused ultrasound stimulation (tFUS) is a noninvasive neuromodulation technique, which can penetrate deeper and modulate neural activity with a greater spatial resolution (on the order of millimeters) than currently available noninvasive brain stimulation methods, such as transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS). While there are several studies demonstrating the ability of tFUS to modulate neuronal activity, it is unclear whether it can be used for producing long-term plasticity as needed to modify circuit function, especially in adult brain circuits with limited plasticity such as the thalamocortical synapses. Here we demonstrate that transcranial low-intensity focused ultrasound (LIFU) stimulation of the visual thalamus (dorsal lateral geniculate nucleus, dLGN), a deep brain structure, leads to NMDA receptor (NMDAR)-dependent long-term depression of its synaptic transmission onto layer 4 neurons in the primary visual cortex (V1) of adult mice of both sexes. This change is not accompanied by large increases in neuronal activity, as visualized using the cFos Targeted Recombination in Active Populations (cFosTRAP2) mouse line, or activation of microglia, which was assessed with IBA-1 staining. Using a model (SONIC) based on the neuronal intramembrane cavitation excitation (NICE) theory of ultrasound neuromodulation, we find that the predicted activity pattern of dLGN neurons upon sonication is state-dependent with a range of activity that falls within the parameter space conducive for inducing long-term synaptic depression. Our results suggest that noninvasive transcranial LIFU stimulation has a potential for recovering long-term plasticity of thalamocortical synapses in the postcritical period adult brain.

NSF DARE-transforming modeling in neurorehabilitation: perspectives and opportunities from US funding agencies.

In recognition of the importance and timeliness of computational models for accelerating progress in neurorehabilitation, the U.S. National Science Foundation (NSF) and the National Institutes of Health (NIH) sponsored a conference in March 2023 at the University of Southern California that drew global participation from engineers, scientists, clinicians, and trainees. This commentary highlights promising applications of computational models to understand neurorehabilitation ("Using computational models to understand complex mechanisms in neurorehabilitation" section), improve rehabilitation care in the context of digital twin frameworks ("Using computational models to improve delivery and implementation of rehabilitation care" section), and empower future interdisciplinary workforces to deliver higher-quality clinical care using computational models ("Using computational models in neurorehabilitation requires an interdisciplinary workforce" section). The authors describe near-term gaps and opportunities, all of which encourage interdisciplinary team science. Four major opportunities were identified including (1) deciphering the relationship between engineering figures of merit-a term commonly used by engineers to objectively quantify the performance of a device, system, method, or material relative to existing state of the art-and clinical outcome measures, (2) validating computational models from engineering and patient perspectives, (3) creating and curating datasets that are made publicly accessible, and (4) developing new transdisciplinary frameworks, theories, and models that incorporate the complexities of the nervous and musculoskeletal systems. This commentary summarizes U.S. funding opportunities by two Federal agencies that support computational research in neurorehabilitation. The NSF has funding programs that support high-risk/high-reward research proposals on computational methods in neurorehabilitation informed by theory- and data-driven approaches. The NIH supports the development of new interventions and therapies for a wide range of nervous system injuries and impairments informed by the field of computational modeling. The conference materials can be found at https://dare2023.usc.edu/ .

Special Issue-Biosensors and Neuroscience: Is Biosensors Engineering Ready to Embrace Design Principles from Neuroscience?

In partnership with the Air Force Office of Scientific Research (AFOSR), the National Science Foundation's (NSF) Emerging Frontiers and Multidisciplinary Activities (EFMA) office of the Directorate for Engineering (ENG) launched an Emerging Frontiers in Research and Innovation (EFRI) topic for the fiscal years FY22 and FY23 entitled "Brain-inspired Dynamics for Engineering Energy-Efficient Circuits and Artificial Intelligence" (BRAID) [...].

Developmental basis of SHH medulloblastoma heterogeneity.

Many genes that drive normal cellular development also contribute to oncogenesis. Medulloblastoma (MB) tumors likely arise from neuronal progenitors in the cerebellum, and we hypothesized that the heterogeneity observed in MBs with sonic hedgehog (SHH) activation could be due to differences in developmental pathways. To investigate this question, here we perform single-nucleus RNA sequencing on highly differentiated SHH MBs with extensively nodular histology and observed malignant cells resembling each stage of canonical granule neuron development. Through innovative computational approaches, we connect these results to published datasets and find that some established molecular subtypes of SHH MB appear arrested at different developmental stages. Additionally, using multiplexed proteomic imaging and MALDI imaging mass spectrometry, we identify distinct histological and metabolic profiles for highly differentiated tumors. Our approaches are applicable to understanding the interplay between heterogeneity and differentiation in other cancers and can provide important insights for the design of targeted therapies.

The impact of access to prenatal health insurance for noncitizen women on child health.

OBJECTIVE: To estimate the effects of prenatal public health insurance targeting noncitizens on the health of U.S.-born children of noncitizen mothers beyond birth outcomes. DATA SOURCES AND STUDY SETTING: This paper uses the restricted version of the 1998-2014 National Health Interview Survey with state-level geographic identifiers. STUDY DESIGN: The empirical strategy compares outcomes in states that adopted the Children's Health Insurance Plan (CHIP) Unborn Child Option with states that never adopted or adopted it at different times, controlling for differences in the pre-treatment period. I use a flexible event-study analysis to quantify the effects of the Unborn Child Option on noncitizen women's health insurance coverage, health care utilization, and their children's health. DATA COLLECTION/EXTRACTION METHODS: All data are derived from pre-existing sources. PRINCIPAL FINDINGS: The study finds that the impact of the Unborn Child Option is a 4.7%-point increase in public health insurance coverage (p < 0.01) and 0.48 more doctor's office visits (p < 0.1) annually among noncitizens of childbearing ages. Subsequently, the reform leads to a 7%-point rise in the rate of parents reporting their 4-6-year-old children are in "excellent" or "very good" health (p < 0.01). While no improvements are evident at birth and at younger ages, observed health improvements begin to appear by preschool age. CONCLUSIONS: The study contributes to the literature by providing evidence that certain benefits of in-utero public health insurance targeting noncitizens may appear several years after birth, specifically around preschool age.

TMEM161B regulates cerebral cortical gyration, Sonic Hedgehog signaling, and ciliary structure in the developing central nervous system.

Sonic hedgehog signaling regulates processes of embryonic development across multiple tissues, yet factors regulating context-specific Shh signaling remain poorly understood. Exome sequencing of families with polymicrogyria (disordered cortical folding) revealed multiple individuals with biallelic deleterious variants in TMEM161B, which encodes a multi-pass transmembrane protein of unknown function. Tmem161b null mice demonstrated holoprosencephaly, craniofacial midline defects, eye defects, and spinal cord patterning changes consistent with impaired Shh signaling, but were without limb defects, suggesting a CNS-specific role of Tmem161b. Tmem161b depletion impaired the response to Smoothened activation in vitro and disrupted cortical histogenesis in vivo in both mouse and ferret models, including leading to abnormal gyration in the ferret model. Tmem161b localizes non-exclusively to the primary cilium, and scanning electron microscopy revealed shortened, dysmorphic, and ballooned ventricular zone cilia in the Tmem161b null mouse, suggesting that the Shh-related phenotypes may reflect ciliary dysfunction. Our data identify TMEM161B as a regulator of cerebral cortical gyration, as involved in primary ciliary structure, as a regulator of Shh signaling, and further implicate Shh signaling in human gyral development.

Bayesian optimization of distributed neurodynamical controller models for spatial navigation.

Dynamical systems models for controlling multi-agent swarms have demonstrated advances toward resilient, decentralized navigation algorithms. We previously introduced the NeuroSwarms controller, in which agent-based interactions were modeled by analogy to neuronal network interactions, including attractor dynamics and phase synchrony, that have been theorized to operate within hippocampal place-cell circuits in navigating rodents. This complexity precludes linear analyses of stability, controllability, and performance typically used to study conventional swarm models. Further, tuning dynamical controllers by manual or grid-based search is often inadequate due to the complexity of objectives, dimensionality of model parameters, and computational costs of simulation-based sampling. Here, we present a framework for tuning dynamical controller models of autonomous multi-agent systems with Bayesian optimization. Our approach utilizes a task-dependent objective function to train Gaussian process surrogate models to achieve adaptive and efficient exploration of a dynamical controller model's parameter space. We demonstrate this approach by studying an objective function selecting for NeuroSwarms behaviors that cooperatively localize and capture spatially distributed rewards under time pressure. We generalized task performance across environments by combining scores for simulations in multiple mazes with distinct geometries. To validate search performance, we compared high-dimensional clustering for high- vs. low-likelihood parameter points by visualizing sample trajectories in 2-dimensional embeddings. Our findings show that adaptive, sample-efficient evaluation of the self-organizing behavioral capacities of complex systems, including dynamical swarm controllers, can accelerate the translation of neuroscientific theory to applied domains.

New and emerging therapies for the treatment of relapsed/refractory diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is the most common form of aggressive non-Hodgkin lymphoma. Approximately 40% of patients with DLBCL will experience disease relapse or will be refractory to first line chemoimmunotherapy, necessitating second-line salvage therapy. This has historically consisted of platinum-based chemotherapy regimens followed by autologous hematopoietic stem cell transplantation with curative intent for transplant-eligible patients or palliative chemotherapy for transplant-ineligible patients. In recent years there have been several new therapeutic agents approved for the treatment of relapsed/refractory DLBCL, thereby expanding the therapeutic landscape. These agents include polatuzumab vedotin, tafasitamab, loncastuximab tesirine, selinexor, and anti-CD19 chimeric antigen receptor T-cell therapies such as axicabtagene ciloleucel, tisagenlecleucel, and lisocabtagene maraleucel. This review summarizes the pharmacology, efficacy, safety, dosing, and administration of new agents recently approved for the treatment of relapsed/refractory DLBCL.

Online learning for orientation estimation during translation in an insect ring attractor network.

Insect neural systems are a promising source of inspiration for new navigation algorithms, especially on low size, weight, and power platforms. There have been unprecedented recent neuroscience breakthroughs with Drosophila in behavioral and neural imaging experiments as well as the mapping of detailed connectivity of neural structures. General mechanisms for learning orientation in the central complex (CX) of Drosophila have been investigated previously; however, it is unclear how these underlying mechanisms extend to cases where there is translation through an environment (beyond only rotation), which is critical for navigation in robotic systems. Here, we develop a CX neural connectivity-constrained model that performs sensor fusion, as well as unsupervised learning of visual features for path integration; we demonstrate the viability of this circuit for use in robotic systems in simulated and physical environments. Furthermore, we propose a theoretical understanding of how distributed online unsupervised network weight modification can be leveraged for learning in a trajectory through an environment by minimizing orientation estimation error. Overall, our results may enable a new class of CX-derived low power robotic navigation algorithms and lead to testable predictions to inform future neuroscience experiments.

Daily Marijuana Use Predicts HIV Seroconversion Among Black Men Who Have Sex with Men and Transgender Women in Atlanta, GA.

We evaluated whether different types of substance use predicted HIV seroconversion among a cohort of 449 Black men who have sex with men (MSM) and transgender women (TGW). A community-based sample was recruited in Atlanta, GA between December 2012 and November 2014. Participants completed a survey and were tested for STIs (Chlamydia and gonorrhoeae using urine samples and rectal swabs) at baseline. HIV testing was conducted at 12-months post enrollment. Multivariable binary logistic regression was used to estimate adjusted odds ratios (aORs) and 95% confidence intervals (CI) for associations between substance use and HIV seroconversion. By 12-month follow-up, 5.3% (n = 24) of participants seroconverted. In multivariable analyses, daily marijuana use was positively associated with HIV seroconversion (aOR 3.07, 95% CI 1.11-8.48, P = 0.030). HIV incidence was high and daily marijuana use was associated with a more than threefold increased odds of HIV seroconversion among a community-based cohort of Black MSM and TGW.

RESUMEN: Evaluamos si diferentes tipos de uso de sustancias predijeron la seroconversión del VIH entre una cohorte de 449 hombres que tienen sexo con hombres (HSH) y mujeres transgénero (TGW) de raza negra. Se reclutó una cohorte en la comunidad en Atlanta, GA, entre diciembre de 2012 y noviembre de 2014. Los participantes completaron una encuesta y se les hizo una prueba de infecciones de transmisión sexual (clamidia y gonorrea usando muestras de orina e hisopos rectales) al inicio del estudio. Los participantes completaron una prueba del VIH al final del estudio. Se utilizó la regresión logística binaria multivariable para estimar proporciones de probabilidades ajustadas (aOR) y los intervalos de confianza (CI) del 95% para las asociaciones entre el uso de sustancias y la seroconversión del VIH. A los 12 meses de seguimiento, 5,3% (n = 24) de los participantes se seroconvirtieron. En análisis multivariable, el consumo diario de marijuana se asoció positivamente con la seroconversión del VIH (aOR 3.07, 95% CI 1.11­8.48, P = 0.030). La incidencia del VIH fue elevada y el uso diario de marijuana se asoció con un aumento de más de 3 veces en las probabilidades de seroconversión del VIH entre una cohorte de HSH y TGW de raza negra reclutado por la comunidad.

Outcomes of colostomy takedown following Hartmann's procedure: successful restoration of continuity comes with a high risk of morbidity.

AIM: Restoration of bowel continuity following a Hartmann's procedure is a major surgical undertaking associated with significant morbidity. The aim of this study was to review the authors' experience with Hartmann's reversal. METHOD: This was a retrospective review of consecutive patients from institutional databases who were selected to undergo open or laparoscopic Hartmann's reversal at two tertiary academic referral centres and a public safety net hospital (2010-2019). The main outcome measure was the rate of successful stoma reversal. Secondary outcomes included 30-day postoperative outcomes and procedural details. RESULTS: One hundred and fifty patients underwent attempted reversal during the study period, which was successful in all but three patients (98%). Patients were 59% Hispanic and 73% male, with a mean age of 48.7 ± 14.1 years, mean American Society of Anesthesiologists classification of 2.2 ± 0.6 and mean body mass index (BMI) of 28.6 ± 5.3 kg/m2 , with 39% of patients having a BMI > 30 kg/m2 . The mean time interval between the index procedure and reversal was 14.4 months, 53% of the index cases were performed at outside institutions and the most common index diagnoses were diverticulitis (54%), abdominal trauma (16%) and colorectal malignancy (15%). In 22% of cases a laparoscopic approach was used, with 42% of these requiring conversion to open. Proximal diverting stomas were created in 32 patients (21%), of which 94% were reversed. The overall morbidity rate was 54%, comprising ileus (32%), wound infection (15%) and anastomotic leak (6%), with a major morbidity rate (Clavien-Dindo ≥ 3) of 23%. CONCLUSION: Hartmann's reversal remains a highly morbid procedure. Our results suggest that operative candidates can be successfully reversed, but there is significant morbidity associated with restoration of intestinal continuity, particularly in obese patients. A laparoscopic approach may decrease morbidity in selected patients but such cases have a high conversion rate.

An Architect of the Hindbrain: DDX3X Regulates Normal and Malignant Development.

Hallmark mutations in WNT and SHH medulloblastoma are usually distinct, but DDX3X is often mutated in both subgroups. In this issue of Developmental Cell, Patmore et al. identify Ddx3x as essential for hindbrain patterning, cell fate determination, and as a tumor suppressor gene that restricts cell lineage progression in tumorigenesis.

Oral Endocrine Therapy Agent, Race/Ethnicity, and Time on Therapy Predict Adherence in Breast Cancer Patients in a Large Academic Institution.

INTRODUCTION: Adherence to oral endocrine therapy (OET) reduces recurrence risk for hormone receptor (HR)-positive breast cancer (BC). Refill data accessed through electronic health records may provide objective assessment of OET adherence. Our goal was to (1) determine the feasibility of reviewing electronic health records for assessing OET adherence, (2) evaluate 6 months' OET adherence in HR-positive BC patients, and (3) identify predictors of low adherence. PATIENTS AND METHODS: A single-center, retrospective study from May through December 2018 was conducted. Primary end point was adherance rate at 6 months. Chi-square and Student t tests were used to compare adherent and nonadherent groups. Multivariable logistic regression models were used to assess predictors of adherence. RESULTS: Of 492 patients, 338 patients were included in adherence analysis. Of 338 patients identified, 82% (n = 277) were adherent at 6 months. In the multivariable logistic model, race/ethnicity, type of endocrine therapy, and time on therapy were found to be significantly associated with adherence. Asian/non-Hispanic and white/Hispanic patients were less likely to be adherent compared to white/non-Hispanics (Asian/non-Hispanic: odds ratio [OR], 0.3; 95% confidence interval [CI], 0.11-0.82; white/Hispanic: OR, 0.27; 95% CI, 0.11-0.64). Patients prescribed aromatase inhibitors were more likely to be adherent compared to patients prescribed tamoxifen (OR, 2.06; 95% CI, 1.02-4.14). Last, patients prescribed OET for 3 to 5 years had lower adherence compared to patients given OET for 2 years or less (OR, 0.29; 95% CI, 0.09-0.91). CONCLUSION: Accessing refill data through electronic health records was found to be feasible. Tamoxifen therapy, Asian/non-Hispanic and white/Hispanic origin, and longer time on therapy predicted nonadherence in our patients.

The EXTrauterine Environment for Neonatal Development Supports Normal Intestinal Maturation and Development.

BACKGROUND AND AIMS: The Extra-Uterine Environment for Neonatal Development (EXTEND) aims to avoid the complications of prematurity, such as NEC. Our goal was to determine if bowel development occurs normally in EXTEND-supported lambs, with specific emphasis on markers of immaturity associated with NEC. METHODS: We compared terminal ileum from 17 pre-term lambs supported on EXTEND for 2- 4 weeks to bowel from age-matched fetal lambs that developed in utero. We evaluated morphology, markers of epithelial integrity and maturation, enteric nervous system structure, and bowel motility. RESULTS: EXTEND-supported lamb ileum had normal villus height, crypt depth, density of mucin-containing goblet cells, and enteric neuron density. Expression patterns for I-FABP, activated caspase-3 and EGFR were normal in bowel epithelium. Transmural resistance assessed in Ussing chambers was normal. Bowel motility was also normal as assessed by ex vivo organ bath and video imaging. However, Peyer's patch organization did not occur normally in EXTEND ileum, resulting in fewer circulating B cells in experimental animals. CONCLUSION: EXTEND supports normal ileal epithelial and enteric nervous system maturation in pre-term lambs. The classic morphologic changes and cellular expression profiles associated with NEC are not seen. However, immune development within the EXTEND supported lamb bowel does not progress normally.

Cognitive swarming in complex environments with attractor dynamics and oscillatory computing.

Neurobiological theories of spatial cognition developed with respect to recording data from relatively small and/or simplistic environments compared to animals' natural habitats. It has been unclear how to extend theoretical models to large or complex spaces. Complementarily, in autonomous systems technology, applications have been growing for distributed control methods that scale to large numbers of low-footprint mobile platforms. Animals and many-robot groups must solve common problems of navigating complex and uncertain environments. Here, we introduce the NeuroSwarms control framework to investigate whether adaptive, autonomous swarm control of minimal artificial agents can be achieved by direct analogy to neural circuits of rodent spatial cognition. NeuroSwarms analogizes agents to neurons and swarming groups to recurrent networks. We implemented neuron-like agent interactions in which mutually visible agents operate as if they were reciprocally connected place cells in an attractor network. We attributed a phase state to agents to enable patterns of oscillatory synchronization similar to hippocampal models of theta-rhythmic (5-12 Hz) sequence generation. We demonstrate that multi-agent swarming and reward-approach dynamics can be expressed as a mobile form of Hebbian learning and that NeuroSwarms supports a single-entity paradigm that directly informs theoretical models of animal cognition. We present emergent behaviors including phase-organized rings and trajectory sequences that interact with environmental cues and geometry in large, fragmented mazes. Thus, NeuroSwarms is a model artificial spatial system that integrates autonomous control and theoretical neuroscience to potentially uncover common principles to advance both domains.

Neurologic outcomes of the premature lamb in an extrauterine environment for neonatal development.

BACKGROUND/PURPOSE: Neurologic injury remains the most important morbidity of prematurity. Those born at the earliest gestational ages can face a lifetime of major disability. Perinatal insults result in developmental delay, cerebral palsy, and other profound permanent neurologic impairments. The EXTracorporeal Environment for Neonatal Development (EXTEND) aims to transition premature neonates through this sensitive period, but it's impact on neurologic development requires analysis. METHODS: Fetal sheep were maintained in a fluid-filled environment for up to 28 days. Physiologic parameters were measured continuously; tissues were subsequently fixed and preserved for myelin quantification, glial cell staining, and structural assessment via magnetic resonance. Surviving animals were functionally assessed. RESULTS: No evidence of fetal brain ischemia or white matter tract injury associated with the EXTEND system was detected, and the degree of myelination was regionally appropriate and consistent with age matched controls. No evidence of neurologic injury or immaturity was visible on magnetic resonance; animals that transitioned from the system had no persistent neurologic deficits. CONCLUSIONS: No evidence of major neurologic morbidity was found in animals supported on the EXTEND system, though more work needs to be done in order to verify its safety during critical periods of neurologic development.

Economics of alternative dosing strategies for pembrolizumab and nivolumab at a single academic cancer center.

BACKGROUND: The FDA initially approved pembrolizumab and nivolumab for doses based on patient weight, but subsequently amended approval to fixed doses. We estimated savings from novel dosing strategies based on real-world patient data from a single cancer center. METHODS: We analyzed all outpatient doses of pembrolizumab and nivolumab administered at three infusion centers affiliated with our academic hospital between July 1, 2018 and Oct 31, 2018. We estimated savings from several dosing strategies with and without vial sharing between patients. RESULTS: A total of 1029 doses of pembrolizumab or nivolumab were administered for multiple cancer types. For 77% of doses, the weight-based dose was less than the fixed dose. "Dose-minimization" (DM), defined as the lesser of weight-based and fixed dose decreased nivolumab spending by 9% without affecting pembrolizumab spending. DM plus vial sharing decreased pembrolizumab spending by 19% without affecting nivolumab. The differences in savings were due to availability of multiple vial sizes for nivolumab but not pembrolizumab. DM plus vial sharing for both drugs would have saved $1.5 million USD over the 4-month study period. CONCLUSION: New dosing strategies for pembrolizumab and nivolumab can generate large savings without anticipated decrease in efficacy. Barriers include FDA dosing labels, hospital policies against vial sharing, and inaccessibility of smaller vial sizes, which are currently available in other worldwide markets.