Cyclin E1/CDK2 activation defines a key vulnerability to WEE1 kinase inhibition in gynecological cancers.

Upregulation of Cyclin E1 and subsequent activation of CDK2 accelerates cell cycle progression from G1 to S phase and is a common oncogenic driver in gynecological malignancies. WEE1 kinase counteracts the effects of Cyclin E1/CDK2 activation by regulating multiple cell cycle checkpoints. Here we characterized the relationship between Cyclin E1/CDK2 activation and sensitivity to the selective WEE1 inhibitor azenosertib.

Sex and estradiol effects in the rodent dorsal striatum.

17β-Estradiol (E2) is a sex hormone that acts on many brain regions to produce changes in neuronal activity and learning. A key brain region sensitive to E2 is the dorsal striatum (also called caudate-putamen), which controls motor behaviour, goal-directed learning and habit learning. In adult rodents, oestrogen receptors (ERs) in the dorsal striatum are localized to the plasma membrane and include ERα, ERβ and G protein-coupled ER (GPER).

A simplified protocol for deriving sterile, infectious murine Heligmosomoides polygyrus bakeri larvae.

Gastrointestinal helminth infection occurs within a diverse microbiome, complicating the interpretation of whether effects are caused by the parasite versus the microbial community. Here, we present a protocol for deriving sterile larvae of the murine helminth, Heligmosomoides polygyrus bakeri (H. polygyrus), providing experimental control of the microbiome.

Genetic mechanisms for impaired synaptic plasticity in schizophrenia revealed by computational modeling.

Schizophrenia phenotypes are suggestive of impaired cortical plasticity in the disease, but the mechanisms of these deficits are unknown. Genomic association studies have implicated a large number of genes that regulate neuromodulation and plasticity, indicating that the plasticity deficits have a genetic origin. Here, we used biochemically detailed computational modeling of postsynaptic plasticity to investigate how schizophrenia-associated genes regulate long-term potentiation (LTP) and depression (LTD).

Mucosal emphysematous head and neck infections: Scoping review and a case of emphysematous tonsillitis.

Objective: This scoping review seeks to understand the existing research in otolaryngological mucosal emphysematous infections and to elucidate gaps in knowledge in the field. We also present a case of bilateral necrotizing tonsillitis in an immunocompromised patient with the first reported imaging findings of emphysematous abscess of the tonsils.

Data Sources: PubMed, Embase, Web of Science.

A service-user digital intervention to collect real-time safety information on acute, adult mental health wards: the WardSonar mixed-methods study.

Background: Acute inpatient mental health services report high levels of safety incidents. The application of patient safety theory has been sparse, particularly concerning interventions that proactively seek patient perspectives.

Objective(s): Develop and evaluate a theoretically based, digital monitoring tool to collect real-time information from patients on acute adult mental health wards about their perceptions of ward safety.

Ultrasonic Shears Decrease Postoperative Hematomas in Head and Neck Microvascular Reconstruction.

Objective: To evaluate postoperative hematoma and takeback rates in a large series of microvascular reconstructions. We sought to determine whether the use of ultrasonic shears reduced these rates.

Study Design: Retrospective cohort study.

Promoting a Patient-Centered Understanding of Safety in Acute Mental Health Wards: A User-Centered Design Approach to Develop a Real-Time Digital Monitoring Tool.

Background: Acute mental health services report high levels of safety incidents that involve both patients and staff. The potential for patients to be involved in interventions to improve safety within a mental health setting is acknowledged, and there is a need for interventions that proactively seek the patient perspective of safety. Digital technologies may offer opportunities to address this need.

Making time and space for calcium control of neuron activity.

Calcium directly controls or indirectly regulates numerous functions that are critical for neuronal network activity. Intracellular calcium concentration is tightly regulated by numerous molecular mechanisms because spatial domains and temporal dynamics (not just peak amplitude) are critical for calcium control of synaptic plasticity and ion channel activation, which in turn determine neuron spiking activity. The computational models investigating calcium control are valuable because experiments achieving high spatial and temporal resolution simultaneously are technically unfeasible.

The Implant-borne Articulation Splint in Fibula Free Flap Mandibular Reconstruction: A Technical Note.

Computer-aided design and computer-aided manufacturing and digitally simulated surgeries have revolutionized maxillomandibular reconstruction. In particular, this technology has increased the accuracy and facilitated the process of dental implantation in fibula free flaps. Despite the efficacy of virtual planning, there is a minor degree of translational difference between digital and intraoperative measurements, which may affect the precision of implant and fibula orientations.

Testosterone Replacement Therapy and Cardiovascular Disease: Balancing Safety and Risks in Hypogonadal Men.

PURPOSE OF REVIEW: The purpose of this review is to analyze the link between testosterone replacement therapy (TRT) and adverse cardiovascular (CV) events. RECENT FINDINGS: A few published studies suggest a link between TRT and CV events. These studies contained flaws, and many other studies reveal a reduction in CV events.

Enhancing reinforcement learning models by including direct and indirect pathways improves performance on striatal dependent tasks.

A major advance in understanding learning behavior stems from experiments showing that reward learning requires dopamine inputs to striatal neurons and arises from synaptic plasticity of cortico-striatal synapses. Numerous reinforcement learning models mimic this dopamine-dependent synaptic plasticity by using the reward prediction error, which resembles dopamine neuron firing, to learn the best action in response to a set of cues. Though these models can explain many facets of behavior, reproducing some types of goal-directed behavior, such as renewal and reversal, require additional model components.

Estradiol Receptors Inhibit Long-Term Potentiation in the Dorsomedial Striatum.

Estradiol, a female sex hormone and the predominant form of estrogen, has diverse effects throughout the brain including in learning and memory. Estradiol modulates several types of learning that depend on the dorsomedial striatum (DMS), a subregion of the basal ganglia involved in goal-directed learning, cued action-selection, and motor skills. A cellular basis of learning is synaptic plasticity, and the presence of extranuclear estradiol receptors ERα, ERβ, and G-protein-coupled estrogen receptor (GPER) throughout the DMS suggests that estradiol may influence rapid cellular actions including those involved in plasticity.

Genetic mechanisms for impaired synaptic plasticity in schizophrenia revealed by computational modelling.

Schizophrenia phenotypes are suggestive of impaired cortical plasticity in the disease, but the mechanisms of these deficits are unknown. Genomic association studies have implicated a large number of genes that regulate neuromodulation and plasticity, indicating that the plasticity deficits have a genetic origin. Here, we used biochemically detailed computational modelling of post-synaptic plasticity to investigate how schizophrenia-associated genes regulate long-term potentiation (LTP) and depression (LTD).

Validation of a Transcriptome-Based Assay for Classifying Cancers of Unknown Primary Origin.

Introduction: Cancers assume a variety of distinct histologies, and may originate from a myriad of sites including solid organs, hematopoietic cells, and connective tissue. Clinical decision-making based on consensus guidelines such as the National Comprehensive Cancer Network (NCCN) is often predicated on a specific histologic and anatomic diagnosis, supported by clinical features and pathologist interpretation of morphology and immunohistochemical (IHC) staining patterns. However, in patients with nonspecific morphologic and IHC findings-in addition to ambiguous clinical presentations such as recurrence versus new primary-a definitive diagnosis may not be possible, resulting in the patient being categorized as having a cancer of unknown primary (CUP).

Medial Sural Artery Perforator Flap: A Middle Ground Between Anterolateral Thigh and Radial Forearm Flaps.

Objective: The medial sural artery perforator (MSAP) flap has gained popularity in head and neck reconstruction primarily as a less morbid alternative to the radial forearm free flap (RFFF). However, no direct comparison of thickness exists among the MSAP, RFFF, and anterolateral thigh (ALT) flaps, which together represent the commonly utilized nonosseus-free flaps in head and neck reconstruction. Thus, this study aimed to compare these flap sites and identify predictors of thickness that will aid in reconstructive surgical planning.

Ghost Cell Odontogenic Carcinoma: A Case Report and Literature Review.

Ghost cell odontogenic carcinoma (GCOC) is an exceptionally rare malignant odontogenic neoplasm with a significant potential for aggressive growth. Although the literature on this tumor is limited, its high recurrence rates suggest that early and multimodal intervention may be beneficial. This study reports a case of GCOC of the mandible that was successfully treated with surgical resection, reconstruction, and radiation.

Synaptic Plasticity Is Predicted by Spatiotemporal Firing Rate Patterns and Robust to In Vivo-like Variability.

Synaptic plasticity, the experience-induced change in connections between neurons, underlies learning and memory in the brain. Most of our understanding of synaptic plasticity derives from in vitro experiments with precisely repeated stimulus patterns; however, neurons exhibit significant variability in vivo during repeated experiences. Further, the spatial pattern of synaptic inputs to the dendritic tree influences synaptic plasticity, yet is not considered in most synaptic plasticity rules.

Combining hypothesis- and data-driven neuroscience modeling in FAIR workflows.

Modeling in neuroscience occurs at the intersection of different points of view and approaches. Typically, hypothesis-driven modeling brings a question into focus so that a model is constructed to investigate a specific hypothesis about how the system works or why certain phenomena are observed. Data-driven modeling, on the other hand, follows a more unbiased approach, with model construction informed by the computationally intensive use of data.

Severe Acute Respiratory Syndrome Coronavirus 2 Is Detected in the Gastrointestinal Tract of Asymptomatic Endoscopy Patients but Is Unlikely to Pose a Significant Risk to Healthcare Personnel.

Background And Aims: Recent evidence suggests that the gut is an additional target for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, whether SARS-CoV-2 spreads via gastrointestinal secretions remains unclear. To determine the prevalence of gastrointestinal SARS-CoV-2 infection in asymptomatic subjects, we analyzed gastrointestinal biopsy and liquid samples from endoscopy patients for the presence of SARS-CoV-2.

An ADAM17-Neutralizing Antibody Reduces Inflammation and Mortality While Increasing Viral Burden in a COVID-19 Mouse Model.

Angiotensin Converting Enzyme 2 (ACE2) is the primary cell entry receptor for SARS-CoV and SARS-CoV-2 viruses. A disintegrin and metalloproteinase 17 (ADAM17) is a protease that cleaves ectodomains of transmembrane proteins, including that of ACE2 and the proinflammatory cytokine TNF-α, from cell surfaces upon cellular activation. We hypothesized that blockade of ADAM17 activity would alter COVID-19 pathogenesis.

Longitudinal Shifts of Solid Tumor and Liquid Biopsy Sequencing Concordance in Metastatic Breast Cancer.

Unlabelled: Tissue-based next-generation sequencing (NGS) in metastatic breast cancer (mBC) is limited by the inability to noninvasively track tumor evolution. Cell-free DNA (cfDNA) NGS has made sequential testing feasible; however, the relationship between cfDNA and tissue-based testing in mBC is not well understood. Here, we evaluate concordance between tissue and cfDNA NGS relative to cfDNA sampling frequency in a large, clinically annotated mBC data set.

Centers for Medicare & Medicaid Services' Models to Improve Late-stage Chronic Kidney Disease and End-stage Renal Disease Care: Leveraging Nephrology Payment Policy to Achieve Value.

This article describes two new and complementary initiatives from the Center for Medicare and Medicaid Innovation at the Centers for Medicare & Medicaid Services-the ESRD Treatment Choices and Kidney Care Choices Models-which focus on Medicare beneficiaries with CKD and ESRD. These models, or time-limited tests, are aimed at testing whether modifying Medicare payment methodologies, while also rewarding certain clinical outcomes, will improve treatment and outcomes and reduce costs. Together, these initiatives comprise a major part of the larger federal effort to improve the lives of people with kidney disease.