Low expression promotes sensitivity to CHK1 inhibition in high-grade serous ovarian cancer.

High-grade serous ovarian cancer (HGSOC), the most lethal epithelial ovarian cancer subtype, faces persistent challenges despite advances in the therapeutic use of PARP inhibitors. Thus, innovative strategies are urgently needed to improve survival rates for this deadly disease. Checkpoint kinase 1 (CHK1) is pivotal in regulating cell survival during oncogene-induced replication stress (RS).

Quality of Life Outcomes in Breast Cancer Patients Receiving Chemotherapy With or Without Radiation Therapy.

Purpose: Understanding quality of life (QOL) implications of individual components of breast cancer treatment is important as systemic therapies continue to improve oncologic outcomes. We hypothesized that adjuvant radiation therapy does not significantly impact QOL domains in breast cancer patients undergoing chemotherapy.

Methods: Data was drawn from three prospective studies in women with localized breast cancer being treated with chemotherapy from March 2014 to December 2019.

The brain can develop conflicting multisensory principles to guide behavior.

Midbrain multisensory neurons undergo a significant postnatal transition in how they process cross-modal (e.g. visual-auditory) signals.

Population data evidence of interdependence of the limbs of hormonal feedback loops.

The fundamental models underlying hormonal physiological regulation and homeostasis remain poorly understood. We aimed to derive quantitative evidence regarding these models from the study of population data of balance points of different parameters and their respective controlling hormones. We studied the slopes of correlations between concentrations of circulating free thyroxine and thyrotropin, calcium and parathyroid hormone, hemoglobin and erythropoietin, and glucose and insulin in such population data, as well as the slopes of the limbs of various feedback loops estimated empirically and by reverse engineering of the population data.

The scaling of metabolic traits differs among larvae and juvenile colonies of scleractinian corals.

Body size profoundly affects organism fitness and ecosystem dynamics through the scaling of physiological traits. This study tested for variation in metabolic scaling and its potential drivers among corals differing in life history strategies and taxonomic identity. Data were compiled from published sources and augmented with empirical measurements of corals in Moorea, French Polynesia.

Basket trials in oncology: a systematic review of practices and methods, comparative analysis of innovative methods, and an appraisal of a missed opportunity.

Background: Basket trials are increasingly used in oncology drug development for early signal detection, accelerated tumor-agnostic approvals, and prioritization of promising tumor types in selected patients with the same mutation or biomarker. Participants are grouped into so-called baskets according to tumor type, allowing investigators to identify tumors with promising responses to treatment for further study. However, it remains a question as to whether and how much the adoption of basket trial designs in oncology have translated into patient benefits, increased pace and scale of clinical development, and de-risking of downstream confirmatory trials.

Cross-modal exposure restores multisensory enhancement after hemianopia.

Hemianopia is a common consequence of unilateral damage to visual cortex that manifests as a profound blindness in contralesional space. A noninvasive cross-modal (visual-auditory) exposure paradigm has been developed in an animal model to ameliorate this disorder. Repeated stimulation of a visual-auditory stimulus restores overt responses to visual stimuli in the blinded hemifield.

Bayesian joint models for multi-regional clinical trials.

In recent years, multi-regional clinical trials (MRCTs) have increased in popularity in the pharmaceutical industry due to their ability to accelerate the global drug development process. To address potential challenges with MRCTs, the International Council for Harmonisation released the E17 guidance document which suggests the use of statistical methods that utilize information borrowing across regions if regional sample sizes are small. We develop an approach that allows for information borrowing via Bayesian model averaging in the context of a joint analysis of survival and longitudinal data from MRCTs.

Availability of cancer care services and the organization of care delivery at critical access hospitals.

Introduction: Critical access hospitals (CAHs) provide an opportunity to meet the needs of individuals with cancer in rural areas. Two common innovative care delivery methods include the use of traveling oncologists and teleoncology. It is important to understand the availability and organization of cancer care services in CAHs due to the growing population with cancer and expected declines in oncology workforce in rural areas.

The role of genetic selection and climatic factors in the dispersal of anatomically modern humans out of Africa.

The evolutionarily recent dispersal of anatomically modern humans (AMH) out of Africa (OoA) and across Eurasia provides a unique opportunity to examine the impacts of genetic selection as humans adapted to multiple new environments. Analysis of ancient Eurasian genomic datasets (~1,000 to 45,000 y old) reveals signatures of strong selection, including at least 57 hard sweeps after the initial AMH movement OoA, which have been obscured in modern populations by extensive admixture during the Holocene. The spatiotemporal patterns of these hard sweeps provide a means to reconstruct early AMH population dispersals OoA.

Predictability alters multisensory responses by modulating unisensory inputs.

The multisensory (deep) layers of the superior colliculus (SC) play an important role in detecting, localizing, and guiding orientation responses to salient events in the environment. Essential to this role is the ability of SC neurons to enhance their responses to events detected by more than one sensory modality and to become desensitized ('attenuated' or 'habituated') or sensitized ('potentiated') to events that are predictable modulatory dynamics. To identify the nature of these modulatory dynamics, we examined how the repetition of different sensory stimuli affected the unisensory and multisensory responses of neurons in the cat SC.

A DUAL MTOR/NAD+ ACTING GEROTHERAPY.

The geroscience hypothesis states that a therapy that prevents the underlying aging process should prevent multiple aging related diseases. The mTOR (mechanistic target of rapamycin)/insulin and NAD+ (nicotinamide adenine dinucleotide) pathways are two of the most validated aging pathways. Yet, it's largely unclear how they might talk to each other in aging.

Bayesian design of multi-regional clinical trials with time-to-event endpoints.

Sponsors often rely on multi-regional clinical trials (MRCTs) to introduce new treatments more rapidly into the global market. Many commonly used statistical methods do not account for regional differences, and small regional sample sizes frequently result in lower estimation quality of region-specific treatment effects. The International Council for Harmonization E17 guidelines suggest consideration of methods that allow for information borrowing across regions to improve estimation.

Facilitation of dependent transfers with functional neuromuscular stimulation: a computer simulation study.

A two-part simulation process was developed to investigate the facilitation of vertical patient lifts with functional neuromuscular stimulation (FNS) in individuals with spinal cord injury (SCI). First, external lifting forces representing caregiver assistance were applied to a 3D musculoskeletal model representing the patient and optimized to enforce a specific lifting trajectory during a forward dynamic simulation. The process was repeated with and without the activation of the knee, hip, and trunk extensor muscles of the patient model to represent contractions of the paralyzed muscles generated via FNS.

Physiological linkage of thyroid and pituitary sensitivities.

Objectives: The sensitivities of the pituitary to thyroxine feedback, and the thyroid to thyrotropin stimulation determine the free thyroxine /thyrotropin feedback loop and can be described mathematically by two curves. It is not well understood how the two curves combine in a healthy population with normal thyroid function to express the individual balance points that are observed. This study was directed at this issue testing the possibilities of random combination and directed linkage between the two curves.

Intrapopulation adaptive variance supports thermal tolerance in a reef-building coral.

Coral holobionts are multi-species assemblages, which adds significant complexity to genotype-phenotype connections underlying ecologically important traits like coral bleaching. Small scale heterogeneity in bleaching is ubiquitous in the absence of strong environmental gradients, which provides adaptive variance needed for the long-term persistence of coral reefs. We used RAD-seq, qPCR and LC-MS/MS metabolomics to characterize host genomic variation, symbiont community and biochemical correlates in two bleaching phenotypes of the vertically transmitting coral Montipora capitata.

Modeling total predation to avoid perverse outcomes from cat control in a data-poor island ecosystem.

Data hungry, complex ecosystem models are often used to predict the consequences of threatened species management, including perverse outcomes. Unfortunately, this approach is impractical in many systems, which have insufficient data to parameterize ecosystem interactions or reliably calibrate or validate such models. Here we demonstrate a different approach, using a minimum realistic model to guide decisions in data- and resource-scarce systems.

Noise-rearing precludes the behavioral benefits of multisensory integration.

Concordant visual-auditory stimuli enhance the responses of individual superior colliculus (SC) neurons. This neuronal capacity for "multisensory integration" is not innate: it is acquired only after substantial cross-modal (e.g.

Airway IL-1β associates with IL-5 production following dust mite allergen inhalation in humans.

Background: Preclinical studies implicate interleukin (IL)-1β as a key mediator of asthma and have shown the efficacy of IL-1 antagonism for treatment of allergic airway inflammation; human studies in this area are lacking.

Objectives: Our aim was to study the relationship of airway IL-1β to features of acute allergen-induced asthma exacerbation in humans.

Methods: Dust mite-allergic adults with mild asthma underwent inhalation challenge with Dermatophagoides farinae.

Thyroid testing paradigm switch from thyrotropin to thyroid hormones-Future directions and opportunities in clinical medicine and research.

Purpose: Recently published papers have demonstrated that particularly in untreated individuals, clinical parameters more often associate with thyroid hormone, particularly free thyroxine (FT4), levels than with thyrotropin (TSH) levels. Clinical and research assessments of the thyroid state of peripheral tissues would therefore be more precise if they were based on FT4 levels rather than on TSH levels. In this paper we describe implications of, and opportunities provided by, this discovery.

Bayesian multiregional clinical trials using model averaging.

Multiregional clinical trials (MRCTs) provide the benefit of more rapidly introducing drugs to the global market; however, small regional sample sizes can lead to poor estimation quality of region-specific effects when using current statistical methods. With the publication of the International Conference for Harmonisation E17 guideline in 2017, the MRCT design is recognized as a viable strategy that can be accepted by regional regulatory authorities, necessitating new statistical methods that improve the quality of region-specific inference. In this article, we develop a novel methodology for estimating region-specific and global treatment effects for MRCTs using Bayesian model averaging.

Impact of the COVID-19 pandemic on South Australia's emergency departments: evidence from two lockdowns.

Objective This study assessed the impact of the COVID-19 pandemic on emergency departments (EDs) in South Australia, measured by changes in the number and casemix of patients in the system over time. Methods Data from the South Australia Emergency Department Dashboard, updated every 30min, were analysed for the period 4 October-21 December 2020. The Dashboard reports live counts of the number and type of patients in each of the six adult metropolitan public EDs in Adelaide, South Australia.

Stimulus value gates multisensory integration.

The brain enhances its perceptual and behavioral decisions by integrating information from its multiple senses in what are believed to be optimal ways. This phenomenon of "multisensory integration" appears to be pre-conscious, effortless, and highly efficient. The present experiments examined whether experience could modify this seemingly automatic process.