MCB-613 exploits a collateral sensitivity in drug resistant -mutant non-small cell lung cancer through covalent inhibition of KEAP1.

Targeted therapies have revolutionized cancer chemotherapy. Unfortunately, most patients develop multifocal resistance to these drugs within a matter of months. Here, we used a high-throughput phenotypic small molecule screen to identify MCB-613 as a compound that selectively targets -mutant, EGFR inhibitor-resistant non-small cell lung cancer (NSCLC) cells harboring diverse resistance mechanisms.

Robotic Spine Surgery in Rhode Island.

Surgical robots were first proposed in the 1960s with subsequent development and clinical implementation in the 1980s and 1990s. Recent advances in technology have led to widespread utilization of robots in many surgical subspecialties. In spine surgery, robots are primarily utilized for pedicle screw placement, with several studies highlighting the potential benefits of improved accuracy and reduction in radiation exposure.

and colonization on plastics influenced by temperature and strain variability.

Marine bacteria often exist in biofilms as communities attached to surfaces, like plastic. Growing concerns exist regarding marine plastics acting as potential vectors of pathogenic , especially in a changing climate. It has been generalized that and often attach to plastic surfaces.

Optimization of a Digital Mass Filter for the Isolation of Intact Protein Complexes in Stability Zone 1,1.

Digital mass filters are advantageous for the analysis of large molecules due to the ability to perform ion isolation of high-/ ions without the generation of very high radio frequency (RF) and DC voltages. Experimentally determined Mathieu stability diagrams of stability zone 1,1 for capacitively coupled digital waveforms show a voltage offset between the quadrupole rod pairs is introduced by the capacitors which is dependent on the voltage magnitude of the waveform and the duty cycle. This changes the ion's value from = 0 to < 0.

Long-term Trajectories of Physical Function Decline in Women With and Without Cancer.

Importance: Patients with cancer experience acute declines in physical function, hypothesized to reflect accelerated aging driven by cancer-related symptoms and effects of cancer therapies. No study has examined long-term trajectories of physical function by cancer site, stage, or treatment compared with cancer-free controls.

Objective: Examine trajectories of physical function a decade before and after cancer diagnosis among older survivors and cancer-free controls.

Methylenetetrahydrofolate reductase deficiency and high-dose FA supplementation disrupt embryonic development of energy balance and metabolic homeostasis in zebrafish.

Folic acid (synthetic folate, FA) is consumed in excess in North America and may interact with common pathogenic variants in methylenetetrahydrofolate reductase (MTHFR); the most prevalent inborn error of folate metabolism with wide-ranging obesity-related comorbidities. While preclinical murine models have been valuable to inform on diet-gene interactions, a recent Folate Expert panel has encouraged validation of new animal models. In this study, we characterized a novel zebrafish model of mthfr deficiency and evaluated the effects of genetic loss of mthfr function and FA supplementation during embryonic development on energy homeostasis and metabolism.

Amyotrophic Lateral Sclerosis Pathoetiology and Pathophysiology: Roles of Astrocytes, Gut Microbiome, and Muscle Interactions via the Mitochondrial Melatonergic Pathway, with Disruption by Glyphosate-Based Herbicides.

The pathoetiology and pathophysiology of motor neuron loss in amyotrophic lateral sclerosis (ALS) are still to be determined, with only a small percentage of ALS patients having a known genetic risk factor. The article looks to integrate wider bodies of data on the biological underpinnings of ALS, highlighting the integrative role of alterations in the mitochondrial melatonergic pathways and systemic factors regulating this pathway across a number of crucial hubs in ALS pathophysiology, namely glia, gut, and the muscle/neuromuscular junction. It is proposed that suppression of the mitochondrial melatonergic pathway underpins changes in muscle brain-derived neurotrophic factor, and its melatonergic pathway mimic, N-acetylserotonin, leading to a lack of metabolic trophic support at the neuromuscular junction.

Depression Pathophysiology: Astrocyte Mitochondrial Melatonergic Pathway as Crucial Hub.

Major depressive disorder (MDD) is widely accepted as having a heterogenous pathophysiology involving a complex mixture of systemic and CNS processes. A developmental etiology coupled to genetic and epigenetic risk factors as well as lifestyle and social process influences add further to the complexity. Consequently, antidepressant treatment is generally regarded as open to improvement, undoubtedly as a consequence of inappropriately targeted pathophysiological processes.

Tumor Microenvironment and Metabolism: Role of the Mitochondrial Melatonergic Pathway in Determining Intercellular Interactions in a New Dynamic Homeostasis.

There is a growing interest in the role of alterations in mitochondrial metabolism in the pathoetiology and pathophysiology of cancers, including within the array of diverse cells that can form a given tumor microenvironment. The 'exhaustion' in natural killer cells and CD8+ t cells as well as the tolerogenic nature of dendritic cells in the tumor microenvironment seems determined by variations in mitochondrial function. Recent work has highlighted the important role played by the melatonergic pathway in optimizing mitochondrial function, limiting ROS production, endogenous antioxidants upregulation and consequent impacts of mitochondrial ROS on ROS-dependent microRNAs, thereby impacting on patterned gene expression.

Stimulation of nucleus accumbens 5-HT6 receptors increases both appetitive and consummatory motivation in an effort-based choice task.

Activity of the serotonin 6(5-HT6) receptor impacts food intake and body weight in animal models and has also shown potential as a target for treatment of anhedonia, a symptom of major depressive disorder. The nucleus accumbens (NAc) is a key region involved in motivational processes and has been implicated in the neural mechanisms underlying anhedonia. Here, we assessed the potential role that 5-HT6 receptors in the NAc play in regulating motivation towards food.

Elarekibep (PRS-060/AZD1402), a new class of inhaled Anticalin medicine targeting IL-4Ra for type 2 endotype asthma.

Background: Type 2 endotype asthma is driven by IL-4 and IL-13 signaling via IL-4Ra, which is highly expressed on airway epithelium, airway smooth muscle, and immunocytes in the respiratory mucosa, suggesting potential advantages of an inhalable antagonist. Lipocalin 1 (Lcn1), a 16 kDa protein abundant in human periciliary fluid, has a robust drug-like structure well suited to protein engineering, but it has never been used to make an inhaled Anticalin protein therapeutic.

Objectives: We sought to reengineer Lcn1 into an inhalable IL-4Ra antagonist and assess its pharmacodynamic/kinetic profile.

A Commentary on "Racism Within the Deaf Community".

In 1972, Glenn Anderson collaborated with New York University colleague Frank Bowe to publish an American Annals of the Deaf article titled "Racism Within the Deaf Community" (Anderson & Bowe, 1972). It was written, in part, due to the influence of the Civil Rights Movement of the 1960s, which affected both the Black Deaf and Black hearing communities, as well as in response to Anderson's experiences with a Deaf club in Detroit. Given that 52 years have passed since the article was published, this updated version, coauthored with Gallaudet University colleague Lindsay Dunn, addresses the following issues, among others: racial inequity in the educational and employment attainment of Black Deaf persons, their personal experiences with institutional and systemic racism, and their perspectives on what must be done to progress toward dismantling institutional and systemic racism in the Deaf community today and tomorrow.

Three-Column Osteotomy for Frail Versus Nonfrail Patients with Adult Spinal Deformity: Assessment of Medical and Surgical Complications, Revision Surgery Rates, and Cost.

Background: Three-column osteotomy (3-CO) is a powerful tool for spinal deformity correction but has been associated with substantial risk and surgical invasiveness. It is incompletely understood how frailty might affect patients undergoing 3-CO.

Methods: The PearlDiver database was used to examine spinal deformity patients with a diagnosis of frailty who had undergone 3-CO.

Heparin Inhibits SARS-CoV-2 Replication in Human Nasal Epithelial Cells.

SARS-CoV-2 is the causative agent of the COVID-19 pandemic. Vaccination, supported by social and public health measures, has proven efficacious for reducing disease severity and virus spread. However, the emergence of highly transmissible viral variants that escape prior immunity highlights the need for additional mitigation approaches.

Assessing the Relative Impact of Diverse Stressors among Canadian Coast Guard and Conservation and Protection Officers.

Public Safety Personnel (PSP), including members of the Canadian Coast Guard (CCG) and Conservation and Protection (C&P) officers, are regularly exposed to potentially psychologically traumatic events (PPTEs) and other occupational stressors (organizational and operational stressors). The current study quantified occupational stressors among CCG and C&P and assessed relationships with PPTEs and mental health disorders. Participants ( = 341; 58.

Central Irisin Signaling Is Required for Normal Timing of Puberty in Female Mice.

Timing of puberty requires exquisite coordination of genes, hormones, and brain circuitry. An increasing level of body adiposity, signaled to the brain via the fat-derived hormone leptin, is recognized as a major factor controlling puberty onset. However, it is clear that leptin is not the only metabolic cue regulating puberty, and that developmental regulation of this process also involves tissues other than adipose, with muscle development potentially playing a role in the timing of puberty.

Mental Health Training, Attitudes toward Support, and Screening Positive for Mental Disorders among Canadian Coast Guard and Conservation and Protection Officers.

Public Safety Personnel (PSP) including members of the Canadian Coast Guard (CCG) and Conservation and Protection (C&P) officers, are regularly exposed to potentially psychologically traumatic events (PPTEs) and other occupational stressors. Several mental health training programs (e.g.

Mental Health Disorder Symptoms among Canadian Coast Guard and Conservation and Protection Officers.

Canadian public safety personnel (PSP) screen positive for one or more mental health disorders, based on self-reported symptoms, at a prevalence much greater (i.e., 44.

Assessing the impact of the Royal Canadian Mounted Police (RCMP) protocol and Emotional Resilience Skills Training (ERST) among diverse public safety personnel.

Background: Public safety personnel (PSP; e.g., border services personnel, correctional workers, firefighters, paramedics, police, public safety communicators) are frequently exposed to potentially psychologically traumatic events.

Proteomic profiling of serum identifies a molecular signature that correlates with clinical outcomes in COPD.

Objective: Novel biomarkers related to main clinical hallmarks of Chronic obstructive pulmonary disease (COPD), a heterogeneous disorder with pulmonary and extra-pulmonary manifestations, were investigated by profiling the serum levels of 1305 proteins using Slow Off-rate Modified Aptamers (SOMA)scan technology.

Methods: Serum samples were collected from 241 COPD subjects in the multicenter French Cohort of Bronchial obstruction and Asthma to measure the expression of 1305 proteins using SOMAscan proteomic platform. Clustering of the proteomics was applied to identify disease subtypes and their functional annotation and association with key clinical parameters were examined.

Growth of Scenedesmus dimorphus in swine wastewater with versus without solid-liquid separation pretreatment.

Scenedesmus dimorphus was cultivated in raw and pretreated swine wastewater (SW) with 6-L photobioreactors (PBRs) to investigate the effect of solid-liquid separation on algal growth. The same aerated PBRs containing no algae were used as control. Moderate COD and nitrogen removal from the SW was achieved with the algal PBRs.