Exploring Orodispersible Films Containing the Proteolysis Targeting Chimera ARV-110 in Hot Melt Extrusion and Solvent Casting Using Polyvinyl Alcohol.

Background/objectives: This project aims to provide valuable insights into the formulation of orodispersible films (ODFs) for the delivery of PROTAC ARV-110. The primary objective of this drug delivery formulation is to enhance the solubility of PROTAC ARV-110, which faces significant challenges due to the low solubility of this active pharmaceutical ingredient, as it belongs to a molecular class that is considered to exceed the "Rule of Five".

Methods: We employed the concept of developing a rapidly disintegrating ODF to enhance the solubility of PROTAC ARV-110, utilizing polyvinyl alcohol as the polymer of choice.

Experiences from Clinical Research and Routine Use of Florbetaben Amyloid PET-A Decade of Post-Authorization Insights.

Florbetaben (FBB) is a radiopharmaceutical approved by the FDA and EMA in 2014 for the positron emission tomography (PET) imaging of brain amyloid deposition in patients with cognitive impairment who are being evaluated for Alzheimer's disease (AD) or other causes of cognitive decline. Initially, the clinical adoption of FBB PET faced significant barriers, including reimbursement challenges and uncertainties regarding its integration into diagnostic clinical practice. This review examines the progress made in overcoming these obstacles and describes the concurrent evolution of the diagnostic landscape.

Alignment of Air Pollution Exposure Inequality Metrics with Environmental Justice and Equity Goals in the United States.

A growing literature within the field of air pollution exposure assessment addresses the issue of environmental justice. Leveraging the increasing availability of exposure datasets with broad spatial coverage and high spatial resolution, a number of works have assessed inequalities in exposure across racial/ethnic and other socioeconomic groupings. However, environmental justice research presents the additional need to evaluate exposure inequity-inequality that is systematic, unfair, and avoidable-which may be framed in several ways.

Health impact assessment of urban and transport developments in Barcelona: A case study.

Background: Urban spaces need to be rethought to address growing health and environmental challenges. Urban density and transport systems contribute significantly to air pollution, negatively impacting public health. Barcelona has begun a transformation by introducing the Superblock model, an urban development with proven health benefits.

Added prognostic value of sentinel lymph node mapping in endometrial cancer to molecular subgroups.

Objective: Treatment approaches for endometrial cancer became more personalized in the last decade, mainly due to two key advancements - sentinel lymph node (SLN) mapping and molecular classification. However, their prognostic interaction remains relatively unexplored.

Methods: This retrospective cohort study included patients with endometrial cancer, who underwent surgical treatment including SLN mapping at the Bern University Hospital, Switzerland.

The Autonomic Nervous System (ANS)-Immune Network in People Living With HIV.

Purpose Pre-clinical studies have demonstrated direct influences of the autonomic nervous system (ANS) on the immune system. However, it remains unknown if connections between the peripheral ANS and immune system exist in humans and contribute to the development of chronic inflammatory disease. This study had three aims: 1.

A bispecific antibody-drug conjugate targeting pCAD and CDH17 has antitumor activity and improved tumor-specificity.

P-cadherin (pCAD) and LI-cadherin (CDH17) are cell-surface proteins belonging to the cadherin superfamily that are both highly expressed in colorectal cancer. This co-expression profile presents a novel and attractive opportunity for a dual targeting approach using an antibody-drug conjugate (ADC). In this study, we used a unique avidity-driven screening approach to generate pCAD x CDH17 bispecific antibodies that selectively target cells expressing both antigens over cells expressing only pCAD or only CDH17.

Diffusion tensor imaging with free-water correction reveals distinctions between severe and attenuated subtypes in Mucopolysaccharidosis type I.

Mucopolysaccharidosis type I (MPS I) is an inherited lysosomal storage disorder leading to deleterious brain effects. While animal models suggested that MPS I severely affects white matter (WM), whole-brain diffusion tensor imaging (DTI) analysis was not performed due to MPS-related morphological abnormalities. 3T DTI data from 28 severe (MPS IH, treated with hematopoietic stem cell transplantation-HSCT), 16 attenuated MPS I patients (MPS IA) enrolled under the study protocol NCT01870375, and 27 healthy controls (HC) were analyzed using the free-water correction (FWC) method to resolve macrostructural partial volume effects and unravel differences in DTI metrics accounting for microstructural abnormalities.

Predicting Antidepressant Treatment Response From Cortical Structure on MRI: A Mega-Analysis From the ENIGMA-MDD Working Group.

Accurately predicting individual antidepressant treatment response could expedite the lengthy trial-and-error process of finding an effective treatment for major depressive disorder (MDD). We tested and compared machine learning-based methods that predict individual-level pharmacotherapeutic treatment response using cortical morphometry from multisite longitudinal cohorts. We conducted an international analysis of pooled data from six sites of the ENIGMA-MDD consortium (n = 262 MDD patients; age = 36.

Spontaneous base flipping helps drive Nsp15's preferences in double stranded RNA substrates.

Coronaviruses evade detection by the host immune system with the help of the endoribonuclease Nsp15, which regulates levels of viral double stranded RNA by cleaving 3' of uridine (U). While prior structural data shows that to cleave double stranded RNA, Nsp15's target U must be flipped out of the helix, it is not yet understood whether Nsp15 initiates flipping or captures spontaneously flipped bases. We address this gap by designing fluorinated double stranded RNA substrates that allow us to directly relate a U's sequence context to both its tendency to spontaneously flip and its susceptibility to cleavage by Nsp15.

The Nonclinical Safety Assessment of a Novel Anti-CEACAM5 Antibody Exatecan Conjugate Predicts a Low Risk for Interstitial Lung Disease (ILD) in Patients-The Putative Mechanism Behind ILD.

The therapeutic window of antibody drug-conjugates (ADC) remains challenging due to safety issues such as interstitial lung disease (ILD) observed with specific deruxtecan-based ADCs. To avoid ILD, we designed M9140 by conjugating the maleimide-containing hydrophilic β-glucuronide linker to exatecan and our anti-CEACAM5 (CarcinoEmbryonic Antigen-related Cell Adhesion Molecule 5) specific antibody. Following repeated iv-infusion at 3 to 30 mg/kg of M9140 every 3 weeks, the pathological findings obtained in cynomolgus monkeys were confined to gastrointestinal and hematolymphoid tissues and resembled the toxicity of exatecan.

Pan-phylum genomes of hornworts reveal conserved autosomes but dynamic accessory and sex chromosomes.

Hornworts, one of the three bryophyte phyla, show some of the deepest divergences in extant land plants, with some families separated by more than 300 million years. Previous hornwort genomes represented only one genus, limiting the ability to infer evolution within hornworts and their early land plant ancestors. Here we report ten new chromosome-scale genomes representing all hornwort families and most of the genera.

EEFSEC deficiency: A selenopathy with early-onset neurodegeneration.

Inborn errors of selenoprotein expression arise from deleterious variants in genes encoding selenoproteins or selenoprotein biosynthetic factors, some of which are associated with neurodegenerative disorders. This study shows that bi-allelic selenocysteine tRNA-specific eukaryotic elongation factor (EEFSEC) variants cause selenoprotein deficiency, leading to progressive neurodegeneration. EEFSEC deficiency, an autosomal recessive disorder, manifests with global developmental delay, progressive spasticity, ataxia, and seizures.

Characteristics Associated With Early Ileocolonic Resection in Pediatric Crohn's Disease.

Introduction: Pediatric-onset Crohn's disease (CD) has a more severe phenotype than adult-onset, and nearly one-third of pediatric CD patients will require surgical therapy. There is limited data on patient/disease characteristics that are associated with earlier surgical management.

Methods: All pediatric CD patients (<22 yrs) who underwent ileocolectomy from 2005 to 2021 were included.

Quantum Thermodynamics of Nonequilibrium Processes in Lattice Gauge Theories.

A key objective in nuclear and high-energy physics is to describe nonequilibrium dynamics of matter, e.g., in the early Universe and in particle colliders, starting from the standard model of particle physics.

Disentangling Sources of Momentum Fluctuations in Xe+Xe and Pb+Pb Collisions with the ATLAS Detector.

High-energy nuclear collisions create a quark-gluon plasma, whose initial condition and subsequent expansion vary from event to event, impacting the distribution of the eventwise average transverse momentum [P([p_{T}])]. Disentangling the contributions from fluctuations in the nuclear overlap size (geometrical component) and other sources at a fixed size (intrinsic component) remains a challenge. This problem is addressed by measuring the mean, variance, and skewness of P([p_{T}]) in ^{208}Pb+^{208}Pb and ^{129}Xe+^{129}Xe collisions at sqrt[s_{NN}]=5.

Combined endurance and resistance exercise training in heart failure with preserved ejection fraction: a randomized controlled trial.

Endurance exercise training (ET) is an effective treatment in heart failure with preserved ejection fraction (HFpEF), but the efficacy of resistance training in this patient population has been only scarcely evaluated. In this multicenter, randomized trial, we evaluated the effects of combined endurance and resistance training over 12 months in patients with HFpEF. The primary endpoint was a modified Packer score, including all-cause mortality, hospitalizations classified as potentially related to heart failure or exercise and changes in peak oxygen consumption ( ), diastolic function (E/e'), New York Heart Association (NYHA) class and global self-assessment (GSA).

Importance of reference group selection in the evaluation of cancer incidence.

Elevated cancer incidence has been reported among World Trade Center (WTC)-exposed responders, with some incidence rate ratios (IRRs) varying over time. This study describes the influence that different reference populations have on relative cancer incidence and temporal trends. Participants from the WTC Combined Rescue/Recovery Cohort (n = 65,691) were observed between 1/1/2002 and 12/31/2015 using data obtained from 13 state cancer registries.

Long-term persistence of glycemic dysregulation in patients with a history of pheochromocytoma/paraganglioma.

Context: Pheochromocytomas and paragangliomas (PPGLs) are rare endocrine tumors that frequently produce catecholamines. Catecholamine-induced cardiometabolic complications substantially contribute to increased morbidity and mortality in PPGL patients prior to surgical resection.

Objective: To determine whether markers of elevated cardiometabolic risk persist in patients following PPGL resection.

Assessing environmental gradients in relation to dark CO fixation in estuarine wetland microbiomes.

Unlabelled: The rising atmospheric concentration of CO is a major concern to society due to its global warming potential. In soils, CO-fixing microorganisms are preventing some of the CO from entering the atmosphere. Yet, the controls of dark CO fixation are rarely studied .

Mathematical modelling and analysis for the co-infection of viral and bacterial diseases: a systematic review protocol.

Introduction: Breaking the chain of transmission of an infectious disease pathogen is a major public health priority. The challenges of understanding, describing and predicting the transmission dynamics of infections have led to a wide range of mathematical, statistical and biological research problems. Advances in diagnostic laboratory procedures with the ability to test multiple pathogens simultaneously mean that co-infections are increasingly being detected, yet little is known about the impact of co-infections in shaping the course of an infection, infectivity, and pathogen replication rate.