Clinical Pharmacology of Cytokine Release Syndrome with T-Cell-Engaging Bispecific Antibodies: Current Insights and Drug Development Strategies.

Cytokine release syndrome (CRS) is a common acute toxicity in T-cell therapies, including T-cell-engaging bispecific antibodies (T-BiSp). Effective CRS management and prevention are crucial in T-BiSp development. Required hospitalization for seven of the nine approved T-BiSp and the need for clinical intervention in severe cases highlight the importance of mitigation strategies to reduce health care burden and improve patient outcomes.

A Novel Step-Up Dosage Regimen for Enhancing the Benefit-to-Risk Ratio of Mosunetuzumab in Relapsed or Refractory Follicular Lymphoma.

Mosunetuzumab, a T-cell engaging bispecific antibody targeting CD20xCD3, is approved for treating relapsed/refractory follicular lymphoma. This research supports the approved intravenous clinical dose regimen, summarizing the exposure-response relationships for clinical safety and efficacy. A population pharmacokinetic model and E logistic regression exposure-response models for safety and efficacy were developed using data from 439 patients with relapsed/refractory non-Hodgkin lymphoma and 159 patients with relapsed/refractory follicular lymphoma, respectively, from a Phase I/II study (NCT02500407).

Population pharmacokinetics and CD20 binding dynamics for mosunetuzumab in relapsed/refractory B-cell non-Hodgkin lymphoma.

Mosunetuzumab (Mosun) is a CD20xCD3 T-cell engaging bispecific antibody that redirects T cells to eliminate malignant B cells. The approved step-up dose regimen of 1/2/60/30 mg IV is designed to mitigate cytokine release syndrome (CRS) and maximize efficacy in early cycles. A population pharmacokinetic (popPK) model was developed from 439 patients with relapsed/refractory B-Cell Non-Hodgkin lymphoma receiving Mosun IV monotherapy, including fixed dosing (0.

Activating Inducible T-cell Costimulator Yields Antitumor Activity Alone and in Combination with Anti-PD-1 Checkpoint Blockade.

Unlabelled: In recent years, there has been considerable interest in mAb-based induction of costimulatory receptor signaling as an approach to combat cancer. However, promising nonclinical data have yet to translate to a meaningful clinical benefit. Inducible T-cell costimulator (ICOS) is a costimulatory receptor important for immune responses.

Skeletal muscle memory.

Skeletal muscle memory is an exciting phenomenon gaining significant traction across several scientific communities, among exercise practitioners, and the public. Research has demonstrated that skeletal muscle tissue can be "primed" by earlier positive encounters with exercise training that can enhance adaptation to later retraining, even following significant periods of exercise cessation or detraining. This review will describe and discuss the most recent research investigating the underlying mechanisms of skeletal muscle memory: ) "cellular" muscle memory and, ) "epigenetic" muscle memory, as well as emerging evidence of how these theories may work in synergy.

Human skeletal muscle methylome after low-carbohydrate energy-balanced exercise.

We aimed to investigate the human skeletal muscle (SkM) DNA methylome after exercise in low-carbohydrate (CHO) energy-balance (with high-fat) conditions compared with exercise in low-CHO energy-deficit (with low-fat) conditions. The objective was to identify novel epigenetically regulated genes and pathways associated with "train-low sleep-low" paradigms. The sleep-low conditions included nine males that cycled to deplete muscle glycogen while reaching a set energy expenditure.

Mimicking exercise in vitro: effects of myotube contractions and mechanical stretch on omics.

The number of studies using skeletal muscle (SkM) cell culture models to study exercise in vitro are rapidly expanding. Progressively, more comprehensive analysis methods, such as different omics approaches including transcriptomics, proteomics, and metabolomics have been used to examine the intra- and extracellular molecular responses to exercise mimicking stimuli in cultured myotubes. Among other techniques, exercise-like electrical pulse stimulation (EL-EPS) and mechanical stretch of SkM cells are the two most commonly used methods to mimic exercise in vitro.

Pharmacokinetics of biologics in gastric cancer.

Gastric cancer (GC) remains one of the leading causes of cancer death worldwide despite improvements in therapeutic options. Several biologics have been investigated in patients with GC, including those approved in other solid tumors; however, the success rate of the pivotal trials that investigated these biologic molecules in GC remains low. Elevation in total clearance and a decrease in systemic pharmacokinetic (PK) exposure in GC compared with other indications have been observed in these biologics across different pathways.

Aerobic exercise training resets the human skeletal muscle methylome 10 years after breast cancer treatment and survival.

Cancer survivors suffer impairments in skeletal muscle in terms of reduced mass and function. Interestingly, human skeletal muscle possesses an epigenetic memory of earlier stimuli, such as exercise. Long-term retention of epigenetic changes in skeletal muscle following cancer survival and/or exercise training has not yet been studied.

Changes in the Dog's and Cat's Behaviors, as Reported by the Owners, before and during the Lockdown in China.

Considering the effects that the COVID-19 pandemic had and still has on human psychological health, it is expected that it might also affect household dogs’ and cats’ welfare. The current study explores the behavioral changes in dogs and cats before (BL) and during the lockdown (DL), as reported by their owners in China. Besides demographic parameters, variables related to the daily management of dogs and cats were analyzed in relation to behavioral problems, stress-related behaviors, and anxiety-related behaviors before and during the lockdown.

Biomarker correlates with response to NY-ESO-1 TCR T cells in patients with synovial sarcoma.

Autologous T cells transduced to express a high affinity T-cell receptor specific to NY-ESO-1 (letetresgene autoleucel, lete-cel) show promise in the treatment of metastatic synovial sarcoma, with 50% overall response rate. The efficacy of lete-cel treatment in 45 synovial sarcoma patients (NCT01343043) has been previously reported, however, biomarkers predictive of response and resistance remain to be better defined. This post-hoc analysis identifies associations of response to lete-cel with lymphodepleting chemotherapy regimen (LDR), product attributes, cell expansion, cytokines, and tumor gene expression.

Ocular Pulse Amplitude Correlates With Ocular Rigidity at Native IOP Despite the Variability in Intraocular Pulse Volume With Each Heartbeat.

Purpose: The purpose of this study was to assess ocular coat mechanical behavior using controlled ocular microvolumetric injections (MVI) of 15 µL of balanced salt solution (BSS) infused over 1 second into the anterior chamber (AC) via a syringe pump.

Methods: Intraocular pressure (IOP) was continuously recorded at 200 Hz with a validated implantable IOP telemetry system in 7 eyes of 7 male rhesus macaques (nonhuman primates [NHPs]) during 5 MVIs in a series at native (3 trials), 15 and 20 mm Hg baseline IOPs, repeated in 2 to 5 sessions at least 2 weeks apart. Ocular rigidity coefficients (K) and ocular pulse volume (PV) were calculated for each trial.

Unanswered Questions and Hypotheses about Domestic Cat Behavior, Ecology, and the Cat-Human Relationship.

After recent publication of several reviews covering research results from the last 35 years of domestic cat studies, a number of important unanswered questions and hypotheses have arisen that could interest active researchers, especially those beginning their academic careers. Some sections of this paper concern methodologies that have yielded new insights and could provide more in the future; other sections concern findings and interpretations of those that need further testing. First, hypotheses arise from combining subjective (or psychological) assessments of cat and human personality traits and observational (ethological) studies of cat-human interactions: e.

The Mechanics of Social Interactions Between Cats and Their Owners.

This is a mini review that summarizes what is known from quantitative observational studies of social interactions between domestic cats and humans in both laboratory colonies and the home setting. Only results from data that have been statistically analyzed are included; hypotheses still to be tested will be declared as such. In some cases, the observational data have been combined with independently collected subjective assessments by the owners of the animals' character and owner personality traits to help interpret the data.

The Comparative Methylome and Transcriptome After Change of Direction Compared to Straight Line Running Exercise in Human Skeletal Muscle.

The methylome and transcriptome signatures following exercise that are physiologically and metabolically relevant to sporting contexts such as team sports or health prescription scenarios (e.g., high intensity interval training/HIIT) has not been investigated.

Mechanical loading of bioengineered skeletal muscle in vitro recapitulates gene expression signatures of resistance exercise in vivo.

Understanding the role of mechanical loading and exercise in skeletal muscle (SkM) is paramount for delineating the molecular mechanisms that govern changes in muscle mass. However, it is unknown whether loading of bioengineered SkM in vitro adequately recapitulates the molecular responses observed after resistance exercise (RE) in vivo. To address this, the transcriptional and epigenetic (DNA methylation) responses were compared after mechanical loading in bioengineered SkM in vitro and after RE in vivo.

Knockdown of the E3 ubiquitin ligase UBR5 and its role in skeletal muscle anabolism.

UBR5 is an E3 ubiquitin ligase positively associated with anabolism, hypertrophy, and recovery from atrophy in skeletal muscle. The precise mechanisms underpinning UBR5's role in the regulation of skeletal muscle mass remain unknown. The present study aimed to elucidate these mechanisms by silencing the UBR5 gene in vivo.

DNA methylation across the genome in aged human skeletal muscle tissue and muscle-derived cells: the role of HOX genes and physical activity.

Skeletal muscle tissue demonstrates global hypermethylation with age. However, methylome changes across the time-course of differentiation in aged human muscle derived cells, and larger coverage arrays in aged muscle tissue have not been undertaken. Using 850K DNA methylation arrays we compared the methylomes of young (27 ± 4.

The genetic profile of elite youth soccer players and its association with power and speed depends on maturity status.

We investigated the association of multiple single nucleotide polymorphisms (SNPs) with athlete status and power/speed performance in elite male youth soccer players (ESP) and control participants (CON) at different stages of maturity. ESP (n = 535; aged 8-23 years) and CON (n = 151; aged 9-26 years) were genotyped for 10 SNPs and grouped according to years from predicted peak-height-velocity (PHV), i.e.

Acute Stress Increases Intraocular Pressure in Nonhuman Primates.

Purpose: To quantify intraocular pressure (IOP) change and time course during stressful activity.

Study Design: Experimental Study.

Subjects: Three nonhuman primates (NHPs).