Neoadjuvant or concurrent atezolizumab with chemoradiation for locally advanced cervical cancer: a randomized phase I trial.

Combined immune checkpoint blockade (ICB) and chemoradiation (CRT) is approved in patients with locally advanced cervical cancer (LACC) but optimal sequencing of CRT and ICB is unknown. NRG-GY017 (NCT03738228) was a randomized phase I trial of atezolizumab (anti-PD-L1) neoadjuvant and concurrent with CRT (Arm A) vs. concurrent with CRT (Arm B) in patients with high-risk node-positive LACC.

Body mass, temperature, and pathogen intensity differentially affect critical thermal maxima and their population-level variation in a solitary bee.

Climate change presents a major threat to species distribution and persistence. Understanding what abiotic or biotic factors influence the thermal tolerances of natural populations is critical to assessing their vulnerability under rapidly changing thermal regimes. This study evaluates how body mass, local climate, and pathogen intensity influence heat tolerance and its population-level variation (SD) among individuals of the solitary bee .

Divergent impacts of the neonicotinoid insecticide, clothianidin, on flight performance metrics in two species of migratory butterflies.

Long-distance flight is crucial for the survival of migratory insects, and disruptions to their flight capacity can have significant consequences for conservation. In this study, we examined how a widely used insecticide, clothianidin (class: neonicotinoid), impacted the flight performance of two species of migratory butterflies, monarchs () and painted ladies (). To do this, we quantified the free-flight energetics and tethered-flight velocity and distance of the two species using flow-through respirometry and flight mill assays.

Hawkmoths regulate flight torques with their abdomen for yaw control.

Many animals use body parts such as tails to stabilize posture while moving at high speed. In flying insects, leg or abdominal inertia can influence flight posture. In the hawkmoth Manduca sexta, the abdomen contributes ∼50% of the total body weight and it can therefore serve to inertially redirect flight forces.

Squash bees host high diversity and prevalence of parasites in the northeastern United States.

The squash bee Eucera (Peponapis) pruinosa is emerging as a model species to study how stressors impact solitary wild bees in North America. Here, we describe the prevalence of trypanosomes, microsporidians and mollicute bacteria in E. pruinosa and two other species, Bombus impatiens and Apis mellifera, that together comprise over 97% of the pollinator visitors of Cucurbita agroecosystems in Pennsylvania (United States).

Impacts of larval host plant species on dispersal traits and free-flight energetics of adult butterflies.

Animals derive resources from their diet and allocate them to organismal functions such as growth, maintenance, reproduction, and dispersal. How variation in diet quality can affect resource allocation to life-history traits, in particular those important to locomotion and dispersal, is poorly understood. We hypothesize that, particularly for specialist herbivore insects that are in co-evolutionary arms races with host plants, changes in host plant will impact performance.

Geographic variation and thermal plasticity shape salamander metabolic rates under current and future climates.

Predicted changes in global temperature are expected to increase extinction risk for ectotherms, primarily through increased metabolic rates. Higher metabolic rates generate increased maintenance energy costs which are a major component of energy budgets. Organisms often employ plastic or evolutionary (e.

Honey bee viruses are highly prevalent but at low intensities in wild pollinators of cucurbit agroecosystems.

Managed and wild bee populations are in decline around the globe due to several biotic and abiotic stressors. Pathogenic viruses associated with the Western honey bee (Apis mellifera) have been identified as key contributors to losses of managed honey bee colonies, and are known to be transmitted to wild bee populations through shared floral resources. However, little is known about the prevalence and intensity of these viruses in wild bee populations, or how bee visitation to flowers impacts viral transmission in agroecosystems.

Operative temperature analysis of the honey bee Apis mellifera.

A key challenge for linking experiments of organisms performed in a laboratory environment to their performance in more complex environments is to determine thermal differences between a laboratory and the energetically complex terrestrial ecosystem. Studies performed in the laboratory do not account for many factors that contribute to the realized temperature of an organism in its natural environment. This can lead to modelling approaches that use experimentally derived data to erroneously link the air temperature in a laboratory to air temperatures in energetically heterogenous ecosystems.

Quality of Life in Adult and Pediatric Patients with Tropomyosin Receptor Kinase Fusion Cancer Receiving Larotrectinib.

Neurotrophic tyrosine receptor kinase (NTRK) gene fusions lead to chimeric tropomyosin receptor kinase (TRK) fusion proteins, which act as primary oncogenic drivers in diverse tumor types in adults and children. Larotrectinib, a highly selective and central nervous system-active TRK inhibitor, has shown high objective response rates, durable disease control, and a favorable safety profile in patients with TRK fusion cancer. The impact of larotrectinib on health-related quality of life (HRQoL) was evaluated in adult and pediatric patients in two phase I/II clinical trials (NAVIGATE; NCT02576431 and SCOUT; NCT02637687).

A phase Ib/II and pharmacokinetic study of EP0057 (formerly CRLX101) in combination with weekly paclitaxel in patients with recurrent or persistent epithelial ovarian, fallopian tube, or primary peritoneal cancer.

Background: EP0057 (formerly CRLX101) is an investigational nanoparticle-drug conjugate (NDC) of a cyclodextrin-based polymer backbone plus camptothecin, a topoisomerase-1 inhibitor. Prior studies showed efficacy in recurrent or persistent, epithelial ovarian, fallopian tube or primary peritoneal cancer (EOC).

Methods: This phase Ib/2 trial assessed safety and efficacy of EP0057 Q2W plus weekly paclitaxel in patients with EOC.

Immune Activation in Patients with Locally Advanced Cervical Cancer Treated with Ipilimumab Following Definitive Chemoradiation (GOG-9929).

Purpose: A phase I clinical trial (GOG-9929) examined the safety and efficacy of adjuvant immune-modulation therapy with the checkpoint inhibitor ipilimumab [anti-CTL antigen-4 (anti-CTLA-4)] following chemoradiation therapy (CRT) for newly diagnosed node-positive human papillomavirus (HPV)-related cervical cancer. To better understand the mechanism of action and to identify predictive biomarkers, immunologic and viral correlates were assessed before, during, and after treatment.

Patients And Methods: Twenty-one patients who received CRT and ≥2 doses of ipilimumab and 5 patients who received CRT only were evaluable for translational endpoints.

Berzosertib plus gemcitabine versus gemcitabine alone in platinum-resistant high-grade serous ovarian cancer: a multicentre, open-label, randomised, phase 2 trial.

Background: High-grade serous ovarian cancers show increased replication stress, rendering cells vulnerable to ATR inhibition because of near universal loss of the G1/S checkpoint (through deleterious TP53 mutations), premature S phase entry (due to CCNE1 amplification, RB1 loss, or CDKN2A mRNA downregulation), alterations of homologous recombination repair genes, and expression of oncogenic drivers (through MYC amplification and other mechanisms). We hypothesised that the combination of the selective ATR inhibitor, berzosertib, and gemcitabine could show acceptable toxicity and superior efficacy to gemcitabine alone in high-grade serous ovarian cancer.

Methods: In this multicentre, open-label, randomised, phase 2 study, 11 different centres in the US Experimental Therapeutics Clinical Trials Network enrolled women (aged ≥18 years) with recurrent, platinum-resistant high-grade serous ovarian cancer (determined histologically) and Eastern Cooperative Oncology Group performance status of 0 or 1, who had unlimited previous lines of cytotoxic therapy in the platinum-sensitive setting but no more than one line of cytotoxic therapy in the platinum-resistant setting.

Larotrectinib in patients with TRK fusion-positive solid tumours: a pooled analysis of three phase 1/2 clinical trials.

Background: The selective TRK inhibitor larotrectinib was approved for paediatric and adult patients with advanced TRK fusion-positive solid tumours based on a primary analysis set of 55 patients. The aim of our analysis was to explore the efficacy and long-term safety of larotrectinib in a larger population of patients with TRK fusion-positive solid tumours.

Methods: Patients were enrolled and treated in a phase 1 adult, a phase 1/2 paediatric, or a phase 2 adolescent and adult trial.

Anti-PD-L1 (atezolizumab) as an immune primer and concurrently with extended-field chemoradiotherapy for node-positive locally advanced cervical cancer.

Background: There is a lack of data exploring the use and optimal timing of immunotherapy and chemoradiation therapy (CRT) in node-positive cervical cancer. Further translational research into mechanisms of response and resistance to immunotherapy in advanced cervical cancer is warranted.

Primary Objectives: To determine if sequencing of atezolizumab and CRT result in differential immune activation, as determined by clonal expansion of T cell receptor beta (TCRB) repertoires in peripheral blood on day 21.

Sequential Ipilimumab After Chemoradiotherapy in Curative-Intent Treatment of Patients With Node-Positive Cervical Cancer.

Importance: Despite standard chemoradiotherapy (CRT), most women with lymph node (LN)-positive cervical cancer experience disease recurrence. Immunotherapy is being investigated in the up-front treatment setting.

Objectives: To assess the safety of sequential immunotherapy after CRT and to investigate human papillomavirus (HPV) genotype and HLA allele status on survival and programmed cell death 1 (PD-1) expression before and after CRT and sequential immunotherapy.

A phase I study of intravenous or intraperitoneal platinum based chemotherapy in combination with veliparib and bevacizumab in newly diagnosed ovarian, primary peritoneal and fallopian tube cancer.

Background: Improvements in disease free survival for epithelial ovarian, peritoneal or fallopian tube cancer (EOC) will only come with improved primary therapy. Incorporation of poly-ADP-ribose inhibitors (PARPi) in the frontline setting may represent one strategy. This study sought to determine the maximum tolerated and feasible doses of the PARPi veliparib in combination with chemotherapy for EOC.

Safety, Tolerability, and Potential Clinical Activity of a Glucocorticoid-Induced TNF Receptor-Related Protein Agonist Alone or in Combination With Nivolumab for Patients With Advanced Solid Tumors: A Phase 1/2a Dose-Escalation and Cohort-Expansion Clinical Trial.

Importance: Multiple immunostimulatory agonist antibodies have been clinically tested in solid tumors to evaluate the role of targeting glucocorticoid-induced tumor necrosis factor (TNF) receptor-related protein in anticancer treatments.

Objective: To evaluate the safety and activity of the fully human glucocorticoid-induced TNF receptor-related protein agonist IgG1 monoclonal antibody BMS-986156 with or without nivolumab in patients with advanced solid tumors.

Design, Setting, And Participants: This global, open-label, phase 1/2a study of BMS-986156 with or without nivolumab enrolled 292 patients 18 years or older with advanced solid tumors and an Eastern Cooperative Oncology Group performance status of 1 or less.

Safety lead-in of the MEK inhibitor trametinib in combination with GSK2141795, an AKT inhibitor, in patients with recurrent endometrial cancer: An NRG Oncology/GOG study.

Objective: We sought to determine safety and efficacy of the AKT inhibitor, GSK2141795, combined with the MEK inhibitor, trametinib, in endometrial cancer.

Methods: Patients with measurable recurrent endometrial cancer were eligible. One to two prior cytotoxic regimens were allowed; prior use of a MEK or PI3K pathway inhibitor was excluded.

Parasitic gut infection in causes functional and molecular resemblance of dragonfly flight muscle to skeletal muscle of obese vertebrates.

We previously demonstrated the existence of a naturally occurring metabolic disease phenotype in dragonflies that shows high similarity to vertebrate obesity and type II diabetes, and is caused by a protozoan gut parasite. To further mechanistic understanding of how this metabolic disease phenotype affects fitness of male , we examined infection effects on muscle performance and molecular traits relevant to dragonfly flight performance in nature. Importantly, these traits were previously shown to be affected in obese vertebrates.

Palmitate- and C6 ceramide-induced pre-mRNA alternative splicing occurs in a PP2A dependent manner.

Background: In a previous study, we showed that consumption of diets enriched in saturated fatty acids causes changes in alternative splicing of pre-mRNAs encoding a number of proteins in rat skeletal muscle, including the one encoding skeletal muscle Troponin T (). However, whether saturated fatty acids act directly on muscle cells to modulate alternative pre-mRNA splicing was not assessed. Moreover, the signaling pathway through which saturated fatty acids act to promote changes in alternative splicing is unknown.

Alisertib in Combination With Weekly Paclitaxel in Patients With Advanced Breast Cancer or Recurrent Ovarian Cancer: A Randomized Clinical Trial.

Importance: There is an unmet medical need for the treatment of recurrent ovarian cancer, and new approaches are needed to improve progression-free survival (PFS) and overall survival.

Objective: This phase 1/2 study evaluated the activity of alisertib in combination with weekly paclitaxel in patients with breast (phase 1) and ovarian cancer (phase 1 and phase 2).

Design, Setting, And Participants: An open-label phase 1 and randomized phase 2 clinical trial conducted from April 16, 2010, for phase 1 and March 28, 2012, to August 12, 2013, for phase 2 was conducted at 33 sites (United States, France, and Poland).