Racial Disparities in Endometrial Cancer Clinical Trial Representation: Exploring the Role of Eligibility Criteria.

BACKGROUND: This study aimed to determine whether Black patients with recurrent endometrial cancer were more likely than White patients to be ineligible for a recently published clinical trial due to specific eligibility criteria. METHODS: Patients with recurrent or progressive endometrial cancer diagnosed from January 2010 to December 2021 who received care at a single institution were identified. Demographic and clinicopathologic information was abstracted and determination of clinical trial eligibility was made based on 14 criteria from the KEYNOTE-775 trial. Characteristics of the eligible and ineligible cohorts were compared, and each ineligibility criterion was evaluated by race. RESULTS: One hundred seventy-five patients were identified, 89 who would have met all inclusion and no exclusion criteria for KEYNOTE-775, and 86 who would have been ineligible by one or more exclusion criteria. Patients in the ineligible cohort were more likely to have lower BMI (median 26.5 vs. 29.2, P <0.001), but were otherwise similar with regard to insurance status, histology, and stage at diagnosis. Black patients had 33% lower odds of being eligible (95% CI: 0.33-1.34) and were more likely to meet the exclusion criterion of having a previous intestinal anastomosis, but the result was not statistically significant. If this criterion were removed, the racial distribution of those ineligible for the trial would be more similar (46.4% Black vs. 42.2% White). CONCLUSIONS: Clinical trial eligibility criteria may contribute to the underrepresentation of racial groups in clinical trials, but other factors should be explored. Studies to quantify and lessen the impact of implicit bias are also needed.

Acheron/Larp6 Is a Survival Protein That Protects Skeletal Muscle From Programmed Cell Death During Development.

The term programmed cell death (PCD) was coined in 1965 to describe the loss of the intersegmental muscles (ISMs) of moths at the end of metamorphosis. While it was subsequently demonstrated that this hormonally controlled death requires de novo gene expression, the signal transduction pathway that couples hormone action to cell death is largely unknown. Using the ISMs from the tobacco hawkmoth Manduca sexta, we have found that Acheron/LARP6 mRNA is induced ∼1,000-fold on the day the muscles become committed to die. Acheron functions as a survival protein that protects cells until cell death is initiated at eclosion (emergence), at which point it becomes phosphorylated and degraded in response to the peptide Eclosion Hormone (EH). Acheron binds to a novel BH3-only protein that we have named BBH1 (BAD/BNIP3 homology 1). BBH1 accumulates on the day the ISMs become committed to die and is presumably liberated when Acheron is degraded. This is correlated with the release and rapid degradation of cytochrome c and the subsequent demise of the cell. RNAi experiments in the fruit fly Drosophila confirmed that loss of Acheron results in precocious ecdysial muscle death while targeting BBH1 prevents death altogether. Acheron is highly expressed in neurons and muscles in humans and drives metastatic processes in some cancers, suggesting that it may represent a novel survival protein that protects terminally differentiated cells and some cancers from death.

Altered lipoprotein profiles in cats with hepatic lipidosis.

OBJECTIVES: The aim of this study was to assess serum lipoprotein profiles using rapid single-spin continuous lipoprotein density profiling (CLPDP) in healthy control cats and cats with hepatic lipidosis (HL). METHODS: Analysis of serum lipoprotein profiles using the CLPDP was performed in 23 cats with HL and 20 healthy control cats. The area under the curve for each lipoprotein fraction, triglyceride (TG)-rich lipoproteins (TRLs), low-density lipoproteins (LDLs) and high-density lipoproteins (HDLs), was calculated. Serum cholesterol and TG concentrations were measured using a clinical chemistry analyzer. RESULTS: Serum cholesterol and TG concentrations were not significantly different between healthy control cats and cats with HL ( P = 0.5075 and P = 0.2541, respectively). LDL content was significantly higher in cats with HL than in healthy control cats ( P = 0.0001), while HDL content was significantly lower in cats with HL than in healthy control cats ( P = 0.0032). TRL content was not significantly different between the two groups ( P = 0.0699). The specific fraction (1.037-1.043 g/ml) within nominal LDL in serum distinguished healthy control cats from cats with HL with a sensitivity of 87% and a specificity of 90%. CONCLUSIONS AND RELEVANCE: Serum lipoprotein profiles were altered in cats with HL, even though serum cholesterol and TG concentrations were not significantly different compared with healthy control cats. The CLPDP might be a useful tool for assessing lipid metabolism in cats with HL.

Use of trazodone to facilitate postsurgical confinement in dogs.

OBJECTIVE: To investigate the safety and efficacy of oral administration of the serotonin antagonist and reuptake inhibitor trazodone hydrochloride to facilitate confinement and calming after orthopedic surgery in dogs. DESIGN: Prospective open-label clinical trial. ANIMALS: 36 client-owned dogs that underwent orthopedic surgery. PROCEDURES: Starting the day after surgery, dogs were administered trazodone (approx 3.5 mg/kg [1.6 mg/lb], PO, q 12 h) with tramadol (4 to 6 mg/kg [1.8 to 2.7 mg/lb], PO, q 8 to 12 h) for pain management. After 3 days, administration of tramadol was discontinued, and the trazodone dosage was increased (approx 7 mg/kg [3.2 mg/lb], PO, q 12 h) and maintained for at least 4 weeks. If needed, trazodone dosage was increased (7 to 10 mg/kg [3.2 to 4.5 mg/lb], PO, q 8 h). Owners completed electronic surveys rating their dogs' confinement tolerance, calmness or hyperactivity level, and responses to specific provocative situations prior to surgery and 1, 2, 3, and 4 weeks after surgery and at the postsurgery evaluation (at 8 to 12 weeks). RESULTS: Most (32/36 [89%]) of owners reported that their dogs, when given trazodone during the 8 to 12 weeks following orthopedic surgery, improved moderately or extremely with regard to confinement tolerance and calmness. Trazodone was well tolerated, even in combination with NSAIDs, antimicrobials, and other medications; no dogs were withdrawn from the study because of adverse reactions. Owner-reported median onset of action of trazodone was 31 to 45 minutes, and median duration of action was ≥ 4 hours. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that oral administration of trazodone was safe and efficacious and may be used to facilitate confinement and enhance behavioral calmness of dogs during the critical recovery period following orthopedic surgery.

Conditioning laboratory cats to handling and transport.

As research subjects, cats have contributed substantially to our understanding of biological systems, from the development of mammalian visual pathways to the pathophysiology of feline immunodeficiency virus as a model for human immunodeficiency virus. Few studies have evaluated humane methods for managing cats in laboratory animal facilities, however, in order to reduce fear responses and improve their welfare. The authors describe a behavioral protocol used in their laboratory to condition cats to handling and transport. Such behavioral conditioning benefits the welfare of the cats, the safety of animal technicians and the quality of feline research data.

A Link between ethylene and auxin uncovered by the characterization of two root-specific ethylene-insensitive mutants in Arabidopsis.

The plant hormone ethylene participates in the regulation of a variety of developmental processes and serves as a key mediator of plant responses to biotic and abiotic stress factors. The diversity of ethylene functions is achieved, at least in part, by combinatorial interactions with other hormonal signals. Here, we show that ethylene-triggered inhibition of root growth, one of the classical effects of ethylene in Arabidopsis thaliana seedlings, is mediated by the action of the WEAK ETHYLENE INSENSITIVE2/ANTHRANILATE SYNTHASE alpha1 (WEI2/ASA1) and WEI7/ANTHRANILATE SYNTHASE beta1 (ASB1) genes that encode alpha- and beta-subunits of a rate-limiting enzyme of Trp biosynthesis, anthranilate synthase. Upregulation of WEI2/ASA1 and WEI7/ASB1 by ethylene results in the accumulation of auxin in the tip of primary root, whereas loss-of-function mutations in these genes prevent the ethylene-mediated auxin increase. Furthermore, wei2 and wei7 suppress the high-auxin phenotypes of superroot1 (sur1) and sur2, two auxin-overproducing mutants, suggesting that the roles of WEI2 and WEI7 in the regulation of auxin biosynthesis are not restricted to the ethylene response. Together, these findings reveal that ASA1 and ASB1 are key elements in the regulation of auxin production and an unexpected node of interaction between ethylene responses and auxin biosynthesis in Arabidopsis. This study provides a mechanistic explanation for the root-specific ethylene insensitivity of wei2 and wei7, illustrating how interactions between hormones can be used to achieve response specificity.