COVID-19 effects on horses in-transition: A survey analysis of United States equine industry perspectives.

The welfare of unwanted horses presents a significant concern for the equine industry. However, there is a lack of research on how unwanted horses are affected by major crises. The drastic changes that resulted from the COVID-19 pandemic presented ample opportunity to investigate how unwanted horses are impacted by challenging circumstances. Study objectives were to evaluate the COVID-19 pandemic's impact on the unwanted horse population and determine the current perceptions of horses in-transition. A 23-question online survey designed using QualtricsTM was administered electronically to adults living in the United States. Questions pertained to effects on equine ownership, equine management, event participation, and perceptions of unwanted horses. Frequency analysis combined with Chi-squared analyses and analyses of variance identified the impacts of COVID-19 on horse owners, non-horse owners, and equine professionals. From survey results, equine ownership, management practices, and time spent with horses proved to be unaffected (P < 0.001) by the coronavirus pandemic. A decreased ability to participate in equine events was evident across all groups (P ≤ 0.03). Financial hardship, unmanageable behavior, and injury were cited as leading causes for horses becoming "in-transition." Euthanasia was the transitioning method perceived as most accessible, while donation to an equine program was least accessible. Based on results, the COVID-19 pandemic had negligible impact on the number of unwanted horses in the United States. Long-term effects of COVID-19 on equine ownership and management decisions should be considered to provide a deeper base of knowledge for how major crises affect the horse in-transition population.

Prevalence and risk factors for gingivitis in a cohort of UK companion cats aged up to 6 years.

OBJECTIVES: Prospectively collected data were used to estimate the prevalence of gingivitis in a cohort of companion cats aged up to 6 years and to investigate factors associated with the risk of gingivitis in cats aged 3 to 4 years. MATERIALS AND METHODS: Data were obtained from a longitudinal study of domestic cats (the Bristol Cats Study), using owner-completed questionnaires and veterinary surgeon-completed oral health scores. Prevalence estimates of veterinary-reported gingivitis for cats aged up to 6 years old (n = 1534) were calculated for different age groups. Cat signalment, diet and dental care were assessed for association with gingivitis in cats aged 3 to 4 years (n = 317) using univariable and multiple logistic regression. RESULTS: The prevalence of gingivitis increased with age and ranged from 24.5% (<12 months old) to 56.3% (5 to 6 years old). Odds of gingivitis in cats aged 3 to 4 years were higher in cats fed a wet only or mixed wet/dry diet compared to dry only (odds ratio: 2.7; 95% confidence interval: 1.4 to 5.1), cats not reported to hunt compared to reported hunters (odds ratio: 2.1; 95% confidence interval: 1.0 to 4.2), cats reported to dribble whilst being stroked at age 6 months compared to reported non-dribblers (odds ratio: 3.2; 95% confidence interval: 1.3 to 8.4) and cats with orange variants in their coat colour compared to non-orange cats (odds ratio: 2.3; 95% confidence interval: 1.0 to 5.3). CLINICAL SIGNIFICANCE: These results will help veterinary surgeons identify cats that may be at a greater risk of gingivitis and provide an evidence base to inform dietary and oral healthcare recommendations aimed at promoting gingival health in cats.

Salivary toxicity from PSMA-targeted radiopharmaceuticals: What we have learned and where we are going.

Clinical trials of prostate-specific membrane antigen (PSMA) targeted radiopharmaceuticals have shown encouraging results. Some agents, like lutetium-177 [177Lu]Lu-PSMA-617 ([177Lu]Lu-PSMA-617), are already approved for late line treatment of metastatic castration-resistant prostate cancer (mCRPC). Projections are for continued growth of this treatment modality; [177Lu]Lu-PSMA-617 is being studied both in earlier stages of disease and in combination with other anti-cancer therapies. Further, the drug development pipeline is deep with variations of PSMA-targeting radionuclides, including higher energy alpha particles conjugated to PSMA-honing vectors. It is safe to assume that an increasing number of patients will be exposed to PSMA-targeted radiopharmaceuticals during the course of their cancer treatment. In this setting, it is important to better understand and mitigate the most commonly encountered toxicities. One particularly vexing side effect is xerostomia. In this review, we discuss the scope of the problem, inventories to better characterize and monitor this troublesome side effect, and approaches to preserve salivary function and effectively palliate symptoms. This article aims to serve as a useful reference for prescribers of PSMA-targeted radiopharmaceuticals, while also commenting on areas of missing data and opportunities for future research.

Antibiotic class with potent in vivo activity targeting lipopolysaccharide synthesis in Gram-negative bacteria.

Here, we describe the identification of an antibiotic class acting via LpxH, a clinically unexploited target in lipopolysaccharide synthesis. The lipopolysaccharide synthesis pathway is essential in most Gram-negative bacteria and there is no analogous pathway in humans. Based on a series of phenotypic screens, we identified a hit targeting this pathway that had activity on efflux-defective strains of Escherichia coli. We recognized common structural elements between this hit and a previously published inhibitor, also with activity against efflux-deficient bacteria. With the help of X-ray structures, this information was used to design inhibitors with activity on efflux-proficient, wild-type strains. Optimization of properties such as solubility, metabolic stability and serum protein binding resulted in compounds having potent in vivo efficacy against bloodstream infections caused by the critical Gram-negative pathogens E. coli and Klebsiella pneumoniae. Other favorable properties of the series include a lack of pre-existing resistance in clinical isolates, and no loss of activity against strains expressing extended-spectrum-ß-lactamase, metallo-ß-lactamase, or carbapenemase-resistance genes. Further development of this class of antibiotics could make an important contribution to the ongoing struggle against antibiotic resistance.

Benchmarking multi-ancestry prostate cancer polygenic risk scores in a real-world cohort.

Prostate cancer is a heritable disease with ancestry-biased incidence and mortality. Polygenic risk scores (PRSs) offer promising advancements in predicting disease risk, including prostate cancer. While their accuracy continues to improve, research aimed at enhancing their effectiveness within African and Asian populations remains key for equitable use. Recent algorithmic developments for PRS derivation have resulted in improved pan-ancestral risk prediction for several diseases. In this study, we benchmark the predictive power of six widely used PRS derivation algorithms, including four of which adjust for ancestry, against prostate cancer cases and controls from the UK Biobank and All of Us cohorts. We find modest improvement in discriminatory ability when compared with a simple method that prioritizes variants, clumping, and published polygenic risk scores. Our findings underscore the importance of improving upon risk prediction algorithms and the sampling of diverse cohorts.

Cosmic mysteries and the hydrogen 21-cm line: bridging the gap with lunar observations.

The hydrogen 21-cm signal is predicted to be the richest probe of the young Universe, including those eras known as the cosmic Dark Ages, the Cosmic Dawn (when the first star and black hole formed) and the Epoch of Reionization. This signal holds the key to deciphering processes that take place at the early stages of cosmic history. In this opinion piece, we discuss the potential scientific merit of lunar observations of the 21-cm signal and their advantages over more affordable terrestrial efforts. The Moon is a prime location for radio cosmology which will enable precision observations of the low-frequency radio sky. The uniqueness of such observations is that they will provide an unparalleled opportunity to test cosmology and the nature of dark matter using the Dark Ages 21-cm signal. No less enticing is the opportunity to obtain a much clearer picture of the Cosmic Dawn than that currently achievable from the ground, which will allow us to determine the properties of the first stars and black holes. This article is part of a discussion meeting issue 'Astronomy from the Moon: the next decades (part 2)'.

Characteristics and outcomes of a hospitalized cohort with reduced mortality from COVID-19, White Mountain apache tribal lands, April 1 - July 31, 2020.

BACKGROUND: Widespread transmission of COVID-19 continues to threaten public health, particularly of rural, American Indian communities. Although COVID-19 risk factors for severe disease and clinical characteristics are well described in the general population, there has been little shared on hospitalized American Indian populations. METHODS: In this observational study, we performed chart extractions on all persons hospitalized with COVID-19 from April 1 through July 31, 2020 among an exclusively American Indian population living on or near Tribal lands in eastern Arizona. We provide descriptive statistics for the cohort stratified by presentation, comparing those who self-presented or were referred by an outreach program. Exploratory analyses were performed to identify risk factors for morbidity and mortality. RESULTS: During the observation period, 2262 persons were diagnosed with COVID-19 and 490 (22%) were hospitalized. Hospitalized persons had a median age of 54 years; 92% had at least one comorbidity, 72% had greater than one comorbidity, and 60% had a BMI of > 30. Most persons required supplemental oxygen (83%), but the majority (62%) only required nasal cannula and only 11% were intubated. The case fatality rates were 1.7% for the population, 7.1% among hospitalizations, and 9.3% among hospitalized patients 50 years and older. All rates that are significantly lower than those reported nationally during the same period. CONCLUSIONS: We observed a cohort of American Indian patients hospitalized secondary to COVID-19 with greater number of comorbidities compared to the general population but with lower mortality rates. We posit that the primary driver of mortality reduction for this population and the hospitalized cohort was a community-based referral program that led to disproportionately lower fatality rates among the oldest persons.

Mild traumatic brain injury in Drosophila melanogaster alters reactive oxygen and nitrogen species in a sex-dependent manner.

Traumatic brain injury (TBI) is an outside force causing a modification in brain function and/or structural brain pathology that upregulates brain inducible nitric oxide synthase (iNOS), instigating increased levels of nitric oxide activity which is implicated in secondary pathology leading to behavioral deficits (Hall et al., 2012; Garry et al., 2015; Kozlov et al., 2017). In mammals, TBI-induced NO production activates an immune response and potentiates metabolic crisis through mitochondrial dysfunction coupled with vascular dysregulation; however, the direct influence on pathology is complicated by the activation of numerous secondary cascades and activation of other reactive oxygen species. Drosophila TBI models have demonstrated key features of mammalian TBI, including temporary incapacitation, disorientation, motor deficits, activation of innate immunity (inflammation), and autophagy responses observed immediately after injury (Katzenberger et al., 2013; Barekat et al., 2016; Simon et al., 2017; Anderson et al., 2018; Buhlman et al., 2021b). We hypothesized that acute behavioral phenotypes would be associated with deficits in climbing behavior and increased oxidative stress. Because flies lack mammalian-like cardiovascular and adaptive immune systems, we were able to make our observations in the absence of vascular disruption and adaptive immune system interference in a system where highly targeted interventions can be rapidly evaluated. To demonstrate the induction of injury, ten-day-old transgenic flies received an injury of increasing angles from a modified high impact trauma (HIT) device where angle-dependent increases occurred for acute neurological behavior assessments and twenty-four-hour mortality, and survival was significantly decreased. Injury caused sex-dependent effects on climbing activity and measures of oxidative stress. Specifically, after a single 60-degree HIT, female flies exhibited significant impairments in climbing activity beyond that observed in male flies. We also found that several measures of oxidative stress, including Drosophila NOS (dNOS) expression, protein nitration, and hydrogen peroxide production were significantly decreased in female flies. Interestingly, protein nitration was also decreased in males, but surpassed sham levels with a more severe injury. We also observed decreased autophagy demand in vulnerable dopaminergic neurons in female, but not male flies. In addition, mitophagy initiation was decreased in females. Collectively, our data suggest that TBI in flies induces acute behavioral phenotypes and climbing deficits that are analogous to mammalian TBI. We also observed that various indices of oxidative stress, including dNOS expression, protein tyrosine nitration, and hydrogen peroxide levels, as well as basal levels of autophagy, are altered in response to injury, an effect that is more pronounced in female flies.

Prostate-Specific Membrane Antigen-Targeting Alpha Emitter via Antibody Delivery for Metastatic Castration-Resistant Prostate Cancer: A Phase I Dose-Escalation Study of 225Ac-J591.

PURPOSE: Novel therapies are needed to extend survival in metastatic castration-resistant prostate cancer (mCRPC). Prostate-specific membrane antigen (PSMA), a cell surface antigen overexpressed in PC, provides a validated target. This dose-escalation study investigated the safety, efficacy, maximum tolerated dose (MTD), and recommended phase II dose (RP2D) for 225Ac-J591, anti-PSMA monoclonal antibody J591 radiolabeled with the alpha emitter actinium-225. METHODS: Following investigational new drug-enabling preclinical studies, we enrolled patients with progressive mCRPC that was refractory to or who refused standard treatment options (including androgen receptor pathway inhibitor and had received or been deemed ineligible for taxane chemotherapy). No selection for PSMA was performed. Patients received a single dose of 225Ac-J591 at one of seven dose-escalation levels followed by expansion at the highest dose. Primary end point of dose-escalation cohort was determination of dose-limiting toxicity (DLT) and RP2D. RESULTS: Radiochemistry and animal studies were favorable. Thirty-two patients received 225Ac-J591 in an accelerated dose-escalation design (22 in dose escalation, 10 in expansion). One patient (1 of 22; 4.5%) experienced DLT in cohort 6 (80 KBq/kg) but none in cohort 7; MTD was not reached, and RP2D was the highest dose level (93.3 KBq/kg). The majority of high-grade adverse events (AEs) were hematologic with an apparent relationship with administered radioactivity. Nonhematologic AEs were generally of low grade. Prostate-specific antigen (PSA) declines and circulating tumor cell (CTC) control were observed: 46.9% had at least 50% PSA decline at any time (34.4% confirmed PSA response), and protocol-defined CTC count response occurred in 13 of 22 (59.1%). CONCLUSION: To our knowledge, this is the first-in-human phase I dose-escalation trial of a single dose of 225Ac-J591 in 32 patients with pretreated progressive mCRPC demonstrated safety and preliminary efficacy signals. Further investigation is underway.

Morpho-Anatomy and Mathematical Modelling in Lilium philippinense Baker from Cordillera Central Range, Philippines.

The study presents the morphology, anatomy and mathematical modelling in Benguet lily (Lilium philippinense Baker), a threatened species from the Cordillera Central Range and was often misidentified with the weedy L. formosanum. The plant is an annual herb with linear, spiral leaves; pure white, perfect, funnel-shaped, showy flowers; septicidal elongated capsule; and, brown, light, winged seeds. New findings in the study include the description of the capsule and seeds, biometric measurements of the different plant organs, the significant correlation and regression model of plant height and stem diameter for certain floral measurement, and its diagnostic characteristics vis-à-vis L. formosanum. Interesting findings on the taxon's anatomy show a cross between a typical monocot and a typical dicot anatomy. It has a bifacial leaf structure (a common dicot character) but its spongy layer is not as widely spaced like in dicot leaf. The stem has a distinct cortex and pith (a dicot character) but has a scattered vascular bundles (a monocot character). Lastly, some roots have a narrow pith at the centre of the stele (a monocot character) while some roots have metaxylem elements at the centermost structure (a dicot character). Further studies need to be conducted to determine the ecological significance of these features.

European Association of Urology Guidelines on Penile Size Abnormalities and Dysmorphophobia: Summary of the 2023 Guidelines.

CONTEXT: Recommendations regarding the management of penile size abnormalities and dysmorphophobia are important in guiding evidence-based clinical practice. OBJECTIVE: To present a summary of the 2023 European Association of Urology sexual and reproductive health evidence-based recommendations for the management of penile size abnormalities and dysmorphophobia. EVIDENCE ACQUISITION: A broad and comprehensive scoping exercise covering all areas of the guidelines was performed. Databases searched included Medline, EMBASE, and the Cochrane Libraries. A level of evidence and a strength of recommendation were assigned for each recommendation according to the evidence identified. The evidence cutoff date for the 2023 guidelines is June 1, 2022. EVIDENCE SYNTHESIS: Well-structured studies reporting high level of evidence, with standardized PROMS were deficient on penile size abnormalities and dysmorphohobia. A shared definition for short penis/micropenis was also lacking. Categorisation of penile abnormalities according to congenital, acquired, and dysmorphophobic aetiology is deemed compulsory. A detailed medical and psychosexual history and precise measurements of penile size are essential in the diagnostic pathway. Patients with normal penile size who are seeking penile augmentation should be referred for psychological evaluation for potential dysmorphophobic disorders. Penile length and girth enhancements can be achieved via a multitude of treatments, but a personalised management plan is crucial for satisfactory results. Endocrinological therapies, when indicated, are effective in the prepubertal setting only. Vacuum therapy has a limited evidence base in treatment protocols, although acceptable outcomes have been reported for penile traction therapy. Surgical techniques to enhance penile length and girth have limited evidence and should only be proposed after extensive patient counselling. CONCLUSIONS: Management of penile abnormalities and dysmorphophobia is a complex issue with considerable ethical concerns. The adoption of a structured diagnostic and therapeutic pathway is crucial, as recommended in the guidelines. PATIENT SUMMARY: Requests for medical/surgical treatments to increase penis size have increased dramatically worldwide. Several conservative and surgical treatments are available. However, few patients receive clear information on the benefits and possible harms of these treatments. These guidelines aim to provide a structured path to guide both physicians and patients in the selection of appropriate treatment(s) to increase penis size.

Long-molecule scars of backup DNA repair in BRCA1- and BRCA2-deficient cancers.

Homologous recombination (HR) deficiency is associated with DNA rearrangements and cytogenetic aberrations1. Paradoxically, the types of DNA rearrangements that are specifically associated with HR-deficient cancers only minimally affect chromosomal structure2. Here, to address this apparent contradiction, we combined genome-graph analysis of short-read whole-genome sequencing (WGS) profiles across thousands of tumours with deep linked-read WGS of 46 BRCA1- or BRCA2-mutant breast cancers. These data revealed a distinct class of HR-deficiency-enriched rearrangements called reciprocal pairs. Linked-read WGS showed that reciprocal pairs with identical rearrangement orientations gave rise to one of two distinct chromosomal outcomes, distinguishable only with long-molecule data. Whereas one (cis) outcome corresponded to the copying and pasting of a small segment to a distant site, a second (trans) outcome was a quasi-balanced translocation or multi-megabase inversion with substantial (10 kb) duplications at each junction. We propose an HR-independent replication-restart repair mechanism to explain the full spectrum of reciprocal pair outcomes. Linked-read WGS also identified single-strand annealing as a repair pathway that is specific to BRCA2 deficiency in human cancers. Integrating these features in a classifier improved discrimination between BRCA1- and BRCA2-deficient genomes. In conclusion, our data reveal classes of rearrangements that are specific to BRCA1 or BRCA2 deficiency as a source of cytogenetic aberrations in HR-deficient cells.

Leflutrozole in male obesity-associated hypogonadotropic hypogonadism: Ph 2b double-blind randomised controlled trial.

OBJECTIVE: Assessment of the efficacy and safety/tolerability of the aromatase inhibitor leflutrozole to normalise testosterone in Obesity-associated Hypogonadotropic Hypogonadism (OHH). DESIGN: Placebo-controlled, double-blind, RCT, in 70 sites in Europe/USA. METHODS: Patient inclusion criteria: men with BMI of 30-50 kg/m2, morning total testosterone (TT) < 10.41 nmol/L, and two androgen deficiency symptoms (at least one of sexual dysfunction). Patients randomised to weekly leflutrozole (0.1/0.3/1.0 mg) or placebo for 24 weeks. Primary endpoint: normalisation of TT levels in ≥75% of patients after 24 weeks. Secondary endpoints (included): time to TT normalisation and change in LH/FSH. Safety was assessed through adverse events and laboratory monitoring. RESULTS AND CONCLUSIONS: Of 2103 screened, 271 were randomised, 81 discontinued. Demographic characteristics were similar across groups. Mean BMI was 38.1 kg/m2 and TT 7.97 nmol/L. The primary endpoint was achieved in all leflutrozole-treated groups by 24 weeks with a dose-tiered response; mean TT 15.89; 17.78; 20.35 nmol/L, for leflutrozole 0.1 mg, 0.3 mg, and 1.0 mg groups respectively, vs 8.04 nmol/L for placebo. LH/FSH significantly increased in leflutrozole vs placebo groups. No improvements in body composition or sexual dysfunction were observed. Semen volume/total motile sperm count improved with leflutrozole vs placebo. Treatment-emergent adverse events, more common in leflutrozole-treated groups included, raised haematocrit, hypertension, increased PSA, and headache. Some reduction in lumbar bone density was observed with leflutrozole (mean -1.24%, -1.30%, -2.09%) and 0.66% for 0.1 mg, 0.3 mg, 1.0 mg, and placebo, respectively, without change at the hip. This RCT of leflutrozole in OHH demonstrated normalisation of TT in obese men. FSH/LH and semen parameter changes support that leflutrozole may preserve/improve testicular function. CLINICAL TRIAL REGISTRATION NUMBER: NCT02730169.

Randomized phase II trial of MRI-guided salvage radiotherapy for prostate cancer in 4 weeks versus 2 weeks (SHORTER).

BACKGROUND: Ultra-hypofractionated image-guided stereotactic body radiotherapy (SBRT) is increasingly used for definitive treatment of localized prostate cancer. Magnetic resonance imaging-guided radiotherapy (MRgRT) facilitates improved visualization, real-time tracking of targets and/or organs-at-risk (OAR), and capacity for adaptive planning which may translate to improved targeting and reduced toxicity to surrounding tissues. Given promising results from NRG-GU003 comparing conventional and moderate hypofractionation in the post-operative setting, there is growing interest in exploring ultra-hypofractionated post-operative regimens. It remains unclear whether this can be done safely and whether MRgRT may help mitigate potential toxicity. SHORTER (NCT04422132) is a phase II randomized trial prospectively evaluating whether salvage MRgRT delivered in 5 fractions versus 20 fractions is non-inferior with respect to gastrointestinal (GI) and genitourinary (GU) toxicities at 2-years post-treatment. METHODS: A total of 136 patients will be randomized in a 1:1 ratio to salvage MRgRT in 5 fractions or 20 fractions using permuted block randomization. Patients will be stratified according to baseline Expanded Prostate Cancer Index Composite (EPIC) bowel and urinary domain scores as well as nodal treatment and androgen deprivation therapy (ADT). Patients undergoing 5 fractions will receive a total of 32.5 Gy over 2 weeks and patients undergoing 20 fractions will receive a total of 55 Gy over 4 weeks, with or without nodal coverage (25.5 Gy over 2 weeks and 42 Gy over 4 weeks) and ADT as per the investigator's discretion. The co-primary endpoints are change scores in the bowel and the urinary domains of the EPIC. The change scores will reflect the 2-year score minus the pre-treatment (baseline) score. The secondary endpoints include safety endpoints, including change in GI and GU symptoms at 3, 6, 12 and 60 months from completion of treatment, and efficacy endpoints, including time to progression, prostate cancer specific survival and overall survival. DISCUSSION: The SHORTER trial is the first randomized phase II trial comparing toxicity of ultra-hypofractionated and hypofractionated MRgRT in the salvage setting. The primary hypothesis is that salvage MRgRT delivered in 5 fractions will not significantly increase GI and GU toxicities when compared to salvage MRgRT delivered in 20 fractions. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04422132. Date of registration: June 9, 2020.

The community engagement course and action network: strengthening community and academic research partnerships to advance health equity.

Background: Historically Black Colleges and Universities and Minority Serving Institutions are uniquely positioned to implement community-campus research partnerships based on a history of service, the pursuit of community trustworthiness and student demographics often similar to surrounding marginalized communities. The Morehouse School of Medicine Prevention Research Center collaborates with members of Historically Black Colleges and Universities, Minority Serving Institutes, and community organizations on the Community Engaged Course and Action Network. This network is the first of its kind and aims to strengthen members' ability to implement Community-Based Participatory Research (CBPR) principles and partnerships. Projects address public health priorities including mental health among communities of color, zoonotic disease prevention, and urban food deserts. Materials and methods: To assess the effectiveness of the network, a Participatory Evaluation framework was implemented to conduct process evaluation which included review of partnership structures, operations, project implementation processes, and preliminary outcomes of the research collaborations. A focus group of Community Engagement Course and Action Network members (community and academic) was also conducted to identify benefits and challenges of the network with emphasis on key areas for improvement to further enhance the relationships between partners and to facilitate their subsequent community-campus research. Results: Network improvements were tied to themes strengthening community-academic partnerships including sharing and fellowship, coalition building and collaboration, and greater connections and awareness of community needs through their current community-academic partnerships. The need to conduct ongoing evaluation during and after implementation, for determining the early adoption of CBPR approaches was also identified. Conclusion: Evaluation of the network's processes, infrastructure, and operation provides early lessons learned to strengthen the network. Ongoing assessment is also essential for ensuring continuous quality improvement across partnerships such as determining CBPR fidelity, assessing partnership synergy, and dynamics, and for quality improvement of research protocol. The implications and potential for advancing implementation science through this and similar networks are great towards advancing leadership in modeling how foundations in community service can advance to CBPR partnership formation and ultimately, health equity approaches, that are local defined and assessed.

Prognostic value of neutrophil-to-lymphocyte ratio in patients with metastatic castration-resistant prostate cancer receiving prostate-specific membrane antigen targeted radionuclide therapy.

BACKGROUND: Neutrophil count:lymphocyte count ratio (NLR) may be a prognostic factor for men with advanced prostate cancer. We hypothesized that it is associated with prostate-specific antigen (PSA) response and survival in men treated with prostate-specific membrane antigen (PSMA)-targeted radionuclide therapy (TRT). METHODS: Data of 180 men with metastatic castration-resistant prostate cancer (mCRPC) who were treated in sequential prospective radionuclide clinical trials from 2002 to 2021 (utilizing 177Lu-J591, 90Y-J591, 177Lu-PSMA-617, or 225Ac-J591) were retrospectively analyzed. We used a logistic regression to determine the association between NLR and ≥50% PSA decline (PSA50) and a Cox proportional hazards model to investigate the association between NLR and overall survival (OS). RESULTS: A total of 94 subjects (52.2%) received 177Lu-J591, 51 (28.3%) 177Lu-PSMA-617, 28 (15.6%) 225Ac-J591, and 7 (3.9%) 90Y-J591. The median NLR of 3.75 was used as cut-off (low vs. high NLR; n = 90, respectively). On univariate analysis, NLR was not associated with PSA50 (HR 1.08; 95% confidence interval [CI] 0.99-1.17, p = 0.067). However, it was associated with worse OS (hazard ratio [HR] 1.06, 95% CI 1.02-1.09, p = 0.002), also after controlling for circulating tumor cell count and cancer and leukemia group B risk group (HR 1.05; 95% CI 1.003-1.11, p = 0.036). Men with high NLR were at a higher hazard of death from all causes (HR 1.43, 95% CI 1.05-1.94, p = 0.024). CONCLUSIONS: NLR provides prognostic information in the setting of patients with mCRPC receiving treatment with PSMA-TRT.

Antibody-drug conjugates for urothelial carcinoma.

The standard of care for advanced urothelial carcinoma includes platinum chemotherapy and immunotherapy. Antibody-drug conjugates (ADCs), originally developed for hematologic malignancies, involve potent cytotoxic agents linked to antibodies that recognize tumor-specific antigens; this rational drug design allows for more on-target efficacy, while mitigating systemic toxicity. Herein, we review the emerging landscape of ADCs in urothelial carcinoma. The anti-Nectin-4 ADC enfortumab vedotin has demonstrated efficacy in prospective studies in patients with advanced urothelial carcinoma in several settings either alone or in combination with pembrolizumab. The anti-Trop-2 ADC sacituzumab govitecan has also shown efficacy in single-armed studies. Both conjugates have full or accelerated approval from the Food and Drug Administration. Common adverse events include rash and neuropathy for enfortumab vedotin and myelosuppression and diarrhea for sacituzumab govitecan. Several anti-human epidermal growth factor receptor 2 ADCs are in clinical trials, and in localized bladder cancer, the anti-epithelial cell adhesion molecule ADC oportuzumab monatox is being studied in patients refractory to intravesical bacillus calmette-guerin therapy. Antibody-drug conjugates for urothelial carcinoma are approved and emerging as therapies for patients with advanced urothelial carcinoma, filling a prior void for treatment of progressive disease. Ongoing studies are also evaluating these agents in the neoadjuvant and adjuvant settings.

Complex implementation factors demonstrated when evaluating cost-effectiveness and monitoring racial disparities associated with [18F]DCFPyL PET/CT in prostate cancer men.

Prostate cancer (PC) staging with conventional imaging often includes multiparametric magnetic resonance (MR) of the prostate, computed tomography (CT) of the chest, abdomen, and pelvis, and whole-body bone scintigraphy. The recent development of highly sensitive and specific prostate specific membrane antigen (PSMA) positron emission tomography (PET) has suggested that prior imaging techniques may be insufficiently sensitive or specific, particularly when evaluating small pathologic lesions. As PSMA PET/CT is considered to be superior for multiple clinical indications, it is being deployed as the new multidisciplinary standard-of-care. Given this, we performed a cost-effectiveness analysis of [18F]DCFPyL PSMA PET/CT imaging in the evaluation of PC relative to conventional imaging and anti-3-[18F]FACBC (18F-Fluciclovine) PET/CT. We also conducted a single institution review of PSMA PET/CT scans performed primarily for research indications from January 2018 to October 2021. Our snapshot of this period of time in our catchment demonstrated that PSMA PET/CT imaging was disproportionately accessed by men of European ancestry (EA) and those residing in zip codes associated with a higher median household income. The cost-effectiveness analysis demonstrated that [18F]DCFPyL PET/CT should be considered as an alternative to anti-3-[18F]FACBC PET/CT and standard of care imaging for prostate cancer staging. [18F]DCFPyL PET/CT is a new imaging modality to evaluate PC patients with higher sensitivity and specificity in detecting disease than other prostate specific imaging studies. Despite this, access may be inequitable. This discrepancy will need to be addressed proactively as the distribution network of the radiotracer includes both academic and non-academic sites nationwide.

Amides as modifiable directing groups in electrophilic borylation.

Amide directed C-H borylation using ≥two equiv. of BBr3 forms borenium cations containing a R2N(R')C[double bond, length as m-dash]O→B(Ar)Br unit which has significant Lewis acidity at the carbonyl carbon. This enables reduction of the amide unit to an amine using hydrosilanes. This approach can be applied sequentially in a one-pot electrophilic borylation-reduction process, which for phenyl-acetylamides generates ortho borylated compounds that can be directly oxidised to the 2-(2-aminoethyl)-phenol. Other substrates amenable to the C-H borylation-reduction sequence include mono and diamino-arenes and carbazoles. This represents a simple method to make borylated molecules that would be convoluted to access otherwise (e.g. N-octyl-1-BPin-carbazole). Substituent variation is tolerated at boron as well as in the amide unit, with diarylborenium cations also amenable to reduction. This enables a double C-H borylation-reduction-hydrolysis sequence to access B,N-polycyclic aromatic hydrocarbons (PAHs), including an example where both the boron and nitrogen centres contain functionalisable handles (N-H and B-OH). This method is therefore a useful addition to the metal-free borylation toolbox for accessing useful intermediates (ArylBPin) and novel B,N-PAHs.