Structure of the Adenosine A1 Receptor Reveals the Basis for Subtype Selectivity.

The adenosine A1 receptor (A1-AR) is a G-protein-coupled receptor that plays a vital role in cardiac, renal, and neuronal processes but remains poorly targeted by current drugs. We determined a 3.2 Å crystal structure of the A1-AR bound to the selective covalent antagonist, DU172, and identified striking differences to the previously solved adenosine A2A receptor (A2A-AR) structure. Mutational and computational analysis of A1-AR revealed a distinct conformation of the second extracellular loop and a wider extracellular cavity with a secondary binding pocket that can accommodate orthosteric and allosteric ligands. We propose that conformational differences in these regions, rather than amino-acid divergence, underlie drug selectivity between these adenosine receptor subtypes. Our findings provide a molecular basis for AR subtype selectivity with implications for understanding the mechanisms governing allosteric modulation of these receptors, allowing the design of more selective agents for the treatment of ischemia-reperfusion injury, renal pathologies, and neuropathic pain.

Positive allosteric mechanisms of adenosine A1 receptor-mediated analgesia.

The adenosine A1 receptor (A1R) is a promising therapeutic target for non-opioid analgesic agents to treat neuropathic pain1,2. However, development of analgesic orthosteric A1R agonists has failed because of a lack of sufficient on-target selectivity as well as off-tissue adverse effects3. Here we show that [2-amino-4-(3,5-bis(trifluoromethyl)phenyl)thiophen-3-yl)(4-chlorophenyl)methanone] (MIPS521), a positive allosteric modulator of the A1R, exhibits analgesic efficacy in rats in vivo through modulation of the increased levels of endogenous adenosine that occur in the spinal cord of rats with neuropathic pain. We also report the structure of the A1R co-bound to adenosine, MIPS521 and a Gi2 heterotrimer, revealing an extrahelical lipid-detergent-facing allosteric binding pocket that involves transmembrane helixes 1, 6 and 7. Molecular dynamics simulations and ligand kinetic binding experiments support a mechanism whereby MIPS521 stabilizes the adenosine-receptor-G protein complex. This study provides proof of concept for structure-based allosteric drug design of non-opioid analgesic agents that are specific to disease contexts.

High-Dose Acetaminophen with Concurrent CYP2E1 Inhibition Has Profound Anticancer Activity without Liver Toxicity.

Acetaminophen (AAP) is metabolized by a variety of pathways such as sulfation, glucuronidation, and fatty acid amide hydrolase-mediated conversion to the active analgesic metabolite AM404. CYP2E1-mediated metabolism to the hepatotoxic reactive metabolite NAPQI (N-acetyl-p-benzoquinone imine) is a minor metabolic pathway that has not been linked to AAP therapeutic benefits yet clearly leads to AAP liver toxicity. N-acetylcysteine (NAC) (an antioxidant) and fomepizole (a CYP2E1 inhibitor) are clinically used for the treatment of AAP toxicity. Mice treated with AAP in combination with fomepizole (plus or minus NAC) were assessed for liver toxicity by histology and serum chemistry. The anticancer activity of AAP with NAC and fomepizole rescue was assessed in vitro and in vivo. Fomepizole with or without NAC completely prevented AAP-induced liver toxicity. In vivo, high-dose AAP with NAC/fomepizole rescue had profound antitumor activity against commonly used 4T1 breast tumor and lewis lung carcinoma lung tumor models, and no liver toxicity was detected. The antitumor efficacy was reduced in immune-compromised NOD-scid IL2Rgammanull mice, suggesting an immune-mediated mechanism of action. In conclusion, using fomepizole-based rescue, we were able to treat mice with 100-fold higher than standard dosing of AAP (650 mg/kg) without any detected liver toxicity and substantial antitumor activity. SIGNIFICANCE STATEMENT: High-dose acetaminophen can be given concurrently with CYP2E1 inhibition to allow for safe dose escalation to levels needed for anticancer activity without detected evidence of toxicity.

Development of Putative Bivalent Dicovalent Ligands for the Adenosine A1 Receptor.

Accumulating evidence suggests that G protein-coupled receptors (GPCRs) can exist and function in homodimer and heterodimer forms. The adenosine A1 receptor (A1R) has been shown to form both homodimers and heterodimers, but there is a lack of chemical tools to study these dimeric receptor populations. This work describes the synthesis and pharmacological evaluation of a novel class of bivalent GPCR chemical tools, where each ligand moiety of the bivalent compound contains a sulfonyl fluoride covalent warhead designed to be capable of simultaneously reacting with each A1R of an A1R homodimer. The novel compounds were characterised using radioligand binding assays, including washout assays, and functionally in cAMP assays. The bivalent dicovalent compounds were competitive A1R antagonists and showed evidence of covalent binding and simultaneous binding across an A1R homodimer. Greater selectivity for A1R over the adenosine A3 receptor was observed for bivalent dicovalent over the equivalent monovalent compounds, indicating subtype selectivity can be achieved with dual occupation by a bivalent dicovalent ligand.

Structure of the adenosine-bound human adenosine A1 receptor-Gi complex.

The class A adenosine A1 receptor (A1R) is a G-protein-coupled receptor that preferentially couples to inhibitory Gi/o heterotrimeric G proteins, has been implicated in numerous diseases, yet remains poorly targeted. Here we report the 3.6 Å structure of the human A1R in complex with adenosine and heterotrimeric Gi2 protein determined by Volta phase plate cryo-electron microscopy. Compared to inactive A1R, there is contraction at the extracellular surface in the orthosteric binding site mediated via movement of transmembrane domains 1 and 2. At the intracellular surface, the G protein engages the A1R primarily via amino acids in the C terminus of the Gαi α5-helix, concomitant with a 10.5 Å outward movement of the A1R transmembrane domain 6. Comparison with the agonist-bound ß2 adrenergic receptor-Gs-protein complex reveals distinct orientations for each G-protein subtype upon engagement with its receptor. This active A1R structure provides molecular insights into receptor and G-protein selectivity.

The role of an abbreviated ultrasound in the evaluation of necrotizing enterocolitis.

BACKGROUND: Bowel ultrasound is a useful diagnostic tool in the diagnosis and management of necrotizing enterocolitis (NEC) but can be time-consuming and requires technical expertise, particularly for assessing pneumatosis. Previous literature on sonographic evaluation of NEC has focused on a full bowel ultrasound protocol, but the utility of an abbreviated protocol primarily aimed at identifying high-risk sonographic findings without focused bowel assessment has not been well studied. OBJECTIVE: This study aims to describe the diagnostic accuracy of an abbreviated ultrasound protocol for identifying high-risk NEC findings. MATERIALS AND METHODS: This is a retrospective, institutional review board-approved study. We identified all abbreviated NEC ultrasounds performed between January 2014 and August 2022 at our institution. Exams were reviewed for the presence of high-risk findings including pneumoperitoneum, fluid collections, and complex free fluid. Clinical outcome was categorized as poor or good depending on if emergent surgical intervention or death related to NEC occurred. The frequency of follow-up NEC ultrasounds was reviewed to determine if new findings affected outcome. Sensitivity, specificity, and positive and negative predictive values were generated to assess the performance of the abbreviated ultrasounds to identify high-risk findings. RESULTS: A total of 84 abbreviated abdominal ultrasounds were performed on 73 children. Median age at the time of ultrasound was 41 days (interquartile range (IQR) 53 days) and median gestational age was 35 weeks and 3 days (IQR 80 days), and 44/73 (60%) were male. Thirteen ultrasounds had at least one high-risk finding with nine (69%) resulting in a poor outcome, including seven surgical interventions and four deaths. Two patients had surgical intervention and died as a result of necrotizing enterocolitis. Ultrasounds without high-risk findings were not associated with poor clinical outcomes. Sensitivity, specificity, positive predictive value, and negative predictive value of the abbreviated NEC ultrasound were 100% (95% CI 60-100%), 95% (95% CI 86-98%), 69% (95% CI 39-90%), and 100% (95% CI 94-100%), respectively. Twelve abbreviated ultrasounds were followed by a second NEC ultrasound within 5 days. Five follow-up ultrasounds demonstrated new high- or low-risk findings, but the new findings did not correlate with a change in outcome as predicted by the initial ultrasound. CONCLUSION: An abbreviated NEC ultrasound can be of clinical utility in predicting poor outcomes, particularly during non-business hours when resources are limited.

Feeding Ration Impacts Larval Pimephales Promelas 7-Day Subchronic Growth Endpoint: Case Study with Perfluorooctanesulfonic Acid.

The larval fathead minnow, Pimephales promelas, 7-day subchronic survival and growth standard toxicity test method is commonly used for research and regulatory testing of effluents and compounds, including emerging contaminants such as Perfluorooctanesulfonic Acid (PFOS). Existing feeding guidelines for testing are described in multiple methods but are open to interpretation. The current study sought to determine the impact of feeding ration on P. promelas survival and biomass during a subchronic exposure to PFOS. The study was conducted in two phases: (1) a control experiment to determine the most significant feeding ration factors that maximize biomass, with consideration to laboratory logistics, and (2) application of down-selected feeding rations in a PFOS exposure to determine toxicity reference values. The control optimization study supported that feeding ration and feeding frequency were significant factors in fish biomass. In the subsequent PFOS study, fish were fed a high or low ration of Artemia twice daily, while exposed to 0.3 to 3.4 mg/L PFOS. Fish fed a high ration of Artemia had significantly (p < 0.05) greater biomass than fish fed a low ration in all exposure concentrations except 3.4 mg/L, where survival was low in both treatments. The feeding ration was not a significant factor on the survival endpoint for either treatment, but the PFOS concentration was (p < 0.0001) (high ration LC50 = 2.44 mg/L; low ration LC50 = 2.25 mg/L). These findings contribute to a better understanding of the impact feeding ration has in toxicity assessments and downstream regulatory decisions.

Ultrasound for necrotizing enterocolitis: how can we optimize imaging and what are the most critical findings?

Necrotizing enterocolitis (NEC) is a common condition in the neonatal intensive care unit that continues to present challenges in terms of diagnosis and management. Traditionally NEC has been diagnosed and managed by clinical and radiographic findings, but US has shown promise in characterizing and prognosticating NEC. In this manuscript we review the abdominal US technique for NEC, the clinical significance of individual sonographic findings of NEC, and how US can be integrated in the clinical decision process for diagnosing and managing NEC. We also discuss the potential value-added role of a limited abdominal US protocol that focuses on the sonographic findings most indicative of a poor prognosis to include pneumoperitoneum, complex free fluid and focal fluid collections.

The ductus arteriosus: a review of embryology to intervention.

This article reviews the physiology of the ductus arteriosus, the pathophysiology of the patent ductus arteriosus (PDA), and the role advanced imaging such as computed tomography (CT) and magnetic resonance imaging (MRI) can play in guiding diagnosis and percutaneous or surgical intervention. A PDA can have variable clinical and radiologic presentations and can be important to characterize in patients with vascular rings, aortic maldevelopment and congenital heart disease. An understanding of the PDA and the application of CT and MRI can allow the radiologist to provide key information to physicians who plan to close a PDA or maintain PDA patency in the setting of ductal-dependent congenital heart disease.

Translating atherosclerosis research from bench to bedside: navigating the barriers for effective preclinical drug discovery.

Cardiovascular disease (CVD) remains the leading cause of death worldwide. An ongoing challenge remains the development of novel pharmacotherapies to treat CVD, particularly atherosclerosis. Effective mechanism-informed development and translation of new drugs requires a deep understanding of the known and currently unknown biological mechanisms underpinning atherosclerosis, accompanied by optimization of traditional drug discovery approaches. Current animal models do not precisely recapitulate the pathobiology underpinning human CVD. Accordingly, a fundamental limitation in early-stage drug discovery has been the lack of consensus regarding an appropriate experimental in vivo model that can mimic human atherosclerosis. However, when coupled with a clear understanding of the specific advantages and limitations of the model employed, preclinical animal models remain a crucial component for evaluating pharmacological interventions. Within this perspective, we will provide an overview of the mechanisms and modalities of atherosclerotic drugs, including those in the preclinical and early clinical development stage. Additionally, we highlight recent preclinical models that have improved our understanding of atherosclerosis and associated clinical consequences and propose model adaptations to facilitate the development of new and effective treatments.

Adenosine receptor signalling in Alzheimer's disease.

Alzheimer's disease (AD) is the most common dementia in the elderly and its increasing prevalence presents treatment challenges. Despite a better understanding of the disease, the current mainstay of treatment cannot modify pathogenesis or effectively address the associated cognitive and memory deficits. Emerging evidence suggests adenosine G protein-coupled receptors (GPCRs) are promising therapeutic targets for Alzheimer's disease. The adenosine A1 and A2A receptors are expressed in the human brain and have a proposed involvement in the pathogenesis of dementia. Targeting these receptors preclinically can mitigate pathogenic ß-amyloid and tau neurotoxicity whilst improving cognition and memory. In this review, we provide an accessible summary of the literature on Alzheimer's disease and the therapeutic potential of A1 and A2A receptors. Although there are no available medicines targeting these receptors approved for treating dementia, we provide insights into some novel strategies, including allosterism and the targeting of oligomers, which may increase drug discovery success and enhance the therapeutic response.

Acute Toxicity of Eight Aqueous Film-Forming Foams to 14 Aquatic Species.

Researchers have developed numerous per- and polyfluoroalkyl substances (PFAS)-free aqueous film-forming foam (AFFF) formulations to replace PFAS-containing AFFF used for fire suppression. As part of the Department of Defense's Strategic Environmental Research and Development Program (SERDP), we examined the direct lethal effects of seven PFAS-free AFFF and a PFAS-containing AFFF on 14 aquatic species using a series of lethal concentration (LC50) tests. We assessed the LC10, LC50, and LC90 values using log-logistic and logit analyses. Across all aquatic species tested, we discovered that exposure to at least one PFAS-free AFFF was more or as toxic as exposure to the PFAS-containing AFFF. For most cases, National Foam Avio F3 Green KHC 3% and Buckeye Platinum Plus C6MILSPEC 3% were the most and least toxic formulations, respectively. Moreover, we found consistency among results from multiple experiments using the same minnow species (Pimephales promelas) and among closely related taxa (e.g., daphnids, amphibians). Lastly, the LC50 values for AFFF formulations trended lower for tested marine species as compared to those of freshwater species. These results dramatically increase the current knowledge on the potentially toxic effects of AFFF but also highlight the need for additional research and the development of new PFAS-free AFFF that are more "ecologically friendly" than those containing persistent PFAS.

Ultrasound imaging of diaphragmatic motion.

The diaphragm is the key muscle of respiration, especially in infants. Diaphragmatic dysfunction and paralysis can have significant implications for medical management and treatment, and they can be challenging to diagnose by clinical parameters alone. Multiple imaging modalities are useful for assessing the diaphragm, but US - specifically M-mode US - offers several distinct advantages and few limitations compared to fluoroscopy, radiography, CT and MRI. The purpose of this manuscript is to discuss the pathophysiology of the diaphragm, review common indications for dynamic diaphragmatic US, describe optimal imaging technique, and discuss how to avoid imaging pitfalls.

Chronic aquatic toxicity of perfluorooctane sulfonic acid (PFOS) to Ceriodaphnia dubia, Chironomus dilutus, Danio rerio, and Hyalella azteca.

Perfluorooctane sulfonic acid (PFOS) is a ubiquitous and persistent contaminant in aquatic ecosystems. Chronic toxicity information for aquatic organisms is limited, therefore we conducted chronic PFOS toxicity tests for four model organisms commonly used for freshwater toxicology assays: Chironomus dilutus (midge), Ceriodaphnia dubia (water flea), Hyalella azteca (amphipod) and Danio rerio (zebrafish). The 16-day survival test with C. dilutus resulted in the lowest PFOS exposure concentrations to cause significant impacts, with reduced survival at 1 µg/L, a LC50 of 7.5 µg/L, and a growth EC10 of 1.5 µg/L. D. rerio was the next most sensitive species, with a 30-day LC50 of 490 µg/L and reduced growth at 260 µg/L. Effects for C. dubia and H. azteca occurred at concentrations a thousand-fold higher than for C. dilutus. H. azteca had a 42-day LC50 of 15 mg/L, an EC50 of 3.8 mg/L for reproduction (neonates per female) and an EC50 of 4.7 mg/L for growth. C. dubia was similarly tolerant of PFOS, with a 6-day LC50 of 20 mg/L for survival and an EC50 of 7 mg/L for reproduction (neonates per adult). H. azteca, C. dubia, and, to a lesser extent, D. rerio, appear tolerant of PFOS concentrations typically found in the environment. However, in agreement with previous studies, C. dilutus was particularly sensitive to PFOS exposure, with lethal and sublethal effects occurring at concentration levels present at highly contaminated sites.

Peripheral Neurectomy With Customized Nerve Reconstruction for Periorbital Neuropathic Pain: Initial Experience and Clinical Outcomes.

PURPOSE: To describe a novel, minimally invasive surgical technique to treat severe, intractable periorbital neuropathic pain. METHODS: A retrospective analysis of patients with severe, treatment-refractory periorbital pain who underwent transection of affected sensory trigeminal branches with nerve repair was performed. Collected data included etiology and duration of neuropathic pain, comorbidities, prior treatment history, surgical technique including site of transected sensory nerves and type of nerve repair, preoperative and postoperative pain scores as well as follow-up duration. Differences between preoperative and postoperative values were analyzed by the Wilcoxon signed-rank test. RESULTS: A total of 5 patients with severe periorbital neuropathic pain underwent transection of affected supraorbital, supratrochlear, infratrochlear, infraorbital, zygomaticotemporal, and zygomaticofacial nerves with customized nerve reconstruction. All 5 had improvement of periorbital pain after surgery, with 3 (60%) noting complete resolution of pain and 2 (40%) experiencing partial pain relief over a median follow-up period of 9 months (interquartile range [IQR], 6-19 months). Of the 3 patients who had complete resolution of pain, all reported continued pain relief. Median McGill pain scores significantly decreased from 8.4 (IQR, 8.2-10.0) preoperatively to 0.0 (IQR, 0.0-4.8; p < 0.001) postoperatively. All patients reported satisfaction with the surgical procedure and stated that they would undergo the procedure again if given the option. One patient with history of postherpetic neuralgia (PHN) had reactivation of herpes zoster at postoperative month 3, which was self-limited, without worsening of her neuropathic pain. Another patient with PHN required a staged procedure to achieve complete pain relief. CONCLUSION: Peripheral neurectomy with customized reconstruction of involved sensory nerves can successfully reduce and even eradicate periorbital neuropathic pain that was previously recalcitrant to combination pharmacotherapy and prior neurolysis procedures.

Backpack health reduces data-sharing barriers between the medical community and individuals with rare diseases.

Technology has changed the way we approach medical care: health data is constantly being generated, medical discoveries are progressing more rapidly, and individuals are more connected across the world than ever before. Backpack Health is a global personal health record platform that harnesses the power of technology to connect users to their primary health data sources, the medical community, and researchers. By syncing with existing patient portals, health data can be stored on the Backpack Health platform and easily accessed and controlled by users in one connected interface. Individuals manage and collate their current and past conditions, genetic test results, symptoms, medications, procedures, labs, and other health data. Users are empowered to disseminate their information to clinicians, researchers, foundations, and pharmaceutical and biotechnology companies they connect with through the Backpack Health application. Here, we describe how two rare disease advocacy groups, The Marfan Foundation and Project Alive, utilize Backpack Health to connect with their target populations. Through secure transfer of pseudonymized data, groups can query their members to improve understanding of clinical features and to facilitate meaningful research. Responses to the groups' surveys show strong member engagement with high completion rates and increases in new Backpack Health users when surveys are deployed. Data from these surveys have been published and used to better inform clinical outcomes for treatment trials. By connecting users directly to the foundations, clinicians, researchers, and industry partners working on their condition, Backpack Health is instrumental in fast-tracking medical discoveries and treatment for rare diseases.

Structure-based discovery of selective positive allosteric modulators of antagonists for the M2 muscarinic acetylcholine receptor.

Subtype-selective antagonists for muscarinic acetylcholine receptors (mAChRs) have long been elusive, owing to the highly conserved orthosteric binding site. However, allosteric sites of these receptors are less conserved, motivating the search for allosteric ligands that modulate agonists or antagonists to confer subtype selectivity. Accordingly, a 4.6 million-molecule library was docked against the structure of the prototypical M2 mAChR, seeking molecules that specifically stabilized antagonist binding. This led us to identify a positive allosteric modulator (PAM) that potentiated the antagonist N-methyl scopolamine (NMS). Structure-based optimization led to compound '628, which enhanced binding of NMS, and the drug scopolamine itself, with a cooperativity factor (α) of 5.5 and a KB of 1.1 µM, while sparing the endogenous agonist acetylcholine. NMR spectral changes determined for methionine residues reflected changes in the allosteric network. Moreover, '628 slowed the dissociation rate of NMS from the M2 mAChR by 50-fold, an effect not observed at the other four mAChR subtypes. The specific PAM effect of '628 on NMS antagonism was conserved in functional assays, including agonist stimulation of [35S]GTPγS binding and ERK 1/2 phosphorylation. Importantly, the selective allostery between '628 and NMS was retained in membranes from adult rat hypothalamus and in neonatal rat cardiomyocytes, supporting the physiological relevance of this PAM/antagonist approach. This study supports the feasibility of discovering PAMs that confer subtype selectivity to antagonists; molecules like '628 can convert an armamentarium of potent but nonselective GPCR antagonist drugs into subtype-selective reagents, thus reducing their off-target effects.

Mode of action evaluation for reduced reproduction in Daphnia pulex exposed to the insensitive munition, 1-methyl-3-nitro-1-nitroguanidine (MeNQ).

The US Department of Defense (DOD) is developing insensitive munitions (IMs) that are resistant to unintended detonation to protect warfighters. To enable material life-cycle analysis for the IM, 1-methyl-3-nitro-1-nitroguanidine (MeNQ), ecotoxicological impacts assessment was required. A previous investigation of MeNQ exposures in Daphnia pulex revealed concentration-responsive decreases in reproduction relative to controls (0 mg/L) across a 174, 346, 709, 1385, and 2286 mg/L exposure range. The present study used those exposures to conduct global transcriptomic expression analyses to establish hypothetical mode(s) of action underlying inhibited reproduction. The number of significantly affected transcripts and the magnitude of fold-change differences relative to controls tended to increase with increasing MeNQ concentration where hierarchical clustering analysis identified separation among the "low" (174 and 346 mg/L) and "high" (709, 1385, and 2286 mg/L) exposures. Vitellogenin is critical to Daphnia reproductive processes and MeNQ exposures significantly decreased transcriptional expression for vitellogenin-1 precursor at the lowest exposure level (174 mg/L) with benchmark dose (BMD) levels closely tracking concentrations that caused inhibited reproduction. Additionally, juvenile hormone-inducible protein, chorion peroxidase, and high choriolytic enzyme transcriptional expression were impacted by MeNQ exposure having potential implications for egg production / maturation and overall fecundity. In concert with these effects on specific genes involved in Daphnia reproductive physiology, MeNQ exposures caused significant enrichment of several canonical-pathways responsible for metabolism of cellular energy substrates where BMD levels for transcriptional expression were observed at ≤100 mg/L. These observations imply possible effects on whole-organism energy budgets that may also incur indirect costs on reproduction.

Multi-species Aquatic Toxicity Assessment of 1-Methyl-3-Nitroguanidine (MeNQ).

The Army is replacing traditional munitions with insensitive munitions (IM) resistant to accidental detonation. The aquatic toxicity of 1-methyl-3-nitroguanidine (MeNQ), which is being assessed for potential use in IM formulations, remains largely untested. The present study fills a number of critical data gaps for MeNQ aquatic toxicity by evaluating effects across two vertebrate and five invertebrate species. Specifically, responses in larval Pimephales promelas, Rana pipiens tadpoles, Chironomus dilutus, Lumbriculus variegatus, Hydra littoralis, Hyalella azteca, and Daphnia pulex were assessed in MeNQ exposures across various acute, subchronic, and chronic bioassays. Overall, survival was unaffected in most of the MeNQ exposures where significant lethal effects were only observed in D. pulex, H. littoralis, and C. dilutus and only at concentrations ≥ 2186 mg/L. Significant sublethal effects on growth were observed for C. dilutus at 903 mg/L and H. azteca at 1098 mg/L in 10-d assays. Significantly decreased reproduction was observed at 2775 mg/L for H. azteca in a chronic 35-d assay and at 174 mg/L for D. pulex in the 11-d three-brood assay representing a sublethal effect one order of magnitude more sensitive than the effective lethal concentration for D. pulex (2987 mg/L). Degradation of MeNQ in ultraviolet light (UV) greatly increased toxicity to D. pulex. Specifically, exposure to a MeNQ solution that was completely UV-degraded prior to D. pulex exposures resulted in an 11-d LC50 of 6.1 mg/L and a 50% reduction in reproduction at 3.125 mg/L, based on the original MeNQ parent-compound concentrations.

Clinical outcomes of dogs with transitional cell carcinoma receiving medical therapy, with and without partial cystectomy.

The objective of this retrospective study was to evaluate the effects of surgery on outcome for dogs with naturally occurring urinary bladder transitional cell carcinoma. Forty-seven dogs met the inclusion criteria. Thirty-one dogs (Group A) were treated with partial cystectomy and adjunctive medical therapy and 16 dogs (Group B) were treated with medical therapy alone. Overall survival was greater in dogs treated with partial cystectomy and adjunctive medical therapy (498 days for Group A versus 335 days for Group B, hazard ratio 2.5; 95% confidence interval: 1.1 to 5.7; P = 0.026). Progression-free survival was not different between groups (85 days for Group A versus 83 days for Group B; P = 0.663). No prognostic factors were identified for progression-free survival. Due to the many cases in Group A that were lost to follow-up, time-to-event survival analysis was performed. No significant difference in overall survival was noted, and no prognostic factors were identified in the time-to-event analysis. Prospective, randomized studies are needed to determine the role of partial cystectomy in the treatment of transitional cell carcinoma.

Résultats cliniques des chiens atteints d'un carcinome à cellules transitionnelles recevant un traitement médical, avec et sans cystectomie partielle. L'objectif de cette étude rétrospective était d'évaluer les effets de la chirurgie sur les résultats chez des chiens atteints d'un carcinome à cellules transitionnelles de la vessie d'origine naturelle. Quarante-sept chiens répondaient aux critères d'inclusion. Trente et un chiens (Groupe A) ont été traités par cystectomie partielle et traitement médical d'appoint et 16 chiens (Groupe B) ont été traités par thérapie médicale seule. La survie globale était plus élevée chez les chiens traités par cystectomie partielle et traitement médical d'appoint (498 jours pour le Groupe A contre 335 jours pour le Groupe B, rapport de risque de 2,5; intervalle de confiance à 95 % : 1,1 à 5,7; P = 0,026). La survie sans progression n'était pas différente entre les groupes (85 jours pour le Groupe A contre 83 jours pour le Groupe B; P = 0,663). Aucun facteur pronostique n'a été identifié pour la survie sans progression. En raison des nombreux cas dans le Groupe A qui ont été perdus de vue lors du suivi, une analyse du temps de survie a été realisée. Aucune différence significative dans la survie globale n'a été notée et aucun facteur pronostique n'a été identifié dans l'analyse du temps de survive. Des études prospectives randomisées sont nécessaires pour déterminer le rôle de la cystectomie partielle dans le traitement du carcinome à cellules transitionnelles.(Traduit par Dr Serge Messier).