Selective Inhibition of FOXO1 Activator/Repressor Balance Modulates Hepatic Glucose Handling.

Insulin resistance is a hallmark of diabetes and an unmet clinical need. Insulin inhibits hepatic glucose production and promotes lipogenesis by suppressing FOXO1-dependent activation of G6pase and inhibition of glucokinase, respectively. The tight coupling of these events poses a dual conundrum: mechanistically, as the FOXO1 corepressor of glucokinase is unknown, and clinically, as inhibition of glucose production is predicted to increase lipogenesis. Here, we report that SIN3A is the insulin-sensitive FOXO1 corepressor of glucokinase. Genetic ablation of SIN3A abolishes nutrient regulation of glucokinase without affecting other FOXO1 target genes and lowers glycemia without concurrent steatosis. To extend this work, we executed a small-molecule screen and discovered selective inhibitors of FOXO-dependent glucose production devoid of lipogenic activity in hepatocytes. In addition to identifying a novel mode of insulin action, these data raise the possibility of developing selective modulators of unliganded transcription factors to dial out adverse effects of insulin sensitizers.

Mitochondrial amidoxime-reducing component 1 p.Ala165Thr increases protein degradation mediated by the proteasome.

OBJECTIVE: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a global health concern with no effective and specific drug treatment available. The rs2642438 minor allele in mitochondrial amidoxime-reducing component 1 (MARC1) results in an aminoacidic substitution (p.Ala165Thr) and associates with protection against MASLD. However, the mechanisms behind this protective effect are unknown. In this study, we examined the consequences of this aminoacidic substitution on protein stability and subcellular localization. METHODS: We overexpressed the human MARC1 A165 (wild-type) or 165T (mutant) in vivo in mice and in vitro in human hepatoma cells (HepG2 and HuH-7), generated several mutants at position 165 by in situ mutagenesis and then examined protein levels. We also generated HepG2 cells stably overexpressing MARC1 A165 or 165T to test the effect of this substitution on MARC1 subcellular localization. RESULTS: MARC1 165T overexpression resulted in lower protein levels than A165 both in vivo and in vitro. Similarly, any mutant at position 165 showed lower protein levels compared to the wild-type protein. We showed that the 165T mutant protein is polyubiquitinated and its degradation is accelerated through lysine-48 ubiquitin-mediated proteasomal degradation. We also showed that the 165T substitution does not affect the MARC1 subcellular localization. CONCLUSIONS: This study shows that alanine at position 165 in MARC1 is crucial for protein stability, and the threonine substitution at this position leads to a hypomorphic protein variant due to lower protein levels. Our result supports the notion that lowering hepatic MARC1 protein level may be a successful therapeutic strategy for treating MASLD.

Therapeutic opportunities for the treatment of NASH with genetically validated targets.

The identification of genetic variants associated with fatty liver disease (FLD) from genome-wide association studies started in 2008 when single nucleotide polymorphisms in PNPLA3, the gene encoding patatin-like phospholipase domain-containing 3, were found to be associated with altered hepatic fat content. Since then, several genetic variants associated with protection from, or an increased risk of, FLD have been identified. The identification of these variants has provided insight into the metabolic pathways that cause FLD and enabled the identification of potential therapeutic targets. In this mini-review, we will examine the therapeutic opportunities derived from genetically validated targets in FLD, including oligonucleotide-based therapies targeting PNPLA3 and HSD17B13 that are currently being evaluated in clinical trials for the treatment of NASH (non-alcoholic steatohepatitis).

Practical advice on variable selection and reporting using Akaike information criterion.

The various debates around model selection paradigms are important, but in lieu of a consensus, there is a demonstrable need for a deeper appreciation of existing approaches, at least among the end-users of statistics and model selection tools. In the ecological literature, the Akaike information criterion (AIC) dominates model selection practices, and while it is a relatively straightforward concept, there exists what we perceive to be some common misunderstandings around its application. Two specific questions arise with surprising regularity among colleagues and students when interpreting and reporting AIC model tables. The first is related to the issue of 'pretending' variables, and specifically a muddled understanding of what this means. The second is related to p-values and what constitutes statistical support when using AIC. There exists a wealth of technical literature describing AIC and the relationship between p-values and AIC differences. Here, we complement this technical treatment and use simulation to develop some intuition around these important concepts. In doing so we aim to promote better statistical practices when it comes to using, interpreting and reporting models selected when using AIC.

Spatial proximity moderates genotype uncertainty in genetic tagging studies.

Accelerating declines of an increasing number of animal populations worldwide necessitate methods to reliably and efficiently estimate demographic parameters such as population density and trajectory. Standard methods for estimating demographic parameters from noninvasive genetic samples are inefficient because lower-quality samples cannot be used, and they assume individuals are identified without error. We introduce the genotype spatial partial identity model (gSPIM), which integrates a genetic classification model with a spatial population model to combine both spatial and genetic information, thus reducing genotype uncertainty and increasing the precision of demographic parameter estimates. We apply this model to data from a study of fishers (Pekania pennanti) in which 37% of hair samples were originally discarded because of uncertainty in individual identity. The gSPIM density estimate using all collected samples was 25% more precise than the original density estimate, and the model identified and corrected three errors in the original individual identity assignments. A simulation study demonstrated that our model increased the accuracy and precision of density estimates 63 and 42%, respectively, using three replicated assignments (e.g., PCRs for microsatellites) per genetic sample. Further, the simulations showed that the gSPIM model parameters are identifiable with only one replicated assignment per sample and that accuracy and precision are relatively insensitive to the number of replicated assignments for high-quality samples. Current genotyping protocols devote the majority of resources to replicating and confirming high-quality samples, but when using the gSPIM, genotyping protocols could be more efficient by devoting more resources to low-quality samples.

Outcomes and clinical features associated with surgically excised canine salivary gland carcinoma: A multi-institutional, retrospective, Veterinary Society of Surgical Oncology study.

OBJECTIVE: The objective of this study was to describe the clinical features, prognostic factors, and outcomes in dogs with surgically treated salivary gland carcinoma. STUDY DESIGN: Multi-institutional retrospective case series. ANIMALS: Seventy-two client-owned dogs from 16 institutions with surgically excised salivary gland carcinoma. METHODS: Medical records of dogs undergoing sialoadenectomy from January 1, 2000 to January 1, 2020 were reviewed for signalment, clinical signs, preoperative staging results, preoperative mass evaluation, complications, histopathologic diagnosis, local recurrence, metastatic disease, and survival times. Survival functions were estimated using the Kaplan-Meier estimator. Factors related to survival were individually tested using the log-rank test. RESULTS: The overall median survival time (MST) associated with salivary carcinoma was 1886 days. Local recurrence occurred in 29/69 (42%) dogs with an overall disease-free interval (DFI) of 191 days. Metastatic disease occurred in 22/69 (31.9%) dogs, with an overall DFI of 299 days. Lymph node metastasis was present at the time of surgery in 11/38 (28.9%) dogs in which lymphadenectomy was performed at the time of surgery; these dogs had a shorter DFI at 98 days (P = .03) and MST at 248 days (P < .001). CONCLUSION: The prognosis for dogs with salivary gland carcinoma treated surgically was more favorable than previously reported. Nodal metastasis was a negative prognostic factor for canine salivary gland carcinoma. CLINICAL SIGNIFICANCE: Surgical intervention should be considered for dogs with salivary carcinoma.

Staphylectomy in nonbrachycephalic dogs: A retrospective study of 27 cases.

Objective: To report the outcomes and complications associated with staphylectomy in nonbrachycephalic dogs. Animal: Twenty-seven nonbrachycephalic dogs with elongated soft palates and undergoing staphylectomy. Procedure: Retrospective study. Results: Increased upper airway noise (70.4%) and dyspnea (44.4%) were the most common presenting clinical signs. Concurrent upper airway abnormalities found in the study population included laryngeal collapse (25.9%) and laryngeal paralysis (14.8%). The most common staphylectomy technique used in this study was sharp excision (66.7%) with sutured oral and nasal mucosal apposition. The dogs in this study had an overall minor postoperative complication rate of 33.3%, with regurgitation/vomiting (11.1%) and coughing (11.1%) occurring most commonly. No dog required supplemental oxygen therapy or temporary tracheostomy. Conclusion: Staphylectomy was well-tolerated in nonbrachycephalic dogs and was associated with a relatively low rate of complications. Concurrent airway abnormalities were common among nonbrachycephalic dogs with elongated soft palates, similar to brachycephalic dogs. Clinical relevance: Clinicians should be aware that elongated soft palate can occur in nonbrachycephalic dogs, and surgical correction can be achieved with rare major or catastrophic complications.

Staphylectomie chez des chiens non-brachycéphales : une étude rétrospective de 27 cas. Objectif: Rapporter les résultats et les complications associés à la staphylectomie chez des chiens non-brachycéphales. Animal: Vingt-sept chiens non-brachycéphales au palais mou allongé et subissant une staphylectomie. Procédure: Étude rétrospective. Résultats: L'augmentation du bruit des voies respiratoires supérieures (70,4 %) et la dyspnée (44,4 %) étaient les signes cliniques les plus fréquents. Les anomalies concomitantes des voies respiratoires supérieures trouvées dans la population étudiée comprenaient un collapsus laryngé (25,9 %) et une paralysie laryngée (14,8 %). La technique de staphylectomie la plus couramment utilisée dans cette étude était l'exérèse fine (66,7 %) avec apposition suturée des muqueuses buccale et nasale. Les chiens de cette étude présentaient un taux global de complications postopératoires mineures de 33,3 %, les régurgitations/vomissements (11,1 %) et la toux (11,1 %) étant les plus fréquents. Aucun chien n'a eu besoin d'une oxygénothérapie supplémentaire ou d'une trachéotomie temporaire. Conclusion: La staphylectomie a été bien tolérée chez les chiens non-brachycéphales et a été associée à un taux relativement faible de complications. Les anomalies concomitantes des voies respiratoires étaient courantes chez les chiens nonbrachycéphales avec des palais mous allongés, semblables aux chiens brachycéphales. Pertinence clinique: Les cliniciens doivent être conscients qu'un palais mou allongé peut survenir chez les chiens non-brachycéphales et qu'une correction chirurgicale peut être obtenue avec de rares complications majeures ou catastrophiques.(Traduit par Dr Serge Messier).

The SGLT2 inhibitor dapagliflozin promotes systemic FFA mobilization, enhances hepatic ß-oxidation, and induces ketosis.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been shown to increase ketone bodies in patients with type 2 diabetes; however, the underlying mechanisms have not been fully elucidated. Here we examined the effect of the SGLT2 inhibitor dapagliflozin (1 mg/kg/day, formulated in a water, PEG400, ethanol, propylene glycol solution, 4 weeks) on lipid metabolism in obese Zucker rats. Fasting FFA metabolism was assessed in the anesthetized state using a [9,10-3H(N)]-palmitic acid tracer by estimating rates of plasma FFA appearance (Ra), whole-body FFA oxidation (Rox), and nonoxidative disposal (Rst). In the liver, clearance (Kß-ox) and flux (Rß-ox) of FFA into ß-oxidation were estimated using [9,10-3H]-(R)-bromopalmitate/[U-14C]palmitate tracers. As expected, dapagliflozin induced glycosuria and a robust antidiabetic effect; treatment reduced fasting plasma glucose and insulin, lowered glycated hemoglobin, and increased pancreatic insulin content compared with vehicle controls. Dapagliflozin also increased plasma FFA, Ra, Rox, and Rst with enhanced channeling toward oxidation versus storage. In the liver, there was also enhanced channeling of FFA to ß-oxidation, with increased Kß-ox, Rß-ox and tissue acetyl-CoA, compared with controls. Finally, dapagliflozin increased hepatic HMG-CoA and plasma ß-hydroxybutyrate, consistent with a specific enhancement of ketogenesis. Since ketogenesis has not been directly measured, we cannot exclude an additional contribution of impaired ketone body clearance to the ketosis. In conclusion, this study provides evidence that the dapagliflozin-induced increase in plasma ketone bodies is driven by the combined action of FFA mobilization from adipose tissue and diversion of hepatic FFA toward ß-oxidation.

Allostatic hypermetabolic response in PGC1α/ß heterozygote mouse despite mitochondrial defects.

Aging, obesity, and insulin resistance are associated with low levels of PGC1α and PGC1ß coactivators and defective mitochondrial function. We studied mice deficient for PGC1α and PGC1ß [double heterozygous (DH)] to investigate their combined pathogenic contribution. Contrary to our hypothesis, DH mice were leaner, had increased energy dissipation, a pro-thermogenic profile in BAT and WAT, and improved carbohydrate metabolism compared to wild types. WAT showed upregulation of mitochondriogenesis/oxphos machinery upon allelic compensation of PGC1α4 from the remaining allele. However, DH mice had decreased mitochondrial OXPHOS and biogenesis transcriptomes in mitochondria-rich organs. Despite being metabolically healthy, mitochondrial defects in DH mice impaired muscle fiber remodeling and caused qualitative changes in the hepatic lipidome. Our data evidence first the existence of organ-specific compensatory allostatic mechanisms are robust enough to drive an unexpected phenotype. Second, optimization of adipose tissue bioenergetics is sufficient to maintain a healthy metabolic phenotype despite a broad severe mitochondrial dysfunction in other relevant metabolic organs. Third, the decrease in PGC1s in adipose tissue of obese and diabetic patients is in contrast with the robustness of the compensatory upregulation in the adipose of the DH mice.

Ex vivo comparison of different thoracoabdominal stapler sizes for typhlectomy in canine cadavers.

OBJECTIVE: To determine the influence of staple size on leakage pressure of typhlectomy sites in canine cadavers. STUDY DESIGN: Randomized, experimental cadaveric study. ANIMALS: Twenty-four fresh canine cadavers. METHODS: Ileocecocolic segments were exteriorized following right paracostal laparotomy after euthanasia. Cecal base length and wall thickness were measured. Each cecum was randomly assigned to 1 of 3 groups (TA 30 V3 2.5 mm, TA 60 3.5 mm, and TA 60 4.8 mm). The cecal base was stapled and the cecum was removed. A 10 cm segment including the stapled cecal excision site was tested for initial leak pressure. RESULTS: The mean ± standard deviation body weights across the groups were 18.7 ± 6.1 kg, 16.2 ± 7.5 kg, and 14.2 ± 5.5 kg for the TA 30 V3 2.5 mm, TA 60 3.5 mm, and TA 60 4.8 mm groups, respectively (P = .48). There were no differences for mean cecal base length or wall thickness. Mean initial leak pressure (ILP) across groups was 182 ± 111 mmHg (TA 30 V3 2.5 mm), 112 ± 57 mmHg (TA 60 3.5 mm), and 77 ± 60 mmHg (TA 60 4.8 mm) (P = .78). CONCLUSION: Each stapler size that was evaluated resulted in a mean ILP in excess of typical intraluminal pressures under normal circumstances. There were no differences among groups. CLINICAL SIGNIFICANCE: The results of this cadaveric study support the use of any of the stapler sizes evaluated in similarly sized dogs. A prospective study is needed to be able to correlate stapler size and clinical outcome.

PCSK9 rs11591147 R46L loss-of-function variant protects against liver damage in individuals with NAFLD.

BACKGROUND AND AIMS: The proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a key role in cholesterol homeostasis, and its inhibition represents an effective therapy to lower low-density lipoprotein cholesterol (LDL-C) levels. In this study, we examined the impact of the PCSK9 rs11591147 loss-of-function (LOF) variant on liver damage in a multicenter collection of patients at risk of nonalcoholic steatohepatitis (NASH), in clinical samples and experimental models. METHODS: We considered 1874 consecutive individuals at risk of NASH as determined by histology. The SNP rs11591147, encoding for the p.R46L variant of PCSK9, was genotyped by TaqMan assays. We also evaluated 1) PCSK9 mRNA hepatic expression in human liver, and 2) the impact of a NASH-inducing diet in mice with hepatic overexpression of human PCSK9. RESULTS: Carriers of PCSK9 rs11591147 had lower circulating LDL-C levels and were protected against nonalcoholic fatty liver disease (NAFLD) (OR: 0.42; 95% CI: 0.22-0.81; P = .01), NASH (OR: 0.48; 95% CI: 0.26-0.87; P = .01) and more severe fibrosis (OR: 0.55; 95% CI: 0.32-0.94; P = .03) independently of clinical, metabolic and genetic confounding factors. PCSK9 hepatic expression was directly correlated with liver steatosis (P = .03). Finally, liver-specific overexpression of human PCSK9 in male mice drives NAFLD and fibrosis upon a dietary challenge. CONCLUSIONS: In individuals at risk of NASH, PCSK9 was induced with hepatic fat accumulation and PCSK9 rs11591147 LOF variant was protective against liver steatosis, NASH and fibrosis, suggesting that PCSK9 inhibition may be a new therapeutic strategy to treat NASH.

Towards the targeted assessment of relevant problems: Optimization of the distress Thermometer for adult neuro-oncological patients.

OBJECTIVE: Generic psychosocial screening tools may not reflect the unique symptom profile of brain tumour patients (BTPs). The aim was to adapt the problem list of the distress thermometer (DT) for BTPs. METHODS: First, items of low relevance for BTPs were identified on basis of retrospective analyses. Second, relevant yet missing problems were identified via an extensive literature search, qualitative interviews with BTPs and experts, as well as an online expert survey. The resulting raw version of the adapted problem list in BTPs was subsequently pretested. RESULTS: In the first part, data of n = 657 BTPs were analysed. Twelve items (20%) were excluded in this step as they proved to be less relevant for BTPs (i.e., items were endorsed by less than 10% and without significant correlations to patients' DT score). In the second part, qualitative interviews and the online survey with 102 professionals led to the addition of 21 new and the modification and condensation of 17 relevant problems specific for BTPs. This adapted list was than successfully pretested in n = 19 patients, leading to the 'distress thermometer brain tumour problem list' (DT-BT), consisting of 42 relevant problems. CONCLUSION: The adapted problem list for the DT particularly reflects the neurological and psychosocial burden of an intracranial tumour and allows for the targeted assessment of the specific burdens and needs of BTPs. Our revised version of the DTs problem list (DT-BT) should in the next step be widely validated in multinational samples.

In vivo genome and base editing of a human PCSK9 knock-in hypercholesterolemic mouse model.

BACKGROUND: Plasma concentration of low-density lipoprotein (LDL) cholesterol is a well-established risk factor for cardiovascular disease. Inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9), which regulates cholesterol homeostasis, has recently emerged as an approach to reduce cholesterol levels. The development of humanized animal models is an important step to validate and study human drug targets, and use of genome and base editing has been proposed as a mean to target disease alleles. RESULTS: To address the lack of validated models to test the safety and efficacy of techniques to target human PCSK9, we generated a liver-specific human PCSK9 knock-in mouse model (hPCSK9-KI). We showed that plasma concentrations of total cholesterol were higher in hPCSK9-KI than in wildtype mice and increased with age. Treatment with evolocumab, a monoclonal antibody that targets human PCSK9, reduced cholesterol levels in hPCSK9-KI but not in wildtype mice, showing that the hypercholesterolemic phenotype was driven by overexpression of human PCSK9. CRISPR-Cas9-mediated genome editing of human PCSK9 reduced plasma levels of human and not mouse PCSK9, and in parallel reduced plasma concentrations of total cholesterol; genome editing of mouse Pcsk9 did not reduce cholesterol levels. Base editing using a guide RNA that targeted human and mouse PCSK9 reduced plasma levels of human and mouse PCSK9 and total cholesterol. In our mouse model, base editing was more precise than genome editing, and no off-target editing nor chromosomal translocations were identified. CONCLUSIONS: Here, we describe a humanized mouse model with liver-specific expression of human PCSK9 and a human-like hypercholesterolemia phenotype, and demonstrate that this mouse can be used to evaluate antibody and gene editing-based (genome and base editing) therapies to modulate the expression of human PCSK9 and reduce cholesterol levels. We predict that this mouse model will be used in the future to understand the efficacy and safety of novel therapeutic approaches for hypercholesterolemia.

Human Multilineage 3D Spheroids as a Model of Liver Steatosis and Fibrosis.

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disorder in western countries. Despite the high prevalence of NAFLD, the underlying biology of the disease progression is not clear, and there are no approved drugs to treat non-alcoholic steatohepatitis (NASH), the most advanced form of the disease. Thus, there is an urgent need for developing advanced in vitro human cellular systems to study disease mechanisms and drug responses. We attempted to create an organoid system genetically predisposed to NAFLD and to induce steatosis and fibrosis in it by adding free fatty acids. We used multilineage 3D spheroids composed by hepatocytes (HepG2) and hepatic stellate cells (LX-2) with a physiological ratio (24:1). HepG2 and LX-2 cells are homozygotes for the PNPLA3 I148M sequence variant, the strongest genetic determinant of NAFLD. We demonstrate that hepatic stellate cells facilitate the compactness of 3D spheroids. Then, we show that the spheroids develop accumulations of fat and collagen upon exposure to free fatty acids. Finally, this accumulation was rescued by incubating spheroids with liraglutide or elafibranor, drugs that are in clinical trials for the treatment of NASH. In conclusion, we have established a simple, easy to handle, in vitro model of genetically induced NAFLD consisting of multilineage 3D spheroids. This tool may be used to understand molecular mechanisms involved in the early stages of fibrogenesis induced by lipid accumulation. Moreover, it may be used to identify new compounds to treat NASH using high-throughput drug screening.

Outcomes and prognostic variables associated with central division hepatic lobectomies: 61 dogs.

OBJECTIVE: To determine the outcome and prognostic variables associated with long-term survival and complications in dogs undergoing hepatic lobectomy of the central division. STUDY DESIGN: Multi-institutional retrospective case series. ANIMALS: Sixty-one client-owned dogs with central division masses. METHODS: Medical records of dogs undergoing hepatic lobectomy of the central division from January 1, 2000 to January 1, 2015 were reviewed for signalment, clinical signs, preoperative staging, preoperative cytology or biopsy results, date of procedure, location of mass, surgical technique, whether cholecystectomy or cholecystopexy was performed, complications, histopathologic diagnosis and margin evaluation, date of local recurrence or detection of metastatic disease, and survival. RESULTS: Hilar resection was associated with increased intraoperative and postoperative complications. Intraoperative complications occurred in 29 dogs, with 20 dogs experiencing intraoperative hemorrhage. Nineteen dogs required transfusions. Immediate postoperative complications occurred in 20 dogs. Perioperative mortality rate was 11%, and 2-week mortality rate was 14.7%. The median survival time for dogs with hepatocellular carcinoma (HCC) was not reached. The 1- and 3-year censored survival rates for dogs with HCC was 82.1% and 82.1%, respectively. Margin status did not impact survival time. CONCLUSION: Hepatic lobectomy of the central division was associated with hemorrhage in approximately 33% of dogs, but there was a relatively low perioperative mortality rate. Hepatic lobectomy for HCC resulted in long-term survival, regardless of margin status. CLINICAL SIGNIFICANCE: Surgeons should anticipate the requirement for blood products in dogs that may require hepatic lobectomy of the central division. Long-term survival can be expected after surgical treatment of HCC, regardless of margin status.

Sentinel lymph node mapping of the canine anal sac using lymphoscintigraphy: A pilot study.

Sentinel lymph node mapping and biopsy are important parts of oncologic staging in human medicine. Sentinel lymph node mapping enables identification of the first lymph node to receive lymphatic drainage while avoiding unnecessary lymph node dissection. Anal sac adenocarcinoma is the most common malignant neoplasm of the canine perineal area. For dogs with anal sac adenocarcinoma, lympadenectomy and metastasis to the iliosacral lymphocentrum are negative prognostics indicators. The objectives of this prospective, two by two, crossover pilot study were to establish the feasibility of lymphoscintigraphy using Technetium-99 sulfur colloid of the canine anal sac of healthy dogs, compare two injection techniques, and the time for identification of sentinel lymph nodes using each technique. We hypothesized that both intramural and perimural injections of the canine anal sac would identify similar sentinel lymph node drainage. The sentinel lymph node was identified in all dogs using either technique. Intramural injection of the canine anal sac showed radiopharmaceutical uptake faster than perimural injection technique (P = 0.040). There was concordance between intramual and perimural techniques for the sentinel lymph node identified in 50% of cases. A sacral lymph node was identified as sentinel in three of eight dogs (37.5%). Lymphoscintigraphy of the canine anal sac is safe and feasible in normal dogs; however, the method of injection technique seems to have a significant effect on the sentinel lymph node identified.

Partial splenectomy for incidentally detected non-ruptured splenic lesions in dogs: 18 cases (2004-2018).

The objective of this retrospective study was to describe the outcome and incidence of splenic malignancy in 18 dogs undergoing partial splenectomy for incidentally detected, non-ruptured splenic lesions. Incidence of splenic malignancy in the present study was 5.6% [95% confidence interval (CI): 0.14% to 27.65%]. Median diameter of splenic nodules was 2 cm (range: 1.5 to 4 cm). Splenic hemangiosarcoma was diagnosed in 1 dog, while the remaining 17 dogs had benign splenic lesions. There was a higher incidence of non-splenic malignancy (50%) than splenic malignancy (5.6%) in the study population. Overall median survival time after surgery was 300 days (range: 4 to 1332 days). Median survival time in dogs with malignant disease (splenic and non-splenic) was 67 days (range: 4 to 425 days) and for non-malignant disease was 727 days (range: 8 to 1332 days). In conclusion, partial splenectomy may be appropriate for small, incidental non-ruptured splenic lesions in dogs.

Splénectomie partielle pour des lésions spléniques non-rupturées détectées de manière fortuite chez des chiens : 18 cas (2004­2018). L'objectif de cette étude rétrospective était de décrire l'issue et la fréquence de malignité splénique chez 18 chiens soumis à une splénectomie partielle pour des lésions spléniques non-rupturées détectées de manière fortuite. La fréquence de malignité splénique dans la présente étude était de 5,6 % [intervalle de confiance de 95 % (CI) : 0,14 % à 27,65 %]. Le diamètre médian des nodules spléniques était de 2 cm (écart : 1,5 à 4 cm). Un hémangiosarcome splénique fut diagnostiqué chez un chien, alors que les 17 autres chiens avaient des lésions spléniques bénignes. Il y avait une plus grande fréquence de malignité non-splénique (50 %) que de malignité splénique (5,6 %) dans la population étudiée. Globalement, le temps de survie médian après la chirurgie était de 300 jours (écart : 4 à 1332 jours). Le temps de survie médian chez les chiens avec une condition maligne (splénique et non-splénique) était de 67 jours (écart : 4 à 425 jours) et pour ceux avec une condition non-maligne il était de 727 jours (écart : 8 à 1332 jours). En conclusion, une splénectomie partielle peut être appropriée pour des petites lésions spléniques secondaires non-rupturées.(Traduit par Dr Serge Messier).

Monoclonal antibody targeting of fibroblast growth factor receptor 1c causes cardiac valvulopathy in rats.

Fibroblast Growth Factors (FGFs) and their receptors (FGFRs) have been proposed as potential drug targets for the treatment of obesity. The aim of this study was to assess the potential toxicity in rats of three anti-FGFR1c mAbs with differential binding activity prior to clinical development. Groups of male rats received weekly injections of either one of two FGFR1c-specific mAbs or an FGFR1c/FGFR4-specific mAb at 10 mg/kg for up to 4 weeks. All three mAbs caused significant reductions in food intake and weight loss leading to some animals being euthanized early for welfare reasons. In all three groups given these mAbs, microscopic changes were seen in the bones and heart valves. In the bones of the femoro-tibial joint, thickening of the diaphyseal cortex of long bones, due to deposition of well organized new lamellar bone, indicated that an osteogenic effect was observed. In the heart, valvulopathy described as an endocardial myxomatous change affecting the mitral, pulmonary, tricuspid and aortic valves was observed in all mAb-treated animals. The presence of FGFR1 mRNA expression in the heart valves was confirmed using in situ hybridization. Targeting the FGF-FGFR1c pathway with anti-FGFR1c mAbs leads to drug induced valvulopathy in rats. In effect, this precluded the development of these mAbs as potential anti-obesity drugs. The valvulopathy observed was similar to that described for fenfluramine and dexafenfluramine. The pathogenesis of the drug-induced valvulopathy is considered FGFR1c-mediated, based on the specificity of the mAbs and FGFR1 mRNA expression in the heart valves.

IMAGING DIAGNOSIS-MAGNETIC RESONANCE IMAGING FEATURES OF A MULTIFOCAL OLIGODENDROGLIOMA IN THE SPINAL CORD AND BRAIN OF A DOG.

An 8-year-old neutered male Toy Poodle was presented with chronic, progressive tetraparesis, and possible seizures. Magnetic resonance images demonstrated an extensive, T1 and T2 hyperintense contrast enhancing mass in the cervical spinal cord. Three nodules were present on the surface of the thalamus, with enhancement most evident on delayed images. A diagnosis of high-grade oligodendroglioma was confirmed with postmortem histopathology and immunohistochemical labeling. Oligodendroglioma should be considered as a differential for T1 hyperintense intraaxial or intramedullary lesions with contrast enhancement. If enhancement is not visualized on postcontrast images, delayed images may be beneficial.