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The magnetic resonance imaging (MRI) appearance of the brain and spinal cord in humans with neuroangiostrongyliasis (NA) due to Angiostrongylus cantonensis infection has been well reported. Equivalent studies in animals are lacking. This case series describes clinical and MRI findings in 11 dogs with presumptively or definitively diagnosed NA. MRI of the brain and/or spinal cord was performed using high-field (1.5 T) or low-field (0.25 T) scanners using various combinations of transverse, sagittal, dorsal and three-dimensional (3D) T1-weighted (T1W), transverse, sagittal and dorsal T2-weighted (T2W), T2W fluid-attenuated inversion recovery (FLAIR) and T2*-weighted (T2*W) gradient echo (GRE), dorsal T2W short tau inversion recovery (STIR) and post-gadolinium transverse, sagittal, dorsal and 3D T1W and transverse T2W FLAIR sequences. In 4/6 cases where the brain was imaged, changes consistent with diffuse meningoencephalitis were observed. Evidence of meningeal involvement was evident even when not clinically apparent. The spinal cord was imaged in 9 dogs, with evidence of meningitis and myelitis detected in regions consistent with the observed neuroanatomical localization. Pathognomonic changes of neural larva migrans, as described in some human patients with NA, were not detected. NA should be considered in the differential diagnosis of dogs with MRI evidence of focal or diffuse meningitis, myelitis and/or encephalitis, especially in areas where A. cantonensis is endemic. If not precluded by imaging findings suggestive of brain herniation, cerebrospinal fluid (CSF) collection for cytology, fluid analysis, real-time polymerase chain reaction (qPCR) and enzyme-linked immunosorbent assay (ELISA) testing should be considered mandatory in such cases after the MRI studies.

OBJECTIVE: To report anconeus muscle injury in a greyhound. ANIMAL: One 11‐month‐old female greyhound. STUDY DESIGN: Case report METHODS: The dog presented with a 6‐week history of mild left foreleg lameness. Moderate pain was noted by palpation over the proximolateral ulna and distolateral humerus and by maximal elbow flexion. A laminar periosteal reaction on the caudodistal humerus was present on radiographs. At ultrasonic examination, disorganization of anconeus muscle fibers, and focal mixed echogenicity were noted. Precontrast and postcontrast computed tomography (CT) revealed a thin rim of periosteal new bone on the caudodistal humerus as well as heterogeneous contrast enhancement of soft tissue immediately caudal to the distal humerus. An unrelated greyhound cadaver dissection confirmed only the anconeus muscle attached to the site of noted periosteal reaction. A partial tear of the anconeus muscle was diagnosed. Treatment consisted of 4 weeks of oral meloxicam. Confinement space and exercise were incrementally increased over 14 weeks. RESULTS: Muscle healing was confirmed by ultrasonography and CT. The dog was able to have a successful racing career spanning 2 years with no lameness attributable to the previous anconeus muscle injury and retired for unrelated reasons. CONCLUSION: Radiography and ultrasonography helped diagnose anconeal muscle injury, and conservative management led to full return to function. CLINICAL SIGNIFICANCE: Clinicians should include anconeus muscle injury as a differential diagnosis in dogs with lameness and pain over the proximolateral ulna or distolateral humerus or on elbow flexion.

We thank CERCA Programme/Generalitat de Catalunya for institutional support. This work was supported by the Health Department PERIS-project no. SLT/002/16/00374 and AGAUR-projects no. 2017SGR1080 of the Catalan Government (Generalitat de Catalunya); Ministerio de Ciencia e Innovación (MCI), Agencia Estatal de Investigación (AEI) and European Regional Development Fund (ERDF) project no. RTI2018-094049-B-I00; the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (Grant agreement No. 743168); the Varda and Boaz Dotan Research Center in Hemato-oncology affiliated to the Tel Aviv University; the Cellex Foundation; and “la Caixa” Banking Foundation (LCF/PR/GN18/51140001). ME is an ICREA Research Professor. Peer Reviewed "Article signat per 12 autors/es: Alberto Bueno-Costa, David Piñeyro, Carlos A. García-Prieto, Vanessa Ortiz-Barahona, Laura Martinez-Verbo, Natalie A. Webster, Byron Andrews, Nitzan Kol, Chen Avrahami, Sharon Moshitch-Moshkovitz, Gideon Rechavi & Manel Esteller"

SINEUPs are a novel class of natural and synthetic non-coding antisense RNA molecules able to increase the translation of a target mRNA. They present a modular organization comprising an unstructured antisense target-specific domain, which sets the specificity of each individual SINEUP, and a structured effector domain, which is responsible for the translation enhancement. In order to design a fully functional

N6-methyladenosine (m6A) is an abundant internal RNA modification1,2 that is catalysed predominantly by the METTL3–METTL14 methyltransferase complex3,4. The m6A methyltransferase METTL3 has been linked to the initiation and maintenance of acute myeloid leukaemia (AML), but the potential of therapeutic applications targeting this enzyme remains unknown5–7. Here we present the identification and characterization of STM2457, a highly potent and selective first-in-class catalytic inhibitor of METTL3, and a crystal structure of STM2457 in complex with METTL3–METTL14. Treatment of tumours with STM2457 leads to reduced AML growth and an increase in differentiation and apoptosis. These cellular effects are accompanied by selective reduction of m6A levels on known leukaemogenic mRNAs and a decrease in their expression consistent with a translational defect. We demonstrate that pharmacological inhibition of METTL3 in vivo leads to impaired engraftment and prolonged survival in various mouse models of AML, specifically targeting key stem cell subpopulations of AML. Collectively, these results reveal the inhibition of METTL3 as a potential therapeutic strategy against AML, and provide proof of concept that the targeting of RNA-modifying enzymes represents a promising avenue for anticancer therapy. Treatment with a specific inhibitor of the N6-methyladenosine methyltransferase METTL3 leads to reduced growth of cancer cells, indicating the potential of approaches targeting RNA-modifying enzymes for anticancer therapy.

BackgroundThe Dachshund is a chondrodystrophic breed of dog predisposed to premature degeneration and calcification, and subsequent herniation, of intervertebral discs (IVDs). This condition is heritable in Dachshunds and breeding candidates are screened for radiographically detectable intervertebral disc calcification (RDIDC), a feature of advanced disc degeneration and a prognostic factor for clinical disease. RDIDC scoring has been previously shown to be consistent within scorers; however, strong scorer effect (subjectivity) was also reported. The aim of this study was to estimate the within- and between-scorer agreement (repeatability and reproducibility, respectively) of computed tomography (CT) scanning and magnetic resonance imaging (MRI) for scoring IVD calcification, and to compare these modalities with radiographic scoring.ResultsTwenty-one Dachshund dogs were screened for IVD calcification using the three imaging modalities. Three scorers scored each case twice, independently. Repeatability was highest for radiography (95.4%), and significantly higher than for CT (90.4%) but not MRI (93.8%). Reproducibility was also highest for radiography (92.9%), but not significantly higher than for CT or MRI (89.4% and 86.4%, respectively). Overall, CT scored IVDs differently than radiography and MRI (64.8% and 62.7% agreement, respectively), while radiography and MRI scored more similarly (85.7% agreement).ConclusionsDespite high precision for radiography, previous evidence of scorer subjectivity was confirmed, which was not generally observed with CT and MRI. The increased consistency of radiography may be related to prior scorer experience with the modality and RDIDC scoring. This study does not support replacing radiography with CT or MRI to screen for heritable IVD calcification in breeding Dachshunds; however, evaluation of dog-level precision and the accuracy of each modality is recommended.

Among dog breeds, the Dachshund has the highest lifetime incidence of intervertebral disc disease (IVDD). Intervertebral disc (IVD) calcification is an indicator of severe degeneration that predisposes to disc herniation. IVDD is heritable in Dachshunds, and in some countries, breeding candidates are screened to reduce IVDD occurrence by selecting dogs according to their score of radiographically detectable intervertebral disc calcification (RDIDC) and excluding dogs with ≥5 RDIDCs from breeding. This study evaluated the precision of scoring spinal radiographs for IVD calcification and subsequent classification of Dachshund dogs for breeding based on their RDIDC score. Digital radiographs of the spine were obtained in 19 clinically healthy, young adult Dachshunds, and scored for RDIDC independently by five scorers with varying levels of experience, three times each. Within scorer (repeatability) and between scorer (reproducibility) variability was estimated both at the individual IVD level and at the whole dog level for breeding classification purposes. At the IVD level, some degree of scorer effect was supported by the pairwise repeatability (92.3%; 95% CI: 88.8-94.7%) being marginally higher than the reproducibility (89.2%; 95% CI: 85.7-91.8%). Scorer-specific patterns confirmed the presence of scorer subjectivity. Repeatability significantly increased with scorer experience but the reproducibility did not. RDIDC scoring repeatability and reproducibility substantially decreased at the cervicothoracic spine region, likely due to anatomical superimpositions. At the dog level, a breeding classification could be repeated by the same scorer for 83.6% (95% CI: 73.8-90.2%) of the dogs, and was reproduced between two scorers for 80.2% (95% CI: 66.6-89.1%) of the dogs. The repeatability of breeding classification also seemed to increase with scorer experience but not the reproducibility. Overall, RDIDC scoring revealed some degree of inconsistency explained by scorer subjectivity and inexperience, and anatomical superimpositions. Scorer training and experience is strongly recommended to improve test precision and ensure appropriate classification of Dachshunds for breeding.

Herein we describe the identification of 4-{[1,2,4]triazolo[1,5-a]pyridin-5-yl}benzonitrile-based inhibitors of the hypoxia-inducible factor prolylhydroxylase domain-1 (PHD-1) enzyme. These inhibitors were shown to possess a novel binding mode by X-ray crystallography, in which the triazolo N1 atom coordinates in a hitherto unreported monodentate interaction with the active site Fe2+ ion, while the benzonitrile group accepts a hydrogen-bonding interaction from the side chain residue of Asn315. Further optimization led to potent PHD-1 inhibitors with good physicochemical and pharmacokinetic properties.

The Sudbury, Ontario, Canada area offers a unique opportunity to develop our understanding of biotic and abiotic lake recovery processes in industrially damaged natural systems. In recent decades, lakes in the Sudbury area have shown improvements in water quality due to decreases in sulfur (S) and metal emissions from area smelters, and reduced acid deposition from more distant sources. However, biological recovery is lagging and mechanisms controlling the lag are not yet clear. Our study examines the roles of two factors, residual metal contamination and altered fish predation, on zooplankton community recovery. Data collected over three decades on six study lakes were analyzed using redundancy analysis (RDA) and partial RDA’s to assess historical and present relationships of water chemistry and fish abundance with zooplankton community recovery. Continuing metal toxicity appears to be the primary cause of the absence of some zooplankton species, particularly Daphnia spp. from metal-contaminated lakes. Conversely, once water quality is suitable and abundant planktivores reestablish, fish planktivory becomes a factor affecting Daphnia spp. establishment. The introduction of piscivores into these lakes may be necessary to facilitate the return of many Daphnia species. Further reductions in metal toxicity will also assist with the complete recovery of zooplankton communities. Studying natural systems over several decades allows us to better understand the intricate steps involved with recovery of industrially damaged lakes, and this knowledge will greatly benefit future restoration efforts in other industrially damaged systems.

After thyroidectomy for primary thyroid malignancies, patients are closely monitored for recurrence or metastasis. Fine needle aspiration (FNA) has been used as the appropriate diagnostic modality for occult masses identified radiographically in the thyroid bed. In this study, we report our institutional experience with FNA of the thyroid bed and propose practical diagnostic categories. A retrospective chart review of all thyroid bed FNAs between April 2008 and January 2013 was performed, and a cohort of 39 patients was retrieved. The cytology diagnoses were divided into 5 categories including nondiagnostic, inflammatory/reactive, bland follicular cells, suspicious for neoplasm/malignancy, and malignant. The follow-up histologic and/or clinical findings were collected for each category. The 39 patients included 9 males and 30 females (ages 15-79 years). Prior thyroidectomies were due to papillary thyroid carcinoma (31 cases), follicular carcinoma (3 cases), medullary carcinoma (1 case), Hurthle cell carcinoma (1 case), malignancy unspecified (1 case), follicular adenoma (1 case), and multinodular goiter (1 case). Overall, 33% (13 cases) of thyroid bed FNAs were nondiagnostic, and 10% (4 cases) were categorized as "inflammatory/reactive." None of the patients in these 2 categories demonstrated evidence of clinical recurrence. One patient with a "bland follicular cells" thyroid bed FNA diagnosis had metastatic papillary thyroid carcinoma on follow-up histology. Of 14 patients in the "suspicious" and "malignant" categories, 10 had malignant follow-up diagnosis on histology. In conclusion, thyroid bed FNA with standardized diagnostic categories is a useful modality for follow-up in patients who have undergone thyroidectomy.

s S51 Conclusions: Incidental thyroid “non-microcarcinomas” (>1 cm) are rare and found in approximately 0.5% of resection specimens. The majority of these represent low-grade carcinomas and the incidenceoffindingoneof the common mutations (40%) is less than that for thyroid carcinomas in general (70%).