Effect of dog breed and body conformation on vertical ground reaction forces, impulses, and stance times

OBJECTIVES: To assess whether fully normalised vertical ground reaction forces and stance times obtained at a trot depend on dog breed or body conformations. METHODS: Peak vertical forces (PVF), vertical impulses (VI), stance times (ST), and ratio of forelimb impulse to total impulse (RVI) of 54 dogs of seven different breeds were normalised to body weight and body size according to the theory of dynamic similarity, and were tested for differences between breeds. Breeds were Borzoi, Bernese Mountain dog, Great Dane, Labrador Retriever, Landseer, Rhodesian Ridgeback, and Rottweiler. Body length ratio (BLR) and body mass index (BMI) were also compared between breeds. RESULTS: Significant differences between breeds were found for the normalised forelimb PVF, VI and ST, and hindlimb PVF. Looking at individual breeds, it was most evident that Borzois had a lower forelimb VI, and a higher hindlimb PVF than the other breeds. This resulted in Borzois having a lower RVI compared to other dogs, indicating a more caudally located centre of gravity. Only a few differences in gait parameters were found between other dog breeds. The BMI was significantly lower in Borzois than in other breeds, but was otherwise not associated with gait parameters. CLINICAL SIGNIFICANCE: Force plate data of dogs of different breeds are not necessarily comparable, even after full normalisation to body weight and body size. Group comparisons should only be made when the groups consist of breeds with similar body conformation

Impact of facial conformation on canine health: Brachycephalic Obstructive Airway Syndrome

The domestic dog may be the most morphologically diverse terrestrial mammalian species known to man; pedigree dogs are artificially selected for extreme aesthetics dictated by formal Breed Standards, and breed-related disorders linked to conformation are ubiquitous and diverse. Brachycephaly–foreshortening of the facial skeleton–is a discrete mutation that has been selected for in many popular dog breeds e.g. the Bulldog, Pug, and French Bulldog. A chronic, debilitating respiratory syndrome, whereby soft tissue blocks the airways, predominantly affects dogs with this conformation, and thus is labelled Brachycephalic Obstructive Airway Syndrome (BOAS). Despite the name of the syndrome, scientific evidence quantitatively linking brachycephaly with BOAS is lacking, but it could aid efforts to select for healthier conformations. Here we show, in (1) an exploratory study of 700 dogs of diverse breeds and conformations, and (2) a confirmatory study of 154 brachycephalic dogs, that BOAS risk increases sharply in a non-linear manner as relative muzzle length shortens. BOAS only occurred in dogs whose muzzles comprised less than half their cranial lengths. Thicker neck girths also increased BOAS risk in both populations: a risk factor for human sleep apnoea and not previously realised in dogs; and obesity was found to further increase BOAS risk. This study provides evidence that breeding for brachycephaly leads to an increased risk of BOAS in dogs, with risk increasing as the morphology becomes more exaggerated. As such, dog breeders and buyers should be aware of this risk when selecting dogs, and breeding organisations should actively discourage exaggeration of this high-risk conformation in breed standards and the show ring

Therapeutic Potential and Challenges of Targeting Receptor Tyrosine Kinase ROR1 with Monoclonal Antibodies in B-Cell Malignancies

Based on its selective cell surface expression in chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), receptor tyrosine kinase ROR1 has recently emerged as a promising target for therapeutic monoclonal antibodies (mAbs). To further assess the suitability of ROR1 for targeted therapy of CLL and MCL, a panel of mAbs was generated and its therapeutic utility was investigated.A chimeric rabbit/human Fab library was generated from immunized rabbits and selected by phage display. Chimeric rabbit/human Fab and IgG1 were investigated for their capability to bind to human and mouse ROR1, to mediate antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and internalization, and to agonize or antagonize apoptosis using primary CLL cells from untreated patients as well as MCL cell lines. A panel of mAbs demonstrated high affinity and specificity for a diverse set of epitopes that involve all three extracellular domains of ROR1, are accessible on the cell surface, and mediate internalization. The mAb with the highest affinity and slowest rate of internalization was found to be the only mAb that mediated significant, albeit weak, ADCC. None of the mAbs mediated CDC. Alone, they did not enhance or inhibit apoptosis.Owing to its relatively low cell surface density, ROR1 may be a preferred target for armed rather than naked mAbs. Provided is a panel of fully sequenced and thoroughly characterized anti-ROR1 mAbs suitable for conversion to antibody-drug conjugates, immunotoxins, chimeric antigen receptors, and other armed mAb entities for preclinical and clinical studies

Molecular map of chronic lymphocytic leukemia and its impact on outcome

Recent advances in cancer characterization have consistently revealed marked heterogeneity, impeding the completion of integrated molecular and clinical maps for each malignancy. Here, we focus on chronic lymphocytic leukemia (CLL), a B cell neoplasm with variable natural history that is conventionally categorized into two subtypes distinguished by extent of somatic mutations in the heavy-chain variable region of immunoglobulin genes (IGHV). To build the ‘CLL map,’ we integrated genomic, transcriptomic and epigenomic data from 1,148 patients. We identified 202 candidate genetic drivers of CLL (109 new) and refined the characterization of IGHV subtypes, which revealed distinct genomic landscapes and leukemogenic trajectories. Discovery of new gene expression subtypes further subcategorized this neoplasm and proved to be independent prognostic factors. Clinical outcomes were associated with a combination of genetic, epigenetic and gene expression features, further advancing our prognostic paradigm. Overall, this work reveals fresh insights into CLL oncogenesis and prognostication

Soluble CD52 is an indicator of disease activity in chronic lymphocytic leukemia

Biological, physical and clinical aspects of cancer treatment with ionising radiatio

Programmed Death-1 and Its Ligand Are Novel Immunotolerant Molecules Expressed on Leukemic B Cells in Chronic Lymphocytic Leukemia

Programmed death-1 (PD-1) is an immunoreceptor predominantly expressed on exhausted T cells, which through an interaction with its ligand (PD-L1), controls peripheral tolerance by limiting effector functions of T lymphocytes. qRT-PCR for PD-1, PD-L1 and their splicing forms as well as flow cytometric assessment of surface expression was performed in a cohort of 58 chronic lymphocytic leukemia (CLL) patients. In functional studies, we assessed the influence of the proliferative response of leukemic B-cells induced by IL-4 and CD40L on PD-1 transcripts and expression on the protein level. The median level of PD-1, but not PD-L1, transcripts in CLL patients was higher in comparison to healthy volunteers (HVs, n = 43, p = 0.0057). We confirmed the presence of PD-1 and PD-L1 on the CLL cell surface, and found the expression of PD-1, but not PD-L1, to be higher among CLL patients in comparison to HVs (47.2% vs. 14.8%, p<0.0001). The Kaplan-Meier curves for the time to progression and overall survival in groups with high and low surface expression of PD-1 and PD-L1 revealed no prognostic value in CLL patients. After stimulation with IL-4 and CD40L, protein expression of PD-1 was significantly increased in samples that responded and up-regulated CD38. PD-1, which is aberrantly expressed both at mRNA and cell surface levels in CLL cells might represent a novel immunotolerant molecule involved in the pathomechanism of the disease, and could provide a novel target for future therapies

The CPT1C 5′UTR Contains a Repressing Upstream Open Reading Frame That Is Regulated by Cellular Energy Availability and AMPK

BACKGROUND: Translational control is utilized as a means of regulating gene expression in many species. In most cases, posttranscriptional regulatory mechanisms play an important role in stress response pathways and can lead to dysfunctional physiology if blocked by mutations. Carnitine Palmitoyltransferase 1 C (CPT1C), the brain-specific member of the CPT 1 family, has previously been shown to be involved in regulating metabolism in situations of energy surplus. PRINCIPAL FINDINGS: Sequence analysis of the CPT1C mRNA revealed that it contains an upstream open reading frame (uORF) in the 5' UTR of its mRNA. Using CPT1C 5' UTR/luciferase constructs, we investigated the role of the uORF in translational regulation. The results presented here show that translation from the CPT1C main open reading frame (mORF) is repressed by the presence of the uORF, that this repression is relieved in response to specific stress stimuli, namely glucose deprivation and palmitate-BSA treatment, and that AMPK inhibition can relieve this uORF-dependent repression. SIGNIFICANCE: The fact that the mORF regulation is relieved in response to a specific set of stress stimuli rather than general stress response, hints at an involvement of CPT1C in cellular energy-sensing pathways and provides further evidence for a role of CPT1C in hypothalamic regulation of energy homeostasis

Comparison of microgyro-based measurements of equine metatarsal/metacarpal bone to a high speed video locomotion analysis system during treadmill locomotion

The aim of this study was to compare an inertial motion system (IMS) to an optical based locomotion analysis system measuring limb sagittal segment angles in horses at the walk and trot. The metatarsal/metacarpal bones of two horses (20 trials) were fitted with optical system markers and an IMS. Between the systems, measuring range of motion (ROM) of the sagittal metatarsal/metacarpal bone angles, the IMS measured higher ROM than the optical system (bias 1.6°; precision at 1.96 standard deviation 1.9°). The same angle data were used to assess inter-limb symmetry by calculating phase shift between the limbs within a stride. This showed essentially no bias and the precision was 0.025%. The IMS has potential for quantification of ROM and phase shift of equine distal limb movement

Kinetische Auswertung des Schrittes von Jungrindern und Kühen auf einem instrumentierten Laufband

Gegenstand und Ziel: Daten über die Schrittcharakteristika oder die Bodenreaktionskräfte von Milchkühen gewinnen zunehmend an Bedeutung. Deshalb wurden kinetische Variablen von gesunden Jungrindern und Kühen, die auf einem Laufband im Schritt gingen, dokumentiert und ausgewertet. Material und Methodik: Neun Jungrinder und 10 Kühe wurden an das Gehen auf dem Laufband gewöhnt. Mit dem mit Kraftaufnehmern versehenen Laufband konnten Bodenreaktionskräfte, Schrittlängen und zeitliche Variablen der Stütz- und Hangbeinphasen für alle Gliedmaßen gleichzeitig aufgezeichnet werden. Ergebnisse: Die Kühe gingen bei einer durchschnittlichen Geschwindigkeit von 1,2 ± 0,05 m/s (Mittelwert ± Standardabweichung) mit einer Doppelschrittkadenz von 43,0 ± 1,9/min und einer Doppelschrittlänge von 1,68 ± 0,1 m. Bei den Jungrindern ergaben sich für die entsprechenden Parameter 1,3 ± 0,04 m/s, 53,7 ± 2,2/min und 1,49 ± 0,05 m. Der zeitliche Anteil der Stützbeinphase relativ zur Dauer eines Doppelschritts war bei Kühen an den Schultergliedmaßen (67%) signifikant größer als an den Beckengliedmaßen (64%). Die Kraft-Zeit-Kurven aller Gliedmaßen waren zweigipflig mit einem Gipfel (FP1) kurz nach dem Auffußen und einem Gipfel (FP2) in der Abstoßphase. Die vertikale Bodenreaktionskraft war an den Beckengliedmaßen bei FP1 am höchsten, an den Schultergliedmaßen bei FP2. Das zwischen den beiden Gipfeln befindliche Minimum lag mit 45–49% der Stützbeinphase kurz vor deren Mitte. Der Anteil beider Schultergliedmaßen am Gesamtimpuls betrug 53,7% bei Kühen und 55,0% bei Jungrindern. Die Lage des Körperschwerpunkts variierte während der einzelnen Bewegungsphasen, war jedoch immer mehr zu den Schultergliedmaßen hin lokalisiert. Schlussfolgerungen: Gesunde Kühe und Jungrinder zeigten einen symmetrischen Gang mit minimalen intraindividuellen Abweichungen. Die Hinterbeine wurden vorwiegend beim Auffußen, die Vorderbeine beim Abstoßen vermehrt belastet. Die Vorderbeine hatten einen größeren Anteil am Gesamtimpuls. Die Untersuchung liefert kinetische Daten für die Ganganalyse von gesunden Kühen und Jungrindern, die bei der automatisierten Erkennung lahmer Rinder nützlich sein können