Pulse-Administered Toceranib Phosphate Plus Lomustine for Treatment of Unresectable Mast Cell Tumors in Dogs.

BackgroundNonresectable mast cell tumors (MCT) in dogs remain a therapeutic challenge, and investigation of novel combination therapies is warranted. Intermittent administration of tyrosine kinase inhibitors (TKI) combined with cytotoxic chemotherapy may effectively chemosensitize canine MCT while decreasing cost and adverse effects associated with either agent administered as monotherapy.Hypothesis/objectivesThe primary study objectives were to (1) identify the maximally tolerated dose (MTD), (2) determine the objective response rate (ORR) and (3) describe the adverse event profile of pulse-administered toceranib phosphate (TOC) combined with lomustine.AnimalsForty-seven client-owned dogs with measurable MCT.MethodsToceranib phosphate was given PO on days 1, 3 and 5 of a 21-day cycle at a target dosage of 2.75 mg/kg. Lomustine was given PO on day 3 of each cycle at a starting dosage of 50 mg/m(2) . All dogs were concurrently treated with diphenhydramine, omeprazole, and prednisone.ResultsThe MTD of lomustine was established at 50 mg/m(2) when combined with pulse-administered TOC; the dose-limiting toxicity was neutropenia. Forty-one dogs treated at the MTD were evaluable for outcome assessment. The ORR was 46% (4 complete response, 15 partial response) and the overall median progression-free survival (PFS) was 53 days (1 to >752 days). On multivariate analysis, variables significantly associated with improved PFS included response to treatment, absence of metastasis, and no previous chemotherapy.Conclusions and clinical importanceCombined treatment with pulse-administered TOC and lomustine generally is well tolerated and may be a reasonable treatment option for dogs with unresectable or metastatic MCT

Predicting the duration of reach-to-grasp movements to objects with asymmetric contact surfaces.

The duration of reach-to-grasp movements is influenced by the size of the contact surfaces, such that grasping objects with smaller contact surface areas takes longer. But what is the influence of asymmetric contact surfaces? In Experiment 1a, participants reached-to-lift wooden blocks off a table top, with the contact locations for the thumb and index finger varying in surface size. The time taken to lift the block was driven primarily by the thumb contact surface, which showed a larger effect size for the dependent variable of movement duration than the index finger's contact surface. In Experiment 1b participants reached-to-grasp (but not lift) the blocks. The same effect was found with duration being largely driven by contact surface size for the thumb. Experiment 2 tested whether this finding generalised to movements towards conical frusta grasped in a different plane mounted off the table top. Experiment 2 showed that movement duration again was dictated primarily by the size of the thumb's contact surface. The thumb contact surface was the visible surface in experiments 1 and 2 so Experiment 3 explored grasping when the index finger's contact surface was visible (participants grasped the frusta with the index finger at the top). An interaction between thumb and finger surface size was now found to determine movement duration. These findings provide the first empirical report of the impact of asymmetric contact surfaces on prehension, and may have implications for scientists who wish to model reach-to-grasp behaviours

Harnessing the Therapeutic Potential of Th17 Cells

Th17 cells provide protective immunity to infections by fungi and extracellular bacteria as well as cancer but are also involved in chronic inflammation. The cells were first identified by their ability to produce interleukin 17A (IL-17A) and, subsequently, associated with chronic inflammation and autoimmunity. Th17 cells have some gene profile similarity with stem cells and can remain dormant in mucosal tissues for long periods. Indeed, recent studies suggest that functionally distinct subsets of pro- and anti-inflammatory Th17 cells can interchange phenotype and functions. For development, Th17 cells require activation of the transcription factors STAT3 and RORγt while RUNX1, c-Maf, and Aiolos are involved in changes of phenotype/functions. Attempts to harness Th17 cells against pathogens and cancer using vaccination strategies are being explored. The cells gain protective abilities when induced to produce interferon γ (IFNγ). In addition, treatment with antibodies to IL-17 is effective in treating patients with psoriasis, psoriatic arthritis, and refectory rheumatoid arthritis. Moreover, since RORγt is a nuclear receptor, it is likely to be a potential future drug target for modulating Th17 functions. This review explores pathways through which Th17 subsets are induced, the molecular basis of their plasticity, and potential therapeutic strategies for their modulation in diseases

Area Regge Calculus and Discontinuous Metrics

Taking the triangle areas as independent variables in the theory of Regge calculus can lead to ambiguities in the edge lengths, which can be interpreted as discontinuities in the metric. We construct solutions to area Regge calculus using a triangulated lattice and find that on a spacelike hypersurface no such discontinuity can arise. On a null hypersurface however, we can have such a situation and the resulting metric can be interpreted as a so-called refractive wave.Comment: 18 pages, 1 figur

Cognitive and sensorimotor function in participants being treated for trigeminal neuralgia pain

Background Trigeminal neuralgia (TN) is an orofacial condition defined by reoccurring, spontaneous, short-lived but excruciating stabbing pain. Pharmacological interventions constitute the first-line treatment for TN, with antiepileptic drugs commonly prescribed. People treated for TN pain with antiepileptic drugs describe cognitive and motor difficulties affecting activities of daily living, and report poorer quality of life. We undertook the first comprehensive objective evaluation of sensorimotor and cognitive performance in participants being treated for TN pain with antiepileptic drugs relative to age-matched controls. Methods Participants (43 TN, 41 control) completed a battery of sensorimotor (steering, aiming and tracking) and cognitive (working memory, processing speed, inhibition) tasks. Results The TN group performed significantly worse than controls on the sensorimotor tracking and aiming tasks and across all cognitive measures. Conclusions The data explain why patients treated with antiepileptic drugs report impairment when conducting activities of daily living (given the need for cognitive and motor capability within most of these). The study is an important first step in: (i) ensuring there is adequate information on the impact of pharmacological treatment; (ii) identifying measures to determine optimal medication dosage and track change over time; (iii) creating an evidence base that could allow scientific justification of alternative pain treatment options for TN (e.g. the costs/benefits of surgery)

Cognitive and sensorimotor function in participants being treated for trigeminal neuralgia pain

Background Trigeminal neuralgia (TN) is an orofacial condition defined by reoccurring, spontaneous, short-lived but excruciating stabbing pain. Pharmacological interventions constitute the first-line treatment for TN, with antiepileptic drugs commonly prescribed. People treated for TN pain with antiepileptic drugs describe cognitive and motor difficulties affecting activities of daily living, and report poorer quality of life. We undertook the first comprehensive objective evaluation of sensorimotor and cognitive performance in participants being treated for TN pain with antiepileptic drugs relative to age-matched controls. Methods Participants (43 TN, 41 control) completed a battery of sensorimotor (steering, aiming and tracking) and cognitive (working memory, processing speed, inhibition) tasks. Results The TN group performed significantly worse than controls on the sensorimotor tracking and aiming tasks and across all cognitive measures. Conclusions The data explain why patients treated with antiepileptic drugs report impairment when conducting activities of daily living (given the need for cognitive and motor capability within most of these). The study is an important first step in: (i) ensuring there is adequate information on the impact of pharmacological treatment; (ii) identifying measures to determine optimal medication dosage and track change over time; (iii) creating an evidence base that could allow scientific justification of alternative pain treatment options for TN (e.g. the costs/benefits of surgery)

Antihypertensive drug class and dyslipidemia: risk association among Chinese patients with uncomplicated hypertension

Factors associated with dyslipidemia in Chinese patients with uncomplicated hypertension were investigated in 1,139 patients newly prescribed a single antihypertensive drug in the public primary healthcare setting in Hong Kong, where their fasting lipid profiles were measured 4 to 16 weeks after the first prescription. Multivariate logistic regression showed that thiazide users were more likely (OR 3.67, 95% C.I. 1.13, 11.88, p=0.030) to have adverse (> 6.2mmol/l) total cholesterol (TC) compared with drugs acting on the renin angiotensin system (RAS), but the absolute difference in mean TC between thiazide users and all patients was small ( 0.14 mmol/l), while advanced age and male gender were also associated with some aspects of dyslipidemia. Clinicians should be aware of the increased risk of dyslipidemia in these groups, but the mild dyslipidemic profile associated with thiazides should not in itself deter its use as a possible first-line antihypertensive agent among Chinese patients

Fibrofog in daily life : An examination of ambulatory subjective and objective cognitive function in fibromyalgia

Research reported in this publication was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health (award number K01AR064275; PI: Kratz). The Michigan Institute for Clinical & Health Research (MICHR: NIH award number UL1TR002240) provided subject recruitment support through the UMHealthResearch.org website. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.Peer reviewedPostprin