Paclitaxel inhibits the activity and membrane localization of PKCα and PKCβI/II to elicit a decrease in stimulated calcitonin gene-related peptide release from cultured sensory neurons

Peripheral neuropathy is a dose-limiting and debilitating side effect of the chemotherapeutic drug, paclitaxel. Consequently, elucidating the mechanisms by which this drug alters sensory neuronal function is essential for the development of successful therapeutics for peripheral neuropathy. We previously demonstrated that chronic treatment with paclitaxel (3–5 days) reduces neuropeptide release stimulated by agonists of TRPV1. Because the activity of TRPV1 channels is modulated by conventional and novel PKC isozymes (c/nPKC), we investigated whether c/nPKC mediate the loss of neuropeptide release following chronic treatment with paclitaxel (300 nM; 3 and 5 days). Release of the neuropeptide, calcitonin gene-related peptide (CGRP), was measured as an index of neuronal sensitivity. Following paclitaxel treatment, cultured dorsal root ganglia sensory neurons were stimulated with a c/nPKC activator, phorbol 12,13-dibutyrate (PDBu), or a TRPV1 agonist, capsaicin, in the absence and presence of selective inhibitors of conventional PKCα and PKCβI/II isozymes (cPKC). Paclitaxel (300 nM; 3 days and 5 days) attenuated both PDBu- and capsaicin-stimulated release in a cPKC-dependent manner. Under basal conditions, there were no changes in the protein expression, phosphorylation or membrane localization of PKC α, βI or βII, however, paclitaxel decreased cPKC activity as indicated by a reduction in the phosphorylation of cPKC substrates. Under stimulatory conditions, paclitaxel attenuated the membrane translocation of phosphorylated PKC α, βI and βII, providing a rationale for the attenuation in PDBu- and capsaicin-stimulated release. Our findings suggest that a decrease in cPKC activity and membrane localization are responsible for the reduction in stimulated peptide release following chronic treatment with paclitaxel in sensory neurons

Implications of Dam Removal: Modeling Streamflow in Lansing, Michigan Using the Soil and Water Assessment Tool

This paper uses hydrologic modeling methods to determine the effects of dam removal in Lansing, Michigan, on the streamflow of the Grand River, flooding risks, and flood mitigation strategies. In Michigan, more than one-half of the state’s dam infrastructure is more than 50 years old, and more than one-third are classified as having a moderate-to high-risk potential. Lansing, Michigan, contains two moderate-to high-risk dams along the Grand River that are a significant hazard to the surrounding community in the event of structural failure. This research utilizes the Soil and Water Assessment Tool (SWAT) to model the impacts of the Moores Park Dam and the North Lansing Dam on streamflow in the greater Lansing area. The purpose of using SWAT was to represent baseline streamflow conditions in the Grand River, compare the differences in streamflow magnitude between baseline conditions and a dam-out environment, and interpret the implications of modeling results for mitigation and management strategies in the study area. Our model exhibited similar streamflow patterns to USGS historical data, with overestimation errors during calibration and validation stemming from groundwater infiltration inaccuracies. The dams-out model for streamflow was higher than the baseline model for streamflow; however, both model iterations require further calibration and validation for the magnitude differences to be considered statistically significant. Despite issues of model calibration and validation, and ongoing model adjustments for accurately representing heavily impounded watershed, the results of this study provide a template for the City of Lansing to adapt their flood mitigation strategies in the study area and further calibrate SWAT with improved sediment, nutrient, and dam attribute data

Profile of Medical Care Costs in Patients With Amyotrophic Lateral Sclerosis in the Medicare Programme and Under Commercial Insurance

Objective: To determine amyotrophic lateral sclerosis (ALS)-associated costs incurred by patients covered by Medicare and/or commercial insurance before, during and after diagnosis and provide cost details. Methods: Costs were calculated from the Medicare Standard Analytical File 5% sample claims data from Parts A and B from 2009, 2010 and 2011 for ALS Medicare patients aged ‰¥70 years (monthly costs) and ‰¥65 years (costs associated with disability milestones). Commercial insurance patients aged 18€“63 years were selected based on the data provided in the Coordination of Benefits field from Truven MarketScan® in 2008€“2010. Results: Monthly costs increased nine months before diagnosis, peaked during the index month (Medicare: $10,398; commercial:$9354) and decreased but remained high post-index. Costs generally shifted from outpatient to inpatient and private nursing after diagnosis; prescriptions and durable medical equipment costs were much higher for commercial patients post-diagnosis. Patients appeared to progress to disability milestones more rapidly as their disease progressed in severity (14.4 months to non-invasive ventilation [NIV] vs. 16.6 months to hospice), and their costs increased accordingly (NIV: $58,973 vs. hospice:$76,179). Conclusions: For newly diagnosed ALS patients in the U.S., medical costs are substantial and increase rapidly and substantially with each disability milestone

Disparities in Use of Human Epidermal Growth Hormone Receptor 2–Targeted Therapy for Early-Stage Breast Cancer

Trastuzumab is a key component of adjuvant therapy for stage I to III human epidermal growth factor receptor 2 (HER2)–positive breast cancer. The rates and patterns of trastuzumab use have never been described in a population-based sample. The recent addition of HER2 information to the SEER-Medicare database offers an opportunity to examine patterns of trastuzumab use and to evaluate possible disparities in receipt of trastuzumab

Toll-Like Receptor 7 Stimulates the Expression of Epstein-Barr Virus Latent Membrane Protein 1

Epstein-Barr virus (EBV) is a ubiquitous human herpesvirus. Toll-like receptor 7 (TLR7) is involved in host innate immunity against pathogens, and its aberrant activation is linked to the development of systemic lupus erythematosus (SLE, also called ‘‘lupus’’). Type I interferons (IFN) are apparently driving forces for lupus pathogenesis. Previously, we found that EBV latent membrane protein 1 (LMP1) primes cells for IFN production. In this report, the relationship among EBV LMP1, TLRs, and IFN production are examined. We find that TLR7 activation increases the expression of EBV LMP1, and IFN regulatory factor 7 (IRF7) is involved in the stimulation process. TLR7 activation did not induce IFNs from EBV-infected cells, but potentiates those cells for IFN production by TLR3 or TLR9 activation. In addition, we find that LMP1 and IFNs are coexpressed in the same cells in some lupus patients. Therefore, the aberrant activation of TLR7 might induce LMP1 expression and LMP1-expression cells may be producing IFNs in lupus patients. These results suggest EBV might be an exacerbating factor in some lupus patients via promoting IFN production

Reldesemtiv in Patients with Spinal Muscular Atrophy: a Phase 2 Hypothesis-Generating Study

This phase 2, double-blind, placebo-controlled, hypothesis-generating study evaluated the effects of oral reldesemtiv, a fast skeletal muscle troponin activator, in patients with spinal muscular atrophy (SMA). Patients ≥ 12 years of age with type II, III, or IV SMA were randomized into 2 sequential, ascending reldesemtiv dosing cohorts (cohort 1: 150 mg bid or placebo [2:1]; cohort 2: 450 mg bid or placebo [2:1]). The primary objective was to determine potential pharmacodynamic effects of reldesemtiv on 8 outcome measures in SMA, including 6-minute walk distance (6MWD) and maximum expiratory pressure (MEP). Changes from baseline to weeks 4 and 8 were determined. Pharmacokinetics and safety were also evaluated. Patients were randomized to reldesemtiv 150 mg, 450 mg, or placebo (24, 20, and 26, respectively). The change from baseline in 6MWD was greater for reldesemtiv 450 mg than for placebo at weeks 4 and 8 (least squares [LS] mean difference, 35.6 m [p = 0.0037] and 24.9 m [p = 0.058], respectively). Changes from baseline in MEP at week 8 on reldesemtiv 150 and 450 mg were significantly greater than those on placebo (LS mean differences, 11.7 [p = 0.038] and 13.2 cm H2O [p = 0.03], respectively). For 6MWD and MEP, significant changes from placebo were seen in the highest reldesemtiv peak plasma concentration quartile (Cmax \u3e 3.29 μg/mL; LS mean differences, 43.3 m [p = 0.010] and 28.8 cm H2O [p = 0.0002], respectively). Both dose levels of reldesemtiv were well tolerated. Results suggest reldesemtiv may offer clinical benefit and support evaluation in larger SMA patient populations

435 Pegasus HNSCC, a platform study of SAR444245 (THOR-707, a pegylated recombinant non-alpha IL-2) with anti-cancer agents in patients with recurrent/metastatic head and neck squamous cell carcinoma

BackgroundSAR444245 (THOR-707) is a recombinant human IL-2 molecule that includes a PEG moiety irreversibly bound to a novel amino acid via click chemistry to block the alpha-binding domain while retaining near-native affinity for the beta/gamma subunits. In animal models, SAR444245 showed anti-tumor benefits, but with no severe side effects, both as single agent and when combined with anti-PD1 comparing with historical data from aldeslukin. Preclinical study demonstrated SAR444245 enhances ADCC function of cetuximab. The HAMMER trial, which is the FIH study shows preliminary encouraging clinical results: initial efficacy and safety profile with SAR444245 monotherapy and in combination with pembrolizumab or with cetuximab support a non-alpha preferential activity, validating preclinical models. The Pegasus Head and Neck Ph 2 study will evaluate the clinical benefit of SAR444245 in combination with other anticancer therapies for the treatment of patients with R/M HNSCC.MethodsThe Pegasus Head and Neck will enroll approximately 272 patients in 4 separate cohorts concurrently. In cohorts A1 & A2, 1L R/M HNSCC patients will receive SAR444245 + pembrolizumab, or SAR444245+ pembrolizumab+ cetuximab respectively. In cohort B1 & B2 patients with 2/3L R/M HNSCC failed a checkpoint based regimen & a platinum containing regimen will receive SAR444245 + pembrolizumab, or SAR444245 + cetuximab. Patients to be enrolled in cohort B2 need to be cetuximab-naïve in R/M setting. SAR444245 is administered intravenously IV at a dose of 24 ug/kg Q3W until disease progression (PD) or completion of 35 cycles. Pembrolizumab is administered at a dose of 200 mg Q3W until PD or completion of 35 cycles. Cetuximab is administered at a dose of 400/250 mg/m2 QW until PD. The study primary objective is to determine the antitumor activity of SAR444245 in combination with other anticancer therapies. Secondary objectives include confirmation of dose and safety profile, assess other indicators of antitumor activity, and assess the pharmacokinetic profile and immunogenicity of SAR444245. The study will be conducted in the US, Canada, France, Germany, Italy, Netherlands, Poland, South Korea, Spain and Taiwan.AcknowledgementsThe Pegasus Head and Neck study is sponsored by Sanofi

Gains Across WHO Dimensions of Function After Robot-Based Therapy in Stroke Subjects

Background Studies examining the effects of therapeutic interventions after stroke often focus on changes in loss of body function/structure (impairment). However, improvements in activities limitations and participation restriction are often higher patient priorities, and the relationship that these measures have with loss of body function/structure is unclear. Objective This study measured gains across WHO International Classification of Function (ICF) dimensions and examined their interrelationships. Methods Subjects were recruited 11 to 26 weeks after hemiparetic stroke. Over a 3-week period, subjects received 12 sessions of intensive robot-based therapy targeting the distal arm. Each subject was assessed at baseline and at 1 month after end of therapy. Results At baseline, subjects (n = 40) were 134.7 ± 32.4 (mean ± SD) days poststroke and had moderate-severe arm motor deficits (arm motor Fugl-Meyer score of 35.6 ± 14.4) that were stable. Subjects averaged 2579 thumb movements and 1298 wrist movements per treatment session. After robot therapy, there was significant improvement in measures of body function/structure (Fugl-Meyer score) and activity limitations (Action Research Arm Test, Barthel Index, and Stroke Impact Scale–Hand), but not participation restriction (Stroke Specific Quality of Life Scale). Furthermore, while the degree of improvement in loss of body function/structure was correlated with improvement in activity limitations, neither improvement in loss of body function/structure nor improvement in activity limitations was correlated with change in participation restriction. Conclusions After a 3-week course of robotic therapy, there was improvement in body function/structure and activity limitations but no reduction in participation restriction

Co-infection with Chikungunya virus alters trafficking of pathogenic CD8(+) T cells into the brain and prevents Plasmodium-induced neuropathology

Arboviral diseases have risen significantly over the last 40 years, increasing the risk of co‐infection with other endemic disease such as malaria. However, nothing is known about the impact arboviruses have on the host response toward heterologous pathogens during co‐infection. Here, we investigate the effects of Chikungunya virus (CHIKV ) co‐infection on the susceptibility and severity of malaria infection. Using the Plasmodium berghei ANKA (PbA) experimental cerebral malaria (ECM ) model, we show that concurrent co‐infection induced the most prominent changes in ECM manifestation. Concurrent co‐infection protected mice from ECM mortality without affecting parasite development in the blood. This protection was mediated by the alteration of parasite‐specific CD8+ T‐cell trafficking through an IFN γ‐mediated mechanism. Co‐infection with CHIKV induced higher splenic IFN γ levels that lead to high local levels of CXCL 9 and CXCL 10. This induced retention of CXCR 3‐expressing pathogenic CD8+ T cells in the spleen and prevented their migration to the brain. This then averts all downstream pathogenic events such as parasite sequestration in the brain and disruption of blood–brain barrier that prevents ECM ‐induced mortality in co‐infected mice