Pathogenic role of delta 2 tubulin in bortezomib-induced peripheral neuropathy

The pathogenesis of chemotherapy-induced peripheral neuropathy (CIPN) is poorly understood. Here, we report that the CIPN-causing drug bortezomib (Bort) promotes delta 2 tubulin (D2) accumulation while affecting microtubule stability and dynamics in sensory neurons in vitro and in vivo and that the accumulation of D2 is predominant in unmyelinated fibers and a hallmark of bortezomib-induced peripheral neuropathy (BIPN) in humans. Furthermore, while D2 overexpression was sufficient to cause axonopathy and inhibit mitochondria motility, reduction of D2 levels alleviated both axonal degeneration and the loss of mitochondria motility induced by Bort. Together, our data demonstrate that Bort, a compound structurally unrelated to tubulin poisons, affects the tubulin cytoskeleton in sensory neurons in vitro, in vivo, and in human tissue, indicating that the pathogenic mechanisms of seemingly unrelated CIPN drugs may converge on tubulin damage. The results reveal a previously unrecognized pathogenic role for D2 in BIPN that may occur through altered regulation of mitochondria motility

‘Brand Israel’: hasbara and Israeli sport

Until relatively recently, the state of Israel was preoccupied with its military security and paid little attention to cultural politics. However, the emergence of other ‘battlegrounds’ has seen a shift to ‘soft power’ in an attempt to generate a more benevolent global image. This paper spotlights an international sporting event which ordinarily attracts very limited interest from the mainstream media. However, when held in Israel, it created much greater interest. The paper identifies the UEFA’s Men’s U-21 tournament, held in Israel in 2013, to assess how different groups responded to the event: celebratory by the host nation and its supporters, the Israeli Football Association and UEFA; critical amongst Palestinians and their supporters in the international community. The paper identifies how the Israeli state is using ‘hasbara’ in an attempt to arrest its deteriorating international image and shows how the concept is empirically operationalized (‘hasbara in action’)

Advances in the treatment of hereditary transthyretin amyloidosis: A review

Introduction: Amyloid transthyretin amyloidosis (ATTR) is a progressive and often fatal disease caused by the buildup of mutated (hereditary ATTR [hATTR]; also known as ATTR variant [ATTRv]) or normal transthyretin (wild-type ATTR) throughout the body. Two new therapies-inotersen, an antisense oligonucleotide therapy, and patisiran, an RNA interference therapy-received marketing authorization and represent a significant advance in the treatment of amyloidosis. Herein, we describe the clinical presentation of ATTR, commonly used procedures in its diagnosis, and current treatment landscape for ATTR, with a focus on hATTR. Methods: A PubMed search from 2008 to September 2018 was conducted to review the literature on ATTR. Results: Until recently, there have been few treatment options for polyneuropathy of hATTR. Inotersen and patisiran substantially reduce the amyloidogenic precursor protein transthyretin and have demonstrated efficacy in patients with early- and late-stage disease and in slowing or improving neuropathy progression. In contrast, established therapies, such as liver transplantation, typically reserved for patients with early-stage disease, and tafamidis, indicated for the treatment of early-stage disease in Europe, or diflunisal, a nonsteroidal anti-inflammatory drug that is used off-label, are associated with side effects and/or unclear efficacy in certain patient populations. Thus, inotersen and patisiran are positioned to be the preferred therapeutic modalities. Conclusions: Important differences between inotersen and patisiran, including formulation, dosing, requirements for premedications, and safety monitoring, require an understanding and knowledge of each treatment for informed decision making.info:eu-repo/semantics/publishedVersio

Soft power and soft disempowerment: Qatar, global sport and football’s 2022 World Cup finals

This paper examines the critical role of global sport within Qatar’s international strategy, most notably through the successful bid to stage the 2022 football World Cup. Our discussion draws particularly on interviews with key stakeholders in the Qatari sport system, as well as fieldwork in Qatar and the analysis of relevant documents and secondary materials. The paper is separated into five main parts. First, we set out our theoretical framework, which draws on the concepts of globalization and soft power; to assist in the analysis of Qatar’s engagement with global sport, we introduce the two further concepts of ‘glocal consciousness’ and ‘soft disempowerment’. Second, we provide the reader with background information on Qatar and Qatari sport. Third, we discuss three key themes that emerged mainly from our interviews on Qatar and global sport: exhibiting Qatar’s supremacies as a microstate; the pursuit of peace, security and integrity; and confronting national health crises. Fourth, we explore issues of soft disempowerment and reputational risk with regard to these three themes and, in particular, critical international comment surrounding Qatar’s hosting of the 2022 World Cup. Fifth, we conclude by arguing that Qatar’s soft disempowerment, although damaging in the short term, leaves the door open for the state to respond in a positive manner, regenerating its soft power capabilities in the process

Inotersen treatment for patients with hereditary transthyretin amyloidosis

BACKGROUND: Hereditary transthyretin amyloidosis is caused by pathogenic single-nucleotide variants in the gene encoding transthyretin ( TTR) that induce transthyretin misfolding and systemic deposition of amyloid. Progressive amyloid accumulation leads to multiorgan dysfunction and death. Inotersen, a 2'- O-methoxyethyl-modified antisense oligonucleotide, inhibits hepatic production of transthyretin. METHODS: We conducted an international, randomized, double-blind, placebo-controlled, 15-month, phase 3 trial of inotersen in adults with stage 1 (patient is ambulatory) or stage 2 (patient is ambulatory with assistance) hereditary transthyretin amyloidosis with polyneuropathy. Patients were randomly assigned, in a 2:1 ratio, to receive weekly subcutaneous injections of inotersen (300 mg) or placebo. The primary end points were the change in the modified Neuropathy Impairment Score+7 (mNIS+7; range, -22.3 to 346.3, with higher scores indicating poorer function; minimal clinically meaningful change, 2 points) and the change in the score on the patient-reported Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) questionnaire (range, -4 to 136, with higher scores indicating poorer quality of life). A decrease in scores indicated improvement. RESULTS: A total of 172 patients (112 in the inotersen group and 60 in the placebo group) received at least one dose of a trial regimen, and 139 (81%) completed the intervention period. Both primary efficacy assessments favored inotersen: the difference in the least-squares mean change from baseline to week 66 between the two groups (inotersen minus placebo) was -19.7 points (95% confidence interval [CI], -26.4 to -13.0; P<0.001) for the mNIS+7 and -11.7 points (95% CI, -18.3 to -5.1; P<0.001) for the Norfolk QOL-DN score. These improvements were independent of disease stage, mutation type, or the presence of cardiomyopathy. There were five deaths in the inotersen group and none in the placebo group. The most frequent serious adverse events in the inotersen group were glomerulonephritis (in 3 patients [3%]) and thrombocytopenia (in 3 patients [3%]), with one death associated with one of the cases of grade 4 thrombocytopenia. Thereafter, all patients received enhanced monitoring. CONCLUSIONS: Inotersen improved the course of neurologic disease and quality of life in patients with hereditary transthyretin amyloidosis. Thrombocytopenia and glomerulonephritis were managed with enhanced monitoring. (Funded by Ionis Pharmaceuticals; NEURO-TTR ClinicalTrials.gov number, NCT01737398 .)

Assessing mNIS+7Ionis and international neurologists' proficiency in a familial amyloidotic polyneuropathy trial

INTRODUCTION: Polyneuropathy signs (Neuropathy Impairment Score, NIS), neurophysiologic tests (m+7Ionis ), disability, and health scores were assessed in baseline evaluations of 100 patients entered into an oligonucleotide familial amyloidotic polyneuropathy (FAP) trial. METHODS: We assessed: (1) Proficiency of grading neurologic signs and correlation with neurophysiologic tests, and (2) clinometric performance of modified NIS+7 neurophysiologic tests (mNIS+7Ionis ) and its subscores and correlation with disability and health scores. RESULTS: The mNIS+7Ionis sensitively detected, characterized, and broadly scaled diverse polyneuropathy impairments. Polyneuropathy signs (NIS and subscores) correlated with neurophysiology tests, disability, and health scores. Smart Somatotopic Quantitative Sensation Testing of heat as pain 5 provided a needed measure of small fiber involvement not adequately assessed by other tests. CONCLUSIONS: Specially trained neurologists accurately assessed neuropathy signs as compared to referenced neurophysiologic tests. The score, mNIS+7Ionis , broadly detected, characterized, and scaled polyneuropathy abnormality in FAP, which correlated with disability and health scores. Muscle Nerve 56: 901-911, 2017

Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis

BACKGROUND Patisiran, an investigational RNA interference therapeutic agent, specifically inhibits hepatic synthesis of transthyretin. METHODS In this phase 3 trial, we randomly assigned patients with hereditary transthyretin amyloidosis with polyneuropathy, in a 2:1 ratio, to receive intravenous patisiran (0.3 mg per kilogram of body weight) or placebo once every 3 weeks. The primary end point was the change from baseline in the modified Neuropathy Impairment Score+7 (mNIS+7; range, 0 to 304, with higher scores indicating more impairment) at 18 months. Other assessments included the Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) questionnaire (range, −4 to 136, with higher scores indicating worse quality of life), 10-m walk test (with gait speed measured in meters per second), and modified body-mass index (modified BMI, defined as [weight in kilograms divided by square of height in meters]×albumin level in grams per liter; lower values indicated worse nutritional status). RESULTS A total of 225 patients underwent randomization (148 to the patisiran group and 77 to the placebo group). The mean (±SD) mNIS+7 at baseline was 80.9±41.5 in the patisiran group and 74.6±37.0 in the placebo group; the least-squares mean (±SE) change from baseline was −6.0±1.7 versus 28.0±2.6 (difference, −34.0 points; P<0.001) at 18 months. The mean (±SD) baseline Norfolk QOL-DN score was 59.6±28.2 in the patisiran group and 55.5±24.3 in the placebo group; the least-squares mean (±SE) change from baseline was −6.7±1.8 versus 14.4±2.7 (difference, −21.1 points; P<0.001) at 18 months. Patisiran also showed an effect on gait speed and modified BMI. At 18 months, the least-squares mean change from baseline in gait speed was 0.08±0.02 m per second with patisiran versus −0.24±0.04 m per second with placebo (difference, 0.31 m per second; P<0.001), and the least-squares mean change from baseline in the modified BMI was −3.7±9.6 versus −119.4±14.5 (difference, 115.7; P<0.001). Approximately 20% of the patients who received patisiran and 10% of those who received placebo had mild or moderate infusion-related reactions; the overall incidence and types of adverse events were similar in the two groups. CONCLUSIONS In this trial, patisiran improved multiple clinical manifestations of hereditary transthyretin amyloidosis

A double-blind, placebo-controlled, randomized trial of PXT3003 for the treatment of Charcot–Marie–Tooth type 1A

Background: Charcot-Marie-Tooth disease type 1A (CMT1A) is a rare, orphan, hereditary neuromuscular disorder with no cure and for which only symptomatic treatment is currently available. A previous phase 2 trial has shown preliminary evidence of efficacy for PXT3003 in treating CMT1A. This phase 3, international, randomized, double-blind, placebo-controlled study further investigated the efficacy and safety of high- or low-dose PXT3003 (baclofen/naltrexone/D-sorbitol [mg]: 6/0.70/210 or 3/0.35/105) in treating subjects with mild to moderate CMT1A. Methods: In this study, 323 subjects with mild-to-moderate CMT1A were randomly assigned in a 1:1:1 ratio to receive 5 mL of high- or low-dose PXT3003, or placebo, orally twice daily for up to 15 months. Efficacy was assessed using the change in Overall Neuropathy Limitations Scale total score from baseline to months 12 and 15 (primary endpoint). Secondary endpoints included the 10-m walk test and other assessments. The high-dose group was discontinued early due to unexpected crystal formation in the high-dose formulation, which resulted in an unanticipated high discontinuation rate, overall and especially in the high-dose group. The statistical analysis plan was adapted to account for the large amount of missing data before database lock, and a modified full analysis set was used in the main analyses. Two sensitivity analyses were performed to check the interpretation based on the use of the modified full analysis set. Results: High-dose PXT3003 demonstrated significant improvement in the Overall Neuropathy Limitations Scale total score vs placebo (mean difference: - 0.37 points; 97.5% CI [- 0.68 to - 0.06]; p = 0.008), and consistent treatment effects were shown in the sensitivity analyses. Both PXT3003 doses were safe and well-tolerated. Conclusion: The high-dose group demonstrated a statistically significant improvement in the primary endpoint and a good safety profile. Overall, high-dose PXT3003 is a promising treatment option for patients with Charcot-Marie-Tooth disease type 1A