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The interaction of CD40L and its receptor CD40 on activated T cells and B cells respectively control pro-inflammatory activation in the pathophysiology of autoimmunity and transplant rejection. Previous studies have implicated signaling pathways involving CD40L (interchangeably referred to as CD154), as well as adaptive and innate immune cell activation, in the induction of neuroinflammation in neurodegenerative diseases. This study aimed to assess the safety, tolerability, and impact on pro-inflammatory biomarker profiles of an anti CD40L antibody, tegoprubart, in individuals with amyotrophic lateral sclerosis (ALS). In this multicenter dose-escalating open-label Phase 2A study, 54 participants with a diagnosis of ALS received 6 infusions of tegoprubart administered intravenously every 2 weeks. The study was comprised of 4 dose cohorts: 1 mg/kg, 2 mg/kg, 4 mg/kg, and 8 mg/kg. The primary endpoint of the study was safety and tolerability. Exploratory endpoints assessed the pharmacokinetics of tegoprubart as well as anti-drug antibody (ADA) responses, changes in disease progression utilizing the Revised ALS Functional Rating Scale (ALSFRS-R), CD154 target engagement, changes in pro-inflammatory biomarkers, and neurofilament light chain (NFL). Seventy subjects were screened, and 54 subjects were enrolled in the study. Forty-nine of 54 subjects completed the study (90.7%) receiving all 6 infusions of tegoprubart and completing their final follow-up visit. The most common treatment emergent adverse events (TEAEs) overall (>10%) were fatigue (25.9%), falls (22.2%), headaches (20.4%), and muscle spasms (11.1%). Mean tegoprubart plasma concentrations increased proportionally with increasing dose with a half-life of approximately 24 days. ADA titers were low and circulating levels of tegoprubart were as predicted for all cohorts. Tegoprubart demonstrated dose dependent target engagement associated and a reduction in 18 pro-inflammatory biomarkers in circulation. Tegoprubart appeared to be safe and well tolerated in adults with ALS demonstrating dose-dependent reduction in pro-inflammatory chemokines and cytokines associated with ALS. These results warrant further clinical studies with sufficient power and duration to assess clinical outcomes as a potential treatment for adults with ALS. Clintrials.gov ID:NCT04322149.

Objective. To evaluate longitudinal cognitive/behavioral change over 12 months in participants enrolled in the ALS Multicenter Cohort Study of Oxidative Stress (ALS COSMOS). Methods. We analyzed data from 294 ALS participants, 134 of whom were studied serially. Change over time was evaluated controlling for age, sex, symptom duration, education, race, and ethnicity. Using multiple regression, we evaluated associations among decline in ALS Functional Rating Scale-Revised (ALSFRS-R) scores, forced vital capacity (FVC), and cognitive/behavioral changes. Change in cognitive/behavioral subgroups was assessed using one-way analyses of covariance. Results. Participants with follow-up data had fewer baseline behavior problems compared to patients without follow-up data. We found significant worsening of behavior (ALS Cognitive Behavioral Screen (ALS CBS) behavioral scale, p<0.001; Frontal Behavioral Inventory-ALS (FBI-ALS) disinhibition subscale, p=0.044). Item analysis suggested change in frustration tolerance, insight, mental rigidity, and interests (p<0.05). Changes in ALSFRS-R correlated with the ALS CBS. Worsening disinhibition (FBI-ALS) did not correlate with ALSFRS-R, FVC, or disease duration. Conclusion. We did not detect cognitive change. Behavioral change was detected, and increased disinhibition was found among patients with abnormal baseline behavioral scores. Disinhibition changes did not correlate with disease duration or progression. Baseline behavioral problems were associated with advanced, rapidly progressive disease and study attrition.

[This corrects the article DOI: 10.1155/2018/5969137.].

Purpose: Kinematic measurements of speech have demonstrated some success in automatic detection of early symptoms of amyotrophic lateral sclerosis (ALS). In this study, we examined how the region of symptom onset (bulbar vs. spinal) affects the ability of data-driven models to detect ALS. Method: We used a correlation structure of articulatory movements combined with a machine learning model (i.e., artificial neural network) to detect differences between people with ALS and healthy controls. The performance of this system was evaluated separately for participants with bulbar onset and spinal onset to examine how region of onset affects classification performance. We then performed a regression analysis to examine how different severity measures and region of onset affects model performance. Results: The proposed model was significantly more accurate in classifying the bulbar-onset participants, achieving an area under the curve of 0.809 relative to the 0.674 achieved for spinal-onset participants. The regression analysis, however, found that differences in classifier performance across participants were better explained by their speech performance (intelligible speaking rate), and no significant differences were observed based on region of onset when intelligible speaking rate was accounted for. Conclusions: Although we found a significant difference in the model's ability to detect ALS depending on the region of onset, this disparity can be primarily explained by observable differences in speech motor symptoms. Thus, when the severity of speech symptoms (e.g., intelligible speaking rate) was accounted for, symptom onset location did not affect the proposed computational model's ability to detect ALS.

Purpose: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects bulbar functions including speech and voice. Voice onset time (VOT) was examined in speakers with ALS in early and late stages to explore the coordination of the articulatory and phonatory systems during speech production. Method: VOT was measured in nonword /bap/ produced by speakers with early-stage ALS (n = 11), late-stage ALS (n = 6), and healthy controls (n = 13), and compared with speech performance decline (a marker of disease progression) in ALS. Results: Overall comparison of the VOT values among the three groups showed a significant difference, F(2,27) = 11.71, p < 0.01. Speakers in late-stage ALS displayed longer voicing lead (negative VOT) than both healthy speakers and speakers in early-stage ALS. VOT was also significantly negatively correlated with speech performance (i.e., Intelligible Speaking Rate), r(15) = 0.74, p < 0.01. Conclusions: Speakers with more severe ALS showed greater occurrence of voicing lead and longer voicing lead. Findings show voicing precedes articulatory onset with disease progression in the production of bilabial stops, which suggests that the relative timing of coordination between the supralaryngeal structures and the phonatory system is affected in the late stage of ALS.

Exposure of clone MTC rat 13672NF mammary adenocarcinoma cells to continuous heating at 42°C or to heating for 20 min at 45°C followed by incubation at 37°C induced or enhanced synthesis of several heat-stress proteins (hsp) detectable by [3 H]leucine pulse labeling, gel electrophoresis, and fluorography. Hsp synthesis occurred during development and expression of thermal resistance. For example, continuous heating of MTC cells at 42°C after a rapid temperature transient (about 4 min) produced thermal resistance within 4 to 5 hr of initiation of heating. Hsp synthesis was observed within 2 hr of the cells reaching 42°C and continued throughout 8 hr of heating; four major hsp appeared at nominal molecular weights of 112, 90, 70, and 22 kDa. A slow temperature transient from 37° to 42°C over a 3-hr period increased thermal resistance by a factor of about 2 relative to a rapid transient or \"shock\" to 42°C. However, hsp synthesis was not significant during the slow heat transient and was either reduced (at 70 and 22 kDa) or not increased (at 112 and 90 kDa) compared with the rates of hsp synthesis at the same time intervals after the rapid transient to 42°C. In these mammary tumor cells, no differences in the number of hsp were detected during heating at 42° or after 45°C heating. Other proteins did not appear to change their relative rates of synthesis, with the exception of a clear decrease in proteins with nominal molecular weights of histones H2A, H2B, H3, and H4. Hsp synthesis was not triggered by cold shock to 23° or 0°C, or by radiation of from 2.5 to 10 Gy. Thus hypothermic stress did not enhance hsp synthesis nor were hsp nonspecifically associated with eventual cell lethality. In these experiments, the synthesis of hsp was generally correlated with the development of thermal resistance. Determining the quantity, function, and location of stress proteins may identify targets for thermal killing and resistance. However, one paradoxical observation remains to be resolved. Under the slow temperature transient conditions, the tumor cells attained more thermal resistance with generally reduced rates of hsp synthesis. These results have two possible implications: (a) one or more hsp were not directly related to thermal resistance, or (b) hsp were involved in thermal resistance but their relative rate of synthesis depended on the severity of the heat transient. The latter would imply that the cells made other regulatory or metabolic adjustments and either utilized the hsp more effectively or required less additional hsp.