Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma.

Glioblastoma is the most common primary malignant brain tumor in adults and is associated with poor survival. The Ivy Foundation Early Phase Clinical Trials Consortium conducted a randomized, multi-institution clinical trial to evaluate immune responses and survival following neoadjuvant and/or adjuvant therapy with pembrolizumab in 35 patients with recurrent, surgically resectable glioblastoma. Patients who were randomized to receive neoadjuvant pembrolizumab, with continued adjuvant therapy following surgery, had significantly extended overall survival compared to patients that were randomized to receive adjuvant, post-surgical programmed cell death protein 1 (PD-1) blockade alone. Neoadjuvant PD-1 blockade was associated with upregulation of T cell- and interferon-γ-related gene expression, but downregulation of cell-cycle-related gene expression within the tumor, which was not seen in patients that received adjuvant therapy alone. Focal induction of programmed death-ligand 1 in the tumor microenvironment, enhanced clonal expansion of T cells, decreased PD-1 expression on peripheral blood T cells and a decreasing monocytic population was observed more frequently in the neoadjuvant group than in patients treated only in the adjuvant setting. These findings suggest that the neoadjuvant administration of PD-1 blockade enhances both the local and systemic antitumor immune response and may represent a more efficacious approach to the treatment of this uniformly lethal brain tumor

ACTION:a randomized phase 3 study of ONC201 (dordaviprone) in patients with newly diagnosed H3 K27M-mutant diffuse glioma

BACKGROUND: H3 K27M-mutant diffuse glioma primarily affects children and young adults, is associated with a poor prognosis, and no effective systemic therapy is currently available. ONC201 (dordaviprone) has previously demonstrated efficacy in patients with recurrent disease. This phase 3 trial evaluates ONC201 in patients with newly diagnosed H3 K27M-mutant glioma.METHODS: ACTION (NCT05580562) is a randomized, double-blind, placebo-controlled, parallel-group, international phase 3 study of ONC201 in newly diagnosed H3 K27M-mutant diffuse glioma. Patients who have completed standard frontline radiotherapy are randomized 1:1:1 to receive placebo, once-weekly dordaviprone, or twice-weekly dordaviprone on 2 consecutive days. Primary efficacy endpoints are overall survival (OS) and progression-free survival (PFS); PFS is assessed by response assessment in neuro-oncology high-grade glioma criteria (RANO-HGG) by blind independent central review. Secondary objectives include safety, additional efficacy endpoints, clinical benefit, and quality of life. Eligible patients have histologically confirmed H3 K27M-mutant diffuse glioma, a Karnofsky/Lansky performance status ≥70, and completed first-line radiotherapy. Eligibility is not restricted by age; however, patients must be ≥10 kg at time of randomization. Patients with a primary spinal tumor, diffuse intrinsic pontine glioma, leptomeningeal disease, or cerebrospinal fluid dissemination are not eligible. ACTION is currently enrolling in multiple international sites.</p

ACTION:a randomized phase 3 study of ONC201 (dordaviprone) in patients with newly diagnosed H3 K27M-mutant diffuse glioma

BACKGROUND: H3 K27M-mutant diffuse glioma primarily affects children and young adults, is associated with a poor prognosis, and no effective systemic therapy is currently available. ONC201 (dordaviprone) has previously demonstrated efficacy in patients with recurrent disease. This phase 3 trial evaluates ONC201 in patients with newly diagnosed H3 K27M-mutant glioma.METHODS: ACTION (NCT05580562) is a randomized, double-blind, placebo-controlled, parallel-group, international phase 3 study of ONC201 in newly diagnosed H3 K27M-mutant diffuse glioma. Patients who have completed standard frontline radiotherapy are randomized 1:1:1 to receive placebo, once-weekly dordaviprone, or twice-weekly dordaviprone on 2 consecutive days. Primary efficacy endpoints are overall survival (OS) and progression-free survival (PFS); PFS is assessed by response assessment in neuro-oncology high-grade glioma criteria (RANO-HGG) by blind independent central review. Secondary objectives include safety, additional efficacy endpoints, clinical benefit, and quality of life. Eligible patients have histologically confirmed H3 K27M-mutant diffuse glioma, a Karnofsky/Lansky performance status ≥70, and completed first-line radiotherapy. Eligibility is not restricted by age; however, patients must be ≥10 kg at time of randomization. Patients with a primary spinal tumor, diffuse intrinsic pontine glioma, leptomeningeal disease, or cerebrospinal fluid dissemination are not eligible. ACTION is currently enrolling in multiple international sites.</p

Crystal structure of a conformational antibody that binds tau oligomers and inhibits pathological seeding by extracts from donors with Alzheimer's disease

Soluble oligomers of aggregated tau accompany the accumulation of insoluble amyloid fibrils, a histological hallmark of Alzheimer disease (AD) and two dozen related neurodegenerative diseases. Both oligomers and fibrils seed the spread of Tau pathology, and by virtue of their low molecular weight and relative solubility, oligomers may be particularly pernicious seeds. Here, we report the formation of in vitro tau oligomers formed by an ionic liquid (IL15). Using IL15-induced recombinant tau oligomers and a dot blot assay, we discovered a mAb (M204) that binds oligomeric tau, but not tau monomers or fibrils. M204 and an engineered single-chain variable fragment (scFv) inhibited seeding by IL15-induced tau oligomers and pathological extracts from donors with AD and chronic traumatic encephalopathy. This finding suggests that M204-scFv targets pathological structures that are formed by tau in neurodegenerative diseases. We found that M204-scFv itself partitions into oligomeric forms that inhibit seeding differently, and crystal structures of the M204-scFv monomer, dimer, and trimer revealed conformational differences that explain differences among these forms in binding and inhibition. The efficiency of M204-scFv antibodies to inhibit the seeding by brain tissue extracts from different donors with tauopathies varied among individuals, indicating the possible existence of distinct amyloid polymorphs. We propose that by binding to oligomers, which are hypothesized to be the earliest seeding-competent species, M204-scFv may have potential as an early-stage diagnostic for AD and tauopathies, and also could guide the development of promising therapeutic antibodies

Development of multidrug-resistant Mycobacterium tuberculosis in the biofilm of a peritoneal-venous shunt

A patient with ascites received a peritoneal-venous shunt for presumed cirrhosis, however surgical specimens grew Mycobacterium tuberculosis (MTb) sensitive to all anti-tuberculous drugs. Directly-Observed-Therapy (DOT) led to improvement followed by relapse with multidrug resistant MTb (MDRTB). We discuss pathways for selection of MDRTB within mycobacterial biofilm. This case illustrates the potential for development of MDRTB in patients with long-term indwelling catheters. We emphasize catheter removal and if not possible continuing follow-up for symptoms and signs of relapse

Development of multidrug-resistant Mycobacterium tuberculosis in the biofilm of a peritoneal-venous shunt

A patient with ascites received a peritoneal-venous shunt for presumed cirrhosis, however surgical specimens grew Mycobacterium tuberculosis (MTb) sensitive to all anti-tuberculous drugs. Directly-Observed-Therapy (DOT) led to improvement followed by relapse with multidrug resistant MTb (MDRTB). We discuss pathways for selection of MDRTB within mycobacterial biofilm. This case illustrates the potential for development of MDRTB in patients with long-term indwelling catheters. We emphasize catheter removal and if not possible continuing follow-up for symptoms and signs of relapse

Sleep as a mediator of the relationship between social class and health in higher education students

A substantial body of research indicates that higher education students from lower social class backgrounds tend to have poorer health than those from higher social class backgrounds. To investigate sleep as a potential mediator of this relationship, online survey responses of students from five large Australian universities, one Irish university and one large Australian technical college were analysed in three studies (Study 1 N = 628; Study 2 N = 376; Study 3 N = 446). The results revealed that sleep quality, sleep duration, sleep disturbances, pre-sleep worries and sleep schedule variability mediated the relationship between social class and physical and mental health. Sleep remained a significant mediator when controlling for related variables and other mediators. Thus, the findings suggest that sleep partly explains social class differences in health. We discuss the importance of addressing sleep issues among students from lower social class backgrounds

Deep learning with backtracking search optimization based skin lesion diagnosis model

Nowadays, quality improvement and increased accessibility to patient data, at a reasonable cost, are highly challenging tasks in healthcare sector. Internet of Things (IoT) and Cloud Computing (CC) architectures are utilized in the development of smart healthcare systems. These entities can support real-time applications by exploiting massive volumes of data, produced by wearable sensor devices. The advent of evolutionary computation algorithms and Deep Learning (DL) models has gained significant attention in healthcare diagnosis, especially in decision making process. Skin cancer is the deadliest disease which affects people across the globe. Automatic skin lesion classification model has a highly important application due to its fine-grained variability in the presence of skin lesions. The current research article presents a new skin lesion diagnosis model i.e., Deep Learning with Evolutionary Algorithm based Image Segmentation (DL-EAIS) for IoT and cloud-based smart healthcare environments. Primarily, the dermoscopic images are captured using IoT devices, which are then transmitted to cloud servers for further diagnosis. Besides, Backtracking Search optimization Algorithm (BSA) with Entropy-Based Thresholding (EBT) i.e., BSA-EBT technique is applied in image segmentation. Followed by, Shallow Convolutional Neural Network (SCNN) model is utilized as a feature extractor. In addition, Deep-Kernel Extreme Learning Machine (D-KELM) model is employed as a classification model to determine the class labels of dermoscopic images. An extensive set of simulations was conducted to validate the performance of the presented method using benchmark dataset. The experimental outcome infers that the proposed model demonstrated optimal performance over the compared techniques under diverse measures

Sleep as a mediator of the relationship between social class and health in higher education students

A substantial body of research indicates that higher education students from lower social class backgrounds tend to have poorer health than those from higher social class backgrounds. To investigate sleep as a potential mediator of this relationship, online survey responses of students from five large Australian universities, one Irish university and one large Australian technical college were analysed in three studies (Study 1 N = 628; Study 2 N = 376; Study 3 N = 446). The results revealed that sleep quality, sleep duration, sleep disturbances, pre-sleep worries and sleep schedule variability mediated the relationship between social class and physical and mental health. Sleep remained a significant mediator when controlling for related variables and other mediators. Thus, the findings suggest that sleep partly explains social class differences in health. We discuss the importance of addressing sleep issues among students from lower social class backgrounds.</p