Evaluation of the Immunomodulatory Effects of Radiation for Chimeric Antigen Receptor T Cell Therapy in Glioblastoma Multiforme.

Standard-of-care treatment for Glioblastoma Multiforme (GBM) is comprised of surgery and adjuvant chemoradiation. Chimeric Antigen Receptor (CAR) T cell therapy has demonstrated disease-modifying activity in GBM and holds great promise. Radiation, a standard-of-care treatment for GBM, has well-known immunomodulatory properties and may overcome the immunosuppressive tumor microenvironment (TME); however, radiation dose optimization and integration with CAR T cell therapy is not well defined.

Locoregional delivery of IL-13Rα2-targeting CAR-T cells in recurrent high-grade glioma: a phase 1 trial.

Chimeric antigen receptor T cell (CAR-T) therapy is an emerging strategy to improve treatment outcomes for recurrent high-grade glioma, a cancer that responds poorly to current therapies. Here we report a completed phase I trial evaluating IL-13Rα2-targeted CAR-T cells in 65 patients with recurrent high-grade glioma, the majority being recurrent glioblastoma (rGBM). Primary objectives were safety and feasibility, maximum tolerated dose/maximum feasible dose and a recommended phase 2 dose plan.

Targeting Wnt signaling for improved glioma immunotherapy.

Introduction: Despite aggressive standard-of-care therapy, including surgery, radiation, and chemotherapy, glioblastoma recurrence is almost inevitable and uniformly lethal. Activation of glioma-intrinsic Wnt/β-catenin signaling is associated with a poor prognosis and the proliferation of glioma stem-like cells, leading to malignant transformation and tumor progression. Impressive results in a subset of cancers have been obtained using immunotherapies including anti-CTLA4, anti-PD-1, and anti-PD-L1 or chimeric antigen receptor (CAR) T cell therapies.

Label-free proteomic comparison reveals ciliary and nonciliary phenotypes of IFT-A mutants.

DIFFRAC is a powerful method for systematically comparing proteome content and organization between samples in a high-throughput manner. By subjecting control and experimental protein extracts to native chromatography and quantifying the contents of each fraction using mass spectrometry, it enables the quantitative detection of alterations to protein complexes and abundances. Here, we applied DIFFRAC to investigate the consequences of genetic loss of Ift122, a subunit of the intraflagellar transport-A (IFT-A) protein complex that plays a vital role in the formation and function of cilia and flagella, on the proteome of .

A randomized prospective trial of an ostomy telehealth intervention for cancer survivors.

Background: Cancer survivors with ostomies face complex challenges. This study compared the Ostomy Self-Management Telehealth program (OSMT) versus attention control usual care (UC).

Methods: Three academic centers randomized participants.

Normalizing salt content by mixing native human airway mucus samples normalizes sample rheology.

Across the globe, millions of people are affected by muco-obstructive pulmonary diseases like cystic fibrosis, asthma, and chronic obstructive pulmonary disease. In MOPDs, the airway mucus becomes hyperconcentrated, increasing viscoelasticity and impairing mucus clearance. Research focused on treatment of MOPDs requires relevant sources of airway mucus both as a control sample type and as a basis for manipulation to study the effects of additional hyperconcentration, inflammatory milieu, and biofilm growth on the biochemical and biophysical properties of mucus.

Label-free proteomic comparison reveals ciliary and non-ciliary phenotypes of IFT-A mutants.

DIFFRAC is a powerful method for systematically comparing proteome content and organization between samples in a high-throughput manner. By subjecting control and experimental protein extracts to native chromatography and quantifying the contents of each fraction using mass spectrometry, it enables the quantitative detection of alterations to protein complexes and abundances. Here, we applied DIFFRAC to investigate the consequences of genetic loss of Ift122, a subunit of the intraflagellar transport-A (IFT-A) protein complex that plays a vital role in the formation and function of cilia and flagella, on the proteome of .

Using an electronic medical record patient portal for warfarin self-management: Empowering children and parents.

Background: Many children taking warfarin perform their international normalized ratio (INR) at home, with results phoned to a clinician who instructs warfarin dosing. Data suggest that parents can be supported to make warfarin dosing decisions themselves, a process known as patient self-management (PSM).

Objectives: This study aimed to determine the suitability and acceptability of warfarin PSM in children using the Epic Patient Portal.

Cilia proteins getting to work - how do they commute from the cytoplasm to the base of cilia?

Cilia are multifunctional organelles that originated with the last eukaryotic common ancestor and play central roles in the life cycles of diverse organisms. The motile flagella that move single cells like sperm or unicellular organisms, the motile cilia on animal multiciliated cells that generate fluid flow in organs, and the immotile primary cilia that decorate nearly all cells in animals share many protein components in common, yet each also requires specialized proteins to perform their specialized functions. Despite a now-advanced understanding of how such proteins are transported within cilia, we still know very little about how they are transported from their sites of synthesis through the cytoplasm to the ciliary base.

Mild Sustainable Amide Alkylation Protocol Enables a Broad Orthogonal Scope.

Herein, the development of a mild sustainable protocol to couple primary alkyl chlorides and bromides with amides is described. In contrast to current methodologies, our system does not require the use of strongly basic conditions, high temperatures, or the addition of an organometallic catalyst, thereby enabling access to a remarkably orthogonal scope. KPO is used to facilitate the formation of secondary and tertiary amides, which are ubiquitous scaffolds in bioactive molecules and natural products.

Engineered IL13 variants direct specificity of IL13Rα2-targeted CAR T cell therapy.

IL13Rα2 is an attractive target due to its overexpression in a variety of cancers and rare expression in healthy tissue, motivating expansion of interleukin 13 (IL13)-based chimeric antigen receptor (CAR) T cell therapy from glioblastoma into systemic malignancies. IL13Rα1, the other binding partner of IL13, is ubiquitously expressed in healthy tissue, raising concerns about the therapeutic window of systemic administration. IL13 mutants with diminished binding affinity to IL13Rα1 were previously generated by structure-guided protein engineering.

Antibody-based redirection of universal Fabrack-CAR T cells selectively kill antigen bearing tumor cells.

Background: Chimeric antigen receptor (CAR) T cells engineered to recognize and target tumor associated antigens have made a profound impact on the quality of life for many patients with cancer. However, tumor heterogeneity and intratumoral immune suppression reduce the efficacy of this approach, allowing for tumor cells devoid of the target antigen to seed disease recurrence. Here, we address the complexity of tumor heterogeneity by developing a universal CAR.

Validation of the PAM-13 instrument in the Hungarian general population 40 years old and above.

Background: Patient activation comprises the skills, knowledge and motivation necessary for patients' effective contribution to their care. We adapted and validated the 13-item Patient Activation Measure (PAM-13) in the ≥ 40 years old Hungarian general population.

Methods: A cross-sectional web survey was conducted among 900 respondents selected from an online panel via quota sampling.

Patient activation and treatment decision-making in the context of cancer: examining the contribution of informal caregivers' involvement.

Purpose: The present work investigated the relationship between patient activation, treatment decision-making, and adherence to the prescribed treatment regimen. Given the role of informal caregivers in patient-reported outcomes, it was additionally assessed whether caregiver involvement acted as a moderator of this relationship.

Methods: Survey data collected from 504 cancer survivors were utilized.

Protein turnover dynamics suggest a diffusion-to-capture mechanism for peri-basal body recruitment and retention of intraflagellar transport proteins.

Intraflagellar transport (IFT) is essential for construction and maintenance of cilia. IFT proteins concentrate at the basal body where they are thought to assemble into trains and bind cargoes for transport. To study the mechanisms of IFT recruitment to this peri-basal body pool, we quantified protein dynamics of eight IFT proteins, as well as five other basal body localizing proteins using fluorescence recovery after photobleaching in vertebrate multiciliated cells.

Morbidity associated with the use of Foley balloon for cervical ripening in women with prior cesarean delivery.

Objective: We evaluated the morbidity of Foley balloon for cervical ripening in comparison to oxytocin alone in women with a prior cesarean delivery.

Study Design: A four-hospital retrospective review of all women with viable singleton pregnancies and history of a single prior cesarean delivery presenting for cervical ripening between 1994 and 2015. Exposure groups were either Foley balloon or oxytocin, at the treating physician's discretion.

Identification and characterisation of serotonin signalling in the potato cyst nematode Globodera pallida reveals new targets for crop protection.

Plant parasitic nematodes are microscopic pathogens that invade plant roots and cause extensive damage to crops. We have used a chemical biology approach to define mechanisms underpinning their parasitic behaviour: We discovered that reserpine, a plant alkaloid that inhibits the vesicular monoamine transporter (VMAT), potently impairs the ability of the potato cyst nematode Globodera pallida to enter the host plant root. We show this is due to an inhibition of serotonergic signalling that is essential for activation of the stylet which is used to access the host root.

IL-2 enhances ex vivo-expanded regulatory T-cell persistence after adoptive transfer.

As regulatory T cell (Treg) adoptive therapy continues to develop clinically, there is a need to determine which immunomodulatory agents pair most compatibly with Tregs to enable persistence and stabilize suppressor function. Prior work has shown that mechanistic target of rapamycin inhibition can increase the stability of thymic Tregs. In this study, we investigated the transcriptomic signatures of ex vivo-expanded Tregs after adoptive transfer in the setting of clinically relevant immunosuppression using a nonhuman primate (NHP) model as a prelude to future transplant studies.

Placental endothelin-converting enzyme-1 is decreased in preeclampsia.

Endothelin-converting enzyme-1(ECE-1) is a key regulatory enzyme in the processing of endothelin-1 (ET-1). We quantified and localized ECE-1 in normal and preeclamptic placentas. Normal (n=6) and preeclamptic (n=6) placentas were serially sectioned for immunofluorescence (IF).

Effect of a Hospital-Initiated Program Combining Transitional Care and Long-term Self-management Support on Outcomes of Patients Hospitalized With Chronic Obstructive Pulmonary Disease: A Randomized Clinical Trial.

Importance: Patients hospitalized for chronic obstructive pulmonary disease (COPD) exacerbations have high rehospitalization rates and reduced quality of life.

Objective: To evaluate whether a hospital-initiated program that combined transition and long-term self-management support for patients hospitalized due to COPD and their family caregivers can improve outcomes.

Design, Setting, And Participants: Single-site randomized clinical trial conducted in Baltimore, Maryland, with 240 participants.