Modeling of Parkinson's Disease Progression and Implications for Detection of Disease Modification in Treatment Trials.

Background: Objectively measuring Parkinson's disease (PD) signs and symptoms over time is critical for the successful development of treatments aimed at halting the disease progression of people with PD.

Objective: To create a clinical trial simulation tool that characterizes the natural history of PD progression and enables a data-driven design of randomized controlled studies testing potential disease-modifying treatments (DMT) in early-stage PD.

Methods: Data from the Parkinson's Progression Markers Initiative (PPMI) were analyzed with nonlinear mixed-effect modeling techniques to characterize the progression of MDS-UPDRS part I (non-motor aspects of experiences of daily living), part II (motor aspects of experiences of daily living), and part III (motor signs).

YTHDC1 mA-dependent and mA-independent functions converge to preserve the DNA damage response.

Cells have evolved a robust and highly regulated DNA damage response to preserve their genomic integrity. Although increasing evidence highlights the relevance of RNA regulation, our understanding of its impact on a fully efficient DNA damage response remains limited. Here, through a targeted CRISPR-knockout screen, we identify RNA-binding proteins and modifiers that participate in the p53 response.

TLR2/4 are novel activating receptors for SARS-CoV-2 spike protein on NK cells.

Background: In early infected or severe coronavirus disease 2019 (COVID-19) patients, circulating NK cells are consistently reduced, despite being highly activated or exhausted. The aim of this paper was to establish whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein (SP) may directly trigger NK cells and through which receptor(s).

Methods: SP-stimulated human NK cells have been evaluated for the expression of activation markers, cytokine release, and cytotoxic activity, as well as for gene expression profiles and NF-kB phosphorylation, and they have been silenced with specific small interfering RNAs.

Cancer-associated fibroblast-derived Dickkopf-1 suppresses NK cell cytotoxicity in breast cancer.

Breast cancer is poorly immunogenic, hence able to evade T cell recognition and respond poorly to immune checkpoint blockade. Breast cancer cells can also evade NK cell-mediated immune surveillance, but the mechanism remains enigmatic. Dickkopf-1 (DKK1) is a Wnt/b-catenin inhibitor, whose levels are increased in breast cancer patients and correlate with reduced overall survival.

Therapeutic inertia in treatment of older adults with type II diabetes at high risk for hypoglycemia.

Patients 80 years or older with HbA1c <7.0% (53 mmol/mol) treated with multiple daily insulin injections had low rates of rapid-acting insulin deprescription and initiation of diabetes medications with lower risk of hypoglycemia. Further investigation is needed to elucidate factors contributing to potentially inappropriately aggressive treatment of these patients.

Reducing pest pressure and insecticide use by increasing hedgerows in the landscape.

Reducing pesticide use while maintaining agricultural production is a key challenge. Ecological theory predicts that landscape simplification is likely to increase insect pest outbreaks and limit their control by natural enemies, and this situation could boost insecticide use. Some studies have indeed detected that simpler landscapes were associated with higher insecticide use, but very few have demonstrated that this association is caused by landscape effects on pest abundance.

Determining Endosomal Toll-Like Receptors Gene Expression in NK Cells After Stimulation with Specific Agonists.

Poor knowledge is currently available about the biology of Toll-like receptors (TLRs) in natural killer (NK) cells. This is particularly due to the old belief that NK cells are unable to specifically eliminate microbes without presensitization. On the contrary, it has been clearly demonstrated that not only they can be activated through the engagement of Toll-like receptors (TLRs) by microbial molecules, but also that this interaction induces NK cells to release cytokines that, in turn, activate other cells of both innate and adaptive immunity.

Alpha-1 Adrenergic Antagonists Sensitize Neuroblastoma to Therapeutic Differentiation.

Unlabelled: Neuroblastoma (NB) is an aggressive childhood tumor, with high-risk cases having a 5-year overall survival probability of approximately 50%. The multimodal therapeutic approach for NB includes treatment with the retinoid isotretinoin (13-cis retinoic acid; 13cRA), which is used in the post-consolidation phase as an antiproliferation and prodifferentiation agent to minimize residual disease and prevent relapse. Through small-molecule screening, we identified isorhamnetin (ISR) as a synergistic compound with 13cRA in inhibiting up to 80% of NB cell viability.

How the Immune System Responds to Allergy Immunotherapy.

IgE-mediated diseases represent a highly diversified and multifactorial group of disorders that can deeply impact the patients' quality of life. Currently, allergy immunotherapy (AIT) still remains the gold standard for the management of such pathologies. In this review, we comprehensively examine and discuss how AIT can affect both the innate and the adaptive immune responses at different cell levels and propose timing-scheduled alterations induced by AIT by hypothesizing five sequential phases: after the desensitization of effector non-lymphoid cells and a transient increase of IgE (phase 1), high doses of allergen given by AIT stimulate the shift from type 2/type 3 towards type 1 response (phase 2), which is progressively potentiated by the increase of IFN-γ that promotes the chronic activation of APCs, progressively leading to the hyperexpression of Notch1L (Delta4) and the secretion of IL-12 and IL-27, which are essential to activate IL-10 gene in Th1 and ILC1 cells.

Trial of Prasinezumab in Early-Stage Parkinson's Disease.

Background: Aggregated α-synuclein plays an important role in the pathogenesis of Parkinson's disease. The monoclonal antibody prasinezumab, directed at aggregated α-synuclein, is being studied for its effect on Parkinson's disease.

Methods: In this phase 2 trial, we randomly assigned participants with early-stage Parkinson's disease in a 1:1:1 ratio to receive intravenous placebo or prasinezumab at a dose of 1500 mg or 4500 mg every 4 weeks for 52 weeks.

Improving biological removal of pharmaceutical active compounds and estrogenic activity in a mesophilic anaerobic osmotic membrane bioreactor treating municipal sewage.

The contamination of water sources by pharmaceutically active compounds (PhACs) and their effect on aquatic communities and human health have become an environmental concern worldwide. Membrane bioreactors (MBRs) are an alternative to improve biological removal of recalcitrant organic compounds from municipal sewage. Their efficiency can be increased by using high retention membranes such as forward osmosis (FO) and membrane distillation (MD).

IL-1R8 silencing improves the anti-tumor function of freshly isolated human NK cells.

The inhibitory receptor interleukin-1 receptor 8 (IL-1R8) has been recently recognized to be expressed also by human natural killer (NK) cells. This study was aimed to design and optimize IL-1R8 silencing conditions in human NK cells to precisely establish the activity of such receptor in these cells. Electroporation of freshly isolated or IL-2-cultured NK cells with small interfering RNA (siRNA), resulted in a marked, even though variable, IL-1R8-silencing.

Prolonged Cardiac Monitoring and Stroke Recurrence: A Meta-analysis.

Background And Objectives: Prolonged poststroke cardiac rhythm monitoring (PCM) reveals a substantial proportion of patients with ischemic stroke (IS) with atrial fibrillation (AF) not detected by conventional rhythm monitoring strategies. We evaluated the association between PCM and the institution of stroke preventive strategies and stroke recurrence.

Methods: We searched MEDLINE and SCOPUS databases to identify studies reporting stroke recurrence rates in patients with history of recent IS or TIA receiving PCM compared with patients receiving conventional cardiac rhythm monitoring.

Toll-like receptor 8 agonists improve NK-cell function primarily targeting CD56CD16 subset.

Background: Toll-like receptors (TLRs) are pattern-recognition sensors mainly expressed in innate immune cells that directly recognize conserved pathogen structures (pathogen-associated molecular patterns-PAMPs). Natural killer (NK) cells have been described to express different endosomal TLRs triggered by RNA and DNA sequences derived from both viruses and bacteria. This study was addressed to establish which endosomal TLR could directly mediate NK activation and function after proper stimuli.

Digenic inheritance of STUB1 variants and TBP polyglutamine expansions explains the incomplete penetrance of SCA17 and SCA48.

Purpose: This study aimed to unravel the genetic factors underlying missing heritability in spinocerebellar ataxia type 17 (SCA17) caused by polyglutamine-encoding CAG/CAA repeat expansions in the TBP gene. Alleles with >49 CAG/CAA repeats are fully penetrant. Most patients, however, carry intermediate TBP alleles that show incomplete penetrance.

A Phase II Study to Evaluate the Safety and Efficacy of Prasinezumab in Early Parkinson's Disease (PASADENA): Rationale, Design, and Baseline Data.

Currently available treatments for Parkinson's disease (PD) do not slow clinical progression nor target alpha-synuclein, a key protein associated with the disease. The study objective was to evaluate the efficacy and safety of prasinezumab, a humanized monoclonal antibody that binds aggregated alpha-synuclein, in individuals with early PD. The PASADENA study is a multicenter, randomized, double-blind, placebo-controlled treatment study.

Actions of the NLRP3 and NLRC4 inflammasomes overlap in bone resorption.

Overwhelming evidence indicates that excessive stimulation of innate immune receptors of the NOD-like receptor (NLR) family causes significant damage to multiple tissues, yet the role of these proteins in bone metabolism is not well known. Here, we studied the interaction between the NLRP3 and NLRC4 inflammasomes in bone homeostasis and disease. We found that loss of NLRP3 or NLRC4 inflammasome attenuated osteoclast differentiation in vitro.

Identifying and Predicting the Goals and Concerns Prioritised by Individuals with Inflammatory Bowel Disease.

Background And Aims: In order to provide high-quality care, providers need to understand their patients' goals and concerns. This study aims to identify and predict the goals and concerns prioritised by patients with inflammatory bowel disease [IBD] in the outpatient setting.

Methods: Mixed-methods analysis was performed to identify the types, frequencies, and predictors of IBD patients' goals and concerns using 4873 surveys collected over 2016-2019 at 25 gastroenterology clinics across the USA participating in the Crohn's & Colitis Foundation's IBD Qorus Learning Health System.

Constitutive activation of NF-κB inducing kinase (NIK) in the mesenchymal lineage using Osterix (Sp7)- or Fibroblast-specific protein 1 (S100a4)-Cre drives spontaneous soft tissue sarcoma.

Aberrant NF-κB signaling fuels tumor growth in multiple human cancer types including both hematologic and solid malignancies. Chronic elevated alternative NF-κB signaling can be modeled in transgenic mice upon activation of a conditional NF-κB-inducing kinase (NIK) allele lacking the regulatory TRAF3 binding domain (NT3). Here, we report that expression of NT3 in the mesenchymal lineage with Osterix (Osx/Sp7)-Cre or Fibroblast-Specific Protein 1 (FSP1)-Cre caused subcutaneous, soft tissue tumors.

Regulation of the Immune System Development by Glucocorticoids and Sex Hormones.

Through the release of hormones, the neuro-endocrine system regulates the immune system function promoting adaptation of the organism to the external environment and to intrinsic physiological changes. Glucocorticoids (GCs) and sex hormones not only regulate immune responses, but also control the hematopoietic stem cell (HSC) differentiation and subsequent maturation of immune cell subsets. During the development of an organism, this regulation has long-term consequences.

Risk Stratification in Primary Care: Value-Based Contributions of Provider Adjudication.

Background: In primary care risk stratification, automated algorithms do not consider the same factors as providers. The process of adjudication, in which providers review and adjust algorithm-derived risk scores, may improve the prediction of adverse outcomes.

Objective: We assessed the patient factors that influenced provider adjudication behavior and evaluated the performance of an adjudicated risk model against a commercial algorithm.

Multi-tissue single-cell analysis deconstructs the complex programs of mouse natural killer and type 1 innate lymphoid cells in tissues and circulation.

Natural killer (NK) cells and type 1 innate lymphoid cells (ILC1s) are heterogenous innate lymphocytes broadly defined in mice as LinNK1.1NKp46 cells that express the transcription factor T-BET and produce interferon-γ. The ILC1 definition primarily stems from studies on liver and small intestinal populations.

Robot-assisted retroperitoneal lymphadenectomy (RPLND): video case report.

Introduction And Objective:: Germ cell tumors account for 90 to 95% of all testicular tumors. Approximately one-half of these cases are seminomas, and the other half constitutes non-seminomatous germ cell tumors (NSGCTs). The standard of care for men with more advanced or disseminated NSGCTs (stage IIB or higher) is to administer chemotherapy.