Senescent cell-derived extracellular vesicles inhibit cancer recurrence by coordinating immune surveillance.

Senescence is a non-proliferative, survival state that cancer cells can enter to escape therapy. In addition to soluble factors, senescence cells secrete extracellular vesicles (EVs), which are important mediators of intercellular communication. To explore the role of senescent cell-derived EVs (senEVs) in inflammatory responses to senescence, we developed an engraftment-based senescence model in wild-type mice and genetically blocked senEV release in vivo, without significantly affecting soluble mediators.

Challenges and Opportunities in Targeting the Complex Pancreatic Tumor Microenvironment.

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related deaths with a 5-year survival rate of 13%. Surgical resection remains the only curative option as systemic therapies offer limited benefit. Poor response to chemotherapy and immunotherapy is due, in part, to the dense stroma and heterogeneous tumor microenvironment (TME).

The polymeric fluoropyrimidine CF10 overcomes limitations of 5-FU in pancreatic ductal adenocarcinoma cells through increased replication stress.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease soon to become the second leading cause of cancer deaths in the US. Beside surgery, current therapies have narrow clinical benefits with systemic toxicities. FOLFIRINOX is the current standard of care, one component of which is 5- Fluorouracil (5-FU), which causes serious gastrointestinal and hematopoietic toxicities and is vulnerable to resistance mechanisms.

Cavitation in blunt impact traumatic brain injury.

Traumatic brain injury (TBI) poses a major public health challenge. No proven therapies for the condition exist so protective equipment that prevents or mitigates these injuries plays a critical role in minimizing the societal burden of this condition. Our ability to optimize protective equipment depends on our capacity to relate the mechanics of head impact events to morbidity and mortality.

Traumatic injury causes selective degeneration and TDP-43 mislocalization in human iPSC-derived -associated ALS/FTD motor neurons.

A hexanucleotide repeat expansion (HRE) in is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, patients with the HRE exhibit a wide disparity in clinical presentation and age of symptom onset suggesting an interplay between genetic background and environmental stressors. Neurotrauma as a result of traumatic brain or spinal cord injury has been shown to increase the risk of ALS/FTD in epidemiological studies.

Bile Acid Metabolism Mediates Cholesterol Homeostasis and Promotes Tumorigenesis in Clear Cell Renal Cell Carcinoma.

Unlabelled: Clear cell renal cell carcinoma (ccRCC) incidence has risen steadily over the last decade. Elevated lipid uptake and storage is required for ccRCC cell viability. As stored cholesterol is the most abundant component in ccRCC intracellular lipid droplets, it may also play an important role in ccRCC cellular homeostasis.

Educational Attainment and Perceived Need for Future ADL Assistance.

The current study examined whether educational attainment was associated with perceived need of assistance with future activities of daily living (ADL) among middle-aged and early older-aged adults in the United States. Data for 54,946 adults aged 40-65 years from the 2011-2014 National Health Interview Survey (NHIS) were analyzed using ordered logistic regression. Adults with more education will on average need less ADL assistance than adults with less education.

Region-Dependent Mechanical Properties of Human Brain Tissue Under Large Deformations Using Inverse Finite Element Modeling.

This study aims to facilitate intracranial simulation of traumatic events by determining the mechanical properties of different anatomical structures of the brain. Our experimental indentation paradigm used fresh, post-operative human tissue, which is highly advantageous in determining mechanical properties without being affected by postmortem time. This study employed an inverse finite element approach coupled with experimental indentation data to characterize mechanical properties of the human hippocampus (CA1, CA3, dentate gyrus), cortex white matter, and cortex grey matter.

Polyurethane Culture Substrates Enable Long-Term Neuron Monoculture in a Human Model of Neurotrauma.

Human induced pluripotent stem cell (hiPSC)-derived cells can reproduce human-specific pathophysiology, patient-specific vulnerability, and gene-environment interactions in neurological disease. Human models of neurotrauma therefore have great potential to advance the field. However, this potential cannot be realized until important biomaterials challenges are addressed.

Targeting the RNA-Binding Protein HuR in Cancer.

The RNA-binding protein human antigen R (HuR) is a well-established regulator of gene expression at the posttranscriptional level. Its dysregulation has been implicated in various human diseases, particularly cancer. In cancer, HuR is considered "active" when it shows increased subcellular localization in the cytoplasm, in addition to its normal nuclear localization.

Postoperative risk of IDH-mutant glioma-associated seizures and their potential management with IDH-mutant inhibitors.

Seizures are a frequent complication of adult-type diffuse gliomas, and are often difficult to control with medications. Gliomas with mutations in isocitrate dehydrogenase 1 or 2 (IDHmut) are more likely than IDH-wild type (IDHwt) gliomas to cause seizures as part of their initial clinical presentation. However, whether IDHmut is also associated with seizures during the remaining disease course, and whether IDHmut inhibitors can reduce seizure risk, are unclear.

Deletion of the mRNA stability factor (HuR) in pancreatic cancer cells disrupts the tumor microenvironment integrity.

Stromal cells promote extensive fibrosis in pancreatic ductal adenocarcinoma (PDAC), which is associated with poor prognosis and therapeutic resistance. We report here for the first time that loss of the RNA-binding protein human antigen R (HuR, ) in PDAC cells leads to reprogramming of the tumor microenvironment. In multiple models, CRISPR deletion of in PDAC cells resulted in a decrease of collagen deposition, accompanied by a decrease of stromal markers (i.

IL-33 mediates Pseudomonas induced airway fibrogenesis and is associated with CLAD.

Background: Long term outcomes of lung transplantation are impacted by the occurrence of chronic lung allograft dysfunction (CLAD). Recent evidence suggests a role for the lung microbiome in the occurrence of CLAD, but the exact mechanisms are not well defined. We hypothesize that the lung microbiome inhibits epithelial autophagic clearance of pro-fibrotic proteins in an IL-33 dependent manner, thereby augmenting fibrogenesis and risk for CLAD.

A Novel 3DNA® Nanocarrier effectively delivers payloads to pancreatic tumors.

Introduction: Standard-of-care systemic chemotherapies for pancreatic ductal adenocarcinoma (PDAC) currently have limited clinical benefits, in addition to causing adverse side effects in many patients. One factor known to contribute to the poor chemotherapy response is the poor drug diffusion into PDAC tumors. Novel treatment methods are therefore drastically needed to improve targeted delivery of treatments.

Reporting Down syndrome on the death certificate for Alzheimer disease/unspecified dementia deaths.

Background: Death certificates are crucial for understanding population health trends including the burden of disease mortality. Accurate reporting of causes of death on these records is necessary in order to implement adequate public health policies and fund disease research. While there is evidence that Alzheimer disease and unspecified dementia are prevalent among people with Down syndrome, a 2014 Centers for Disease Control and Prevention (CDC) rule change instructing that Down syndrome should be reported as the underlying cause of death in instances when death occurred from Alzheimer disease or unspecified dementia threatens the accuracy and the utility of death certificates for this population.

Connected Droplet Shape Analysis for Nanoflow Quantification in Thin Electroosmotic Micropumps and a Tunable Convex Lens Application.

Thin electroosmotic flow (EOF) micropumps can generate flow in confined spaces such as lab-on-a-chip microsystems and implantable drug delivery devices. However, status quo methods for quantifying flow and other important parameters in EOF micropumps depend on microfluidic interconnects or fluorescent particle tracking: methods that can be complex and error-prone. Here, we present a novel connected droplet shape analysis (CDSA) technique that simplifies flow rate and zeta potential quantification in thin EOF micropumps.

COVID-19 mortality burden and comorbidity patterns among decedents with and without intellectual and developmental disability in the US.

Background: While there is ample evidence of increased COVID-19 mortality risk among people with intellectual and developmental disability (IDD), research has not documented whether this higher risk resulted in increased COVID-19 mortality burden in the US or whether comorbidity patterns among COVID-19 deaths are similar or distinct for people with IDD.

Objective: To determine the differences in COVID-19 mortality burden between decedents with and without IDD during the first year of the pandemic.

Methods: This study uses 2020 US death certificate data to compare COVID-19 mortality burden and comorbidity patterns among decedents with and without IDD.

Progress on Designing a Chemical Retinal Prosthesis.

The last major review of progress toward a chemical retinal prosthesis was a decade ago. Many important advancements have been made since then with the aim of producing an implantable device for animal testing. We review that work here discussing the potential advantages a chemical retinal prosthesis may possess, the spatial and temporal resolutions it might provide, the materials from which an implant might be constructed and its likely effectiveness in stimulating the retina in a natural fashion.

Maternal Anxiety Symptoms and Chinese Adolescents' Mental Health During the COVID-19 Pandemic: The Protective Role of Adolescents' Self-Compassion.

The COVID-19 outbreak triggered dramatic changes to family life. Parents, especially mothers, were found to experience more psychological distress during the pandemic, which may have had an impact on their children's mental health. The primary goal of this study was to examine the potential protective role of adolescents' self-compassion in the relationship between maternal anxiety and adolescents' mental health during the COVID-19 pandemic.

Factors associated with the reporting of Down syndrome as the underlying cause of death on US death certificates.

Background: Efforts aimed at preventing premature mortality for people with Down syndrome are hindered by the practice of reporting disability as the underlying cause of death. Prior research suggests this form of diagnostic overshadowing may be the result of increased uncertainty surrounding the death.

Methods: This study uses bivariable analysis and multivariable logistic regression models to investigate associations between sociodemographic characteristics, comorbidities, and death context and processing characteristics with the reporting of Down syndrome as the underlying cause of death in 2005-2017 US Multiple Cause of Death data files.

Region-Dependent Viscoelastic Properties of Human Brain Tissue Under Large Deformations.

This study characterizes the mechanical properties of human brain tissue resected during the course of surgery under multistep indentation loading up to 30% strain. The experimental characterization using fresh, post-operative, human brain tissue is highly advantageous since postmortem times can affect its biomechanical behavior. Although the quasilinear theory of viscoelasticity (QLV) approach has been widely used to model brain tissue mechanical properties, our analysis concluded that the linear viscoelastic approach provided a better fit to the experimental data overall.

Biofidelic dynamic compression of human cortical spheroids reproduces neurotrauma phenotypes.

Fundamental questions about patient heterogeneity and human-specific pathophysiology currently obstruct progress towards a therapy for traumatic brain injury (TBI). Human in vitro models have the potential to address these questions. Three-dimensional spheroidal cell culture protocols for human-origin neural cells have several important advantages over their two-dimensional monolayer counterparts.

Mesenchymal Lineage Heterogeneity Underlies Nonredundant Functions of Pancreatic Cancer-Associated Fibroblasts.

Cancer-associated fibroblast (CAF) heterogeneity is increasingly appreciated, but the origins and functions of distinct CAF subtypes remain poorly understood. The abundant and transcriptionally diverse CAF population in pancreatic ductal adenocarcinoma (PDAC) is thought to arise from a common cell of origin, pancreatic stellate cells (PSC), with diversification resulting from cytokine and growth factor gradients within the tumor microenvironment. Here we analyzed the differentiation and function of PSCs during tumor progression .