Mechanism- and Immune Landscape-Based Ranking of Therapeutic Responsiveness of 22 Major Human Cancers to Next Generation Anti-CTLA-4 Antibodies.

Background: CTLA-4 was the first immune checkpoint targeted for cancer therapy and the first target validated by the FDA (Food and Drug Administration) after approval of the anti-CTLA-4 antibody, Ipilimumab. However, clinical response rates to anti-CTLA-4 antibodies are lower while the rates of immunotherapy-related adverse events (irAE) are higher than with anti-PD-1 antibodies. As a result, the effort to target CTLA-4 for cancer immunotherapy has stagnated.

Topical Trabodenoson Is Neuroprotective in a Rodent Model of Anterior Ischemic Optic Neuropathy (rNAION).

Purpose: Nonarteritic anterior ischemic optic neuropathy (NAION) is the leading cause of sudden optic nerve-related vision loss currently without effective treatment. We evaluated the neuroprotective potential of ocular (topical) delivery of trabodenoson, a selective A receptor mimetic, in a rodent model of NAION (rNAION).

Methods: Daily topical delivery of 3% trabodenoson or vehicle administered in both eyes 3 days prior to rNAION induction and for 21 days post induction.

Therapeutic compounds targeting Lipid II for antibacterial purposes.

Resistance against commonly used antibiotics has emerged in all bacterial pathogens. In fact, there is no antibiotic currently in clinical use against which resistance has not been reported. In particular, rapidly increasing urbanization in developing nations are sites of major concern.

CHAMP: A cluster randomized-control trial to prevent obesity in child care centers.

Foundational elements of lifelong health are formed during the preschool years. Child care attendance has nearly doubled in the past 5 years making child care centers an ideal setting to establish healthy habits that prevent pediatric obesity. Despite the promising evidence of efficacy of child care-based obesity prevention interventions, limited attention has been directed to criteria needed for implementation at scale.

Hijacking antibody-induced CTLA-4 lysosomal degradation for safer and more effective cancer immunotherapy.

It remains unclear why the clinically used anti-CTLA-4 antibodies, popularly called checkpoint inhibitors, have severe immunotherapy-related adverse effects (irAEs) and yet suboptimal cancer immunotherapeutic effects (CITE). Here we report that while irAE-prone Ipilimumab and TremeIgG1 rapidly direct cell surface CTLA-4 for lysosomal degradation, the non-irAE-prone antibodies we generated, HL12 or HL32, dissociate from CTLA-4 after endocytosis and allow CTLA-4 recycling to cell surface by the LRBA-dependent mechanism. Disrupting CTLA-4 recycling results in robust CTLA-4 downregulation by all anti-CTLA-4 antibodies and confers toxicity to a non-irAE-prone anti-CTLA-4 mAb.

Toddler Bedtime Routines and Associations With Nighttime Sleep Duration and Maternal and Household Factors.

Study Objectives: The aims of this study were to examine (1) relationships among implementing a bedtime routine, nighttime awakenings, and nighttime sleep duration in toddlers from low-income, minority families and (2) differences in maternal and household characteristics between mothers who did versus those who did not implement a nightly bedtime routine for their toddler.

Methods: Data were collected from mothers of toddlers on maternal and household characteristics and toddler sleep, measured using the Children's HealthWatch Survey and the Extended Brief Infant Sleep Questionnaire (BISQ). A path analysis model was tested to investigate whether nighttime awakenings mediated the relation between implementing a bedtime routine and toddlers' nighttime sleep duration.

Optimization of a small-molecule Lipid II binder.

Lipid II is an essential precursor of bacterial cell wall biosynthesis and an attractive target for antibiotics. Lipid II is comprised of specialized lipid (bactoprenol) linked to a hydrophilic head group consisting of a peptidoglycan subunit (N-acetylglucosamine (GlcNAc)-N-acetylmuramic acid (MurNAc) disaccharide coupled to a short pentapeptide moiety) via a pyrophosphate. We previously identified a (E)-2,4-bis(4-bromophenyl)-6-(4-(dimethylamino)styryl)pyrylium boron tetrafluoride salt, termed 6jc48-1, that interacts with the MurNAc moiety, the phosphate cage and the isoprenyl tail of Lipid II.

Pleiotropic Anti-Infective Effects of Defensin-Derived Antimicrobial Compounds.

We identified low-molecular weight compounds derived from the antimicrobial peptide human neutrophil peptide-1 that bind to Lipid II, an essential precursor of bacterial cell wall biosynthesis. These compounds act as antibacterials on multiple biosynthesis pathways with specificity against gram-positive organisms. Here, we have tested a small subset of our most promising leads against the bacterium and sporozoites of , an intracellular protozoan parasite that causes intestinal disease in poultry.

Mechanosensing and Mechanoregulation of Endothelial Cell Functions.

Vascular endothelial cells (ECs) form a semiselective barrier for macromolecules and cell elements regulated by dynamic interactions between cytoskeletal elements and cell adhesion complexes. ECs also participate in many other vital processes including innate immune reactions, vascular repair, secretion, and metabolism of bioactive molecules. Moreover, vascular ECs represent a unique cell type exposed to continuous, time-dependent mechanical forces: different patterns of shear stress imposed by blood flow in macrovasculature and by rolling blood cells in the microvasculature; circumferential cyclic stretch experienced by the arterial vascular bed caused by heart propulsions; mechanical stretch of lung microvascular endothelium at different magnitudes due to spontaneous respiration or mechanical ventilation in critically ill patients.

Eighteen-Year Trends in the Prevalence of, and Health Care Use for, Noncancer Pain in the United States: Data from the Medical Expenditure Panel Survey.

We used data from the nationally representative Medical Expenditure Panel Survey to determine the 18-year trends in the overall rates of noncancer pain prevalence and pain-related interference, as well as in health care use attributable directly to pain management. The proportion of adults reporting painful health condition(s) increased from 32.9% (99.

Effects of Cigarette Smoking and Clozapine Treatment on 20-Year All-Cause & Cardiovascular Mortality in Schizophrenia.

To estimate 20-year mortality risk in people with schizophrenia treated with second-generation antipsychotics (SGA) and examine the effects of cigarette smoking on mortality. Of the 1199 individuals with schizophrenia in the study, estimated 20-year all-cause mortality risk by Kaplan Meier Curve was 30% and leading causes of death included 27% cardiovascular disease, 13% cancer, 12% non-HIV infection, 5% respiratory causes, 20% other causes and 18% had unknown cause of death. For all-cause mortality, we found that white race and male sex were significant risk factors (HR = 1.

Construction and next-generation sequencing analysis of a large phage-displayed V single-domain antibody library from six naïve nurse sharks.

Shark new antigen receptor variable domain (V) antibodies can bind restricted epitopes that may be inaccessible to conventional antibodies. Here, we developed a library construction method based on polymerase chain reaction (PCR)-Extension Assembly and Self-Ligation (named "EASeL") to construct a large V antibody library with a size of 1.2 × 10 from six naïve adult nurse sharks ().

Possible Contribution of Wnt-Responsive Chondroprogenitors to the Postnatal Murine Growth Plate.

Active cell proliferation and turnover in the growth plate is essential for embryonic and postnatal bone growth. We performed a lineage tracing of Wnt/β-catenin signaling responsive cells (Wnt-responsive cells) using Axin2 ;Rosa26ZsGreen mice and found a novel cell population that resides in the outermost layer of the growth plate facing the Ranvier's groove (RG; the perichondrium adjacent to growth plate). These Wnt-responsive cells rapidly expanded and contributed to formation of the outer growth plate from the neonatal to the growing stage but stopped expanding at the young adult stage when bone longitudinal growth ceases.

How Does an Anti-CTLA-4 Antibody Promote Cancer Immunity?

Anti-CTLA-4 antibodies can induce lasting protection for some melanoma patients. However, their therapeutic potential is limited by significant immunotherapy-related adverse effects (irAE). Here, we argue that the therapeutic effect may be based on an agonist activity that is fundamentally distinct, and can be therapeutically differentiated, from the antagonist activity responsible for irAE.

Independent and Combined Effects of Chronic HIV-Infection and Tobacco Smoking on Brain Microstructure.

HIV-infected individuals (HIV+) have 2-3 times higher prevalence of tobacco smoking than the general U.S. population.

Cortisol reactivity and weight gain among adolescents who vary in prenatal drug exposure.

Objective: Low inhibitory control is linked with weight gain among youth. Inhibitory problems are associated with disruption to the hypothalamic-pituitary-adrenal axis cortisol response. Increased cortisol predicts appetite and weight gain (though may be gender specific).

Clay-induced DNA breaks as a path for genetic diversity, antibiotic resistance, and asbestos carcinogenesis.

Natural clays and synthetic nanofibres can have a severe impact on human health. After several decades of research, the molecular mechanism of how asbestos induces cancer is not well understood. Different fibres, including asbestos, can penetrate cell membranes and introduce foreign DNA in bacterial and eukaryotic cells.

Cell adhesion properties of human defensins.

Effector peptides of innate immunity play an important role in host defense. They act directly by inactivating microbes but also link innate to adaptive immunity. A variety of innate immune functions has been described for these peptides, including chemoattraction and cytokine release.

Neutralization of Pseudomonas auruginosa Exotoxin A by human neutrophil peptide 1.

Pseudomonas aeruginosa produces a large number of virulence factors, including the extracellular protein, Exotoxin A (ETA). Human Neutrophil Peptide 1 (HNP1) neutralizes the Exotoxin A. HNP1 belongs to the family of α-defensins, small effector peptides of the innate immune system that combat against microbial infections.

BMI and disordered eating in urban, African American, adolescent girls: The mediating role of body dissatisfaction.

Objective: This study examined the mediating role of body dissatisfaction between Body Mass Index (BMI) and subsequent disordered eating (e.g. dieting and restricting/purging) among early adolescent African American girls.

Imaging Analysis of the Neuromuscular Junction in Dystrophic Muscle.

Duchenne muscular dystrophy (DMD), caused by the absence of the protein dystrophin, is characterized as a neuromuscular disease in which muscle weakness, increased susceptibility to muscle injury, and inadequate repair appear to underlie the pathology. Considerable attention has been dedicated to studying muscle fiber damage, but there is little information to determine if damage from contraction-induced injury also occurs at or near the nerve terminal axon. Interestingly, both human patients and the mouse model for DMD (the mdx mouse) present fragmented neuromuscular junction (NMJ) morphology.