BTN3A1 governs antitumor responses by coordinating αß and γδ T cells.

Gamma delta (γδ) T cells infiltrate most human tumors, but current immunotherapies fail to exploit their in situ major histocompatibility complex-independent tumoricidal potential. Activation of γδ T cells can be elicited by butyrophilin and butyrophilin-like molecules that are structurally similar to the immunosuppressive B7 family members, yet how they regulate and coordinate αß and γδ T cell responses remains unknown. Here, we report that the butyrophilin BTN3A1 inhibits tumor-reactive αß T cell receptor activation by preventing segregation of N-glycosylated CD45 from the immune synapse. Notably, CD277-specific antibodies elicit coordinated restoration of αß T cell effector activity and BTN2A1-dependent γδ lymphocyte cytotoxicity against BTN3A1+ cancer cells, abrogating malignant progression. Targeting BTN3A1 therefore orchestrates cooperative killing of established tumors by αß and γδ T cells and may present a treatment strategy for tumors resistant to existing immunotherapies.

Prior opioid exposure influences parents' sharing of their children's CYP2D6 research results.

AIM: To determine parents' use of their children's CYP2D6 research result. We hypothesized that perceived utility, likelihood of sharing and actual sharing of results would differ between parents with children previously exposed (cases) or unexposed (controls) to opioids. METHODS: We returned results by phone (baseline). We surveyed parents about perceived utility and likelihood of sharing their child's research result at baseline, and actual sharing at 3 and 12 months. RESULTS: Cases were more likely than controls to agree that they (p = 0.022) and the doctors (p = 0.041) could use the results to care for their child, to report higher likelihood of sharing (p = 0.042) and to actually share results with the child's doctor (p = 0.026). CONCLUSION: Prior opioid exposure influenced perceived clinical utility and sharing behaviors.

Length of Stay, Mortality, Cost, and Perceptions of Care Associated With Transition From an Open to Closed Staffing Model in the Cardiac Intensive Care Unit.

BACKGROUND: Organizational models in the intensive care unit (ICU) have classically been described as either closed or open, depending on the presence or absence of a dedicated ICU team. Although a closed model has been shown to improve patient outcomes in medical and surgical ICUs, the merits of various care models have not been previously explored in the cardiac ICU (CICU) setting. METHODS: From November 2012 to March 2014, data were prospectively collected on all admissions before and after transition from an open to closed CICU at our institution. Baseline clinical variables, illness severity, admission and discharge diagnoses, resource use, and outcomes were recorded. Anonymous surveys were also collected from nursing and resident trainee participants to evaluate the influence of unit structure on perceptions of care. Descriptive statistics were used, and logistic regression modeling was performed to examine the impact of unit structure on mortality. RESULTS: The study consisted of 670 patients, 332 (49.6%) of whom were admitted to the open CICU model and 338 (50.4%) of whom were admitted to the closed model. Neither CICU nor hospital mortality differed between the open and closed units, though length of stay was shorter in the closed CICU. Additionally, nurses and resident trainees reported that the closed CICU allowed for better communication, collaboration, and education. CONCLUSIONS: Although there was no significant impact of unit structure on patient outcomes in this single-center study, the closed CICU model was associated with better perceptions of care.

Hereditary Lysozyme Amyloidosis Variant p.Leu102Ser Associates with Unique Phenotype.

Lysozyme amyloidosis (ALys) is a rare form of hereditary amyloidosis that typically manifests with renal impairment, gastrointestinal (GI) symptoms, and sicca syndrome, whereas cardiac involvement is exceedingly rare and neuropathy has not been reported. Here, we describe a 40-year-old man with renal impairment, cardiac and GI symptoms, and peripheral neuropathy. Renal biopsy specimen analysis revealed amyloidosis with extensive involvement of glomeruli, vessels, and medulla. Amyloid was also detected in the GI tract. Echocardiographic and electrocardiographic findings were consistent with cardiac involvement. Proteomic analysis of Congo red-positive renal and GI amyloid deposits detected abundant lysozyme C protein. DNA sequencing of the lysozyme gene in the patient and his mother detected a heterozygous c.305T>C alteration in exon 3, which causes a leucine to serine substitution at codon 102 (Human Genome Variation Society nomenclature: p.Leu102Ser; legacy designation: L84S). We also detected the mutant peptide in the proband's renal and GI amyloid deposits. PolyPhen analysis predicted that the mutation damages the encoded protein. Molecular dynamics simulations suggested that the pathogenesis of ALys p.Leu102Ser is mediated by shifting the position of the central ß-hairpin coordinated with an antiparallel motion of the C-terminal helix, which may alter the native-state structural ensemble of the molecule, leading to aggregation-prone intermediates.

Mucolipidosis type IV protein TRPML1-dependent lysosome formation.

Lysosomes are dynamic organelles that undergo cycles of fusion and fission with themselves and with other organelles. Following fusion with late endosomes to form hybrid organelles, lysosomes are reformed as discrete organelles. This lysosome reformation or formation is a poorly understood process that has not been systematically analyzed and that lacks known regulators. In this study, we quantitatively define the multiple steps of lysosome formation and identify the first regulator of this process.

Systematic screens for proteins that interact with the mucolipidosis type IV protein TRPML1.

Mucolipidosis type IV is a lysosomal storage disorder resulting from mutations in the MCOLN1 gene, which encodes the endosomal/lysosomal Transient Receptor Potential channel protein mucolipin-1/TRPML1. Cells isolated from Mucolipidosis type IV patients and grown in vitro and in in vivo models of this disease both show several lysosome-associated defects. However, it is still unclear how TRPML1 regulates the transport steps implicated by these defects. Identifying proteins that associate with TRPML1 will facilitate the elucidation of its cellular and biochemical functions. We report here two saturation screens for proteins that interact with TRPML1: one that is based on immunoprecipitation/mass spectrometry and the other using a genetic yeast two-hybrid approach. From these screens, we identified largely non-overlapping proteins, which represent potential TRPML1-interactors., Using additional interaction assays on some of the potential interactors from each screen, we validated some proteins as candidate TRPML1 interactors In addition, our analysis indicates that each of the two screens not only identified some false-positive interactors, as expected from any screen, but also failed to uncover potential TRPML1 interactors. Future studies on the true interactors, first identified in these screens, will help elucidate the structure and function of protein complexes containing TRPML1.

Derlin-dependent retrograde transport from endosomes to the Golgi apparatus.

Cells have to maintain stable plasma membrane protein and lipid compositions under normal conditions and to remodel their plasma membranes in response to stimuli. This maintenance and remodeling require that integral membrane proteins at the plasma membrane that become misfolded, because of the relatively harsher extracellular milieu or carbohydrate and amino acid sequence changes, are degraded. We had previously shown that Derlin proteins, required for quality control mechanisms in the endoplasmic reticulum, also localize to endosomes and function in the degradation of misfolded integral membrane proteins at the plasma membrane. In this study, we show that Derlin proteins physically associate with sorting nexins that function in retrograde membrane transport from endosomes to the Golgi apparatus. Using genetic studies in Caenorhabditis elegans and ricin pulse-chase analyses in murine RAW264.7 macrophages, we show that the Derlin-sorting nexin interaction is physiologically relevant. Our studies suggest that at least some integral membrane proteins that are misfolded at the plasma membrane are retrogradely transported to the Golgi apparatus and ultimately to the endoplasmic reticulum for degradation via resident quality control mechanisms.

Clenbuterol increases lean muscle mass but not endurance in patients with chronic heart failure.

Clenbuterol, a beta(2)-agonist with potent anabolic properties, has been shown to improve skeletal muscle function in healthy subjects, and in high doses, promotes cardiac recovery in patients with left ventricular assist devices. In a small, randomized controlled study, we investigated the effect of clenbuterol on skeletal muscle function, cardiac function, and exercise capacity in patients with chronic heart failure. Clenbuterol was well tolerated and led to a significant increase in both lean mass and the lean/fat ratio. Maximal strength increased significantly with both clenbuterol (27%) and placebo (14%); however, endurance and exercise duration decreased after clenbuterol. Prior data support combining exercise training with clenbuterol to maximize performance, and on-going studies will evaluate this approach.

Information for disasters, information disasters, and disastrous information.

Information is needed to support humanitarian responses in every phase of a disaster. Participants of a multilateral working group convened to examine how best to meet these information needs. Although information systems based on routine reporting of diseases are desirable because they have the potential to identify trends, these systems usually do not deliver on their promise due to inadequate organization and management to support them. To identify organizational and management characteristics likely to be associated with successful information systems in disaster settings, evaluations of the Integrated Disease Surveillance and Response (IDSR) programs in 12 participating countries were reviewed. Characteristics that were mentioned repeatedly in the evaluations as associated with success were grouped into nine categories: (1) human resources management and supervision; (2) political support; (3) strengthened laboratory capacity; (4) communication and feedback (through many mechanisms); (5) infrastructure and resources; (6) system design and capacity; (7) coordination and partnerships with stakeholders; (8) community input; and (9) evaluation. Selected characteristics and issues within each category are discussed. Based on the review of the IDSR evaluations and selected articles in the published literature, recommendations are provided for improving the short- and long-term organization and management of information systems in humanitarian responses associated with disasters. It is suggested that information systems that follow these recommendations are more likely to yield quality information and be sustainable even in disaster settings.