Purpose:The aim of this study was to determine the clinical and molecular characteristics of 2,079 patients who underwent hereditary cancer multigene panel testing.Methods:Panels included comprehensive analysis of 14–22 cancer susceptibility genes (BRCA1 and BRCA2 not included), depending on the panel ordered (BreastNext, OvaNext, ColoNext, or CancerNext). Next-generation sequencing and deletion/duplication analyses were performed for all genes except EPCAM (deletion/duplication analysis only). Clinical histories of ColoNext patients harboring mutations in genes with well-established diagnostic criteria were assessed to determine whether diagnostic/testing criteria were met.Results:Positive rates were defined as the proportion of patients with a pathogenic mutation/likely pathogenic variant(s) and were as follows: 7.4% for BreastNext, 7.2% for OvaNext, 9.2% for ColoNext, and 9.6% for CancerNext. Inconclusive results were found in 19.8% of BreastNext, 25.6% of OvaNext, 15.1% of ColoNext, and 23.5% of CancerNext tests. Based on information submitted by clinicians, 30% of ColoNext patients with mutations in genes with well-established diagnostic criteria did not meet corresponding criteria.Conclusion:Our data point to an important role for targeted multigene panels in diagnosing hereditary cancer predisposition, particularly for patients with clinical histories spanning several possible diagnoses and for patients with suspicious clinical histories not meeting diagnostic criteria for a specific hereditary cancer syndrome.

No abstract

Excess triglyceride (TG) accumulation in the liver underlies fatty liver disease, a highly prevalent ailment. TG occurs in the liver sequestered in lipid droplets, the major lipid storage organelle. Lipid droplets are home to the lipid droplet proteins, the most abundant of which are the perilipins (PLINs), encoded by 5 different genes, Plin1 to Plin5. Of the corresponding gene products, PLIN2 is the only constitutive and ubiquitously expressed lipid droplet protein that has been used as a protein marker for lipid droplets. We and others reported that plin2 mice have an ∼60% reduction in TG content, and are protected against fatty liver disease. Here we show that PLIN2 overexpression protects lipid droplets against macroautophagy/autophagy, whereas PLIN2 deficiency enhances autophagy and depletes hepatic TG. The enhanced autophagy in plin2 mice protects against severe ER stress-induced hepatosteatosis and hepatocyte apoptosis. In contrast, hepatic TG depletion resulting from other genetic and pharmacological manipulations has no effect on autophagy. Importantly, PLIN2 deficiency lowers cellular TG content in wild-type mouse embryonic fibroblasts (MEFs) via enhanced autophagy, but does not affect cellular TG content in atg7 MEFs that are devoid of autophagic function. Conversely, adenovirus-shAtg7-mediated hepatic Atg7 knockdown per se does not alter the hepatic TG level, suggesting a more complex regulation in vivo. In sum, PLIN2 guards its own house, the lipid droplet. PLIN2 overexpression protects against autophagy, and its downregulation stimulates TG catabolism via autophagy.

No abstract

Progressive pancreatic β cell failure underlies the transition of impaired glucose tolerance to overt diabetes; endoplasmic reticulum (ER) stress expedites β cell failure in this situation. ER stress can be elicited by lipotoxicity and an increased demand for insulin in diabetes. We previously reported that the lipid droplet protein perilipin 2 (PLIN2) modulates lipid homeostasis in the liver. Here, we show that PLIN2 modulates the unfolded protein response (UPR) and ER stress in pancreatic β cells. PLIN2 expression goes up when β cells are exposed to a lipid load or to chemical ER stress inducers. Downregulation of PLIN2 ameliorates the effects of fatty acid- and chemical-induced ER stress, whereas PLIN2 overexpression exacerbates them. Diabetic Akita mice, which carry a heterozygous C96Y Ins2 mutation, exhibit elevated PLIN2 expression and ER stress in their β cells. Genetic ablation of Plin2 in Akita mice leads to mitigation of ER stress, forestalling β cell apoptosis, partially restoring β cell mass, and ameliorating diabetes. Mechanistic experiments showed that PLIN2 downregulation is associated with enhanced autophagic flux and accelerated ER stress resolution. In sum, we have identified a crucial role for PLIN2 in modulating autophagy, ER stress resolution, and β cell apoptosis and survival.

No abstract

ACP in CF often occurs late in the disease course. Important decisions default to surrogates when opportunities for ACP are missed. Provision of ACP varies significantly among adult CF care programs. Careful evaluation of opportunities to enhance ACP and implementation of recommended approaches may lead to better practices in this important aspect of CF care.

OBJECTIVES: Racial disparities in the United States healthcare system are well described across a variety of clinical settings. The ICU is a clinical environment with a higher acuity and mortality rate, potentially compounding the impact of disparities on patients. We sought to systematically analyze the literature to assess the prevalence of racial disparities in the ICU. DATA SOURCES:We conducted a comprehensive search of PubMed/ MEDLINE, Scopus, CINAHL, and the Cochrane Library. STUDY SELECTION:We identified articles that evaluated racial differences on outcomes among ICU patients in the United States. Two authors independently screened and selected articles for inclusion. DATA EXTRACTION:We dual-extracted study characteristics and outcomes that assessed for disparities in care (e.g., in-hospital mortality, ICU length of stay). Studies were assessed for bias using the Newcastle-Ottawa Scale.DATA SYNTHESIS: Of 1,325 articles screened, 25 articles were included (n = 751,796 patients). Studies demonstrated race-based differences in outcomes, including higher mortality rates for Black patients when compared with White patients. However, when controlling for confounding variables, such as severity of illness and hospital type, mortality differences based on race were no longer observed. Additionally, results revealed that Black patients experienced greater financial impacts during an ICU admission, were less likely to receive early tracheostomy, and were less likely to receive timely antibiotics than White patients. Many studies also observed differences in patients' end-of-life care, including lower rates on the quality of dying, less advanced care planning, and higher intensity of interventions at the end of life for Black patients. CONCLUSIONS:This systematic review found significant differences in the care and outcomes among ICU patients of different races. Mortality differences were largely explained by accompanying demographic and patient factors, highlighting the effect of structural inequalities on racial differences in mortality in the ICU. This systematic review provides evidence that structural inequalities in care persist in the ICU, which contribute to racial disparities in care. Future research should evaluate interventions to address inequality in the ICU.