High fat diet-induced obesity is associated with insulin resistance (IR) and other chronic, diet related illnesses, including dementia. Alzheimer disease is the most common form of dementia, and is ...characterized by the presence of amyloid plaques and neurofibrillary tangles in brain. This study was designed to determine whether diet-induced changes in peripheral insulin sensitivity could contribute to alterations in brain insulin signaling and cognitive functions. Six week old, male C57BL/6NHsd mice were randomly assigned a high fat diet (40% energy from fat) with 42g/L liquid sugar (HFS) added to the drinking water or a normal chow diet (12% energy from fat) for 14weeks. Metabolic phenotypes were characterized for energy expenditure, physical activity, and food intake, and glucose and insulin tolerance tests. In addition, we examined the changes in protein expression related to brain insulin signaling and cognitive function. Mice fed HFS exhibited a statistically significant increase in obesity, and lower glucose and insulin tolerance as compared to animals fed the normal chow diet. In brain, HFS elicited IR as evidenced by a significant decrease in tyrosine phosphorylation of insulin receptor and an increase serine phosphorylation of IRS-1. These changes were accompanied by inflammatory (NFκB, JNK) and stress responses (p38 MAPK, CHOP) in whole brain lysate. In addition, HFS mouse brain exhibited biochemical changes related to increased amyloid beta deposition and neurofibrillary tangle formation, and decreased synaptic plasticity. These results suggested changes in insulin sensitivity might contribute to cognitive impairment associated with the HFS diet in mice.
•Consumption of high fat diet and sugary drink (HFS) leads to abnormal metabolic phenotype in mice•Feeding of HFS also leads to impairment of brain insulin signaling linked with neuroinflammation.•Insulin resistant due to HFS associated with biochemical changes in markers related with Alzheimer disease pathology.
OBJECTIVE:HDL (high-density lipoprotein) infusion reduces atherosclerosis in animal models and is being evaluated as a treatment in humans. Studies have shown either anti- or proinflammatory effects ...of HDL in macrophages, and there is no consensus on the underlying mechanisms. Here, we interrogate the effects of HDL on inflammatory gene expression in macrophages.
APPROACH AND RESULTS:We cultured bone marrow–derived macrophages, treated them with reconstituted HDL or HDL isolated from APOA1;Ldlr mice, and challenged them with lipopolysaccharide. Transcriptional profiling showed that HDL exerts a broad anti-inflammatory effect on lipopolysaccharide-induced genes and proinflammatory effect in a subset of genes enriched for chemokines. Cholesterol removal by POPC (1-palmitoyl-2-oleoyl-glycero-3-phosphocholine) liposomes or β-methylcyclodextrin mimicked both pro- and anti-inflammatory effects of HDL, whereas cholesterol loading by POPC/cholesterol-liposomes or acetylated LDL (low-density lipoprotein) before HDL attenuated these effects, indicating that these responses are mediated by cholesterol efflux. While early anti-inflammatory effects reflect reduced TLR (Toll-like receptor) 4 levels, late anti-inflammatory effects are due to reduced IFN (interferon) receptor signaling. Proinflammatory effects occur late and represent a modified endoplasmic reticulum stress response, mediated by IRE1a (inositol-requiring enzyme 1a)/ASK1 (apoptosis signal-regulating kinase 1)/p38 MAPK (p38 mitogen-activated protein kinase) signaling, that occurs under conditions of extreme cholesterol depletion. To investigate the effects of HDL on inflammatory gene expression in myeloid cells in atherosclerotic lesions, we injected reconstituted HDL into Apoe or Ldlr mice fed a Western-type diet. Reconstituted HDL infusions produced anti-inflammatory effects in lesion macrophages without any evidence of proinflammatory effects.
CONCLUSIONS:Reconstituted HDL infusions in hypercholesterolemic atherosclerotic mice produced anti-inflammatory effects in lesion macrophages suggesting a beneficial therapeutic effect of HDL in vivo.
Background
Robotic techniques are routinely used in urological and gynecological procedures; however, their role in general surgical procedures is limited. A robotic technique has been successfully ...adopted for a minimally invasive Heller myotomy procedure for achalasia. This study aims to compare perioperative outcomes following open, laparoscopic, and robotic Heller myotomy.
Methods
This study is a multicenter, retrospective analysis utilizing a large administrative database. The University Health System Consortium (UHC) is an alliance between academic medical centers and affiliate hospitals. The UHC database was accessed using International Classification of Diseases, Ninth Revision, Clinical Modification codes and analyzed.
Results
2,683 patients with achalasia underwent Heller myotomy between October 2007 and June 2011. Myotomy was performed by open surgery (OM) in 418 patients, by laparoscopic approach (LM) in 2,116, and by robotic approach (RM) in 149. Comparison between LM and RM groups demonstrated no significant difference in mortality (0.14 vs. 0.0%;
P
= 1), morbidity (5.19 vs. 4.02%;
P
= 0.7), intensive care unit (ICU) admission (6.62 vs. 3.36%;
P
= 0.12), length of stay (LOS) (2.70 ± 3.87 days vs. 2.42 ± 2.69 days;
P
= 0.34), or 30-day readmission (1.41 vs. 2.84%;
P
= 0.27). However, hospital costs were significantly lower for the LM group (US $7,441 ± 7,897 vs. US $9,415 ± 5,515;
P
= 0.0028). Comparison between OM and RM demonstrated significant lower morbidity (9.08 vs. 4.02%;
P
= 0.02), ICU admission rate (14.01 vs. 3.36%,
P
= 0.0002), and LOS (4.42 ± 5.25 days vs. 2.42 ± 2.69 days;
P
= 0.0001).
Conclusions
The perioperative outcomes are superior in LM and RM groups when compared with OM. The outcomes for the LM and RM group are comparable, with the robotic group having slightly improved results, although with increased costs. We conclude that robotic surgery is equivalent in safety and efficacy to laparoscopic Heller myotomy, and feel that the increased cost should come down as surgeons and manufacturers work together on cost reduction strategies.
This study sought to evaluate surgical outcomes, cost, and opiate utilization of patients who underwent laparoscopic (LC) or robotic cholecystectomy (RC).
The Vizient database was queried for ...patients admitted with mild to moderate severity of illness (SOI) scores who underwent LC or RC from January 2015 through December 2017. Rates of overall complications, postoperative infection, mortality, LOS, cost, and opiate utilization were compared between groups using IBM SPSS v.25.0, α = 0.05.
91,849 patients (LC:N = 89,878; RC:N = 1,971) met the inclusion criteria. Robotic approach was associated with more complications (LC:0.9%, RC:1.7%; p < 0.001), postoperative infections (LC:0.2%, RC:0.4%; p = 0.033) and a higher direct cost (LC:$6782 ± 3421, RC:$9354 ± 5497; p < 0.001). Opiates were prescribed more frequently in the laparoscopic group (LC:98.3%, RC:97.2%; p = 0.002).
The direct cost of RC is significantly higher than LC with no added benefit. Routine use of the robotic platform for cholecystectomy should be discouraged until costs are reduced.
•Cost of robotic cholecystectomy remains significantly higher than laparoscopy.•Robotic approach is associated with increased rate of complications and infection.•Use of the robotic platform does not improve outcomes for patients with obesity.
The Vizient database was queried for patients admitted with mild to moderate severity of illness scores who subsequently underwent laparoscopic or robotic cholecystectomy for biliary disease. Robotic approach was associated with a significantly higher direct cost and slightly increased rates of overall complications and postoperative infection.
RATIONALE:HDL (high-density lipoprotein) may be cardioprotective because it accepts cholesterol from macrophages via the cholesterol transport proteins ABCA1 (ATP-binding cassette transporter A1) and ...ABCG1 (ATP-binding cassette transporter G1). The ABCA1-specific cellular cholesterol efflux capacity (ABCA1 CEC) of HDL strongly and negatively associates with cardiovascular disease risk, but how diabetes mellitus impacts that step is unclear.
OBJECTIVE:To test the hypothesis that HDL’s cholesterol efflux capacity is impaired in subjects with type 2 diabetes mellitus.
METHODS AND RESULTS:We performed a case-control study with 19 subjects with type 2 diabetes mellitus and 20 control subjects. Three sizes of HDL particles, small HDL, medium HDL, and large HDL, were isolated by high-resolution size exclusion chromatography from study subjects. Then we assessed the ABCA1 CEC of equimolar concentrations of particles. Small HDL accounted for almost all of ABCA1 CEC activity of HDL. ABCA1 CEC―but not ABCG1 CEC―of small HDL was lower in the subjects with type 2 diabetes mellitus than the control subjects. Isotope dilution tandem mass spectrometry demonstrated that the concentration of SERPINA1 (serpin family A member 1) in small HDL was also lower in subjects with diabetes mellitus. Enriching small HDL with SERPINA1 enhanced ABCA1 CEC. Structural analysis of SERPINA1 identified 3 amphipathic α-helices clustered in the N-terminal domain of the protein; biochemical analyses demonstrated that SERPINA1 binds phospholipid vesicles.
CONCLUSIONS:The ABCA1 CEC of small HDL is selectively impaired in type 2 diabetes mellitus, likely because of lower levels of SERPINA1. SERPINA1 contains a cluster of amphipathic α-helices that enable apolipoproteins to bind phospholipid and promote ABCA1 activity. Thus, impaired ABCA1 activity of small HDL particles deficient in SERPINA1 could increase cardiovascular disease risk in subjects with diabetes mellitus.
Fetuin-A (Fet-A) is a liver-secreted phosphorylated protein, known to impair insulin signaling, which has been shown to be associated with obesity, insulin resistance, and incident diabetes. Fet-A ...interacts with the insulin-stimulated insulin receptor (IR) and inhibits IR tyrosine kinase activity and glucose uptake. It has been shown that high glucose increases Fet-A expression through the ERK1/2 signaling pathway. However, factors that downregulate Fet-A expression and their potential mechanisms are unclear. We examined the effect of AMP-activated protein kinase (AMPK) on high-glucose induced Fet-A expression in HepG2 cells, Hep3B cells and primary rat hepatocytes. High glucose increased Fet-A and phosphorylated (Ser312) fetuin-A (pFet-A) expression, which are known to impair insulin signaling. AICAR-induced AMPK activation significantly down-regulated high glucose-induced Fet-A expression and secretion of pFet-A while treatment with Compound C (AMPK inhibitor), SB202190 (p38 MAPK inhibitor) or p38 MAPK siRNA transfection prevented AICAR-induced downregulation of Fet-A expression. In addition, activation of p38 MAPK, by anisomycin, decreased the hepatic expression of Fet-A. Further, we our studies have shown that short-term effect of AICAR-treatment on Fet-A expression was mediated by proteosomal degradation, and long-term treatment of AICAR was associated with decrease in hepatic expression of C/EBP beta, an important transcription factor involved in the regulation of Fet-A. Taken together, our studies implicate a critical role for AMPK-p38 MAPK-C/EBPb-ubiquitin-proteosomal axis in the regulation of the expression of hepatic Fet-A.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract Long non-coding RNAs (lncRNAs) represent an emerging layer of cancer biology, contributing to tumor proliferation, invasion, and metastasis. Here, we describe a role for the oncogenic lncRNA ...PCAT-1 in prostate cancer proliferation through cMyc. We find that PCAT-1 –mediated proliferation is dependent on cMyc protein stabilization, and using expression profiling, we observed that cMyc is required for a subset of PCAT-1 –induced expression changes. The PCAT-1 –cMyc relationship is mediated through the post-transcriptional activity of the MYC 3′ untranslated region, and we characterize a role for PCAT-1 in the disruption of MYC -targeting microRNAs. To further elucidate a role for post-transcriptional regulation, we demonstrate that targeting PCAT-1 with miR-3667-3p, which does not target MYC , is able to reverse the stabilization of cMyc by PCAT-1 . This work establishes a basis for the oncogenic role of PCAT-1 in cancer cell proliferation and is the first study to implicate lncRNAs in the regulation of cMyc in prostate cancer.
Metastatic castration-resistant prostate cancer (mCRPC) is the lethal form of the disease. Several recent studies have identified genomic alterations in mCRPC, but the clinical implications of these ...genomic alterations have not been fully elucidated.
To use whole-genome sequencing (WGS) to assess the association between key driver gene alterations and overall survival (OS), and to use whole-transcriptome RNA sequencing to identify genomic drivers of enzalutamide resistance.
We performed survival analyses and gene set enrichment analysis (GSEA) on WGS and RNA sequencing results for a cohort of 101 mCRPC patients.
OS was the clinical endpoint for all univariate and multivariable survival analyses. Candidate drivers of enzalutamide resistance were identified in an unbiased manner, and mutations of the top candidate were further assessed for enrichment among enzalutamide-resistant patients using Fisher's exact test.
Harboring two DNA alterations in RB1 was independently predictive of poor OS (median 14.1 vs 42.0mo; p=0.007) for men with mCRPC. GSEA identified the Wnt/β-catenin pathway as the top differentially modulated pathway among enzalutamide-resistant patients. Furthermore, β-catenin mutations were exclusive to enzalutamide-resistant patients (p=0.01) and independently predictive of poor OS (median 13.6 vs 41.7mo; p=0.025).
The presence of two RB1 DNA alterations identified in our WGS analysis was independently associated with poor OS among men with mCRPC. The Wnt/β-catenin pathway plays an important role in enzalutamide resistance, with differential pathway expression and enrichment of β-catenin mutations in enzalutamide-resistant patients. Moreover, β-catenin mutations were predictive of poor OS in our cohort.
We observed a correlation between genomic findings for biopsy samples from metastases from men with metastatic castration-resistant prostate cancer (mCRPC) and clinical outcomes. This work sheds new light on clinically relevant genomic alterations in mCRPC and provides a roadmap for the development of new personalized treatment regimens in mCRPC.
The presence of two DNA alterations in RB1 is associated with poor overall survival independently of other clinicopathologic factors in metastatic castration-resistant prostate cancer. In addition, Wnt/β-catenin pathway activation and β-catenin mutations are associated with enzalutamide resistance and poor overall survival.
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