Finite Element Analysis of Perforated Casing High Stress Area Compressed Volume Coefficient

In view of the problem that perforation completion result in casing damage, from the perspective of perforating casing overall stress, on the basis of plate and shell opening mechanics model, establishing the cloth of spiral casing perforation holes finite element mechanics model, reflecting the area around the hole stress change after the casing perforation clearly. Comparing different perforation parameters before and after perforating casing under the condition of high stress area volume ratio, concluding the high stress area compressed volume coefficient, Analysis of the differential pressure under the condition of normal production, the influence of different perforation parameters (bore diameter, shooting density, phase angle) to the perforated casing compressed volume coefficient. The results of the analysis shows that different perforation parameters on the perforated casing all affect the compressed volume coefficient. According to the characteristics of the different effect law to different parameters, providing the optimization scheme of perforating parameters that reducing the volume coefficient of perforated casing high stress area. On the whole to reduce perforated casing high stress area compressed volume under normal production conditions.Key words: Perforation; Casing failure; Finite element method; High stress area; Compressed volume coefficien

The relationship between BSP mRNA expression and 25(OH)D/OPG in peripheral blood of newly diagnosed T2DM patients with different bone mass

Introduction: The objective of the study was to detect the levels of osteoprotegerin (OPG) and 25-hydroxyvitamin D [25(OH)D], as well as the expression of bone sialoprotein (BSP) mRNA, in the peripheral blood of patients with newly diagnosed type 2 diabetes mellitus (T2DM) under different bone mass conditions, and to explore its role and significance in the development process of T2DM combined with osteoporosis (OP). Material and methods: A total of 225 patients hospitalised in the Endocrinology Department and General Department from May 2017 to May 2018 were enrolled and categorised into five groups: the pure T2DM group (group A, 45 patients), the bone mass reduction group (group B, 45 patients), the T2DM + bone mass reduction group (group C, 45 patients), the OP group (group D, 45 patients), and the T2DM + OP group (group E, 45 patients); meanwhile, age-matched healthy subjects undergoing physical examination in our hospital were collected as the normal control group (group NC, 45 cases). Logistic regression analysis was used to analyse the influencing factors of bone mass in patients with T2DM. Results: Compared with group B, the expression levels of glycated haemoglobin (HbA1c), 25(OH)D, N-terminal propeptide of type I procollagen (PINP), fasting plasma glucose (FPG), fasting plasma insulin (FINS), high-density lipoprotein cholesterol (HDL-C), and BSP mRNA were significantly increased while OPG and b-collagen degradation products (b-CTX) were significantly decreased in group A. Conclusion: The expression of BSP mRNA and the decrease of 25(OH)D and OPG in peripheral blood may participate in the development of diabetes and osteoporosis

Nivolumab Versus Sorafenib as First-Line Therapy for Advanced Hepatocellular Carcinoma: A Cost-Effectiveness Analysis

Objective: Nivolumab improves overall survival (OS) and is associated with fewer adverse events than sorafenib for the treatment of advanced hepatocellular carcinoma (aHCC). However, the cost-effectiveness of nivolumab compared with sorafenib treatment for aHCC remains unclear. This study evaluated the cost-effectiveness of nivolumab and sorafenib in the treatment of aHCC.Materials and methods: A partitioned survival model that included three mutually exclusive health states was used to evaluate the cost-effectiveness of nivolumab and sorafenib for treating aHCC. The clinical characteristics and outcomes of the patients in the model were obtained from the CheckMate 459. We performed deterministic one-way sensitivity and probabilistic sensitivity analyses to evaluate the robustness of the model. Subgroup analyses were also performed. Costs, life-years, quality-adjusted life-years (QALYs), incremental cost-effectiveness ratio (ICER), incremental net health benefits (INHB), and incremental net monetary benefits (INMB) were measured.Results: The base case analysis showed that compared with sorafenib, treatment with nivolumab was associated with an increment of 0.50 (2.45 vs. 1.95) life-years and an increment of 0.32 (1.59 vs. 1.27) QALYs, as well as a $69,762 increase in cost per patient. The ICER was$220,864/QALY. The INHB and INMB were −0.15 QALYs and −$22,362 at a willingness-to-pay (WTP) threshold of$150,000/QALY, respectively. The probabilistic sensitivity analysis demonstrated that the probability of nivolumab being cost-effective was only 10.38% at a WTP threshold of $150,000/QALY. The model was most sensitive to the costs of sorafenib and nivolumab according to the one-way sensitivity analysis. When the price of sorafenib exceeded$0.93/mg or nivolumab was less than 24.23/mg, nivolumab was more cost-effective. The subgroup analysis illustrated that the probability of cost-effectiveness was >50% in the Barcelona Clinic Liver Cancer Stage B subgroups for nivolumab at a WTP threshold of 150,000/QALY. This study also showed that the probability of cost-effectiveness was <50% in most subgroups.Conclusion: Nivolumab was not cost-effective, although it was associated with better clinical benefit and a favorable safety profile for the treatment of aHCC compared with sorafenib from the third-party payer perspective in the United States. If the price of nivolumab is substantially reduced, favorable cost-effectiveness can be achieved among patients with aHCC

Golgi-associated LC3 lipidation requires V-ATPase in noncanonical autophagy

Autophagy is an evolutionarily conserved catabolic process by which cells degrade intracellular proteins and organelles in the lysosomes. Canonical autophagy requires all autophagy proteins (ATGs), whereas noncanonical autophagy is activated by diverse agents in which some of the essential autophagy proteins are dispensable. How noncanonical autophagy is induced and/or inhibited is still largely unclear. In this study, we demonstrated that AMDE-1, a recently identified chemical that can induce canonical autophagy, was able to elicit noncanonical autophagy that is independent of the ULK1 (unc-51-like kinase 1) complex and the Beclin1 complex. AMDE-1-induced noncanonical autophagy could be specifically suppressed by various V-ATPase (vacuolar-type H(+)-ATPase) inhibitors, but not by disturbance of the lysosome function or the intracellular ion redistribution. Similar findings were applicable to a diverse group of stimuli that can induce noncanonical autophagy in a FIP200-independent manner. AMDE-1-induced LC3 lipidation was colocalized with the Golgi complex, and was inhibited by the disturbance of Golgi complex. The integrity of the Golgi complex was also required for multiple other agents to stimulate noncanonical LC3 lipidation. These results suggest that the Golgi complex may serve as a membrane platform for noncanonical autophagy where V-ATPase is a key player. V-ATPase inhibitors could be useful tools for studying noncanonical autophagy

Identification and characterization of four immune-related signatures in keloid

A keloid is a fibroproliferative disorder of unknown etiopathogenesis that requires ill-defined treatment. Existing evidence indicates that the immune system plays an important role in the occurrence and development of keloid. However, there is still a lack of research on the immune-related signatures of keloid. Here we identified immune-related signatures in keloid and explored their pathological mechanisms. Transcriptomic datasets (GSE7890, GSE92566, and GSE44270) of keloid and normal skin tissues were obtained from the Gene Expression Omnibus database. The overlap of differentially expressed genes and immune-related genes was considered as differentially expressed immune-related genes (DEIGs). Functional analysis, expression, and distribution were applied to explore the function and characteristics of DEIGs, and the expression of these DEIGs in keloid and normal skin tissues was verified by immunohistochemistry. Finally, we conducted interactive network analysis and immune infiltration analysis to determine the therapeutic potential and immune correlation. We identified four DEIGs (LGR5, PTN, JAG1, and DKK1). In these datasets, only GSE7890 met the screening criteria. In the GSE7890 dataset, DKK1 and PTN were downregulated in keloid, whereas JAG1 and LGR5 were upregulated in keloid. In addition, we obtained the same conclusion through immunohistochemistry. Functional analysis indicated that these four DEIGs were mainly involved in stem cell, cell cycle, UV response, and therapy resistance. Through interactive network analysis, we found that these DEIGs were associated with drugs currently used to treat keloid, such as hydrocortisone, androstanolone, irinotecan, oxaliplatin, BHQ-880, and lecoleucovorin. Finally, many immune cells, including CD8+ T cells, resting memory CD4+ T cells, and M1 macrophages, were obtained by immune infiltration analysis. In conclusion, we identified four immune signaling molecules associated with keloid (LGR5, PTN, JAG1, and DKK1). These immune-related signaling molecules may be important modules in the pathogenesis of keloid. Additionally, we developed novel therapeutic targets for the treatment of this challenging disease

Leveraging 16S rRNA Microbiome Sequencing Data to Identify Bacterial Signatures for Irritable Bowel Syndrome

Irritable bowel syndrome (IBS) is a chronic gastrointestinal disorder characterized by abdominal pain or discomfort. Previous studies have illustrated that the gut microbiota might play a critical role in IBS, but the conclusions of these studies, based on various methods, were almost impossible to compare, and reproducible microorganism signatures were still in question. To cope with this problem, previously published 16S rRNA gene sequencing data from 439 fecal samples, including 253 IBS samples and 186 control samples, were collected and processed with a uniform bioinformatic pipeline. Although we found no significant differences in community structures between IBS and healthy controls at the amplicon sequence variants (ASV) level, machine learning (ML) approaches enabled us to discriminate IBS from healthy controls at genus level. Linear discriminant analysis effect size (LEfSe) analysis was subsequently used to seek out 97 biomarkers across all studies. Then, we quantified the standardized mean difference (SMDs) for all significant genera identified by LEfSe and ML approaches. Pooled results showed that the SMDs of nine genera had statistical significance, in which the abundance of Lachnoclostridium, Dorea, Erysipelatoclostridium, Prevotella 9, and Clostridium sensu stricto 1 in IBS were higher, while the dominant abundance genera of healthy controls were Ruminococcaceae UCG-005, Holdemanella, Coprococcus 2, and Eubacterium coprostanoligenes group. In summary, based on six published studies, this study identified nine new microbiome biomarkers of IBS, which might be a basis for understanding the key gut microbes associated with IBS, and could be used as potential targets for microbiome-based diagnostics and therapeutics

Impact of the Location of CpG Methylation within the GSTP1 Gene on Its Specificity as a DNA Marker for Hepatocellular Carcinoma

Hypermethylation of the glutathione S-transferase π 1 (GSTP1) gene promoter region has been reported to be a potential biomarker to distinguish hepatocellular carcinoma (HCC) from other liver diseases. However, reports regarding how specific a marker it is have ranged from 100% to 0%. We hypothesized that, to a large extent, the variation of specificity depends on the location of the CpG sites analyzed. To test this hypothesis, we compared the methylation status of the GSTP1 promoter region of the DNA isolated from HCC, cirrhosis, hepatitis, and normal liver tissues by bisulfite–PCR sequencing. We found that the 5′ region of the position −48 nt from the transcription start site of the GSTP1 gene is selectively methylated in HCC, whereas the 3′ region is methylated in all liver tissues examined, including normal liver and the HCC tissue. Interestingly, when DNA derived from fetal liver and 11 nonhepatic normal tissue was also examined by bisulfite-PCR sequencing, we found that methylation of the 3′ region of the promoter appeared to be liver-specific. A methylation-specific PCR assay targeting the 5′ region of the promoter was developed and used to quantify the methylated GSTP1 gene in various diseased liver tissues including HCC. When we used an assay targeting the 3′ region, we found that the methylation of the 5′-end of the GSTP1 promoter was significantly more specific than that of the 3′-end (97.1% vs. 60%, p<0.0001 by Fisher's exact test) for distinguishing HCC (n = 120) from hepatitis (n = 35) and cirrhosis (n = 35). Encouragingly, 33.8% of the AFP-negative HCC contained the methylated GSTP1 gene. This study clearly demonstrates the importance of the location of CpG site methylation for HCC specificity and how liver-specific DNA methylation should be considered when an epigenetic DNA marker is studied for detection of HCC