Multi-omics approach identifies PI3 as a biomarker for disease severity and hyper-keratinization in psoriasis

BACKGROUND: Psoriasis is an immune-mediated inflammatory skin disease. Psoriasis severity evaluation is important for clinicians in the assessment of disease severity and subsequent clinical decision making. However, no objective biomarker is available for accurately evaluating disease severity in psoriasis. OBJECTIVE: To define and compare biomarkers of disease severity and progression in psoriatic skin. METHODS: We performed proteome profiling to study the proteins circulating in the serum from patients with psoriasis, psoriatic arthritis and ankylosing spondylitis, and transcriptome sequencing to investigate the gene expression in skin from the same cohort. We then used machine learning approaches to evaluate different biomarker candidates across several independent cohorts. In order to reveal the cell-type specificity of different biomarkers, we also analyzed a single-cell dataset of skin samples. In-situ staining was applied for the validation of biomarker expression. RESULTS: We identified that the peptidase inhibitor 3 (PI3) was significantly correlated with the corresponding local skin gene expression, and was associated with disease severity. We applied machine learning methods to confirm that PI3 was an effective psoriasis classifier, Finally, we validated PI3 as psoriasis biomarker using in-situ staining and public datasets. Single-cell data and in-situ staining indicated that PI3 was specifically highly expressed in keratinocytes from psoriatic lesions. CONCLUSION: Our results suggest that PI3 may be a psoriasis-specific biomarker for disease severity and hyper-keratinization

Activating Transcription Factor 4 Confers a Multidrug Resistance Phenotype to Gastric Cancer Cells through Transactivation of SIRT1 Expression

BACKGROUND: Multidrug resistance (MDR) in gastric cancer remains a major challenge to clinical treatment. Activating transcription factor 4 (ATF4) is a stress response gene involved in homeostasis and cellular protection. However, the expression and function of ATF4 in gastric cancer MDR remains unknown. In this study, we investigate whether ATF4 play a role in gastric cancer MDR and its potential mechanisms. METHODOLOGY/PRINCIPAL FINDINGS: We demonstrated that ATF4 overexpression confered the MDR phenotype to gastric cancer cells, while knockdown of ATF4 in the MDR variants induced re-sensitization. In this study we also showed that the NAD(+)-dependent histone deacetylase SIRT1 was required for ATF4-induced MDR effect in gastric cancer cells. We demonstrated that ATF4 facilitated MDR in gastric cancer cells through direct binding to the SIRT1 promoter, resulting in SIRT1 up-regulation. Significantly, inhibition of SIRT1 by small interfering RNA (siRNA) or a specific inhibitor (EX-527) reintroduced therapeutic sensitivity. Also, an increased Bcl-2/Bax ratio and MDR1 expression level were found in ATF4-overexpressing cells. CONCLUSIONS/SIGNIFICANCE: We showed that ATF4 had a key role in the regulation of MDR in gastric cancer cells in response to chemotherapy and these findings suggest that targeting ATF4 could relieve therapeutic resistance in gastric cancer

MiR-218 Inhibits Invasion and Metastasis of Gastric Cancer by Targeting the Robo1 Receptor

MicroRNAs play key roles in tumor metastasis. Here, we describe the regulation and function of miR-218 in gastric cancer (GC) metastasis. miR-218 expression is decreased along with the expression of one of its host genes, Slit3 in metastatic GC. However, Robo1, one of several Slit receptors, is negatively regulated by miR-218, thus establishing a negative feedback loop. Decreased miR-218 levels eliminate Robo1 repression, which activates the Slit-Robo1 pathway through the interaction between Robo1 and Slit2, thus triggering tumor metastasis. The restoration of miR-218 suppresses Robo1 expression and inhibits tumor cell invasion and metastasis in vitro and in vivo. Taken together, our results describe a Slit-miR-218-Robo1 regulatory circuit whose disruption may contribute to GC metastasis. Targeting miR-218 may provide a strategy for blocking tumor metastasis

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

The efficacy and safety of different does of intravenous tranexamic acid on blood loss in fresh foot and ankle fractures: a prospective, randomized controlled study

Abstract Background There are a few studies on the effectiveness and safety of intravenous administration of tranexamic acid(TXA) in patients who underwent foot and ankle surgery, especially for preoperative hidden blood loss in patients with freshfoot and ankle fractures. Thus, the aim of this study was to investigate whether intravenous administration of different doses of TXA can effectively reduce perioperative blood loss and blood loss before surgery and to determine its safety. Methods A total of 150 patients with fresh closed foot and ankle fractures from July 2021 to July 2023 were randomly divided into a control group (placebo controlled [PC]), standard-dose group (low-dose group [LD], 1 g/24 h; medium-dose group [MD], 2 g/24 h), and high-dose group (HD, 3 g/24 h; ultrahigh-dose group [UD], 4 g/24 h). After admission, all patients completed hematological examinations as soon as possible and at multiple other time points postsurgery. Results There was a significant difference in the incidence of hidden blood loss before the operation between the TXA group and the control group, and the effect was greater in the overdose groups than in the standard-dose groups. There were significant differences in surgical blood loss (intraoperative and postoperative), postoperative HGB changes, and hidden blood loss among the groups. The TXA groups showed a significant decrease in blood loss compared to that of the control group, and the overdose groups had a more significant effect than the standard-dose groups. A total of 9 patients in the control group had early wound infection or poor healing, while only 1 patient in the other groups had this complication, and the difference among the groups was significant. No patients in any group suffered from late deep wound infection, cardiovascular or cerebrovascular events or symptomatic VTE. Conclusion This is the first study on whether TXA can reduce preoperative hidden blood loss in patients with freshfoot and ankle fractures. In our study, on the one hand, intravenous application of TXA after foot and ankle fractures as soon as possible can reduce preoperative blood loss and postoperative blood loss. On the other hand, TXA can also lower wound complications, and over-doses of TXA are more effective than standard doses. Moreover, overdoses of TXA do not increase the incidence of DVT

Experimental investigations on a cascaded steam-/organic-Rankine-cycle (RC/ORC) system for waste heat recovery (WHR) from diesel engine

A novel cascaded RC/ORC system that comprises a steam Rankine cycle as the high-temperature loop (H-RC) and an organic Rankine cycle as the low-temperature loop (L-ORC) was constructed and experimentally investigated to recover waste heat from exhaust gas of a heavy-duty diesel engine (DE). By monitoring key parameters of the RC/ORC system against time, good system stability and satisfying thermal states of working fluids were observed. Impacts that the engine operations have on this proposed waste-heat-recovery (WHR) system were studied, indicating that waste heat recovered from the gas increases gradually and greatly as the engine load increases, yet decreases slightly as the speed grows. At full loads at speeds lower than 2050 rpm, up to 101.5 kW of waste heat can be abstracted from the gas source, showing a promising heat transfer potential. Besides, observations of key exergy states as well as estimations and comparisons of potential output power were carried out stepwise. Results indicated that up to 12.7 kW of output power could be obtained by the novel RC/ORC system under practical estimations. Comparing to the basic diesel engine, the power increment reaches up to 5.6% by equipping the cascaded RC/ORC system

The Structural Characterization of a Polysaccharide from the Dried Root of <i>Salvia miltiorrhiza</i> and Its Use as a Vaccine Adjuvant to Induce Humoral and Cellular Immune Responses

In order to supplement the research gap concerning Salvia miltiorrhiza polysaccharide extracted from Danshen in NMR analysis, and to clarify its immune enhancement effect as an adjuvant, we isolated and purified SMPD–2, which is composed of nine monosaccharides such as Ara, Gal, and Glc from Danshen. Its weight average molecular weight was 37.30 ± 0.096 KDa. The main chain was mainly composed of →4)-α-D-Galp-(1→, →3,6)-β-D-Glcp-(1→ and a small amount of α-L-Araf-(1→. After the subcutaneous injection of SMPD–2 as an adjuvant to OVA in mice, we found that it enhanced the immune response by activating DCs from lymph nodes, increasing OVA-specific antibody secretion, stimulating spleen lymphocyte activation, and showing good biosafety. In conclusion, SMPD–2 could be a promising candidate for an adjuvant

Design and Modeling of Parallel Two-degree-of-freedom Variable Stiffness Actuator

Abstract In this paper, a new 2-DOF variable stiffness actuator based on a 2-DOF spherical wrist parallel mechanism is proposed. A 2-DOF VSA based on a parallel ball wrist mechanism and a parallel arrangement of leaf spring sets is used. Control its stiffness adjustment, analysis its variable stiffness principle and actuator mechanical structure. The parallel arrangement of the leaf spring groups reduces the mass and volume of the joints, enabling simultaneous adjustment of the stiffness. The analytical formula of the rotational stiffness of the actuator is established according to the geometric nonlinearity of the large deflection of the leaf spring

Medial malleolar window approach for varus-type tibial pilon fractures: a retrospective study

Abstract Purpose Choosing a suitable surgical approach is crucial and challenging for type C pilon fractures. This article aims to explore the clinical efficacy of the medial malleolar window approach for varus-type tibial pilon fractures. Methods A retrospective analysis was conducted on 38 patients with type C varus-type pilon fractures treated between May 2018 and June 2021. In total, 16 cases underwent surgical treatment through the medial malleolar window approach and 22 cases were treated with the traditional anteromedial approach combined with a posterior approach. The operation time, hospitalization time, fracture healing time, the American Orthopedic Foot and Ankle score, Visual Analogue Scale, and complications were recorded to comprehensively evaluate the clinical efficacy of the technique. Fracture reduction quality was evaluated using the criteria proposed by Burwell and Charnley. Results All patients were followed up. No patients presented delayed union or nonunion. Compared with the conventional approach, the medial malleolar window approach had the advantage of better clinical effect recovery and better fracture reduction (P < 0.05). Meanwhile, the medial malleolar window approach had a shorter operation time, although the statistics suggest no significant difference with the control group. No implant exposure or infection occurred. There was good wound healing at two weeks after surgery in all but two cases. Local wound edge necrosis developed in one case in the medial malleolar window approach group, and the wound could not be closed at one stage in another case in the conventional group because of excessive tension, requiring secondary closure. Conclusion The medial malleolar window approach provides excellent exposure to type C pilon fractures, allowing for satisfactory fracture reduction and functional rehabilitation. The medial window approach is recommended for varus-type pilon fractures, which can effectively avoid a posterior incision and reduce the operation time