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Tisagenlecleucel demonstrated high response rates and a manageable safety profile in adults with relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL) in the JULIET trial. However, lack of response and chimeric antigen receptor (CAR) T-cell exhaustion were observed in patients with programmed cell death protein 1 (PD-1) overexpression. Hence, pembrolizumab, a PD-1 inhibitor, was hypothesized to improve efficacy and cellular expansion of CAR T-cells in vivo. Here, we report the final analysis of the PORTIA trial in adult patients with r/r DLBCL who had ≥2 prior lines of therapy and had an Eastern Cooperative Oncology Group performance status of ≤1. Patients received 1 tisagenlecleucel infusion on day 1. Pembrolizumab (200 mg) was given every 21 days, for up to 6 doses. Three cohorts initiated pembrolizumab on days 15 (n = 4), 8 (n = 4), or –1 (n = 4). Safety, efficacy, cellular kinetics, and biomarker analyses were included. Tisagenlecleucel plus pembrolizumab was feasible and showed a manageable safety profile, without dose-limiting toxicities. Emerging efficacy with tisagenlecleucel was observed when pembrolizumab was given the day before tisagenlecleucel; however, the limited patient sample and short follow-up do not allow for definitive conclusions. Adding pembrolizumab to tisagenlecleucel did not augment the cellular expansion of tisagenlecleucel but delayed peak expansion if given the day before tisagenlecleucel (NCT03630159).

Objective. Uterine corpus endometrial carcinoma (UCEC) is a frequent epithelial cancer in females. The rate of UCEC occurrence increases year by year and the age is getting younger and younger, which requires more active treatments to improve its prognosis. Ferroptosis is a kind of regulatory cell death that relies on iron and may be triggered by sorafenib, which has been elucidated in several cancers, but the mechanism of ferroptosis-related genes in UCEC has yet to be fully defined and will need more investigation. Methods. The mRNA expression profiles and accompanying clinical data of UCEC patients included in this research were obtained from a publicly available database. We subsequently classified the patients into experimental and training sets. Next, utilizing the least absolute shrinkage and selection operator (LASSO) Cox regression model, we established the multigene features of the TCGA experimental set and verified them in the validation set. Results. Per the findings of our investigation, the TCGA experimental set cohort had four differentially expressed genes (DEGs) that were linked to overall survival (OS). An analysis was conducted using univariate Cox regression (with all variables corrected for P < 0.05 ). To stratify the patients into two distinct categories, high- and low-risk, a diagnostic model premised on the identified four genes was formulated. In contrast with the low-risk population, the high-risk category exhibited a considerably lower OS ( P < 0.0001 ). The findings of the multivariate Cox regression analysis illustrated that the risk score independently served as a predictor of OS (HR > 1, P < 0.01 ). The predictive capability of the model was verified by ROC curve analysis. Immune-related pathway enrichment was found using functional analysis, which illustrated that the two risk groups had significantly different immunological statuses. Conclusions. A unique model of genes linked to ferroptosis has the potential to be a treatment option for UCEC and can be utilized for the prognostic prediction of the disease.

Jie Zhao,1,2 Teng Zhang,2,3 Zhe Deng,1,2 Xia Han,1,2 Tao Ma,2,3,&ast; Keliang Xie1,2,&ast; 1Department of Critical Care Medicine, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China; 2Tianjin Medical University, Tianjin, People’s Republic of China; 3Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Tao Ma, Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Tianjin, 300052, People’s Republic of China, Tel +86 13702172328, Email taoma@tmu.edu.cn Keliang Xie, Department of Critical Care Medicine, Tianjin Medical University General Hospital, 154 Anshan Road, Tianjin, 300052, People’s Republic of China, Tel +86 15332112099, Email xiekeliang2009@hotmail.comPurpose: Intra-abdominal infection is considered the second most common cause of sepsis and results in localized or diffused inflammation of the peritoneum. The main treatment for abdominal sepsis is an emergency laparotomy for source control. However, surgical trauma also causes inflammation, and patients become susceptible to postoperative complications. Therefore, it is necessary to identify biomarkers that can be used to distinguish sepsis from abdominal infection. This prospective study investigated whether cytokine levels in the peritoneum could predict complications and indicate severity of sepsis following emergency laparotomy.Methods: We prospectively observed 97 patients with abdominal infection admitted to the Intensive Care Unit (ICU). After emergency laparotomy,SEPSIS-3 criteria were used for the diagnosis of sepsis or septic shock. Blood and peritoneal fluid samples were drawn at postoperative admission to the ICU and cytokine concentrations were measured by flow cytometry.Results: Fifty-eight postoperative patients were enrolled. We found significant elevations in the peritoneal concentrations of IL-1β, IL-6, TNF-α, IL-17, and IL-2 in patients with sepsis or septic shock compared to the patients without sepsis after surgery. Positive correlations between levels of these peritoneal cytokines with APACHE II scores were found: IL-6, in particular, had the highest correlation coefficient of 0.833. Meanwhile, IL-10 in blood, MCP-1 and IL-8 in both blood and peritoneum were simultaneously increased in patients with sepsis and septic shock, and also positively correlated with disease severity.Conclusion: The cytokine storm that occurs in the abdominal cavity after emergency laparotomy may be the main mechanism leading to sepsis. It may be valuable to measure IL-1β, IL-6, TNF-α,IL-17, IL-2, MCP-1, and IL-8 in the peritoneal fluid, combined with serum IL-10, MCP-1 and IL-8, in a panel of cytokines, to assess the severity of sepsis and predict mortality from abdominal infection after emergency laparotomy.Keywords: abdominal infection, emergency laparotomy, peritoneal cytokine, cytokine storm

Periconception folic acid supplementation has been suggested to protect against congenital heart disease (CHD), but the association between maternal red blood cell (RBC) folate, the gold-standard biomarker of folate exposure, and subsequent offspring CHD risk is lacking.To quantify the association between periconception maternal RBC folate and offspring CHD risk.Prospective, nested, case-control study and 1-sample Mendelian randomization. (ClinicalTrials.gov: NCT02737644).29 maternity institutions in 12 districts of Greater Shanghai, China.All 197 mothers of offspring with CHD and 788 individually matched mothers of unaffected offspring from the SPCC (Shanghai Preconception Cohort).Maternal RBC folate was measured before or at early pregnancy. Odds ratios [ORs] were estimated using conditional logistic regression after adjustment for covariates. Mendelian randomization was done using the methylenetetrahydrofolate reductase (Case patients had lower median maternal RBC folate concentrations than control participants (714 nmol/L [interquartile range, 482 to 1008 nmol/L] vs. 788 nmol/L [557 to 1094 nmol/L]). Maternal RBC folate concentrations were inversely associated with offspring CHD (adjusted OR per 100 nmol/L, 0.93 [95% CI, 0.89 to 0.99]). The adjusted OR for mothers with periconception RBC folate of 906 nmol/L or more (vs.906 nmol/L) was 0.61 (CI, 0.40 to 0.93). Mendelian randomization showed that each 100-nmol increase in maternal RBC folate concentrations was significantly associated with reduced offspring CHD risk (OR, 0.75 [CI, 0.61 to 0.92]).Potential confounding due to unmeasured covariates in the nested case-control study.Higher maternal RBC folate is associated with reduced offspring CHD risk. For primary CHD prevention, higher target RBC folate levels than currently recommended for neural tube defect prevention may be needed and warrant further study.National Key Research and Development Program of China, National Natural Science Foundation of China, China Postdoctoral Science Foundation, and Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences.

Jiequn Huang,1 Changzhi Liu,1 Zhujiang Zhou,1 Han Xia,2 Zhensheng Zhu,2 Jianhai Lu,1 Jingcheng Lin,1 Zhen Chen,1 Qimei Ye,1 Liuer Zuo1 1Department of Intensive Care Unit, Shunde Hospital, Southern Medical University (The First People’s Hospital of Shunde Foshan), Foshan, Guangdong, People’s Republic of China; 2Department of Scientific Affairs, Hugobiotech Co, Ltd, Beijing, People’s Republic of ChinaCorrespondence: Liuer Zuo, Department of Intensive Care Unit, Shunde Hospital, Southern Medical University (The First People’s Hospital of Shunde, Foshan), Foshan, Guangdong, People’s Republic of China, Email 13500276597@163.comBackground: Pneumonia infected by Chlamydia abortus (C. abortus) is rare, especially complicated with severe acute respiratory distress syndrome (ARDS) and multiple organ dysfunction syndrome (MODS).Case Presentation: We presented the clinical details of a 44-year-old male who was diagnosed with C. abortus pneumonia, which rapidly progressed and ultimately led to ARDS, sepsis and MODS. Although he was initially diagnosed with pneumonia upon admission, no pathogenic bacteria were detected in sputum by conventional tests. Empirical intravenous infusion of meropenem and moxifloxacin was administered, but unfortunately, his condition deteriorated rapidly, especially respiratory status. On Day 2 after extracorporeal membrane oxygenation (ECMO) initiation, metagenomic next-generation sequencing (mNGS) was performed on the patient’s bronchoalveolar lavage fluid, which indicated an infection with C. abortus. The patient’s antimicrobial therapy was adjusted to oral doxycycline (0.1g every 12h), intravenous azithromycin (0.5g every day), and imipenem and cilastatin sodium (1g every 6h). The patient’s condition improved clinically and biologically. However, the patient was discharged due to financial reasons and unfortunately passed away eight hours later.Conclusion: Infections with C. abortus can result in severe ARDS and serious visceral complications which necessitate prompt diagnosis and active intervention by clinicians. The case highlights the significance of mNGS as an essential diagnostic tool for uncommon pathogens. Tetracyclines, macrolides or their combinations are effective choices for treatment of C. abortus pneumonia. Further study is needed to explore the transmission routes of C. abortus pneumonia and establish precise guidelines for antibiotic treatment.Keywords: Chlamydia abortus, ECMO, pneumonia, acute respiratory distress syndrome, metagenomic next-generation sequencing

Resistance to chemotherapeutic drugs is a significant problem in the treatment of colorectal cancer, resulting in low response rates and decreased survival. Recent studies have shown that shikonin, a naphthoquinone derivative, promotes apoptosis in colon cancer cells and cisplatin-resistant ovarian cells, raising the possibility that this compound may be effective in drug-resistant colorectal cancer. The aim of this study was to characterize the molecular mechanisms underpinning shikonin-induced apoptosis, with a focus on endoplasmic reticulum (ER) stress, in a 5-fluorouracil-resistant colorectal cancer cell line, SNU-C5/5-FUR. Our results showed that shikonin significantly increased the proportion of sub-G1 cells and DNA fragmentation and that shikonin-induced apoptosis is mediated by mitochondrial Ca2+ accumulation. Shikonin treatment also increased the expression of ER-related proteins, such as glucose regulatory protein 78 (GRP78), phospho-protein kinase RNA-like ER kinase (PERK), phospho-eukaryotic initiation factor 2 (eIF2α), phospho-phosphoinositol-requiring protein-1 (IRE1), spliced X-box-binding protein-1 (XBP-1), cleaved caspase-12, and C/EBP-homologous protein (CHOP). In addition, siRNA-mediated knockdown of CHOP attenuated shikonininduced apoptosis, as did the ER stress inhibitor TUDCA. These data suggest that ER stress is a key factor mediating the cytotoxic effect of shikonin in SNU-C5/5-FUR cells. Our findings provide an evidence for a mechanism in which ER stress leads to apoptosis in shikonin-treated SNU-C5/5-FUR cells. Our study provides evidence to support further investigations on shikonin as a therapeutic option for 5-fluorouracil-resistant colorectal cancer.

Supplementary Data from Next-Generation Sequencing of Minimal Residual Disease for Predicting Relapse after Tisagenlecleucel in Children and Young Adults with Acute Lymphoblastic Leukemia

We assessed minimal residual disease (MRD) detection and B-cell aplasia after tisagenlecleucel therapy for acute lymphoblastic leukemia (ALL) to define biomarkers predictive of relapse (N = 143). Next-generation sequencing (NGS) MRD detection >0 in bone marrow (BM) was highly associated with relapse. B-cell recovery [signifying loss of functional chimeric antigen receptor (CAR) T cells] within the first year of treatment was associated with a hazard ratio (HR) for relapse of 4.5 [95% confidence interval (CI), 2.03–9.97; P < 0.001]. Multivariate analysis at day 28 showed independent associations of BMNGS-MRD >0 (HR = 4.87; 95% CI, 2.18–10.8; P < 0.001) and B-cell recovery (HR = 3.33; 95% CI, 1.44–7.69; P = 0.005) with relapse. By 3 months, the BMNGS-MRD HR increased to 12 (95% CI, 2.87–50; P < 0.001), whereas B-cell recovery was not independently predictive (HR = 1.27; 95% CI, 0.33–4.79; P = 0.7). Relapses occurring with persistence of B-cell aplasia were largely CD19− (23/25: 88%). Detectable BMNGS-MRD reliably predicts risk with sufficient time to consider approaches to relapse prevention such as hematopoietic cell transplantation (HCT) or second CAR-T cell infusion.Significance:Detectable disease by BMNGS-MRD with or without B-cell aplasia is highly predictive of relapse after tisagenlecleucel therapy for ALL. Clonotypic rearrangements used to follow NGS-MRD did not change after loss of CD19 or lineage switch. High-risk patients identified by these biomarkers may benefit from HCT or investigational cell therapies.See related commentary by Ghorashian and Bartram, p. 2.This article is highlighted in the In This Issue feature, p. 1

Figure S1. Peak analyses of Twist1 ChIP-Seq Data Sets. (A) Heat map view of signals observed in the presence of Twist1. (B) Density graph of the Twist1 peak locations in relation to the nearest transcriptional start sites (TSS). The x-axis represents the distance from the peak center to the nearest TSS, where zero is the position of the TSS. The y-axis represents the proportion of detected bindings that are located within each distance interval. (C) Twist1 ChIP-seq peak density on the Cul2.

Figure S6. The Twist1 and Vimentin expression in HCC. (A) Twist1 was positive correlated with Vimentin. (B) The co-expression of Twist1 and Vimentin presented a shorter survival time. The median survival times were 12.5 month and 62.5 month in Twist1/Vimentin positive and negative groups, respectively.

Figure S2. The relationship between circ-10720 expression and patients parameters in HCC. (A) The circ-10720 expression in carbohydrate antigen 199 (CA-199), smoking, drinking negative and positive groups, in female and male groups and whether circ-10720 expression is associated with the origin of bile duct carcinoma (AFP- CA199+). (B) The relationship between circ-10720 expression and enzymes related to liver function (LDH, ALP, ALT, AST). (C) The relationship between circ-10720 expression and albumin (ALB), albumin/ globulin (A/G), carbohydrate antigen 125 (CA-125) and age.

Table S1．The plasmids information. Table S2．The primers of overexpressed vectors and siRNA. Table S3．The primers of RT-PCR. Table S4．Clinical characteristics of the patients used for developing PDTX models. Table S5．The sequences of circRNAs probe for FISH.

Figure S4. Gene expression profile analysis by GSEA and GO established the differential expression under circ-10720 overexpression. (A) GSEA plots for gene sets in PLC-PRF-5 cells overexpressing circ-10720 or control vectors. (B) Statistical analysis of up-regulated biological processes, molecular function, and cellular component of PLC-PRF-5 cells after circ-10720 overexpression. (C) Up-regulated genes associated with growth factor activity and wound healing in circ-10720 overexpressed PLC-PRF-5 cells were analyzed.

Figure S3. The bioinformatic prediction of circ-10720-miRNAs, miRNA-Vimentin binding site. (A)The bioinformatic prediction (circInteractome datebase) of the putative binding sites of circ-10720 with miRNAs and mutated each miRNA target site of the circ-10720 sequence. (B)The bioinformatic prediction (microRNA datebase) of the putative binding sites of Vimentin 3'-UTR with miR-1246, miR-578, miR-490-5p and mutated miRNA sequence. (C) Expression level of miR-1246, miR-578, and miR-490-5p in human normal tissues and hepatocellular carcinoma tissues.

Figure S5. Proteomic analysis by GSEA and GO analysis assay established the differential expression under circ-10720 overexpression. (A) GSEA plots for the gene sets in PLC-PRF-5 cells overexpressed circ-10720 or control vectors. (B) Statistical analysis of the up-regulated biological processes, molecular function and cellular component of PLC-PRF-5 cells after circ-10720 overexpression. (C) Up-regulated genes associated with intracellular transport, invadopodia proteins, TGF-β receptor signaling pathways and so on in circ-10720 overexpressed PLC-PRF-5 cells was analyzed.

Twist is a critical epithelial–mesenchymal transition (EMT)–inducing transcription factor that increases expression of vimentin. How Twist1 regulates this expression remains unclear. Here, we report that Twist1 regulates Cullin2 (Cul2) circular RNA to increase expression of vimentin in EMT. Twist1 bound the Cul2 promoter to activate its transcription and to selectively promote expression of Cul2 circular RNA (circ-10720), but not mRNA. circ-10720 positively correlated with Twist1, tumor malignance, and poor prognosis in hepatocellular carcinoma (HCC). Twist1 promoted vimentin expression by increasing levels of circ-10720, which can absorb miRNAs that target vimentin. circ-10720 knockdown counteracted the tumor-promoting activity of Twist1 in vitro and in patient-derived xenograft and diethylnitrosamine-induced TetOn-Twist1 transgenic mouse HCC models. These data unveil a mechanism by which Twist1 regulates vimentin during EMT. They also provide potential therapeutic targets for HCC treatment and provide new insight for circular RNA (circRNA)-based diagnostic and therapeutic strategies.Significance: A circRNA-based mechanism drives Twist1-mediated regulation of vimentin during EMT and provides potential therapeutic targets for treatment of HCC.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/15/4150/F1.large.jpg. Cancer Res; 78(15); 4150–62. ©2018 AACR.

Figure S8. Kaplan-Meier survival analysis the relationship between survival time of multiple tumors and Twist1 expression. (A) Kaplan-Meier survival analysis of Kaplan-Meier plotter for the relationship between survival time of breast, gastric, ovarian and lung cancer and their expression of Twist1. (B) The relationship between survival time of 75 cases HCC and the Twist1 expression.

Figure S7. The formation and sequences of circ-10720 in mice. (A)Schematic diagram of the formation of circRNA-10720 in mice. (B) The sequence alignment of circRNA-10720 in human (Query 1) and mice (Sbjct 1).

Supplementary Figures 1-8 from The Mechanisms of Differential Sensitivity to an Insulin-like Growth Factor-1 Receptor Inhibitor (BMS-536924) and Rationale for Combining with EGFR/HER2 Inhibitors

Supplementary Tables 1-4 from The Mechanisms of Differential Sensitivity to an Insulin-like Growth Factor-1 Receptor Inhibitor (BMS-536924) and Rationale for Combining with EGFR/HER2 Inhibitors

Supplementary Information and Figures 1-3 from Identification of Candidate Molecular Markers Predicting Sensitivity in Solid Tumors to Dasatinib: Rationale for Patient Selection

Craniofacial morphogenesis requires complex interactions involving different tissues, signaling pathways, secreted factors and organelles. The details of these interactions remain elusive. In this study, we have analyzed the molecular mechanisms and homeostatic cellular activities governing soft palate development to improve regenerative strategies for individuals with cleft palate. We have identified canonical Wnt signaling as a key signaling pathway primarily active in cranial neural crest (CNC)-derived mesenchymal cells surrounding soft palatal myogenic cells. Using Osr2-Cre;β-cateninfl/fl mice, we show that Wnt signaling is indispensable for mesenchymal cell proliferation and subsequently for myogenesis through mediating ciliogenesis. Specifically, we have identified that Wnt signaling directly regulates expression of the ciliary gene Ttll3. Impaired ciliary disassembly leads to differentiation defects in mesenchymal cells and indirectly disrupts myogenesis through decreased expression of Dlk1, a mesenchymal cell-derived pro-myogenesis factor. Moreover, we show that siRNA-mediated reduction of Ttll3 expression partly rescues mesenchymal cell proliferation and myogenesis in the palatal explant cultures from Osr2-Cre;β-cateninfl/fl embryos. This study highlights the role of Wnt signaling in palatogenesis through the control of ciliary homeostasis, which establishes a new mechanism for Wnt-regulated craniofacial morphogenesis.

Venom systems are ideal models to study genetic regulatory mechanisms that underpin evolutionary novelty. Snake venom glands are thought to share a common origin, but there are major distinctions between venom toxins from the medically significant snake families Elapidae and Viperidae, and toxin gene regulation in elapids is largely unexplored. Here, we used high-throughput RNA-sequencing to profile gene expression and microRNAs between active (milked) and resting (unmilked) venom glands in an elapid (Eastern Brown Snake,Pseudonaja textilis), in addition to comparative genomics, to identifycis- andtrans- acting regulation of venom production in an elapid in comparison to viperids (Crotalus viridisandC. tigris). Although there is conservation in high-level mechanistic pathways regulating venom production, there are histone methylation, transcription factor, and microRNA regulatory differences between these two snake families. Histone methyltransferases (KMT2A, KMT2C and KMT2D) and transcription factor (TF) specificity protein 1 (Sp1) were highly upregulated in the milked elapid venom gland, whereas nuclear factor I (NFI) TFs were upregulated after viperid venom milking. Sp1 and NFIcis-regulatory elements were common to toxin gene promoter regions, but many unique elements were also present between elapid and viperid toxins. microRNA profiles were distinctive between milked and unmilked venom glands for both snake families, and microRNAs were predicted to target different toxin transcripts. Our comparative transcriptomic and genomic analyses between toxin genes and isoforms in elapid and viperid snakes suggests independent toxin evolution between these two snake families, demonstrating multiple toxin genes and regulatory mechanisms converged to underpin a highly venomous phenotype.

A new coordination polymer {[Cd(BIPA)(DCPS)](H2O)} n (1) was constructed with bis(4-(1H-imidazole-1-yl)phenyl)amine and 4,4′-sulfonyldibenzoate ligands. The complex 1 features (BIPA–Cd–BIPA) n and (DCPS–Cd–DCPS) n helical chains in a 3D architecture assembled via hydrogen bonds. A spectroscopic study of complex 1 in the crystalline state showed an intense red-shifted photoluminescence as compared with the ligands BIPA and DCPS2−, which can be attributed to the ligand-to-metal charge transfer (LMCT) transitions.

This paper aims to propose an evidential reasoning (ER) rule considering the parameter uncertainty. As the essential parameters, the evidence weight and reliability make the ER rule constitute a generalized reasoning framework. Theoretically, the weight is affected by subjective cognition, while the reliability mainly reflects objective variation. However, most of the recent researches have focused on the quantitative calculation methods, which makes the differences in the property of the two parameters ignored. In this work, a relatively different idea from previous studies is provided, in which multi-source uncertainty of parameters is fully considered. On the one hand, the weight is profiled by interval variable with lower and upper bounds. On the other hand, the reliability is modeled by random variable with probability distribution function (PDF). Then, a unified inference model for evidence aggregation is developed based on the inference process of the ER rule. In addition, some basic properties of the model are clearly presented to illustrate the rationality of parameter uncertainty. Finally, a practical example is given to show the potential applications of the proposed model.

The application of tube-filled concrete composite columns is becoming more and more popular. The traditional tube-filled column is easy to rust and expensive to maintain, which leads to the practical need of replacing high-strength aluminum alloy. 7A04 aluminum alloy has high strength and strong corrosion resistance, which is more in line with the material requirements of modern building structures. In view of this, four groups of 7A04 aluminum alloy tube concrete short columns were tested under axial compression, and the corresponding ABAQUS finite element simulation was established. The influence of tube thickness and concrete strength grade on compressive strength, ductility, transverse deformation coefficient, and improvement coefficient of strong concrete strength of composite column is considered in this paper. The results show that the failure mode of composite short columns is central uplift or shear failure. The tube thickness of high-strength aluminum tube has a great influence on the strength of specimens, and the ductility of composite columns decreases with the decrease of the collar coefficient. The finite element model can well reflect the development trend of the load-strain curve, and the formula of composite column bearing capacity proposed by regression analysis can well predict the strength of 7A04 aluminum alloy tubular concrete short column. The research results have a certain reference significance for the structural design of high strength aluminum concrete-filled columns.

The long noncoding RNA DARS-AS1 was aberrantly expressed and participated in several human cancer progressions, whereas whether DARS-AS1 is involved in human gastric cancer remains unclear. This study aimed to investigate the influence of DARS-AS1 on gastric cancer progression and explore the potential regulatory network of DARS-AS1/miR-330-3p/NAT10. The expression levels of DARS-AS1, miR-330-3p, and NAT10 were measured by quantitative real-time polymerase chain reaction. The CCK-8 assay and Transwell assay were used to determine the cell viability, migration, and invasion capacities, respectively. The target association between miR-330-3p and DARS-AS1 or NAT10 was confirmed using a luciferase reporter assay. In result, DARS-AS1 levels were elevated in tumor tissues and associated with shorter overall survival in patients with gastric cancer. Knockdown of DARS-AS1 could hamper cell viability, migration, and invasion in gastric cancer cells. DARS-AS1 acts as a competitive endogenous RNA to regulate the NAT10 expression by sponging miR-330-3p in gastric cancer cells. In conclusion, DARS-AS1 was elevated in gastric cancer, and DARS-AS1/miR-330-3p/NAT10 signaling offered some new horizons for predicting prognosis and a novel therapeutic method for the treatment of gastric cancer.

The regulation of the hydrophilic–hydrophobic balance of polymers has an important influence on their aggregation behavior in aqueous solution, their adhesion properties on the substrate surface, and the applications of the modified surfaces.

The interfacial charge transfer (CT) that plays an important role in enhancing the photoelectric conversion efficiency of dye-sensitized solar cells (DSSCs) has not always been fully explored. Here, TiO2@N719@Ag DSSCs system was constructed, and the CT processes have been monitored by surface-enhanced Raman scattering (SERS) spectra. Meanwhile, it is well known that as one of the most common external stimulis, high pressure can increase the free carrier density of TiO2 NPs and cause the band gap to narrow. In the high pressure SERS experiment, we observed a significant enhancement of N719 dye in the TiO2@N719@Ag system up to 2.48 GPa, which is consistent with the variation trend of charge transfer degree (ρCT). It is indicated that band gap changes will strongly affect the CT process, further influence the SERS signal intensity (or ρCT), and thus increase the CT probability of DSSCs. Futhermore, the decoration of Ag NPs in the TiO2@N719@Ag DSSCs system can introduce localized surface plasmon resonance (LSPR), enhance the light trapping ability and offer additional CT pathways. Importantly, it is possible to improve the photoelectric conversion performance of DSSCs via high pressure method and the introducing of Ag NPs. Finally, in order to observe the CT process of DSSCs more clearly, the models describing the CT mechanism have been proposed. SERS spectroscopy is expected to be a promising technique for the exploration of the interfacial CT behavior in DSSCs devices, which may further broaden the thoughts of improvement of efficiency of cells.

In this paper, the effects of the sulfur vacancy (VS) distribution in 2H–MoS2 monolayer on the H2 evolution mechanism and activity are researched by density functional theory (DFT) calculations. The calculation results reveal that the H2 generation on VS follows the Volmer-Heyrovsky mechanism with the Heyrovsky reaction as the rate determined step (RDS) with an energy barrier of 18.5 kcal/mol. When two VS are separated by one S atom, the H2 evolution on VS remains the Heyrovsky-step-determined Volmer-Heyrovsky mechanism and the RDS energy barrier increases to 20.0 kcal/mol. Removing adjacent S of VS causes that the Tafel-step-determined Volmer-Tafel mechanism works for HER and the barrier of RDS increases to 21.4 kcal/mol. Though the barriers of RDS ascend when the concentration of VS is enhanced by these two strategies, the Tafel step can take place at a lower potential and more VS are exposed. Therefore, two adjacent or next-near VS may obtain better H2 generation performance. Three adjacent or spaced out VS by one S may be less favorable for HER.

Mesenchymal stem cells (MSCs) reside in microenvironments, referred to as niches, which provide structural support and molecular signals. Sensory nerves are niche components in the homeostasis of tissues such as skin, bone marrow and hematopoietic system. However, how the sensory nerve affects the behavior of MSCs remains largely unknown. Here we show that the sensory nerve is vital for mesenchymal tissue homeostasis and maintenance of MSCs in the continuously growing adult mouse incisor. Loss of sensory innervation leads to mesenchymal disorder and a decrease in MSCs. Mechanistically, FGF1 from the sensory nerve directly acts on MSCs by binding to FGFR1 and activates the mTOR/autophagy axis to sustain MSCs. Modulation of mTOR/autophagy restores the MSCs and rescues the mesenchymal tissue disorder of Fgfr1 mutant mice. Collectively, our study provides insights into the role of sensory nerves in the regulation of MSC homeostasis and the mechanism governing it.

Background: Meteorological factors and air pollutants are believed to be associated with cardiovascular disease. Ischemic heart disease (IHD) is a major public health issue worldwide. Few studies have investigated the associations among meteorological factors, air pollutants and IHD daily hospital admissions in Lanzhou, China. Methods: We conducted a distributed lag non-linear model (DLNM) on the basis of five years data, aiming at disentangling the impact of meteorological factors and air pollutants on IHD hospital admissions. All IHD daily hospital admissions recorded from January 1, 2015 and December 31, 2019 were obtained from three hospitals in Lanzhou, China. Daily air pollutant concentrations and meteorological data were synchronously collected from Gansu Meteorological Administration and Lanzhou Environmental Protection Administration. Stratified analyses were performed by sex and two age-groups. Results: A total of 23555 IHD hospital admissions were recorded, of which 10477 admissions were for coronary artery disease (CAD), 13078 admissions were for acute coronary syndrome (ACS). Our results showed that there was a non-linear (J-shaped) relationship between temperature and IHD hospital admissions. The number of IHD hospital admissions were positively correlated with NO2, O3, humidity and pressure, indicating an increased risk of hospital admissions for IHD under NO2, O3, humidity and pressure exposure. Meanwhile, both extremely low (-12ºC) and high (30ºC) temperature reduced IHD hospital admissions, but the harmful effect increased with the lag time in Lanzhou, China, while the cold effect was more pronounced and long-lasting than the heat effect. Subgroup analysis demonstrated that the risk on CAD hospital admissions increased significantly in female and Conclusion: Our findings added to the growing evidence regarding the potential impact of meteorological factors, air pollutants on policymaking from the perspective of hospital management efficiency.

Grain sorghum has been a significant contributor to global food security since the prehistoric period and may contribute even more to the security of both food and energy in the future. Globally, precise management techniques are crucial for increasing grain sorghum productivity. In China, with diverse ecological types, variety introduction occasionally occurs across ecological zones. However, few information is available on the effect of ecological type on genotype performance and how plant spacing configuration influences grain yield in various ecological zones. Hence, a series of two-year field experiments were conducted in 2020 and 2021 in four ecological zones of China, from the northeast to the southwest. The experiments included six widely adapted sorghum varieties under six plant spacing configurations (two row spacing modes: equidistant row spacing (60 cm) mode and wide (80 cm)-narrow (40 cm) row spacing mode; three in-row plant spacings: 10 cm, 15 cm, and 20 cm). Our results indicated that ecological type, variety, and plant spacing configuration had a significant effect on sorghum yield. Ecological type contributed the highest proportion to the yield variance (49.8%), followed by variety (8.3%), while plant spacing configuration contributed 1.8%. Sorghum growth duration was highly influenced by the ecological type, accounting for 87.2% of its total variance, whereas plant height was mainly affected by genotype, which contributed 81.6% of the total variance. All test varieties, developed in the south or north, can reach maturity within 94-108 d, just before fall sowing in central China. Generally, sorghum growth duration becomes longer when a variety is introduced from south to north. A late-maturing variety, developed in the spring sowing and late-maturing regions, possibly could not reach maturity in the early-maturing region. The row spacing modes had no significant affect on sorghum yield, but the equal-row spacing mode consistently caused higher yields with only one exception; this might imply that equal-row spacing mode was more advantageous for boosting sorghum yield potential. In contrast, decreasing in-row plant spacing showed significant positive linear associations with sorghum grain yield in most cases. In addition, these results demonstrated that sorghum is a widely adapted crop and enables success in variety introduction across ecological zones.

Purpose Methods and materials Results Conclusion Personal information and conflict of interest References, Purpose: Our aim in this study is to evaluate the diagnostic performance of quantitative parameters derived from DLCT for the differentiation of benign and malignant breast...

Supplementary Material 1

Large language models have unlocked strong multi-task capabilities from reading instructive prompts. However, recent studies have shown that existing large models still have difficulty with information extraction tasks. For example, gpt-3.5-turbo achieved an F1 score of 18.22 on the Ontonotes dataset, which is significantly lower than the state-of-the-art performance. In this paper, we propose InstructUIE, a unified information extraction framework based on instruction tuning, which can uniformly model various information extraction tasks and capture the inter-task dependency. To validate the proposed method, we introduce IE INSTRUCTIONS, a benchmark of 32 diverse information extraction datasets in a unified text-to-text format with expert-written instructions. Experimental results demonstrate that our method achieves comparable performance to Bert in supervised settings and significantly outperforms the state-of-the-art and gpt3.5 in zero-shot settings.

Purpose Methods and materials Results Conclusion Personal information and conflict of interest References, Purpose: We aim to evaluate the ability of quantitative parameters from the SDCT for distinguishing between metastatic and non-metastatic sentinel lymph nodes in breast...

We assessed minimal residual disease (MRD) detection and B-cell aplasia after tisagenlecleucel therapy for acute lymphoblastic leukemia (ALL) to define biomarkers predictive of relapse (N = 143). Next-generation sequencing (NGS) MRD detection >0 in bone marrow (BM) was highly associated with relapse. B-cell recovery [signifying loss of functional chimeric antigen receptor (CAR) T cells] within the first year of treatment was associated with a hazard ratio (HR) for relapse of 4.5 [95% confidence interval (CI), 2.03–9.97; P < 0.001]. Multivariate analysis at day 28 showed independent associations of BMNGS-MRD >0 (HR = 4.87; 95% CI, 2.18–10.8; P < 0.001) and B-cell recovery (HR = 3.33; 95% CI, 1.44–7.69; P = 0.005) with relapse. By 3 months, the BMNGS-MRD HR increased to 12 (95% CI, 2.87–50; P < 0.001), whereas B-cell recovery was not independently predictive (HR = 1.27; 95% CI, 0.33–4.79; P = 0.7). Relapses occurring with persistence of B-cell aplasia were largely CD19− (23/25: 88%). Detectable BMNGS-MRD reliably predicts risk with sufficient time to consider approaches to relapse prevention such as hematopoietic cell transplantation (HCT) or second CAR-T cell infusion. Significance: Detectable disease by BMNGS-MRD with or without B-cell aplasia is highly predictive of relapse after tisagenlecleucel therapy for ALL. Clonotypic rearrangements used to follow NGS-MRD did not change after loss of CD19 or lineage switch. High-risk patients identified by these biomarkers may benefit from HCT or investigational cell therapies. See related commentary by Ghorashian and Bartram, p. 2. This article is highlighted in the In This Issue feature, p. 1

Using survey data on Chinese multinational enterprises (MNEs), we examine the effect of home-government diplomatic support on Chinese firms’ overseas performance. The findings indicate that the level of diplomatic support offered by the home government has a positive association with the overseas performance of Chinese MNEs. Strong political relations between China and the host country can further boost the effect of home-country diplomatic support on the subsidiary performance of these firms. Our study helps to resolve the puzzle concerning why emerging market MNEs tend to operate in countries where the political conditions are risky. State capitalism plays a key role in enabling emerging market MNEs to compete in overseas markets where strong political relations between a firm’s home government and the host country are in place.

Pain relief by vibrotactile touch is a common human experience. Previous neurophysiological investigations of its underlying mechanism in animals focused on spinal circuits, while human studies suggested the involvement of supraspinal pathways. Here, we examine the role of primary somatosensory cortex (S1) in touch-induced mechanical and heat analgesia. We found that, in mice, vibrotactile reafferent signals from self-generated whisking significantly reduce facial nociception, which is abolished by specifically blocking touch transmission from thalamus to the barrel cortex (S1B). Using a signal separation algorithm that can decompose calcium signals into sensory-evoked, whisking, or face-wiping responses, we found that the presence of whisking altered nociceptive signal processing in S1B neurons. Analysis of S1B population dynamics revealed that whisking pushes the transition of the neural state induced by noxious stimuli toward the outcome of non-nocifensive actions. Thus, S1B integrates facial tactile and noxious signals to enable touch-mediated analgesia.

As key components of antifouling material surfaces, the design and screening of polymer molecules grafted on the substrate are critical. However, current experimental and computational models still retain an empirical flavor due to the complex structure of polymers. Here, we report a simple and general strategy that enables multi-scale design and screening of easily synthesized functional polymer molecules to address this challenge. Specifically, the required functions of the antifouling material are decomposed and assigned to different modules of the polymer molecules. By designing different modules, a novel bio-inspired polymer with three zwitterionic poly (sulfobetaine methacrylate) (PSBMA) chains, three catechol (DOPA) anchors (tri-DOPA-PSBMA), and a tris(2-aminoethyl) amine (TREN) scaffold were screened out. Moreover, it was successfully synthesized via an atom transfer radical polymerization (ATRP). The excellent performance of tri-DOPA-PSBMA with a versatile and convenient grafting strategy makes it a promising material for marine devices, biomedical devices, and industrial applications.