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Archaeologists frequently invoke climate change as driving cause for ancient expansions of human populations, but geomorphic changes can also play an important role in opening or closing routes of migration. In China, archaeological evidence demonstrates that valleys in the Jialing River's watershed were important routes for the movement of Neolithic populations from the catchments of the Yellow River to the Yangtze River. Here, we examine how fluvial geomorphological regime shifts may have also influenced the migration pathways and adaptive strategies of Neolithic people into the Sichuan Basin by using a combination of sedimentological and palynological analysis at Luojiaba, an archaeological site located on one of the eastern tributaries of the Jialing River. The results show that people settled on seasonally stable landforms, including the Zhonghe River floodplain at Luojiaba (5300?4800?cal. B.P.). They carried out fishing and hunting activities on the front edge of the floodplain close to the river channel and built dwelling features on the higher ground at the back edge of the floodplain, which was not affected by seasonal floods. We hypothesize that during the Holocene Climatic Optimum before 5500?cal. B.P., high water levels as well as severe surface erosion caused by a strong East Asian Summer Monsoon (EASM) blocked pathways into the upper reaches of the Jialing River watershed. Only after a series of cold, dry climate events driven by a decrease in EASM intensity ca. 5500?5000?cal. B.P. did water levels recede significantly. This allowed alluvial aggradation to occur, which created floodplains and terraces along the valley that may have opened a new route for the migration into the Sichuan Basin. Our results reveal the human?environment dynamics surrounding Luojiaba in the uplands of southwestern China and highlight the impact of coupled climatic-geomorphic regime shifts on human settlement and subsistence strategies, across both space and time. 1 Introduction 1.1 Study area 1.2 Luojiaba site 2 Methods 3 Results 3.1 Landforms and fluvial terraces around the Luojiaba site 3.2 AMS radiocarbon dating 3.3 Particle size analysis 3.4 Chromaticity, magnetic susceptibility, and chemical elemental analysis 3.5 Soil micromorphological analysis 3.6 Pollen analysis 3.6.1 Zone 1 (Layers 12−8, 5300–4800 cal. B.P.) 3.6.2 Zone 2 (Layers 7−5, 4800–4500 cal. B.P.) 3.6.3 Zone 3 (Layer 4, 2500–2200 cal. B.P.) 3.6.4 Zone 4 (Layer 3, 2500–2200 cal. B.P.) 3.7 Ordination analysis 4 Discussion 4.1 Climate‐vegetation change and sedimentary process at Luojiaba 4.1.1 Lower part of the late Neolithic period (Layers 8–12, 5300–4800 cal. B.P.) 4.1.2 Upper part of the late Neolithic period (Layers 5–7, 4800–4500 cal. B.P.) 4.1.3 Late Ba cultural period (Layers 3–4, 2500–2200 cal. B.P.) 4.2 Settlement, land use patterns, and reverse adaptation at Luojiaba 4.2.1 Ash pit formation and land use patterns 4.2.2 Reverse adaptation and the possible environmental factors 4.3 Climate change, evolution of regional fluvial geomorphologies, and their impact on prehistoric mobility 4.3.1 Stage 1 (before 5500 cal. B.P.) 4.3.2 Stage 2 (5500–4500 cal. B.P.) 4.3.3 Stage 3 (after 3000 cal. B.P.) 5 Conclusion

Using hand-collected data on financial asset portfolios and exploiting the 2014 oil price crisis as an exogenous cash flow shock, we investigate financial risk-taking at distressed firms. We find that distressed firms, with high debt rollover risk proxied for by short-term liabilities, substantially increase their investments in risky financial assets, including corporate debt, equity, and mortgage-backed securities. The effects are stronger for unhedged firms with low collateral assets. Overall, we provide new evidence that distressed firms take risk using financial assets camouflaged as cash reserves, which, compared to real assets, are less visible and carry lower transaction costs and accelerated payoffs. (JEL G32, G34) Received March 12, 2022; editorial decision October 9, 2022 by Editor Andrew Ellul.

Background Acute pancreatitis (AP) is a common digestive disease with increased incidence globally but without internationally licenced pharmacological therapy. Moderately severe and severe acute pancreatitis (MSAP/SAP) contributes predominately for its morbidities and mortality and has been managed in West China Hospital for decades using the traditional Chinese medicinal formula chaiqin chengqi decoction (CQCQD). The current study tests whether the early administration of CQCQD will result in improved clinical outcomes in predicted MSAP/SAP patients. Methods This is a single-centre, randomised, controlled, double-blind pragmatic clinical trial. AP patients aged 18–75 admitted within 72 h of onset will be assessed at admission for enrolment. We excluded the predicted mild acute pancreatitis (Harmless Acute Pancreatitis Score > 2 at admission) and severe organ failure (Sequential Organ Failure Assessment [SOFA] score of respiratory, cardiovascular, or renal systems > 3) at admission. Eligible patients will be randomly allocated on a 1:1 basis to CQCQD or placebo control administration based on conventional therapy. The administration of CQCQD and placebo is guided by the Acute Gastrointestinal Injury grade-based algorithm. The primary outcome measure will be the duration of respiratory failure (SOFA score of respiratory system ≥ 2) within 28 days after onset. Secondary outcome measures include occurrence of new-onset any organ failure (SOFA score of respiratory, cardiovascular, or renal system ≥ 2) and new-onset persistent organ failure (organ failure lasts > 48 h), dynamic surrogate biochemical markers and clinical severity scores, gut-centred treatment modalities, local complications status, intensive care need and duration, surgical interventions, mortality, and length of hospital stay. Follow-up will be scheduled on 6, 12, and 26 weeks after enrolment to assess AP recurrence, local complications, the requirement for surgical interventions, all-cause mortality, and patient-reported outcomes. Discussion The results of this study will provide high-quality evidence to appraise the efficacy of CQCQD for the early management of AP patients. Trial registration Chictr.org.cn Registry (ChiCTR2000034325). Registered on 2 July, 2020.

We present a rationale for bidder termination provisions that considers their effect on bidders’ and targets’ joint takeover gains. The provision’s inclusion can create value by enabling termination when the target becomes less valuable to the bidder than on its own, but creates a trade-off because termination may also occur when the target is more valuable to the bidder than on its own. This trade-off explains why the provision is included in only some deals, and explains variation in termination fees. Inclusion of the provision is associated with larger combined announcement returns, provided that the termination fee is priced appropriately.

By decomposing firm size into horizon-based components, the authors find that the changes in firm size in prior years, instead of its recent level, drive the size premium. Specifically, size five years ago explains 80% of the current firm size but has little predictive power for the size premium. In contrast, the change in size over the prior two to five years explains only 18% of the size but almost completely captures the size premium. Their decomposition indicates that not all small stocks earn a size premium. Only small stocks that had significant losses in market value in the prior two to five years earn a premium. This analysis also offers new insights into the disappearance of the size premium and the return behaviors of new entrants. TOPICS:Security analysis and valuation, analysis of individual factors/risk premia, quantitative methods, statistical methods, performance measurement Key Findings ▪ The authors decompose firm size into horizon-based components and find the size premium is driven by the size change during the prior two to five years. As such, a better strategy for investors who are interested in the size premium is to trade on the prior two- to five-year size change. ▪ Not all small stocks earn a size premium. Only small stocks that had significant losses in market value in the prior two to five years earn a premium. ▪ Although the size premium is documented to have disappeared between the early 1980s and early 2000s, the premium related to the prior two- to five-year size change remains strong during this period.

We find strong empirical support for the risk-shifting mechanism to account for the puzzling negative relation between idiosyncratic volatility and future stock returns. First, equity holders take on investments with high idiosyncratic risk when their firms are in distress and receive less monitoring from institutional holders as well as when the aggregate economy is in a bad state. Second, the strategically increased idiosyncratic volatility decreases equity betas, particularly in bad states when the market risk premium is high. The negative covariance between the equity beta and the market risk premium causes low and negative returns and alphas in firms with high idiosyncratic volatility. This paper was accepted by Tomasz Piskorski, finance.

Background Lymph node (LN) metastasis is associated with decreased survival following resection for pancreatic ductal adenocarcinoma (PDAC). In N0 disease, increasing total evaluated LN (ELN) correlates with improved outcomes suggesting patients may be understaged when LNs are undersampled. We aim to assess the optimal number of examined lymph nodes (ELN) following pancreatectomy. Methods Data from 1837 patients undergoing surgery were prospectively collected. The binomial probability law was utilized to analyze the minimum number of examined LNs (minELN) and accurately characterize each histopathologic stage. LN ratio (LNR) was compared to American Joint Committee on Cancer (AJCC) guidelines. Results As ELN total increased, the likelihood of finding node positive disease increased. An evaluation based upon the binomial probability law suggested an optimal minELN of 12 for accurate AJCC N staging. As the number of ELNs increased, the discriminatory capacity of alternative strategies to characterize LN disease exceeded that offered by AJCC N stage. Conclusion This is the first study dedicated to optimizing histopathologic staging in PDAC using models of minELN informed by the binomial probability law. This study highlights two separate cutoffs for ELNs depending upon prognostic goal and validates that 12 LNs are adequate to determine AJCC N stage for the majority of patients.

Graphical abstract, Highlights • Early recognition of chronic pancreatitis (CP) is still lacking. In the setting of CP injury, activated pancreatic stellate cell (PSC) is the central mediator of pancreatic fibrosis. We systematically define highly and uniquely expressed PSC genes and show that these genes are enriched in pancreatic diseases. • Unresolved or recurrent injury causes dysregulation of biological process following AP, which would cause CP. We demonstrated subset genes that may be associated with the progression from AP to CP. Furthermore, SPARC was identified as a candidate marker for the disease progression. • Increased expression of SPARC and canonical PSC genes were verified during AP recovery, especially in recurrent AP mice models., Chronic pancreatitis (CP) is characterized by irreversible fibro-inflammatory changes induced by pancreatic stellate cell (PSC). Unresolved or recurrent injury causes dysregulation of biological process following AP, which would cause CP. Here, we systematically identify genes whose expressions are unique to PSC by comparing transcriptome profiles among total pancreas, pancreatic stellate, acinar, islet and immune cells. We then identified candidate genes and correlated them with the pancreatic disease continuum by performing intersection analysis among total PSC and activated PSC genes, and genes persistently differentially expressed during acute pancreatitis (AP) recovery. Last, we examined the association between candidate genes and AP, and substantiated their potential as biomarkers in experimental AP and recurrent AP (RAP) models. A total of 68 genes were identified as highly and uniquely expressed in PSC. The PSC signatures were highly enriched with extracellular matrix remodeling genes and were significantly enriched in AP pancreas compared to healthy control tissues. Among PSC signature genes that comprised a fibrotic phenotype, 10 were persistently differentially expressed during AP recovery. SPARC was determined as a candidate marker for the pancreatic disease continuum, which was not only persistently differentially expressed even five days after AP injury, but also highly expressed in two clinical datasets of CP. Sparc was also validated as highly elevated in RAP compared to AP mice. This work highlights the unique transcriptional profiles of PSC. These PSC signatures’ expression may help to identify patients with high risk of AP progression to CP.

Objectives: DNA damage inducible transcript 4 (DDIT4) plays a key role in different cancers, but the role of DDIT4 in lung adenocarcinoma (LUAD) is not completely understood. The aim of this study was to evaluate the utility of DDIT4 as a prognostic biomarker for LUAD. Methods: First, DDIT4 mRNA expression in LUAD cell lines (A549, H1299 and HBE) and tissues (89 cases) was assessed by RT-PCR. Next, DDIT4 protein expression in LUAD tissues and normal tissues was assessed by immunohistochemistry (75 cases). Then, the correlation between DDIT4 expression and overall survival was analyzed using the Kaplan-Meier method. After that, we verified the utility of the DDIT4 gene as a prognostic marker of lung cancer in the TCGA database (1133 cases). Finally, the possible mechanism of the DDIT4 gene as a prognostic marker of LUAD was preliminarily explored. Results: mRNA levels of DDIT4 in HBE cells were significantly lower than in A549 and H1299 cells (P0.05). The survival analysis demonstrated that high DDIT4 expression was correlated with shorter overall survival (P < 0.05). Univariate and multivariate analyses indicated that DDIT4 was an independent predictor of overall survival for LUAD, which was confirmed by data from the TCGA database. Finally, we found that DDIT4 gene expression was significantly increased in the hypoxic environment compared to the normal oxygen environment, indicating that the DDIT4 gene may play an important role in the hypoxic microenvironment of tumor tissue. Conclusion: High expression levels of DDIT4 correlated with poor overall survival in patients with LUAD, and DDIT4 was an independent predictor of overall survival. These findings provide new insight for understanding the development of LUAD.

Yanqiu He,1,&ast; Cheng Hu,1,&ast; Shiyu Liu,1 Mingjie Xu,1 Ge Liang,2 Dan Du,3 Tingting Liu,1 Fei Cai,1 Zhiyao Chen,1 Qingyuan Tan,1 Lihui Deng,1 Qing Xia1 1Pancreatitis Centre, Department and Laboratory of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, People’s Republic of China; 2Laboratory of Clinical Proteomics and Metabolomics, Institutes for Systems Genetics, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, People’s Republic of China; 3Advanced Mass Spectrometry Center, Research Core Facility, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Lihui Deng, Pancreatitis Centre, Department and Laboratory of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, People’s Republic of China, Email denglihui@scu.edu.cnBackground: Acute pancreatitis (AP) is an inflammatory disorder of the exocrine pancreas without specific treatment. Shenmai injection (SMI) was reported to eliminate the severity of experimental AP. This study aimed to explore the mechanisms underlying the synergistic protective effects of SMI on AP based on network pharmacology and experimental validation.Methods: Network pharmacology analysis and molecular docking based on identified components were performed to construct the potential therapeutic targets and pathways. The principal components of SMI were detected via ultra-high-performance liquid chromatography-coupled with quadrupole time-of-flight mass spectrometry (UHPLC-QTOF/MS). Effect of SMI and the identified components on cellular injury and IL6/STAT3 signaling was assessed on mouse pancreatic acinar cell line 266– 6 cells. Finally, 4% sodium taurocholate (NaT) was used to induce AP model to assess the effects of SMI in treating AP and validate the potential molecular mechanisms.Results: By searching the TCMSP and ETCM databases, 119 candidate components of SMI were obtained. UHPLC-QTOF/MS analysis successfully determined the representative components of SMI: ginsenoside Rb1, ginsenoside Rg1, ginsenoside Re, and ophiopogonin D. Fifteen hub targets and eight related pathways were obtained to establish the main pharmacology network. Subnetwork analysis and molecular docking indicated that the effects of these four main SMI components were mostly related to the interleukin (IL) 6/STAT3 pathway. In vitro, SMI, ginsenoside Rb1, ginsenoside Rg1, ginsenoside Re, and ophiopogonin D increased the cell viability of NaT-stimulated mouse pancreatic acinar 266– 6 cells and decreased IL6 and STAT3 expression. In vivo, 10 mL/kg SMI significantly alleviated the pancreatic histopathological changes and the expression of IL6 and STAT3 in the AP mice.Conclusion: This study demonstrated SMI may exert anti-inflammatory effects against AP by suppressing IL6/STAT3 activation, thus providing a basis for its potential use in clinical practice and further study in treating AP.Keywords: acute pancreatitis, Shenmai injection, network pharmacology, molecular docking, IL6/STAT3 signaling pathway

Porphyrin metal-organic frameworks (PMOFs) are emerging as heterogeneous photocatalysts owing to the well-designed frameworks incorporated with powerful light-harvesting porphyrin chromophores. The porous and stable framework Ir-PCN-224 (which is also denoted as Ir-PMOF-1), which has been prepared by the self-assembly of Ir(TCPP)Cl (TCPP=tetrakis(4-carboxyphenyl)porphyrin) and ZrCl4 , is reported herein to be efficient for the aerobic cross-dehydrogenative carbon-phosphorus coupling reaction, giving rise to a high turn-over number (TON) of up to 17200 under visible light irradiation (λ≥420 nm). Electron paramagnetic resonance (EPR) experiments disclose that the active species might be the superoxide radical anion (O2 .- ). Additionally, the intermediate imine cation has been detected by high-resolution mass spectrometry (HRMS).

Aspect-based (aspect-level) sentiment analysis is an important task in fine-grained sentiment analysis, which aims to automatically infer the sentiment towards an aspect in its context. Previous studies have shown that utilizing the attention-based method can effectively improve the accuracy of the aspect-based sentiment analysis. Despite the outstanding progress, aspect-based sentiment analysis in the real-world remains several challenges. (1) The current attention-based method may cause a given aspect to incorrectly focus on syntactically unrelated words. (2) Conventional methods fail to identify the sentiment with the special sentence structure, such as double negatives. (3) Most of the studies leverage only one vector to represent context and target. However, utilizing one vector to represent the sentence is limited, as the natural languages are delicate and complex. In this paper, we propose a knowledge guided capsule network (KGCapsAN), which can address the above deficiencies. Our method is composed of two parts, a Bi-LSTM network and a capsule attention network. The capsule attention network implements the routing method by attention mechanism. Moreover, we utilize two prior knowledge to guide the capsule attention process, which are syntactical and n-gram structures. Extensive experiments are conducted on six datasets, and the results show that the proposed method yields the state-of-the-art.

BackgroundLymphangio vascular invasion (LVI) and perineural invasion (PNI) are associated with survival following resection for gastrointestinal cancer. But the relationship between LVI/PNI and survival of esophageal squamous cell carcinoma (ESCC) is still unclear. We aim to demonstrate the prognostic significance of LVI/PNI in ESCC.MethodsA total of 195 ESCC patients underwent curative surgery from 2012 to 2018 was collected in the 2nd Affiliated Hospital of Fujian Medical University. All the patients were divided into four groups based on the status of the neurovascular invasion: (1) neither LVI nor PNI (V0N0); (2) LVI alone (V1N0); (3) PNI alone (V0N1); (4) combined LVI and PNI (V1N1). First, the analysis included the Kaplan-Meier survival estimates with the Log rank test were performed to determine median overall survival (OS) in different groups divided according to the clinical factor, respectively. And the association between OS with multi clinical factors was examined using Cox regression analysis. Next, the risk factors for recurrence in patients with V1N1 were analyzed with univariate and multivariate logistic regression analyses, respectively.ResultsThe cases in V0N0, V1N0, V0N1, and V1N1 groups were 91 (46.7%), 62 (31.8%), 9 (4.6%) and 33 (16.9%), respectively. The OS in the four groups was different (P< 0.001). The 1-, 3- and 5-year OS in V0N0 group was higher than that in V1N1 group, respectively (1-year OS: 93.4%vs75.8%, 3-year OS: 53.8 %vs24.2%, 5-year OS: 48.1%vs10.5%). The OS in stage I-II for patients with V1N1 was significantly lower than that in the other groups (V0N0, V1N0, V0N1) (P< 0.001). The postoperative adjuvant chemotherapy was a significant impact factor of OS for ESCC patients with V1N1 (P= 0.004). Lymphatic invasion and LVI were significantly prognosis factors associated (P= 0.036,P= 0.030, respectively). The ulcerative type is a risk factor for V1N1 occurance (P= 0.040).ConclusionsThe LVI and PNI are important prognosis factors for ESCC patients. ESCC patients with simultaneous lymphangio vascular and perineural invasion (V1N1) showed worse OS than patients with either lymphangio vascular or perineural invasion alone (V1N0 or V0N1) or none (V0N0). In addition, adjuvant chemotherapy may prolong the OS for ESCC patients with V1N1.

Early prediction of persistent organ failure (POF) is crucial for patients with acute pancreatitis (AP). Growth differentiation factor 15 (GDF15), also known as macrophage inhibitory cytokine 1 (MIC-1), is associated with inflammatory responses. We investigated changes in plasma GDF15 and assessed its predictive value in AP.The study included 290 consecutive patients with AP admitted within 36 h after symptoms onset. Clinical data obtained during hospitalization were collected. Plasma GDF15 levels were determined using enzyme-linked immunosorbent assays. The predictive value of GDF15 for POF was analyzed.There were 105 mild, 111 moderately severe, and 74 severe AP patients. Plasma GDF15 peak level were measured on admission, and significantly declined on the 3rd and 7th day. Admission GDF15 predicted POF and mortality with areas under the curve (AUC) of 0.847 (95% confidence interval [CI] 0.798-0.895) and 0.934 (95% CI 0.887-0.980), respectively. Admission GDF15, Bedside Index of Severity in Acute Pancreatitis, and hematocrit were independent factors for POF by univariate and multivariate logistic regression, and the nomogram built on these variables showed good performance (optimism-corrected c-statistic = 0.921). The combined predictive model increased the POF accuracy with an AUC 0.925 (95% CI 0.894-0.956), a net reclassification improvement of 0.3024 (95% CI: 0.1482-0.4565, P 0.001), and an integrated discrimination index of 0.11 (95% CI 0.0497-0.1703; P 0.001).Plasma GDF15 measured within 48 h of symptom onset could help predict POF and mortality in AP patients.

It is known that variations in the concentrations of certain elements in humans may be an indication of cancers. In this work, a method for the quantitative analysis of 22 elements in non-tumor and esophageal squamous cell carcinoma (ESCC) tissues from the same individual is reported. Based on the optimized platform combined with multivariate analysis, diagnostic models of ESCC were established using principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA), showing excellent classification of cancerous and non-cancerous group by metallomic profiling. Elemental concentrations of 10 elements (Mn, Se, Cu, Ti, Mg, Fe, Co, Zn, Sr, Ca) showed significant difference (p 0.001) in tumor and non-tumor tissues, in which Mn, Se, Cu and Ti are the top 4 elements of statistical significance and a shift towards higher concentration levels has also been observed in the tumor samples. These results confirm the considerable potential of elemental studies for biomedical purposes. To our knowledge, previous studies on elemental concentration in esophageal cancer were performed in serum or plasma levels; and this is the first study to evaluate the association of tissue elemental concentrations with ESCC.

Circulating tumour DNA (ctDNA) is a potential proxy for tumour tissues. However, the analysis of mutations and mutational abundance using ctDNA remains challenging because ctDNA is present at low levels. In addition, the concordance between plasma and tumour tissues requires further investigation by high-sensitivity techniques. Here, we established an ultrasensitive, quantitative method for detecting rare mutations in plasma samples based on a dual PNA clamping-mediated LNA-PNA PCR clamp (LNA-dPNA PCR clamp). The novelty of our method is the coupling of PNA clamping with one-tube nested PCR to dually block wild-type DNA amplification and efficiently amplify mutant DNA. Then, four hotspot EGFR mutations (EGFR L858R, EGFR Exon 19 deletion, EGFR T790M, and EGFR C797S) were detected by our proposed method. Finally, we evaluated the concordance between plasma and tumour tissues by simultaneously detecting EGFR L858R by ddPCR and LNA-dPNA PCR clamp in 132 tissues and matched plasma samples from patients with NSCLC. For the four EGFR mutations, the amplification sensitivity of the LNA-dPNA PCR clamp was 100 copies per reaction, and the linearity was from 100 to 106-107 copies per reaction. The limit of detection for the LNA-dPNA PCR clamp was 0.01%-0.1%. The LNA-dPNA PCR clamp was similarly consistent with ddPCR in quantifying mutational abundance (R2 = 0.9568) and exhibited similar limit of detection (0.01%-0.1% vs. 0.01%), sensitivity (19.6 vs. 21.7), specificity (94.2 vs. 91.9), and concordance (68.2 vs. 67.4) to those of ddPCR for ctDNA detection. In conclusion, the LNA-dPNA PCR clamp will provide a labour-saving, cost-saving, ultrasensitive tool for detecting and quantifying plasma EGFR mutations.

In our previous study we have found that miR-548k has oncogenic roles in esophageal squamous cell carcinoma (ESCC) via repressing long noncoding RNA (lncRNA)-LET and further upregulating nuclear factor 90 (NF90). However, the upstream factors controlling miR-548k expression are still unknown. In this study, we found NF90 directly binds pri-miR-548k, increases the stability of pri-miR-548k, and upregulates the expression of pri-miR-548k and miR-548k. Therefore, NF90, miR-548k and lncRNA-LET forms a feedback loop. Gain-of-function and loss-of-function assays demonstrated that in accordance with the roles of miR-548k, NF90 also promotes ESCC cell proliferation and migration. Furthermore, we verified the regulatory feedback loop between NF90, miR-548k, and lncRNA-LET. We found NF90 upregulated miR-548k and downregulated lncRNA-LET. miR-548k downregulated lncRNA-LET and upregulated NF90. lncRNA-LET downregulated NF90 and miR-548k. Through the reciprocal regulations between each other, the NF90/miR-548k/lncRNA-LET feedback loop controls the expressions of NF90 targets (HIF-1α and VEGF), miR-548k targets (KLF10 and EGFR), and lncRNA-LET target (p53). Further functional assays demonstrated that activation of the NF90/miR-548k/lncRNA-LET feedback loop via simultaneously overexpressing NF90 and miR-548k and simultaneously depleting lncRNA-LET significantly promotes ESCC cell proliferation and migration in vitro and ESCC tumor growth in vivo. Targeting the NF90/miR-548k/lncRNA-LET feedback loop via simultaneously depleting NF90 and miR-548k and simultaneously overexpressing lncRNA-LET significantly inhibits ESCC cell proliferation and migration in vitro and ESCC tumor growth in vivo. In summary, our findings identified a crucial oncogenic NF90/lncRNA-LET/miR-548k feedback amplification loop, which may be promising therapeutic targets for ESCC.

Background：Esophageal squamous cell carcinoma (ESCC) is one of the most common malignant tumors in the world, and its mechanism is related to tumor microenvironment. Immune / stromal score can be used to identify differential expressed genes (DEGs) of cancer, but it has not been reported in ESCC.Methods: The expression profile and clinicopathological information of patients with ESCC were downloaded from The Cancer Genome Atlas (TCGA) database. The immune score and stromal score of patients with ESCC were calculated by ESTIMATE algorithm. The relationship between immune / stromal score and clinicopathological characteristics and survival prognosis of patients with ESCC was analyzed. DEGs were identified according to the score, followed by gene ontology (GO) and Kyoto Encyclopedia of Gene and Genome (KEGG) analysis. The DEGs with prognostic value were revealed by overall survival analysis. Protein-protein interaction (PPI) network analysis was performed on these DEGs. Finally, the DEGs were verified by Chinese Cancer Genomic Database-Esophageal Squamous-Cell Carcinoma (CCGD-ESCC) database. Results: Immune and stromal scores were related to the prognosis of patients with ESCC. 223 DEGs were screened according to immune / stromal scores. GO and KEGG analysis showed that the selected DEGs was mainly related to plasma membrne, immune response and inflammatory response. Overall survival analysis showed that 68 genes were associated with prognosis. PPI network analysis showed that the core genes were CD86, LCP2, TLR7, CSF1R, C1QA, IRF8, CTLA4 and so on. A total of 17 genes with prognostic value were verified by CCGD-ESCC database. Conclusions: we screened and verified tumor microenvironment-related genes that have prognostic value and are expected to be used as therapeutic targets for patients with ESCC.

We propose the debt-equity spread (DES) as a measure of the valuation gap between debt and equity at firm level. DES strongly predicts stock and bond returns in opposite directions. A strategy that takes long positions in firms with low DES, whose stocks are cheap relative to bonds, and short those with high DES generates an average stock return of 6% per annum and bond return of -3.3% per annum. The return predictability is consistently stronger among small, illiquid, and difficult-to-short stocks and bonds. In addition, higher debt-equity spreads are associated with (i) higher probability for negative revision of long-term earnings growth forecasts; (ii) more equity issuance and debt repurchase, resulting in a low leverage ratio; (iii) stronger preferences for stock payments in acquisitions; and (iv) more insider stock selling. Together, these results suggest that the return prediction of DES is likely driven by mispricing rather than risk exposures.

Over the past decades, therapeutic drug monitoring (TDM) of tyrosine kinase inhibitors (TKIs) and their main active metabolites has shown benefits in improving treatment efficacy and safety. Therefore, a sensitive, simple and economical ultrahigh-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for the determination of six oral tyrosine kinase inhibitors (TKIs) and two active metabolites, including imatinib (IMA), N-desmethyl imatinib (NDIMA), sunitinib (SUNI), N-desethyl sunitinib (NDSUNI), regorafenib (REGO), nilotinib (NILO), dasatinib (DASA) and osimertinib (OSI) in human plasma for therapeutic drug monitoring. The plasma samples were deproteinated with acetonitrile after spiking with two deuterated internal standards (ISs, [ 2 H 8 ]-imatinib and [ 2 H 10 ]-sunitinib) and separated on a 40 °C ACQUITY UPLC® BEH C 18 column (1.7 μm, 2.1 mm×50 mm). The mobile phase was composed of acetonitrile (solution A) and water-formic acid-ammonium acetate (1M)(994:1:5, v/v/v, solution B). Gradient elution was applied at a flow rate of 0.4 mL/min. Detection was carried out using a Triple Quad 5500 tandem mass spectrometer coupled with an electrospray ionization (ESI) source in positive mode. The method was validated over the calibration curve (CV) range of 2-400 ng/mL for NDSUNI and DASA, 2.5-500 ng/mL for SUNI, 10-2000 ng/mL NDIMA and OSI, 20-4000 ng/mL for NILO, 30-6000 ng/mL for REGO and 50-10000 ng/mL for IMA using linear regression and 1/x 2 weighting. No difference was observed in the matrix effect (ME) among blank human plasma, hemolytic plasma and lipemic plasma samples in general. And the intra- and inter-batch precision and accuracy of all eight components were acceptable. To provide a clinical reference for the operation, the stability of the whole process from sample collection to drug detection was verified. SUNI and NDSUNI showed obvious photoisomerization under light exposure. Therefore, strict light protection was applied for all sample collection and handling steps of SUNI and NDSUNI. Compared with heparin anticoagulant tubes, the stability of the eight compounds in both whole blood and plasma was better in K3-EDTA and sodium citrate anticoagulant tubes. Given that all the analytes were stable in plasma at 4 °C for 48 h and in whole blood at room temperature for 48 h but OSI and REGO were unstable in whole blood and plasma at room temperature, samples should be centrifuged as soon as possible to be preserved as plasma at 4 °C when OSI or REGO is detected. In conclusion, this validated method can provide support for clinical practice, such as therapeutic drug monitoring (TDM) and pharmacokinetic studies of these six TKIs and two active metabolites.

Over the past decades, therapeutic drug monitoring (TDM) of tyrosine kinase inhibitors (TKIs) and their main active metabolites has shown benefits in improving treatment efficacy and safety. Therefore, a sensitive, simple and economical ultrahigh-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for the determination of six oral tyrosine kinase inhibitors (TKIs) and two active metabolites, including imatinib (IMA), N-desmethyl imatinib (NDIMA), sunitinib (SUNI), N-desethyl sunitinib (NDSUNI), regorafenib (REGO), nilotinib (NILO), dasatinib (DASA) and osimertinib (OSI) in human plasma/serum for therapeutic drug monitoring. The plasma/serum samples were deproteinated with acetonitrile after spiking with two deuterated internal standards (ISs, [

Operating leverage increases profitability and reduces optimal financial leverage. Thus, operating leverage generates a negative relation between profitability and financial leverage that is thought to be inconsistent with the trade-off theory but is commonly observed in the data. We demonstrate the effect of operating leverage on firms’ profitability and financial leverage, as well as on the empirical relation between profitability and financial leverage, by using China’s entry into the World Trade Organization in 2001 and its effect on the capital–labor ratio of U.S. firms.

Background Methicillin-resistant Staphylococcus aureus (MRSA) causes a wide variety of serious infections worldwide. There are few studies on the prevalence, antimicrobial susceptibility, and molecular characteristics of MRSA contamination in the environment of airports. Materials and methods A cross-sectional survey was conducted in Guangzhou Baiyun Airport. Environmental surface sampling was conducted in frequently touched locations for S. aureus analysis. All isolates were characterized by multilocus sequence typing (MLST) and tested for antimicrobial susceptibility, resistance genes, and virulence genes. Data were analyzed by chi-squared test and correspondence analysis. Results Of the 1,054 surface samples, the contamination rate was 7.2% (76/1,054) for S. aureus and 2.2% (23/1,054) for MRSA. There were 62.9% (56/89) S. aureus isolates classified as multidrug resistant (MDR), with six linezolid-resistant isolates and two cfr-carrying isolates. The most prevalent S. aureus genotypes were CC6 (ST6), CC59 (ST59), and CC188 (ST188), with ST59-MRSA-IV (pvl-) as the predominant MRSA. There were significant differences between methicillin-resistant and methicillin-sensitive isolates in rates of resistance to tetracycline (P

Dan Guo, Yangqun Liu, Changlin Han, Zhiyao Chen, Xiaohua Ye Laboratory of Molecular Epidemiology, School of Public Health, Guangdong Pharmaceutical University, Guangzhou, China Background: Routine non-therapeutic antimicrobial use and overcrowding in animal farming may facilitate the propagation of methicillin-resistant Staphylococcus aureus (MRSA). This study aimed to examine the carriage prevalence and phenotype–genotype characteristics of MRSA and methicillin-susceptible S. aureus isolated from pigs. Methods: Nasal swabs were collected from 1,458 pigs in 9 pig farms and 3 slaughterhouses. All strains were tested for antimicrobial susceptibility, resistance genes, and virulence genes, and characterized by multilocus sequence typing. The correspondence analysis was conducted to explore the relationships between multiple phenotypic and molecular characteristics of S. aureus isolates. Results: In the 1,458 pigs, the carriage prevalence was 9.5% for S. aureus, 3.3% for MRSA, and 9.3% for multidrug-resistant S. aureus. Notably, 97.1% S. aureus isolates were multidrug resistant, and the predominant resistance pattern was non-susceptible to clindamycin, tetracycline, and erythromycin. The predominant genotype was CC9 (ST9) for S. aureus and MRSA isolates. Importantly, all S. aureus isolates were negative for the scn gene and resistant to tetracycline. Notably, all 9 linezolid-resistant isolates were classified as multidrug resistance, including 1 expressing the cfr gene and 6 expressing the optrA gene. The correspondence analysis showed a significant relationship between clonal complexes and resistance pattern or virulence genes. For example, CC9 was associated with extensive drug-resistance and co-carrying chp, sak, and hlb, and CC1 was associated with multidrug resistance and co-carrying sak and hlb. Conclusion: The significant correspondence relationship between multiple characteristics provides some implication for vaccine strategies and new ideas for monitoring new epidemiologic clones. Keywords: livestock, animals, Staphylococcus aureus, antimicrobial susceptibility, multidrug resistance, molecular characterization

We develop and estimate a dynamic model of risk-shifting over the business cycle. First, equity holders with Epstein-Zin preferences increase their taking of idiosyncratic risk substantially more than the standard model in repeated games, because they perceive the arrival probability of bad states to be higher than the actual probability and prefer an early resolution of macroeconomic uncertainty. Second, sudden switches to bad states and large shocks in the bad states induce the countercyclical and “synchronized” idiosyncratic risk. Third, combined with the high market risk premium in the bad states, clustered risk-taking generates a countercyclical idiosyncratic volatility discount on equity returns.Received July 1, 2017; editorial decision January 22, 2018 by Editor Stijn Van Nieuwerburgh. Authors have furnished an Internet Appendix, which is available on the Oxford University Press Web site next to the link to the final published paper online.

Dysregulated noncoding RNAs have been observed in diverse cancers. MIR458K is frequently amplified in esophageal squamous cell carcinoma (ESCC). However, the expression, clinical significances, and action mechanisms of miR-548k in ESCC are still unclear. In this study, we found that miR-548k is significantly up-regulated in ESCC tissues and cell lines. Up-regulated miR-548k expression is significantly correlated with advanced invasion depth, lymph node metastasis, advanced TNM stage, and poor overall survival. Gain-of- and loss-of-function assays demonstrated that miR-548k promotes the proliferation and migration of ESCC cells in vitro and tumor growth in vivo. Mechanistically, we found that miR-548k directly targets and represses the expression of long noncoding RNA-LET (lncRNA-LET), and further down-regulates p53 and up-regulates NF90. In addition, we found that lncRNA-LET is down-regulated and inversely correlated with miR-548k in ESCC. Down-regulated lncRNA-LET also indicated poor overall survival of ESCC patients. Functional assays demonstrated that lncRNA-LET inhibits the proliferation and migration of ESCC cells, and the effects of miR-548k on ESCC are dependent on the negative regulation of lncRNA-LET. In summary, our data revealed the critical roles of miR-548k-lncRNA-LET regulation axis in ESCC and suggested that the miR-548k-lncRNA-LET regulation axis may be promising prognostic biomarkers and therapeutic targets for ESCC.

As a unique member of the cadherin superfamily, T-cadherin (T-cad) has been demonstrated to be associated with gastric cancer (GC) prognosis. To elucidate the function of T-cad in GC in vitro, the present study firstly examined T-cad protein expression in normal and gastric cancer tissues and cell lines, and it was demonstrated to be significantly downregulated in gastric cancer samples compared with normal samples. Control and T-cad expression vectors were then transfected into the MGC8-03 and AGS GC cell lines. Utilizing MTT, clonogenic, flow cytometry, wound healing and Transwell invasion assays in addition to Western blotting, the present study demonstrated that the overexpression of T-cad suppressed GC cell growth and colony formation via cell cycle arrest at the G0/G1 phase via downregulating the expression of cyclin dependent kinase 4 and Cyclin D1. In addition, overexpression of T-cad significantly inhibited GC cell migration and invasion by increasing E-cadherin and decreasing Vimentin expression. These findings suggest T-cad may be important in GC cell proliferation and metastasis and serve as a promising target for the treatment of GC in the future.

To achieve a microarray universal to any SNP, we proposed a new way to construct a genotyping-microarray by ligating a universal fluorescence-probe with SNP-encoded flaps cleaved from invasive reactions on a slide surface. Our proposed microarray is labor-saving and cost-saving in setting up a new experiment for genotyping multiple SNPs, which is related to personalized medicine.