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Qiushi Wang,1 Jianghong Mou,1 Xin Yang,1 Yong He,2 Zengpeng Li,1 Qingya Luo,1 Yanqing Li,1 Li Lin,1 Yu Ma,1 Hualiang Xiao11Department of Pathology, 2Department of Respiration, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, People’s Republic of ChinaBackground: The clinical characteristics of epidermal growth factor receptor (EGFR) hotspot mutations, such as deletions in exon 19, substitution of L858R in exon 21, and mutations in exon 20, have been widely reported in nonsmall cell lung cancer. However, the clinical features of other low frequency EGFR mutations in these four exons (especially the relationship with smoking history), eg, substitutions of G719S/A/C in exon 18 and L861Q in exon 21, remain unclear. This study investigated the relationship between G719S/A/C and L861Q mutations (in exon 18 and 21) and smoking history.Methods: Specimens from 194 patients with lung adenocarcinoma were analyzed for EGFR mutations in exons 18–21 by high-resolution melting curve analysis and amplification refractory mutation technology to establish the relationship between G719S/A/C and L861Q mutations and smoking history.Results: Ninety-six of 194 tumors (49.5%) were confirmed to be EGFR mutation-positive. Among these mutations, 71 of 104 (68.3%) were from never smokers, six of 17 (35.3%) were from former smokers, and 19 of 73 (26.0%) were from current smokers (P < 0.001). The mutation rate in heavy smokers (5/23, 21.7%) was significantly lower than in light smokers (20/67, 29.9%) and never smokers (71/104, 68.3%, P < 0.001). Seven low frequency EGFR mutations (four substitutions of G719S, and G719 A, respectively, and three of L861Q in exon 21) were identified. Five of these mutations were derived from smokers (one former light smoker, one current heavy smoker, and three current light smokers). Four of these patients had been treated with tyrosine kinase inhibitors and all had a partial response, with median overall survival (14.5 months) and median progression-free survival (6.8 months), being longer than in patients with similarly staged lung adenocarcinoma without EGFR mutation or treatment with tyrosine kinase inhibitors (6.8 and 3.1 months, respectively, according to data from an as yet unpublished study at our institution).Conclusion: This study provides further evidence that smoking status, include years of smoking and number of cigarettes smoked per day, plays an important role in EGFR mutation in patients with lung adenocarcinoma. Five of seven specimens with G719S/A or L861Q mutations coming from smokers indicates that there may be a relationship between G719S/A or L861Q mutation and smoking history. However, regardless of the influence of smoking, the effectiveness of tyrosine kinase inhibitors was satisfactory in four patients harboring G719S/A and L861Q EGFR mutation.Keywords: EGFR, lung adenocarcinoma, G719S/A, L861Q, smoking history

The current strategies for the treatment of vitiligo using phototherapy usually involve treatment for two-three times per week; however, in practice, the number of patient sessions does not meet this standard. The present study found that phototherapy once a week was also effective. The present study was designed to examine the efficacy of weekly light therapy. For this purpose, 296 patients with vitiligo were included and divided into five sub-samples of the neck, face, trunk, extremities and scalp according to the site of phototherapy, and were treated once or twice weekly with phototherapy. The difference in efficacy between phototherapy performed once and twice weekly was observed using a Chi-squared test. It was concluded that there was a minimal difference between phototherapy performed twice weekly compared to once weekly for the treatment of vitiligo on the face, neck, torso, limbs and scalp. Thus, phototherapy once a week is valid for the treatment of vitiligo, although weekly light therapy takes longer to restore color for the first time., Competing Interests: The authors declare that they no competing interests., (Copyright: © Wang et al.)

Objective: Worldwide, there is a growing trend that college students are consuming more and more sugar-sweetened beverages (SSBs). In order to develop effective intervention strategies, it is important to explore what social-cognitive factors impact on college students' SSB consumption. Building on the temporal self-regulation theory (TST), the current study aimed to examine the effects of intention, behavioral prepotency, and self-regulatory capacity on SSB consumption among college students., Design: Data were collected from five hundred Chinese college students online. Participants self-reported their intention, behavioral prepotency (environmental cues and habits), self-regulatory capacity, and behaviors of SSB consumption., Results: Study findings showed that intention, behavioral prepotency, and self-regulatory capacity accounted for 32.9% of variance in SSB consumption. In terms of the direct effects, intention, behavioral prepotency, and self-regulatory capacity were significantly associated with the SSB consumption among college students. In addition, self-regulatory capacity and habits but not the environmental cues showed significant moderation effects on the intention-SSB consumption path, indicating that individual factors rather than environmental cues influenced the intention-behavior path of SSB consumption among college students., Conclusion: Findings of the current study demonstrated that the TST can be used to explain and understand the impacts of social-cognitive factors on college students' SSB consumption. Future research can apply TST to develop effective intervention programs targeting the reduction of SSB consumption among college students., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Background: Bacteremia, which is a major cause of mortality in patients with acute cholangitis, induces hyperactive immune response and mitochondrial dysfunction. Presepsin is responsible for pathogen recognition by innate immunity. Acylcarnitines are established mitochondrial biomarkers., Aim: To clarify the early predictive value of presepsin and acylcarnitines as biomarkers of severity of acute cholangitis and the need for biliary drainage., Methods: Of 280 patients with acute cholangitis were included and the severity was stratified according to the Tokyo Guidelines 2018. Blood presepsin and plasma acylcarnitines were tested at enrollment by chemiluminescent enzyme immunoassay and ultra-high-performance liquid chromatography-mass spectrometry, respectively., Results: The concentrations of presepsin, procalcitonin, short- and medium-chain acylcarnitines increased, while long-chain acylcarnitines decreased with the severity of acute cholangitis. The areas under the receiver operating characteristic curves (AUC) of presepsin for diagnosing moderate/severe and severe cholangitis (0.823 and 0.801, respectively) were greater than those of conventional markers. The combination of presepsin, direct bilirubin, alanine aminotransferase, temperature, and butyryl-L-carnitine showed good predictive ability for biliary drainage (AUC: 0.723). Presepsin, procalcitonin, acetyl-L-carnitine, hydroxydodecenoyl-L-carnitine, and temperature were independent predictors of bloodstream infection. After adjusting for severity classification, acetyl-L-carnitine was the only acylcarnitine independently associated with 28-d mortality (hazard ratio 14.396; P < 0.001) (AUC: 0.880). Presepsin concentration showed positive correlation with direct bilirubin or acetyl-L-carnitine., Conclusion: Presepsin could serve as a specific biomarker to predict the severity of acute cholangitis and need for biliary drainage. Acetyl-L-carnitine is a potential prognostic factor for patients with acute cholangitis. Innate immune response was associated with mitochondrial metabolic dysfunction in acute cholangitis., Competing Interests: Conflict-of-interest statement: There are no conflicts of interest to report., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Acute pancreatitis (AP) is an inflammatory disorder of the pancreas with an unpredictable course of illness. A major challenge of AP is the early identification of patients at high-risk for organ failure and death. However, scoring systems are complicated and time consuming, and the predictive values for the clinical course are vague., Aim: To determine whether the dynamic changes in presepsin levels can be used to evaluate the severity of disease and outcome of AP., Methods: In this multicentric cohort study, 133 patients with AP were included. Clinical severity was dynamically evaluated using the 2012 revised Atlanta Classification. Blood presepsin levels were measured at days 1, 3, 5 and 7 after admission by chemiluminescent enzyme immunoassay., Results: The median concentration of presepsin increased and the clearance rate of presepsin decreased with disease severity and organ failure in AP patients. The presepsin levels on days 3, 5 and 7 were independent predictors of moderately severe and severe AP with time-specific area under the curve (AUC) values of 0.827, 0.848 and 0.867, respectively. The presepsin levels positively correlated with bedside index of severity in AP, Ranson, acute physiology and chronic health evaluation II, computed tomography severity index and Marshall scores. Presepsin levels on days 3, 5 and 7 were independent predictors of 28-d mortality of AP patients with AUC values of 0.781, 0.846 and 0.843, respectively., Conclusion: Blood presepsin levels within 7 d of admission were associated with and may be useful to dynamically predict the severity of disease course and 28-d mortality in AP patients., Competing Interests: Conflict-of-interest statement: There are no conflicts of interest to report., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Alternative splicing (AS) is a universal post-transcriptional regulation process in cells, and increasing evidences have validated its crucial role in tumors. We collected AS event, gene expression, and clinical data of 178 AML patients from The Cancer Genome Atlas (TCGA) project. More than 1,000 AS events were found associated with overall survival (OS), and alternate promoter (AP) events were the most significant. The expression of the KIAA0930 transcript was the most significantly different AS event selected from AP events and significantly correlated with the expression of the splicing factor (SF) polypyrimidine tract-binding protein 1 (PTBP1). Then, the roles of PTBP1 on AS of the KIAA0930 and the proliferation of AML cells were confirmed. KIAA0930 variant 1 (KIAA0930-1) was upregulated and variant 2 (KIAA0930-2) downregulated with knockdown PTBP1 expression of AML cells by specific shRNA. A low level of PTBP1 can decrease the proliferation ability of AML cells. In conclusion, the results showed that PTBP1 might be a potential target for AML therapy.

Background: Acute pulmonary embolism (APE) with cardiac arrest (CA) is characterized by high mortality in emergency due to pulmonary arterial hypertension (PAH). This study aims to determine whether early pulmonary artery remodeling occurs in PAH caused by massive APE with CA and the protective effects of increasing angiotensin-converting enzyme (ACE) 2-angiotensin (Ang) (1-7)-Mas receptor axis and ACE-Ang II-Ang II type 1 receptor (AT1) axis (ACE2/ACE axes) ratio on pulmonary artery lesion after return of spontaneous circulation (ROSC)., Methods: To establish a porcine massive APE with CA model, autologous thrombus was injected into the external jugular vein until mean arterial pressure dropped below 30 mmHg (1 mmHg=0.133 kPa). Cardiopulmonary resuscitation and thrombolysis were delivered to regain spontaneous circulation. Pigs were divided into four groups of five pigs each: control group, APE-CA group, ROSC-saline group, and ROSC-captopril group, to examine the endothelial pathological changes and expression of ACE2/ACE axes in pulmonary artery with or without captopril., Results: Histological analysis of samples from the APE-CA and ROSC-saline groups showed that pulmonary arterioles were almost completely occluded by accumulated endothelial cells. Western blotting analysis revealed a decrease in the pulmonary arterial ACE2/ACE axes ratio and increases in angiopoietin-2/angiopoietin-1 ratio and expression of vascular endothelial growth factor (VEGF) in the APE-CA group compared with the control group. Captopril significantly suppressed the activation of angiopoietin-2/angiopoietin-1 and VEGF in plexiform lesions formed by proliferative endothelial cells after ROSC. Captopril also alleviated endothelial cell apoptosis by increasing the B-cell lymphoma-2 (Bcl-2)/Bcl-2-associated X (Bax) ratio and decreasing cleaved caspase-3 expression., Conclusion: Increasing the ACE2/ACE axes ratio may ameliorate pulmonary arterial remodeling by inhibiting the apoptosis and proliferation of endothelial cells after ROSC induced by APE., Competing Interests: Conflicts of interest: No conflicts of interest declared., (Copyright: © World Journal of Emergency Medicine.)

Asthma is regarded as a chronic inflammation of the airway. Research has highlighted the significance of Vitamin D in asthma. This study explored the mechanism of vitamin D on asthma. The asthma mouse model was established by ovalbumin (OVA) sensitization and treated with vitamin D (50 or 100 ng/ml). The morphological changes of the airway were observed by HE staining. The serum IgE contents and MDA, ROS, and SOD expressions in the bronchoalveolar lavage fluid (BALF) were detected by ELISA. The Th17 and Treg cells were detected using flow cytometry. The RORγt and Foxp 3 expressions were detected by Reverse transcription quantitative polymerase chain reaction (RT-qPCR). IL-17, IL-10, and TGF-β1 expressions were detected using ELISA. The NF-κB pathway was blocked using the NF-κB pathway inhibitor, Andrographolide sulfonate. The NF-κB pathway-related indexes were detected by western blotting. After blockade of the NF-κB pathway, the IL-17, IL-10, and TGF-G1 expressions were detected. OVA-sensitized asthma induced airway remodeling and elevated IgE content in mice, which was downregulated after vitamin D treatment. MDA and ROS were upregulated and SOD was downregulated in asthmatic mice, while vitamin D inverted the changes. Th17/Treg ratio was imbalanced, RORγt and IL-17 were upregulated, and Foxp 3, IL-10, and TGF-β1 were downregulated after OVA sensitization, while vitamin D treatment inverted these changes and inhibited the NF-κB-p65 phosphorylation level. After blockade of the NF-κB pathway, IL-17 was downregulated and IL-10 and TGF-β1 were upregulated. In conclusion, vitamin D rectified the Th17/Treg balance and alleviated airway inflammation by inhibiting the NF-κB pathway in asthmatic mice., (© 2021 The Authors. The Kaohsiung Journal of Medical Sciences published by John Wiley & Sons Australia, Ltd on behalf of Kaohsiung Medical University.)

BACKGROUND Moxibustion therapy has been found to ameliorate clinical symptoms of functional dyspepsia (FD). We aimed to examine the regulatory effect of moxibustion on the gastrointestinal (GI) motility in FD and explore the underlying mechanism based on the hyperpolarization-activated cyclic nucleotide-gated cation channel 1 (HCN1). MATERIAL AND METHODS Moxibustion therapy was used in FD rats induced by using classic tail-pinch and irregular feeding. Weight gain and food intake were recorded weekly, followed by detecting gastric residual rate (GRR) and small intestine propulsion rate (IPR). Next, western blotting was performed to determine the expression levels of HCN1 in the gastric antrum. qRT-PCR was used to detect HCN1 in the small intestine and hypothalamic satiety center. Double immunolabeling was used for HCN1 and ICCs in gastric antrum and small intestine. RESULTS The obtained results suggested that moxibustion treatment could increase weight gain and food intake in FD rats. The GRR and IPR were compared among the groups, which showed that moxibustion treatment could decrease GRR and increase IPR. Moxibustion increased the expression of HCN1 in the gastric antrum, small intestine, and hypothalamic satiety center. Histologically, the co-expressions of HCN1 and ICCs tended to increase in gastric antrum and small intestine. Meanwhile, HCN channel inhibitor ZD7288 prevented the above-mentioned therapeutic effects of moxibustion. CONCLUSIONS The results of the present study suggest that moxibustion can effectively improve the GI motility of FD rats, which may be related to the upregulation of HCN1 expression in gastric antrum, small intestine, and satiety center.

The purpose of the present study was to investigate whether catalpol exhibited neuroprotective effects in chronic unpredictable mild stress (CUMS) mice through oxidative stress-mediated nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin-domain-containing 3 (NLRP3) inflammasome and neuroinflammation. Deficits in behavioral tests, including open field test (OFT), forced swim test (FST), and elevated plus-maze test (EPM), were ameliorated following catalpol administration. To study the potential mechanism, western blots, quantitative real-time PCR (qRT-PCR) analysis and immunofluorescence imaging were performed on the hippocampus samples. We found that the defects of behavioral tests induced by CUMS could be reversed by the absence of NLRP3 and NLRP3 inflammasome might be involved in the antidepressant effects of catalpol on CUMS mice. Similar to the NLRP3 inflammasome, the expression of interleukin-1 beta (IL-1β), tumor necrosis factor alpha (TNF-α), and inducible nitride oxide synthase (iNOS) were increased after CUMS. The current study demonstrated that catalpol possessed anti-inflammatory effect on CUMS mice and inhibited microglial polarization to the M1 phenotype. In addition, the activity of mitochondrial oxidative stress might be involved in the NLRP3 activation, which was proved by the downregulation of NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC), and cleaved IL-1β, after the administration of mitochondrion-targeted antioxidant peptide SS31. Taken together, we provided evidence that catalpol exhibited antidepressive effects on CUMS mice possibly via the oxidative stress-mediated regulation of NLRP3 and neuroinflammation.

Mechanical properties of fiber-reinforced soil after soaking in heavy metal ion solution have great influences on safety and stability of the reinforcement, herein the mechanical properties of optimum moisture content of different concentrations of zinc ions contaminated soil were studied through shear test, compression test and triaxial test. The compressive modulus, compression coefficient and porosity ratio of different concentrations of the zinc-ion contaminated soil under different pressure were studied, and the variation characteristics of internal friction angle and cohesion were also investigated, thereafter, the causes of the change of cohesion and internal friction angle were analyzed from the microscopic perspective. The results show that the shear strength of contaminated reinforced soil increases with the increase of confining pressure at the same zinc ions concentration. And at the same confining pressure, with the increase of zinc ions concentration, the shear strength of contaminated reinforced soil first increases and then decreases. With the increase of zinc ions concentration, the internal friction angle and compression coefficient increase, the cohesion and the modulus of compression decrease. With the increase of normal stress, the compression coefficient decreases firstly and then increases, and the compression modulus increases and then decreases. With the concentration of zinc ions increases at lower normal stress, the amount of shrinkage increases and the compression coefficient decreases. While at higher normal stress, the compressive modulus decreases and the compression coefficient increases.

Background: Aberrant activation of Wnt/β-catenin signaling by dysregulated post-translational protein modifications, especially ubiquitination is causally linked to cancer development and progression. Although Lys48-linked ubiquitination is known to regulate Wnt/β-catenin signaling, it remains largely obscure how other types of ubiquitination, such as linear ubiquitination governs its signaling activity., Methods: The expression and regulatory mechanism of linear ubiquitin chain assembly complex (LUBAC) on Wnt/β-catenin signaling was examined by immunoprecipitation, western blot and immunohistochemical staining. The ubiquitination status of β-catenin was detected by ubiquitination assay. The impacts of SHARPIN, a core component of LUBAC on malignant behaviors of gastric cancer cells were determined by various functional assays in vitro and in vivo., Results: Unlike a canonical role in promoting linear ubiquitination, SHARPIN specifically interacts with β-catenin to maintain its protein stability. Mechanistically, SHARPIN competes with the E3 ubiquitin ligase β-Trcp1 for β-catenin binding, thereby decreasing β-catenin ubiquitination levels to abolish its proteasomal degradation. Importantly, SHARPIN is required for invasiveness and malignant growth of gastric cancer cells in vitro and in vivo, a function that is largely dependent on its binding partner β-catenin. In line with these findings, elevated expression of SHARPIN in gastric cancer tissues is associated with disease malignancy and correlates with β-catenin expression levels., Conclusions: Our findings reveal a novel molecular link connecting linear ubiquitination machinery and Wnt/β-catenin signaling via SHARPIN-mediated stabilization of β-catenin. Targeting the linear ubiquitination-independent function of SHARPIN could be exploited to inhibit the hyperactive β-catenin signaling in a subset of human gastric cancers.

With the application of fiber-reinforcement technology, the mechanical properties of silty clay are improved with fiber reinforcement. However, the variation of permeability coefficient and other parameters of flax-fiber reinforced silty clay have not been sufficiently studied. In this study, the permeability of flax-fiber reinforced silty clay soaked with zinc-contaminated solution under different osmotic pressure was tested by a flexible-wall permeameter, and the effects of zinc-ion concentration and confining pressure on the permeability of flax-fiber reinforced silty clay were studied. Genius XRF was employed to detect the types and quantity of metal elements in the specimens, thereafter, the reasons for the change of permeability were explained from chemical and microscopic perspective. The results showed that the permeability coefficient of flax-fiber reinforced silty clay decreased significantly with the increase of zinc-ion concentration in a low concentration (about 1-10 mg L -1 ). While in a high concentration (about 100 mg L -1 ), the permeability coefficient of flax-fiber reinforced silty clay changed little with the increase of zinc-ion concentration. While the flax-fiber reinforced silty clay was not soaked with zinc-ion solution, the permeability coefficient of the specimen increased with the increase of confining pressure. However, when the flax-fiber reinforced silty clay was soaked with zinc-contaminated solution, the permeability coefficient first decreased and then tended to be constant with the increase of confining pressure. With the increase of confining pressure, the porosity of flax-fiber reinforced silty clay decreased, and with the increase of zinc-ion concentration, the porosity of flax-fiber reinforced silty clay first increased and then decreased.

Objective: To investigate the pathological characteristics and the clinical significance of novel coronavirus (2019-nCoV)-infected pneumonia (termed by WHO as coronavirus disease 2019, COVID-19). Methods: Minimally invasive autopsies from lung, heart, kidney, spleen, bone marrow, liver, pancreas, stomach, intestine, thyroid and skin were performed on three patients died of novel coronavirus pneumonia in Chongqing, China. Hematoxylin and eosin staining (HE), transmission electron microcopy, and histochemical staining were performed to investigate the pathological changes of indicated organs or tissues. Immunohistochemical staining was conducted to evaluate the infiltration of immune cells as well as the expression of 2019-nCoV proteins. Real time PCR was carried out to detect the RNA of 2019-nCoV. Results: Various damages were observed in the alveolar structure, with minor serous exudation and fibrin exudation. Hyaline membrane formation was observed in some alveoli. The infiltrated immune cells in alveoli were majorly macrophages and monocytes. Moderate multinucleated giant cells, minimal lymphocytes, eosinophils and neutrophils were also observed. Most of infiltrated lymphocytes were CD4-positive T cells. Significant proliferation of type Ⅱ alveolar epithelia and focal desquamation of alveolar epithelia were also indicated. The blood vessels of alveolar septum were congested, edematous and widened, with modest infiltration of monocytes and lymphocytes. Hyaline thrombi were found in a minority of microvessels. Focal hemorrhage in lung tissue, organization of exudates in some alveolar cavities, and pulmonary interstitial fibrosis were observed. Part of the bronchial epithelia were exfoliated. Coronavirus particles in bronchial mucosal epithelia and type Ⅱ alveolar epithelia were observed under electron microscope. Immunohistochemical staining showed that part of the alveolar epithelia and macrophages were positive for 2019-nCoV antigen. Real time PCR analyses identified positive signals for 2019-nCoV nucleic acid. Decreased numbers of lymphocyte, cell degeneration and necrosis were observed in spleen. Furthermore, degeneration and necrosis of parenchymal cells, formation of hyaline thrombus in small vessels, and pathological changes of chronic diseases were observed in other organs and tissues, while no evidence of coronavirus infection was observed in these organs. Conclusions: The lungs from novel coronavirus pneumonia patients manifest significant pathological lesions, including the alveolar exudative inflammation and interstitial inflammation, alveolar epithelium proliferation and hyaline membrane formation. While the 2019-nCoV is mainly distributed in lung, the infection also involves in the damages of heart, vessels, liver, kidney and other organs. Further studies are warranted to investigate the mechanism underlying pathological changes of this disease.

Background: Condylomata acuminata (CA) are a common sexually transmitted disease. The recurrence rate of condyloma acuminatum using traditional treatments is higher than that of applying photodynamic therapy, and a variety of adverse reactions after treatment. At the same time, different parts of condyloma acuminatum after treatment recurrence rate is also different, especially for intra anal-rectal warts. Objective: To evaluate whether using photodynamic therapy (PDT) can effectively reduce recurrence of condylomata acuminata for intra anal-rectal warts. Methods: After the confirmation of the diagnosis of intra anal-rectal warts, the patients were treated with PDT with 5-aminolevulinic acid hydrochloride (ALA). PDT was performed with irradiation of 18-36 J/cm 2 at an irradiance of 20-40 mW/cm 2 with light-emitting diode (LED) light energy, wavelength 635 nm. We used a special PDT light equipment for intra anal-rectal area warts. PDT was repeated once every week for 4 weeks. Results: After PDT, the complete clearance rate was 76.1% (35 of 46 patients). At the end of the 12 weeks followed, recurrence occurred in five cases. We recorded pain in all 46 patients and the average visual analog scale (VAS) pain score was 6.96 ± 1.41 points. Conclusion: The treatment with PDT is effective in reducing the high rate of recurrence for intra anal-rectal warts. Pain is still a great challenge for the therapy.

Lung cancer is the most common cause of cancer-associated mortality in China with 85% of patients having non-small cell lung cancer (NSCLC). Identifying NSCLC driver genes and prognostic markers is critical to reducing these numbers. The studies of retinoblastoma binding protein 6 (RBBP6) performed on NSCLC is limited. The present study aimed to investigate the molecular function and the prognostic potential of RBBP6 in NSCLC using the A549 cell line and patient samples, respectively. The functional effect on cancer cell proliferation and prognostic value of RBBP6 were examined in vitro and in vivo using reverse transcription-quantitative PCR, immunofluorescence, immunohistochemistry (IHC) and xenograft implantation. The results demonstrated that RBBP6 mRNA expression was significantly higher in NSCLC tissues compared with in adjacent normal samples. When RBBP6 mRNA expression was interfered with using short hairpin RNA, A549 cell proliferation and xenograft tumor growth were reduced. Additionally, IHC and survival analysis demonstrated that patients with NSCLC with high expression levels of RBBP6 had a shorter median overall survival time compared with patients with low RBBP6 expression (31 vs. 51.5 months), and this was more prominent in stage I-II patients (43 vs. >67 months). High expression levels of RBBP6 indicated poor prognosis in patients with NSCLC. This may be due to the ability of RBBP6 to promote cancer cell proliferation. RBBP6 may be a potential prognostic biomarker and a therapeutic target for NSCLC., (Copyright: © Wang et al.)

Gastrointestinal stromal tumors (GISTs) are the most commonly diagnosed primary mesenchymal tumors of the gastrointestinal tract and 30% of GISTs are associated with a high recurrence risk or metastasis. The current risk classification criteria of the National Comprehensive Cancer Network are based on tumor size, mitotic activity and localization. Investigating additional biomarkers associated with clinical risk may aid in the diagnosis of GIST and improves prediction of patient prognosis. In the present study, the value of using the expression levels of the oncoprotein ski as a prognostic predictor for GISTs was investigated. The results demonstrated that high ski expression levels were correlated with high risk and recurrence rates and indicated poor prognosis regarding median disease-free survival. Overall, the present study suggests that ski expression levels may serve as a predictor for clinical risk and prognosis of patients with GISTs., (Copyright: © Wang et al.)

Purpose: Preclinical and retrospective studies suggested a role for metformin in sensitizing patients who have diabetes with non-small cell lung cancer (NSCLC) to EGFR tyrosine kinase inhibitors (TKIs). We therefore examined its effects in combination with gefitinib in patients without diabetes harboring EGFR mutations (EGFRm)., Patients and Methods: A total of 224 patients without diabetes with treatment-naïve stage IIIB-IV EGFRm NSCLC were randomly assigned in a 1:1 ratio to receive gefitinib plus either metformin or placebo. The primary endpoint was progression-free survival (PFS) rate at 1 year and secondary endpoints included overall survival (OS), PFS, objective response rate (ORR), and safety. Serum levels of IL6 were also examined in an exploratory analysis., Results: The median duration of follow-up was 19.15 months. The estimated 1-year PFS rates were 41.2% [95% confidence interval (CI), 30.0-52.2] with gefitinib plus metformin and 42.9% (95% CI, 32.6-52.7) with gefitinib plus placebo ( P = 0.6268). Median PFS (10.3 months vs. 11.4 months) and median OS (22.0 months vs. 27.5 months) were numerically lower in the metformin group, while ORRs were similar between the two arms (66% vs. 66.7%). No significant treatment group differences were detected across all subgroups with respect to PFS, including those with elevated levels of IL6. Metformin combined with gefitinib resulted in a remarkably higher incidence of diarrhea compared with the control arm (78.38% vs. 43.24%)., Conclusions: Our study showed that addition of metformin resulted in nonsignificantly worse outcomes and increased toxicity and hence does not support its concurrent use with first-line EGFR-TKI therapy in patients without diabetes with EGFRm NSCLC., (©2019 American Association for Cancer Research.)

Cancer metastasis, a leading cause of death in patients, is associated with aberrant expression of epigenetic modifiers, yet it remains poorly defined how epigenetic readers drive metastatic growth and whether epigenetic readers are targetable to control metastasis. Here, we report that bromodomain-containing protein 4 (BRD4), a histone acetylation reader and emerging anticancer therapeutic target, promotes progression and metastasis of gastric cancer. The abundance of BRD4 in human gastric cancer tissues correlated with shortened metastasis-free gastric cancer patient survival. Consistently, BRD4 maintained invasiveness of cancer cells in vitro and their dissemination at distal organs in vivo . Surprisingly, BRD4 function in this context was independent of its putative transcriptional targets such as MYC or BCL2, but rather through stabilization of Snail at posttranslational levels. In an acetylation-dependent manner, BRD4 recognized acetylated lysine 146 (K146) and K187 on Snail to prevent Snail recognition by its E3 ubiquitin ligases FBXL14 and β-Trcp1, thereby inhibiting Snail polyubiquitination and proteasomal degradation. Accordingly, genome-wide transcriptome analyses identified that BRD4 and Snail regulate a partially shared metastatic gene signature in gastric cancer cells. These findings reveal a noncanonical posttranscriptional regulatory function of BRD4 in maintaining cancer growth and dissemination, with immediate translational implications for treating gastric metastatic malignancies with clinically available bromodomain inhibitors. SIGNIFICANCE: These findings reveal a novel posttranscriptional regulatory function of the epigenetic reader BRD4 in cancer metastasis via stabilizing Snail, with immediate translational implication for treating metastatic malignancies with clinically available bromodomain inhibitors. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/79/19/4869/F1.large.jpg., (©2019 American Association for Cancer Research.)

This study aimed to understand the stoichiometric characteristics of carbon (C), nitrogen (N) and phosphorus (P) and soil nutrients in rhizosphere and non-rhizosphere soils and to obtain information on the status of soil and microbial nutrient limitation in degraded alpine meadow. We collected soil samples from rhizosphere (0-2 mm) of dominant plant species and non-rhizosphere (0-10 cm) of the alpine meadow with four different degraded degrees in the Qilian Mountains. We measured the concentration of C, N and P and extractable C, N, P (Ext-C, Ext-N, Ext-P), the activity and proportion of extracellular enzymes (β-1, 4-glucosidase, β-1, 4-N-acetylglucosaminidase, leucine aminopeptidase and acid phosphatase) involved in C, N, P cycles, as well as soil microbial biomass (MBC, MBN, MBP). The results showed that nutrient concentrations in the rhizosphere of dominant species was higher than that in non-rhizosphere. With the increases of degradation degree, soil C:N:P changed significantly, and resulted in a serious imbalance of C:N and severe N limitation. In the degraded alpine meadows, the ratio of log-transformed rhizosphere C-, N- and P-extracellular enzymes deviated from the 1:1:1 of global ecosystem, indicating that nutrient supply was mainly restricted by N and followed by P. The contents of soil total nutrients in degraded alpine meadow was relatively high, but the contents of soil available nutrients were low, which would hinder plant growth.

Objective: To explore the predictive significance of exhaled breath temperature (EBT) for airway inflammation changes in children with asthma., Methods: A total of 60 children with asthma who met the inclusion criteria at the first visit were chosen as the asthma group, and 60 healthy children were selected as the control group. The EBT level was measured by the latest third-generation product (X-halo). The Childhood Asthma Control Test (C-ACT) score was recorded. EBT level and C-ACT score were compared between the asthma and control groups. At the subsequent visit one month later, the children were divided into well-controlled, partially-controlled, and uncontrolled groups according to their C-ACT scores. The EBT level and the FeNO level of the three groups were measured. EBT level and C-ACT score were compared among the three groups. The correlation between EBT and FeNO was analyzed. The data of initial diagnosis were reviewed, the EBT level and C-ACT score at the first visit were compared among the three groups, and the differences in EBT level and C-ACT score among the three groups at the second and first visits were evaluated., Results: At the first visit, the asthma group had a significantly higher EBT and a significantly lower C-ACT score compared with the control group (P<0.05). At the time of the subsequent visit, there was a significant difference in EBT level between the three groups, i.e., uncontrolled group > partially-controlled group > well-controlled group (P<0.05), and there was also a significant difference in C-ACT score between the three groups, i.e., well-controlled group > partially-controlled group > uncontrolled group (P<0.05). There were no significant differences in EBT level and C-ACT score at the first visit between the three groups. From the first visit to the subsequent visit, EBT level was significantly decreased in the well-controlled group (P<0.05), but significantly increased in both partially-controlled group uncontrolled groups (P<0.05); C-ACT score was significantly increased in the well-controlled and partially-controlled groups (P<0.05), but significantly decreased in the uncontrolled group (P<0.05). EBT and FeNO levels at the subsequent visit were positively correlated with each other in the uncontrolled group (P<0.05)., Conclusions: EBT has predictive significance for the changes in airway inflammation in children with asthma.

Background: Management of neuroendocrine tumors (NETs) depends on the primary site, but the location of many well-differentiated (WD) NETs is elusive. Organ-specific markers are required for pathological diagnosis from biopsy. Transcription factors with good organ specificity include TTF1 (thyroid transcription factor 1; lung), CDX2 (caudal type homeobox transcription factor 2; midgut), and ISL1 (ISL LIM homeobox 1) and PAX8 (paired box 8) for the pancreas and rectum. SATB2 (SATB homeobox 2) has shown high sensitivity and specificity in colorectal adenocarcinoma. This study determined the viability of SATB2 and other transcription factors as markers, single or in combination, for WD-NETs of various sites., Methods: Immunohistochemical staining of 81 WD-NETs from 8 organ sites was performed to identify SATB2, TTF1, CDX2, ISL1, and PAX8. Receiver operating characteristic (ROC) curves were constructed for different combinations of the 5 markers to determine sensitivity and specificity., Results: Among the WD-NETs, SATB2 was predominantly found in those of the rectum; TTF1 in the lung, larynx, and esophagus; and ISL1 in the duodenum and rectum. PAX8 and CDX2 showed poor organ specificity. ROC profiles showed 50% sensitivity and 96% specificity to lung for TTF1 + ISL1-; and 65% sensitivity and 100% specificity to rectum for SATB2 + ISL1- TTF1-. ISL1 + SATB2- TTF1- showed 83% sensitivity and 85% specificity to the duodenum, and 44% sensitivity and 87% specificity to the pancreas. A literature search showed that there was no significant difference in the expression rates of the five transcription factors (TTF1, CDX2, SATB2, PAX8 and ISL1) between primary and metastatic WD-NETs at the same organ when there was a large sample size., Conclusion: Among the 5 transcription factors tested, SATB2 may be a viable marker of WE-NETs of the rectum. The combination of SATB2, ISL1, and TTF1 may help estimate the locations of WD-NETs of unknown origin., (Copyright © 2019. Published by Elsevier GmbH.)

Acute pulmonary embolism (APE) with cardiac arrest (CA) is associated with a high mortality rate. Even upon return of the spontaneous circulation (ROSC), APE‑CA survivors are prone to myocardial cell apoptosis, a key cellular mechanism that induces heart failure. A recent study by our group discovered a post‑resuscitation imbalance in the serum angiotensin‑converting enzyme (ACE)2/ACE axis of the renin‑angiotensin system (RAS), as well as regressive cardiac function in a porcine model of APE‑CA. However, it has remained elusive how this imbalance in the ACE2/ACE axis affects myocardial cell apoptosis. In the present study, western blot and immunohistochemical analyses demonstrated that the RAS was only activated in the left myocardium, as evidenced by a decreased ACE2/ACE ratio following APE‑CA and ROSC, but not the right myocardium. Ultrastructural analysis confirmed myocardial apoptosis in the left and right myocardium. Furthermore, B‑cell lymphoma 2 (Bcl‑2)‑associated X protein (Bax) and caspase‑3 levels were elevated and Bcl‑2 levels were decreased in the left myocardium following APE‑CA and ROSC. Treatment with the ACE inhibitor captopril for 30 min after initiation of ROSC prevented the increase in Bax and the decrease in Bcl‑2 in the left myocardium compared with that in saline‑treated pigs. Captopril also inhibited the activation of extracellular signal‑regulated kinase (ERK)1/2 in the left myocardium. The results of the present study suggest that an imbalance in the ACE2/ACE axis has an important role in myocardial apoptosis following APE‑CA, which may be attributed to decreased ERK1/2 activation. In addition, it was indicated that captopril prevents apoptosis in the left myocardium after ROSC.

Early invasive growth along specific anatomical structures, especially the white matter tract, is regarded as one of the main causes of poor therapeutic outcome of people with gliomas. We show that some glioma stem cells (GSCs) are preferentially located along white matter tracts, which exhibit a demyelinated phenotype, at the invasive frontier of glioma tissues. These GSCs are CD133 + Notch1 + , whereas the nerve fibers express the Notch ligand Jagged1. The Notch-induced transcription factor Sox9 promotes the transcription of SOX2 and the methylation level of the NOTCH1 promoter is attenuated by the upregulation of SOX2 to reinforce NOTCH1 expression in GSCs. This positive-feedback loop in a cohort of glioma subjects is correlated with a poor prognosis. Inhibition of Notch signaling attenuates the white-matter-tract tropism of GSCs. These findings provide evidence indicating that the NOTCH1-SOX2 positive-feedback loop controls GSC invasion along white matter tracts.

The evolutionarily conserved Hippo signaling pathway is a key regulator of stem cell self-renewal, differentiation, and organ size. While alterations in Hippo signaling are causally linked to uncontrolled cell growth and a broad range of malignancies, genetic mutations in the Hippo pathway are uncommon and it is unclear how the tumor suppressor function of the Hippo pathway is disrupted in human cancers. Here, we report a novel epigenetic mechanism of Hippo inactivation in the context of hepatocellular carcinoma (HCC). We identify a member of the microrchidia (MORC) protein family, MORC2, as an inhibitor of the Hippo pathway by controlling upstream Hippo regulators, neurofibromatosis 2 (NF2) and kidney and brain protein (KIBRA). Mechanistically, MORC2 forms a complex with DNA methyltransferase 3A (DNMT3A) at the promoters of NF2 and KIBRA, leading to their DNA hyper-methylation and transcriptional repression. As a result, NF2 and KIBRA are crucial targets of MORC2 to regulate confluence-induced activation of Hippo signaling and contact inhibition of cell growth under both physiological and pathological conditions. The MORC2-NF2/KIBRA axis is critical for maintaining self-renewal, sorafenib resistance, and oncogenicity of HCC cells in vitro and in nude mice. Furthermore, MORC2 expression is elevated in HCC tissues, associated with stem-like properties of cancer cells, and disease progression in patients. Collectively, MORC2 promotes cancer stemness and tumorigenesis by facilitating DNA methylation-dependent silencing of Hippo signaling and could be a potential molecular target for cancer therapeutics.

Background: Melioidosis is endemic in Southeast Asia and northern Australia. Infection usually follows percutaneous inoculation or inhalation or ingestion of the causative bacterium, Burkholderia pseudomallei, which is present in soil and surface water in endemic regions. Japanese encephalitis (JE) is a vector-borne viral zoonosis caused by Japanese encephalitis virus (JEV), leading to epidemic encephalitis in Southeast Asia. Both B. pseudomallei and JEV have spread dominantly in the Hainan and Guangdong provinces in China. Here we reported the first case of co-infection of B. pseudomallei and JEV, which was discovered in Huizhou in the Guangdong province in June 2016., Case Presentation: A 52-year-old man was admitted to the hospital with acute febrile illness and headache, diagnosed as respiratory infection, central nervous system (CNS) infection, septicemia, and hepatic dysfunction. Based on B. pseudomallei-positive blood and cerebrospinal fluid (CSF) cultures, the patient was diagnosed with melioidosis and treated aggressively with antibiotics. However, the patient failed to make a full recovery. Further laboratory tests focused on CNS infection were conducted. The co-infection of B. pseudomallei and JEV was confirmed after the positive IgM antibodies of JEV were detected in both CSF and blood. After diagnosis of co-infection with B. pseudomallei and JEV, the patient was provided supportive care in hospital and recovered after approximately 3 weeks., Conclusion: Given the possibility of co-infection of B. pseudomallei and JEV, as well as variable case presentations, it is critical to enhance the awareness, detection, and treatment of co-infection in regard to melioidosis.

The microvascular profile has been included in the WHO glioma grading criteria. Nevertheless, microvessels in gliomas of the same WHO grade, e.g., WHO IV glioblastoma (GBM), exhibit heterogeneous and polymorphic morphology, whose possible clinical significance remains to be determined. In this study, we employed a fractal geometry-derived parameter, microvascular fractal dimension (mvFD), to quantify microvessel complexity and developed a home-made macro in Image J software to automatically determine mvFD from the microvessel-stained immunohistochemical images of GBM. We found that mvFD effectively quantified the morphological complexity of GBM microvasculature. Furthermore, high mvFD favored the survival of GBM patients as an independent prognostic indicator and predicted a better response to chemotherapy of GBM patients. When investigating the underlying relations between mvFD and tumor growth by deploying Ki67/mvFD as an index for microvasculature-normalized tumor proliferation, we discovered an inverse correlation between mvFD and Ki67/mvFD. Furthermore, mvFD inversely correlated with the expressions of a glycolytic marker, LDHA, which indicated poor prognosis of GBM patients. Conclusively, we developed an automatic approach for mvFD measurement, and demonstrated that mvFD could predict the prognosis and response to chemotherapy of GBM patients.

Acute pulmonary embolism (APE) is frequently reported in patients with cardiac arrest (CA) in emergency care. Pneumocyte apoptosis is commonly observed in the lungs following an APE. An important pathological mechanism evoking apoptosis during a lipopolysaccharide‑induced acute lung injury is the angiotensin‑converting enzyme 2 (ACE2)/ACE imbalance. The present study uses a porcine model to examine the anti‑apoptotic effects of captopril on APE‑CA and the return of spontaneous circulation (ROSC). Pigs were randomly assigned into four groups: Control, APE‑CA, ROSC‑saline, and ROSC‑captopril. Surviving pigs were euthanized at 6 h and lungs were isolated for analysis using several biochemical assays. Compared with the control group, the ACE2/ACE ratio was lower in the APE‑CA and ROSC pigs. In addition, APE‑CA pigs had higher Bcl‑2‑associated X protein (Bax) and cleaved caspase‑3 levels, and lower B‑cell lymphoma‑2 (Bcl‑2) level compared to control pigs. Captopril treatment reduced lung apoptosis, as demonstrated by lower TUNEL‑positive cells, higher Bcl‑2, and lower cleaved caspase‑3 protein levels in the lung. Notably, the ACE2/ACE ratio was positively correlated with Bcl‑2 protein levels and Bcl‑2/Bax ratio. In conclusion, captopril has a protective effect against lung apoptosis following ROSC and that maintaining the balance of the ACE2/ACE axis is important for inhibiting pulmonary apoptosis during APE.

Background: The chimeric antigen receptor (CAR) consists of an antigen recognition moiety from a monoclonal antibody fused to an intracellular signalling domain capable of activating T cells. The specific structure of the CAR molecule has been used in various basic research and clinical settings to detect CAR expression, but it is necessary to develop more specific and simpler monitoring methods to observe real-time changes., Materials and Methods: To develop a quantitative assay for the universal detection of DNA from anti-CD19 CAR-T cells, a TaqMan real-time quantitative polymerase chain reaction (qPCR) assay was developed using primers based on FMC63-28Z gene sequences. We identified the numbers of copies of CAR gene on T cells transduced with the CAR gene that were obtained from peripheral blood., Results: The assay had a minimum detection limit of 10 copies/μL and a strong linear standard curve (y = -3.3682x + 38.594; R 2  = 0.999) within the range of the input CAR gene (10-10 7 copies/μL). The reproducibility test showed a coefficient of variation ranging from 0.63%-1.65%. Real-time qPCR is a highly sensitive, specific, reproducible, and universal method that can be used to detect anti-CD19 CAR-T cells in peripheral blood., (Copyright © 2017 Elsevier Inc. All rights reserved.)

We established a diagnostic model to predict acute Mycoplasma pneumoniae (M. pneumonia) infection in elderly Community-acquired pneumonia (CAP) patients. We divided 456 patients into acute and non-acute M. pneumoniae infection groups. Binary logistic regression and receiver operating characteristic (ROC) curves were used to establish a predictive model. The following independent factors were identified: age ⋝ 70 years; serum cTNT level ⋝ 0.05 ng/mL; lobar consolidation; mediastinal lymphadenopathy; and antibody titer in the acute phase ⋝ 1:40. The area under the ROC curve of the model was 0.923 and a score of ⋝ 7 score predicted acute M. pneumoniae infection in elderly patients with CAP. The predictive model developed in this study has high diagnostic accuracy for the identification of elderly acute M. pneumoniae infection., (Copyright © 2017 The Editorial Board of Biomedical and Environmental Sciences. Published by China CDC. All rights reserved.)

Waste tires have excellent mechanical performance and have been used as reinforcing material in geotechnical engineering; however, their interface properties are poorly understood. To further our knowledge, this paper examines the pull-out characteristics of waste tire strips in a compacted sand, together with uniaxial and biaxial geogrids also tested under the same conditions. The analysis of the results shows that the interlocking effect and pull-out resistance between the tire strip and the sand is very strong and significantly higher than that of the geogrids. In the early stages of the pull-out test, the resistance is mainly provided by the front portion of the embedded tire strips, as the pull-out test continues, more and more of the areas towards the end of the tire strips are mobilized, showing a progressive failure mechanism. The deformations are proportional to the frictional resistance between the tire-sand interface, and increase as the normal stresses increase. Tire strips of different wear intensities were tested and presented different pull-out resistances; however, the pull-out resistance mobilization patterns were generally similar. The pull-out resistance values obtained show that rubber reinforcement can provide much higher pull-out forces than the geogrid reinforcements tested here, showing that waste tires are an excellent alternative as a reinforcing system, regardless of the environmental advantages., Competing Interests: The authors declare no conflict of interest.

Background: Study of lung function in survivor from cardiac arrest (CA) caused by pulmonary thromboembolism (PTE) was rare. The aim of this study was to investigate the variations of postresuscitation lung function after thrombolysis treatment in a CA porcine model caused by PTE., Methods: After 2 min of untreated CA, pigs of 10-12 weeks with a weight of 30 ± 2 kg (n = 24) were treated with recombinant human tissue plasminogen activator (50 mg). Cardiopulmonary resuscitation (CPR) and ventilation were initiated after drug administration. Pulmonary function and arterial blood gas parameters were measured at baseline, return of spontaneous circulation (ROSC) immediately, and 1 h, 2 h, 4 h, and 6 h after ROSC., Results: The dynamic lung compliance decreased significantly at ROSC immediately and 1 h after ROSC compared to baseline (21.86 ± 2.00 vs. 26.72 ± 2.20 ml/mmHg and 20.38 ± 1.31 vs. 26.72 ± 2.20 ml/mmHg, respectively; P < 0.05; 1 mmHg = 0.133 kPa). Compared with baseline, airway resistance increased significantly at ROSC immediately and 1 h after ROSC (P < 0.05). Respiratory index also increased after ROSC and showed significant differences among baseline, ROSC immediately, and 2 h after ROSC (P < 0.05). Oxygen delivery decreased at ROSC immediately compared to baseline (P < 0.05). The oxygenation index decreased significantly at any time after ROSC compared to baseline (P < 0.05). Extravascular lung water index and pulmonary vascular permeability index (PVPI) showed significant differences at ROSC immediately compared to baseline and 1 h after ROSC (P < 0.05); PVPI at ROSC immediately was also different from 6 h after ROSC (P < 0.05). Ventilation/perfusion ratios increased after ROSC (P < 0.05). Histopathology showed fibrin effusion, bleeding in alveoli, and hemagglutination in pulmonary artery., Conclusions: Lung function remains abnormal even after CPR with thrombolysis therapy; it is essential to continue anticoagulation and symptomatic treatment after ROSC.

Collagen components in the tumor microenvironment substantially influence cancer pathogenesis and progression. Nevertheless, in gastric cancer, collagen status and its prognostic role remain unclear. Using picrosirius red staining and immunohistochemistry, we found that collagen deposition was significantly increased in gastric cancer when compared with non-neoplastic tissues, and in cancer stroma, more immature collagen components were present, suggesting a qualitative change. Furthermore, the morphology of collagen fibers could be weakly, moderately or strongly changed in gastric cancer; when weakly or moderately changed, they appeared similar to normal collagen fibers, except for a higher linearization and density; when strongly changed, they were thicker and less eosinophilic, sharply differently from their normal counterparts. In addition, we found abundant myofibroblasts and elevated expression of lysyl oxidase-like 2 (the enzyme that mediates crosslinking of collagen molecules) in cancer stroma, which might contribute to the increased collagen deposition and crosslinking. Last, five collagen architectural parameters (alignment, density, width, length and straightness) were analyzed with second harmonic generation imaging, a highly specific technology for detection of collagen fibers, and our data indicated that all the parameters were significantly increased in the tumor microenvironment. Of the five parameters, collagen width was the most powerful parameter in predicting 5-year overall survival, and increased collagen width was associated with reduced survival. The prognostic value of collagen width was superior to traditional clinicopathological parameters, and this was validated in two unrelated gastric cancer cohorts that contained 225 and 151 patients. Collectively, the collagen status (content, maturity, morphology and architecture) was profoundly reorganized in the tumor microenvironment of gastric cancer, and collagen width could serve as a valuable prognostic indicator., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Purpose: To evaluate the prognostic value and pathobiological significance of Glasgow microenvironment score (GMS), a parameter based on tumor stroma percentage and inflammatory cell infiltration, in gastric cancer., Methods: A total of 225 cases of gastric cancer were histologically reviewed, and GMS was evaluated for each case. The association between GMS and patients' survival was investigated. Then the relationship between GMS and mismatch repair (MMR) status, Epstein-Barr virus (EBV) infection were determined using immunohistochemistry (IHC) and in situ hybridization, and the expression of PD1/PD-L1 was examined. Furthermore, the amount of cancer-associated fibroblasts (CAFs), the content and maturity of collagen components were detected using IHC, Picrosirius Red staining and second harmonic generation imaging., Results: GMS was significantly associated with clinical outcomes of gastric cancer, and multivariate analysis indicated that GMS was an independent factor (HR 1.725, P = 0.002). Low GMS was a manifestation of better prognosis and inflammatory tumor microenvironment, which was related to MMR deficiency (P = 0.042) and EBV infection (P = 0.032), and within this microenvironment, expression of PD-L1 in carcinoma cells (P = 0.030) or in inflammatory cells (P = 0.029) was significantly higher. In contrast, high GMS linked to a poorer survival and desmoplastic stroma, in which there existed markedly increased CAFs and collagen deposition., Conclusion: GMS can serve as a useful prognostic factor for gastric cancer, and according to GMS, the tumor microenvironment in this cancer type may be partially classified as inflammatory or desmoplastic microenvironment that possesses different pathobiological features.

Background: Central nervous system (CNS) brain metastasis of advanced non-small cell lung cancer (NSCLC) patients confers a worse quality of life and prognosis. The efficacy comparison of two first-generation epidermal growth factor receptor (EGFR) inhibitors erlotinib or gefitinib as first-line treatment for CNS metastasis NSCLC patients with EGFR-sensitizing mutations is yet to be elucidated., Methods: A retrospective analysis was done on cerebral metastasis rate after erlotinib or gefitinib as first-line treatment for advanced NSCLC patients with EGFR-sensitizing mutations. Time to neurological progression (nTTP) and median progression-free survival (mPFS) were calculated., Results: The study involved 279 patients (erlotinib group: 108, gefitinib group: 171). After a median follow-up of 22 months, 27 patients (25%) in the erlotinib group and 60 patients (35.1%) in the gefitinib group showed CNS progression. The HR of CNS progression for erlotinib versus gefitinib was 0.695 [95% confidence interval (CI), 0.406-1.190], suggesting a risk reduction of 30.5% although not achieving statistical significance. The 6-, 12- and 18-month cumulative CNS progression rates were 0.9, 3.7 and 12% for erlotinib compared with corresponding rates of 5.8, 9.4 and 17% for gefitinib (P = 0.181). However, for those patients with preexisting brain metastases prior to EGFR-TKI treatment, erlotinib as first line treatment significantly extended the median nTTP in comparison to gefitinib (30 months vs 15.8 months, p = 0.024)., Conclusions: Our data show that nTTP can be effectively extended in preexisting brain metastases patients with EGFR-sensitizing mutations initially treated with erlotinib compared with gefitinib. If confirmed, our results indicate that erlotinib may play an important role in controlling CNS progression from EGFR mutation-positive NSCLC.

Background: Acute abdominal pain is a common symptom of emergency patients. The severity was always evaluated based on physicians' clinical experience. The aim of this study was to establish an early risk stratification method (ERSM) for addressing adults with acute abdominal pain, which would guide physicians to take appropriate and timely measures following the established health-care policies., Methods: In Cohort 1, the records of 490 patients with acute abdominal pain that developed within the past 72 h were enrolled in this study. Measurement data and numeration data were compared with analysis of variance and Chi-square test, respectively. Multiple regression analysis calculated odd ratio (OR) value. P and OR values showed the impacts of factors. ERSM was established by clinical experts and statistical experts according to Youden index. In Cohort 2, data from 305 patients with acute abdominal pain were enrolled to validate the accuracy of the ERSM. Then, ERSM was prospectively used in clinical practice., Results: The ERSM was established based on the scores of the patient's clinical characteristics: right lower abdominal pain + 3 × diffuse abdominal pain + 3 × cutting abdominal pain + 3 × pain frequency + 3 × pain duration + fever + 2 × vomiting + 5 × stop defecation + 3 × history of abdominal surgery + hypertension history + diabetes history + hyperlipidemia history + pulse + 2 × skin yellowing + 2 × sclera yellowing + 2 × double lung rale + 10 × unconsciousness + 2 × right lower abdominal tenderness + 5 × diffuse abdominal tenderness + 4 × peritoneal irritation + 4 × bowel sounds abnormal + 10 × suspicious diagnosis + white blood cell count + hematocrit + glucose + 2 × blood urea nitrogen + 3 × creatine + 4 × serum albumin + alanine aminotransferase + total bilirubin + 3 × conjugated bilirubin + amylase. When the score was <18, the patient did not need hospitalization. A score of ≥18 and <38 indicated that the patient should be under observation or hospitalized. A score of ≥38 and <50 indicated the need for an emergent operation. A score of ≥50 indicated the need for admission to the Intensive Care Unit. The area under the receiver operating characteristic curve of the ERSM in Cohorts 1 and 2 were 0.979 and 0.988, respectively., Conclusions: This ERSM was an accurate and reliable method for making an early determination of the severity of acute abdominal pain. There was the strong correlation between scores of ERSM and health-care decision-making.

Objective: To observe the influence of electroacupuncture (EA) intervention on hippocampal glutamate (Glu) and Ca 2+ contents, and expression of Glu-N-methyl-D-aspartic acid receptor(NMDAR) and the learning-memory ability in vascular dementia (VD) rats, so as to reveal its mechanisms underlying improvement of VD., Methods: SD rats were rando-mized into sham operation (sham) group ( n =9), model group ( n =11) and EA groups ( n =10). The VD model was established by repeated bilateral common carotid arteries occlusion and reperfusion plus intraperitoneal injection of sodium nitroprusside. EA (2 Hz, 2 mA) was applied to "Baihui" (GV 20)-"Housanli" (ST 36) and "Geshu" (BL 17)-"Dazhui" (GV 14) for 10 min, once a day for 15 consecutive days. The neurological function was assessed by using stroke index (0-10 points) and neurological deficit scaling(0-10 points). The learning-memory ability was evaluated by using step-down tests. The contents of Glu and Ca 2+ in the right hippocampal tissue were determined by using aspectrophotometer and the expression of NMDAR protein in the right hippocampus was detected by immunoblotting., Results: Compared with the sham group, the stroke index and neurological deficit scores, and the reaction latency and the error times of step-down tests, as well as the contents of Glu and Ca 2+ and the expression level of NMDAR in the right hippocampus were significantly increased in the model group ( P <0.05, P <0.01), while the step-through latency was considerably decreased ( P <0.01), suggesting a neurological disorder and a cognitive decline. After EA intervention, the reaction latency and error times of step-down tests, the contents of Glu and Ca 2+ and the expression level of NMDAR in the right hippocampus were significantly down-regulated, and the step-through latency was notably increased in comparison with the model group ( P <0.01)., Conclusions: EA intervention is able to improve the cognitive ability of VD rats, which may be associated with its effects in reducing the excitatory neurotoxicity of hippocampal Glu-NMDAR and lowering cellular Ca 2+ load to resist neuronal injury.

In recent years, there are increasing articles concerning Epstein-Barr virus associated lymphoproliferative disorder (EBV+ LPD), and the name of EBV+ LPD is used widely. However, the meaning of EBV+ LPD used is not the same, which triggered confusion of the understanding and obstacles of the communication. In order to solve this problem. Literature was reviewed with combination of our cases to clarify the concept of EBV+ LPD and to expound our understanding about it. In general, it is currently accepted that EBV+ LPD refers to a spectrum of lymphoid tissue diseases with EBV infection, including hyperplasia, borderline lesions, and neoplastic diseases. According to this concept, EBV+ LPD should not include infectious mononucleosis (IM) and severe acute EBV infection (EBV+ hemophagocytic lymphohistiocytosis, fatal IM, fulminant IM, fulminant T-cell LPD), and should not include the explicitly named EBV+ lymphomas (such as extranodal NK/T cell lymphoma, aggressive NK cell leukemia, Burkitt lymphoma, and Hodgkin lymphoma, etc.) either. EBV+ LPD should currently include: (1) EBV+ B cell-LPD: lymphomatoid granulomatosis, EBV + immunodeficiency related LPD, chronic active EBV infection-B cell type, senile EBV+ LPD, etc. (2) EBV+ T/NK cell-LPD: CAEBV-T/NK cell type, hydroa vacciniforme, hypersensitivity of mosquito bite, etc. In addition, EBV+ LPD is classified, based on the disease process, pathological and molecular data, as 3 grades: grade1, hyperplasia (polymorphic lesions with polyclonal cells); grade 2, borderline (polymorphic lesions with clonality); grade 3, neoplasm (monomorphic lesions with clonality). There are overlaps between EBV+ LPD and typical hyperplasia, as well as EBV+ LPD and typical lymphomas. However, the most important tasks are clinical vigilance, early identification of potential severe complications, and treating the patients in a timely manner to avoid serious complications, as well as the active treatment to save lives when the complications happened.

Background: To explore the relationship between age, sex, the level of Helicobacter pylori (HP) infection and serum pepsinogen (PG) in healthy people undergoing a medical examination., Methods: A total of 6,596 "healthy" individuals undergoing a medical examination were selected as subjects in this study. The concentrations of serum pepsinogen I (PGI) and serum pepsinogen II (PGII) were tested for each of the subjects using time-resolved fluorescence immunoassay characterized with high sensitivity and wide measuring range. The infection ratio and level of HP were tested using a 13C-urea breath test to analyze the relationship between age, sex, HP infection, and serum PGs., Results: The PGI, PGII and PGI-to-PGII ratio (x¯±S) were higher in males than in females. The serum PGI and PGII levels gradually increased with age. HP infection rate was 48.83%, and the serum PGI, PGII and PGI-to-PGII ratio (x¯±S) were 187.05 ± 73.50µg/L, 18.09 ± 8.68µg/L and 11.67 ± 5.44, respectively in the HP-positive group and 150.39 ± 67.04µg/L, 11.50 ± 7.45µg/L and 15.67 ± 8.19, respectively in the HP-negative group. There was significant difference in the detection rate of an abnormal PG between the 2 groups as with the worsening of HP infection, 13C-urea breath test and serum PGI and PGII levels increased, but the PGI-to-PGII ratio decreased significantly., Conclusions: Serum PGI and PGII levels were correlated with age, sex and the level of HP infection. Therefore, the influencing factors of age, sex and the level of HP infection should be considered when screening stomach diseases using PG., (Copyright © 2016 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.)

Acute pulmonary embolism (APE) has a very high mortality rate, especially at cardiac arrest and even after the return of spontaneous circulation (ROSC). This study investigated the protective effect of the angiotensin-converting enzyme (ACE) inhibitor captopril on postresuscitation hemodynamics, in a porcine model of cardiac arrest established by APE. Twenty-nine Beijing Landrace pigs were infused with an autologous thrombus leading to cardiac arrest and subjected to standard cardiopulmonary resuscitation and thrombolysis. Ten resuscitated pigs were randomly and equally apportioned to receive either captopril (22.22 mg/kg) infusion or the same volume saline, 30 min after ROSC. Hemodynamic changes and ACE-Ang II-angiotensin II type 1 receptor (AT1R) and ACE2/Ang-(1-7)/Mas receptor axis levels were determined. APE was associated with a decline in mean arterial pressure and a dramatic increase in pulmonary artery pressure and mean right ventricular pressure. After ROSC, captopril infusion was associated with significantly lower mean right ventricular pressure and systemic and pulmonary vascular resistance, faster heart rate, and higher Ang-(1-7) levels, ACE2/ACE, and Ang-(1-7)/Ang II, compared with the saline infusion. The ACE2/Ang-(1-7)/Mas pathway correlated negatively with external vascular lung water and pulmonary vascular permeability and positively with the right cardiac index. In conclusion, in a pig model of APE leading to cardiac arrest, captopril infusion was associated with less mean right ventricular pressure overload after resuscitation, compared with saline infusion. The reduction in systemic and pulmonary vascular resistance associated with captopril may be by inhibiting the ACE-Ang II-AT1R axis and activating the ACE2/Ang-(1-7)/Mas axis.

Verticillium wilt, caused by the Verticillium dahliae phytopathogen, is a devastating disease affecting many economically important crops. Previous studies have shown that the exoproteome of V. dahliae plays a significant role in this pathogenic process, but the components and mechanisms that underlie this remain unclear. In this study, the exoproteome of V. dahliae was induced in a cotton-containing C'zapek-Dox (CCD) medium and quantified using the high-throughput isobaric tag technique for relative and absolute quantification (iTRAQ). Results showed that the abundance of 271 secreted proteins was affected by the CCD medium, of which 172 contain typical signal peptides generally produced by the Golgi/endoplasmic reticulum (ER). These enhanced abundance proteins were predominantly enriched in carbohydrate hydrolases; 126 were classified as carbohydrate-active (CAZymes) and almost all were significantly up-regulated in the CCD medium. Results showed that CAZymes proteins 30 and 22 participate in pectin and cellulose degradation pathways, corresponding with the transcription levels of several genes encoded plant cell wall degradation enzyme activated significantly during cotton infection. In addition, targeted deletion of two pectin lyase genes ( VdPL3.1 and VdPL3.3 ) impaired wilt virulence to cotton. This study demonstrates that the V. dahliae exoproteome plays a crucial role in the development of symptoms of wilting and necrosis, predominantly via the pathogenic mechanisms of plant cell wall degradation as part of host plant infection.

Background: The success rate of resuscitation in cardiac arrest (CA) caused by pulmonary thromboembolism (PTE) is low. Furthermore, there are no large animal models that simulate clinical CA. The aim of this study was to establish a porcine CA model caused by PTE and to investigate the pathophysiology of CA and postresuscitation., Methods: This model was induced in castrated male pigs (30 ± 2 kg; n = 21) by injecting thrombi (10-15 ml) via the left external jugular vein. Computed tomographic pulmonary angiography (CTPA) was performed at baseline, CA, and return of spontaneous circulation (ROSC). After CTPA during CA, cardiopulmonary resuscitation (CPR) with thrombolysis (recombinant tissue plasminogen activator 50 mg) was initiated. Hemodynamic, respiratory, and blood gas data were monitored. Cardiac troponins T, cardiac troponin I, creatine kinase-MB, myoglobin, and brain natriuretic peptide (BNP) were measured by enzyme-linked immunosorbent assay. Data were compared between baseline and CA with paired-sample t-test and compared among different time points for survival animals with repeated measures analysis of variance., Results: Seventeen animals achieved CA after emboli injection, while four achieved CA after 5-8 ml more thrombi. Nine animals survived 6 h after CPR. CTPA showed obstruction of the pulmonary arteries. Mean aortic pressure data showed occurrence of CA caused by PTE (Z = -2.803, P = 0.002). The maximal rate of mean increase of left ventricular pressure (dp/dtmax) was statistically decreased (t = 6.315, P = 0.000, variation coefficient = 0.25), and end-tidal carbon dioxide partial pressure (PetCO2) decreased to the lowest value (t = 27.240, P = 0.000). After ROSC (n = 9), heart rate (HR) and mean right ventricular pressure (MRVP) remained different versus baseline until 2 h after ROSC (HR, P = 0.036; MRVP, P = 0.027). Myoglobin was statistically increased from CA to 1 h after ROSC (P = 0.036, 0.026, 0.009, respectively), and BNP was increased from 2 h to 6 h after ROSC (P = 0.012, 0.014, 0.039, respectively)., Conclusions: We established a porcine model of CA caused by PTE. The dp/dtmaxand PetCO2may be important for the occurrence of CA, while MRVP may be more important in postresuscitation.

Objective: To investigate the risk factors for the development of congenital anal atresia in neonates., Methods: A total of 70 neonates who were admitted to 17 hospitals in Foshan, China from January 2011 to December 2014 were enrolled as case group, and another 70 neonates who were hospitalized during the same period and had no anal atresia or other severe deformities were enrolled as control group. Univariate and multivariate logistic regression analyses were used to investigate the risk factors for the development of congenital anal atresia., Results: The univariate analysis revealed that the age of mothers, presence of oral administration of folic acid, infection during early pregnancy, and polyhydramnios, and sex of neonates showed significant differences between the case and control groups (P<0.05). The multivariate logistic regression analysis revealed that infection during early pregnancy (OR=18.776) and male neonates (OR=9.304) were risk factors for congenital anal atresia, and oral administration of folic acid during early pregnancy was the protective factor (OR=0.086)., Conclusions: Infection during early pregnancy is the risk factor for congenital anal atresia, and male neonates are more likely to develop congenital anal atresia than female neonates. Supplementation of folic acid during early pregnancy can reduce the risk of congenital anal atresia.

The aim of this study was to evaluate the association of GSTM1 null/present, GSTT1 null/present, and GSTP1 IIe105Val polymorphisms with the chemotherapy response and overall survival of advanced NSCLC. Two hundred and sixty-two patients with histologically confirmed advanced NSCLC (inoperable TNM stages IIIA, IIIB, and IV) were enrolled to this hospital-based study between May 2009 and May 2012. The GSTM1 null/present, GSTT1 null/present, and GSTP1 IIe105Val polymorphisms were genotyped by polymerase chain reaction coupled with restriction fragment length polymorphism. A logistic regression analysis revealed a correlation between the null genotype of GSTM1 and improved response to chemotherapy [odds ratio = 1.82; 95% confidence interval (CI) = 1.06-3.14]. Analyses with the Cox proportional hazards model also indicated that the null genotype of GSTM1 was associated with lower risk of death (hazard ratio = 0.40; 95%CI = 0.23-0.69). In conclusion, the null genotype of GSTM1 was found to be correlated with improved response to chemotherapy and lower risk of death in advanced NSCLC patients.

Myelolipomas are benign tumors, consisting of hematopoietic cells and mature adipose tissue, which mainly occur within the adrenal gland. Extra-adrenal myelolipomas are rare, and fewer than 60 cases have been reported in the literature. Here, we report a case of intrasplenic myelolipoma in a 42-year-old man with more than 1 month of abdominal pain. Computed tomography scanning revealed a giant, heterogeneous, well-demarcated mass in the spleen. Splenectomy was performed, and an intrasplenic giant mass was completely excised. The diagnosis of myelolipoma was made based on morphological examination. To the best of our knowledge, this is the third reported case of myelolipoma in the human spleen., (© The Author(s) 2015.)

Background and Purpose: Vascular proliferation is a major criterion for grading gliomas on the basis of histology. Relative cerebral blood volume can provide pathophysiologic information about glioma grading. Vessel size imaging, in some animals, can be used to estimate the microvascular caliber of a glioma, but its clinical use remains unclear. Herein, we aimed to compare the predictive power of relative cerebral blood volume and vessel size imaging in glioma grading, with grading based on histology., Materials and Methods: Seventy patients with glioma participated in the study; 30 patients underwent MR perfusion imaging with a spin-echo sequence and vessel size imaging with a gradient-echo and spin-echo sequence successively at 24-hour intervals before surgery. We analyzed the vessel size imaging values and relative cerebral blood volume of differently graded gliomas. The microvessel parameters were histologically evaluated and compared with those on MR imaging. The cutoff values of vessel size imaging and relative cerebral blood volume obtained from receiver operating characteristic curve analyses were used to predict glioma grading in another 40 patients., Results: Vessel size imaging values and relative cerebral blood volume were both increased in high-grade gliomas compared with low-grade gliomas (P < .01). Moreover, vessel size imaging values had higher specificity and sensitivity in differentiating high-grade from low-grade gliomas compared with relative cerebral blood volume. In addition, a significant correlation was observed between vessel size imaging values and microvessel diameters (r > 0.8, P < .05) and between relative cerebral blood volume and microvessel area (r = 0.6579, P < .05). Most important, the use of vessel size imaging cutoff values to predict glioma grading was more accurate (100%) than use of relative cerebral blood volume (85%) values., Conclusions: Vessel size imaging can provide more accurate information on glioma grading and may serve as an effective biomarker for the prognosis of patients with gliomas., (© 2016 by American Journal of Neuroradiology.)