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Background In bladder cancer, up to 70% of patients will relapse after resection within 5 years, in which the mechanism underlying the recurrence remains largely unclear. Methods Quantitative real-time PCR, western blot and immunohistochemistry were conducted. The assays of tumor sphere formation and tumor xenograft were further performed to assess the potential biological roles of ATF5 (activating transcription factor 5). Chromatin immunoprecipitation-qPCR and luciferase activity assays were carried out to explore the potential molecular mechanism. A two-tailed paired Student's t-test, χ2 test, Kaplan Meier and Cox regression analyses, and Spearman's rank correlation coefficients were used for statistical analyses. Results ATF5 is elevated in bladder urothelial cancer (BLCA) tissues, especially in recurrent BLCA, which confers a poor prognosis. Overexpressing ATF5 significantly enhanced, whereas silencing ATF5 inhibited, the capability of tumor sphere formation in bladder cancer cells. Mechanically, ATF5 could directly bind to and stimulate the promoter of DVL1 gene, resulting in activation of Wnt/β-catenin pathway. Conclusions This study provides a novel insight into a portion of the mechanism underlying high recurrence potential of BLCA, presenting ATF5 as a prognostic factor or potential therapeutic target for preventing recurrence in BLCA.

Background Although transcatheter technology has achieved some success in the field of mitral valves, the feasibility of applying it to patients with degenerated mitral valve bioprostheses (valve-in-valve, ViV), failure of mitral valvuloplasty (valve-in-ring, ViR) and serious mitral annulus calcification (vale-in-MAC, ViMAC) has not been effectively evaluated. Methods By searching published literature before December 5, 2020 in four databases, we found all the literature related to the evaluation of feasibility assessment of TMViV, TMViR and TMViMAC. Outcomes focused on all-cause mortality within 30 days, bleeding and LVOT obstruction. Results A total of six studies were included, and all of them were followed up for at least 30 days. After analysis of the ViV–ViR group, we obtained the following results: the all-cause mortality within 30 days of the ViV group was lower than that of the ViR group. Life-threatening or fatal bleeding was more likely to occur in the ViR group after surgery. At the same time, the ViR group was more prone to left ventricular outflow tract obstruction. However, in the ViMAC–ViR group, only the all-cause mortality within 30 days and stroke were statistically significant. In the indirect comparison, we found that TMViV had the best applicability, followed by TMViR. There were few TMViMAC available for analysis, and it requires further studies to improve the accuracy of the results. Conclusion TMViV and TMViR had good applicability and could benefit patients who underwent repeat valve surgery. The feasibility of TMViMAC needs to be further explored and improved.

Chemoresistance is the most significant reason for the failure of cancer treatment following radical cystectomy. The response rate to the first-line chemotherapy of cisplatin and gemcitabine does not exceed 50%. In our previous research, elevated BMI1 (B-cell specific Moloney murine leukemia virus integration region 1) expression in bladder cancer conferred poor survival and was associated with chemoresistance. Herein, via analysis of The Cancer Genome Atlas database and validation of clinical samples, BMI1 was elevated in patients with bladder cancer resistant to cisplatin and gemcitabine, which conferred tumor relapse and progression. Consistently, BMI1 was markedly increased in the established cisplatin- and gemcitabine-resistant T24 cells (T24/DDP&GEM). Functionally, BMI1 overexpression dramatically promoted drug efflux, enhanced viability and decreased apoptosis of bladder cancer cells upon treatment with cisplatin or gemcitabine, whereas BMI1 downregulation reversed this effect. Mechanically, upon interaction with p53, BMI1 was recruited on the promoter of miR-3682-3p gene concomitant with an increase in the mono-ubiquitination of histone H2A lysine 119, leading to transcription repression of miR-3682-3p gene followed by derepression of ABCB1 (ATP binding cassette subfamily B member 1) gene. Moreover, suppression of P-glycoprotein by miR-3682-3p mimics or its inhibitor XR-9576, could significantly reverse chemoresistance of T24/DDP&GEM cells. These results provided a novel insight into a portion of the mechanism underlying BMI1-mediated chemoresistance in bladder cancer.

The impact of different first-line epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI)s to the clinical efficacy of osimertinib in EGFR-mutant non-small-cell lung cancer (NSCLC) patients with acquired T790M was still unclear. We enrolled 733 advanced EGFR-mutant NSCLC patients with gefitinib, erlotinib or afatinib as first-line EGFR-TKIs treatment for analysis. 373 patients received re-biopsies after progressive disease to first-line EGFR-TKIs treatment, and the total positive rate of T790M was 51.7%. 151 patients who harbored T790M received osimertinib as subsequent treatment. Among them, the median progression-free survival (PFS) of first-line EGFR-TKI (PFS1) was 14.0 months, and the median PFS of osimertinib (PFS2) was 10.1 months. The median PFS1 + PFS2 was 27.5 months, and the median overall survival from first-line EGFR-TKI was 61.3 months. Concerning different first-line EGFR-TKIs, the median PFS2 was 10.9 months in the gefitinib group, 10.0 months in the erlotinib group, and 6.7 months in the afatinib group (p = 0.534). The median PFS1 + PFS2 was 27.7 months, 26.8 months and 24.0 months in the gefitinib, erlotinib, and afatinib group, respectively (p = 0.575). In conclusion, both first-generation and second-generation EGFR-TKIs sequential osimertinib treatment provided good clinical efficacy in advanced EGFR-mutant NSCLC patients with acquired T790M mutation.

Accurate methods for identifying pelvic lymph node metastasis (LNM) of prostate cancer (PCa) prior to surgery are still lacking. We aimed to investigate the predictive value of peripheral monocyte count (PMC) for LNM of PCa in this study. Two hundred and ninety-eight patients from three centers were divided into a training set (n = 125) and a validation set (n = 173). In the training set, the independent predictors of LNM were analyzed using univariate and multivariate logistic regression analyses, and the optimal cutoff value was calculated by the receiver operating characteristic (ROC) curve. The sensitivity and specificity of the optimal cutoff were authenticated in the validation cohort. Finally, a nomogram based on the PMC was constructed for predicting LNM. Multivariate analyses of the training cohort demonstrated that clinical T stage, preoperative Gleason score, and PMC were independent risk factors for LNM. The subsequent ROC analysis showed that the optimal cutoff value of PMC for diagnosing LNM was 0.405 × 109 l-1 with a sensitivity of 60.0% and a specificity of 67.8%. In the validation set, the optimal cutoff value showed significantly higher sensitivity than that of conventional magnetic resonance imaging (MRI) (0.619 vs 0.238, P < 0.001). The nomogram involving PMC, free prostate-specific antigen (fPSA), clinical T stage, preoperative Gleason score, and monocyte-to-lymphocyte ratio (MLR) was generated, which showed a robust predictive capacity for predicting LNM before the operation. Our results indicated that PMC as a single agent, or combined with other clinical parameters, showed a robust predictive capacity for LNM in PCa. It can be employed as a complementary factor for the decision of whether to conduct pelvic lymph node dissection.

Heart auscultation is a convenient tool for early diagnosis of heart diseases and is being developed to be an intelligent tool used in online medicine. Currently, there are few studies on intelligent diagnosis of pediatric murmurs due to congenital heart disease (CHD). The purpose of the study was to develop a method of intelligent diagnosis of pediatric CHD murmurs. Phonocardiogram (PCG) signals of 86 children were recorded with 24 children having normal heart sounds and 62 children having CHD murmurs. A segmentation method based on the discrete wavelet transform combined with Hadamard product was implemented to locate the first and the second heart sounds from the PCG signal. Ten features specific to CHD murmurs were extracted as the input of classifier after segmentation. Eighty-six artificial neural network classifiers were composed into a classification system to identify CHD murmurs. The accuracy, sensitivity, and specificity of diagnosis for heart murmurs were 93%, 93.5%, and 91.7%, respectively. In conclusion, a method of intelligent diagnosis of pediatric CHD murmurs is developed successfully and can be used for online screening of CHD in children.

Besides being a predictive biomarker of response to immunotherapy in lung cancer in general, programmed death-ligand 1 (PD-L1) is not so well correlated with treatment outcomes of lung adenocarcinoma (ADC) harbouring epidermal growth factor receptor (EGFR) mutations, as reported studies are inconclusive and seldom addressed the issues of response to treatment and resistance. The primary objective is to evaluate the association of PD-L1 and EGFR tyrosine kinase inhibitor (TKI) efficacy, resistance, and relevant clinical outcomes. The secondary objective is to further explore the tumour microenvironments of EGFR mutant tumours with different PD-L1 expression.Using immunohistochemical (IHC) staining, we retrospectively tested PD-L1 expression (Dako 22C3) in the pre-treatment tumours from advanced EGFR mutant lung ADC patients, of whom all were treated with TKIs. Multiplex IHC assay was applied for exploring immune cells in tumour microenvironments.A total of 153 Taiwanese patients were enrolled in our study, of whom a majority of cases were female (58.9%) and non-smokers (75.8%). The objective response rate (ORR) to EGFR TKI and progression-free survival (PFS) were better in patients with PD-L1 expression50% (ORR/PFS in PD-L1 0% versus 1-49% versus ≥50%: 65.6%/12.5 months versus 56.4%/12.8 months versus 38.9%/5.9 months, P 0.05). The multivariate analysis showed that PD-L150% was an independent prognostic factor for longer PFS (hazard ratio (HR) 0.433, 95% confidence interval (CI) 0.250-0.751, P = 0.003). Furthermore, tumours with higher PD-L1 expression were less likely to develop a secondary T790M mutation (T790M+ in PD-L1 0% versus 1-49% versus ≥50%: 53.7% versus 35.7% versus 10%, P = 0.024). Multiplex IHC tests were applied in 15 cases and revealed a potential correlation between PD-L1, immune cells, and EGFR TKI responses.Lower pre-treatment PD-L1 is associated with better ORR, PFS, and higher frequency of T790M resistance in EGFR TKI-treated lung ADC patients.

Objective: To investigate the optimal age for the baseline serum prostate-specific antigen (PSA) test and for repeat screening and its economic burden in a single center in China. Materials and Methods: 35,533 men with PSA screening were retrospectively enrolled in this study. Follow-ups were conducted in 1,586 men with PSA >4 ng/mL, and receiver-operating characteristic (ROC) curves were employed to investigate the optimal cutoffs. Results: ROC analysis indicated that the optimal age for initial PSA screening was 57.5 years (AUC = 0.84), 62.5 years (AUC = 0.902), 60.5 years (AUC = 0.909), and 61.5 years (AUC = 0.890) for individuals with PSA >4 and >10 ng/mL, a diagnosis of prostate cancer (PCa), and clinically significant PCa defined as the focus events, respectively. For Chinese men aged 50–59, 60–69, and >70 years, the initial PSA levels of 1.305 ng/mL (AUC = 0.699), 1.975 ng/mL (AUC = 0.711), and 2.740 ng/mL (AUC = 0.720) might have a PSA velocity >0.75 ng/mL per year during the follow-up. In addition, the total cost amounts to CNY 13,609,260 in these cases, but only 60 of the 35,533 (0.17%) men gained benefit from PSA screening. Conclusion: In our opinion, the optimal starting age for initial PSA testing was 57.5 years. The necessity for repeat screening should be based on the first PSA level depending on age. A cost-­benefit analysis should be included in population-based screening.

Background: Accumulations of stressful life events result in the onset of major depressive disorder (MDD). Comprehensive genomic analysis is required to elucidate pathophysiological changes and identify applicable biomarkers. Methods: Transcriptomic analysis was performed on different brain parts of a chronic mild stress (CMS)-induced MDD mouse model followed by systemic analysis. QPCR and ELISA were utilized for validation in mice and patients. Results: The highest numbers of genes with significant changes induced by CMS were 505 in the amygdala followed by 272 in the hippocampus (twofold changes, FDR, p &lt, 0.05). Enrichment analysis indicated that the core-enriched genes in CMS-treated mice were positively enriched for IFN-γ response genes in the amygdala, and hedgehog signaling in the hippocampus. Transthyretin (TTR) was severely reduced in CMS-treated mice. In patients with diagnosed MDD, serum concentrations of TTR were reduced by 48.7% compared to controls (p = 0.0102). Paired samples from patients with MDD demonstrated a further 66.3% increase in TTR at remission compared to the acute phase (p = 0.0339). Conclusions: This study provides comprehensive information on molecular networks related to MDD as a basis for further investigation and identifies TTR for MDD monitoring and management. A clinical trial with bigger patient cohort should be conducted to validate this translational study.

PurposeThe aim of this study was to investigate the efficacy of various epidermal growth factor receptor (EGFR)–tyrosine kinase inhibitors (TKIs) plus bevacizumab in advanced EGFR-mutant lung adenocarcinoma patients.Materials and MethodsFrom August 2016 to October 2020, we enrolled advanced lung adenocarcinoma patients harboring exon 19 deletion or L858R receiving gefitinib, erlotinib and afatinib plus bevacizumab as the first-line treatment for the purposes of analysis.ResultsA total of 36 patients were included in the final analysis. Three patients received gefitinib, 17 received erlotinib, and 16 received afatinib combined with bevacizumab as the first-line treatment. The objective response rate was 77.8%, and disease control rate was 94.4%. The overall median progression-free survival (PFS) was 16.4 months, while the median PFS was 17.1 months in patients with exon 19 deletion, and 16.2 months in patients with L858R mutation (p=0.311). Regarding the use of different EGFR-TKIs, the median PFS was 17.1 months in the erlotinib group and 21.6 months in the afatinib group (p=0.617). In patients with brain metastasis at baseline, the median PFS was 18.9 months in the erlotinib group and 16.4 months in the afatinib group (p=0.747). Amongst patients harboring exon 19 deletion, the median PFS was 16.2 months in the erlotinib group and not-reached in the afatinib group (p=0.141). In patients with L858R mutation, the median PFS was 18.9 months in the erlotinib group and 16.2 months in the afatinib group (p=0.481).ConclusionOur research demonstrates that not only erlotinib combined with bevacizumab, but also afatinib plus bevacizumab as first-line treatment, provides solid clinical efficacy in advanced EGFR-mutant lung adenocarcinoma patients.

The development of congenital heart disease (CHD) is a complicated process and affected by multiple environmental factors, as genetic factors, and the interactions among those factors. Previous studies have shown that intrauterine hypoxic environment exposure is a risk factor of CHD, but the genetic factors involved in the process are not clear. In this study, given that tetralogy of Fallot (TOF) is a CHD with hypoxemia as its primary pathophysiological manifestation, an in silico analysis was performed to reveal the relationship between potential target genes (miR-124) with the energy metabolism in non-syndromic TOF patients’ cardiomyocyte. Furthermore, the study investigated the correlation between the primary miR-124 (rs531564) polymorphism and CHD susceptibility in 432 sporadic patients and 450 controls from two different altitude provinces (city) in China. Our study indicated that the minor C allele of rs531564 correlated with reduced risk of CHD in the low altitude city. Besides, the C allele has elevated frequency in the high-altitude group. Therefore, our findings suggest that the minor C allele of rs531564 SNP may be involved in the reduction of the risk of CHD in a way that interacts with the intrauterine hypoxic environmental factors. Electronic supplementary material The online version of this article (10.1007/s11356-019-05350-4) contains supplementary material, which is available to authorized users.

Objective Histologic transformation from adenocarcinoma to small cell lung cancer (SCLC) is one of the mechanisms of acquired resistance after epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment. Furthermore, de novo combined SCLC/non-small cell lung cancer (NSCLC) have occasionally been reported; however, their mutational statuses and clinicopathological features have not yet been elucidated. In this study, we aimed to profile the genetic backgrounds of these 2 different histologic components by investigating patients with de novo combined SCLC/NSCLC as well as those with lung adenocarcinoma who experienced SCLC transformation after TKI treatment. Materials and methods Four patients with de novo combined SCLC/NSCLC were investigated, as were 4 other patients with lung adenocarcinoma who experienced SCLC transformation after TKI treatment. The different histologic components of the tumors in each patient were tested for thyroid transcription factor-1, p40, synaptophysin, chromogranin A, p53, retinoblastoma protein (Rb), and achaete-scute homolog 1 (ASCL1) via immunohistochemistry, and were macroscopically dissected for mutational analysis using next-generation sequencing with the Oncomine Focus Assay and Comprehensive Assay panel. Results The distinct histologic components in patients with de novo combined SCLC/NSCLC and those with adenocarcinoma exhibiting small cell transformation showed high consistency in EGFR/TP53/RB1 mutations, and expression patterns of p53 and Rb. A high frequency of activating mutations involving PI3K/AKT1 signaling pathway was observed in SCLC. Nuclear ASCL1 expression was present in SCLC but absent or barely present in adenocarcinoma in 7 cases. Conclusions Our data imply that inactivation of TP53/RB1 function is a possible early event in the histogenesis of synchronous and metachronous SCLC/NSCLC. Moreover, the non-adenocarcinoma (SCLC) component might arise from the adenocarcinoma (NSCLC) component through a mechanism that involves the activation of the ASCL1 and PI3K/AKT1 signaling pathways.

BACKGROUND We performed the present study to better elucidate the correlation of reduced folate carrier-1 (RFC1) A80G (rs1051266) polymorphism with the risk of congenital heart disease (CHD). MATERIAL AND METHODS According to the designed search strategy, a systematic literature search was performed through the PubMed, Cochrane Library, Web of Science, EMBASE, CNKI, VIP, and Wan Fang databases to collect published case-control studies on the correlation between RFC1 A80G polymorphism and CHD. All relevant studies up to October 1, 2019 were identified. The odds ratio (OR) and 95% confidence interval (CI) of the genotype distribution were used as the effect indicators. RESULTS A total of 6 eligible studies was finally included in our meta-analysis, including 724 children with CHD, 760 healthy children, 258 mothers of the children with CHD, and 334 mothers of healthy control children. The meta-analysis revealed that for fetal analysis, only in the heterozygous model (GA vs GG, OR=1.36, 95% CI [1.06, 1.75], P=0.02) was RFC1 A80G polymorphism associated with risk of CHD. In maternal analysis, 3 genetic models of RFC1 A80G polymorphism increased the risk of CHD: the allelic model (A vs G, OR=1.36, 95% CI [1.07, 1.71], P=0.01), the homozygote model (AA vs GG, OR=2.99, 95%CI [1.06, 8.41], P=0.04), and the dominance model (GA+AA vs GG, OR=1.53, 95%CI [1.08, 2.16], P=0.02). CONCLUSIONS The maternal RFC1 A80G polymorphism has a strong correlation with CHD. Compared with the G allele, the A allele increases the risk of CHD by 0.36-fold.

Formation of glioma stem cells (GSCs) is considered as one of the main reasons of temozolomide (TMZ) resistance in glioma patients. Recent studies have shown that tumor microenvironment-derived signals could promote GSCs formation. But the critical molecule and underlying mechanism for GSCs formation after TMZ treatment is not entirely identified. Our study showed that TMZ treatment promoted GSCs formation by glioma cells; TMZ treatment of biopsy-derived glioblastoma multiforme cells upregulated HMGB1; HMGB1 altered gene expression profile of glioma cells with respect to mRNA, lncRNA and miRNA. Furthermore, our results showed that TMZ-induced HMGB1 increased the formation of GSCs and when HMGB1 was downregulated, TMZ-mediated GSCs formation was attenuated. Finally, we showed that the effect of HMGB1 on glioma cells was mediated by TLR2, which activated Wnt/β-catenin signaling to promote GSCs. Mechanistically, we found that HMGB1 upregulated NEAT1, which was responsible for Wnt/β-catenin activation. In conclusion, TMZ treatment upregulates HMGB1, which promotes the formation of GSCs via the TLR2/NEAT1/Wnt pathway. Blocking HMGB1-mediated GSCs formation could serve as a potential therapeutic target for preventing TMZ resistance in GBM patients.

Rhabdomyosarcoma (RMS) is a heterogeneous soft tissue neoplasm most frequently found in children and adolescents. As the prognosis for recurrent and metastatic RMS remains poor, immunotherapies are hoped to improve quality of life and survival. CD137 is a member of tumor necrosis factor receptor family and a T cell costimulatory molecule which induces potent cellular immune responses that are able to eliminate malignant cells. Therefore, it was puzzling to find expression of CD137 on an RMS tissue microarray by multiplex staining. CD137 is not only expressed by infiltrating T cells but also by malignant RMS cells. Functional in vitro experiments demonstrate that CD137 on RMS cells is being transferred to adjacent antigen-presenting cells by trogocytosis, where it downregulates CD137 ligand, and thereby reduces T cell costimulation which results in reduced killing of RMS cells. The transfer of CD137 and the subsequent downregulation of CD137 ligand is a physiological negative feedback mechanism that is likely usurped by RMS, and may facilitate its escape from immune surveillance. In addition, CD137 signals into RMS cells and induces IL-6 and IL-8 secretion, which are linked to RMS metastasis and poor prognosis. However, the ectopic expression of CD137 on RMS cells is an Achilles’ heel that may be utilized for immunotherapy. Natural killer cells expressing an anti-CD137 chimeric antigen receptor specifically kill CD137-expressing RMS cells. Our study implicates ectopic CD137 expression as a pathogenesis mechanism in RMS, and it demonstrates that CD137 may be a novel target for immunotherapy of RMS.

The drug response sensitivity and related prognosis of prostate cancer varied from races, while the original mechanism remains rarely understood. In this study, the comprehensive signature including transcriptomics, epigenome and single nucleotide polymorphisms (SNPs) of 485 PCa cases- including 415 Whites, 58 Blacks and 12 Asians from the TCGA database were analyzed to investigate the drug metabolism differences between races. We found that Blacks and Whites had a more prominent drug metabolism, cytotoxic therapy resistance, and endocrine therapy resistance than Asians, while Whites were more prominent in drug metabolism, cytotoxic therapy resistance and endocrine therapy resistance than Blacks. Subsequently, the targeted regulation analysis indicated that the racial differences in cytotoxic therapy resistance, endocrine therapy resistance, might originate from drug metabolisms, and 19 drug metabolism-related core genes were confirmed in the multi-omics network for subsequent analysis. Furthermore, we verified that CYP1A1, CYP3A4, CYP2B6, UGT2B17, UGT2B7, UGT1A8, UGT2B11, GAS5, SNHG6, XIST significantly affected antineoplastic drugs sensitivities in PCa cell lines, and these genes also showed good predictive efficiency of drug response and treatment outcomes for PCa in this cohort of patients. These findings revealed a comprehensive signature of drug metabolism differences for the Whites, Blacks and Asians, and it may provide some evidence for making individualized treatment strategies.

Schools play a major role in delivering behavioral health services to autistic youth. School culture and climate are strong predictors of the extent to which these services incorporate evidence-based practices; however, little is known about how school leaders shape culture and climate. Drawing on the concept of culture and climate embedding mechanisms, we conducted a qualitative study to understand the ways in which school principals embed cultures and climates that support effective implementation of evidence-based practices for youth with autism. Semi-structured interviews with 32 teachers in schools that implemented three closely related evidence-based practices for youth with autism (discrete trial training, pivotal response training, and visual schedules) explored teachers’ experiences regarding (a) implementation of the three evidence-based practices, (b) perceptions of school culture and climate, and (c) principals’ behaviors, practices, and decisions that supported or detracted from the aspects of culture and climate that supported successful implementation. Thematic analysis detailed seven mechanisms that principals used to embed cultures and climates that shaped evidence-based practice implementation. These mechanisms represent actionable targets for school leaders and inform strategies to improve the implementation of evidence-based practices for youth with autism in schools. Lay abstract Schools play a major role in providing services to youth with autism; however, not all schools use evidence-based practices, defined as interventions that are proven to improve youth well-being through rigorous research. School culture and climate are strong predictors of whether or not a school uses evidence-based practices; however, little is known about how principals can create school cultures and climates that support the use of these practices. This study interviewed 32 teachers in elementary schools that implemented three closely related evidence-based practices for youth with autism to better understand how principals create school cultures and climates that support effective services. Analysis of the teachers’ responses identified seven strategies principals can use to create school cultures and climates that support the implementation of effective practices for youth with autism. The strategies include the following: (a) support teachers to obtain professional development focused on autism, (b) align performance expectations and evaluations with the needs of students with autism and evidence-based practice delivery, (c) allocate resources to ensure adequate staff, materials, and training are available to implement evidence-based practices, (d) be open and flexible to allow teachers to use the building and resources as needed to meet students’ needs, (e) provide direct assistance, feedback, and coaching to troubleshoot challenges or involve outside experts to do so, (f) openly value the work of special education teachers and provide recognition to those who develop expertise in evidence-based practices, and (g) look for opportunities to integrate special and general education teachers and students to foster a truly inclusive climate.

Background and Objective Necrotizing enterocolitis (NEC) is one of the most common and urgent neonatal emergencies in the neonatal intensive care unit. This disease leads to considerable morbidity and mortality; it also imposes a huge financial burden on patient family and society. Thus, Treatment and prevention of NEC are crucial. This meta-analysis aims to investigate the effect and safety of Saccharomyces boulardii for NEC in pre-term infants. Methods A comprehensive search was retrieved in six major databases. The search included randomized controlled trials (RCTs) reporting the incidence of NEC (stage ≥ II), sepsis, mortality, feeding intolerance, full feeding days, time to regain birth weight, days of hospitalization and adverse effects. The random model was used to calculate risk ratio (RR), the standard mean difference (SMD) and its 95% confidence interval (95% CI) between the S. boulardii group and control group. Statistical analyses were conducted using Cochrane systematic review software, Rev Man (version 5.3). Results In total, 10 RCTs involving 1264 participants met the inclusion criteria. There were significant reductions in the incidence of NEC [RR = 0.56, 95% CI (0.36–0.89)], feeding intolerance [RR = 0.52, 95% CI (0.39–0.68)], full feeding days [SMD = −1.25, 95% CI (−2.06 to −0.45)] and hospitalization days [SMD = −1.33, 95% CI (−2.64 to −0.02)] in the study group compared with the control group. However, there were no significant differences in sepsis [RR = 0.84, 95% CI (0.61–1.17)], death [RR = 1.12, 95% CI (0.46–2.70)] and the time to regain birth weight [SMD = −0.93, 95% CI (−1.88 to 0.03)] between the two groups. The adverse effect of S. boulardii was not reported. The overall methodological quality was evaluated as moderate by the Cochrane Bias Risk Assessment Tool. Conclusion According to this evidence we recommend S. boulardii to prevent NEC, reduce the feeding intolerance, shorten the full feeding days and hospitalization days. However, S. boulardii might be invalid on the incidence of sepsis, mortality and the time to regain birth weight. Registration This review has been registered to the PROSPERO (International prospective register of systematic reviews) on 5 December 2019 (ID: CRD42019147896).

Objectives: The characteristics and efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) in advanced EGFR-mutant lung adenocarcinoma patients with primary tumor resection (PTR) is not yet clear. Methods: We enrolled advanced EGFR-mutant lung adenocarcinoma patients with EGFR-TKI as first-line therapy to access the impact of PTR on the outcomes. Results: A total of 466 patients were enrolled with 76 patients (16.3%) undergoing PTR; 59 patients recurred after curative surgery, while 17 patients underwent surgery as diagnostic purposes. PTR patients displayed a better performance status, a lower metastatic burden, and much less measurable diseases (30.3 vs. 97.4%, p < 0.001). PTR patients experienced a significantly longer progression-free survival (25.1 [95% CI 16.6–33.7] vs. 9.4 [95% CI 8.4–10.4] months; aHR 0.40 [95% CI 0.30–0.54], p < 0.001) and overall survival (56.8 [95% CI 36.3–77.2] vs. 31.8 [95% CI 28.2–35.4] months; aHR 0.57 [95% CI 0.39–0.84], p = 0.004). Survival advantage was still observed while comparing PTR patients with the better performance and lower metastatic burden subgroup found within the non-resection group. Moreover, the progression-free survival and overall survival of 11 patients who were found having pleural metastases during surgery and underwent PTR plus pleural biopsy, were also longer than those with pure N0--1/M1a-malignant pleural effusion disease in the non-resection group (n = 19) (p < 0.001 and p = 0.002, respectively). Conclusion: PTR was associated with significantly better outcomes in advanced lung adenocarcinoma patients treated with EGFR-TKI. Further studies are needed to evaluate the biological role of PTR among these patients.

Objective Our study aimed to examine psychiatric diagnoses and treatment preceding a schizophrenia diagnosis in adolescents, stratified by sex and race/ethnicity. Methods Using Medicaid physical and behavioral health and pharmacy claims data, we identified 1,459 adolescents who were aged 9-17 years and diagnosed with schizophrenia between January 2006 through June 2009. Psychiatric diagnosis, mental health service use including psychiatric hospitalization, residential treatment and outpatient therapy and psychotropic medication use preceding schizophrenia were identified. Results Forty-five percent of the adolescents were diagnosed with one or more psychiatric conditions. More than 40% of the adolescents were hospitalized or placed in a residential treatment facility for other psychiatric conditions preceding schizophrenia. Overall, 72% of the adolescents were prescribed with one or more psychotropic medications and 22% were prescribed with three or more psychotropic medications in the year prior to their first schizophrenia diagnosis. We found that sex and race/ethnicity influence preceding psychiatric conditions and psychiatric treatment use. Conclusions Careful screening and evaluation to validate diagnoses is important as the presence of certain psychiatric morbidity is common among adolescents with schizophrenia during the prodromal period. Developing acceptable and accessible interventions that will reduce psychiatric hospitalization and residential treatment care and improve care connection for schizophrenia treatment is important to mitigate complexity in treatment for adolescents and reduce cost burden for families and the society. Integrating health claims data in the development of schizophrenia risk conversion models can be useful in effectively predicting ideal timing of tailored interventions for adolescents with preceding psychiatric conditions.

Background Although varicocele is considered to be one of the leading causes of male infertility, the precise mechanism underlying how varicocele leads to male infertility is not completely understood. We found the lactate concentration on the varicocele side of the patients was decreased compare with peripheral venous blood. In the testicles, the lactate produced by the sertoli cells through the glycolysis pathway provides most of the energy needed for spermatogenesis, the reduction of lactate will affect spermatogenesis. The objective of this study was to investigate the mechanism of this abnormal energy metabolism phenomenon in varicocele. Methods In this study, we collected the testicular tissue from patients with varicocele, the glycolysis related proteins PHGDH was identified by iTRAQ proteomics technology. Experimental rat varicocele model was constructed according to our new clip technique, the mRNA and protein expression levels of PHGDH were examined with qRT-PCR and Western blotting. We constructed a sertoli cell of PHGDH down-regulation model, and then detected the glucose consumption, LDH activities and lactate production in the sertoli cells. Western blot was conducted to investigate the effects of PHGDH on the expression of phosphoserine phosphatase (PSPH) and Pyruvate kinase M2 (PKM2). Flow cytometry was used to detect the cell apoptosis and cell cycle in sertoli cells. Results The results showed that testicular protein PHGDH was down-regulated in patients with varicocele and in experimental rat varicocele model. Down-regulation of PHGDH in sertoli cells significantly decreased the glucose consumption, LDH activities and lactate production in the sertoli cells, indicating that the low expression of PHGDH ultimately led to a decrease in lactate production by affecting the glycolysis. The Western blot results showed that the down-regulation of PHGDH significantly reduced the expression of pathway protein PSPH and PKM2, leading to the reduction of lactate production. Moreover, PHGDH knockdown can promote apoptosis and inhibit cell cycle to affect cell growth. Conclusions Overall, we conformed that varicocele lead to the decreasing of testis lactate production. Down-regulation of PHGDH in sertoli cells may mediate the process of abnormal glucose metabolism. Our study provide new insight into the mechanisms underlying metabolism-associated male infertility and suggests a novel therapeutic target for male infertility.

Background Programmed death-ligand 1 (PD-L1) expression is associated with clinical outcomes of epidermal growth factor receptor (EGFR) mutant lung adenocarcinoma (ADC) treated with tyrosine kinase inhibitors (TKIs). However, whether PD-L1 expression plays a role in anaplastic lymphoma kinase (ALK)-positive lung ADC is unknown. We aimed to evaluate the impact of PD-L1 in patients with ALK-positive lung ADC receiving crizotinib. Materials and Methods PD-L1 expression was identified by immunohistochemistry (IHC). Reverse transcriptase-polymerase chain reaction was used for ALK variant detection, and immunofluorescence-based multiplex staining was applied for exploring immune cells in tumor microenvironments. Results A total of 78 patients with ALK-positive advanced ADC were enrolled in our study, of whom 52 received crizotinib. Compared with EGFR/ALK wild-type tumors, PD-L1 expression was lower in ALK-positive ADC. ALK fusion variants were identified in 32 patients, and those with variant 3 and 5 (short variants) had higher PD-L1 expression than those with other variants. The crizotinib objective response rate (ORR) and progression-free survival (PFS) was better in tumors with negative PD-L1 expression (ORR/PFS in PD-L1 0% vs. 1%–49% vs. 50%–100%: 60.7%/11.8 months vs. 38.5%/6.5 months vs. 36.4%/4.0 months, p = .007/.022). The multivariate Cox proportional hazards model revealed that PD-L1 0% (vs. ≥1%) was an independent factor for longer PFS (adjusted hazard ratio 0.322, 95% confidence interval 0.160–0.650, p = .002). Multiplex IHC in three cases showed a varied extent of immune cell infiltrations in tumors with different PD-L1 expression. Conclusion Positive PD-L1 expression was associated with unfavorable clinical outcomes in patients with ALK-positive lung ADC receiving crizotinib. Implications for Practice Not all lung adenocarcinoma with sensitizing driver mutations experienced durable responses to small-molecule tyrosine kinase inhibitors (TKIs). Similar to the negative impact of programmed death-ligand 1 (PD-L1) in epidermal growth factor receptor mutant tumors treated with TKIs, this study demonstrated that positive PD-L1 expression was also associated with worse response rate and shorter progression-free survival of anaplastic lymphoma kinase (ALK)-positive adenocarcinoma treated with crizotinib. Among different ALK fusion partners, tumors with short variants (V3 and V5) had higher PD-L1 compared with long variants (V1, V2, and V6). Testing PD-L1 before initiating crizotinib for ALK-positive lung cancer could be a simple method to provide important prognostic information.

Several interventions have demonstrated efficacy in improving social outcomes for children with autism, but they often are not used in schools. This study examined individual and organizational factors associated with the use of a research-informed social engagement intervention, Remaking Recess, for children with autism in elementary schools. A total of 28 school personnel from 12 schools in 5 districts in the northeastern United States participated. Schools were randomized to (1) training in Remaking Recess only or (2) training in Remaking Recess with implementation support. School personnel rated their attitudes about evidence-based practices, organizational readiness, and fidelity. Independent observers rated school personnel’s fidelity at baseline (pre-intervention training) and exit (post-intervention training). The results suggest that self-rated fidelity was lower when staff perceived the use of Remaking Recess was required; however, observer-rated fidelity was lower when staff rated Remaking Recess as appealing. In addition, self-rated fidelity was higher when there was a sufficient number of staff, positive individual growth, and organizational adaptability. The results also indicated higher observer-rated fidelity when staff perceived a positive influence over their coworkers. The results suggest that both individual (attitudes) and organizational (influence, staffing, growth, adaptability) characteristics may affect implementation success in schools. A collaborative decision-making approach for evidence-based practice use is recommended. Lay abstract Several interventions or treatment programs have been shown through research to improve social outcomes for children with autism, but they often are not used in schools. This study examined individual (school personnel) and organizational (school level) factors associated with the use of a research-informed social engagement intervention, Remaking Recess, for children with autism in elementary schools. A total of 28 school personnel from 12 schools in 5 districts in the northeastern United States participated. Schools were randomly assigned to (1) training in Remaking Recess only or (2) training in Remaking Recess with implementation support (tailored strategies to remove barriers to increase use of Remaking Recess). School personnel rated their attitudes about research-informed interventions, organizational readiness (school’s readiness to use a research-informed intervention), and fidelity or the degree to which an intervention is used as it was originally designed. Observers rated school personnel’s fidelity at baseline (pre-intervention training) and exit (post-intervention training). The results suggest that self-rated fidelity was lower when staff perceived the use of Remaking Recess was required; however, observer-rated fidelity was lower when staff rated Remaking Recess as appealing. In addition, self-rated fidelity was higher when there was a sufficient number of staff, positive individual growth, and organizational adaptability. The results also indicated higher observer-rated fidelity when staff perceived positive influence over their coworkers. The results suggest that both individual (attitudes) and organizational (influence, staffing, growth, adaptability) characteristics may affect implementation success in schools. A collaborative decision-making approach for evidence-based practice use is recommended.

This qualitative study aimed to understand how community-level cultural beliefs affect families’ and professionals’ care for children with autism and developmental delays in immigrant communities, as a first step towards promoting early identification and access to early intervention services. The study was part of the larger New York City (NYC) Korean Community Autism Project, which was designed to identify strategies to increase awareness of autism and reduce delays in treatment seeking within the NYC Korean-American community. Our study elicited early childcare workers’ and church leaders’ beliefs about autism and developmental disorders and, in particular, early intervention. We also elicited responses to newly developed outreach materials targeting this community. An inductive approach was used to identify concepts and categories associated with autism. Our study confirmed that discomfort, stigma and discrimination are the prevailing community attitudes toward autism and developmental disorders in the Korean-American community. Families’ and professionals’ understanding of autism and their care for children are affected by these community beliefs. Approaching immigrant communities with general information about child development and education rather than directly talking about autism and developmental disorders is likely to engage more families and professionals in need for diagnostic evaluation and early intervention for autism.

Background While a growing body of research suggests that talk therapies can reduce anxiety and depression in adults with autism spectrum disorder (ASD), we know little about what community treatment for these disorders looks like for them. The present study investigated whether treatment utilization differs between adults with and without ASD who have anxiety or depression. Method Using Pennsylvania Medicaid claims data, adults aged 18–65 years diagnosed with ASD and depression or anxiety (n = 268) were matched 1:4 to adults with depression or anxiety disorder without ASD (n = 1072). Chi-square tests and generalized linear models were used to estimate differences in diagnoses and psychiatric treatment between groups. Results While the proportion of people prescribed benzodiazepine and antidepressants did not differ between groups, the ASD group had more days per month prescribed for all medications. Adults with ASD also were more likely to be prescribed multiple medications concurrently and to use case management. Adults without ASD were more likely to receive talk therapy for anxiety/depression. Among those receiving talk therapy, adults with ASD averaged more individual visits per month. Conclusions Findings suggest that therapists may need more session time for adults with ASD, although it is unclear if this time is dedicated to anxiety or depression treatment. The greater use of psychotropic medications among adults with ASD may suggest unresponsiveness to the talk therapy they receive or greater clinical complexity.

Objectives:This study sought to identify whether pregnancy complications differ between women with and without a psychiatric disorder diagnosis prior to pregnancy.Methods:Women who gave birth between 2007 and 2009 in Pennsylvania and were enrolled in Medicaid from one year prior to their pregnancy until their delivery were included (N=9,930); those with psychiatric disorders were compared with a matched control group (N=4,965 for each). Logistic regression analysis estimated the odds of having a pregnancy complication among those with a psychiatric diagnosis prior to pregnancy, adjusting for demographic characteristics and chronic general medical conditions.Results:Compared with the control group, women with a psychiatric disorder prior to pregnancy had greater odds of having at least one pregnancy complication (odds ratio=1.48, 95% confidence interval=1.37–1.61). Compared with the control group, their odds of antepartum hemorrhage were 1.50 times higher, their odds of preterm labor were 1.45 times higher...

Purpose: The comprehensive understanding of mechanisms involved in the tumor metastasis is urgently needed for discovering novel metastasis-related genes for developing effective diagnoses and treatments for lung cancer. Experimental Design: FAM198B was identified from an isogenic lung cancer metastasis cell model by microarray analysis. To investigate the clinical relevance of FAM198B, the FAM198B expression of 95 Taiwan lung adenocarcinoma patients was analyzed by quantitative real-time PCR and correlated to patients' survivals. The impact of FAM198B on cell invasion, metastasis, and tumor growth was examined by in vitro cellular assays and in vivo mouse models. In addition, the N-glycosylation–defective FAM198B mutants generated by site-directed mutagenesis were used to study protein stability and subcellular localization of FAM198B. Finally, the microarray and pathway analyses were used to elucidate the underlying mechanisms of FAM198B-mediated tumor suppression. Results: We found that the high expression of FAM198B was associated with favorable survival in Taiwan lung adenocarcinoma patients and in a lung cancer public database. Enforced expression of FAM198B inhibited cell invasion, migration, mobility, proliferation, and anchorage-independent growth, and FAM198B silencing exhibited opposite activities in vitro. FAM198B also attenuated tumor growth and metastasis in vivo. We further identified MMP-1 as a critical downstream target of FAM198B. The FAM198B-mediated MMP-1 downregulation was via inhibition of the phosphorylation of ERK. Interestingly deglycosylation nearly eliminated the metastasis suppression activity of FAM198B due to a decrease of protein stability. Conclusions: Our results implicate FAM198B as a potential tumor suppressor and to be a prognostic marker in lung adenocarcinoma. Clin Cancer Res; 24(4); 916–26. ©2017 AACR.

Summary Background Osimertinib is approved for the treatment of non-small-cell lung cancer in patients who develop the EGFR Thr790Met mutation after treatment with epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitors (TKIs). We assessed outcomes in patients with non-small-cell lung cancer and the EGFR Thr790Met mutation who were treated with osimertinib, a third-generation EGFR TKI, after previous treatment failure with one or more other EGFR TKIs. Methods Eligible patients had been enrolled at one centre in the AURA study, had shown resistance to a previous EGFR TKI, and had EGFR -activating mutations and acquired Thr790Met mutation detectable in tumour tissue or plasma. Patients took 20–240 mg osimertinib per day until disease progression or development of intolerable side-effects. Plasma samples were collected every 6 weeks and tumour tissue biopsy was done at study entry and was optional after disease progression. We tested samples for resistance mechanisms, including EGFR -activating, Thr790Met, and Cys797Ser mutations, and assessed associations with overall survival, progression-free survival, and survival after disease progression. Findings Of 71 patients enrolled in AURA, 53 were eligible for this analysis. Median progression-free survival was 11·1 months (95% CI 8·4–13·9) and overall survival was 16·9 months (11·7–29·1). 47 patients had disease progression. Median overall survival after osimertinib progression was 5·4 months (95% CI 4·1–10·0). Plasma samples were available for 40 patients after disease progression. 12 (30%) of these had the Thr790Met mutation (four of whom also had Cys797Ser mutations). Patients without detectable EGFR -activating mutations in plasma before treatment had the best overall and post-progression survival (22·4 months, 95% CI 15·6–not reached, and 10·8 months, 7·2–not reached, respectively). Loss of the Thr790Met mutation but presence of EGFR -activating mutations in plasma were associated with the shortest progression-free survival (median 2·6 months, 95% CI 1·3–not reached). In 22 post-progression tumour samples, we found one squamous cell and two small-cell transformations. We detected Thr790Met in nine (50%) of 18 samples, Cys797Ser in two (17%) of 12, cMET amplification in five (50%) of ten, BRAF mutation in one (8%) of 13, and KRAS mutation in one (8%) of 13. Interpretation Heterogeneous resistance mechanisms developed in patients receiving osimertinib. Differences in resistance mechanisms might dictate future development strategies for osimertinib in clinical trials. Funding AstraZeneca, Taiwan Ministry of Science and Technology.

Background: Immunotherapy that targets programmed death protein-1 (PD-1) provides improved treatment efficacy and survival in patients with metastatic non-small cell lung cancer (NSCLC), especially those with high tumor expression of PD-L1. However, data on this treatment are mostly from clinical trials enrolling highly selected patients. The real-world experience of anti-PD-1 treatment and the usefulness of tumor PD-L1 expression in prediction of treatment response are largely unknown. Methods: We retrospectively reviewed patients with stage IIIB/ IV NSCLC who received monotherapy with nivolumab or pembrolizumab, and evaluated response using RECIST 1.1 criteria. Factors associated with treatment response, progression free survival (PFS), and overall survival (OS) were determined. Results: Seventy-four NSCLC patients out of 116 examined patients were included, most of whom had adenocarcinoma (48/74, 64.9%) and received immunotherapy as a third-line or subsequent treatment (51/74, 68.9%). The median PFS and OS were 1.8 and 7.9 months, respectively. The objective response rate was 32%, but only 47 of 74 patients were evaluable. Through multivariate analysis, epidermal growth factor receptor (EGFR) mutation was independently associated with a poor treatment response. Good performance status (ECOG≤1) and smoking were independently associated with better PFS and OS. Data on tumor PD-L1 expression were available in 43 patients (58%); higher PD-L1 expression correlated with better treatment response and longer PFS. Severe treatment-related adverse events were uncommon. Conclusion: The efficacy and safety of anti-PD-1 medications for advanced NSCLC were comparable in real-world and clinical settings, except in those with poor ECOG scores. Prediction of treatment response from tumor PD-L1 expression seemed practical.

Objective This study compared psychiatric treatment discontinuation rates among pregnant women using psychotropic medications, outpatient psychotherapy, or both before conception. Methods Using data from Pennsylvania Medicaid Fee-For-Service and Managed Care Organization claims and Medicaid enrollment, 3030 women were identified who gave birth between 2007 and 2009, had ≥ 1 claim for psychiatric treatment during the 120 days prior to pregnancy, and were enrolled in Medicaid until they delivered. Kaplan–Meier and Cox regression analyses were used to estimate psychiatric treatment dropout rate during pregnancy and examine relationships between treatment dropout and age, race/ethnicity, and pre-pregnancy psychiatric diagnosis and treatment pattern. Results After the first trimester, the probability of discontinuing psychotropic medications was 83 versus 37.8% for cessation of psychotherapy among combined treatment users. Two or more psychotherapy sessions in the 4 months prior to pregnancy were associated with decreased psychotherapy dropout during pregnancy. Psychotherapy during pregnancy was associated with prenatal psychotropic medication adherence. Conclusions To retain women in treatment during pregnancy, when discontinuation from care is common, innovative models of care should consider type of pre-pregnancy mental healthcare and individual characteristics.

Purpose In the current targeted therapy era, information on the effect of smoking in epidermal growth factor receptor (EGFR)-mutant lung cancer patients is scarce. Results In total, 11,678 adenocarcinoma patients were enrolled. Of these, 33.3% and 91.8% of male and female patients were non-smokers, respectively. An increased amount of smoking (P < 0.001 for trend), fewer smoke-free years (P < 0.001 for trend), and younger age of smoking initiation (P = 0.034 for trend) were all associated with significantly lower EGFR mutation rates. Smokers had a shorter median overall survival (OS) among both EGFR-mutant and EGFR-wild type patients (17.8 vs. 21.1 months, and 7.9 vs. 11.4 months respectively; both P < 0.001). Among patients with EGFR-mutant adenocarcinoma, younger smokers were associated with shorter OS (P = 0.047). In multivariate analysis, female gender was an independent prognostic factor for OS (hazard ratio: 0.86 [95% confidence interval {CI}: 0.80-0.93]; P < 0.001 in the EGFR-mutant group and 0.88 [95% CI: 0.81-0.96]; P = 0.004 in the EGFR-wild type group). Materials and Methods We reviewed the National Lung Cancer database (Taiwan) to assess the impact of smoking on the EGFR mutation rate and survival in advanced lung adenocarcinoma patients during 2011 and 2014 retrospectively. Conclusions Smoking was associated with lower incidence of EGFR mutation rate and reduced OS of advanced lung adenocarcinoma patients in a dose-dependent manner. In addition to EGFR mutation and smoking, gender also plays an important role in survival among these patients.

BACKGROUND We examined racial/ethnic disparities in school-based behavioral health service use for children with psychiatric disorders. METHODS Medicaid claims data were used to compare the behavioral healthcare service use of 23,601 children aged 5-17 years by psychiatric disorder (autism, attention deficit hyperactivity disorder [ADHD], conduct/oppositional defiant disorder, and “other”) and by race/ethnicity (African-American, Hispanic, white, and other). Logistic and generalized linear regression analyses were used. RESULTS Differences in service use by racial/ethnic group were identified within and across diagnostic groups, both for in-school service use and out-of-school service use. For all disorders, Hispanic children had significantly lower use of in-school services than white children. Among children with ADHD, African-American children were less likely to receive in-school services than white children; however, there were no differences in adjusted annual mean Medicaid expenditures for in-school services by race/ethnicity or psychiatric disorders. Statistically significant differences by race/ethnicity were found for out-of-school service use for children with ADHD and other psychiatric disorders. There were significant differences by race/ethnicity in out-of-school service use for each diagnostic group. CONCLUSIONS Differences in the use of school-based behavioral health services by racial and ethnic groups suggest the need for culturally appropriate outreach and tailoring of services to improve service utilization.

Early childhood obesity is a serious worldwide problem, and fundamental movement skills (FMS) are very important factors in human movement. Thus, several advanced studies have examined the associations between FMS and body mass index (BMI). The purpose of this study was to investigate BMI and FMS (locomotion and object control skills) in Korean preschool and to explore correlations between FMS and BMI. A total of 216 preschoolers, including five-year-olds (47 boys, 62 girls) and six-year-olds (55 boys, 52 girls), participated in this study. FMS were measured using the Test of Gross Motor Development-II (TGMD-II), and BMI was calculated as the weight (kg) divided by the square of the height (m) [weight/ height2]. The results indicated that the children’s FMS (locomotion and object control skills) did not correlate with their BMI levels. In addition, most of correlation coefficients between BMI and locomotion skills, as well as correlation between BMI and object control skills were not significant. These re...

Inflammatory leukocytes infiltration is orchestrated by mechanisms involving chemokines, selectins, addressins and other adhesion molecules derived from endothelial cells (ECs), but how they respond to inflammatory cues and coordinate leukocyte transmigration remain elusive. In this study, using hepatic ischemia/reperfusion injury (HIRI) as a model, we identified that endothelial Notch activation was rapidly and dynamically induced in liver sinusoidal endothelial cells (LSECs) in acute inflammation. In mice with EC-specific Notch activation (NICeCA), HIRI induced exacerbated liver damage. Consistently, endothelial Notch activation enhanced neutrophil infiltration and tumor necrosis factor (TNF)-α expression in HIRI. Transcriptome analysis and further qRT-PCR as well as immunofluorescence indicated that endomucin (EMCN), a negative regulator of leukocyte adhesion, was downregulated in LSECs from NICeCA mice. EMCN was downregulated during HIRI in wild-type mice and in vitro cultured ECs insulted by hypoxia/re-oxygenation injury. Notch activation in ECs led to increased neutrophil adhesion and transendothelial migration, which was abrogated by EMCN overexpression in vitro. In mice deficient of RBPj, the integrative transcription factor of canonical Notch signaling, although overwhelming sinusoidal malformation aggravated HIRI, the expression of EMCN was upregulated; and pharmaceutical Notch blockade in vitro also upregulated EMCN and inhibited transendothelial migration of neutrophils. The Notch activation-exaggerated HIRI was compromised by blocking LFA-1, which mediated leukocyte adherence by associating with EMCN. Therefore, endothelial Notch signaling controls neutrophil transmigration via EMCN to modulate acute inflammation in HIRI.

BackgroundCadherin-11 (CDH11) is a type II cadherin and reported to function as an oncogene in various cancers. Our present study aims to investigate the role of CDH11 in bladder cancer (BCA).MethodsBioinformatics analysis was performed in four independent microarray data including 56 non-muscle-invasive bladder cancer (NMIBC) and 132 muscle-invasive bladder cancer (MIBC) tissues from Gene Expression Omnibus to screen out differentially expressed genes. Next, we detected CDH11 expression in BCA specimens and cell lines by qPCR and western blotting assays. Immunohistochemical analyses were performed in 209 paraffin-embedded BCA samples and 30 adjacent normal bladder tissues.ResultsBioinformatics analysis revealed that CDH11 had a higher expression level in MIBC tissues than in NMIBC, which was consistent with our clinical BCA specimens and cell lines at both mRNA and protein levels. Immunohistochemical analysis demonstrated that over-expression of CDH11 was closely related to the histological grade, pT status, tumour size and poor outcomes of BCA patients. What’s more, CDH11 (area under curve (AUC) = 0.673 and 0.735) had a better predictive value than E-cadherin (AUC = 0.629 and 0.629) and a similar discrimination with the European Organization for Research and Treatment of Cancer (EORTC) score system (AUC = 0.719 and 0.667) in evaluating potential recurrence and progression of NMIBC. Moreover, combination of CDH11 and EORTC score system was the best predictive model in predicting recurrence of NMIBC (AUC = 0.779) among the three models.ConclusionsCDH11 was a reliable therapeutic target in BCA and a useful index to predict the possibilities of recurrence and progression in NMIBC patients.

Phlorizin (PHZ), a type of dihydrochalcone widely found in Rosaceae such as apples, is the first compound discovered as a sodium-glucose cotransporter (SGLT) inhibitor. It has been confirmed to improve the symptoms of diabetes and diabetic complications effectively. Like other flavonoids, the bioavailability challenge of PHZ is the wide phase I and II metabolism in the digestive tract. In this study, we investigated the pharmacokinetics and contribution of phase II metabolism after the oral and intravenous administrations of PHZ in rats having type 2 diabetes (T2D) and in normal rats. The phase II metabolism characteristics of PHZ were investigated by treating plasma samples with β-glucuronidase/sulfatase. The contribution ratio of phase II metabolism of PHZ ranged from 41.9% to 69.0% after intravenous injection with three doses of PHZ in normal rats. Compared with the observations for normal rats, AUC0-t and Cmax of PHZ significantly increased and T1/2 of PHZ significantly decreased in T2D rats. PHZ was converted into phloretin (PHT) through an enzyme-catalyzed hydrolysis reaction, and PHT was further transformed into conjugates with glycose after both oral and intravenous administrations. Moreover, it was found that the bioavailability of PHZ was about 5% in T2D rats, which was significantly higher than that in normal rats (0%). In conclusion, compared with the observations for normal rats, the pharmacokinetic characteristics of PHZ significantly changed in T2D rats through oral and intravenous administrations. The bioavailability of PHZ significantly increased in T2D rats. Besides, the phase II metabolites of PHT were the major existing forms in blood after oral and intravenous administrations. Our results indicated that the phase II metabolism characteristics of PHZ should be considered when PHZ is applied for the treatment of diabetes as a drug or functional food.

Background: Depressed colorectal neoplasms exhibit a high malignant potential and may become invasive rapidly but their genomic alterations remain unknown. We investigated the genomic alterations of depressed neoplasms and potential implications on long-term survival. Methods: We examined 20 depressed neoplasms and 15 polypoid neoplasms by genome-wide copy number analysis. Subsequently, we validated the identified copy number alterations in an independent sample of 37 depressed and 42 polypoid neoplasms. Specific copy number alterations were tested in 530 colorectal cancers in order to clarify the clinical outcome of depressed colorectal neoplasms. Findings: Copy number alterations in MYC, CCNA1, and BIRC7 were significantly enriched in depressed neoplasms and designated as the D-marker panel. In the validation set, the panel presented a positive predictive value, sensitivity and accuracy of 80·0%, 75·7% and 79·7% respectively for discriminating the depressed neoplasms. colorectal cancers developing from depressed neoplasms account for 22·1% of all colorectal cancers and have a significantly more unfavorable progression-free survival compared with colorectal cancer without those biomarkers, especially in stage I, T1+2, and proximal cancers. Interpretation: In this article, we characterize the genome-wide landscape in the depressed neoplasm and its specific biosignature. The D-marker panel may help to optimize the treatment of depressed neoplasms and surveillance strategies, and develop more effective molecular screening tests in the future. Funding Statement: Funding by the National Taiwan University Hospital (Grand Number: NTUH 107-M3990, NTUH 108-M4209), Ministry of Science and Technology, Taiwan (Grant Number: MOST-105-2314-B-002-047, MOST106-2319-B-002-002, MOST107-2319-B-002-002), and as well as the “Center of Precision Medicine” from The Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan. Declaration of Interests: The authors declare that they have no conflicts of interest. Ethics Approval Statement: Before initiation, this study received approval (No. 201712033RINC) from the Institutional Review Board and Ethical Committee of National Taiwan University Hospital.

Several ultra-sensitive methods for T790M in plasma cell-free DNA (cfDNA) have been developed for lung cancer. The correlation between mutation-allele frequency (MAF) cut-off, drug responsiveness, and outcome prediction is an unmet needs and not fully addressed. An innovative combination of peptide nucleic acid (PNA) and Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry (MALDI-TOF MS) was used to proof of concept for monitoring cfDNA T790M in EGFR-mutant patients. Mutant enrichment by PNA was optimized and the detection limit was evaluated through serial dilutions. The cut-off value was identified by receiver-operating-characteristic (ROC) curve analysis utilizing serial sampled plasmas of patients from EGFR-tyrosine kinase inhibitor (TKI) pretreatment to progressive-disease (PD). Results, comparisons, and objective response rate (ORR) were analyzed in 103 patients' tumor and cfDNA T790M, with 20 of them receiving an additional COBAS test. The detection limit was 0.1% MAF. The cut-off for PD and imminent PD was 15% and 5% with an ROC area under the curve (AUC) of 0.96 and 0.82 in 2 ml plasma. Detection sensitivity of cfDNA T790M was 67.4% and overall concordance was 78.6%. ORR was similar in T790M-positive cfDNA (69.6%) and tumor samples (70.6%) treated with osimertinib. Among 65 T790M-positive tumors, 15 were negative in cfDNA (23.1%). Seven of 38 T790M-positive cfDNA samples were negative in the tumors (18.4%). PNA-MALDI-TOF MS had a higher detection rate than COBAS. In conclusion, identification of T790M cut-off value in cfDNA improves cancer managements. We provide a strategy for optimizing testing utility, flexibility, quality, and cost in the clinical practice.

Natural products generally contain complex and multiple bioactive compounds that are responsible for the effects on health through complicated synergistic and/or suppressive actions. As an important raw material of local ethnic minority tea, ethnomedicines and food supplements in southwestern areas of China, Docynia indica (Wall.) Decne (DID) mainly consists of phlorizin (PHZ), which is the main active component. In this study, the holistic activities and the interactions of components of PHZ, non-phlorizin (NP) in the DID extract (DIDE) were evaluated. A rapid and effective high-speed counter-current chromatography (HSCCC) was performed to knock out PHZ from DIDE and the purity of PHZ was 96.01% determined by HPLC, with a recovery rate of 96.76%. After 13 weeks of treatment course in a high-fat diet (HFD)-induced obese mice model, the results revealed that the DIDE and PHZ significantly decreased weight gain, blood lipid levels, hyperplasia of adipocytes and alleviated inflammation (p &lt, 0.05). Both DIDE and PHZ improves insulin resistance (p &lt, 0.001). Meanwhile, the intestinal barrier function was improved compared to HFD group, through the determination of serum lipopolysaccharides (LPS), glucagon-likepeptide-2 (GLP-2) and hematoxylin-eosin staining of jejunum. Interestingly, after NP treatment, the metabolic syndrome of the HFD-induced obesity appeared to have a similar improvement. All the experiments showed that there is a synergistic weakening phenomenon when PHZ and NP interact with each other in the mixed state. In conclusion, for the PHZ and NP showing a good effect on anti-obesity, anti-inflammation, and intestinal barrier function, DIDE could be a good source of functional food to prevent obesity.

Introduction: Kras mutation is the most common driver oncogene present in patients with NSCLC. Recently, the precision medicine for patients with Kras-mutated NSCLC has been under investigation, but the best treatment is still unknown. This study aimed to analyze the clinical characteristics, immune checkpoint inhibitor (ICI) response, and prognostic factors of patients with NSCLC with different Kras mutation subtypes. Methods: From 2005 to 2018, we collected nonsquamous NSCLC tissue samples for Kras mutation analysis using direct Sanger sequencing or MassARRAY genotyping (Agena Bioscience, San Diego, CA) at the National Taiwan University Hospital. Clinical characteristics, ICI treatment effectiveness, time-to-tumor recurrence (TTR), and overall survival (OS) were analyzed using multivariate Cox models, to estimate adjusted hazard ratios (HRs). Results: Among 5278 patients with nonsquamous NSCLC, 246 (4.7%) had Kras mutations. The major Kras mutation subtypes were G12C (32.9%), G12D (23.7%), and G12V (18.9%). Patients with Kras-G12C had a higher proportion of male individuals (p = 0.018) and smokers (p < 0.001). Among the 25 patients treated with ICIs, patients with Kras-G12C had a higher response rate (53.8% versus 8.3%, p = 0.030) and longer progression-free survival (4.8 mo versus 2.1 mo, p = 0.028) than those with Kras-non-G12C. For the 85 patients with early-stage NSCLC, those with G12C had shorter TTR (22.8 mo) than those with Kras-non-G12C (97.7 mo, p = 0.004). For the 143 patients with advanced-stage NSCLC, there was a significant difference in OS between patients with Kras-G12C and Kras-non-G12C (7.7 mo versus 6.0 mo, p = 0.018) and patients with Kras-G12V had the shortest OS (5.2 mo). Multivariate analysis revealed association of shorter OS with Kras-G12V (HR = 2.47, p = 0.002), stage IV disease status (HR = 2.69, p = 0.008), and NSCLC—not otherwise specified histology (HR = 3.12, p = 0.002). Conclusions: Kras-G12C was associated with favorable ICI treatment effectiveness in patients with NSCLC. Kras-G12C mutation was associated with shorter TTR in patients with early-stage NSCLC, and Kras-G12V mutation was associated with shorter OS in patients with advanced-stage NSCLC when comparing with Kras-G12C.

Phlorizin (PHZ) is one of phytonutrients in apples that contributes to the health-promoting effect implicated by the saying, ‘an apple a day keeps the doctor away’. PHZ was firstly identified as a competitive inhibitor of sodium-glucose co-transporters-2 (SGLT2); however, its low bioavailability makes it hard to fully explain its pharmacological mechanisms. This study aimed to investigate the ameliorating effect of PHZ on high-fat diet (HFD)-induced obesity via modulating the “gut microbiota-barrier axis”. Firstly, C57BL/6 J mice were fed a normal chow diet (NCD) or HFD coadministered with or without PHZ for 12 weeks. Our results showed that PHZ supplementation significantly reduced HFD-induced body weight gain (P

Bronchogenic cyst (BC) is a rare congenital disease with pre-embryonic intestinal malformation. BC of the stomach is rare. The present study reported on the case of a 68-year-old male who presented with a spleen and stomach space mass detected incidentally upon a routine health examination. The patient underwent laparotomy. Postoperative histopathological diagnosis confirmed BC of the stomach. Postoperative recovery was smooth and the patient is currently under follow-up. A literature review suggested that BC is a rare disease and the location of the stomach is very rare. Indications of surgical intervention remain controversial for asymptomatic cases. Owing to no specific clinical or radiologic features to define the disease profile for diagnosis, surgery may be a good choice for both diagnosis and therapy if the patient's condition permits.

Aim To determine the frequency of expression of the tumor-associated antigens (TAAs) melanoma-associated antigen A3 (MAGE-A3) and preferentially expressed antigen of melanoma (PRAME) and the rate of EGFR mutations in a Taiwanese non–small cell lung cancer (NSCLC) population including only adenocarcinomas and squamous cell carcinomas. Furthermore, to investigate associations between TAA expression and EGFR mutations and to evaluate these TAAs as prognostic markers for overall survival. The occurrence of single nucleotide polymorphisms in MAGEA3 and PRAME was also assessed. Methods Archival fresh-frozen tumor tissue specimens were tested by quantitative reverse transcription polymerase chain reaction assays to detect MAGE-A3 and PRAME expression. EGFR mutations were detected by mass spectroscopy and single nucleotide polymorphisms by gene sequencing. Results Of the 156 adenocarcinomas examined, 3.3% expressed MAGE-A3, 32.2% expressed PRAME and 62.8% had EGFR mutations. Of the 128 squamous cell carcinomas, 29.8% expressed MAGE-A3, 59.2% expressed PRAME and 20.5% harbored EGFR mutations. TAA expression was similar across subgroups determined by patient or tumor characteristics. There was no association between TAA expression and EGFR mutation status and TAA expression was found not to be a prognostic marker for survival. Single nucleotide polymorphisms were identified, one of which with a possible impact on MAGE-A3 expression. Conclusions In this NSCLC population, expression of MAGE-A3 and PRAME was more frequent in squamous cell carcinomas than in adenocarcinomas tumors. EGFR mutations were not associated with TAA expression for either histology and were three times more frequent in adenocarcinomas than in squamous cell carcinomas tumors.

Despite the advancement of epidermal growth factor receptor (EGFR) inhibitors in lung cancer therapy, it remains unclear whether EGFR mutation status in familial lung cancers is different from that of sporadic cases. In this multicenter retrospective study, we compared both the EGFR mutation frequency and patterns between familial and sporadic cases. The results explored that family history of lung cancer is an independent predictor for higher EGFR mutation rate in 1713 lung adenocarcinoma patients (Odd ratio 1.68, 95% CI 1.06-2.67, P = 0.028). However, the distribution of EGFR mutation subtypes was similar to that of sporadic cases. Part of our study involved 40 lung cancer families with at least 2 tumor tissues available within each single family (n = 88) and there was no familial aggregation pattern in EGFR mutation subtypes. There were two families harboring the YAP1 R331W germline risk allele and EGFR mutation statuses among YAP1 family members also varied. These phenomena may hint at the direction of future research into lung carcinogenesis and EGFR mutagenesis.

// Poyin Huang 1, 2, 3, 4 , Chiou-Ling Cheng 5 , Ya-Hsuan Chang 6 , Chia-Hsin Liu 6 , Yi-Chiung Hsu 6 , Jin-Shing Chen 7 , Gee-Chen Chang 8, 9, 10 , Bing-Ching Ho 5 , Kang-Yi Su 5 , Hsuan-Yu Chen 6 , Sung-Liang Yu 5, 11, 12, 13, 14 1 Department of Neurology, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan 2 Department of Neurology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan 3 Ph.D. Program in Translational Medicine, Kaohsiung Medical University and Academia Sinica, Taiwan 4 Department of Neurology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan 5 Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan 6 Institute of Statistical Science, Academia Sinica, Taipei, Taiwan 7 Department of Traumatology, National Taiwan University Hospital, Taipei, Taiwan 8 Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan 9 Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan 10 Comprehensive Cancer Center, Taichung Veterans General Hospital, Taichung, Taiwan 11 Center of Genomic Medicine, National Taiwan University, Taipei, Taiwan 12 Center for Optoelectronic Biomedicine, College of Medicine, National Taiwan University, Taipei, Taiwan 13 Graduate Institute of Pathology, College of Medicine, National Taiwan University, Taipei, Taiwan 14 Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan Correspondence to: Hsuan-Yu Chen, email: hychen@stat.sinica.edu.tw Sung-Liang Yu, email: slyu@ntu.edu.tw Keywords: non–small cell lung cancer, TaqMan Low-Density Array, risk score, gene signature, prognosis Received: March 28, 2016 Accepted: June 30, 2016 Published: July 16, 2016 ABSTRACT The current staging system for non–small cell lung cancer (NSCLC) is inadequate for predicting outcome. Risk score, a linear combination of the values for the expression of each gene multiplied by a weighting value which was estimated from univariate Cox proportional hazard regression, can be useful. The aim of this study is to analyze survival-related genes with TaqMan Low-Density Array (TLDA) and risk score to explore gene-signature in lung cancer. A total of 96 NSCLC specimens were collected and randomly assigned to a training ( n = 48) or a testing cohort ( n = 48). A panel of 219 survival-associated genes from published studies were used to develop a 6-gene risk score. The risk score was used to classify patients into high or low-risk signature and survival analysis was performed. Cox models were used to evaluate independent prognostic factors. A 6-gene signature including ABCC4, ADRBK2, KLHL23, PDS5A, UHRF1 and ZNF551 was identified. The risk score in both training (HR = 3.14, 95% CI: 1.14–8.67, p = 0.03) and testing cohorts (HR = 5.42, 95% CI: 1.56–18.84, p = 0.01) was the independent prognostic factor. In merged public datasets including GSE50081, GSE30219, GSE31210, GSE19188, GSE37745, GSE3141 and GSE31908, the risk score (HR = 1.50, 95% CI: 1.25–1.80, p < 0.0001) was also the independent prognostic factor. The risk score generated from expression of a small number of genes did perform well in predicting overall survival and may be useful in routine clinical practice.

// Jeng-Sen Tseng 1, 2, * , Kang-Yi Su 3, 4, * , Tsung-Ying Yang 1, 2 , Kun-Chieh Chen 1 , Kuo-Hsuan Hsu 5, 6 , Hsuan-Yu Chen 7, 8, 9 , Chi-Ren Tsai 10, 11 , Sung-Liang Yu 3, 4, 12, 13, 14 , Gee-Chen Chang 1, 2, 15 1 Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan 2 Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan 3 Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan 4 Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan 5 Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan 6 Division of Critical Care and Respiratory Therapy, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan 7 Institute of Statistical Science, Academia Sinica, Taipei, Taiwan 8 College of Medicine, National Taiwan University, Taipei, Taiwan 9 College of Life Science, National Taiwan University, Taipei, Taiwan 10 Department of Pediatrics, Taichung Veterans General Hospital, Taichung, Taiwan 11 Institute of Molecular Biology, National Chung-Hsing University, Taichung, Taiwan 12 Center of Genomic Medicine, National Taiwan University College of Medicine, Taipei, Taiwan 13 Department of Pathology and Graduate Institute of Pathology, College of Medicine, National Taiwan University, Taipei, Taiwan 14 Center for Optoelectronic Biomedicine, College of Medicine, National Taiwan University, Taipei, Taiwan 15 Comprehensive Cancer Center, Taichung Veterans General Hospital, Taichung, Taiwan * Co-first authors, these authors contributed equally to this work Correspondence to: Gee-Chen Chang, email: august@vghtc.gov.tw Sung-Liang Yu, email: slyu@ntu.edu.tw Keywords: T790M, epidermal growth factor receptor (EGFR), lung adenocarcinoma, acquired resistance, rebiopsy Received: April 19, 2016 Accepted: May 29, 2016 Published: June 30, 2016 ABSTRACT Different growth kinetics occurring between the sensitive and T790M-containing cells may result in the repopulation of tumor cells over time. Little information has yet been uncovered on whether rebiopsy timing influences the T790M detection rate. We enrolled a total of 98 epidermal growth factor receptor (EGFR) -mutant lung adenocarcinoma patients, who had a history of acquired resistance to EGFR-tyrosine kinase inhibitor (TKI) and available rebiopsy tumor specimens for reassessment of EGFR mutations. Rebiopsy was performed at the time of first EGFR-TKI progression in 54 patients (55.1%); for the other 44 patients (44.9%), rebiopsy was done with an interval from first EGFR-TKI progression (median 470.5 days, range 46-1742 days). Our results indicated that rebiopsy timing did not influence the detection rate of T790M and that the mutation could be identified in patients with a long EGFR-TKI-free interval. For patients without suitable lesions for rebiopsy at the time of EGFR-TKI progression, an attempt to rebiopsy should be considered during the subsequent treatment courses.

// Yi-Jing Hsiao 1 , Kang-Yi Su 1, 2, 3 , Yi-Chiung Hsu 4 , Gee-Chen Chang 5, 6 , Jin-Shing Chen 7 , Hsuan-Yu Chen 2, 4 , Qi-Sheng Hong 1 , Shih-Chun Hsu 1 , Po-Hsiang Kang 1 , Chia-Ying Hsu 1 , Bing-Ching Ho 1 , Tsung-Hui Yang 1 , Chia-Yu Wang 1 , Yuh-Shan Jou 8 , Pan-Chyr Yang 2, 8, 9 , Sung-Liang Yu 1, 2, 3, 10, 11, 12 1 Department of Clinical and Laboratory Sciences and Medical Biotechnology, National Taiwan University College of Medicine, Taipei, Taiwan 2 Center of Genomic Medicine, National Taiwan University College of Medicine, Taipei, Taiwan 3 Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan 4 Institute of Statistical Science, Academia Sinica, Taipei, Taiwan 5 Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan 6 Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan 7 Division of Thoracic Surgery and Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan 8 Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan 9 Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan 10 Department of Pathology and Graduate Institute of Pathology, National Taiwan University College of Medicine, Taipei, Taiwan 11 Center for Optoelectronic Biomedicine, National Taiwan University College of Medicine, Taipei, Taiwan 12 Institute of Medical Device and Imaging, National Taiwan University College of Medicine, Taipei, Taiwan Correspondence to: Sung-Liang Yu, email: slyu@ntu.edu.tw Keywords: SPANX family, AP-1, SLUG, E-cadherin, metastasis Received: January 07, 2016 Accepted: June 01, 2016 Published: June 15, 2016 ABSTRACT SPANXA (Sperm Protein Associated with the Nucleus on the X-chromosome, family members A1/A2) acts as a cancer-testis antigen expressed in normal testes, but dysregulated in various tumors. We found that SPANXA is highly expressed in low-invasive CL1-0 cells compared with isogenous high-invasive CL1-5 cells. SPANXA was preferably expressed in tumor tissues and associated with the prolonged survival of lung adenocarcinomas. SPANXA suppressed the invasion and metastasis of lung cancer cells in vitro and in vivo . By the expression microarray and pathway analysis, we found that the SPANXA-altered genes were enriched in the epithelial–mesenchymal transition (EMT) pathway. SPANXA reduced SNAI2 expression resulted in up-regulating E-cadherin . c-JUN acts as the positive-regulator of EMT. Silencing SPANXA increased c-JUN mRNA expression and blockage of c-JUN led to SNAI2 down-regulation. Our results clearly characterized SPANXA as an EMT inhibitor by suppressing c-JUN-SNAI2 axis in lung adenocarcinoma.

HLJ1 (DNAJB4), a DNAJ/Hsp40 chaperone, has emerged as a novel prognostic marker in lung cancers; however, the molecular contribution and functionality in neoplastic diseases remain to be established. This study demonstrated that HLJ1 inhibits epithelial-mesenchymal transition in vitro and reduces lung cancer metastasis in vivo. Using shRNA silencing and ectopic expression of HLJ1, we found that HLJ1 not only suppresses catalytic activity of Src but also downregulates the formation of oncogenic complexes associated with the EGFR, FAK and STAT3 signaling pathways. A screen of specimens from HLJ1-knockout mice and lung cancer patients validated that HLJ1 expression is inversely correlated with Src activity. Mechanistically, HLJ1 protein directly bound to catalytic and protein-binding domains of Src through its amino acid Y172 and the P301/P304 motif. Following Src-induced HLJ1 phosphorylation at Y172, HLJ1-Src interaction was elevated, resulting in Src inhibition and malignancy suppression. Interestingly, both Src-binding regions also occurred in other DNAJB family members and contributed to anti-invasive activities of DNAJB proteins. We conclude that HLJ1 is an endogenous Src inhibitor that can suppress cancer metastasis through complex interacting mechanisms. This HLJ1-Src complex might provide a promising molecular model for developing new anticancer strategies.

This study compared use of and associated expenditures for Medicaid-reimbursed school-based and out-of-school services for children with autism spectrum disorder (ASD) and those with other psychiatric disorders.Philadelphia County Medicaid claims were used to identify children ages five to 17 who received behavioral health services through Medicaid any time between October 2008 and September 2009 (N=24,271). Children were categorized into four diagnostic groups: autism spectrum disorder (ASD), conduct disorder or oppositional defiant disorder (conduct-ODD), attention-deficit hyperactivity disorder (ADHD), and other psychiatric disorders. Logistic regression analysis compared use of in-school and out-of-school behavioral health services between children with ASD and children with other psychiatric disorders. Generalized linear models with gamma distribution were used to estimate differences in Medicaid expenditures for in-school and out-of-school services and total Medicaid expenditures for both service types by disorder, with adjustments for age, sex, and race-ethnicity.The most common diagnosis was ADHD (40%); 35% had other psychiatric disorders, 21% had conduct-ODD, and 4% had ASD. A significantly greater proportion of children with ASD (52%) received in-school behavioral health services (conduct-ODD, 5%; ADHD, 8%; and other psychiatric disorders, 1.7%) Per-child expenditures for both school-based and out-of-school behavioral health services were significantly higher for children with ASD than for children in the other groups.Medicaid represents an important source of in-school and out-of-school care for children with ASD and their families. States that expand Medicaid under the Affordable Care Act should give careful consideration to covering school-based mental health services for children with ASD.