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Background: To review the changes and survey on status quo of the surgical treatment for esophageal cancer in China. The differences in diagnosis and treatment for esophageal cancer among hospitals in different regions across China were also investigated., Methods: We sent questionnaires to 46 hospitals across China, investigating the volume of esophageal cancer surgeries, surgical procedures, and perioperative management under the guidance of esophageal surgery chiefs., Results: A total of 46 questionnaires were sent out and collected. The survey results showed that in the past 5 years, the volume of surgeries for esophageal cancer remained stable by 23.9% of those hospitals, increased by 30.4%, and decreased by 45.7%. Of those patients treated by surgery, 19.1% were in the early stages, and 80.9% were in locally advanced stages. In terms of surgical procedures, 73.4% of the patients were treated by minimally invasive surgery and 85.7% of esophageal substitutes were a gastric conduit, 93.1% of the substitutes were pulled to the neck through the esophageal bed. For the lymph node dissection, 78.5% of the patients had a complete two-field lymph node dissection including the para-recurrent laryngeal nerve lymph nodes. Of the patients with neoadjuvant therapy, 53.5% received chemotherapy or chemotherapy plus immunotherapy (47.0%), and 43.5% had chemoradiation., Conclusions: Currently, in China, minimally invasive surgery-oriented multimodality treatment, including complete two-field lymph node dissection, has become the standard approach for esophageal cancer management. Over the past decade, this standardized approach has significantly improved prognosis compared to previous decades., (© 2024 The Author(s). Thoracic Cancer published by John Wiley & Sons Australia, Ltd.)

In dimorphic fungi, the yeast-to-filament transition critical for cell survival under nutrient starvation is controlled by both activators and repressors. However, very few filamentation repressors are known. Here we report that, in the dimorphic yeast Yarrowia lipolytica, the conserved transcription factor YlNrg1 plays a minor role whereas Fts1, a newly identified Zn(II) 2 Cys 6 zinc cluster transcription factor, plays a key role in filamentation repression. FTS1 deletion caused hyperfilamentation whereas Fts1 overexpression drastically reduced filamentation. The expression of FTS1 is downregulated substantially during the yeast-to-filament transition. Transcriptome sequencing revealed that Fts1 represses 401 genes, including the filamentation-activating transcription factor genes MHY1, YlAZF1, and YlWOR4 and key cell wall protein genes. Tup1-Ssn6, a general transcriptional corepressor, is involved in the repression of many cellular functions in fungi. We show that both YlTup1 and YlSsn6 strongly repress filamentation in Y. lipolytica. YlTup1 and YlSsn6 together repress 1383 genes, including a large number of transcription factor and cell wall protein genes, which overlap substantially with Fts1-repressed genes. Fts1 interacts with both YlTup1 and YlSsn6, and LexA-Fts1 fusion represses a lexAop-promoter-lacZ reporter in a Tup1-Ssn6-dependent manner. Our findings suggest that Fts1 functions as a transcriptional repressor, directing the repression of target genes through the Tup1-Ssn6 corepressor., (© 2022 John Wiley & Sons Ltd.)

The yeast-to-filament transition is an important cellular response to environmental stimulations in dimorphic fungi. In addition to activators, there are repressors in the cells to prevent filament formation, which is important to keep the cells in the yeast form when filamentation is not necessary. However, very few repressors of filamentation are known so far. Here, we identify a novel repressor of filamentation in the dimorphic yeast Yarrowia lipolytica, Fts2, which is a C 2 H 2 -type zinc finger transcription factor. We show that fts2 Δ cells exhibited increased filamentation under mild filament-inducing conditions and formed filaments under non-filament-inducing conditions. We also show that Fts2 interacts with YlSsn6, component of the Tup1-Ssn6 transcriptional corepressor, and Fts2-LexA represses a lexAop-P YlACT1 -lacZ reporter in a Tup1-Ssn6-dependent manner, suggesting that Fts2 has transcriptional repressor activity and represses gene expression via Tup1-Ssn6. In addition, we show that Fts2 represses a large number of cell wall protein genes and transcription factor genes, some of which are implicated in the filamentation response. Interestingly, about two-thirds of Fts2-repressed genes are also repressed by Tup1-Ssn6, suggesting that Fts2 may repress the bulk of its target genes via Tup1-Ssn6. Lastly, we show that Fts2 expression is downregulated in response to alkaline pH and the relief of negative control by Fts2 facilitates the induction of filamentation by alkaline pH. IMPORTANCE The repressors of filamentation are important negative regulators of the yeast-to-filament transition. However, except in Candida albicans, very few repressors of filamentation are known in dimorphic fungi. More importantly, how they repress filamentation is often not clear. In this paper, we report a novel repressor of filamentation in Y. lipolytica. Fts2 is not closely related in amino acid sequence to CaNrg1 and Rfg1, two major repressors of filamentation in C. albicans, yet it represses gene expression via the transcriptional corepressor Tup1-Ssn6, similar to CaNrg1 and Rfg1. Using transcriptome sequencing, we determined the whole set of genes regulated by Fts2 and identified the major targets of Fts2 repression, which provide clues to the mechanism by which Fts2 represses filamentation. Our results have important implications for understanding the negative control of the yeast-to-filament transition in dimorphic fungi.

Background: Left thoracic approach (LTA) has been a favorable selection in surgical treatment for esophageal cancer (EC) patients in China before minimally invasive esophagectomy (MIE) is popular. This study aimed to demonstrate whether right thoracic approach (RTA) is superior to LTA in the surgical treatment of middle and lower thoracic esophageal squamous cell carcinoma (TESCC)., Methods: Superiority clinical trial design was used for this multicenter randomized controlled two-parallel group study. Between April 2015 and December 2018, cT1b-3N0-1M0 TESCC patients from 14 centers were recruited and randomized by a central stratified block randomization program into LTA or RTA groups. All enrolled patients were followed up every three months after surgery. The software SPSS 20.0 and R 3.6.2. were used for statistical analysis. Efficacy and safety outcomes, 3-year overall survival (OS) and disease-free survival (DFS) were calculated and compared using the Kaplan-Meier method and the log-rank test., Results: A total of 861 patients without suspected upper mediastinal lymph nodes (umLN) were finally enrolled in the study after 95 ineligible patients were excluded. 833 cases (98.7%) were successfully followed up until June 1, 2020. Esophagectomies were performed via LTA in 453 cases, and via RTA in 408 cases. Compared with the LTA group, the RTA group required longer operating time (274.48±78.92 vs . 205.34±51.47 min, P<0.001); had more complications (33.8% vs. 26.3% P=0.016); harvested more lymph nodes (LNs) (23.61±10.09 vs. 21.92±10.26, P=0.015); achieved a significantly improved OS in stage IIIa patients (67.8% vs. 51.8%, P=0.022). The 3-year OS and DFS were 68.7% and 64.3% in LTA arm versus 71.3% and 63.7% in RTA arm (P=0.20; P=0.96)., Conclusions: Esophagectomies via both LTA and RTA can achieve similar outcomes in middle or lower TESCC patients without suspected umLN. RTA is superior to LTA and recommended for the surgical treatment of more advanced stage TESCC due to more complete lymphadenectomy., Trial Registration: ClinicalTrials.gov NCT02448979., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-22-3810/coif). YSM, SGG, YL, ALH, JFL, XFL, THR, JHF, JQM, MQX, RQZ, GMX, XNF, KNC, WMM, YYL, HXL, ZRZ, YF, DHF, XDW, LGY, SM, WQW, YBG, JH report that this work was supported by the grants from National Science and Technology Support Program (Study ID Number: NKTRDP-2015BAI12B08-01, YSM). The other authors have no conflicts of interest to declare., (2022 Annals of Translational Medicine. All rights reserved.)

Insulin resistance is the main sign of type 2 diabetes mellitus and is often accompanied by the infiltration of inflammatory factors. These inflammatory factors are mainly produced and secreted by macrophages. The purpose of the current study was to explore the relationship between macrophages and insulin resistance, and to determine its underlying mechanism. The insulin resistance of macrophages was induced by palmitic acid (PA) in vitro . The glucose uptake rate of macrophages, the expression levels of inflammatory cytokines and the expression levels of insulin resistance-related proteins were detected. The protein expression levels of Krüppel-like factor 4 (KLF4), toll-like receptor 4 (TLR4), NF-κB and Galectin-3 (Gal-3) were detected via western blotting and recovery experiments were performed by combining the Gal-3 and TLR4 inhibitors GB1107 and TAK242. The results revealed that PA-induced macrophages demonstrated insulin resistance. Additionally, KLF4 protein was inhibited and the sugar uptake rate was significantly lower than that of the control group. Western blotting and immunofluorescence assays revealed that the expression of Gal-3 in PA-induced macrophages was significantly upregulated. The addition of the Gal-3 inhibitor GB1107 significantly increased glucose utilization and reduced insulin resistance in PA-treated cells. Inhibitor of TLR4 inhibited the protein expression level of the TLR4/NF-κB pathway. In conclusion, PA promoted the TLR4/phosphorylated-NF-κB signaling pathway by inhibiting KLF4, promoted the upregulation of Gal-3 expression and improved the insulin resistance of macrophages., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Li et al.)

Environmental pH influences cell growth and differentiation. In the dimorphic yeast Yarrowia lipolytica , neutral-alkaline pH strongly induces the yeast-to-filament transition. However, the regulatory mechanism that governs alkaline pH-induced filamentation has been unclear. Here, we show that the pH-responsive transcription factor Y. lipolytica Rim101 (YlRim101) is a major regulator of alkaline-induced filamentation, since the deletion of Yl RIM101 severely impaired filamentation at alkaline pH, whereas the constitutively active Yl RIM101 1-330 mutant mildly induced filamentation at acidic pH. YlRim101 controls the expression of the majority of alkaline-regulated cell wall protein genes. One of these, the cell surface glycosidase gene Yl PHR1 , plays a critical role in growth, cell wall function, and filamentation at alkaline pH. This finding suggests that YlRim101 promotes filamentation at alkaline pH via controlling the expression of these genes. We also show that, in addition to YlRim101, the Msn2/Msn4-like transcription factor Mhy1 is highly upregulated at alkaline pH and is essential for filamentation. However, unlike YlRim101, which specifically regulates alkaline-induced filamentation, Mhy1 regulates both alkaline- and glucose-induced filamentation, since the deletion of MHY1 abolished them both, whereas the overexpression of MHY1 induced strong filamentation irrespective of the pH or the presence of glucose. Finally, we show that YlRim101 and Mhy1 positively coregulate seven cell wall protein genes at alkaline pH, including Yl PHR1 and five cell surface adhesin-like genes, three of which appear to promote filamentation. Together, these results reveal a conserved role of YlRim101 and a novel role of Mhy1 in the regulation of alkaline-induced filamentation in Y. lipolytica IMPORTANCE The regulatory mechanism that governs pH-regulated filamentation is not clear in dimorphic fungi except in Candida albicans Here, we investigated the regulation of alkaline pH-induced filamentation in Yarrowia lipolytica , a dimorphic yeast distantly related to C. albicans Our results show that the transcription factor YlRim101 and the Msn2/Msn4-like transcription factor Mhy1 are the major regulators that promote filamentation at alkaline pH. They control the expression of a number of cell wall protein genes important for cell wall organization and filamentation. Our results suggest that the Rim101/PacC homologs play a conserved role in pH-regulated filamentation in dimorphic fungi., (Copyright © 2021 Shu et al.)

Background: The purpose of this study was to explore the prognostic factors of oesophageal signet ring cell (SRC) carcinoma and to construct a nomogram for predicting the outcome of SRC carcinoma of oesophagus., Methods: A total of 968 cases of oesophageal SRC carcinoma were extracted from the Surveillance, Epidemiology, and End Results (SEER) database between 2004 and 2016. Cases were divided into training cohort and validation cohort. Univariate and multivariable Cox analyses was performed to select the predictors of overall survival (OS for the nomogram. The performance of nomogram was validated with Harrell's concordance index (C-index), calibration curves and decision curve analysis (DCA)., Results: The 1- and 5-year OS in the training cohort were 0.446 and 0.146, respectively, and the 1- and 5-year OS in the validation cohort were 0.459 and 0.138. The independent prognostic factors for establishing the nomogram were marital status, invasion of the surrounding tissue, lymph node metastasis, distant metastasis, surgery and chemotherapy. The Harrell's c-index value of the training cohort and validation cohort were 0.723 and 0.708. In the calibration curves, the predicted survival probability and the actual survival probability have a considerable consistency. DCA indicated the favourable potential clinical utility of the nomogram., Conclusions: A nomogram to predict the OS of patients with oesophageal SRC carcinoma was established. The validation of the nomogram fully demonstrates its great performance., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/jtd-20-3084). The authors have no conflicts of interest to declare., (2021 Journal of Thoracic Disease. All rights reserved.)

Background: Signet ring cell carcinoma is a rare type of oesophageal cancer, and we hypothesized that log odds of positive lymph nodes (LODDS) is a better prognostic factor for oesophageal signet ring cell carcinoma., Aim: To explore a novel prognostic factor for oesophageal signet ring cell carcinoma by comparing two lymph node-related prognostic factors, log odds of positive LODDS and N stage., Methods: A total of 259 cases of oesophageal signet ring cell carcinoma after oesopha-gectomy were obtained from the Surveillance, Epidemiology, and End Results database between 2006 and 2016. The prognostic value of LODDS and N stage for oesophageal signet ring cell carcinoma was evaluated by univariate and multivariate analyses. The Akaike information criterion and Harrell's C-index were used to assess the value of two prediction models based on lymph nodes. External validation was performed to further confirm the conclusion., Results: The 5-year cancer-specific survival (CSS) and 5-year overall survival (OS) rates of all the cases were 41.3% and 27.0%, respectively. The Kaplan-Meier method showed that LODDS had a higher score of log rank chi-squared (OS: 46.162, CSS: 41.178) than N stage (OS: 36.215, CSS: 31.583). Univariate analyses showed that insurance, race, T stage, M stage, TNM stage, radiation therapy, N stage, and LODDS were potential prognostic factors for OS ( P < 0.1). The multivariate Cox regression model showed that LODDS was an significant independent prognostic factor for oesophageal signet ring carcinoma patients after surgical resection ( P < 0.05), while N stage was not considered to be a significant prognostic factor ( P = 0.122). Model 2 (LODDS) had a higher degree of discrimination and fit than Model 1 (N stage) (LODDS vs N stage, Harell's C-index 0.673 vs 0.656, P < 0.001; Akaike information criterion 1688.824 vs 1697.519, P < 0.001). The results of external validation were consistent with those in the study cohort., Conclusion: LODDS is a superior prognostic factor to N stage for patients with oesophageal signet ring cell carcinoma after oesophagectomy., Competing Interests: Conflict-of-interest statement: All the authors have no conflict of interest related to the article., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Total pancreatectomy (TP) is usually considered a therapeutic option for pancreatic cancer in which Whipple surgery and distal pancreatectomy are undesirable, but brittle diabetes and poor quality of life (QoL) remain major concerns. A subset of patients who underwent TP even died due to severe hypoglycemia. For pancreatic cancer involving the pancreatic head and proximal body but without invasion to the pancreatic tail, we performed partial pancreatic tail preserving subtotal pancreatectomy (PPTP-SP) in selected patients, in order to improve postoperative glycemic control and QoL without compromising oncological outcomes., Aim: To evaluate the efficacy of PPTP-SP for patients with pancreatic cancer., Methods: We retrospectively reviewed 56 patients with pancreatic ductal adenocarcinoma who underwent PPTP-SP ( n = 18) or TP ( n = 38) at our institution from May 2014 to January 2019. Clinical outcomes were compared between the two groups, with an emphasis on oncological outcomes, postoperative glycemic control, and QoL. QoL was evaluated using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30 and EORTC PAN26). All patients were followed until May 2019 or until death., Results: A total of 56 consecutive patients were enrolled in this study. Perioperative outcomes, recurrence-free survival, and overall survival were comparable between the two groups. No patients in the PPTP-SP group developed cancer recurrence in the pancreatic tail stump or splenic hilum, or a clinical pancreatic fistula. Patients who underwent PPTP-SP had significantly better glycemic control, based on their higher rate of insulin-independence ( P = 0.014), lower hemoglobin A1c (HbA1c) level ( P = 0.046), lower daily insulin dosage ( P < 0.001), and less frequent hypoglycemic episodes ( P < 0.001). Global health was similar in the two groups, but patients who underwent PPTP-SP had better functional status ( P = 0.036), milder symptoms ( P = 0.013), less severe diet restriction ( P = 0.011), and higher confidence regarding future life ( P = 0.035)., Conclusion: For pancreatic cancer involving the pancreatic head and proximal body, PPTP-SP achieves perioperative and oncological outcomes comparable to TP in selected patients while significantly improving long-term glycemic control and QoL., Competing Interests: Conflict-of-interest statement: We declare that we have no conflicts of interest related to this study., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)

Preoperative nutritional status plays an important role in predicting postoperative outcomes. Prognostic Nutritional Index (PNI) and Controlling Nutritional Status (CONUT) are good tools to assess patients' nutritional status. They have been used in predicting outcomes in various malignancies, but few studies have focused on pancreatic adenocarcinoma (PDAC) patients. Totally, 306 PDAC patients were enrolled. The propensity score matching (PSM) method was introduced to eliminate the baseline inequivalence. Patients with different PNI (or CONUT) scores showed inequivalence baseline characteristics, and patients with compromised nutritional status were related with a more advanced tumour stage. After PSM, the baseline characteristics were well balanced. Both low PNI (≤45) and high CONUT (≥3) were independent risk factors for poor overall survival (P < 0·05), and the result remained the same after PSM. Survival analysis demonstrated both patients with low PNI and high CONUT score were associated with poorer survival, and the result remained the same after PSM. The results of AUC indicated that CONUT might have a higher sensitivity and specificity in predicting complications and survival. Preoperative low PNI (≤45) and high CONUT (≥3) scores might be reliable predictors of prognosis and surgical complications in PDAC patients. Compared with PNI, CONUT might be more effective.

Nanodiamonds (NDs) are considered to be relatively safe carbon nanomaterials used for the transmission of DNA, proteins and drugs. The feasibility of utilizing the NDs to deliver CRISPR-Cas9 system for gene editing has not been clearly studied. Therefore, in this study, we aimed to use NDs as the carriers of CRISPR-Cas9 components designed to introduce the mutation in RS1 gene associated with X-linked retinoschisis (XLRS). ND particles with a diameter of 3 nm were functionalized by carboxylation of the surface and covalently conjugated with fluorescent mCherry protein. Two linear DNA constructs were attached to the conjugated mCherry: one encoded Cas9 endonuclease and GFP reporter, another encoded sgRNA and contained insert of HDR template designed to introduce RS1 c.625C>T mutation. Such nanoparticles were successfully delivered and internalized by human iPSCs and mouse retinas, the efficiency of internalization was significantly improved by mixing with BSA. The delivery of ND particles led to introduction of RS1 c.625C>T mutation in both human iPSCs and mouse retinas. Rs1 gene editing in mouse retinas resulted in several pathological features typical for XLRS, such as aberrant photoreceptor structure. To conclude, our ND-based CRISPR-Cas9 delivery system can be utilized as a tool for creating in vitro and in vivo disease models of XLRS. STATEMENT OF SIGNIFICANCE: X-linked retinoschisis (XLRS) is a prevalent hereditary retinal disease, which is caused by mutations in RS1 gene, whose product is important for structural organization of the retina. The recent development of genome editing techniques such as CRISPR-Cas9 significantly improved the prospects for better understanding the pathology and development of treatment for this disease. Firstly, gene editing can allow development of appropriate in vitro and in vivo disease models; secondly, CRISPR-Cas9 can be applied for gene therapy by removing the disease-causative mutation in vivo. The major prerequisite for these approaches is to develop safe and efficient CRISPR-Cas9 delivery system. In this study, we tested specifically modified nanodiamonds for such a delivery system. We were able to introduce Rs1 mutation into the mouse retina and, importantly, observed several XLRS-specific effects., (Copyright © 2019 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Background: The abnormal expression of leucine-rich-alpha-2-glycoprotein 1 (LRG-1) is reported to be associated with multiple malignancies, but its role in the progression of pancreatic ductal adenocarcinoma (PDAC) remains to be determined., Methods: The expression of LRG-1 was assessed in PDAC tissues by RT-PCR, Western blot and immunohistochemistry. LRG-1-silenced or overexpressed cell lines were constructed using shRNA or LRG-1-overexpressing plasmids. EdU incorporation assay, Transwell invasion and wound-healing assays were performed to evaluate the proliferation, invasion and migration of PDAC cells. In addition, protein expression of the mitogen-activated protein kinase (MAPK) pathway was detected using Western blot. Finally, Co-immunoprecipitation assay was conducted in search of the potential interaction between LRG-1 and epidermal growth factor receptor (EGFR)., Results: The expression of LRG-1 in PDAC tissue was significantly higher than that in adjacent normal tissue, and high LRG-1 expression predicted poor survival and a late tumor stage. In addition, LRG-1 markedly promoted the viability, proliferation, migration and invasion of PDAC cells in vitro and facilitated tumor growth in vivo. More importantly, we revealed that these bioactivities of LRG-1 might result from its selective interaction with EGFR, which might further activate the p38/MAPK signaling pathways., Conclusion: LRG-1 may prove to be a promising biomarker for predicting prognosis of PDAC patients. Inhibition of LRG-1 or its downstream pathway could be a potential therapeutic target for the treatment of PDAC.

Background: Esophageal cancer is one of the most prevalent malignancies with a high incidence and mortality in China, the main treatment for esophageal cancer at present is still surgery-based multimodality treatment, and surgery is still the most effective measure. However, the modes of surgical treatment for esophageal cancer have been diverse. The surgical approaches can be mainly divided into the left thoracic approach and right thoracic approach in China. The long-term survival of the patients treated through right approach was reported better than that through left thoracic approach, but until now no statistically significant difference was found between two approaches, especially, for those with middle and lower thoracic esophageal cancer without suspected upper mediastinal lymph node metastasis in preoperative examinations, no definite conclusion have been made on selection of the approach, therefore, this studies try to compare the long-term survival between two approaches ., Methods: The data of 402 cases with complete resection and two-field lymph node dissection from January, 2011 to December, 2011 in the Cancer Hospital, Chinese Academy of Medical Sciences was retrospectively reviewed and analyzed. Propensity score matching (PSM) analysis and life-table in SPSS 22.0 and Stata 14.0 were used to analyze the survival., Results: Totally, 402 cases were surgically treated either via left or right thoracic approach. The overall 5-year survival rate of this series was 38%, it was 37% in 281 cases surgically treated through left approach, and 39% in 121 cases through right approach (P=0.908). The 5-year survival of 256 patients without suspected lymph node metastasis in the upper mediastinum based on the preoperative examinations surgically treated through left approach was 38% versus 43% of 88 cases through right approach (P=0.404). After PSM, the 5-year survival of 110 cases surgically treated through left approach was 32% versus 40% of another matched 110 cases through right approach (P=0.146). for the patients without suspected lymph node metastasis in the upper mediastinum based on preoperative examinations, the 5-year survival of 88 surgically treated through left approach was 33% versus 44% of another matched 88 cases through right approach (P=0.239)., Conclusions: For the middle and lower thoracic esophageal cancer patients, whether or not who has suspected lymph node metastasis in the upper mediastinum based on preoperative CT and EUS, the surgical treatment through right thoracic approach can achieve better but not significantly better overall survival than that through left thoracic approach. Further prospective randomized clinical trials are still needed to verify this disputed issue on approach selection., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Breast cancer-specific gene 1 (BCSG1), also referred to as γ-synuclein (SNCG), is highly expressed in human infiltrating breast carcinomas, but not in normal or benign breast tissue. The present study aimed to evaluate the effects of BCSG1 siRNA delivered by lentiviral vector on breast cancer cells and investigate the underlying mechanisms. BCSG1 RNAi lentiviral vector was constructed and transfected into MDA-MB-231 cells. BCSG1 mRNA levels were determined by quantitative polymerase chain reaction analysis. Cell proliferation, migration and apoptosis were evaluated by using the cell counting kit‑8, Transwell assay and flow cytometry, respectively, followed by western blotting to determine the relative levels of AKT, extracellular signal‑regulated kinase (ERK), p-AKT and p-ERK expression. BCSG1 mRNA levels were significantly reduced in MDA-MB‑231 cells following transfection of BCSG1 siRNA delivered by lentiviral vector. Cell migration and proliferation were significantly decreased and the cell cycle was arrested. Western blot analysis indicated that the protein levels of p-AKT and p-ERK were significantly lower in the BCSG1 siRNA-treated groups compared with the control and negative control groups. Therefore, BCSG1 siRNA delivered by lentiviral vector was able to significantly reduce BCSG1 expression, suppress cell migration and proliferation, possibly through the reduction of the protein levels of p-AKT and p-ERK.

The MALAT1 (Metastasis-Associated Lung Adenocarcinoma Transcript 1) gene encodes a noncoding RNA that is processed into a long nuclear retained transcript (MALAT1) and a small cytoplasmic tRNA-like transcript (mascRNA). Using an RNA sequence- and structure-based covariance model, we identified more than 130 genomic loci in vertebrate genomes containing the MALAT1 3' end triple-helix structure and its immediate downstream tRNA-like structure, including 44 in the green lizard Anolis carolinensis. Structural and computational analyses revealed a co-occurrence of components of the 3' end module. MALAT1-like genes in Anolis carolinensis are highly expressed in adult testis, thus we named them testis-abundant long noncoding RNAs (tancRNAs). MALAT1-like loci also produce multiple small RNA species, including PIWI-interacting RNAs (piRNAs), from the antisense strand. The 3' ends of tancRNAs serve as potential targets for the PIWI-piRNA complex. Thus, we have identified an evolutionarily conserved class of long noncoding RNAs (lncRNAs) with similar structural constraints, post-transcriptional processing, and subcellular localization and a distinct function in spermatocytes., (Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Thymoma is an uncommon tumor without a widely accepted standard care to date. We aimed to investigate the clinicopathologic variables of patients with thymoma and identify possible predictors of survival and recurrence after initial resection., Methods: We retrospectively selected 307 patients with thymoma who underwent complete resection at the Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (Beijing, China) between January 2003 and December 2014. The associations of patients' clinical characteristics with prognosis were estimated using Cox regression and Kaplan-Meier survival analyses., Results: During follow-up (median, 86 months; range, 24-160 months), the 5- and 10-year disease-free survival (DFS) rates were 84.0% and 73.0%, respectively, and the 5- and 10-year overall survival (OS) rates were 91.0% and 74.0%, respectively. Masaoka stage (P < 0.001), World Health Organization (WHO) histological classification (P < 0.001), and postoperative radiotherapy after initial resection (P = 0.006) were associated with recurrence (52/307, 16.9%). Multivariate analysis revealed that, after initial resection, WHO histological classification and Masaoka stage were independent predictors of DFS and OS. The pleura (25/52, 48.0%) were the most common site of recurrence, and locoregional recurrence (41/52, 79.0%) was the most common recurrence pattern. The recurrence pattern was an independent predictor of post-recurrence survival. Patients with recurrent thymoma who underwent repeated resection had increased post-recurrence survival rates compared with those who underwent therapies other than surgery (P = 0.017)., Conclusions: Masaoka stage and WHO histological classification were independent prognostic factors of thymoma after initial complete resection. The recurrence pattern was an independent predictor of post-recurrence survival. Locoregional recurrence and repeated resection of the recurrent tumor were associated with favorable prognosis.

Background: The aim of this study was to compare the short-term outcomes and three-year survival between dual-incision esophagectomy (DIE) and total minimally invasive McKeown esophagectomy (MIME) for esophageal cancer patients with negative upper mediastinal lymph nodes requiring esophagectomy and neck anastomosis., Methods: One hundred and fifty patients underwent DIE, while 361 patients received total MIME. Perioperative outcomes and three-year survival were compared in unmatched and propensity score matched data between two groups., Results: Both unmatched and matched analysis demonstrated that there were no significant differences in the number of lymph nodes harvested, or major or minor complication rates between the DIE and MIME groups. Compared with patients who underwent DIE, patients who underwent total MIME had longer operation duration (310 minutes vs. 345 minutes; P  = 0.002). However, there was significantly less intraoperative blood loss in the total MIME compared with the DIE group (191 mL vs. 287 mL, respectively; P  < 0.001). Kaplan-Meier analysis demonstrated a trend that patients who underwent MIME had longer overall (79.5% vs. 64.1%; P  = 0.063) and disease-free three-year survival (65.3% vs. 82.8%; P  = 0.058) compared with patients who underwent DIE., Conclusions: Both total MIME and DIE are feasible for the surgical treatment of esophageal cancer patients with negative upper mediastinal lymph nodes requiring esophagectomy and neck anastomosis. However, MIME was associated with better overall and disease-free three-year survival compared with DIE., (© 2017 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Background: The aim of this study was to investigate the perioperative outcomes and 3-year overall survival (OS) of 2 approaches including Sweet and open Ivor Lewis esophagectomy in the surgical treatment of middle and lower third esophageal squamous cell carcinoma., Methods: The medical records of 1,746 consecutive patients who underwent esophagectomy for middle and lower esophageal cancer between January 2009 and September 2015 at the First Department of Thoracic Oncologic Surgery of Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College were retrospectively reviewed. The clinical variables and 3-year survival were compared between Sweet (n=1,701) and open Ivor Lewis (n=45) approaches in unmatched and propensity score matching analysis., Results: Patients who received esophagectomy by Sweet approach had shorter duration of surgery (mean 212 vs. 390 min; P<0.001), more lymph nodes removed (mean 24 vs. 19; P=0.005), lower overall complications rate (24.4% vs. 11.7%; P=0.009), lower total hospital cost (¥77,200 vs. 106,000; P=0.045) compared with patients who received open Ivor Lewis approach. After propensity score matching analysis, Sweet approach was still associated with decreased duration of surgery (mean 210 vs. 390 min; P<0.001), more lymph nodes removed (mean 24 vs. 19; P=0.050), and lower total hospital cost (¥86,800 vs. 106,000; P=0.045) compared with Ivor Lewis approach. However, there were no significant differences in overall complication rates (24.4% vs. 24.4%; P=1.000) between two approaches. There was no significant difference in 3-year OS between Sweet and open Ivor Lewis approaches (59.9% vs. 61.4%; P=0.637) in unmatched analysis and in matched analysis (77.8% vs. 61.4%; P=0.264)., Conclusions: In this cohort, for middle and lower third esophageal squamous cell carcinoma patients, both Sweet and open Ivor Lewis approaches are feasible in terms of perioperative outcomes and 3-year OS., Competing Interests: The authors have no conflicts of interest to declare.

Background: The prognostic value of serum lactate dehydrogenase (LDH) has been demonstrated in various solid tumors. We attempted to determine whether serum LDH was predictive of survival in thymic carcinoma after surgical resection., Methods: Ninety-five patients with thymic carcinoma treated in our hospital between January 2005 and December 2015 were retrospectively enrolled. Serum LDH was measured before surgery and categorized as low or high relative to the upper limit of normal (ULN) (225 U/L). The relationships of serum LDH level and other clinical variables with survival were estimated by Cox regression and Kaplan-Meier survival analysis., Results: Serum LDH levels were found to be significantly associated with overall survival (OS) and progression-free survival (PFS) of these patients. The 1-, 3-, and 5-year PFS were 76%, 51%, and 38%, and the 1-, 3- and 5-year OS were 97%, 75%, and 46%, respectively. Univariate analysis found that high serum LDH (>225 U/L) was associated with both lower OS [hazard ratio (HR) =2.710; 95% confidence interval (CI): 1.363-1.5.391; P=0.004] and PFS (HR =3.365; 95% CI: 1.776-6.374; P<0.001). Multivariate analysis found that high serum LDH was associated with lower PFS (HR =2.122; 95% CI: 1.056-4.267; P=0.035). Moreover, high LDH was significantly associated with advanced Masaoka stage (P=0.001)., Conclusions: High serum LDH (>225 U/L) was an independent predictor of decreased PFS in thymic carcinoma patients. It was also significantly associated with reduced OS, but was not an independent predictor of death in those patients., Competing Interests: The authors have no conflicts of interest to declare.

Background: To summarize our experiences of single-port, two-port vs. three-port VATS pulmonary resection for lung cancer patients., Methods: Data of consecutive 1,553 patients who underwent video assisted thoracoscopic surgery (VATS) pulmonary resection for lung cancer in the Department of Thoracic Surgery of Cancer Hospital of Chinese Academy of Medical Sciences and Peking Union Medical College between November 2014 and January 2016 were prospectively collected and analyzed. A propensity-matched analysis was used to compare the short-term outcomes of lung cancer patients who received VATS single-port, two-port and three-port pulmonary resection., Results: There were 716 males and 837 females. The mean age was 58.90 years (range, 25-82 years) and the conversion rate was 2.7% (42/1,553) in this cohort. After propensity score matching, there were 207 patients in single-port and two-port group, and 680 patients in three-port group. Propensity-matched analysis demonstrated that there were no significant differences in duration of operation (129 vs. 131 min, P=0.689), intra-operative blood loss (63 vs. 70 mL, P=0.175), number of dissected lymph nodes (12 vs. 13, P=0.074), total hospital expense (﹩9,928 vs. ﹩9,956, P=0.884) and cost of operation (﹩536 vs. ﹩535, P=0.879) between VATS single-port, two-port and conventional three-port pulmonary resection groups. There was no significant difference in the complication rate between two groups (5.3% vs. 4.7%, P=0.220). However, compared with three-port group, patients who underwent single port and two-port experienced shorter postoperative length of stay (6.24 vs. 5.61 d, P=0.033), shorter duration of chest tube (4.92 vs. 4.25 d, P=0.008), and decreased volume of drainage (926 vs. 791 d, P=0.003)., Conclusions: The short term outcomes between VATS single-port, two-port and conventional three-port groups for the surgical treatment of lung cancer were comparable. However, compared with three-port VATS pulmonary resection, single-port and two-port were associated with shorter postoperative length of stay, shorter duration of chest tube, and decreased volume of drainage.

Background: Preoperative neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) have prognostic value in patients with various operable tumors. The aim of our study was to determine whether NLR and PLR are predictive of survival in thymic carcinoma patients after complete resection., Methods: A total of seventy-nine patients who underwent complete resection of thymic carcinoma at our hospital between January 2005 and December 2015 were retrospectively enrolled. Differential leukocyte counts were collected before surgery, and the relationships of NLR, PLR, and other patient clinical variables with survival were estimated by Cox regression analysis and Kaplan-Meier survival analysis., Results: Univariate analysis found that a high level of NLR was associated with lower disease-free survival (DFS) (HR: 3.385, 95% CI: 1.073-10.678, P=0.037) and lower overall survival (OS) (HR: 12.836, 95% CI: 1.615-101.990, P=0.016). The optimal NLR threshold of 4.1 could stratify the patients with high risk of recurrence or metastasis (P=0.026) and death (P=0.006). Meanwhile, the NLR value of >4.1 in those patients was associated with bigger tumor size (P=0.035) and more advanced Masaoka stages (P=0.040) compared with NLR ≤4.1. However, the PLR and other variables were not significantly associated with survival in thymic carcinoma patients., Conclusions: The preoperative NLR of >4.1 was significantly associated with larger tumor size, more advanced Masaoka stages and reduced DFS and OS, but was not an independent predictor of survival in thymic carcinoma patients after complete resection.

Aim: To update our experiences with minimally invasive McKeown esophagectomy for esophageal cancer., Methods: We retrospectively reviewed the medical records of 445 consecutive patients who underwent minimally invasive McKeown esophagectomy between January 2009 and July 2015 at the Cancer Hospital of Chinese Academy of Medical Sciences and used 103 patients who underwent open McKeown esophagectomy in the same period as controls. Among 375 patients who underwent total minimally invasive McKeown esophagectomy, 180 in the early period were chosen for the study of learning curve of total minimally invasive McKeown esophagectomy. These 180 minimally invasive McKeown esophagectomies performed by five surgeons were divided into three groups according to time sequence as group 1 (n = 60), group 2 (n = 60) and group 3 (n = 60)., Results: Patients who underwent total minimally invasive McKeown esophagectomy had significantly less intraoperative blood loss than patients who underwent hybrid minimally invasive McKeown esophagectomy or open McKeown esophagectomy (100 mL vs 300 mL vs 200 mL, P = 0.001). However, there were no significant differences in operation time, number of harvested lymph nodes, or postoperative morbidity including incidence of pulmonary complication and anastomotic leak between total minimally invasive McKeown esophagectomy, hybrid minimally invasive McKeown esophagectomy and open McKeown esophagectomy groups. There were no significant differences in 5-year survival between these three groups (60.5% vs 47.9% vs 35.6%, P = 0.735). Patients in group 1 had significantly longer duration of operation than those in groups 2 and 3. There were no significant differences in intraoperative blood loss, number of harvested lymph nodes, or postoperative morbidity including incidence of pulmonary complication and anastomotic leak between groups 1, 2 and 3., Conclusion: Total minimally invasive McKeown esophagectomy was associated with reduced intraoperative blood loss and comparable short term and long term survival compared with hybrid minimally invasive McKeown esophagectomy or open Mckeown esophagectomy. At least 12 cases are needed to master total minimally invasive McKeown esophagectomy in a high volume center.

Objective: To study the effect of venlafaxine on the expression of brain-derived neurotrophic factor (BDNF) in rat hippocampal neurons, as well as its inhibitory effect on apoptosis of hippocampal neurons., Methods: Differences in behavioral ability between the depression model group and the Venlafaxine treatment group were observed using behavioral, sucrose-water and open field tests. The rat hippocampal tissue was sliced, stained and observed for BDNF distribution by immunohistochemistry. Apoptosis of hippocampal neurons was detected by TUNEL. BDNF expression in the hippocampal tissue was detected by Western blot. Injury and apoptosis of the hippocampal tissue were observed by electron microscopy., Results: Behavioral test showed that venlafaxine effectively improved the behavioral abilities of depressed rats. Immunohistochemistry showed that venlafaxine markedly increased the BDNF expression in the rat hippocampus. TUNEL showed that venlafaxine markedly inhibited apoptosis of hippocampal neurons, which was also confirmed by electron microscopic observation of the pathologic sections., Conclusion: Venlafaxine improved the expression of BDNF through working on PI3k/PKB/eNOS pathway and repressed the apoptosis of hippocampal neurons.

Background: Due to the popularity of video-assisted thoracic surgery (VATS) techniques in clinical, thymoma patients via VATS thymectomy are increasing rapidly. However, compared with open thymectomy, the potential superiorities and defects of VATS thymectomy remain controversial., Methods: A number of 129 patients who underwent thymectomy of early stage thymoma (Masaoka stage I and stage II) in one single center from January 2007 to September 2013 were selected in this retrospective study. Of those patients, 38 thymoma patients underwent VATS thymectomy (VATS group) and 91 underwent open thymectomy (open group) via either transsternal [44] or transthoracic approach [47] in the same period. The postoperative variables, which included postoperative hospital length of stay (LOS), the intensive care unit (ICU) LOS, the entire resection ratio, the number of thoracic drainage tubes, the quantity of output and duration of drainage, were analyzed. Meanwhile, the operation time and blood loss were considered as intraoperative variables., Results: All thymoma patients in the analysis included 19 thymoma patients with myasthenia gravis, among which five patients via VATS thymectomy and 14 patients via open thymectomy respectively. There was no death or morbidity due to the surgical procedures perioperatively. The ICU LOS, operation time, entire resection ratio, and the number of chest tubes were not significantly different in two groups. The postoperative hospital LOS of VATS thymectomy was shorter than that of open thymectomy (5.26 versus 8.32 days, P<0.001). The blood loss of VATS thymectomy was less than open thymectomy (114.74 versus 194.51 mL, P=0.002). Postoperatively, the quantity of chest tubes output in VATS group was less than that in open thymectomy group (617.86 versus 850.08 mL, P=0.007) and duration of drainage in VATS group was shorter than that in open thymectomy group (3.87 versus 5.22 days, P<0.001)., Conclusions: VATS thymectomy is a safe and practicable treatment for early-stage thymoma patients. Thymoma according with Masaoka staging I-II without evident invading seems to be performed through VATS approach appropriately, which has shorter postoperative hospital LOS, less blood loss and less restrictions to activities, hence patients will recover sooner.

Aim: To investigate the prevalence and risk factors of polypoid lesions of the gallbladder (PLGs) in petrochemical employees in Ningbo, Zhejiang Province, China., Methods: All active and retired employees aged 20-90 years (n = 11098) of a refinery and chemical plant in eastern China were requested to participate in a health survey. The participants were subjected to interview, physical examination, laboratory assessments and ultrasonography. All the participants were invited to have a physical examination after a face-to-face interview. Fasting blood samples were obtained from the antecubital vein, and the samples were used for the analysis of biochemical values. Abdominal ultrasonography was conducted., Results: A total of 10461 (7331 men and 3130 women) current and former petrochemical employees attended for screening. The overall prevalence of post-cholecystectomy, gallstones and PLGs was 0.9%, 5.2% and 7.4%, respectively. Compared with the increased prevalence of either gallstones or post-cholecystectomy in older persons, PLGs were more common in the middle-aged, peaking in those aged 40-59 years. Excluding the patients with gallstones, gallstones mixed with PLGs, or those who had undergone cholecystectomy, in the remaining 9828 participants, the prevalence of PLGs in men (8.9%) was significantly higher than that in women (5.5%, P < 0.001). The analyzed risk factors with increased OR for the development of PLGs were male gender (OR = 1.799, P < 0.001), age ≥ 30 years (OR = 2.699, P < 0.001) and hepatitis B surface antigen (HBsAg) positivity (OR = 1.374, P = 0.006)., Conclusion: PLGs are not rare among Chinese petrochemical employees. Male gender, HBsAg positivity, and middle age are risk factors for developing PLGs.

Objective: To evaluate the short-term outcomes of video-assisted thoracic surgery (VATS) for thoracic tumors., Methods: The data of 1,790 consecutive patients were retrospectively reviewed. These patients underwent VATS pulmonary resections, VATS esophagectomies, and VATS resections of mediastinal tumors or biopsies at the Cancer Institute & Hospital, Chinese Academy of Medical Sciences between January 2009 and January 2012., Results: There were 33 patients converted to open thoracotomy (OT, 1.84%). The overall morbidity and mortality rate was 2.79% (50/1790) and 0.28% (5/1790), respectively. The overall hospitalization and chest tube duration were shorter in the VATS lobectomy group (n=949) than in the open thoracotomy (OT) lobectomy group (n=753). There were no significant differences in morbidity rate, mortality rate and operation time between the two groups. In the esophageal cancer patients, no significant difference was found in the number of nodal dissection, chest tube duration, morbidity rate, mortality rate, and hospital length of stay between the VATS esophagectomy group (n=81) and open esophagectomy group (n=81). However, the operation time was longer in the VATS esophagectomy group. In the thymoma patients, there was no significant difference in the chest tube duration, morbidity rate, mortality rate, and hospital length of stay between the VATS thymectomy group (n=41) and open thymectomy group (n=41). However, the operation time was longer in the VATS group. The median tumor size in the VATS thymectomy group was comparable with that in the OT group., Conclusions: In early-stage (I/II) non-small cell lung cancer patients who underwent lobectomies, VATS is comparable with the OT approach with similar short-term outcomes. In patients with resectable esophageal cancer, VATS esophagectomy is comparable with OT esophagectomy with similar morbidity and mortality. VATS thymectomy for Masaoka stage I and II thymoma is feasible and safe, and tumor size is not contraindicated. Longer follow-ups are needed to determine the oncologic equivalency of VATS lobectomy, esophagectomy, and thymectomy for thymoma vs. OT.

Genome-wide studies have identified thousands of long noncoding RNAs (lncRNAs) lacking protein-coding capacity. However, most lncRNAs are expressed at a very low level, and in most cases there is no genetic evidence to support their in vivo function. Malat1 (metastasis associated lung adenocarcinoma transcript 1) is among the most abundant and highly conserved lncRNAs, and it exhibits an uncommon 3'-end processing mechanism. In addition, its specific nuclear localization, developmental regulation, and dysregulation in cancer are suggestive of it having a critical biological function. We have characterized a Malat1 loss-of-function genetic model that indicates that Malat1 is not essential for mouse pre- and postnatal development. Furthermore, depletion of Malat1 does not affect global gene expression, splicing factor level and phosphorylation status, or alternative pre-mRNA splicing. However, among a small number of genes that were dysregulated in adult Malat1 knockout mice, many were Malat1 neighboring genes, thus indicating a potential cis-regulatory role of Malat1 gene transcription., (Copyright © 2012 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: As a rare benign lung tumor, pulmonary sclerosing hemangioma (PSH) occurs predominantly in Asian women in their fifth and sixth decades of life. PSH is considered to be evolved from primitive undifferentiated respiratory epithelium. In this study, we summarized our experience in 89 cases of PSH., Method: There were a total of 89 patients who received surgical resection and were histopathologically diagnosed as PSH during the period January 2001 to December 2010 in department of thoracic surgery, Cancer Institute and Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences. The clinical data of these patients including symptoms, disease courses, image characteristics and surgical procedures were collected and reviewed retrospectively., Results: The PSHs were most frequently (50.6%) found in the patients aged 41 to 60 years with a median age of 51 years (range: 24 - 71), and the sex ratio (male/female) was approximately 1:7 in this series. In the 89 patients, 53 (59.6%) were asymptomatic while the other 36 (40.4%) had some non-special symptoms such as cough (30.3%), hemoptysis (24.7%). There were only 3 cases (3.4%) with multiple PSHs, 4 cases (4.5%) combined with synchronous primary lung cancer, and 13 cases (14.6%) with lesions located in the hilar region. The median diameter of the 92 lesions was 2.3 cm (range: 0.3 - 6.0 cm), of which 38% located in the right lower lobe and 26.1% in the right middle lobe, and only about 1/3 were assumed as PSHs preoperatively based on CT imaging. One of the five patients who underwent PET-CT scan had been misdiagnosed as malignant. Of the 92 lesions, 47 were resected by enucleation, 29 by wedge resection, 14 by lobectomy, and 2 by pneumonectomy., Conclusion: PSH frequently occurs in the middle-aged women. Most individuals with PSH are asymptomatic or have some non-specific symptoms. Their lesions are usually found accidentally by chest imaging. Although PSH often shows typical imaging characteristics of benign neoplasm of the lung, it is difficult to establish a defined pathological diagnosis preoperatively. The significant error or deferred rate of intraoperative frozen-section evaluation for PSH may result in some unnecessarily extensive surgical procedures. The complete surgical resection is considered the only effective treatment for PSH, and the normal pulmonary tissue should be reserved as possible.

Here we investigate the role of Phosphatidylinositol (4,5) bisphosphate (PIP(2)) in the physiological activation of primary murine T cells by antigen presenting cells (APC) by addressing two principal challenges in PIP(2) biology. First, PIP(2) is a regulator of cytoskeletal dynamics and a substrate for second messenger generation. The relative importance of these two processes needs to be determined. Second, PIP(2) is turned over by multiple biosynthetic and metabolizing enzymes. The joint effect of these enzymes on PIP(2) distributions needs to be determined with resolution in time and space. We found that T cells express four isoforms of the principal PIP(2)-generating enzyme phosphatidylinositol 4-phosphate 5-kinase (PIP5K) with distinct spatial and temporal characteristics. In the context of a larger systems analysis of T cell signaling, these data identify the T cell/APC interface and the T cell distal pole as sites of differential PIP(2) turnover. Overexpression of different PIP5K isoforms, as corroborated by knock down and PIP(2) blockade, yielded an increase in PIP(2) levels combined with isoform-specific changes in the spatiotemporal distributions of accessible PIP(2). It rigidified the T cell, likely by impairing the inactivation of Ezrin Moesin Radixin, delayed and diminished the clustering of the T cell receptor at the cellular interface, reduced the efficiency of T cell proximal signaling and IL-2 secretion. These effects were consistently more severe for distal PIP5K isoforms. Thus spatially constrained cytoskeletal roles of PIP(2) in the control of T cell rigidity and spatiotemporal organization dominate the effects of PIP(2) on T cell activation.

Background: It is still unclear whether pulmonary function tests (PFTs) are sufficient for predicting perioperative risk, and whether all patients or only a subset of them need a cardiopulmonary exercise test (CPET) for further assessment. Thus, this study was designed to evaluate the CPET and compare the results of CPET and conventional PFTs to identify which parameters are more reliable and valuable in predicting perioperative risks for high risk patients with lung cancer., Methods: From January 2005 to August 2008, 297 consecutive lung cancer patients underwent conventional PFTs (spirometry + single-breath carbon monoxide diffusing capacity of the lungs (DLCOsb) for diffusion capacity) and CPET preoperatively. The correlation of postoperative cardiopulmonary complications with the parameters of PFT and CPET was retrospectively analyzed using the chi-square test, independent sample t test and binary Logistic regression analysis., Results: Of the 297 patients, 78 did not receive operation due to advanced disease stage or poor cardiopulmonary function. The remaining 219 underwent different modes of operations. Twenty-one cases were excluded from this study due to exploration alone (15 cases) and operation-related complications (6 cases). Thus, 198 cases were eligible for evaluation. Fifty of the 198 patients (25.2%) had postoperative cardiopulmonary complications. Three patients (1.5%) died of complications within 30 postoperative days. The patients were stratified into groups based on VO(2)max/pred (≥ 70.0%, < 70.0%); VO(2)max×kg(-1)×min(-1) (≥ 20.0 ml, 15.0 - 19.9 ml, < 15.0 ml) and FEV1 (≥ 2.0 L, 1.2 - 1.99 L, < 1.2 L), respectively. The rate of postoperative cardiopulmonary complications was significantly higher in the group with VO(2)max/pred< 70.0% or VO(2)max×kg(-1)×min(-1) < 15.0 ml or FEV1 < 1.2 L than that in the group with VO(2)max/pred ≥ 70.0% or VO(2)max×kg(-1)×min(-1) ≥ 15.0 ml or FEV1 ≥ 1.2 L, respectively. Logistic regression analysis revealed that postoperative cardiopulmonary complications were significantly correlated with age, comorbidities, and poor PFT and CPET results., Conclusions: FEV1 in spirometry, VO(2)max×kg(-1)×min(-1) and VO(2)max/pred in cardiopulmonary exercise tests can all be used to stratify the patients' cardiopulmonary function status and to predict the risk of postoperative cardiopulmonary complications for the high risk patients with lung cancer. FEV1 and VO(2)max×kg(-1)×min(-1) are better than VO(2)max/pred in predicting perioperative risk. If available, cardiopulmonary exercise testing is strongly suggested for high-risk lung cancer patients in addition to conventional pulmonary function tests, and both should be combined to assess cardiopulmonary function status.

Background: The prevalence and the spectrum of thyroid dysfunction in the mainland of China are not adequately understood. We performed a population-based study to determine the prevalence of major thyroid dysfunctions including overt and subclinical hyper- and hypothyroidism in a stable cohort., Methods: All active and retired employees aged 20 years and older (11 067) of Sinopec Zhenhai Refining & Chemical Company in Ningbo participated in the cross-sectional survey with a questionnaire and blood samples., Results: A total of 10 405 individuals attended for screening. Using biochemical definitions 95.5% were euthyroid. The prevalence of former diagnosed hyperthyroidism was 1.1% in females and 0.4% in males, hypothyroidism 1.7% and 0.3%, and thyroid surgery 1.2% and 0.3%, respectively. In both sex the prevalence increased with age. Twenty-four percent of individuals with thyroid surgery or medications had abnormal thyroid-stimulating hormone (TSH) levels. In individuals without a history of thyroid disease, the prevalence of pathological TSH values in females and males were TSH > or = 10 mU/L 0.60% and 0.29%; TSH 4.8-9.9 mU/L 5.71% and 2.25%; TSH < 0.3 mU/L 0.87% and 0.41%, respectively. Overt hyper- and hypothyroidism were uncommon (0.2%, 0.3%, respectively). The prevalence of subclinical hyper- and hypothyroidism was 0.4% and 3.4%, respectively. Subclinical hypothyroidism was more common in females (male 2.4% vs. female 5.8%, P < 0.001) and with increasing age (P < 0.001)., Conclusions: The prevalence of thyroid dysfunction is 4.5% in the cohort. Among individuals with thyroid medications or surgery, only 75.7% were within the normal range of TSH. These results indicate that thyroid dysfunction is common in Chinese adults.

Objective: To evaluate the diagnostic yield of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) in cases of undiagnosed intrapulmonary lesions., Methods: A total of 89 patients with intrathoracic lesions underwent EBUS-TBNA, including 56 pulmonary lesions, 7 lymph node staging in lung cancer patients, 21 unknown hilar and/or mediastinal lymphadenopathies and 5 mediastinal tumors. All samples were evaluated for cytological and pathological examinations., Results: No complication of EBUS-TBNA was observed. Among 89 cases, 76 had positive results, 5 negative and 5 cases excluded as unsatisfied samples. In 56 patients with pulmonary lesions, EBUS-TBNA demonstrated 45 malignant tumors, 5 benign diseases, 3 suspicious cancers, 1 negative and 2 unsatisfied samples. In 7 lung cancer patients staged by EBUS-TBNA, 5 showed metastasis and 2 showed no metastasis. In 21 cases with mediastinal and/or hilar lymphadenopathy, EBUS-TBNA demonstrated 3 malignant tumors, 13 benign diseases, 2 negative and 3 unsatisfied samples. All 5 mediastinal lesions were malignant. Three suspicious cancers were confirmed, 1 by CT-guided percutaneous transthoracic needle biopsy and 2 by clinical follow-ups. In 2 lung cancer patients EBUS-TBNA showed negative, 1 surgical sample showed metastasis and another no metastasis by PET-CT. Three negative cases were diagnosed as benign by clinical follow-ups. The diagnostic sensitivity, specificity, positive predictive value and negative predictive value of EBUS-TBNA were 95%, 100%, 100% and 20% respectively., Conclusion: EBUS-TBNA is both effective and safe in making a diagnosis of intrathoracic lesions.

Objective: To evaluate the indication and safety of video assisted thoracic surgery (VATS) for chest tumors., Methods: Data of 144 consecutive patients receiving VATS between January and November 2009 in Cancer hospital Chinese Academy of Medical Sciences were retrospectively reviewed., Results: There was no conversion to open thoracotomy. Overall morbidity rate was 2.08% (3/144) and mortality rate was 0.69% (1/144). There were no significant differences for operative time, number of nodal dissection, morbidity rate, mortality rate, overall hospitalization and postoperative length of stay between VATS lobectomy group and open thoracotomy (OT) lobectomy group. Chest tube duration was shorter in the VATS lobectomy group than OT lobectomy group and more early-stage lung cancer patients were found in VATS group. There were no significant differences for number of nodal dissection, chest tube duration, morbidity rate, mortality rate, and postoperative length of stay between VATS lung wedge resection group and OT lung wedge resection group. Operative time and overall hospitalization were shorter in the VATS wedge resection group than OT wedge resection group., Conclusion: Morbidity and mortality rate of VATS were acceptable. VATS lobectomy can be used as an alternative surgical technique for early-stage lung cancer. For lung wedge resection, VATS was superior than OT.

Phosphatidylinositol 4,5-bisphosphate (PIP(2)) has many essential functions and its homeostasis is highly regulated. We previously found that hypertonic stress increases PIP(2) by selectively activating the beta isoform of the type I phosphatidylinositol phosphate 5-kinase (PIP5Kbeta) through Ser/Thr dephosphorylation and promoting its translocation to the plasma membrane. Here we report that hydrogen peroxide (H(2)O(2)) also induces PIP5Kbeta Ser/Thr dephosphorylation, but it has the opposite effect on PIP(2) homeostasis, PIP5Kbeta function, and the actin cytoskeleton. Brief H(2)O(2) treatments decrease cellular PIP(2) in a PIP5Kbeta-dependent manner. PIP5Kbeta is tyrosine phosphorylated, dissociates from the plasma membrane, and has decreased lipid kinase activity. In contrast, the other two PIP5K isoforms are not inhibited by H(2)O(2). We identified spleen tyrosine kinase (Syk), which is activated by oxidants, as a candidate PIP5Kbeta kinase in this pathway, and mapped the oxidant-sensitive tyrosine phosphorylation site to residue 105. The PIP5KbetaY105E phosphomimetic is catalytically inactive and cytosolic, whereas the Y105F non-phosphorylatable mutant has higher intrinsic lipid kinase activity and is much more membrane associated than wild type PIP5Kbeta. These results suggest that during oxidative stress, as modeled by H(2)O(2) treatment, Syk-dependent tyrosine phosphorylation of PIP5Kbeta is the dominant post-translational modification that is responsible for the decrease in cellular PIP(2).

Phosphatidylinositol 4-kinases play essential roles in cell signaling and membrane trafficking. They are divided into type II and III families, which have distinct structural and enzymatic properties and are essentially unrelated in sequence. Mammalian cells express two type II isoforms, phosphatidylinositol 4-kinase IIalpha (PI4KIIalpha) and IIbeta (PI4KIIbeta). Nearly all of PI4KIIalpha, and about half of PI4KIIbeta, associates integrally with membranes, requiring detergent for solubilization. This tight membrane association is because of palmitoylation of a cysteine-rich motif, CCPCC, located within the catalytic domains of both type II isoforms. Deletion of this motif from PI4KIIalpha converts the kinase from an integral to a tightly bound peripheral membrane protein and abrogates its catalytic activity ( Barylko, B., Gerber, S. H., Binns, D. D., Grichine, N., Khvotchev, M., Sudhof, T. C., and Albanesi, J. P. (2001) J. Biol. Chem. 276, 7705-7708 ). Here we identify the first two cysteines in the CCPCC motif as the principal sites of palmitoylation under basal conditions, and we demonstrate the importance of the central proline for enzymatic activity, although not for membrane binding. We further show that palmitoylation is critical for targeting PI4KIIalpha to the trans-Golgi network and for enhancement of its association with low buoyant density membrane fractions, commonly termed lipid rafts. Replacement of the four cysteines in CCPCC with a hydrophobic residue, phenylalanine, substantially restores catalytic activity of PI4KIIalpha in vitro and in cells without restoring integral membrane binding. Although this FFPFF mutant displays a perinuclear distribution, it does not strongly co-localize with wild-type PI4KIIalpha and associates more weakly with lipid rafts.

The actin cytoskeleton is dynamically remodeled during Fcgamma receptor (FcgammaR)-mediated phagocytosis in a phosphatidylinositol (4,5)-bisphosphate (PIP(2))-dependent manner. We investigated the role of type I phosphatidylinositol 4-phosphate 5-kinase (PIP5K) gamma and alpha isoforms, which synthesize PIP(2), during phagocytosis. PIP5K-gamma-/- bone marrow-derived macrophages (BMM) have a highly polymerized actin cytoskeleton and are defective in attachment to IgG-opsonized particles and FcgammaR clustering. Delivery of exogenous PIP(2) rescued these defects. PIP5K-gamma knockout BMM also have more RhoA and less Rac1 activation, and pharmacological manipulations establish that they contribute to the abnormal phenotype. Likewise, depletion of PIP5K-gamma by RNA interference inhibits particle attachment. In contrast, PIP5K-alpha knockout or silencing has no effect on attachment but inhibits ingestion by decreasing Wiskott-Aldrich syndrome protein activation, and hence actin polymerization, in the nascent phagocytic cup. In addition, PIP5K-gamma but not PIP5K-alpha is transiently activated by spleen tyrosine kinase-mediated phosphorylation. We propose that PIP5K-gamma acts upstream of Rac/Rho and that the differential regulation of PIP5K-gamma and -alpha allows them to work in tandem to modulate the actin cytoskeleton during the attachment and ingestion phases of phagocytosis.

Objective: To analyzed the indication and prognostic factors of surgical treatment of lung cancer invading left atrium and great vessels (T4)., Methods: We retrospectively reviewed the database of 136 T4 lung cancer (tumors invading left atrium and great vessels) patients who received surgical treatment in Cancer Hospital of Chinese Academy of Medical Science (CAMS) from September 1981 to January 2007. There are 114 men and 22 women, the median age was 58 years (range 28 - 76). All patients were divided into three subgroups according to the invading site: tumor invading left atrium group, tumor invading superior vena cava group and tumor invading pulmonary artery group. All patients were divided into two subgroups according to the character of operation: complete resection group and incomplete resection group. Patients were divided into three subgroups according to pathological lymph node status: N0, N1 and N2 group., Results: One hundred and thirty six lung cancer patients received resection of primary lesions plus arterioplasty of pulmonary artery (PA) (n = 83) and/or angioplasty of superior vena cava (SVC) (n = 21) and/or partial resection of left atrium (LA) (n = 32). Complete resection was possible in 120 patients and 16 patients underwent incomplete resection. Five-year survival was 43.0% for entire group, 52. 8% for PA group, 18.2% for SVC group and 18.4% for LA group. Factors significantly influencing the overall 5-year survival were the pathologic N status (5-year survival 15.1% for N2, 5-year survival 44.9% for N1, 5-year survival 74% for N0 group; N2 versus N1 versus N0, P = 0.028) and the completeness of resection (5-year survival 37.5% for complete resection, 5-year survival 22.4% for incomplete resection group; complete versus incomplete, P = 0.042). Pathological lymph node status but not histology and character of operation was an independent prognostic factor using Cox regression analysis (P = 0.01, RR = 1.923, 95% CI: 1.172 -3. 157)., Conclusion: Pathological lymph node status is an independent prognostic factor for T4 lung cancer. Patients with pathological N0-1 lung cancer invading left atrium and great vessels (T4) may benefit from surgical treatment. In the preoperative workup, every possible effort should be made to achieve a careful evaluation of mediastinal lymph noda status. Compared with incomplete resection group, complete resection group may have a better prognosis. Tumor invading extrapericardial PA may be defined as T2.

Aim: To investigate biogenesis and intracellular localizations of clusterin to elucidate the potential molecular mechanisms implicated in tumorigenesis of esophageal mucosa., Methods: Semi-quantitative RT-PCR for multi-region alteration analysis, Western blot for different transcriptional forms and immunohistochemical staining for intracellular localizations of clusterin were carried out in both tissues and cell lines of ESCC., Results: The N-terminal deletions of the clusterin gene and the appearance of a 50-53 ku nuclear clusterin, an uncleaved, nonglycosylated, and disulfide-linked isoform, were the major alterations in cancer cells of esophagus. Naturally the 40 ku clusterin was located in the connective tissue of the lamina propria of epithelial mucosa and right under the basal membrane of epithelia, but it was disappeared in stromal mucosa of esophagus and the pre-matured clusterin was found positive in cancerous epithelia., Conclusion: The N-terminal deletion of clusterin may be essential for its alterations of biogenesis in ESCC.

Trimodality therapy has been shown in preliminary studies to increase survival in esophageal cancer. Distant recurrence remains the main pattern of failure. A case of aggressive treatment of two metachronous solitary visceral metastases is presented.

Aim: To identify the differentially secreted proteins or polypeptides associated with tumorigenesis of esophageal squamous cell carcinoma (ESCC) from serum and to find potential tumor secreted biomarkers., Methods: Proteins from human ESCC tissue and its matched adjacent normal tissue; pre-surgery and post-surgery serum; and pre-surgery and normal control serum were separated by two-dimensional electrophoresis (2-DE) to identify differentially expressed proteins. The silver-stained 2-DE were scanned with digital ImageScanner and analyzed with ImageMaster 2D Elite 3.10 software. A cluster of protein spots differentially expressed were selected and identified with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). One of the differentially expressed proteins, clusterin, was down-regulated in cancer tissue and pre-surgery serum, but it was reversed in post-surgery serum. The results were confirmed by semi-quantitative reverse-transcription (RT)-PCR and western blot., Results: Comparisons of the protein spots identified on the 2-DE maps from human matched sera showed that some proteins were differentially expressed, with most of them showing no differences in composition, shape or density. Being analyzed by MALDI-TOF-MS and database searching, clusterin was differentially expressed and down-regulated in both cancer tissue and pre-surgery serum compared with their counterparts. The results were also validated by RT-PCR and western blot., Conclusion: The differentially expressed clusterin may play a key role during tumorigenesis of ESCC. The 2DE-MS based proteomic approach is one of the powerful tools for discovery of secreted markers from peripheral.

Aim: To investigate the alteration of the annexin I subcellular localization in esophageal squamous cell carcinoma (ESCC) and the correlation between the translocation and the tumorigenesis of ESCC., Methods: The protein localization of annexin I was detected in both human ESCC tissues and cell line via the indirect immunofluorescence strategy., Results: In the normal esophageal epithelia the annexin I was mainly located on the plasma membrane and formed a consecutive typical trammels net. Annexin I protein also expressed dispersively in cytoplasm and the nuclei without specific localization on the nuclear membrane. In esophageal cancer annexin I decreased very sharply with scattered disappearance on the cellular membrane, however it translocated and highly expressed on the nuclear membrane, which was never found in normal esophageal epithelia. In cultured esophageal cancer cell line annexin I protein was also focused on the nuclear membrane, which was consistent with the result from esophageal cancer tissues., Conclusion: This observation suggests that the translocation of annexin I protein in ESCC may correlate with the tumorigenesis of the esophageal cancer.

Background: P53 protein overexpression in esophageal cancer and its correlation with response and survival after chemoradiation was retrospectively investigated., Methods: Pretreatment and resection specimens were stained by automatic p53 immunohistochemical staining technique., Results: P53 was expressed in 84.0% of esophagoscopy (EGD) biopsies; 71.4% of patients with metastasis of thoracoscopy/laparoscopy lymph nodes (TS/LS LN) identified by hematoxylin/eosin (H/E) were p53 (+); 14.2% of patients with negative TS/LS LN by H/E were p53 (+). Eleven out of 18 patients with p53 (+) in pretreatment EGD remained p53 (+) after chemoradiation; 38.8% of these patients had a pathological complete response (pCR). The median survival of this group was 15 months. Of 4 patients with p53 (-) pretreatment EGD, all of those were still p53 (-) after chemoradiation; 75% of these patients had pCR. The median survival was 30 months. In patients with p53 (+) TS/LS LN, 23% had a pCR after chemoradiation with a median survival of 16 months. In patients with p53 (-) TS/LS LN, 50.0% had a pCR with a median survival of 31.5 months., Conclusions: P53 protein overexpression in pretreatment EGD and TS/LS LN may predict response to chemoradiation and survival in esophageal cancer patients.

Introduction: This study was designed to compare thoracoscopy/laparoscopy (TS/LS) staging with non-invasive clinical staging by CT and EUS for patients with esophageal carcinoma., Methods and Results: CT and EUS followed by TS/LS were used to stage 88 patients with EGD proven esophageal carcinoma. Thoracoscopic staging was done in 82 patients and found N1 in 11 patients. Fifty-four patients had laparoscopy which detected N1 in 21 patients. Thirty-four cases had chemoradiation followed by surgery. Esophagectomy was performed in 47 patients after thoracoscopic staging and 33 with laparoscopic staging. Of these 47 resected patients, thoracoscopic staging showed N0 in 42 patients and N1 in five patients with an accuracy of 93.6%. Laparoscopic staging detected normal celiac lymph nodes in 20 patients and diseased LN in 11 patients with an accuracy of 93.9%. Comparing with final resection pathology, the sensitivity, specificity and positive predictive value of staging for N1 disease in the chest was 62.5, 100.0 and 100.0% by TS; 75.0, 75.6, and 23.1% by CT and 0.0, 51.4 and 5.5% by EUS, respectively. For N1 disease in the abdomen it was 84.6, 100.0 and 100.0% by Ls; 0.0, 97.1 and 0.0% by CT and 22.2, 81.5 and 28.6% by EUS, respectively., Conclusion: TS/LS staging of esophageal cancer patients with or without preoperative chemoradiation has a higher specificity and accuracy than CT and EUS, especially for N1 disease in the chest. It also allows individualization of preoperative radiotherapy fields.