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Background Matrix metalloproteinase‐14 (MMP‐14) is known to be a key regulator of oncogenesis and tumor progression. The present study was designed to assess the relationship between the downregulation of MMP‐14 and the in vitro proliferative, migratory, and invasive activity of esophageal squamous cell carcinoma (ESCC) cells. Methods MMP‐14 expression in human ESCC and paracancerous normal esophageal tissue samples was evaluated via immunohistochemistry, and correlations between MMP‐14 staining and patient clinicopathological features were examined. In addition, siRNA was used to knockdown MMP‐14 in ESCC cells, and the proliferation and invasive activity of these cells were then evaluated via MTT and Transwell assays, respectively. Flow cytometry was additionally used to assess cell cycle progression, while Western blotting was employed to measure protein levels within these cells. Results ESCC samples were found to exhibit MMP‐14 overexpression relative to paracancerous tissue samples, and this overexpression was positively correlated with tumor T classification (T1‐2 vs. T3; P, The results of this study indicate that MMP‐14 upregulation commonly occurs in human ESCC and is correlated with to tumor T classification, N classification, degree of differentiation, and clinical stage of ESCC patients. MMP‐14 knockdown can additionally compromise the proliferative and invasive activity of these tumor cells, suggesting that MMP‐14 may be a viable therapeutic target for the treatment of ESCC, although further research will be needed to validate these findings. Furthermore, downregulation of the MMP‐14 expression level decreased cell proliferation and invasion ability.

Chest wall tumors are a relatively uncommon disease in clinical practice. Most of the published studies about chest wall tumors are usually single-center retrospective studies, involving few patients. Therefore, evidences regarding clinical conclusions about chest wall tumors are lacking, and some controversial issues have still to be agreed upon. In January 2019, 73 experts in thoracic surgery, plastic surgery, science, and engineering jointly released the Chinese Expert Consensus on Chest Wall Tumor Resection and Chest Wall Reconstruction (2018 edition). After that, numerous experts put forward new perspectives on some academic issues in this version of the consensus, pointing out the necessity to further discuss the points of contention. Thus, we conducted a survey through the administration of a questionnaire among 85 experts in the world. Consensus has been reached on some major points as follows. (I) Wide excision should be performed for desmoid tumor (DT) of chest wall. After excluding the distant metastasis by multi-disciplinary team, solitary sternal plasmacytoma can be treated with extensive resection and adjuvant radiotherapy. (II) Wide excision with above 2 cm margin distance should be attempted to obtain R0 resection margin for chest wall tumor unless the tumor involves vital organs or structures, including the great vessels, heart, trachea, joints, and spine. (III) For patients with chest wall tumors undergoing unplanned excision (UE) for the first time, it is necessary to carry out wide excision as soon as possible within 1-3 months following the previous surgery. (IV) Current Tumor Node Metastasis staging criteria (American Joint Committee on Cancer) of bone tumor and soft tissue sarcoma are not suitable for chest wall sarcomas. (V) It is necessary to use rigid implants for chest wall reconstruction once the maximum diameter of the chest wall defect exceeds 5 cm in adults and adolescents. (VI) For non-small cell lung cancer (NSCLC) invading the chest wall, wide excision with neoadjuvant and/or adjuvant therapy are recommended for patients with stage T3-4N0-1M0. As clear guidelines are lacking, these consensus statements on controversial issues on chest wall tumors and resection could possibly serve as further guidance in clinical practice during the upcoming years. ispartof: TRANSLATIONAL LUNG CANCER RESEARCH vol:10 issue:11 pages:4057-4083 ispartof: location:China status: published

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive disease with unknown etiology and unfavorable prognosis. Ferroptosis is a form of regulated cell death with an iron-dependent way that is involved in the development of various diseases. Whereas the prognostic value of ferroptosis-related genes (FRGs) in IPF remains uncertain and needs to be further elucidated.Methods: The FerrDb database and the previous studies were screened to explore the FRGs. The data of patients with IPF were obtained from the GSE70866 dataset. Wilcoxon's test and univariate Cox regression analysis were applied to identify the FRGs that are differentially expressed between normal and patients with IPF and associated with prognosis. Next, a multigene signature was constructed by the least absolute shrinkage and selection operator (LASSO)-penalized Cox model in the training cohort and evaluated by using calibration and receiver operating characteristic (ROC) curves. Then, 30% of the dataset samples were randomly selected for internal validation. Finally, the potential function and pathways that might be affected by the risk score-related differently expressed genes (DEGs) were further explored.Results: A total of 183 FRGs were identified by the FerrDb database and the previous studies, and 19 of them were differentially expressed in bronchoalveolar lavage fluid (BALF) between IPF and healthy controls and associated with prognosis (p < 0.05). There were five FRGs (aconitase 1 [ACO1], neuroblastoma RAS viral (v-ras) oncogene homolog [NRAS], Ectonucleotide pyrophosphatase/phosphodiesterase 2 [ENPP2], Mucin 1 [MUC1], and ZFP36 ring finger protein [ZFP36]) identified as risk signatures and stratified patients with IPF into the two risk groups. The overall survival rate in patients with high risk was significantly lower than that in patients with low risk (p < 0.001). The calibration and ROC curve analysis confirmed the predictive capacity of this signature, and the results were further verified in the validation group. Risk score-related DEGs were found enriched in ECM-receptor interaction and focal adhesion pathways.Conclusion: The five FRGs in BALF can be used for prognostic prediction in IPF, which may contribute to improving the management strategies of IPF.

Background. The article is devoted to the piano work of the famous Chinese composer Zhang Zhao. The focus is on the “Pihuang” Fantasy, which embodies the national characteristics of Peking opera. This work won an honorary award at the 2007 Chinese composition competition for high artistic qualities and deep content. The article examines, how the composer uses the musical elements of the Chinese opera tradition to create a certain drama of the work, how the sound specificity of the timbre colors of the voice, the techniques of vocal sound production and recitation, the image of Chinese instruments is embodied on the piano. The role of the first performer of the work – the famous pianist Li Yundi – is revealed to popularize the works of Zhang Zhao in China and around the world. The importance of considering the performing aspect of the realization of this music is proved. It is emphasized, that such an analysis creates a wide field for creative research in the interpretation of the music by Chinese authors, takes into account modern requirements that contribute to the development of independence and initiative among young pianists. Objectives. The purpose of the article is to identify the universal mechanism for interpreting the piano compositions of ZhangZhao by the example of his Fantasy “Pihuang”. For the disclosing of the research theme the complex methodological approach, combining the principle of musical-theoretical, musical-historical and performing analysis is taken. Results. The composer also embodied the centuries-old traditions of Chinese instrumental folk art, its timbre specificity and unique rhythm in the piano sound of the Fantasy “Pihuang”. An important point is the formal and dramaturgical organization of this composition. Zhang Zhao organically combines the traditional mosaic structure of the Beijing opera with the Western genre of opera transcription, which allowed to give the whole musical composition “elasticity” within the framework of a fixed large form. This work attracts not only with the beauty of its melodies, the richness and originality of a harmonic language, the perfection of a form, various requirements for a performer, but also because all these features of his music are inextricably linked with the disclosure of the philosophical depth of content and eternal vital themes in it. A performer should be ready for frequent changes in images and moods, since the work of Zhang Zhao is romantic, rich in figurative and emotional content. From this point of view, one need to imagine different plot scenes and relate them to the sections of the music. The various characteristics of the sections will help a pianist to some extent decide, which timbres, tempo and mood are most appropriate. Throughout the performance, a pianist must be in the determined “role”. The piece opens by the loose improvisatory introduction, Rubato. The pianist must listen in advance to the Beijing opera in order to imagine how this music should sound, to understand and feel the free movement of its rhythmic organization (sang-bang). To achieve expressiveness in melodies, preeminently, one needs to have a flowing, singing sound. Sound quality is determined by the style and nature of the work, where each of the episodes and even a separate voice in polyphony require special coloring and special sound production. The task of the performer is to show as more clearly the features that are essential for various types of the texture presentation: in the same material one can emphasize the melodic beginning or the character of the chord movement, give preference to the bass part or soprano echo; finally, highlighting a certain chord sound, one can strengthen the latter’s attraction to a particular functional sphere. It is well known, that a performer can, without deviating from the pitch line given by a composer, but actively using the means of dynamics, articulation, agogy, create an individual version of the melodic pattern with its own logical emphasizes, its own types of breath and plasticity. It is obvious, that the study of the laws expressing the substantial characteristics of the texture is of practical importance for the performer, since the texture is directly related to the problem of figurative-sound versatility of performance – one of the most acute for musical interpretation. Therefore, a performer’s attention to a significant extent should be focused on which figurative-semantic characteristics are concentrated in each texture layer, what of these characteristics are dominant and what constitute the psychological complement of the image or act as an opposing force. Conclusions. “Pihuang” attracts the attention of performers with the uplifting and joy of vitality, original, artistic language, specificity of rhythm, and improvisation. This work reflects the highest achievements of the Chinese pianistic school, the importance of which has long crossed national boundaries, occupying one of the honorable places in the education of young pianistsperformers. The study of the performing interpretation of the piano works by Zhang Zhao, the identification of the relationship between expressive techniques and the peculiarities of the author’s style has many-sided significance. Based on the analysis of the interpretation of the Piano Fantasy “Pihuang” by the outstanding Chinese pianist Yundi Li, as well as checking the conclusions of theoretical analysis with the practice of concert performances, we establish certain connections in Zhang Zhao’s piano work, which can be traced as stable signs of his style. It should be noted that different performers can reveal a significantly different understanding of the same work and sometimes we have to talk about the difference in the very content of the sounding work. Auditory impressions from listening to Beijing opera, the sound of Chinese folk instruments should be the basis for the realization of the objective properties of the piano texture, reproduction on the piano laid in the musical notation features of rhythm, dynamics, agogics, timbres etc. This not only clarifies the understanding of the composer’s style, but also the specifics of all Chinese performing arts.

Rui Zhao, Shan Gao, Haiqi He, Jia Zhang, Guangjian Zhang, Xiaopeng Wen Department of Thoracic Surgery, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710061, People’s Republic of ChinaCorrespondence: Xiaopeng WenDepartment of Thoracic Surgery, First Affiliated Hospital of Xi’an Jiaotong University, #277 West Yanta Road, Xi’an City, Shaanxi Province, 710061, People’s Republic of ChinaEmail xiaopengwmd@163.comObjective: To evaluate the distribution of high frequency mutant genes and the expression of PDL1 in different types of lung cancer.Methods: This retrospective analysis was conducted on 330 patients who were diagnosed with primary lung cancer and treated in our hospital from October 2018 to October 2020. The patients were listed into non-small cell carcinoma group (101 cases), squamous carcinoma group (28 cases) and adenocarcinoma group (201 cases) according to their pathological results. The gene mutations were detected using EGFR, KRAS, and BRAF gene mutation detection kits, and the expression of PDL1 was detected by immunostaining. The mutation of EGFR, KRAS and BRAF genes and PDL1 expression in patients with different types of lung cancer were compared.Results: The patients in the adenocarcinoma group had the highest incidence of EGFR gene mutation, the mutation rate of the gene whose mutation location was exon 18 was significantly higher, and the difference between each group was statistically significant (P < 0.05). The patients in the adenocarcinoma group had the highest incidence of KRAS gene mutation, the mutation rate of the gene whose mutation location was exon 2 was obviously the highest, exon 15 was the lowest, and the difference between each group was statistically significant (P < 0.05). There was no significant difference in the distribution of BRAF gene mutations among groups, and all mutations occurred on exon 15, with no statistically significant difference between each group (P > 0.05). PD-L1 expression in NSCLC patients was significantly higher than that in other lung cancer patients (P < 0.05).Conclusion: EGFR and KRAS genes showed obvious specific expressions in patients with different types of lung cancer and they were more common in patients with lung adenocarcinoma. Gene mutation and PDL1 expression are high in patients with lung adenocarcinoma.Keywords: lung cancer, typing, gene mutation, PD-L1

Background: Tracheal Squamous Cell Carcinoma (SCC) is a rare primary tumour. Currently, surgery is the main treatment, but it becomes the biggest obstacle to surgery when the tumour invades the trachea for more than 6 cm. Case presentation: A 56-year-old Asian man presented with expectoration and asthma as his initial symptoms. Because of the particularity of tumour location and volume, we removed the 7 cm bronchus and performed carinau reconstruction. Conclusion: How to treat the rare tumours at tracheal carina is a valuable and rare example that could be reference in many centres.

There is an increasing need to analyze multivariate time series data due to the rapid development of data collection tools such as smartphone APPs, wearable sensors, and brain imaging techniques. P-technique factor analysis allows researchers to establish a measurement model for these time series. Analyzing such data is challenging because they are often non-normal (e.g., steps, heart rate, sleep, mood, and brain signals) and correlated at nearby time points. We propose using a bootstrap procedure to accommodate both the non-normality and the dependency of nearby time points. We explore the statistical properties with simulated data and illustrate the test with two empirical data sets. The results of the simulation study include (1) the bootstrap procedure performed better than an existing analytic procedure for time series data with excessive kurtosis (2) an existing analytic procedure performed better than the bootstrap procedure for normal time series and skewed time series.

Background The incidence of congenital bronchoesophageal fistulas in adults is rare. Most fistulas discovered in adulthood are often small and can be repaired with a simple one-step method. Case presentation A 46-year-old female patient complained of a 2-month history of chocking, coughing, and a 12 kg drop in weight. The bronchofiberscopy and gastroscopy showed a large fistula, which extended from the esophagus to the main bronchus on both sides, thus forming a special three-way channel which has never been reported. This case was challenging both to the anesthetists and surgeons. The patient was intubated with a sengstaken-blakemore tube, and then received segmental esophageal resection, anastomotic reconstruction, and double-flap repair with esophagus segment in situ. Conclusion When the fistula in BEF is large or complicated, appropriate surgical methods should be meticulously designed according to the condition of the patient. The problem of anesthesia intubation should be solved first, to allow a smooth operation. Secondly, a double-layer repair of the airway fistula by using esophageal wall tissues as patch materials is proposed.

Hydrodynamic cavitation is a complex two-phase flow phenomenon involving mass and heat transfer between liquid and vapor. It occurs in many widely-used hydraulic machines, such as pumps and marine propellers, and often leads to undesired effects like material erosion, noise, and vibration. To control these detrimental effects, the visualization of two-phase flow morphology inside the opaque cavity is a crucial point to improve the physical and numerical models of cavitation. The major challenge in experimental measurements of cavitating flow fields is the fact that multiple scattering and a direct reflection of visible light from phase boundaries make the flow optically opaque. In recent years, unlike traditional local measurements using various probes, the development of the third-generation synchrotron radiation sources promotes the application of Xray phase-contrast imaging, which enables clear visualization of boundaries between phases with different refractive indices. In this study, the partial cavity is formed in a convergent-divergent (Venturi) channel with a small contraction ratio where the relatively stable cavitation regime can be sustained in a wide range of cavitation numbers. The experiment performed at Advanced Photon Source (APS) of Argonne uses the short high-flux X-ray pulses emitted from synchrotron sources to capture fast dynamic events and minimize motion blur. The internal two-phase structures and bubble development dynamics inside the quasi-stable sheet cavitation can be identified. Aside from the detailed illustration of two-phase morphology, X-ray phase-contrast images were also used to perform velocimetry by tracking either seeded particles or phase interfaces inside the opaque regions. Through appropriate postprocessing to the recorded X-ray images of cavitation, the time resolved velocity and void fraction fields are obtained simultaneously. These unprecedented experimental data will be further explored in understanding fluid mechanics underneath the cavity, estimating slip velocity between fluid-vapor interactions, and reconstructing pressure fields for compressible flows.

Objective The correlation between immune-related adverse events (irAEs) and prognosis remains controversial in advanced non–small cell lung cancer (NSCLC). The aim of this study was to systematically evaluate the effect of irAEs, especially checkpoint inhibitor pneumonitis (CIP), on the survival and treatment response in advanced NSCLC. Methods The primary outcomes were overall survival (OS) and objective response rate (ORR). Databases were searched for relevant studies, and meta-analysis was conducted with RevMan. Results A total of 51 studies involving 12,600 participants were included. The development of irAEs had an advantageous effect on OS and ORR in advanced NSCLC (OS: hazard ratio [HR], 0.56 [95% confidence interval [CI] 0.46 to 0.67]; ORR: odds ratio [OR], 3.13 [2.41 to 4.06]). The occurrence of endocrine and skin irAEs had advantageous effects on both OS and ORR (endocrine OS, HR, 0.47 [–0.37 to 0.59]; endocrine ORR: OR, 1.90 [1.27 to 2.84]; skin OS: HR, 0.48 [0.38 to 0.61]; skin ORR: OR, 4.30 [2.68 to 6.91]). Severe-grade irAEs resulted in shorter OS than low-grade irAEs (HR, 1.49 [1.06, 2.09]), and multiple irAEs resulted in better ORR compared with 1 irAE (OR, 2.04 [1.41 to 2.94]). The occurrence of CIP had no significant effect on OS (HR, 1.14 [0.70 to 1.86]), but it was associated with better ORR (OR, 2.12 [1.06 to 4.25]). Severe-grade CIP had no effect on OS or ORR, but CIP leading to treatment discontinuation resulted in shorter OS (HR, 2.35 [1.17 to 4.72]). Conclusion The development of irAEs had advantageous effects on survival and response in advanced NSCLC. CIP had no effect on survival, but it predicted better response.

Objectives: Cerebral ischemic/reperfusion injury (CI/RI) is the clinical manifestation of cerebral ischemic stroke, which severely affects the health and life of the patients. We aimed to investigate the regulatory mechanism of long non-coding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) on CI/RI in this study.Methods: The expression of lncRNA MALAT1 and miR-375 was detected by qRT-PCR. MTT was utilized to measure the viability of PC-12 cells. The levels of lactate dehydrogenase (LDH), superoxide dismutase (SOD), and reactive oxygen species (ROS) were detected by LDH assay, SOD assay, and ROS assay, respectively. The apoptosis rate of PC-12 cells was measured by flow cytometry analysis. Through enzyme-linked immunosorbent assay, the levels of NF-α, IL-1β, and IL-6 were determined. The interactions between miR-375 and MALAT1/PDE4D were predicted by Starbase/Targetscan software and verified by the dual-luciferase reporter assay. Western blot assay was performed to determine the protein expression of Bcl-2, Caspase-3, and PDE4D.Results: LncRNA MALAT1 expression was highly upregulated in the middle cerebral artery occlusion (MCAO)/reperfusion (R) model of rats. Both MALAT1 downregulation and miR-375 upregulation reversed the inhibitory effect of oxygen and glucose deprivation (OGD)/R on cell viability and the promoting effects on LDH level, cell apoptosis, and inflammatory factors levels. MALAT1 targeted miR-375, whereas miR-375 targeted PDE4D. Overexpression of miR-375 attenuated OGD/R-induced injury in PC-12 cells by targeting PDE4D. Both the low expression of miR-375 and high expression of PDE4D reversed the promoting effect of MALAT1 knockdown on SOD level and the inhibitory effects on ROS level, inflammatory factor levels, and cell apoptosis.Conclusion: Suppression of MALAT1 alleviates CI/RI of rats through regulating the miR-375/PDE4D axis. This study provides a possible therapeutic strategy for human CI/RI in clinic.

Introduction: The mechanistic basis for the development of esophageal squamous cell carcinoma (ESCC) remains poorly understood. The goal of the present study was thus to characterize mRNA and long noncoding RNA (lncRNA) expression profiles associated with ESCC in order to identify key hub genes associated with the pathogenesis of this cancer. Materials and Methods: The GSE26866 and GSE45670 datasets from the Gene Expression Omnibus (GEO) database were used to conduct a weighted gene co-expression network analysis (WGCNA), after which Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted. Cytoscape was additionally used to construct lncRNA-mRNA networks, after which hub genes were identified and validated through the assessment of TCGA datasets and clinical samples. Results: Two gene modules were found to be closely linked to ESCC tumorigenesis. These genes were enriched in cell cycle, MAPK signaling, JAK-STAT signaling, pyrimidine metabolism, arachidonic acid metabolism, and P53 signaling pathway activity, all of which are directly linked with the development of cancer. In total, we identified and validated 9 hub genes associated with ESCC (DDX18, DNMT1, NCAPG, WDHD1, PRR11, VOPP1, ZKSCAN5, LC35C2, and PHACTR2). Conclusion: In summary, we identified key gene modules and hub genes associated with ESCC development, and we constructed a lncRNA-mRNA network pertaining to this cancer type. These results provide a foundation for future research regarding the mechanistic basis of ESCC.

New data-collection methods (smartphones; wearable devices) afford researchers opportunities for studying psychological processes in detail. Data collected in these studies are often non-normal mul...

R mRNA in the mPFC was significantly decreased to 5-Hydroxytryptamine7 (5-HT7) receptors in the medial prefrontal cortex (mPFC) play a critical role in complex cognitive impairment in schizophrenia. The mouse model of schizophrenia was established through the neonatal administration of phencyclidine (nPCP). Recombinant adeno-associated virus-mediated gene knockdown was used to investigate the role of mPFC 5-HT7 receptor in the schizophrenia-like symptoms in mice. Under baseline conditions in the 5-choice serial reaction time task (5-CSRTT), nPCP produced a significant attentional impairment that was exacerbated when mice were tested under LITI. Premature and perseverative responding in nPCP mice were both increased, thus suggesting deficits in inhibitory response control. The deficits in attentional performance and premature responding of nPCP mice were improved or fully rescued by 5-HT7 receptor downregulation under heavy perceptual load. Downregulation of the 5-HT7 receptor in the mPFC ameliorated spatial working memory and had no effects on nPCP-induced impairments in recognition memory and MA-induced hyperlocomotion. These results suggest that 5-HT7 receptor is involved in the cognitive outcomes of schizophrenia-like symptoms similar to humans. Downregulation of the 5-HT7 receptor in the mPFC exert complex effects in a mouse model of schizophrenia and may be of benefit in treating schizophrenia-related impulsive actions.

The aim of this study was to assess the usefulness of integrin imaging with 99mTc-PEG4-E[PEG4-c(RGDfK)]2 (99mTc-3PRGD2) single photon emission computed tomography (SPECT)/computed tomography (CT) in detecting recurrent disease in patients with differentiated thyroid cancer (DTC), negative radioiodine whole-body scan (WBS) and high serum thyroglobulin (Tg). Thirty-seven patients who underwent total thyroidectomy followed by radioactive iodine ablation and had negative radioiodine WBS but elevated Tg levels were included. 99mTc-3PRGD2 SPECT/CT was performed 1 week after the negative diagnostic 131I WBS. Diagnostic performance indicators, including sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), for 99mTc-3PRGD2 SPECT/CT was calculated. The correlations between SPECT/CT results and clinic-pathological characteristics were examined. In 30 (81.1%) of the 37 patients, 99mTc-3PRGD2 SPECT/CT showed positive uptake. The sensitivity, specificity, PPV, and NPV of SPECT/CT to detect recurrent disease at follow-up were 96.6%, 75%, 93.3% and 85.7%, respectively. The sensitivity and PPV of SPECT/CT increased with increasing serum Tg levels. 99mTc-3PRGD2 SPECT/CT showed high sensitivity and PPV in the detection of recurrence among DTC patients with higher Tg levels and negative WBS, and the probability of obtaining a positive SPECT/CT result was related with the level of Tg.

Background: Lacuna anatomy has been studied widely in various organs to improve the operative approach and surgical procedure. However, there are few studies about the peri-esophageal lacuna (PEL). The aim of this study was to describe minimally invasive esophagectomy (MIE) with a focus on PEL anatomy.Methods: From August 2012 to December 2015, patients with esophageal carcinoma underwent MIE by the same group of surgeons at our institution. A double lumen endotracheal tube was used with left lung ventilation without pneumothorax for patients in group 1. A single lumen endotracheal tube was used with two-lung ventilation and right artificial pneumothorax for patients in group 2. The methods that we used for thoracic esophagus mobilization and modularized lymph node dissection, based on the American joint committee on cancer (AJCC) staging manual, in the peri-esophageal space are described. We evaluated the surgical effect, postoperative complications and follow-up results.Results: A total of 147 patients (107 men; mean ± standard deviation age 63.1 ± 7.7 years) were enrolled. Among them, 67 were placed in group 1 and 80 in group 2. There was no significant difference between the two groups in terms of age, gender, tumor location, T stage, N stage or comorbidities. The mean operation duration (283±46 vs 307±69 minutes; p=0.007) and blood loss (129±84 vs 260±225 mL; p=0.000) was less in group 2 than group 1. Group 2 also yielded a larger number of lymph nodes compared with group 1 (22.5 ± 11.1 vs 16.4 ± 7.4; p=0.007). Complication rates were similar between the two groups, with hoarseness developing in a significantly smaller number of patients in group 1 than group 2 (1% vs 21%; p=0.000). There was no significant difference between the two groups in one-year (78.3% vs 84.2%; p=0.345) and three-year (52.1% vs 62.7%; p=0.210) survival rates for group 1 (a double lumen endotracheal tube with left lung ventilation without pneumothorax) versus group 2 (a single lumen endotracheal tube with two-lung ventilation and right artificial pneumothorax).Conclusion: Esophageal mobilization based on PEL and the modularized lymph node dissection based on the AJCC cancer staging manual improves surgical outcomes.

Background: Minimally invasive esophagectomy (MIE) has become a good option in the surgical treatment of esophageal cancer. Cervical esophagogastric anastomoses (CEGA) are widely used during esophagectomy. However, CEGA are related with a higher incidence of anastomotic complications. In the present study, a new procedure of T-shaped linear-stapled cervical esophagogastric anastomosis was used during MIE and the short-term outcomes are presented. Methods: From May 2014 to December 2018, 32 consecutive patients with esophageal cancer who underwent total MIE followed by T-shaped linear-stapled cervical esophagogastric anastomosis were included. Postoperative outcomes were analyzed. Results: Fifteen men and 17 women were included this pilot study. The histology of all cases was squamous cell carcinoma. Mean operation time of T-shaped linear-stapled cervical esophagogastric anastomosis was 17.6 minutes. There were no early or late mortalities. A minor cervical anastomotic leakage occurred in 1 patient. No complications of anastomotic stenosis occurred in this study. Conclusion: The T-shaped linear-stapled cervical esophagogastric anastomosis is efficient, reliable, easy to perform, and associated with lower postoperative complication rate.

IL-10, IL-18 and IL-12 are reported to participate in the inflammation process. The potential influences of IL-10, IL-18 and IL-12 polymorphisms on non-small cell lung cancer (NSCLC) risk were explored in this study.Six candidate SNPs from 500 NSCLC patients and 500 controls were genotyped. The correlation between the SNPs and NSCLC risk was evaluated by logistic regression analysis.Comparisons of the allele and genotype frequencies showed that five SNPs were correlated with NSCLC risk. The minor allele 'G' of IL-18 rs5744256 and rs1834481 and IL-10 rs3021094 was correlated with a decreased risk of NSCLC (p 0.05). In contrast, the minor allele 'T' of IL-18 rs5744224 and the minor allele 'G' of IL-12B rs3212227 were correlated with an increased risk of NSCLC (p 0.05). By genetic model analysis, we found that rs5744256 and rs1834481 were associated with a decreased risk of NSCLC under dominant and log-additive models (p 0.05). Rs3021094 was correlated with a decreased risk of NSCLC under all three models (p 0.05). In contrast, rs5744224 was associated with an increased risk of NSCLC under the recessive model (p = 0.005), and rs3212227 was associated with an increased risk of NSCLC under all three models (p 0.05). Finally, the GGA haplotype of rs5744256, rs1834481 and rs5744224 and the GT haplotype of rs3021094 and rs3790622 were associated with a decreased risk of NSCLC (p 0.05).Our results provided new candidate SNPs for the prediction and prevention of NSCLC.

Background: The current management of papillary thyroid micro carcinoma (PTMC) has become more conservative. However, high-risk characteristics that can only be revealed post-surgically exist. Patients and clinicians need to estimate the risks and understand the prognostic meaning of these factors. Methods: We retrospectively analyzed 246 consecutive patients with PTMC who underwent surgery at our institution between 2015 and 2017. Clinical and histopathological parameters that may indicate recurrent disease were investigated. The responses to therapy in cases with different risks of recurrence were analyzed. Results: A total of 79.26% (195/246) of patients received total thyroidectomy (TT), of whom 177 (90.77%) also received central lymph node dissection. Radioiodine ablation (RAI) was applied in 64.23% (158/246) of patients. Intermediate-high risk features were identified in 27.64% (68/246) after primary treatment. After a median follow-up of 18 months (range, 6-39 months), 121 of 158 (76.58%) patients who received TT+RAI were evaluated as an excellent response. An incomplete response (IR) was observed in 14.56% (23/158) of this group of PTMC. Multivariate analysis identified extra thyroid extension (P = 0.001) and intermediate-high risk stratification (P = 0.014) as significant and independent risk factors for an IR. Conclusions: A total of 27.64% of PTMC cases evaluated as a low risk of recurrence pre-surgery showed intermediate to high risk disease post-surgery, and this leads to a higher rate of IR.

Introduction: This study aims to identify the prognostic factors that influence therapeutic modalities for thyroid carcinoma showing thymus-like elements (CASTLE). Materials and Methods: Reported studies with CASTLE patients published between 2004 and 2018 were retrieved from a cross-database literature search. Three patients treated in our institute were also included as one case series. Standardized data collection was performed; data pertaining to clinical stages, treatment regimens, and survival time were collected and statistically analyzed. Results: Up to 26 case series of CASTLE were selected, including 51 males and 38 females with a median age of 48 years. Follow-up time ranged from 2 to 362 months and the median survival time was 158.03 months. Lymph node metastasis and tumor invasion of adjacent tissue both showed a significant negative effect on survival (p = 0.001 and 0.013, respectively). Radiotherapy significantly improved survival (p = 0.034), while neck dissection significantly prolonged survival only in patients with extrathyroidal extension (p = 0.043). Conclusions: Extrathyroidal infiltration and nodal metastasis are important factors in cancer outcomes. Radiation therapy appears to be important for better outcomes in CASTLE patients, and neck dissection is recommended for patients with extrathyroidal extension.

Aim: We aimed to investigate risk factors and current treatment effects in male breast cancer patients. Methods: Kaplan–Meier plot, log-rank test, COX model, nomograms and propensity score matching were used. Results: Among stage I–III patients, surgery was associated with better prognosis. In subgroup analysis, performing surgery and no radiation or chemotherapy led to worse prognosis in research group. Among stage IV patients, chemotherapy correlated with better prognosis and radiation led to better breast cancer-specific survival. In addition, brain and liver metastasis correlated with worse prognosis; and lung correlated with worse breast cancer-specific survival. Conclusion: For stage I–III patients, surgery and chemotherapy were recommended. And not applying radiation or chemotherapy could be carefully considered for ER(+) HER-2(-) patients. For stage IV patients, chemotherapy and radiation were commended.

Time-dependent cloud cavitation around the 2-D Clark-Y hydrofoil was investigated in this paper based on an improved filter based model and a density correction method. The filter-scale in filter based model simulation was discussed and validated according to the grid size. Numerical results show that in the transition from sheet cavitation to cloud cavitation, the sheet cavity grows slowly to the maximum length during the re-entrant jet develops. The mild shedding bubble cluster convects downwards the hydrofoil and continues to grow up after detaching from the suction surface of hydrofoil, and a bubble cluster introduced at the rear part of hydrofoil. While the sheet cavity generates, the bubble cluster breakups.

Background With the development of thoracic surgeries, one-lung ventilation (OLV) has been routinely used to facilitate surgical exposure. However, OLV can cause lung injury during the surgical process and becomes an important factor affecting the outcomes. To date, effective treatments for the prevention of lung injury caused by OLV are lacking. Hydrogen has been demonstrated to have effective protection against tissue injuries caused by oxidative stress, inflammation, and apoptosis. This study investigated the efficacy of hydrogen water consumption on the prevention of lung injury induced by OLV in rats. Materials and Methods Male Sprague–Dawley rats ( n = 32, 240–260 g) were divided randomly into the following four groups: sham group, sham + H2 group, OLV group, OLV + H2 group. The rats drank hydrogen water or degassed hydrogen water for 4 wk before the operation and received OLV for 60 min and two-lung ventilation for 60 min. Lung tissues were assayed for wet-to-dry ratio, oxidative stress variables, proinflammatory cytokines, and hematoxylin–eosin staining. Results Hydrogen water consumption reduced wet-to-dry weight ratio, malondialdehyde and myeloperoxidase activity and decreased the concentration of TNF-α, IL-1β, and IL-6 in the lung tissues compared with sham group and sham + H2 group. Hydrogen water consumption further attenuated NF-κB activation and caused histopathologic alterations. Conclusions Our data demonstrated that hydrogen water consumption ameliorated OLV-induced lung injury, and it may exert its protective role by its anti-inflammation, antioxidation and reducing NF-κB activity in the lung tissues.

Background As 3D printing technology emerge, there is increasing demand for a more customizable implant in the repair of chest-wall bony defects. This article aims to present a custom design and fabrication method for repairing bony defects of the chest wall following tumour resection, which utilizes three-dimensional (3D) printing and rapid-prototyping technology. Methods A 3D model of the bony defect was generated after acquiring helical CT data. A customized prosthesis was then designed using computer-aided design (CAD) and mirroring technology, and fabricated using titanium-alloy powder. The mechanical properties of the printed prosthesis were investigated using ANSYS software. Results The yield strength of the titanium-alloy prosthesis was 950 ± 14 MPa (mean ± SD), and its ultimate strength was 1005 ± 26 MPa. The 3D finite element analyses revealed that the equivalent stress distribution of each prosthesis was unifrom. The symmetry and reconstruction quality contour of the repaired chest wall was satisfactory. No rejection or infection occurred during the 6-month follow-up period. Conclusion Chest-wall reconstruction with a customized titanium-alloy prosthesis is a reliable technique for repairing bony defects.

Polymorphous low-grade adenocarcinoma (PLGA) is a low-grade malignant infiltrative tumor of the minor salivary glands. According to data from PubMed (National Center for Biotechnology), one case of PLGA involving the left main bronchus and one case involving the right main and upper lobar bronchi have previously been reported. Here, we describe the first case of PLGA originating in the trachea with metastasis to the right middle lobe bronchus, all initially misdiagnosed as adenoid cystic carcinoma (ACC). It is particularly important to distinguish this tumor from other types of salivary gland tumors, especially ACC. Complete surgical excision is the curative treatment of choice for PLGA.

Objectives: To evaluate the efficacy of 99mTc-PEG4-E[PEG4-c (RGDfK)]2 (99mTc-3PRGD2) single photon emission computed tomography (SPECT) in monitoring the recurrence of malignancies. Materials and Methods:99mTc-3PRGD2 SPECT was performed on 28 patients (10 females and 18 males; median age 49.2 years) suspected of recurrent malignancies due to an asymptomatically reelevated carcinoembryonic antigen level. The SPECT was performed 0.5 h after an intravenous injection of 11.1 MBq/kg (0.3 mCi/kg) of 99mTc-3PRGD2. The SPECT and concurrent contrast-enhanced computed tomography (ceCT) findings were analyzed with reference to the histopathological findings and/or clinical follow-up data. Results: Recurrences were identified in 20 out of the 28 patients (prevalence 71.4%) with altogether 26 lesions. Fifteen lesions were confirmed by histopathological findings, and the other 11 lesions were confirmed by serial radiological or clinical follow-up. Of the 20 patients with recurrent malignancies, 12 (60%) were correctly identified by 99mTc-3PRGD2 SPECT. In the patient-based analysis, the sensitivity and specificity of 99mTc-3PRGD2 SPECT were 60 and 100%, respectively, and the positive and negative predictive values were 100 and 50%, respectively. In the lesion-based evaluation, the sensitivity and specificity were 62 and 100%, respectively. The sensitivity and specificity of the ceCT in the patient-based evaluation were 60 and 75%, respectively, and the positive and negative predictive values were 86 and 40%, respectively. In the lesion-based evaluation, the sensitivity and specificity of the ceCT were 70 and 84%, respectively. Conclusions:99mTc-3PRGD2, as a new SPECT tracer targeting the integrin αvβ3 receptor, was more useful in distinguishing recurrences as compared to ceCT.

In the working process of Double-Fed Wind Turbines (DFWT), it is very important to monitor and predict the temperature of the high-speed output shaft of the gearbox timely and effectively. Support vector machine has more advantages in the temperature prediction of wind turbines. Least squares support vector machine is suitable for online prediction due to reducing the computational complexity of support vector machine. In order to solve the sparsity of least squares support vector machine, an improved least squares support vector machine based on pruning algorithm is proposed in this paper to predict the temperature of the high-speed output shaft of gearbox using the practical data of Double-Fed Wind Turbines. At the same time, in order to improve the prediction accuracy and to solve the problem of few links between different feature parameters in common normalization method, the paper uses the method of joint normalization to preprocess the data. The principal component analysis is used to reduce the dimension of the data. Particle swarm optimization algorithm is used to optimize the parameters of the pruning least squares support vector machine. The proposed model that is established in this paper is a new model to forecast the temperature of the high-speed output shaft. The results show that its prediction accuracy is higher than that of other algorithms.

Aims To investigate the association between angiogenetic activity of hyperplastic thymus and serum thyroglobulin (Tg) level in differentiated thyroid carcinoma patients with thyroglobulin (Tg)-elevated Negative Iodine Scintigraphy (TENIS) Syndrome. Methods A cohort of 30 consecutive patients who underwent total thyroidectomy followed by radioiodine ablation and had TENIS syndrome received integrin αvβ3 targeted imaging with 99mTc-HYNIC-PEG4-E[PEG4-c(RGDfk)]2 (99mTc-3PRGD2). The correlation of angiogenetic activity of the thymus and the serum Tg levels was evaluated in patients with enlarged thymus. Results Enlarged thymus was detected in 9 out of the 30 TENIS patients and all hyperplastic thymus showed an increased accumulation of the tracer (median tumor/background ratio: 2.8). Five of them had only mediastinal uptake and surgical removal of the mediastinal mass in one provided histopathologic evidence of thymic tissue. The other four were not assigned further treatment and were free of disease in the follow-up, though their stimulated Tg levels consistently increased. Four out of the 9 patients showed 99mTc-3PRGD2 uptake outside the mediastinum were assigned surgery followed by radioiodine treatment. Their stimulated Tg levels decreased after iodine ablation, but not drop back to normal. A significant linear correlation was observed between serum Tg levels and the degree of angiogenesis in the hyperplastic thymus. Conclusions The angiogenetic activity in hyperplastic thymus was related with the consistently elevated serum Tg levels in TENIS syndrome patients. Based on the existing literature and current data, we propose further intervention for patients with RGD uptake outside thymus, while close follow-up for patients with only mediastinal uptake.

Ectopic papillary thyroid carcinoma (PTC) usually occurs along the cervical midline and was barely reported in FDG PET studies. We present a rare case of ectopic PTC within the esophagus with focal FDG activity on FDG PET in a 43-year-old woman who was previously diagnosed as having esophageal cancer based on the endoscopy and PET findings. Surgical pathology revealed the presence of PTC lesion within the muscular layer of the esophagus. Combining this with the negative imaging and laboratory results suggesting a normal thyroid gland led to a diagnosis of primary ectopic PTC.

Background Surgical resection with radical lymphadenectomy is a pivotal component in the multidisciplinary therapy of esophageal cancer. Minimally invasive esophagectomy was shown to be effective in reducing the morbidity and was adopted increasingly. As a novel minimally invasive technique, robot-assisted esophagectomy remains in the initial stage ofapplication. This study describes the single-institution experience of robotic esophagectomy. Methods Between March 2016 and October 2017, 20 consecutive patients underwent robot assisted esophagectomy at our institute. The thoracic and abdominal mobilization were all performed with the assistance of the robot. We retrospectively collected the operative data and postoperative outcomes. Results The majority of patients were male (80%), and the median age was 62 years. The average operative time was 342 minutes (range 280–440). The average blood loss was 112 ml (range 50–400). No patient experienced conversion to a thoracotomy or laparotomy. R0 resection was achieved in all patients, the mean number of dissected lymph nodes was 19 (range 8–32). No 90-day operative mortality was observed, and postoperative complications were present in 8 of 20 patients (40.0%). Pulmonary complications were the most common event and were observed in 3 patients. Two patients experienced an anastomotic leak. Conclusion Our study demonstrated that robot-assisted esophagectomy is a safe and technically feasible alternative to conventional thoraco-laparoscopic esophagectomy. Disclosure All authors have declared no conflicts of interest.

Summary Chemotherapy has been the first-choice treatment for small-cell esophageal cancer (SCEC), etoposide plus cisplatin or carboplatin (EP/CP) is the most commonly recommended chemotherapeutical strategy. However, the choice of chemotherapy in treating SCEC has not been validated by studies of large cohorts of cases because of the rarity of the malignancy, and the efficacy superiority of EP/CP over other chemotherapy combinations has not been confirmed. The present case series analysis was conducted to address the above issues. Reported studies of SCEC patients were retrieved. Case series with more than five patients were enrolled. Eight patients treated in our institute were also included as another case series. Data pertaining to clinical stages, treatment regimens, and survival time were collected and analyzed. Altogether, 19 SCEC case series were enrolled, including 164 male and 61 female patients with a median age of 63.5 years. The follow-up time ranged from 0.1 to 221 months (median 12.3 months). The median survival time (MST) was 19 months for limited disease (LD) patients (124 cases) and 9 months for extensive disease (ED) patients (88 cases) (P 0.05). EP/CP did not result in significantly longer MST, compared with that of the cases treated by other chemotherapy combinations (P > 0.05, for either LD or ED cases). Chemotherapy prolongs the survival time of the LD SCEC patients, which indicates that chemotherapeutical treatment is effective for SCEC. EP/CP, as commonly recommended multidrug chemotherapy regimen, is not superior to other chemotherapy combinations.

Etiologies of benign esophageal dysphagia are diverse and a panel of clinical and laboratory investigations should be taken to make the right diagnosis. We report herein two cases of benign esophageal dysphagia of non-infectious origin. Imaging tests identified changes similar to malignancies, while only inflamed granulation tissue was discovered in biopsy specimens. Surgical resection was finally applied due to severe symptoms and the histological study revealed only granulation tissue. They were diagnosed as idiopathic cases when all the known non-infectious pathogenesis were carefully ruled out by sound examination results. The differetail diagnosis of benign esophageal dysphagia is quite important as observational data shows that medical therapy should be applied in certain pathogenesis, while esophagectomy might be the most effective solution for other etiologies. Subsequently a comparison of the manifestations of the two cases and those of esophageal dysphagia induced by other non-infectious etiologies was done to shine some light on the differencial diagnosis of benign esophageal dysphagia.

// Nanzheng Chen 1, * , Xiaomei Yang 2, * , Wen Guo 3 , Jiangtao You 1 , Qifei Wu 1 , Guangjian Zhang 1 , Haijun Li 1 , Donghong Geng 4 , Tianbo Jin 5 , Junke Fu 1 , Yong Zhang 1 1 Department of Thoracic Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi, China 2 Hospital 521 of China’s Ordnance Industry Group, Xi’an 710065, Shaanxi, China 3 Inner Mongolia Medical University, Hohhot 010050, Inner Mongolia, China 4 School of Continuing Education of Xi’an Jiaotong University, Xi’an 710061, Shaanxi, China 5 School of Life Sciences, Northwest University, Xi’an 710069, Shaanxi, China * These authors have contributed equally to this work Correspondence to: Junke Fu, email: aniywn666888@163.com Yong Zhang, email: cj163.cool@163.com Keywords: association study, lung cancer, telomere-related gene, single nucleotide polymorphisms (SNPs) Received: August 26, 2016 Accepted: October 14, 2016 Published: December 10, 2016 ABSTRACT Single nucleotide polymorphisms (SNPs) in the telomere-associated gene ACYP2 are associated with increased lung cancer risk. We explored the correlation between ACYP2 SNPs and lung cancer susceptibility in the Chinese Han population. A total of 554 lung cancer patients and 603 healthy controls were included in this study. Thirteen SNPs in ACYP2 were selected. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated using unconditional logistic regression analysis. Multivariate logistic regression analysis was used assess the correlation between SNPs and lung cancer. We found that rs1682111 was associated with increased lung cancer risk in the recessive model (crude, OR=1.50, 95%CI: 1.04-2.16, p=0.029; adjusted for age, OR=1.55, 95%CI: 1.04-2.30, p=0.029), as was rs11896604 in the codominant model (crude, OR=0.65, 95%CI: 0.33-1.28, p=0.045; adjusted for age, OR=0.74, 95%CI: 0.36-1.53, p=0.049) and over-dominant model (crude, OR=1.30, 95%CI: 1.02-1.66, p=0.032; adjusted for age, OR=1.37, 95%CI: 1.05-1.78, p=0.020). Finally, rs843720 was associated with increased lung cancer risk in the recessive model (crude, OR=1.43, 95%CI: 1.02-2.02, p=0.040; adjusted for age, OR=1.48, 95%CI: 1.02-2.15, p=0.040). Thus three SNPs in ACYP2 (rs1682111, rs11896604 and rs843720) associate with lung cancer in the Chinese Han population.

Possible thyroiditis was suspected in a 56-year-old man who initially presented sore throat because laboratory examinations revealed decreased serum thyroid hormone and the Tc-pertechnetate scintigraphy showed no tracer uptake by the thyroid gland. However, subsequent examination demonstrated that the absence of pertechnetate activity in the thyroid was due to complete replacement of thyroid gland by the metastasis from lung adenocarcinoma, which was unknown at the initial presentation.

Background Esophageal foreign bodies refer to objects that are accidentally or intentionally swallowed, or that are naturally swallowed during medication or eating, temporarily staying in or resting in the esophagus. Esophageal foreign body is one of the common emergency of esophageal surgery, more common in the elderly and children. This paper study clinical features of esophageal foreign body in northwestern China in order to improve the abilities of diagnosis and treatment for the disease. Methods Clinical data of 202 patients admitted in for esophageal foreign body was analyzed retrospectively. The general information of the patients were collected, and the types of foreign bodies, the location, diagnostic methods, methods of taking out and related complications, hospitalization days, et al were analyzed statistically. Results The types of esophageal foreign body included jujube pit (61.8%), animal bones (12.9%) and non-food foreign bodies (24.3%). It mainly occurred in the upper orifice of the esophagus (65.8%). Diagnostic methods were mainly consisted of esophageal angiography (57.9%), chest X-ray (19.8%) and endoscopy (16.4%). Most of the patients (189, 93.6%) were treated with esophagoscopy. Altogether 26 cases presented with complications, and 18 of them were admitted in for jujube pit. Conclusion The main cause of esophageal foreign body is jujube pit. Early diagnose and timely management is essential for the disease. How to guide the population as far as possible to avoid ingesting jujube pit wrongly and reduce the incidence of esophageal foreign body is of practical significance. Disclosure All authors have declared no conflicts of interest.

INTRODUCTION AND OBJECTIVES: The direct phenotypic effects of BCG on human urothelial carcinoma (UC) cells include cell cycle arrest, apoptotic resistance, and caspase-independent cell death. These effects are associated with increased expression of the cyclin dependant kinase inhibitor (CDKI) p21. This study assessed the role of p21 expression in mediating the phenotypic effects observed in response to BCG. METHODS: Inducible systems for the autocrine expression of p21, or the shRNA mediated blockade of p21 expression in response to BCG, were established in the human UC line T24. The effect of increasing or inhibiting p21 expression on tumor phenotype was assessed using assays for cell cycle compartmentalization (flow cytometry), apoptotic sensitivity (Caspase 3 activation), and cytotoxicity (vital dye exclusion). Results were compared to the phenotypic changes observed in response to BCG alone. RESULTS: BCG treatment alone resulted in cell cycle arrest in G0/G1, apoptotic resistance and caspase-independent cytotoxicity. p21 overexpression resulted in cell cycle arrest with a significant increase in the percentage of the cell in G0/G1 phase when compared with the untreated group (p = 0.006). p21 expression decreased basal caspase-3 expression when compared with untreated group and significantly reversed Camptothecin induced caspase-3 activity when compared with the Camptothecin alone group (p = 0.001). p21 overexpression increased BCG’s direct cytotoxicity (p = 0.0003). Inhibition of p21 expression in response to BCG failed to reverse BCG induced changes in cell cycle compartmentalization. p21 inhibition significantly reversed the antiapoptotic effect of BCG (p = 0.048). The expression of p21 was required for the direct cytotoxic effect of BCG (p = 0.004) CONCLUSIONS: p21 expression is sufficient but not necessary for BCG induced CCA. It is both sufficient and necessary for the full anti-apoptotic effect of BCG. p21 expression alone is not sufficient for caspase-independent cytotoxicity but is necessary for BCGs’ direct cytotoxic effect. These findings support a central role for p21 in mediating the phenotypic response of the tumor to BCG exposure.

OBJECTIVE To evaluate the ability of bacille-Calmette Guerin (BCG) to induce caspase-independent cell death and release the necrosis-associated chemokine high molecular group box protein 1 (HMGB1) from urothelial carcinoma (UC) cells; a correlative clinical trial determined if BCG treatment resulted in increased urinary levels of HMGB1. PATIENTS, MATERIALS AND METHODS The human UC cell lines 253 J and T24 were pretreated with apoptosis inhibitors, exposed to BCG, and cell viability and ultrastructural changes measured. HMGB1 levels were assessed in cell culture supernatant after BCG treatment. The expression/function of HMGB1 receptors on the UC cell lines was determined by reverse transcription-polymerse chain reaction and the ability of exogenous HMGB1 to activate nuclear factor (NF)-κB signalling assessed. An HMGB1 enzyme-linked immunosorbent assay was used to measure HMGB1 levels in urine obtained from BCG-treated patients. RESULTS Inhibition of apoptotic pathways failed to inhibit BCG-induced cell death in UC cells. Electron microscopy showed BCG-dependent ultrastructural changes consistent with cellular necrosis. BCG exposure resulted in a binary increase in cell culture supernatant levels of HMGB1. UCs expressed multiple HMGB1 receptors. Treatment of UCs with HMGB1 activated NF-κB. In the clinical setting, six of seven patients had increased urinary levels of HMGB1 at 24 h after BCG treatment. CONCLUSIONS BCG causes direct cytotoxicity in a subpopulation of UC cells. This cytotoxicity is caspase-independent and associated with ultrastructural changes and cellular protein release (HMGB1), characteristic of necrosis. Urinary levels of HMGB1 can be elevated in patients after BCG treatment. The expression and function of HMGB1 receptors in UC cells, coupled with the known role of HMGB1 on the host immune response, suggest a role for necrosis and HMGB1 release in the antitumour effect of BCG.

A central problem in the application of exploratory factor analysis is deciding how many factors to retain (m). Although this is inherently a model selection problem, a model selection perspective is rarely adopted for this task. We suggest that Cudeck and Henly's (1991) framework can be applied to guide the selection process. Researchers must first identify the analytic goal: identifying the (approximately) correct m or identifying the most replicable m. Second, researchers must choose fit indices that are most congruent with their goal. Consistent with theory, a simulation study showed that different fit indices are best suited to different goals. Moreover, model selection with one goal in mind (e.g., identifying the approximately correct m) will not necessarily lead to the same number of factors as model selection with the other goal in mind (e.g., identifying the most replicable m). We recommend that researchers more thoroughly consider what they mean by "the right number of factors" before they choose fit indices.

Attenuated mycobacterium bacillus Calmette-Guérin is widely used as intravesical immunotherapy of nonmuscle invasive urothelial carcinoma. Currently there are limited data on the relationship between bacillus Calmette-Guérin dose intensity and tumor response. We evaluated the dose-response relationship of bacillus Calmette-Guérin to nonmuscle invasive bladder cancer in vitro using urothelial carcinoma cell lines and in vivo using an orthotopic mouse model.Two human urothelial carcinoma cell lines were used to study the effect of bacillus Calmette-Guérin dose on the tumor cell response. Internalization, activation of signaling pathways, gene transactivation, cell viability, lactate dehydrogenase and HMGB1 release were study end points. An orthotopic tumor model was used to compare the effect of different doses on the antitumor efficacy of bacillus Calmette-Guérin.Bacillus Calmette-Guérin internalization by urothelial carcinoma cells increased as a function of time and dose with a plateau at higher doses and/or long exposure times. Intracellular signaling demonstrated a similar direct, dose dependent increase. Cytokine expression by urothelial carcinoma cells as a function of dose was variable. Some genes increased progressively but others showed a decrease at the highest dose. While nonviable cell number increased in proportion to dose, the number of cells undergoing necrotic cell death decreased at higher doses. A higher dose of bacillus Calmette-Guérin (1:200) showed a better antitumor effect than a standard dose (1:50) (p0.01).Bacillus Calmette-Guérin dose has a direct impact on urothelial carcinoma cell biology. Increased dose intensity, particularly in nonresponders, may represent a strategy to increase bacillus Calmette-Guérin treatment efficacy.

for induction of protective T cell immunity. In vivo studies have shown that TDM injection resulted in suppression of tumor growth in hepatoma and ocular squamous cell carcinoma. To date, the effect of TDM on Urothelial carcinoma (UC) cells has not been studied. The objectives of this study were to measure the cytotoxic effects of TDM on BCG sensitive and BCG resistant UC cell lines and determine its mechanism of action relative to BCG. METHODS: BCG sensitive (253J, T24) and BCG resistant (RT4) UC cell lines were used to study the effect of TDM. The biologic response to TDM was compared with the response to BCG. Response endpoints included viability, LDH release, HMGB1 release, caspase-3 activity, intracellular signaling pathways (NF-kB), gene transactivation and global profiling of reactive oxygen species(ROS) and nitrogen species (RNS). RESULTS: TDM cytotoxicity was similar in both BCG sensitive and resistant cell lines. TDM significantly decreased viability (T24, p

INTRODUCTION The attenuated mycobacterium Bacille Calmette Guerin is widely utilized as intravesical immunotherapy for the treatment of non-muscle invasive urothelial carcinoma. At present, there is limited data on the relationship between BCG dose intensity and tumor response. This study evaluated dose-response relationship of BCG to NMIBC in vitro using urothelial carcinoma cell lines and in vivo using orthotopic mouse model.

released by a portion of urothelial carcinoma (UC) tumor cells following BCG exposure. Elevated levels of HMGB1 have been observed in the urine of patients following intravesical BCG therapy. Most importantly, in vivo in models have demonstrated that tumor cells engineered to have reduced HMGB1 release fail to respond to intravesical BCG administration. Given the apparent importance of HMGB1 release for in vivo anti-tumor activity, this study evaluated the role of specific elements of BCG/tumor cell interaction in contributing to maximal HMGB1 release. METHODS: Two human UC cell lines, T24 and 253J, were employed. HMGB1 concentrations in cell culture supernatant, with and without BCG treatment, served as the principal end point to assess the role of potentially involved variables. Specific techniques were utilized to determine the role of 5 1 antigen receptor crosslinking, BCG adherence, BCG internalization, BCG viability, iNOS expression/NO production, and p21 expression in mediating HMGB1 release by UC cells in response to BCG. RESULTS: Crosslinking of 5 1 integrin was insufficient to induce HMGB1 release. HMGB1 release by crosslinked cells was not significantly different than untreated controls (p 0.5). Treatment of cells with the peptide GRDGS to block 5 1 integrin and inhibit BCG adherence significantly inhibited HMGB1 release (p 0.001). Inhibition of BCG internalization by pretreatment of cells with Cytochalasin B significantly decreased HMGB1 release relative to BCG alone (p 0.0001). Both viable and heat killed BCG significantly increased HMGB1 release by UC cells relative to controls (p 0.01) The use of heat killed BCG significantly reduced HMGB1 release to 50% of values observed in response to viable BCG (p 0.0001). HMGB1 release by iNOS inhibited cells was significantly reduced (p 0.01). Inducible knockdown of p21 expression in response to BCG significantly reduced HMGB1 release following BCG treatment (p 0.01). CONCLUSIONS: BCG induced non-apoptotic cell death and HMGB1 release occurs as a consequence of a complex multi-step process. Optimal HMGB1 release requires the adherence and internalization of viable BCG, iNOS activity, and p21 expression. An understanding of the steps and mechanisms involved in BCG induced HMGB1 release affords an opportunity for targeted strategies to improve BCG treatment efficacy.