Integrated convolution and self-attention for improving peptide toxicity prediction.

MOTIVATION: Peptides are promising agents for the treatment of a variety of diseases due to their specificity and efficacy. However, the development of peptide-based drugs is often hindered by the potential toxicity of peptides, which poses a significant barrier to their clinical application. Traditional experimental methods for evaluating peptide toxicity are time-consuming and costly, making the development process inefficient. Therefore, there is an urgent need for computational tools specifically designed to predict peptide toxicity accurately and rapidly, facilitating the identification of safe peptide candidates for drug development. RESULTS: We provide here a novel computational approach, CAPTP, which leverages the power of convolutional and self-attention to enhance the prediction of peptide toxicity from amino acid sequences. CAPTP demonstrates outstanding performance, achieving a Matthews correlation coefficient of approximately 0.82 in both cross-validation settings and on independent test datasets. This performance surpasses that of existing state-of-the-art peptide toxicity predictors. Importantly, CAPTP maintains its robustness and generalizability even when dealing with data imbalances. Further analysis by CAPTP reveals that certain sequential patterns, particularly in the head and central regions of peptides, are crucial in determining their toxicity. This insight can significantly inform and guide the design of safer peptide drugs. AVAILABILITY AND IMPLEMENTATION: The source code for CAPTP is freely available at https://github.com/jiaoshihu/CAPTP.

Advancing cancer driver gene detection via Schur complement graph augmentation and independent subspace feature extraction.

Accurately identifying cancer driver genes (CDGs) is crucial for guiding cancer treatment and has recently received great attention from researchers. However, the high complexity and heterogeneity of cancer gene regulatory networks limit the precition accuracy of existing deep learning models. To address this, we introduce a model called SCIS-CDG that utilizes Schur complement graph augmentation and independent subspace feature extraction techniques to effectively predict potential CDGs. Firstly, a random Schur complement strategy is adopted to generate two augmented views of gene network within a graph contrastive learning framework. Rapid randomization of the random Schur complement strategy enhances the model's generalization and its ability to handle complex networks effectively. Upholding the Schur complement principle in expectations promotes the preservation of the original gene network's vital structure in the augmented views. Subsequently, we employ feature extraction technology using multiple independent subspaces, each trained with independent weights to reduce inter-subspace dependence and improve the model's expressiveness. Concurrently, we introduced a feature expansion component based on the structure of the gene network to address issues arising from the limited dimensionality of node features. Moreover, it can alleviate the challenges posed by the heterogeneity of cancer gene networks to some extent. Finally, we integrate a learnable attention weight mechanism into the graph neural network (GNN) encoder, utilizing feature expansion technology to optimize the significance of various feature levels in the prediction task. Following extensive experimental validation, the SCIS-CDG model has exhibited high efficiency in identifying known CDGs and uncovering potential unknown CDGs in external datasets. Particularly when compared to previous conventional GNN models, its performance has seen significant improved. The code and data are publicly available at: https://github.com/mxqmxqmxq/SCIS-CDG.

Krüppel-like Factor 10 as a Prognostic and Predictive Biomarker of Radiotherapy in Pancreatic Adenocarcinoma.

The prognosis of pancreatic adenocarcinoma (PDAC) remains poor, with a 5-year survival rate of 12%. Although radiotherapy is effective for the locoregional control of PDAC, it does not have survival benefits compared with systemic chemotherapy. Most patients with localized PDAC develop distant metastasis shortly after diagnosis. Upfront chemotherapy has been suggested so that patients with localized PDAC with early distant metastasis do not have to undergo radical local therapy. Several potential tissue markers have been identified for selecting patients who may benefit from local radiotherapy, thereby prolonging their survival. This review summarizes these biomarkers including SMAD4, which is significantly associated with PDAC failure patterns and survival. In particular, Krüppel-like factor 10 (KLF10) is an early response transcription factor of transforming growth factor (TGF)-ß. Unlike TGF-ß in advanced cancers, KLF10 loss in two-thirds of patients with PDAC was associated with rapid distant metastasis and radioresistance; thus, KLF10 can serve as a predictive and therapeutic marker for PDAC. For patients with resectable PDAC, a combination of KLF10 and SMAD4 expression in tumor tissues may help select those who may benefit the most from additional radiotherapy. Future trials should consider upfront systemic therapy or include molecular biomarker-enriched patients without early distant metastasis.

Tracheal tunica adventitia invasion after lobectomy in patients with non-small cell lung cancer.

BACKGROUND: For patients with non-small cell lung cancer, a negative margin status is required for radical pulmonary surgery. Residual disease of the margin has been thoroughly studied in the past few decades. However, the prognostic significance of tracheal tunica adventitia invasion after lobectomy remains unclear. In this study, we aimed to investigate the clinical influence of tracheal tunica adventitia invasion after lobectomy. METHODS: We retrospectively collected the clinical data of 591 patients who consecutively underwent pulmonary lobectomy, including sleeve lobectomy, between 2012 and 2018 at Shanghai Chest Hospital. According to the tracheal tunica adventitia invasion status, we allocated the patients into 2 groups (tracheal tunica adventitia invasion and non-tracheal tunica adventitia). Disease-free and overall survival were evaluated, and we discussed the necessity of radiotherapy in patients with tracheal tunica adventitia. RESULTS: After propensity score matching to balance baseline characteristics, there were 167 individuals in the tracheal tunica adventitia invasion and non-tracheal tunica adventitia groups. In the hazard analysis, we found that tracheal tunica adventitia increased the risk of recurrence (hazard ratio: 0.652; P = .002) and impaired long-term survival (P < .001). Subgroup analysis revealed that tracheal tunica adventitia was an important risk factor, especially when the hilar lymph nodes were positive. In addition, tracheal tunica adventitia invasion promoted extra-thoracic lymph node metastasis. We discovered that radiotherapy did not improve the prognosis of patients in the tracheal tunica adventitia invasion group. CONCLUSIONS: After lobectomy, tracheal tunica adventitia invasion is a risk factor for non-small cell lung cancer and potentially increases extra-thoracic lymph node metastasis. Moreover, tracheal tunica adventitia invasion is not sensitive to postoperative radiotherapy.

The Implication of Liquid Biopsy in the Non-small Cell Lung Cancer: Potential and Expectation.

Nowadays, lung cancer has remained the most lethal cancer, despite great advances in diagnosis and treatment. However, a large proportion of patients were diagnosed with locally advanced or metastatic disease and have poor prognosis. Immunotherapy and targeted drugs have greatly improved the survival and prognosis of patients with advanced lung cancer. However, how to identify the optimal patients to accept those therapies and how to monitor therapeutic efficacy are still in dispute. In the past few decades, tissue biopsy, including percutaneous fine needle biopsy and surgical excision, has still been the gold standard for examining the gene mutation such as EGFR, ALK, ROS, and PD-1/PD/L1, which can indicate the follow-up treatment. Nevertheless, the biopsy techniques mentioned above were invasive and unrepeatable, which were not suitable for advanced patients. Liquid biopsy, accounting for heterogeneity compared with tissue biopsy, is an alternative technique for monitoring the mutation, and a large quantity of research has demonstrated its feasibility to detect the circulating tumor cell, cell-free DNA, circulating tumor DNA, and extracellular vesicles from peripheral venous blood. The proposal of the concept of precision medicine brings a novel medical model developed with the rapid progress of genome sequencing technology and the cross-application of bioinformation, which was based on personalized medicine. The emerging method of liquid biopsy might contribute to promoting the development of precision medicine. In this review, we intend to describe the liquid biopsy in non-small cell lung cancer in detail in the aspect of screening, diagnosis, monitoring, treatment, and drug resistance.

shRNA­mediated knockdown of KNTC1 inhibits non-small-cell lung cancer through regulating PSMB8.

In view of the important roles played by Kinetochore proteins in mitosis, we believed that they may contribute to the development and progression of human cancers, which has been reported recently elsewhere. Kinetochore-associated 1 (KNTC1) participates in the segregation of sister chromatids during mitosis, the effects of which on non-small-cell lung cancer (NSCLC) remain unclear. Here, we sought to identify the biological significance of KNTC1 in NSCLC. KNTC1 protein expression in NSCLC tissues was investigated by immunohistochemistry. Lentivirus delivered short hairpin RNA (shRNA) was utilized to establish KNTC1 silence NSCLC cell lines. The effects of KNTC1 depletion on NSCLC cell proliferation, migration, apoptosis, and tumor formation were analyzed by MTT assay, wound-healing assay, transwell assay, flow cytometry assay, and in nude mouse models in vivo. After KNTC1 reduction, NSCLC cell viability, proliferation, migration, and invasion were restrained. A xenograft tumor model was also provided to demonstrate the inhibited tumorigenesis in NSCLC. In addition, the downstream mechanism analysis indicated that KNTC1 depletion was positively associated with PSMB8. The findings of the present study suggested that KNTC1 may have a pivotal role in mediating NSCLC progression and may act as a novel therapeutic target for NSCLC.

Homologous recombination deficiency (HRD) can predict the therapeutic outcomes of immuno-neoadjuvant therapy in NSCLC patients.

BACKGROUND: Neoadjuvant immunotherapy is emerging as novel effective intervention in lung cancer, but study to unearth effective surrogates indicating its therapeutic outcomes is limited. We investigated the genetic changes between non-small cell lung cancer (NSCLC) patients with varied response to neoadjuvant immunotherapy and discovered highly potential biomarkers with indicative capability in predicting outcomes. METHODS: In this study, 3 adenocarcinoma and 11 squamous cell carcinoma NSCLC patients were treated by neoadjuvant immunotherapy with variated regimens followed by surgical resection. Treatment-naive FFPE or fresh tissues and blood samples were subjected to whole-exome sequencing (WES). Genetic alternations were compared between differently-responded patients. Findings were further validated in multiple public cohorts. RESULTS: DNA damage repair (DDR)-related InDel signatures and DDR-related gene mutations were enriched in better-responded patients, i.e., major pathological response (MPR) group. Besides, MPR patients exhibited provoked genome instability and unique homologous recombination deficiency (HRD) events. By further inspecting alternation status of homology-dependent recombination (HR) pathway genes, the clonal alternations were exclusively enriched in MPR group. Additionally, associations between HR gene alternations, percentage of viable tumor cells and HRD event were identified, which orchestrated tumor mutational burden (TMB), mutational intratumor heterogeneity (ITH), somatic copy number alteration (SCNA) ITH and clonal neoantigen load in patients. Validations in public cohorts further supported the generality of our findings. CONCLUSIONS: We reported for the first time the association between HRD event and enhanced neoadjuvant immunotherapy response in lung cancer. The power of HRD event in patient therapeutic stratification persisted in multifaceted public cohorts. We propose that HR pathway gene status could serve as novel and additional indicators guiding immune-neoadjuvant and immunotherapy treatment decisions for NSCLC patients.

The outcomes of margin status after sleeve lobectomy for patients of non-small cell lung cancer.

BACKGROUND: Sleeve lobectomy is recognized as an alternative surgical operation to pneumonectomy because it preserves the most pulmonary function and has a considerable prognosis. In this study, we aimed to investigate the implications of residual status for patients after sleeve lobectomy. METHODS: In this retrospective cohort study, we summarized 58 242 patients who underwent surgeries from 2015 to 2018 in Shanghai Chest Hospital and found 456 eligible patients meeting the criteria. The status of R2 was excluded. The outcomes were overall survival (OS) and recurrence-free survival (RFS). We performed a subgroup analysis to further our investigation. RESULTS: After the propensity score match, the baseline characteristic was balanced between two groups. The survival analysis showed no significant difference of overall survival and recurrence-free survival between R0 and R1 groups (OS: p = 0.053; RFS: p = 0.14). In the multivariate Cox analysis, we found that the margin status was not a dependent risk factor to RFS (p = 0.119) and OS (p = 0.093). In the patients of R1, N stage and age were closely related to OS, but we did not find any significant risk variable in RFS for R1 status. In the subgroup analysis, R1 status may have a worse prognosis on patients with more lymph nodes examination. On further investigation, we demonstrated no differences among the four histological types of margin status. CONCLUSION: In our study, we confirmed that the margin status after sleeve lobectomies was not the risk factor to prognosis. However, patients with more lymph nodes resection should pay attention to the margin status.

Identification of a 7-miRNA signature for predicting the prognosis of patients with lung adenocarcinoma.

The role of microRNAs (miRNAs) in tumor diagnosis and patients' prognosis has recently gained extensive research attention. This study was designed to analyze miRNA in lung adenocarcinoma (LUAD) using bioinformatics analysis and to identify novel biomarkers to predict overall survival (OS) for LUAD patients. Differential miRNA expression analysis was performed on LUAD, and normal tissues were extracted from The Cancer Genome Atlas (TCGA). Univariate Cox risk regression and least absolute shrinkage and selection operator (LASSO) Cox analysis were used to screen prognostic miRNAs and develop a risk score model. The prognostic performance of the system was examined utilizing the Kaplan-Meier and receiver operating characteristic (ROC) curves. Independent prognostic factors of LUAD were determined by multivariate Cox regression analysis. Nomogram was constructed according to the independent prognostic factors to evaluate the patients' one-, three- and five-year OS. A 7-miRNA signature based on miR-584-5p, miR-31-3p, miR-490-3, miR-4661-5p, miR-30e-5p, miR-582-5p, and miR-148a-3p was established. To categorize patients into high- and low-risk groups, the risk score was computed. The OS of the low-risk group was significantly longer than the high-risk group, and the signature showed high sensitivity and specificity in anticipating the one-, three- and five-year OS. The system was an independent factor in predicting the OS of LUAD patients and performed better when combined with the N stage in nomogram. A 7-miRNA signature developed in this study could accurately predict LUAD survival.

The significance of systematic lymph node dissection in surgery for early-stage non-small cell lung cancer patients aged ≤40 years.

BACKGROUND: Surgery remains the best option for treating early-stage non-small cell lung cancer (NSCLC), and lymph node dissection (LND) is an important step in this approach. However, the extent of LND in the general age population, especially in young patients, is controversial. This retrospective study aimed to investigate the correlation between systematic lymph node dissection (SLND) and prognosis in young (≤40 years) patients with stage IA NSCLC. METHODS: Clinicopathological data of 191 patients aged ≤40 years who underwent surgical pulmonary resection for stage IA NSCLC between January 2010 and December 2016 were retrospectively collected. Of the patients, 104 received SLND (SLND group), while the other 87 patients underwent sampling or no LND (non-SLND group). The disease-free survival (DFS) and overall survival (OS) curves of the patients from each group were plotted using the Kaplan-Meier method, and the correlations of the patients' clinical factors with prognosis were also analyzed. RESULTS: The median follow-up period was 55 months. During follow-up, 7 patients died, and recurrence or metastasis was detected in 16 patients. Kaplan-Meier analysis revealed no difference in DFS (P=0.132) between the SLND and non-SLND group, but a significant difference was found between the groups in OS (P=0.022). Additionally, there was no statistically pronounced difference in OS or DFS between male and female patients. Multivariate survival analysis showed that the type of SLND, as well as tumor size, is an independent prognostic factor for DFS (HR, 3.530; 95% CI, 1.120-11.119; P=0.031) and OS (HR, 13.076; 95% CI, 1.209-141.443; P=0.034). CONCLUSIONS: For young (age ≤40) stage IA NSCLC patients with pathological invasive adenocarcinoma, intraoperative SLND can improve the DFS and OS. Further studies are needed to verify the most optimal degree of LND in young patients.

CERBERUS is critical for stabilization of VAPYRIN during rhizobial infection in Lotus japonicus.

CERBERUS (also known as LIN) and VAPYRIN (VPY) are essential for infection of legumes by rhizobia and arbuscular mycorrhizal fungi (AMF). Medicago truncatula LIN (MtLIN) was reported to interact with MtVPY, but the significance of this interaction is unclear and the function of VPY in Lotus japonicus has not been studied. We demonstrate that CERBERUS has auto-ubiquitination activity in vitro and is localized within distinct motile puncta in L. japonicus root hairs and in Nicotiana benthamiana leaves. CERBERUS colocalized with the trans-Golgi network/early endosome markers. In L. japonicus, two VPY orthologs (LjVPY1 and LjVPY2) were identified. CERBERUS interacted with and colocalized with both LjVPY1 and LjVPY2. Co-expression of CERBERUS with LjVPY1 or LjVPY2 in N. benthamiana led to increased protein levels of LjVPY1 and LjVPY2, which accumulated as mobile punctate bodies in the cytoplasm. Conversely, LjVPY2 protein levels decreased in cerberus roots after rhizobial inoculation. Mutant analysis indicates that LjVPY1 and LjVPY2 are required for rhizobial infection and colonization by AMF. Our data suggest that CERBERUS stabilizes LjVPY1 and LjVPY2 within the trans-Golgi network/early endosome, where they might function to regulate endocytic trafficking and/or the formation or recycling of signaling complexes during rhizobial and AMF symbiosis.

A Predictive Model of Live Birth Based on Obesity and Metabolic Parameters in Patients With PCOS Undergoing Frozen-Thawed Embryo Transfer.

Aims: To determine the clinical predictors of live birth in women with polycystic ovary syndrome (PCOS) undergoing frozen-thawed embryo transfer (F-ET), and to determine whether these parameters can be used to develop a clinical nomogram model capable of predicting live birth outcomes for these women. Methods: In total, 1158 PCOS patients that were clinically pregnant following F-ET treatment were retrospectively enrolled in this study and randomly divided into the training cohort (n = 928) and the validation cohort (n = 230) at an 8:2 ratio. Relevant risk factors were selected via a logistic regression analysis approach based on the data from patients in the training cohort, and odds ratios (ORs) were calculated. A nomogram was constructed based on relevant risk factors, and its performance was assessed based on its calibration and discriminative ability. Results: In total, 20 variables were analyzed in the present study, of which five were found to be independently associated with the odds of live birth in univariate and multivariate logistic regression analyses, including advanced age, obesity, total cholesterol (TC), triglycerides (TG), and insulin resistance (IR). Having advanced age (OR:0.499, 95% confidence interval [CI]: 0.257 - 967), being obese (OR:0.506, 95% CI: 0.306 - 0.837), having higher TC levels (OR: 0.528, 95% CI: 0.423 - 0.660), having higher TG levels (OR: 0.585, 95% CI: 0.465 - 737), and exhibiting IR (OR:0.611, 95% CI: 0.416 - 0.896) were all independently associated with a reduced chance of achieving a live birth. A predictive nomogram incorporating these five variables was found to be well-calibrated and to exhibit good discriminatory capabilities, with an area under the curve (AUC) for the training group of 0.750 (95% CI, 0.709 - 0.788). In the independent validation cohort, this model also exhibited satisfactory goodness-of-fit and discriminative capabilities, with an AUC of 0.708 (95% CI, 0.615 - 0.781). Conclusions: The nomogram developed in this study may be of value as a tool for predicting the odds of live birth for PCOS patients undergoing F-ET, and has the potential to improve the efficiency of pre-transfer management.

Bioengineered carina reconstruction using In-Vivo Bioreactor technique in human: proof of concept study.

BACKGROUNDS: Long-segment airway defect reconstruction, especially when carina is invaded, remains a challenge in clinical setting. Previous attempts at bioengineered carina reconstruction failed within 90 days due to delayed revascularization and recurrent infection. METHODS: To establish the feasibility of carina bioengineering use In-Vivo Bioreactor technique. Uncontrolled single-center cohort study including three patients with long-segment airway lesions invading carina. Radical resection of the lesions was performed using standard surgical techniques. After resection, In-Vivo Bioreactor airway reconstruction was performed using a nitinol stent wrapped in two layers of acellularized dermis matrix (ADM). Two Port-a-Cath catheters connected to two portable peristaltic pumps were inserted between the ADM layers. The implanted bioengineered airway was continuously perfused with an antibiotic solution via the pump system. Peripheral total nucleated cells (TNCs) were harvested and seeded into the airway substitute via a Port-a-Cath twice a week for 1 month. The patients were treated as a bioreactor for in situ regeneration of their own bioengineered airway substitute. RESULTS: Three patients were included in the study (mean age, 54.7 years). The first patient underwent 8 cm long trachea and carina reconstruction, the second patient 6 cm long trachea, carina and main bronchus reconstruction. The third patient right main bronchus and carina reconstruction. Major morbidity included gastric retention and pneumonia. All three patients survived till last follow-up and bronchoscopy follow-up showed well-vascularized regenerated tissue without leakage. CONCLUSIONS: In this uncontrolled study, In-Vivo Bioreactor technique demonstrated potential to be applied for long-segment trachea, carina and bronchi reconstruction. Further research is needed to assess efficacy and safety.

Relationship between Methylation of FHIT and CDH13 Gene Promoter Region and Liver Cancer.

In order to demonstrate the relationship between methylation of fragile histidine triad (FHIT) and T-cadherin/H-cadherin (CDH13) genes and liver cancer, the methylation status of FHIT and CDH13 was detected in healthy individuals and in Mongolian and Han patients with liver cancer. The phenol-chloroform method was used to extract genomic DNA. The methylation specific polymerase chain reaction method was applied to detect the methylation status of FHIT and CDH13. The relationship between smoking and alcohol consumption and gene (FHIT and CDH13) methylation was analyzed. There was significant difference in methylation rate of FHIT (72.67%, 34.67%) and CDH13 (72.0%, 28.0%) between liver cancer patients and healthy individuals of Mongolian descent (P<0.05), as well as that of FHIT (68%, 30.67%) and CDH13 (64%, 26%) between liver cancer patients and healthy individuals of Han individuals (P<0.05). There was also a relationship between smoking and drinking and the methylation of FHIT and CDH13 (P<0.05). Thus, the methylation of FHIT and CDH13 had a relationship with liver cancer incidence. Smoking and alcohol ingestion may promote the methylation of FHIT and CDH13.

Simple continuous suture to strengthen the closure of intra-muscle used in the removal of uni-portal video-assisted thoracoscopic surgery thoracic drainage tube.

BACKGROUND: Uni-portal video-assisted thoracoscopic surgery (VATS) has become a popular type of thoracic surgery. However, improvements to the closure of the single drainage tube hole are still in need. METHODS: From February 2019 to May 2019, we included 50 patients who received uni-portal VATS for lung disease or mediastinal disease and simple continuous suture to strengthen the closure of intra-muscle combined with removal-free stitches on the skin. Follow-up items included incision length, chest tube drainage amount, chest tube drainage time, incision effusion leakage, postoperative subcutaneous emphysema, postoperative pain score. RESULTS: A total of 50 patients were included in this study, including 23 males and 27 females, with an average age of 60.08±9.73 years old. The mean drainage on the first day after operation was 236.56±141.50 mL, while the mean pain score on the first day after operation was 4.16±1.70. Among 50 patients, only two cases of subcutaneous emphysema occurred. CONCLUSIONS: Applying innovative simple continuous suture to strengthen the closure of intra-muscle combined with removal-free stitches on the skin into the closure of uni-portal VATS is safe and feasible.

Decreased expression level and DNA-binding activity of specificity protein 1 via cyclooxygenase-2 inhibition antagonizes radiation resistance, cell migration and invasion in radiation-resistant lung cancer cells.

Radiation is able to inhibit tumor growth, promote tumor cell apoptosis and prolong patient survival. However, radiation resistance remains a major impediment to radiotherapy. Local and metastatic recurrences following radiation are still large impediments to overall survival. Although cyclooxygenase-2 (COX-2) inhibitors may induce radiation sensitivity in cancer cells, the underlying mechanisms are not fully understood. The present study demonstrated high potential for cell proliferation, migration and invasion in radiation-resistant lung cancer cell lines. The present study observed the overexpression of specificity protein 1 (Sp1) in these cells, and the overexpression of Sp1 induced upregulation of matrix metalloproteinase (MMP)-2, MMP-9, B cell lymphoma-2, in addition to a high potential for radiation resistance, migration and invasion in these cells. The present study revealed that the COX-2 selective inhibitor, celecoxib, enhanced radiation sensitivity and inhibited migration and invasion in these cells by inhibiting the expression and DNA-binding activity of Sp1. Furthermore, celecoxib downregulated Sp1 by inhibiting c-Jun N-terminal kinase (JNK). Taken together, the present study demonstrated that Sp1 overexpression in radiation-resistant cancer cells and COX-2 inhibitors enhanced radiation sensitivity and inhibited the migration and invasion of cancer cells, at least partially, via inactivation of the JNK/Sp1 signaling pathway and a decrease in Sp1 DNA-binding activity.

Uniportal video assisted thoracic surgery with 2 cm skin incision for right middle lobectomy with systematic lymphadenectomy.

Today, video-assisted thoracic surgery (VATS) was very popular and more and more common, which could be carried out at all levels of medical centers, most of which used multiple-ports VATS techniques. However, uniportal VATS was more difficult technique compared with multiple-ports VATS, and was not yet completely universal. Uniportal port VATS with 2 cm incision was more difficult surgery, and asked the surgeon to master more surgical techniques and good collaborations with each other, however, which not only could reduce the postoperative pain and skin numbness but supply cosmetology and psychological comfort for patients. To reduce unnecessary damage to patients, we minimized the incision to 2 cm. Therefore, we called it precise uniportal port VATS technique in our surgical center and introduced it here.

Clinic application of tissue engineered bronchus for lung cancer treatment.

BACKGROUND: Delayed revascularization process and substitute infection remain to be key challenges in tissue engineered (TE) airway reconstruction. We propose an "in-vivo bioreactor" design, defined as an implanted TE substitutes perfused with an intra-scaffold medium flow created by an extracorporeal portable pump system for in situ organ regeneration. The perfusate keeps pre-seeded cells alive before revascularization. Meanwhile the antibiotic inside the perfusate controls topical infection. METHODS: A stage IIIA squamous lung cancer patient received a 5-cm TE airway substitute, bridging left basal segment bronchus to carina, with the in-vivo bioreactor design to avoid left pneumonectomy. Continuous intra-scaffold Ringer's-gentamicin perfusion lasted for 1 month, together with orthotopic peripheral total nucleated cells (TNCs) injection twice a week. RESULTS: The patient recovered uneventfully. Bronchoscopy follow-up confirmed complete revascularization and reepithelialization four months postoperatively. Perfusate waste test demonstrated various revascularization growth factors secreted by TNCs. The patient received two cycles of chemotherapy and 30 Gy radiotherapy thereafter without complications related to the TE substitute. CONCLUSIONS: In-vivo bioreactor design combines the traditionally separated in vitro 3D cell-scaffold culture system and the in vivo regenerative processes associated with TE substitutes, while treating the recipients as bioreactors for their own TE prostheses. This design can be applied clinically. We also proved for the first time that TE airway substitute is able to tolerate chemo-radiotherapy and suitable to be used in cancer treatment.

Integrated discovery of FOXO1-DNA stabilizers from marine natural products to restore chemosensitivity to anti-EGFR-based therapy for metastatic lung cancer.

The transcription factor forkhead box O1 (FOXO1) negatively regulates activated EGFR signaling by turning on the gene expression of tumor suppressor Kruppel-like factor 6. Here, we propose that the chemosensitivity to anti-EGFR-based lung cancer therapy can be restored by stabilization of the FOXO1-DNA complex architecture using small-molecule marine natural medicines. A synthetic protocol that integrates computational ligand-protein-DNA binding analysis and an experimental fluorescence binding assay was applied against a large library of structurally diverse, drug-like marine natural products to discover novel stabilizers of DNA-bound FOXO1 conformation. The screening utilized chemical similarity analysis to exclude structurally redundant compounds, and then carried out high-throughput molecular docking and computational binding analysis to identify potential marine natural product candidates. Consequently, eight commercially available hits were selected and tested in vitro, from which four marine natural product compounds (tanzawaic acid D, hymenidin, cribrostatin 6 and barbamide) were found to have high or moderate potency to selectively bind to the FOXO1 DNA-binding domain (DBD) in the presence of its cognate DNA partner. Atomistic molecular dynamics (MD) simulations revealed that the identified stabilizers do not directly interact with DNA; instead, they can effectively stabilize the free FOXO1 DBD domain in the DNA-bound conformation and thus promote the binding of FOXO1 to DNA.

Survivin protein expression is involved in the progression of non-small cell lung cancer in Asians: a meta-analysis.

BACKGROUND: Surviving expression might serve as a prognostic biomarker predicting the clinical outcome of non-small cell lung cancer (NSCLC). The study was conducted to explore the potential correlation of survivin protein expression with NSCLC and its clinicopathologic characteristics. METHODS: PubMed, Medline, Cochrane Library, CNKI and Wanfang database were searched through January 2016 with a set of inclusion and exclusion criteria. Data was extracted from these articles and all statistical analysis was conducted by using Stata 12.0. RESULTS: A total of 28 literatures (14 studies in Chinese and 14 studies in English) were enrolled in this meta-analysis, including 3206 NSCLC patients and 816 normal controls. The result of meta-analysis demonstrated a significant difference of survivin positive expression between NSCLC patients and normal controls (RR = 7.16, 95 % CI = 4.63-11.07, P < 0.001). To investigate the relationship of survivin expression and clinicopathologic characteristics, we performed a meta-analysis in NSCLC patients. Our results indicates survivin expression was associated with histological differentiation, tumor-node-metastasis (TNM) stage and lymph node metastasis (LNM) (RR = 0.80, 95 % CI = 0.73-0.87, P < 0.001; RR = 0.75, 95 % CI = 0.67-0.84, P < 0.001; RR = 1.14, 95 % CI = 1.01-1.29, P = 0.035, respectively), but not pathological type and tumor size. (RR = 1.00, 95 % CI = 0.93-1.07, P = 0.983; RR = 0.95, 95 % CI = 0.86-1.05, P = 0.336, respectively). CONCLUSION: Higher expression of survivin in NSCLC patients was found when compared to normal controls. Survivin expression was associated with the clinicopathologic characteristics of NSCLC and may serves as an important biomarker for NSCLC progression.