Artificial intelligence-driven computer aided diagnosis system provides similar diagnosis value compared with doctors' evaluation in lung cancer screening.

OBJECTIVE: To evaluate the consistency between doctors and artificial intelligence (AI) software in analysing and diagnosing pulmonary nodules, and assess whether the characteristics of pulmonary nodules derived from the two methods are consistent for the interpretation of carcinomatous nodules. MATERIALS AND METHODS: This retrospective study analysed participants aged 40-74 in the local area from 2011 to 2013. Pulmonary nodules were examined radiologically using a low-dose chest CT scan, evaluated by an expert panel of doctors in radiology, oncology, and thoracic departments, as well as a computer-aided diagnostic(CAD) system based on the three-dimensional(3D) convolutional neural network (CNN) with DenseNet architecture(InferRead CT Lung, IRCL). Consistency tests were employed to assess the uniformity of the radiological characteristics of the pulmonary nodules. The receiver operating characteristic (ROC) curve was used to evaluate the diagnostic accuracy. Logistic regression analysis is utilized to determine whether the two methods yield the same predictive factors for cancerous nodules. RESULTS: A total of 570 subjects were included in this retrospective study. The AI software demonstrated high consistency with the panel's evaluation in determining the position and diameter of the pulmonary nodules (kappa = 0.883, concordance correlation coefficient (CCC) = 0.809, p = 0.000). The comparison of the solid nodules' attenuation characteristics also showed acceptable consistency (kappa = 0.503). In patients diagnosed with lung cancer, the area under the curve (AUC) for the panel and AI were 0.873 (95%CI: 0.829-0.909) and 0.921 (95%CI: 0.884-0.949), respectively. However, there was no significant difference (p = 0.0950). The maximum diameter, solid nodules, subsolid nodules were the crucial factors for interpreting carcinomatous nodules in the analysis of expert panel and IRCL pulmonary nodule characteristics. CONCLUSION: AI software can assist doctors in diagnosing nodules and is consistent with doctors' evaluations and diagnosis of pulmonary nodules.

The multifaceted functions of DNA-PKcs: implications for the therapy of human diseases.

The DNA-dependent protein kinase (DNA-PK), catalytic subunit, also known as DNA-PKcs, is complexed with the heterodimer Ku70/Ku80 to form DNA-PK holoenzyme, which is well recognized as initiator in the nonhomologous end joining (NHEJ) repair after double strand break (DSB). During NHEJ, DNA-PKcs is essential for both DNA end processing and end joining. Besides its classical function in DSB repair, DNA-PKcs also shows multifaceted functions in various biological activities such as class switch recombination (CSR) and variable (V) diversity (D) joining (J) recombination in B/T lymphocytes development, innate immunity through cGAS-STING pathway, transcription, alternative splicing, and so on, which are dependent on its function in NHEJ or not. Moreover, DNA-PKcs deficiency has been proven to be related with human diseases such as neurological pathogenesis, cancer, immunological disorder, and so on through different mechanisms. Therefore, it is imperative to summarize the latest findings about DNA-PKcs and diseases for better targeting DNA-PKcs, which have shown efficacy in cancer treatment in preclinical models. Here, we discuss the multifaceted roles of DNA-PKcs in human diseases, meanwhile, we discuss the progresses of DNA-PKcs inhibitors and their potential in clinical trials. The most updated review about DNA-PKcs will hopefully provide insights and ideas to understand DNA-PKcs associated diseases.

A deep learning-based model (DeepMPM) to help predict survival in patients with malignant pleural mesothelioma.

Background: Malignant pleural mesothelioma (MPM) is a rare disease with limited treatment and poor prognosis, and a precise and reliable means to predicting MPM remains lacking for clinical use. Methods: In the population-based cohort study, we collected clinical characteristics from the Surveillance, Epidemiology, and End Results (SEER) database. According to the time of diagnosis, the SEER data were divided into 2 cohorts: the training cohort (from 2010 to 2016) and the test cohort (from 2017 to 2019). The training cohort was used to train a deep learning-based predictive model derived from DeepSurv theory, which was validated by both the training and the test cohorts. All clinical characteristics were included and analyzed using Cox proportional risk regression or Kaplan-Meier curve to determine the risk factors and protective factors of MPM. Results: The survival model included 3,130 cases (2,208 in the training cohort and 922 in the test cohort). As for model's performance, the area under the receiver operating characteristics curve (AUC) was 0.7037 [95% confidence interval (CI): 0.7030-0.7045] in the training cohort and 0.7076 (95% CI: 0.7067-0.7086) in the test cohort. Older age; male sex, sarcomatoid mesothelioma; and T4, N2, and M1 stage tended to be the risk factors for survival. Meanwhile, epithelioid mesothelioma, surgery, radiotherapy, and chemotherapy tended to be the protective factors. The median overall survival (OS) of patients who underwent surgery combined with radiotherapy was the longest, followed by those who underwent a combination of surgery, radiotherapy, and chemotherapy. Conclusions: Our deep learning-based model precisely could predict the survival of patients with MPM; moreover, multimode combination therapy might provide more meaningful survival benefits.

Neural network-based model for evaluating inert nodules and volume doubling time in T1 lung adenocarcinoma: a nested case-control study.

Objective: The purpose of this study is to establish model for assessing inert nodules predicting nodule volume-doubling. Methods: A total of 201 patients with T1 lung adenocarcinoma were analysed retrospectively pulmonary nodule information was predicted by an AI pulmonary nodule auxiliary diagnosis system. The nodules were classified into two groups: inert nodules (volume-doubling time (VDT)>600 days n=152) noninert nodules (VDT<600 days n=49). Then taking the clinical imaging features obtained at the first examination as predictive variables the inert nodule judgement model >(INM) volume-doubling time estimation model (VDTM) were constructed based on a deep learning-based neural network. The performance of the INM was evaluated by the area under the curve (AUC) obtained from receiver operating characteristic (ROC) analysis the performance of the VDTM was evaluated by R2(determination coefficient). Results: The accuracy of the INM in the training and testing cohorts was 81.13% and 77.50%, respectively. The AUC of the INM in the training and testing cohorts was 0.7707 (95% CI 0.6779-0.8636) and 0.7700 (95% CI 0.5988-0.9412), respectively. The INM was effective in identifying inert pulmonary nodules; additionally, the R2 of the VDTM in the training cohort was 0.8008, and that in the testing cohort was 0.6268. The VDTM showed moderate performance in estimating the VDT, which can provide some reference during a patients' first examination and consultation. Conclusion: The INM and the VDTM based on deep learning can help radiologists and clinicians distinguish among inert nodules and predict the nodule volume-doubling time to accurately treat patients with pulmonary nodules.

Development and validation of a prognostic predictive model of pulmonary spindle cell carcinoma from the surveillance, epidemiology and end results database.

Background: Pulmonary spindle cell carcinoma (PSCC) is a rare type of non-small cell lung cancer (NSCLC). The prognostic influent factors and therapeutic methods of PSCC are unclear, for there are only some case reports or small samples' analysis. This study aims to find prognosis related factors of PSCC, develop and validate a nomogram to predict their survival probability. Methods: The Surveillance, Epidemiology, and End Results (SEER) 18 Registries database (2000-2018) was searched to study PSCC. According to diagnosed time, data was divided into primary cohort (2000-2015) and validation cohort (2016-2018), both followed until December 31 2018. Chosen by Least Absolute Shrinkage and Selection Operator (LASSO) regression, age, sex, stage, surgery, chemotherapy, N, size and history of malignancy were taken out as predictive variables. The primary cohort was used to develop a nomogram to predict 1-, 3- and 5-year overall survival (OS) probability, and be validated by the validation cohort using concordance index (C-index) and calibration curves. Both cohorts were used to conduct a Cox regression to find the influential factors on OS of PSCC. Results: The nomogram shows a good concordance and discrimination on the prediction of OS, both internal (n=457 and C-index is 0.79) and external validation (n=100 and C-index is 0.76). The median survival time of PSCC is 4 months, with 20.1% OS possibility in 5 years. Multivariate analysis identified patients of older age [hazard ratio (HR), 1.02; 95% confidence interval (CI): 1.01-1.04], larger size of neoplasm (HR, 1.01; 95% CI: 1.01-1.01), M1 (HR, 2.96; 95% CI: 2.17-4.04), N2 (HR, 2.55; 95% CI: 1.81-3.59) or N3 (HR, 2.99; 95% CI: 1.58-5.66), regional stages (HR, 2.11; 95% CI: 1.29-3.44) and distant stages (HR, 6.17; 95% CI: 3.83-9.94) had a lower OS possibility, while surgery (HR, 0.39; 95% CI: 0.28-0.53) and history of malignancy (HR, 0.68; 95% CI: 0.48-0.98) was protective factors for PSCC. PSCC survived longer with surgery performed instead of chemotherapy or radiotherapy. Conclusions: Patients of PSCC have a poor prognosis, and using the nomogram developed by this study can predict their 1-, 3- and 5-year OS probability. Surgery is a better choice for PSCC and more studies are necessary to find potential treatment like targeted therapy, programmed death-1 (PD-1) and programmed death ligand 1 (PD-L1).

Long non-coding RNA BZRAP1-AS1 functions in malignancy and prognosis for non-small-cell lung cancer.

Purpose: The function of BZRAP1-AS1 is unknown in lung cancer. We evaluated the clinicopathologic significance of BZRAP1-AS1, and its role in non-small-cell lung cancer (NSCLC) progression. Patient and methods: Sixty-three NSCLC patients from Beijing Chest Hospital were included. The expression of BZRAP1-AS1 was detected by real-time quantitative polymerase chain reaction (RT-qPCR) in tumor tissues and adjacent normal tissues. Then, the clinicopathological significance and prognostic value of BZRAP1-AS1 were analyzed by using our cohort and TCGA cohort. Finally, the effect of BZRAP1-AS1 on proliferation and motility of NSCLC cell lines were evaluated by cell growth assay, colony formation assay, xenograft tumorigenesis experiment in nude mice and transwell assays respectively. Results: Compared with adjacent normal tissues, BZRAP1-AS1 showed lower expression in NSCLC tumor tissues. As for the relationship between BZRAP1-AS1 and clinical characteristics, our results were consistent with those of TCGA data. BZRAP1-AS1 was lower in T1 than T2-T4 patients, N1-N3 than N0 patients. Low level BZRAP1-AS1 was related to shorter overall survival time (OS) in lung adenocarcinoma (LUAD), and poor first progression time (FP) in LUAD and lung squamous cell carcinoma (LUSC) patients. BZRAP1-AS1 was significantly associated with the prognosis of NSCLC patients. Overexpression of BZRAP1-AS1 inhibited proliferation and migration of H1299 and HCC827 cells. Conclusion: BZRAP1-AS1 expression decreases in tumor tissues with the increase of malignancy grades in NSCLC. BZRAP1-AS1 plays an anticancer role by inhibiting cell proliferation, invasion, and metastasis, and has a potential prognostic value in NSCLC. BZRAP1-AS1 may serve as a diagnostic marker and therapeutic target for NSCLC.

Long-Read Sequencing Annotation of the Transcriptome in DNA-PK Inactivated Cells.

The DNA-dependent protein kinase catalytic subunit (DNA-PKcs) with a Ku70/Ku80 heterodimer constitutes the intact DNA-PK kinase, which is an upstream component of the DNA repair machinery that signals the DNA damage, orchestrates the DNA repair, and serves to maintain genome integrity. Beyond its role in DNA damage repair, the DNA-PK kinase is also implicated in transcriptional regulation and RNA metabolism, with an illuminated impact on tumor progression and therapeutic responses. However, the efforts to identify DNA-PK regulated transcriptomes are limited by short-read sequencing to resolve the full complexity of the transcriptome. Therefore, we leveraged the PacBio Single Molecule, Real-Time (SMRT) Sequencing platform to study the transcriptome after DNA-PK inactivation to further underscore the importance of its role in diseases. Our analysis revealed additional novel transcriptome and complex gene structures in the DNA-PK inactivated cells, identifying 8,355 high-confidence new isoforms from 3,197 annotated genes and 523 novel genes. Among them, 380 lncRNAs were identified. We validated these findings using computational approaches and confirmatory transcript quantification with short-read sequencing. Several novel isoforms representing distinct splicing events have been validated through PCR experiments. Our analyses provide novel insights into DNA-PK function in transcriptome regulation and RNA metabolism.

Identification of solamargine as a cisplatin sensitizer through phenotypical screening in cisplatin-resistant NSCLC organoids.

Although Cisplatin (DDP) is a widely used first-line chemotherapy medication, DDP resistance is one of the main causes of treatment failure in advanced lung cancer. Therefore, it is urgent to identify DDP sensitizers and investigate the underlying molecular mechanisms. Here we utilized DDP-resistant organoids established from tumor biopsies of patients with relapsed lung cancers. In this study, we identified Solamargine as a potential DDP sensitizer through screening a natural product library. Mechanically, Solamargine induced G0/G1-phase arrest and apoptosis in DDP-resistant lung cancer cell lines. Gene expression analysis and KEGG pathway analysis indicated that the hedgehog pathway was suppressed by Solamargine. Moreover, Gli responsive element (GRE) reporter gene assay and BODIPY-cyclopamine binding assay showed that Solamargine inhibited the hedgehog pathway via direct binding to SMO protein. Interestingly, Solamargine and DDP showed a synergetic effect in inhibiting DDP-resistant lung cancer cell lines. Taken together, our work herein revealed Solamargine as a hedgehog pathway inhibitor and DDP-sensitizer, which might provide a new direction for further treatment of advanced DDP-resistant lung cancer patients.

Effect of Preoperative Thoracic Paravertebral Blocks on Emergence Agitation During Tracheal Extubation: A Randomized Controlled Trial.

Objective: This study aims to compare the effects of preoperative thoracic paravertebral blocks (TPVB) with intercoastal nerve blocks (ICNB) on emergence agitation (EA) during tracheal extubation in patients who underwent thoracoscopic lobectomy. Design Setting and Participants: A randomized clinical trial was conducted in patients undergoing thoracoscopic lobectomy at Beijing Chest Hospital between June 2019 and December 2020. Interventions: Patients were randomly assigned 1:1 to receive either ultrasound-guided preoperative TPVB or ICNB. Main Outcomes and Measures: The primary outcome was the occurrence of emergency agitation, which was evaluated by Aono's four-point scale (AFPS). Secondary outcomes included hemodynamics [mean arterial pressure (MAP) and heart rate (HR)]; and post-operative pain intensity [visual analog scale (VAS), Ramsay sedation score (RSS), and patient-controlled analgesia (PCA) demand times]. Results: Among the 100 patients aged 55-75 years old, 50 were randomized to each group; 97 patients completed the trial. Compared to the ICNB group, the occurrence of EA in the TPVB group was significantly lower [31.3% (15/48) vs. 12.2% (6/49), relative risk = 1.276, 95% CI: 1.02-1.60, P = 0.028]. For patients in the TPVB group, the MAP and HR at 5, 10, and 30 min after extubation were significantly lower; the intraoperative details including emergence time, extubation time, and consumption of sufentanil were significantly shorter than that in the ICNB group. Additionally, patients in the TPVB group showed significantly lower VAS at rest or coughing and significantly lower RSS at 60 and 240 min after extubation than patients in the ICNB group (all P < 0.05). Conclusion: Preoperative TPVB was associated with less EA during tracheal extubation when compared with ICNB in patients undergoing thoracoscopic lobectomy. Clinical Trial Registration: [http://www.chictr.org.cn/index.aspx], identifier [ChiCTR1900023852].

Re-evaluating the need for mediastinal lymph node dissection and exploring lncRNAs as biomarkers of N2 metastasis in T1 lung adenocarcinoma.

Background: Although a well-acknowledged component of curative surgery for lung cancer, investigators have recently questioned the need for mediastinal lymph node dissection (MLND) in early-stage lung cancer cases. As such, the accurate prediction of N2 stage prior to surgery has become increasingly critical. But diagnostic biomarkers predicting N2 metastases are deficient, which are urgently needed. Methods: We extracted the data of non-small cell lung cancer (NSCLC) patients whose clinical information and follow-up data are complete and without preoperative induction therapy from the Surveillance, Epidemiology, and End Results (SEER) database. The SEER program registries routinely collect demographic and clinic data on patients. And the prognostic differences were analyzed according to the presence or absence of MLND in their lung resection using the R package. Subsequently, the correlations between pN2 metastasis and clinical characteristics were analyzed. In parallel, the long non-coding RNAs (lncRNAs) associated with pN2 status were screened in The Cancer Genome Atlas (TCGA) database by expression difference analysis between pN0-N1 and pN2 patients using limma. Their diagnostic efficiency for detecting N2 metastases was evaluated using receiver operating characteristic (ROC) curves, and a combined diagnostic model was constructed using logistic regression and ROC curve analyses in lung adenocarcinoma (LUAD). Results: There were 16,772 patients in MLND group, and 2,699 cases in no-MLND group. The clinical data from SEER showed that the incidence of N2 metastasis was low in pT1 NSCLC (1,023/16,772, 6.10%), but the prognosis of no-MLND patients was poorer than those who underwent MLND (P<0.001, HR =1.605). Pathological N2 metastasis was correlated with age, histologic type, and tumor size. On the other hand, five lncRNAs (LINC00892, AC099522.2, LINC01481, SCAMP1-AS1, and AC004812.2) were screened and confirmed as potential diagnostic biomarkers for detecting N2 metastasis in pT1 LUAD. The AUC of the combined indicators was 0.857. Conclusions: MLND may be oncologically necessary for selected T1 NSCLC patients based on the metastasis incidence and prognosis. A diagnostic model combining LINC00892, AC099522.2, LINC01481, SCAMP1-AS1, and AC004812.2 expression levels may have the potential to be a diagnostic biomarker for detecting N2 metastasis in pT1 LUAD. This study suggests that MLND might be omitted in patients with lower expression level of this diagnostic model.

The Effects of Programmed Intermittent Paravertebral Bolus Infusion on Postoperative Analgesia in Patients Undergoing Video-Assisted Thoracoscopic Surgery: A Prospective, Randomized, Controlled Study.

OBJECTIVES: To compare the effects of programmed intermittent bolus infusion (PIBI), continuous thoracic paravertebral infusion (CTPI), and continuous intravenous infusion (CII) on postoperative analgesia in patients undergoing video-assisted thoracoscopic surgery (VATS). DESIGN: Prospective, randomized, controlled. SETTING: The operating room, post-anesthesia care unit, and patient ward of a university hospital. PARTICIPANTS: Ninety patients with American Society of Anesthesiologists (ASA) physical status Ι to II, aged 35-70 years, and scheduled for VATS. INTERVENTIONS: Postoperative analgesia was randomized to PIBI, CTPI, and CII. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the numeric rating scale (NRS) score at rest and during coughing at 1, 4, 24, and 48 hours after surgery. The secondary outcomes included the actual and effective numbers of patient-controlled analgesia (PCA), ropivacaine use, Ramsay sedation scale score, quality of recovery-15 (QoR-15) score, values of hemodynamic parameters at different periods, intraoperative consumption of anesthetic drugs, and postoperative adverse events. Postoperatively, the NRS score was reduced in the PIBI group compared with the CTPI and CII groups at rest and during coughing (p < 0.05). The number of PCAs was significantly lower in the PIBI group compared with the CTPI and CII groups (p < 0.05). The QoR-15 score noticeably increased in the PIBI group compared with the CTPI and CII groups (p = 0.001 and p = 0.000, respectively). CONCLUSIONS: PIBI outperformed CTPI and CII in inducing analgesia for postoperative pain in patients undergoing VATS.

Preclinical study of peripheral parenchymal lymphatic drainage in lung.

Background: This study aims to determine the regularity of sentinel lymph nodes of peripheral lung parenchyma and the lymphatic drainage between adjacent pulmonary segments in experimental animals. Methods: Thoracotomy was performed on 12 experimental Guizhou miniature pigs, and 1 mL methylene blue was injected into the superior segment of the lower lobe (S6) and the anterior segment of the upper lobe (S3), successively, to observe lymphatic drainage, in sentinel lymph nodes and the lymphatic drainage between adjacent segments. Results: A total of 161 lymphatic vessels were observed in 48 pulmonary segments, with an average of 3.4 lymphatic vessels per segment: RS6 (superficial 1.0±0.61, deep 2.5±1.00), RS3 (superficial 1.0±0.51, deep 2.0±1.07), LS6 (superficial 3.0±0.42, deep 1.0±0.38), LS3 (superficial 1.0±0.43, deep 2.0±0.62). There were significantly more lymphatic vessels in deep plexus than in superficial (p<0.01). As for sentinel lymph nodes, LS6 drained to the hilar, subcarinal and 4L lymph nodes; RS6 drained to the hilar and subcarinal lymph nodes; LS3 drained to the hilar and 4L lymph nodes; and RS3 drained to the hilar and 4R lymph nodes. In addition, methylene blue could drain from peripheral lung tissue of S3 and S6 directly to mediastinal lymph nodes through superficial plexuses. Lymphatic drainage regularity of S3 and S6 to adjacent pulmonary segments were also observed. The R6 rarely drained to the basal segment, while R3 could possibly drain to the posterior segment. Conclusion: The regularity of peripheral pulmonary parenchymal lymphatic drainage in experimental animals can provide a basis for the management of lymph nodes in pulmonary segmentectomy in humans, to a certain extent.

Subsegmentectomy versus segmentectomy resection for the treatment of operable patients with stage IA non-small cell lung cancer: A meta-analysis.

Background: There were new points of interest in performing subsegmentectomy and segmentectomy for patients with early stage non-small cell lung cancer (NSCLC). However, whether patients who underwent subsegmentectomy could obtain satisfactory clinical outcomes remains unclear. The present study aimed to compare the clinical outcomes and security of surgical procedures between subsegmentectomy and segmentectomy. Methods: A systematic review and meta-analysis was performed through five online databases to identify the included literatures which presented intact clinical outcome data among different surgical procedures. The included studies were evaluated based on precise and predefined inclusion criteria. Results: There were 4 published studies identified in this meta-analysis. A total of 325 patients who underwent subsegmentectomy and 904 patients who underwent segmentectomy were involved in this analysis. The duration of drainage [MD -0.19; 95%CI (-0.36, -0.02), p = 0.03] and postoperative hospital stay [MD -0.30; 95%CI (-0.58, -0.02), p = 0.009] of subsegmentectomy were significantly less than that of segmentectomy. There was no statistically significant difference among recurrence rate [OR 0.85; 95%CI (0.21, 3.42), p = 0.82], operation time, blood loss, incidence of complications [OR 0.83; 95%CI (0.58, 1.20), p = 0.33] between subsegmentectomy and segmentectomy in patients with stage IA NSCLC. Conclusion: The meta-analysis was firstly performed to compare perioperative outcomes among surgical procedures. The perioperative outcomes were comparable between subsegmentectomy and segmentectomy. Subsegmentectomy might be an alternative treatment for the deep tumor with size less than 1.5 cm and mainly composed of Ground Glass Opacity (GGO).

[Preliminary Efficacy Evaluation of Neoadjuvant Immunotherapy Combined with 
Chemotherapy in Resectable Non-small Cell Lung Cancer].

BACKGROUND: Preliminary researches conformed that neoadjuvant immunotherapy combined with chemotherapy had a significant short-term effect in resectable non-small cell lung cancer (NSCLC), but there were few clinical trials about neoadjuvant chemoimmunotherapy in China. We aimed to assess retrospectively the antitumour activity and safety of neoadjuvant chemoimmunotherapy for resectable stage Ib-IIIb NSCLC. METHODS: Twenty patients who had been diagnosed as stage Ib-IIIb NSCLC and received chemoimmunotherapy as neoadjuvant treatment between November 2019 and December 2020, in Beijing Chest Hospital, Capital Medical University were recruited. These patients received neoadjuvant treatment for 21 days as a cycle and antitumour activity and safety were evaluated every two cycles. RESULTS: Of 20 patients received neoadjuvant chemoimmunotherapy, 17 patients underwent surgical resection. 16 patients had R0 resection (no residual tumor resection) and 1 patient had R1 resection (microscopic residual tumor resection). Radiographic objective response rate (ORR) was 85.0% (4 complete response, 13 partial response). 5.0% (1/20) of patients had stable disease, and 10.0% (2/20) of patients had progression disease. The major pathologic response (MPR) was 47.1% (8/17), and complete pathologic response (CPR) was 29.4% (5/17). 1 case developed grade IV immune-related pneumonia (IRP) and 9 (45.0%) cases had grade III hematologic toxicity. CONCLUSIONS: Immunotherapy combined with chemotherapy as neoadjuvant therapy has a better efficiency and tolerable adverse effects for patients with resectable NSCLC in stage Ib-IIIb.

Clinical Significance of miR-183-3p and miR-182-5p in NSCLC and Their Correlation.

PURPOSE: Accumulating evidence has indicated that dysregulated microRNAs (miRNAs) are involved in cancer progression. In this study, we evaluated the clinicopathologic significance of miR-183-3p and miR-182-5p, and the role of miR-183-3p in non-small-cell lung cancer (NSCLC) progression. PATIENTS AND METHODS: Seventy-six NSCLC patients from Beijing Chest Hospital were included. The expression of miR-183-3p and miR-182-5p was evaluated by real-time quantitative polymerase chain reaction (RT-qPCR). Then, cell growth curve assays and colony formation assays were performed. Bioinformatics analysis of TCGA database was performed to explore the clinicopathological significance and prognostic value. RESULTS: miR-183-3p and miR-182-5p were significantly increased in NSCLC tumor tissues (both P < 0.0001) and were positively correlated (r = 0.8519, P < 0.0001). miR-183-3p (P = 0.0444) and miR-182-5p (P = 0.0132) were correlated with tumor size. In addition, miR-183-3p (P = 0.0135) and miR-182-5p (P = 0.0009) were upregulated in normal lung tissues from smokers. In vitro, miR-183-3p was correlated with cell proliferation. In addition, bioinformatics analysis indicated that miR-183-3p was correlated with poor prognosis (P = 0.0466) and tumor size (P = 0.0017). In addition, miR-183-3p was higher in lung squamous carcinoma (LUSC) tissue (P < 0.0001) than in lung adenocarcinoma (LUAD) tissue, and miR-183-3p was higher in the tumor tissue of smokers (P = 0.0053) than in that of nonsmokers. CONCLUSION: Upregulation of miR-183-3p and miR-182-5p may play an oncogenic role in NSCLC. miR-183-3p could be used as a potential prognostic biomarker and therapeutic target to manage lung cancer.

Acquisition of clofazimine resistance following bedaquiline treatment for multidrug-resistant tuberculosis.

OBJECTIVES: We described the prevalence of clofazimine (CFZ) resistance in a multidrug-resistant tuberculosis (MDR-TB) cohort in China. We also aimed to identify dynamic changes in CFZ susceptibility and its molecular mechanism after exposure to bedaquiline (BDQ) and/or CFZ. METHODS: The experimental settings were conducted based on our MDR-TB cohort receiving BDQ-containing regimens. Sequential isolates were obtained from patients. CFZ and BDQ susceptibility of isolates were determined using the minimum inhibitory concentration (MIC) method. The fragments of Rv0678 and pepQ were sequenced. RESULTS: A total of 277 patients infected with MDR-TB were included in our study. CFZ resistance was noted in 23 (23/277, 8.3%) isolates. The rate of acquired CFZ resistance (12/189, 6.3%) was significantly greater than that of primary resistance (11/88, 12.5%, P = 0.028). Out of 23 CFZ-resistant isolates, five (5/23) were BDQ-resistant, and the other 18 (18/23) were susceptible to BDQ. Of note, nine 9/23) out of 23 CFZ-resistant isolates had mutations within either target genes. Kaplan-Meier analysis demonstrated that the baseline CFZ resistance had no influence on time to culture conversion in our cohort (P = 0.828). Acquired CFZ resistance emerged in eight (8/94, 8.5%) patients during treatment for MDR-TB, including three patients receiving regimens without CFZ. CONCLUSIONS: Our results demonstrate the high rate of CFZ resistance among MDR-TB patients in China. Patients treated with BDQ-containing regimens achieve comparative culture conversion rate regardless of baseline CFZ susceptibility. The presence of acquired CFZ-resistance following BDQ treatment without known mutation indicates that other mechanisms conferring cross resistance to these two compounds may exist.

Copy number variation in plasma as a tool for lung cancer prediction using Extreme Gradient Boosting (XGBoost) classifier.

BACKGROUND: The main cause of cancer death is lung cancer (LC) which usually presents at an advanced stage, but its early detection would increase the benefits of treatment. Blood is particularly favored in clinical research given the possibility of using it for relatively noninvasive analyses. Copy number variation (CNV) is a common genetic change in tumor genomes, and many studies have indicated that CNV-derived cell-free DNA (cfDNA) from plasma could be feasible as a biomarker for cancer diagnosis. METHODS: In this study, we determined the possibility of using chromosomal arm-level CNV from cfDNA as a biomarker for lung cancer diagnosis in a small cohort of 40 patients and 41 healthy controls. Arm-level CNV distributions were analyzed based on z score, and the machine-learning algorithm Extreme Gradient Boosting (XGBoost) was applied for cancer prediction. RESULTS: The results showed that amplifications tended to emerge on chromosomes 3q, 8q, 12p, and 7q. Deletions were frequently detected on chromosomes 22q, 3p, 5q, 16q, 10q, and 15q. Upon applying a trained XGBoost classifier, specificity and sensitivity of 100% were finally achieved in the test group (12 patients and 13 healthy controls). In addition, five-fold cross-validation proved the stability of the model. Finally, our results suggested that the integration of four arm-level CNVs and the concentration of cfDNA into the trained XGBoost classifier provides a potential method for detecting lung cancer. CONCLUSION: Our results suggested that the integration of four arm-level CNVs and the concentration from of cfDNA integrated withinto the trained XGBoost classifier could become provides a potentially method for detecting lung cancer detection. KEY POINTS: Significant findings of the study: Healthy individuals have different arm-level CNV profiles from cancer patients. Amplifications tend to emerge on chromosome 3q, 8q, 12p, 7q and deletions tend to emerge on chromosome 22q, 3p, 5q, 16q, 10q, 15q. WHAT THIS STUDY ADDS: CfDNA concentration, arm 10q, 3q, 8q, 3p, and 22q are key features for prediction. Trained XGBoost classifier is a potential method for lung cancer detection.

An Overview of Tuberculosis-Designated Hospitals in China, 2009-2015: A Longitudinal Analysis of National Survey Data.

DESIGN: A national tuberculosis- (TB-) designated hospital survey was conducted in 2015 to identify significant changes since 2009 in implementation of TB-testing services within hospitals of various types and administrative levels in various regions in China. METHODS: In 2015, all TB-designated hospitals were required to complete questionnaires designed by the National Clinical Center for TB. Community hospitals also completed simplified questionnaires as part of the study. RESULTS: Overall, in 2015 there were 1685 TB-designated hospitals in China, consisting of 1335 (79.2%) county-level hospitals and 350 (20.8%) hospitals at the prefecture level and above. The percentage of counties with TB-designated hospitals in the western region (57.4%) was significantly lower than corresponding percentages for eastern and middle regions (70.3% and 96.5, respectively). Based on data recorded on hospital surveys in both 2009 and 2015, significant differences were noted between years in proportions of general hospitals with TB wards and of specialized infectious disease hospitals (P < 0.01). Of 1256 county-level laboratories conducting smear microscopy, only 979 (79%) performed external quality control evaluations of test results in 2015. For prefecture-level hospitals, 70% (234/334), 76% (155/203), and 67% (66/98) of hospitals obtained external quality control validations of smear microscopy, phenotypic DST, and molecular test results, respectively. CONCLUSIONS: Although China's health reform efforts have resulted in improved TB patient access to quality health care, more attention should be paid to balancing the distribution of medical facilities across different regions. In addition, laboratory capabilities and quality control systems should be strengthened to ensure delivery of high-quality laboratory services by TB-designated hospitals throughout China.

Epidemiology of Extrapulmonary Tuberculosis among Inpatients, China, 2008-2017.

We investigated the epidemiology of extrapulmonary tuberculosis (TB) among patients admitted to Beijing Chest Hospital, Beijing, China, during January 2008-December 2017. Of 19,279 hospitalized TB patients, 33.4% (6,433) had extrapulmonary TB and 66.6% (12,846) had pulmonary TB. The most frequent forms of extrapulmonary TB observed were skeletal TB (41.1%) and pleural TB (26.0%). Younger, female patients from rural areas were more likely to have extrapulmonary TB. However, patients with diabetes mellitus were less likely to have extrapulmonary TB compared with patients without diabetes. A higher proportion of multidrug-resistant (MDR) TB was observed among patients with extrapulmonary TB than among patients with pulmonary TB. We observed a large increase in MDR TB, from 17.3% to 35.7%, for pleural TB cases. The increasing rate of drug resistance among extrapulmonary TB cases highlights the need for drug susceptibility testing and the formulation of more effective regimens for extrapulmonary TB treatment.

Diagnostic value of multiple tumor-associated autoantibodies in lung cancer.

BACKGROUND: Lung cancer is the leading cause of cancer-related deaths. Survival rate improves significantly with early detection of lung cancer. Effective methods of early detection can reduce lung cancer mortality to a large extent as well as benefit the whole public health. The diagnostic value of one single marker is relatively low. Combined autoantibodies (AABs) can improve the sensitivity significantly rather than rely on one AAB and serve as good reservoir for early detection of lung cancer. PATIENTS AND METHODS: We designed three parts in our experiment. In training set we measured the expression levels of AABs in 100 non-small-cell lung cancer (NSCLC) patients and 60 healthy controls by using ELISA detection method. A blinded validation was subsequently performed in 254 NSCLC patients, 125 healthy controls, and 71 nodule patients. A prospective expansion set was performed to evaluate the diagnosis value of AABs combined detection. RESULTS: Both in training set and validation set, the concentrations of SOX2, GAGE 7, MAGE A1, and P53 in NSCLC group increased prominently when compared to the healthy group (P<0.05). The concentration of GBU4-5 in adenocarcinoma group was higher than in the squamous cell carcinoma (SCC) group (P<0.05); the PGP9.5, which was opposite, in SCC group was higher than in the adenocarcinoma group (P<0.05). The positive rate of each AAB did not show any bias with age, gender, smoking history, and tumor location. Most importantly, different choice of biomarkers led to different detection results. CONCLUSION: Our study confirmed the diagnostic value of tumor-associated AABs. They may be useful as latent tumor markers to facilitate the detection of early lung cancer.