Phosphorylation of PDHA by AMPK Drives TCA Cycle to Promote Cancer Metastasis.

Cancer metastasis accounts for the major cause of cancer-related deaths. How disseminated cancer cells cope with hostile microenvironments in secondary site for full-blown metastasis is largely unknown. Here, we show that AMPK (AMP-activated protein kinase), activated in mouse metastasis models, drives pyruvate dehydrogenase complex (PDHc) activation to maintain TCA cycle (tricarboxylic acid cycle) and promotes cancer metastasis by adapting cancer cells to metabolic and oxidative stresses. This AMPK-PDHc axis is activated in advanced breast cancer and predicts poor metastasis-free survival. Mechanistically, AMPK localizes in the mitochondrial matrix and phosphorylates the catalytic alpha subunit of PDHc (PDHA) on two residues S295 and S314, which activates the enzymatic activity of PDHc and alleviates an inhibitory phosphorylation by PDHKs, respectively. Importantly, these phosphorylation events mediate PDHc function in cancer metastasis. Our study reveals that AMPK-mediated PDHA phosphorylation drives PDHc activation and TCA cycle to empower cancer cells adaptation to metastatic microenvironments for metastasis.

Primary Mediastinal Large B-Cell Lymphoma Achieved by Non-Cautery Assisted Transbronchial Mediastinal Cryobiopsy.

Transbronchial mediastinal cryobiopsy is a novel sampling strategy that shows improved diagnostic utility for mediastinal lesions, particularly in rare tumors and benign disorders, as compared to standard endobronchial ultrasound-guided transbronchial needle aspiration. During this procedure, electrocautery incision is frequently needed to advance the cryoprobe through the airway into the mediastinal lesion, which however results in increased operative difficulty and prolonged procedural time. Here we present a case of mediastinal large B-cell lymphoma successfully diagnosed by transbronchial mediastinal cryobiopsy without cautery-induced airway incision.

Endobronchial Ultrasound-Guided Transbronchial Incision and Drainage in the Treatment of Mediastinal Abscess.

Mediastinal abscess, mostly resulting from esophageal perforation or cardiothoracic surgery, is a serious condition carrying high morbidity and mortality. Antibiotic therapy alone normally did not achieve a satisfactory outcome, due to poor circulation of abscess that hampers drug delivery. Surgical intervention for debridement and drainage is recommended, but it poses a high risk in patients with poor health status and could lead to various complications. Recent studies proposed endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) as an effective alternative to surgery; however, repeated TBNA procedures are usually needed for complete clearance of the lesion, thus causing increased patient suffering and medical expenses. Here, we present the first case of successful application of EBUS-guided transbronchial incision and drainage, which provides a novel, safe, and effective treatment for patient with mediastinal abscess unwilling or unsuitable to undergo surgical intervention.

MicroRNA profile of tumorigenic cells during carcinogenesis of lung adenocarcinoma.

To obtain microRNA (miRNA) profile and clarify their biological function in tumorigenic Sca-1(+) CD34(+) cells during carcinogenesis of lung adenocarcinoma. After intranasal infection with recombinant Adeno-Cre viruses (AdV-Cre), lung adenocarcinoma was identified pathologically in Lox-stop-lox Kras (LSL-Kras) G12D mice. Sca-1(+) CD34(+) cells were sorted by flow cytometry and tested for tumor-initiating ability, self-renewal and tumorigenicity. MiRNA profiles were obtained using microarray and further confirmed by real-time RT-PCR (qRT-PCR). MiRNA functions were predicted bioinformatically, and miR-294 function was verified to explore its role in tumor migration and invasion. Lung adenocarcinoma was induced in LSL-Kras G12D mice within 30 days. In vivo, the tumorigenicity of Sca-1(+) CD34(+) cells was 25 times stronger than Sca-1(-) CD34(-) cells. During tumorigenesis of lung adenocarcinoma, the expression of 145 miRNAs in Sca-1(+) CD34(+) cells increased and 72 miRNAs decreased (P < 0.01). Four successively up-regulated miRNAs (miR-15a*, miR-203, miR-294 and miR-295*) and three successively down-regulated ones (miR-19b, miR-483 and miR-615-5p) were identified. Among them, miR-294 could constitutively bind to 3'-UTR of matrix metalloproteinase 3 (MMP3), and down-regulate MMP3 protein expression. MiR-294 also significantly inhibited migration and invasion of Lewis lung cancer cells. MiRNAs are characteristically expressed in tumor-initiating Sca-1(+) CD34(+) cells of lung adenocarcinoma, and may play important roles during the carcinogenesis of lung adenocarcinoma.

Resveratrol-4-O-D-(2'-galloyl)-glucopyranoside isolated from Polygonum cuspidatum exhibits anti-hepatocellular carcinoma viability by inducing apoptosis via the JNK and ERK pathway.

Resveratrol-4-O-D-(2'-galloyl)-glucopyranoside (RESG) is one of the active compounds isolated from Polygonum cuspidatum. The purpose of our present study was to investigate the anti-hepatocellular carcinoma effect of RESG in vitro and in vivo, and the possible mechanisms in vitro. In vitro, our results showed that RESG could significantly inhibit the human hepatocellular carcinoma viability in the MTT assay, in a dose- and time-dependent manner. Furthermore, our results demonstrated that RESG could induce SMMC-7721 cell apoptosis and activate caspases 3 and caspases 9 by using Annexin V-FITC staining and western blot, respectively. In vivo, RESG also showed efficacy in SMMC-7721 xenograft model in nude mice, and further molecule mechanisms were investigated in vitro. The results showed that RESG up-regulated the p-JNK expressions, whereas it down-regulated the p-ERK expressions. Above results demonstrated that RESG is a potential therapeutic agent for hepatocellular carcinoma via JNK and ERK pathway to induce apoptosis. Our finding provided a basis for further development of RESG as an anticancer agent.

NK cell transfer overcomes resistance to PD-(L)1 therapy in aged mice.

BACKGROUND: Cancer is the leading cause of death among older adults. Although the integration of immunotherapy has revolutionized the therapeutic landscape of cancer, the complex interactions between age and immunotherapy efficacy remain incompletely defined. Here, we aimed to elucidate the relationship between aging and immunotherapy resistance. METHODS: Flow cytometry was performed to evaluate the infiltration of immune cells in the tumor microenvironment (TME). In vivo T cell proliferation, cytotoxicity and migration assays were performed to evaluate the antitumor capacity of tumor antigen-specific CD8+ T cells in mice. Real-time quantitative PCR (qPCR) was used to investigate the expression of IFN-γ-associated gene and natural killer (NK)-associated chemokine. Adoptive NK cell transfer was adopted to evaluate the effects of NK cells from young mice in overcoming the immunotherapy resistance of aged mice. RESULTS: We found that elderly patients with advanced non-small cell lung cancer (aNSCLC) aged ≥ 75 years exhibited poorer progression-free survival (PFS), overall survival (OS) and a lower clinical response rate after immunotherapy. Mechanistically, we showed that the infiltration of NK cells was significantly reduced in aged mice compared to younger mice. Furthermore, the aged NK cells could also suppress the activation of tumor antigen-specific CD8+ T cells by inhibiting the recruitment and activation of CD103+ dendritic cells (DCs). Adoptive transfer of NK cells from young mice to aged mice promoted TME remodeling, and reversed immunotherapy resistance. CONCLUSION: Our findings revealed the decreased sensitivity of elderly patients to immunotherapy, as well as in aged mice. This may be attributed to the reduction of NK cells in aged mice, which inhibits CD103+ DCs recruitment and its CD86 expression and ultimately leads to immunotherapy resistance.

A real-world retrospective study of incidence and associated factors of endocrine adverse events related to PD-1/PD-L1 inhibitors.

Background: The adverse events (AEs) related to immune checkpoint inhibitors (ICIs) have been mostly described in clinical trials, however, such trials are restricted to selection criteria and the results cannot wholly represent the real-world setting. We aimed to evaluate the real-world endocrine AEs associated with programmed death receptor-1/programmed death ligand-1 (PD-1/PD-L1) inhibitors in Chinese population. Methods: This retrospective study included cancer patients who were treated with PD-1/PD-L1 inhibitors between January 2018 and December 2020 at Xinqiao Hospital, the Third Military Medical University. The information of 581 patients was reviewed, and data on clinical characteristics, PD-1/PD-L1 use, occurrence of endocrine AEs, and response to PD-1 blockade treatment were collated. The definition of endocrine AEs relied on diagnostic tests. Fisher's exact test or Pearson's chi-squared test was used to analyze the associations between endocrine variables and several categorical variables. Multivariate analyses were performed using a logistic regression model. Results: Endocrine AEs were observed in 116 of the 581 patients (20.0%). The median time to onset of endocrine AEs was approximately 12 weeks. Pembrolizumab was associated with a significantly higher incidence of endocrine AEs compared to other anti-PD-1 agents (38.5%; P=0.0002); PD-1/PD-L1 inhibitor treatment combined with antiangiogenic therapy or with two other therapies (chemotherapy and antiangiogenic therapy) was associated with a significantly increased occurrence of endocrine AEs, compared to PD-1 blockade treatment alone (41.2%; P=0.015), both based on multivariate analysis. Patients who developed endocrine AEs had significantly higher overall response rates (ORRs; 33.3% vs. 23.1%, P=0.045) and disease control rates (DCRs; 91.1% vs. 79.1%, P=0.008) compared to patients without endocrine AEs. In multivariate analysis, endocrine AEs remained an independent factor for both ORR (OR: 1.764, 95% CI: 1.052-2.957, P=0.031) and DCR (OR: 2.896, 95% CI: 1.324-6.332, P=0.008) after adjusting for the confounding factors. Conclusions: A real-world Chinese population receiving PD-1/PD-L1 treatment, pembrolizumab administrated and triple therapy treatment modalities had a higher incidence of endocrine AEs. Patients who developed endocrine AEs demonstrated a favorable response to PD-l blockade treatment.

Identification of the shared gene signatures and molecular mechanisms between multiple sclerosis and non-small cell lung cancer.

Introduction: The association between multiple sclerosis (MS) and non-small cell lung cancer (NSCLC) has been the subject of investigation in clinical cohorts, yet the molecular mechanisms underpinning this relationship remain incompletely understood. To address this, our study aimed to identify shared genetic signatures, shared local immune microenvironment, and molecular mechanisms between MS and NSCLC. Methods: We selected multiple Gene Expression Omnibus (GEO) datasets, including GSE19188, GSE214334, GSE199460, and GSE148071, to obtain gene expression levels and clinical information from patients or mice with MS and NSCLC. We employed Weighted Gene Co-expression Network Analysis (WGCNA) to investigate co-expression networks linked to MS and NSCLC and used single-cell RNA sequencing (scRNA-seq) analysis to explore the local immune microenvironment of MS and NSCLC and identify possible shared components. Results: Our analysis identified the most significant shared gene in MS and NSCLC, phosphodiesterase 4A (PDE4A), and we analyzed its expression in NSCLC patients and its impact on patient prognosis, as well as its molecular mechanism. Our results demonstrated that high expression of PDE4A was associated with poor prognoses in NSCLC patients, and Gene Set Enrichment Analysis (GSEA) revealed that PDE4A is involved in immune-related pathways and has a significant regulatory effect on human immune responses. We further observed that PDE4A was closely linked to the sensitivity of several chemotherapy drugs. Conclusion: Given the limitation of studies investigating the molecular mechanisms underlying the correlation between MS and NSCLC, our findings suggest that there are shared pathogenic processes and molecular mechanisms between these two diseases and that PDE4A represents a potential therapeutic target and immune-related biomarker for patients with both MS and NSCLC.

Feasibility of omitting the clinical target volume under PET-CT guidance in unresectable stage III non-small-cell lung cancer: A phase II clinical trial.

BACKGROUND: This clinical trial aims at investigate the feasibility of CTV-omitted, positron-emission tomography computed tomography (PET-CT) combined with intensity-modulated radiation therapy (IMRT) for unresectable stage III NSCLC. METHODS AND MATERIALS: This was a single-center, phase II clinical trial initiated in July 2016. Patients with unresectable stage III NSCLC undergoing routine IMRT were randomly enrolled into the study group (CTV-omitted under PET-CT guidance) and the control group (CTV-delineated). Patients received platinum-based dual-drug concurrent chemoradio therapy. In the study group, the PGTV dose was 60 Gy given in 30 daily 2 Gy fractions; in the control group, the PCTV dose was 54 Gy given in 30 daily 1.8 Gy fractions, and the PGTV dose was 60 Gy given in 30 daily 2 Gy fractions. The primary endpoint was the incidence of radiation respiratory events or esophagitis with grade 3 or higher. The secondary endpoints included objective response rate (ORR), locate control rate, progression-free survival (PFS), failure pattern and overall survival (OS). RESULTS: A total of 90 patients were enrolled between July 2016 and March 2019. The incidence of radiation respiratory events or esophagitis with grade 3 or higher was 11.1 % in the study group, significantly lower than the rate of 28.9 % in the control group (P = 0.035), basically due to the reduced irradiated volumes of the lungs and esophagus in the study group. The median PFS was 9.0 months versus 10.0 months (P = 0.597), and the median OS 31.0 months versus 26.0 months (P = 0.489) in the study group and the control group, respectively. The failure pattern was not significantly different between the two groups (P = 0.826). CONCLUSION: Omitting the CTV under PET-CT guidance has high feasibility to reduce severe radiation associated toxicity in IMRT for unresectable stage III NSCLC, without compromising the efficacy.

Transbronchial needle aspiration combined with cryobiopsy in the diagnosis of mediastinal diseases: a multicentre, open-label, randomised trial.

BACKGROUND: Transbronchial mediastinal cryobiopsy is a novel sampling technique for mediastinal disease. Despite the possibility of lung cancer misdiagnosis, the improved diagnostic yield of this approach for non-lung-cancer lesions compared with standard endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) highlights its diagnostic potential as a complementary technique to conventional biopsy. We aimed to evaluate the safety profile and added value of the combined use of transbronchial mediastinal cryobiopsy and standard EBUS-TBNA for the diagnosis of mediastinal diseases. METHODS: We conducted an open-label, randomised trial at three hospital sites in Europe and Asia. Eligible patients were aged 15 years or older, with at least one mediastinal lesion of 1 cm or longer in the short axis that required diagnostic bronchoscopy. Participants were randomly assigned (1:1) using a block randomisation scheme generated by a computer (block size of four participants based on a random table from an independent statistician) to the combined use of EBUS-TBNA and transbronchial mediastinal cryobiopsy (combined group) or EBUS-TBNA alone (control group). Because of the nature of the intervention, neither participants nor investigators were masked to group assignment. The coprimary outcomes were differences in procedure-related complications and diagnostic yield (defined as the proportion of participants for whom mediastinal biopsy led to a definitive diagnosis), assessed in the full analysis set, including all the patients who met the eligibility criteria and had a biopsy. A fully paired, intraindividual diagnostic analysis in participants who had both needle aspiration and mediastinal cryobiopsy was conducted, in addition to interindividual comparisons. This trial is now complete and is registered with ClinicalTrials.gov, NCT04572984. FINDINGS: Between Oct 12, 2020, and Sept 9, 2021, 297 consecutive patients were assessed for eligibility and 271 were enrolled and randomly assigned to the combined group (n=136) or the control group (n=135). The addition of cryobiopsy to standard sampling significantly increased the overall diagnostic yield for mediastinal lesions, as shown by both interindividual (126 [93%] of 136 participants in the combined group vs 109 [81%] of 135 in the control group; risk ratio [RR] 1·15 [95% CI 1·04-1·26]; p=0·0039) and intraindividual (126 [94%] of 134 vs 110 [82%] of 134; RR 1·15 [95% CI 1·05-1·25]; p=0·0026) analyses. In subgroup analyses in the intraindividual population, diagnostic yields were similar for mediastinal metastasis (68 [99%] of 69 participants in the combined group vs 68 [99%] of 69 in the control group; RR 1·00 [95% CI 0·96-1·04]; p=1·00), whereas the combined approach was more sensitive than standard needle aspiration in benign disorders (45 [94%] of 48 vs 32 [67%] of 48; RR 1·41 [95% CI 1·14-1·74]; p=0·0009). The combined approach also resulted in an improved suitability of tissue samples for molecular and immunological analyses of non-small-cell lung cancer. The incidence of adverse events related to the biopsy procedure did not differ between trial groups, as grade 3-4 airway bleeding occurred in three (2%) patients in the combined group and two (1%) in the control group (RR 0·67 [95% CI 0·11-3·96]; p=1·00). There were no severe complications causing death or disability. INTERPRETATION: The addition of mediastinal cryobiopsy to standard EBUS-TBNA resulted in a significant improvement in diagnostic yield for mediastinal lesions, with a good safety profile. These data suggest that this combined approach is a valid first-line diagnostic tool for mediastinal diseases. FUNDING: National Natural Science Foundation of China.

CD200+ cytotoxic T lymphocytes in the tumor microenvironment are crucial for efficacious anti-PD-1/PD-L1 therapy.

Anti-PD-1/PD-L1 therapy, either by anti-PD-1 antibody or anti-PD-L1 antibody, has efficacy by reinvigorating tumor-infiltrating CD8+ T cells in a subset of patients with cancer, but it has unequal effects on heterogeneous CD8+ T cell populations. Hence, the subset crucial to efficacious PD-1 blockade therapy remains elusive. Here, we found an increase in tumor-infiltrating CD200+ cytotoxic T lymphocytes (CTLs) upon PD-1/PD-L1 blockade, with higher proportions of CD200+ T cells positively related to a favorable clinical outcome to anti-PD-1/PD-L1 therapy in three independent cohorts of patients with cancer. Using multiple mouse tumor models, we demonstrated that CD200+ CTLs are essential for efficacious anti-PD-L1 therapy. Mechanistically, we observed a unique chromatin landscape in CD200+ CTLs and found that these cells are enriched for tumor antigen-specific CTLs and have antitumor effector functions. Coinoculation of CD200+ CTLs with tumor cells led to robust tumor regression in two transplanted mouse models. Clinically, we found that infiltration of CD200+ CTLs into tumors could predict immunotherapy efficacy in six patient cohorts. Together, our findings reveal that CD200+ CTLs in the tumor microenvironment are crucial for efficacious anti-PD-1/PD-L1 therapy and could serve as a predictor of successful immunotherapy in the clinic.

Novel molecular beacons to monitor microRNAs in non-small-cell lung cancer.

Lung cancer is the leading cause of cancer death worldwide. There is no effective early diagnostic technology for lung cancer. microRNAs (miRNAs) are noncoding RNA molecules which regulate the process of cell growth and differentiation in human cancers. Hsa-miR-155 (miR-155), highly expressed in non-small-cell lung cancer (NSCLC), can be used as a diagnostic marker for NSCLC. Dynamic observation of miR-155 is critical to diagnose NSCLC. A novel molecular beacon (MB) of miR-155 was designed to image the expression of miR-155 in NSCLC. Then miR-155 was detected in vitro by laser confocal microscopy and in vivo by stereomicroscope imaging system, respectively. The present study demonstrated that intracellular miR-155 could be successfully and quickly detected by novel miR-155 MBs. As a noninvasive monitoring approach, MBs could be used to diagnose lung cancer at early stage through molecular imaging.

SIRPγ-expressing cancer stem-like cells promote immune escape of lung cancer via Hippo signaling.

Cancer stem-like cells (CSLCs) acquire enhanced immune checkpoint responses to evade immune cell killing and promote tumor progression. Here we showed that signal regulatory protein γ (SIRPγ) determined CSLC properties and immune evasiveness in a small population of lung adenocarcinoma (LUAD) cancer cells. A SIRPγhi population displayed CSLC properties and transmitted the immune escape signal through sustaining CD47 expression in both SIRPγhi and SIRPγlo/- tumor cells. SIRPγ bridged MST1 and PP2A to facilitate MST1 dephosphorylation, resulting in Hippo/YAP activation and leading to cytokine release by CSLCs, which stimulated CD47 expression in LUAD cells and consequently inhibited tumor cell phagocytosis. SIRPγ promoted tumor growth and metastasis in vivo through YAP signaling. Notably, SIRPγ targeting with genetic SIRPγ knockdown or a SIRPγ-neutralizing antibody inhibited CSLC phenotypes and elicited phagocytosis that suppressed tumor growth in vivo. SIRPG was upregulated in human LUAD and its overexpression predicted poor survival outcome. Thus, SIRPγhi cells serve as CSLCs and tumor immune checkpoint-initiating cells, propagating the immune escape signal to the entire cancer cell population. Our study identifies Hippo/YAP signaling as the first mechanism by which SIRPγ is engaged and reveals that targeting SIRPγ represents an immune- and CSLC-targeting strategy for lung cancer therapy.

The effects of artesunate on the expression of EGFR and ABCG2 in A549 human lung cancer cells and a xenograft model.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer death worldwide. Clinical and laboratory studies have suggested that multi-targeting approaches against neoplastic cells could help to increase patient survival and might reduce the emergence of cells that are resistant to single-target inhibitors. Artesunate (ART) is one of the most potent and rapidly acting antimalarial agents known, and it also exerts a profound cytotoxic activity toward cancer cells and reverses multi-drug resistance. In the present study, we found that artesunate inhibited NSCLC A549 cell growth and proliferation, induced apoptosis and suppressed tumor growth in a dose-dependent manner in A549 cells and a mouse xenograft model. Furthermore, artesunate down-regulated the expression of epidermal growth factor receptor (EGFR), Akt and ATP-binding cassette subfamily G member 2 (ABCG2) at the mRNA and protein levels in vitro and in vivo. In conclusion, artesunate is an effective anti-cancer drug that may enhance the effectiveness of other anticancer drugs and may reverse multi-drug resistance by suppressing the transcription of ABCG2, which inhibits drug efflux.

Joint Depth and Defocus Estimation From a Single Image Using Physical Consistency.

Estimating depth and defocus maps are two fundamental tasks in computer vision. Recently, many methods explore these two tasks separately with the help of the powerful feature learning ability of deep learning and these methods have achieved impressive progress. However, due to the difficulty in densely labeling depth and defocus on real images, these methods are mostly based on synthetic training dataset, and the performance of learned network degrades significantly on real images. In this paper, we tackle a new task that jointly estimates depth and defocus from a single image. We design a dual network with two subnets respectively for estimating depth and defocus. The network is jointly trained on synthetic dataset with a physical constraint to enforce the physical consistency between depth and defocus. Moreover, we design a simple method to label depth and defocus order on real image dataset, and design two novel metrics to measure accuracies of depth and defocus estimation on real images. Comprehensive experiments demonstrate that joint training for depth and defocus estimation using physical consistency constraint enables these two subnets to guide each other, and effectively improves their depth and defocus estimation performance on real defocused image dataset.

The Efficacy and Safety of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Combined With Thymosin in Advanced Non-Small Cell Lung Cancer Patients Harboring Active Epidermal Growth Factor Receptor Mutations.

OBJECTIVE: To explore the efficacy and safety of EGFR-TKI combined with thymosin therapy in advanced non-small cell lung cancer (NSCLC) patients harboring active EGFR mutations. METHODS: Patients confirmed as advanced NSCLC with active EGFR mutations were recruited from August 2008 to July 2018 retrospectively. Patients treated with EGFR-TKI were classified as the EGFR-TKI group. And those received EGFR-TKI and thymosin therapy were designated as the EGFR-TKI plus thymosin group. The primary endpoint was progression-free survival (PFS). The secondary endpoints included overall survival (OS), tumor response and adverse effects. RESULTS: The median PFS was significantly longer in EGFR-TKI plus thymosin group than that in EGFR-TKI group (14.4 months vs. 9.2 months; HR=0.433, 95% CI 0.322 - 0.582, P<0.0001). The median OS was also prolonged in EGFR-TKI plus thymosin group than that in EGFR-TKI group (29.5 months vs. 19.8 months; HR=0.430, 95% CI 0.319 - 0.580, P<0.0001). The objective response rate in EGFR-TKI plus thymosin group and EGFR-TKI group were 60.0% versus 60.8% (P=0.918). The disease control rate was 96.9% in EGFR-TKI plus thymosin group and 97.7% in EGFR-TKI group (P=1.000). There were no significant differences in adverse effects between the two groups. The number of CD3+T cells in peripheral blood decreased significantly after treatment including both CD3+CD4+T and CD3+CD8+T subsets in EGFR-TKI group, but not in EGFR-TKI plus thymosin group. CONCLUSIONS: Combination of EGFR-TKI and thymosin can significantly prolong the PFS and OS compared with EGFR-TKI monotherapy without more adverse events, which offers a new strategy in clinic.

Mutational burden and chromosomal aneuploidy synergistically predict survival from radiotherapy in non-small cell lung cancer.

Therapeutic radiation can result in substantially different survival outcomes for patients with non-small cell lung cancer (NSCLC). Measures for identification of patients who can benefit most throughout radiotherapy remain limited. In this retrospective study, survival analysis was performed based on a discovery cohort from TCGA and a validation cohort from three independent hospitals. Tumor mutational burden (TMB) and chromosomal aneuploidy (ANE) were derived from the whole exome sequencing (WES) data from treatment-naïve tumors. Integrated risk scores were derived from TMB and ANE by a multivariate Cox proportional hazards model. TCGA reveal that TMB and ANE are associated positively and negatively, respectively, with survival throughout radiotherapy. Additionally, the synergistically predictive significance of these two genomic alterations, in differing responders and non-responders to radiotherapy is identified. These biomarkers may have clinical potential to improve personalized treatment management by rationally identifying highly likely responders to therapeutic radiation in patients with NSCLC.

Somatosensory stimulation treatments for postoperative analgesia of mixed hemorrhoids: Protocol for a systematic review and network meta-analysis.

BACKGROUND: Pain after hemorrhoidal surgery bothers both clinicians and patients. Somatosensory stimulation treatments have shown promising effect on the pain after hemorrhoidal surgery, but the comparative effectiveness between them has not been studied. We aim to determine the relative effectiveness among these treatments on pain relief after hemorrhoidal surgery by using network meta-analysis. METHOD: We will search the following electronic databases: MEDLINE, EMBASE, the Cochrane library, Chinese Biomedicine database (CBM), China National Knowledge Infrastructure (CNKI). We will include randomized controlled trials (RCTs) that examine the effect of somatosensory stimulation treatments on pain after hemorrhoidal surgery. The primary outcome will be the responder rate after treatment. The secondary outcomes will include the assessments with pain intensity scales (visual analog scale, numeric rating scale, or other scales) on day 1 to 7 after surgery. Two independent reviewers will extract needed information from eligible trials using standardized electronic forms. Network meta-analysis will be performed using a frequentist framework based on electrical network theory. The relative effectiveness of the treatments will be ranked by using P score, which is the mean probability of a treatment ranking the best in all treatments. Meta-regression will be performed to assess the impact of surgery type, anesthesia methods, and funding source on the treatment ranking. The quality of the eligible RCTs will be evaluated by the Cochrane risk of bias tool. ETHICS AND DISSEMINATION: The result of this network meta-analysis will clarify which is the relatively best somatosensory-stimulation treatment in relieving postoperative pain caused by hemorrhoidal surgery, and the review will, therefore, guide the management of postoperative pain after hemorrhoidal surgery for clinicians and patients. This review does not require ethical approval and will be reported in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: PROSPERO CRD42018115558.