Inhibition of NF-κB signaling unveils novel strategies to overcome drug resistance in cancers.

Drug resistance in cancer remains a major challenge in oncology, impeding the effectiveness of various treatment modalities. The nuclear factor-kappa B (NF-κB) signaling pathway has emerged as a critical player in the development of drug resistance in cancer cells. This comprehensive review explores the intricate relationship between NF-κB and drug resistance in cancer. We delve into the molecular mechanisms through which NF-κB activation contributes to resistance against chemotherapeutic agents, targeted therapies, and immunotherapies. Additionally, we discuss potential strategies to overcome this resistance by targeting NF-κB signaling, such as small molecule inhibitors and combination therapies. Understanding the multifaceted interactions between NF-κB and drug resistance is crucial for the development of more effective cancer treatment strategies. By dissecting the complex signaling network of NF-κB, we hope to shed light on novel therapeutic approaches that can enhance treatment outcomes, ultimately improving the prognosis for cancer patients. This review aims to provide a comprehensive overview of the current state of knowledge on NF-κB and its role in drug resistance, offering insights that may guide future research and therapeutic interventions in the fight against cancer.

Integrative Analysis of Bioinformatics and Machine Learning Algorithms Identifies a Novel Diagnostic Model Based on Costimulatory Molecule for Predicting Immune Microenvironment Status in Lung Adenocarcinoma.

Costimulatory molecules are an indispensable signal for activating immune cells. However, the features of many costimulatory molecule genes (CMGs) in lung adenocarcinoma (LUAD) are poorly understood. This study systematically explored expression patterns of CMGs in the tumor immune microenvironment (TIME) status of patients with LUAD. Their expression profiles were downloaded from The Cancer Genome Atlas and the Gene Expression Omnibus databases. Two robust TIME subtypes ("hot" and "cold") were classified by K-means clustering and estimation of stromal and immune cells in malignant tumor tissues using expression data. The "hot" subtype presented higher infiltration in activated immune cells and enrichments in the immune cell receptor signaling pathway and adaptive immune response. Three CMGs (CD80, LTB, and TNFSF8) were screened as final diagnostic markers by means of Least Absolute Shrinkage Selection Operator and Support Vector Machine-Recursive Feature Elimination algorithms. Accordingly, the diagnostic nomogram for predicting individualized TIME status showed satisfactory diagnostic accuracy in The Cancer Genome Atlas training cohort as well as GSE31210 and GSE180347 validation cohorts. Immunohistochemistry staining of 16 specimens revealed an apparently positive correlation between the expression of CMG biomarkers and pathologic response to immunotherapy. Thus, this diagnostic nomogram provided individualized predictions in TIME status of LUAD patients with good predictive accuracy, which could serve as a potential tool for identifying ideal candidates for immunotherapy.

Identification and Validation of Serum CST1 as a Diagnostic Marker for Differentiating Early-Stage Non-Small Cell Lung Cancer from Pulmonary Benign Nodules.

BACKGROUND: Effective means for early diagnosis are imperative to reduce death rate of non-small cell lung cancer (NSCLC) patients. We aimed to find out high-performance serologic markers to distinguish early-stage NSCLC patients from benign pulmonary nodule patients and healthy controls (HC). Cystatin-SN (CST1) is an active cysteine protease inhibitor of the CST superfamily, involving in the processes of inflammation and tumorigenesis. This is the first exploration of the diagnostic and prognostic values of serum CST1 in NSCLC. METHODS: We analyzed the transcriptome data from The Cancer Genome Atlas and the Gene Expression Omnibus database, screened biomarkers for NSCLC, and verified the candidate markers via the ONCOMINE database. Then, we performed ELISA, western blotting, and immunohistochemistry analysis to detect the expression levels of CST1 in NSCLC cell lines, tumor tissues, and serum samples of clinical cohorts. RESULTS: We identified 3 up-regulated secreted protein-encoding genes, validated the expression levels of CST1 in NSCLC tumor tissues and cell lines, and found that serum CST1 levels of NSCLC (4289 ± 2405 pg/mL) were significantly higher than those of PBN patients (1558 ± 441 pg/mL, P < .0001) and healthy controls (1529 ± 416 pg/mL, P < .0001). The AUC of the combination of CST1, Cytokeratin 19 fragment (Cyfra21-1), and Carcinoembryonic antigen (CEA) for distinguishing early-stage NSCLC from PBN/HC was as high as .914/0.925. Furthermore, our results suggested that the NSCLC patient with low serum CST1 level had a better survival rate. CONCLUSIONS: Serum CST1 may serve as a novel diagnostic marker for differentiating early-stage NSCLC from PBN and HC, and could be used as a prognosis predictor in NSCLC patients.

Modelling soil salinity effects on salt water uptake and crop growth using a modified denitrification-decomposition model: A phytoremediation approach.

Soil salinization is a widespread problem affecting global food production. Phytoremediation is emerging as a viable and cost-effective technology to reclaim salt-affected soil. However, its efficiency is not clear due to the uncertainty of plant responses in saline soils. The main objective of this paper is to propose a phytoremediation dynamic model (PDM) for salt-affected soil within the process-based biogeochemical denitrification-decomposition (DNDC) model. The PDM represents two salinity processes of phytoremediation: plant salt uptake and salt-affected biomass growth. The salt-soil-plant interaction is simulated as a coupled mass balance equation of water and salt plant uptake. The salt extraction ability by plant is a combination of salt uptake efficiency (F) and transpiration rate. For water filled pore space (WFPS), the statistical measures RMSE, MAE, and R2 during the calibration period are 2.57, 2.14, and 0.49, and they are 2.67, 2.34, and 0.56 during the validation period, respectively. For soil salinity, RMSE, MAE, and R2 during the calibration period are 0.02, 0.02, and 0.92, and 0.06, 0.04, and 0.68 during the validation period, respectively, which are reasonably good for further scenario analysis. Over the four years, cumulative salt uptake varied based on weather conditions. At the optimal salt uptake efficiency (F = 20), cumulative salt uptake from soil was 16-90% for alfalfa, 11-70% for barley, and 10-80% for spring wheat. While at the lowest salt uptake efficiency (F = 40), cumulative salt uptake was nearly zero for all crops. Although barley has the highest peak transpiration flux, alfalfa and spring wheat have greater cumulative salt uptake because their peak transpiration fluxes occurred more frequently than in barley. For salt-tolerant crops biomass growth depends on their threshold soil salinity which determines their ability to take up salt without affecting biomass growth. In order to phytoremediate salt-affected soil, salt-tolerant crops having longer duration of crop physiological stages should be used, but their phytoremediation effectiveness will depend on weather conditions and the soil environment.

Sintilimab plus a bevacizumab biosimilar (IBI305) versus sorafenib in unresectable hepatocellular carcinoma (ORIENT-32): a randomised, open-label, phase 2-3 study.

BACKGROUND: China has a high burden of hepatocellular carcinoma, and hepatitis B virus (HBV) infection is the main causative factor. Patients with hepatocellular carcinoma have a poor prognosis and a substantial unmet clinical need. The phase 2-3 ORIENT-32 study aimed to assess sintilimab (a PD-1 inhibitor) plus IBI305, a bevacizumab biosimilar, versus sorafenib as a first-line treatment for unresectable HBV-associated hepatocellular carcinoma. METHODS: This randomised, open-label, phase 2-3 study was done at 50 clinical sites in China. Patients aged 18 years or older with histologically or cytologically diagnosed or clinically confirmed unresectable or metastatic hepatocellular carcinoma, no previous systemic treatment, and a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 were eligible for inclusion. In the phase 2 part of the study, patients received intravenous sintilimab (200 mg every 3 weeks) plus intravenous IBI305 (15 mg/kg every 3 weeks). In the phase 3 part, patients were randomly assigned (2:1) to receive either sintilimab plus IBI305 (sintilimab-bevacizumab biosimilar group) or sorafenib (400 mg orally twice daily; sorafenib group), until disease progression or unacceptable toxicity. Randomisation was done using permuted block randomisation, with a block size of six, via an interactive web response system, and stratified by macrovascular invasion or extrahepatic metastasis, baseline α-fetoprotein, and ECOG performance status. The primary endpoint of the phase 2 part of the study was safety, assessed in all patients who received at least one dose of study drug. The co-primary endpoints of the phase 3 part of the study were overall survival and independent radiological review committee (IRRC)-assessed progression-free survival according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT03794440. The study is closed to new participants and follow-up is ongoing for long-term outcomes. FINDINGS: Between Feb 11, 2019 and Jan 15, 2020, we enrolled 595 patients: 24 were enrolled directly into the phase 2 safety run-in and 571 were randomly assigned to sintilimab-bevacizumab biosimilar (n=380) or sorafenib (n=191). In the phase 2 part of the trial, 24 patients received at least one dose of the study drug, with an objective response rate of 25·0% (95% CI 9·8-46·7). Based on the preliminary safety and activity data of the phase 2 part, in which grade 3 or worse treatment-related adverse events occurred in seven (29%) of 24 patients, the randomised phase 3 part was started. At data cutoff (Aug 15, 2020), the median follow-up was 10·0 months (IQR 8·5-11·7) in the sintilimab-bevacizumab biosimilar group and 10·0 months (8·4-11·7) in the sorafenib group. Patients in the sintilimab-bevacizumab biosimilar group had a significantly longer IRRC-assessed median progression-free survival (4·6 months [95% CI 4·1-5·7]) than did patients in the sorafenib group (2·8 months [2·7-3·2]; stratified hazard ratio [HR] 0·56, 95% CI 0·46-0·70; p<0·0001). In the first interim analysis of overall survival, sintilimab-bevacizumab biosimilar showed a significantly longer overall survival than did sorafenib (median not reached [95% CI not reached-not reached] vs 10·4 months [8·5-not reached]; HR 0·57, 95% CI 0·43-0·75; p<0·0001). The most common grade 3-4 treatment-emergent adverse events were hypertension (55 [14%] of 380 patients in the sintilimab-bevacizumab biosimilar group vs 11 [6%] of 185 patients in the sorafenib group) and palmar-plantar erythrodysaesthesia syndrome (none vs 22 [12%]). 123 (32%) patients in the sintilimab-bevacizumab biosimilar group and 36 (19%) patients in the sorafenib group had serious adverse events. Treatment-related adverse events that led to death occurred in six (2%) patients in the sintilimab-bevacizumab biosimilar group (one patient with abnormal liver function, one patient with both hepatic failure and gastrointestinal haemorrhage, one patient with interstitial lung disease, one patient with both hepatic faliure and hyperkalemia, one patient with upper gastrointestinal haemorrhage, and one patient with intestinal volvulus) and two (1%) patients in the sorafenib group (one patient with gastrointestinal haemorrhage and one patient with death of unknown cause). INTERPRETATION: Sintilimab plus IBI305 showed a significant overall survival and progression-free survival benefit versus sorafenib in the first-line setting for Chinese patients with unresectable, HBV-associated hepatocellular carcinoma, with an acceptable safety profile. This combination regimen could provide a novel treatment option for such patients. FUNDING: Innovent Biologics. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Impact of Examined Lymph Node Count for Esophageal Squamous Cell Carcinoma in Patients who Underwent Right Transthoracic Esophagectomy.

BACKGROUND: The impact of the number of examined lymph nodes (ELNs) on stage correction and prognostication in patients with esophageal squamous cell carcinoma (ESCC) who underwent right transthoracic esophagectomy is still unclear. METHODS: Patients with ESCC who underwent right transthoracic esophagectomy at Sun Yat-sen University Cancer Center between January 1997 and December 2013 were retrospectively enrolled. The Cox proportional hazards regression model was used to determine the effect of ELN count on overall survival. The impact of ELN count on stage correction was evaluated using the hypergeometric distribution and Bayes theorem and ß-binomial distribution estimation, respectively. The threshold of ELNs was determined using the LOWESS smoother and piecewise linear regression. RESULTS: Among the 875 included patients, greater ELNs were associated with a higher rate of nodal metastasis. Significant association between staging bias and the number of ELNs is only observed through the Bayes method. The ELN count did not impact 90-day mortality but significantly impacted long-term survival (adjusted hazard ratio [aHR] 0.986), especially in those patients with node-negative disease (aHR 0.972). In patients with node-negative disease, cut-point analysis showed a threshold ELN count of 21. CONCLUSIONS: A greater number of ELNs is associated with more accurate node staging and better long-term survival in resected ESCC patients. We recommended harvesting at least 21 LNs to acquire accurate staging and long-term survival information for patients with declared node-negative disease using the right thoracic approach.

Computed Tomography‒Guided Microwave Ablation Combined with Osteoplasty for the Treatment of Bone Metastases: A Multicenter Clinical Study.

PURPOSE: To evaluate the efficacy and safety of combined microwave ablation (MWA) and osteoplasty as a palliative therapy for painful bone metastases. MATERIALS AND METHODS: As an extension of a previous limited single-center study, a retrospective review was conducted for 147 patients (77 male, 70 female) with painful bone metastases who underwent MWA combined with osteoplasty. In total, 102 (69.4%), 41 (27.9%), and 4 (2.7%) patients had spinal metastases, extraspinal metastases, and both, respectively. Treatment efficacy was determined by comparing visual analog scale (VAS) scores, daily morphine equivalent opioid consumption, and Oswestry disability index (ODI) scores before treatment and during the follow-up period (mean follow-up, 9.8 months; range 3-16). RESULTS: The mean VAS score significantly declined from 6.4 ± 2.3 before treatment to 3.2 ± 2.1, 1.9 ± 1.6, 1.8 ± 1.6, 1.8 ± 1.6, and 1.9 ± 1.6 at 24 hours, 1 week, 4 weeks, 12 weeks, and 24 weeks after treatment, respectively (P < .01). Furthermore, the mean daily morphine equivalent opioid consumption was significantly reduced from 81.5 ± 32.8 mg before treatment to 40.0 ± 20.6, 32.4 ± 10.2, 26.4 ± 10.0, 21.5 ± 8.3, and 19.3 ± 7.4 mg. The mean ODI score also declined after treatment (P < .0001). Major complications occurred in 4 of 147 patients, with 1 pathologic fracture, 1 nerve injury, and 2 mild skin infections. Minor cement leakages were observed at 69 sites (32.8%). CONCLUSIONS: MWA combined with osteoplasty is an effective and safe treatment for painful bone metastases.

CircRNA Hsa_circ_0001017 Inhibited Gastric Cancer Progression via Acting as a Sponge of miR-197.

BACKGROUND: Gastric cancer (GC) is one of the most common digestive system diseases and yet lacks effective therapeutic regimen. AIMS: The aim of our present research was to probe the value of hsa_circ_0001017 in GC treatment. METHODS: qRT-PCR and Western blot were performed to detect gene and protein expressions, respectively. CCK-8 assay and clone formation assay were used to ensure the proliferation of GC cell lines. Transwell assay was performed to measure the migration and invasion of GC cell lines. The relationship between hsa_circ_0001017 and miR-197 and that between miR-197 and RHOB 3'-UTR were ensured using the luciferase reporter assay. RESULTS: Decreased hsa_circ_0001017 was discovered in GC, and upregulation of hsa_circ_0001017 notably repressed proliferation, migration, and invasion of GC cell lines. We further certificated that hsa_circ_0001017 served as miR-197 sponge and suppressed the expression of miR-197. Moreover, hsa_circ_0001017 upregulation meaningfully accelerated RHOB expression in both gene and protein levels, and RHOB was a downstream target of miR-197. Overexpression of miR-197 could markedly restrain hsa_circ_0001017-induced RHOB increasing and stifle inhibition of hsa_circ_0001017 to the malignant phenotype of GC cell lines. Next, our results further confirmed that hsa_circ_0001017 increasing notably inhibited tumor growth, impeded miR-197 production, while it enhanced the expression of RHOB in vivo. CONCLUSION: Our data demonstrated that upregulation of hsa_circ_0001017 could notably muffle the proliferation as well as the metastasis of GC cell lines and impede the formation of GC tumor via targeting to miR-197/RHOB signaling pathway. Our results evidenced that hsa_circ_0001017 may act as a rising biomarker for GC treatment.

The automated processing algorithm to correct the test result of serum neuron-specific enolase affected by specimen hemolysis.

INTRODUCTION: Serum neuron-specific enolase (NSE) is an important tumor marker for small cell lung cancer and neuroblastoma. However, the test of serum NSE compromised by specimen hemolysis is presented as a falsely higher result, which seriously disturbs clinical decision. This study aimed to establish a solution integrated with laboratory information system to clear the bias from hemolysis on serum NSE test. METHODS: The reference range of serum hemolysis index (HI) was first established, and specimen hemolysis rate was compared between HI test and visual observation. NSE concentration in serum pool with normal HI was spiked with serial diluted lysates from red blood cells to deduce individual corrective equation. The agreement between individual corrective equation and original NSE test was assayed by Bland and Altman plots. RESULTS: The high HI existed in 32.6% of specimens from patients. The NSE median of hemolyzed specimens was significant higher than the baseline (p = 0.038), while the corrected NSE median had no difference compared with the baseline (p = 0.757). The mean difference of corrected NSE and initial NSE was 1.92%, the SD of difference was 5.23%, and furthermore, the difference was independent of tendency of HI (Spearman r = -0.069, p = 0.640). The 95% confidence interval of mean difference (from -8.33% to 12.17%) was less than the acceptable bias range (±20%). CONCLUSION: The agreement between individual correction equation and NSE assay was satisfied. Our automated processing algorithm for serum NSE could provide efficient management of posttest data and correct positive bias from specimen hemolysis.

Modeling the effect of salt-affected soil on water balance fluxes and nitrous oxide emission using modified DNDC.

Soil salinity restricts plant growth, affects soil water balance and nitrous oxide (N2O) fluxes and can contaminate surface and groundwater. In this study, the Denitrification Decomposition (DNDC) model was modified to couple salt and water balance equations (SALT-DNDC) to investigate the effect of salinity on water balance and N2O fluxes. The model was examined against four growing seasons (2008-11) of observed data from Lethbridge, Alberta, Canada. Then, the model was used to simulate water filled pore space (WFPS), salt concentration and the N2O flux from agricultural soils. The results show that the effects of salinity on WFPS vary in different soil layers. Within shallow soil layers (<20 cm from soil surface) the salt concentration does not affect the average WFPS when initial salt concentrations range from 5 to 20 dS/m. However, in deeper soil layers (>20 cm from soil surface), when the initial salt concentration ranges from 5 to 20 dS/m it could indirectly affect the average WFPS due to changes of osmotic potential and transpiration. When AW is greater than 40%, the average growing season N2O emissions increase to a range of 0.6-1.0 g-N/ha/d at initial salt concentrations (5-20 dS/m) from a range of 0.5-0.7 g-N/ha/d when the salt concentrations is 0 dS/m. The newly developed SALT-DNDC model provides a unique tool to help investigate interactive effects among salt, soil, water, vegetation, and weather conditions on N2O fluxes.

Superovulation with human chorionic gonadotropin (hCG) trigger and gonadotropin releasing hormone agonist (GnRHa) trigger differentially alter essential angiogenic factors in the endometrium in a mouse ART model†.

Gonadotropin-releasing hormone agonists (GnRHa) are used as an alternative to human chorionic gonadotropin (hCG) to trigger ovulation and decrease the risk of ovarian hyperstimulation syndrome. GnRHa is less potent at inducing ovarian vascular endothelial growth factor (VEGF), but may also affect endometrial angiogenesis and early placental development. In this study, we explore the effect of superovulation on endometrial angiogenesis during critical periods of gestation in a mouse model. We assigned female mice to three groups: natural mating or mating following injection with equine chorionic gonadotropin and trigger with GnRHa or hCG trigger. Females were killed prior to implantation (E3.5), post-implantation (E7.5), and at midgestation (E10.5), and maternal serum, uterus, and ovaries were collected. During peri-implantation, endometrial Vegfr1 and Vegfr2 mRNA were significantly increased in the GnRHa trigger group (P < 0.02) relative to the hCG group. Vegfr1 is highly expressed in the endometrial lining and secretory glands immediately prior to implantation. At E7.5, the ectoplacental cone expression of Vegfa and its receptor, Vegfr2, was significantly higher in the hCG trigger group compared to the GnRHa group (P < 0.05). Soluble VEGFR1 and free VEGFA were much higher in the serum of mice exposed to the hCG trigger compared to GnRHa group. At midgestation, there was significantly more local Vegfa expression in the placenta of mice triggered with hCG. GnRHa and hCG triggers differentially disrupt the endometrial expression of key angiogenic factors during critical periods of mouse gestation. These results may have significant implications for placental development and neonatal outcomes following human in vitro fertilization.

Microwave ablation plus chemotherapy versus chemotherapy in advanced non-small cell lung cancer: a multicenter, randomized, controlled, phase III clinical trial.

OBJECTIVES: This prospective trial was performed to verify whether microwave ablation (MWA) in combination with chemotherapy could provide superior survival benefit compared with chemotherapy alone. MATERIALS AND METHODS: From March 1, 2015, to June 20, 2017, treatment-naïve patients with pathologically verified advanced or recurrent non-small cell lung cancer (NSCLC) were randomly assigned to MWA plus chemotherapy group or chemotherapy group. The primary endpoint was progression-free survival (PFS), while the secondary endpoints included overall survival (OS), time to local progression (TTLP), and objective response rate (ORR). The complications and adverse events were also reported. RESULTS: A total of 293 patients were randomly assigned into the two groups. One hundred forty-eight patients with 117 stage IV tumors were included in the MWA plus chemotherapy group. One hundred forty-five patients with 113 stage IV tumors were included in the chemotherapy group. The median follow-up period was 13.1 months and 12.4 months, respectively. Median PFS was 10.3 months (95% CI 8.0-13.0) in the MWA plus chemotherapy group and 4.9 months (95% CI 4.2-5.7) in the chemotherapy group (HR = 0.44, 95% CI 0.28-0.53; p < 0.0001). Median OS was not reached in the MWA plus chemotherapy group and 12.6 months (95% CI 10.6-14.6) in the chemotherapy group (HR = 0.38, 95% CI 0.27-0.53; p < 0.0001) using Kaplan-Meier analyses with log-rank test. The median TTLP was 24.5 months, and the ORR was 32% in both groups. The adverse event rate was not significantly different in the two groups. CONCLUSIONS: In patients with advanced NSCLC, longer PFS and OS can be achieved with the treatment of combined MWA and chemotherapy than chemotherapy alone. KEY POINTS: • Patients treated with MWA plus chemotherapy had superior PFS and OS over those treated with chemotherapy alone. • The ORR of patients treated with MWA plus chemotherapy was similar to that of those treated with chemotherapy alone. • Complications associated with MWA were common but tolerable and manageable.

Significance of accurate hilar and intrapulmonary lymph node examination and prognostication in stage IA-IIA non-small cell lung cancer, a retrospective cohort study.

BACKGROUND: The examination of lymph nodes (LNs) plays an important role in the nodal staging of non-small cell lung cancer (NSCLC). For patients without LN metastasis, the main role of thorough LN examination is accurate staging, which weakens the effect of staging migration. To date, the role of hilar and intrapulmonary (N1) station LNs has not been fully appreciated. In this study, we aimed to confirm the significance of N1 LNs in long-term survival for stage IA-IIA NSCLC patients and to find the minimum number of LN to examine. METHODS: The data of patients who underwent radical lobectomy and were confirmed as having non-metastatic LNs from January 2008 to March 2018 were retrospectively screened. Pathology records were reviewed for the number of LNs examined. The Kaplan-Meier method and Cox regression model were used to identify survival and prognostic factors. RESULTS: The median number of resected N1 LNs was 8. The number of patients with 0-2 N1 LNs, 3-5 N1 LNs, 6-8 N1 LNs, 9-11 N1 LNs, and more than 11 N1 LNs examined was 181, 425, 477, 414, and 531, respectively. Sex (P = 0.004), age (P < 0.001), tumor size (P = 0.004), differentiation degree (P = 0.001), and number of N1 LNs examined (P = 0.008) were independent prognostic factors of overall survival. Gender (P = 0.006), age (P = 0.031), tumor size (P = 0.001), differentiation degree (P = 0.001), vascular invasion (P = 0.034), and number of N1 LNs examined (P = 0.007) were independent prognostic factors of disease-free survival. Compared with patients with 0-5 N1 LNs examined, patients with more than 5 N1 LNs examined had better OS (P = 0.015) and had better DFS (P = 0.015) if only a landmark 5-year follow-up was performed. CONCLUSION: Increasing the number of N1 LN examination might improve the long-term survival of T1-2N0 NSCLC patients. These data indicate that at least 6 N1 nodes examined is an essential part in surgical and pathological management but cannot prove this. This finding should be confirmed in a large, prospective randomized clinical study.

Differential expression profiles of long noncoding RNAs in synchronous multiple and solitary primary esophageal squamous cell carcinomas: A microarray analysis.

As a unique subtype of esophageal cancer, synchronous multiple primary esophageal squamous cell carcinomas (ESCCs) mostly occur in Asian patients with alcohol and/or tobacco abuse, or with a family history of cancer. Multiple ESCCs are associated with poor clinical outcomes. Growing evidence has addressed that long noncoding RNAs (lncRNAs) are involved in the carcinogenesis of various malignancies. We compared the lncRNA and messenger RNA (mRNA) profiles between solitary and multiple ESCC tissues through microarray analysis, aiming at studying their different mechanisms in tumor development. As a result, in multiple ESCCs, a total of 5257 lncRNAs and 3371 mRNAs were consistently differentially expressed compared with solitary ESCC, including 2986 upregulated and 2271 downregulated lncRNAs, and 2313 upregulated, and 1058 downregulated mRNAs. We validated the results in four differentially expressed lncRNAs using quantitative real-time polymerase chain reaction. There were 38 and 20 pathways significantly related to up- and downregulated transcripts. The pathways associated with mostly enriched up- and downregulated mRNAs were hsa01200 (carbon metabolism) and hsa05221 (acute myeloid leukemia- homo sapiens [human]). Gene ontology analysis suggested that upregulated and downregulated mRNAs were mainly enriched in bounding membrane of organelle involved in the cellular component and positive regulation of transport involved in the biological process. Further analysis identified 189 differentially expressed paired antisense lncRNAs and relative sense mRNA, as well as 2134 differentially expressed long intergenic noncoding RNAs and their adjacent mRNA pairs. In conclusion, the aberrantly expressed lncRNAs might play a role in the carcinogenesis of multiple ESCCs and could be candidates as diagnostic biomarkers and therapeutic targets.

Intratumor heterogeneity comparison among different subtypes of non-small-cell lung cancer through multi-region tissue and matched ctDNA sequencing.

Understanding of intratumor heterogeneity (ITH) among different non-small cell lung cancer (NSCLC) subtypes is necessary. Whether circulating tumor DNA (ctDNA) profile could represent these ITH is still an open question. We performed 181 multi-region tumor tissues sequencing and matched ctDNA sequencing from 32 operative NSCLC to compare ITH among different NSCLC subtypes, including EGFR-mutant lung adenocarcinoma (LUAD), KRAS-mutant LUAD, EGFR&KRAS-wild-type LUAD, and lung squamous cell carcinoma (LUSC), and examine potential value of ctDNA for ITH analysis. ITH is evaluated by ITH index (ITHi). If the somatic genetic alteration is shared by all the tissue regions, it is defined as trunk mutation. Otherwise, it is called branch mutation. The ITHi will be higher, if the tumor has less trunk mutations. We found EGFR-mutant LUAD showed significantly higher ITHi than KRAS-mutant LUAD/wild-type LUAD (P = 0.03) and numerically higher ITH than LUSC. For trunk mutations, driver mutations were identified at a higher proportion than passenger mutations (60% vs. 40%, P = 0.0023) in overall, especially in EGFR-mutant LUAD (86% vs. 14%, P = 0.0004), while it was opposite in KRAS-mutant LUAD (40% vs. 60%, P = 0.18). For branch mutations, the proportions of driver mutations and passenger mutations were similar for each NSCLC subtype. ctDNA analysis showed unsatisfactory detections of tumor-derived trunk and branch mutations (43% vs. 23%, P = 4.53e-6) among all NSCLC subtypes. In summary, EGFR-mutant LUAD has the highest ITH than other NSCLC subtypes, offering further understanding of tumorigenesis mechanisms among different NSCLC subtypes. Besides, ctDNA maybe not an appropriate method to reflect ITH.

Interplay of transcriptional signaling by progesterone, cyclic AMP, and inflammation in myometrial cells: implications for the control of human parturition.

Parturition involves cellular signaling changes driven by the complex interplay between progesterone (P4), inflammation, and the cyclic adenosine monophosphate (cAMP) pathway. To characterize this interplay, we performed comprehensive transcriptomic studies utilizing eight treatment combinations on myometrial cell lines and tissue samples from pregnant women. We performed genome-wide RNA-sequencing on the hTERT-HM${}^{A/B}$ cell line treated with all combinations of P4, forskolin (FSK) (induces cAMP), and interleukin-1$\beta$ (IL-1$\beta$). We then performed gene set enrichment and regulatory network analyses to identify pathways commonly, differentially, or synergistically regulated by these treatments. Finally, we used tissue similarity index (TSI) to characterize the correspondence between cell lines and tissue phenotypes. We observed that in addition to their individual anti-inflammatory effects, P4 and cAMP synergistically blocked specific inflammatory pathways/regulators including STAT3/6, CEBPA/B, and OCT1/7, but not NF$\kappa$B. TSI analysis indicated that FSK + P4- and IL-1$\beta$-treated cells exhibit transcriptional signatures highly similar to non-laboring and laboring term myometrium, respectively. Our results identify potential therapeutic targets to prevent preterm birth and show that the hTERT-HM${}^{A/B}$ cell line provides an accurate transcriptional model for term myometrial tissue.

Finding lost genes in GWAS via integrative-omics analysis reveals novel sub-networks associated with preterm birth.

Maternal genome influences associate with up to 40% of spontaneous preterm births (PTB). Multiple genome wide association studies (GWAS) have been completed to identify genetic variants associated with PTB. Disappointingly, no highly significant SNPs have replicated in independent cohorts so far. We developed an approach combining protein-protein interaction (PPI) network data with tissue specific gene expression data to "find" SNPs of modest significance to identify candidate genes of functional importance that would otherwise be overlooked. This approach is based on the assumption that "high-ranking" SNPs falling short of genome wide significance may nevertheless indicate genes that have substantial biological value in understanding PTB. We mapped highly-ranked candidate SNPs from a meta-analysis of PTB-GWAS to coding genes and developed a PPI network enriched with PTB-SNP carrying genes. This network was scored with gene expression data from term and preterm myometrium to identify subnetworks of PTB-SNP associated genes coordinately expressed with labour onset in myometrial tissue. Our analysis consistently identified significant sub-networks associated with the interacting transcription factors MEF2C and TWIST1, genes not previously associated with PTB, both of which regulate processes clearly relevant to birth timing. Other genes in the significant sub-networks were also associated with inflammatory pathways, as well as muscle function and ion channels. Gene expression level dysregulation was confirmed for eight of these networks by qRT-PCR in an independent set of term and pre-term subjects. Our method identifies novel genes dysregulated in PTB and provides a generalized framework to identify GWAS SNPs that would otherwise be overlooked.

HuR Stabilizes lnc-Sox5 mRNA to Promote Tongue Carcinogenesis.

Long noncoding RNAs (lncRNAs) have been recently regarded as systemic regulators in multiple biological processes including tumorigenesis. In this study, we report an ultra-highly expressed lncRNA, lnc-Sox5, in tongue tumor tissues. The results imply that lnc-Sox5 may play vital role in tongue carcinoma progression. We observed that the growth of Tca8113 cells was suppressed by lnc-Sox5 downregulation. Additionally, lnc-Sox5 knockdown simultaneously increased Tca8113 cell apoptosis, but the cell cycle was arrested. RNA immunoprecipitation suggested that HuR directly bound to and stabilized lnc-Sox5 RNA. Consistently, HuR knockdown reduced the level of lnc-Sox5 in Tca8113 cells. However, overexpression of HuR induced more lnc-Sox5 in Tca8113 cells. Both lnc-Sox5 knockdown and HuR knockdown suppressed Tca8113 cell tumorigenesis in xenograft models. These results suggest that lnc-Sox5, which was stabilized by HuR, could regulate carcinogenesis of tongue cancer and may serve as a predicted target for tongue carcinoma therapies.

Cytotoxic and Antitumor Effects of Curzerene from Curcuma longa.

Curzerene is a sesquiterpene and component used in oriental medicine. It was originally isolated from the traditional Chinese herbal medicine Curcuma rhizomes. In this study, anticancer activity of curzerene was examined in both in vitro and in vivo models. The result of the MTT assay showed that curzerene exhibited antiproliferative effects in SPC-A1 human lung adenocarcinoma cells in a time-dependent and dose-dependent manner. The anticancer IC50s were 403.8, 154.8, and 47.0 µM for 24, 48, and 72 hours, respectively. The flow cytometry analysis indicated curzerene arrested the cells in the G2/M cell cycle and promoted or induced apoptosis of SPC-A1 cells. The percentage of cells arrested in the G2/M phase increased from 9.26 % in the control group cells to 17.57 % in the cells treated with the highest dose (100 µM) of curzerene. Western blot and RT-PCR analysis demonstrated that curzerene induced the downregulation of GSTA1 protein and mRNA expressions in SPC-A1 cells. Tumor growth was significantly inhibited in SPC-A1 cell-bearing nude mice by using curzerene (135 mg/kg daily), meanwhile, curzerene did not significantly affect body mass and the organs of the mice, which may indicate that curzerene has limited toxicity and side effects in vivo. In conclusion, curzerene could inhibit the proliferation of SPC-A1 human lung adenocarcinoma cells line in both in vitro and in vivo models. Focusing on its relationship with GSTA1, curzerene could induce the downregulation of GSTA1 protein and mRNA expressions in SPC-A1 cells. Curzerene might be used as an anti-lung adenocarcinoma drug candidate compound for further development.

[Analgesic effect and safety of intercostal nerve cryoanalgesia after the video-assisted thoracoscopic surgery].

OBJECTIVE: To investigate the analgesic efficacy and safety of intercostal nerve cryoanalgesia after video-assisted thoracoscopic surgery (VATS). METHODS: This was a prospective randomized controlled study. From May 2014 to April 2015, 80 patients who would undergoing selective surgery performed by the same surgeon team were chosen, and were randomly divided into cryoanalgesia group and intravenous analgesia group by a random number table. Visual analogue scale (VAS) at resting and movement were measured on postoperative 4 h, 1 d, 2 d, 3 d, and the amount of supplemental morphine use and adverse reactions were recorded; plasma concentration of cortisol, blood glucose, C-reactive protein (CRP) and interleukin-6 (IL-6) were detected on preoperative and postoperative 4 h,1 d,2 d. RESULTS: Seventy-one patients with complete test process were included in the statistical analysis, including cryoanalgesia group (35 cases) and intravenous group (36 cases). No statistical differences were found in terms of age, gender, body mass index (BMI) between the two groups. VAS scores of cryoanalgesia group at movement on postoperative 4 h, 1 d, 2 d, 3 d were 5(5,7), 4(3,6), 3(3,4), 3(0,3), and in intravenous group were 5(5,6), 5(3,5), 3(3,4), 2(0,3), respectively, but there was no statistically different between two groups (P>0.05). Resting VAS scores of cryoanalgesia group on postoperative 4 h, 1 d, 2 d, 3 d were 3(2,4), 0(0,3), 0(0,0), 0(0,0), and in intravenous group were 3(0.5,4), 2(0,3), 0(0,1.5), 0(0,0) respectively, but there was no statistically different between two groups (P>0.05). Resting analgesic effectiveness (VAS≤5) of cryoanalgesia group were 91.4%, and in intravenous group were 97.2%, respectively. Median of morphine dosage was equal between two groups on postoperative 4 h, 1 d, 2 d, cumulative amount of morphine of cryoanalgesia group was higher than intravenous group, but the difference between the two groups was not statistically significant. Incidence of nausea and vomiting for intravenous group was 36.1%, significantly higher than cryoanalgesia group (17.1%, χ(2)=4.148, P<0.05). The change of plasma concentration of cortisol, C-response protein (CRP), interleuken-6(IL-6) was noticeable, but there was no statistical significance in each time point. CONCLUSION: The analgesic effect of both Intercostal nerve cryoanalgesia and intravenous analgesia after VATS is almost the same.Compare with intravenous analgesia, incidence of the adverse reactions of cryoanalgesia is lower, and there is no increasing in the stress response.