Expression and functional significance of phosphoenolpyruvate carboxykinase 1 in uveal melanoma.

Uveal melanoma (UVM), an uncommon yet potentially life-threatening ocular cancer, arises from melanocytes in the uveal tract of the eye. The exploration of novel oncotargets for UVM is of paramount importance. In this study, we show that PCK1 (phosphoenolpyruvate carboxykinase 1) expression is upregulated in various UVM tissues as well as in primary UVM cells and immortalized lines. Furthermore, bioinformatics studies reveal that PCK1 overexpression in UVM correlates with advanced disease stages and poor patient survival. Genetic silencing (utilizing viral shRNA) or knockout (via CRISPR/Cas9) of PCK1 significantly curtailed cell viability, proliferation, cell cycle progression, and motility, while provoking apoptosis in primary and immortalized UVM cells. Conversely, ectopic overexpression of PCK1, achieved through a viral construct, bolstered UVM cell proliferation and migration. Gαi3 expression and Akt phosphorylation were reduced following PCK1 silencing or knockout, but increased after PCK1 overexpression in UVM cells. Restoring Akt phosphorylation through a constitutively active mutant Akt1 (S473D) ameliorated the growth inhibition, migration suppression, and apoptosis induced by PCK1 silencing in UVM cells. Additionally, ectopic expression of Gαi3 restored Akt activation and counteracted the anti-UVM cell effects by PCK1 silencing. In vivo, the growth of subcutaneous xenografts of primary human UVM cells was significantly inhibited following intratumoral injection of adeno-associated virus (aav) expressing PCK1 shRNA. PCK1 depletion, Gαi3 downregulation, Akt inhibition, proliferation arrest, and apoptosis were detected in PCK1-silenced UVM xenografts. Collectively, our findings demonstrate that PCK1 promotes UVM cell growth possibly by modulating the Gαi3-Akt signaling pathway.

Direct Synthesis of α- and ß-2'-Deoxynucleosides with Stereodirecting Phosphine Oxide via Remote Participation.

2'-Deoxynucleosides and analogues play a vital role in drug development, but their preparation remains a significant challenge. Previous studies have focused on ß-2'-deoxynucleosides with the natural ß-configuration. In fact, their isomeric α-2'-deoxynucleosides also exhibit diverse bioactivities and even better metabolic stability. Herein, we report that both α- and ß-2'-deoxynucleosides can be prepared with high yields and stereoselectivity using a remote directing diphenylphosphinoyl (DPP) group. It is particularly efficient to prepare α-2'-deoxynucleosides with an easily accessible 3,5-di-ODPP donor. Instead of acting as a H-bond acceptor on a 2-(diphenylphosphinoyl)acetyl (DPPA) group in our previous studies for syn-facial O-glycosylation, the phosphine oxide moiety here acts as a remote participating group to enable highly antifacial N-glycosylation. This proposed remote participation mechanism is supported by our first characterization of an important 1,5-briged P-heterobicyclic intermediate via variable-temperature NMR spectroscopy. Interestingly, antiproliferative assays led to a α-2'-deoxynucleoside with IC50 values in the low micromole range against central nervous system tumor cell lines SH-SY5Y and LN229, whereas its ß-anomer exhibited no inhibition at 100 µM. Furthermore, the DPP group significantly enhanced the antitumor activities by 10 times.

Surgery for stage IIB-IIIB small cell lung cancer.

PURPOSE: The NCCN guidelines do not recommend surgery for T3-4N0M0/T1-4N1-2M0 small cell lung cancer (SCLC) due to a lack of evidence. METHODS: Data of patients with T3-4N0M0/T1-4N1-2M0 SCLC were extracted from the Surveillance, Epidemiology, and End Results (SEER) database to determine the impact of surgery on this population. The Kaplan-Meier method, univariable and multivariable Cox proportional hazard regression, and propensity score matching (PSM) were used to compare the overall survival (OS) between the surgery and non-surgery groups. In addition, we explored whether sublobectomy, lobectomy, and pneumonectomy could provide survival benefits. RESULTS: In total, 8572 patients with SCLC treated without surgery and 342 patients treated with surgery were included in this study. The PSM-adjusted hazard ratio (HR, 95% CI) for surgery vs. no surgery, sublobectomy vs. no surgery, lobectomy vs. no surgery, pneumonectomy vs. no surgery, and lobectomy plus adjuvant chemoradiotherapy vs. chemoradiotherapy were 0.71 (0.61-0.82) (P < 0.001), 0.91 (0.70-1.19) (P = 0.488), 0.60 (0.50-0.73) (P < 0.001), 0.57 (0.28-1.16) (P = 0.124), and 0.73 (0.56-0.96) (P = 0.023), respectively. The subgroup analysis demonstrated consistent results. CONCLUSIONS: Lobectomy improved OS in patients with T3-4N0M0/T1-4N1-2M0 SCLC, while pneumonectomy also demonstrated a tendency to improve OS without statistical significance; however, sublobectomy showed no survival benefit.

Macrophage/microglia polarization for the treatment of diabetic retinopathy.

Macrophages/microglia are immune system defense and homeostatic cells that develop from bone marrow progenitor cells. According to the different phenotypes and immune responses of macrophages (Th1 and Th2), the two primary categories of polarized macrophages/microglia are those conventionally activated (M1) and alternatively activated (M2). Macrophage/microglial polarization is a key regulating factor in the development of inflammatory disorders, cancers, metabolic disturbances, and neural degeneration. Macrophage/microglial polarization is involved in inflammation, oxidative stress, pathological angiogenesis, and tissue healing processes in ocular diseases, particularly in diabetic retinopathy (DR). The functional phenotypes of macrophages/microglia affect disease progression and prognosis, and thus regulate the polarization or functional phenotype of microglia at different DR stages, which may offer new concepts for individualized therapy of DR. This review summarizes the involvement of macrophage/microglia polarization in physiological situations and in the pathological process of DR, and discusses the promising role of polarization in personalized treatment of DR.

Hypoxia-induced AFAP1L1 regulates pathological neovascularization via the YAP-DLL4-NOTCH axis.

BACKGROUND: Pathological neovascularization plays a pivotal role in the onset and progression of tumors and neovascular eye diseases. Despite notable advancements in the development of anti-angiogenic medications that target vascular endothelial growth factor (VEGF) and its receptors (VEGFRs), the occurrence of adverse reactions and drug resistance has somewhat impeded the widespread application of these drugs. Therefore, additional investigations are warranted to explore alternative therapeutic targets. In recent years, owing to the swift advancement of high-throughput sequencing technology, pan-cancer analysis and single-cell sequencing analysis have emerged as pivotal methodologies and focal areas within the domain of omics research, which is of great significance for us to find potential targets related to the regulation of pathological neovascularization. METHODS: Pan-cancer analysis and scRNA-seq data analysis were employed to forecast the association between Actin filament-associated protein 1 like 1 (AFAP1L1) and the development of tumors and endothelial cells. Tumor xenograft model and ocular pathological neovascularization model were constructed as well as Isolectin B4 (IsoB4) staining and immunofluorescence staining were used to assess the effects of AFAP1L1 on the progression of neoplasms and neovascular eye diseases in vivo. Transwell assay, wound scratch assay, tube forming assay, three-dimensional germination assay, and rhodamine-phalloidin staining were used to evaluate the impact of AFAP1L1 on human umbilical vein endothelial cells (HUVECs) function in vitro; Dual luciferase reporting, qRT-PCR and western blot were used to investigate the upstream and downstream mechanisms of pathological neovascularization mediated by AFAP1L1. RESULTS: Our investigation revealed that AFAP1L1 plays a crucial role in promoting the development of various tumors and demonstrates a strong correlation with endothelial cells. Targeted suppression of AFAP1L1 specifically in endothelial cells in vivo proves effective in inhibiting tumor formation and ocular pathological neovascularization. Mechanistically, AFAP1L1 functions as a hypoxia-related regulatory protein that can be activated by HIF-1α. In vitro experiments demonstrated that reducing AFAP1L1 levels can reverse hypoxia-induced excessive angiogenic capacity in HUVECs. The principal mechanism of angiogenesis inhibition entails the regulation of tip cell behavior through the YAP-DLL4-NOTCH axis. CONCLUSION: In conclusion, AFAP1L1, a newly identified hypoxia-related regulatory protein, can be activated by HIF-1α. Inhibiting AFAP1L1 results in the inhibition of angiogenesis by suppressing the germination of endothelial tip cells through the YAP-DLL4-NOTCH axis. This presents a promising therapeutic target to halt the progression of tumors and neovascular eye disease.

Comparation between novel online models and the AJCC 8th TNM staging system in predicting cancer-specific and overall survival of small cell lung cancer.

Background: Most of previous studies on predictive models for patients with small cell lung cancer (SCLC) were single institutional studies or showed relatively low Harrell concordance index (C-index) values. To build an optimal nomogram, we collected clinicopathological characteristics of SCLC patients from Surveillance, Epidemiology, and End Results (SEER) database. Methods: 24,055 samples with SCLC from 2010 to 2016 in the SEER database were analyzed. The samples were grouped into derivation cohort (n=20,075) and external validation cohort (n=3,980) based on America's different geographic regions. Cox regression analyses were used to construct nomograms predicting cancer-specific survival (CSS) and overall survival (OS) using derivation cohort. The nomograms were internally validated by bootstrapping technique and externally validated by calibration plots. C-index was computed to compare the accuracy and discrimination power of our nomograms with the 8th of version AJCC TNM staging system and nomograms built in previous studies. Decision curve analysis (DCA) was applied to explore whether the nomograms had better clinical efficiency than the 8th version of AJCC TNM staging system. Results: Age, sex, race, marital status, primary site, differentiation, T classification, N classification, M classification, surgical type, lymph node ratio, radiotherapy, and chemotherapy were chosen as predictors of CSS and OS for SCLC by stepwise multivariable regression and were put into the nomograms. Internal and external validations confirmed the nomograms were accurate in prediction. C-indexes of the nomograms were relatively satisfactory in derivation cohort (CSS: 0.761, OS: 0.761) and external validation cohort (CSS: 0.764, OS: 0.764). The accuracy of the nomograms was superior to that of nomograms built in previous studies. DCA showed the nomograms conferred better clinical efficiency than 8th version of TNM staging system. Conclusions: We developed practical nomograms for CSS (https://guowei2020.shinyapps.io/DynNom-CSS-SCLC/) and OS (https://drboidedwater.shinyapps.io/DynNom-OS-SCLC/) prediction of SCLC patients which may facilitate clinicians in individualized therapeutics.

The role of PIWIL4 and piRNAs in the development of choroidal neovascularization.

Wet age-related macular degeneration (wAMD) is the leading cause of blindness among the elderly in industrialized nations. Anti-vascular epidermal growth factor (VEGF) therapy via intravitreal injection is the most effective clinical treatment for wAMD due to high concentrations of VEGF that promote choroidal neovascularization. While PIWI proteins participate in various biological processes, their function in AMD remains unclear. In this study, we discovered that PIWIL4 expression is elevated in a laser-induced choroidal neovascularization (CNV) model and that it regulates angiogenesis in vitro and in vivo. Differentially expressed piwi-interacting RNAs (piRNAs) were identified in a CNV model and were shown to potentially regulate angiogenesis via bioinformatics analysis. PIWIL4 knockdown inhibits VEGF secretion and VEGFR2 phosphorylation. Overall, PIWIL4 may serve as a novel target to block pathological choroidal neovascularization, and the study of the PIWI-piRNAs pathway in wAMD highlights its broad function in somatic cells.

Construction and validation of nomograms based on the log odds of positive lymph nodes to predict the prognosis of lung neuroendocrine tumors.

Background: This research aimed to investigate the predictive performance of log odds of positive lymph nodes (LODDS) for the long-term prognosis of patients with node-positive lung neuroendocrine tumors (LNETs). Methods: We collected 506 eligible patients with resected N1/N2 classification LNETs from the Surveillance, Epidemiology, and End Results (SEER) database between 2004 and 2015. The study cohort was split into derivation cohort (n=300) and external validation cohort (n=206) based on different geographic regions. Nomograms were constructed based on the derivation cohort and validated using the external validation cohort to predict the 1-, 3-, and 5-year cancer-specific survival (CSS) and overall survival (OS) of patients with LNETs. The accuracy and clinical practicability of nomograms were tested by Harrell's concordance index (C-index), integrated discrimination improvement (IDI), net reclassification improvement (NRI), calibration plots, and decision curve analyses. Results: The Cox proportional-hazards model showed the high LODDS group (-0.79≤LODDS) had significantly higher mortality compared to those in the low LODDS group (LODDS<-0.79) for both CSS and OS. In addition, age at diagnosis, sex, histotype, type of surgery, radiotherapy, and chemotherapy were also chosen as predictors in Cox regression analyses using stepwise Akaike information criterion method and included in the nomograms. The values of C-index, NRI, and IDI proved that the established nomograms were better than the conventional eighth edition of the TNM staging system. The calibration plots for predictions of the 1-, 3-, and 5-year CSS/OS were in excellent agreement. Decision curve analyses showed that the nomograms had value in terms of clinical application. Conclusions: We created visualized nomograms for CSS and OS of LNET patients, facilitating clinicians to bring individually tailored risk assessment and therapy.

Characterization of Fatty Acid Metabolism in Lung Adenocarcinoma.

Background: Lung adenocarcinoma (LUAD) is the most common subtype of non-small cell lung cancer. Fatty acid metabolism takes part in malignancy progression. However, the roles fatty acid metabolism plays in LUAD are still unclear. Methods: The transcriptomic and clinical data of LUAD patients from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were extracted. ssGSEA, WGCNA, univariable Cox regression, and LASSO Cox regression analyses were performed to identify the fatty acid metabolism-related genes which influenced the overall survival (OS) and build a fatty acid-related risk score (FARS) model. A nomogram was established based on the FARS and other clinicopathological features, and ROC and calibration plots were used to validate the prediction accuracy. The tumor microenvironment (TME) of patients with high and low FARS was compared. Results: A total of 38 genes were identified to be independently related to the survival outcome and put into a FARS model. High FARS patients exhibited significantly worse OS. The nomogram included the FARS and pathological stage, and the AUC of the nomogram predicting 1-, 2-, 3-, 4-, and 5-year OS was 0.789, 0.807, 0.798, 0.809, and 0.753, respectively. Calibration plots also indicated good accuracy. Moreover, the samples of the high FARS had higher expression of PDL1. Conclusion: We constructed a FARS model which could accurately predict the survival outcome of the LUAD patients. The genes of the FARS are related to the tumor microenvironment and patients with high FARS can potentially benefit more from anti-PD1/PDL1 immunotherapy. In addition, the mechanisms of the genes in the FARS affecting prognosis are worthy of further research to develop new gene-targeted drugs.

Role of Pneumonectomy in T1-4N2M0 Non-Small Cell Lung Cancer: A Propensity Score Matching Analysis.

Background: N2 stage disease constitutes approximately 20%-30% of all non-small cell lung cancer (NSCLC). Concurrently, surgery remains the first-choice treatment for patients with N2 NSCLC if feasible. However, the role of pneumonectomy in N2 NSCLC has rarely been investigated and remains controversial. Methods: We enrolled 26,798 patients with T1-4N2M0 NSCLC (stage IIIA/IIIB) from the Surveillance, Epidemiology, and End Results (SEER) database between 2004 and 2015. We compared the overall survival (OS) and cancer-specific survival (CSS) between patients who received pneumonectomy and those who did not receive surgery. The Kaplan-Meier method, Cox regression analyses, and propensity score matching (PSM) were applied to demonstrate the effect of pneumonectomy. Results: Patients receiving pneumonectomy had a significantly better OS and CSS than those without pneumonectomy both before [adjusted-HR (95% CI): 0.461 (0.425-0.501) for OS, 0.444 (0.406-0.485) for CSS] and after PSM [adjusted-HR (95% CI): 0.499 (0.445-0.560) for OS, 0.457 (0.405-0.517) for CSS] with all p-values <0.001. Subgroup analysis demonstrated concordant results stratified by demographic or clinicopathological variables. In sensitivity analysis, no significant difference was observed between patients receiving single pneumonectomy and chemoradiotherapy without surgery in OS and CSS both before [unadjusted-HR (95% CI): 1.016 (0.878-1.176) for OS, 0.934 (0.794-1.099) for CSS, p = 0.832] and after PSM [unadjusted-HR (95% CI): 0.988 (0.799-1.222) for OS, 0.938 (0.744-1.182) for CSS] with all p-values >0.4. Conclusion: For patients with T1-4N2M0 NSCLC (stage IIIA/IIIB), pneumonectomy is an independent protective factor of OS and should be considered when applicable.

Evaluation of log odds of positive lymph nodes in predicting the survival of patients with non-small cell lung cancer treated with neoadjuvant therapy and surgery: a SEER cohort-based study.

BACKGROUND: Log odds of positive lymph nodes (LODDS) is a novel lymph node (LN) descriptor that demonstrates promising prognostic value in many tumors. However, there is limited information regarding LODDS in patients with non-small cell lung cancer (NSCLC), especially those receiving neoadjuvant therapy followed by lung surgery. METHODS: A total of 2059 patients with NSCLC who received neoadjuvant therapy and surgery were identified from the Surveillance, Epidemiology, and End Results (SEER) database. We used the X-tile software to calculate the LODDS cutoff value. Kaplan-Meier survival analysis and receiver operating characteristic (ROC) curve analysis were performed to compare predictive values of the American Joint Committee on Cancer (AJCC) N staging descriptor and LODDS. Univariate and multivariate Cox regression and inverse probability of treatment weighting (IPTW) analyses were conducted to construct a model for predicting prognosis. RESULTS: According to the survival analysis, LODDS had better differentiating ability than the N staging descriptor (log-rank test, P < 0.0001 vs. P = 0.031). The ROC curve demonstrated that the AUC of LODDS was significantly higher than that of the N staging descriptor in the 1-, 3-, and 5-year survival analyses (all P < 0.05). Univariate and multivariate Cox regression analyses showed that LODDS was an independent risk factor for patients with NSCLC receiving neoadjuvant therapy followed by surgery both before and after IPTW (all P < 0.001). A clinicopathological model with LODDS, age, sex, T stage, and radiotherapy could better predict prognosis. CONCLUSIONS: Compared with the AJCC N staging descriptor, LODDS exhibited better predictive ability for patients with NSCLC receiving neoadjuvant therapy followed by surgery. A multivariate clinicopathological model with LODDS demonstrated a sound performance in predicting prognosis.

Orally administered bismuth drug together with N-acetyl cysteine as a broad-spectrum anti-coronavirus cocktail therapy.

The emergence of SARS-CoV-2 variants of concern compromises vaccine efficacy and emphasizes the need for further development of anti-SARS-CoV-2 therapeutics, in particular orally administered take-home therapies. Cocktail therapy has shown great promise in the treatment of viral infection. Herein, we reported the potent preclinical anti-SARS-CoV-2 efficacy of a cocktail therapy consisting of clinically used drugs, e.g. colloidal bismuth subcitrate (CBS) or bismuth subsalicylate (BSS), and N-acetyl-l-cysteine (NAC). Oral administration of the cocktail reduced viral loads in the lung and ameliorated virus-induced pneumonia in a hamster infection model. The mechanistic studies showed that NAC prevented the hydrolysis of bismuth drugs at gastric pH via the formation of the stable component [Bi(NAC)3], and optimized the pharmacokinetics profile of CBS in vivo. Combination of bismuth drugs with NAC suppressed the replication of a panel of medically important coronaviruses including Middle East respiratory syndrome-related coronavirus (MERS-CoV), Human coronavirus 229E (HCoV-229E) and SARS-CoV-2 Alpha variant (B.1.1.7) with broad-spectrum inhibitory activities towards key viral cysteine enzymes/proteases including papain-like protease (PLpro), main protease (Mpro), helicase (Hel) and angiotensin-converting enzyme 2 (ACE2). Importantly, our study offered a potential at-home treatment for combating SARS-CoV-2 and future coronavirus infections.

Lobectomy Versus Sublobectomy in Stage IIIA/N2 Non-Small Cell Lung Cancer: A Population-Based Study.

BACKGROUND: The role lobectomy plays in stage IIIA/N2 non-small cell lung cancer (NSCLC) is controversial for a long time. What's more, no previous study concentrates on whether sublobectomy can improve survival outcome for these patients, so we performed this population-based study to investigate whether stage IIIA/N2 NSCLC can benefit from these two surgery types and compare survival outcomes after lobectomy and sublobectomy. METHODS: A total of 21,638 patients diagnosed with stage IIIA/N2 NSCLC between 2004 and 2015 from the Surveillance, Epidemiology, and End Results (SEER) database matched our selection criteria. The study cohort included patients who received no surgery (n = 15,951), sublobectomy (n = 628) and lobectomy (n = 5,059). Kaplan-Meier method, Cox regression analyses, and inverse probability of treatment weighting (IPTW)-adjusted Cox regression were used to illustrate the influence of sublobectomy and lobectomy on overall survival (OS) rates in the study cohort and compare these two surgery types. RESULTS: Multivariable Cox regression analysis showed sublobectomy [HR: 0.584 (95%CI: 0.531-0.644), P-value <0.001; IPTW-adjusted HR: 0.619 (95%CI: 0.605-0.633), P-value <0.001] and lobectomy [HR: 0.439 (95%CI: 0.420-0.459), P-value <0.001; IPTW-adjusted HR: 0.441 (95%CI: 0.431-0.451), P-value <0.001] were both related to better OS rates compared with no surgery, and lobectomy exhibited better survival than sublobectomy [HR: 0.751 (95%CI: 0.680-0.830), P-value <0.001; IPTW-adjusted HR: 0.713 (95%CI: 0.696-0.731), P-value <0.001]. Moreover, the results in subgroup analyses based on age, tumor size and radiotherapy and chemotherapy strategy in all study cohort were consistent. CONCLUSION: Stage IIIA/N2 NSCLC patients could benefit from sublobectomy or lobectomy, and lobectomy provided better OS rates than sublobectomy.

Nerve growth factor enhances the therapeutic effect of mesenchymal stem cells on diabetic periodontitis.

Patients with diabetes frequently suffer from periodontitis, which progresses rapidly and is difficult to cure. Mesenchymal stem cell (MSC) transplantation may effectively treat periodontitis, but high glucose limits its therapeutic effect in diabetes. Nerve growth factor (NGF) has the functions of cell protection, anti-apoptosis and immune regulation, and may have potential application in diabetic periodontitis. In the present study, flow cytometry indicated that NGF inhibited MSC apoptosis induced by high glucose. Of note, high glucose promoted the transformation of MSCs into the proinflammatory type. NGF inhibited this transformation of MSCs under diabetic conditions and further decreased the proportion of T cells and monocytes/macrophages among lymphocytes. An animal model of diabetic periodontitis was constructed and MSC transplantation was demonstrated to reduce alveolar bone loss caused by diabetes. NGF enhanced the therapeutic effect of MSCs and maintained transplanted MSC survival in periodontal tissue of diabetic mice. Immunohistochemical analysis of periodontal tissues suggested that in the NGF group, infiltration of T cells and macrophages was reduced. Neurotrophic receptor tyrosine kinase 1 was indicated to have a key role in these effects of NGF. In conclusion, NGF may enhance the therapeutic effect of MSCs on diabetic periodontitis by protecting the cells and promoting the transformation of MSCs into the immunosuppressive type.

Dynamic nomograms combining N classification with ratio-based nodal classifications to predict long-term survival for patients with lung adenocarcinoma after surgery: a SEER population-based study.

BACKGROUND: The prognostic roles of three lymph node classifications, number of positive lymph nodes (NPLN), log odds of positive lymph nodes (LODDS), and lymph node ratio (LNR) in lung adenocarcinoma are unclear. We aim to find the classification with the strongest predictive power and combine it with the American Joint Committee on Cancer (AJCC) 8th TNM stage to establish an optimal prognostic nomogram. METHODS: 25,005 patients with T1-4N0-2M0 lung adenocarcinoma after surgery between 2004 to 2016 from the Surveillance, Epidemiology, and End Results database were included. The study cohort was divided into training cohort (13,551 patients) and external validation cohort (11,454 patients) according to different geographic region. Univariate and multivariate Cox regression analyses were performed on the training cohort to evaluate the predictive performance of NPLN (Model 1), LODDS (Model 2), LNR (Model 3) or LODDS+LNR (Model 4) respectively for cancer-specific survival and overall survival. Likelihood-ratio χ2 test, Akaike Information Criterion, Harrell concordance index, integrated discrimination improvement (IDI) and net reclassification improvement (NRI) were used to evaluate the predictive performance of the models. Nomograms were established according to the optimal models. They're put into internal validation using bootstrapping technique and external validation using calibration curves. Nomograms were compared with AJCC 8th TNM stage using decision curve analysis. RESULTS: NPLN, LODDS and LNR were independent prognostic factors for cancer-specific survival and overall survival. LODDS+LNR (Model 4) demonstrated the highest Likelihood-ratio χ2 test, highest Harrell concordance index, and lowest Akaike Information Criterion, and IDI and NRI values suggested Model 4 had better prediction accuracy than other models. Internal and external validations showed that the nomograms combining TNM stage with LODDS+LNR were convincingly precise. Decision curve analysis suggested the nomograms performed better than AJCC 8th TNM stage in clinical practicability. CONCLUSIONS: We constructed online nomograms for cancer-specific survival and overall survival of lung adenocarcinoma patients after surgery, which may facilitate doctors to provide highly individualized therapy.

Steroid 5α-Reductase Type I Induces Cell Viability and Migration via Nuclear Factor-κB/Vascular Endothelial Growth Factor Signaling Pathway in Colorectal Cancer.

Colorectal cancer (CRC) is a common malignant tumor of the digestive system. Steroid 5α-reductase type I (SRD5A1), as an important part of the steroid metabolism, converts testosterone to dihydrotestosterone and regulates sex hormone levels, which accommodates tumor occurrence or development. However, the underlying molecular mechanism of SRD5A1 in CRC remains unclear. We compared SRD5A1 expression in CRC tissues with normal controls by immunohistochemistry and found that elevated SRD5A1 in CRC was relevant for poor patient prognosis. Furthermore, inducible downregulation of SRD5A1 by small hairpin RNA reduced cell viability, promoted cell cycle arrest, and induced cell apoptosis and cellular senescence of CRC cells, as well as attenuated cell migration ability. In the following experiments, we used dutasteride (an inhibitor of SRD5A1/2) to explore its inhibitory effect on the biological processes of CRC cells, as mentioned earlier. Further mechanism study demonstrated that the repression of SRD5A1 abolished the expression of p65 and vascular endothelial growth factor, suggesting that SRD5A1 might regulate cell viability and migration through nuclear factor-κB/vascular endothelial growth factor signaling pathway. Collectively, these findings implicate SRD5A1 acting as a novel biomarker for CRC diagnosis and prognosis and provide compelling evidence for the future evaluation of dutasteride as a promising candidate for CRC treatment.

Bismuth Porphyrin Antagonizes Cisplatin-Induced Nephrotoxicity via Unexpected Metallothionein-Independent Mechanisms.

Cisplatin (CDDP) has been a highly successful anticancer drug in cancer therapy; however, its further application suffers severe nephrotoxicity. Herein, we identify bismuth tetraphenylporphyrinate [Bi(TPP)] as a potent protective agent against CDDP-induced nephrotoxicity. Bi(TPP) attenuates CDDP-induced acute kidney injury and prevents the death of mice exposed to a lethal dose of CDDP. The protective potency of bismuth porphyrin complexes could be optimized by varying lipophilic TPP ligands with ideal ClogP values of 8-14. Unexpectedly, Bi(TPP) exhibited a protective role via metallothionein-independent pathways, i.e., maintenance of redox homeostasis and energy supplement, elimination of accumulated platinum in the kidney, and inactivation of caspases cascade in apoptotic pathway. Significantly, Bi(TPP) does not compromise the antitumor activity of CDDP in the orthotopic tumor xenograft mouse model. These findings suggest that Bi(TPP) could be incorporated into current CDDP-based cancer therapy as a nephroprotective agent.

Sublobectomy versus lobectomy for long-term survival outcomes of early-stage non-small cell lung cancer with a tumor size ≤2 cm accompanied by visceral pleural invasion: a SEER population-based study.

BACKGROUND: The optimal surgical strategy for early-stage non-small cell lung cancer (NSCLC) with visceral pleural invasion (VPI) remains unclear. Due to limited prospective comparative data for these surgical modalities, the objective of the current study was to compare the long-term survival outcomes of sublobectomy (Sub) versus lobectomy (Lob) for NSCLC with a tumor size ≤2 cm and VPI. METHODS: Patients with early-stage NSCLC characterized by VPI diagnosed between 2004 and 2013 were identified from the Surveillance, Epidemiology, and End Results (SEER) program. The baseline demographic and cancer characteristics, treatment information as well as survival outcome data were extracted from the SEER database, and confounders were balanced by propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) analyses. Lung disease-specific survival (DSS) and overall survival (OS) rates were compared with Cox proportional hazards (PH) regression models based on the unmatched cohort, the propensity-based matched cohort, and the IPTW cohort. RESULTS: Of the 1,386 patients enrolled, 1,000 (72.15%) and 386 (27.85%) underwent lobectomy and sublobectomy, respectively. The 5-year DSS rate was 78.64% for the lobectomy group and 59.47% for the sublobectomy group. Cox regression models demonstrated that the operation type (Sub vs. Lob) was an independent prognostic factor for early-stage NSCLC with VPI based on the three different cohorts. Patients who underwent lobectomy showed better long-term DSS and OS rates than those treated with sublobectomy after PSM [DSS: hazard ratio (HR) 0.689, 95% confidence interval (CI): 0.490-0.968, P=0.032; OS: HR 0.723, 95% CI: 0.549-0.953, P=0.021]. The IPTW analysis yielded similar results. CONCLUSIONS: Lobectomy showed superior long-term survival compared with sublobectomy in patients with early-stage NSCLC with a tumor size ≤2 cm and VPI.

Identification and characterization of circular RNAs in atrial appendage of patients with atrial fibrillation.

Circular RNAs (circRNAs) have emerged as a novel type of non-coding RNA (ncRNA) of interest in gene regulation, especially for its vital function underlying many diseases. Atrial fibrillation is the most common sustained arrythmia. However, the expression spectrum and function of circRNAs in atrial appendage of patients with atrial fibrillation (AF) has seldomly been investigated. Human atrial appendage tissues were acquired during cardiac surgery, which were divided into the AF group and the Sinus rhythm (SR) group. The expression characterization of circRNAs of two groups was revealed by high-throughput sequencing. The dysregulated circRNAs were identified and analyzed by bioinformatics methods, and further validated by realtime PCR. A total 18109 circRNAs in human atrial appendage tissues were targeted. Among them, 147 differentially expressed circRNAs (102 up-regulated and 45 down-regulated) were found between AF group and SR group. Gene ontology (GO) and KEGG pathway analysis indicated that many mRNAs transcribed from the host genes of altered circRNAs were implicated in regulation of sequence-specific DNA binding transcription factor activity, as well as nicotinate and nicotinamide metabolism pathways. Analysis of the association between differently expressed circRNA and miRNA were explored, which revealed an ample interaction. Our study firstly revealed the expression spectrum of circRNAs in both left and right atrial appendage of patients with or without AF. Differentially expressed circRNAs in the atrial appendage were also identified, analyzed and validated. The results of this study may provide novel biomarkers and potential therapeutic targets for AF.

Unusual Drug Fever Caused by Imipenem/Cilastatin and a Review of Literature.

INTRODUCTION: Drug fever is a febrile reaction caused by initiation of one drug or varieties of drugs and often disappears after cessation of the drug(s). Clinically, drug fever is frequently induced by antibiotics, anticonvulsants, and antineoplastics. There are few previous reports about drug fever caused by imipenem/cilastatin. CASE PRESENTATION: Here, we described a 66-year-old man undergoing the Ivor Lewis esophagectomy for esophageal carcinoma, who developed drug fever. The patient had a high temperature with shivering after administration of imipenem/cilastatin for 7 days. Furthermore, his temperature came down after discontinuing imipenem/cilastatin and receiving steroids. Body temperature increased rapidly 4 hours after intravenous readministration of imipenem/cilastatin and rapidly decreased to normal after discontinuing imipenem/cilastatin and administering steroids. CONCLUSION: Thorough history, blood tests, physical examination, and computed tomography (CT) did not reveal any evidence of fever. Drug fever caused by imipenem/cilastatin was considered. We also present a review of relevant literature and provide a point of reference for the clinical diagnosis and therapy of patients with drug fever.