Development and validation of a nomogram to predict the five-year risk of revascularization for non-culprit lesion progression in STEMI patients after primary PCI.

Background: Acute ST-segment elevation myocardial infarction (STEMI) patients after primary PCI were readmitted for revascularization due to non-culprit lesion (NCL) progression. Objective: To develop and validate a nomogram that can accurately predict the likelihood of NCL progression revascularization in STEMI patients following primary PCI. Methods: The study enrolled 1,612 STEMI patients after primary PCI in our hospital from June 2009 to June 2018. Patients were randomly divided into training and validation sets in a 7:3 ratio. The independent risk factors were determined by LASSO regression and multivariable logistic regression analysis. Multivariate logistic regression analysis was utilized to develop a nomogram, which was then evaluated for its performance using the concordance statistics, calibration plots, and decision curve analysis (DCA). Results: The nomogram was composed of five predictors, including age (OR: 1.007 95% CI: 1.005-1.009, P < 0.001), body mass index (OR: 1.476, 95% CI: 1.363-1.600, P < 0.001), triglyceride and glucose index (OR: 1.050, 95% CI: 1.022-1.079, P < 0.001), Killip classification (OR: 1.594, 95% CI: 1.140-2.229, P = 0.006), and serum creatinine (OR: 1.007, 95% CI: 1.005-1.009, P < 0.001). Both the training and validation groups accurately predicted the occurrence of NCL progression revascularization (The area under the receiver operating characteristic curve values, 0.901 and 0.857). The calibration plots indicated an excellent agreement between prediction and observation in both sets. Furthermore, the DCA demonstrated that the model exhibited clinical efficacy. Conclusion: A convenient and accurate nomogram was developed and validated for predicting the occurrence of NCL progression revascularization in STEMI patients after primary PCI.

Beneficial effects of flavonoids on animal models of atherosclerosis: A systematic review and meta-analysis.

Atherosclerosis is the main cause of cardiovascular diseases that seriously endanger human health. The existing treatment drugs are effective, but they have some side effects. Accumulating evidence suggests that flavonoids have attracted wide attention due to their multiple cardioprotective effects and fewer side effects. PubMed, Web of Science database, Embase, and Cochrane Library were searched for studies evaluating the effects of flavonoids against atherosclerosis. 119 studies published from August 1954 to April 2023 were included. Random-effects models were performed for synthesis. Compared with the control group, flavonoids significantly reduced longitudinal and cross-sectional plaque area. The findings indicated that flavonoids significantly reduced the concentrations of serum TC, TG, and LDL-C and increased serum HDL-C concentrations. Besides, flavonoids reduced the levels of circulating pro-inflammatory factors, including TNF-α, IL-1ß, and IL-6, and increased the serum IL-10 level. This study provides evidence for the potential cardiovascular benefits of flavonoids.

Association between triglyceride glucose-body mass index and heart failure in subjects with diabetes mellitus or prediabetes mellitus: a cross-sectional study.

Background: The triglyceride glucose-body mass index (TyG-BMI) is a surrogate indicator of insulin resistance. However, the association of TyG-BMI with heart failure (HF) in individuals with diabetes mellitus or prediabetes mellitus is unknown. Methods: This study included 7,472 participants aged 20-80 years old with prediabetes or diabetes from the National Health and Nutrition Examination Survey (2007-2018). The TyG-BMI was calculated as Ln [triglyceride (mg/dL) × fasting blood glucose (mg/dL)/2] × BMI, and individuals were categorized into tertiles based on TyG-BMI levels. The relationship of TyG-BMI with HF was analyzed using multiple logistic regression models. Subgroup analyses were stratified by gender, age, hypertension, and diabetes mellitus status. Results: This cross-sectional study had 7,472 participants (weighted n = 111,808,357), including 329 HF participants. Participants with a high TyG-BMI were prone to HF. The highest tertile group with a fully adjusted model was more likely to have HF compared to the lowest tertile group (odds ratio [OR], 2.645; 95% CI, 1.529-4.576). Restricted cubic spline analysis showed a significant dose-response relationship between TyG-BMI and HF (P < 0.001). In subgroup analyses, similar results were seen in terms of age (≥50 years old), gender, hypertension, and diabetes mellitus status. Conclusion: A high TyG-BMI is significantly associated with HF risk in participants with diabetes mellitus or prediabetes mellitus.

Association of low-level lead exposure with all-cause and cardiovascular disease mortality in US adults with hypertension: evidence from the National Health and Nutrition Examination Survey 2003-2010.

BACKGROUND: To explore the association of low-level lead exposure with all-cause mortality and cardiovascular disease (CVD) mortality among hypertensive patients. METHODS: This cohort study enrolled 6453 adults with hypertension from the National Health and Nutrition Examination Survey 2003-2010 and followed mortality information through December 31, 2019. The baseline population were divided into four groups based on quartiles of blood lead levels (Q1: < 1.2 µg/dL, Q2: 1.2-1.6 µg/dL, Q3: 1.7-2.4 µg/dL, Q4: 2.5-4.9 µg/dL). The correlation of blood lead levels to mortality was investigated by Kaplan-Meier survival curves, restricted cubic spline (RCS), proportional hazard regression model, and subgroup analysis. RESULTS: During a median follow-up period of 136 (interquartile range 113, 164) months, a total of 1943 (30.1%) deaths were documented, among which 553 (28.5%) were due to CVD. Blood lead showed a linear dose-response relationship with all-cause and CVD mortality. After adequate adjusting for confounders, the risk of all-cause death rose by 23% for each unit increase in continuous variable blood lead (hazard ratio (HR): 1.23; 95% confidence interval (CI):1.16-1.30). When blood lead was a quartile group variable, participants in the Q 4 group had a 73% higher risk of death than those in the Q 1 group (HR:1.73; 95% CI: 1.43-2.10; P for trend < 0.001). The association for CVD mortality was analogous. The concordant results were achieved in the subgroup analysis. CONCLUSION: Elevated blood lead levels were strongly associated with an increased all-cause and CVD mortality in adults with hypertension, even at the reference range of blood lead.

The binding affinity of human pediatric respiratory syncytial virus Phosphoprotein's C-terminal tail to nucleocapsid can be improved by a rationally designed halogen-bonded system.

Human respiratory syncytial virus (hRSV) is a common contagious virus that causes infections of pediatric pneumonia and specifically impacts infants and small children. The hRSV phosphoprotein is a key component of the viral RNA polymerase, which can interact with nucleocapsid and other partners through its C-terminal tail (CTT) to promote the formation of viral transcriptase complex, where the Phe241 is a key anchor residue. Based on the crystal template-modeled complex structure of hRSV nucleocapsid with a peptidic segment derived from the phosphoprotein's CTT, we successfully introduced a rationally designed halogen-bonded system to the complex interface by substituting para (p)-position of the side-chain phenyl moiety of CTT Phe241 residue with a halogen atom X (X = F, Cl, Br or I). The halogen-bonded system consists of a halogen bond (X-bond) between nucleocapsid Ser131 residue and CTT Phe241 residue as well as a hydrogen bond (H-bond) between nucleocapsid Ser131 residue and nucleocapsid Glu128 residue; the X-bond and H-bond share a common hydroxyl group of nucleocapsid Ser131 residue. High-level theoretical calculations suggested that bromine Br is the best choice that can render strong potency for the X-bond and can confer high affinity to the nucleocapsid-CTT binding. Affinity analysis revealed that the p-brominated CTT ([p]bCTT) exhibited 6.3-fold affinity improvement relative to its nonhalogenated counterpart. In contrast, the Br-substitutions at ortho (o)- and meta (m)-positions, which resulted in two negative controls of o-brominated [o]bCTT and m-brominated [m]bCTT, respectively, were unable to form effective X-bond with nucleocapsid according to theoretical investigation and did not improve the binding affinity essentially relative to native CTT.

Development and Validation of a Clinical and Laboratory-Based Nomogram for Predicting Coronary Microvascular Obstruction in NSTEMI Patients After Primary PCI.

OBJECTIVE: Cardiac microvascular obstruction (CMVO) remains a severe complication in non-ST elevation myocardial infarction (NSTEMI) patients with reperfusion therapy. We aimed at developing and validating the nomogram to predict the possibility of CMVO after primary percutaneous coronary intervention (PCI) by integrating clinical and laboratory-based information. METHODS: A total of 325 patients undergoing primary PCI for NSTEMI were recruited and divided into the training cohort (n=226) and the validating cohort (n = 99). The development of the nomogram was based on independent predictors of CMVO, and these variables were selected by multivariable logistic regression analysis. RESULTS: Independent predictors contained in nomogram were identified by multivariable logistic regression analysis, and these independent predictors included neutrophils (OR 1.166, 95% CI 1.044-1.303, P<0.01), hemoglobin (OR 1.037, 95% CI 1.013-1.062, P<0.01), triglyceride (OR 1.343, 95% CI 1.059; 1.704, P=0.015), Killip grade (OR 2.190, 95% CI 1.065-4.503, P=0.033), high thrombus load (OR 3.146, 95% CI 1.424-6.952, P<0.01), no-reflow (OR 3.142, 95% CI 1.419-6.955, P<0.01) and ischemic postconditioning (OR 0.445, 95% CI 0.209-0.944, P=0.035). The nomogram accurately predicted the presentation of CMVO in both the training set and validating set (AUC, 0.835 and 0.881, respectively). The results predicted by nomogram were confirmed to be highly consistent with the results of DE-CMR, both the training and validating cohorts, by Calibration plot and Hosmer-Lemeshow test. Decision curve analysis (DCA) also suggested that the nomogram was applicable in the clinic. CONCLUSION: The nomogram showed good performance in predicting CMVO, and it could help clinicians optimize the clinical treatments to improve the prognosis of NSTEMI patients.

Nivolumab and Hypofractionated Radiotherapy in Patients With Advanced Lung Cancer: ABSCOPAL-1 Clinical Trial.

BACKGROUND: More clinical practice need to be performed to verify the toxicity of the hypofractionated radiotherapy (HFRT) combined with PD-1 blockade in lung cancer. This phase I study aimed to investigate the safety and efficacy of nivolumab combined with HFRT in patients with progressive advanced lung cancer following multiline treatment. METHODS: We enrolled 31 patients with advanced lung cancer pathologically confirmed to have progressive disease and treated with first-line or a higher therapy. Selected lesions were treated using HFRT, and nivolumab was administered within 7 days subsequently. Nivolumab was administered once a month following partial remission. Peripheral blood was collected before and after 1 month of treatment to evaluate relevant cytokines between nivolumab responders and non-responders. RESULTS: Overall, 23 patients who completed the treatment were evaluated. Of them, 9 and 14 patients underwent hypofractionated brachytherapy with 30 Gy in a single fraction via percutaneous interstitial implantation of (192)Ir and 40-50 Gy in 5 fractions via stereotactic body radiation therapy, respectively. The median follow-up period was 11 months. At the 1-year follow-up, no patient developed grade ≥ 3 pneumonitis. The overall objective response and complete remission rates were 39.13% and 13.04%, respectively. The 1-year overall survival and median progression-free survival were 60.9% and 6 months, respectively. The plasma levels of interleukin IL-6, IL-10, and IL-17A were significantly reduced after treatment in nivolumab responders. CONCLUSIONS: HFRT could increase the responsivity to nivolumab and reduce its administration frequency. This combination treatment is well tolerated with acceptable toxicity and thus merits further trials to validate benefits. CLINICAL TRIAL REGISTRATION: http://www.chictr.org.cn/index.aspx, identifier ChiCTR-1900027768.

Intratumoral Injection of Anlotinib Hydrogel Combined With Radiotherapy Reduces Hypoxia in Lewis Lung Carcinoma Xenografts: Assessment by Micro Fluorine-18-fluoromisonidazole Positron Emission Tomography/Computed Tomography Hypoxia Imaging.

Hypoxia is a common feature of solid tumors that increases tumor invasiveness and resistance to radiotherapy (RT) and chemotherapy. Local application of anlotinib (AL) might increase the regulation of new blood vessel growth and improve tumor hypoxia in RT. Therefore, it is essential to fully understand the drug delivery system of AL. Herein, we applied hypoxia imaging using micro fluorine-18-fluoromisonidazole positron emission tomography/computed tomography (micro 18F-FMISO PET/CT) to assess responses to intratumoral injections of an AL hydrogel (AL-HA-Tyr) combined with RT in mice bearing Lewis lung carcinoma (LLC). We formed AL-HA-Tyr by encapsulating AL with hyaluronic acid-tyramine (HA-Tyr) conjugates via the oxidative coupling of tyramine moieties catalyzed by H2O2 and horseradish peroxidase. AL-HA-Tyr restrained the proliferation of human umbilical endothelial cells (HUVECs) in colony formation assays in vitro (p < 0.001). We established a subcutaneous LLC xenograft model using C57BL/6J mice that were randomly assigned to six groups that were treated with AL, HA-Tyr, AL-HA-Tyr, RT, and RT+AL-HA-Tyr, or untreated (controls). Tumor volume and weight were dynamically measured. Post treatment changes in hypoxia were assessed in some mice using micro 18F-FMISO PET/CT, and survival was assessed in others. We histopathologically examined toxicity in visceral tissues and Ki-67, VEGF-A, γ-H2AX, and HIF-1α expression using immunohistochemistry. Direct intratumoral injections of AL-HA-Tyr exerted anti-tumor effects and improved hypoxia like orally administered AL (p > 0.05), but reduced visceral toxicity and prolonged survival. The uptake of 18F-FMISO did not significantly differ among the AL, AL-HA-Tyr, and RT+AL-HA-Tyr treated groups. Compared with the other agents, RT+AL-HA-Tyr decreased HIF-1α, Ki67, and VEGF-A expression, and increased γ-H2AX levels in tumor cells. Overall, compared with AL and AL-HA-Tyr, RT+AL-HA-Tyr improved tumor hypoxia, enhanced anti-tumor effects, and prolonged the survival of mice bearing LLC.

Positron Emission Tomography-Based Short-Term Efficacy Evaluation and Prediction in Patients With Non-Small Cell Lung Cancer Treated With Hypo-Fractionated Radiotherapy.

BACKGROUND: Positron emission tomography is known to provide more accurate estimates than computed tomography when staging non-small cell lung cancer. The aims of this prospective study were to contrast the short-term efficacy of the two imaging methods while evaluating the effects of hypo-fractionated radiotherapy in non-small cell lung cancer, and to establish a short-term efficacy prediction model based on the radiomics features of positron emission tomography. METHODS: This nonrandomized-controlled trial was conducted from March 2015 to June 2019. Thirty-one lesions of 30 patients underwent the delineation of the regions of interest on positron emission tomography and computed tomography 1 month before, and 3 months after hypo-fractionated radiotherapy. Each patient was evaluated for the differences in local objective response rate between the two images. The Kaplan Meier method was used to analyze the local objective response and subsequent survival duration of the two imaging methods. The 3D Slicer was used to extract the radiomics features based on positron emission tomography. Least absolute shrinkage and selection operator regression was used to eliminate redundant features, and logistic regression analysis was used to develop the curative-effect-predicting model, which was displayed through a radiomics nomogram. Receiver operating characteristic curve and decision curve were used to evaluate the accuracy and clinical usefulness of the prediction model. RESULTS: Positron emission tomography-based local objective response rate was significantly higher than that based on computed tomography [70.97% (22/31) and 12.90% (4/31), respectively (p<0.001)]. The mean survival time of responders and non-responders assessed by positron emission tomography was 28.6 months vs. 11.4 months (p=0.29), whereas that assessed by computed tomography was 24.5 months vs. 26 months (p=0.66), respectively. Three radiomics features were screened to establish a personalized prediction nomogram with high area under curve (0.94, 95% CI 0.85-0.99, p<0.001). The decision curve showed a high clinical value of the radiomics nomogram. CONCLUSIONS: We recommend positron emission tomography for evaluating the short-term efficacy of hypo-fractionated radiotherapy in non-small cell lung cancer, and that the radiomics nomogram could be an important technique for the prediction of short-term efficacy, which might enable an improved and precise treatment. REGISTRATION NUMBER/URL: ChiCTR1900027768/http://www.chictr.org.cn/showprojen.aspx?proj=46057.

Anti-tumor effect of local injectable hydrogel-loaded endostatin alone and in combination with radiotherapy for lung cancer.

Endostatin (ES) can effectively inhibit neovascularization in most solid tumors and has the potential to make oxygen delivery more efficient and increase the efficacy of radiotherapy (RT). With a short half-life, ES is mainly administered systemically, which leads to low intake in tumor tissue and often toxic systemic side effects. In this study, we used hyaluronic acid-tyramine as a carrier to synthesize an ES-loaded hydrogel drug (ES/HA-Tyr) that can be injected locally. ES/HA-Tyr has a longer half-life and fewer systemic toxic side effects, and it exerts a better anti-angiogenic effect and anti-tumor effect with RT. In vitro, ES/HA-Tyr showed sustained release in the release assay and a stronger ability to inhibit the proliferation of human umbilical vascular endothelial cells (HUVECs) in the MTT assay; it exhibited a more potent effect against HUVEC invasion and a stronger anti-angiogenic effect on HUVECs in tube formation. In vivo, ES/HA-Tyr increased local drug concentration, decreased blood drug concentration, and caused less systemic toxicity. Further, ES/HA-Tyr effectively reduced tumor microvessel density, increased tumor pericyte coverage, decreased tumor hypoxia, and increased RT response. ES/HA-Tyr + RT also had increased anti-tumor and anti-angiogenic effects in Lewis lung cancer (LLC) xenograft models. In conclusion, ES/HA-Tyr showed sustained release, lower systemic toxicity, and better anti-tumor effects than ES. In addition, ES/HA-Tyr + RT enhanced anti-angiogenic effects, reduced tumor hypoxia, and increased the efficacy of RT in LLC-bearing mice.

Elevated circulating level of P2X7 receptor is related to severity of coronary artery stenosis and prognosis of acute myocardial infarction.

BACKGROUND: Acute myocardial infarction (AMI) is a severely life-threatening cardiovascular disease. Previous research has identified an association between the P2X7 receptor (P2X7R) and the development of atherosclerosis. However, the correlation of its expression with the clinical prognosis of patients with AMI remains unclear. The present study aimed to investigate the potential role of P2X7R in Chinese patients with AMI. METHODS: Seventy-nine patients with AMI and 48 controls were consecutively enrolled in this prospective observational study. Circulating P2X7R mRNA expression levels and other clinical variables were determined upon admission to the hospital. Patients were followed up for 360 days, and the end-point was considered as the occurrence of major adverse cardiovascular events (MACE). RESULTS: Circulating P2X7R mRNA expression level in peripheral blood mononuclear cells of patients with AMI were significantly higher than those in controls and had promising diagnostic ability of AMI with an area under the curve of 0.928. Furthermore, P2X7R was demonstrated to be correlated positively with the severity of coronary artery stenosis. Additionally, this is the first study to indicate that higher P2X7R mRNA expression is associated with a higher rate of MACE within 360 days after AMI. CONCLUSIONS: The present study showed that the circulating level of P2X7R was elevated in AMI patients and was closely associated with the severity of coronary artery stenosis and prognosis of AMI.

Curcumin attenuates endothelial cell fibrosis through inhibiting endothelial-interstitial transformation.

Curcumin (Cur) has various pharmacological activities, including anti-inflammatory, antiapoptotic and anticancer effects. However, there is no report on the effect of Cur on endothelial cell fibrosis. This study was designed to investigate the effect and mechanism of Cur on endothelial cell fibrosis. An endothelial cell fibrosis model was established by using transforming growth factor (TGF) induction. Proliferation assays, qRT-PCR, western blotting and immunostaining were performed to investigate the effects and mechanism of Cur on endothelial cell fibrosis. We found that in human umbilical vein endothelial cells (HUVECs), TGF-ß1 treatment significantly decreased the expression of nuclear factor erythroid-2-related factor 2 (NRF-2), dimethylarginine dimethylaminohydrolase-1 (DDAH1), and VE-cadherin, the secretion of cellular nitric oxide (NO) and the activity of nitrous oxide synthase (NOS), while asymmetric dimethylarginine (ADMA) and the release of inflammatory factors were elevated. Immunofluorescence showed decreased CD31 and increased α-smooth muscle actin (α-SMA). Overexpression of NRF-2 significantly attenuated the effects of TGF-ß1, while downregulation of DDAH1 potently counteracted the effect of NRF-2. In addition, ADMA treatment resulted in similar results to those of TGF-ß1, and Cur significantly attenuated the effect of TGF-ß1, accompanied by increased VE-cadherin, DDAH1 and NRF-2 and decreased matrix metalloproteinase-9 (MMP-9) and extracellular regulated protein kinases 1/2 (ERK1/2) phosphorylation. The NRF-2 inhibitor ML385 had the opposite effect as that of Cur. These results demonstrated that Cur inhibits TGF-ß1-induced endothelial-to-mesenchymal transition (EndMT) by stimulating DDAH1 expression via the NRF-2 pathway, thus attenuating endothelial cell fibrosis.

Hypofractionated 192Ir source stereotactic ablative brachytherapy with coplanar template assistance in the primary treatment of peripheral lung cancer.

PURPOSE: In this study, we reported the safety and efficacy of hypofractionated 192Ir source stereotactic ablative brachytherapy (SABT) with coplanar template assistance for peripheral lung cancer, and compared the dosimetric parameters between SABT and stereotactic body radiotherapy (SBRT). MATERIAL AND METHODS: Thirty-three peripheral lung cancer patients, with the gross lung tumor volume (GTVL) < 5 cm in diameter were enrolled in this study. We assessed the safety and efficacy of SABT, and compared the dosimetric parameters between SABT and SBRT. RESULTS: Chest computed tomography (CT) of post-SABT revealed mild pneumothorax in 2 of 33 patients. Complete response (CR) plus partial response (PR) rate for GTVL at 6-month was 100%. Local control (LC) rate for GTVL at 1-year was 96.9%. For organs at risk (OARs), D1000 cm3, and D1500 cm3 for lung in 1, 3, and 5 fractions were not statistically different between SABT and SBRT (all p > 0.05); the remaining dosimetric parameters were significantly lower in SABT than in SBRT (all p < 0.01). CONCLUSIONS: SABT can provide safe and effective treatment, and warrant generalization for peripheral lung cancer.

Template-assisted 192Ir-based stereotactic ablative brachytherapy as a neoadjuvant treatment for operable peripheral non-small cell lung cancer: a phase I clinical trial.

PURPOSE: To evaluate safety, feasibility, and efficacy of template-assisted 192Ir-based stereotactic ablative brachytherapy (SABT), combined with surgery for peripheral non-small cell lung cancer (NSCLC). MATERIAL AND METHODS: Patients with pathologically confirmed operable peripheral NSCLC, who underwent template-assisted SABT (30 Gy delivered in one fraction) and were scheduled for tumor resection 4-6 weeks after SABT were included in this study. The perioperative adverse reactions of SABT were recorded to evaluate safety and feasibility of SABT for neoadjuvant therapy. Dosimetric data from both simulated and actual plans were collected and compared. Imaging with 18F-fluorodeoxyglucose-positron emission tomography/computed tomography (18F-FDG-PET/CT) and dynamic contrast-enhanced computed tomography were scheduled before SABT and surgery to evaluate the efficacy of the neoadjuvant therapy with SABT. RESULTS: Patients did not experience any serious adverse events. None of the patients had a delay in receiving surgery. After 4-6 weeks, the indicators for the efficacy of neoadjuvant therapy significantly decreased in all patients: gross tumor volume (p < 0.001), maximum standardized uptake value (p < 0.001), tumor blood volume (p < 0.001), and tumor blood flow (p = 0.008). Dosimetric parameters in the delivered SABT plan slightly changed from the preoperative simulation, but the difference was not statistically significant (p > 0.05). CONCLUSIONS: The efficacy of template-assisted SABT for neoadjuvant therapy was significant in operable peripheral NSCLC. Moreover, no serious adverse reactions were observed; when the coplanar template guidance technique was applied, dosimetric parameters were in good agreement between the actual SABT plan and the preoperative simulated plan.

Up-regulation of Insulin-like Growth Factor Binding Protein-3 Is Associated with Brain Metastasis in Lung Adenocarcinoma.

The brain is the most common metastatic site of lung adenocarcinoma; however, the mechanism of this selective metastasis remains unclear. We aimed to verify the hypothesis that exposure of tumor cells to the brain microenvironment leads to changes in their gene expression, which promotes their oriented transfer to the brain. A549 and H1299 lung adenocarcinoma cells were exposed to human astrocyte-conditioned medium to simulate the brain microenvironment. Microarray analysis was used to identify differentially expressed genes, which were confirmed by quantitative real-time PCR and western blotting. Knockdown experiments using microRNAs and the overexpression of genes by cell transfection were performed in addition to migration and invasion assays. In vitro findings were confirmed in clinical specimens using immunohistochemistry. We found and confirmed a significant increase in insulin-like growth factor binding protein-3 (IGFBP3) levels. Our results also showed that the up-regulation of IGFBP3 promoted A549 cell epithelial-mesenchymal transition, migration, and invasion, while the knockdown of IGFBP3 resulted in decreased cell motility. We also found that Transforming growth factor-ß (TGF-ß)/Mothers against decapentaplegic homolog 4 (Smad4)-induced epithelial-mesenchymal transition was likely IGFBP3-dependent in A549 cells. Finally, expression of IGFBP3 was significantly elevated in pulmonary cancer tissues and intracranial metastatic tissues. Our data indicate that up-regulation of IGFBP3 might mediate brain metastasis in lung adenocarcinoma, which makes it a potential therapeutic target.

Synergistic effect and reduced toxicity by intratumoral injection of cytarabine-loaded hyaluronic acid hydrogel conjugates combined with radiotherapy on lung cancer.

The aim of this study was to explore the synergistic anti-tumor effects of cytarabine hyaluronic acid-tyramine (Ara-HA-Tyr) hydrogel conjugates and radiotherapy (RT) in the Lewis lung cancer (LLC) xenograft model, and the mechanisms involved. The radiotherapy sensitization ratio (SER) of 0.5 µg cytarabine (Ara-C) was 1.619 in the LLC cells. Ara-HA-Tyr was prepared by encapsulating Ara-C into hyaluronic acid-tyramine (HA-Tyr) conjugates. The hydrogels were formed through the oxidative coupling of tyramines by hydrogen peroxide (H2O2) and horseradish peroxidase (HRP). Mice engrafted with the LLC cells were given intra-tumoral injections of saline, Ara-C or Ara-HA-Tyr, with or without RT. The combination of Ara-HA-Tyr and RT increased survival compared to free Ara-C and RT (p < 0.05), and prolonged tumor growth delay (TGD). Furthermore, the RT + Ara-HA-Tyr combination therapy significantly reduced 18F-FDG uptake, induced cell cycle arrest at G2/M-phase, increased apoptosis and histone H2AX phosphorylation (γ-H2AX), and decreased the proliferation index (Ki67) in tumor cells compared to either monotherapy. Taken together, Ara-C encapsulated with HA-Tyr effectively sensitized tumor xenografts to RT and showed significantly less systemic toxicity. Graphical abstract In this work, Ara-C encapsulated with hyaluronic acid-tyramine conjugates (HA-Tyr) was prepared and used to investigate its synergistic anti-tumor efficacy by combination with radiotherapy in the Lewis lung cancer xenograft model. The synergistic mechanism may be related to tumor cell cycle redistribution, apoptosis and expression of histone H2AX phosphorylation.

Alternative RNA splicing associated with axon regeneration after rat peripheral nerve injury.

The intrinsic axon regeneration capacity is crucial for peripheral nerve regeneration after injury. Identifying key molecules involved in this process makes great contribution to the investigation of peripheral nerve injury repair. Alternative splicing (AS) is an important regulation mode of eukaryotic gene expression, which has been widely studied both in physiological and pathological processes. However, less is known about the role of AS in peripheral nerve regeneration. In this work, to identify the AS events associated with axon regeneration capacity, we analyzed the AS events during sciatic nerve injury repair by RNA sequencing (RNA-Seq) and replicate multivariate analysis of transcript splicing (rMATS). The differential AS events were underwent gene ontology enrichment and pathway analyses. Moreover, we identified a significantly increased AS event of neuronal cell adhesion molecule Nrcam (Nrcam-S), and demonstrated down-regulation of Nrcam-S by specific siRNAs inhibited axon regeneration of Dorsal Root Ganglion (DRG) neurons after sciatic nerve injury in vitro and in vivo. Additionally, we found expression levels of RNA binding proteins (RBPs) CUGBP Elav-like family member 3 (CELF3) and RNA binding protein fox-1 homolog 2 (Rbfox2) were markedly increased after sciatic nerve injury. Our data may serve as a resource useful for further understanding how AS contributes to molecular regulations in DRG during sciatic nerve regeneration.

Computational redesign of human respiratory syncytial virus epitope as therapeutic peptide vaccines against pediatric pneumonia.

Human respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infections in infants and young children. Here, the RSV fusion (F) glycoprotein epitope FFL was redesigned based on its complex crystal structure with motavizumab, an mAb drug in development for the prevention of RSV infections, aiming to obtain therapeutic peptide vaccines with high affinity to induce RSV-specific neutralizing antibodies. Computational modeling and analysis found that only a small region covering the helix-turn-helix (HTH) motif of FFL can directly interact with motavizumab and confer stability and specificity to the complex system, while the rest of the epitope primarily serves as a structural scaffold that stabilizes the HTH conformation of motavizumab-binding site. Molecular dynamics simulations revealed a large flexibility and intrinsic disorder for the isolated linear HTH peptide, which would incur a considerable entropy penalty upon binding to motavizumab. In this respect, the FFL epitope was redesigned by truncation, mutation, and cyclization to derive a number of small cyclic peptide immunogens. We also employed in vitro fluorescence-based assays to demonstrate that the linear epitope peptide has no observable affinity to motavizumab, whereas redesigned versions of the peptide can bind with a moderate or high potency. Graphical abstract Computationally modeled complex structure of RSV F glycoprotein with motavizumab and zoom up of the complex binding site.

Treatment outcomes after reduction of the target volume of intensity-modulated radiotherapy following induction chemotherapy in patients with locoregionally advanced nasopharyngeal carcinoma: A prospective, multi-center, randomized clinical trial.

PURPOSE: To investigate whether reducing the target volume of intensity-modulated radiotherapy (IMRT) after induction chemotherapy (IC) improves the quality of life (QOL) in locoregionally advanced nasopharyngeal carcinoma (NPC) without decreasing the local control and survival rate. PATIENTS AND METHODS: A total number of 212 NPC patients staged as III-IVb were randomly assigned to group A (n=97) or group B (n=115) in this prospective clinical trial. All patients received IC followed by cisplatin concurrent with IMRT. IMRT was planned using the images of pre-IC in group A and post-IC in group B. RESULTS: The dose received by normal tissues in group B was lower than that of group A (P<0.05). The recovery of the dry mouth symptoms in group B was significantly improved than group B. The quality of life (QOL) scores in group B were higher than group A. With a median follow-up of 35months, the 1-year estimated overall survival (OS), progression-free survival (PFS), locoregional failure-free survival (LRFFS), distant metastasis-free survival (DMFS) in group A versus group B were 97.9% vs 97.3%, 90.7% vs 92,2%, 99.0% vs 98.2%, 91.8% vs 94.8%. The 2-year OS, PFS, LRFFS, DMFS in group A versus group B were 93.7% vs 92.9%, 83.4% vs 84.3%, 96.8% vs 95.5%, 86.5% vs 89.5%. The 3-year OS, PFS, LRFFS, DMFS in group A versus group B were 82.3% vs 87%, 74.7% vs 83.4%, 91.8 vs 93.9%, 81.3% vs 88.6%, respectively. CONCLUSION: Reducing the IMRT target volume after IC did not reduce the local control and survival rate in locoregionally advanced NPC but the doses received by normal tissues were decreased, and the QOL scores were improved.

Identification of peptide-mediated interactions between human PTTG and SH3 domains in pALL gene expression profile.

Human pituitary tumor-transforming gene (PTTG) plays an essential role in the development and progression of pediatric acute lymphoblastic leukemia (pALL). PTTG has two SH3-binding peptide motifs that can be recognized by a variety of SH3-containing proteins in the pALL through peptide-mediated interactions. In this study, the gene expression profile of pALL was examined in detail by integrating computational modeling and experimental assay, aiming to identify those potential partner proteins of human PTTG. The binding potency of domain candidates to peptide motifs was ranked using knowledge-based scoring and fluorescence titration. A number of SH3 domains found in a variety of pALL proteins were identified as potent binders with moderate or high affinity for PTTG. It is revealed that the PTTG peptide motifs show different affinity profiles for various candidate proteins, indicating that the PTTG selectivity is optimized across pALL gene expression space. The PTTG peptides were then mutated rationally to target the SH3 domains of identified partner proteins by competing with the native peptide motifs.