Hainanenin-1, an oncolytic peptide, triggers immunogenic cell death via STING activation in triple-negative breast cancer.

BACKGROUND: In triple-negative breast cancer (TNBC) therapy, insufficient tumor infiltration by lymphocytes significantly hinders the efficacy of immune checkpoint inhibitors. We have previously demonstrated that Hainanenin-1 (HN-1), a host defense peptide (HDP) identified from Hainan frog skin, induces breast cancer apoptosis and boots anti-tumor immunity via unknown mechanism. METHODS: We used in vitro experiments to observe immunogenic cell death (ICD) indicators in HN-1-treated TNBC cell lines, a mouse tumor model to verify HN-1 promotion of mice anti-tumor immune response, and an in vitro drug sensitivity test of patient-derived breast cancer cells to verify the inhibitory effect of HN-1. RESULTS: HN-1 induced ICD in TNBC in a process during which damage-associated molecular patterns (DAMPs) were released that could further increase the anti-tumor immune response. The secretion level of interleukin 2 (IL-2), IL-12, and interferon γ in the co-culture supernatant was increased, and dendritic cells (DCs) were activated via a co-culture with HN-1-pretreated TNBC cells. As a result, HN-1 increased the infiltration of anti-tumor immune cells (DCs and T lymphocytes) in the mouse model bearing both 4T1 and EMT6 tumors. Meanwhile, regulatory T cells and myeloid-derived suppressor cells were suppressed. In addition, HN-1 induced DNA damage, and double-strand DNA release in the cytosol was significantly enhanced, indicating that HN-1 might stimulate ICD via activation of STING pathway. The knockdown of STING inhibited HN-1-induced ICD. Of note, HN-1 exhibited inhibitory effects on patient-derived breast cancer cells under three-dimensional culture conditions. CONCLUSIONS: Collectively, our study demonstrated that HN-1 could be utilized as a potential compound that might augment immunotherapy effects in patients with TNBC.

Antioxidant peptides, the guardian of life from oxidative stress.

Reactive oxygen species (ROS) are produced during oxidative metabolism in aerobic organisms. Under normal conditions, ROS production and elimination are in a relatively balanced state. However, under internal or external environmental stress, such as high glucose levels or UV radiation, ROS production can increase significantly, leading to oxidative stress. Excess ROS production not only damages biomolecules but is also closely associated with the pathogenesis of many diseases, such as skin photoaging, diabetes, and cancer. Antioxidant peptides (AOPs) are naturally occurring or artificially designed peptides that can reduce the levels of ROS and other pro-oxidants, thus showing great potential in the treatment of oxidative stress-related diseases. In this review, we discussed ROS production and its role in inducing oxidative stress-related diseases in humans. Additionally, we discussed the sources, mechanism of action, and evaluation methods of AOPs and provided directions for future studies on AOPs.

Nutritional Therapy Strategies Targeting Tumor Energy Metabolism.

Cancer is the second leading cause of mortality worldwide. The heightened nutrient uptake, particularly glucose, and elevated glycolysis observed in rapidly proliferating tumor cells highlight the potential targeting of energy metabolism pathways for the treatment of cancer. Numerous studies and clinical trials have demonstrated the efficacy of nutritional therapy in mitigating the adverse effects of chemotherapy and radiotherapy, enhancing treatment outcomes, prolonging survival, and improving the overall quality of life of patients. This review article comprehensively examines nutritional therapy strategies that specifically address tumor energy metabolism. Moreover, it explores the intricate interplay between energy metabolism and the gut microbiota in the context of nutritional therapy. The findings aim to provide valuable insights for future clinical research endeavors in this field.

A unique inflammation-related mechanism by which high-fat diets induce depression-like behaviors in mice.

BACKGROUND: High-fat diet (HFD) consumption is an important reason for promoting depression, but the mechanism is unclear. The present study aims to explore the relationship between metabolic disturbance and HFD-induced depression-like behaviors. METHODS: Depression models were established by HFD consumption and chronic unpredictable mild stress (CUMS) in mice. Enzyme-linked immunosorbent assay, western blotting, real-time polymerase chain reaction, gas chromatography and metabolomic analysis were undertaken to investigate the 5-hydroxytryptamine (5-HT) system, neuroinflammation and to identify altered lipid metabolic pathways. RESULTS: Depression-like behaviors, impaired 5-HT neurotransmission and disordered lipid metabolism were observed upon HFD consumption. Despite a similar reduction of high-density lipoprotein cholesterol in CUMS and HFD group, high levels of body low-density lipoprotein cholesterol in the HFD group could help distinguish HFD from CUMS. Levels of interleukin (IL)-1ß, IL-6, tumor necrosis factor (TNF)-α and inflammation-related metabolites were increased in HFD mice, so a link between depression and inflammation was postulated. Different metabolites were enriched in the two groups. The linoleic acid (LA) metabolic pathway and expression of fatty acid desaturase (FADS)1 and FADS2 (key enzymes in LA metabolic pathway) were enhanced significantly in HFD mice compared with the control group. LIMITATIONS: Causality analyses for HFD and inflammation-related features were not undertaken. CONCLUSIONS: HFD-induced depression-like behaviors was characterized by more severely disordered metabolism of lipids (especially in the LA metabolic pathway) and increased levels of inflammatory mediators, which might be the reasons for the disturbance of serotonergic system in hippocampus.

Rationally Designed Nonapeptides with Great Skin Photoprotective Effect through Producing Type 1 Collagen and Blocking the mTOR Pathway.

Ultraviolet (UV), as the most common environmental stress factor to human skin, causes redox imbalance and leads to photoaging and the development of cancer. In this work, we screened a nonapeptide (PWH) with good activities of antioxidant, promoting the secretion of type 1 collagen (COL-1) and repairing damaged skin from a series of rationally designed novel short peptides. PWH could alleviate UV-A-induced oxidative stress, restrain pro-inflammatory cytokine production, protect mitochondrial function, and maintain autophagy activity. We also first indicated that inhibiting the PI3K/AKT/mTOR signaling pathway and restoration of autophagy activity might delay the photoaging process in skin cells. Topical applications of PWH were further demonstrated to exhibit significant protection in full-wavelength UV-induced skin aging in mice models both in the prophylaxis and treatment way. In addition, given the good stability and without unwanted toxicity and anaphylaxis, PWH could be a promising candidate for cosmetics and pharmaceuticals.

Reducing VEGFB expression regulates the balance of glucose and lipid metabolism in mice via VEGFR1.

In recent years, studies have demonstrated that vascular endothelial growth factor B (VEGFB) can affect the metabolism of fatty acids and glucose, and it is expected to become a target for the diagnosis and treatment of metabolic diseases such as obesity and diabetes. At present, the specific mechanism that VEGFB regulates lipid and glucose metabolism balance is not completely understood. The present study used systemic VEGFB gene­knockout mice to investigate the effects of downregulation of the VEGFB gene on lipid metabolism and insulin secretion, and to explore the mechanism of the VEGFB pathway involved in the regulation of glucose and lipid metabolism. The morphological changes in the liver and pancreas of mice after VEGFB gene deletion were observed under a light microscope and a scanning electron microscope, and the effects of VEGFB gene deletion on lipid metabolism and blood glucose balance were detected by a serological technique. The detection indexes included total cholesterol (TC), triglyceride (TG), low­density lipoprotein cholesterol (LDL­C) and high­density lipoprotein cholesterol. Simultaneously, fasting blood glucose, glycosylated hemoglobin A1c (HbA1c), fasting insulin and glucagon were measured. Insulin sensitivity was assessed by using the insulin tolerance tests and glucose tolerance tests, and function of ß­cell islets was evaluated by using the insulin resistance index (HOMA­IR) and pancreatic ß­cell secretion index (HOMA­ß). Τhe protein expression changes of vascular endothelial growth factor receptor 1 (VEGFR1) and vascular endothelial growth factor receptor 2 (VEGFR2) in mouse islets were detected by western blotting and reverse transcription­quantitative polymerase chain reaction (RT­qPCR) after the VEGFB gene was knocked down to analyze the mechanism of VEGFB that may be involved in glucose and lipid metabolism. It was observed that after VEGFB was knocked down, mouse hepatocytes exhibited steatosis and increased secretory vesicles in islet cells. The lipid metabolism indexes such as TG, TC and LDL increased significantly; however, the levels of FBS, postprandial blood glucose and HbA1c decreased, whereas the glucose tolerance increased. Serum insulin secretion increased and HOMA­IR decreased since VEGFB was knocked down. Western blotting and RT­qPCR results revealed that the expression levels of VEGFR1 and neuropilin­1 decreased after the VEGFB gene was knocked down, while the expression levels of VEGFA and VEGFR2 increased. The absence of VEGFB may be involved in the regulation of glucose and lipid metabolism in mice by activating the VEGFA/VEGFR2 signaling pathway. VEGFB is expected to become a new target for the treatment of metabolic diseases such as obesity and diabetes. At present, the mechanism of VEGFB involved in regulating lipid metabolism and glucose metabolism is not completely clear. It was identified that downregulating VEGFB improved lipid metabolism and insulin resistance. The role of VEGFB/VEGFR1 pathway and other family members in regulating glucose and lipid metabolism was detected, which provided a theoretical and experimental basis for VEGFB to affect the regulation of glucose and lipid metabolism balance.

A clinical variable-based nomogram could predict the survival for advanced NSCLC patients receiving second-line atezolizumab.

OBJECTIVE: A nomogram model based on clinical variables was conducted to predict the survival in patients with non-small cell lung cancer (NSCLC) receiving second-line atezolizumab. METHODS: Four hundred and twenty-four patients with NSCLC receiving atezolizumab from OAK study were regarded as the training cohort. Next, a nomogram model based on clinical variables in the training cohort was established to predict the survival of patients receiving atezolizumab. The concordance index, area under curve (AUC), and calibration plots were used to assess the performance of the nomogram model. In addition, 144 patients with NSCLC receiving atezolizumab from POPLAR study were regarded as the test cohort to validate the nomogram model. Using Kaplan-Meier and log-rank test, we compared the survival difference between the high- and low-risk groups, atezolizumab and docetaxel treatment groups, respectively. RESULTS: We successfully constructed a nomogram model based on different variable scores for predicting the survival in NSCLC patients receiving atezolizumab using the training cohort. According to risk score, patients receiving atezolizumab were divided into the high- and low-risk groups. Importantly, in the training cohort, patients had worse overall survival (OS) in high-risk group compared with the low-risk group (median survival: 252.3 vs. 556.9 days; p < 0.0001). As expected, in the test cohort, the high-risk patients also showed a worse OS (median survival: 288.8 vs. 529.3 days, p = 0.0003). In addition, all the patients from the training and test cohorts could be found the OS benefit from atezolizumab compared with docetaxel (all, p < 0.05). CONCLUSIONS: The clinical variable-based nomogram model could predict the survival benefit for NSCLC patients receiving second-line atezolizumab.

A novel nomogram containing acute radiation esophagitis predicting radiation pneumonitis in thoracic cancer receiving radiotherapy.

BACKGROUND: Radiation-induced pneumonitis (RP) is a non-negligible and sometimes life-threatening complication among patients with thoracic radiation. We initially aimed to ascertain the predictive value of acute radiation-induced esophagitis (SARE, grade ≥ 2) to symptomatic RP (SRP, grade ≥ 2) among thoracic cancer patients receiving radiotherapy. Based on that, we established a novel nomogram model to provide individualized risk assessment for SRP. METHODS: Thoracic cancer patients who were treated with thoracic radiation from Jan 2018 to Jan 2019 in Shandong Cancer Hospital and Institute were enrolled prospectively. All patients were followed up during and after radiotherapy (RT) to observe the development of esophagitis as well as pneumonitis. Variables were analyzed by univariate and multivariate analysis using the logistic regression model, and a nomogram model was established to predict SRP by "R" version 3.6.0. RESULTS: A total of 123 patients were enrolled (64 esophageal cancer, 57 lung cancer and 2 mediastinal cancer) in this study prospectively. RP grades of 0, 1, 2, 3, 4 and 5 occurred in 29, 57, 31, 0, 3 and 3 patients, respectively. SRP appeared in 37 patients (30.1%). In univariate analysis, SARE was shown to be a significant predictive factor for SRP (P < 0.001), with the sensitivity 91.9% and the negative predictive value 93.5%. The incidence of SRP in different grades of ARE were as follows: Grade 0-1: 6.5%; Grade 2: 36.9%; Grade 3: 80.0%; Grade 4: 100%. Besides that, the dosimetric factors considering total lung mean dose, total lung V5, V20, ipsilateral lung mean dose, ipsilateral lung V5, and mean esophagus dose were correlated with SRP (all P < 0.05) by univariate analysis. The incidence of SRP was significantly higher in patients whose symptoms of RP appeared early. SARE, mean esophagus dose and ipsilateral mean lung dose were still significant in multivariate analysis, and they were included to build a predictive nomogram model for SRP. CONCLUSIONS: As an early index that can reflect the tissue's radiosensitivity visually, SARE can be used as a predictor for SRP in patients receiving thoracic radiation. And the nomogram containing SARE may be fully applied in future's clinical work.

Incorporating the Number of PLN into the AJCC Stage Could Better Predict the Survival for Patients with NSCLC: A Large Population-Based Study.

PURPOSE: This study aimed to investigate the application of the number of positive lymph nodes (PLNs) in tumor, node, metastasis (TNM) staging system of non-small cell lung cancer (NSCLC) patients. Patients and Methods. We screened a total of 15820 patients with resected NSCLC between 2004 and 2015 from SEER database. The X-tile model was used to determine the cutoff values of the number of PLNs. Overall survival (OS) curves were plotted using the Kaplan-Meier method, and the differences among the individual groups were defined using the log-rank test. Cox regression model was used to perform univariate and multivariate analyses and to assess the association between the number of PLNs and OS. RESULTS: In this study, using the X-tile model, we screened three different cutoff values, including nN0, nN1-3, and nN4-. Survival curves demonstrated that our defined nN stage had a significant predictive value for OS (P < 0.001). In the univariate and multivariate Cox analyses, the result showed that nN stage was a significant prognostic factor of OS for NSCLC patients (P < 0.001). Subsequently, we classified the patients into five subgroups based on the combination of pN and nN stages, including pN0 + nN0, pN1 + nN1-3, pN2 + nN1-3, pN1 + nN4-, and pN2 + nN4-. Moreover, survival curves revealed significant differences among these five groups (P < 0.001). CONCLUSION: A combination of pathological LNs (pN) and the number of LN (nN) involvement in NSCLC patients had a better prognostic value than the current TNM staging system based on only pN stage.

A Novel Nomogram including AJCC Stages Could Better Predict Survival for NSCLC Patients Who Underwent Surgery: A Large Population-Based Study.

OBJECTIVE: In this study, we aimed to establish a novel nomogram model which was better than the current American Joint Committee on Cancer (AJCC) stage to predict survival for non-small-cell lung cancer (NSCLC) patients who underwent surgery. Patients and Methods. 19617 patients with initially diagnosed NSCLC were screened from Surveillance Epidemiology and End Results (SEER) database between 2010 and 2015. These patients were randomly divided into two groups including the training cohort and the validation cohort. The Cox proportional hazard model was used to analyze the influence of different variables on overall survival (OS). Then, using R software version 3.4.3, we constructed a nomogram and a risk classification system combined with some clinical parameters. We visualized the regression equation by nomogram after obtaining the regression coefficient in multivariate analysis. The concordance index (C-index) and calibration curve were used to perform the validation of nomogram. Receiver operating characteristic (ROC) curves were used to evaluate the clinical utility of the nomogram. RESULTS: Univariate and multivariate analyses demonstrated that seven factors including age, sex, stage, histology, surgery, and positive lymph nodes (all, P < 0.001) were independent predictors of OS. Among them, stage (C-index = 0.615), positive lymph nodes (C-index = 0.574), histology (C-index = 0.566), age (C-index = 0.563), and sex (C-index = 0.562) had a relatively strong ability to predict the OS. Based on these factors, we established and validated the predictive model by nomogram. The calibration curves showed good consistency between the actual OS and predicted OS. And the decision curves showed great clinical usefulness of the nomogram. Then, we built a risk classification system and divided NSCLC patients into two groups including high-risk group and low-risk group. The Kaplan-Meier curves revealed that OS in the two groups was accurately differentiated in the training cohort (P < 0.001). And then, we validated this result in the validation cohort which also showed that patients in the high-risk group had worse survival than those in the low-risk group. CONCLUSION: The results proved that the nomogram model had better performance to predict survival for NSCLC patients who underwent surgery than AJCC stage. These tools may be helpful for clinicians to evaluate prognostic indicators of patients undergoing operation.

A 5-Gene Signature Is Closely Related to Tumor Immune Microenvironment and Predicts the Prognosis of Patients with Non-Small Cell Lung Cancer.

PURPOSE: Establishing prognostic gene signature to predict clinical outcomes and guide individualized adjuvant therapy is necessary. Here, we aim to establish the prognostic efficacy of a gene signature that is closely related to tumor immune microenvironment (TIME). METHODS AND RESULTS: There are 13,035 gene expression profiles from 130 tumor samples of the non-small cell lung cancer (NSCLC) in the data set GSE103584. A 5-gene signature was identified by using univariate survival analysis and Least Absolute Shrinkage and Selection Operator (LASSO) to build risk models. Then, we used the CIBERSORT method to quantify the relative levels of different immune cell types in complex gene expression mixtures. It was found that the ratio of dendritic cells (DCs) activated and mast cells (MCs) resting in the low-risk group was higher than that in the high-risk group, and the difference was statistically significant (P < 0.001 and P < 0.001 and P < 0.001 and P < 0.001 and P < 0.001 and P < 0.001 and P < 0.001 and P < 0.001 and P < 0.001 and P < 0.001 and P < 0.001 and P < 0.001 and. CONCLUSION: The 5-gene signature is a powerful and independent predictor that could predict the prognosis of NSCLC patients. In addition, our gene signature is correlated with TIME parameters, such as DCs activated and MCs resting. Our findings suggest that the 5-gene signature closely related to TIME could predict the prognosis of NSCLC patients and provide some reference for immunotherapy.

Different distant metastasis patterns based on tumor size could be found in extensive-stage small cell lung cancer patients: a large, population-based SEER study.

BACKGROUND: Small-cell lung cancer (SCLC) is a malignant cancer with the ability to metastasize quickly. The relationship between tumor size and the distant metastasis patterns of Extensive-Stage Small Cell Lung Cancer (ES-SCLC) has not been reported. OBJECTIVES: The aim of this study was to determine the different distant metastasis patterns as they related to tumor size in ES-SCLC. PATIENTS AND METHODS: We used Surveillance, Epidemiology, and End Results (SEER) population-based data collected from 2010 through 2013 to identify 11058 ES-SCLC patients with definite evidence of distant metastases. Multivariate logistic regression analysis was used to demonstrate the association between tumor size and distant metastasis patterns including bone, liver, brain, and lung metastases. Age, race, sex, and N stage were also selected in the logistic regression model. RESULTS: Subtle differences in metastasis patterns were found among patients based on different tumor sizes. Patients with tumors 3-7 cm have a higher risk of bone metastasis compared with those that have tumors ≤3 cm (OR 1.165, 95% CI [1.055-1.287], P = 0.003) and patients with tumors ≥7 cm have a higher risk of lung metastasis (OR 1.183, 95% CI [1.039-1.347], P = 0.011). In addition, patients with tumors ≥7 cm had a lower risk of brain metastasis and liver metastasis than patients with tumors ≤3 cm (OR 0.799, 95% CI [0.709-0.901], P < 0.001; OR 0.747, 95% CI [0.672-0.830], P < 0.001). Interestingly, there was no correlation between a larger tumor and a higher risk of metastasis. However, the tumor metastasis pattern did have some correlation with age, gender, race and N-status. CONCLUSION: The pattern of distant metastasis of ES-SCLC is related to the tumor size and the tumor size is indicative of the metastatic site. Larger tumor sizes did not correlate with a higher risk of distant metastasis, but the size is related to the pattern of distant metastasis. The study of different distant metastasis patterns based on tumor size and other clinical features (e.g., age, race, sex, and N stage) in ES-SCLC is clinically valuable.

A small cytotoxic peptide from frog elicits potent antitumor immunity to prevent local tumor growth and metastases.

Aim: Anticancer immunochemotherapy represents an attractive paradigm to improve therapeutic responses and reduce side effects. Results & methodology: Here, we show that a naturally occurring host defense peptide, HN-1 inhibited multiple malignant cells proliferation and tumor growth in a xenografted human breast tumor model. Acting through MAPK/NF-κB pathways, HN-1 induced a caspase-independent mitochondrial apoptosis, as indicated by a p53-dependent increase of Bax/Bcl-2 ratio and the nuclear translocation of apoptosis inducing factor. Besides, HN-1 augmented CD4+/CD8+ T cells in 4T1 mammary carcinoma model, by enhancing the serum levels of cancer immunity-associated effectors. Meanwhile, HN-1 decreased the angiogenesis and infiltration of the tumor-associated macrophages. Conclusion: HN-1 induces caspase-independent cancer cells apoptosis and boosts cancer-resolving immunity without inducing potentially harmful pro-inflammatory responses.

[Progress in the mechanisms of anticancer peptides].

In recent years, cancer has become a major concern in relation to human morbidity and mortality. Anticancer peptides (ACPs) are the bioactive peptide with antitumor activity and found in many organisms, including mammals, amphibians, insects, plants and microorganisms. ACPs have been suggested as promising agents for antitumor therapy due to their numerous advantages over traditional chemical agents such as low molecular masses, relatively simple structures, greater tumor selectivity, fewer adverse reactions, ease of absorption, a variety of routes of administration and low risk for inducing multi-drug resistance. Combining with the related research in our group, we summarized the mechanisms of ACPs to provide some directions for research and development of peptide-based anticancer drugs.

Development of a novel assay of molecularly imprinted membrane by design-based gaussian pattern for vancomycin determination.

A molecularly imprinted membrane (MIM) with vancomycin (VCM) as a template and other related different material membranes (organic nylon microporous membranes, polyvinylidene fluoride (PVDF) membranes, polypropylene membranes) as a support respectively were synthesized by surface imprinting for the selective absorption of VCM, which can be used for pretreatment biological samples and rapid determination of VCM. The optimal ratio of template and functional monomer was 1:4, which was simulate by Gaussian, and the results showed that PVDF MIM had the best selectivity of the other three synthesized membranes to be used in the experiment. The maximum load on PVDF MIM was 23.8µg/cm2, and on non-molecularly imprinted membrane was 1.7µg/cm2. Additionally, performance of PVDF MIM, including surface structure, adsorption capacity, selective adsorption capacity, were also examined in this work. VCM in sample was enriched and separated effectively by PVDF MIM, and was quantitatively analyzed significantly by UV. The optimum eluent was 0.1 mol/L KOH aqueous solution in methanol (v/v=1/4), which desorption time was around 20 min. Also, recovery rate, precision, stability, linearity and repeatability for the novel assay were investigated respectively. The results indicated that separation and enrichment of VCM in biological samples by VCM MIM was reliable. The development of the assay, across a range of analytical and separated techniques for which MIM appeared to be the best support, was giving rise to increased interest in the determination of antibiotics as speedy assay for the blood concentration in clinical.

Diversity, immunoregulatory action and structure-activity relationship of green sea turtle cathelicidins.

Cathelicidins are a family of gene-encoded immune effectors in vertebrate innate immunity. Here, we reported the diversity and biological activity of cathelicidins in green sea turtle, a marine reptile species known for long lifespan and disease resistance. Four novel cathelicidins (Cm-CATH1-4) were identified from green sea turtle. All of them, especially Cm-CATH2, exhibited potent, broad-spectrum and rapid bactericidal and anti-biofilm activities by inducing the disruption of cell membrane integrity. Additionally, Cm-CATH2 effectively induced the macrophages/monocytes and neutrophils trafficking to the infection site, and inhibited the LPS-induced production of inflammatory cytokines, by blocking TLR4/MD2 complex and the downstream signaling pathway activation. In mouse peritonitis and pneumonia models, Cm-CATH2 exhibited evident protection against drug-resistant bacterial infections. Taken together, the diverse structures and functions of Cm-CATHs indicated their pleiotropic role in innate immunity of green sea turtle, and the potent antimicrobial, anti-biofilm and immunomodulatory properties make them ideal candidates for the development of novel anti-infective drugs.

A Megavoltage CT Image Enhancement Method for Image-Guided and Adaptive Helical TomoTherapy.

Purpose: To propose a novel method to improve the mega-voltage CT (MVCT) image quality for helical TomoTherapy while maintaining the stability on dose calculation. Materials and Methods: The Block-Matching 3D-transform (BM3D) and Discriminative Feature Representation (DFR) methods were combined into a novel BM3D + DFR method for their respective advantages. A phantom (Catphan504) and three serials of clinical (head & neck, chest, and pelvis) MVCT images from 30 patients were acquired using the helical TomoTherapy system. The contrast-to-noise ratio (CNR) and edge detection algorithm (canny) was employed for image quality comparisons between the original and BM3D + DFR enhanced MVCT. A simulated rectangular field of 6 MV X-ray beams were vertically delivered on the original and post-processed MVCT serials of the same CT density phantom, and the dose curves on both serials were compared to test the effects of image enhancement on dose calculation accuracy. Results: In total, 466 transversal MVCT slices were acquired and processed by both BM3D and the proposed BM3D + DFR methods. Compared to the original MVCT image, the BM3D + DFR method presented a remarkable improvement in terms of the soft tissue contrast and noise reduction. For the phantom image, the CNR of the region of interest (ROI) was improved from 1.70 to 4.03. The average CNR of ROIs for 10 patients from each anatomical group, were increased significantly from 1.45 ± 1.51 to 2.09 ± 1.68 for the head & neck (p < 0.001), from 0.92 ± 0.78 to 1.36 ± 0.85 for the chest (p < 0.001), and from 1.12 ± 1.22 to 1.76 ± 1.31 for the pelvis (p < 0.001), respectively. The canny edge detection operator showed that BM3D + DFR provided clearer organ boundaries with less chaos. The root-mean-square of the dosimetry difference on the iso-center passed horizontal dose profile curves and vertical percentage depth dose curves were only 0.09% and 0.06%, respectively. Conclusions: The proposed BM3D + DFR method is feasible to improve the soft tissue contrast for the original MVCT images with coincidence in dose calculation and without compromising resolution. After integration in clinical workflow, the post-processed MVCT may be better applied on image-guided and adaptive helical TomoTherapy.

Effects of C-terminal amidation and heptapeptide ring on the biological activities and advanced structure of amurin-9KY, a novel antimicrobial peptide identified from the brown frog, Rana kunyuensis.

Rana kunyuensis is a species of brown frog that lives exclusively on Kunyu Mountain, Yantai, China. In the current study, a 279-bp cDNA sequence encoding a novel antimicrobial peptide (AMP), designated as amurin-9KY, was cloned from synthesized double-strand skin cDNA of R. kunyuensis. The amurin-9KY precursor was composed of 62 amino acid (aa) residues, whereas the mature peptide was composed of 14 aa and contained two cysteines forming a C-terminal heptapeptide ring (Rana box domain) and an amidated C-terminus. These structural characters represent a novel amphibian AMP family. Although amurin-9KY exhibited high similarity to the already identified amurin-9AM from R. amurensis, little is known about the structures and activities of amurin-9 family AMPs so far. Therefore, amurin-9KY and its three derivatives (amurin-9KY1-3) were designed and synthesized. The structures and activities were examined to evaluate the influence of C-terminal amidation and the heptapeptide ring on the activities and structure of amurin-9KY. Results indicated that C-terminal amidation was essential for antimicrobial activity, whereas both C-terminal amidation and the heptapeptide ring played roles in the low hemolytic activity. Circular dichroism (CD) spectra showed that the four peptides adopted an a-helical conformation in THF/H2O (v/v 1:1) solution, but a random coil in aqueous solution. Elimination of the C-terminal heptapeptide ring generated two free cysteine residues with unpaired thiol groups, which greatly increased the concentration-dependent anti-oxidant activity. Scanning electron microscopy (SEM) was also performed to determine the possible bactericidal mechanisms.

Interaction between toll-like receptor 4 (TLR4) gene and alcohol drinking on Parkinson's disease risk in Chinese Han population.

The aim of this study was to investigate the association of several single nucleotide polymorphisms (SNPs) within Toll-like receptor 4 (TLR4) gene, additional SNP- SNP and gene- alcohol drinking interaction with Parkinson's disease (PD) risk. Generalized multifactor dimensionality reduction (GMDR) was used to screen the best interaction combination among 4 SNPs within TLR4 gene and alcohol drinking. Logistic regression was performed to calculate the ORs (95%CI) for association between 4 SNPs within TLR4 gene, additional gene- alcohol drinking interaction and PD risk. PD risk was significantly higher for carriers with the rs7873784- G allele, or with the rs19279149- C allele of within TLR4 gene than those with wild genotypes, adjusted ORs (95%CI) were 0.72 (0.55-0.95) and 0.69 (0.51-0.95). However, we did not find any significant association of rs4986791 and rs11536889 with PD susceptibility after covariates adjustment for age, sex, smoking, alcohol drinking and BMI. GMDR analysis indicated a significant two-locus model (p = 0.0010) involving rs1927914 and alcohol drinking, the cross-validation consistency of the two- locus models was 10/ 10, and the testing accuracy was 60.11%. In logistic regression analysis, we found that never alcohol- drinkers with rs1927914- TC or CC genotype within TLR4 gene have the lowest PD risk, compared to drinkers with rs1927914- TT genotype, OR (95%CI) = 0.42 (0.28-0.61), after covariates adjustment. The rs7873784- G and rs19279149- C allele within TLR4 gene, interaction between rs1927914 and alcohol drinking were associated with decreased PD risk.

De Novo Molecular Design of a Novel Octapeptide That Inhibits In Vivo Melanogenesis and Has Great Transdermal Ability.

Cutaneous hyperpigmentation from excess melanogenesis causes serious pigmentary disorders and even melasma. Short peptides (SPs) are garnering attention lately owing to their therapeutic potential in dermatological diseases and low systemic side effects. Here, we show an octapeptide, ansin2, designed de novo from antioxidant SPs we previously reported, significantly inhibiting melanogenesis in B16 cells by decreasing tyrosinase production via regulating the MITF pathway. Ansin2 could also inhibit tyrosinase function by covering its catalytic pocket, which was simulated in docking and LIGPLOT studies. Topical application of ansin2 exhibited evident protection in UVB-induced pigmentation in guinea pig models both in terms of prophylaxis and treatment. Interestingly, unlike other hydrophilic and peptidic drugs that need delivery systems, ansin2 can be efficiently delivered topically to the epidermis and dermis per se without an affiliated moiety. Given that ansin2 lacks unwanted toxicities and immunogenicity, it holds great potential in treating hyperpigmentation in the cosmetics and pharmaceutical industries.