Transcytosable Peptide-Paclitaxel Prodrug Nanoparticle for Targeted Treatment of Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is an extremely aggressive subtype associated with a poor prognosis. At present, the treatment for TNBC mainly relies on surgery and traditional chemotherapy. As a key component in the standard treatment of TNBC, paclitaxel (PTX) effectively inhibits the growth and proliferation of tumor cells. However, the application of PTX in clinical treatment is limited due to its inherent hydrophobicity, weak penetrability, nonspecific accumulation, and side effects. To counter these problems, we constructed a novel PTX conjugate based on the peptide-drug conjugates (PDCs) strategy. In this PTX conjugate, a novel fused peptide TAR consisting of a tumor-targeting peptide, A7R, and a cell-penetrating peptide, TAT, is used to modify PTX. After modification, this conjugate is named PTX-SM-TAR, which is expected to improve the specificity and penetrability of PTX at the tumor site. Depending on hydrophilic TAR peptide and hydrophobic PTX, PTX-SM-TAR can self-assemble into nanoparticles and improve the water solubility of PTX. In terms of linkage, the acid- and esterase-sensitive ester bond was used as the linking bond, with which PTX-SM-TAR NPs could remain stable in the physiological environment, whereas PTX-SM-TAR NPs could be broken and PTX be released at the tumor site. A cell uptake assay showed that PTX-SM-TAR NPs were receptor-targeting and could mediate endocytosis by binding to NRP-1. The vascular barrier, transcellular migration, and tumor spheroids experiments showed that PTX-SM-TAR NPs exhibit great transvascular transport and tumor penetration ability. In vivo experiments, PTX-SM-TAR NPs showed higher antitumor effects than PTX. As a result, PTX-SM-TAR NPs may overcome the shortcomings of PTX and present a new transcytosable and targeted delivery system for PTX in TNBC treatment.

Transcription Factor MafB Promotes Hepatocellular Carcinoma Cell Proliferation through Up-Regulation of Cyclin D1.

BACKGROUND/AIMS: MafB, a member of the Maf transcription factor family, plays a key role in the regulation of pancreatic alpha and beta cell differentiation. However, its function in the control of cancer cell proliferation remains unknown. METHODS: The mRNA and protein expression levels of MafB in hepatocellular carcinoma tissues and adjacent non-tumor normal specimens were determined by real-time RT-PCR and Western blot, respectively. Report assay was performed to determine whether the regulation of Cyclin D1 by MafB is at the transcriptional level. The binding of MafB to the Cyclin D1 promoter was determined by Chromatin Immunoprecipitation (ChIP) assays. To determine the potential oncogenic effects of MafB in vivo, HepG2 cells transfected with adenovirus containing empty vector or MafB were injected subcutaneously to the skin under the front legs of the nude mice. RESULTS: In the current study, we showed that MafB was markedly up-regulated in hepatocellular carcinoma (HCC) tissues and cells. Enforced overexpression of MafB enhanced, while its deficiency inhibited HCC cell proliferation. Mechanistically, Cyclin D1, an important regulator of cell cycle progression, was identified as a direct transcriptional target of MafB. Consistently, knockdown of Cyclin D1 largely attenuated the proliferative roles of MafB in HCC cells. Importantly, MafB overexpression significantly promoted cancer cell growth in mice. CONCLUSIONS: Collectively, our results identified a novel HCC regulatory pathway involving MafB and Cyclin D1, the dysfunction of which drives proliferative character in HCC.

Spatial distribution and source analysis of heavy metals in the marine sediments of Hong Kong.

A data matrix, obtained during a 3-year monitoring period (2010-2012) from 45 sampling locations in the marine of Hong Kong, was subjected to pollution indicator and multivariate statistical technique analysis to investigate the spatial distribution and origin of the selected 12 heavy metals. Results suggested that V, Ni, and Ba were at safe levels, and there was a significant anthropogenic effect on Zn, Pb, Cu, Cd, and Cr, which were moderate to severe enrichment at some locations. Sampling locations 1, 2, 7, 9, 12, 13, 14, 30, 31, and 32 were identified as pollution hot spots. Principal component analysis and cluster analysis showed that Zn, Pb, Cu, Cd, and Cr were primarily controlled by anthropogenic sources and Ni, Ba, and V by natural sources. Whereas, Al, Fe, Mn, and As were controlled by both anthropogenic and natural sources. Cluster analysis classified 45 sampling sites into five groups and analysis of variance indicated there were significant differences between different groups. The pollution hot spots were classified into moderate or high polluted groups, and the influential factor of the heavy metal distribution was analyzed.

DAX-1 inhibits hepatocellular carcinoma proliferation by inhibiting ß-catenin transcriptional activity.

BACKGROUND/AIMS: Hepatocellular carcinoma (HCC) represents the most common type of liver cancer. DAX1 (dosage-sensitive sex reversal adrenal hypoplasia congenital critical region on X chromosome, gene 1), an atypical member of the nuclear receptor family due to lack of classical DNA-binding domains, has been known for its fundamental roles in the development, especially in the sex determination and steroidogenesis. Previous studies also showed that DAX-1 played a critical role in endocrine and sex steroid-dependent neoplasms such as adrenocortical, pituitary, endometrial, and ovarian tumors. However, its biological roles in the development of HCC remain largely unexplored. METHODS: Real-time PCR and Western blot were used to detect the expression of DAX-1 in HCC tissues and cell lines. Immunoprecipitation (IP) assay was used to show the interaction between DAX-1 and ß-Catenin. Small interfering RNA (siRNA) was used to silence the expression of DAX-1. BrdU incorporation and Cell-cycle assays were used to detect the role of DAX-1 in HCC cells proliferation. Migration and invasion assays were carried out to test the metastasis ability of DAX-1 in HCC cells. RESULTS: In the present study, we found that mRNA and protein levels of DAX-1 were down-regulated in HCC tissues and cell lines. Furthermore, overexpression of DAX-1 could inhibit while its knockdown using small interfering RNA promoted cell proliferation in several HCC cell lines. At the molecular level, we demonstrated that DAX-1 could interact with ß-Catenin and attenuate its transcriptional activity. CONCLUSION: Therefore, our results suggest a previously unknown DAX-1/ß-Catenin molecular network controlling HCC development.

MicroRNA-195 regulates steroid receptor coactivator-3 protein expression in hepatocellular carcinoma cells.

Multiple studies have shown that steroid receptor coactivator-3 (SRC-3) is upregulated and promotes cell proliferation in several human cancers, including breast, lung, and prostate carcinoma. However, its molecular determinants remain largely unexplored. In the current study, by way of informatics software, we found that MicroRNA-195 (miR-195) could negatively regulate protein levels of SRC-3 through targeting its 3'-untranslated region (3'-UTR) in hepatocellular carcinoma (HCC) cells. As a result, miR-195 mimics inhibited while its antisense enhanced SRC-3 protein levels. Furthermore, miR-195 could modulate cell proliferation and tumor growth in vivo and in vitro. Therefore, our results demonstrate a novel molecular mechanism for the dysregulated expression of SRC-3 in hepatocellular carcinoma.

Preparation and characterization of curdlan-chitosan conjugate nanoparticles as mucosal adjuvants for intranasal influenza H1N1 subunit vaccine.

Intranasal vaccination offers crucial protection against influenza virus pandemics. However, antigens, especially subunit antigens, often fail to induce effective immune responses without the help of immune adjuvants. Our research has demonstrated that a polyelectrolyte complex, composed of curdlan sulfate/O-(2-hydroxyl) propyl-3-trimethyl ammonium chitosan chloride (CS/O-HTCC), effectively triggers both mucosal and systemic immune responses when administrated intranasal. In this study, stable nanoparticles formed by curdlan-O-HTCC conjugate (CO NP) were prepared and characterized. Furthermore, the efficacy of CO NP was evaluated as a mucosal adjuvant in an intranasal influenza H1N1 subunit vaccine. The results revealed that CO NP exhibits uniform and spherical morphology, with a size of 190.53 ± 4.22 nm, and notably, it remains stable in PBS at 4 °C for up to 6 weeks. Biological evaluation demonstrated that CO NP stimulates the activation of antigen-presenting cells (APCs), including macrophages and dendritic cells (DCs), both in vitro and in vivo. Furthermore, intranasal administration of CO NP effectively elicits cellular and humoral immune responses, notably enhancing mucosal immunity. Thus, CO NP emerges as a promising mucosal adjuvant for influenza subunit vaccines.

Preparation and immunological activity evaluation of an intranasal protein subunit vaccine against ancestral and mutant SARS-CoV-2 with curdlan sulfate/O-linked quaternized chitosan nanoparticles as carrier and adjuvant.

Chitosan and its derivatives are ideal nasal vaccine adjuvant to deliver antigens to immune cells. Previously, we successfully used a chitosan derivative, O-(2-Hydroxyl) propyl-3-trimethyl ammonium chitosan chloride (O-HTCC), and a ß-glucan derivative, curdlan sulfate (CS), to prepare a nanoparticle adjuvant CS/O-HTCC which could deliver ovalbumin to antigen presenting cells (APCs) through nasal inhalation. In this article, we used SARS-CoV-2 spike receptor binding domain (S-RBD) as the antigen and CS/O-HTCC nanoparticles as the adjuvant to develop a nasal mucosal protein subunit vaccine, CS/S-RBD/O-HTCC. The humoral immunity, cell-mediated immunity and mucosal immunity induced by vaccines were evaluated. The results showed that CS/S-RBD/O-HTCC could induce desirable immunization with single or bivalent antigen through nasal inoculation, giving one booster vaccination with mutated S-RBD (beta) could bring about a broad cross reaction with ancestral and different mutated S-RBD, and vaccination of the BALB/c mice with CS/S-RBD/O-HTCC containing S-RBD mix antigens (ancestral and omicron) could induce the production of binding and neutralizing antibodies against both of the two antigens. Our results indicate that CS/O-HTCC is a promising nasal mucosal adjuvant to prepare protein subunit vaccine for both primary and booster immunization, and the adjuvant is suitable for loading more than one antigen for preparing multivalent vaccines.

Rakicidin J and K, two cytotoxic and antibacterial cyclic depsipeptides from the marine bacterium Micromonospora chalcea.

Rakicidin J (1) and rakicidin K (2), two new cyclic depsipeptides, were isolated from culture broth of Micromonospora chalcea FIM-R150103. Their structures were elucidated by extensive analysis of NMR, HR-ESI-MS, and electronic circular dichroism (ECD) data. The two compounds showed strong cytotoxic activity against human colon carcinoma HCT-8 and human pancreatic cancer PANC-1 cells under normoxic and hypoxic conditions in the range of IC50 values from 0.024 to 0.79 µg/mL. Moreover, compounds 1 and 2 also showed moderate antibacterial activity against ten Gram-positive bacterial strains with MIC values ranging from 4 to more than 32 µg/mL. Structure-activity relationship of these two compounds with a close analogue, rakicidin B1, is also discussed.

Association between XRCC1 Arg399Gln polymorphism and hepatitis virus-related hepatocellular carcinoma risk in Asian population.

To investigate the association between X-ray repair cross-complementing group 1 (XRCC1) Arg399Gln polymorphism and hepatitis virus-related hepatocellular carcinoma risk, we performed a systematic meta-analysis of eligible case-control studies. Eligible studies were identified from the PubMed, Embase, and Chinese National Knowledge Infrastructure databases up to March 2013. The odds ratios (ORs) and corresponding 95 % confidence interval (95 % CI) of XRCC1 Arg399Gln polymorphism in hepatitis virus-related hepatocellular carcinoma cases compared with those in controls were calculated. The meta-analysis was performed using fixed-effect or random-effect methods according to the absence or presence of heterogeneity. This meta-analysis included 1,558 cases with hepatitis virus-related hepatocellular carcinoma and 1,338 controls. Meta-analysis of available data showed that there was no association between XRCC1 Arg399Gln polymorphism and risk of hepatitis virus-related hepatocellular carcinoma under all contrast models (Gln vs. Arg: fixed-effect OR = 0.92, 95 % CI 0.82-1.04, P = 0.18; GlnGln vs. ArgArg: random-effect OR = 0.79, 95 % CI 0.50-1.25, P = 0.32; GlnGln/ArgGln vs. ArgArg: fixed-effect OR = 0.92, 95 % CI 0.79-1.07, P = 0.28; and GlnGln vs. ArgArg/ArgGln: random-effect OR = 0.83, 95 % CI 0.52-1.34, P = 0.45). Sensitivity analysis further showed that there was no association between XRCC1 Arg399Gln polymorphism and risk of hepatitis B-related hepatocellular carcinoma under all contrast models (Gln vs. Arg: fixed-effect OR = 0.93, 95 % CI 0.82-1.05, P = 0.25; GlnGln vs. ArgArg: fixed-effect OR = 0.86, 95 % CI 0.64-1.16, P = 0.32; GlnGln/ArgGln vs. ArgArg: fixed-effect OR = 0.93, 95 % CI 0.80-1.10, P = 0.41; and GlnGln vs. ArgArg/ArgGln: fixed-effect OR = 0.85, 95 % CI 0.63-1.13, P = 0.26). Our meta-analysis of the available data did not find an obvious effect of XRCC1 Arg399Gln polymorphism on hepatitis-related hepatocellular carcinoma. More well-designed studies with large sample are needed to further verify the effect.

Association between X-ray repair cross-complementation group 1 rs25487 polymorphism and pancreatic cancer risk.

Previous published studies suggested that genetic polymorphisms in DNA repair genes could modify the DNA repair capacity and could be associated with pancreatic cancer risk. However, previous studies on the association between X-ray repair cross-complementation group 1 (XRCC1) rs25487 (Arg399Gln) polymorphism and pancreatic cancer risk reported inconsistent results. To obtain a more precise estimation of the association between XRCC1 rs25487 polymorphism and pancreatic cancer risk, we performed a meta-analysis of previous published studies by calculating the pooled odds ratio (OR) with a 95% confidence interval (95% CI). Eight individual studies with 5,542 subjects from six publications were finally included into this meta-analysis. The meta-analysis of total eight studies showed that there was no association between XRCC1 rs25487 polymorphism and pancreatic cancer risk in total population under all four genetic models (Gln versus Arg: OR = 1.10, 95% CI 0.95-1.28, P = 0.199; GlnGln versus ArgArg: OR = 1.15, 95% CI 0.93-1.41, P = 0.191; GlnGln/ArgGln versus ArgArg: OR = 1.10, 95% CI 0.97-1.25, P = 0.127; GlnGln versus ArgArg/ArgGln: OR = 1.12, 95% CI 0.92-1.36, P = 0.253). Subgroup analysis showed that there was no association between XRCC1 rs25487 polymorphism and pancreatic cancer risk in Caucasians, but XRCC1 rs25487 polymorphism was associated with pancreatic cancer risk in Asians (GlnGln/ArgGln versus ArgArg: OR = 1.24, 95% CI 1.01-1.53, P = 0.040). Therefore, the meta-analysis suggests that XRCC1 rs25487 polymorphism is associated with pancreatic cancer risk in Asians. Further studies with more participants are needed to provide a more precise estimation on the association above.

Significant association between XRCC3 C241T polymorphism and increased risk of hepatocellular carcinoma: a meta-analysis.

Many studies were published to examine the association between XRCC3 C241T polymorphism and hepatocellular carcinoma risk, but their results were inconsistent. To assess the association between XRCC3 C241T polymorphism and hepatocellular carcinoma risk more precisely, a meta-analysis was performed. PubMed, Embase and Wanfang databases were searched for relevant case-control studies. Data were extracted, and the pooled odds ratios (OR) with 95 % confidence intervals (95% CI) were calculated. Finally, seven studies comprising 2,288 cases with hepatocellular carcinoma and 3,249 controls were included into the meta-analysis. Overall, there was an obvious association between XRCC3 C241T polymorphism and increased risk of hepatocellular carcinoma (TT versus CC: OR = 3.31, 95% CI 1.52-7.19, P = 0.003; TT versus CC/CT: OR = 3.31, 95% CI 1.81-6.06, P < 0.001). After adjusting for heterogeneity, there was still an obvious association between XRCC3 C241T polymorphism and increased risk of hepatocellular carcinoma (TT versus CC: OR = 1.92, 95 % CI 1.13-3.26, P = 0.016; TT versus CC/CT: OR = 2.10, 95% CI 1.25-3.55, P = 0.005). Overall, there is a significant association between XRCC3 C241T polymorphism and increased risk of hepatocellular carcinoma. Further studies are needed to further assess the association in Caucasians.

Celastrol exerts synergistic effects with PHA-665752 and inhibits tumor growth of c-Met-deficient hepatocellular carcinoma in vivo.

PHA665752 (PHA), a selective small molecule c-Met Inhibitor, potently inhibited HGF-stimulated and constitutive c-Met phosphorylation, as well as HGF and c-Met-driven phenotypes of a variety of tumor cells including hepatocellular carcinoma cells. However, these effects were impaired in c-Met-deficient cancer cells. In the present study, we investigated the potential anti-human c-Met-deficient hepatocellular carcinoma effects of Celastrol, a novel triterpene, and its combination with PHA. Human hepatocellular carcinoma cells BEL-7402 (c-Met-positive) and Huh7 (c-Met-deficient) were treated with different dose of PHA with or without equal dose of Celastrol, and cell growth, cell cycle and apoptosis were evaluated, respectively, by MTT assay, flow cytometry and Caspase3/7 activity. Nude mice bearing Huh7 xenografts were used to assess the in vivo anti-tumor activity. Our results showed that Celastrol at high concentration (>1.0 µM) induced G2/M arrest and apoptosis with the activation of Caspase3/7 in Huh7 cells whereas at low concentration (<1.0 µM) had no obvious effects. Low concentration Celastrol presented significant combined effects with PHA on Huh7 cells and Huh7 xenografts in terms of growth inhibition, migration inhibition and apoptosis induction. These results suggest that Celastrol and its combination with PHA present the therapeutic potential on c-Met-deficient hepatocellular carcinoma, and deserve further preclinical and clinical studies.

Spatial distribution and source identification of persistent pollutants in marine sediments of Hong Kong.

A data matrix, obtained during a 3-year monitoring period (2007-2009) from 45 sampling sites in Hong Kong marine, was subjected to determine the spatial characterization and identify the sources of main pollutants. Indicator analyses indicated that polycyclic aromatic hydrocarbons (PAHs), nickel, manganese, and arsenic (As) were at safe levels. Five heavy metals (zinc, lead, cupper, cadmium, chromium (Cr)) were moderate to severe enrichment at some sites. Inner Deep Bay and Victoria Harbor were considered as hot spots for PAHs and the heavy metals, while Tolo Harbor was highly polluted by the heavy metals. Cluster analysis classified the 45 sampling sites into three groups, representing different pollution levels. Principal component analysis/factor analysis identified four principal components (PCs) and explained 84.9 % of the total variances, standing for persistent pollution, N factor, P and Cr factor, and As factor, respectively. Group A was highly polluted by persistent pollution, group B was the less polluted group, and subgroup B1 was less affected by PC3 and PC4 than subgroup B2. Group C, considered as the moderately polluted group, was greatly affected by N factor or persistent pollution, while subgroup C2 received more N pollution than subgroup C1.

Meta-analysis of the timing of laparoscopic cholecystectomy after endoscopic retrograde cholangiopancreatography in patients with cholecystolithiasis and choledocholithiasis.

Endoscopic retrograde cholangiopancreatography (ERCP) combined with laparoscopic cholecystectomy plays an important role in the treatment of cholecystolithiasis combined with choledocholithiasis; however, there is no unified standard for the interval of ERCP before laparoscopic cholecystectomy. We conducted a literature search, data extraction and meta-analysis on this topic. Twelve articles with 1142 patients were included, including 567 patients in the E-laparoscopic cholecystectomy group (laparoscopic cholecystectomy performed within 72 h after ERCP) and 575 patients in the D-laparoscopic cholecystectomy group (laparoscopic cholecystectomy performed 72 h after ERCP). The results showed that: compared with the D-laparoscopic cholecystectomy group, the duration of cholecystectomy was shorter in the E-laparoscopic cholecystectomy group [weighted mean difference (WMD) = -16.18, 95% confidence interval (CI) (-22.27 to -10.08), P  < 0.00001], and the postoperative hospitalization was shorter [WMD = -1.24, 95% CI (-1.98 to -0.50), P  < 0.0001]. There were fewer complications [odds ratio (OR) = 0.25, 95% CI (0.39-0.62), P  < 0.0001], lower conversion rate [OR = 0.39, 95% CI (0.21-0.71), P  = 0.002], lower high sensitivity C-reactive protein at 3 days after surgery [WMD = -8.76, 95% CI (-12.59 to -4.93), P  < 0.00001], and fewer neutrophils in the ampulla of gallbladder specimen [WMD = -4.21, 95% CI (-4.55 to -3.88), P < 0.00001]. Therefore, in the treatment of cholecystolithiasis combined with choledocholithiasis by laparoscopic cholecystectomy within 72 h after ERCP, the degree of inflammation before and after surgery is less, the operation time and hospital stay are shortened, the postoperative complications and the conversion rate are reduced, which is a more appropriate time for surgery.

Protective effects of melatonin in cisplatin-induced cardiac toxicity: possible role of BDNF-TNF-α signaling pathway.

PURPOSE: The present study explored the role of melatonin in cisplatin-induced cardiac injury along with the possible role of brain-derived neurotrophic factor (BDNF) in melatonin-mediated effects. METHODS: Wistar rats were administered cisplatin (10 mg/kg), and cardiac injury was assessed by measuring the levels of cardiac troponin (cTnT) and lactate dehydrogenase (LDH-1).The extent of apoptosis was measured by measuring caspase-3 (pro-apoptotic) and Bcl-2 (anti-apoptotic) in hearts. The levels of BDNF, tumour necrosis factor α (TNF-α) and reduced glutathione were measured in heart. Melatonin (5 and 10 mg/kg) was administered for 15 days, and the role of BDNF was identified by co-administering BDNF inhibitor, ANA-12 (0.25 and 0.5 mg/kg). RESULTS: Melatonin attenuated cTnT and LDH-1 levels along with reduction in caspase-3 and increase in Bcl-2. It also increased cisplatin-induced decrease in BDNF, increase in TNF-α and decrease in reduced glutathione levels. Moreover, ANA-12 abolished the cardioprotective effects, anti-inflammatory and antioxidant effects of melatonin suggesting the role of BDNF in melatonin-mediated effects in cisplatin-induced cardiac injury. CONCLUSIONS: Melatonin is useful in cisplatin-induced cardiac injury, which may be due to an increase in BDNF, decrease in inflammation and increase in antioxidant activities.

PRELP promotes myocardial fibrosis and ventricular remodelling after acute myocardial infarction by the wnt/ß-catenin signalling pathway.

OBJECTIVES: Proline/arginine-rich end leucine-rich repeat protein (PRELP) has been reported to contribute to the remodelling of cardiovascular tissues in the ischaemia-reperfusion injury model. However, research is lacking on the role of PRELP in myocardial fibrosis and ventricular remodelling, and the mechanism through which PRELP brings about these changes is not clear. This study aimed to evaluate the role of PRELP in ventricular remodelling and myocardial fibrosis following acute myocardial infarction (AMI) and to explore the underlying mechanism. METHODS: In this study, we established AMI mouse and cellculture models in an oxygen-glucose deprivation environment. RESULTS: We found that over-expression of PRELP increased the infarct size and interstitial fibrotic area. Expression of the wnt/ß-catenin pathway molecules, which are downstream of PRELP, increased more in the PRELP over-expression group than in the AMI group. CONCLUSIONS: Our results showed that PRELP, through the wnt/ß-catenin signalling pathway, led to myocardial fibrosis and ventricular remodelling following AMI.

Widespread decline in winds promoted the growth of vegetation.

Vegetation dynamics are sensitive to climate change. Wind is an important climate factor that can affect carbon fluxes by altering carbon uptake and emission rates; however, the impact of wind has not been fully considered in previous studies; therefore, exploring the characteristics of vegetation responses to wind speed is crucial to sustainable natural resource utilization and ecological restoration. In this study, the global leaf area index (LAI) from 1984 to 2013 was used to investigate the vegetation spatial heterogeneities, change processes, and relative contributions of climate change. The differences in vegetation responses to climate factors, such as precipitation (PRE), temperature (TEM), and wind speed (WD), were compared by considering the effects of wind. The results revealed that (1) the global vegetation (86.24%) exhibited a greening trend, among which evergreen broad-leaved forests (0.0052 a-1) changed the most. (2) The wind speed explained 31.54% of the vegetation variations, which is higher than the contribution of other factors. (3) Reduction of wind speed had a positive impact on vegetation changes. The contribution of climate to vegetation growth increased by 8.14% when considering the effects wind speed, particularly in India and South America. Wind speed effects were essential for enhancing the vegetation dynamics assessment and improving the prediction accuracy of the model.

Two new rakicidin derivatives from marine Micromonospora chalcea FIM-R160609.

The establishment of structure activity relationship (SAR) for rakicidin derivatives is pretty vital to develop rakicidins as a new type of anti-cancer agents. Herein, two novel rakicidin derivatives, compounds B1-1 (1) and B1-2 (2), a cyclic depsipeptide and a chain lipopeptide, respectively, were isolated from culture broth of Micromonospora chalcea FIM-R160609, and their structures were elucidated clearly by extensive NMR and HR-ESI-MS analyses. Following, their cytotoxic activities were evaluated against HCT-8 and PANC-1 human cancer cell lines under hypoxic and normoxic conditions. Their activities were significantly decreased when compared with that of rakicidin B1. These results demonstrated that the double bond located on the position 9 and 10 of conjugated diene unit and cycle-type structure plays an important role in keeping the biological activity of rakicidins. Furthermore, the positive effect of double bond and cycle form on the anti-bacterial activities were also confirmed by testing their inhibitory activities against gram positive bacteria. This work will definitely diversify the SAR of rakicidins and provide the guidance for the design of new potent rakicidin analogues.

Association of Genetic Variants in miR-217 Gene with Risk of Coronary Artery Disease: A Case-Control Study.

OBJECTIVE: To evaluate the associations of genetic variants of the miR-217 gene with coronary artery disease (CAD) risk, as well as plasma level of vascular endothelial growth factor (VEGF). METHODS: A case-control study with 498 CAD patients and 499 frequency-matched healthy controls was conducted to evaluate the associations of four tagSNPs of the miR-217 gene, including rs6724872, rs4999828, rs10206823, and rs41291177, with CAD risk and plasma level of VEGF. RESULTS: SNP rs6724872 and rs4999828 were significantly associated with increased risk of CAD (P value was smaller than 0.05 even after Bonferroni multiple adjustment). Compared with the G allele, C allele of rs6724872 was significantly associated with 1.73-fold increased risk of CAD (95% CI: 1.25-2.39; P = 0.001). While C allele of rs4999828 was significantly associated with 1.75-fold increased risk of CAD, compared with T allele (95% CI: 1.34-2.29; P = 4 × 10-5). Meanwhile, rs6724872 and rs4999828 were also significantly associated with higher level of VEGF (P < 0.001). CONCLUSION: These findings highlighted the important role of genetic variants of the miR-217 gene in the pathogenesis of CAD and potential targets for intervention.

Vegetation responses to extreme climatic indices in coastal China from 1986 to 2015.

Climate extremes have resulted in substantial vegetation changes in the marine-terrestrial transitional zone. As a climatically-sensitive region, coastal China is currently experiencing prominent environmental climate change. To identify how climatic extremes affect ecosystem function, we calculated eleven indices of climatic extremes and four mean indices for six sub-regions of coastal China. Deseasonalized thirty-year (1986-2015) net primary productivity (NPP) was used as an indicator of ecosystem productivity, and its relationships with the climate indices were investigated at multiple scales (annual and seasonal) explicitly. The results demonstrated that: (1) annual NPP indicated an overall greening trend (in 73.71% of the study area) and partial degradation (in 26.29% of the study area) over the last thirty decades years; (2) coastal areas had experienced warming overall, with higher increases in nighttime temperatures relative to daytime temperatures; (3) in southern areas, maximum/ minimum daily maximum temperature had driven increases in NPP, whereas in northern areas, this effect varied between vegetation types; (4) Diurnal temperature range (DTR) and NPP were negatively correlated in the north and positively correlated in the south; and (5) Maximum 1-day precipitation promoted vegetation production across the whole study area. Maximum 5-day precipitation promoted vegetation growth in the north but had the opposite effect in the south. Our study advances understanding of vegetation dynamics and its driving mechanisms, and provides support for scientifically informed ecological management practices in coastal China.