LncRNA HOTAIR promotes DNA damage repair and radioresistance by targeting ATR in colorectal cancer.

Long non-coding RNAs (lncRNAs) have been implicated in cancer progression and drug resistance development. Moreover, there is evidence that lncRNA HOX transcript antisense intergenic RNA (HOTAIR) is involved in colorectal cancer (CRC) progression. The present study aimed to examine the functional role of lncRNA HOTAIR in conferring radiotherapy resistance in CRC cells, as well as the underlying mechanism. The relative expression levels of HOTAIR were examined in 70 pairs of CRC tumor and para-cancerous tissues, as well as in radiosensitive and radioresistant samples. The correlations between HOTAIR expression levels and clinical features of patients with CRC were assessed using the Chi-square test. Functional assays such as cell proliferation, colony formation and apoptosis assays were conducted to determine the radiosensitivity in CRC cells with HOTAIR silencing after treatment with different doses of radiation. RNA pull-down assay and fluorescence in situ hybridization (FISH) were used to determine the interaction between HOTAIR and DNA damage response mediator ataxia-telangiectasia mutated- and Rad3-related (ATR). HOTAIR was significantly upregulated in CRC tumor tissues, especially in radioresistant tumor samples. The elevated expression of HOTAIR was correlated with more advanced histological grades, distance metastasis and the poor prognosis in patients with CRC. Silencing HOTAIR suppressed the proliferation and promoted apoptosis and radiosensitivity in CRC cells. HOTAIR knockdown also inhibited the tumorigenesis of CRC cells and enhanced the sensitivity to radiotherapy in a mouse xenograft model. Moreover, the data showed that HOTAIR could interact with ATR to regulate the DNA damage repair signaling pathway. Silencing HOTAIR impaired the ATR-ATR interacting protein (ATRIP) complex and signaling in cell cycle progression. Collectively, the present results indicate that lncRNA HOTAIR facilitates the DNA damage response pathway and promotes radioresistance in CRC cells by targeting ATR.

Discovery of CC-99677, a selective targeted covalent MAPKAPK2 (MK2) inhibitor for autoimmune disorders.

As an anti-inflammatory strategy, MAPK-activated protein kinase-2 (MK2) inhibition can potentially avoid the clinical failures seen for direct p38 inhibitors, especially tachyphylaxis. CC-99677, a selective targeted covalent MK2 inhibitor, employs a rare chloropyrimidine that bonds to the sulfur of cysteine 140 in the ATP binding site via a nucleophilic aromatic substitutions (SNAr) mechanism. This irreversible mechanism translates biochemical potency to cells shown by potent inhibition of heat shock protein 27 (HSP27) phosphorylation in LPS-activated monocytic THP-1 cells. The cytokine inhibitory profile of CC-99677 differentiates it from known p38 inhibitors, potentially suppressing a p38 pathway inflammatory response while avoiding tachyphylaxis. Dosed orally, CC-99677 is efficacious in a rat model of ankylosing spondylitis. Single doses, 3 to 400 mg, in healthy human volunteers show linear pharmacokinetics and apparent sustained tumor necrosis factor-α inhibition, with a favorable safety profile. These results support further development of CC-99677 for autoimmune diseases like ankylosing spondylitis.

[Pyrolysis and gas emissions characteristics of six tree species in Heilongjiang Province, China]. / 黑龙江省6种乔木叶片热解特性及气体释放特征.

Forest fuels are the basis of fire occurrences, while ground dead fuels are an important part of forest fuels. Undestanding the pyrolysis characteristics and gas emissions of forest fuels is of great significance to explore the effects of forest fire on atmospheric environment and carbon balance, as well as to prevent and combat forest fire. In this study, the thermogravimetric analysis and gas emission analysis were conducted on leaf litter of six tree species (Pinus sylvestris var. mongolica, Picea koraiensis, Fraxinus mandshurica, Juglans mandshurica, Quercus mongolica, Betula platyphylla) in Heilongjiang Province to explore the pyrolysis process and combustibility of forest fuels, to analyze their pyrolysis characteristics, pyrolysis kinetics characteristics, gas emission characteristics. A four-dimensional evaluation of their combustibility was conducted based on pyrolysis parameters. The results showed that the pyrolysis temperature of holocellulose in the leaves of those six tree species ranged in 143.31-180.48 ℃ at the beginning and 345.04-394.38 ℃ at the end, lignin pyrolysis temperature ranged in 345.04-394.38 ℃ at the beginning and 582.85-609.31 ℃ at the end. The pyrolysis of the six kinds of arbor blades during the pyrolysis process affected fuel ash content, quality and temperature of the total pyrolysis. The activation energies of two main pyrolysis stages of leaves of six tree species were 18.88-27.08 kJ·mol-1 and 13.25-27.54 kJ·mol-1, respectively, and the pre-exponential factors were 3.13-26.28 min-1 and 1.30-22.55 min-1. The holocellulose activation energy and pre-exponential factor of the pyrolysis stage for P. koraiensis, F. mandshurica, Q. mongolica, and B. platyphylla were greater than that of the lignin pyrolysis stage, while the opposite was true for P. sylvestris var. mongolica and J. mandshurica. The release amounts of CO and CO2 at the pyrolysis stage of the holocellulose was 535.16-880.11 mg·m-3 and 7004.97-10302.05 mg·m-3, and that at the pyrolysis stage of lignin was 240.31-1104.67 mg·m-3 and 20425.60-33946.68 mg·m-3, respectively. The release of CO and CO2 at the pyrolysis stage of healdellulose was less, but mass loss was greater than that at the pyrolysis stage of lignin. In the four-dimensional combustibility ranking of the six tree species leaves, B. platyphylla was the best ignitable, P. koraiensis was the most combustible, and P. sylvestris var. mongolica was the most sustainable and consumable. The ignitability was significantly positively correlated with pyrolysis kinetics parameters of the holocellulose, while the sustainability was negatively correlated with that of lignin.

Small molecule allosteric inhibitors of RORγt block Th17-dependent inflammation and associated gene expression in vivo.

Retinoic acid receptor-related orphan nuclear receptor (ROR) γt is a member of the RORC nuclear hormone receptor family of transcription factors. RORγt functions as a critical regulator of thymopoiesis and immune responses. RORγt is expressed in multiple immune cell populations including Th17 cells, where its primary function is regulation of immune responses to bacteria and fungi through IL-17A production. However, excessive IL-17A production has been linked to numerous autoimmune diseases. Moreover, Th17 cells have been shown to elicit both pro- and anti-tumor effects. Thus, modulation of the RORγt/IL-17A axis may represent an attractive therapeutic target for the treatment of autoimmune disorders and some cancers. Herein we report the design, synthesis and characterization of three selective allosteric RORγt inhibitors in preclinical models of inflammation and tumor growth. We demonstrate that these compounds can inhibit Th17 differentiation and maintenance in vitro and Th17-dependent inflammation and associated gene expression in vivo, in a dose-dependent manner. Finally, RORγt inhibitors were assessed for efficacy against tumor formation. While, RORγt inhibitors were shown to inhibit tumor formation in pancreatic ductal adenocarcinoma (PDAC) organoids in vitro and modulate RORγt target genes in vivo, this activity was not sufficient to delay tumor volume in a KP/C human tumor mouse model of pancreatic cancer.

The relationship between shale gas production and natural gas prices: An environmental investigation using structural breaks.

This paper investigates the long-run cointegration relationship between shale gas production and natural gas prices during the period from January 2007 to December 2016 for 16 states in the U.S., by utilizing the Generalized Least Squares (GLS) based univariate unit root test, the PANICCA panel unit root test, the cointegration tests of Gregory and Hansen (1996), Westerlund and Edgerton (2008) as well as Banerjee and Carrión-i-Silvestre (2015) tests with structural breaks. The empirical finding shows that the mean-reverting property exists in both variables, and most structural breaks emerge around 2007-2009 and 2011-2014, during the period when shale gas production sharply increased, the global financial crisis erupted, and external energy shocks emerged. We also find a strong cointegrated relationship, denoting a long-run equilibrium property appears among the variables. Overall, we demonstrate an interaction nexus between price and production variables and put forward some vital implications for authorities and gas market participants.

Establishment of animal model of gastroesophageal reflux disease by per-oral endoscopic tunneling: a preliminary study.

BACKGROUND: Although a variety of antireflux procedures and medications are used to treat gastroesophageal reflux disease (GERD), reliable large-animal models of GERD that can be used to objectively compare the efficacy of these treatments are lacking. We developed a method to establish large animal models of GERD by endoscopic sphincterotomy to develop an endoscopic treatment for GERD. METHODS: In this study six flesh swine carcasses were used. A full thickness incision was made at the esophageal site 5 cm above the dentate line by per-oral endoscopic tunneling. Esophageal radiography was conducted before and after surgery to observe changes at the site of the lower esophagus 5 cm above the dentate line and in the cardia. RESULTS: There was no significant change in the diameter of the esophageal site 5 cm above the dentate line before and after surgery, while the cardiac orifice significantly relaxed after surgery and enabled the contrast agent to smoothly travel through. The difference in diameter was statistically significant (P<0.05). CONCLUSIONS: Our experiments showed that it is a minimally invasive and mature technology of establishing GERD animal models by using the per-oral endoscopic tunneling technique, and might be a new method to establishing GERD large animal models.

Peroral endoscopic cardial constriction in gastroesophageal reflux disease.

Gastroesophageal reflux disease (GERD) is a major digestive health problem with a high and increasing incidence worldwide. Peroral endoscopic cardial constriction (PECC) was developed by our group to provide a less invasive treatment for GERD.In this preliminary follow-up study, 16 patients were enrolled and 13 patients with GERD were targeted for analysis according to the Los Angeles classification of reflux esophagitis. The GERD health-related quality of life (GERD-HRQL) scale and esophageal pH monitoring were applied to assess clinical efficiency at 3 and 6 months after PECC treatment, respectively.All GERD patients successively received PECC, and no severe treatment-related complication was reported. Before PECC treatment, the GERD-HRQL scale was 19.92 ±â€Š7.89. At 3 and 6 months after treatment, the GERD-HRQL scale was 4.46 ±â€Š4.31 and 5.69 ±â€Š5.07, respectively. DeMeester score was 125.50 ±â€Š89.64 before PECC treatment, and 16.97 ±â€Š12.76 and 20.32 ±â€Š15.22 at 3 and 6 months after PECC treatment. Furthermore, the fraction time of a pH below 4 significantly decreased at 3 and 6 months after PECC treatment. Fraction time at pH <4 was 35.55 ±â€Š26.20 before PECC treatment and 7.96 ±â€Š13.03 and 4.72 ±â€Š3.78 at 3 and 6 months after PECC treatment, respectively. These results suggest that PECC treatment could significantly reduce the GERD-HRQL scale and DeMeester score (P < .01).PECC is a feasible, safe, and effective method to treatment GERD through narrowing the diameter of the cardia and preventing the reflux of stomach contents.

Hsa-let-7g miRNA regulates the anti-tumor effects of gastric cancer cells under oxidative stress through the expression of DDR genes.

Oxidative stress is linked to increased risk of gastric cancer (GC). Recent reports have found that hsa-let-7 g microRNA (miRNA) has properties of anti-tumor and resistance to damages induced by oxidized low-density lipoprotein (ox-LDL). Dysregulation of hsa-let-7 g was present in GC in vivo and in vitro under exogenous stress. However, we didn't know whether there are regulatory mechanisms of hsa-let-7 g in GC under oxidative stress. This study was aimed at investigating the effects of hsa-let-7 g microRNA (miRNA) on GC under oxidative stress. The results showed that H2O2 induced the increase of DNA damage response (DDR) genes (ATM, H2AX and Chk1) and downregulation of hsa-let-7 g in GC cells. Further study confirmed Hsa-let-7 g caused the apoptosis and loss of proliferation in GC cells exposed to H2O2 associated with repression of DDR system. Yet, we found let-7 g didn't target DDR genes (ATM, H2AX and Chk1) directly. In addition, data revealed hsa-let-7 g miRNA increased the sensitivity of GC to X-rays involving in ATM regulation as well according to application of X-rays (another DDR inducer). In conclusion, Hsa-let-7 g miRNA increased the sensitivity of GC to oxidative stress by repression activation of DDR indirectly. Let-7 g improved the effects of X-rays on GC cells involving in DDR regulation as well.

[Preliminary experience with endoscopic gastric submucosal tumor resection through the submucosal tunnel using double tunnel and double flex endoscope].

OBJECTIVE: To examine the feasibility and safety of gastric submucosal tunnel dissection of gastric submucosal tumors (SMTs) by double tunnel and double flex endoscope. METHODS: Fifty patients with gastric SMTs detected by gastric endoscopy and endoscopic ultrasonography between January, 2012 and August, 2013 were enrolled in this study. Using carbon dioxide throughout the procedure, the mucous in the arc was incised along the margins of the lesion to separate the submucosa and create a tunnel. The exposed SMTs were resected completely and the mucosa was covered by endoscopic forceps followed by clipping of the incision. The complication, clinical outcomes, hospital stays and operation time were evaluated. RESULTS: Of the 50 lesions, 50 were located in the gastric fundus, 17 in the gastric antrum and 5 in the gastric body. The lesions were completely resected in all the patients. The diameter of the resected lesions ranged from 0.5 to 2.5 cm (mean 1.1 ± 0.6 cm), and the operation lasted for 35.3 ± 16.2 min (range 23-76 min). In 5 cases (10%), perforation occurred during the operation and was closed by clipping the incision with endoclips after the lesion resection; these patients were discharged after conservative management. Intraoperative bleeding occurred in 16 cases and was successfully managed through endoscopic methods. No delayed postoperative bleeding or perforation occurred in these patients. None of the 48 patients followed up showed tumor recurrence at one year after the operation, and 2 patients were lost for follow up. CONCLUSION: Endoscopic submucosal dissection of gastric SMTs is effective and safe using double tunnel and double flex endoscope.

Engineering of a Pluronic F127 functionalized magnetite/graphene nanohybrid for chemophototherapy.

In this study, a multifunctional graphene based nanohybrid, termed as GN/Fe3O4/PF127, is engineered via a facile one-pot process consisting of simultaneous reduction of graphene oxide/Fe3O4 and subsequent assembly of Pluronic F127 (PF127) onto graphene nanosheets (GNs). The unique aromatic and planar structure of GNs allows the attachment of multiple functional components including MRI contrast agent (Fe3O4 nanoparticles) and an aromatic anticancer drug like doxorubicin (DOX), as well as PF127 coating which imparts physiological dispersivity and stability to the nanohybrid. The successful assembly process is revealed by TEM observation, size and FITR monitoring. In contrast with the primitive graphene or its oxide derivative, the resulting GN/Fe3O4/PF127 nanohybrids have shown high biological dispersion and MRI effect for diagnosis due to the incorporation of superparamagnetic Fe3O4 nanoparticles without evident cytotoxicity. Moreover, the GN/Fe3O4/PF127 nanohybrid exhibits a photothermal effect due to the considerable optical absorption in the near-infrared region of GNs. The GN/Fe3O4/PF127 nanohybrid could be a further platform for chemophototherapy assisted by the therapeutic DOX. Cellular toxicity assays indicated that the DOX-loaded GN/Fe3O4/PF127 nanohybrid showed a remarkable cytotoxicity to HeLa cells and the cytotoxic effect was intensified when subjected to photoirradiation. Confocal laser scanning microscopy (CLSM) and flow cytometric analysis (FCAS) revealed that the nanohybrid could be easily uptaken into HeLa cells.

[Endoscopic esophageal submucosal tunnel resection of cardiac benign tumors originating from muscularis propria].

OBJECTIVE: To summarize the experiences of resecting cardiac muscularis propria benign tumors though esophageal submucosal tunnel and examine the occurrence rate of complications. METHODS: A total of 17 cases of cardiac muscularis propria benign tumor as diagnosed by endoscopy and endoscopic ultrasonography underwent endoscopic submucosal tunnel dissection from January 2012 to October 2013. And the appearances of lesions and the operative complications were recorded and analyzed. RESULTS: All lesions were successfully resected with a mean diameter of 1.6 (0.8-3.5) cm. There was no recurrence. The mean operative duration was 43 (26-105) min. The appearances of lesions were regular (n = 5) and irregular (n = 12). There was no instance of severe bleeding or perforation. Resection of muscularis propria was performed for 3 cases. The complications included pneumoderm (n = 3) and pneumoperitoneum (n = 3). All the above cases were discharged after conservative treatment. CONCLUSION: Endoscopic submucosal tunnel dissection is safe, reliable, convenient and fast for cardiac muscularis propria tumors method.

Discovery of bacterial NAD⁺-dependent DNA ligase inhibitors: improvements in clearance of adenosine series.

Optimization of clearance of adenosine inhibitors of bacterial NAD(+)-dependent DNA ligase is discussed. To reduce Cytochrome P-450-mediated metabolic clearance, many strategies were explored; however, most modifications resulted in compounds with reduced antibacterial activity and/or unchanged total clearance. The alkyl side chains of the 2-cycloalkoxyadenosines were fluorinated, and compounds with moderate antibacterial activity and favorable pharmacokinetic properties in rat and dog were identified.

Engineering of a novel pluronic F127/graphene nanohybrid for pH responsive drug delivery.

Herein, a novel Pluronic F127/graphene nanosheet (PF127/GN) hybrid was prepared via an one-pot process including the simultaneous reduction of graphene oxide and assembly of PF127 and GN. The nanohybrid exhibits high water dispersibility and stability in physiological environment with the hydrophilic chains of PF127 extending to the solution while the hydrophobic segments anchoring at the surface of graphene via hydrophobic interaction. The PF127/GN nanohybrid is found to be capable of effectively encapsulating doxorubicin (DOX) with ultrahigh drug-loading efficiency (DLE; 289%, w/w) and exhibits a pH responsive drug release behavior. The superb DLE of the PF127/GN nanohybrid relies on the introduction of GN which is structurally compatible with DOX. Cellular toxicity assays performed on human breast cancer MCF-7 cells demonstrate that the PF127/GN nanohybrid displays no obvious cytotoxicity, whereas the PF127/GN-loaded DOX (PF127/GN/DOX) shows remarkable cytotoxicity to the MCF-7. Cell internalization study reveals that PF127/GN nanohybrid facilitates the transfer of DOX into MCF-7 cells, evidenced by the image of confocal laser scanning microscopy. The above results indicate the potential application of this novel nanocarrier in biomedicine.

Anti-tumor effects of a novel retinoic acid metabolism blocking agent VN/14-1 in the N-methyl-N-nitrosourea-induced rat mammary carcinoma model and its effects on the uterus.

VN/14-1 [4-(±)-(1H-Imidazol-1-yl)-(E)-retinoic acid], a novel retinoic acid metabolism blocking agent (RAMBA), works by inhibiting the breakdown of all-trans-retinoic acid. The purpose of this study was to evaluate the anti-tumor effects of VN/14-1 on the N-methyl-N-nitrosourea (MNU)-induced rat mammary carcinoma model, and peripheral organ effects on the uteri of immature ovariectomized (OVX) rats. In tumor burden experiments, after 56 days of administration of VN/14-1 5, 10, and 20 mg/kg/day, significant tumor reductions in mean tumor weight of 19.1, 34.4, and 44.3%, compared to tumors in control animals occurred. Cumulative tumor growth was also significantly slower in a dose-dependent manner in groups receiving 5, 10, and 20 mg/kg/day of VN/14-1 compared to growth rates in the control group. Tumor apoptosis was significant increases in animals treated with 5, 10, and 20 mg/kg/day of VN/14-1. In uterotrophic experiments, immature OVX rats given VN/14-1 significantly reduced uterine weight and blocked endometrial stimulation induced by unopposed ß-estradiol (E2). In both rat models, adverse toxicities included weakness, anorexia, and reduction in body weight in the groups given the highest dose of 20 mg/kg/day. In summary, VN/14-1 inhibited tumor growth in the MNU-induced estrogen receptor (ER)-positive rat mammary tumor model, and antagonized the stimulatory effect of estrogens on the uterus. The studies suggest that VN/14-1 may be a useful novel therapy for ER-positive breast cancer.

Discovery of (+)-N-(3-aminopropyl)-N-[1-(5-benzyl-3-methyl-4-oxo-[1,2]thiazolo[5,4-d]pyrimidin-6-yl)-2-methylpropyl]-4-methylbenzamide (AZD4877), a kinesin spindle protein inhibitor and potential anticancer agent.

Structure-activity relationship analysis identified (+)-N-(3-aminopropyl)-N-[1-(5-benzyl-3-methyl-4-oxo-[1,2]thiazolo[5,4-d]pyrimidin-6-yl)-2-methylpropyl]-4-methylbenzamide (AZD4877), from a series of novel kinesin spindle protein (KSP) inhibitors, as exhibiting both excellent biochemical potency and pharmaceutical properties suitable for clinical development. The selected compound arrested cells in mitosis leading to the formation of the monopolar spindle phenotype characteristic of KSP inhibition and induction of cellular death. A favorable pharmacokinetic profile and notable in vivo efficacy supported the selection of this compound as a clinical candidate for the treatment of cancer.

Comparing the effects of atamestane, toremifene and tamoxifen alone and in combination, on bone, serum lipids and uterus in ovariectomized rats.

Complete estrogen blockade remains under investigation as a means to optimize anti-estrogen therapy in breast cancer thus both the efficacy and end-organ toxicities are of interest with combinations. We hypothesized that a steroidal aromatase inhibitor (AI) atamestane (ATA) alone, and in combination with the anti-estrogens tamoxifen (TAM) or toremifene (TOR) would have beneficial effects in ovariectomized (OVX) rats on key end-organ functions including bone and lipid metabolism and on the endometrium. Significant positive effects on bone were noted with ATA, TOR, TAM, ATA+TOR, or ATA+TAM. TOR, TAM, ATA+TOR, or ATA+TAM caused significant decreases in serum cholesterol and low-density lipoprotein cholesterol whereas ATA had no effect. Uterine weight and epithelium lining height were not increased by ATA but were by TOR and TAM. No significant differences were found in the key parameters outlined above between OVX rats given TOR and ATA+TOR, or TAM and ATA+TAM. Our data show that ATA in combination with TOR or TAM is equivalent to TOR or TAM alone in terms of end-organ effects within a range of clinically relevant doses. Further studies of combinations of AIs with anti-estrogens on end-organ function are merited.

[Estimation of total carbon-containing gas emission from main tree species in forest fires in Daxing' an mountains].

By the method of emission factor (EF), this paper estimated the total carbon-containing gas emission from five main tree species in Daxing' an Mountains in forest fires from 1980 to 2005. The results showed that different tree species had different EF. Pinus sylvesstris var. mongolica and Populus davidiana had the maximum and minimum EF of CO2, respectively. Larix gmelinii and Betula platyphylla had the maximun EF of CO and C(x)H(y), while B. platyphylla and L. gmelinii had the minimum EF of CO and C(x)H(y). Based on the carbon storage in different organs and the total biomass of the tree, it was estimated that the total emission of CO2, CO and C(x)H(y) from the five tree in the 25 years was 16.58 Tg, 1.61 Tg and 0.54 Tg, and the contributions of L. gmelinii, P. sylvesstris var. mongolica, B. platyphylla, P. davidiana, and Quercus mongolica were 5.00 Tg, 0.63 Tg and 0.05 Tg, 0.225 Tg, 0.023 Tg and 0.003 Tg, 11.22 Tg, 0.83 Tg and 0.41 Tg, 0.0022 Tg, 0.004 Tg and 0.00034 Tg, and 3.12 Tg, 0.13 Tg and 0.062 Tg, respectively.

[Characteristics of gas release during combustion of main arbor and shrub species in Xiaoxing'an Mountain].

The amounts of CO2, CO, CxHy, SO2 and NO released from the combustion of 10 arbor and 9 shrub species in Liangshui Forest Farm of Xiaoxing'an Mountain were determined, with the release amounts and emission factors of these gases calculated. The results showed that the released CO2, the total amount of carbon-containing gases, and the mean value of the total amount of the 5 gases during combustion were larger for arbors than for shrubs, being 1277.04 and 1149.06 mg x g(-1), 1476.27 and 1147.18 mg x g(-1), and 1486.21 and 1459.67 mg x g(-1), respectively, while an opposite pattern of the mean release of CO, NO and SO2 was observed, being 231.58 and 282.93 mg x g(-1), 3.61 and 5.03 mg x g(-1), and 6.32 and 7.46 mg x g(-1) for the arbor and shrub species, respectively. The emission factors of CO2 and CO were also larger for arbors than for shrubs, being 2.8853 and 2.7718, and 0.4558 and 0.2425, respectively.