Attenuation of hedgehog/GLI signaling by NT1721 extends survival in pancreatic cancer.

BackgroundPancreatic cancer is one of the most lethal malignancies due to frequent late diagnosis, aggressive tumor growth and metastasis formation. Continuously raising incidence rates of pancreatic cancer and a lack of significant improvement in survival rates over the past 30 years highlight the need for new therapeutic agents. Thus, new therapeutic agents and strategies are urgently needed to improve the outcome for patients with pancreatic cancer. Here, we evaluated the anti-tumor activity of a new natural product-based epidithiodiketopiperazine, NT1721, against pancreatic cancer.MethodsWe characterized the anticancer efficacy of NT1721 in multiple pancreatic cancer cell lines in vitro and in two orthotopic models. We also compared the effects of NT1721 to clinically used hedgehog inhibitors and the standard-of-care drug, gemcitabine. The effect of NT1721 on hedgehog/GLI signaling was assessed by determining the expression of GLI and GLI target genes both in vitro and in vivo.ResultsNT1721 displayed IC50 values in the submicromolar range in multiple pancreatic cancer cell lines, while largely sparing normal pancreatic epithelial cells. NT1721 attenuated hedgehog/GLI signaling through downregulation of GLI1/2 transcription factors and their downstream target genes, which reduced cell proliferation and invasion in vitro and significantly decreased tumor growth and liver metastasis in two preclinical orthotopic mouse models of pancreatic cancer. Importantly, treatment with NT1721 significantly improved survival times of mice with pancreatic cancer compared to the standard-of-care drug, gemcitabine.ConclusionsFavorable therapeutics properties, i.e. 10-fold lower IC50 values than clinically used hedgehog inhibitors (vismodegib, erismodegib), a 90% reduction in liver metastasis and significantly better survival times compared to the standard-of-care drug, gemcitabine, provide a rational for testing NT1721 in the clinic either as a single agent or possibly in combination with gemcitabine or other therapeutic agents in PDAC patients overexpressing GLI1/2. This could potentially result in promising new treatment options for patients suffering from this devastating disease

A study on cavitation erosion behavior of AlSi10Mg fabricated by selective laser melting (SLM)

Cavitation erosion causes serious problems for hydraulic machinery. Selective laser melting (SLM), is a type of additive manufacturing that can produce metal parts directly and it has begun to be used in various industrial settings. However, the erosion properties of the SLM processed parts have only rarely been reported. The paper addresses the cavitation erosion behavior of AlSi10Mg samples fabricated by SLM at different laser scanning speeds. A wrought sample was also tested to provide a basis for comparison. Sample hardness and microstructure were investigated. Results showed the cavitation erosion behaviors of SLM samples to differ greatly from that of the wrought sample. The erosion rate of SLM samples was found to peak in the first 30 s. This was accompanied by the removal of particles inside pores. After peaking, the erosion rate of the SLM samples decreased significantly. SLM samples showed an extremely low erosion rate entering the steady-state period. Large, deep craters which were common wear marks on the wrought sample, were not present on the SLM samples. Different scanning speeds resulted in different max erosion rates

Polymorphisms of CYP1A1 I462V and GSTM1 genotypes and lung cancer susceptibility in Mongolian

Aim: To study the genotype of cytochrome P450 1A1(CYP1A1) I462V and glutathions S-transferase M1( GSTM1) and the relationship of the genetic polymorphism of them with the susceptibility of lung cancer in Mongolia of China. 

Methods: Allele-specific PCR and a multiplex PCR were employed to identify the genotypes of I462V of CYP1A1 and GSTM1 in a case-control study of 210 lung cancer patients with bronchoscopy diagnosis and 210 matched controls free of malignancy.

Results: The frequencies of the variant CYP1A1(Val/Val) genotypes and GSTM1(-) in lung cancer groups were higher than that in control groups (15.24% vs 7.4% and 56.67% vs 40.95% ). The individuals who carried with CYP1A1(Val/Val) or GSTM1(-) genotype had a significantly higher risk of lung cancer, the OR is 2.56 and 1.89 respectively. Stratified histologically the relative risk increased to 2.6 - fold when the patients carried with two valine alleles than the ones carried one valine allele in cases of SCC. GSTM1(-) genotype is the risk factor of SCC (OR=2.39) and AC(OR=2.16). The presence of at least one Val allele of CYP1A1 and GSTM1(-), the risk of lung cancer was increased, the OR was 4.15 for one Val allele and GSTM1(-) and 2.67 for two Val alleles and GSTM1 Considering ages and smoking status, the risk of lung cancer increased when the age less than 50 who carried with CYP1A1 valine (one or two) alleles or the age during the 51 to 65 who carried with GSTM1(-) genotype. The light smokers with CYP1A1 valine alleles and GSTM1(-) have a high risk for lung cancer. No association was found between the light and heavy drinkers with the susceptibility of lung cancer and the genetic polymorphisms of CYP1A1 I462V and GSTM1(-). 

Conclusion: The valine allele of CYP1A1 was the risk factors of lung cancer especially for SCC and GSTM1(-) also was the risk factor of lung cancer and especially for SCC and AC of Mongolian, China. Light smoking has a influence each other with genotype of CYP1A1 I462V and GSTM1(-) and susceptibility of lung cancer. No relationship was found between the susceptibility of lung cancer and drinkers with genetic polymorphisms of CYP1A1 I462V and GSTM1(-). The influence of genotypes on the susceptibility of lung cancer may depend on the ages. There may be a synergetic interaction between CYP1A1 valine allele and GSTM1(-) genotypes on the elevated susceptibility of lung cancer. So do those genotypes with light smokers. Key words polymorphism; genotype; lung cancer; cytochrome P450；glutathione S-transferase Abbreviations: SCC, squamous cell carcinoma; AC, adenocarcinoma; SCLC, small cell lung cancer; LCLC, large cell lung cance

Styrene-assisted maleic anhydride grafted poly(lactic acid) as an effective compatibilizer for wood flour/poly(lactic acid) bio-composites

This study aimed to evaluate the effect of styrene-assisted maleic anhydride-grafted poly(lactic acid) (PLA-g-St/MAH) on the interfacial properties of wood flour/poly(lactic acid) (PLA) bio-composites. PLA-g-St/MAH was synthesized by free-radical melt grafting using styrene as a comonomer and dicumyl peroxide as an initiator. The structure of PLA-g-St/MAH was characterized by Fourier transform infrared spectroscopy. Wood flour/PLA composites were prepared by compression molding using PLA-g-St/MAH as a compatibilizer. The effects of PLA-g-St/MAH on the rheological and mechanical properties, as well as on the fractured surface morphology of the composites were investigated. Results indicated that storage modulus, complex viscosity, equilibrium torque, and shear heat were significantly increased. The mechanical properties of the wood flour/PLA composites were also significantly increased after the addition of PLA-g-St/MAH. The maximum values were achieved at the loading rate of 3 wt % because of the improved interfacial adhesion between the wood flour and the PLA matrix

Validity of the “Streitberger” Needle in a Chinese Population with Acupuncture: A Randomized, Single-Blinded, and Crossover Pilot Study

We studied the validity of a “Streitberger” needle as a valid approach in a Chinese population with experience of acupuncture. Volunteers were recruited from students of the School of Acupuncture and Moxibustion, Guangzhou University of Chinese Medicine. Sixty students receiving education in acupuncture theory and experience in practical acupuncture were tested in study determining whether needling with the placebo needle felt any different from conventional acupuncture. Outcomes included measures of penetration sensation, VAS ratings, and Deqi sensation questionnaire. As a result, needle penetration, VAS ratings for either needle and Deqi sensation were not significantly different between two kinds of needles. Our findings show that the use of “Streitberger” needle is credible in a Chinese population with acupuncture experience

3,3,12,12-Tetra­methyl-1,5,10,14-tetra­oxa­dispiro­[5.2.5.2]hexa­deca­ne

The mol­ecule of the title compound, C16H28O4, is centrosymmetric. The cyclo­hexane ring and both six-membered dioxane rings adopt chair conformations. In the crystal, the mol­ecules lie in layers in the (100) planes and the shortest inter­molecular contacts are H⋯H (2.30 Å)