Stefania Asciutti

Novel Soy Germ Pasta Improves Endothelial Function, Blood Pressure, and Oxidative Stress in Patients With Type 2 Diabetes

OBJECTIVE To compare the effects of a novel soy germ–enriched pasta, containing isoflavone aglycons, with conventional pasta on endothelial function and cardiovascular risk markers in patients with type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS This randomized controlled double-blind crossover study compared one serving/day of soy germ pasta and conventional pasta for 8 weeks for effects on brachial artery flow-mediated vasodilation, blood pressure, plasma lipids, oxidized LDL cholesterol, 8-iso-PGF2α, total antioxidant capacity (TAC), glutathione (GSH), and homocysteine. RESULTS Isoflavone-enriched pasta significantly improved arterial stiffness (P = 0.005) and reduced systolic (P = 0.026) and diastolic (P = 0.017) blood pressures. Plasma TAC increased (P = 0.0002), oxidized LDL cholesterol decreased (P = 0.009), 8-iso-PGF2α decreased (P = 0.001), GSH levels increased (P = 0.0003), and homocysteine decreased (P = 0.009) consistent with a reduction in oxidative stress. No significant changes were observed with conventional pasta. CONCLUSIONS Pasta enriched with biologically active isoflavone aglycons improved endothelial function and had beneficial effects on cardiovascular risk markers in patients with T2D.

HCV vertical transmission in pregnancy: New horizons in the era of DAAs

R outine prenatal hepatitis C virus (HCV) screening is not recommended in women lacking risk factors for infection. This is partially because of the absence of options in the management of maternal to neonatal transmission and the perceived low prevalence of HCV in pregnancy. Vertical transmission rates of HCV have been reported to be as high as 8%. Reducing maternal viremia may be beneficial given its role as a requirement for vertical transmission. Recent advances in HCV infection combination therapy have made high rates of sustained virological response and HCV-RNA clearance in nonpregnant adults achievable. Currently, there are no therapies to prevent HCV vertical transmission. However, certain direct-acting antiviral agents (DAAs) may have substantially more favorable profiles in pregnancy in comparison to past medications. Given that maternal viremia has been linked to vertical neonatal transmission, the use of DAAs may considerably lower HCV vertical transmission in pregnancy and warrant future studies. The prevalence of HCV infection in pregnancy has been estimated to be similar to the reported 0.5%-1.4% seropositivity in low-risk blood donors. Presently, routine prenatal HCV screening is not recommended by the American College of Obstetricians and Gynecologists and Centers for Disease Control and Prevention, except for women with significant risk factors for infection. This policy is the result of a lack of any available preor postnatal pharmacological, immunological, or interventional measures to decrease the risk of vertical transmission. HCV vertical transmission rates have been reported between 2% and 10% and HCV chronically infects an estimated 25,000-50,000 children with 750 new cases a year acquired through vertical transmission. Furthermore, though high rates of spontaneous resolution have been reported for children acquiring HCV infection at birth, many still become chronically infected. Current long-term outcome data on these chronically infected children is significantly limited given that HCV disease morbidity in general takes longer than two decades to develop. Clinicians frequently delay treatment for HCV until after pregnancy given limited experience with the use of interferon (IFN) in pregnancy and the absolute contraindication for ribavirin (RBV) use. Recent developments in HCV infection combination therapy have made persistent normalization of transaminase levels and HCV-RNA clearance in nonpregnant adults possible. Given that maternal viremia has been linked to vertical neonatal transmission, the use of DAAs for prevention of HCV transmission alone or in association with IFN warrants more-intense future study.

Farnesoid X receptor expression is decreased in colonic mucosa of patients with primary sclerosing cholangitis and colitis-associated neoplasia.

Background:The expression and distribution of farnesoid X receptor (FXR) in colitis and colitis-associated neoplasia (CAN) is unknown. We investigated FXR expression in neoplastic and nonneoplastic tissue from ulcerative colitis (UC) patients, with or without primary sclerosing cholangitis (PSC), as well as the role of DNA methylation in FXR expression in colorectal cancer (CRC) cell lines. Methods:Samples from the right (RC) and left (LC) colon of patients with UC, with and without PSC, and with or without CAN, were stained by immunohistochemistry and scored semiquantitatively for nuclear FXR expression. FXR expression was analyzed by western blot and polymerase chain reaction (PCR) in nine different CRC cell lines before and after demethylation with 5-azacytidine. Results:In nondysplastic samples, FXR expression demonstrated a diminishing expression from proximal to distal colon (strong FXR expression: 39% RC samples vs. 14% LC samples; P = 0.007). With moderate-to-severe inflammation, FXR expression was almost always absent or weak in both UC and PSC-UC, regardless of location. With quiescent/mild inflammation, 56% of UC samples in the RC retained strong FXR expression versus 24% of PSC-UC samples (P= 0.017). FXR was absent in 72% of the neoplastic samples, with an inverse association with the grade of dysplasia. FXR expression was absent in all CRC cell lines, in some cases due to DNA methylation. Conclusions:FXR expression is inversely correlated with neoplastic progression and severity of inflammation in UC. Patients with PSC-UC have diminished FXR expression in the proximal colon compared to UC patients. This finding could contribute to the higher risk of proximal neoplasia in PSC patients.

Design, synthesis, crystallographic studies, and preliminary biological appraisal of new substituted triazolo[4,3-b]pyridazin-8-amine derivatives as tankyrase inhibitors.

Searching for selective tankyrases (TNKSs) inhibitors, a new small series of 6,8-disubstituted triazolo[4,3-b]piridazines has been synthesized and characterized biologically. Structure-based optimization of the starting hit compound NNL (3) prompted us to the discovery of 4-(2-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-8-ylamino)ethyl)phenol (12), a low nanomolar selective TNKSs inhibitor working as NAD isostere as ascertained by crystallographic analysis. Preliminary biological data candidate this new class of derivatives as a powerful pharmacological tools in the unraveling of TNKS implications in physiopathological conditions.

Diverse mechanisms of Wnt activation and effects of pathway inhibition on proliferation of human gastric carcinoma cells

Human gastric carcinomas are among the most treatment-refractory epithelial malignancies. Increased understanding of the underlying molecular aberrations in such tumors could provide insights leading to improved therapeutic approaches. In this study, we characterized diverse genetic aberrations leading to constitutive Wnt signaling activation in a series of human gastric carcinoma cell lines. Downregulation of TCF signaling by stable transduction of dominant negative TCF4 (DNTCF4) resulted in inhibition of proliferation in Wnt-activated AGS tumor cells. c-Myc downregulation and the associated upregulation of its repression target, p21 observed in these tumor cells, as well as the profound growth inhibition induced by c-Myc small hairpin RNA (shRNA) implied their c-Myc addiction. In striking contrast, Wnt-activated MKN-28 and MKN-74 tumor cells appeared refractory to DNTCF4 inhibition of proliferation despite comparably decreased c-Myc expression levels. The resistance of these same tumor cells to growth inhibition by c-Myc shRNA established that their refractoriness to DNTCF was because of their independence from c-Myc for proliferation. There was no correlation between this resistance phenotype and the presence or absence of constitutive mitogen-activated protein kinase (MAPK) and/or AKT pathway activation, commonly observed in gastrointestinal tumors. However, in both DNTCF-sensitive and -resistant tumor cells with MAPK and/or AKT pathway activation, the ability of small molecule antagonists directed against either pathway to inhibit tumor cell growth was enhanced by Wnt pathway inhibition. These findings support the concept that although certain Wnt-activated tumors may escape c-Myc dependence for proliferation, disruption of other oncogenic pathways can unmask cooperative antiproliferative effects for Wnt pathway downregulation.

Scaffold hopping approach on the route to selective tankyrase inhibitors

A virtual screening procedure was applied to identify new tankyrase inhibitors. Through pharmacophore screening of a compounds collection from the SPECS database, the methoxy[l]benzothieno[2,3-c]quinolin-6(5H)-one scaffold was identified as nicotinamide mimetic able to inhibit tankyrase activity at low micromolar concentration. In order to improve potency and selectivity, tandem structure-based and scaffold hopping approaches were carried out over the new scaffold leading to the discovery of the 2-(phenyl)-3H-benzo[4,5]thieno[3,2-d]pyrimidin-4-one as powerful chemotype suitable for tankyrase inhibition. The best compound 2-(4-tert-butyl-phenyl)-3H-benzo[4,5]thieno[3,2-d]pyrimidin-4-one (23) displayed nanomolar potencies (IC50s TNKS-1 = 21 nM and TNKS-2 = 29 nM) and high selectivity when profiled against several other PARPs. Furthermore, a striking Wnt signaling, as well as cell growth inhibition, was observed assaying 23 in DLD-1 cancer cells.

Rate of second primary tumors following diagnosed choriocarcinoma: A SEER analysis (1973–2010)

OBJECTIVE Approximately 1 in 6 of new cancers has been reported to represent a second primary tumor (SPT). Choriocarcinomas (CCs) are of interest in regard to the rate of SPTs because of the potential exposure to carcinogenic therapy and reports of the benefits of its high human gonadotropin (hCG) levels on cancer incidence. METHODS We used the Surveillance, Epidemiology, and End Results (SEER) database to identify patients with gestational CC who subsequently developed a SPT. This is a retrospective study, following a cohort of patients during the period 1973-2010. RESULTS We found 818 patients with primary gestational CC. Nineteen patients had a SPT after the CC. Occurrence of several types of cancer resulted significantly higher when compared to the incidence rate in the general population. In particular the highest incidence rate ratios (IRRs) were registered for acute myeloid leukemia (AML) (6.3) and thyroid cancer (2.6). The expected rate of lung, breast, colorectal and uterine corpus cancers instead resulted lower than the rate in the general population. Regarding the IRR in the population under 50 years of age, the higher IRRs were related to AML (20) and non-Hodgkin lymphoma (NHL) (5). CONCLUSION The association of thyroid cancer and CC has not been described previously. Increases in hematological cancer following CC lend further support to the established data. The decrease in breast and colon cancers in all age groups supports past data and decreases in uterine and lung cancers are new observations meriting further study.