1-[(4-tert-Butyl­phen­yl)sulfon­yl]-1H-benzimidazole

The title compound, C17H18N2O2S, was synthesized by aryl­sulfonyl­ation of 1-hy­droxy­methyl-1H-benzimidazole in the presence of triethyl­amine. The benzimidazole and benzene rings form a dihedral angle of 84.1 (1)°. The tert-butyl group was treated as rotationally disordered over two orientations in a 0.51 (2):0.49 (2) ratio. In the crystal, weak inter­molecular C—H⋯O hydrogen bonds link the mol­ecules into chains propagating in [010]

Effect of different cytokines on mammaglobin and maspin gene expression in normal leukocytes: possible relevance to the assays for the detection of micrometastatic breast cancer

In cancer patients, the ability to detect disseminated tumour cells in peripheral blood or bone marrow could improve prognosis and consent both early detection of metastatic disease and monitoring of the efficacy of systemic therapy. These objectives remain elusive mainly due to the lack of specific genetic markers for solid tumours. The use of surrogate tissue-specific markers can reduce the specificity of the assays and give rise to a clinically unacceptable false-positive rate. Mammaglobin (MAM) and maspin are two putative breast tissue-specific markers frequently used for detection of occult tumour cells in the peripheral blood, bone marrow and lymph nodes of breast cancer patients. In this study, it was evaluated whether MAM and maspin gene expression may be induced in the normal blood and bone marrow cells exposed to a panel of cytokines, including chemotactic factors (C5a, interleukin (IL)-8), LPS, proinflammatory cytokines (TNF-α, IL-1β) and growth factors (IL-3, granulocyte-macrophage colony-stimulating factor, granulocyte colony-stimulating factor). The experimental data show that all cytokines included in the panel, except for IL-8, were able to induce maspin expression; on the contrary, MAM gene was never induced. These results suggest that MAM is more specific than maspin and that the possible interference of cytokines should be taken into account in interpreting molecular assays for detection of isolated tumour cells

Catastrophic NAD+ Depletion in Activated T Lymphocytes through Nampt Inhibition Reduces Demyelination and Disability in EAE

Nicotinamide phosphoribosyltransferase (Nampt) inhibitors such as FK866 are potent inhibitors of NAD+ synthesis that show promise for the treatment of different forms of cancer. Based on Nampt upregulation in activated T lymphocytes and on preliminary reports of lymphopenia in FK866 treated patients, we have investigated FK866 for its capacity to interfere with T lymphocyte function and survival. Intracellular pyridine nucleotides, ATP, mitochondrial function, viability, proliferation, activation markers and cytokine secretion were assessed in resting and in activated human T lymphocytes. In addition, we used experimental autoimmune encephalomyelitis (EAE) as a model of T-cell mediated autoimmune disease to assess FK866 efficacy in vivo. We show that activated, but not resting, T lymphocytes undergo massive NAD+ depletion upon FK866-mediated Nampt inhibition. As a consequence, impaired proliferation, reduced IFN-γ and TNF-α production, and finally autophagic cell demise result. We demonstrate that upregulation of the NAD+-degrading enzyme poly-(ADP-ribose)-polymerase (PARP) by activated T cells enhances their susceptibility to NAD+ depletion. In addition, we relate defective IFN-γ and TNF-α production in response to FK866 to impaired Sirt6 activity. Finally, we show that FK866 strikingly reduces the neurological damage and the clinical manifestations of EAE. In conclusion, Nampt inhibitors (and possibly Sirt6 inhibitors) could be used to modulate T cell-mediated immune responses and thereby be beneficial in immune-mediated disorders

Genomic characterization of large rearrangements of the LDLR gene in Czech patients with familial hypercholesterolemia

<p>Abstract</p> <p>Background</p> <p>Mutations in the <it>LDLR </it>gene are the most frequent cause of Familial hypercholesterolemia, an autosomal dominant disease characterised by elevated concentrations of LDL in blood plasma. In many populations, large genomic rearrangements account for approximately 10% of mutations in the <it>LDLR </it>gene.</p> <p>Methods</p> <p>DNA diagnostics of large genomic rearrangements was based on Multiple Ligation dependent Probe Amplification (MLPA). Subsequent analyses of deletion and duplication breakpoints were performed using long-range PCR, PCR, and DNA sequencing.</p> <p>Results</p> <p>In set of 1441 unrelated FH patients, large genomic rearrangements were found in 37 probands. Eight different types of rearrangements were detected, from them 6 types were novel, not described so far. In all rearrangements, we characterized their exact extent and breakpoint sequences.</p> <p>Conclusions</p> <p>Sequence analysis of deletion and duplication breakpoints indicates that intrachromatid non-allelic homologous recombination (NAHR) between <it>Alu </it>elements is involved in 6 events, while a non-homologous end joining (NHEJ) is implicated in 2 rearrangements. Our study thus describes for the first time NHEJ as a mechanism involved in genomic rearrangements in the <it>LDLR </it>gene.</p

More Evidence that Depressive Symptoms Predict Mortality in COPD Patients: Is Type D Personality an Alternative Explanation?

The present study attempted to replicate our previous finding that depressive symptoms are a risk factor for mortality in stable chronic obstructive pulmonary disease (COPD), but in a different population with a different measure of depressive symptoms. We further investigated whether type D personality is associated with mortality in patients with COPD and whether it explains any relationship observed between depressive symptoms and mortality. In 122 COPD patients, mean age 60.8 +/- 10.3 years, 52% female, and mean forced expiratory volume in 1 s (FEV(1)) 41.1 +/- 17.6%pred, we assessed body mass index, post bronchodilator FEV(1), exercise capacity, depressive symptoms with the Hospital Anxiety and Depression Scale, and type D with the Type D Scale. In the 7 years follow-up, 48 (39%) deaths occurred. The median survival time was 5.3 years. Depressive symptoms (hazard ratio = 1.07, 95% confidence intervals = 1.00-1.14) were an independent risk factor for mortality. Type D was not associated with mortality. We can rule out type D as an explanation for the relationship between depressive symptoms and mortality observed in this sample. However, ambiguity remains as to the interpretation of the value of depressive symptoms in predicting death

Metabolic disorders across hepatocellular carcinoma in Italy

BACKGROUND: Metabolic disorders are well-known risk factors for HCC. Conversely, their impact on the natural history of HCC is not established. This study aimed at evaluating the impact of metabolic disorders on clinical features, treatment and survival of HCC patients regardless of its aetiology. METHODS: We analysed the ITA.LI.CA database regarding 839 HCC patients prospectively collected. The following metabolic features were analysed: BMI, diabetes, arterial hypertension, hypercholesterolaemia and hypertriglyceridaemia. According to these features, patients were divided into 3 groups: 0-1, 2 and 3-5 metabolic features. RESULTS: As compared with patients with 0-1 metabolic features, patients with 3-5 features showed lower percentage of HCC diagnosis on surveillance (P = .021), larger tumours (P = .038), better liver function (higher percentage of Child-Pugh class A [P = .007] and MELD &lt; 10 [P = .003]), higher percentage of metastasis (P = .024) and lower percentage of portal vein thrombosis (P = .010). The BCLC stage and treatment options were similar among the 3 groups, with the exception of a less frequent access to loco-regional therapies for BCLC stage B patients with 3-5 features (P = .012). Overall survival and survival according to BCLC stage and/or treatment did not significantly differ among the 3 groups. Only using a probabilistic sensitivity analysis, diabetic patients showed a lower survival (P = .046). MELD score, HCC morphology, nodule size, BCLC stage, portal vein thrombosis and metastasis were independent predictors of lead-time adjusted survival. CONCLUSIONS: Our "real world" study suggests that metabolic disorders shape the clinical presentation of HCC but do not seem to play a major role in setting patient survival.Background: Metabolic disorders are well-known risk factors for HCC. Conversely, their impact on the natural history of HCC is not established. This study aimed at evaluating the impact of metabolic disorders on clinical features, treatment and survival of HCC patients regardless of its aetiology. Methods: We analysed the ITA.LI.CA database regarding 839 HCC patients prospectively collected. The following metabolic features were analysed: BMI, diabetes, arterial hypertension, hypercholesterolaemia and hypertriglyceridaemia. According to these features, patients were divided into 3 groups: 0-1, 2 and 3-5 metabolic features. Results: As compared with patients with 0-1 metabolic features, patients with 3-5 features showed lower percentage of HCC diagnosis on surveillance (P&nbsp;=.021), larger tumours (P&nbsp;=.038), better liver function (higher percentage of Child-Pugh class A [P&nbsp;=.007] and MELD&nbsp;&lt;&nbsp;10 [P&nbsp;=.003]), higher percentage of metastasis (P&nbsp;=.024) and lower percentage of portal vein thrombosis (P&nbsp;=.010). The BCLC stage and treatment options were similar among the 3 groups, with the exception of a less frequent access to loco-regional therapies for BCLC stage B patients with 3-5 features (P&nbsp;=.012). Overall survival and survival according to BCLC stage and/or treatment did not significantly differ among the 3 groups. Only using a probabilistic sensitivity analysis, diabetic patients showed a lower survival (P&nbsp;=.046). MELD score, HCC morphology, nodule size, BCLC stage, portal vein thrombosis and metastasis were independent predictors of lead-time adjusted survival. Conclusions: Our \u201creal world\u201d study suggests that metabolic disorders shape the clinical presentation of HCC but do not seem to play a major role in setting patient survival

Mantle Pb paradoxes : the sulfide solution

Author Posting. © Springer, 2006. This is the author's version of the work. It is posted here by permission of Springer for personal use, not for redistribution. The definitive version was published in Contributions to Mineralogy and Petrology 152 (2006): 295-308, doi:10.1007/s00410-006-0108-1.There is growing evidence that the budget of Pb in mantle peridotites is largely contained in sulfide, and that Pb partitions strongly into sulfide relative to silicate melt. In addition, there is evidence to suggest that diffusion rates of Pb in sulfide (solid or melt) are very fast. Given the possibility that sulfide melt ‘wets’ sub-solidus mantle silicates, and has very low viscosity, the implications for Pb behavior during mantle melting are profound. There is only sparse experimental data relating to Pb partitioning between sulfide and silicate, and no data on Pb diffusion rates in sulfides. A full understanding of Pb behavior in sulfide may hold the key to several long-standing and important Pb paradoxes and enigmas. The classical Pb isotope paradox arises from the fact that all known mantle reservoirs lie to the right of the Geochron, with no consensus as to the identity of the “balancing” reservoir. We propose that long-term segregation of sulfide (containing Pb) to the core may resolve this paradox. Another Pb paradox arises from the fact that the Ce/Pb ratio of both OIB and MORB is greater than bulk earth, and constant at a value of 25. The constancy of this “canonical ratio” implies similar partition coefficients for Ce and Pb during magmatic processes (Hofmann et al. 1986), whereas most experimental studies show that Pb is more incompatible in silicates than Ce. Retention of Pb in residual mantle sulfide during melting has the potential to bring the bulk partitioning of Ce into equality with Pb if the sulfide melt/silicate melt partition coefficient for Pb has a value of ~ 14. Modeling shows that the Ce/Pb (or Nd/Pb) of such melts will still accurately reflect that of the source, thus enforcing the paradox that OIB and MORB mantles have markedly higher Ce/Pb (and Nd/Pb) than the bulk silicate earth. This implies large deficiencies of Pb in the mantle sources for these basalts. Sulfide may play other important roles during magmagenesis: 1). advective/diffusive sulfide networks may form potent metasomatic agents (in both introducing and obliterating Pb isotopic heterogeneities in the mantle); 2). silicate melt networks may easily exchange Pb with ambient mantle sulfides (by diffusion or assimilation), thus ‘sampling’ Pb in isotopically heterogeneous mantle domains differently from the silicate-controlled isotope tracer systems (Sr, Nd, Hf), with an apparent ‘de-coupling’ of these systems.Our intemperance should not be blamed on the support we gratefully acknowledge from NSF: EAR- 0125917 to SRH and OCE-0118198 to GAG

Material deprivation affects the management and clinical outcome of hepatocellular carcinoma in a high-resource environment

none94Aim: This study investigated how material deprivation in Italy influences the stage of hepatocellular carcinoma (HCC) at diagnosis and the chance of cure. Methods: 4114 patients from the Italian Liver Cancer database consecutively diagnosed with HCC between January 2008 and December 2018 were analysed about severe material deprivation (SMD) rate tertiles of the region of birth and region of managing hospitals, according to the European Statistics on Income and Living Conditions. The main outcomes were HCC diagnosis modalities (during or outside surveillance), treatment adoption and overall survival. Results: In more deprived regions, HCC was more frequently diagnosed during surveillance, while the incidental diagnosis was prevalent in the least deprived. Tumour characteristics did not differ among regions. The proportion of patients undergoing potentially curative treatments progressively decreased as the SMD worsened. Consequently, overall survival was better in less deprived regions. Patients who moved from most deprived to less deprived regions increased their probability of receiving potentially curative treatments by 1.11 times (95% CI 1.03 to 1.19), decreasing their mortality likelihood (hazard ratio 0.78 95% CI 0.67 to 0.90). Conclusions: Socioeconomic status measured through SMD does not seem to influence HCC features at diagnosis but brings a negative effect on the chance of receiving potentially curative treatments. Patient mobility from the most deprived to the less deprived regions increased the access to curative therapies, with the ultimate result of improving survival.openCucchetti A.; Gramenzi A.; Johnson P.; Giannini E.G.; Tovoli F.; Rapaccini G.L.; Marra F.; Cabibbo G.; Caturelli E.; Gasbarrini A.; Svegliati-Baroni G.; Sacco R.; Zoli M.; Morisco F.; Di Marco M.; Mega A.; Foschi F.G.; Biasini E.; Masotto A.; Nardone G.; Raimondo G.; Azzaroli F.; Vidili G.; Brunetto M.R.; Farinati F.; Trevisani F.; Avanzato F.; Biselli M.; Caraceni P.; Garuti F.; Neri A.; Santi V.; Pellizzaro F.; Imondi A.; Sartori A.; Penzo B.; Sanmarco A.; Granito A.; Muratori L.; Piscaglia F.; Sansone V.; Forgione A.; Dajti E.; Marasco G.; Ravaioli F.; Cappelli A.; Golfieri R.; Mosconi C.; Renzulli M.; Cela E.M.; Facciorusso A.; Cacciato V.; Casagrande E.; Moscatelli A.; Pellegatta G.; de Matthaeis N.; Allegrini G.; Lauria V.; Ghittoni G.; Pelecca G.; Chegai F.; Coratella F.; Ortenzi M.; Missale G.; Olivani A.; Inno A.; Marchetti F.; Busacca A.; Camma C.; Di Martino V.; Maria Rizzo G.E.; Franze M.S.; Saitta C.; Sauchella A.; Berardinelli D.; Bevilacqua V.; Borghi A.; Gardini A.C.; Conti F.; Dall'Aglio A.C.; Ercolani G.; Adotti V.; Arena U.; Di Bonaventura C.; Campani C.; Dragoni G.; Gitto S.; Laffi G.; Coccoli P.; Malerba A.; Guarino M.; Capasso M.; Oliveri F.; Romagnoli V.Cucchetti, A.; Gramenzi, A.; Johnson, P.; Giannini, E. G.; Tovoli, F.; Rapaccini, G. L.; Marra, F.; Cabibbo, G.; Caturelli, E.; Gasbarrini, A.; Svegliati-Baroni, G.; Sacco, R.; Zoli, M.; Morisco, F.; Di Marco, M.; Mega, A.; Foschi, F. G.; Biasini, E.; Masotto, A.; Nardone, G.; Raimondo, G.; Azzaroli, F.; Vidili, G.; Brunetto, M. R.; Farinati, F.; Trevisani, F.; Avanzato, F.; Biselli, M.; Caraceni, P.; Garuti, F.; Neri, A.; Santi, V.; Pellizzaro, F.; Imondi, A.; Sartori, A.; Penzo, B.; Sanmarco, A.; Granito, A.; Muratori, L.; Piscaglia, F.; Sansone, V.; Forgione, A.; Dajti, E.; Marasco, G.; Ravaioli, F.; Cappelli, A.; Golfieri, R.; Mosconi, C.; Renzulli, M.; Cela, E. M.; Facciorusso, A.; Cacciato, V.; Casagrande, E.; Moscatelli, A.; Pellegatta, G.; de Matthaeis, N.; Allegrini, G.; Lauria, V.; Ghittoni, G.; Pelecca, G.; Chegai, F.; Coratella, F.; Ortenzi, M.; Missale, G.; Olivani, A.; Inno, A.; Marchetti, F.; Busacca, A.; Camma, C.; Di Martino, V.; Maria Rizzo, G. E.; Franze, M. S.; Saitta, C.; Sauchella, A.; Berardinelli, D.; Bevilacqua, V.; Borghi, A.; Gardini, A. C.; Conti, F.; Dall'Aglio, A. C.; Ercolani, G.; Adotti, V.; Arena, U.; Di Bonaventura, C.; Campani, C.; Dragoni, G.; Gitto, S.; Laffi, G.; Coccoli, P.; Malerba, A.; Guarino, M.; Capasso, M.; Oliveri, F.; Romagnoli, V

Laser ablation is superior to TACE in large-sized hepatocellular carcinoma: A pilot case-control study

Background:Limited therapies are available for large ( 6540 mm) unresectable hepatocellular carcinoma (HCC). Currently, the standard treatment with transarterial chemoembolisation (TACE) is unsatisfactory with high recurrence rate and limited effect on survival. Laser Ablation (LA) has emerged as a relatively new technique characterized by high efficacy and good safety. This study is aimed to evaluate the efficacy of LA in comparison to TACE in patients with large HCC. Methods: Eighty-two patients with a single HCC nodule 6540 mm (BCLC stage A or B) were enrolled in this case-control study. Forty-one patients were treated with LA and 41 patients were treated with TACE. Response to therapy was evaluated according to the mRECIST criteria. Survival was calculated with Kaplan-Meier from the time of cancer diagnosis to death with values censored at the date of the last follow-up. Results: Twenty-six (63.4%) and 8 (19.5%) patients had a complete response after LA and TACE, respectively (p &lt; 0.001). Subsequently we stratified the HCCs in 3 categories according to the nodule size: 40-50 mm, 51-60 mm, and &gt; 60 mm. LA resulted superior to TACE especially in nodules ranging between 51 and 60 mm in diameter, with a complete response rate post-LA and post-TACE of 75% and 14.3%, respectively (p = 0.0133). The 36 months cumulative survival rate in patients treated with LA and TACE was 55.4% and 48.8%, respectively. The disease recurrence rates after LA and TACE were 19.5% and 75.0%, respectively. Conclusions: LA is a more effective therapeutic option than TACE in patients with solitary large HCC