Calpain system protein expression in carcinomas of the pancreas, bile duct and ampulla

Background: Pancreatic cancer, including cancer of the ampulla of Vater and bile duct, is very aggressive and has a poor five year survival rate; improved methods of patient stratification are required. Methods: We assessed the expression of calpain-1, calpain-2 and calpastatin in two patient cohorts using immunohistochemistry on tissue microarrays. The first cohort was composed of 68 pancreatic adenocarcinomas and the second cohort was composed of 120 cancers of the bile duct and ampulla. Results: In bile duct and ampullary carcinomas an association was observed between cytoplasmic calpastatin expression and patient age (P = 0.036), and between nuclear calpastatin expression and increased tumour stage (P = 0.026) and the presence of vascular invasion (P = 0.043). In pancreatic cancer, high calpain-2 expression was significantly associated with improved overall survival (P = 0.036), which remained significant in multivariate Cox-regression analysis (hazard ratio = 0.342; 95% confidence interva l = 0.157-0.741; P = 0.007). In cancers of the bile duct and ampulla, low cytoplasmic expression of calpastatin was significantly associated with poor overall survival (P = 0.012), which remained significant in multivariate Cox-regression analysis (hazard ratio = 0.595; 95% confidence interval = 0.365-0.968; P = 0.037). Conclusion: The results suggest that calpain-2 and calpastatin expression is important in pancreatic cancers, influencing disease progression. The findings of this study warrant a larger follow-up study. Keywords: Calpain, Calpastatin, Pancreas, Ampulla, Bile duct, Cance

Caspase-3 and caspase-8 expression in breast cancer: caspase-3 is associated with survival

Impaired apoptosis is one of the hallmarks of cancer. Caspase-3 and -8 are key regulators of the apoptotic response and have been shown to interact with the calpain family, a group of cysteine proteases, during tumorigenesis. The current study sought to investigate the prognostic potential of caspase-3 and -8 in breast cancer, as well as the prognostic value of combinatorial caspase and calpain expression. A large cohort (n = 1902) of early stage invasive breast cancer patients was used to explore the expression of caspase-3 and -8. Protein expression was examined using standard immunohistochemistry on tissue microarrays. High caspase-3 expression, but not caspase-8, is significantly associated with adverse breast cancer-specific survival (P = 0.008 and P = 0.056, respectively). Multivariate analysis showed that caspase-3 remained an independent factor when confounding factors were included (hazard ratio (HR) 1.347, 95% confidence interval (CI) 1.086–1.670; P = 0.007). The analyses in individual subgroups demonstrated the significance of caspase-3 expression in clinical outcomes in receptor positive (ER, PR or HER2) subgroups (P = 0.001) and in non-basal like subgroup (P = 0.029). Calpain expression had been previously assessed. Significant association was also found between high caspase-3/high calpain-1 and breast cancer-specific survival in the total patient cohort (P = 0.005) and basal-like subgroup (P = 0.034), as indicated by Kaplan–Meier analysis. Caspase-3 expression is associated with adverse breast cancer-specific survival in breast cancer patients, and provides additional prognostic values in distinct phenotypes. Combinatorial caspase and calpain expression can predict worse prognosis, especially in basal-like phenotypes. The findings warrant further validation studies in independent multi-centre patient cohorts

Trypanocidal and leishmanicidal activity of six limonoids

Six limonoids [kotschyienone A and B (1, 2), 7-deacetylgedunin (3), 7-deacetyl-7-oxogedunin (4), andirobin (5) and methyl angolensate (6)] were investigated for their trypanocidal and leishmanicidal activities using bloodstream forms of Trypanosoma brucei and promastigotes of Leishmania major. Whereas all compounds showed anti-trypanosomal activity, only compounds 1–4 displayed anti-leishmanial activity. The 50% growth inhibition (GI 50) values for the trypanocidal and leishmanicidal activity of the compounds ranged between 2.5 and 14.9 μM. Kotschyienone A (1) was found to be the most active compound with a minimal inhibition concentration (MIC) value of 10 μM and GI 50 values between 2.5 and 2.9 μM. Only compounds 1 and 3 showed moderate cytotoxicity against HL-60 cells with MIC and GI 50 values of 100 μM and 31.5–46.2 μM, respectively. Compound 1 was also found to show activity against intracellular amastigotes of L. major with a GI 50 value of 1.5 μM. The results suggest that limonoids have potential as drug candidates for the development of new treatments against trypanosomiasis and leishmaniasis

Personality and the creativity of frontline service employees: linear and curvilinear effects

Previous studies have investigated the relationship between the Five Factor model of personality and creativity. As this model has been criticised for providing a limited account of an individual’s personality, this study considers additional personality traits that have recently been investigated in the literature as determinants of employee behaviour. Moreover, we also contribute to the existing body of literature by conducting this study in a services setting, for which we predict personality traits will exert differentiated effects on creativity when compared to other settings. Finally, while past research has focused on linear effects, this study examines the existence of non-linear effects between personality and creativity. The results indicate that personality traits apart from the Five Factor model have an impact on creativity and that the effects of several personality traits on the creativity of frontline service employees differ from those obtained in other settings. Lastly, the findings also show that five of the personality traits have non-linear effects on creativity, and this may be a stimulus for a new stream of research in the human resources literature

Facile access to a heterocyclic, sp3-rich chemical scaffold via a tandem condensation/intramolecular nitrone–alkene [3+2] cycloaddition strategy

A heterocyclic, sp3-rich chemical scaffold was synthesised in just 6 steps via a highly regio- and diastereo-selective tandem nitrone formation/intramolecular nitrone–alkene [3+2] cycloaddition reaction. A library of 543 lead-like compounds based on the scaffold core has been produced

Magnetic field-dependent interplay between incoherent and Fermi liquid transport mechanisms in low-dimensional tau phase organic conductors

We present an electrical transport study of the 2-dimensional (2D) organic conductor tau-(P-(S,S)-DMEDT-TTF)_2(AuBr)_2(AuBr_2)_y (y = 0.75) at low temperatures and high magnetic fields. The inter-plane resistivity rho_zz increases with decreasing temperature, with the exception of a slight anomaly at 12 K. Under a magnetic field B, both rho_zz and the in-plane resistivity plane rho_xx show a pronounced negative and hysteretic magnetoresistance with Shubnikov de Haas (SdH)oscillations being observed in some (high quality)samples above 15 T. Contrary to the predicted single, star-shaped, closed orbit Fermi surface from band structure calculations (with an expected approximate area of 12.5% of A_FBZ), two fundamental frequencies F_l and F_h are detected in the SdH signal. These orbits correspond to 2.4% and 6.8% of the area of the first Brillouin zone(A_FBZ), with effective masses F_l = 4.0 +/- 0.5 and F_h = 7.3 +/- 0.1. The angular dependence, in tilted magnetic fields of F_l and F_h, reveals the 2D character of the FS and Angular dependent magnetoresistance (AMRO) further suggests a FS which is strictly 2-D where the inter-plane hopping t_c is virtually absent or incoherent. The Hall constant R_xy is field independent, and the Hall mobility increases by a factor of 3 under moderate magnetic fields. Our observations suggest a unique physical situation where a stable 2D Fermi liquid state in the molecular layers are incoherently coupled along the least conducting direction. The magnetic field not only reduces the inelastic scattering between the 2D metallic layers, but it also reveals the incoherent nature of interplane transport in the AMRO spectrum. The apparent ferromagnetism of the hysteretic magnetoresistance remains an unsolved problem.Comment: 33 pages, 11 figure

On the appearance of nitrite anion in [PdX(OAc)L₂] and [Pd(X)(C∧N)L] syntheses (X = OAc or NO₂): Photocrystallographic identification of metastable Pd(η¹-ONO)(C∧N)PPh₃

Pd3(OAc)5NO2, an impurity in “Pd(OAc)2” {formally Pd3(OAc)6}, emerges as a serious issue in the synthesis of pure PdII complexes derived from Pd(OAc)2, for example in our C–H activation precatalyst, Pd(OAc)2(pip)2 (pip = piperidine). A previous proposal that nitrite anion can be formed by oxidation of CH3CN by metallic Pd and air, leading to cyclo(ortho)palladated complexes containing nitrite anion, e.g. Pd(NO2)(C^N)L (C^N = papaverine; L = CH3CN or DMSO) can be explained by Pd3(OAc)5NO2 acting as the nitrite source. Finally, photocrystallographic metastable linkage isomerisation and complete conversion to an oxygen-bound nitrito complex Pd(η1-ONO)(C^N)PPh3 has been observed