Pancreatic ductal adenocarcinoma (PDAC) is almost universally fatal. The annual number of deaths equals the number of newly diagnosed cases, despite maximal treatment. The overall 5-year survival ...rate of <5% has remained stubbornly unchanged over the last 30 years, despite tremendous efforts in preclinical and clinical science. There is unquestionably an urgent need to further improve our understanding of pancreatic cancer biology, treatment response and relapse, and to identify novel therapeutic targets. Rigorous research in the field has uncovered genetic aberrations that occur during PDAC development and progression. In most cases, PDAC is initiated by oncogenic mutant KRAS, which has been shown to drive pancreatic neoplasia. However, all attempts to target KRAS directly have failed in the clinic and KRAS is widely assumed to be undruggable. This has led to intense efforts to identify druggable critical downstream targets and nodes orchestrated by mutationally activated KRAS. This includes context-specific KRAS effector pathways, synthetic lethal interaction partners and KRAS-driven metabolic changes. Here, we review recent advances in oncogenic KRAS signalling and discuss how these might benefit PDAC treatment in the future.
Abstract Purpose Meningiomas are mostly benign, however atypical or malignant subtypes with more aggressive clinical course and higher recurrence rates can also be seen. The purpose of this study was ...to determine whether histopathological subtypes of meningiomas could be assessed preoperatively using apparent diffusion coefficient (ADC) values. Materials and methods Conventional magnetic resonance (MR) and diffusion-weighted (DW) imaging of 177 adult patients with pathologically proven meningiomas were retrospectively evaluated. Tumor size and the degree of associated edema were noted. The signal intensity of the lesions on DW imaging was evaluated and graded. Mean ADC values were obtained as the mean of measurements from three regions of interests within the mass. ADC ratios of meningioma/contralateral normal appearing subcortical parietal white matter were also calculated. Results The histopathological analysis revealed 135 benign, 37 atypical and 5 malignant lesions. With classification according to the subtype, the mean ADC values and ratios of benign meningiomas were as 0.99 ± 0.12 × 10−3 mm2 /s and 1.22 ± 0.07, respectively. ADC values for atypical and malignant groups were both 0.84 ± 0.1 × 10−3 mm2 /s. The ADC ratios were 1.05 ± 0.1 and 0.96 ± 0.2 for atypical and malignant subtypes, respectively. There was no statistically significant difference between the mean ADC ratios of the three subtypes (ANOVA test; P ≥ 0.05). Gender, age of the patients and tumor size showed no statistically significant difference between the different histological groups. Conclusion DW MR imaging was not found to have any additional value in determining histological behaviour nor in differentiating histopathological subtypes of meningiomas.
Dinitrogen complexes of the type Tp(R,R)Cr-N2-CrTp(R,R) are not the most labile precursors for Cr(i) chemistry, as they are sterically protected from obligatory associative ligand substitution. A ...mononuclear alkyne complex - Tp(tBu,Me)Cr(η(2)-C2(SiMe3)2) - proved to be much more reactive.
Bulky β-diketones have rarely exceeded dipivaloylmethane (DPM) in steric demand, largely due to synthetic limitations of the Claisen condensation. This work demonstrates hindered acid chlorides to be ...selective electrophiles in noncoordinating solvents for condensations with enolates. An improved synthesis of DPM is described (90% yield), and crowded β-diketones featuring bulky o-biphenyl or m-terphenyl fragments were prepared in good to excellent yields. These compounds are anticipated to have a steric profile far greater than that of DPM. General reaction conditions and mechanistic considerations are included.
The synthesis of a sterically encumbered β-diketone ligand (Aracac) substituted with 2,6-(2,4,6-Me3C6H2)2C6H3 is described. Coordination complexes of the type M(Aracac)2Cl(solv) (M = Ti, V, Cr; ...solv = THF, CH3CN) were prepared by the reaction of Aracac with MCl3 (M = V, Cr) or with TiCl4 to generate Ti(Aracac)2Cl2, followed by reduction. These complexes show a trend of alternating the cis/trans geometric preference with increasing d n electron count (n = 0, 1, 2, 3), which is rationalized in part by the unusual ability of β-diketonates to behave as either a weak π donor or a π acceptor in the cis and trans geometries, respectively. In this way, the bis-β-diketonate platform can accommodate the varying electronic demands of the coordinated metal ion. These results demonstrate the ability to limit the coordination of β-diketonates on metal complexes for the first time, providing a chemically robust and coordinatively versatile platform for mechanistic investigations, metal functionalization, and improved catalyst design.
This study analyzes the selectivity of Pd (1 wt %) catalysts supported on different activated carbons to produce olefins from hydrodechlorination of chloroform. It was found that selectivity to ...olefins was favored by a higher zerovalent to electrodeficient Pd ratio (Pd0/Pdn+) and by a lower amount of oxygen-containing surface functional groups on the activated carbon supports. Thus, the highest selectivity to olefins was obtained by catalysts supported on FeCl3- and ZnCl2-activated carbons. Conversely, the catalysts supported on KOH-, NaOH-, and H3PO4-activated carbons gave the lowest selectivity to olefins. These catalysts showed higher surface concentrations of electro-deficient Pd as well as high concentrations of oxygen functional groups that enhance the adsorption of reactants and intermediates. This leads to complete hydrogenation of reaction intermediates and poisoning of active sites by the adsorption of chlorocarbon compounds. ZnCl2-derived catalysts with the highest selectivity to olefins also showed an outstanding stability, most likely due to redispersion into very small and well-distributed Pd particles during the reaction. However, FeCl3-derived catalysts gave rise to sintering of Pd particles, resulting in a marked loss of activity.
To investigate the role of anti-human heat shock protein 60 (hHsp60) antibody positivity in the pathogenesis of ectopic pregnancy, following Chlamydia trachomatis (CT) infection.
In a case-control ...study, serological tests for anti-hHsp60 were performed in ectopic pregnancies (study group) and parturients with normal reproductive histories (control group). All participants in both groups were CT IgG(+). hHsp60 IgG(+) prevalences were compared between the two groups, by semiquantitative ELISA. Data were evaluated using nonparametric and parametric tests and multivariable regression.
After an initial pilot study, two groups were formed: 63 ectopic gestations (study group) and 95 normal parturients (control group), all CT IgG(+). Blood samples from all cases were tested for anti-hHsp60 IgG. Age, gravidity, and practising contraception were higher in the control group, while a history of pelvic infections were more common in the study group. Hsp60 IgG(+) was found to be significantly higher in the control group (63/95, 66.3%) compared to study group (30/63, 47.6%). Regression analysis revealed anti-hHsp60 positivity was an independent factor delineating the two groups.
Immunity to hHsp60 is less common in CT IgG(+) ectopic pregnancies than CT IgG(+) fertile subjects without a history of ectopic pregnancies. Hence, our findings suggest that hHsp60 seropositivity may decrease the probability of an ectopic gestation in subjects with previous CT infections.
A chromium(I) dinitrogen complex reacts rapidly with O2 to form the mononuclear dioxo complex TptBu,MeCrV(O)2 (TptBu,Me=hydrotris(3‐tert‐butyl‐5‐methylpyrazolyl)borate), whereas the analogous ...reaction with sulfur stops at the persulfido complex TptBu,MeCrIII(S2). The transformation of the putative peroxo intermediate TptBu,MeCrIII(O2) (S=3/2) into TptBu,MeCrV(O)2 (S=1/2) is spin‐forbidden. The minimum‐energy crossing point for the two potential energy surfaces has been identified. Although the dinuclear complex (TptBu,MeCr)2(μ‐O)2 exists, mechanistic experiments suggest that O2 activation occurs on a single metal center, by an oxidative addition on the quartet surface followed by crossover to the doublet surface.
Forbidden or allowed? The four‐electron oxidative addition of O2 to TpCrI complexes (Tp=tris(pyrazolyl)borate) is spin‐forbidden, and yet, it proceeds by a non‐adiabatic crossing from a quartet to a doublet potential energy surface at the minimum‐energy crossing point, the structure of which is shown.
A population-based cancer registry, covering the province of Izmir (population 2.7 million, 1993–1994) in Western Turkey was established in 1992. Results for 1993–1994 are presented. Overall cancer ...incidence was higher in males than in females (age-standardised rates 157.5 and 94.0 per 100 000, respectively), as in previous non-population-based series. The principal cancers in males were tobacco-related — lung (age-standardised incidence rate (ASR) 61.6), bladder (ASR 11.0) and larynx (ASR 10.6), consistent with the high prevalence of smoking, and use of traditional high-tar tobaccos. Skin cancers were also relatively common (ASR 11.5 for cancers excluding melanoma). Gastrointestinal cancers were relatively rare. In women, breast cancer was by far the most common malignancy (ASR 24.4); cervical cancer was relatively rare (ASR 5.4). There is probably an underestimate of incidence, due to an inability to use data from certain sources (e.g. death certificates), resulting in a rather high proportion of histologically verified cases (93.7% overall). Nevertheless, the overall profile is an accurate reflection of incidence in this region of Turkey and provides much of the information required for planning strategies to control cancer.
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