Dasatinib inhibits CXCR4 signaling in chronic lymphocytic leukaemia cells and impairs migration towards CXCL12

Chemokines and their ligands play a critical role in enabling chronic lymphocytic leukaemia (CLL) cells access to protective microenvironmental niches within tissues, ultimately resulting in chemoresistance and relapse: disruption of these signaling pathways has become a novel therapeutic approach in CLL. The tyrosine kinase inhibitor dasatinib inhibits migration of several cell lines from solid-organ tumours, but effects on CLL cells have not been reported. We studied the effect of clinically achievable concentrations of dasatinib on signaling induced by the chemokine CXCL12 through its' receptor CXCR4, which is highly expressed on CLL cells. Dasatinib pre-treatment inhibited Akt and ERK phosphorylation in CLL cells upon stimulation with CXCL12. Dasatinib also significantly diminished the rapid increase in actin polymerisation observed in CLL cells following CXCL12 stimulation. Moreover, the drug significantly inhibited chemotaxis in a transwell assay, and reduced the percentage of cells able to migrate beneath a CXCL12-expressing murine stromal cell line. Dasatinib also abrogated the anti-apoptotic effect of prolonged CXCL12 stimulation on cultured CLL cells. These data suggest that dasatinib, akin to other small molecule kinase inhibitors targeting the B-cell receptor signaling pathway, may redistribute CLL cells from protective tissue niches to the peripheral blood, and support the investigation of dasatinib in combination strategies

Pathological study of non-neoplastic skin lesions by punch biopsy

Background: Accurate diagnosis of skin disorders is of utmost importance as treatment is varied for different skin disorders presenting with the similar clinical lesions. Thus biopsy becomes inevitable in various skin disorders to confirm diagnosis and initiate treatment. The present study was to analyse the age and sex distribution of dermatological disorders presenting to Bhaskar Medical College & Hospital (tertiary care centre), Telangana and assess their histo-pathological profile. The objective was to analyse the histo-pathological profile of skin disorders presenting to the Dermatology department of the hospital, determine the age and sex distribution of various skin diseases and to classify the most common disorders into their subtypes and thus assess the most common subtypes prevalent in the surrounding community.Methods: This was a prospective study carried out at the department of Pathology and department of Dermatology, Bhaskar Medical College & Hospital for a period of three years. Necessary clinical details were obtained in a proforma, punch biopsy taken and sent to the histopathology section for final report. Formalin fixed, paraffin embedded sections were prepared & slides were routinely stained with H & E and special stains applied wherever necessary. Data obtained was tabulated and analysed.Results: Total number of cases analysed were 92. The age group of 21-30 years constituted 31.5% of the total cases. There was a male predominance. Hyperpigmented patch/plaque was the most common clinical lesion (36.9%). Lichenoid lesions was the most common histopathological diagnosis reported (26%) followed by Hansen’s disease(23.9%). Lichen planus was the most common histopathological subtype of lichenoid lesion s(58.3%).

Synthesis of dibenzyl carbonate: Towards a sustainable catalytic approach

At 90 °C, in the presence of CsF/alpha-Al2O3 or [P8,8,8,1][H3COCO2] as catalysts, a straightforward protocol was set up for the synthesis of dibenzyl carbonate (DBnC) via the transesterification of dimethyl carbonate (DMC) with an excess of benzyl alcohol. The two catalysts were used in amounts as low as 1% mol (with respect to the limiting reagent DMC). Best results were achieved with CsF/alpha-Al2O3 that allowed a simpler and reproducible isolation of DBnC in yields up to 70%. Moreover, both the catalyst and the excess BnOH were recovered and could be recycled. The evaluation of mass index (MI) and cost index for the investigated procedure confirmed the economic sustainability and the choice of a rational mass flow throughout the reaction: the method was in the top 7 among 21 protocols selected as the best available options for the synthesis of DBnC

Selective Catalytic Etherification of Glycerol Formal and Solketal with Dialkyl Carbonates and K2CO3

At T ≥ 200 ◦ C,in the presence of K2CO3 as a catalyst, an original etherification procedure of non-toxic acetals such as glycerol formal (GlyF) and solketal has been investigated by using dialkyl carbonates as safe alkylating agents. The effects of parameters including the temperature, the reaction time, and the loading of both the catalyst and the dialkyl carbonate have been detailed for the model case of dimethyl carbonate (DMC). Both GlyF and solketal were efficiently alkylated by DMC to produce the corresponding O-methyl ethers with selectivity up to 99% and excellent yields (86–99%, by GC). The high selectivity could be accounted for by a mechanistic study involving a combined sequence of methylation, carboxymethylation, decarboxylation and hydrolysis processes. The O-methylation of GlyF and solketal could be successfully scaled up for multigram synthesis even operating with a moderate excess (5 molar equiv.) of DMC and in the absence of additional solvent. Notwithstanding the advantageous reduction of the process mass index, scale up experiments provided evidence that prolonged reaction times may induce the decomposition of DMC mainly by the loss of CO2.TheK2CO3-catalyzed etherification of solketal with other carbonates such as dibenzyl and diethyl carbonate (DBnC and DEC, respectively), proceeded with the same good selectivity observed for DMC. However, at 220 ◦ C, the solketal conversion did not exceed 81% since both DBnC and DEC were extensively consumed in competitive decarboxylation and hydrolysis reactions

Potential cellular and biochemical mechanisms of exercise and physical activity on the ageing process

Exercise in young adults has been consistently shown to improve various aspects of physiological and psychological health but we are now realising the potential benefits of exercise with advancing age. Specifically, exercise improves cardiovascular, musculoskeletal, and metabolic health through reductions in oxidative stress, chronic low-grade inflammation and modulating cellular processes within a variety of tissues. In this this chapter we will discuss the effects of acute and chronic exercise on these processes and conditions in an ageing population, and how physical activity affects our vasculature, skeletal muscle function, our immune system, and cardiometabolic risk in older adults

Correlation between the Basicity of Solid Bases and their Catalytic Activity towards the Synthesis of Unsymmetrical Organic Carbonates.

The correlation between the basic properties of solid catalysts and the reaction rate of the selective synthesis of unsym. org. carbonates via direct condensation of di-Et carbonate (DEC) and alcs. was investigated. A detailed kinetic study of the transesterification of 1-phenylethanol and DEC was made with catalysts with different basic strengths. The solids included fluorinated hydrotalcite, MgLa mixed oxides, CsF (pure or supported on alpha- and gamma-aluminas), KF (pure or supported on alpha- and gamma-aluminas), anatase, rutile, and zirconia. Basic properties were detd. by the adsorption of CO2, measured by gravimetry coupled with mass spectrometry and by calorimetry. Both techniques show a higher basicity for MgLa mixed oxides. The rate of the reaction was roughly proportional to the no. of strongly basic sites present on the catalyst, except for CsF/alpha-Al2O3, which showed higher activity for several different substrates in spite of a lower no. and strength of basic sites. This is attributed to the high nucleophilicity of the alcoholate formed as an intermediate. The addn. of water to the reaction medium induces two effects: inhibition of the reaction and the promotion of etherification of the substrate by ethanol as a side reaction. The catalysts can be reused several times with a small loss of activity