Targeting MYC-driven replication stress in medulloblastoma with AZD1775 and gemcitabine

Journal of Neuro-Oncology - MYC-driven medulloblastomas are highly aggressive childhood tumors with dismal outcomes and a lack of new treatment paradigms. We identified that targeting replication...     

HLA and altered sex ratios in juvenile rheumatoid arthritis sibships

Analysis of sex ratio in 301 siblings of 150 patients with early-onset pauciarticular juvenile rheumatoid arthritis revealed a male-to-female ratio of 1:2.00 in sibships with an HLA-B44⁺ proband, compared with a ratio of 1:1.05 in other sibships (G² = 6.07, df = 1, p = 0.014). The siblings had a sex ratio of 1:0.8, when the HLA-B44 antigen was present in either parent but not transmitted to the proband. The capacity to distort the sex ratio was limited therefore to disease-associated HLA-B44 haplotypes.     

Spectrum of immune reactivity to mycobacterial (BCG) antigens in healthy hospital contacts in south India

In an effort to study the immunological responses to antigens of tubercle bacilli, 49 tuberculin positive and 41 tuberculin negative hospital contacts aged 20-29 years (staff nurses and students working in Government Rajaji Hospital, Madurai, South India) were studied for serum antibodies (IgG, IgM and IgA classes) to BCG by ELISA and diameter of induration to PPD by Mantoux procedures. The two immunological parameters were correlated in regression analysis. The results have revealed higher anti-BCG serum antibody levels in hospital contacts than in non-contacts, significantly higher antibodies in tuberculin negative hospital contacts than in tuberculin positive hospital contacts, an inverse correlation of tuberculin reactivity and antibodies and a bimodal decline (regression) of antibodies against the increase in skin test induration. This study has thus suggested the existence of an immunological spectrum in hospital contacts from south India; persons at one pole of the spectrum were tuberculin negative and possessed significantly elevated antibody levels and those at the other pole of the spectrum were tuberculin positive and possessed low antibody levels. Thus the spectrum of immune reactivity may be due to an inherent susceptibility/resistance of an individual to Mycobacterium tuberculosis.     

Solid self-nanoemulsifying drug delivery system (S-SNEDDS) containing phosphatidylcholine for enhanced bioavailability of highly lipophilic bioactive carotenoid lutein

The objectives of this study was to prepare solid self-nanoemulsifying drug delivery system (S-SNEDDS) containing phosphatidylcholine (PC), an endogenous phospholipid with excellent in vivo solubilization capacity, as oil phase for the delivery of bioactive carotenoid lutein, by spray drying the SNEDDS (liquid system) containing PC using colloidal silica (Aerosil® 200 VV Pharma) as the inert solid carrier, and to evaluate the enhanced bioavailability (BA) of lutein from S-SNEDDS. The droplet size analyses revealed droplet size of less than 100 nm. The solid state characterization of S-SNEDDS by SEM, DSC, and XRPD revealed the absence of crystalline lutein in the S-SNEDDS. The bioavailability study performed in rabbits resulted in enhanced values of C_max and AUC for S-SNEDDS. The enhancement of C_max for S-SNEDDS was about 21-folds and 8-folds compared with lutein powder (LP) and commercial product (CP), respectively. The relative BA of S-SNEDDS compared with CP or LP was 2.74-folds or 11.79-folds, respectively. These results demonstrated excellent ability of S-SNEDDS containing PC as oil phase to enhance the BA of lutein in rabbits. Thus, S-SNEDDS containing PC as oil phase could be a useful lipid drug delivery system for enhancing the BA of lutein in vivo.     

The effects of exercise stress testing on soluble E‐selectin,von Willebrand factor,and circulating endothelial cells as indices of endothelial damage/dysfunction

Background. The quantification of circulating endothelial cells (CECs) in whole blood is an increasingly recognized index of endothelial damage/dysfunction. Abnormal CECs have been linked to the severity of coronary artery disease (CAD).

Objective. We assessed the relationship of CECs to other markers of endothelial dysfunction (von Willebrand factor (vWF) and soluble E‐selectin (sEsel)) during exercise stress testing (EST) in a cohort of patients with suspected CAD.

Methods. We studied a cohort of patients referred to our chest pain clinic with a history of exertional chest pain. Treadmill EST was performed, using a full Bruce exercise protocol. Blood for CECs (immunobead method), vWF and sEsel (both ELISA) were collected immediately before (pre‐exercise), immediately following exercise, and at 30 minutes post‐EST.

Results. We studied 31 patients (84% male; mean (SD) age 58.4 (9.8) years). Of the entire cohort, 14 patients (45.2%) had a positive EST. Exercise led to significant increases in levels of CECs, sEsel, vWF, white blood cells (WBC), heart rate, mean and systolic blood pressure compared with base‐line (all P<0.05). There was a significant correlation between the change (Δ (immediate post–pre‐exercise)) in CECs and ΔvWF (r = 0.45; 95% CI 0.11–0.69: P = 0.01) and ΔsEsel (r = 0.41; 0.05–0.7: P = 0.02), as well as between ΔvWF and ΔsEsel (r = 0.55; 0.25–0.76: P = 0.001). Neither absolute nor ΔCEC counts were predictive of exercise work‐load/functional capacity, nor the presence of positive EST results.

Conclusion. EST led to a significant increase in endothelial markers (CECs, vWF, and sEsel) compared with base‐line levels. The rise in CECs correlated with the increases in other endothelial markers, but was not related to the either exercise work‐load/capacity or to the presence of a positive EST.