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Abstract Combination antiretroviral therapies (cARTs) are linked with multiple-organ system (MOS) toxicities in laboratory animals, and in humans undertaking treatment for HIV/AIDS. The ameliorative potential of low-dose quercetin following cART-associated MOS-toxicities in cardio-hepato-renal organs was evaluated in in vivo model. Oral administration of cART (Dolutegravir 50 mg, Lamivudine 300 mg and Tenofovir disoproxil fumarate 300 mg [DLT]) at 9.29 mg/kg, was challenged against low-dose quercetin 25 mg/kg body weight (bw) in Wistar rats. Group 1, the normal control (NC) received distilled water (5 mL), while groups 2 to 4 received quercetin (25 mg), DLT (9.29 mg), and DLT + quercetin (9.29 mg + 25 mg respectively), per kg bw. All administrations lasted for 14 days, and thereafter animals were humanely sacrificed after intraperitoneal anesthesia injection with 100 mg ketamine /5 mg xylazine per kg bw followed by cervical dislocation. Blood and organs were harvested for analyses using standard protocols. The serum concentrations of lipid parameters [total cholesterol, triglycerides, LDL-cholesterol, and VLDL-cholesterol], liver biomarkers (total-bilirubin, direct-bilirubin, and transaminases], and kidney biomarkers [urea and creatinine] were significantly increased (p

Combination antiretroviral therapies (cARTs) are linked with multiple-organ system (MOS) toxicities in laboratory animals, and in humans undertaking treatment for HIV/AIDS. The ameliorative potential of low-dose quercetin following cART-associated MOS-toxicities in cardio-hepato-renal organs was evaluated in in vivo model. Oral administration of cART (Dolutegravir 50 mg, Lamivudine 300 mg and Tenofovir disoproxil fumarate 300 mg [DLT]) at 9.29 mg/kg, was challenged against low-dose quercetin 25 mg/kg body weight (bw) in Wistar rats. Group 1, the normal control (NC) received distilled water (5 mL), while groups 2 to 4 received quercetin (25 mg), DLT (9.29 mg), and DLT + quercetin (9.29 mg + 25 mg respectively), per kg bw. All administrations lasted for 14 days, and thereafter animals were humanely sacrificed after intraperitoneal anesthesia injection with 100 mg ketamine /5 mg xylazine per kg bw followed by cervical dislocation. Blood and organs were harvested for analyses using standard protocols. The serum concentrations of lipid parameters [total cholesterol, triglycerides, LDL-cholesterol, and VLDL-cholesterol], liver biomarkers (total-bilirubin, direct-bilirubin, and transaminases], and kidney biomarkers [urea and creatinine] were significantly increased (p < 0.05) while electrolytes (Na+, K+, Cl− and HCO3−) were significantly decreased (p < 0.05) in DLT group but improved in DLT + Q group. Histopathology demonstrated distorted myocytes, hepatocytes and renal tubules, fatty liver with vacuolization, dystrophied glomeruli and distorted renal interstitium in DLT group, compared with normal appearing histoarchitectural features in NC and DLT + Q groups. In conclusion, oral administration of low-dose quercetin (25 mg/kg) ameliorated cART-associated cardio-hepato-renal toxicities in rats, improving their biomarkers and histoarchitecture. [ABSTRACT FROM AUTHOR]

Arch Dis Child 2004;89:330-335. doi: 10.1136/adc.2003.032052 Aims: To assess the effectiveness of two different educational interventions plus free cycle helmets, in increasing cycle helmet ownership and use. Methods: A cluster [...]

Aims: To describe cycle helmet owning and wearing among children in a deprived area and to investigate the association between helmet ownership and wearing and socioeconomic deprivation. Methods: Cross sectional [...]

Triple negative breast cancer (TNBC) accounts for 15–20% of all breast cancers and mainly affects pre-menopausal and minority women. Because of the lack of ER, PR or HER2 expression in TNBC, there are limited options for tailored therapies. While TNBCs respond initially to standard of care chemotherapy, tumor recurrence commonly occurs within 1 to 3 years post-chemotherapy and is associated with early organ metastasis and a high incidence of mortality. One of the major mechanisms responsible for drug resistance and emergence of organ metastasis is activation of epithelial to mesenchymal transition (EMT) reprogramming. EMT-mediated cancer cell plasticity also promotes the enrichment of cancer cells with a CD44high/CD24low and/or ALDHhigh cancer stem-like phenotype [cancer stem cells (CSCs)], characterized by an increased capacity for tumor self-renewal, intrinsic drug resistance, immune evasion and metastasis. In this study we demonstrate for the first time a positive feedback loop between AURKA and intra-tumoral PD-L1 oncogenic pathways in TNBC. Genetic targeting of intra-tumoral PD-L1 expression impairs the enrichment of ALDHhigh CSCs and enhances the therapeutic efficacy of AURKA-targeted therapy. Moreover, dual AURKA and PD-L1 pharmacological blockade resulted in the strongest inhibition of tumor growth and organ metastatic burden. Taken together, our findings provide a compelling preclinical rationale for the development of novel combinatorial therapeutic strategies aimed to inhibit cancer cell plasticity, immune evasion capacity and organ metastasis in patients with advanced TNBC.

D.S.C.H. Shostakovich on DVD-ROM. Colchester, England: Chandos Multimedia CT-IAN 50001/CHAN 55001, 2000. [Requires IBM PC with 266MHz Pentium or higher with Windows 95/98/ME or higher, or Macintosh Power PC with [...]