Targeting the BCR signalosome in B cell malignancies

Chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and Waldenström macroglobulinemia (WM) are B-cell malignancies which are still incurable. In these lymphomas, the cells proliferate in specialized niches in lymph nodes and bone marrow, in which they are provided by stromal-derived growth and survival factors. At least for CLL and MCL, several studies indicate that the B-cell antigen receptor (BCR) is activated in these niches. The first clinical trials with the novel BCR signalosome inhibitors ibrutinib (BTK inhibitor), idelalisib (PI3Kδ inhibitor), and fostamatinib (SYK inhibitor) were very promising. However, although a rapid and sustained reduction of lymphadenopathy was observed in the patients, this was unexpectedly accompanied by (transient) lymphocytosis. We studied the mechanism of action of ibrutinib at a molecular and cellular level. We observed that ibrutinib did not target the viability of CLL, MCL, and WM cells in a direct manner, but it strongly inhibited BCR-controlled signaling and integrin-mediated adhesion. Furthermore, ibrutinib partially inhibited chemokine-induced signaling, adhesion, and migration of CLL and MCL cells. Idelalisib was also able to inhibit BCR-controlled integrin-mediated adhesion, and in combination with ibrutinib this inhibition was strongly synergistic in CLL and MCL. Thus, our findings indicate that inhibition of the BCR signalosome overcomes BCR-controlled integrin-mediated retention of the malignant CLL, MCL, and WM cells in their growth- and survival-supporting lymphoid tissue microenvironment, which results in clinically evident disease regression. Furthermore, our preclinical studies indicate that the combination of ibrutinib and idelalisib is beneficial to the patients and may prevent drug-resistance

Immunochemical detection of metabolites of parent and nitro polycyclic aromatic hydrocarbons in urine samples from persons occupationally exposed to diesel exhaust

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Heterogeneous contributions of change in population distribution of body mass index to change in obesity and underweight

From 1985 to 2016, the prevalence of underweight decreased, and that of obesity and severe obesity increased, in most regions, with significant variation in the magnitude of these changes across regions. We investigated how much change in mean body mass index (BMI) explains changes in the prevalence of underweight, obesity, and severe obesity in different regions using data from 2896 population-based studies with 187 million participants. Changes in the prevalence of underweight and total obesity, and to a lesser extent severe obesity, are largely driven by shifts in the distribution of BMI, with smaller contributions from changes in the shape of the distribution. In East and Southeast Asia and sub-Saharan Africa, the underweight tail of the BMI distribution was left behind as the distribution shifted. There is a need for policies that address all forms of malnutrition by making healthy foods accessible and affordable, while restricting unhealthy foods through fiscal and regulatory restrictions. © Copyright