Targeting gut microbial nitrogen recycling and cellular uptake of ammonium to improve bortezomib resistance in multiple myeloma.

The gut microbiome has been found to play a crucial role in the treatment of multiple myeloma (MM), which is still considered incurable due to drug resistance. In previous studies, we demonstrated that intestinal nitrogen-recycling bacteria are enriched in patients with MM. However, their role in MM relapse remains unclear. This study highlights the specific enrichment of Citrobacter freundii (C. freundii) in patients with relapsed MM. Through fecal microbial transplantation experiments, we demonstrate that C. freundii plays a critical role in inducing drug resistance in MM by increasing levels of circulating ammonium. The ammonium enters MM cells through the transmembrane channel protein SLC12A2, promoting chromosomal instability and drug resistance by stabilizing the NEK2 protein. We show that furosemide sodium, a loop diuretic, downregulates SLC12A2, thereby inhibiting ammonium uptake by MM cells and improving progression-free survival and curative effect scores. These findings provide new therapeutic targets and strategies for the intervention of MM progression and drug resistance.

[Relation of body mass index and waist circumference with clustering of other risk factors for cardiovascular disease].

OBJECTIVE: To assess the relationship of body mass index (BMI) and waist circumference (WC) with clustering of other risk factors for cardiovascular disease (CVD). METHODS: A total of 30 561 participants aged 35 - 59 from different parts of China were surveyed for risk factors of CVD in two independent cross-sectional studies carried out in 1992 - 1994 and 1998. Data were pooled to analyze clustering rate of risk factors for CVD and relative risk of their clustering at varied levels of BMI and WC. Clustering of other risk factors for CVD was defined as any participant who had any two or more risk factors, such as high blood pressure, high serum total cholesterol, low HDL-C, high fasting plasma glucose. Clustering rate of other risk factors for CVD at different levels of BMI and WC was estimated. RESULTS: Clustering rate of other risk factors for CVD significantly increased with rising of BMI and WC. In most of varied BMI groups, clustering rate of other risk factor increased with rise of WC in both men and women (P value for trend < 0.05), and in most of varied WC groups, clustering rate of other risk factor significantly increased with rise of BMI (P value for trend < 0.05). Clustering rate of other risk factors for CVD adjusted for age was 11.1% and 10.4% with BMI < 24.0 kg/m(2) and WC < 85/80 cm, 24.0% and 17.0% with BMI of 24 - 27.9 kg/m(2) and WC < 85/80 cm, 34.3% and 24.0% with BMI of 24 - 27.9 kg/m(2) and WC of 85 - 95.9/80 - 89.9 cm, 40.8% and 29.6% with BMI of 24 - 27.9 kg/m(2) and WC >/= 95/90 cm, 44.2% and 29.9% with BMI >/= 28 kg/m(2) and WC of 85 - 95.9/80 - 89.9 cm, and 54.7% and 35.4% with BMI >/= 28 kg/m(2) and WC >/= 95/90 cm, for men and women, respectively. CONCLUSIONS: BMI and WC were independently and positively associated with clustering rate of other risk factors for CVD. It is very important for health to keep both BMI and WC in normal level.