Ricolinostat (ACY‐1215) induced inhibition of aggresome formation accelerates carfilzomib‐induced multiple myeloma cell death

Proteasome inhibition induces the accumulation of aggregated misfolded/ubiquitinated proteins in the aggresome; conversely, histone deacetylase 6 (HDAC6) inhibition blocks aggresome formation. Although this rationale has been the basis of proteasome inhibitor (PI) and HDAC6 inhibitor combination studies, the role of disruption of aggresome formation by HDAC6 inhibition has not yet been studied in multiple myeloma (MM). The present study aimed to evaluate the impact of carfilzomib (CFZ) in combination with a selective HDAC6 inhibitor (ricolinostat) in MM cells with respect to the aggresome‐proteolysis pathway. We observed that combination treatment of CFZ with ricolinostat triggered synergistic anti‐MM effects, even in bortezomib‐resistant cells. Immunofluorescent staining showed that CFZ increased the accumulation of ubiquitinated proteins and protein aggregates in the cytoplasm, as well as the engulfment of aggregated ubiquitinated proteins by autophagosomes, which was blocked by ricolinostat. Electron microscopy imaging showed increased autophagy triggered by CFZ, which was inhibited by the addition of ACY‐1215. Finally, an in vivo mouse xenograft study confirmed a decrease in tumour volume, associated with apoptosis, following treatment with CFZ in combination with ricolinostat. Our results suggest that ricolinostat inhibits aggresome formation, caused by CFZ‐induced inhibition of the proteasome pathway, resulting in enhanced apoptosis in MM cells.     

Intrafamilial variability of XYLT2-related spondyloocular syndrome

Spondyloocular syndrome is characterized by generalized osteoporosis, multiple fractures and severe ocular findings. The causative XYLT2 mutations have recently been identified with the use of whole exome sequencing. We report on two siblings with spondyloocular syndrome who presented with varying clinical severity. A novel XYLT2 missense mutation was detected in a region evolutionary conserved across the species. This report along with the previous reports demonstrates that variable expressivity may be possible even within the same family. These two siblings with a novel mutation further expand the clinical and mutational spectrum of spondyloocular syndrome.     

Serum and synovial fluid leptin levels and markers of inflammation in rheumatoid arthritis

This study was designed to investigate the serum and synovial fluid leptin levels, and inflammatory markers in rheumatoid arthritis (RA) patients. Serum and synovial fluid leptin levels were significantly higher (P > 0.05) in RA patients than control group; RA patients with moderate disease activity (DAS < 2.7) having significantly higher leptin levels (P > 0.05) than those with low disease activity (DAS < 2.7). Leukocytes and erythrocyte sedimentation rate (ESR) were found to be significantly higher in moderate disease activity RA group compared to low activity group (P > 0.05, P < 0.001, respectively). Serum leptin level is found to be independent of age and inflammatory markers. ESR is positively correlated with DAS activity and CRP values. Our finding of no correlation between leptin and BMI shows that regulation of leptinemia is complex, and leptin levels cannot be used to assess RA activity.     

High prevalence of diabetes in Adana, a southern province of Turkey

OBJECTIVE: To determine the prevalence of diabetes and glucose intolerance and their relationship with risk factors in Adana, a southern province of Turkey, where risk factors are more prominent, probably because of social and economic reasons. RESEARCH DESIGN AND METHODS: The study population included 1637 randomly selected adults aged 20-79 years. Diagnosis of diabetes was based on plasma glucose values using the 1999 diagnostic criteria recommended by the World Health Organization. RESULTS: The crude prevalence of diabetes was 12.9% in men and 10.9% in women (P = 0.207). Total prevalence of diabetes was 11.6%. The screening process identified previously undiagnosed diabetes in 4.2% of individuals and impaired glucose homeostasis (consisting of impaired glucose tolerance and impaired fasting glucose) in an additional 4.3% of subjects. The prevalence of hypertension was 26.4% among men and 36.6% among women (P < 0.0001). Total prevalence of hypertension was 32.9%, and prevalence of obesity was 43.4%. Age, sex, BMI, waist circumference, hypertension, family history of diabetes, and triglycerides were independently associated with diabetes. CONCLUSIONS: The prevalence of diabetes in Adana is higher than expected in both urban and rural areas. Obesity and hypertension also seem to be common metabolic disorders in this area. Age, hypertension, obesity, high triglyceride level, and family history of diabetes are independently associated with diabetes. Therefore, primary prevention through lifestyle modifications may have a critical role in the control of diabetes.