The effect of two doses of dried plum on bone density and bone biomarkers in osteopenic postmenopausal women: a randomized, controlled trial.

UNLABELLED: Daily consumption of 50 g of dried plum (equivalent to 5-6 dried plums) for 6 months may be as effective as 100 g of dried plum in preventing bone loss in older, osteopenic postmenopausal women. To some extent, these results may be attributed to the inhibition of bone resorption with the concurrent maintenance of bone formation. INTRODUCTION: The objective of our current study was to examine the possible dose-dependent effects of dried plum in preventing bone loss in older osteopenic postmenopausal women. METHODS: Forty-eight osteopenic women (65-79 years old) were randomly assigned into one of three treatment groups for 6 months: (1) 50 g of dried plum; (2) 100 g of dried plum; and (3) control. Total body, hip, and lumbar bone mineral density (BMD) were evaluated at baseline and 6 months using dual-energy X-ray absorptiometry. Blood biomarkers including bone-specific alkaline phosphatase (BAP), tartrate-resistant acid phosphatase (TRAP-5b), high-sensitivity C-reactive protein (hs-CRP), insulin-like growth factor-1 (IGF-1), and sclerostin were measured at baseline, 3 months, and 6 months. Osteoprotegerin (OPG), receptor activator of nuclear factor kappa-B ligand (RANKL), calcium, phosphorous, and vitamin D were measured at baseline and 6 months. RESULTS: Both doses of dried plum were able to prevent the loss of total body BMD compared with that of the control group (P < 0.05). TRAP-5b, a marker of bone resorption, decreased at 3 months and this was sustained at 6 months in both 50 and 100 g dried plum groups (P < 0.01 and P < 0.04, respectively). Although there were no significant changes in BAP for either of the dried plum groups, the BAP/TRAP-5b ratio was significantly (P < 0.05) greater at 6 months in both dried plum groups whereas there were no changes in the control group. CONCLUSIONS: These results confirm the ability of dried plum to prevent the loss of total body BMD in older osteopenic postmenopausal women and suggest that a lower dose of dried plum (i.e., 50 g) may be as effective as 100 g of dried plum in preventing bone loss in older, osteopenic postmenopausal women. This may be due, in part, to the ability of dried plums to inhibit bone resorption. This clinical trial was registered at ClinicalTrials.gov: NCT02325895 .

Urinary TIMP-1 and MMP-2 levels detect the presence of pancreatic malignancies.

BACKGROUND: A majority of patients with pancreatic malignancies, including both pancreatic ductal adenocarcinoma (PDAC) and pancreatic neuroendocrine tumours (pNETs), present with advanced disease due to a lack of specific symptoms and current diagnostic limitations, making this disease extremely difficult to detect. Our goal was to determine whether urinary matrix metalloproteases (uMMPs) and/or their endogenous inhibitors, urinary tissue inhibitor of metalloproteases (uTIMPs), could be detected in the urine of patients with pancreatic malignancies and whether they may serve as independent predictors of disease status. METHODS: Retrospective analyses of urine samples (n=139) from PDAC and pNET patients as well as age- and sex-matched controls were conducted. Urinary MMP-2 and uTIMP-1 levels were determined using ELISA and zymography. Biomarker expression in tumour and normal pancreatic tissues was analysed via immunohistochemistry (IHC). RESULTS: Multivariable logistic regression analyses indicated that, when controlling for age and sex, uMMP-2 (P<0.0001) and uTIMP-1 (P<0.0001) but not uMMP-9, were significant independent predictors for distinguishing between PDAC patients and healthy controls. Our data also indicated that uMMP-2 was an independent predictor of the presence of pNET. In addition, uTIMP-1 levels could differentiate the two cancer groups, PDAC and pNET, respectively. Immunohistochemistry analysis confirmed that MMP-2 and TIMP-1 protein expression is significantly upregulated in PDAC tissue compared with the normal pancreas. CONCLUSIONS: Taken together, our results suggest that the detection of uMMP-2 and uTIMP-1 may have diagnostic value in the detection of pancreatic malignancies and that uTIMP-1 may be useful in distinguishing between pancreatic adenocarcinoma and neuroendocrine tumours.

Cardiovagal baroreflex and aortic hemodynamic responses to isometric exercise and post-exercise muscle ischemia in resistance trained men.

Arterial stiffness is associated with reduced baroreflex sensitivity (BRS) and resistance training; thus a potentially increased cardiovascular risk in resistance-trained (RT) individuals. The effects of resistance training on arterial stiffness and BRS have been evaluated at rest, but cardiovascular abnormalities that are not shown at rest may be revealed during recovery after exercise. Aortic systolic (aSBP) and diastolic blood pressure (aDBP), stroke volume (SV), augmentation index (AIx), vagal activity, BRS responses to isometric handgrip (IHG), and post-exercise muscle ischemia (PEMI) were evaluated in 10 RT and 10 untrained (UT) men (21+/-1 years). Resting aDBP and AIx were lower in RT compared with UT. Heart rate recovery, BRS, and vagal reactivation during PEMI were similar in both groups. Increases in aSBP (13+/-11 mmHg), AIx (5+/-10%), and SV (12+/-12%) during IHG further increased during PEMI (8+/-14 mmHg, 12+/-6%, and 10+/-8%). Increases in aDBP from rest to PEMI were higher in RT (17+/-9 mmHg) compared with UT (7+/-8 mmHg). The lower resting aDBP and the enhanced response to PEMI suggest beneficial adaptations in RT men. Wave reflection, aortic SBP, and cardiovagal BRS responses to IHG and PEMI are not affected by resistance training in young healthy men.

Prognostic and predictive value of common mutations for treatment response and survival in patients with metastatic colorectal cancer.

BACKGROUND: We address the prognostic and predictive value of KRAS, PIK3CA and BRAF mutations for clinical outcomes in response to active agents in the treatment of metastatic colorectal cancer (mCRC). METHODS: We determined KRAS, BRAF and PIK3CA mutations in tumours from 168 patients treated for mCRC at two institutions. All patients received 5-FU-based first-line chemotherapy and treatment outcome was analysed retrospectively. RESULTS: KRAS, BRAF and PIK3CA mutations were present in 62 (37%), 13 (8%) and 26 (15%) cases, respectively. Multivariate analysis uncovered BRAF mutation as an independent prognostic factor for decreased survival (hazard ratio (HR) 4.0, 95% confidence interval (CI) 2.1-7.6). In addition, patients with BRAF-mutant tumours had significantly lower progression-free survival (PFS: HR 4.0, 95% CI 2.2-7.4) than those whose tumors that carried wild-type BRAF. Among 92 patients treated using chemotherapy and cetuximab as salvage therapy, KRAS mutation was associated with lack of response (P=0.002) and shorter PFS (P=0.09). BRAF (P=0.0005) and PIK3CA (P=0.01) mutations also predicted reduced PFS in response to cetuximab salvage therapy. CONCLUSIONS: These results underscore the potential of mutational profiling to identify CRCs with different natural histories or treatment responses. The adverse significance of BRAF mutation should inform patient selection and stratification in clinical trials.

Differential DNA methylation patterns of small B-cell lymphoma subclasses with different clinical behavior.

Non-Hodgkin's lymphoma (NHL) is a group of malignancies of the immune system with variable clinical behaviors and diverse molecular features. Despite the progress made in classification of NHLs based on classical methods, molecular classifications are a work in progress. Toward this goal, we used an array-based technique called differential methylation hybridization (DMH) to study small B-cell lymphoma (SBCL) subtypes. A total of 43 genomic DMH experiments were performed. From these results, several statistical methods were used to generate a set of differentially methylated genes for further validation. Methylation of LHX2, POU3F3, HOXC10, NRP2, PRKCE, RAMP, MLLT2, NKX6.1, LRP1B and ARF4 was validated in cell lines and patient samples and demonstrated subtype-related preferential methylation patterns. For LHX2 and LRP1B, bisulfite sequencing, real-time reverse transcriptase-polymerase chain reaction and induction of gene expression following treatment with the demethylating agent, 5'-aza-2'-deoxycytidine, were confirmed. This new epigenetic information is helping to define molecular portraits of distinct subtypes of SBCL that are not recognized by current classification systems and provides valuable potential insights into the biology of these tumors.

Soy affects trabecular microarchitecture and favorably alters select bone-specific gene expressions in a male rat model of osteoporosis.

We have recently reported that soy isoflavones particularly when provided in the context of soy protein are capable of preventing loss of bone mineral density due to orchidectomy in F344 rats. We hypothesize, that soy isoflavones also exert beneficial effects on bone microstructural properties, in part, by enhancing bone formation. Therefore, in the present study, we examined the dose-dependent effects of soy isoflavones on femoral bone microarchitectural properties and select bone-specific gene expressions in the same rat model. Seventy-two, 13-month old rats were either orchidectomized (ORX; 5 groups) or sham-operated (Sham; 1 group) and immediately placed on dietary treatments for 180 days. Four of the ORX groups were fed either casein- or soy protein-based diets each with one of two doses of isoflavones either 600 or 1200 mg/kg diet. Rats in the remaining ORX control and Sham groups were fed a control casein-based diet. Soy protein at the high isoflavone dose, and to a lesser extent with the lower dose, reduced the magnitude of the ORX-induced decreases in trabecular bone volume (BV/TV) and trabecular number (Th.N) and increase in trabecular separation (Tb.Sp) at the femoral neck site. These modulations of trabecular microstructural properties by isoflavones may be due to increased mRNA levels of alkaline phosphatase (ALP), collagen type I (COL), and osteocalcin (OC), which are associated with enhanced bone formation. These findings confirm our earlier observations that the modest bone protective effects of soy isoflavones are due to increased rate of bone formation.