Objectives: Many patients with Crohn's disease (CD) have low bone mineral density (BMD) that may not be solely attributable to glucocorticoid use. We hypothesised that low BMD in patients with CD is associated with elevated circulating levels of the active form of vitamin D, 1,25-dihydroxyvitamin D (1,25(OH) 2 D). We further hypothesised that this was secondary to increased synthesis of 1,25(OH) 2 D by inflammatory cells in the intestine. The aim of this study was to examine the relationship between 1,25(OH) 2 D levels and BMD in patients with CD. Methods: An IRB approved retrospective review of medical records from patients with CD (n = 138) or ulcerative colitis (UC, n = 29). Measurements of vitamin D metabolites and immunoreactive parathyroid hormone (iPTH) were carried out. BMD results were available for 88 CD and 20 UC patients. Immunohistochemistry or real time reverse transcription-polymerase chain reaction (RT-PCR) for the enzyme 1a-hydroxylase was performed on colonic biopsies from patients with CD (14) or UC (12) and normal colons (4). Results: Inappropriately high levels of serum 1,25(OH) 2 D (.60 pg/ml) were observed in 42% of patients with CD compared with only 7% in UC, despite no differences in mean iPTH. Serum 1,25(OH) 2 D levels were higher in CD (57 pg/ml) versus UC (41 pg/ml) (p = 0.0001). In patients with CD, there was a negative correlation between 1,25(OH) 2 D levels and lumbar BMD (r = 20.301, p = 0.005) independent of therapeutic glucocorticoid use. 1,25(OH) 2 D levels also correlated with CD activity. Lastly, immunohistochemistry and RT-PCR demonstrated increased expression of intestinal 1a-hydroxylase in patients with CD.Conclusions: These data demonstrate that elevated 1,25(OH) 2 D is more common in CD than previously appreciated and is independently associated with low bone mineral density. The source of the active vitamin D may be the inflamed intestine. Treatment of the underlying inflammation may improve metabolic bone disease in this subgroup of patients.A serious and silent complication of inflammatory bowel disease (IBD) is the development of osteoporosis. [1][2][3][4] Estimates of osteopenia in IBD range from 31% to 59% 5 6 and osteoporosis from 5% to 41%. 1 7-10 Some studies have found that osteoporosis is more prevalent in patients with Crohn's disease (CD) than in those with ulcerative colitis (UC).1 4 11-13 Other studies however, have found similar degrees of bone loss in CD and UC.14 15 Lower bone mineral density (BMD) may be present at diagnosis, 13 16 suggesting factors other than medication may contribute to bone loss. The consequences of low BMD in patients with IBD include an increased risk of vertebral or hip fractures and their associated morbidity. [17][18][19][20] Indeed, recent data suggest that the risk of fractures in patients with CD may be underestimated. In a prospective study of CD patients, asymptomatic fractures were found in 14% of steroid free patients (including steroid naïve patients) and 15% of steroid dependent patients. 21Similar results were repor...

Histone ubiquitination participates in multiple cellular processes, including the DNA damage response. However, the molecular mechanisms involved are not clear. Here, we have identified that RAP80/UIMC1 (ubiquitin interaction motif containing 1), a functional partner of BRCA1, recognizes ubiquitinated histones H2A and H2B. The interaction between RAP80 and ubiquitinated histones H2A and H2B is increased following DNA damage. Since RAP80 facilitates BRCA1's translocation to DNA damage sites, our results indicate that ubiquitinated histones H2A and H2B could be upstream partners of the BRCA1/RAP80 complex in the DNA damage response. Moreover, we have found that RNF8 (ring finger protein 8), an E3 ubiquitin ligase, regulates ubiquitination of both histones H2A and H2B. In RNF8-deficient mouse embryo fibroblasts, ubiquitination of both histones H2A and H2B is dramatically reduced, which abolishes the DNA damage-induced BRCA1 and RAP80 accumulation at damage lesions on the chromatin. Taken together, our results suggest that ubiquitinated histones H2A and H2B may recruit the BRCA1 complex to DNA damage lesions on the chromatin.Cells encounter enormous DNA damage that is induced by both external and internal hazards. Among various types of DNA damage, DNA double-stand breaks are the most deleterious type of damage, which may substantially alter genetic information. The proper cellular response to DNA doublestand breaks, including activation of DNA damage checkpoint pathways and DNA repair systems, allows cells to repair damage lesions and to avoid genetic instability (16,45,46,69). Following DNA double-stand breaks, a group of DNA damage response factors are accumulated at the DNA damage sites, which is essential to activate DNA damage checkpoints and repair damage lesions (53). One of these important DNA damage response proteins is BRCA1.BRCA1 (breast cancer susceptibility gene 1) is an 1,873-amino-acid nuclear polypeptide that contains an N-terminal ring domain and a C-terminal BRCT domain. Accumulated evidence suggests that BRCA1 participates in the DNA damage response, including both DNA damage checkpoint activation and DNA damage repair (39,50,56). Following DNA double-strand breaks, BRCA1 is phosphorylated by upstream ATM and ATR kinases (8, 12, 13, 55) and controls downstream Chk1 kinase activity (65), which regulates the damageinduced intra-S-phase checkpoint and the G 2 /M checkpoint (29,63,65). BRCA1 also associates with Rad51 (49) and mediates homologous recombination (37), which is an important mechanism for DNA double-strand break repair in S and G 2 phases.The prerequisite for BRCA1 to participate in these DNA damage responses is that BRCA1 recognizes DNA damage sites. Following DNA double-strand breaks, BRCA1 translocates to DNA damage sites and forms nuclear foci, which is also the most direct and obvious evidence of BRCA1 functioning in the DNA damage response (41, 48). However, the mechanism underlying this cellular phenomenon is not clear. The C-terminal BRCT domain of BRCA1, a phosphoprotein binding...

Voltage-gated calcium channels (VGCCs) comprise five subtypes: The L-type; R-type; N-type; P/Q-type; and T-type, which are encoded by α1 subunit genes. Calcium ion channels also have confirmed roles in cellular functions, including mitogenesis, proliferation, differentiation, apoptosis and metastasis. An association between VGCCs, a reduction in proliferation and an increase in apoptosis in prostate cancer cells has also been reported. Therefore, in the present study, the online clinical database Oncomine was used to identify the alterations in the mRNA expression level of VGCCs in 19 cancer subtypes. Overall, VGCC family genes exhibited under-expression in numerous types of cancer, including brain, breast, kidney and lung cancers. Notably, the majority of VGCC family members (CACNA1C, CACNA1D, CACNA1A, CACNA1B, CACNA1E, CACNA1H and CACNA1I) exhibited low expression in brain tumors, with mRNA expression levels in the top 1–9% of downregulated gene rankings. A total of 5 VGCC family members (CACNA1A, CACNA1B, CACNA1E, CACNA1G and CACNA1I) were under-expressed in breast cancer, with a gene ranking in the top 1–10% of the low-expressed genes compared with normal tissue. In kidney and lung cancers, CACNA1S, CACNA1C, CACNA1D, CACNA1A and CACNA1H exhibited low expression, with gene rankings in the top 1–8% of downregulated genes. In conclusion, the present findings may contribute to the development of new cancer treatment approaches by identifying target genes involved in specific types of cancer.

Objective: The hemoglobin, albumin, lymphocyte, and platelet (HALP) score has been shown to be an important prognostic marker in some tumor types. The aim of this study was to evaluate the prognostic impact of the preoperative HALP score, with the intent to develop a new prognostic index for patients with metastatic prostate cancer (mPCA) after cytoreductive radical prostatectomy (cRP).Methods: We retrospectively analyzed the data from 82 patients with mPCA after cRP in our institution. Of these patients, 70 patients were diagnosed with oligometastatic prostate cancer (oPCA). The main outcome measure was prostate-specific antigen (PSA) progression-free survival (PFS), which was assessed using Kaplan-Meier curves with log-rank statistics. In addition, univariate and multivariate Cox regression analyses were performed to determine the prognostic factors associated with PSA-PFS. The prediction accuracy was evaluated by assessing the area under the receiver operating characteristic (AUC) curve.Results: The median follow-up time for all patients was 17.47 months (range: 11.73-24.38 months). Based on the Kaplan-Meier curve analysis, it was noticed that a low preoperative HALP value (<32.4) was significantly associated with a decreased PSA-PFS in both the mPCA and oPCA subgroups (P < 0.001, P = 0.002, respectively). In addition, multivariate analysis predicted that a low HALP score was a common independent prognostic factor of an overall shorter PSA-PFS (HR: 0.352; range: 0.154-0.804; P = 0.013). However, among the different subgroups, a low HALP score (HR: 0.275; range: 0.116-0.653; P = 0.003) was confirmed to be an independent predictor of a shorter PSA-PFS in patients from the oPCA subgroup. Furthermore, the effective combination of the pathologic Gleason score (PGS) and the HALP score (HALPG) as a new index was found to be an independent risk factor. Also, the AUC of the HALPG score for PSA-PFS was observed to be higher than other conventional clinical indices.Conclusion: Overall, our results confirmed the HALP score as an independent prognostic factor for PSA-PFS in patients with mPCA or oPCA after cRP. Moreover, the new index, HALPG, also appeared to be an independent prognostic factor and was better than the HALP score. Importantly, it is evident that this new prognostic index has the ability to accurately identify patients at low, intermediate, and high risk of recurrence, thus easily allowing informed treatment decisions to be made.