Neoadjuvant chemoradiotherapy (NCRT) for advanced rectal cancer (RC) is a well-evidenced therapy; however, some RC patients have no therapeutic response. Patient selection for NCRT so that non-responsive patients are excluded has been subjective. To date, no molecular markers indicating radiation sensitivity have been reported.We irradiated six colorectal cancer (CRC) cell lines and identified HCT116 cells as radiation-sensitive and HCT15 and DLD-1 cells as radiation resistant. Using a microarray, we selected candidate radiation sensitivity marker genes by choosing genes whose expression was consistent with a radiation-resistant or sensitive cell phenotype.Among candidate genes, cellular retinol binding protein 1 (CRBP1) was of particular interest because it was not only induced in HCT116 cells by tentative 10 Gy radiation treatments, but also its expression was increased in HCT116-derived radiation-resistant cells vs parental cells. Forced expression of CRBP1 decreased the viability of both HCT15 and DLD-1 cells in response to radiation therapy. We also confirmed that CRBP1 was epigenetically silenced by hypermethylation of its promoter DNA, and that the quantitative methylation value of CRBP1 significantly correlated with histological response in RC patients with NCRT (P=0.031).Our study identified CRBP1 as a radiation-sensitive predictor in RC.
Although DNA methylation is considered to play an important role during myogenic differentiation, chronological alterations in DNA methylation and gene expression patterns in this process have been poorly understood. Using the Infinium HumanMethylation450 BeadChip array, we obtained a chronological profile of the genome-wide DNA methylation status in a human myoblast differentiation model, where myoblasts were cultured in low-serum medium to stimulate myogenic differentiation. As the differentiation of the myoblasts proceeded, their global DNA methylation level increased and their methylation patterns became more distinct from those of mesenchymal stem cells. Gene ontology analysis revealed that genes whose promoter region was hypermethylated upon myoblast differentiation were highly significantly enriched with muscle-related terms such as 'muscle contraction' and 'muscle system process'. Sequence motif analysis identified 8-bp motifs somewhat similar to the binding motifs of ID4 and ZNF238 to be most significantly enriched in hypermethylated promoter regions. ID4 and ZNF238 have been shown to be critical transcriptional regulators of muscle-related genes during myogenic differentiation. An integrated analysis of DNA methylation and gene expression profiles revealed that de novo DNA methylation of non-CpG island (CGI) promoters was more often associated with transcriptional down-regulation than that of CGI promoters. These results strongly suggest the existence of an epigenetic mechanism in which DNA methylation modulates the functions of key transcriptional factors to coordinately regulate muscle-related genes during myogenic differentiation.
A 16-year-old girl with prolactin secreting pituitary adenoma was treated with 2.5 to 30 mg/day of bromocriptine for about eight months, followed by transsphenoidal surgery. The preadministration baseline value of prolactin (PRL) was 13, 886 ng/ml, which markedly decreased to 6.6 ng/ml after bromocriptine treatment. Computed tomography (CT) performed before bromocriptine administration showed the presence of a large, irregularly shaped suprasellar extension of the tumor. About eight months after bromocriptine treatment, reduction of tumor size was revealed by CT scans, but a small enhanced mass was still present in the sella turtica and suprasellar areas. Postoperatively, administration of bromocriptine was suspended for about two weeks and the blood PRL value increased rapidly to 2, 960 ng/ml. Histology of the tumor tissue consisted mainly of two components, i.e., island-like, shrunken tumor cell nests and acellular spaces which surrounded these tumor cell nests. The acellular spaces were considered to be the spaces left after the majority of the prolactinoma cells had died and disappeared. Thus, the marked tumor size reduction and marked decrease of blood PRL level in this case can be explained by the “cytocidal” and “cytostatic” effects of bromocriptine on prolactinoma cells.
The present study aimed prospectively to investigate the effect of a combination of tumour necrosis factor inhibitors and bisphosphonates (TNFi with BP) on bone mineral density (BMD) and bone and cartilage biomarkers compared to that of BP alone at 1 year in patients with rheumatoid arthritis (RA).Two groups of patients with RA and osteoporosis were enrolled. One group (37 patients) had already received BP, while the other group (37 patients) had already received TNFi with BP. The serum bone resorption and formation markers, cartilage markers, BMD in the lumbar spine, femoral neck, and distal radius were prospectively investigated at the beginning of the study and at 6 and 12 months.The percentages of change recorded for the various assessment categories were as follows in the TNFi with BP group: (1) tartrate-resistant acid phosphatase-5b had significantly decreased and osteocalcin had increased; (2) matrix metalloproteinase-3 and cartilage oligomeric matrix protein had significantly decreased; and (3) each BMD did not differ significantly between the groups.Our data suggested that TNFi with BP therapy not only suppressed cartilage degradation and bone resorption but also increased bone formation; however, this treatment did not affect the BMD at 1 year.
Inbred mouse strains that differing widely in their susceptibility to multistage skin carcinogenesis provide useful models for studying the genetic factors involved and advancing our understanding of the biochemical and molecular events associated with this process. The process of skin tumor initiation appears to be somewhat similar in various strains of mice, and most data in the literature suggest that differences in response to skin tumor promoters are a major determinant in controlling susceptibility to multistage skin carcinogenesis. A model system has been developed for examining the genetics of susceptibility to skin tumor promotion. The susceptibility to phorbol ester skin tumor promotion in crosses between DBA/2 and C57BL/6 mice is inherited as an incomplete dominant trait, and neither X-chromosome nor cytoplasmic genetic determinants appear to play a major role in determining susceptibility in these two inbred strains. In addition, two or more genetic loci contribute to the higher sensitivity of DBA/2 mice than C57BL/6 mice to TPA-induced skin tumor promotion. Further studies to characterize these genes will contribute greatly to our understanding of the mechanisms of phorbol ester skin tumor promotion. In addition, much work should now be directed at understanding the cellular, biochemical, and molecular mechanisms for differential responsiveness not only to phorbol esters but also to other classes of tumor promoters.
We reported the impact of joint diseases on modified health assessment questionnaire (MHAQ) scores determined using 2011 data from NinJa (National Database of Rheumatic Diseases by iR-net in Japan). The MHAQ score was significantly associated with disease in almost all joints and physical ability tended to become aggravated. We also developed a joint-weighted scoring system from odds ratios. Respective integer scores assigned to disease in bilateral and unilateral joints comprised shoulder, 4 and 2; elbow, 3 and 2; wrist, 2 and 2; hip, 0 and 3; knee, 3 and 2; ankle, 2 and 2; finger, 1 and 1. Statistical analyses indicated a cut-off at 3 points using this system (Ono K, et al., Modern Rheumatology, 2016).
Objectives
To validate the weighted scoring system using NinJa data from 2009 and 2014.
Methods
We analyzed data from 7,189 and 13,459 patients listed in the NinJa database during 2009 and 2014. The presence or absence of disease in each joint (swelling and/or tenderness were considered to indicate active disease) and whether the disease was bilateral or unilateral were investigated. We calculated joint scores for each patient using a weighted scoring system and then created ROC curves for each patient based on total scores.
Results
Patients in the 2009 and 2014 groups were aged 62.4±12.6 and 64.1±12.8 years, median DAS28 CRP values were 2.9 and 2.4, and total joint scores were 3.4 and 2.4 with a significant difference (p<0.05; Wilcoxon signed-rank test) between the two groups. Analyses of ROC curves generated from scores derived using the new system and MHAQ revealed a cut-off of 3 points (same as 2011); AUC, 0.72, 0.68 (Table 1).
Conclusions
Disease activity changed from moderate to low in the NinJa cohorts and the scoring system was validated for the years 2009 and 2014. The weighted scoring system appears useful to predict functional disability in a simpler way by examining each joint rather than changes in disease activity among patients with RA.
References
Ono K, et al., The impact of joint disease on the Modified Health Assessment Questionnaire scores in rheumatoid arthritis patients: A cross-sectional study the National Database of Rheumatic Diseases by iR-Net in Japan. Modern Rheumatology, 2016(4): 529–533.
Heterotopic ossification (HO) is an ectopic formation of the lamellar bone in the soft tissues. Some authors have previously reported HO or calcific tendinitis of the peroneus longus tendon at the level of the cuboid bone, while the HO of the peroneus longus tendon in the retromalleolar portion has not been reported. The purpose of this report is to describe clinical, radiological, and histological features of this rare ossification and its treatment. To the best of our knowledge, this is the first report presenting a case of HO of the peroneus longus tendon, which developed in the retromalleolar portion.
