Correlation of enhanced cell proliferation with decreased density of vitamin D receptor in parathyroid hyperplasia in chronic dialysis patients

Summary: The decreased density of the vitamin D receptor (VDR) plays an important role in the pathogenesis and progression of parathyroid hyperplasia in renal failure. In chronic dialysis patients, VDR density is less in nodular hyperplasia than in diffuse hyperplasia and the difference of cell proliferation has been also suggested by DNA analysis. to prove a more direct correlation between VDR density and cell proliferation, VDR density and proliferating cell nuclear antigen (PCNA) were detected in situ by immunohistochemistry in serial sections of surgically excised parathyroid glands from 10 chronic dialysis patients. Among 28 excised glands, 20 glands were nodular hyperplasia and eight glands were diffuse hyperplasia. Vitamin D receptor positive cells were much fewer in nodular hyperplasia (13.1 ± 4.8%) than in diffuse hyperplasia (383 ± 5.6%). In contrast, mean PCNA positive cell numbers per one 400 x field were much higher in nodular hyperplasia (2.0± 1.2) than in diffuse hyperplasia (0.1±0.2). These two parameters, simultaneously detected in the same area of the serial sections, showed strong negative correlation (r= -0.719, P <0.0001). Remarkable differences in VDR and PCNA were evident between nodules and the surrounding diffuse hyperplasia in the same section. These data suggest more direct relationship between the decrease of VDR density and parathyroid cell proliferation in chronic renal failure as a pathophysiological mechanism.     

Development of human renal cell carcinoma (RCC)--the responsible genes for the development of hereditary and sporadic human RCCs

Renal Cell Carcinoma (RCC) is classified into six cell pathological types by the Thoenes classification (5). Deletion of DNA (loss of heterozeigosity: LOH) is seen with a high frequency in human RCC of all 6 types at chromosome 3p 14-25. The presence of at least three tumor suppressor genes at this domain has been pointed out. The VHL gene, one of the tumor suppressor genes (TSG), was identified in 1993 at chromosome 3p25-26 as the gene responsible for VHL disease. As a consequence, it was demonstrated that inactivation of the von Hippel-Lindau (VHL) gene is responsible for sporadic clear cell RCC. Activating mutations of c-Met receptor type tyrosine kinase has been demonstrated in papillary renal cell carcinoma families. Possible involvement of the FHIT tumor suppressor gene, located at the fragile site (FRA3B) of chromosome 3p14, has been detected in sporadic RCC. Recently, methylation of RASSF1A at chromosome 3p21.3 was pointed out in sporadic RCC. Thus, it has become apparent that chromosome 3p14-25 3 has possible TSGs for RCC. Furthermore, it was pointed out in April that germline mutation of fumarate hydratase, a Krebs cycle enzyme (FH), is present in multiple cutaneous and uterine leiomyomatosis families that develop papillary RCC. The functional significance in these genes for the development of RCC is still not apparent, except for the VHL gene. Thus, there is still a long way to go before we find all responsible TSGs in all pathological subtypes in sporadic RCC.     

ASC/TMS1, a caspase-1 activating adaptor,is downregulated by aberrant methylation in human melanoma

ASC/TMS1 is an adaptor protein activating caspase-1 that stimulates processing of proIL-1beta and proIL-18. ASC was reported to be aberrantly methylated and silenced in human breast cancers. In our present study, ASC expression was examined in 12 melanoma cell lines by Western blot analysis and in 18 benign melanocytic nevi and 32 melanoma tissues by immunohistochemical staining. ASC expression was absent or reduced in 7 of 12 (58.3%) cell lines and in 20 of 32 (62.5%) melanoma tissues, whereas all 18 benign melanocytic nevi showed intensive ASC expression. To investigate whether ASC silencing in melanoma is involved in aberrant methylation, methylation specific PCR was carried out. Five of ten (50%) melanoma tissues exhibited methylation in CpG island of ASC companied with reduced ASC expression. Six of twelve (50%) melanoma cell lines showed aberrant methylation in the ASC gene, and 4 of the 6 (66.7%) methylation positive cell lines exhibited reduced ASC expression. We characterized methylation patterns in melanoma cell lines by using bisulfite genomic sequencing, and found that the degree of aberrant methylation correlated with the level of reductive ASC expression. Treatment with demethylating agent 5-aza-2'-deoxycytidine resulted in both demethylation of the ASC gene and the upregulation of ASC expression in the methylation positive melanoma cell lines. Our study shows that ASC is downregulated in melanoma, and that its suppression is partially mediated by aberrant methylation.     

Single-nucleotide polymorphisms of DNA damage response genes are associated with overall survival in patients with pancreatic cancer.

PURPOSE: The goals of this study were to determine if single-nucleotide polymorphisms in DNA damage repair genes and cell cycle regulating genes affect clinical response to combined gemcitabine radiation therapy and the overall survival (OS) of patients with pancreatic cancer. EXPERIMENTAL DESIGN: We evaluated six single-nucleotide polymorphisms of the ATM, ATM and Rad3-related (ATR), CHEK1, and CHEK2 genes in 119 patients with potentially resectable pancreatic cancer who were enrolled in clinical trials at The University of Texas M. D. Anderson Cancer Center from February 1999 to January 2006, with follow-up until February 2007. Patients received neoadjuvant concurrent gemcitabine and radiation therapy with or without gemcitabine-cisplatin induction therapy. Genotypes were determined and tested for associations with OS by Kaplan-Meier estimation, the log-rank test, and Cox regression analysis. P values of 相似文献   

Downregulation of stomach cancer-associated protein tyrosine phosphatase-1 (SAP-1) in advanced human hepatocellular carcinoma

SAP-1 (stomach cancer-associated protein tyrosine phosphatase-1) is a transmembrane-type protein tyrosine phosphatase that has been implicated as a negative regulator of integrin-mediated signaling. The potential role of this enzyme in hepatocarcinogenesis has now been investigated by examining its expression in 32 surgically excised human hepatocellular carcinoma (HCC) specimens. Both immunohistochemical and immunoblot analyses revealed that normal liver tissue, as well as tissue affected by chronic hepatitis or cirrhosis, contained substantial amounts of SAP-1. The expression level of SAP-1 in 75% of well-differentiated HCCs was similar to or higher than that observed in the surrounding noncancerous tissue. In contrast, the abundance of SAP-1 in 85.7% of moderately differentiated HCCs and in all poorly differentiated HCCs was greatly reduced compared with that in the adjacent tissue. Indeed, SAP-1 was almost undetectable in 83.3% of poorly differentiated HCCs. Furthermore, expression of recombinant SAP-1 in two highly motile human HCC cell lines resulted in a change in morphology and a marked reduction in both migratory activity and growth rate. In conclusion, these results indicate that SAP-1 expression is downregulated during the dedifferentiation of human HCC, and that this downregulation may play a causal role in disease progression.     

Positive KL-6 mucin expression combined with decreased membranous beta-catenin expression indicates worse prognosis in colorectal carcinoma

Interaction of MUC1 with beta-catenin plays a significant role in tumor progression and invasion. However, the clinical significance of coexpression of MUC1 and subcellular beta-catenin expression in colorectal carcinoma remains unclear. The present study evaluated the clinicopathological significance of their combined expression for predicting prognosis. Seventy-seven colorectal carcinomas were subjected to immunohistochemical staining with anti-MUC1 KL-6 mucin and anti-beta-catenin monoclonal antibody. Positive KL-6 mucin expression was correlated with decreased membranous beta-catenin expression (P=0.022), while no correlation was found between positive KL-6 expression and nuclear beta-catenin expression (P=0.142). Preservation of membranous beta-catenin expression was detected in 35 cases (45.5%) and decreased membranous beta-catenin expression was found in 42 cases (54.5%). Negative KL-6 expression was detected in 31 cases (41.3%) and positive expression was seen in 46 cases (59.7%). Combined positive KL-6 expression and decreased membranous beta-catenin expression was found in 30 patients (39.0%), whose survival was significantly worse than that of patients with other expression patterns for these two molecules (53.3 vs. 84.4%, P=0.005). Multivariate analysis showed that this combination was as an independent predictor of survival. We concluded that the combined pattern of positive KL-6 expression and decreased membranous beta-catenin expression by colorectal carcinoma is a useful biomarker for distinguishing a subgroup of patients with a worse prognosis.     

Atrophic dermatofibrosarcoma protuberans with diffuse eosinophilic infiltrate

Atrophic dermatofibrosarcoma protuberans (atrophic DFSP) is a variant of dermatofibrosarcoma protuberans (DFSP), and is clinically characterized by depressed lesions. We report a patient with a typical atrophic DFSP lesion with marked eosinophilic infiltration. The patient was a 55-year-old woman with a dark-red, depressed lesion in the epigastric region. Histopathological examination of the lesion showed proliferation of fibroblast-like cells in a storiform pattern in the dermis and subcutaneous tissue. Immunohistochemical staining of tumor cells was positive for CD34. The lesion was histopathologically typical of DFSP, but no elevated lesion was clinically observed. Thus, a diagnosis of atrophic DFSP was made. Moreover, this tumor tissue exhibited marked eosinophilic infiltration. To our knowledge, they are no reports of eosinophilic infiltration in DFSP tissue. Therefore, this seems to be an extremely rare case of DFSP.     

Effects of four volatile anesthesics on postanesthetic ventilation: a comparison of halothane,enflurane, isoflurane,and sevoflurane

To investigate the effects of four volatile anesthetics (halothane, enflurane, isoflurane, and sevoflurane) on postanesthetic ventilation and levels of consciousness, we enrolled 24 patients undergoing tympanoplasty in this study. Anesthesia was maintained with 67% nitrous oxide and one of four volatile anesthetics. We measured end-tidal carbon dioxide concentration (C_ETco₂), minute volume ( ) and respiratory rate (RR), and determined the volatile anesthetic concentration in whole arterial blood (C_BAnesth) and arterial carbon dioxide tension (Paco₂) at 20 min and 2h after tracheal extubation. We also observed the level of consciousness (awake, drowsy, and asleep) before the measurement. Ventilatory variables were similar among the four groups at 20 min, although the ratio of volatile anesthetic concentration in the alveoli to the minimum alveolar concentration (MAC) (C_AAnesth/MAC ratio) calculated from C_BAnesth in the halothane group was twice those in the other groups. In the halothane group, Paco₂ was significantly higher, and and RR were significantly lower compared with the isoflurane and sevoflurane groups at 2h. Halothane tended to prolong the recovery of levels of consciousness. We conclude that isoflurane and sevoflurane provide clinical advantages over halothane on postanesthetic ventilation and recovery of levels of consciousness.     

Characterization of [3H]YM617, R-(-)-5-[2-[[2[ethoxyring(n)-3H](o-ethoxyphenoxy)ethyl]amino]- propyl]-2-methoxybenzenesulfonamide HCl, a potent and selective alpha-1 adrenoceptor radioligand.

The binding properties of a new radioligand, R(-)-5-[2-[[2[ethoxyring(n)-3H](o- ethoxyphenoxy)ethyl]amino]propyl]-2-methoxybenzenesulfonamide++ + HCl ([3H]YM617), were studied in membranes of the rat hippocampus and spleen. [3H]YM617 rapidly associated with its binding sites in both membranes and reached steady state by 20 min at 25 degrees C. The specific binding of [3H]YM617 appeared to be saturable, and Scatchard analysis revealed a linear plot, suggesting a single population of binding sites with a dissociation constant of 0.170 +/- 0.016 nM (n = 6) in the hippocampus and 0.195 +/- 0.036 (n = 4) in the spleen. The maximal binding sites in the hippocampus and spleen were 203.0 +/- 43.2 (n = 6) and 72.4 +/- 17.0 (n = 4) fmol/mg protein, respectively. Chlorethylclonidine (10(-5) M for 10 min) treatment reduced the Bmax values of [3H]YM617 and [3H]prazosin to a similar degree in the rat hippocampus (10-15%) and spleen (40-50%). Alpha adrenoceptor agonists and antagonists competed with [3H]YM617 for binding sites in the following order: YM617 > prazosin > WB4101 > bunazosin > 5-methylurapidil > S(+)-isomer of YM617 > phentolamine > yohimbine > norepinephrine = phenylephrine > methoxamine in the hippocampus, and prazosin > YM617 > bunazosin > WB4101 > 5-methylurapidil > phentolamine > S(+)-isomer of YM617 > yohimbine > norepinephrine > phenylephrine > methoxamine in the spleen. In the hippocampus, prazosin and bunazosin produced biphasic displacement of [3H]YM617, but not [3H]prazosin binding. In contrast, only monophasic curves were obtained against either radioligand in the spleen.(ABSTRACT TRUNCATED AT 250 WORDS)