Frequent loss of heterozygosity at the Hcr1 (hepatocarcinogenesis resistance) locus on chromosome 10 in primary hepatocellular carcinomas from LFF1 rat strain

Hepatocarcinogenesis sensitivity (Hcs1, 2) and resistance (Hcr1-3) loci have been identified by linkage analysis on rat chromosomes 7 and 1, and 10, 4, and 8, respectively. Cytogenetic studies documented deletions on chromosomes 3 and 6 of neoplastic rat hepatocytes. Hepatocellular carcinomas (HCCs) were produced in F1 hybrid rats between Long-Evans (LE) and Fisher 344 (F344) rats. Scanning of the above chromosomes for loss of heterozygosity (LOH) showed allelic imbalance (AI) at multiple regions on chromosomes 6, 7, and 10q. Detailed deletion mapping of chromosome 10 localized a putative suppressor Hcr1 gene to within a 3.2-cM interval flanked by D10Rat51 and D10Rat121. Two other distinct regions with frequent AIs were found inside the Hcr1 locus, at marker loci including DNaseI and Mrp genes, and in a segment including 4 consecutive markers (D10Rat64, D10Rat182, D10Rat113, D10Rat216). In 40% of HCCs, AI was seen at the p53 locus. AI on chromosome 7 occurred at the Hcs1 locus, where is located c-myc, which is amplified in HCCs, suggesting allelic gain. Most AIs occurred in poorly/moderately differentiated carcinomas, and a few events were seen in well-differentiated tumors on chromosomes 7 and 10. These data suggest that alteration of a cluster of oncosuppressor genes on 10q is important for HCC progression. The existence of AI on segments of rat chromosomes 6, 7, and 10, syntenic to chromosomal segments of human HCCs where chromosomal gains or deletions occur, suggests a commonality of some molecular events in the pathogenesis of HCCs in rats and humans. Our map provides information toward cloning putative oncosuppressor genes associated with this carcinoma.     

Epstein-Barr virus associated B cell lymphoproliferative disorders following bone marrow transplantation

B cell lymphoproliferative disorders (BLPD) developed in eight patients following bone marrow transplantation (BMT) for leukemia (five patients) or immunodeficiency (three patients). Recipients of T depleted marrow from a mismatched donor were at particularly high risk of this complication. Six of 25 (24%) recipients of mismatched T depleted bone marrow developed BLPD. In contrast, none of 47 matched T depleted transplants, one of ten (10%) who received non-depleted marrow from an unrelated donor, and only one of 424 matched non-depleted transplants were associated with BLPD. Epstein-Barr virus (EBV) specific serology and DNA hybridization studies demonstrating five to 50 copies of EBV genome/cell in involved tissues implicate this virus as an associated etiologic agent. Restriction fragment length polymorphism (RFLP) and cytogenetic analysis of involved tissue demonstrated donor origin (five of seven) or host origin (two of seven). Histologic appearance was similar to EBV-induced polymorphic B cell proliferations described following solid organ transplantation, or which occur de novo in primary immunodeficiency. Six of seven patients with adequate tissue available for study were found to have monoclonal proliferations by: in situ immunofluorescence (six of seven), and/or immunoglobulin gene rearrangement, (four of six). Cytogenetic analysis of involved tissues from four patients showed a normal karyotype, whereas two had multiple clonal chromosomal abnormalities. Seven patients died despite aggressive attempts at therapy with combinations of antiviral, immunologic, and chemotherapeutic agents.     

Risk and significance of endoscopic/radiological evidence of recurrent Crohn's disease

BACKGROUND & AIMS: The aim of this study was to determine the risk of endoscopic/radiological recurrence of Crohn's disease postoperatively and the long-term outcome. METHODS: A randomized placebo-controlled trial was performed to determine the effectiveness of mesalamine in preventing recurrent Crohn's disease postoperatively. Patients in the control group were examined endoscopically/radiologically before entry into and annually during the trial. Findings were classified as minimal or severe. RESULTS: There were 76 patients (49 men and 37 women; mean age, 37.1 +/- 13.2 years). Fifty (61.7%) had terminal ileal resections. Overall, 55 endoscopic/radiological recurrences were observed in 51 patients (67.1%). Expressed actuarially, the recurrence rate was 27.5% at 1 year (95% confidence interval [CI], 15.8%-37.6%), 60.8% at 2 years (95% CI, 46%-71.3%), and 77.3% at 3 years (95% CI, 62.7%-86.3%). Nineteen (37%) were symptomatic and 12 (24%) were initially asymptomatic but later became symptomatic (mean, 13.0 +/- 8.8 months), whereas 20 (39%) remained asymptomatic (mean, 16.9 +/- 17.4 months). Patients with severe endoscopic/radiological disease were significantly more likely to be or become symptomatic than those with minimal disease (23 of 32 vs. 8 of 19, respectively; P = 0.0437). CONCLUSIONS: This study suggests that postoperative endoscopic/radiological recurrences occur later than previously reported. Furthermore, many of these patients, especially with minimal disease, will remain asymptomatic. (Gastroenterology 1997 Dec;113(6):1823-7)     

The Hippo–Salvador pathway restrains hepatic oval cell proliferation,liver size,and liver tumorigenesis

Loss of Hippo signaling in Drosophila leads to tissue overgrowth as a result of increased cell proliferation and decreased cell death. YAP (a homolog of Drosophila Yorkie and target of the Hippo pathway) was recently implicated in control of organ size, epithelial tissue development, and tumorigenesis in mammals. However, the role of the mammalian Hippo pathway in such regulation has remained unclear. We now show that mice with liver-specific ablation of WW45 (a homolog of Drosophila Salvador and adaptor for the Hippo kinase) manifest increased liver size and expansion of hepatic progenitor cells (oval cells) and eventually develop hepatomas. Moreover, ablation of WW45 increased the abundance of YAP and induced its localization to the nucleus in oval cells, likely accounting for their increased proliferative capacity, but not in hepatocytes. Liver tumors that developed in mice heterozygous for WW45 deletion or with liver-specific WW45 ablation showed a mixed pathology combining characteristics of hepatocellular carcinoma and cholangiocarcinoma and seemed to originate from oval cells. Together, our results suggest that the mammalian Hippo–Salvador pathway restricts the proliferation of hepatic oval cells and thereby controls liver size and prevents the development of oval cell–derived tumors.     

Effectiveness of radial shock-wave therapy for calcific tendinitis of the shoulder: single-blind, randomized clinical study

BACKGROUND AND PURPOSE: Radial shock-wave therapy (RSWT) is a pneumatically generated, low- to medium-energy type of shock-wave therapy. This single-blind, randomized, "less active similar therapy"-controlled study was performed to evaluate the effectiveness of RSWT for the management of calcific tendinitis of the shoulder. SUBJECTS: Ninety patients with radiographically verified calcific tendinitis of the shoulder were tested. METHODS: Subjects were randomly assigned to either a treatment group (n=45) or a control group (n=45). Pain and functional level were evaluated before and after treatment and at a 6-month follow-up. Radiographic modifications in calcifications were evaluated before and after treatment. RESULTS: The treatment group displayed improvement in all of the parameters analyzed after treatment and at the 6-month follow-up. Calcifications disappeared completely in 86.6% of the subjects in the treatment group and partially in 13.4% of subjects; only 8.8% of the subjects in the control group displayed partially reduced calcifications, and none displayed a total disappearance. DISCUSSION AND CONCLUSION: The results suggest that the use of RSWT for the management of calcific tendinitis of the shoulder is safe and effective, leading to a significant reduction in pain and improvement of shoulder function after 4 weeks, without adverse effects.     

P2Y receptors and atherosclerosis in apolipoprotein E-deficient mice

Background and purpose:

P2Y nucleotide receptors are involved in the regulation of vascular tone, smooth muscle cell (SMC) proliferation and inflammatory responses. The present study investigated whether they are involved in atherosclerosis.

Experimental approach:

mRNA of P2Y receptors was quantified (RT-PCR) in atherosclerotic and plaque-free aorta segments of apolipoprotein E-deficient (apoE^–/–) mice. Macrophage activation was assessed in J774 macrophages, and effects of non-selective purinoceptor antagonists on atherosclerosis were evaluated in cholesterol-fed apoE^–/– mice.

Key results:

P2Y₆ receptor mRNA was consistently elevated in segments with atherosclerosis, whereas P2Y₂ receptor expression remained unchanged. Expression of P2Y₁ or P2Y₄ receptor mRNA was low or undetectable, and not influenced by atherosclerosis. P2Y₆ mRNA expression was higher in cultured J774 macrophages than in cultured aortic SMCs. Furthermore, immunohistochemical staining of plaques demonstrated P2Y₆-positive macrophages, but few SMCs, suggesting that macrophage recruitment accounted for the increase in P2Y₆ receptor mRNA during atherosclerosis. In contrast to ATP, the P2Y₆-selective agonist UDP increased mRNA expression and activity of inducible nitric oxide synthase and interleukin-6 in J774 macrophages; this effect was blocked by suramin (100–300 µM) or pyridoxal-phosphate-6-azophenyl-2′-4′-disulphonic acid (PPADS, 10–30 µM). Finally, 4-week treatment of cholesterol-fed apoE^–/– mice with suramin or PPADS (50 and 25 mg·kg⁻¹·day⁻¹ respectively) reduced plaque size, without changing plaque composition (relative SMC and macrophage content) or cell replication.

Conclusions and implications:

These results suggest involvement of nucleotide receptors, particularly P2Y₆ receptors, during atherosclerosis, and warrant further research with selective purinoceptor antagonists or P2Y₆ receptor-deficient mice.     

miR-10a is aberrantly overexpressed in Nucleophosmin1 mutated acute myeloid leukaemia and its suppression induces cell death

Background

Semaphorins act as chemotactic cues for cell movement via their transmembrane receptors, plexins. Somatic missense mutations in the plexinB1 gene coupled with overexpression of the protein frequently occur in prostate tumours, indicating a role for plexinB1 in the pathogenesis of prostate cancer.

Results

Two specific mutations found in prostate cancer enhance RhoD binding and one other mutation results in loss of inhibition of Rac-dependent Pak1 phosphorylation and lamellipodia formation and in impairment of trafficking of plexinB1 to the membrane. None of the three characterised mutations affect PDZRhoGEF binding, RhoA activity, the interaction of plexinB1with the oncogenes ErbB2 or c-Met or ErbB2 phosphorylation. The mutations have the net effect of increasing cell motility by blocking plexinB1-mediated inhibition of Rac while enhancing the interaction with RhoD, an anti-migratory factor.

Conclusions

PlexinB1 mutations block plexinB1-mediated signalling pathways that inhibit cell motility.     

Asynchronism of the recovery of baroreflex sensitivity, blood pressure, and consciousness from anesthesia in rats

Anesthesia inhibits arterial baroreflex functions such as baroreflex sensitivity （BRS）. The main objective of the present study was to determine the time course of BRS recovery from anesthesia and to determine whether BRS recovery is synchronous with the recovery of consciousness and blood pressure （BP）. Experiments were performed in male Sprague-Dawley rats using different commonly used anesthetics at routine doses through intraperitoneal administration： （1） diazepam/ketamine,     

Synergism of atenoloi and nitrendipine on hemodynamic amelioration and organ protection in hypertensive rats

OBJECTIVE： This study was designed to investigate the possible synergism of atenolol and nitrendipine on blood pressure （BP） and blood pressure variability （BPV） reductions, baroreflex sensitivity （BRS） amelioration, and organ protection in hypertensive rats. METHOD： The dose was 20 mg/kg for atenolol, 10 mg/kg for nitrendipine and 20 ＋ 10 mg/kg for the combination of these two drugs. In an acute study, a single dose was given via a catheter previously inserted into the stomach in spontaneously hypertensive rats （SHR）.