Non-Random Pattern of Integration for Epstein-Barr Virus with Preference for Gene-Poor Genomic Chromosomal Regions into the Genome of Burkitt Lymphoma Cell Lines

Background: Epstein-Barr virus (EBV) is an oncogenic virus found in about 95% of endemic Burkitt lymphoma (BL) cases. In latently infected cells, EBV DNA is mostly maintained in episomal form, but it can also be integrated into the host genome, or both forms can coexist in the infected cells. Methods: In this study, we mapped the chromosomal integration sites of EBV (EBV-IS) into the genome of 21 EBV+ BL cell lines (BL-CL) using metaphase fluorescence in situ hybridization (FISH). The data were used to investigate the EBV-IS distribution pattern in BL-CL, its relation to the genome instability, and to assess its association to common fragile sites and episomes. Results: We detected a total of 459 EBV-IS integrated into multiple genome localizations with a preference for gene-poor chromosomes. We did not observe any preferential affinity of EBV to integrate into common and rare fragile sites or enrichment of EBV-IS at the chromosomal breakpoints of the BL-CL analyzed here, as other DNA viruses do. Conclusions: We identified a non-random integration pattern into 13 cytobands, of which eight overlap with the EBV-IS in EBV-transformed lymphoblastoid cell lines and with a preference for gene- and CpGs-poor G-positive cytobands. Moreover, it has been demonstrated that the episomal form of EBV interacts in a non-random manner with gene-poor and AT-rich regions in EBV+ cell lines, which may explain the observed affinity for G-positive cytobands in the EBV integration process. Our results provide new insights into the patterns of EBV integration in BL-CL at the chromosomal level, revealing an unexpected connection between the episomal and integrated forms of EBV.     

Occult Micrometastases in Axillary Lymph Nodes Predict Subsequent Distant Metastases in Stage I Breast Cancer: A Case-Control Study with 15-Year Follow-Up

Background The prognostic significance of occult axillary metastases was evaluated in patients with stage I breast cancer.Methods Ninety-six patients with pT1 breast carcinoma who underwent axillary lymph node dissection had negative nodes in routine microscopic examination. Forty-eight patients developed distant metastases within 15 years after surgery (M group) and are compared to 48 age-matched patients who were disease-free for 15 years (NM group). We reexamined 1539 lymph nodes from these patients, using three levels and cytokeratin immunostain.Results Occult metastases were detected in 21 patients: 16 of 48 (34%) in the M group and 5 of 48 (11%) in the NM group (P = .007). All metastases measured 2.0 mm or less and were classified as micrometastases (>0.2 mm to 2.0 mm) in 11 cases and as individual tumor cells (individual cells or clusters measuring 0.2 mm) in 10 cases. Micrometastases were 10 times more frequent in the M group than in the NM group (10/48 vs. 1/48; P = .004). Although there was no difference in tumor size, histologic type, estrogen receptor status, or type of treatment between the two patient groups, tumors in the M group were of a higher grade, had higher mitotic index and showed lymphovascular invasion. In multiple logistic regression, only high mitotic index and presence of micrometastases showed an independent significant correlation with the subsequent occurrence of distant metastases.Conclusions The presence of micrometastases (>0.2 to 2.0 mm) in axillary nodes is significantly associated with the development of distant metastases in patients with T1 breast cancer.     

Why are collagenoses dangerous for pregnancy?

It is well known that certain autoimmune disorders are associated with pregnancy loss. Increased perinatal and maternal mortality as well as increased incidence of disease deterioration during pregnancy are correlated to preconceptual disease regulation, incidence of super-imposed gestosis and renal failure and, recently, with some sorts of antiphospholipid antibodies. Indeed, investigators have attempted to establish an association between recurrent pregnancy loss and the presence of specific antibodies, irrespective of the presence of other clinical signs or complications of collagenosis. The most serious appears to be the presence of anticardiolipin antibodies and lupus anticoagulant while the significance of other autoantibodies that can be found appears to be much less defined. In the present paper pregnancy complicated by various collagenoses and therapeutic modalities are discussed.     

The CRF(1) receptor antagonist DMP696 produces anxiolytic effects and inhibits the stress-induced hypothalamic-pituitary-adrenal axis activation without sedation or ataxia in rats

Abstract Rationale. CRF₁ antagonists may be effective in the treatment of anxiety disorders while having fewer side effects compared with classical benzodiazepines. Objectives. The effects of a small molecule selective CRF₁ antagonist DMP696 on anxiety-like behaviors and stress-induced increases in corticosterone in rats exposed to a novel environment and on locomotor activity and motor coordination were determined in rats. These effects of DMP696 were compared with those produced by the classical benzodiazepine chlordiazepoxide (CDP). Methods. DMP696 or CDP were administered PO, 60 minutes before behavioral testing in rats. Their effects on latency to exit a dark chamber and stress-induced increase in corticosterone in the Defensive Withdrawal test (an animal model of anxiety), locomotor activity, and rotorod performance (measure of ataxia) were determined. Results. DMP696 significantly reduced exit latency and reversed the stress-induced increase in corticosterone in the Defensive Withdrawal test at doses of 3.0–10 mg/kg and higher. In contrast, CDP significantly decreased exit latency at 10 and 30 mg/kg, but not at 100 mg/kg, due to concurrent non-specific side effects. Unlike DMP696, CDP had no effect on the stress-induced increase in corticosterone at lower doses, but resulted in a significant increase at higher doses. DMP696 did not reduce locomotor activity or impair motor coordination at doses up to 30-fold higher than doses effective in the Defensive Withdrawal model. In contrast, CDP produced significant sedation and ataxia at the same doses that were effective in reducing exit latency. Conclusions. These data suggest that the CRF₁ antagonist DMP696 might retain the therapeutic benefits of classical benzodiazepines but have fewer motoric side effects. Electronic Publication     

Hedgehog signaling pathway and vitamin D receptor gene variants as potential risk factors in odontogenic cystic lesions

Clinical Oral Investigations - Genetic variants in the hedgehog signaling pathway and VDR gene are involved in inflammatory responses and neoplastic transformation. Current study investigated...     

Low performance of the MSKCC nomogram in preoperatively ultrasonically negative axillary lymph node in breast cancer patients

BACKGROUND AND OBJECTIVES: In order to predict the nonsentinel lymph node (NSLN) metastases in sentinel lymph node (SLN) positive patients a nomogram was created at the Memorial Sloan Kettering Cancer Centre (MSKCC). The aim of our study was to validate the MSKCC nomogram in patients grouped by the preoperative ultrasound (US) examination of the axillary lymph nodes. METHODS: The MSKCC nomogram was validated separately in three groups of patients: (US-0) only clinically preoperatively negative axillary lymph nodes (126 patients), (US-1) US negative axillary lymph nodes (109 patients), and (US-2) US suspicious but fine needle aspiration biopsy (FNAB) negative axillary lymph nodes (41 patients). RESULTS: The predicted probability underestimates the actual probability with the mean absolute error equal to 0.116 in the US-0 group (P = 0.003), and overestimates the actual probability (mean absolute error equal to 0.084) in US-1 group (P = 0.033) and US-2 group (mean absolute error is 0.110) (P = 0.275). CONCLUSION: We found that the MSKCC nomogram overestimates the probability of the NSLN metastases in breast cancer patients with (i) preoperatively US negative or (ii) US suspicious, but FNAB negative axillary lymph nodes. We also found that MSKCC nomogram has only limited value in patients with only clinically negative axillary lymph nodes.