Genome-wide scan for prostate cancer susceptibility genes using families from the University of Michigan prostate cancer genetics project finds evidence for linkage on chromosome 17 near BRCA1

BACKGROUND: Previous linkage studies have suggested prostate cancer susceptibility genes located on chromosomes 1, 20, and X. Several putative prostate cancer candidate genes have also been identified including RNASEL, MSR1, and ELAC2. Presently, these linkage regions and candidate genes appear to explain only a small proportion of hereditary prostate cancer cases suggesting the need for additional whole genome analyses. METHODS: A genome-wide mode-of-inheritance-free linkage scan, using 405 genetic markers, was conducted on 175 pedigrees, the majority containing three or more affected individuals diagnosed with prostate cancer. Stratified linkage analyses were performed based on previously established criteria. RESULTS: Results based on the entire set of 175 pedigrees showed strong suggestive evidence for linkage on chromosome 17q (LOD = 2.36), with strongest evidence coming from the subset of pedigrees with four or more affected individuals (LOD = 3.27). Race specific analyses revealed strong suggestive evidence for linkage in our African-American pedigrees on chromosome 22q (LOD = 2.35). CONCLUSIONS: Genome-wide analysis of a large set of prostate cancer families indicates new areas of the genome that may harbor prostate cancer susceptibility genes. Specifically, our linkage results suggest that there is a prostate cancer susceptibility gene on chromosome 17 that is independent of ELAC2. Further research including combined analyses of independent genome-wide scan data may clarify the most important regions for future investigation.     

Massive Immune Hemolysis Caused by Anti-D After Dual Kidney Transplantation

Massive immune hemolysis due to passenger lymphocyte-derived anti-D has not been reported in renal transplantation. A 50-year-old (B-positive) male received a dual deceased-donor kidney transplant (B-negative) for diabetic renal failure. Two weeks post-transplant, the patient developed severe hemolytic anemia. The donor anti-D titer was 1:8. The recipient anti-D titer (zero pre-transplant) increased from 1:4 to 1:16 over 4 days. Rapid hemolysis caused severe anemia, minimum Hb = 4.2 g/dL, while selectively lysing the patient's autologous red cells during this time. The hemolytic anemia did not impair the allografts and subsided without monoclonal B-cell pharmacotherapy or apheresis. The anti-D titer decreased to barely detectable levels at four months and had cleared when checked 2 years post-transplant. Transfusion support subsided after two months. If complications of anemia can be avoided, the deleterious effects of hemolysis may be well tolerated by renal allografts using antigen negative transfusion alone.     

Liposarcoma of the head and neck: The University of Texas M. D. Anderson Cancer Center experience

Background.

Our aim was to review our experience with liposarcoma of the head and neck region.

Methods.

This is a retrospective case series at a comprehensive cancer center (1945–2005).

Results.

Of 30 patients, 10 (33%) were initially misdiagnosed. Local recurrences were common (overall rate = 53%), and 4 patients (13%) developed distant metastases. Decreased crude disease‐specific survival rates were significantly associated with recurrence (especially distant recurrence [0%]), age less than 38 years (40%), and pleomorphic subtype (45%); however, in Kaplan‐Meier analyses, only larger tumor size, negative margins, round cell subtype, and pleomorphic subtype were associated with significantly decreased disease‐specific survival (log‐rank test p = .048, .041, .021, and .012, respectively).

Conclusions.

Based on this limited experience and existing literature, we continue to recommend surgery with negative margins as the treatment of choice and that adjuvant therapies should be considered in patients with high‐grade histology, large tumors, positive margins, or certain subsites. © 2008 Wiley Periodicals, Inc. Head Neck, 2009     

Single Port Access (SPA) Cholecystectomy: Two Year Follow-up

Introduction:

Laparoscopy is a constantly evolving field of surgery. New technology, applications, and benefits prompt continual improvement. We have developed a Single Port Access (SPA) surgical technique that allows for the entire cholecystectomy to be performed through a single incision within the umbilicus while maintaining safe standard dissection and retraction techniques of currently performed multi-port laparoscopic cholecystectomy.

Methods:

Fifteen consecutive patients underwent SPA cholecystectomy. Indications were cholelithiasis, cholecystitis, CBD stones, and biliary akinesia. The entire procedure was performed through a single umbilical incision measuring <1.8 cm within the umbilicus. Three trocars and a rigid grasper were inserted through separate fascial sites within the same skin incision. The cholecystectomy procedures are then performed in the standard fashion described in multi-port cholecystectomy.

Results:

Fifteen patients successfully underwent Single Port Access cholecystectomy. One patient required a second 5-mm port site secondary to difficulty with retraction of a large liver. Operative times averaged 107 minutes. Blood loss, patient recovery, and outcomes have been comparable to those of standard multi-port procedures. No umbilical hernias have been seen at 2 years of follow-up.

Conclusion:

We present the SPA cholecystectomy as an alternative to multi-port cholecystectomy. In the first 2 years, SPA surgery has evolved into a technique easily taught and performed without the restrictions of new equipment or added cost.     

Congenital biliary atresia: liver injury begins at birth

Background

The timing of onset of liver injury in biliary atresia (BA) is not known, although in approximately 10% of cases, biliary pathologic condition associated with the biliary atresia splenic malformation syndrome must begin well before birth.

Methods

The study involved retrospective case-note review for infants with definite BA who underwent laparotomy within first week of life.

Results

Three infants were identified who had occlusive BA evident on the first day of life. In all cases, their liver was grossly normal, and histologic changes were trivial.

Conclusion

This suggests that the detrimental cholestatic liver injury, later characteristic of BA, only begins from the time of birth despite a prenatal occlusive biliary pathology. It may be that tissue injury only occurs with the onset of the perinatal bile surge initiating periductal bile leakage and the triggering of an inflammatory and ultimately fibrotic response.     

Potential cancer therapy with the fragile histidine triad gene: review of the preclinical studies.

CONTEXT: The fragile histidine triad gene (FHIT) encompasses a human common fragile site, FRA3B, that is susceptible to environmental carcinogens. Deletion and inactivation of FHIT have been seen in a number of human premalignant and malignant lesions. OBJECTIVE: To review and evaluate preclinical studies of cancer therapy using the FHIT tumor suppressor gene and related studies involving Fhit protein expression. DATA SOURCES: A MEDLINE search of articles published from 1996 to June 2001 was performed; article reference lists were used to retrieve additional relevant articles. STUDY SELECTION: Immunohistochemical studies of primary tumors or relevant lesions were selected to evaluate Fhit expression in premalignant or malignant stages. Preclinical studies on antitumorigenic or therapeutic introduction of FHIT were reviewed for the effects of exogenous Fhit expression. For the immunohistochemical analyses, 26 studies were included that analyzed at least 15 cases of a single type of tumor. For precancerous lesions, 9 studies were included that analyzed at least 4 cases. For studies of FHIT introduction, 9 published studies were included. DATA EXTRACTION: Using primary data from each of the studies, we assessed the rationale and potential contribution of FHIT cancer therapy. Data was independently abstracted by 2 authors and study quality was assessed by 2 other authors. DATA SYNTHESIS: Overall, 60% (1162/1948 cases) of primary tumors showed absent or markedly reduced Fhit protein expression in cancer cells. Studies of preneoplastic lesions or early-stage cancer showed absence or marked reduction of Fhit protein expression in 0% to 93% of samples (overall, 31% [127/408 cases]). Preclinical studies using 26 cancer-derived cell lines from human lung, head and neck, esophageal, gastric, cervical, pancreatic, and kidney cancers, showed that reintroduction of FHIT resulted in inhibition of in vitro tumor cell growth or of in vivo tumorigenicity in 17 (57%) of 30 cell line experiments. Model systems for human preventive cancer therapy suggested that oral introduction of viral vector-mediated FHIT into Fhit-deficient mice may prevent carcinogen-induced tumor development in some cases. CONCLUSION: These findings show that FHIT gene therapy may potentially be clinically useful for treatment of cancer and also prevention of carcinogen-induced tumor development, suggesting a rationale for further research involving FHIT introduction.     

Discovery of an Anion-Dependent Farnesyltransferase Inhibitor from a Phenotypic Screen

By employing a phenotypic screen, a set of compounds, exemplified by 1, were identified which potentiate the ability of histone deacetylase inhibitor vorinostat to reverse HIV latency. Proteome enrichment followed by quantitative mass spectrometric analysis employing a modified analogue of 1 as affinity bait identified farnesyl transferase (FTase) as the primary interacting protein in cell lysates. This ligand-FTase binding interaction was confirmed via X-ray crystallography and temperature dependent fluorescence studies, despite 1 lacking structural and binding similarity to known FTase inhibitors. Although multiple lines of evidence established the binding interaction, these ligands exhibited minimal inhibitory activity in a cell-free biochemical FTase inhibition assay. Subsequent modification of the biochemical assay by increasing anion concentration demonstrated FTase inhibitory activity in this novel class. We propose 1 binds together with the anion in the active site to inhibit farnesyl transferase. Implications for phenotypic screening deconvolution and HIV reactivation are discussed.     

Lung vascular cell heterogeneity: endothelium, smooth muscle, and fibroblasts

The pulmonary circulation represents a unique vascular bed, receiving 100% of the cardiac output while maintaining low blood pressure. Multiple different cell types, including endothelium, smooth muscle, and fibroblasts, contribute to normal vascular function, and to the vascular response to injury. Our understanding of the basic cell biology of these various cell types, and the roles they play in vascular homeostasis and disease, remains quite limited despite several decades of study. Recent advances in approaches that enable the mapping of cell origin and the study of the molecular basis of structure and function have resulted in a rapid accumulation of new information that is essential to vascular biology. A recent National Institutes of Health workshop was held to discuss emerging concepts in lung vascular biology. The findings of this workshop are summarized in this article.