HIV prevalence and risk behaviours for HIV transmission in South Australian prisons

During the latter half of 1989, HIV prevalence in South Australian prisoners was 1.4%. The prevalence of HIV infection across the prison system did not change significantly during 1989 but there was clustering of HIV-infected prisoners in some prisons. Almost half the prisoners from all of the South Australian prisons agreed to participate in our studies, from which we estimate that about 42% of prisoners engage in risk behaviours at least once while incarcerated. Prisoners estimated that 36% of all prisoners inject drugs intravenously at some stage during their stay and that 12% engage in anal intercourse at least once. Interviews with former prisoners who had a history of intravenous drug use revealed that about half had injected themselves while in prison, 60% shared needles and most did not clean shared needles adequately. Most of these prisoners injected themselves once a month or less frequently. The conditions for spread of HIV within the prison system exist but at the current prevalence of infection, transmission can be expected to be infrequent. The opportunity exists now to improve and expand preventive measures.     

Radiotherapy in the management of solitary extramedullary plasmacytoma

BACKGROUND: Solitary extramedullary plasmacytoma (SEP) is a rare tumour for which the standard treatment remains local radiotherapy (RT). We present a study of a multi-institutional experience, between 1980 and 1999, in an attempt to better understand the natural history of SEP and to identify possible prognostic factors. METHODS: The records at Radiation Oncology Victoria and Peter MacCallum Cancer Centre, Melbourne, were used for the identification of patients. The inclusion criteria were as follows: (i) histological confirmation of clonal plasma cells involving a single extramedullary site with or without lymph node involvement; (ii) no histological evidence of bone marrow involvement; (iii) no evidence of distant bone lesion on radiographic skeletal survey (bone erosions adjacent to the primary thought to be due to contiguous involvement were permitted) and (iv) no anaemia, hypercalcaemia or renal impairment due to plasma cell dyscrasia. RESULTS: A total of 16 patients was identified, with a median follow up of 66 months (range 12-211 months). The head and neck region accounted for the majority of presentations (88%). Among all patients, a serum mono-clonal paraprotein was found in three patients and bone erosion was identified in seven patients. All patients received local RT, although two patients also received elective nodal irradiation (ENI). The median RT dose was 45 Gy (range 40-50.4 Gy). Local control was achieved in all patients (100%), however, regional recurrence outside the RT fields occurred in 2/16. Multiple myeloma (MM) developed in five patients, all within 5 years. The predicted 10-year myeloma free survival is 75% and 10-year overall survival is 54%. CONCLUSION: RT can achieve excellent local control of SEP. The rate of conversion to MM is 31%. Moderate dose RT of at least 40 Gy using limited radiation fields is recommended, although ENI should be considered if toxicity is not increased.     

Investigation of the Relationship Between Prostate Cancer and MSMB and NCOA4 Genetic Variants and Protein Expression

Two genome‐wide association studies (GWAS) identified the β‐microseminoprotein (MSMB) promoter SNP, rs10993994:C>T, as significantly associated with prostate cancer (PC) risk. Follow‐up studies demonstrate that the variant allele directly affects expression of the MSMB‐encoded protein, PSP94, and also suggest that it affects mRNA expression levels of an adjacent gene, NCOA4, which is involved in androgen receptor transactivation. In a population‐based study of 1,323 cases and 1,268 age‐matched controls, we found the NCOA4 SNP, rs7350420:T>C, was associated with a 15% reduction in PC risk, but the association was not significant after adjustment for the rs10993994:C>T genotype. Tumor tissue microarrays of 519 radical prostatectomy patients were used to measure PSP94 and NCOA4 protein expression. Taken together, these data confirm that the rs10993994:C>T variant allele is associated with decreased PSP94 expression, and the association is stronger in tumor compared to normal prostate tissue. No association was observed between rs10993994:C>T and NCOA4 expression, and only moderate associations were seen between two NCOA4 SNPs, rs10761618:T>C and rs7085433:G>A, and NCOA4 protein expression. These data indicate that the increase in PC risk associated with rs10993994:C>T is likely mediated by the variant's effect on PSP94 expression; however, this effect does not extend to NCOA4 in the data presented here.     

Proline at the P2 position in protein C is important for calcium- mediated regulation of protein C activation and secretion

Protein C is a vitamin K-dependent plasma serine protease zymogen, which upon activation, functions as an anticoagulant. Protein C activation is catalyzed by a complex of thrombin (T) with thrombomodulin (TM). This activation is Ca(2+)-dependent, but Ca2+ inhibits protein C activation by thrombin alone. In most proteases, specificity is determined primarily by the residues that lie near the scissile bond. In protein C, the P2 position is Pro, whereas in the fibrinogen A chain, P2 is Val. We have expressed a Pro-->Val mutant of protein C (P168V) in mammalian cells. At saturating Ca2+, the P168V and wild-type proteins were activated by the T-TM complex equivalently, but half maximal rates of activation were obtained at 50 mumol/L Ca2+ for wild type and approximately 5 mmol/L Ca2+ for the P168V mutant. In the absence of TM, Ca2+ no longer inhibited the activation of the P168V mutant. These results indicate that Pro168 influences the Ca(2+)- dependent conformational changes in protein C that control activation. Recently, a patient with thrombotic complications has been identified with a Pro168-->Leu substitution. Both the P168V and the P168L mutation lead to impaired secretion caused by retention within the cell.     

Autologous bone marrow transplantation in acute myelogenous leukemia: in vitro treatment with myeloid cell-specific monoclonal antibodies

Second or third chemotherapy-induced remissions in acute myelogenous leukemia (AML) are limited by early relapse of the leukemia. We developed monoclonal antibodies (MoAbs) that are cytotoxic to myeloid leukemia cells to treat bone marrow from these patients ex vivo for autologous transplantation. In this pilot study, bone marrow was harvested from ten patients with AML in remission, treated with one or two complement-fixing MoAbs, PM-81 and AML-2-23, which react with myeloid differentiation antigens, incubated with rabbit complement, and cryopreserved. These MoAbs were chosen because they have broad reactivity with AML cells but not with pluripotent progenitor cells. At the time of transplant, 6 patients were in second complete remission, 1 each was in third complete or partial remission, and 2 were in early first relapse. The patients were treated with cyclophosphamide (60 mg/kg a day for 2 days) and total body irradiation (200 cGy twice a day for 3 days) and given infusions of MoAb-treated bone marrow. Full bone marrow reconstitution was observed in eight patients; two patients did not recover platelets. Seven of the ten patients are surviving and disease-free at 21.0, 15.0, 13.0, 10.0, 6.0, 3.0, and 2.0 months posttransplant. Treating bone marrow with MoAbs to myeloid differentiation antigens does not interfere with pluripotential stem cell engraftment. Longer follow-up and a controlled study are necessary to prove that the apparent efficacy of this therapeutic approach in some patients is attributable to MoAb-mediated killing of leukemia cells.     

De Novo Donor‐Specific HLA Antibodies Are Associated With Rapid Loss of Graft Function Following Islet Transplantation in Type 1 Diabetes

Outcomes after islet transplantation continue to improve but etiology of graft failure remains unclear. De novo donor‐specific human leukocyte antigen (HLA) antibodies (DSA) posttransplant are increasingly recognized as a negative prognostic marker. Specific temporal associations between DSA and graft function remain undefined particularly in programs undertaking multiple sequential transplants. Impact of de novo DSA on graft function over 12 months following first islet transplant was determined prospectively in consecutive recipients taking tacrolimus/mycophenolate immunosuppression at a single center. Mixed‐meal tolerance test was undertaken in parallel with HLA antibody assessment pretransplant and 1–3 months posttransplant. Sixteen participants received a total of 26 islet transplants. Five (19%) grafts were associated with de novo DSA. Five (31%) recipients were affected: three post–first transplant; two post–second transplant. DSA developed within 4 weeks of all sensitizing grafts and were associated with decreased stimulated C‐peptide (median [interquartile range]) at 3 months posttransplant (DSA negative: 613(300–1090); DSA positive 106(34–235) pmol/L [p = 0.004]). De novo DSA directed against most recent islet transplant were absolutely associated with loss of graft function despite maintained immunosuppression at 12 months in the absence of a rescue nonsensitizing transplant. Alemtuzumab induction immunosuppression was associated with reduced incidence of de novo DSA formation (p = 0.03).     

A catalogue of genes in the cardiovascular system as identified by expressed sequence tags.

The heart, which is composed of all the cellular components of the circulatory system, is a representative organ for obtaining genes expressed in the cardiovascular system in normal and disease states. We used partial sequences of cDNA clones, or expressed sequence tags, to identify and tag genes expressed in this organ. More than 3500 partial sequences representing > 3000 cDNA clones have been obtained from either the 5' or 3' end of inserts derived from human heart cDNA libraries. Of 3132 cDNA clones analyzed by sequence similarity searching against the GenBank/EMBL data bases, 1485 (47.4%) were found to represent additional, previously undiscovered genes, whereas 267 clones were matched to human brain expressed sequence tags. Clones matching to known genes were catalogued according to their putative structural and cellular functions. cDNA probes from reverse-transcribed mRNAs of fetal and adult hearts were used to study differential expression of selected clones in cardiac development. Cataloguing genes expressed in the heart may provide insight into the genes involved in health and cardiovascular disease.     

Prognostic and predictive values of Nrf2, Keap1, p16 and E-cadherin expression in ovarian epithelial carcinoma

Objectives: Despite considerable interest in the Nuclear factor-erythroid 2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein-1 (Keap1), p16 and epithelial cadherin (E-cadherin) activation in carcinoma progression, contradictory results regarding association of Nrf2/Keap1/E-cadherin and p16 expression with clinico-pathological features and prognosis have been reported. The predictive value of these markers in ovarian carcinoma is unknown. Methods/Materials: In this retrospective study, 108 cases were evaluated immunohistochemically with antibodies to Nrf2, Keap1, estrogen receptor (ER), p16 and E-cadherin. The results were compared with histological and clinical data, disease-free survival (DFS) and overall survival (OS). Results: A cohort of 108 ovarian carcinomas (47 serous, 23 mucinous, 13 endometrioid and 25 clear cell), including 68 FIGO stage I-II cases and 40 FIGO stage III-IV cases was studied. The age of patients (P=0.005), FIGO stage (P<0.001), immunohistochemical expression of Keap1 (P<0.000), E-cadherin (P=0.045), p53 (P=0.003), p16 (P<0.001) and ER (P=0.004) were significant factors between different histological subtypes. Patients with serous carcinoma were older in age, presented with more advanced stage disease, worst prognosis, highest Keap1 expression and least percentage of E-cadherin immunoreactivity. In univariate analysis, FIGO staging (P=0.000 for DFS; P=0.000 for OS), Nrf2 (P=0.010 for DFS; P=0.001 for OS), and p16 (P=0.004 for DFS; P=0.019 for OS) were associated with worse prognosis. After multivariate analysis, FIGO staging and Nrf2 remained significance prognostic factors. Conclusions: There were differences in the expression of Nrf2, Keap1, p16 and E-cadherin between different ovarian carcinoma subtypes. In multivariate analysis, FIGO stage and Nrf2 expression were associated with poorer DFS and OS.