Comparison of molecular changes in lung cancers in HIV-positive and HIV-indeterminate subjects

CONTEXT: Human immunodeficiency virus (HIV) infection has been associated with an increasing incidence of malignancy, and HIV-infected persons have an increased incidence of primary lung carcinoma compared with the general population. OBJECTIVE: To investigate the molecular changes present in HIV-associated lung tumors and compare them with those present in lung carcinomas arising in HIV-indeterminate subjects ("sporadic tumors"). DESIGN: Convenience sample. SUBJECTS: Archival tissues from 11 HIV-positive persons and from 35 persons of indeterminate HIV status. SETTING: University-based medical centers and affiliated hospitals. MAIN OUTCOME MEASURES: Analysis of frequency of loss of heterozygosity (LOH) and microsatellite alteration (MA) using polymerase chain reaction and 16 polymorphic microsatellite markers at 8 chromosomal regions frequently deleted in lung cancer. Presence of HIV and human papillomavirus (HPV) sequences. RESULTS: The overall frequency of LOH at all chromosomal regions tested and the frequencies at most of the individual regions were similar in the 2 groups. Frequency of MA present in the HIV-associated tumors (0.18) was 6-fold higher than in sporadic tumors (0.03) (P<.001). At least 1 MA was present in 10 (91%) of 11 HIV-associated tumors vs 17 (48%) of 35 sporadic tumors (P=.02). Molecular changes were independent of tumor stage and gender. HIV and HPV sequences were not detected in the HIV-associated lung carcinomas. CONCLUSIONS: Microsatellite alterations, which reflect widespread genomic instability, occur at greatly increased frequency in HIV-associated lung carcinomas. Although the mechanism underlying the development of increased MAs is unknown, it may play a crucial role in the development of many HIV-associated tumors.     

Predicting dementia from the Mini-Mental State Examination in an elderly population: the role of education

Steroid hormone regulation and cell-type specific expression of the jun-D protooncogene in rat uterus was examined. Adult, ovariectomized rats were injected with progesterone, testosterone, 17beta-estradiol (E2-17beta), 16alpha-estradiol (E2-16alpha), dexamethasone or cycloheximide. Uteri were collected between 0 and 6 h post-treatment. Northern blot analysis of uterine RNA revealed that induction of jun-D was specific for estrogenic steroids, as progesterone and testosterone had no effect on expression of this member of the jun gene family. Treatment with E2-17beta increased jun-D mRNA levels by approx. 5-fold, with expression reaching peak levels at 3 h after treatment and declining thereafter. Administration of E2-16alpha, a short-acting estrogen that does not cause uterine cell proliferation, increased expression of jun-D but with different kinetics compared to the long-acting E2-17beta. The mRNA levels of jun-D increased by 3-fold 1 h after administration of E2-16alpha but declined soon after. Slight induction of jun-D mRNA by dexamethasone was apparent, but to a much lesser extent compared to estrogen. The protein synthesis inhibitor, cycloheximide, did not block jun-D induction, indicating that this is an "immediate early" response. Expression of Jun-D protein was examined by immunohistochemical methods. E2-17beta treatment activated jun-D primarily in the nuclei of luminal and glandular epithelial cells of the endometrium. These results demonstrate that hormonal induction of jun-D is specific for estrogens and that uterine expression of this protooncogene occurs in a cell-type specific manner.     

Continuous-flow solid (gel)-phase peptide synthesis using unsupported ultrahigh-load polymers: Fmoc/t-butyl strategy

The technique of continuous-flow solid-phase peptide synthesis using unsupported polymers has been extended to cover the use of N alpha-Fmoc protected amino acids. This approach to peptide synthesis uses (but is not limited to) a phenolic bead-form polymer at 5 mmol g-1 loading. The success of the technique is based upon "layered displacement" to efficiently remove spent reagents and washing solutions from within the flow reactor under low pressure conditions. This system has been successfully employed in synthesizing the test peptides, [Leu5]-enkephalin, neurotensin and the notoriously difficult decapeptide sequence (65-74) of the acyl carrier protein.     

Microwave Circuit of a Parallel-Coupled Accelerating Structure

The microwave circuit of a parallel-coupled accelerating structure containing accelerating resonators excited by the common high-Q transmission resonator has been investigated. The relations determining the structure operation mode, tuning conditions, and the power supplied to the resonators have been derived.     

Determinants of transmission success of individual clones from mixed-clone infections of the rodent malaria parasite, Plasmodium chabaudi

PURPOSE: To compare the permeation characteristics of amide bond-containing HIV-1 protease inhibitors and their pyrrolinone-containing counterparts across Caco-2 cell monolayers, a model of the intestinal mucosa. METHODS: Transepithelial transport and cellular uptake of three pairs of amide bond-containing and pyrrolinone-based peptidomimetics were assessed in the presence and absence of cyclosporin A using the Caco-2 cell culture model. The potential of the peptidomimetics to interact with biological membranes was estimated by IAM chromatography. RESULTS: In the absence of cyclosporin A, apical (AP) to basolateral (BL) flux of all compounds studied was less than the flux determined in the opposite direction (i.e., BL-to-AP). The ratio of the apparent permeability coefficients (Papp) calculated for the BL-to-AP and AP-to-BL transport (P(BL-->AP)/P(AP-->BL)) varied between 1.7 and 36.2. When individual pairs were ompared, P(BL-->AP)/P(AP-BL) ratios of the pyrrolinone-containing compounds were 1.5 to 11.5 times greater than those determined for the amide bond-containing analogs. Addition of 25 microM cyclosporin A to the transport buffer reduced the P(BL-->AP)/P(AP-->BL) ratios for all protease inhibitors to a value close to unity. Under these conditions, the amide bond-containing peptidomimetics were at least 1.6 to 2.8 times more able to permeate Caco-2 cell monolayers than were the pyrrolinone-containing compounds. The intrinsic uptake characteristics into Caco-2 cells determined in the presence of 25 microM cyclosporin A were slightly greater for the amide bond-containing protease inhibitors than for the pyrrolinone-containing analogs. These uptake results are consistent with the transepithelial transport results determined across this in vitro model of the intestinal mucosa. CONCLUSIONS: The amide bond-containing and pyrrolinone-based peptidomimetics are substrates for apically polarized efflux systems present in Caco-2 cell monolayers. The intrinsic permeabilities of the amide bond-containing protease inhibitors are slightly greater than the intrinsic permeabilities of the pyrrolinone-based analogs through Caco-2 cell monolayers.     

Expression of genes that contribute to proliferative and metastatic ability in breast cancer resected during various menstrual phases

BACKGROUND: Retrospective studies show significant improvements in survival among women who had breast cancer resected during the luteal phase of their menstrual cycle compared with the follicular phase. We hypothesised that tumour tissue would show cyclical changes in expression of genes whose products might contribute to metastatic potential. METHODS: We studied 32 premenopausal women with operable breast cancer. We assayed hormones to define more accurately the menstrual phase during which surgery was done. We used northern blot analysis of RNA from fresh-frozen tumour specimens to study the patterns of expression of genes for proteolytic enzymes (cysteine proteinase cathepsin L and aspartyl proteinase cathepsin D; matrix metalloproteinases MMP-9 and MMP-2), tissue inhibitors of metalloproteinases TIMP-1 and TIMP-2, and TP53. RESULTS: There was a significantly higher level of expression of RNA for cathepsin L, MMP-9, and TP53 (p=0.005, 0.03, 0.03, respectively) in tumours that were resected during the follicular and periovulatory phases of the menstrual cycle than at other times in the cycle. A similar but non-significant trend was seen for MMP-2 and cathepsin D. A non-significant trend in the opposite direction was seen for TIMP-1 and TIMP-2. INTERPRETATION: We found that tumour expression of genes that may contribute to proliferative capacity and metastatic potential can change in breast cancer during the course of the menstrual cycle. The finding could provide a molecular explanation for the reports of improved survival in some breast-cancer patients whose tumours were removed during the luteal phase of the menstrual cycle. Larger studies are required to extend our study, assess mechanisms of gene regulation, and verify any relevant influence in long-term survival.