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At least 1,045 records · Page 58Linked to original sources
PubMed2002

Chemotherapy with gemcitabine-containing regimens for locally recurrent or metastatic nasopharyngeal carcinoma.

BACKGROUND: Results from Phase II trials conducted in Asia have shown that gemcitabine alone (GEM) or with cisplatin (GC) is active among patients with metastatic or locally recurrent nasopharyngeal carcinoma (NPC). METHODS: At the Princess Margaret Hospital (PMH), Toronto, 32 patients with NPC were treated with GEM (n = 18) or GC (n = 14) from January 2000 to October 2001. Patients either received 1000 mg/m(2) GEM on Days 1, 8, and 15 every 28 days as a single agent, or with cisplatin (CG) given on day 2 at 70 mg/m(2). RESULTS: Most patients (91%) were of Southeast Asian ancestry and 29 (91%) had Type 2 (World Health Organization 1991 classification) nonkeratinizing histology. Sixteen of the GEM (89%) and five (36%) of the GC patients had received chemotherapy before entering the study. Median follow-up was 32 weeks (range, 2-97 weeks) for both groups. In the GEM group, there were five (28%) partial responses (PR) and one (6%) complete response (CR), giving an overall response rate of 34% (95% confidence interval [CI], 13.59). In the GC group, there were two (14%) CRs and seven PRs (50%), giving an overall response of 64% (95% CI, 35-87). Hematologic toxicity was dose limiting but uncomplicated. Nonhematologic toxicity included one patient with reversible reactivation of hepatitis, one with Grade 3 cisplatin-related sensory neuropathy, and three with cardiovascular events that were possibly related to chemotherapy. The median duration of response for the GEM and GC patients was 17 and 24 weeks and the 1-year survival rate was 48% (95% CI, 18-78) and 69% (95% CI, 40-99), respectively. Median survival has not been reached. CONCLUSIONS: Our study confirms that GEM is an active and tolerable drug for patients with NPC.

Adenocarcinoma↗
PubMed2003

Multicenter study of pegylated liposomal doxorubicin in patients with cutaneous T-cell lymphoma.

BACKGROUND: In single center studies and case reports, it was shown that pegylated liposomal doxorubicin (PEG-DOXO) was effective as second-line therapy for patients with cutaneous T-cell lymphoma (CTCL). The objective of this study was to evaluate the efficacy and toxicity of single-agent PEG-DOXO as second-line chemotherapy in patients with CTCL. METHODS: A retrospective, multicenter study was performed evaluating 34 patients (31 male patients and 3 female patients). Twenty-seven patients received PEG-DOXO 20 mg/m(2), 5 patients received PEG-DOXO 20-30 mg/m(2), and 2 patients received PEG-DOXO 40 mg/m(2). PEG-DOXO was administered intravenously every 2 weeks in 6 patients, every 2-3 weeks in 4 patients, and every 4 weeks in 23 patients. One patient received only a single course of PEG-DOXO. Outcomes were evaluated, and adverse effects were recorded. RESULTS: Thirty-four patients received at least 1 cycle of PEG-DOXO. Disease was classified as mycosis fungoides in 28 patients, mycosis fungoides with follicular mucinosis in 2 patients, small or medium-sized pleomorphic CTCL in 2 patients, Sèzary syndrome in 1 patient, and CD30 positive CTCL in 1 patient. Fifteen patients achieved a complete response (CR), including patients who achieved a CR and patients who achieved a CR defined by clinical criteria only with no biopsy (CRu), and 15 patients achieved a partial response (PR), resulting in a response rate (CRs, CRus, and PRs) of 88.2%. Two patients dropped out: one patient after a single PEG-DOXO infusion because of Grade 3 capillary leakage syndrome and one patient after two cycles because of a suicide attempt that was not related to treatment or to CTCL. All other patients received at least four cycles of PEG-DOXO. Overall survival was 17.8 months +/- 10.5 months (n = 33 patients), event-free survival was 12.0 months +/- 9.5 months, and disease-free survival was 13.3 +/- 10.5 months (n = 16 patients). Adverse effects were seen in 14 of 34 patients (41.2%); they were temporary and generally mild. Only 6 patients had Grade 3 or 4 adverse effects. CONCLUSIONS: This multicenter study provided evidence of high efficacy of PEG-DOXO monotherapy with a low rate of severe adverse effects compared with other chemotherapy protocols in patients with CTCL.

Adult↗
PubMed2003

K-ras mutation in tamoxifen-related endometrial polyps.

BACKGROUND: K-ras mutation is thought to occur at an early stage of neoplastic progression in the endometrium. The authors investigated mutations in codon 12 of K-ras in tamoxifen (TAM)-related endometrial polyps. METHODS: DNA was extracted from 11 frozen endometrial polyps from TAM-treated patients with breast carcinoma. Mutations were detected using the mutant allele-specific amplification method. The results subsequently were analyzed for correlations with immunohistochemical data that were obtained using antibodies against estrogen receptors (ERs; alpha and beta forms), progesterone receptors (PRs; A and B forms), and Ki-67. RESULTS: Mutations in codon 12 of K-ras were observed in 7 of 11 TAM-related endometrial polyps. Expression levels of ER-alpha and PR-B were high in the glandular epithelium and low in the stroma. PR-A expression was high in both the glandular epithelium and the stroma. In the glandular epithelium, expression of ER-beta appeared to be lower than expression of ER-alpha. The Ki-67 index in the glandular epithelium ranged from 2 to 38, whereas the index ranged from 0 to 4 in the stroma (P < 0.01). CONCLUSIONS: The incidence of mutations in codon 12 of K-ras in TAM-related endometrial polyps (64%) was greater than the incidence of these same mutations in sporadic endometrial hyperplasias (4.5-23%). High expression levels of ER-alpha, PR-A, and PR-B in the glandular epithelium were observed in all polyps, regardless of K-ras codon 12 mutation status and Ki-67 index. The authors' findings may support the hypothesis that the polyp-carcinoma sequence partly indicates the development of endometrial carcinoma in postmenopausal women who have been treated with TAM.

Aged↗
PubMed2006

Phase III study of PSC-833 (valspodar) in combination with vincristine, doxorubicin, and dexamethasone (valspodar/VAD) versus VAD alone in patients with recurring or refractory multiple myeloma (E1A95): a trial of the Eastern Cooperative Oncology Group.

BACKGROUND: Preliminary studies have shown valspodar (PSC-833: Novartis Pharmaceuticals, East Hanover, NJ) to be a potent inhibitor of multidrug resistance (MDR), one cause of resistance to chemotherapy. An international randomized control study (Phase III) evaluated the use of vincristine, doxorubicin, and dexamethasone (VAD) with (n = 46) and without (n = 48) valspodar in the treatment of patients with recurring or refractory multiple myeloma. METHODS: Patients with documented recurrence or refractory myeloma were stratified based on prior treatment exposure and creatinine and randomized. Because of interaction of valspodar with vincristine and doxorubicin, the doses of these drugs were reduced compared with the VAD-alone arm, and the doxorubicin was further reduced in the last 15 patients when given with valspodar based on pharmacokinetic and toxicity studies. RESULTS: There were no complete or near-complete responses. There were 29% partial responses (PRs) in the VAD-alone arm and 44% with valspodar (P = 0.2). Median progression-free survival was 7 months with VAD alone and 4.9 months with valspodar (P = 0.50). Subjective response was 19% with VAD alone and 17% with valspodar (P = 1.0). Median survival with VAD alone was 18.5 months and 15.3 with the addition of valspodar (P = 0.055). Toxicity of Grade 3 or greater was higher (P < 0.0001) in the valspodar arm (89%) compared with the VAD-alone arm (58%). The reduction of doxorubicin dose reduced toxicity but not significantly (P = 0.11). CONCLUSION: The addition of the MDR-modulating agent valspodar to VAD did not improve treatment outcome. Toxicity was increased in the valspodar-treated group compared with VAD alone.

Administration, Oral↗
PubMed2006

Superiority of prolonged low-dose azanucleoside administration? Results of 5-aza-2'-deoxycytidine retreatment in high-risk myelodysplasia patients.

BACKGROUND: The optimal treatment duration with decitabine (DAC) in patients with myelodysplastic syndromes (MDS) remains a matter of debate. Although at least 2 consolidating courses after best response usually are performed, the response to treatment after disease recurrence has not been systematically studied to date. METHODS: In the current study, the authors report on 22 of 108 patients with MDS (20%) treated with low-dose DAC in 3 Phase II trials who received DAC as retreatment at the time of disease recurrence. RESULTS: According to the International Prognostic Scoring System (IPSS) at the time of initial treatment, 5 of 22 patients (23%) had a score of intermediate-1 (Int-1), 4 patients (18%) had a score of Int-2, and 13 patients (59%) were scored as high-risk. Patients initially received a median of 6 courses of DAC (range, 2 courses-6 courses), which resulted in a complete remission (complete response [CR]) in 12 of the 22 patients (55%). Retreatment with DAC at the time of disease recurrence was initiated at a median of 11 months (range, 3 mos-27 mos) after the last course of initial treatment. With regard to DAC retreatment, patients received a median of 3 courses (range, 1 courses-6 courses), with 10 of 22 patients (45%) responding (1 with a CR and 2 with partial remissions [partial response (PR)]; all 3 patients achieved a CR at the time of initial treatment) and 7 patients demonstrating a hematologic improvement (HI) (at the time of initial treatment there were 2 CRs, 4 PRs, and 1 HI). Twelve of the 22 patients (55%) did not demonstrate any objective responses to retreatment, including 4 patients with primary resistance to the first course of retreatment. The median survival of all patients from the initiation of the first DAC course was 27.5 months (range, 15 mos-50+ mos). The median survival of 43 patients who also had achieved a response to the initial treatment with DAC but who received best supportive care (n = 33 patients) or induction chemotherapy (n = 10 patients) was 18 months (range, 5 mos-72 mos). Second responders to DAC retreatment were found less frequently in the IPSS high-risk group compared with nonresponders (40% vs. 83%). Age, French-American-British classification subtype, serum lactate dehydrogenase level at retreatment, and previous response to DAC were not found to strongly differ between the groups; however, the subgroups were too small to perform a statistical analysis. CONCLUSIONS: Retreatment with DAC was found to result in objective responses in 45% of previously DAC-responsive patients. However, the quality and duration of the second disease remissions were found to be inferior. Therefore, DAC-responsive patients might derive more clinical benefit from continuation of the initial treatment.

Aged↗
PubMed2006

Bevacizumab combination therapy in recurrent, platinum-refractory, epithelial ovarian carcinoma: A retrospective analysis.

BACKGROUND: The study was undertaken to determine the safety and efficacy of the monoclonal, antivascular endothelial growth factor antibody bevacizumab in combination with cytotoxic chemotherapy for women with platinum-refractory ovarian cancer. METHODS: A retrospective analysis of women who received bevacizumab in combination with a cytotoxic agent was performed. Response was determined by measurable disease or assessment of serial cancer antigen (CA) 125 measurements. RESULTS: Twenty-three patients were identified. The patients were heavily pretreated with a median of 7 prior regimens including a median of 3 prior platinum regimens. The combination regimen included cyclophosphamide in 15 (65%), 5-fluorouracil (5-FU) in 6 (26%), docetaxel in 1 (4%), and gemcitibine/liposomal doxorubicin in 1 (4%). Two (9%) women developed chylous ascites during treatment. CTC Grade 4-5 toxicities occurred in 4 (17%) subjects. Gastrointestinal perforation occurred in 2 (9%) patients. Measurable disease was present in 22. The overall best response rate was 35% and all 8 were partial responses (PRs). Stable disease was found in a further 10 (44%) women, whereas progressive disease was observed in 5 (22%). The median time to progression was 5.6 months in patients with a PR and 2.3 months in subjects with stable disease. Three (13%) women experienced a progression-free interval (PFI) of >6 months. At last follow-up, 8 (35%) subjects had died of disease, whereas 15 (65%) women were alive with disease. CONCLUSIONS: Combination bevacizumab therapy demonstrated activity in heavily pretreated women with ovarian cancer. Gastrointestinal perforations were identified in 9%. Despite the toxicity of the regimen, prospective studies, particularly in less heavily pretreated patients, are warranted.

Adult↗
PubMed2006

Phase II study of oxaliplatin in children with recurrent or refractory medulloblastoma, supratentorial primitive neuroectodermal tumors, and atypical teratoid rhabdoid tumors: a pediatric brain tumor consortium study.

BACKGROUND: An open-label Phase II study of oxaliplatin was conducted to evaluate its safety and efficacy in children with recurrent or refractory medulloblastoma (MB), supratentorial primitive neuroectodermal tumors (SPNET), and atypical teratoid rhabdoid tumor (ATRT). METHODS: Patients were stratified as follows: stratum IA, first recurrence MB with measurable disease; IB, recurrent MB with only cerebral spinal fluid (CSF) positivity or linear leptomeningeal disease (LLD); IC, MB > or =second recurrence; stratum II, recurrent SPNET; stratum III, recurrent ATRT. Patients received oxaliplatin, 130 mg/m(2) intravenously over 2 hours every 3 weeks. The primary objective was to estimate the sustained response rate in stratum 1A. Plasma ultrafiltrate platinum pharmacokinetics were evaluated. RESULTS: A total of 43 patients with a median age of 8.5 years (range, 0.6-18.9 years) were enrolled. In stratum 1A, 2 of 15 had partial responses (PRs, 1 sustained PR). No responses were observed in other strata. The most frequent Grade 3 and 4 toxicities included thrombocytopenia (25.6%), neutropenia (16.3%), leukopenia (12%), increase in serum alanine transaminase (ALT) (7%), vomiting (4.7%), and sensory neuropathy (4.7%). No severe ototoxicity or nephrotoxicity was reported. Plasma ultrafiltrate platinum pharmacokinetic parameters were similar to adults, with a median clearance of 12.2 L/hr (range, 4.4-30 L/hr) and median area under the curve (AUC(0-infinity)) of 9.4 microg/mL/hr (range, 6.2-13.9 microg/mL/hr). CONCLUSIONS: Oxaliplatin was well tolerated in children but has limited activity in children with recurrent CNS embryonal tumors previously treated with platinum compounds.

Adolescent↗
PubMed2005

Photoreceptor differentiation in Drosophila: from immature neurons to functional photoreceptors.

How a pool of equipotent cells acquires a multitude of distinct fates is a major question in developmental biology. The study of photoreceptor (PR) cell differentiation in Drosophila has been used to address this question. PR differentiation is a process that extends over a period of 5 days: It begins in the larval eye imaginal disc when PRs are recruited and commit to particular PR fates, and it culminates in the pupal eye disc with the morphogenesis of the rhabdomeres and the initiation of rhodopsin expression. Several models for PR specification agree that the Ras and Notch signaling pathways are important for the specification of different PR subtypes (Freeman [1997] Development 124:261-270; Cooper and Bray [2000] Curr. Biol. 10:1507-1510; Tomlinson and Struhl [2001] Mol. Cell. 7:487-495). In the first part of this review, we briefly describe the different signaling pathways and transcription factors required for the specification and differentiation of the different PR subtypes in the larval eye disc. In the second part, we review the roles of several transcription factors, which are required for the terminal photoreceptor differentiation and rhodopsin expression.

Animals↗
PubMed1998

Effect of interferon therapy on hepatitis C virus RNA in whole blood, plasma, and peripheral blood mononuclear cells.

Fifty-two patients with chronic hepatitis C virus (HCV) infection were treated with standard doses of interferon alfa-2b. During treatment, HCV RNA detection was studied in samples of whole blood (WB), plasma (Pl), and peripheral blood mononuclear cells (PBMCs). Individuals were classified as sustained responders (SRs), complete responders with relapse (CRs), partial responders (PRs), or nonresponders (NRs) according to normalization of serum alanine transaminase (ALT) during treatment and follow-up. Before treatment, 100% of WB samples and more than 95% of Pl and PBMC samples were positive for HCV RNA. During treatment, there was progressive clearance of HCV RNA from Pl and PBMCs in SRs and CRs, but CRs had significantly more positive WB samples during and following treatment (P <.0001). At 6 months, only 10% of CR patients were positive by Pl assay, but 50% were positive by WB assay (P <.01). In the PR group, all WB samples remained positive throughout treatment, although 25% to 40% of PBMC and Pl samples became negative for HCV RNA during the first 2 months of therapy (WB > Pl or PBMC; P < .001). However, at later times during treatment most Pl and PBMC samples in the PR group were positive. Samples from the NR group showed no clearance of HCV RNA from WB, Pl, or PBMC fractions. These data document the increased sensitivity of WB assays for detecting HCV RNA in the peripheral blood of patients during interferon therapy. Furthermore, our findings suggest that WB analysis of HCV RNA may be a useful parameter to monitor in determining the end point of interferon therapy.

Adult↗
PubMed2002

Gender-dependent hypoxic tolerance mediated via gender-specific mechanisms.

Primary hypoxic tolerance and preconditioning are gender dependent and modulated in females during the estrus cycle. The underlying mechanisms, however, remain to be determined. mRNA of estrogen receptor-alpha (EAR), progesterone receptor (PR), and adenosine receptor subtypes A1 and A3 (A1R and A3R) were investigated with reverse transcriptase-PCR in hippocampi from control male and female mice and animals treated in vivo with a single i.p. injection of 20 mg/kg body weight 3-nitropropionate (3NP) 1 or 24 hr prior to preparation. Results were analyzed relative to expression in hippocampi from untreated males. mRNA levels of EAR and A1R were alike in males and females and unaltered by preconditioning with 3NP. In contrast, PR mRNA levels were alike in males and females during proestrus but lower during estrus and diestrus (85% +/- 15%, P < 0.05; and 80% +/- 10%, P < 0.05, respectively). Upon preconditioning, PR mRNA decreased to 67% +/- 19% (P < 0.05) and 56% +/- 13% (P < 0.05) during proestrus and diestrus, respectively, but was unaltered during estrus and in males. On preconditioning, A3R mRNA decreased from 115% +/- 16% to 86% +/- 29% (P < 0.05) during diestrus but remained at the control level during proestrus and estrus. With low-level expression of PRs, as achieved upon preconditioning, hypoxic tolerance is increased. Other than in males, adenosine A3 receptors are not up-regulated upon preconditioning in females. Thus, not only is net hypoxic tolerance gender dependent but mechanisms conferring hypoxic tolerance are gender specific.

Adaptation, Physiological↗
PubMed2006

Adductor T and H reflexes in humans.

In the belief that changes in the adductor reflex (AR) may be helpful in evaluating lumbar root and plexus lesions, expression of the AR was studied in 43 healthy human subjects. ARs elicited with an electronic reflex hammer were recorded from the inner side of the proximal thigh using needle and surface electrodes, and patellar reflexes (PRs) were recorded simultaneously. These reflexes were obtained by tapping the ipsilateral medial aspect of the knee, the contralateral patellar tendon, the ipsilateral and contralateral anterior superior iliac spines, and the Achilles tendon. The H reflex of the obturator nerve was also evaluated in 17 cases. ARs were evoked consistently by tapping the ipsilateral medial aspect of the knee and by contralateral patellar tap, and by tapping ipsilateral and contralateral anterior superior iliac spines when a needle recording electrode was used. Sometimes an Achilles tendon tap also elicited the AR ipsilaterally. By contrast, the PR could only be elicited by a tap to the ipsilateral patellar tendon. ARs have somewhat different features than other well-known tendon reflexes such as the PR and are recorded consistently when a needle electrode is used, being elicited from both distal and proximal areas of the legs by tapping the Achilles tendon or anterior superior iliac spines unilaterally or bilaterally. Their role in evaluating lumbar root disease and monitoring adductor spasticity merits investigation.

Achilles Tendon↗
PubMed1990

Steroid receptors and Ki-67 reactivity in ovarian cancer and in normal ovary: correlation with DNA flow cytometry, biochemical receptor assay, and patient survival.

Steroid hormone receptors and reactivity for Ki-67 proliferation antigen were studied immunohistochemically in non-neoplastic post-menopausal human ovary and in 29 ovarian cancers. In the normal ovary, oestrogen (OR) and progesterone receptors (PR) were found in the surface epithelium and PR also in the ovarian stroma. Of the ovarian carcinomas 38 per cent (11/29) contained OR and 69 per cent (20/29) PR. Oestrogen receptor expression was confined to malignant cells, whereas PR was present occasionally also in the tumour stroma. In most cases, ORs and PRs were found only in a small population of cancer cells. The growth fractions assessed by the percentage of Ki-67-positive cells ranged from 1 to 59 per cent (mean 19.7 per cent) with a significant correlation (r = 0.74, P less than 0.0001) to S-phase values (mean 12.9 per cent, range 1.2-25.9 per cent) determined by DNA flow cytometry. High Ki-67 (greater than or equal to 15 per cent) and S-phase levels (greater than or equal to 7.5 per cent) correlated with advanced disease stage and patient survival but not with OR or PR status, suggesting that hormone-receptor pathways and proliferative activity are not related in ovarian cancer. Positive OR status, however, identified patients with a better prognosis (P = 0.02), suggesting a correlation with tumour differentiation. The independent prognostic value of oestrogen receptor status and Ki-67 remains to be determined, but the prognostic impact of Ki-67 was comparable to that of S-phase values.

Adult↗
PubMed2001

A new family of yeast vectors and S288C-derived strains for the systematic analysis of gene function.

The yeast genome has been shown to contain a significant number of gene families with more than three members. In order to study these families it is often necessary to generate strains carrying deletions of all members of the family, which can require a wide range of auxotrophic markers. To facilitate such studies, we have generated yeast strains containing deletions of a selection of nutritional marker genes (ade2, ade4, ade8, met3 and met14). We have also cloned the corresponding cognate genes, allowing their use in PCR-based gene disruptions. Two new pRS family Saccharomyces cerevisiae-Escherichia coli shuttle vectors containing ADE8 (one low-copy, pRS4110, and one high-copy, pRS4210) have been produced for use in conjunction with the new strains. A system for easier synthetic lethal screening using one of these new markers is also presented. The ADE8 and HIS3 genes have been cloned together on a high-copy vector (pRS4213), providing a plasmid for red-white colour screening in the ade2 Delta 0 ade8 Delta 0 strains we have generated. In contrast to some conventional systems, this plasmid allows for screening using gene libraries constructed in URA3 plasmids.

Base Sequence↗
PubMed1997

cAMP-dependent transactivation involving the homeodomain protein Pbx1.

Pbx1 is a DNA-binding homeodomain protein originally discovered in the t(1;19) chromosomal translocation associated with pediatric pre-B acute lymphoblastic leukemia. Previously we reported a cAMP-regulatory sequence (CRS1) in the promoter region of the bovine CYP17 gene encoding steroid 17alpha-hydroxylase cytochrome P450 (P450c17) to be the first endogenous Pbx1 binding site and that overexpression of Pbx1 in mouse adrenal Y1 tumor cells enhances cAMP-dependent transcription mediated by this element. Here we report further characterization of Pbx1 binding site in CRS1 and role of Pbx1 in cAMP-dependent, CRS1-mediated transcription. By gel shift analysis utilizing nuclear extracts from Y1 cells, a high-affinity Pbx-binding sequence has been determined to be TTGAT(T/G)GA(T/C)A which represents the 5' portion of CRS1. An artificial Pbx-binding sequence (PRS), previously determined by random PCR analysis, is similar to the Pbx1-binding sequence in CRS1 and by both gel shift analysis and transfection studies shows characteristics very similar to CRS1. Upon overexpression, Pbx1 is found capable of enhancing CRS1-mediated transcription in both steroidogenic (Y1, JEG3) and nonsteroidogenic (HepG2 and S194) cells when coexpressed with the catalytic subunit of cAMP-dependent protein kinase A. Thus even though Pbx1 has been found to be involved only in cAMP-dependent transcription of a gene involved in steroidogenesis (CYP17), Pbx1 is capable of participating in cAMP-dependent transcription of target genes without complex formation with steroidogenic tissue-specific nuclear factors.

Adrenal Glands↗
PubMed2002

The murine endogenous retrovirus MIA14 encodes an active aspartic proteinase that is functionally similar to proteinases from D-type retroviruses.

Murine intracisternal A-type particles (IAPs) are endogenous retroviruses showing sequence homologies to B/D- and avian C-type retroviruses and a gene expression strategy similar to that of D-type retroviruses. These viruses form immature particles in the endoplasmic reticulum and do not release extracellular virions, but are competent for retrotransposition within the virus-producing cell. It had been assumed that lack of polyprotein processing and maturation is due to a defect in the viral proteinase (PR), but recent experiments have shown that polyprotein processing occurs when assembly of the mouse IAP MIA14 is artificially directed to the plasma membrane. We have expressed and purified recombinant MIA14 PR and show that it undergoes N- and C-terminal autoprocessing at defined sites. Using peptide cleavage and inhibition assays and in vitro cleavage of recombinant HIV-1 and MIA14 Gag polyproteins, we show that MIA14 PR is a catalytically competent enzyme comparable in its efficiency to PRs from type D exogenous retroviruses. MIA14 PR is related to the PR of Mason-Pfizer monkey virus both functionally and with respect to its expression strategy, and is distinct from HIV-1 PR with respect to substrate specificity and catalytic efficiency. These findings reveal a functional and possibly evolutionary relationship between MIA14 and D-type retroviruses and imply that a functional PR may be relevant for intracellular retrotransposition even in the case of an endogenous retrovirus that does not produce extracellular virus.

Amino Acid Sequence↗
PubMed1995

Characterization of SFP2, a putative sulfate permease gene of Saccharomyces cerevisiae.

The SFP2 gene of Saccharomyces cerevisiae has been characterized. The deduced amino acid sequence contained twelve highly hydrophobic domains and showed 50, 47, 44 and 48% homologies to Neurospora crassa sulfate permease II (CYS14), soybean GMAK170 nodulin, human colon mucosa protein (DRA) and a putative open reading frame (ORF) downstream of Escherichia coli prs (phosphoribosyl pyrophosphatate synthetase) gene, respectively, in the aligned regions. Cells lacking SFP2 were viable and displayed no obvious decrease in their growth rate. Southern blot analysis revealed that SFP2 exists as a single copy in haploid genome. Northern blot analysis showed that SFP2 produced a 2.8-kb transcript which was highly expressed under sulfur derepressing condition. SFP2 mRNA was found to turn over with a half-life of approximately 15 min, which may contribute to the regulation of sulfate permease function, and reached its maximal level in about 22 h after depression.

Amino Acid Sequence↗
PubMed1997

A randomized trial of paracentesis plus intraperitoneal tumor necrosis factor-alpha versus paracentesis alone in patients with symptomatic ascites from recurrent ovarian carcinoma.

PURPOSE: Previous phase I and II studies of intraperitoneal recombinant human tumor necrosis factor-alpha (rhTNF-alpha) suggested a high degree of efficacy in reducing or eliminating ascitic fluid. To more accurately determine the efficacy of this agent, the role of paracentesis versus paracentesis plus intraperitoneal rhTNF-alpha was studied in a randomized trial. PATIENTS AND METHODS: Thirty-nine patients with symptomatic ascites with a volume of > 1000 ml from recurrent epithelial ovarian carcinoma or primary peritoneal carcinoma, which was refractory to standard therapy, were randomized either to receive 0.06 mg/m2 rhTNF-alpha (Knoll, Canada) (the dose determined optimal from phase I and II studies) intraperitoneally after drainage of fluid or to receive drainage alone. A maximum of three treatments were given at weekly intervals. Eighteen patients were randomized to receive rhTNF-alpha. RESULTS: None of 18 evaluable rhTNF-alpha patients had either a complete response (CR) (no clinical evidence of ascites and < 400 ml of fluid on ultrasound) or a partial response (PR) (asymptomatic ascites and < or = 1000 ml of fluid ultrasound). There were no CRs or PRs in the 17 evaluable patients who received drainage alone. The intraperitoneal infusion of rhTNF-alpha was generally well tolerated. Moderate to severe toxicity consisted of pain/discomfort in 42.1%, fever/chills in 36.9%, nausea/vomiting in 10.5%, edema in 10.5%, and hypotension in 5.3% of patients receiving rhTNF-alpha. CONCLUSION: rhTNF-alpha, as given in this study, was not effective in preventing recurrence of ascites in this patient population.

Ascites↗
PubMed1994

Genomic and non-genomic actions of progesterone in the control of female hamster sexual behavior.

Progesterone (P) in both the ventromedial hypothalamus (VMH) and the ventral tegmental area (VTA) is necessary to facilitate sexual receptivity in estrogen-primed hamsters. The mechanism of P may be different in the VMH and VTA, as there are many intracellular progestin receptors (PR) in the VMH but few in the VTA. Progesterone conjugated to bovine serum albumin (P-3-BSA) does not bind well to intracellular PR or permeate the surface of neuronal membranes. However, VTA application of P-3-BSA rapidly increases sexual receptivity if P has been applied earlier to the VMH. P-3-BSA is ineffective when applied to the VMH. The membrane-limited effect of P may be related to the ability of some progestins to modulate the GABAA-benzodiazepine receptor complex (GBRC). We have found that infusions of a GABAA agonist, muscimol, into the VTA enhance and a GABAA antagonist, bicuculline, inhibit receptivity. Because P itself is not highly effective at the GBRC, and since the most potent modulators of the GBRC, the 5 alpha-reduced progestins, do not bind well to PRs, progestin metabolites were applied to the VTA. Only the potent GBRC modulators facilitated sexual receptivity when applied to the VTA concurrent with P to the VMH. The reverse treatment, with a progestin metabolite implanted into the VMH, was ineffective. VTA infusions of an inhibitor of 5 alpha-reductase also attenuated behavioral estrus in hamsters.(ABSTRACT TRUNCATED AT 250 WORDS)

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗