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At least 559 records · Page 31Linked to original sources
PubMed1981

Follicular phase treatment of luteal phase dysfunction.

Previously, we demonstrated that selective suppression of serum follicle-stimulating hormone (FSH) in monkeys treated with charcoal-extracted porcine follicular fluid (pFF) in the early follicular phase induced luteal defects resembling those which occur spontaneously in women and monkeys. Here, we assessed whether luteal phase defects arising in association with induced FSH deficiencies during the early follicular phase can be treated by early FSH therapy. Rhesus monkeys were treated with pFF and human menopausal gonadotropin (hMG) (FSH:luteinizing hormone [LH], 3:1) on cycle days 1 to 3 or day 4, respectively. Daily femoral blood samples were analyzed for LH, FSH, and estradiol by radioimmunoassay. In the monkeys treated with the pFF-hMG combination, a single ovulation was uniformly noted at laparoscopy, and initial luteal phase elevations in serum progesterone levels were nearer those of normal ovulatory cycles than after pFF alone. These results suggest that FSH/LH treatment in the early follicular phase compensated, in part, for the pFF-induced deficiency in endogenous FSH levels.

Animals↗
PubMed1993

Differences in adverse drug reactions in phase III and phase IV of the drug evaluation process.

The study of medications in routine use is called "Phase IV" of the drug evaluation process. Information gathered about drugs in Phases I through III does not provide a sufficient basis for final conclusions about the clinical value of medications after marketing. Changes in preferred indications, patient characteristics (e.g., multimorbidity), treatment mode, or treatment setting in routine as compared to controlled scientific studies lead to changes in causes, incidence, prevalence, predictability, meaning, consequences, and cost-benefit ratios of adverse drug reactions (ADRs). Rare but serious ADRs are only one aspect of postmarketing surveillance; other questions are at least as important. In contrast to Phase III, which has a single study design--the controlled, randomized, double-blind study--Phase IV requires different designs for each of the many different questions. Established methodologies include spontaneous reports, stimulated spontaneous reports, comprehensive observation studies, Phase IV intervention studies, case control studies, prescription event record linkage, and data bank comparisons.

Clinical Trials, Phase III as Topic↗
PubMed1996

BCR/ABL-negative primitive progenitors suitable for transplantation can be selected from the marrow of most early-chronic phase but not accelerated-phase chronic myelogenous leukemia patients.

We have previously reported that selection of marrow cells on the basis of the CD34+HLA-DR- phenotype (34+DR-) may result in the recovery of Philadelphia chromosome (Ph)- and BCR/ABL-negative long-term culture-initiating cells (LTC-IC) in selected patients with chronic myelogenous leukemia (CML). We now present data on 27 early chronic-phase ([ECP] studied within 1 year after diagnosis) and 23 advanced-phase ([AP] late chronic phase, ie, studied >1 year from diagnosis, or accelerated phase) CML patients. Fluorescence-activated call-sorting (FACS)-selected 34+DR- and 34+DR+ cells were subjected to reverse transcriptase-polymerase chain reaction and fluorescence in situ hybridization. These cells were also cultured in long-term bone marrow culture for 1 to 5 weeks to examine the number of LTC-IC and the presence or absence of the BCR/ABL gene rearrangement in progeny of primitive LTC-IC. The number of 34+DR- cells and LTC-IC present in ECP CML marrow was similar to that in normal (NL) marrow, whereas the numbers were reduced in AP CML. Furthermore, 34+DR- cells from more than 80% of ECP CML patients were BCR/ABL mRNA- and Ph-negative and contained only BCR/ABL mRNA- and Ph-negative LTC-IC, whereas 34+DR- cells and LTC-IC from less than 40% of AP CML patients were BCR/ABL mRNA- and Ph-negative. In contrast to NL marrow, 34+DR+ cells from CML marrow, irrespective of clinical stage, contained large numbers of LTC-IC. CML 34+DR+ cells and LTC-IC were BCR/ABL mRNA- and Ph-positive. Since these studies suggested that a population of primitive progenitors that are Ph-negative can be selected from steady-state marrow in some ECP CML patients, we determined if similar results could be obtained when large quantities of marrow sufficient for transplantation are processed. We demonstrate that 1 to 3 x 10(5) BCR/ABL mRNA-negative 34+DR- cells/kg recipient body weight, containing only BCR/ABL mRNA-negative LTC-IC, can be obtained from a 2- to 2.5-L marrow collection by sequential COBE Spectra apheresis (COBE BCT, Lakewood, CO), CD34+ enrichment using the CEPRATE SC Cell-Concentrator (CellPro, Bothell, WA), and high-speed FACS. Thus, large-scale selection of a BCR/ABL mRNA- and Ph-negative 34+DR- cell population is possible in a fraction of chronic-phase CML patients, in whom these cells could be used to reconstitute the hematopoietic compartment following autologous transplantation.

Antigens, CD34↗
PubMed2005

Phase behavior of amorphous molecular dispersions II: Role of hydrogen bonding in solid solubility and phase separation kinetics.

PURPOSE: To determine the factors influencing "solid solubility" and phase separation kinetics of drugs from amorphous solid dispersions. METHODS: Solid dispersions of griseofulvin-poly(vinyl pyrrolidone) (PVP) and indoprofen-PVP were prepared using solvent evaporation technique. Dispersions demonstrating single Tg were exposed to 40 degrees C/69% RH for 90 days. Drug solid solubility in the polymer and phase separation rates were determined from changes in Tg of solid dispersions. FTIR spectroscopy and XRD were used to characterize drug-polymer interactions and drug crystallinity, respectively. RESULTS: Freshly prepared solid dispersion of up to 30% w/w griseofulvin and indoprofen were molecularly miscible with PVP. Hydrogen bonding was evident in indoprofen-PVP, but not in griseofulvin-PVP dispersions. When exposed to 40 degrees C/69% RH, griseofulvin phase separated completely, whereas the solid solubility of indoprofen was determined as 13% w/w. The first-order rate constants of phase separation for 10%. 20%, and 30% w/w griseofulvin dispersions were estimated as 4.66, 5.19, and 12.50 (x10(2)) [day(-1)], and those of 20% and 30% w/w indoprofen dispersions were 0.62 and 1.25 (x10(2)) [day(-1)], respectively. CONCLUSIONS: Solid solubility of griseofulvin and indoprofen in PVP is approximately 0% w/w and approximately 13% w/w, respectively. Drug-polymer hydrogen bonding in indoprofen-PVP dispersions favors solid solubility. Phase separation rate of drug from the solid dispersions depends on the initial drug content and the nature of drug-polymer interactions.

Hot Temperature↗
PubMed1993

Fission yeast cut5+, required for S phase onset and M phase restraint, is identical to the radiation-damage repair gene rad4+.

Fission yeast cut5 mutants cause cytokinesis in the absence of normal nuclear division. We show here that cut5+ is required for both the onset of S phase and the restraint of M phase before the completion of S phase. The primary defects in cut5 mutants occur prior to S phase, but cells suffer lethal damage during M phase. Mitosis and cytokinesis occur in the presence of hydroxyurea or in the double mutant cdc10-cut5 (the cdc10 mutation alone blocks progression from G1 to S). Gene cloning shows that cut5+ is identical to the fission yeast rad4+ gene, which is similar to human XRCC1. The rad4+/cut5+ gene is unique in its positive role for replication/repair and in its negative role for mitosis/cytokinesis. We propose a single/twin chromatid marking model for rad4+/cut5+ function in cell cycle control.

Amino Acid Sequence↗
PubMed2006

Dependence of chymosin and pepsin partition coefficient with phase volume and polymer pausidispersity in polyethyleneglycol-phosphate aqueous two-phase system.

The influence of the phase volume ratio and polymer pausidispersity on chymosin and pepsin partition in polyethylenglycol-phosphate aqueous two-phase systems was studied. Both proteins showed a high affinity for the polyethylenglycol rich phase with a partition coefficient from 20 to 100 for chymosin and from 20 to 180 for pepsin, when the polyethyleneglycol molecular mass in the system varied between 1450 and 8000. The partition coefficient of chymosin was not affected by the volume phase ratio, while the pepsin coefficient showed a significant decrease in its partition coefficient with the increase in the top/bottom phase volume ratio.

Chemical Fractionation↗
PubMed1994

Effects of menstrual phase on intake of nicotine, caffeine, and alcohol and nonprescribed drugs in women with late luteal phase dysphoric disorder.

To investigate the possibility that cigarette smoking and other drug use are affected by menstrual phase in smokers with Late Luteal Phase Dysphoric Disorder (LLPDD), we examined daily diaries rating menstrual symptomatology, smoking, alcohol and nonprescription drug use, and caffeine intake in nine female smokers meeting criteria for LLPDD. Menstrual symptomatology peaked during the premenstrual phase. Smoking, alcohol, and nonprescription drug intake were increased during menses; caffeine intake was unaffected by phase. No systematic intrasubject correlation between symptomatology and smoking was detected. It was concluded that in women with LLPDD, smoking and alcohol and nonprescription drug intake appear to vary as a function of menstrual phase. The lack of intrasubject correlations between symptomatology and intake, and the failure of peak intake to coincide with peak symptomatology, however, indicate that these effects cannot be explained simply as "self-medication" of acute episodes of dysphoric mood.

Adult↗
PubMed1998

Hypoxia induces p53 accumulation in the S-phase and accumulation of hypophosphorylated retinoblastoma protein in all cell cycle phases of human melanoma cells.

Hypoxia has been shown to induce accumulation of p53 and of hypophosphorylated retinoblastoma protein (pRb) in tumour cells. In this study, the cell cycle dependence of p53 accumulation and pRb hypophosphorylation in four human melanoma cell lines that are wild type for p53 was investigated using two-parameter flow cytometry measurements of p53 or pRb protein content and DNA content. The hypoxia-induced increase in p53 protein was higher in S-phase than in G1 and G2 phases in all cell lines. The accumulation of p53 in S-phase during hypoxia was not related to hypoxia-induced apoptosis or substantial cell cycle specific cell inactivation during the first 24 h of reoxygenation. pRb was hypophosphorylated in all cell cycle phases by hypoxia treatment. The results did not support a direct link between p53 and pRb during hypoxia because p53 was induced in a cell cycle-specific manner, whereas no cell cycle-dependent differences in pRb hypophosphorylation were detected. Only a fraction of the cell populations (0.60+/-0.10) showed hypophosphorylated pRb. Thus, pRb is probably not the only mediator of the hypoxia-induced cell cycle block seen in all cells and all cell cycle phases. Moreover, the cell cycle-dependent induction of p53 by hypoxia suggests that the primary function of p53 accumulation during hypoxia is other than to arrest the cells.

Apoptosis↗
PubMed1997

Comparison of patient characteristics and outcome between a single-institution phase II trial and a cooperative-group phase II trial with identical eligibility in metastatic melanoma.

Differences in overall survival and response rates are often noted when promising single-institution phase II treatment regimens are evaluated in a cooperative group setting. One reason for this discrepancy may be the differences in patient characteristics at the time of registration. In the metastatic melanoma literature, the prognostic factors for survival that are most frequently identified are the number of metastatic sites, visceral involvement, performance status, liver involvement, and possibly the disease-free interval and gender. A prognostic factor for response appears to be sites of involvement. A comparison of patient characteristics and outcome was conducted for patients entered in similar phase II melanoma trials at a single institution versus those in a cooperative group. Sixty-four patients at Wayne State University (WSU) were compared with 96 patients who had nearly identical eligibility criteria and were registered in the Southwest Oncology Group (SWOG). All patients were receiving comparable phase II treatments for metastatic melanoma. Southwest Oncology Group patients were significantly older (p < 0.001), had worse performance status (p = 0.03), had more visceral involvement (p = 0.001), and were more likely to have two or more metastatic sites (p = 0.02). No significant differences in gender (p = 0.55), absence or presence of liver involvement (p = 0.12), or disease-free interval were noted. These disparities, despite similar eligibility, may partly explain the observed differences in survival (WSU median = 10 months, SWOG median = 7 months; p = 0.13) and response rates (WSU = 31%, SWOG = 15%; p = 0.02) between the two groups of patients. Investigators should report these important patient characteristics in treatment reports. These differences highlight the difficulty in comparing single-institution and cooperative-group phase II trials, even with comparable patient eligibility. This serves to emphasize the need for well-designed phase III trials when comparing treatment approaches and stratification for the prognostic factors identified.

Adult↗
PubMed1998

Roles for ORC in M phase and S phase.

The origin recognition complex (ORC), a six-subunit protein, functions as the replication initiator in the yeast Saccharomyces cerevisiae. Initiation depends on the assembly of the prereplication complex in late M phase and activation in S phase. One subunit of ORC, Orc5p, was required at G1/S and in early M phase. Asynchronous cells with a temperature-sensitive orc5-1 allele arrested in early M phase. In contrast, cells that were first synchronized in M phase, shifted to the restrictive temperature, and then released from the block arrested at the G1/S boundary. The G1/S arrest phenotype could not be suppressed by introducing wild-type Orc5p during G1. Although all orc2 and orc5 mutations were recessive in the conventional sense, this dominant phenotype was shared with other orc5 alleles and an orc2 allele. The dominant inhibition to cell-cycle progression exhibited by the orc mutants was restricted to the nucleus, suggesting that chromosomes with mutant ORC complexes were capable of sending a signal that blocked initiation on chromosomes containing functional origins.

CDC28 Protein Kinase, S cerevisiae↗
PubMed2006

The products of the herpes simplex virus type 1 immediate-early US1/US1.5 genes downregulate levels of S-phase-specific cyclins and facilitate virus replication in S-phase Vero cells.

Herpes simplex virus type 1 ICP22-/U(S)1.5- mutants initiate viral gene expression in all cells; however, in most cell types, the replication process stalls due to an inability to express gamma2 late proteins. Although the function of ICP22/U(S)1.5 has not been established, it has been suggested that these proteins activate, induce, or repress the activity of cellular proteins during infection. In this study, we hypothesized that cell cycle-associated proteins are targets of ICP22/U(S)1.5. For this purpose, we first isolated and characterized an ICP22-/U(S)1.5- mutant virus, 22/n199. Like other ICP22-/U(S)1.5- mutants, 22/n199 replicates in a cell-type-specific manner and fails to induce efficient gamma2 late gene expression in restrictive cells. Although synchronization of restrictive human embryonic lung cells in each phase of the cell cycle did not overcome the growth restrictions of 22/n199, synchronization of permissive Vero cells in S phase rendered them less able to support 22/n199 plaque formation and replication. Consistent with this finding, expression of cellular S-phase cyclins was altered in an ICP22/U(S)1.5-dependent manner specifically when S-phase Vero cells were infected. Collectively, these observations support the notion that ICP22/U(S)1.5 deregulates the cell cycle upon infection of S-phase permissive cells by altering expression of key cell cycle regulatory proteins either directly or indirectly.

Animals↗
PubMed1993

Serum and acute phase protein modulation of the effector phase of lymphokine-activated killer cells.

An understanding of the role that immunomodulatory factors play in the effector phase of lymphokine-activated killer (LAK) activity is essential for the development of biologic response modifiers for use in the treatment of advanced carcinoma. Fifteen head and neck cancer patients were studied. Single-donor killer cells activated by recombinant interleukin-2 (10 U/mL) and induced in either a complete medium or complete medium plus a 10% autologous serum solution were used. Effector phase solutions of 25% autologous serum were used in chromium 51 release assays to determine sera immunomodulation of LAK cell cytotoxicity. Both K562 and squamous carcinoma (MDA686-Ln) tumor cell lines were tested. Significant effector phase inhibition (EPI) of cytotoxicity occurred in 40% of studied patients. Seventy percent of patients with stage III or IV or recurrent disease exhibited EPI, whereas only 20% of patients with stage I or II disease and 30% of controls did so. EPI of cancer patient serum correlated directly with alpha 1-antitrypsin, alpha 1-acid glycoprotein, and C-reactive protein (CRP) levels (MDA686-Ln targets) (r = 0.6, 0.7, and 0.6, respectively) (P < .02). Neither EPI against K562 targets nor EPI in control patients correlated with acute phase protein levels. These findings suggest that advances in in vivo immunomodulatory therapy will be dependent upon further elucidation of serologic inhibition of the effector phase of the LAK cell phenomenon. The relationship between LAK cell recognition and EPI requires further investigation.

Acute-Phase Proteins↗
PubMed2004

Quantitative phase-contrast imaging of cells with phase-sensitive optical coherence microscopy.

We describe a method for en face phase-contrast imaging of cells with a fiber-based differential phase-contrast optical coherence microscopy system. Recorded en face images are quantitative phase-contrast maps of cells due to spatial variation of the refractive index and (or) thickness of various cellular components. Quantitative phase-contrast images of human epithelial cheek cells obtained with the fiber-based differential phase-contrast optical coherence microscopy system are presented.

Cheek↗
PubMed2006

Full-field quantitative phase imaging by white-light interferometry with active phase stabilization and its application to biological samples.

We report a Koehler-illumination-based full-field, actively stabilized, low-coherence phase-shifting interferometer, which is built on a white-light Michelson interferometer. By using a phase-stepping technique we can obtain full-field phase images of the sample. An actively stabilized phase-lock circuit is employed in the system to reduce phase noise. An application to human epithelial cells (HeLa cells) is achieved in our experiment. The advancement of this technique rests in its ability to take images of unstained biological samples quantitatively and on a nanometer scale.

Equipment Design↗
PubMed1999

Phase I study of arabinosyl-5-azacytidine (fazarabine) in adult acute leukemia and chronic myelogenous leukemia in blastic phase.

Fazarabine has demonstrated a broad spectrum of antitumor activity in experimental models including P388 and L1210 cell lines. Previous phase I clinical trials using a 3-day continuous infusion schedule of Fazarabine have shown myelosuppression to be the dose limiting toxicity in solid tumors. Based on this clinical and preclinical experience we designed a phase I study to determine the toxicity, maximum tolerated dose (MTD), and antileukemic efficacy of Fazarabine using a 3-day continuous infusion schedule in patients with refractory or relapsed acute leukemia or chronic myelogenous (CML) in blastic phase. Adults with a diagnosis of acute leukemia or blastic phase CML who were refractory or had relapsed on salvage chemotherapy were entered on study. Fazarabine was administered as a continuous infusion over 3 days every 3 to 4 weeks. The initial dose was 2 mg/m2/hour x 72 hours. Results showed that the MTD was 425 mg/m2/hour infused over 72 hours every 3 to 4 weeks. At this dose level neurotoxicity and fluid overload were the dose limiting toxicities. Among 71 patients treated, we observed one complete remission, one partial remission and one hematologic improvement. No obvious dose response relationship could be determined. In conclusion, Fazarabine has not shown a beneficial effect in the therapy of acute leukemia. Since 71 patients and 20 dose levels were required to determine the MTD of Fazarabine, a reassessment of our phase I study designs should be considered to provide patients with better potential toxic: therapeutic benefits in such trials.

Adolescent↗
PubMed1998

[Semiquantitative measurement of progesterone receptors in luteal-phase-defect endometrial cells during secretory phase].

To investigate the changes of endometrial progesterone receptor (PR) of luteal-phase-defect (LPD) patients during the secretory phase, thirteen patients with complaints of infertility or habitual abortion were studied. During the early-mid secretory phase, endometrial tissue was obtained by dilatation and curettage (D & C) for histological and receptor study: meanwhile serum E2, P, FSH, LH and PRL were measured. Based on histologic diagnosis, the patients were divided into two groups: the LPD group (n = 7) and the normal control group(n = 6). PR content was determined by immunohisto-chemical (IHC) assay. The results showed that during the early-mid luteal phase a significantly low PR content on endometrial glandular nucleus was observed in LPD group, compared with normal control(6.75 +/- 2.57 vs 9.50 +/- 1.64 P < 0.05), but no difference in serum progesterone was noted between the two groups. These findings suggest that during early-mid secretory phase, PR content on endometrial glandular nucleus decreases in LPD cases, which results in deficient response of endometrium to proper stimulus of progesterone. This change may cause endometrial secretory deficiency and blockade of embreyo implantation. That is why infertility or habitual abortion happened.

Abortion, Habitual↗
PubMed2003

Effect of early luteal phase administration of a single dose mifepristone on immunohistochemical distribution of interleukin 1 alpha (IL-1 alpha) and transforming growth factor beta 1 (TGF-beta 1) in mid-luteal phase ovary of the rhesus monkey.

A single low dose administration of a high affinity anti-progestin agent like mifepristone during the early luteal phase inhibits blastocyst implantation in human and non-human primates. Though it has been observed that luteal phase serum concentrations of estradiol and progesterone were not affected by the application of anti-nidatory dose of early luteal phase mifepristone suggesting that ovarian steroidogenic function is not compromised, it is nevertheless possible that ovarian physiology at the local tissue level is affected in this treatment schedule. In the present study, healthy, mature, proven fertile female rhesus monkeys were divided into two groups. Group 2 animals were treated with a single dose of mifepristone (2 mg/kg body weight), while group 1 animals were injected with vehicle (1:4 benzoyl benzoate: olive oil, v/v, s.c.) on day 2 post-ovulation. The morphological examination including that of vascularity, as well as, histometric determination of profiles of immunopositivity for IL-1alpha and TGF-beta1 in stromal, follicular and luteal compartments of mid-luteal phase ovaries from animals with or without a single, anti-nidatory dose of mifepristone applied on day 2 after ovulation failed to reveal any significant change between the two groups. Thus, it appears that early luteal phase administration of a single antinidatory dose of mifepristone does not affect the ovarian physiology in the treatment cycle.

Animals↗
PubMed1996

P2U purinergic activation leads to the cell cycle progression from the G1 to the S and M phases but not from the G0 to G1 phase in vascular smooth muscle cells in primary culture.

The regulation of the cell cycle by extracellular UTP was investigated in rat aortic smooth muscle cells in primary culture (VSMCs) by means of an immunocytochemical analysis of cell cycle-specific nuclear antigens. UTP induced a rise in the cytosolic Ca2+ concentration ([Ca2+]i) of VSMCs, which was desensitized by pretreatment with ATP, but not with 2-methylthioATP nor alpha, beta-methyleneATP. The incubation of serum-deprived G0 cells with platelet derived growth factor (PDGF) induced cell cycle progression into the G1 phase without any further progression into the S and M phases, while none of the nucleotides had any effect on the cell cycle of the G0 cells. The incubation of the PDGF-pretreated cells at the G1 phase with 2-methylthioATP or alpha, beta-methyleneATP had no effect on the cell cycle of G1 cells, while the incubation of the G1 cells with UTP, ATP, and ATP gamma S stimulated cell cycle progression into the S and M phases. These results thus indicate that P2U purinergic activation mediates a [Ca2+]i transient and a progression growth factor effect of nucleotides in VSMCs.

Adenosine Triphosphate↗