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PubMed1994

p53 alteration correlates with negative ER, negative PgR, and high histologic grade in breast cancer.

Seventy tumors of invasive ductal carcinoma of the breast were examined for p53 alteration by the RT-PCR-SSCP method. Sixty-five samples (92.9%) were investigated in the regions of codons 101-200 and 201-300. In total, 16 samples (24.6%) showed p53 gene alteration. We found that p53 gene alteration showed a correlation with (1) a negative ER status, (2) a negative PgR status, and (3) a high histologic grade (especially numerous mitotic figures) of the tumor. However, we found no correlation between p53 gene alteration and the lymph node status or clinical stage. Thus, p53 gene alteration in breast cancer may occur in highly malignant breast cancer other than advanced clinical stage cancer or node-positive cancer.

Adult↗

PubMed1992

Ph-negative and bcr-negative atypical chronic myelogenous leukemia: biological features and clinical outcome.

We report the clinical, hematologic, cytogenetic, and molecular characteristics of 13 patients with Philadelphia-negative (Ph-), bcr-negative atypical chronic myelogenous leukemia (CML). In the majority of cases, the phenotypic features at presentation resembled those of typical CML. However, these patients presented with a higher median age, lower median hemoglobin levels, and lower leukocyte and platelet counts than patients with Ph-positive CML. Cytogenetic analysis showed an abnormal karyotype in only one case. Southern blot investigation, using probes exploring the entire M-bcr region, demonstrated the absence of genomic bcr-abl rearrangements. The assessment of clonality in five patients (study of X-methylation patterns in females heterozygous at the DXS255 locus) indicated the proliferation of a monoclonal cell population. Disease evolution was mostly characterized by bone marrow failure, extramedullary infiltrates, and poor response to chemotherapy, without evidence of overt acute transformation. Our observations suggest that some hematologic and clinical features and the modalities of disease progression are presently the most helpful factors in distinguishing these bcr/abl-negative patients from those with typical bcr+CML. The differences existing also with chronic myelomonocytic leukemia (CMMoL), allow the consideration of ph-/bcr- CML as a separate entity, the nature of which remains to be elucidated.

Cytogenetics↗

PubMed1997

Analyses of Saccharomyces cerevisiae Cdc7 kinase point mutants: dominant-negative inhibition of DNA replication on overexpression of kinase-negative Cdc7 proteins.

Saccharomyces cerevisiae Cdc7 kinase is required for initiation of S phase, and its kinase activity, which is positively regulated by Dbf4 protein, reaches maximum at the G1/S boundary. In this study, we constructed Cdc7 point mutants (T281E, T281A, D182N, D163N, and T167E) and examined the effect of each mutant on growth. All the mutants lost the ability to complement temperature-sensitive growth of cdc7(ts) mutants at a low protein level, whereas T281A (putative target of phosphorylation) and T167E (residue involved in substrate recognition) restored the growth of cdc7(ts) when overproduced to a high level. Three putative kinase-negative mutants (T281E, D182N, and D163N) inhibited growth when overexpressed in a wild-type strain. Analyses of DNA content and morphology revealed that most cells were arrested as dumbbells with 1C DNA, indicative of a block in the G1 to S transition. This growth inhibition was suppressed by co-overexpression of the wild-type Cdc7 or Dbf4 protein. Furthermore, deletion of the Dbf4 protein-binding region in each Cdc7 mutant resulted in loss of growth inhibitory effect. Thus, dominant-negative effects of T281E, D182N, and D163N on growth can be best explained by inactivation of the wild-type Cdc7 function through titration of Dbf4 by these inactive kinases. Our results are consistent with the notion that association of Dbf4 with Cdc7 is essential for the G1 to S transition in S. cerevisiae.

Amino Acid Sequence↗

PubMed1993

The effect of positive and negative pH-gradients on the stability of small unilamellar vesicles of negatively charged phospholipids.

The stability of small unilamellar vesicles (SUV) made from negatively-charged phosphatidate by ultrasonication or pH-jump has been investigated. As criteria for the vesicle stability are used: (I) the bilayer integrity as judged from the permeability of the fluorescent probe carboxyfluorescein (CF) and (II) the susceptibility of the phospholipid vesicles to fusion as judged by gel filtration and freeze-fracture electron microscopy. Egg phosphatidate SUV (PA-SUV) whose internal cavity is in equilibrium with the dispersion medium are strictly speaking thermodynamically unstable by these criteria. They may, however, be regarded as stable from a practical point of view. CF-release is observed with a half-time of 14 days and also some vesicle fusion, particularly at low temperature (4 degrees C). The small effects observed, e.g., the small tendency of the vesicles to undergo fusion is probably due to the high surface charge density of PA bilayers. A main finding of this work is that the same positive pH-gradient which is used in the pH-jump method to drive the formation of SUV from large phosphatidic acid bilayer sheets has a stabilizing effect on the resulting PA-SUV. Stabilization is achieved by positive pH-gradients of about two pH-units or more with the pH of the external medium exceeding the pH of the vesicle cavity. Under these conditions, up to about 8 weeks no significant loss of entrapped CF and no fusion of SUV was observed both at 4 degrees C and room temperature. In contrast, a reverse or negative pH-gradient of several pH units applied to PA-SUV (with the external pH being lower than that of the vesicle cavity) destabilizes PA-SUV. Such a gradient can be shown to lead to a dramatic perturbation of the lipid bilayer packing as evident from a significant increase in CF permeability. The local perturbation of the phospholipid bilayer is accompanied by massive vesicle fusion which is prominent at low temperature (4 degrees C).

Drug Stability↗

PubMed1996

Establishment and characterization of a human-papillomavirus negative, p53-mutation negative human cervical cancer cell line.

A human cervical cancer cell line, CX, was established from a patient with squamous cell carcinoma of the uterine cervix. The CX cells were epithelial in morphology with relatively large vesicular nuclei, and prominent nucleoli. Cytoplasmic organelles were generally sparse but tonofilaments were relatively abundant. The cells grew as a compact sheet with close membrane approximation interconnected by desmosome-like junctions. CX cells contained cytokeratin, but not vimentin. Elevated levels of squamous cell carcinoma antigen and carcinoembryonic antigen were detected in the cell supernatants. Population doubling time was estimated to be about 20 h. CX cells were not able to grow in soft agar and not tumorigenic in nude mice. Chromosome analysis revealed that CX cells were heterogeneous and mainly had a female diploid karyotype. Unlike cervical cancer cell lines published previously, CX cells were demonstrated to be human papillomavirus-negative, p53 mutation-negative. Based on the distinct characteristics, CX cell line may prove to be a useful tool for the study of human cervical carcinogenesis.

Antigens, Neoplasm↗

PubMed1995

Protein tyrosine phosphatase 1C negatively regulates antigen receptor signaling in B lymphocytes and determines thresholds for negative selection.

Motheaten viable (mev) mice are deficient in the cytosolic protein tyrosine phosphatase, PTP1C, and exhibit severe B cell immunodeficiency and autoantibody production. The role of PTP1C in B cell selection and function was analyzed by breeding immunoglobulin transgenes specific for a defined antigen, hen egg lysozyme, into mev mice. Antigen triggered a greater and more rapid elevation of intracellular calcium in PTP1C-deficient B cells, indicating that this phosphatase negatively regulates immunoglobulin signaling. Elimination of self-reactive B cells carrying this signal-enhancing mutation was triggered during their development by binding a lower valency form of self-antigen than is normally required. These findings establish that activation of distinct repertoire-censoring mechanisms depends on quantitative differences in antigen receptor signaling, whose thresholds are determined by negative regulation through PTP1C.

Animals↗

PubMed2005

[Analysis of lymph mode recurrence in patients with melanoma and negative sentinel lymph node negative. Retrospective study at the Hospital Saint-Louis, Paris].

Melanoma is a malignant tumor, with dominant lymphatic extension. Sentinel lymph node is the first lymph node touched by melanoma. Our retrospective and monocentric study is about 87 patients, between July 1999 and July 2003. The inclusion criteria were malignant melanoma with Breslow level superior or equal 1.5 mm, and/or Clark level superior or equal IV, and/or ulcerated, and/or in regression. Sentinel lymph node has been negative on histological analysis in 75 patients (86.2%). About these 75 patients, we found five metastatic lymph node recurrence (6.66%) in a short notice (median 10.2 months). For the five patients with recurrence, the original slides and tissue blocks were available for reexamination. Then, we found micrometastasis in two patients (40% of occult metastasis). Our rate of lymph node recurrence in patients with sentinel lymph node negative is about 6.66%. Our analysis make us believe that early recurrence are essentially linked to histological analysis limits, and maybe to skip metastasis existence.

Adolescent↗

PubMed2005

Human-immunodeficiency-virus-negative, human-herpes-virus-8-negative abdominal cavity primary effusion lymphoma.

Primary effusion lymphoma (PEL) is an unusual class of non-Hodgkin's lymphoma, which is characterised by lymphomatous effusions in body cavities, but no associated mass lesions. It is usually associated with an immunodeficient state most often with the human immunodeficiency virus (HIV). We describe a case of a man with HIV-negative, human-herpes-virus-8 (HHV8)-negative PEL, with a history of heavy alcohol intake. The abdominal cavity was the only area involved; no solid tumour masses were observed on scanning, and the bone-marrow investigations were normal. The ascites contained numerous pleomorphic lymphoid, lymphoplasmacytoid cells of B-cell origin. The immunophenotyping was moderately positive for CD 38 and 138, and strongly positive for Ki 67. It is postulated that the immunosuppressed state in this patient may have been caused by the long history of heavy alcohol intake.

Abdominal Cavity↗

PubMed2003

Mismatch negativity and late discriminative negativity in sleeping human newborns.

Event-related potentials were recorded from sleeping newborns to compare amplitudes and latencies of mismatch negativity (MMN) and late discriminative negativity (LDN) in active and quiet sleep stages. MMN and LDN were obtained in response to changes in semi-synthesized vowels from 20 healthy newborn infants. MMN and LDN responses were significant for both active and quiet sleep. The amplitude and latency of MMN or LDN did not differ between the sleep stages. Thus, in contrast to adult studies that show a significant drop in the MMN amplitude and an increase in the MMN latency as the sleep gets deeper, arousal stages do not seem to effect either MMN or LDN characteristics in newborns. These results suggest functional differences between infant and adult sleep.

Acoustic Stimulation↗

PubMed1997

When is a negative study not negative?

Results of Phase III randomized clinical trials can be categorized into three groups: positive, null, and negative. The jargon used in discussing results of comparative studies requires clarification because misclassification can result in incorrect interpretation. A positive result indicates that the experimental therapy(ies) is(are) superior to standard therapy. A null result indicates that no statistically significant difference between therapies was found; hence, standard therapy should not be replaced. A negative result indicates that the experimental therapy had a deleterious effect compared to standard therapy. This article presents a discussion of these categories and examples of each.

Clinical Trials, Phase III as Topic↗

PubMed2003

Rho A negatively regulates cytokine-mediated inducible nitric oxide synthase expression in brain-derived transformed cell lines: negative regulation of IKKalpha.

The present study describes the role of RhoA as a negative regulator of iNOS expression via the inactivation of NF-kappaB in transformed brain cell lines [C(6) glioma, human astrocytoma (T98G, A172), neuroblastoma (NEB), and immortal rat astrocytes]. Treatment with lovastatin resulted in the induction of LPS/IFN-gamma-mediated iNOS mRNA and increased nitric oxide (NO) production. The addition of mevalonate and geranylgeranylpyrophosphate (GGPP) reversed the lovastatin-mediated effect, whereas FPP had no effect. An inhibitor of geranylgeranyltransferase inhibitor (GGTI 298) further induced the cytokine and lovastatin-mediated iNOS expression, suggesting the involvement of geranylgeranylated proteins in the regulation of iNOS. Bacterial toxin B (inactivates RhoA, B, and C; CDC42; Rac proteins), C3 ADP-ribosyltransferase (C3) toxin from C. botulinum (inactivates RhoA, B, and C proteins), and Y-27632 (selective inhibitor of Rho-associated kinases) increased the LPS/IFN-gamma-mediated iNOS expression. Lovastatin treatment induced NO by increasing NF-kappaB translocation and its association with the CREB-binding protein (CBP/p300) via the downregulation of RhoA. Inhibition of RhoA resulted in increased activation of IKKalpha. Cotransfection studies with dominant-negative form of RhoA and iNOS-luciferase or NF-kappaB-luciferase reporter constructs further support these observations. Taken together, these studies show that downregulation of RhoA by lovastatin resulted in increased iNOS expression via the activation of NF-kappaB-CBP/p300 pathway in transformed brain cells.

Animals↗

PubMed2002

The relationship between mismatch negativity and arousal level. Can mismatch negativity be an index for evaluating the arousal level in infants?

BACKGROUND: Electrophysiological and behavioral studies have shown that stimulus relevance contributes to auditory processing in sleep and auditory stimuli changes the sleep stages. So we observed changes in auditory processing due to sleep stages by recording infant mismatch negativity (MMN) during different states and investigated the arousal mechanisms. METHODS: Auditory event-related potentials (ERPs) of 26 neonates were recorded using high-density EGI EEG system. Stimuli consisted of 1000 Hz tones with 90% probability as standard and 1200 Hz with 10% probability as deviant. Study 1 was designed for the confirmation of the recording of MMN from neonates and Study 2 for investigating whether an appropriate stimulus onset asynchrony (SOA) of the stimulus would induce a clear difference in the latency or amplitude. RESULTS: (Study 1) MMN were obtained from all subjects. No differences of the latencies, amplitudes and distribution due to arousal or sleep stage were observed. After the MMN response occurred, a prominent negativity like Nc was seen in response to deviant stimuli in active sleep and waking state. (Study 2) No distinct differences between the difference states were seen in any SOA. CONCLUSIONS: Only MMN did not characterize the arousal or sleep stage. But the modality of the auditory evoked potentials (AEPs) may differ according to the state, so further detailed investigation could enable the detection of the infants' state using the AEP.

Journal Article↗

PubMed1994

Purification and characterization of nuclear factors binding to the negative regulatory element D of human apolipoprotein A-II promoter: a negative regulatory effect is reversed by GABP, an Ets-related protein.

We have previously shown that transcription of the human apolipoprotein A-II (apoA-II) gene is controlled by a complex set of regulatory elements [Cardot et al. (1993) Biochemistry 32, 9080-9093]. We have also identified previously described, as well as new activities which bind to these elements and influence to varying degrees the transcription of the apoA-II gene. DNA binding and competition assays indicated that element D binds three new activities, designated AIID1, AIID2, and AIID4, as well as an activity related to C/EBP. Activities AIID1, AIID2, and AIID4 were purified and characterized further in order to determine their function on the transcriptional regulation of human apoA-II gene. SDS-PAGE analysis as well as photoaffinity cross-linking of the affinity-purified AIID2 showed that it consists of three proteins with molecular masses ranging between 54 and 63 kDa. The amino acid sequence of tryptic peptides obtained from AIID2 protein bands revealed that it is homologous to GABP, an Ets-related protein. Similar analysis showed that affinity-purified AIID4 has an apparent molecular mass of 130 kDa. AIID1 activity was purified partially; in addition to binding to the apoA-II promoter, AIID1 also binds to the regulatory element C of apoCIII and may play a role in the transcriptional regulation of both genes. Methylation interference of G residues and permanganate modification of T residues indicated that the binding sites of AIID2 and AIID4 were contiguous on element D. However, the binding site of AIID1 overlaps with the binding sites of both AIID2 and AIID4. This suggests that the binding of AIID1 and AIID2 or of AIID1 and AIID4 may be mutually exclusive, whereas AIID2 and AIID4 may bind simultaneously. Transcription from a minimal promoter containing elements AB, C, and D of apoA-II increased 1.5- to 1.6-fold when element D is deleted, as well as by promoter mutations which eliminated the binding of both AIID1 and/or AIID4 to element D, but permitted the binding of AIID2/GABP. The findings suggest that element D has a negative regulatory role on apoA-II gene transcription when it is occupied by protein AIID1 and/or AIID4. This negative effect is reversed when element D is occupied only by the regulatory factor AIID2/GABP.

Amino Acid Sequence↗

PubMed2004

Health-related quality of life in axillary node-negative, estrogen receptor-negative breast cancer patients undergoing AC versus CMF chemotherapy: findings from the National Surgical Adjuvant Breast and Bowel Project B-23.

PURPOSE: NSABP Protocol B-23 compared two chemotherapy regimens: (1) cyclophosphamide, methotrexate, and 5-fluorouracil (CMF); and (2) doxorubicin and cyclophosphamide (AC) in terms of relapse-free survival, event-free survival, and overall survival in node-negative and estrogen receptor-negative breast cancer patients. There are no previous data regarding the comparison of quality of life (QOL) between the two regimens in this population of breast cancer patients. QOL information was considered especially relevant given the possibility that the two chemotherapy regimens would prove equivalent in terms of clinical outcome. PATIENTS AND METHODS: One hundred and sixty patients participated in the NSABP B-23 QOL study. Patients in B-23 were randomly assigned to one of four arms: CMF plus 5 years of tamoxifen (TAM), CMF, Comparative health item and general health item plus placebo, AC plus TAM, or AC plus placebo. The questionnaires included the Functional Assessment of Cancer Therapy (FACT-B), the vitality scale from the Medical Outcomes Study 36-item Short Form Health Status Survey (MOS SF-36), a symptom checklist and additional items regarding overall QOL; and return to normal activity. Statistical comparisons between treatment arms were performed with area under the curve analyses, repeated measures analyses, and Fisher exact tests. RESULTS: Overall QOL as measured by the FACT-B did not significantly differ between chemotherapy treatment arms. However, the pattern of vitality over time during treatment differed between chemotherapy groups. The AC group vitality scores dropped more sharply during treatment and returned to baseline levels more quickly after treatment. Patients in the CMF arm were bothered by bladder problems and diarrhea significantly more often than were patients in the AC arm. Otherwise, no significant differences were found between AC and CMF for any of the QOL outcomes in terms of (1) overall QOL during the first 9 months after randomization, (2) the average QOL during treatment, or (3) the rate of recovery to baseline levels of QOL 1year after randomization. CONCLUSION: Overall QOL is equivalent between the two chemotherapy regimens, with some differences in symptoms and in patterns of vitality over time.

Activities of Daily Living↗

PubMed2005

Negative priming with masked distractor-only prime trials: awareness moderates negative priming.

The literature yields inconsistent evidence for negative priming (NP) following masked distractor-only prime trials. We contrast two different hypotheses on the inconsistent findings: one - which is most compatible with the temporal discrimination theory - that relates the sign of priming effects to the absence vs. presence of prime awareness and one -which is most compatible with the inhibition and episodic retrieval accounts - that relates the sign of priming effects to the prime event being categorized as a to-be-attended vs. to-be-ignored event. In two experiments, it turned out that participants' awareness of the masked stimuli caused the different results (with participants being not aware of the primes showing NP), whereas the factor prime color = probe target color vs. prime color = probe distractor color (i.e., the prime contains the to-be-attended vs. the to-be-ignored signal) did not moderate NP. These findings are discussed with regard to theories of negative priming and the debate on conscious vs. unconscious perception.

Adult↗

PubMed1983

Reactivity of normal and VMH-lesion rats to quinine-adulterated foods: negative evidence for negative finickiness.

Much of the evidence for the existence of a negative finickiness component in the ventromedial hypothalamic (VMH) syndrome comes from studies comparing the relative reactivities of VMH and normal rats to quinine adulteration. The present experiments addressed two major questions regarding the response of normal and VMH animals to quinine: (a) Do the anorexic properties of quinine depend on quinine's sensory properties (i.e., its bitter taste) or on its postingestive effects; (b) do VMH rats in fact overrespond to quinine adulteration? These issues were examined by comparing the feeding adjustments to quinine by VMH and normal animals in a sham-feeding situation and under normal feeding circumstances, on animals' initial exposure to this drug. The results were consistent with the view that the sensory properties of quinine alone were sufficient to induce large changes of food intake in both groups. In terms of whether lesion rats were more reactive to the taste of quinine, it is argued that previous research had measured reactivity in two dissimilar ways. The present data were used to illuminate how use of these two procedures for measuring reactivity lead to diametrically opposed conclusions regarding the existence of negative finickiness in the VMH syndrome. It is suggested that when the more appropriate measure of reactivity is adopted and when the confound of body weight differences between normal and VMH animals is eliminated, little evidence exists for a conclusion that VMH rats are more reactive than normals to quinine-adulterated foods.

Animals↗

PubMed1989

A randomized clinical trial evaluating sequential methotrexate and fluorouracil in the treatment of patients with node-negative breast cancer who have estrogen-receptor-negative tumors.

We evaluated the postoperative use of sequential methotrexate and fluorouracil followed by leucovorin in 679 patients with primary breast cancer, histologically negative axillary nodes, and estrogen-receptor-negative (less than 10 fmol) tumors. No survival advantage was observed with this therapy as compared with no postoperative therapy during four years of follow-up (87 percent vs. 86 percent; P = 0.8). However, there was a significant prolongation of disease-free survival among women who received this therapy as compared with those who did not (80 percent vs. 71 percent; P = 0.003). An advantage was observed in both the patients less than or equal to 49 years old and those greater than or equal to 50. At four years, treatment failure was reduced by 24 percent in the younger group and by 50 percent in the older group. The rates of both local and regional and distant metastases were decreased. These benefits, achieved without the use of an alkylating agent, were associated with tolerable side effects. Multivariate analysis testing for potential interactions failed to identify subgroups of patients who did not benefit from the therapy. These results, although promising, do not obviate the need for additional trials to evaluate potentially better regimens of therapy, but they do suggest that sequential methotrexate-fluorouracil should be used in the control arm in such studies. Their use is also justified for the treatment of patients who refuse to participate in clinical trials, provided the patients meet the eligibility criteria of the present study. Since women with tumors too small for conventional analysis of estrogen-receptor and progesterone-receptor concentrations were not included in this study, we do not recommend systemic treatment for them outside of a clinical trial.

Aged↗

PubMed1995

Negative transcriptional regulation of the interferon-gamma promoter by glucocorticoids and dominant negative mutants of c-Jun.

Interferon-gamma (IFN-gamma) is an immunoregulatory cytokine expressed in large granular lymphocytes and T cells. However, the molecular mechanisms underlying IFN-gamma gene transcription have not been fully defined. Here, we analyze the mechanisms responsible for the inhibition of IFN-gamma promoter activity by the glucocorticoid hormone dexamethasone. Cotransfection assays performed in Jurkat T cells demonstrated that the activity of the initial 108 base pairs of the IFN-gamma promoter was down-regulated in the presence of dexamethasone. Furthermore, utilizing electrophoretic mobility shift analysis, we identified activator protein 1 AP-1-cAMP response element binding protein-activating transcription factor (CREB-ATF) binding elements situated in positions of the IFN-gamma promoter previously identified as essential for promoter activity. Moreover, dominant negative mutants of the c-Jun proto-oncogene were able to mimic the same down-regulatory effect exerted by dexamethasone, and mutations that abolished the binding of the AP-1 CREB-ATF factors were able to block the glucocorticoid effect. These results suggest a model involving the inhibition of IFN-gamma AP-1 CREB-ATF DNA binding complexes as one of the mechanisms involved in the negative regulatory action of glucocorticoids on IFN-gamma gene expression and support the relevance of AP-1 CREB-ATF binding factors during the transcriptional activation of the IFN-gamma promoter in T cells.

Base Sequence↗