Fulminant hepatic failure after 2'-deoxycoformycin (pentostatin)
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Aged↗
Biomedical subjects
M Sanchez
Publications and source records attributed to M Sanchez.
Kampanols: novel Ras farnesyl-protein transferase inhibitors from Stachybotrys kampalensis.
Farnesyl-protein transferase (FPTase) is a critical enzyme that participates in the post-translational modification of the Ras protein. Inhibitors of this enzyme have the potential of being novel anticancer agents for tumors in which the ras oncogene is found mutated and contributes to cell transformation. Continued screening of natural product extracts led to the isolation of kampanols, which are novel and specific inhibitors of FPTase. The most active kampanols exhibited IC50 values between 7 to 13 microM against human recombinant FPTase. The isolation, structure determination, and biological activity of these compounds are described.
Alkyl and Aryl Transferases↗
The deletion of six ORFs of unknown function from Saccharomyces cerevisiae chromosome VII reveals two essential genes: YGR195w and YGR198w.
We have deleted six different ORFs of unknown function located on the right arm of Saccharomyces cerevisiae chromosome VII; namely, YGR187c/HGH1, YGR189c, YGR194c, YGR195w, YGR196c and YGR198w. No basic phenotypes could be attributed to the strains deleted in any of genes YGR187c/HGH1, YGR189c, YGR194c and YGR196c. These deletants did not show mating, sporulation or growth defects under any of the conditions tested. However, spores bearing deletions in either the YGR195w or YGR198w genes were unable to develop into macroscopical colonies. The YGR195w gene product shows significant homology with bacterial ribonuclease PH, an enzyme hitherto undescribed in yeasts, and its deletion causes a loss of viability after one to three rounds of cell division. Overexpression of this gene, using a tetracycline-regulatable promoter system, did not cause any effect on the cells. Contrary to what has been reported for prokaryotic homologs, this enzyme could play an essential role in yeast cell biology. The product encoded by the other essential ORF, YGR198w, shows no significant homology with any protein of known function in the databases. Spores bearing the deletion usually germinate and give rise to microcolonies of 50-100 non-viable cells.
Chromosomes, Fungal↗
Fractal characterization of chromatin appearance for diagnosis in breast cytology.
This study explores the use of fractal analysis in the numerical description of chromatin appearance in breast cytology. Images of nuclei from fine-needle aspiration biopsies of the breast are characterized in terms of their Minkowski and spectral fractal dimensions, for 19 patients with benign epithelial cell lesions and 22 with invasive ductal carcinomas. Chromatin appearance in breast epithelial cell nuclear images is demonstrated to be fractal, suggesting that the three-dimensional chromatin structure in these cells also has fractal properties. A statistically significant difference between the mean spectral dimensions of the benign and malignant cases is demonstrated. The two fractal dimensions are very weakly correlated. A statistically significant difference between the benign and malignant cases in lacunarity, a fractal property characterizing the size of holes or gaps in a texture, is found over a wide range of scales. These differences are particularly pronounced at the smallest and largest scales, corresponding respectively to fine-scale texture, indicating whether chromatin is clumped or fine, and to large-scale structures like nucleoli. Logistic regression and artificial neural network classification models are developed to classify unknown cases on the basis of fractal measures of chromatin texture. Using leave-one-out cross-validation, the best logistic regression classifier correctly diagnoses 95.1 per cent of the cases. The best neural network model can correctly classify all of the cases, but it is unclear whether this is due to overtraining. Fractal dimensions and lacunarity are useful tools for the quantitative characterization of chromatin appearance, and can potentially be incorporated into image analysis devices to assure the quality and reproducibility of diagnosis by breast fine-needle aspiration biopsy.
Biopsy, Needle↗
Characterisation of two human dendritic cell-lines that express CD1a, take-up, process and present soluble antigens and induce MLR.
Dendritic cells (DC) are bone marrow derived cells present in diverse tissues and organs including the skin, mucosae and blood. DC have a capital role in the afferent pathway of the immune response because of its role in up-take, processing and presenting antigens to immune cells. Human DC are usually identified by the expression of surface CD1a and HLA-DR. Despite the significant recent developments for in vitro generation of DC derived from blood by using cytokines like GM-CSF and IL-4, the studies on DC and specially on human Langerhans cells (LC) have been hampered by the laborious isolation procedure and the small yield of cells obtained by the various methods of isolation used so far. Therefore, a priority has been a search for monoclonal dendritic cell-lines with LC characteristics in order to facilitate the research in this area. The present study reports on the generation of two stable, self-replicant, adherent, dendritic, CD1a+, HLA-DR , CD45RO , CD23/FcERII+ cell-lines that up-take and process soluble antigens but also inducing MLR and antigen-dependent T-cell response.
Antigen Presentation↗
Clavaric acid: a triterpenoid inhibitor of farnesyl-protein transferase from Clavariadelphus truncatus.
Farnesyl-protein transferase (FPTase) catalyses the specific transfer of farnesyl to Ras-peptides that is essential for oncogenic activity in oncogene-mediated tumors. Specific inhibition of FPTase activity has been shown to reduce tumor development in nude mice challenged with oncogenic forms of ras, thereby establishing FPTase as a viable therapeutic target. Our continued efforts to discover inhibitors of FPTase has led to the discovery of a triterpenoidal inhibitor, clavaric acid (1). This compound inhibits rHFPTase with an IC50 value of 1.3 microM. Structure elucidation, structure modifications, and biological activity of clavaric acid are herein described.
Alkyl and Aryl Transferases↗
Thymus-independent T-cell differentiation in vitro.
The generation of large quantities of novel human T-cell clones ex vivo would make a wide range of gene- and immuno-therapies for tumours and viral infections possible. Several techniques have been described to generate, in vitro and in vivo (using xenogenic hosts), mature T cells from fetal-neonatal and adult human CD34+ cells. All these techniques are cumbersome and cannot be easily translated into clinical protocols because they involve co-cultivation of CD34+ cells with thymic fragments from either human or murine fetuses. We report that the mononuclear cells of human cord blood contain a cell population that supports the differentiation of CD34+ cells into CD4+ or CD8+ naive T cells in serum-deprived cultures stimulated with stem cell factor and interleukin 7. CD4+ or CD8+ CD45RA+ TCRalphabeta+ T cells were continuously produced in vitro over a period of 20 d under these conditions. The generation of T cells in these cultures was a dynamic process and clones of T cells expressing new T-cell receptor beta-chain rearrangements were generated over time. These results pave the way for the development of very simple culture conditions for ex-vivo production of naive helper or cytotoxic T cells which could be very useful for gene- and immuno-therapy of human diseases.
Adult↗
Compliance with disposition to primary care physicians and psychiatrists in elderly homebound mentally ill patients.
In a naturalistic study, the authors evaluated homebound mentally ill elderly patients as part of a psychiatric outreach team in two rural/semi-urban regions. Of the 80 patients evaluated in the two counties, 15 patients were admitted to nursing homes and were excluded from the analyses of follow-up data. Of the remaining 65 patients, 36 were referred to a primary care physician and 29 to a psychiatrist. The follow-up rate with primary care physicians (75%) was significantly greater than with psychiatrists (41% [P < 0.006]). At 3- to 6-month follow-up by telephone, patients who were compliant showed significantly greater clinical improvement than those who were not compliant (P < 0.0001). Overall, the higher follow-up rate for primary care physicians, compared with psychiatrists, reinforces the importance of educating and training primary care physicians in the diagnosis and management of mental disorders in elderly patients.
Aged↗
Prognosis value of the monoclonal blood plasma cells in multiple myeloma.
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Adult↗
DNA sequence analysis of a 23,002 bp DNA fragment of the right arm of Saccharomyces cerevisiae chromosome VII.
We report the sequence of a 23,002 bp fragment located on the right arm of Saccharomyces cerevisiae chromosome VII. Analysis of this region revealed 14 complete open reading frames (ORFs) wit more than 300 base pairs. Six of them correspond to previously known genes. G7164 is the QCR9 gene coding for subunit 9 of the cytochrome c reductase; G7168 is UBR1, encoding an ubiquitin protein ligase; G7522 is the TYS1 gene, which encodes for the tyrosyl tRNA synthetase; G7526 is TFG1, the gene coding for the RNA polymerase transcription initiation factor TFIIF (factor G); G7538 is the gene HGH1 which encodes a protein related to the mammalian HMG1 and HMG2 proteins. G7542 is the BUB1 gene which encodes a ser/thr protein kinase involved in spindle assembly during the cell cycle. One of the ORFs, G7553, shares significant homologies with the gene UTR2 from S. cerevisiae. None of the seven remaining ORFs shows similarity to any of the sequences within the public databases. Three ORFs are internal ORFs of the above-described known genes, and two small ORFs are completely contained in larger ORFs on the complementary strand, and therefore probably do not correspond to real genes. This region also contains three genes specifying tRNAs for Leu, Lys and Trp, and several LTR elements.
Amino Acid Sequence↗
Femoral hernia in childhood: review of 38 cases.
Femoral hernias rarely occur at any age, but are extremely rare in infancy. We present 38 cases of femoral hernia treated in our pediatric surgery department during the last 15 years. The number of patients who underwent surgery was high compared with other series reviewed. This might be due to the fact that these hernias were considered in the differential diagnosis of inguinal pathology in childhood. The preoperative diagnosis was correct in 22 cases (57. 8%). After surgical treatment no recurrence was reported.
Child↗
Melanin-concentrating hormone (MCH) antagonizes the effects of alpha-MSH and neuropeptide E-I on grooming and locomotor activities in the rat.
The intraventricular (i.c.v.) administration of the neuropeptide melanocyte stimulating hormone (alpha-MSH) is known to elicit a series of behaviors in the rat which include excessive grooming and other motor activities. In bony fish, the pigmentary effects of alpha-MSH can be antagonized by the neuropeptide melanin-concentrating hormone (MCH). We therefore examined whether MCH or its sister peptide neuro-peptide E-I (NEI), derived from the same precursor molecule, would modulate the effect of alpha-MSH on grooming and motor activity in the rat, or perhaps elicit some responses of their own. Rats were injected i.c.v. with either artificial cerebrospinal fluid, alpha-MSH, MCH, NEI, or with two peptides together, and behavioral responses were monitored over the next 65 min. The i.c.v. injection of 1 microgram MSH significantly enhanced grooming behavior. NEI at the same dose increased grooming, rearing, and locomotor activities. MCH alone had no behavioral effects but it annulled the behavioral responses induced by either alpha-MSH or NEI. alpha-MSH also antagonized the locomotor and rearing behavior induced by NEI. The physiological significance of these observations is discussed.
Animals↗
Sezary cell-like leukemia with atypical immunophenotype.
We describe the clinical and laboratory features of an unusual case with Sezary cell-like leukemia. Clinical manifestations were: anemia (Hb 9.4 g/dl), severe thrombocytopenia (5 x 10(9)/l), lymphocytosis (43 x 10(9)/l) and splenomegaly. There was no lymphadenopathy, hepatomegaly or skin lesions. Bone marrow trephine showed diffuse infiltration by atypical lymphoid cells. By ultrastructural analysis the cells were small to medium-size lymphocytes with nuclear features identical to Sezary cells. Immunophenotyping showed that most peripheral blood mononuclear cells were negative with B lymphoid, myeloid, and stem cell-associated markers and were also negative with most T lymphoid markers (CD2, CD4, membrane/cytoplasmic CD3, CD5 and CD8). However, they were positive with CD38 (70%), CD7 (25%) and TIA-2 (25%). Molecular analysis showed a clonal rearrangement of the TCR beta and gamma chain genes. The patient was initially treated with vincristine, doxorubicin and asparaginase and then with six cycles of CHOP, achieving a complete remission and remaining free of disease 22 months from diagnosis. Aberrant immunophenotypes are not frequent in primary T cell leukemias. This is the first case of a rare type of T cell neoplasm, Sezary cell-like leukemia, in which cells lacked most of the T cell-associated antigens.
Adult↗
Reproducibility and accuracy of interactive segmentation procedures for image analysis in cytology.
The segmentation of nuclear images is a crucial step in the development of procedures using image analysis for the cytological diagnosis of cancer. The purpose of this study is to evaluate the reproducibility and accuracy of several interactive segmentation methods which can be used in this context. Four methods were studied: a thresholding-based method enabling selection of intensity histogram contrast and brightness, manual tracing with a stylus, and arc- and ellipse-fitting routines. Features of nuclear size and shape were derived from nuclei segmented on repeated occasions by several individuals. Variance component models provided a statistical framework for evaluating the intraobserver and interobserver variability of these measurements in terms of their intraclass correlation coefficients. Of the methods tested, the arc-fitting segmentation method gave the most reproducible results, and thresholding the least. Reproducibility was generally very high both between individuals and for repeated segmentations by a single individual. Accuracies of area measurements for the various methods, as determined with respect to point counting, paralleled the reproducibilities of the methods. Sample size requirements were observed to be more dependent on the biological variability of the tissue sampled than on the particular segmentation method or on the number of individuals performing segmentation.
Cell Biology↗
Attentional modulation of the cardiac defense response in humans.
How cardiac components of the defense reaction are modulated by attentional factors related to sensory intake versus sensory rejection was examined. Forty-eight men participated in a test of the heart rate response to three presentations of an intense auditory stimulus while performing one of three attentional tasks during the 80 s following stimulus onset: (a) internal (rejection) task, (b) external (intake) task, and (c) no task. Results showed a potentiation of the defense response only under the external attention condition. We concluded that defensive reactions, far from provoking the rejection of the aversive stimulus, require allocation of attention to processing that stimulus in detail.
Acoustic Stimulation↗
Sialic acid-dependent recognition of laminin and fibrinogen by Aspergillus fumigatus conidia.
In an attempt to define the molecular basis of the adherence of Aspergillus fumigatus conidia to the host tissues, a step which might be mediated by the recognition of basement membrane laminin or fibrinogen, we analyzed the binding of these glycoproteins by flow cytometry and a microtiter plate adherence assay. Flow cytometry revealed that the binding of fluorescein isothiocyanate-labeled laminin to conidia was saturable and specific. Moreover, the ability of conidia to bind laminin increased with their maturation. Competition experiments showed a cross-reactivity between laminin and fibrinogen binding and a lack of interactions with glycosaminoglycans. In addition, the binding of laminin was not inhibited by the different adhesive synthetic peptides tested. Furthermore, the microtiter plate assay of adherence to chymotrypsin degradation products of laminin or fibrinogen purified by gel filtration suggested a unique binding site common to sequential degradation fragments or the presence of multiple binding sites on the two ligands. Therefore, the role of carbohydrates in the recognition process was investigated. Among the carbohydrates tested, constitutive of the conidial wall or of the oligosaccharide side chains of laminin and fibrinogen, only N-acetylneuraminic acid and sialyllactose inhibited the binding of these glycoproteins to conidia. In conclusion, these results strengthen the idea that the laminin and fibrinogen receptors in A. fumigatus are identical and suggest an interaction mediated by a sialic acid-specific lectin of the conidial wall.
Aspergillus fumigatus↗
Chronic actinic dermatitis associated with human immunodeficiency virus infection.
Chronic actinic dermatitis is a photodistributed, eczematous dermatitis that preferentially affects elderly men and persists for months to years. Its occurrence in individuals infected with human immunodeficiency virus (HIV) has been described in five patients. We report four additional cases of this uncommon, chronic photodermatosis associated with HIV infection. In two of the patients, photosensitivity was a presenting disorder leading to the diagnosis of HIV infection. All patients were men of skin type VI with a mean age of 50 years, all had decreased minimal erythema doses to ultraviolet B, three of the four patients had decreased minimal erythema doses to ultraviolet A and all had CD4 cell counts of < 200 x 10(6)/L.
Adult↗
Counterselection against D mu is mediated through immunoglobulin (Ig)alpha-Igbeta.
The pre-B cell receptor is a key checkpoint regulator in developing B cells. Early events that are controlled by the pre-B cell receptor include positive selection for cells express membrane immunoglobulin heavy chains and negative selection against cells expressing truncated immunoglobulins that lack a complete variable region (D mu). Positive selection is known to be mediated by membrane immunoglobulin heavy chains through Ig alpha-Ig beta, whereas the mechanism for counterselection against D mu has not been determined. We have examined the role of the Ig alpha-Ig beta signal transducers in counterselection against D mu using mice that lack Ig beta. We found that D mu expression is not selected against in developing B cells in Ig beta mutant mice. Thus, the molecular mechanism for counterselection against D mu in pre-B cells resembles positive selection in that it requires interaction between mD mu and Ig alpha-Ig beta.
Animals↗