The JAK2 V617F mutation is rare in RARS but common in RARS-T.
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Aged↗
Biomedical subjects
J Cervera
Publications and source records attributed to J Cervera.
The JAK2 V617F mutation identifies a subgroup of MDS patients with isolated deletion 5q and a proliferative bone marrow.
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Adult↗
MRS as endogenous molecular imaging for brain and prostate tumors: FP6 project "eTUMOR".
Molecular imaging has become during the last years in an important tool for supporting cancer diagnosis and prognosis. PET and SPECT are the most common molecular imaging techniques, although very promising and specific biological molecular agent contrast for CT and MRI are being recently developed. However, the above imaging techniques require exogenous contrast agents and usually a sole molecular image can be obtained at once. On the contrary, in vivo magnetic resonance spectroscopy (MRS), in particular 1H MRS can simultaneously provide several molecular images using endogenous metabolites. In addition to biochemical spatial information from molecular imaging spectroscopy, MRS can also provide average metabolite profile of the selected affected tissue region. Initially MRS, especially 1H MRS, was extensively applied to complete and improve the diagnosis and prognosis of central nervous system (CNS) pathologies, in particular brain tumors. However, during the last years the MRS applications have been extent to the diagnosis of different very common cancer types such as breast, prostate, colon carcinoma, and ovarian, among others. Likewise, MRS has been also used for lymph node assessment. In this contribution, the added value of MRS for the diagnosis, prognosis, and treatment selection of two different, important types of cancer: (1) brain tumors and (2) prostate, will be presented and discussed. Brain tumors are the leading cause of death in children under 15, and although in adults, brain cancers are proportionately less common than other cancers, it is a devastating disease with high mortality. There is a great need to increase our understanding of brain tumor biology to improve diagnosis and to develop new treatments. 1H MRS is currently the only noninvasive method that can be used to investigate molecular profile of brain tumors and also provide molecular images, more than six in one acquisition, of the distribution of chemicals in a tumor, which are also generally heterogeneous. A summary of the applications of 1H MRS to the in vivo diagnosis and prognosis of brain tumors will be presented. In addition, examples of metabolite limits, infiltration and high cellularity location for neurosurgery applications by MRS molecular images will be shown. Likewise, new ex vivo methods of studying the detailed biochemistry of tumor biopsies as metabolomic (high resolution magic angle spinning [HR-MAS]) and transcriptomic (DNA microarrays) will be discussed as complementary to in vivo MRS (FP6 European project eTUMOR). A preliminary comparison between molecular images from PET and 1H MRS will be also presented. Finally, the application of 1H MRS to the improvement of prostate diagnosis and prognosis, the second leading cause of cancer death, will also discussed, with particular attention to the location cancer contribution from MRS molecular images.
Brain Neoplasms↗
Theoretical description of the ion transport across nanopores with titratable fixed charges: analogies between ion channels and synthetic pores.
Recently developed nanometer-sized synthetic pores display several properties so far believed to be distinctive features of a large variety of biological wide ion channels. Thus conductance in the pS-nS range, pH-dependent ion selectivity, fluctuations of current between open and closed states, flux inhibition caused by protons or divalent cations, current rectification, and the ability to perform selective macromolecule sizing and counting are found in synthetic and biological channels alike. Despite other differences such as pore size and geometry, the similarities open a new field for exploring specific technological applications via the chemical modification of synthetic pores with biological molecules. This article reviews some of the basic concepts and theories relevant to ion transport in nanopores with titratable charges stressing the analogies between synthetic pores and biological ion channels. The ultimate goal is to show that continuum theories may account for the essential features of these systems. A simple electrodiffusion model and its comparison with experimental results are chosen as a case study.
Ion Channels↗
Genetic abnormalities associated with the t(12;21) and their impact in the outcome of 56 patients with B-precursor acute lymphoblastic leukemia.
The ETV6/RUNX1 rearrangement is found in 20-30% of children with B-cell precursor acute lymphoblastic leukemia and is associated with a good outcome. To determine the cytogenetic and molecular abnormalities associated with the ETV6/RUNX1 rearrangement and the influence of this rearrangement in patients' evolution, we analyzed the molecular cytogenetic profiles of 56 children with this rearrangement and B-cell precursor acute lymphoblastic leukemia. Secondary changes detected with conventional cytogenetics and with fluorescence in situ hybridization were found in 71.4% of cases, the most frequent being the loss of the normal ETV6 allele, 12p aberrations, duplication of the fusion gene, and trisomy 21, as in replicating the results of previous studies. In this preliminary series, with a mean follow-up of 69.3 months, secondary abnormalities did not influence patients' outcome. It seems therefore that the prognostic value of the t(12;21) does not vary and that ETV6/RUNX1 rearrangement is an independent indicator of good prognosis.
Child↗
[Cochlear implant in congenital malformations].
OBJECTIVE: The main objective is to evaluate the complications and problems encountered in a population with inner ear congenital malformation undergoing cochlear implantation. MATERIALS AND METHODS: The present study includes 33 patients with congenital inner ear malformation, from a total population of 346 cochlear implant patients, implanted from February 1993 to March 2004. Radiological evaluation and neurological exams were performed to all these patients in order to evaluate all the preoperative conditions. RESULTS: The most common cochlear anomalies we found were: cochlear hypoplasia, Incomplete partition and Common cavity (n=15). In 4 cases an enlarge aqueduct was also associated to the cochlear anomaly. We also found 6 cases with labyrinthine anomalies. The surgical procedure was performed in 23 cases, and in 18 of them we obtained an electrical stimulation of the neural elements. CONCLUSIONS: There are no differences between patients with Incomplete Partition of the cochlea and mild Cochlea hypoplasia, if compared with those with normal cochlea. Severe malformations as Common Cavity or severe hypoplasia may have a higher rate of surgical complications and the outcome cannot be predicted.
Adult↗
Calculation of the wetting parameter from a cluster model in the framework of nanothermodynamics.
The critical wetting parameter omega(c) determines the strength of interfacial fluctuations in critical wetting transitions. In this Brief Report, we calculate omega(c) from considerations on critical liquid clusters inside a vapor phase. The starting point is a cluster model developed by Hill and Chamberlin in the framework of nanothermodynamics [Proc. Natl. Acad. Sci. USA 95, 12779 (1998)]. Our calculations yield results for omega(c) between 0.52 and 1.00, depending on the degrees of freedom considered. The findings are in agreement with previous experimental results and give an idea of the universal dynamical behavior of the clusters when approaching criticality. We suggest that this behavior is a combination of translation and vortex rotational motion (omega(c)=0.84).
Journal Article↗
[Patient consent to "antimicrobial treatment of tonsillitis"].
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Anti-Bacterial Agents↗
Standardized, unrelated donor cord blood transplantation in adults with hematologic malignancies.
The potential role of unrelated donor cord blood transplantation (UD-CBT) in adults remains unclear. This study reports the results of UD-CBT in 22 adults with hematologic malignancies following conditioning with thiotepa, busulfan, cyclophosphamide, and antithymocyte globulin in 21, with thiotepa, fludarabine, and antithymocyte globulin in 1, and graft-versus-host disease (GVHD) prophylaxis with cyclosporine and prednisone. Median age was 29 years (range, 18-46 years), and median weight was 69.5 kg (range, 41-85 kg). HLA match was 6 of 6 in 1 case, 5 of 6 in 13 cases, and 4 of 6 in 8 cases. Median number of nucleated cells infused was 1.71 x 10(7)/kg (range, 1.01 x 10(7)/kg to 4.96 x 10(7)/kg). All 20 patients surviving more than 30 days had myeloid engraftment, and only 1, who received the lowest cell dose, developed secondary graft failure. Median time to reach an absolute neutrophil count of at least 0.5 x 10(9)/L was 22 days (range, 13-52 days). Median time to platelets numbered at least 20 x 10(9)/L was 69 days (range, 49-153 days). Seven patients (32%) developed acute GVHD above grade II, and 9 of 10 patients at risk developed chronic GVHD, which became extensive in 4 patients. Twelve patients remained alive and disease-free 3 to 45 months after transplantation. Disease-free survival (DFS) at 1 year was 53%. Age strongly influenced DFS (P =.01). For patients aged 30 years or younger, the DFS at 1 year was 73%. These preliminary results suggest that UD-CBT should be considered a reasonable alternative in young adults with hematologic malignancy and no appropriate bone marrow donor.
Adult↗
Radiology forum: imaging quiz case 1. Diagnosis: unsuspected laryngotracheal foreign body (FB).
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Bronchoscopy↗
Recent improvements in outcome for elderly patients with de novo acute myeloblastic leukemia.
A retrospective analysis was performed on 263 consecutive patients aged over 60 with de novo acute myeloid leukemia (AML) diagnosed in a single institution between 1979 and 1998. Eighty-nine patients (33%) received only palliative treatment, while 174 patients (67%) were treated with different intensive chemotherapy regimens. The 5- and 10-year overall survival (OS) for the whole series was 7.7+/-1.2 and 4.3+/-1.6%, respectively. For patients receiving chemotherapy, OS was 10.5+/-2.5 and 7+/-2.6%, while for those patients receiving supportive treatment it was 1.1+/-1.1 and 0%, respectively (P=0.002). Within the group of patients receiving chemotherapy, the complete remission (CR) rate was 46%; treatment failure rate was 54% (36% due to treatment-related mortality and 18% due to resistant disease). Variables influencing CR rate were FAB subtype, CD7 positivity, chemotherapy regimen, creatinine level, hepatomegaly, and period of diagnosis. Median disease-free survival (DFS) duration was 8.4 months with a probability of being disease-free at 10 years of 10+/-5%. There were no significant differences in DFS according to age. According to the period of diagnosis (1979-1986 vs. 1987-1998), improvements in the CR rate (27 vs. 56%, P=0.0002), and OS (10.9 vs. 15.7 months, P=0.0007) were observed. This large single-center study of unselected de novo AML elderly patients substantiates the progressive improvement achieved in the management of elderly patients with AML, probably due to an improvement in supportive care and the administration of conventional induction chemotherapy.
Aged↗
Heterogeneous lack of expression of the tumour suppressor PTEN protein in human neoplastic tissues.
PTEN, a tumour suppressor gene located at chromosome 10q23 and commonly mutated or deleted in a variety of tumours, encodes a dual-specific/phosphatidylinositol-3,4,5-triphosphate (PIP3) phosphatase. We report the generation of an anti-PTEN monoclonal antibody (MAb) that recognises an epitope at the C-terminus of PTEN, and describe the heterogeneous lack of expression of the PTEN protein in human tumour tissues, as demonstrated by immunohistochemical methods. Our anti-PTEN MAb provides a useful tool for the study of PTEN protein expression in tumour samples, in the search for tumour prognostic molecular markers.
Animals↗
Unrelated donor cord blood transplantation in adults with chronic myelogenous leukemia: results in nine patients from a single institution.
The potential role of unrelated donor cord blood transplantation (UD-CBT) in adults is not well established. We report the results of UD-CBT in nine adult patients with chronic myeloid leukemia (CML). The median age was 27 years (range, 19-41 years), and the median weight was 62 kg (range, 45-78 kg). At transplant, six patients were in chronic phase (five in first, and one in second), two in blast crisis, and one in accelerated phase. Eight had received intensive chemotherapy, and three had undergone autologous peripheral blood hematopoietic stem cell transplantation. Four had received interferon with no cytogenetic response, and only three underwent UD-CBT within 1 year of diagnosis. After serological typing for class I antigens, and high-resolution DNA typing for DRB1, the degree of HLA match between patients and cord blood (CB) units was 4/6 in six cases and 5/6 in three cases. The median number of nucleated cells infused was 1.7 x 10(7)/kg (range, 1.2 to 4.9 x 10(7)/kg), and was above 2 x 10(7)/kg in only two cases. All patients received thiotepa, busulfan, cyclophosphamide and anti-thymocyte globulin as conditioning; cyclosporine and prednisone for graft-versus-host disease (GVHD) prophylaxis; and G-CSF from day +7 until engraftment. All seven evaluable cases engrafted. The median time to reach an absolute neutrophil count > or =0.5 x 10(9)/l and > or =1 x 10(9)/l was 22 days (range, 19-52 days) and 28 days (range, 23-64 days), respectively. In the four patients evaluable for platelet recovery time to levels of > or =20 x 10(9) platelets/l, > or =50 x 10(9) platelets/l, and > or =100 x 10(9) platelets/l, these ranged from 50 to 128 days, 60 to 139 days, and 105 to 167 days, respectively. Three patients developed acute GVHD above grade II, and three of the five patients at risk developed extensive chronic GVHD. Four patients, all transplanted in chronic phase, remain alive in molecular remission more than 18, 19, 24 and 42 months after transplantation. These preliminary results suggest that UD-CBT may be considered a reasonable alternative in adults with CML who lack an appropriate bone marrow donor.
Acute Disease↗
Additional cytogenetic changes do not influence the outcome of patients with newly diagnosed acute promyelocytic leukemia treated with an ATRA plus anthracyclin based protocol. A report of the Spanish group PETHEMA.
BACKGROUND AND OBJECTIVES: To analyze in patients with de novo acute promyelocytic leukemia (APL) treated with an ATRA plus anthracyclin-based protocol if the presence of additional cytogenetic aberrations to the t(15;17) influences: 1. clinical and biological presenting features; 2. disease outcome. DESIGN AND METHODS: One hundred and thirteen patients with newly diagnosed APL enrolled in the APL-96 protocol of the Spanish PETHEMA group were studied by conventional karyotyping, FISH and RT-PCR for the PML-RARa fusion. Treatment was homogeneous in all cases and consisted of anthracyclines and ATRA. RESULTS: Additional chromosome aberrations were observed in 30% of cases. The most frequent secondary changes were +8 (14 cases), and abnormalities of chromosomes 9 or 3 (4 patients each), and of chromosomes 1 and 8 (3 cases each). No clinical, biological, morphological, immunophenotypic or molecular differences were observed between the group of APLs with t(15;17) alone and the group of patients with additional changes. Patients with additional changes had a higher rates of complete remission (CR) and 4-year disease-free survival (DFS) (97%, and 97%, respectively) than patients with t(15;17) alone (CR, 70% and DFS, 84%) but these differences were not statistically significant. INTERPRETATION AND CONCLUSIONS: Patients with APL and additional cytogenetic abnormalities do not show different clinical, biological, morphological or molecular features as compared to patients with t(15;17) alone. The prognosis of patients with APL and t(15;17) alone and those with additional changes is similar in both groups. This study indicates that there is no rationale for administering more intensive treatment in APL patients with additional cytogenetic abnormalities receiving ATRA plus anthracycline-based chemotherapy.
Adolescent↗
Carbamate kinase can replace in vivo carbamoyl phosphate synthetase. Implications for the evolution of carbamoyl phosphate biosynthesis.
The exclusive involvement of carbamate kinase (CK) in fermentative ATP production and of carbamoyl phosphate synthetase (CPS) in the production of carbamoyl phosphate (CP) for pyrimidines and arginine biosynthesis was challenged by the finding of CK as the only activity synthesising CP in the archaea Pyrococcus furiosus and Pyrococcus abyssi. We now show that CK can replace CPS in vivo: transformation of Escherichia coli devoid of the CPS gene with plasmids encoding the CK from P. furiosus or from Enterococcus faecalis (which uses CK for making ATP) restores the ability of CPS-deficient E. coli to grow in the absence of arginine and uracil if ammonia and bicarbonate are present.
Ammonia↗
Site-directed mutagenesis of the regulatory domain of Escherichia coli carbamoyl phosphate synthetase identifies crucial residues for allosteric regulation and for transduction of the regulatory signals.
Carbamoyl phosphate (CP), the essential precursor of pyrimidines and arginine, is made in Escherichia coli by a single carbamoyl phosphate synthetase (CPS) consisting of 41.4 and 117.7 kDa subunits, which is feed-back inhibited by UMP and activated by IMP and ornithine. The large subunit catalyzes CP synthesis from ammonia in three steps, and binds the effectors in its 15 kDa C-terminal domain. Fifteen site-directed mutations were introduced in 13 residues of this domain to investigate the mechanism of allosteric modulation by UMP and IMP. Two mutations, K993A and V994A, decreased significantly or abolished enzyme activity, apparently by interfering with the step of carbamate synthesis, and one mutation, T974A, negatively affected ornithine activation. S948A, K954A, T974A, K993A and K993W/H995A abolished or greatly hampered IMP activation and UMP inhibition as well as the binding of both effectors, monitored using photoaffinity labeling and ultracentrifugation binding assays. V994A also decreased significantly IMP and UMP binding. L990A, V991A, H995A, G997A and G1008A had more modest effects or affected more the modulation by and the binding of one than of the other nucleotide. K993W, R1020A, R1021A and K1061A were without substantial effects. The results confirm the independence of the regulatory and catalytic centers, and also confirm functional predictions based on the X-ray structure of an IMP-CPS complex. They prove that the inhibitor UMP and the activator IMP bind in the same site, and exclude that the previously observed binding of ornithine and glutamine in this site were relevant for enzyme activation. K993 and V994 appear to be involved in the transmission of the regulatory signals triggered by UMP and IMP binding. These effectors possibly change the position of K993 and V994, and alter the intermolecular contacts mediated by the regulatory domain.
Allosteric Regulation↗
The goodpasture autoantigen. Identification of multiple cryptic epitopes on the NC1 domain of the alpha3(IV) collagen chain.
Goodpasture (GP) disease is an autoimmune disorder in which autoantibodies against the alpha3(IV) chain of type IV collagen bind to the glomerular and alveolar basement membranes, causing progressive glomerulonephritis and pulmonary hemorrhage. Two major conformational epitope regions have been identified on the noncollagenous domain of type IV collagen (NC1 domain) of the alpha3(IV) chain as residues 17-31 (E(A)) and 127-141 (E(B)) (Netzer, K.-O. et al. (1999) J. Biol. Chem. 274, 11267-11274). To determine whether these regions are two distinct epitopes or form a single epitope, three GP sera were fractionated by affinity chromatography on immobilized NC1 chimeras containing the E(A) and/or the E(B) region. Four subpopulations of GP antibodies with distinct epitope specificity for the alpha3(IV)NC1 domain were thus separated and characterized. They were designated GP(A), GP(B), GP(AB), and GP(X), to reflect their reactivity with E(A) only, E(B) only, both regions, and neither, respectively. Hence, regions E(A) and E(B) encompass critical amino acids that constitute three distinct epitopes for GP(A), GP(B), and GP(AB) antibodies, respectively, whereas the epitope for GP(X) antibodies is located in a different unknown region. The GP(A) antibodies were consistently immunodominant, accounting for 60-65% of the total immunoreactivity to alpha3(IV)NC1; thus, they probably play a major role in pathogenesis. Regions E(A) and E(B) are held in close proximity because they jointly form the epitope for Mab3, a monoclonal antibody that competes for binding with GP autoantibodies. All GP epitopes are sequestered in the hexamer configuration of the NC1 domain found in tissues and are inaccessible for antibody binding unless dissociation of the hexamer occurs, suggesting a possible mechanism for etiology of GP disease. GP antibodies have the capacity to extract alpha3(IV)NC1 monomers, but not dimers, from native human glomerular basement membrane hexamers, a property that may be of fundamental importance for the pathogenesis of the disease.
Anti-Glomerular Basement Membrane Disease↗
Incidence, characterization and prognostic significance of chromosomal abnormalities in 640 patients with primary myelodysplastic syndromes. Grupo Cooperativo Español de Citogenética Hematológica.
Recently, a consensus International Prognostic Scoring System (IPSS) for predicting outcome and planning therapy in the myelodysplastic syndromes (MDS) has been developed. However, the intermediate-risk cytogenetic subgroup defined by the IPSS includes a miscellaneous number of different single abnormalities for which real prognosis at present is uncertain. The main aims of this study were to evaluate in an independent series the prognostic value of the IPSS and to identify chromosomal abnormalities with a previously unrecognized good or poor prognosis in 640 patients. In univariate analyses, cases with single 1q abnormalities experienced poor survival, whereas those with trisomy 8 had a higher risk of acute leukaemic transformation than the remaining patients (P = 0.004 and P = 0.009 respectively). Patients with single del(12p) had a similar survival to patients with a normal karyotype and showed some trend for a better survival than other cases belonging to the IPSS intermediate-risk cytogenetic subgroup (P = 0.045). Multivariate analyses demonstrated that IPSS cytogenetic prognostic subgroup, proportion of bone marrow blasts and haemoglobin level were the main prognostic factors for survival, and the first two characteristics and platelet count were the best predictors of acute leukaemic transformation risk. A large international co-operative study should be carried out to clarify these findings.
Adult↗