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Search Results: 1 - 10 of 325541 matches for " Sabri S. Sanabani "
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Two successful pregnancies in a woman with chronic myeloid leukemia exposed to nilotinib during the first trimester of her second pregnancy: case study
Monika Conchon, Sabri S Sanabani, Israel Bendit, Fernanda Santos, Mariana Serpa, Pedro Dorliac-Llacer
Journal of Hematology & Oncology , 2009, DOI: 10.1186/1756-8722-2-42
Abstract: Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder that occurs as a result of a reciprocal translocation between chromosome 22 and chromosome 9, or the Philadelphia translocation [1]. This translocation creates a fusion gene-breakpoint cluster region bcr-abl proto-oncogene, which encodes an oncoprotein that has constitutively active abl tyrosine kinase (TK) activity. The introduction of the TK inhibitor (TKI) imatinib in 1998 indisputably advanced the clinical management of cancer. Imatinib has demonstrated its efficacy by increasing overall survival and substantially improving the life expectancy and quality of life of patients with CML. As a result, patients who are of childbearing age and are currently being treated with imatinib now find themselves contemplating reproductive opportunities that would not have otherwise been possible. However, the occurrence of CML during pregnancy poses a unique clinical challenge for physicians treating these patients and requires balancing concerns between maternal survival and fetal health in both the short- and long-term. Because imatinib was teratogenic in rats, it was strongly advised that effective contraception be used during therapy to prevent pregnancy [2]. The inability of patients to tolerate treatment and the emergence of bcr-abl mutations that reduced the binding affinity of imatinib prompted pharmaceutical research that led to the discovery of similarly effective, targeted, second generation TKIs such as nilotinib (Novartis) and dasatinib (Bristol-Myers Squibb). There is still insufficient efficacy and safety data on these newer medications to warrant their safety in pregnant women with CML. In this study, we are reporting the outcome of a patient with CML who became pregnant twice successfully. The patient was only observed without active intervention for the duration of her first pregnancy while received nilotinib at the time of her second conception.In February 2006, during a routine antenata
Correlation between LTR point mutations and proviral load levels among Human T cell Lymphotropic Virus type 1 (HTLV-1) asymptomatic carriers
Walter K Neto, Antonio C Da-Costa, Ana Carolina S de Oliveira, Vanessa P Martinez, Youko Nukui, Ester C Sabino, Sabri S Sanabani
Virology Journal , 2011, DOI: 10.1186/1743-422x-8-535
Abstract: nfected cells and alter the proviral load (PvL). To test this hypothesis, we conducted a cross-sectional genetic analysis to compare the near-complete LTR nucleotide sequences that cover the TRE1 region in a sample of HTLV-1 asymptomatic carriers with different PvL burden.A total of 94 asymptomatic HTLV-1 carriers with both sequence from the 5' long terminal repeat (LTR) and a PvL for Tax DNA measured using a sensitive SYBR Green real-time PCR were studied. The 94 subjects were divided into three groups based on PvL measurement: 31 low, 29 intermediate, and 34 high. In addition, each group was compared based on sex, age, and viral genotypes. In another analysis, the median PvLs between individuals infected with mutant and wild-type viruses were compared.Using a categorical analysis, a G232A substitution, located in domain A of the TRE-1 motif, was detected in 38.7% (12/31), 27.5% (8/29), and 61.8% (21/34) of subjects with low, intermediate, or high PvLs, respectively. A significant difference in the detection of this mutation was found between subjects with a high or low PvL and between those with a high or intermediate PvL (both p < 0.05), but not between subjects with a low or intermediate PvL (p > 0.05). This result was confirmed by a non-parametric analysis that showed strong evidence for higher PvLs among HTLV-1 positive individuals with the G232A mutation than those without this mutation (p < 0.03). No significant difference was found between the groups in relation to age, sex or viral subtypes (p > 0. 05).The data described here show that changes in domain A of the HTLV-1 TRE-1 motif resulting in the G232A mutation may increase HTLV-1 replication in a majority of infected subjects.Human T-cell leukemia virus type I (HTLV-I) is the retrovirus responsible for adult T-cell leukemia (ATL) and the chronic neurological disorder HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) [1-4]. The virus has also been implicated in a variety of inflammatory
Successful Pregnancy and Delivery in a Patient with Chronic Myeloid Leukemia while on Dasatinib Therapy
Monika Conchon,Sabri S. Sanabani,Mariana Serpa,Mafalda M. Y. Novaes,Luciana Nardinelli,Patrícia B. Ferreira,Pedro Enrique Dorliac-Llacer,Israel Bendit
Advances in Hematology , 2010, DOI: 10.1155/2010/136252
Abstract: Here we report the case of an 18-year-old woman with chronic myeloid leukemia (CML) who became pregnant while undergoing treatment with dasatinib. Before pregnancy, she received imatinib mesylate therapy but could not tolerate the treatment. The regimen was then changed to dasatinib at a dose of 70?mg b.i.d. While she was in hematological remission and on dasatinib therapy, she became pregnant. The unplanned pregnancy was identified after the patient had experienced four weeks of amenorrhea. Because the patient elected to continue the pregnancy to term, dasatinib was stopped immediately. Meanwhile, CML hematological relapse occurred and then she was treated with interferon- (IFN- ) (9 million IU/day) throughout the pregnancy without a complete hematological response. She successfully gave birth to a male baby at 33 weeks by cesarean section delivery with no sequelae or malformations. Although this experience is limited to a single patient, it provides a useful contribution for counselling patients inadvertently exposed to dasatinib during pregnancy. 1. Introduction CML is a myeloproliferative disorder of blood stem cells [1]. The causative molecular defect is the bcr-abl protein, which is encoded by the Philadelphia chromosome (Ph) [2]. This genetic anomaly arises from an exchange of genetic material between chromosomes 9 and 22, which results in the fusion of the breakpoint cluster region (bcr) and the Abelson leukemia virus (abl) genes. The resulting gene encodes a constitutively active protein kinase that activates a number of proteins involved in cell-cycle regulation that hasten cell division and affect DNA repair. A new class of medications known as TKIs has been developed to selectively inhibit the activity of this abnormal enzyme. Imatinib mesylate is a TKI able to produce long-term suppression of CML in the majority of patients [3]. The drug has become a first-line therapy for newly diagnosed CML patients. As a result, female patients with CML who are of childbearing age and are currently being treated with imatinib now find themselves contemplating reproductive opportunities that would not have otherwise been possible. However, the advantages of this therapy in women of reproductive age are balanced by concerns of imatinib increasing the risk of birth defects. Dasatinib is an oral TKI that binds to active and inactive forms of bcr-abl kinase. It is licensed for the treatment of adults with chronic, accelerated, or blast-phase CML with resistance or intolerance to prior therapy, including imatinib. However, the safety profile of inadvertent
The Use of Imatinib Mesylate as a Lifesaving Treatment of Chronic Myeloid Leukemia Relapse after Bone Marrow Transplantation
Monika Conchon,Sabri S. Sanabani,Israel Bendit,Carla Luana Dinardo,Lucia Dias,Dalton de Alencar Fischer Chamone,Pedro Enrique Dorlhiac-Llacer,Frederico Luiz Dulley
Journal of Transplantation , 2009, DOI: 10.1155/2009/357093
Abstract: We describe the response of imatinib as lifesaving treatment of chronic myeloid leukemia (CML) relapse in seven patients who underwent allogeneic bone marrow transplantation (alloBMT) at our institution over a period of 4 years. Retrospective analysis of their medical records revealed that a mean age at transplant was 45.2 years. The median time to diagnosis was 7.4 years after transplant. At relapse, four, two, and one patients were classified as having hematologic, major molecular, and cytogenetic relapse, respectively. At imatinib initiation, five had CML in a chronic phase, while one patient was diagnosed as having accelerated phase and blast crisis. All these patients could be evaluated for the therapeutic efficacy. At a mean of follow-up of 1.9 years of therapy, all evaluable patients achieved major molecular response without compromising safety. Consistent with available data, our results indicate that imatinib is safe and effective treatment option for patients with relapse after BMT.
Low-Cost Ultra-Wide Genotyping Using Roche/454 Pyrosequencing for Surveillance of HIV Drug Resistance
Dawn M. Dudley, Emily N. Chin, Benjamin N. Bimber, Sabri S. Sanabani, Leandro F. Tarosso, Priscilla R. Costa, Mariana M. Sauer, Esper G. Kallas, David H. O.’Connor
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0036494
Abstract: Background Great efforts have been made to increase accessibility of HIV antiretroviral therapy (ART) in low and middle-income countries. The threat of wide-scale emergence of drug resistance could severely hamper ART scale-up efforts. Population-based surveillance of transmitted HIV drug resistance ensures the use of appropriate first-line regimens to maximize efficacy of ART programs where drug options are limited. However, traditional HIV genotyping is extremely expensive, providing a cost barrier to wide-scale and frequent HIV drug resistance surveillance. Methods/Results We have developed a low-cost laboratory-scale next-generation sequencing-based genotyping method to monitor drug resistance. We designed primers specifically to amplify protease and reverse transcriptase from Brazilian HIV subtypes and developed a multiplexing scheme using multiplex identifier tags to minimize cost while providing more robust data than traditional genotyping techniques. Using this approach, we characterized drug resistance from plasma in 81 HIV infected individuals collected in S?o Paulo, Brazil. We describe the complexities of analyzing next-generation sequencing data and present a simplified open-source workflow to analyze drug resistance data. From this data, we identified drug resistance mutations in 20% of treatment na?ve individuals in our cohort, which is similar to frequencies identified using traditional genotyping in Brazilian patient samples. Conclusion The developed ultra-wide sequencing approach described here allows multiplexing of at least 48 patient samples per sequencing run, 4 times more than the current genotyping method. This method is also 4-fold more sensitive (5% minimal detection frequency vs. 20%) at a cost 3–5× less than the traditional Sanger-based genotyping method. Lastly, by using a benchtop next-generation sequencer (Roche/454 GS Junior), this approach can be more easily implemented in low-resource settings. This data provides proof-of-concept that next-generation HIV drug resistance genotyping is a feasible and low-cost alternative to current genotyping methods and may be particularly beneficial for in-country surveillance of transmitted drug resistance.
Molecular measurement of BCR-ABL transcript variations in chronic myeloid leukemia patients in cytogenetic remission
Mariana Serpa, Sabri S Sanabani, Pedro Dorliac-Llacer, Monika Conchon, Thales Pereira, Luciana Nardinelli, Juliana Costa, Mafalda Novaes, Patricia Ferreira, Israel Bendit
BMC Blood Disorders , 2010, DOI: 10.1186/1471-2326-10-7
Abstract: The absolute level of BCR-ABL transcript from peripheral blood was serially measured every 4 to 12 weeks by RT-qPCR. Only level variations > 0.5%, according to the international scale, was considered positive. Sequential cytogenetic analysis was also performed in bone marrow samples from all patients using standard protocols.Based on sequential analysis of BCR-ABL transcripts, the 91 patients were divided into three categories: (A) 57 (62.6%) had no variation on sequential analysis; (B) 30 (32.9%) had a single positive variation result obtained in a single sample; and (C) 4 (4.39%) had variations of BCR-ABL transcripts in at least two consecutive samples. Of the 34 patients who had elevated levels of transcripts (group B and C), 19 (55.8%) had a < 1% of BCR-ABL/BCR ratio, 13 (38.2%) patients had a 1% to 10% increase and 2 patients had a >10% increase of RT-qPCR. The last two patients had lost a CCyR, and none of them showed mutations in the ABL gene. Transient cytogenetic alterations in Ph-negative cells were observed in five (5.5%) patients, and none of whom lost CCyR.Despite an increase levels of BCR-ABL/BCR ratio variations by RT-qPCR, the majority of CML patients with MMR remained in CCyR. Thus, such single variations should neither be considered predictive of subsequent failure and nor an indication for altering imatinib dose or switching to second generation therapy. Changing of imatinib on the basis of BCR-ABL/BCR% sustained increase and mutational studies is a prudent approach for preserving other therapeutic options in imatinib-resistant patients.CML is a myeloproliferative disorder of blood stem cells [1]. The causative molecular defect is the BCR-ABL protein, which is encoded by the Philadelphia chromosome (Ph) [2]. This genetic anomaly arises from an exchange of genetic material between chromosomes 9 and 22, which results in the fusion of the breakpoint cluster region (BCR) and the Abelson leukemia virus (ABL) protooncogene [3,4]. The resulting gene enco
Unexpected Diversity of Cellular Immune Responses against Nef and Vif in HIV-1-Infected Patients Who Spontaneously Control Viral Replication
Leandro F. Tarosso,Mariana M. Sauer,Sabri Sanabani,Maria Teresa Giret,Helena I. Tomiyama,John Sidney,Shari M. Piaskowski,Ricardo S. Diaz,Ester C. Sabino,Alessandro Sette,Jorge Kalil-Filho,David I. Watkins,Esper G. Kallas
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0011436
Abstract: HIV-1-infected individuals who spontaneously control viral replication represent an example of successful containment of the AIDS virus. Understanding the anti-viral immune responses in these individuals may help in vaccine design. However, immune responses against HIV-1 are normally analyzed using HIV-1 consensus B 15-mers that overlap by 11 amino acids. Unfortunately, this method may underestimate the real breadth of the cellular immune responses against the autologous sequence of the infecting virus.
Expansion in CD39+ CD4+ Immunoregulatory T Cells and Rarity of Th17 Cells in HTLV-1 Infected Patients Is Associated with Neurological Complications
Fabio E. Leal equal contributor,Lishomwa C. Ndhlovu equal contributor,Aaron M. Hasenkrug,Fernanda R. Bruno,Karina I. Carvalho,Harry Wynn-Williams,Walter K. Neto,Sabri S. Sanabani,Aluisio C. Segurado,Douglas F. Nixon,Esper G. Kallas
PLOS Neglected Tropical Diseases , 2013, DOI: 10.1371/journal.pntd.0002028
Abstract: HTLV-1 infection is associated with several inflammatory disorders, including the neurodegenerative condition HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). It is unclear why a minority of infected subjects develops HAM/TSP. CD4+ T cells are the main target of infection and play a pivotal role in regulating immunity to HTLV and are hypothesized to participate in the pathogenesis of HAM/TSP. The CD39 ectonucleotidase receptor is expressed on CD4+ T cells and based on co-expression with CD25, marks T cells with distinct regulatory (CD39+CD25+) and effector (CD39+CD25?) function. Here, we investigated the expression of CD39 on CD4+ T cells from a cohort of HAM/TSP patients, HTLV-1 asymptomatic carriers (AC), and matched uninfected controls. The frequency of CD39+ CD4+ T cells was increased in HTLV-1 infected patients, regardless of clinical status. More importantly, the proportion of the immunostimulatory CD39+CD25? CD4+ T-cell subset was significantly elevated in HAM/TSP patients as compared to AC and phenotypically had lower levels of the immunoinhibitory receptor, PD-1. We saw no difference in the frequency of CD39+CD25+ regulatory (Treg) cells between AC and HAM/TSP patients. However, these cells transition from being anergic to displaying a polyfunctional cytokine response following HTLV-1 infection. CD39?CD25+ T cell subsets predominantly secreted the inflammatory cytokine IL-17. We found that HAM/TSP patients had significantly fewer numbers of IL-17 secreting CD4+ T cells compared to uninfected controls. Taken together, we show that the expression of CD39 is upregulated on CD4+ T cells HAM/TSP patients. This upregulation may play a role in the development of the proinflammatory milieu through pathways both distinct and separate among the different CD39 T cell subsets. CD39 upregulation may therefore serve as a surrogate diagnostic marker of progression and could potentially be a target for interventions to reduce the development of HAM/TSP.
HTLV-1 Tax Specific CD8+ T Cells Express Low Levels of Tim-3 in HTLV-1 Infection: Implications for Progression to Neurological Complications
Lishomwa C. Ndhlovu equal contributor ,Fabio E. Leal equal contributor,Aaron M. Hasenkrug,Aashish R. Jha,Karina I. Carvalho,Ijeoma G. Eccles-James,Fernanda R. Bruno,Raphaella G. S. Vieira,Vanessa A. York,Glen M. Chew,R. Brad Jones,Yuetsu Tanaka,Walter K. Neto,Sabri S. Sanabani,Mario A. Ostrowski,Aluisio C. Segurado,Douglas F. Nixon ?,Esper G. Kallas ?
PLOS Neglected Tropical Diseases , 2011, DOI: 10.1371/journal.pntd.0001030
Abstract: The T cell immunoglobulin mucin 3 (Tim-3) receptor is highly expressed on HIV-1-specific T cells, rendering them partially “exhausted” and unable to contribute to the effective immune mediated control of viral replication. To elucidate novel mechanisms contributing to the HTLV-1 neurological complex and its classic neurological presentation called HAM/TSP (HTLV-1 associated myelopathy/tropical spastic paraparesis), we investigated the expression of the Tim-3 receptor on CD8+ T cells from a cohort of HTLV-1 seropositive asymptomatic and symptomatic patients. Patients diagnosed with HAM/TSP down-regulated Tim-3 expression on both CD8+ and CD4+ T cells compared to asymptomatic patients and HTLV-1 seronegative controls. HTLV-1 Tax-specific, HLA-A*02 restricted CD8+ T cells among HAM/TSP individuals expressed markedly lower levels of Tim-3. We observed Tax expressing cells in both Tim-3+ and Tim-3? fractions. Taken together, these data indicate that there is a systematic downregulation of Tim-3 levels on T cells in HTLV-1 infection, sustaining a profoundly highly active population of potentially pathogenic T cells that may allow for the development of HTLV-1 complications.
Characterization and frequency of a newly identified HIV-1 BF1 intersubtype circulating recombinant form in S?o Paulo, Brazil
Sabri Sanabani, évelyn de Souza Pastena, Walter Neto, Vanessa Martinez, Ester Sabino
Virology Journal , 2010, DOI: 10.1186/1743-422x-7-74
Abstract: Initially, we selected 36 samples from 888 adult patients residing in S?o Paulo who had previously been diagnosed as being infected with subclade F1 based on pol subgenomic fragment sequencing. Proviral DNA integrated in peripheral blood mononuclear cells (PBMC) was amplified from the purified genomic DNA of all 36-blood samples by five overlapping PCR fragments followed by direct sequencing. Sequence data were obtained from the five fragments that showed identical genomic structure and phylogenetic trees were constructed and compared with previously published sequences. Genuine subclade F1 sequences and any other sequences that exhibited unique mosaic structures were omitted from further analysisOf the 36 samples analyzed, only six sequences, inferred from the pol region as subclade F1, displayed BF1 identical mosaic genomes with a single intersubtype breakpoint identified at the nef-U3 overlap (HXB2 position 9347-9365; LTR region). Five of these isolates formed a rigid cluster in phylogentic trees from different subclade F1 fragment regions, which we can now designate as CRF46_BF1. According to our estimate, the new CRF accounts for 0.56% of the HIV-1 circulating strains in S?o Paulo. Comparison with previously published sequences revealed an additional five isolates that share an identical mosaic structure with those reported in our study. Despite sharing a similar recombinant structure, only one sequence appeared to originate from the same CRF46_BF1 ancestor.We identified a new circulating recombinant form with a single intersubtype breakpoint identified at the nef-LTR U3 overlap and designated CRF46_BF1. Given the biological importance of the LTR U3 region, intersubtype recombination in this region could play an important role in HIV evolution with critical consequences for the development of efficient genetic vaccines.The immense genetic variability of HIV-1 viruses is considered the key factor that frustrates efforts to halt the virus epidemic and poses a ser
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