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Find video protocols related to scientific articles indexed in Pubmed.
Liver fibrosis progression despite HCV cure with antiviral therapy in HIV-HCV-coinfected patients.
Antivir. Ther. (Lond.)
PUBLISHED: 10-15-2014
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Accelerated liver fibrosis and more frequent hepatic decompensation events and liver-related deaths are characteristically seen in chronic hepatitis C patients coinfected with HIV compared to HCV-monoinfected individuals. Quantitative estimates of long-term clinical benefits derived from curing HCV with antiviral therapy in coinfected patients are scarce, despite being needed for accurate cost-effectiveness decisions using expensive DAA in this population.
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Histone deacetylase 11: A novel epigenetic regulator of myeloid derived suppressor cell expansion and function.
Mol. Immunol.
PUBLISHED: 08-23-2014
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Myeloid-derived suppressor cells (MDSCs), a heterogeneous population of cells capable of suppressing anti-tumor T cell function in the tumor microenvironment, represent an imposing obstacle in the development of cancer immunotherapeutics. Thus, identifying elements essential to the development and perpetuation of these cells will undoubtedly improve our ability to circumvent their suppressive impact. HDAC11 has emerged as a key regulator of IL-10 gene expression in myeloid cells, suggesting that this may represent an important targetable axis through which to dampen MDSC formation. Using a murine transgenic reporter model system where eGFP expression is controlled by the HDAC11 promoter (Tg-HDAC11-eGFP), we provide evidence that HDAC11 appears to function as a negative regulator of MDSC expansion/function in vivo. MDSCs isolated from EL4 tumor-bearing Tg-HDAC11-eGFP display high expression of eGFP, indicative of HDAC11 transcriptional activation at steady state. In striking contrast, immature myeloid cells in tumor-bearing mice display a diminished eGFP expression, implying that the transition of IMC to MDSC's require a decrease in the expression of HDAC11, where we postulate that it acts as a gate-keeper of myeloid differentiation. Indeed, tumor-bearing HDAC11-knockout mice (HDAC11-KO) demonstrate a more suppressive MDSC population as compared to wild-type (WT) tumor-bearing control. Notably, the HDAC11-KO tumor-bearing mice exhibit enhanced tumor growth kinetics when compare to the WT control mice. Thus, through a better understanding of this previously unknown role of HDAC11 in MDSC expansion and function, rational development of targeted epigenetic modifiers may allow us to thwart a powerful barrier to efficacious immunotherapies.
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A novel role for histone deacetylase 6 in the regulation of the tolerogenic STAT3/IL-10 pathway in APCs.
J. Immunol.
PUBLISHED: 08-08-2014
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APCs are critical in T cell activation and in the induction of T cell tolerance. Epigenetic modifications of specific genes in the APC play a key role in this process, and among them histone deacetylases (HDACs) have emerged as key participants. HDAC6, one of the members of this family of enzymes, has been shown to be involved in regulation of inflammatory and immune responses. In this study, to our knowledge we show for the first time that genetic or pharmacologic disruption of HDAC6 in macrophages and dendritic cells results in diminished production of the immunosuppressive cytokine IL-10 and induction of inflammatory APCs that effectively activate Ag-specific naive T cells and restore the responsiveness of anergic CD4(+) T cells. Mechanistically, we have found that HDAC6 forms a previously unknown molecular complex with STAT3, association that was detected in both the cytoplasmic and nuclear compartments of the APC. By using HDAC6 recombinant mutants we identified the domain comprising amino acids 503-840 as being required for HDAC6 interaction with STAT3. Furthermore, by re-chromatin immunoprecipitation we confirmed that HDAC6 and STAT3 are both recruited to the same DNA sequence within the Il10 gene promoter. Of note, disruption of this complex by knocking down HDAC6 resulted in decreased STAT3 phosphorylation--but no changes in STAT3 acetylation--as well as diminished recruitment of STAT3 to the Il10 gene promoter region. The additional demonstration that a selective HDAC6 inhibitor disrupts this STAT3/IL-10 tolerogenic axis points to HDAC6 as a novel molecular target in APCs to overcome immune tolerance and tips the balance toward T cell immunity.
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Ibrutinib (imbruvica): a novel targeted therapy for chronic lymphocytic leukemia.
P T
PUBLISHED: 08-02-2014
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Ibrutinib (Imbruvica): a novel targeted therapy for chronic lymphocytic leukemia.
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Inhibition of ER stress-associated IRE-1/XBP-1 pathway reduces leukemic cell survival.
J. Clin. Invest.
PUBLISHED: 05-08-2014
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Activation of the ER stress response is associated with malignant progression of B cell chronic lymphocytic leukemia (CLL). We developed a murine CLL model that lacks the ER stress-associated transcription factor XBP-1 in B cells and found that XBP-1 deficiency decelerates malignant progression of CLL-associated disease. XBP-1 deficiency resulted in acquisition of phenotypes that are disadvantageous for leukemic cell survival, including compromised BCR signaling capability and increased surface expression of sphingosine-1-phosphate receptor 1 (S1P1). Because XBP-1 expression requires the RNase activity of the ER transmembrane receptor IRE-1, we developed a potent IRE-1 RNase inhibitor through chemical synthesis and modified the structure to facilitate entry into cells to target the IRE-1/XBP-1 pathway. Treatment of CLL cells with this inhibitor (B-I09) mimicked XBP-1 deficiency, including upregulation of IRE-1 expression and compromised BCR signaling. Moreover, B-I09 treatment did not affect the transport of secretory and integral membrane-bound proteins. Administration of B-I09 to CLL tumor-bearing mice suppressed leukemic progression by inducing apoptosis and did not cause systemic toxicity. Additionally, B-I09 and ibrutinib, an FDA-approved BTK inhibitor, synergized to induce apoptosis in B cell leukemia, lymphoma, and multiple myeloma. These data indicate that targeting XBP-1 has potential as a treatment strategy, not only for multiple myeloma, but also for mature B cell leukemia and lymphoma.
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Increased genomic instability may contribute to the development of kinase domain mutations in chronic myeloid leukemia.
Int. J. Hematol.
PUBLISHED: 04-18-2014
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Imatinib resistance in chronic myeloid leukemia (CML) is commonly due to BCR-ABL kinase domain mutations (KDMs). In this single-institution retrospective analysis, patients with KDMs were identified from a cohort of patients treated for CML at our institution. Clinical outcomes were assessed based on the characteristics of the KDMs and results of cytogenetic analysis. In total, we compared 26 patients with KDM to those without; 46 % (n = 12) versus 20 % (n = 57) progressed to advanced phase (P = 0.003). Median overall survival was 22 months, 109 months, and not reached in patients with P-loop, T315I, and non-P-loop mutations (P = 0.127). KDM patients had a median progression-free survival (PFS) and overall survival of 75 and 109 months; however, neither was reached in the non-mutation cohort (P = 0.0007, P = 0.235). Median PFS in patients with single versus compound or double mutations was not reached versus 10 months (P = 0.014). We conclude that T315I, P-loop, and compound mutations may worsen prognosis in CML.
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Genomic aberrations deletion 11q and deletion 17p independently predict for worse progression-free and overall survival after allogeneic hematopoietic cell transplantation for chronic lymphocytic leukemia.
Leuk. Res.
PUBLISHED: 04-04-2014
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Chronic lymphocytic leukemia remains incurable despite availability of potent chemoimmunotherapy regimens. Allogeneic hematopoietic cell transplantation (HCT) is the only modality that offers the possibility of cure. To identify predictors of progression-free and overall survival, we evaluated outcomes of 43 consecutive patients who received an allograft for advanced CLL. The majority received a reduced intensity conditioning regimen (n=37). Donors were HLA matched-related (n=18), matched-unrelated (n=15), mismatched-unrelated (n=7), or umbilical cord blood (n=3). The median progression-free (PFS) and overall survival (OS) were 31.4 months and 46.4 months respectively. Twenty (46.5%) patients were alive and in complete remission at a median follow-up of 31.4 months. NRM was higher than previously published series for CLL, likely due to a high burden of comorbidity (22 patients with HCT-CI ? 2) and a high proportion receiving HLA mismatched-unrelated donor or umbilical cord blood cells. Presence of del (11q), del(17p), or progressive disease at HCT are independent predictors of worse PFS and OS. New strategies are needed to improve survival outcomes in CLL associated with poor risk cytogenetics.
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Working conditions and health in Central America: a survey of 12,024 workers in six countries.
Occup Environ Med
PUBLISHED: 03-20-2014
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To describe the survey methodology and initial general findings of the first Central American Survey of Working Conditions and Health.
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Divergent roles of histone deacetylase 6 (HDAC6) and histone deacetylase 11 (HDAC11) on the transcriptional regulation of IL10 in antigen presenting cells.
Mol. Immunol.
PUBLISHED: 02-17-2014
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The anti-inflammatory cytokine IL-10 is a key modulator of immune responses. A better understanding of the regulation of this cytokine offers the possibility of tipping the balance of the immune response toward either tolerance, or enhanced immune responses. Histone deacetylases (HDACs) have been widely described as negative regulators of transcriptional regulation, and in this context, the primarily nuclear protein HDAC11 was shown to repress il-10 gene transcriptional activity in antigen-presenting cells (APCs). Here we report that another HDAC, HDAC6, primarily a cytoplasmic protein, associates with HDAC11 and modulates the expression of IL-10 as a transcriptional activator. To our knowledge, this is the first demonstration of two different HDACs being recruited to the same gene promoter to dictate divergent transcriptional responses. This dynamic interaction results in dynamic changes in the expression of IL-10 and might help to explain the intrinsic plasticity of the APC to determine T-cell activation versus T-cell tolerance.
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Clinical advances in the management of chronic myelogenous leukemia: focus on bosutinib and patient considerations.
Patient Prefer Adherence
PUBLISHED: 01-01-2014
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The treatment for chronic myeloid leukemia has changed significantly over the past 15 years, and as of now, there are five BCR-ABL1 (breakpoint cluster region-Abelson murine leukemia viral oncogene homolog 1) tyrosine kinase inhibitors that have gained approval for treatment of this disease. All five are very effective drugs, and the decision surrounding which to use in specific patients is based on numerous factors. Bosutinib is one of the newer tyrosine kinase inhibitors to gain approval, and has been studied in the first-line setting as well as after failure of other tyrosine kinase inhibitors. It is an SRC-ABL1 (steroid receptor co-activator-ABL1) inhibitor that works in the presence of most kinase domain mutations. The primary side effects of bosutinib are gastrointestinal upsets. In the appropriate clinical setting, bosutinib can be considered a valuable addition to the armamentarium of treatments available for chronic myeloid leukemia.
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Chronic Myelogenous Leukemia, Version 1.2014.
J Natl Compr Canc Netw
PUBLISHED: 11-15-2013
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The 2014 NCCN Clinical Practice Guidelines in Oncology for Chronic Myelogenous Leukemia recommend quantitative reverse-transcription polymerase chain reaction (QPCR) standardized to International Scale (IS) as the preferred method for monitoring molecular response to tyrosine kinase inhibitor (TKI) therapy. A BCR-ABL1 transcript level of 10% or less (IS) is now included as the response milestone at 3 and 6 months. Change of therapy to an alternate TKI is recommended for patients with BCR-ABL1 transcript levels greater than 10% (IS) at 3 months after primary treatment with imatinib. Continuing the same dose of TKI or switching to an alternate TKI are options for patients with BCR-ABL1 transcript levels greater than 10% (IS) at 3 months after primary treatment with dasatinib or nilotinib. The guidelines recommend 6-month evaluation with QPCR (IS) for patients with BCR-ABL1 transcript levels greater than 10% at 3 months. Monitoring with QPCR (IS) every 3 months is recommended for all patients, including those who meet response milestones at 3, 6, 12, and 18 months (BCR-ABL1 transcript level ?10% [IS] at 3 and 6 months, complete cytogenetic response at 12 and 18 months).
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The one-two punch: Combination treatment in chronic myeloid leukemia.
Crit. Rev. Oncol. Hematol.
PUBLISHED: 05-31-2013
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Despite the success of tyrosine kinase inhibitor (TKI) therapy in patients with chronic myeloid leukemia (CML), minimal residual disease persists, requiring indefinite treatment. Accumulated evidence has shown that leukemic stem cells (LSCs) in the bone marrow can survive TKI treatment via downstream BCR-ABL1-independent signaling pathways that are activated by soluble growth factors and interactions with the extracellular matrix in the bone marrow microenvironment. Research efforts have therefore turned to the identification and development of agents that target LSCs, and together with TKIs, have the potential to eradicate CML. A number of such agents are now under clinical investigation, and others are soon to enter early-phase studies. This review examines the pathways, molecular targets, and potential new therapeutics that, with TKIs, may provide an effective "one-two punch" to cure CML.
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Biomarkers for determining the prognosis in chronic myelogenous leukemia.
J Hematol Oncol
PUBLISHED: 03-28-2013
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The introduction of BCR-ABL1 tyrosine kinase inhibitors (TKIs) for treatment of chronic myelogenous leukemia in chronic phase (CML-CP) has revolutionized therapy, altering the outcome from one of shortened life expectancy to long-term survival. With over 10 years of long-term treatment with imatinib and several years of experience with the next generation of TKIs, including nilotinib, dasatinib, bosutinib, and ponatinib, it is becoming clear that many clinical parameters have great impact on the prognosis of patients with CML. Emerging novel gene expression profiling and molecular techniques also provide new insights into CML pathogenesis and have identified potential prognostic markers and therapeutic targets. This review presents the supporting data and discusses how certain clinical characteristics at diagnosis, the depth of early response, the presence of certain kinase domain mutations, and additional molecular changes serve as prognostic factors that may guide individualized treatment decisions for patients with CML-CP.
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Phase II study of CD4+-guided pentostatin lymphodepletion and pharmacokinetically targeted busulfan as conditioning for hematopoietic cell allografting.
Biol. Blood Marrow Transplant.
PUBLISHED: 02-05-2013
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One limitation of reduced-intensity preparative regimens is potential for graft failure. We have developed a regimen that targets CD4(+) lymphodepletion to ensure early and durable engraftment. The primary endpoint was achievement of ?50% CD3(+) donor chimerism by day +28. Forty-two patients (median age, 53 years; range, 29 to 73 years) received pentostatin 4 mg/m(2) i.v. on days -28, -21, and -14 when the CD4(+) cell count was >100 cells/?L and on days -4 and -3 regardless of CD4(+) level. Rituximab 375 mg/m(2) was administered to patients with CD20(+) malignancies on days -21, -14, -7, +1, and +8. Busulfan 200 mg/m(2) i.v. was administered on days -4 and -2 at a dose to target a cumulative AUC dose of 16,000 (±10%) ?mol·min/L. Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus plus methotrexate in 86% of patients. Donors were matched-related (47%), matched unrelated (43%), or mismatched unrelated (10%). Chronic lymphocytic leukemia (45%) and follicular non-Hodgkin lymphoma (14%) were the most common diagnoses. Disease status at initiation of the preparative regimen was complete remission in 22%, partial response in 55%, and stable/progression in 24%. The median percent CD4(+) cell count decrease from baseline (day -28) was 52% to day -21, 66% to day -14, 62% to day -7, and 91% to day 0. At day +28, all 42 patients (100%) had ?50% CD3(+) donor chimerism. No patient experienced graft failure. Overall response rate was 82% (complete remisson, 67%). The day +100 cumulative incidence of grade II-IV acute GVHD was 59% (grade III-IV acute GVHD, 19%), and the 2 year cumulative incidence of chronic GVHD was 69% (moderate/severe, 58%). Nonrelapse mortality was 2% at day +100 and 17% at 2 years. Two-year PFS was 55%, and OS was 68%. This regimen ensures durable engraftment, is effective against persistent disease, and results in relatively low mortality from causes other than relapse.
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Validation of the revised International Prognostic Scoring System in treated patients with myelodysplastic syndromes.
Am. J. Hematol.
PUBLISHED: 01-19-2013
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The International Prognostic Scoring System (IPSS) was recently revised (IPSS-R) under the auspices of the MDS Foundation as a collaborative international effort to refine its prognostic power. Our purpose was to externally validate this new risk model using a large single-institution cohort, determine its prognostic power in patients receiving active treatment, and explore its utility in guiding therapeutic decisions. Data were collected retrospectively from our myelodysplastic syndrome (MDS) database and verified by chart review. Of the data available for 1,088 patients, 152 (14%), 353 (32%), 237 (22%), 190 (18%), and 156 (14%) patients were classified as very low, low, intermediate, high, and very high risk, respectively, with median overall survival (OS) of 90 (95%CI 71-109), 54 (95%CI 50-59), 34 (95%CI 26-43), 21 (95%CI 17-25), and 13 months (95%CI 11-15), respectively (P?
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Developing strategies in the immunotherapy of leukemias.
Cancer Control
PUBLISHED: 01-11-2013
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In the current treatment paradigms for leukemias, hematopoietic stem cell transplant (HSCT) is considered the best option with a curative potential although more often than not it simply delays disease progression. Advances are needed, both in current therapies and in the development of new strategies. Partly from studying the nuances of the curative potential of stem cell transplant, we have come to appreciate the relevance of the immune response and the potential of immunotherapy.
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Ibrutinib: an evidence-based review of its potential in the treatment of advanced chronic lymphocytic leukemia.
Core Evid
PUBLISHED: 01-01-2013
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Chronic lymphocytic leukemia (CLL) is a heterogeneous disease with a variable course, and remains an incurable disease. Frequent relapses and eventual resistance to fludarabine characterize symptomatic CLL and portends a dismal prognosis for patients. Growing evidence has shown that signaling pathways such as the B cell receptor and NFkB are implicated in the survival and proliferation of the CLL cells which are ultimately associated with persistence of the disease. The Brutons tyrosine kinase pathway regulates downstream activation of the B cell receptor and has emerged as an attractive target. Ibrutinib inhibits the Brutons tyrosine kinase pathway, and consequently induces apoptosis of B cells. Phase I and II studies have shown impressive response rates with an excellent safety profile in patients with refractory/relapsed CLL and elderly treatment-naïve CLL patients. This paper reviews the preclinical and clinical data for ibrutinib when used in the treatment of CLL. Recent studies showing the benefit of combination therapy using ibrutinib, monoclonal antibodies, and chemoimmunotherapy are also discussed.
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Potentiation of Nilotinib-mediated cell death in the context of the bone marrow microenvironment requires a promiscuous JAK inhibitor in CML.
Leuk. Res.
PUBLISHED: 10-14-2011
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In this study, we show that conditioned media (CM) generated from bone marrow (BM)-derived mesenchymal stromal cells lead to BCR-ABL independent STAT3 activation. Activation of STAT3 is important not only for survival of CML cells but also for its protection against Nilotinib (NI), within the BM microenvironment. Reducing the expression of both JAK2 and TYK2 or utilizing a pan-JAK inhibitor blocked CM-mediated STAT3 activation and sensitized CML cells to NI-mediated cell death. Finally, we demonstrate that in patient-derived primitive leukemic cells, co-cultured with BM stromal cells, inhibition of BCR-ABL and JAK activity was a successful strategy to potentiate their elimination.
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Ofatumumab in the treatment of low-grade non-Hodgkins lymphomas and chronic lymphocytic leukemia.
Expert Rev Clin Immunol
PUBLISHED: 05-21-2011
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Ofatumumab is a novel anti-CD20 monoclonal antibody recently approved for the treatment of chronic lymphocytic leukemia refractory to alemtuzumab and fludarabine. Ofatumumab has also demonstrated activity in other low-grade non-Hodgkins lymphomas. However, the optimal time to use ofatumumab and in what patient population is debatable. This article will review some of the key clinical studies that led to the drugs approval, current recommended usage of the drug and significant future directions.
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Impact of IL28B polymorphisms on response to peginterferon and ribavirin in HIV–hepatitis C virus-coinfected patients with prior nonresponse or relapse.
AIDS
PUBLISHED: 05-04-2011
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IL28B polymorphisms predict treatment response in chronic hepatitis C. However, no information exists in prior treatment failures. A total of 62 HIV/hepatitis C virus (HCV) patients who completed retreatment with peginterferon-?/ribavirin were examined, of whom 25 (40%) had been cured. Predictors of response [odds ratio, OR (95% confidence interval, CI)] were HCV genotypes 2/3 [16.1 (2.7-90.9)], prior relapse [9.6 (1.5-62.4)] and ribavirin plasma trough concentrations at week 4 [4.9 (1.3-18.4)]. IL28B-CC only predicted response in prior nonresponders carrying HCV genotypes 1/4 [25.1 (1.9-337)].
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Role of ofatumumab in treatment of chronic lymphocytic leukemia.
J Blood Med
PUBLISHED: 04-29-2011
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The management of chronic lymphocytic leukemia (CLL) has dramatically improved in the past decade with the addition of anti-CD20 monoclonal antibodies to the treatment armamentarium. Ofatumumab is a novel anti-CD20 monoclonal antibody recently approved in the US and Europe for the treatment of CLL refractory to alemtuzumab and fludarabine. Preclinical data showed improved complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity compared with rituximab. Clinical studies have shown single-agent activity for ofatumumab in CLL and in other low-grade non-Hodgkins lymphomas. Combination studies are being conducted to enhance the therapeutic efficacy of ofatumumab. This paper reviews some of the key clinical studies that led to approval of ofatumumab, and future directions.
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Minimal cross-intolerance with nilotinib in patients with chronic myeloid leukemia in chronic or accelerated phase who are intolerant to imatinib.
Blood
PUBLISHED: 04-05-2011
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Nilotinib has significant efficacy in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) and in patients with CML-CP or CML in accelerated phase (CML-AP) after imatinib failure. We investigated the occurrence of cross-intolerance to nilotinib in imatinib-intolerant patients with CML. Only 1/75 (1%) patients with nonhematologic imatinib intolerance experienced a similar grade 3/4 adverse event (AE), and 3/75 (4%) experienced a similar persistent grade 2 nonhematologic AE on nilotinib. Only 7/40 (18%) patients with hematologic imatinib intolerance discontinued nilotinib, all because of grade 3/4 thrombocytopenia. Ninety percent of imatinib-intolerant patients with CML-CP who did not have complete hematologic response (CHR) at baseline (n = 52) achieved CHR on nilotinib. Nilotinib induced a major cytogenetic response in 66% and 41% of patients with imatinib-intolerant CML-CP and CML-AP (complete cytogenetic response in 51% and 30%), respectively. Minimal cross-intolerance was confirmed in patients with imatinib-intolerant CML. The favorable tolerability of nilotinib in patients with imatinib intolerance leads to alleviation of AE-related symptoms and significant and durable responses. In addition to its established clinical benefit in patients with newly diagnosed CML and those resistant to imatinib, nilotinib is effective and well-tolerated for long-term use in patients with imatinib intolerance. This study is registered at http://www.clinicaltrials.gov as NCT00471497.
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Histone deacetylase inhibitor LAQ824 augments inflammatory responses in macrophages through transcriptional regulation of IL-10.
J. Immunol.
PUBLISHED: 03-02-2011
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APCs are important in the initiation of productive Ag-specific T cell responses and the induction of T cell anergy. The inflammatory status of the APC at the time of encounter with Ag-specific T cells plays a central role in determining such divergent T cell outcomes. A better understanding of the regulation of proinflammatory and anti-inflammatory genes in its natural setting, the chromatin substrate, might provide novel insights to overcome anergic mechanisms mediated by APCs. In this study, we show for the first time, to our knowledge, that treatment of BALB/c murine macrophages with the histone deacetylase inhibitor LAQ824 induces chromatin changes at the level of the IL-10 gene promoter that lead to enhanced recruitment of the transcriptional repressors HDAC11 and PU.1. Such an effect is associated with diminished IL-10 production and induction of inflammatory cells able of priming naive Ag-specific T cells, but more importantly, capable of restoring the responsiveness of anergized Ag-specific CD4(+) T cells.
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NCCN Task Force report: tyrosine kinase inhibitor therapy selection in the management of patients with chronic myelogenous leukemia.
J Natl Compr Canc Netw
PUBLISHED: 02-22-2011
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The advent of imatinib has dramatically improved outcomes in patients with chronic myelogenous leukemia (CML). It has become the standard of care for all patients with newly diagnosed chronic-phase CML based on its successful induction of durable responses in most patients. However, its use is complicated by the development of resistance in some patients. Dose escalation might overcome this resistance if detected early. The second-generation tyrosine kinase inhibitors (TKIs) dasatinib and nilotinib provide effective therapeutic options for managing patients resistant or intolerant to imatinib. Recent studies have shown that dasatinib and nilotinib provide quicker and potentially better responses than standard-dose imatinib when used as a first-line treatment. The goal of therapy for patients with CML is the achievement of a complete cytogenetic response, and eventually a major molecular response, to prevent disease progression to accelerated or blast phase. Selecting the appropriate TKI depends on many factors, including disease phase, primary or secondary resistance to TKI, the agents side effect profile and its relative effectiveness against BCR-ABL mutations, and the patients tolerance to therapy. In October 2010, NCCN organized a task force consisting of a panel of experts from NCCN Member Institutions with expertise in the management of patients with CML to discuss these issues. This report provides recommendations regarding the selection of TKI therapy for the management of patients with CML based on the evaluation of available published clinical data and expert opinion among the task force members.
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A database of reaction monitoring mass spectrometry assays for elucidating therapeutic response in cancer.
Proteomics Clin Appl
PUBLISHED: 01-28-2011
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The Quantitative Assay Database (QuAD), http://proteome.moffitt.org/QUAD/, facilitates widespread implementation of quantitative mass spectrometry in cancer biology and clinical research through sharing of methods and reagents for monitoring protein expression and modification.
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A molecular and functional analysis of large granular lymphocyte expansions in patients with chronic myelogenous leukemia treated with tyrosine kinase inhibitors.
Leuk. Lymphoma
PUBLISHED: 01-27-2011
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Tyrosine kinase inhibitor (TKI) therapy has become the standard treatment for chronic myelogenous leukemia (CML). Off-target kinase inhibition has been implicated in the appearance of unique adverse effects, such as colitis and pleural effusions. In addition, some patients present oligoclonal expansions of large granular lymphocytes (LGLs). We sought to further investigate this phenomenon in 64 patients treated with five different TKIs. Clonal expansions of cytotoxic T lymphocytes (CTLs) were identified in all TKI-treated patient groups, but only in dasatinib-treated patients were these expansions characterized as LGLs. Survival factors known to be important in LGL leukemia (interleukin-15 [IL-15] transpresentation, plasma platelet-derived growth factor [PDGF]-BB levels, nuclear factor-?B [NF-?B] and T-bet activation) were found to be associated with TKI-induced LGL expansions. Interestingly, patients with LGL expansions had increased cytotoxicity against non-transformed endothelial cells, which may play a role in observed autoimmune-like side effects. Our results indicate that patients with CML treated with TKIs can develop T cell expansions, which can in certain cases be related to some adverse effects.
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Epigenetic repolarization of T lymphocytes from chronic lymphocytic leukemia patients using 5-aza-2-deoxycytidine.
Leuk. Res.
PUBLISHED: 01-19-2011
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T cell immune dysfunction has an important role in the profound immune suppression that characterizes chronic lymphocytic leukemia (CLL). Improper polarization of T cells has been proposed as one of the mechanism involved. Mounting data implicates chromatin regulation, namely promoter methylation, in the plasticity of naïve human T cells. Recent in vitro evidence indicates that this plasticity may be phenotypically altered by using methylation inhibitors which are approved for clinical use in certain types of cancer. These results beg the question: can the ineffective polarization of T lymphocytes in the context of CLL be effectively modulated using methylation inhibitors in a sustainable therapeutic fashion? To answer this question our laboratory has studied the effects of 5-aza-2-deoxycytidine (5A2) in helper and cytotoxic T lymphocytes from healthy donors and CLL patients in well characterized molecular and epigenetic signaling pathways involved in effective polarization. Moreover, we sought to investigate the consequences of methylation inhibitor treatment on lymphocyte survival, activation intensity, and naïve cell polarization. Our data indicates that 5A2 treatment can depolarize Th2 cells to effectively secrete interferon gamma, signal via T-bet, and achieve demethylation of critical Th1 specific promoters. Moreover, we demonstrate that 5A2 can force Th1 polarization of naïve T cells despite a strong IL-4 stimuli and a lack of IL-12. In conclusion our data seeks to define a modality in which improper or ineffective T cell polarization can be altered by 5AZA and could be incorporated in future therapeutic interventions.
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Outcome of diffuse large B-Cell lymphoma in the United States has improved over time but racial disparities remain: review of SEER data.
Clin Lymphoma Myeloma Leuk
PUBLISHED: 01-01-2011
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Diffuse large B-cell non-Hodgkin lymphoma (DLBCL) outcome in the United States has not been reported outside the context of clinical trials.
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Nilotinib is effective in patients with chronic myeloid leukemia in chronic phase after imatinib resistance or intolerance: 24-month follow-up results.
Blood
PUBLISHED: 11-22-2010
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Nilotinib is a potent selective inhibitor of the BCR-ABL tyrosine kinase approved for use in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP), and in CML-CP and CML-accelerated phase after imatinib failure. Nilotinib (400 mg twice daily) was approved on the basis of the initial results of this phase 2 open-label study. The primary study endpoint was the proportion of patients achieving major cytogenetic response (CyR). All patients were followed for ? 24 months or discontinued early. Of 321 patients, 124 (39%) continue on nilotinib treatment. Overall, 59% of patients achieved major CyR; this was complete CyR (CCyR) in 44%. Of patients achieving CCyR, 56% achieved major molecular response. CyRs were durable, with 84% of patients who achieved CCyR maintaining response at 24 months. The overall survival at 24 months was 87%. Adverse events were mostly mild to moderate, generally transient, and easily managed. This study indicates that nilotinib is effective, with a manageable safety profile, and can provide favorable long-term benefits for patients with CML-CP after imatinib failure.
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Salvage chemotherapy regimens for acute myeloid leukemia: Is one better? Efficacy comparison between CLAG and MEC regimens.
Leuk. Res.
PUBLISHED: 06-16-2010
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There is no standard salvage regimen for AML. We retrospectively compared two commonly used regimens at our institution: CLAG and MEC. The complete response rate (CR) was 37.9% for CLAG (n=97) and 23.8% for MEC (n=65) (P=0.048), with median overall survival (OS) of 7.3 and 4.5 months, respectively (P=0.05). In primary refractory disease, CR was 45.5% for CLAG and 22.2% for MEC (P=0.09), with median OS of 11 and 4.5 months, respectively (P=0.07). In first relapse, CR was 36.8% and 25.9% (P=0.35) and median OS was 6.7 and 6.7 months, respectively (P=0.87). Our data support use of CLAG for RR-AML.
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Intolerance to tyrosine kinase inhibitors in chronic myeloid leukemia: Definitions and clinical implications.
Cancer
PUBLISHED: 05-11-2010
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Tyrosine kinase inhibitor (TKI) treatment targeting breakpoint cluster region-Abelson murine leukemia virus, the cause of chronic myeloid leukemia (CML), has revolutionized therapy for patients with this disease. The majority of patients with CML maintain favorable responses with long-term imatinib therapy; however, the availability of the second-generation TKIs nilotinib and dasatinib limits the need for patients intolerant to imatinib to continue with therapy. Unfortunately, there is currently no standard definition of intolerance to imatinib. Common Toxicity Criteria for grading adverse events, designed to identify acute toxicities, are often used to determine intolerance. However, because CML therapies are long-term, patient quality of life may provide a better measure of true intolerance. Several general methods of quantifying patient quality of life are in use for patients with CML, and a CML-specific variant of the M. D. Anderson Symptom Inventory is in development. An appropriate and consistent definition of intolerance will provide clinicians with an algorithm for managing their patients with severe or chronic adverse events during treatment with imatinib. As more long-term data become available for newer TKIs, the definition of intolerance in the context of CML treatment will continue to evolve to maximize the likelihood of durable responses and superior quality of life for patients.
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Restoring the functional immunogenicity of chronic lymphocytic leukemia using epigenetic modifiers.
Leuk. Res.
PUBLISHED: 04-28-2010
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Chronic lymphocytic leukemia (CLL) is a malignancy arising from immune cells (B-lymphocytes) endowed with intrinsic antigen-presenting capabilities. Such a function however is lost during malignant transformation and CLL cells are well known for their inability to process and present antigens to the T-cell arm of the immune system. Instead, malignant CLL cells elicit a vast array of immune regulatory mechanisms conducive to T-cell dysfunction and immunosuppression. Previously, we have shown that treatment of CLL cells with the demethylating agent 5-aza-2-deoxycytidine unleashed target antigen expression. Here we show for the first time that combining two epigenetic modifiers, 5-aza-2-deoxycytidine and the histone deacetylase inhibitor LAQ824 effectively restores the immunogenicity of CLL cell lines as well as primary cells obtained from CLL patients. Indeed, such a combination induces the expression of novel and highly antigenic cancer-testis antigens (CTAs) and costimulatory molecules. These changes facilitate the formation of robust supramolecular activation complexes (SMAC) between CLL cells and responder T-cells leading to intracellular signaling, lytic granule mobilization, and polarization of functional and relevant T-cell responses. This cascade of T-cell activating events triggered by CLL cells with restored APC function, points to combined epigenetic modifier treatment as a potential immunotherapeutic strategy for CLL patients.
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Chronic lymphocytic leukemia: putting new treatment options into perspective.
Cancer Control
PUBLISHED: 04-21-2010
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Chronic lymphocytic leukemia (CLL) is a monoclonal B-cell malignancy that afflicts mainly older individuals. Since many patients are diagnosed in the earliest stages, the course of the disease may be indolent and asymptomatic, requiring no therapy. For those who are diagnosed in advanced stages or whose disease becomes symptomatic, treatment is indicated. Advances in identifying prognostic factors, such as cytogenetics, IgHV mutational status, CD38, TP53, and ZAP-70, are helping physicians better predict who is more likely to have progressive disease and thus needs more frequent monitoring. Some of these prognostic factors are also helping to guide therapy choices as they can predict response to treatment and/or duration of response. Recent advances in treatment options have moved beyond traditional management with alkylating agents and purine analogs into regimens combining these two chemotherapy classes with monoclonal antibodies targeting CD20. Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR) has become the most effective therapy option to date for CLL. Compared with fludarabine and cyclophosphamide, FCR has shown higher complete response rates and longer progression-free survival. Bendamustine, a unique alkylating agent with purine analog properties, has recently been approved by the FDA for treatment of CLL and provides a new alternative to existing therapies. Initial trials combining bendamustine with rituximab are showing promise for both untreated and relapsed/refractory disease. Other agents recently approved and/or being tested, such as ofatumumab, flavopiridol, and lenalidomide, are demonstrating activity in the relapsed setting.
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Vaccination with synthetic analog peptides derived from WT1 oncoprotein induces T-cell responses in patients with complete remission from acute myeloid leukemia.
Blood
PUBLISHED: 04-16-2010
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A pilot study was undertaken to assess the safety, activity, and immunogenicity of a polyvalent Wilms tumor gene 1 (WT1) peptide vaccine in patients with acute myeloid leukemia in complete remission but with molecular evidence of WT1 transcript. Patients received 6 vaccinations with 4 WT1 peptides (200 microg each) plus immune adjuvants over 12 weeks. Immune responses were evaluated by delayed-type hypersensitivity, CD4+ T-cell proliferation, CD3+ T-cell interferon-gamma release, and WT1 peptide tetramer staining. Of the 9 evaluable patients, 7 completed 6 vaccinations and WT1-specific T-cell responses were noted in 7 of 8 patients. Three patients who were HLA-A0201-positive showed significant increase in interferon-gamma-secreting cells and frequency of WT1 tetramer-positive CD8+ T cells. Three patients developed a delayed hypersensitivity reaction after vaccination. Definite related toxicities were minimal. With a mean follow-up of 30 plus or minus 8 months after diagnosis, median disease-free survival has not been reached. These preliminary data suggest that this polyvalent WT1 peptide vaccine can be administered safely to patients with a resulting immune response. Further studies are needed to establish the role of vaccination as viable postremission therapy for acute myeloid leukemia.
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Phase 1 study of INNO-406, a dual Abl/Lyn kinase inhibitor, in Philadelphia chromosome-positive leukemias after imatinib resistance or intolerance.
Cancer
PUBLISHED: 03-24-2010
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: INNO-406, a dual v-abl Abelson murine leukemia viral oncogene homolog (Abl)/v-yes-1 Yamaguchi sarcoma viral-related oncogene homolog (Lyn) tyrosine kinase inhibitor (TKI), has demonstrated specific Lyn kinase inhibitory activity with no or limited activity against other sarcoma (Src) family member kinases. Several breakpoint cluster region (Bcr)-Abl kinase domain mutations are sensitive to INNO-406 in vitro, including mutations that involve a phenylalanine-to-leucine or phenylalanine-to-valine substitution at codon 317 (F317L and F317V, respectively). In the current study, the authors evaluated the use of INNO-406 in patients with Philadelphia (Ph) chromosome-positive chronic myelogenous leukemia (CML) or acute lymphocytic leukemia (ALL) after imatinib resistance or intolerance.
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Eligibility for and outcome of treatment of latent tuberculosis infection in a cohort of HIV-infected people in Spain.
BMC Infect. Dis.
PUBLISHED: 02-17-2010
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Previous studies have demonstrated the efficacy of treatment for latent tuberculosis infection (TLTBI) in persons infected with the human immunodeficiency virus, but few studies have investigated the operational aspects of implementing TLTBI in the co-infected population.The study objectives were to describe eligibility for TLTBI as well as treatment prescription, initiation and completion in an HIV-infected Spanish cohort and to investigate factors associated with treatment completion.
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Enhanced CD8 T cell cross-presentation by macrophages with targeted disruption of STAT3.
Immunol. Lett.
PUBLISHED: 02-11-2010
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CD8 T cell tolerance, once thought to be largely a result of clonal deletion, is now appreciated to be much more complex, additionally involving multiple permutations of partial loss of effector function in residual clonal populations. This is especially important in the context of tumor immunity, in which persistent tolerized cytotoxic CD8 T cells (CTL), if reactivated, could potentially mount a protective response. Previously we have shown that antigen-presenting cells (APCs) with a targeted disruption of STAT3 break tolerance in CD4 T cells. Here we evaluate the STAT3-defective APC in terms of its ability to induce a productive CTL response. Our data demonstrate that macrophages derived from conditional STAT3 knockout mice are superior to wild-type macrophages in terms of their ability to prime cognate CTL responses, and to cross-present tumor-derived antigen to CTLs in vitro. CTLs cultured with STAT3-deficient APCs demonstrated a stronger proliferative response and produced increased amounts of IFN-gamma and TNF-alpha, all of which have been shown to be diminished in tumor-tolerized CD8 T cells. Targeting STAT3 signaling represents therefore an enticing strategy to augment CTL responses in the tumor-bearing host.
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Circumventing immune tolerance through epigenetic modification.
Curr. Pharm. Des.
PUBLISHED: 01-30-2010
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In recent decades our understanding of immune cell activation and homeostasis has significantly expanded. Such progress helped to better define the cellular, molecular, and epigenetic networks involved in the immune response in the tumor microenvironment and renewed the enthusiasm towards the potential power of cancer immunotherapy. However, successful translation of novel mechanistic discoveries into effective immunotherapy was hindered by a number of obstacles, among them the ability of tumors to tolerize host lymphocytes rendering them functionally incompetent and the tumors ability to evade antigen-specific immune recognition through a variety of genetic, epigenetic, and stromal factors. These immunosuppressive strategies have, thus far, blunted our efforts to effectively unleash anti-cancer immunity. Fortunately, the wealth of new information regarding the interactions between tumors and the immune system and the regulation of certain highly antigenic tumor proteins has led to novel approaches with the potential to render cancer cells helpless towards immune attack. Here we summarize recent findings on cancer-induced T-lymphocyte tolerance and discuss a novel "vaccinate-induce" strategy conceived to counteract these effects at an epigenetic level.
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Rate and predictors of success in the retreatment of chronic hepatitis C virus in HIV/hepatitis C Virus coinfected patients with prior nonresponse or relapse.
J. Acquir. Immune Defic. Syndr.
PUBLISHED: 01-27-2010
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In hepatitis C virus (HCV)/HIV-coinfected patients who failed a course of suboptimal hepatitis C therapy, retreatment with adequate doses and duration of pegylated interferon (pegIFN) plus ribavirin (RBV) is advisable in the presence of compensated advanced liver fibrosis.
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New agents in the treatment of chronic myelogenous leukemia.
J Natl Compr Canc Netw
PUBLISHED: 07-11-2009
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The discovery of molecularly targeted agents that selectively inhibit bcr-abl tyrosine kinase activity, such as imatinib, has revolutionized the treatment and natural history of chronic myelogenous leukemia (CML). Treatment of chronic-phase CML with imatinib showed complete cytogenetic response rates of more than 40% in patients after failure of interferon-alpha, and more than 80% in patients with newly diagnosed CML. Patients with CML can now expect excellent long-term survival, often without major side effects. In most patients, however, residual leukemic burden remains detectable using a sensitive reverse transcription-polymerase chain reaction method. In addition, many patients undergoing imatinib therapy will either not respond or lose their response over time because of resistance or intolerance. The introduction of second-generation tyrosine kinase inhibitors (TKIs) re-establishes response in approximately half of these patients. Several agents are being developed for treating patients who experience suboptimal response to second-generation TKIs and for those who develop resistance caused by the emergence of highly resistant BCR-ABL1 mutations. This article provides an overview of novel targeted agents available for CML.
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[Factors related to non-prescription of tuberculin skin testing in a cohort of HIV-infected people].
Enferm. Infecc. Microbiol. Clin.
PUBLISHED: 06-12-2009
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Tuberculin skin testing (TST) for tuberculosis (TB) is recommended for all patients with HIV infection because of the known relationship between these two conditions. In this report we analyze the incidence and variables associated with non-prescription of TST in a cohort of HIV-infected people.
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Treatment of chronic lymphocytic leukemia with a hypomethylating agent induces expression of NXF2, an immunogenic cancer testis antigen.
Clin. Cancer Res.
PUBLISHED: 04-28-2009
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Critical to the success of active immunotherapy against cancer is the identification of immunologically recognized cancer-specific proteins with low tolerogenic potential. Cancer testis antigens (CTA), in particular, fulfill this requirement as a result of their aberrant expression restricted to cancer cells and lack of expression in normal tissues bypassing tolerogenic mechanisms against self. Although CTAs have been extensively studied in solid malignancies, little is known regarding their expression in chronic lymphocytic leukemia (CLL).
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The biological basis for immunotherapy in patients with chronic myelogenous leukemia.
Cancer Control
PUBLISHED: 04-02-2009
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Chronic myelogenous leukemia (CML) has long been recognized as an entity responsive to immunotherapeutic interventions. Despite the success of the tyrosine kinase inhibitors (TKIs) in this disease, CML remains incurable. Only allogeneic bone marrow transplantation can provide long-term eradication of CML.
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Signaling networks associated with BCR-ABL-dependent transformation.
Cancer Control
PUBLISHED: 04-02-2009
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The fusion protein BCR-ABL results in constitutive tyrosine kinase activity. It also affects downstream targets as well as the subcellular location of the normally tightly regulated Abl tyrosine kinase.
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The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance.
Nat. Immunol.
PUBLISHED: 01-31-2009
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Antigen-presenting cells (APCs) induce T cell activation as well as T cell tolerance. The molecular basis of the regulation of this critical decision is not well understood. Here we show that HDAC11, a member of the HDAC histone deacetylase family with no prior defined physiological function, negatively regulated expression of the gene encoding interleukin 10 (IL-10) in APCs. Overexpression of HDAC11 inhibited IL-10 expression and induced inflammatory APCs that were able to prime naive T cells and restore the responsiveness of tolerant CD4+ T cells. Conversely, disruption of HDAC11 in APCs led to upregulation of expression of the gene encoding IL-10 and impairment of antigen-specific T cell responses. Thus, HDAC11 represents a molecular target that influences immune activation versus immune tolerance, a critical decision with substantial implications in autoimmunity, transplantation and cancer immunotherapy.
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Quality of life outcomes in patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors: a controlled comparison.
Support Care Cancer
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Tyrosine kinase inhibitors (TKIs) are now standard treatment for chronic myeloid leukemia (CML). While TKIs have less toxicity than previous treatments, they have side effects that can impact quality of life (QOL).
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Hypoalbuminemia is an independent prognostic factor for overall survival in myelodysplastic syndromes.
Am. J. Hematol.
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We hypothesized that hypoalbuminemia is an independent prognostic factor in patients with myelodysplastic syndromes (MDS). We analyzed records of 767 patients treated at Moffitt Cancer Center between January 2001 and December 2009 to evaluate the relationship between serum albumin (SA) at the time of presentation and overall survival (OS). Patients (median age of 69 years) were stratified into three groups based on SA concentration (?3.5, 3.6-4.0, and >4.0 g/dL). Two-thirds of the patients had low or intermediate-1 International Prognostic Scoring System (IPSS)-based risk for MDS. Median OS by SA concentration of ?3.5, 3.6-4.0, and >4.0 g/dL was 11, 23, and 34 months, respectively (P < 0.005), whereas rate of acute myeloid leukemia progression was highest in patients with low SA (?3.5 g/dL). The SA level offered prognostic discrimination for outcomes within the lower and higher IPSS risk groups, as well as with the MD Anderson risk model. In multivariable analysis, SA was a significant independent co-variate for OS after adjustment for IPSS, age, serum ferritin, and transfusion dependence (hazard ratio = 0.8; 95% CI 0.6-0.9; P = 0.004). Our findings indicate that hypoalbuminemia is an independent prognostic biomarker that may serve as a surrogate representative of disease biology or comorbidities in patients with MDS.
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Molecular action of lenalidomide in lymphocytes and hematologic malignancies.
Adv Hematol
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The immunomodulatory agent, lenalidomide, is a structural analogue of thalidomide approved by the US Food and Drug Administration for the treatment of myelodysplastic syndrome (MDS) and multiple myeloma (MM). This agent is also currently under active investigation for the treatment of chronic lymphocytic leukemia (CLL) and non-Hodgkins lymphoma (NHL), as well as in drug combinations for some solid tumors and mantle cell lymphoma (MCL). Although treatment with lenalidomide has translated into a significant extension in overall survival in MM and MDS and has superior safety and efficacy relative to thalidomide, the mechanism of action as it relates to immune modulation remains elusive. Based on preclinical models and clinical trials, lenalidomide, as well as other structural thalidomide derivatives, enhances the proliferative and functional capacity of T-lymphocytes and amplifies costimulatory signaling pathways that activate effector responses and suppress inflammation. This paper summarizes our current understanding of T- and natural killer (NK) cell pathways that are modified by lenalidomide in hematopoietic neoplasms to inform future decisions about potential combination therapies.
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Stat3 inhibition augments the immunogenicity of B-cell lymphoma cells, leading to effective antitumor immunity.
Cancer Res.
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Mantle cell lymphoma (MCL) is an aggressive and incurable subtype of B-cell non-Hodgkin lymphomas. Although patients often respond initially to first-line treatment with chemotherapy plus monoclonal antibodies, relapse and decreased response to further lines of treatment eventually occurs. Harnessing the immune system to elicit its exquisite specificity and long-lasting protection might provide sustained MCL immunity that could potentially eradicate residual malignant cells responsible for disease relapse. Here, we show that genetic or pharmacologic disruption of Stat3 in malignant B cells augments their immunogenicity leading to better activation of antigen-specific CD4(+) T cells and restoration of responsiveness of tolerized T cells. In addition, treatment of MCL-bearing mice with a specific Stat3 inhibitor resulted in decreased Stat3 phosphorylation in malignant B cells and anti-lymphoma immunity in vivo. Our findings therefore indicate that Stat3 inhibition may represent a therapeutic strategy to overcome tolerance to tumor antigens and elicit a strong immunity against MCL and other B-cell malignancies.
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Optimizing premedications in the prevention of bendamustine infusion-related reactions.
Cancer Control
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Bendamustine is indicated for the treatment of chronic lymphocytic leukemia (CLL) and rituximab refractory indolent non-Hodgkin lymphoma. Clinical trials have reported a 25% incidence of infusion-related reactions (IRRs) in patients receiving bendamustine. While these reactions are well documented, there is no consensus on the optimal premedication regimen for the prevention of these adverse effects. At our center, we utilize a regimen of ondansetron 16 mg orally and dexamethasone 10 mg IV push prior to each infusion of bendamustine. This report describes our experience with our current premedication regimen with regard to IRRs and the incidence of febrile neutropenia (FN).
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Overexpression of TCL1 activates the endoplasmic reticulum stress response: a novel mechanism of leukemic progression in mice.
Blood
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Chronic lymphocytic leukemia (CLL) represents 30% of adult leukemia. TCL1 is expressed in ~ 90% of human CLL. Transgenic expression of TCL1 in murine B cells (E?-TCL1) results in mouse CLL. Here we show for the first time that the previously unexplored endoplasmic reticulum (ER) stress response is aberrantly activated in E?-TCL1 mouse and human CLL. This includes activation of the IRE-1/XBP-1 pathway and the transcriptionally up-regulated expression of Derlin-1, Derlin-2, BiP, GRP94, and PDI. TCL1 associates with the XBP-1 transcription factor, and causes the dysregulated expression of the transcription factors, Pax5, IRF4, and Blimp-1, and of the activation-induced cytidine deaminase. In addition, TCL1-overexpressing CLL cells manufacture a distinctly different BCR, as we detected increased expression of membrane-bound IgM and altered N-linked glycosylation of Ig? and Ig?, which account for the hyperactive BCR in malignant CLL. To demonstrate that the ER stress-response pathway is a novel molecular target for the treatment of CLL, we blocked the IRE-1/XBP-1 pathway using a novel inhibitor, and observed apoptosis and significantly stalled growth of CLL cells in vitro and in mice. These studies reveal an important role of TCL1 in activating the ER stress response in support for malignant progression of CLL.
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The expanding options for front-line treatment in patients with newly diagnosed CML.
Crit. Rev. Oncol. Hematol.
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The past decade has seen remarkable advances in the treatment of chronic myeloid leukemia (CML). The discovery of the underlying cause of CML, a chromosomal translocation resulting in the expression of an aberrant tyrosine kinase, has enabled the rational development of targeted therapy with tyrosine kinase inhibitors (TKIs). The first available TKI, imatinib, dramatically improved survival rates and demonstrated the potential for long-term treatment. A number of additional strategies have been tested to further maximize outcomes in patients with newly diagnosed CML, including newer TKIs, imatinib dose escalation, and combination therapy. The advanced, more potent TKIs, nilotinib and dasatinib, have proven effective for newly diagnosed patients and for those who experience inadequate response or intolerance to imatinib. Randomized phase 3 studies have shown that nilotinib and dasatinib are more efficacious than imatinib in achieving primary study endpoints. Nilotinib was superior to imatinib in the rate of major molecular response at 12 months; dasatinib was superior to imatinib in the rate of complete cytogenetic response by 12 months. These phase 3 studies are ongoing to further define longer-term efficacy and safety. Research on additional contributing signaling pathways in CML, T315I mutations, and other causes of treatment resistance has identified additional potential treatments that are now in early stages of clinical development, with encouraging preliminary results. With continued advances, it is conceivable that the ultimate goal - a cure for CML - is in our sights.
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