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Find video protocols related to scientific articles indexed in Pubmed.
Do Dissolving Objects Converge to a Universal Shape?
Langmuir
PUBLISHED: 11-20-2014
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Surprisingly, macroscopic objects such as melting ice cubes and growing stalactites approach non-intuitive geometric ideals. Here we investigate the shape of dissolving cylinders in a large volume of water. The cylinders are oriented vertically and consist of amorphous glucose or polyethylene glycol. The dissolution causes density differences in the surrounding fluid, which induce gravity-driven convection downwards along the object. The resulting concentration gradient shapes the cylinder according to fast dissolution at the tip and slow dissolution at the base. The contour of the object approaches a power law of the form z ? R(2) where z is the vertical distance from the tip and R is the corresponding radius. We suggest that this paraboloidal shape is the geometric attractor for the dissolution of non-crystalline objects in the presence of gravity.
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Commentary: STRATUM CORNEUM ACIDIFICATION: HOW AND WHY?
Exp. Dermatol.
PUBLISHED: 11-20-2014
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Sources of the Acid Mantle: Although the acid mantle initially was assumed to result from exogenous sources, such as sebum-derived free fatty acids, several endogenous acidifying mechanisms instead account for up to 2 pH units (a 200-fold increase in protons) of the overall pH of the stratum corneum (SC) (Table 1). The sodium-protein antiporter, type 1 (NHE1), which selectively acidifies extracellular domains at the stratum granulosum (SG)/SC interface (1), accounts for ? ¼ unit of the bulk pH of the SC (1). This critically-important site is where sphingomyelin and glucosylceramides are processed into ceramides by two acidic pH-dependent enzymes, acidic sphingomyelinase (aSMase) and ?-glucocerebrosidase (?-GlcCer'ase), thereby generating the permeability barrier. This article is protected by copyright. All rights reserved.
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An Endoplasmic Reticulum Stress-Initiated Sphingolipid Metabolite, Ceramide-1-Phosphate, Regulates Epithelial Innate Immunity by Stimulating ?-Defensin Production.
Mol. Cell. Biol.
PUBLISHED: 10-13-2014
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Antimicrobial peptides (AMP) are ubiquitous innate immune elements in epithelial tissues. We recently discovered that a signaling lipid, the ceramide metabolite sphingosine-1-phosphate (S1P), regulates production of a major AMP, cathelicidin antimicrobial peptide (CAMP), in response to a subtoxic level of endoplasmic reticulum (ER) stress that can be induced by external perturbants in keratinocytes. We hypothesized that an ER stress-initiated signal could also regulate production of another major class of AMPs: i.e., the human beta-defensins 2 (hBD2) and 3 (hBD3). Keratinocytes stimulated with a pharmacological ER stressor, thapsigargin (Tg), increased hBD2/hBD3 as well as CAMP mRNA expression. While inhibition of sphingosine-1-phosphate production did not alter hBD expression following ER stress, blockade of ceramide-1-phosphate (C1P) suppressed Tg-induced hBD2/hBD3 but not CAMP expression. Exogenous C1P also increased hBD2/hBD3 production, indicating that C1P stimulates hBD expression. We showed further that C1P-induced hBD2/hBD3 expression is regulated by a novel pathway in which C1P stimulates downstream hBD via a cPLA2a?15d-PGJ2?PPAR?/PPAR?/??Src kinase?STAT1/STAT3 transcriptional mechanism. Finally, conditioned medium from C1P-stimulated keratinocytes showed antimicrobial activity against Staphylococcus aureus. In summary, our present and recent studies discovered two new regulatory mechanisms of key epidermal AMP, hBD2/hBD3 and CAMP. The C1P and S1P pathways both signal to enhance innate immunity in response to ER stress.
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BFR (bendamustine, fludarabine, and rituximab) allogeneic conditioning for chronic lymphocytic leukemia/lymphoma: reduced myelosuppression and GVHD.
Blood
PUBLISHED: 08-21-2014
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Myelosuppression, graft-versus-host disease (GVHD), and relapse remain major causes of morbidity after stem cell transplantation for relapsed lymphoma. In this phase 1/2 study, we tested the safety and efficacy of escalating doses of bendamustine (70, 90, 110, and 130 mg/m2 per day for 3 days), coupled with our historical fixed doses of fludarabine and rituximab (BFR), as a nonmyeloablative allogeneic conditioning regimen for patients with relapsed lymphoma (n = 41) and chronic lymphocytic leukemia (CLL) (n = 15). Ten patients entered the phase 1 study; none experienced a dose-limiting toxicity. Forty-six additional patients were then treated in the phase 2 study at the maximum dose of 130 mg/m2 per day for 3 days. The proportions of transplants from matched siblings or unrelated donors were 54% and 46%. Remarkably, 55% of patients did not experience severe neutropenia. Forty-nine patients (88%) did not require platelet transfusion. The incidence of acute grade II-IV GVHD was 11%. The 2-year rate of extensive chronic GVHD was 26%. After a median follow-up duration of 26 months (range, 6-50 months), the 2-year overall and progression-free survival rates were 90% and 75%. In conclusion, our new BFR regimen is safe and effective for relapsed CLL and lymphoma patients.
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Mechanisms of abnormal lamellar body secretion and the dysfunctional skin barrier in patients with atopic dermatitis.
J. Allergy Clin. Immunol.
PUBLISHED: 08-15-2014
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I review how diverse inherited and acquired abnormalities in epidermal structural and enzymatic proteins converge to produce defective permeability barrier function and antimicrobial defense in patients with atopic dermatitis (AD). Although best known are mutations in filaggrin (FLG), mutations in other member of the fused S-100 family of proteins (ie, hornerin [hrn] and filaggrin 2 [flg-2]); the cornified envelope precursor (ie, SPRR3); mattrin, which is encoded by TMEM79 and regulates the assembly of lamellar bodies; SPINK5, which encodes the serine protease inhibitor lymphoepithelial Kazal-type trypsin inhibitor type 1; and the fatty acid transporter fatty acid transport protein 4 have all been linked to AD. Yet these abnormalities often only predispose to AD; additional acquired stressors that further compromise barrier function, such as psychological stress, low ambient humidity, or high-pH surfactants, often are required to trigger disease. T(H)2 cytokines can also compromise barrier function by downregulating expression of multiple epidermal structural proteins, lipid synthetic enzymes, and antimicrobial peptides. All of these inherited and acquired abnormalities converge on the lamellar body secretory system, producing abnormalities in lipid composition, secretion, and/or extracellular lamellar membrane organization, as well as antimicrobial defense. Finally, I briefly review therapeutic options that address this new pathogenic paradigm.
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Phase II Study of Methotrexate, Vincristine, Pegylated-Asparaginase, and Dexamethasone (MOpAD) in Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia.
Am. J. Hematol.
PUBLISHED: 08-12-2014
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Newer approaches are needed for the treatment of relapsed and refractory acute lymphoblastic leukemia (ALL). Asparaginase-based regimens are active in the treatment of pediatric ALL and may be important in salvage therapy for adult patients. We conducted a pilot trial combining methotrexate, vincristine, PEGylated-asparaginase, and dexamethasone (MOpAD) in adults with relapsed or refractory ALL. We added tyrosine kinase inhibitors in patients with Philadelphia chromosome positive (Ph+) ALL and rituximab in patients with CD20 positive B-cell ALL. Among 37 patients treated (median age 42 years; median 2 prior therapies), the complete remission (CR) rate was 28% and an overall response rate (ORR) was 39%. The median CR duration was 4.3 months. Patients with Ph+ ALL had CR and ORR of 50% and 67%, respectively and the CR and ORR in patients with T-cell leukemia were 45% and 56%, respectively. The median survival in patients with CR/CRp was 10.4 vs. 3.4 months in nonresponders (p=0.02). The most common grade 3 or 4 non-hematologic toxicities were elevations in bilirubin and transaminases, nausea, peripheral neuropathy, and hyperglycemia, which were managed with supportive care, dose adjustments, and interruptions.
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Prognostic factors for outcome in patients with refractory and relapsed acute lymphocytic leukemia treated with inotuzumab ozogamicin, a cd22 monoclonal antibody.
Am. J. Hematol.
PUBLISHED: 07-28-2014
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Background: Inotuzumab ozogamicin was found to be highly active in patients with refractory-relapsed acute lymphocytic leukemia (ALL), with an overall response rate of 58% and a median survival of 6.3 months. Identifying factors associated with different outcomes on inotuzumab therapy may help select patients for this treatment and advice of prognosis. Methods: A total of 89 patients treated with inotuzumab on previous studies were analyzed. Inotuzumab was given at 1.3-1.8mg/m(2) intravenously (IV) x 1 every 3-4 weeks or weekly (0.8mg/m(2) Day 1, 0.5mg/m(2) Days 8 and 15) every 3-4 weeks. Pretreatment factors associated with achieving marrow complete response (CR) and with survival were analyzed using standard statistical methods. Results: The median survival of patients with at least marrow CR was 9.2 months versus 3.4 months for those without marrow CR (p<0.001). By multivariate analysis, a high peripheral blood absolute blast count and low platelet count were independently associated with a lower likelihood of achieving at least marrow CR. Baseline characteristics independently associated with worse survival included adverse cytogenetics [complex karyotype, translocation (4;11), translocation (9;22), abnormal chromosome 17], disease beyond first salvage, and high peripheral blood absolute count. Patients with 0, 1-2 or 3 adverse factors had a median survival of 39+, 7.5, and 2.4 months, respectively. Conclusions: Our current analyses identified a subset of adult patients with ALL in whom outcome of therapy with inotuzumab ozogamicin can be differentially predicted. This article is protected by copyright. All rights reserved.
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Deacetylase Inhibitors for the Treatment of Myelodysplastic Syndromes.
Leuk. Lymphoma
PUBLISHED: 07-25-2014
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Abstract Myelodysplastic syndromes (MDS) are a diverse group of myeloid disorders, with patients being at risk for cytopenias or progression to acute myeloid leukemia. Several classification and prognostic scoring systems have been developed. High-intensity treatments are not appropriate for all patients. Two demethylating agents, azacitidine and decitabine, are approved for treatment of MDS, though many patients do not derive long-term benefit and eventually progress. Deacetylase inhibitors have emerged as novel treatment candidates based on mechanistic rationale and preliminary data. This article reviews existing data on MDS treatment and discusses the rationale and potential for combination with deacetylase inhibitors.
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Myeloid neoplasms after breast cancer: "therapy-related" not an independent poor prognostic factor.
Leuk. Lymphoma
PUBLISHED: 07-23-2014
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Two hundred and thirty-five consecutive patients presenting to a single center with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) after breast cancer treatment were compared with matched patients with de novo AML or MDS. There was no significant difference in median overall survival (OS) times between patients with therapy-related AML and those with de novo AML (8.7 months vs.10.2 months; p = 0.17). Patients with therapy-related MDS had slightly lower median baseline platelet counts and a higher frequency of poor cytogenetics than those with de novo MDS, but the two groups had similar OS times (13.6 months vs. 18.9 months; p = 0.06). Multivariate analysis revealed that cytogenetic risk, baseline white blood cell count, age and performance status were predictive for OS time in AML and that cytogenetic risk and performance status were predictive for OS time in MDS. Having therapy-related disease is not an independent risk factor in patients with myeloid neoplasms and with a history of breast cancer. Clinical trials should be designed to serve both populations.
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Characteristics and Outcomes of Patients With Multiple Myeloma Who Develop Therapy-Related Myelodysplastic Syndrome, Chronic Myelomonocytic Leukemia, or Acute Myeloid Leukemia.
Clin Lymphoma Myeloma Leuk
PUBLISHED: 07-15-2014
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Patients with multiple myeloma (MM) have had significant improvements in outcomes. An increased risk of therapy-related myeloid neoplasms (t-MNs) has also developed. Little is known about the characteristics and outcomes of these patients.
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Topical hesperidin prevents glucocorticoid-induced abnormalities in epidermal barrier function in murine skin.
Exp. Dermatol.
PUBLISHED: 06-19-2014
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Systemic and topical glucocorticoids (GC) can cause significant adverse effects not only on the dermis, but also on epidermal structure and function. In epidermis, a striking GC-induced alteration in permeability barrier function occurs that can be attributed to an inhibition of epidermal mitogenesis, differentiation and lipid production. As prior studies in normal hairless mice demonstrated that topical applications of a flavonoid ingredient found in citrus, hesperidin, improve epidermal barrier function by stimulating epidermal proliferation and differentiation, we assessed here whether its topical applications could prevent GC-induced changes in epidermal function in murine skin and the basis for such effects. When hairless mice were co-treated topically with GC and 2% hesperidin twice-daily for 9 days, hesperidin co-applications prevented the expected GC-induced impairments of epidermal permeability barrier homoeostasis and stratum corneum (SC) acidification. These preventive effects could be attributed to a significant increase in filaggrin expression, enhanced epidermal ?-glucocerebrosidase activity and accelerated lamellar bilayer maturation, the last two likely attributable to a hesperidin-induced reduction in stratum corneum pH. Furthermore, co-applications of hesperidin with GC largely prevented the expected GC-induced inhibition of epidermal proliferation. Finally, topical hesperidin increased epidermal glutathione reductase mRNA expression, which could counteract multiple functional negative effects of GC on epidermis. Together, these results show that topical hesperidin prevents GC-induced epidermal side effects by divergent mechanisms.
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Allogeneic stem cell transplant in patients with chronic lymphocytic leukemia with 17p deletion: consult-transplant versus consult- no-transplant analysis.
Leuk. Lymphoma
PUBLISHED: 06-11-2014
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Allogeneic stem cell transplant (alloSCT) can overcome the adverse prognosis of chronic lymphocytic leukemia with 17p deletion (17p- CLL). However, its applicability remains unclear. Since 2007, our leukemia service has referred patients with 17p- CLL for alloSCT at presentation. In this study, the outcomes of these patients were reviewed retrospectively to determine whether they underwent alloSCT and why patients did not undergo alloSCT. Fifty-two patients with 17p- CLL who were referred to the transplant service from 2007 to 2010 were identified. Of these patients, 32 (62%) did not undergo alloSCT, mainly because of treatment- or disease-related complications (n = 15). The 2-year post-referral overall survival rates of the alloSCT and non-SCT groups were 64% and 25%, respectively (p = 0.001). These findings suggest that while alloSCT is an effective therapy in patients with 17p- CLL, pre-SCT complications may preclude a significant proportion of patients from undergoing the procedure.
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The effect of decitabine dose modification and myelosuppression on response and survival in patients with myelodysplastic syndromes.
Leuk. Lymphoma
PUBLISHED: 05-22-2014
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Myelosuppression in myelodysplastic syndromes (MDS) is associated with the hypomethylating agent decitabine. A retrospective pooled analysis of two decitabine clinical trials in patients with MDS conducted Cox regression analyses of red blood cell or platelet dependence, myelosuppression, dose modification, cycle delay or dose reduction, and survival effects. In 182 patients, baseline platelet dependence was a predictor for dose modification, reduction or delay, and death (modification: p = 0.006, hazard ratio [HR] = 2.04; reduction/delay: p = 0.011, HR = 2.00; death: p = 0.003, HR = 1.94). Patients with dose modifications had significantly higher overall response rates versus those with none (22% vs. 10%; p = 0.015). Patients with no dose modifications had faster progression to acute myeloid leukemia (AML) versus patients with dose modifications (p = 0.004). Without dose modifications, patients tended to drop out due to disease progression or other reasons. Decitabine dose modifications on treatment may indicate response to treatment.
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Gemtuzumab ozogamicin with fludarabine, cytarabine, and granulocyte colony stimulating factor (FLAG-GO) as front-line regimen in patients with core binding factor acute myelogenous leukemia.
Am. J. Hematol.
PUBLISHED: 04-30-2014
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Despite being considered "good-risk" acute myelogenous leukemia (AML), long term outcomes in core binding factor (CBF) AML suggest room for improvement. We report on a regimen consisting of fludarabine, cytarabine, granulocyte colony stimulating factor, and low dose gemtuzumab ozogamicin (FLAG-GO) as front-line therapy of patients with CBF AML. Forty-five patients were enrolled (median age 48 years). Remission rate was 95% with 5% induction deaths. The overall survival (OS) and relapse free survival (RFS) probability at 3 years are 78% and 85%, respectively. FLAG-GO regimen results in high rates of RFS and OS in CBF AML. Our data along with recent data from several large groups strongly argues in favor of incorporation of gemtuzumab ozogamicin in frontline regimens for CBF AML.
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Phase II trial of hyper CVAD and dasatinib in patients with relapsed Philadelphia chromosome positive acute lymphoblastic leukemia or blast phase chronic myeloid leukemia.
Am. J. Hematol.
PUBLISHED: 04-30-2014
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Dasatinib is a second generation tyrosine kinase inhibitor, with activity in imatinib resistant Ph-positive ALL.We have treated 34 patients with relapsed Philadelphia chromosome positive acute lymphoblastic leukemia(ALL) (n519) or lymphoid blast phase of chronic myelogenous leukemia (CML-LB) (n515) with the combination of dasatinib and the hyper CVAD regimen. Prior regimens included hyper CVAD plus imatinib(n511, 4 had transplant in first CR), other combination chemotherapy (n512), monotherapy with kinase inhibitors other than dasatinib (n59), and investigational agents (n52). Pretreatment ABL mutations were noted in 10 patients. The overall response rate was 91%, with 24 patients (71%) achieving complete response(CR), and 7(21%) CR with incomplete platelet recovery (CRp). Two patients died during induction and one had progressive disease. Twenty-six patients (84%) achieved complete cytogenetic remission after one cycle of therapy. Overall, 13 patients (42%) achieved complete molecular response, and 11 patients (35%) had major molecular response (BCR-ABL/ABL<0.1%). Nine patients proceeded to allogeneic transplantation.Grades 3 and 4 toxicities included hemorrhage, pleural and pericardial effusions and infections. The median follow-up for patients with CML-LB is 37.5 months (range, 7–70 months) with a 3-year overall survival of 70%;68% remained in CR at 3 years. For ALL patients, the median follow-up is 52 months (range, 45–59 months)with a 3-year survival of 26%; 30% remain in CR at 3 years. The combination of Hyper CVAD regimen with dasatinib is effective in patients with relapsed Ph-positive ALL and CML-LB.
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Phase II study of pomalidomide in combination with prednisone in patients with myelofibrosis and significant anemia.
Leuk. Res.
PUBLISHED: 04-15-2014
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We evaluated pomalidomide with prednisone for myelofibrosis (MF) with significant anemia (hemoglobin < 10 g/dL). Patients (n = 29; 18 RBC-transfusion dependent) received 0.5mg pomalidomide daily in continuous 28-day cycles with prednisone given for the first 3 cycles only. Six (21%) patients responded (median response duration 11.4 months), including four who achieved RBC-transfusion-independence per the Delphi criteria and two who achieved clinical improvement (in platelets and spleen, respectively) per the International Working Group for Myelofibrosis Research and Treatment criteria. Grade 3 toxicity occurred in 1 patient (fatigue). Pomalidomide with prednisone is safe therapy with modest activity in patients with MF and anemia. ClinicalTrials.gov Identifier: NCT00946270.
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Cytogenetics, donor type, and use of hypomethylating agents in myelodysplastic syndrome with allogeneic stem cell transplantation.
Biol. Blood Marrow Transplant.
PUBLISHED: 04-12-2014
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We investigated the impact of patient and disease characteristics, including cytogenetics, previous therapy, and depth of response, on the outcome of allogeneic hematopoietic stem cell transplantation (HSCT) for patients with myelodysplastic syndrome (MDS). We analyzed 256 MDS patients who underwent transplantation from a matched related (n = 133) or matched unrelated (n = 123) donor after 2001. Of the 256, 78 (30.5%) did not receive cytoreductive therapy before HSCT; 40 (15.6%) received chemotherapy, 122 (47.7%) received hypomethylating agents (HMA), and 16 (6.2%) received both (chemo+HMA). Disease status at HSCT defined by International Working Criteria was complete remission in 46 (18%) patients. There were significant differences between therapy groups: there were more therapy-related MDS and higher use of matched related donor in the untreated group. The chemotherapy group had higher serum ferritin levels at HSCT. Patients were older and had more high-risk disease by revised International Prognostic Scoring in the HMA group. Despite those differences, transplantation outcomes were similar in patients who were untreated and who received cytoreductive therapy before HSCT. Three-year event-free survival (EFS) was 44.2%, 30.6%, 34.2%, and 32.8% for untreated, chemotherapy, HMA, and chemo+HMA groups, respectively (P = .50). Multivariate analyses revealed that older age (hazard ratio [HR], 1.3; P = .001); high-risk histologic subtypes, including refractory anemia with excess blasts (HR, 1.5; P = .05) and chronic myelomonocytic leukemia (HR, 2.1; P = .03), high-risk cytogenetics with monosomal karyotype (MK) (HR, 4.0; P < .0001) and high serum ferritin level at HSCT (HR, 1.8; P = .002) were poor prognostic factors for EFS. Bone marrow blast count 5% or higher at HSCT (HR, 1.6; P = .01) and MK (HR, 4.2; P < .0001) were the only prognostic factors for increased relapse incidence after HSCT. Patients with MK represented a poor prognostic group, with 3-year EFS of 11.4% and relapse incidence of 60.9%. In this analysis, various therapy approaches before HSCT did not lead to different transplantation outcomes. Cytogenetics defined by MK was able to identify a very poor prognostic groups that innovative transplantation approaches to improve outcomes are urgently needed.
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Safety and clinical activity of 5-aza-2'-deoxycytidine (decitabine) with or without Hyper-CVAD in relapsed/refractory acute lymphocytic leukaemia.
Br. J. Haematol.
PUBLISHED: 04-02-2014
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To test the safety and activity of 5-aza-2'-deoxycytidine (decitabine) in patients with relapsed/refractory acute lymphocytic leukaemia (ALL), we conducted a phase 1 study with two parts: administering decitabine alone or in combination with Hyper-CVAD (fractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone alternating with high-dose methotrexate and cytarabine). Patients participated in either part of the study or in both parts sequentially. In the initial part, decitabine was administered intravenously at doses of 10-120 mg/m(2)  per d for 5 d every other week in cycles of 28 d. In the combination part, patients were treated on the first 5 d of Hyper-CVAD with intravenous decitabine at 5-60 mg/m(2)  per d. A total of 39 patients received treatment in the study: 14 in the first part only, 16 sequentially in both parts and 9 in the second part only. Decitabine was tolerated at all doses administered, and grade 3 or 4 toxic effects included non-life-threatening hepatotoxicity and hyperglycaemia. Induction of DNA hypomethylation was observed at doses of decitabine up to 80 mg/m(2) . Some patients who had previously progressed on Hyper-CVAD alone achieved a complete response when decitabine was added. Decitabine alone or given with Hyper-CVAD is safe and has clinical activity in patients with advanced ALL.
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Analysis of anchor-size effects on pinned scroll waves and measurement of filament rigidity.
Phys Rev E Stat Nonlin Soft Matter Phys
PUBLISHED: 04-02-2014
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Inert, spherical heterogeneities can pin three-dimensional scroll waves in the excitable Belousov-Zhabotinsky reaction. Three pinning sites cause initially circular rotation backbones to approach equilateral triangles. The resulting stationary shapes show convex deviations that increase with decreasing anchor radii. This dependence is interpreted as a transition between filament termination at large surfaces and true, local pinning of a continuous curve. The shapes of the filament segments are described by a hyperbolic cosine function which is predicted by kinematic theory that considers filament tension and rigidity. The latter value is measured as (1.0±0.7)×10-6 cm4/s.
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Outcomes of patients with myelodysplatic syndrome and chronic myelomonocytic leukemia post clofarabine failure.
Ther Adv Hematol
PUBLISHED: 04-02-2014
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The outcome of patients with myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) post clofarabine is unknown.
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Results of phase 2 randomized study of low-dose decitabine with or without valproic acid in patients with myelodysplastic syndrome and acute myelogenous leukemia.
Cancer
PUBLISHED: 03-28-2014
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Hypomethylating agents have demonstrated activity in patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Preclinical and single-arm trials have suggested that adding histone deacetylase (HDAC) inhibitors may synergize the epigenetic modulation of hypomethylating agents and improve treatment results.
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Paradoxical benefits of psychological stress in inflammatory dermatoses models are glucocorticoid mediated.
J. Invest. Dermatol.
PUBLISHED: 03-20-2014
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Acute psychological stress (PS) mobilizes metabolic responses that are of immediate benefit to the host, but the current medical paradigm holds that PS exacerbates systemic and cutaneous inflammatory disorders. Although the adverse consequences of PS are usually attributed to neuroimmune mechanisms, PS also stimulates an increase in endogenous glucocorticoids (GCs) that compromises permeability barrier homeostasis, stratum corneum cohesion, wound healing, and epidermal innate immunity in normal skin. Yet, if such PS-induced increases in GC were uniformly harmful, natural selection should have eliminated this component of the stress response. Hence, we hypothesized here instead that stress-induced elevations in endogenous GC could benefit, rather than aggravate, cutaneous function and reduce inflammation in three immunologically diverse mouse models of inflammatory diseases. Indeed, superimposed exogenous (motion-restricted) stress reduced, rather than aggravated inflammation and improved epidermal function in all three models, even normalizing serum IgE levels in the atopic dermatitis model. Elevations in endogenous GC accounted for these apparent benefits, because coadministration of mifepristone prevented stress-induced disease amelioration. Thus, exogenous stress can benefit rather than aggravate cutaneous inflammatory dermatoses through the anti-inflammatory activity of increased endogenous GC.
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Ultrastructure of skin from Refsum disease with emphasis on epidermal lamellar bodies and stratum corneum barrier lipid organization.
Arch. Dermatol. Res.
PUBLISHED: 02-26-2014
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Classic Refsum disease (RD) is a rare, autosomal recessively-inherited disorder of peroxisome metabolism due to a defect in the initial step in the alpha oxidation of phytanic acid (PA), a C16 saturated fatty acid with four methyl side groups, which accumulates in plasma and lipid enriched tissues (please see van den Brink and Wanders, Cell Mol Life Sci 63:1752-1765, 2006). It has been proposed that the disease complex in RD is in part due to the high affinity of phytanic acid for retinoid X receptors and peroxisome proliferator-activated receptors. Structurally, epidermal hyperplasia, increased numbers of cornified cell layers, presence of cells with lipid droplets in stratum basale and reduction of granular layer to a single layer have been reported by Blanchet-Bardon et al. (The ichthyoses, SP Medical & Scientific Books, New York, pp 65-69, 1978). However, lamellar body (LB) density and secretion were reportedly normal. We recently examined biopsies from four unrelated patients, using both OsO4 and RuO4 post-fixation to evaluate the barrier lipid structural organization. Although lamellar body density appeared normal, individual organelles often had distorted shape, or had non-lamellar domains interspersed with lamellar structures. Some of the organelles seemed to lack lamellar contents altogether, showing instead uniformly electron-dense contents. In addition, we also observed mitochondrial abnormalities in the nucleated epidermis. Stratum granulosum-stratum corneum junctions also showed co-existence of non-lamellar and lamellar domains, indicative of lipid phase separation. Also, partial detachment or complete absence of corneocyte lipid envelopes (CLE) was seen in the stratum corneum of all RD patients. In conclusion, abnormal LB contents, resulting in defective lamellar bilayers, as well as reduced CLEs, likely lead to impaired barrier function in RD.
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Dynamics of land use and land cover and its effects on hydrologic responses: case study of the Gilgel Tekeze catchment in the highlands of Northern Ethiopia.
Environ Monit Assess
PUBLISHED: 02-21-2014
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Unprecedented land use and land cover (LULC) changes in the Gilgel Tekeze catchment of the upper Nile River basin in Ethiopia may have far-reaching consequences for the long-term sustainability of the natural resources base. This study analyzed the dynamics and hydrologic effects of LULC changes between 1976 and 2003 as shown in satellite imagery. The effects of these LULC changes on the hydrologic response were investigated using the WetSpa model to estimate spatially distributed average annual evapotranspiration, surface runoff, and groundwater recharge. Digital image analysis revealed major increments of cultivated land and settlements of 15.4 and 9.9 %, respectively, at the expense of shrubland and grazing lands. Population growth and the associated demand for land were found to be the major driving forces. The WetSpa simulation showed an increase in annual surface runoff of 101 mm and a decrease in groundwater recharge of 39 mm over the period 1976-2003. These results signify an increasing threat of moisture unavailability in the study area and suggest that appropriate land management measures under the framework of the integrated catchment management (ICM) approach are urgently needed.
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Chronic myeloid leukemia: 2014 update on diagnosis, monitoring, and management.
Am. J. Hematol.
PUBLISHED: 02-03-2014
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Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm with an incidence of 1-2 cases per 100,000 adults, and accounts for ?15% of newly diagnosed cases of leukemia in adults.
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Acute myeloid leukemia after myelodysplastic syndrome and failure of therapy with hypomethylating agents: an emerging entity with a poor prognosis.
Clin Lymphoma Myeloma Leuk
PUBLISHED: 01-23-2014
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We assessed the outcomes of 63 patients with acute myeloid leukemia (AML) arising from myelodysplastic syndrome (MDS) after hypomethylating agent failure. Their median age was 63 years. All 63 patients had received ? 1 salvage regimens for AML, and 35 patients (55%) had received ? 2. Of the 31 patients (49%) who had received high-dose cytarabine (HDAC) at first relapse, 2 (6%) achieved complete remission (CR) and 4 (13%) CR with incomplete platelet recovery (overall response rate, 19%). Of the 32 patients (51%) who had received other treatments, including investigational agents, 4 (12%) achieved CR and 4 (12%) CR with incomplete platelet recovery (overall response rate, 24%). The median response duration was 20 weeks. With a median follow-up of 42 months from the AML diagnosis, the median survival (21 weeks) was similar between the 2 groups. The 1- and 2-year survival rate was 19% and 8%, respectively. Multivariate analysis identified low albumin, HDAC treatment, and platelet count < 50 × 10(9)/L as independent adverse factors for CR and a platelet count < 50 × 10(9)/L and age > 65 years as independent adverse factors for survival. Thus, the outcome of AML evolving from MDS after hypomethylating agent failure is poor and not improved with HDAC. Novel therapies directed toward this emerging entity are urgently needed.
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Impact of comorbidities by ACE-27 in the revised-IPSS for patients with myelodysplastic syndromes.
Am. J. Hematol.
PUBLISHED: 01-16-2014
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Comorbidities significantly affect the prognosis and outcomes of patients with hematological malignancies. We have previously reported the impact of comorbidities on the International Prognostic Scoring System (IPSS) score. The aim of this study was to determine whether comorbidities continued to have a significant impact when patients were reclassified according to the Revised-IPSS (IPSS-R). The medical records of 600 consecutive myelodysplastic syndrome patients who presented to MD Anderson Cancer Center between January 2002 and June 2004 were reviewed. The Adult Comorbidity Evaluation-27 (ACE-27) was used to assess the severity of comorbid conditions. Four hundred and two (67%) patients were male. Median age at presentation was 66.6 years (17-94). Mean duration of follow-up was 54 months (1-100). Five hundred and two (84%) patients died, and 54 (9%) patients underwent stem cell transplantation. Overall median survival was 16.8 months (1-100). Median survival by IPSS-R was 47, 34, 21, 16, and 6 months for patients in very low, low, intermediate, high, and very high-risk groups, respectively (P?65 years (P?=?0.18). Assessment of comorbidity may enhance the prognostic ability of the IPSS-R.
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Targeting the phosphoinositide 3-kinase pathway in hematologic malignancies.
Haematologica
PUBLISHED: 01-16-2014
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The phosphoinositide 3-kinase pathway represents an important anticancer target because it has been implicated in cancer cell growth, survival, and motility. Recent studies show that PI3K may also play a role in the development of resistance to currently available therapies. In a broad range of cancers, various components of the phosphoinositide 3-kinase signaling axis are genetically modified, and the pathway can be activated through many different mechanisms. The frequency of genetic alterations in the phosphoinositide 3-kinase pathway, coupled with the impact in oncogenesis and disease progression, make this signaling axis an attractive target in anticancer therapy. A better understanding of the critical function of the phosphoinositide 3-kinase pathway in leukemias and lymphomas has led to the clinical evaluation of novel rationally designed inhibitors in this setting. Three main categories of phosphoinositide 3-kinase inhibitors have been developed so far: agents that target phosphoinositide 3-kinase and mammalian target of rapamycin (dual inhibitors), pan-phosphoinositide 3-kinase inhibitors that target all class I isoforms, and isoform-specific inhibitors that selectively target the ?, -?, -?, or -? isoforms. Emerging data highlight the promise of phosphoinositide 3-kinase inhibitors in combination with other therapies for the treatment of patients with hematologic malignancies. Further evaluation of phosphoinositide 3-kinase inhibitors in first-line or subsequent regimens may improve clinical outcomes. This article reviews the role of phosphoinositide 3-kinase signaling in hematologic malignancies and the potential clinical utility of inhibitors that target this pathway.
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Clofarabine in the treatment of myelodysplastic syndromes.
Expert Opin Investig Drugs
PUBLISHED: 01-14-2014
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Clofarabine is a second-generation purine nucleoside analog approved in 2004 for the treatment of pediatric patients with relapsed or refractory acute lymphocytic leukemia (ALL) following failure of at least two prior regimens. Clofarabine is a hybrid of fludarabine and cladribine, designed to overcome the pharmacologic limitations associated with its predecessors, while retaining their beneficial properties. In addition to providing a valuable treatment option for pediatric patients with ALL, clofarabine alone and in combination with cytarabine (Ara-C) has demonstrated substantial activity against myelodysplastic syndrome (MDS), thus rendering this agent a potential therapeutic option for MDS.
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Predicting outcomes in patients with chronic myeloid leukemia at any time during tyrosine kinase inhibitor therapy.
Clin Lymphoma Myeloma Leuk
PUBLISHED: 01-05-2014
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Current recommendations for monitoring patients with chronic myeloid leukemia (CML) provide recommendations for response assessment and treatment only at 3, 6, 12, and 18 months. These recommendations are based on clinical trial outcomes computed from treatment start. Conditional survival estimates take into account the changing hazard rates as time from treatment elapses as a continuum.
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Early response with dasatinib or imatinib in chronic myeloid leukemia: 3-year follow-up from a randomized phase 3 trial (DASISION).
Blood
PUBLISHED: 12-05-2013
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This analysis explores the impact of early cytogenetic and molecular responses on the outcomes of patients with chronic myeloid leukemia in chronic phase (CML-CP) in the phase 3 DASISION trial with a minimum follow-up of 3 years. Patients with newly diagnosed CML-CP were randomized to receive 100 mg dasatinib (n = 259) or 400 mg imatinib (n = 260) once daily. The retrospective landmark analysis included patients evaluable at the relevant time point (3, 6, or 12 months). Median time to complete cytogenetic response was 3 versus 6 months with dasatinib versus imatinib. At 3 and 6 months, the proportion of patients with BCR-ABL transcript levels ? 10% was higher in the dasatinib arm. Deeper responses at 3, 6, and 12 months were observed in a higher proportion of patients on dasatinib therapy and were associated with better 3-year progression-free survival (PFS) and overall survival (OS) in both arms. First-line dasatinib resulted in faster and deeper responses compared with imatinib. The achievement of an early molecular response was predictive of improved PFS and OS, supporting new milestones for optimal response in patients with early CML-CP treated with tyrosine kinase inhibitors. This study was registered at ClinicalTrials.gov: NCT00481247.
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Skin-cleansing and care principles for special pediatric populations.
Semin Cutan Med Surg
PUBLISHED: 10-26-2013
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Good skin care has two overall goals: to support and maintain healthy stratum corneum function and to help restore barrier function perturbed by disease processes or injuries. In this article, we discuss the special attention that is required in the initial skin care of newborns, and we address what measures, beyond the basic skin care principles, are required for patients with conditions such as atopic dermatitis, acne, contact and allergic dermatitis, and diaper rash.
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A lifetime of well skin care: practical recommendations for clinicians and patients.
Semin Cutan Med Surg
PUBLISHED: 10-26-2013
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The skin is an indicator of overall health throughout life, and the skins lifelong care and environment are reflected with aging. The goal of skin care education by clinicians is to teach and reinforce habits that will support and maintain optimum stratum corneum barrier function throughout life and, when dermatologic conditions or injuries arise, that will aid in recovery of barrier function.
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The chemistry of skin cleansers: an overview for clinicians.
Semin Cutan Med Surg
PUBLISHED: 10-26-2013
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Cleansers and other skin care products can be agents either of stratum corneum damage and skin barrier dysfunction or of maintaining or restoring healthy stratum corneum barrier structure and function. To guide patients toward beneficial choices most suitable for their individual skin conditions and needs, clinicians must be aware of and understand the ingredients in such skin care products and their potential effects on the stratum corneum barrier. In cleansers specifically, clinicians should be aware particularly of the benefits and potential problems associated with chemical components of surfactants, preservatives, and fragrances.
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Update on the structure and function of the skin barrier: atopic dermatitis as an exemplar of clinical implications.
Semin Cutan Med Surg
PUBLISHED: 10-26-2013
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The healthy stratum corneum allows optimum permeability of water and provides the first line of defense against pathogenic and environmental assaults. The barrier functions of the stratum corneum are interrelated, coregulated, and interdependent. Research has demonstrated that three lipid species, which usually comprise 10% of the stratum corneum, are crucial to both its structure and its function; these must be present in sufficient quantities and in the correct proportions to provide optimum barrier function. The clinical implications of how the skin barrier works--and is supported and restored--can be seen in the current and emerging understanding of atopic dermatitis management.
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Understanding skin barrier differences: a demographic, cultural, and medical diversity viewpoint.
Semin Cutan Med Surg
PUBLISHED: 10-26-2013
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Important differences exist in the physiology of the stratum corneum barrier according to demographic, cultural, and medical factors. Understanding these differences is crucial to choosing strategies for optimum clinical management.
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Targeted therapies in hematology and their impact on patient care: chronic and acute myeloid leukemia.
Semin. Hematol.
PUBLISHED: 10-03-2013
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Advances in the genetic and molecular characterizations of leukemias have enhanced our capabilities to develop targeted therapies. The most dramatic example of targeted therapy in cancer to date is the use of targeted BCR-ABL protein tyrosine kinase inhibitors (TKI), which has revolutionized the treatment of chronic myeloid leukemia (CML). Inhibition of the signaling activity of this kinase has proved to be a highly successful treatment target, transforming the prognosis of patients with CML. In contrast, acute myeloid leukemia (AML) is an extremely heterogeneous disease with outcomes that vary widely according to subtype of the disease. Targeted therapy with monoclonal antibodies and small molecule kinase inhibitors are promising strategies to help improve the cure rates in AML. In this review, we will highlight the results of recent clinical trials in which outcomes of CML and AML have been influenced significantly. Also, novel approaches to sequencing and combining available therapies will be covered.
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Ten-year publication trends in dermatology in mainland China.
Int. J. Dermatol.
PUBLISHED: 08-22-2013
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China has been experiencing huge changes in all aspects, including dermatologic research, since its reform in 1978. However, it is not known how the economic and intellectual development has influenced the publication trends in the field of dermatology, which could mirror the scientific development in other medical disciplines. In the present study, we analyzed publication trends from dermatology departments in mainland China from 2002 to 2011.
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Role of cholesterol sulfate in epidermal structure and function: Lessons from X-linked ichthyosis.
Biochim. Biophys. Acta
PUBLISHED: 08-15-2013
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X-linked ichthyosis is a relatively common syndromic form of ichthyosis most often due to deletions in the gene encoding the microsomal enzyme, steroid sulfatase, located on the short area of the X chromosome. Syndromic features are mild or unapparent unless contiguous genes are affected. In normal epidermis, cholesterol sulfate is generated by cholesterol sulfotransferase (SULT2B1b), but desulfated in the outer epidermis, together forming a cholesterol sulfate cycle that potently regulates epidermal differentiation, barrier function and desquamation. In XLI, cholesterol sulfate levels my exceed 10% of total lipid mass (?1% of total weight). Multiple cellular and biochemical processes contribute to the pathogenesis of the barrier abnormality and scaling phenotype in XLI. This article is part of a Special Issue entitled The Important Role of Lipids in the Epidermis and their Role in the Formation and Maintenance of the Cutaneous Barrier.
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Patient-driven discontinuation of tyrosine kinase inhibitors: single institution experience.
Leuk. Lymphoma
PUBLISHED: 08-10-2013
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With improved outcome for patients with chronic myeloid leukemia (CML) treated with tyrosine kinase inhibitors (TKIs), treatment discontinuation has become increasingly attractive to patients. We analyzed the outcomes of patients who chose to discontinue TKI therapy regardless of their ongoing response. Thirty-five patients with chronic phase CML discontinued TKI in complete cytogenetic response. Of them, 51% discontinued due to adverse effects, 23% due to long complete molecular response (CMR) (> 5 years), 9% due to pregnancy and 17% due to financial problems. After TKI discontinuation, patients were followed for a median of 16 months. Among 27 patients (77%) who discontinued TKIs in CMR, 11 (41%) had a molecular relapse after a median of 3.5 months. In univariate analysis we observed that patients with ? 64 months of CMR before TKI discontinuation had superior cumulative proportions of sustained CMR and major molecular response (MMR) at 12 months after discontinuation: 88.9% vs. 45.5% (p = 0.02) and 100% vs. 75% (p = 0.05), respectively. Patients treated with high dose imatinib or second generation TKIs had a higher cumulative proportion of sustained MMR at 12 months after discontinuation than patients treated with standard dose imatinib: 100% vs. 72.2% (p = 0.03), respectively. Of the five patients who stopped TKI in MR(4.5) (molecular response of 4.5-log reduction) one lost cytogenetic response. All three patients who discontinued TKIs in MMR lost cytogenetic response; one progressed to accelerated phase. Thirteen patients (37%) restarted TKIs after loss of response: 11 improved their response, and for two it is too early to assess. Treatment discontinuation can lead to sustained CMR in some patients, but risk of relapse is higher if patients discontinue TKIs when not in CMR.
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Role of lipids in the formation and maintenance of the cutaneous permeability barrier.
Biochim. Biophys. Acta
PUBLISHED: 08-08-2013
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The major function of the skin is to form a barrier between the internal milieu and the hostile external environment. A permeability barrier that prevents the loss of water and electrolytes is essential for life on land. The permeability barrier is mediated primarily by lipid enriched lamellar membranes that are localized to the extracellular spaces of the stratum corneum. These lipid enriched membranes have a unique structure and contain approximately 50% ceramides, 25% cholesterol, and 15% free fatty acids with very little phospholipid. Lamellar bodies, which are formed during the differentiation of keratinocytes, play a key role in delivering the lipids from the stratum granulosum cells into the extracellular spaces of the stratum corneum. Lamellar bodies contain predominantly glucosylceramides, phospholipids, and cholesterol and following the exocytosis of lamellar lipids into the extracellular space of the stratum corneum these precursor lipids are converted by beta glucocerebrosidase and phospholipases into the ceramides and fatty acids, which comprise the lamellar membranes. The lipids required for lamellar body formation are derived from de novo synthesis by keratinocytes and from extra-cutaneous sources. The lipid synthetic pathways and the regulation of these pathways are described in this review. In addition, the pathways for the uptake of extra-cutaneous lipids into keratinocytes are discussed. This article is part of a Special Issue entitled The Important Role of Lipids in the Epidermis and their Role in the Formation and Maintenance of the Cutaneous Barrier.
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Lipid abnormalities and lipid-based repair strategies in atopic dermatitis.
Biochim. Biophys. Acta
PUBLISHED: 08-07-2013
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Prior studies have revealed the key roles played by Th1/Th2 cell dysregulation, IgE production, mast cell hyperactivity, and dendritic cell signaling in the evolution of the chronic, pruritic, inflammatory dermatosis that characterizes atopic dermatitis (AD). We review here increasing evidence that the inflammation in AD results primarily from inherited abnormalities in epidermal structural and enzymatic proteins that impact permeability barrier function. We also will show that the barrier defect can be attributed to a paracellular abnormality due to a variety of abnormalities in lipid composition, transport and extracellular organization. Accordingly, we also review the therapeutic implications of this emerging pathogenic paradigm, including several current and potentially novel, lipid-based approaches to corrective therapy.
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Formation and functions of the corneocyte lipid envelope (CLE).
Biochim. Biophys. Acta
PUBLISHED: 07-30-2013
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Corneocytes in mammalian stratum corneum are surrounded by a monolayer of covalently bound ?-OH-ceramides that form the corneocyte (-bound) lipid envelope (CLE). We review here the structure, composition, and possible functions of this structure, with insights provided by inherited and acquired disorders of lipid metabolism. This article is part of a Special Issue entitled The Important Role of Lipids in the Epidermis and their Role in the Formation and Maintenance of the Cutaneous Barrier.
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HCVAD plus imatinib or dasatinib in lymphoid blastic phase chronic myeloid leukemia.
Cancer
PUBLISHED: 07-26-2013
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Chronic myeloid leukemia (CML) may progress to blast phase (BP) at the rate of 1% to 1.5% per year. With the use of single-agent tyrosine kinase inhibitors, median overall survival ranges between 7 and 11 months.
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Assessment at 6 months may be warranted for patients with chronic myeloid leukemia with no major cytogenetic response at 3 months.
Haematologica
PUBLISHED: 06-28-2013
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Response to tyrosine kinase inhibitors at three months is a predictor for long-term outcome in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors. We analyzed 456 newly diagnosed chronic myeloid leukemia patients treated with tyrosine kinase inhibitors to determine their outcome based on their response at six months. Forty-four (10%) patients did not achieve major cytogenetic response at three months: 18 of 67 (27%) patients treated with imatinib 400; 18 of 196 (9%) with imatinib 800; and 8 of 193 (4%) with 2nd generation tyrosine kinase inhibitors. Among them, 19 (43%) achieved major cytogenetic response at six months and subsequently had an overall outcome similar to the patients who achieved a major cytogenetic response at three months. In conclusion, the response to tyrosine kinase inhibitors at three months is a static, one-time measure. Assessing the response at six months of patients with poor response at three months may provide a better predictor for long-term outcome.
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Acute lymphoblastic leukemia in adults: encouraging developments on the way to higher cure rates.
Leuk. Lymphoma
PUBLISHED: 06-21-2013
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Conventional cytotoxic chemotherapy for adult acute lymphoblastic leukemia (ALL) is not adequate to cure most patients of the disease. Complete remission is achieved in the majority of patients, but responses are often not durable. Allogeneic stem cell transplant is used for patients with high risk features, including those who are positive for minimal residual disease after induction and consolidation therapy. Nevertheless, transplant is a toxic intervention, and does not guarantee long-term disease-free survival. Monoclonal antibodies target surface antigens present on leukemic blasts, with the aim of minimizing off-target toxicity. Rituximab, an antibody directed against CD20, prolongs the survival of younger adults with ALL when added to chemotherapy in the frontline setting. Novel agents, such as the cytotoxin-antibody conjugate inotuzumab, and the bispecific T-cell engaging compound blinatumomab, have exhibited marked antileukemic activity in the relapsed setting. As these agents continue in clinical development, it will be important to eventually incorporate them in the frontline treatment approach. We review current strategies for treating adult ALL, with a focus on novel and targeted therapies that are under development.
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Acquisition of cytogenetic abnormalities in patients with IPSS defined lower-risk myelodysplastic syndrome is associated with poor prognosis and transformation to acute myelogenous leukemia.
Am. J. Hematol.
PUBLISHED: 06-08-2013
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We hypothesized that the dynamic acquisition of cytogenetic abnormalities (ACA) during the follow up of myelodysplastic syndromes (MDS) could be associated with poor prognosis. We conducted a retrospective analysis of 365 patients with IPSS low or intermediate-1 risk MDS who had at least two consecutive cytogenetic analyses during the follow up. Acquisition of cytogenetic abnormalities was detected in 107 patients (29%). The most frequent alteration involved chromosome 7 in 21% of ACA cases. Median transformation-free and overall survival for patients with and without ACA were 13 vs. 52 months (P = 0.01) and 17 vs. 62 months (P = 0.01), respectively. By fitting ACA as a time-dependent covariate, multivariate Cox regression analysis showed that patients with ACA had increased risk of transformation (HR = 1.40; P = 0.03) or death (HR = 1.45; P = 0.02). Notably, female patients with therapy-related MDS (t-MDS) had an increased risk of developing ACA (OR = 5.26; P < 0.0001), although subgroup analysis showed that prognostic impact of ACA was not evident in t-MDS. In conclusion, ACA occurs in close to one third of patients with IPSS defined lower risk MDS, more common among patients with t-MDS, but has a significant prognostic impact on de novo MDS.
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Randomized open-label phase II study of decitabine in patients with low- or intermediate-risk myelodysplastic syndromes.
J. Clin. Oncol.
PUBLISHED: 06-03-2013
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This open-label, randomized phase II trial assessed efficacy and tolerability of two low-dose regimens of subcutaneous (SC) decitabine in patients with low- or intermediate-1-risk myelodysplastic syndrome (MDS).
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Decitabine can be safely reduced after achievement of best objective response in patients with myelodysplastic syndrome.
Clin Lymphoma Myeloma Leuk
PUBLISHED: 05-08-2013
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Decitabine is standard therapy in patients with myelodysplastic syndrome (MDS). Current recommendations suggest a dose of 20 mg/m(2) intravenously (IV) daily for 5 days every 4 weeks. However, this therapy is associated with frequent grade 3/4 hematologic toxicity, requiring dose delays and/or dose reductions (DD/DR).
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Biological and clinical features of trisomy 21 in adult patients with acute myeloid leukemia.
Clin Lymphoma Myeloma Leuk
PUBLISHED: 05-06-2013
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Trisomy 21 is frequently noted in patients with AML. In adults, +21 has traditionally been considered an intermediate-risk cytogenetic aberration.
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Clofarabine, idarubicin, and cytarabine (CIA) as frontline therapy for patients ?60 years with newly diagnosed acute myeloid leukemia.
Am. J. Hematol.
PUBLISHED: 05-02-2013
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Clofarabine is a second generation nucleoside analogue with activity in adults with acute myeloid leukemia (AML). A phase I trial of clofarabine, idarubicin, and cytarabine (CIA) in relapsed and refractory AML had shown an overall response rate (ORR) of 48%. To explore this combination further, we conducted a phase II study of (CIA) in patients with newly diagnosed AML ?60 years. Patients ?18-60 years with AML and adequate organ function were enrolled. Induction therapy consisted of clofarabine (C) 20 mg m?² IV daily (days 1-5), idarubicin (I) 10 mg m?² IV daily (days 1-3), and cytarabine (A) 1 g m?² IV daily (days 1-5). Patients in remission received up to six consolidation cycles (C 15 mg m?² × 3, I 8 mg m?² × 2, and A 0.75 g m?² × 3). Fifty-seven patients were evaluable. ORR was 79%. With a median follow up of 10.9 months, the median overall survival (OS) was not reached, the median event-free survival (EFS) was 13.5 months. Most toxicities were ?grade 2. Four week mortality was 2%. In subgroup analysis, patients ?40 years had better OS (P?=?0.04) and EFS (P?=?0.04) compared to patients >40 years. Compared to historical patients treated with idarubicin and cyarabine (IA), the OS and EFS were significantly longer for CIA treated patients. In multivariate analysis, CIA retained its favorable impact on OS compared to IA. Thus, CIA is an effective and safe therapy for patients ?60 years with newly diagnosed AML.
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Early responses predict better outcomes in patients with newly diagnosed chronic myeloid leukemia: results with four tyrosine kinase inhibitor modalities.
Blood
PUBLISHED: 04-25-2013
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Early responses to tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML)-chronic phase (CP) are associated with improved outcome. We analyzed the impact of such a response on outcomes among patients treated with 4 TKI modalities as frontline therapy in CML-CP. A total of 483 patients who received 400 or 800 mg imatinib, nilotinib, or dasatinib were analyzed. The median follow-up was 72 mo. Landmark analysis at 3 mo by molecular response showed that the cumulative proportions of 3-y event-free survival (EFS) for 3-mo BCR-ABL levels was 95% for those with ?1%, 98% for >1% to 10%, and 61% for those with >10% (P = .001). The corresponding values by cytogenetic responses were 97% if Ph+ = 0%, 89% if Ph+ = 1% to 35%, and 81% if Ph+ >35% (P = .001). Cytogenetic response at 3 mo significantly discriminated for 3-y overall survival (OS): 98%, 96%, and 92%, respectively (P = .01). In multivariate analysis, young patients, high Sokal index, and treatment with imatinib 400 significantly predicted for poor (>35%) cytogenetic response at 3 mo. Early responses are predictive for EFS and failure-free survival and to a lesser extent OS, regardless of the treatment modality, although therapies other than standard-dose imatinib result in higher rates of deep early responses.
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Management of imatinib-resistant patients with chronic myeloid leukemia.
Ther Adv Hematol
PUBLISHED: 04-24-2013
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Since its approval in 2001 for frontline management of chronic myelogenous leukemia (CML), imatinib has proven to be very effective in achieving high remission rates and improving prognosis. However, up to 33% of patients will not achieve optimal response. This has led researchers to develop new second- and third-generation tyrosine kinase inhibitors. In this article, we review the mechanisms of resistance, recommendations for monitoring, assessment of milestones, and management options for patients with CML who are resistant to imatinib therapy. We further explain the potential pitfalls that can lead to unnecessary discontinuation, the prognosis of patients whose condition fails to respond to treatment, and the upcoming therapies.
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Modest activity of pomalidomide in patients with myelofibrosis and significant anemia.
Leuk. Res.
PUBLISHED: 04-04-2013
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We evaluated single agent pomalidomide for myelofibrosis-associated anemia. First, 21 patients received pomalidomide 3.0mg/day on 21-day-on/7-day-off schedule. Due to poor tolerance the study was quickly suspended. Second, 29 patients received pomalidomide 0.5mg/day continuously. Three patients (10%) experienced clinical improvement in hemoglobin per International-Working-Group criteria (median time to response 1.6 months; median response duration 6.7 months). Ten patients were RBC-transfusion-dependent per Delphi criteria; 2 (20%) achieved RBC-transfusion-independence (time to response 0.9 months in both; response duration of 8.3 and 15 months). One grade 3/4 toxicity (neutropenia) occurred. Pomalidomide at low dose is well tolerated but has modest clinical activity in myelofibrosis.
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Tyrosine Kinase Inhibitors as Initial Therapy for Patients With Chronic Myeloid Leukemia in Accelerated Phase.
Clin Lymphoma Myeloma Leuk
PUBLISHED: 03-25-2013
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Accelerated phase CML most frequently represents a progression state in CML. However, some patients present with AP features at the time of diagnosis. There is limited information on the outcome of these patients who received TKIs as initial therapy.
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Similar outcome of patients with chronic myeloid leukemia treated with imatinib in or out of clinical trials.
Clin Lymphoma Myeloma Leuk
PUBLISHED: 03-19-2013
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Outcomes of CML-CP patients treated in clinical trials are frequently perceived to be not representative of those treated outside of clinical trials.
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Expectations of serious adverse events at the end of life of patients with acute myeloid leukemia who receive salvage therapy.
Clin Lymphoma Myeloma Leuk
PUBLISHED: 03-08-2013
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Patients with AML and refractory disease receive investigational therapies within 2 months of their death. The attribution of serious AEs in this phase to disease progression vs. drug toxicity is tenuous. We aimed to determine the incidence of serious AEs in the last 2 weeks of life of patients with refractory-relapsed AML undergoing salvage therapy (ST).
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Retrospective analysis of prognostic factors associated with response and overall survival by baseline marrow blast percentage in patients with myelodysplastic syndromes treated with decitabine.
Clin Lymphoma Myeloma Leuk
PUBLISHED: 03-01-2013
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After the World Health Organization (WHO) changed the definition of acute myeloid leukemia (AML) to ? 20% blasts, the International Working Group (IWG) response criteria for myelodysplasia were updated. This retrospective analysis evaluated response to decitabine using updated IWG criteria in patients pooled from 2 decitabine trials.
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A critical review of trials of first-line BCR-ABL inhibitor treatment in patients with newly diagnosed chronic myeloid leukemia in chronic phase.
Clin Lymphoma Myeloma Leuk
PUBLISHED: 02-15-2013
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The characteristic expression of the constitutively active oncoprotein, BCR-ABL tyrosine kinase, in chronic myeloid leukemia (CML) was the basis for the development of BCR-ABL tyrosine kinase inhibitors for treatment. Three BCR-ABL inhibitors, imatinib, nilotinib, and dasatinib, have been approved by the US Food and Drug Administration for first-line treatment of patients with newly diagnosed CML in chronic phase (CML-CP).
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Results of inotuzumab ozogamicin, a CD22 monoclonal antibody, in refractory and relapsed acute lymphocytic leukemia.
Cancer
PUBLISHED: 02-04-2013
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CD22 expression occurs in >90% of patients with acute lymphocytic leukemia (ALL). Inotuzumab ozogamicin, a CD22 monoclonal antibody bound to calicheamicin, is active in ALL.
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Prognostic impact of RAS mutations in patients with myelodysplastic syndrome.
Am. J. Hematol.
PUBLISHED: 01-28-2013
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RAS is an oncogene frequently mutated in human cancer. RAS mutations have been reported in 10-15% of cases of acute myeloid leukemia (AML) but they appear to be less frequent among patients with myelodysplastic syndrome (MDS). The impact of RAS mutations in patients with MDS is unclear. We conducted a retrospective study in 1,067 patients with newly diagnosed MDS for whom RAS mutational analysis was available. Overall, 4% of patients carried mutant RAS alleles. Notably, FLT3 mutations, which were found in 2% of patients, were mutually exclusive with RAS mutations. Patients with RAS mutations had a higher white blood cell count as well as bone marrow blasts compared with patients carrying wild-type RAS. However, no differences were observed between both groups regarding the risk of AML transformation (9% vs. 7%) and overall survival (395 days vs. 500 days, P = 0.057). In summary, RAS mutations are infrequent in patients with MDS and do not appear to negatively impact their outcome.
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Altered sphingoid base profiles predict compromised membrane structure and permeability in atopic dermatitis.
J. Dermatol. Sci.
PUBLISHED: 01-25-2013
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Ceramide hydrolysis by ceramidase in the stratum corneum (SC) yields both sphingoid bases and free fatty acids (FFA). While FFA are key constituents of the lamellar bilayers that mediate the epidermal permeability barrier, whether sphingoid bases influence permeability barrier homeostasis remains unknown. Pertinently, alterations of lipid profile, including ceramide and ceramidase activities occur in atopic dermatitis (AD).
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Allogeneic hematopoietic stem cell transplantation versus hypomethylating agents in patients with myelodysplastic syndrome: a retrospective case-control study.
Am. J. Hematol.
PUBLISHED: 01-24-2013
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Allogeneic stem cell transplantation (allo-SCT) is the only potentially curative treatment for myelodysplastic syndrome (MDS). Recently, hypomethylating agents (HMAs) have been shown to improve survival in patients with high-risk MDS. We conducted a retrospective case-control study to compare survival with these treatment modalities in patients with untreated MDS. Controls were identified using a departmental database and transplant patients were matched in at least three of the following five criteria: year of diagnosis, age, blast percentage, International Prognostic Scoring System cytogenetic risk, and time from diagnosis to treatment. Median overall survival (OS) was 26 and 25 months for, respectively, allo-SCT [(n = 53); range, 2-210 months] and HMA [(n = 40); range, 2-98 months] (P = 0.89). Four-year survival rates were 24 and 23% for allo-SCT patients and the nontransplant cohort, respectively. Patients undergoing allo-SCT after 2000 had longer median OS compared with those transplanted before 2000 (41 versus 7 months, P=0.001). These results would suggest that prospective studies are needed to delineate the timing and efficacy of allo-SCT in the HMA era.
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Outcome after failure of second generation tyrosine kinase inhibitors treatment as first-line therapy for patients with chronic myeloid leukemia.
Clin Lymphoma Myeloma Leuk
PUBLISHED: 01-17-2013
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The outcome of patients with CML who discontinue 2G-TKI initial therapy is unknown. We analyzed the characteristics of patients in whom treatment with first-line 2G-TKIs had failed.
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Effect of NPM1 and FLT3 mutations on the outcomes of elderly patients with acute myeloid leukemia receiving standard chemotherapy.
Clin Lymphoma Myeloma Leuk
PUBLISHED: 01-16-2013
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The effect of prognostically important gene mutations (MUTs), nucleophosmin (nucleolar phosphoprotein B23, numatrin) (NPM1) and fms-related tyrosine kinase 3 (FLT3), in elderly patients with acute myeloid leukemia (AML) is not well defined.
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The achievement of a 3-month complete cytogenetic response to second-generation tyrosine kinase inhibitors predicts survival in patients with chronic phase chronic myeloid leukemia after imatinib failure.
Clin Lymphoma Myeloma Leuk
PUBLISHED: 01-12-2013
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We assessed whether the achievement of a 3-month complete cytogenetic response (CCyR) in 123 patients with chronic myeloid leukemia (CML) in the chronic phase, which was treated with second-generation tyrosine kinase inhibitors (2nd-TKI) after imatinib failure could predict for survival.
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Chronic myeloid leukemia: mechanisms of resistance and treatment.
Hematol. Oncol. Clin. North Am.
PUBLISHED: 10-19-2011
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Imatinib mesylate has revolutionized the treatment landscape for patients with newly diagnosed chronic myeloid leukemia. Follow-up has shown excellent response rates, progression-free survival, and overall survival after 8 years. However, some patients develop resistance to imatinib treatment because of a multitude of reasons. Strategies to overcome resistance include dose escalation of imatinib or switching to a second-generation tyrosine kinase inhibitor or to one of the newer non-tyrosine kinase inhibitors. This article guides the treating physician with a rational approach in the management of patients with chronic myeloid leukemia who fail initial treatment with imatinib or lose response while on therapy with imatinib.
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Topical herbal extract (Huangdang mixture) exhibits both preventive and therapeutic effects in murine acute irritant contact dermatitis.
Int. J. Dermatol.
PUBLISHED: 10-19-2011
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Contact dermatitises, including allergic contact dermatitis and irritant contact dermatitis, are among the most common skin disorders in humans. Chinese herbal medicines (CHM) have been used in treating contact dermatitises for centuries. Systemic administration of CHM, including ingredients in huangdang mixture containing Chinese angelica, radix Paeonlae rubra, cat nut, and phelloden dron, rhizoma alismatis, rhizoma smilacis glabrae, and rhizome of swordlike, improves allergic contact dermatitis induced by l-fluoro-2,4-dinitrobenzene. Whether topical applications of these herbal extracts display preventive and/or therapeutic effects on contact dermatitis, thereby avoiding the potential side effects of systemic CHM, remains largely unknown.
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What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

How does it work?

We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

Video X seems to be unrelated to Abstract Y...

In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.