Serial studies have demonstrated that induction therapy with FLAM flavopiridol (alvocidib) 50 mg/m(2) days 1-3, cytarabine 667 mg/m(2)/day continuous infusion days 6-8, and mitoxantrone (FLAM) 40 ...mg/m(2) day 9 yields complete remission rates of nearly 70% in newly diagnosed poor-risk acute myeloid leukemia. Between May 2011-July 2013, 165 newly diagnosed acute myeloid leukemia patients (age 18-70 years) with intermediate/adverse-risk cytogenetics were randomized 2:1 to receive FLAM or 7+3 (cytarabine 100 mg/m(2)/day continuous infusion days 1-7 and daunorubicin 90 mg/m(2) days 1-3), across 10 institutions. Some patients on 7+3 with residual leukemia on day 14 received 5+2 (cytarabine 100 mg/m(2)/day continuous infusion days 1-5 and daunorubicin 45 mg/m(2) days 1-2), whereas patients on FLAM were not re-treated based on day 14 bone marrow findings. The primary objective was to compare complete remission rates between one cycle of FLAM and one cycle of 7+3. Secondary end points included safety, overall survival and event-free survival. FLAM led to higher complete remission rates than 7+3 alone (70% vs. 46%; P=0.003) without an increase in toxicity, and this improvement persisted after 7+3+/-5+2 (70% vs. 57%; P=0.08). There were no significant differences in overall survival and event-free survival in both arms but post-induction strategies were not standardized. These results substantiate the efficacy of FLAM induction in newly diagnosed AML. A phase III study is currently in development. This study is registered with clinicaltrials.gov identifier: 01349972.
Venous thromboembolism (VTE) is increasingly diagnosed among individuals with hematologic malignancies. However, the risk of VTE among patients undergoing hematopoietic stem cell transplantation ...(HSCT) is unclear. We examined the incidence and risk factors for VTE and bleeding among 1514 patients undergoing in-patient HSCT. No protocolized VTE prophylaxis was used. By HSCT day 180, 75 symptomatic VTE occurred in 70 patients (4.6%; 95% confidence interval CI, 3.6%-5.8%). Fifty-five (3.6%) were catheter-associated, 11 (0.7%) were non–catheter-associated deep venous thromboses, and 9 (0.6%) were pulmonary emboli. Thirty-four percent of VTE occurred at a platelet count less than 50 ×109/L; 13% occurred at a platelet count less than 20 ×109/L. In multivariate analysis, VTE was associated with prior VTE (odds ratio OR, 2.9; 95% CI, 1.3-6.6) and with graft-versus-host disease (GVHD; OR, 2.4; 95% CI, 1.4-4.0). Clinically significant bleeding occurred in 230 patients (15.2%; 95% CI, 13.4%-17.1%); 55 patients (3.6%; 95% CI, 2.7%-4.7%) had fatal bleeding. Bleeding was associated with anticoagulation (OR, 3.1; 95% CI, 1.8-5.5), GVHD (OR, 2.4; 95% CI, 1.8-3.3), and veno-occlusive disease (OR, 2.2; 95% CI, 1.4-3.6). In HSCT patients, VTE is primarily catheter-related and 3-fold less common than clinically significant bleeding. These findings warrant consideration when selecting VTE prophylaxis in HSCT patients.
Multiple myeloma (MM) is an aggressive cancer that originates from antibody-secreting plasma cells. Although genetically and transcriptionally well characterized, the aberrant gene regulatory ...networks that underpin this disease remain poorly understood. Here, we mapped regulatory elements, open chromatin, and transcription factor (TF) footprints in primary MM cells. In comparison with normal antibody-secreting cells, MM cells displayed consistent changes in enhancer activity that are connected to superenhancer (SE)-mediated deregulation of TF genes. MM cells also displayed widespread decompaction of heterochromatin that was associated with activation of regulatory elements and in a major subset of patients' deregulation of the cyclic adenosine monophosphate pathway. Finally, building SE-associated TF-based regulatory networks allowed identification of several novel TFs that are central to MM biology. Taken together, these findings significantly add to our understanding of the aberrant gene regulatory network that underpins MM.
•Gene regulatory features in MM patients reveal a key regulatory network and epigenetic changes that underpin the disease.
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Abstract Aplastic anemia (AA) is a disease characterized by pancytopenia and hypoplastic bone marrow caused by the decrease of hematopoietic stem cells. The pathogenesis of AA is complex and involves ...an abnormal hematopoietic microenvironment, hematopoietic stem cell/progenitor cell deficiencies and immunity disorders. Survival in severe aplastic anemia (SAA) has markedly improved in the past 4 decades because of advances in hematopoietic stem cell transplantation, immunosuppressive and biologic drugs, and supportive care. Herein, we will update the main issues concern AA according to our literature review.
After failure of hypomethylating agents (HMA), patients with myelodysplastic syndromes (MDS) have dismal survival and no approved treatment options.
We conducted a phase 1b investigator-initiated ...trial of ipilimumab in patients with higher risk MDS who have failed HMAs. Patients received monotherapy at two dose levels (DL; 3 and 10 mg/kg) with an induction followed by a maintenance phase. Toxicities and responses were evaluated with CTCAE.4 and IWG-2006 criteria, respectively. We also performed immunologic assays and T-cell receptor sequencing on serial samples.
Twenty-nine patients from 7 centers were enrolled. In the initial DL1 (3 mg), 3 of 6 patients experienced grade 2-4 immune-related adverse events (IRAE) that were reversible with drug discontinuation and/or systemic steroids. In DL2, 4 of 5 patients experienced grade 2 or higher IRAE; thus, DL1 (3 mg/kg) was expanded with no grade 2-4 IRAEs reported in 18 additional patients. Best responses included marrow complete response (mCR) in one patient (3.4%). Prolonged stable disease (PSD) for ≥46 weeks occurred in 7 patients (24% of entire cohort and 29% of those treated with 3 mg/kg dose), including 3 patients with more than a year of SD. Five patients underwent allografting without excessive toxicity. Median survival for the group was 294 days (95% CI, 240-671+). Patients who achieved PSD or mCR had significantly higher frequency of T cells expressing ICOS (inducible T-cell co-stimulator).
Our findings suggest that ipilimumab dosed at 3 mg/kg in patients with MDS after HMA failure is safe but has limited efficacy as a monotherapy. Increased frequency of ICOS-expressing T cells might predict clinical benefit.
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Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of the skin and internal organs. Key players mediating fibrosis are myofibroblasts (MF) that, following transforming growth ...factor β (TGFβ) exposure, produce a collagen-rich extracellular matrix (ECM) that induces myofibroblast differentiation. Myofibroblasts express αvβ3 integrin (a membrane receptor for thyroid hormones) and miRNA-21 that promotes deiodinase-type-3 expression (D3), causing the degradation of triiodothyronine (T3) that attenuates fibrosis. We hypothesized that αvβ3 affects the fibrotic processes through its thyroid hormones (THs) binding site. To test this, dermal fibroblasts (DF) were cultured with/without TGFβ and removed with a base, leaving only normal/fibrotic ECMs in wells. Then, DF were cultured on the ECMs with/without tetrac (αvβ3 ligand, T4 antagonist), and evaluated for pro-fibrotic characteristics, αvβ3, miRNA-21, and D3 levels. Blood free-T3 (fT3), miRNA-21 levels, and the modified Rodnan skin score (MRSS) were evaluated in SSc patients. We found that the "fibrotic-ECM" significantly increased the pro-fibrotic characteristics of DF and the levels of miRNA-21, D3, and αvβ3, compared to the "normal-ECM." Tetrac significantly inhibited the effects of the "fibrotic-ECM" on the cells. In accordance with tetrac's effect on D3/miRNA-21, a negative correlation was found between the patients' fT3 to miRNA-21 levels, and to the development of pulmonary arterial hypertension (PAH). We conclude that occupying the THs binding site of αvβ3 may delay the development of fibrosis.
Several studies have been conducted related to dropouts from on-campus and distance education courses. However, no clear definition of dropout from academic courses was provided. Consequently, this ...study proposes a clear and precise definition of dropout from academic courses in the context of e-learning courses. Additionally, it is documented in literature that students attending e-learning courses dropout at substantially higher rates than their counterparts in on-campus courses. Little attention has been given to the key factors associated with such substantial difference. This study explores two main constructs: (1) academic locus of control; and, (2) students’ satisfaction with e-learning. Results show that students’ satisfaction with e-learning is a key indicator in students’ decision to dropout from e-learning courses. Moreover, dropout students (non-completers) reported to have significantly lower satisfaction with e-learning than students who successfully completed (completers or persistent students) the same e-learning courses. Additionally, results of this study show that the academic locus of control appears to have no impact on students’ decision to drop from e-learning courses.
Prolonged steroid treatment has a suppressive effect on the immune system, however, its effect on the cellular response to mRNA vaccine is unknown. Here we assessed the impact of prolonged steroid ...treatment on the T-cell and humoral response to the SARS-CoV-2 spike (S) peptide following the third dose of the BNT162b2 vaccine in systemic autoimmune rheumatic disease patients. We found that CD4 T-cell response to the S peptide in patients on high-dose long-term steroid treatment showed significantly less S-peptide specific response, compare to low-dose or untreated patients. Remarkably, these results were not reflected in their humoral response, since almost all patients in the cohort had sufficient antibody levels. Moreover, S-peptide activation failed to induce significant mRNA levels of IFNγ and TNFα in patients receiving high-dose steroids. RNA-sequencing datasets analysis implies that steroid treatments' inhibitory effect of nuclear factor kappa-B signaling may interfere with the activation of S-specific CD4 T-cells. This reveals that high-dose steroid treatment inhibits T-cell response to the mRNA vaccine, despite having sufficient antibody levels. Since T-cell immunity is a crucial factor in the immune response to viruses, our findings highlight the need for enhancing the efficiency of vaccines in immune-suppressive patients, by modulation of the T-cell response.
Abstract Philosophical orthodoxy has it that intentional action consists in one's intention appropriately causing a motion of one's body, placing the latter (conceptually and/or metaphysically) prior ...to the former. Here, I argue that this standard schema should be reversed: acting intentionally is at least conceptually prior to intending. The argument is modelled on a Williamsonian argument for the priority of knowledge developed by Jenifer Nagel. She argues that children acquire the concept KNOWS before they acquire BELIEVES, building on this alleged developmental priority of knowledge to establish its conceptual priority. I start by taking a closer look at Nagel's argument, canvassing extant objections todo both with the empirical adequacy of her claims and their philosophical implications. Doing so allows me, in the second part of the paper, to draw lessons that inform the construction of a revamped parallel argument for the priority of ACTS INTENTIONALLY.
Systemic sclerosis (SSc) or scleroderma, is a rare, systemic autoimmune connective tissue disease that can cause fibrosis of cutaneous tissue and visceral organs. Facial involvement can have a ...deleterious effect on patients' function, cosmetic appearance and quality of life. This study describes our experience and results with total facial autologous fat grafting for treating scleroderma. It includes 14 women and 3 men with SSc, at an average age of 51.3 years who underwent 32 autologous fat grafting surgeries between 2017-2022. The surgical technique is further described and demographic and surgical data, including preoperative and postoperative measurements were analyzed. Patients who had multiple surgeries ultimately received grafts with twice the volume of fat than in the first procedure. The oral opening increased an average of 33%. All patients reported improvement in quality of life and were very satisfied with the aesthetic outcomes. The use of autologous fat grafting to treat SSc patients successfully increased oral openings and improved facial manifestations. The procedure is reproducible, safe and leads to improvement in facial manifestations and patients' quality of life. It can be repeated over time to preserve or enhance the results.
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