Polymers that depolymerize back to monomers can be repeatedly chemically recycled, thereby reducing their environmental impact. Polyphthalaldehyde is a metastable polymer that can rapidly and ...quantitatively depolymerize due to its low ceiling temperature. However, the effect of substitution on the physical and chemical properties of polyphthalaldehyde derivatives has not been systematically studied. Herein, we investigate the cationic polymerization of seven o-phthalaldehyde derivatives and demonstrate that judicious choice of substituent results in materials with a wide range of ceiling temperatures (<−60 to 106 °C) and decomposition temperatures (109–196 °C). We anticipate that these new polymers and their derivatives will enable researchers to access degradable materials with tunable thermal, physical, and chemical properties.
Allogeneic stem cell transplantation remains the only curative treatment for sickle cell anemia (SCA), but the place of myeloablative conditioning in the procedure remains to be defined. The aim of ...the present study was to analyze long-term outcomes, including chimerism, SCA-related events and biological data (hemoglobin, reticulocytes, HbS%), and fertility in a French series of 234 SCA patients under 30 years of age who, from 1988 to 2012, received a matched-sibling-donor stem cell transplantation following standardized myeloablative conditioning busulfan, cyclophosphamide and rabbit antithymocyte globulin (ATG). Since the first report of the series (1988-2004), 151 new consecutive patients with SCA have been similarly transplanted. Considering death, non-engraftment or rejection (donor cells <5%) as events, the 5-year event-free survival was 97.9% (95% confidence interval: 95.5-100%), confirming, since the year 2000, an at least 95% chance of cure. In the overall cohort (n=234, median follow up 7.9 years), event-free survival was not associated with age, but chronic-graft-
-host disease (cGvHD) was independently associated with recipient's age >15 years (hazard ratio=4.37;
=0.002) and lower (5-15
20 mg/kg) ATG dose (hazard ratio=4.55;
=0.001). At one year, 44% of patients had mixed chimerism (5-95% donor cells), but those prepared with ATG had no graft rejection. No events related to SCA occurred in patients with mixed chimerism, even those with 15-20% donor cells, but hemolytic anemia stigmata were observed with donor cells <50%. Myeloablative transplantation with matched-sibling donor currently has a higher event-free survival (98%) in patients under 30 years of age than that reported for non-myeloablative conditioning (88%). Nevertheless, the risk of cGvHD in older patients and the need to preserve fertility might be indications for a non-myeloablative conditioning.
Blood Brain Barrier (BBB) breakdown is a secondary form of brain injury which has yet to be fully elucidated mechanistically. Existing research suggests that breakdown of tight junction proteins ...between endothelial cells is a primary driver of increased BBB permeability following injury, and intercellular signaling between primary cells of the neurovascular unit: endothelial cells, astrocytes, and pericytes; contribute to tight junction restoration. To expound upon this body of research, we analyzed the effects of severely injured patient plasma on each of the cell types in monoculture and together in a triculture model for the transcriptional and translational expression of the tight junction proteins Claudins 3 and 5, (CLDN3, CLDN5) and Zona Occludens 1 (ZO-1). Conditioned media transfer studies were performed to illuminate the cell type responsible for differential tight junction expression. Our data show that incubation with 5% human ex vivo severely injured patient plasma is sufficient to produce a differential response in endothelial cell tight junction mRNA and protein expression. Endothelial cells in monoculture produced a significant increase of CLDN3 and CLDN5 mRNA expression, (3.98 and 3.51 fold increase vs. control respectively, p<0.01) and CLDN5 protein expression, (2.58 fold change vs. control, p<0.01), whereas in triculture, this increase was attenuated. Our triculture model and conditioned media experiments suggest that conditioned media from astrocytes and pericytes and a triculture of astrocytes, pericytes and endothelial cells are sufficient in attenuating the transcriptional increases of tight junction proteins CLDN3 and CLDN5 observed in endothelial monocultures following incubation with severely injured trauma plasma. This data suggests that inhibitory molecular signals from astrocytes and pericytes contributes to prolonged BBB breakdown following injury via tight junction transcriptional and translational downregulation of CLDN5.
Rhodium-catalyzed intramolecular carboacylation of alkenes, achieved using quinolinyl ketones containing tethered alkenes, proceeds via the activation and functionalization of a carbon–carbon single ...bond. This transformation has been demonstrated using RhCl(PPh3)3 and Rh(C2H4)2Cl2 catalysts. Mechanistic investigations of these systems, including determination of the rate law and kinetic isotope effects, were utilized to identify a change in mechanism with substrate. With each catalyst, the transformation occurs via rate-limiting carbon–carbon bond activation for species with minimal alkene substitution, but alkene insertion becomes rate-limiting for more sterically encumbered substrates. Hammett studies and analysis of a series of substituted analogues provide additional insight into the nature of these turnover-limiting elementary steps of catalysis and the relative energies of the carbon–carbon bond activation and alkene insertion steps.
To evaluate the efficacy of vinblastine for relapsed/refractory anaplastic large-cell lymphoma (ALCL).
Data were reviewed on all 36 patients included prospectively in the French database for ...pediatric ALCL who were treated with vinblastine (6 mg/m(2)/wk) for resistant primary disease (one), a first relapse (15), or subsequent relapses (20). Fifteen patients had undergone hematopoietic stem-cell transplantation (HSCT) for a previous relapse.
Six patients were not evaluable for response, 25 (83%) of 30 evaluable patients achieved a complete remission (CR), and five experienced progressive disease. Among the 31 patients who achieved a CR with vinblastine or before its initiation, six patients were treated with HSCT and 25 with vinblastine alone (median duration, 14 months). Overall, nine of 25 patients treated with vinblastine alone have remained in CR (median, 7 years since the end of treatment), and 16 patients have relapsed. Vinblastine was still efficient for subsequent relapses. With a median follow-up of 9.2 years, 12 patients have died (four as a result of toxicity after HSCT and eight as a result of disease), and 24 patients are alive (15 following treatment with single-agent vinblastine for the last event). Five-year overall survival is 65% (95% CI, 48% to 79%), and 5-year event-free survival is 30% (95% CI, 17% to 47%).
Vinblastine is highly efficient in relapsed ALCL and may produce durable remissions. The optimal treatment duration still has to be assessed. These results should be borne in mind when designing future phase II studies with the targeted therapies directed against anaplastic lymphoma kinase.
Imatinib is the standard of care in adults with chronic myeloid leukemia (CML) in chronic phase (CP). Only a few studies to assess efficacy in children have been performed. We report on the results ...of the French prospective trial (ClinicalTrials.gov identifier NCT00845221) conducted in children and adolescents with newly diagnosed CML in CP.
A total of 44 patients from age 10 months to 17 years with newly diagnosed CML in CP received daily imatinib 260 mg/m(2). Progression-free survival, responses, and tolerance were evaluated.
With a median follow-up times of 31 months (range, 11 to 64 months), the estimated progression-free survival rate at 36 months was 98% (95% CI, 85% to 100%). A complete hematologic response was achieved in 98% of the patients. The rates of complete cytogenetic response (CCyR) and major molecular response (MMR) were 61% and 31% at 12 months, respectively. During follow-up, CCyR and MMR were achieved in 36 children (77%) and 25 children (57%), respectively. Overall, 30% of the patients discontinued imatinib, mainly because of unsatisfactory response. The most common adverse events were neutropenia and musculoskeletal events.
Imatinib is effective in children with CML in CP with response rates similar to rates reported in adults. The adverse effects are acceptable, but longer follow-up studies are required to fully assess the long-term impact.
Dexamethasone could be more effective than prednisolone at similar anti-inflammatory doses in the treatment of childhood acute lymphoblastic leukemia. In order to check if this "superiority" of ...dexamethasone might be dose-dependent, we conducted a randomized phase III trial comparing dexamethasone (6 mg/m(2)/day) to prednisolone (60 mg/m(2)/day) in induction therapy. All newly diagnosed children and adolescents with acute lymphoblastic leukemia in the 58951 EORTC trial were randomized on prephase day 1 or day 8. The main endpoint was event-free survival; secondary endpoints were overall survival and toxicity. A total of 1947 patients with acute lymphoblastic leukemia were randomized. At a median follow-up of 6.9 years, the 8-year event-free survival rate was 81.5% in the dexamethasone arm and 81.2% in the prednisolone arm; the 8-year overall survival rates were 87.2% and 89.0% respectively. The 8-year incidences of isolated or combined central nervous system relapse were 2.9% and 4.5% in the dexamethasone and prednisolone arms, respectively. The incidence of grade 3-4 toxicities during induction and the frequency of osteonecrosis were similar in the two arms. In conclusion, dexamethasone and prednisolone, used respectively at the doses of 6 and 60 mg/m(2)/day during induction, were equally effective and had a similar toxicity profile. Dexamethasone decreased the 8-year central nervous system relapse incidence by 1.6%. This trial was registered at www.clinicaltrials.gov as #NCT00003728.
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