Density fluctuations of water-glucose mixtures studied by Inelastic Ultra-Violet Scattering

International audienceThe dynamics of density fluctuations of glucose aqueous solutions has been studied in the water rich region by means of Brillouin ultra-violet scattering. The temperature behavior of position and line-width of inelastic peaks gives evidence of a strong relaxation process located in the picosecond timescale. In the approximation of a single exponential process, the relaxation time τ has been obtained for different glucose concentrations, its temperature dependence well described by an Arrhenius law characterized by an activation energy comparable to that of pure water. This result supports the hypothesis that the microscopic mechanism responsible for the main relaxation process in sugar-water solutions is the continuum rearrangement of the H-Bond network. A comparison is also reported with previous results on water trehalose solutions, showing that the acoustic absorption scales with the number of glucoside units for both glucose and trehalose aqueous solutions

Oncogene-induced senescence in hematopoietic progenitors features myeloid restricted hematopoiesis, chronic inflammation and histiocytosis

ABSTRACTActivating mutations in the BRAF-MAPK pathway have been reported in histiocytoses, hematological inflammatory neoplasms characterized by multi-organ dissemination of pro-inflammatory myeloid cells. Here, we generate a humanized mouse model of transplantation of human hematopoietic stem and progenitor cells (HSPCs) expressing the activated form of BRAF (BRAFV600E). All mice transplanted with BRAFV600E-expressing HSPCs succumb to bone marrow failure, displaying myeloid-restricted hematopoiesis and multi-organ dissemination of aberrant mononuclear phagocytes. At the basis of this aggressive phenotype, we uncover the engagement of a senescence program, characterized by DNA damage response activation and a senescence-associated secretory phenotype, which affects also non-mutated bystander cells. Mechanistically, we identify TNFα as a key determinant of paracrine senescence and myeloid-restricted hematopoiesis and show that its inhibition dampens inflammation, delays disease onset and rescues hematopoietic defects in bystander cells. Our work establishes that senescence in the human hematopoietic system links oncogene-activation to the systemic inflammation observed in histiocytic neoplasms.</jats:p

High Resolution Donor/Recipient HLA Matching Level in Unrelated Hematopoietic Stem Cell Transplantation and Impact on the Transplant Outcome: The Italian Experience on Behalf of GITMO, IBMDR and Aibt

Abstract Introduction: HLA molecules play an important role for immunoreactivity in allogeneic hematopoietic stem cell transplantation (HSCT). To elucidate the effect and the potential identification of "permissive" and "non permissive" I and II class HLA mismatching (mm) loci on the early and long term transplant outcome, we conducted a retrospective/prospective observational analysis on 1789 patients transplanted with unmanipulated haematopoietic stem cells from a volunteer unrelated donor (URD). Methods Between January 2012 to December 2015, 1789 adult patients with a median age of 49 years (18-70) affected by haematological malignant diseases, performed an unrelated HSCT, coordinated by the Italian Bone Marrow Donor Registry (IBMDR). All patients have been typed by high resolution (HR) HLA typing for HLA-A/B/C/DRB1/DQB1 loci, at the start of the donor's search process. Patient and donor characteristics are shown in Table 1. As conditioning regimen and GVHD prophylaxis, 71% of patients received a myeloablative conditioning and 76% a combination of anti-Thymoglobuline, Cyclosporine and Metotrexate short course. Total Body Irradiation was part of conditioning regimen in 14% of cases and PBSC was used as stem cell source in 80% of transplants. Median follow for survivors was 38 months (1-76). Regarding to the allelic compatibility, 890 (50%) of donor/recipient (D/R) pairs were 10/10 HLA matched, 677 (38%) showed 1 mm for A, B, C, DRB1 or DQB1 in 249, 141, 173, 2 and 112 cases, respectively and 222 (12%) received HSCT from a 8/10 or less HLA matched donor. Results: Overall 90% and 79% of patients achieved PMN and PLTS engraftment within 30 and 90 days, respectively. Probabilities of 3-y Overall Survival (3-yr OS), Progression Free Survival (3-yr PFS), and Graft Relapse Free Survival (3-yr GRFS) were 52%, 42%, and 30%, respectively. The 3-y CI of Transplant Related Mortality (TRM) was 26%, with a 100-days CI of acute GVHD ≥2 of 26%, whereas the 3-yr CI of chronic GVHD was 30%, of which 10% extensive. Cox multivariate analysis showed that, compared to 10/10 HLA-matched HSCT, 9/10 and ≤8/10 HLA-matched HSCT were associated with worse outcomes in terms of OS (HR 1.16, p=0.04 and HR 1.3, p=0.007, respectively), GRFS (HR 1.2, p=0.005 and HR 1.2, p=0.07, respectively), TRM (HR 1.3, p=0.007 and HR 1.6, p&lt;0.0001, respectively), grade 3-4 aGVHD (HR 1.8, p=0.0001 and HR 1.8, p=0.01, respectively) and cGvHD (HR 1.3, p=0.005 and HR 1.1, p=0.35, respectively). Notably, no significant differences occurred through the comparison between ≤8/10 and 9/10 matching. Univariate comparisons are shown in Figure 1. Moreover, in order to identify permissive and non permissive allelic mismatching, we analyzed the donor/recipient pairs with a single HLA mm with a frequency &gt; 5%: the presence of A02:01 in the patient's HLA, after adjustment for HLA matching at the other loci and other clinical variables known to affect HSCT outcome, was associated with significant higher risk of TRM (HR 1.9, p= 0.03) and worst OS (HR 1.7, p=0.04). Patient's age &gt; 49 years (p&lt;0.0001), advanced disease stage (p&lt;0.0001), presence of 1 or more co- morbidity according to the Sorror Hematopoietic Cell Transplant-Comorbidity Index (p=0.01) were associated with a hazard risk of 1.4, 2, 1.2 for OS and 1.6, 1.75, 1.4 for TRM. Moreover, the Italian origin of recipient and donor resulted in reduced grade 2-4 acute (HR=0.6, p=0.001) and chronic GVHD (p=0.002, HR=0.4). Finally, the Transplant Program expertise (&gt;10 HSCT/year) is associated with reduced TRM (HR 0.8, p=0.0001), HSCT from female donor to male recipient was associated with higher risk of extensive cGvHD (HR 1.4, p=0.03), and CMV negative/negative status versus other combinations had protective effect on development of grade 3-4 aGVHD (HR 0.56, p=0.04). Conclusions: Our large cohort data of homogeneously treated 1789 URD transplants, show that 10/10 HLA matching remains a significantly favorable prognostic factor for OS, TRM, GRFS and acute/chronic GVHD, whereas there are no significant differences between 8/10 and 9/10 matching transplants. Moreover, the HLA A02:01 as single mm seems to play a "non permissive" role. Finally the Italian origin of recipient and donor is related to a reduced development of GVHD probably due to the matching of the extended MHC haplotypes in individuals of the same geographic origin. Disclosures Rambaldi: Amgen Inc.: Consultancy; Pfizer: Consultancy; Celgene: Consultancy; Omeros: Consultancy; Roche: Consultancy; Novartis: Consultancy; Italfarmaco: Consultancy. Vago:Moderna TX: Research Funding; GENDX: Research Funding. Patriarca:Janssen: Other: Advisory role; Jazz: Other: Travel, accommodations, expenses; Medac: Other: Travel, accommodations, expenses; Celgene: Other: Advisory Role; Travel, accommodations, expenses; MSD Italy: Other: Advisory Role. </jats:sec

Allelic HLA Matching and Pair Origin Are Favorable Prognostic Factors for Unrelated Hematopoietic Stem Cell Transplantation in Neoplastic Hematologic Diseases: An Italian Analysis by the Gruppo Italiano Trapianto di Cellule Staminali e Terapie Cellulari, Italian Bone Marrow Donor Registry, and Associazione Italiana di Immunogenetica e Biologia dei Trapianti

: HLA molecules are important for immunoreactivity in allogeneic hematopoietic stem cell transplantation (HSCT). The Gruppo Italiano Trapianto di Cellule Staminali e Terapie Cellulari, Italian Bone Marrow Donor Registry, and Associazione Italiana di Immunogenetica e Biologia dei Trapianti promoted a retrospective observational study to evaluate HLA matching and the impact of allelic HLA mismatching and non-HLA factors on unrelated Italian HSCT outcomes. From 2012 to 2015, 1788 patients were enrolled in the study. The average donor age was 29 years and the average recipient age was 49 years. As a conditioning regimen, 71% of the patients received myeloablative conditioning. For GVHD prophylaxis, 76% received either antithymocyte or anti-T lymphocyte globulin, cyclosporine A, and methotrexate. Peripheral blood was the stem cell source in 80%. The median duration of follow-up was 53 months. Regarding HLA matching, 50% of donor-recipient pairs were 10/10 matched, 38% had 1 mismatch, and 12% had 2 or more mismatches. A total of 302 pairs shared Italian origin. Four-year overall survival (OS), progression-free survival, GVHD-free relapse-free survival, and relapse rates were 49%, 40%, 22%, and 34%, respectively. The 4-year NRM was 27%, and the 100-day cumulative incidence of grade ≥II acute GVHD (aGVHD) was 26%. In multivariate analysis, 9/10 and ≤8/10 HLA allele-matched pairs were associated with worse OS (P = .04 and .007, respectively), NRM (P = .007 and P < .0001, respectively), and grade III-IV aGVHD (P = .0001 and .01, respectively). Moreover, the incidences of grade II-IV aGVHD (P = .001) and chronic GVHD (P = .002) were significantly lower in Italian pairs. In conclusion, 10/10 HLA matching is a favorable prognostic factor for unrelated HSCT outcome in the Italian population. Moreover, the presence of 2 HLA-mismatched loci was associated with a higher NRM (P < .0001) and grade II-IV aGVHD (P = .006) and a poorer OS (P = .001) compared with 1 HLA-mismatched locus in early or intermediate disease phases. Finally, we found that Italian donor and recipient origin is a favorable prognostic factor for GVHD occurrence

Allelic HLA Matching and Pair Origin Are Favorable Prognostic Factors for Unrelated Hematopoietic Stem Cell Transplantation in Neoplastic Hematologic Diseases: An Italian Analysis by the Gruppo Italiano Trapianto di Cellule Staminali e Terapie Cellulari, Italian Bone Marrow Donor Registry, and Associazione Italiana di Immunogenetica e Biologia dei Trapianti

: HLA molecules are important for immunoreactivity in allogeneic hematopoietic stem cell transplantation (HSCT). The Gruppo Italiano Trapianto di Cellule Staminali e Terapie Cellulari, Italian Bone Marrow Donor Registry, and Associazione Italiana di Immunogenetica e Biologia dei Trapianti promoted a retrospective observational study to evaluate HLA matching and the impact of allelic HLA mismatching and non-HLA factors on unrelated Italian HSCT outcomes. From 2012 to 2015, 1788 patients were enrolled in the study. The average donor age was 29 years and the average recipient age was 49 years. As a conditioning regimen, 71% of the patients received myeloablative conditioning. For GVHD prophylaxis, 76% received either antithymocyte or anti-T lymphocyte globulin, cyclosporine A, and methotrexate. Peripheral blood was the stem cell source in 80%. The median duration of follow-up was 53 months. Regarding HLA matching, 50% of donor-recipient pairs were 10/10 matched, 38% had 1 mismatch, and 12% had 2 or more mismatches. A total of 302 pairs shared Italian origin. Four-year overall survival (OS), progression-free survival, GVHD-free relapse-free survival, and relapse rates were 49%, 40%, 22%, and 34%, respectively. The 4-year NRM was 27%, and the 100-day cumulative incidence of grade ≥II acute GVHD (aGVHD) was 26%. In multivariate analysis, 9/10 and ≤8/10 HLA allele-matched pairs were associated with worse OS (P = .04 and .007, respectively), NRM (P = .007 and P < .0001, respectively), and grade III-IV aGVHD (P = .0001 and .01, respectively). Moreover, the incidences of grade II-IV aGVHD (P = .001) and chronic GVHD (P = .002) were significantly lower in Italian pairs. In conclusion, 10/10 HLA matching is a favorable prognostic factor for unrelated HSCT outcome in the Italian population. Moreover, the presence of 2 HLA-mismatched loci was associated with a higher NRM (P < .0001) and grade II-IV aGVHD (P = .006) and a poorer OS (P = .001) compared with 1 HLA-mismatched locus in early or intermediate disease phases. Finally, we found that Italian donor and recipient origin is a favorable prognostic factor for GVHD occurrence