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Investigative Ophthalmology & Visual... Nov 2023The proliferative and neurogenic potential of retinal Müller glia after injury varies widely across species. To identify the endogenous mechanisms regulating the...
PURPOSE
The proliferative and neurogenic potential of retinal Müller glia after injury varies widely across species. To identify the endogenous mechanisms regulating the proliferative response of mammalian Müller glia, we comparatively analyzed the expression and function of nestin, an intermediate filament protein established as a neural stem cell marker, in the mouse and rat retinas after injury.
METHODS
Nestin expression in the retinas of C57BL/6 mice and Wistar rats after methyl methanesulfonate (MMS)-induced photoreceptor injury was examined by immunofluorescence and Western blotting. Adeno-associated virus (AAV)-delivered control and nestin short hairpin RNA (shRNA) were intravitreally injected to rats and Müller glia proliferation after MMS-induced injury was analyzed by BrdU incorporation and immunofluorescence. Photoreceptor removal and microglia/macrophage infiltration were also analyzed by immunofluorescence.
RESULTS
Rat Müller glia re-entered the cell cycle and robustly upregulated nestin after injury whereas Müller glia proliferation and nestin upregulation were not observed in mice. In vivo knockdown of nestin in the rat retinas inhibited Müller glia proliferation while transiently stimulating microglia/macrophage infiltration and phagocytic removal of dead photoreceptors.
CONCLUSIONS
Our findings suggest a critical role for nestin in the regulation of Müller glia proliferation after retinal injury and highlight the importance of cross species analysis to identify the molecular mechanisms regulating the injury responses of the mammalian retina.
Topics: Animals; Mice; Rats; Cell Proliferation; Eye Injuries; Methyl Methanesulfonate; Mice, Inbred C57BL; Nestin; Rats, Wistar; Neuroglia
PubMed: 37934159
DOI: 10.1167/iovs.64.14.8 -
Transplantation and Cellular Therapy Feb 2023Patients with refractory or relapsed and refractory myeloid malignancies have a poor prognosis. Allogeneic hematopoietic cell transplantation (HCT) with myeloablative...
Patients with refractory or relapsed and refractory myeloid malignancies have a poor prognosis. Allogeneic hematopoietic cell transplantation (HCT) with myeloablative conditioning (MAC) in patients with active, chemotherapy-refractory myeloid disease is historically associated with high rates of relapse and nonrelapse mortality (NRM). A MAC regimen combining clofarabine with busulfan (Clo/Bu4) has been reported to exhibit antileukemic activity with acceptable toxicity in patients age ≤70 years. Here we describe the clinical outcomes of a real-world population of patients with active myeloid malignancies undergoing allogeneic HCT with Clo/Bu4 MAC. In a single-center retrospective descriptive analysis, we identified patients who underwent HCT for myeloid malignancies not in remission using Clo/Bu4 MAC between 2012 and 2020. We report event-free survival (EFS) and overall survival (OS), cumulative incidences of relapse and NRM, and the incidence and severity of acute and chronic graft-versus-host disease (GVHD). We identified 69 patients with a median age of 60 years (range, 22 to 70 years). Most patients had relapsed/refractory or primary refractory acute myelogenous leukemia (AML; n = 55) or refractory myelodysplastic syndrome (MDS; n = 12); 1 patient had chronic myelogenous leukemia, and 1 patient had a blastic plasmacytoid dendritic cell neoplasm. Fifty patients (72.5%) had complete remission at day 100 post-transplantation. Two-year EFS and OS were 30% (95% confidence interval [CI], 20% to 44%) and 40% (95% CI, 29% to 54%), respectively. Patients with AML had a 2-year EFS and OS of 28% (95% CI, 18% to 44%) and 38% (95% CI, 27% to 54%), respectively; those with MDS had a 2-year EFS and OS of 47% (95% CI, 25% to 88%) and 56% (95% CI, 33% to 94%), respectively. The cumulative incidence of relapse at 2 years was 39% (95% CI, 27% to 51%) for all patients, including 45% (95% CI, 31% to 58%) in the patients with AML and 18% (95% CI, 2% to 45%) in those with MDS. NRM at 2 years was 31% (95% CI, 20% to 42%), including 27% (95% CI, 15% to 39%) in patients with AML and 35% (95% CI, 10% to 63%) in those with MDS. The total incidence of acute GVHD (aGVHD) of any severity was 80%, and the incidence of grade III-IV aGVHD was 22%. In patients who achieved remission, those who required systemic immunosuppression for aGVHD (58%) had poorer 2-year EFS (29% versus 54%; P = .05) and 2-year OS (39% versus 70%; P = .04) compared to those who did not. The 2-year cumulative incidence of chronic GVHD was 44% (95% CI, 28% to 58%). Clo/Bu4 MAC followed by allogeneic HCT for patients with active myeloid malignancies is an effective transplantation strategy for patients up to age 70, particularly those with advanced MDS. The high incidence of and poor outcomes associated with aGVHD highlight the importance of optimizing preventative strategies.
Topics: Humans; Young Adult; Adult; Middle Aged; Aged; Busulfan; Clofarabine; Retrospective Studies; Myeloablative Agonists; Transplantation, Homologous; Hematopoietic Stem Cell Transplantation; Myeloproliferative Disorders; Leukemia, Myeloid, Acute; Graft vs Host Disease; Recurrence
PubMed: 36336258
DOI: 10.1016/j.jtct.2022.10.027 -
Cancer Medicine Aug 2023The present study aimed to examine the association between the conditioning intensity and height growth in pediatric patients who underwent allogeneic hematopoietic stem... (Review)
Review
BACKGROUND
The present study aimed to examine the association between the conditioning intensity and height growth in pediatric patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT).
METHODS
We reviewed the clinical records of 89 children with malignant diseases who underwent initial allo-HSCT between 2003 and 2021. Height measurements were standardized using standard height charts prepared by the Japanese Society for Pediatric Endocrinology to calculate standard deviation score (SDS). We defined short stature as a height SDS less than -2.0 in that reference. Myeloablative conditioning (MAC) comprised total-body irradiation at more than 8 Gy and busulfan administration at more than 8 mg/kg (more than 280 mg/m ). Other conditioning regimens were defined as reduced intensity conditioning (RIC).
RESULTS
A total of 58 patients underwent allo-HSCT with MAC, and 31 patients received allo-HSCT with RIC. There were significant differences in the height SDS at 2 and 3 years after allo-HSCT between MAC and RIC group (-1.33 ± 1.20 vs. -0.76 ± 1.12, p = 0.047, -1.55 ± 1.28 vs. -0.75 ± 1.11, p = 0.022, respectively). Multivariate logistic regression analysis with the adjustments for potential confounding factors of patients less than 10 years of age at allo-HSCT and chronic graft-versus host disease demonstrated that MAC regimen was associated with a markedly increased risk of a short stature at 3 years after allo-HSCT (adjusted odds ratio, 5.61; 95% confidence interval, 1.07-29.4; p = 0.041).
CONCLUSION
The intensity of conditioning regimen may be associated with short statures after allo-HSCT.
Topics: Humans; Child; Graft vs Host Disease; Transplantation, Homologous; Hematopoietic Stem Cell Transplantation; Busulfan; Bronchiolitis Obliterans Syndrome; Transplantation Conditioning; Retrospective Studies
PubMed: 37434385
DOI: 10.1002/cam4.6336 -
Bone Marrow Transplantation Jun 2023The optimal reduced intensity conditioning (RIC) regimen is a matter of debate. We retrospectively compared conditioning with fludarabine plus fractionated total body...
Fludarabine/TBI 8 Gy versus fludarabine/treosulfan conditioning in patients with AML in first complete remission: a study from the Acute Leukemia Working Party of the EBMT.
The optimal reduced intensity conditioning (RIC) regimen is a matter of debate. We retrospectively compared conditioning with fludarabine plus fractionated total body irradiation of 8 Gy (FluTBI) and fludarabine plus treosulfan 30, 36 or 42 g/m (FluTreo) in 754 patients with AML above the age of 40 years undergoing an allogeneic hematopoietic stem cell transplant (HSCT) in first complete remission (CR). After balancing patient characteristics by propensity score matching of 115 patients in each group, FluTBI was associated with a significantly lower probability of relapse compared to FluTreo (18.3% vs. 34.7%, p = 0.018) which was counteracted by a higher non-relapse mortality (NRM, 16.8% vs. 5.3%, p = 0.02). Thus, overall survival and graft-versus-host disease-free and relapse-free survival at 2 years were similar between groups (OS 66.9% vs. 67.8%, GRFS 50.3% vs. 45.6%). Univariate analysis by age group demonstrated a higher NRM exclusively in patients ≥55 years of age treated with FluTBI compared to FluTreo (27.6% vs. 5.8%, p = 0.02), while a similarly low NRM was observed in patients <55 years in both groups (6.0% vs. 4.7%, p = ns). We conclude that both conditioning regimens are effective and safe, but FluTBI may better be reserved for younger patients below the age of 55 years.
Topics: Humans; Adult; Middle Aged; Retrospective Studies; Whole-Body Irradiation; Busulfan; Leukemia, Myeloid, Acute; Acute Disease; Vidarabine; Recurrence; Transplantation Conditioning; Hematopoietic Stem Cell Transplantation; Graft vs Host Disease
PubMed: 37002412
DOI: 10.1038/s41409-023-01965-x -
Internal and Emergency Medicine Nov 2020
Topics: Animals; COVID-19; Coronavirus Infections; Disease Models, Animal; Esters; Gabexate; Guanidines; Japan; Mesylates; Mice; Pandemics; Pneumonia, Viral; Serine Endopeptidases
PubMed: 32347443
DOI: 10.1007/s11739-020-02345-9 -
Blood Advances May 2023There is no consensus on the best donor for children with nonmalignant disorders and immune deficiencies in the absence of a matched related donor (MRD). We evaluated... (Clinical Trial)
Clinical Trial
There is no consensus on the best donor for children with nonmalignant disorders and immune deficiencies in the absence of a matched related donor (MRD). We evaluated the 2-year overall survival (OS) after umbilical cord blood transplantation (UCBT) in patients with nonmalignant disorders from 2009 to 2020 enrolled in a prospective clinical trial using either 5/6 or 6/6 UCB as the cell source. Patients receive a fully ablative busulfan, cyclophosphamide, and fludarabine without serotherapy. Fifty-five children were enrolled, median age 5 months (range, 1-111 months); primary immune deficiency (45), metabolic (5), hemophagocytic lymphohistiocytosis (1), and hematologic disorders (4). Twenty-six patients had persistent infections before transplant. Nineteen of them (34%) were 6/6 matched, and 36 (66%) were 5/6 human leukocyte antigen-matched. The OS at 2 years was 91% (95% cumulative incidence, 79-96), with a median follow-up of 4.3 years. The median time to neutrophil and platelet recovery were 17 days (range, 5-39 days) and 37 days (range, 20-92 days), respectively. All but one evaluable patient achieved full donor chimerism. The cumulative incidence of acute GVHD grades 2-4 on day 100 was 16% (n = 9). All patients with viral infections at the time of transplant cleared the infection at a median time of 54 days (range, 44-91 days). All evaluable patients underwent correction of their immune or metabolic defects. We conclude that in the absence of MRD, UCBT following myeloablative conditioning without serotherapy is an excellent curative option in young children with nonmalignant disorders. This trial has been registered at www.clinicaltrials.gov as NCT00950846.
Topics: Child; Child, Preschool; Humans; Infant; Busulfan; Cord Blood Stem Cell Transplantation; Cyclophosphamide; Hematopoietic Stem Cell Transplantation; Prospective Studies
PubMed: 36453638
DOI: 10.1182/bloodadvances.2022009038 -
Acta Crystallographica. Section E,... May 2020The solid-state structure of bis-(1-mesityl-1-imidazole-κ )di-phenyl-boron tri-fluoro-methane-sulfonate, CHBN ·CFSO or (), is reported. Bis(1-mesityl-1-imidazole-κ...
The solid-state structure of bis-(1-mesityl-1-imidazole-κ )di-phenyl-boron tri-fluoro-methane-sulfonate, CHBN ·CFSO or (), is reported. Bis(1-mesityl-1-imidazole-κ )di-phenyl-boron ( ) is a bulky ligand that crystallizes in the ortho-rhom-bic space group . The asymmetric unit contains one cationic ligand and one tri-fluoro-methane-sulfonate anion that balances the positive charge of the ligand. The tetra-hedral geometry around the boron center is distorted as a result of the steric bulk of the phenyl groups. Weak inter-actions, such as π-π stacking are present in the crystal structure.
PubMed: 32431931
DOI: 10.1107/S2056989020005058 -
Turkish Journal of Medical Sciences Feb 2023Since well-designed prospective comparative trials are lacking, haploidentical hematopoietic stem cell transplantations approach should be based on the expertise of a...
BACKGROUND
Since well-designed prospective comparative trials are lacking, haploidentical hematopoietic stem cell transplantations approach should be based on the expertise of a particular center. In this study, we aimed to report the results and outcomes of patients who underwent haploidentical hematopoietic stem cell transplantation.
METHODS
: Thirty-nine patients who underwent transplantation in our clinic between 2015 and 2022 were retrospectively analyzed. Primary end point of this study is to find out the survival rates of the patients.
RESULTS
The overall survival of patients was 29.9 ± 4.9 months. The disease-free survival of the patients was 37.8 ± 5.7 months. The 3-year overall survival rate of the patients was %50 and the 3-year disease-free survival rate of the patients was %53. Nineteen patients were nonsurvivors among a total of 39 patients. Busulfan-fludarabine-thiotepa was the most frequently used conditioning regimen for transplantation. Busulfan-fludarabin-antithymocyte globulin regimen is the second preferred conditioning regimen. Cyclosporine- cyclophosphamide-mycophenolate mofetil was the most widely used graft-versus-host disease prophylaxis regimen. Sixteen patients had graft-versus-host disease, 28% of the patients had acute graft-versus-host disease, and 13% had chronic graft-versus-host disease. Gastrointestinal system consists of the most involved organs in graft-versus-host disease since 15% of the patients had gastrointestinal graft-versus-host disease. First-degree relatives (parent/child) were the most frequent donor source for haploidentical hematopoietic stem cell transplantation. Sepsis was the most frequent reason of death among transplant patients.
DISCUSSION
In our center, we prefer to use high dose posttransplantation cyclophosphamide after haploidentical hematopoietic stem cell transplantation for graft-versus-host disease prophylaxis. With this approach, our center's overall survival and disease-free survival rates are comparable and compatible with the literature findings.
Topics: Child; Humans; Busulfan; Retrospective Studies; Prospective Studies; Hematopoietic Stem Cell Transplantation; Cyclophosphamide; Cyclosporine; Graft vs Host Disease; Mycophenolic Acid; Hematologic Neoplasms
PubMed: 36945951
DOI: 10.55730/1300-0144.5591 -
Clinical Pharmacology and Therapeutics Jan 2024A toxicity-reduced conditioning regimen with treosulfan, fludarabine, and thiotepa in patients with high-risk β-thalassemia major has significantly improved...
A toxicity-reduced conditioning regimen with treosulfan, fludarabine, and thiotepa in patients with high-risk β-thalassemia major has significantly improved hematopoietic stem cell transplantation (HCT) outcomes. However, complications resulting from regimen-related toxicities (RRTs), mixed chimerism, and graft rejection remain a challenge. We evaluated the dose-exposure-response relationship of treosulfan and its active metabolite S, S-EBDM, in a uniform cohort of patients with β-thalassemia major to identify whether therapeutic drug monitoring (TDM) and dose adjustment of treosulfan is feasible. Plasma treosulfan/S, S-EBDM levels were measured in 77 patients using a validated liquid chromatography with tandem mass spectrometry method, and the pharmacokinetic parameters were estimated using nlmixr2. The influence of treosulfan and S, S-EBDM exposure, and GSTA1/NQO1 polymorphisms on graft rejection, RRTs, chimerism status, and 1-year overall survival (OS), and thalassemia-free survival (TFS) were assessed. We observed that treosulfan exposure was lower in patients with graft rejection than those without (1,655 vs. 2,037 mg•h/L, P = 0.07). Pharmacodynamic modeling analysis to identify therapeutic cutoff revealed that treosulfan exposure ≥1,660 mg•hour/L was significantly associated with better 1-year TFS (97% vs. 81%, P = 0.02) and a trend to better 1-year OS (90% vs. 69%, P = 0.07). Further, multivariate analysis adjusting for known pre-HCT risk factors also revealed treosulfan exposure <1,660 mg•h/L (hazard ratio (HR) = 3.23; 95% confidence interval (CI) = 1.12-9.34; P = 0.03) and GSTA1*B variant genotype (HR = 3.75; 95% CI = 1.04-13.47; P = 0.04) to be independent predictors for inferior 1-year TFS. We conclude that lower treosulfan exposure increases the risk of graft rejection and early transplant-related mortality affecting TFS. As no RRTs were observed with increasing treosulfan exposure, TDM-based dose adjustment could be feasible and beneficial.
Topics: Humans; beta-Thalassemia; Busulfan; Hematopoietic Stem Cell Transplantation; Thiotepa; Transplantation Conditioning; Graft vs Host Disease
PubMed: 37846495
DOI: 10.1002/cpt.3078 -
Biology of Blood and Marrow... Jul 2019We report the outcomes of 51 patients who underwent unmanipulated haploidentical hematopoietic stem cell transplantation (haplo-HSCT) with post-transplantation... (Clinical Trial)
Clinical Trial
We report the outcomes of 51 patients who underwent unmanipulated haploidentical hematopoietic stem cell transplantation (haplo-HSCT) with post-transplantation cyclophosphamide (PT-Cy) and antithymocyte globulin (ATG), from peripheral blood stem cells (PBSCs) or bone marrow, after receipt of a TBF (thiotepa, busulfan, and fludarabine) conditioning regimen. Their median age was 55 years (range, 16 to 72 years). Hematologic diagnoses included acute leukemias (n = 31), lymphoid neoplasm (n = 12), myeloproliferative neoplasm (n = 5), and myelodysplastic syndromes (n = 3). Thirty-seven patients (73%) were in complete remission. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and mycophenolate for all patients, associated with ATG in 39 patients (76.5%). The median time to neutrophil engraftment was 17 days (range, 12 to 34 days). The cumulative incidences of grade II-IV and grade III-IV acute GVHD were 27.5% and 14%, respectively. In patients receiving a PBSC graft and ATG prophylaxis, grade II-IV aGVHD occurred in 16% of patients. The use of ATG and a lower thiotepa dose (5 mg/kg versus 10 mg/kg) were associated with a reduced cumulative incidence of grade II-IV acute GVHD (P = .03 and .005, respectively). The 2-year cumulative incidence of chronic GVHD was 29% and was significantly reduced to 13% with the lower thiotepa dose (P = .002). After a median follow-up of 25 months (range, 12 to 62 months), the cumulative incidences of nonrelapse mortality, relapse, overall survival (OS), disease-free survival (DFS), and GVHD-free, relapse-free survival (GFRFS) were 20%, 22.5%, 67%, 58%, and 51%, respectively. Pretransplantation disease status (complete remission versus others) was the main factor associated with OS, DFS, and GFRFS. In conclusion, the TBF conditioning regimen is an appealing platform in the haplo-HSCT setting with PT-Cy in terms of engraftment rate, toxicity, and disease control. We found no benefit of a thiotepa dose of 10 mg/kg compared with a dose of 5 mg/kg. ATG reduced the risk of acute GVHD without comprising outcomes.
Topics: Adolescent; Adult; Aged; Busulfan; Cyclosporine; Disease-Free Survival; Female; Graft vs Host Disease; HLA Antigens; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Male; Middle Aged; Mycophenolic Acid; Retrospective Studies; Survival Rate; T-Lymphocytes; Thiotepa; Transplantation Conditioning; Vidarabine
PubMed: 30871978
DOI: 10.1016/j.bbmt.2019.02.025