[The prognostic value of colonoscopy grading for acute graft-versus-host disease in patients with malignant hematological disorders after unrelated cord blood transplantation].

Objective: To investigate the prognostic value of enteroscopic grading for the prognostic assessment of patients with malignant hematological diseases who developed intestinal acute graft-versus-host disease (IT-aGVHD) after unrelated cord blood transplantation (UCBT) . Methods: Fifty patients with IT-aGVHD who developed hormone resistance after UCBT from June 2016 to June 2023 at Anhui Provincial Hospital were collected to compare the effective and survival rates of IT-aGVHD treatment in the group with milder enteroscopic mucosal injury (27 cases, enteroscopic grading of Ⅰ and Ⅱ) and the group with more severe injury (23 cases, enteroscopic grading of Ⅲ and Ⅳ) and to retrospectively analyze the factors affecting patients' prognosis. Results: Patients in the mild and severe groups had an effective rate of 92.6% and 47.8% at 28 days after colonoscopy (P<0.001), 81.5% and 39.1% at 56 days after colonoscopy (P=0.002), with optimal effective rate of 92.6% and 65.2% (P=0.040), respectively, and the differences were statistically significant. The multifactorial analysis found that enteroscopic grading was an independent risk factor affecting the effective rate of IT-aGVHD treatment. The overall survival rate at 2 years after colonoscopy was 70.4% (95% CI 52.0% -88.8% ) and 34.8% (95% CI 14.8% -54.8% ) for patients in the mild and severe groups, respectively, and the difference was statistically significant (P=0.003). Multifactorial analysis revealed that enteroscopic grading, cytomegalovirus infection status, second-line treatment regimen, and patients' age were independent risk factors for survival. Conclusion: The treatment efficacy and prognosis of patients in the group with less severe enteroscopic injury (grades Ⅰ and Ⅱ) were better than those in the group with more severe injury (grades Ⅲ and Ⅳ) .

Successful treatment of acyclovir-resistant herpes simplex virus infection with amenamevir in a patient who received umbilical cord blood transplantation for T-cell prolymphocytic leukemia.

A 34-year-old woman received umbilical cord blood transplantation for refractory T-cell prolymphocytic leukemia after salvage therapy with alemtuzumab. She developed right angular cheilitis on the 46th day after transplantation, which worsened after receiving systemic steroid therapy for extensive chronic graft versus host disease. The treatment dosage of acyclovir (ACV), ganciclovir, and vidarabine ointment was not effective due to ACV-resistant mutations of the herpes simplex virus type 1 (HSV-1) in the thymidine kinase domain. Foscarnet is expected to be effective against ACV-resistant HSV-1 infection. However, it could not be used because the patient developed renal dysfunction. Several viral thymidine kinase mutations related to ACV resistance were found in the patient's sample. Nevertheless, amenamevir, a helicase-primase complex inhibitor, was effective in our patient who was significantly immunocompromised after allogeneic hematopoietic stem cell transplantation (allo-HSCT). ACV-resistant HSV infection after allo-HSCT is an rare but important complication in the era of low-dose long-term ACV prophylaxis. To date, there is no established treatment against ACV-resistant HSV infection. This case report showed that amenamevir could be a promising treatment option for ACV-resistant HSV infection in patients with renal failure after allo-HSCT.

Hybrid cord blood banking in a private-public-partnership: Women's perspectives.

BACKGROUND: The increasing demand for umbilical cord blood (UCB) used in stem cell transplantation led to the establishment of cord blood (CB) banks worldwide. These include public foreign donor banks and private family-directed donor banks. Recently, our department has introduced a third banking model within a private-public-partnership. This hybrid banking allows for storage of family-directed CB units, while also getting Human leukocyte antigen (HLA)-typed and included in the national stem cell donor registry. So if the need arises, the HLA-compatible CB unit can be released to an unrelated recipient as a foreign donor stem cell graft. OBJECTIVES: The aim of this study was to evaluate women's perspectives on the different CB banking options as well as retrospective satisfaction with their decisions. METHODS: We performed a prospective survey study in postpartum women, using a validated questionnaire. RESULTS: A total of 157 women were included in this survey study; 68% of them decided to have their UCB stored or donated. Among those women, 25% of them opted for hybrid storage, 72% of respondents stored UCB publicly, and 3% decided for private family-directed storage. CONCLUSIONS: Our study shows the potential of hybrid banking as an attractive UCB storage option, as an alternative to family-directed banking rather than a substitute for public donation. Hybrid storage potentially combines advantages of family-directed banking as well as unrelated CB donation expanding the number of registered CB units available for transplantation and giving every pregnant woman the possibility to store UCB.

Umbilical cord blood-derived therapy for preterm lung injury: a systematic review and meta-analysis.

INTRODUCTION: Lung injuries, such as bronchopulmonary dysplasia (BPD), remain a major complication of preterm birth, with limited therapeutic options. One potential emerging therapy is umbilical cord blood (UCB)-derived therapy. OBJECTIVES: To systematically assess the safety and efficacy of UCB-derived therapy for preterm lung injury in preclinical and clinical studies. METHODS: A systematic search of MEDLINE, Embase, CENTRAL, ClinicalTrials.gov, and WHO International Trials Registry Platform was performed. A meta-analysis was conducted with Review Manager (5.4.1) using a random effects model. Data was expressed as standardized mean difference (SMD) for preclinical data and pooled relative risk (RR) for clinical data, with 95% confidence intervals (CI). Potential effect modifiers were investigated via subgroup analysis. Certainty of evidence was assessed using the GRADE system. RESULTS: Twenty-three preclinical studies and six clinical studies met eligibility criteria. Statistically significant improvements were seen across several preclinical outcomes, including alveolarization (SMD, 1.32, 95%CI [0.99, 1.65]), angiogenesis (SMD, 1.53, 95%CI [0.87, 2.18]), and anti-inflammatory cytokines (SMD, 1.68, 95%CI [1.03, 2.34]). In clinical studies, 103 preterm infants have received UCB-derived therapy for preterm lung injury and no significant difference was observed in the development of BPD (RR, 0.93, 95%CI [0.73, 1.18]). Across both preclinical and clinical studies, administration of UCB-derived therapy appeared safe. Certainty of evidence was assessed as "low." CONCLUSIONS: Administration of UCB-derived therapy was associated with statistically significant improvements across several lung injury markers in preclinical studies. Early clinical studies demonstrated the administration of UCB-derived therapy as safe and feasible but lacked data regarding efficacy.

Hospitalization and Healthcare Resource Utilization of Omidubicel-Onlv versus Umbilical Cord Blood Transplantation for Hematologic Malignancies: Secondary Analysis from a Pivotal Phase 3 Clinical Trial.

A phase 3 trial (ClincialTrials.gov identifier NCT02730299) of omidubicel-onlv, a nicotinamide-modified allogeneic hematopoietic progenitor cell therapy manufactured from a single umbilical cord blood (UCB) unit, showed faster hematopoietic recovery, reduced rate of infections, and shorter hospital stay compared with patients randomized to standard UCB. This prospective secondary analysis of the phase 3 trial characterized resource utilization in the first 100 days post-transplantation with omidubicel-onlv compared with UCB. This analysis examined resource utilization, including hospital length of stay, hospital care setting, visits by provider type, rate of transfusions, and readmissions, among the 108 treated patients (omidubicel-onlv, n = 52; UCB, n = 56) from day 0 to day 100 post-transplantation. Demographics were generally balanced between the 2 arms, except a higher proportion of females (52% versus 37%) and older median age (40 years versus 36 years) were noted in the omidubicel-onlv arm. Compared with patients receiving UCB transplantation, patients receiving omidubicel-onlv had a shorter average total hospital length of stay (mean, 41.2 days versus 50.8 days; P = .027) in the first 100 days post-transplantation and more days alive and out of the hospital (mean, 55.8 days versus 43.7 days; P = .023). Fewer patients died in the omidubicel-onlv arm compared with the UCB arm (12% vs 16%) before day 100 post-transplantation. During primary hospitalization (ie, time from transplantation to discharge), fewer patients receiving omidubicel-onlv required intensive care unit (ICU) admission (10% versus 23%) and spent fewer days in the ICU (mean, .4 day versus 4.7 days; P = .028) and transplant unit (mean, 25.3 days versus 32.9 days; P = .022) compared with those receiving UCB. Patients receiving omidubicel-onlv required fewer outpatient consultant and nonconsultant visits and fewer platelet or other transfusions within 100 days from transplantation. Our findings suggest that faster hematopoietic recovery in omidubicel-onlv patients is associated with significantly shorter hospital stay and reduced healthcare resource use compared with UCB.

A Biosafety Study of Human Umbilical Cord Blood Mononuclear Cells Transduced with Adenoviral Vector Carrying Human Vascular Endothelial Growth Factor cDNA In Vitro.

The biosafety of gene therapy remains a crucial issue for both the direct and cell-mediated delivery of recombinant cDNA encoding biologically active molecules for the pathogenetic correction of congenital or acquired disorders. The diversity of vector systems and cell carriers for the delivery of therapeutic genes revealed the difficulty of developing and implementing a safe and effective drug containing artificial genetic material for the treatment of human diseases in practical medicine. Therefore, in this study we assessed changes in the transcriptome and secretome of umbilical cord blood mononuclear cells (UCB-MCs) genetically modified using adenoviral vector (Ad5) carrying cDNA encoding human vascular endothelial growth factor (VEGF165) or reporter green fluorescent protein (GFP). A preliminary analysis of UCB-MCs transduced with Ad5-VEGF165 and Ad5-GFP with MOI of 10 showed efficient transgene expression in gene-modified UCB-MCs at mRNA and protein levels. The whole transcriptome sequencing of native UCB-MCs, UCB-MC+Ad5-VEGF165, and UCB-MC+Ad5-GFP demonstrated individual sample variability rather than the effect of Ad5 or the expression of recombinant vegf165 on UCB-MC transcriptomes. A multiplex secretome analysis indicated that neither the transduction of UCB-MCs with Ad5-GFP nor with Ad5-VEGF165 affects the secretion of the studied cytokines, chemokines, and growth factors by gene-modified cells. Here, we show that UCB-MCs transduced with Ad5 carrying cDNA encoding human VEGF165 efficiently express transgenes and preserve transcriptome and secretome patterns. This data demonstrates the biosafety of using UCB-MCs as cell carriers of therapeutic genes.

Efficacy and safety of allogeneic hematopoietic cell transplantation in acute myeloid leukemia patients aged > 65 years with unfavorable cytogenetics.

Unrelated donor bone marrow transplantation (UR-BMT), unrelated donor cord blood stem cell transplantation (UR-CBT), and haploidentical peripheral blood stem cell transplantation (Haplo-PBSCT) are the main alternative stem cell sources for allogeneic hematopoietic cell transplantation (HCT) in Japan. The present study aimed to identify factors associated with the outcomes of UR-BMT, UR-CBT, and Haplo-PBSCT in older patients with acute myeloid leukemia (AML) and intermediate- or poor-risk cytogenetics to improve the clinical efficacy and safety of allogeneic HCT. We retrospectively analyzed data for 448 AML patients aged > 65 years who received UR-BMT (n = 102), UR-CBT (n = 250), or Haplo-PBSCT (n = 96) between 2014 and 2020. Overall survival (OS) in the UR-BMT group was superior (P = 0.033) to that in the other groups. However, all patients without complete remission (non-CR) who had Karnofsky performance status (KPS) < 80 at HCT and poor-risk cytogenetics died within 1 year after HCT. Multivariate Cox regression analysis identified KPS <80 at HCT and poor-risk cytogenetics as independent predictors of worse OS in non-CR patients. KPS < 80 may be an alternative indicator for non-CR AML patients with poor-risk cytogenetics during the selection of HCT, alternative treatments, or best supportive therapy, and the optimal KPS is important for the success of HCT.

Factors Influencing the Efficacy of Umbilical Cord Blood-Derived Cell Therapy for Perinatal Brain Injury.

INTRODUCTION: We have previously described preclinical literature which supports umbilical cord blood-derived cell (UCBC) therapy as an efficacious treatment for perinatal brain injury. However, efficacy of UCBCs may be influenced by different patient population and intervention characteristics. OBJECTIVES: To systematically review the effects of UCBCs on brain outcomes in animal models of perinatal brain injury across subgroups to better understand the contribution of model type (preterm versus term), brain injury type, UCB cell type, route of administration, timing of intervention, cell dosage, and number of doses. METHODS: A systematic search of MEDLINE and Embase databases was performed to identify studies using UCBC therapy in animal models of perinatal brain injury. Subgroup differences were measured by chi2 test where possible. RESULTS: Differential benefits of UCBCs were seen across a number of subgroup analyses including intraventricular hemorrhage (IVH) vs. hypoxia ischemia (HI) model (apoptosis white matter (WM): chi2 = 4.07; P = .04, neuroinflammation-TNF-α: chi2 = 5.99; P = .01), UCB-derived mesenchymal stromal cells (MSCs) vs. UCB-derived mononuclear cells (MNCs) (oligodendrocyte WM: chi2 = 5.01; P = .03, neuroinflammation-TNF-α: chi2 = 3.93; P = .05, apoptosis grey matter (GM), astrogliosis WM), and intraventricular/intrathecal vs. systemic routes of administration (microglial activation GM: chi2 = 7.51; P = .02, astrogliosis WM: chi2 = 12.44; P = .002). We identified a serious risk of bias and overall low certainty of evidence. CONCLUSIONS: Preclinical evidence suggests UCBCs to show greater efficacy in the injury model of IVH compared to HI, the use of UCB-MSCs compared to UCB-MNCs and the use of local administrative routes compared to systemic routes in animal models of perinatal brain injury. Further research is needed to improve certainty of evidence and address knowledge gaps.

Salvage haploidentical or cord-blood allogeneic stem cell transplantation after a prior alternative allograft in hematologic malignancies: A retrospective study from the SFGM-TC.

BACKGROUND: Haploidentical (haplo-) donors and cord-blood (CB) stem cells provide alternative transplant options in patients lacking an HLA-matched donor. In case of relapse or graft failure after a first alternative allogeneic hematopoietic stem cell transplant (HSCT), a second alternative HSCT (HSCT2) is rarely considered due to a high risk of toxicity. METHODS: A retrospective French multicentre study was performed, including patients with hematologic malignancies who underwent two consecutive HSCT from alternative donors. All data were exported from the national ProMISE database between 2000 and 2016. RESULTS: Forty-three patients (61.4%) received a CB-HSCT2 and 27 (38.6%) a haplo-HSCT2. Indications for HSCT were graft failure (51.4%) or disease progression (48.6%). Two-years probabilities of overall survival, progression-free survival and toxicity-related mortality were 18.5%, 17.8% and 55.8%, respectively. In multivariate analysis, complete remission status at HSCT2 and year of HSCT2 ≥ 2012 were significantly associated with a better outcome (with respectively hazard ratio [HR] = 0.42, p = .002 and HR = 0.5, p = .051). CONCLUSIONS: Neither the indication of HSCT2 nor the source of stem cell was more advantageous towards overall patient survival. A salvage haploidentical or cord-blood stem cell transplantation is a high-risk procedure, that may be considered for patients achieving a complete remission before receiving the second HSCT.

Tislelizumab bridging to umbilical cord blood transplantation therapy for relapsed/refractory acute myeloid leukemia: report of 1 case and review of literature / 白血病·淋巴瘤

Objective:To explore the efficacy of tislelizumab combined with umbilical cord blood transplantation (UCBT) in relapsed/refractory acute myeloid leukemia (R/R AML) patients.Methods:The diagnosis and treatment of 1 patient with R/R AML who received tislelizumab bridging to UCBT after the failure of re-induction treatment in the First Affiliated Hospital of Soochow University in November 2021 was retrospectively analyzed.Results:The 59-year-old male patient with R/R AML achieved a complete remission after initial induction chemotherapy regimen of decitabine and venetoclax, and then additional consolidation therapy regimens of decitabine and middle-dose cytarabine, middle-dose cytarabine and idarubicin were performed. The patient relapsed 16 months later and failed to achieve a second remission after re-induction therapy regimens of cladribine, azacitidine, venetoclax combined with chemotherapy, and homoharringtonine, cytarabine combined with granulocyte colony-stimulating factor. Tislelizumab significantly reduced tumor burden and the patient achieved the complete remission after bridging to UCBT. After transplantation, the patient was given maintenance treatment with azacitidine and he had sustained remission without severe transplant-related complications during 9-month follow-up.Conclusions:The use of tislelizumab bridging UCBT can be a potential therapeutic strategy for R/R AML patients.

Durable Cord Blood Cell Engraftment in a Patient with Severe Aplastic Anemia after a Matched Sibling Bone Marrow Transplantation and an Unrelated Cord Blood Transplantation.

OBJECTIVE: Severe aplastic anemia (SAA) is a fatal bone marrow failure disease. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) with a matched sibling donor is the first-line treatment for older SAA patients. However, the number of CD34+ cells collected from a matched donor is often lower than expected. To overcome the problem, this study was conducted to combine a matched sibling donor with an unrelated cord blood transplantation for the treatment of a patient with SAA. CASE REPORT: A 45-year-old male patient with SAA was treated with a sibling-matched allo-HSCT. Due to the low amount of donor CD34+ cells, an unrelated umbilical cord blood stem cell transplantation (UCBT) with 9/10 HLA matching was subsequently carried out. Successful hematopoietic reconstitution was achieved by the dual transplantation. Unexpectedly, beginning in the fourth month after transplantation, the sibling donor chimerism was transformed to a stable and complete UCB source. CONCLUSION: This study provides evidence that UCB-derived HSCs have a higher capacity for hematopoietic reconstitution, suggesting that UCB plus an HLA-matched sibling donor is a good alternative for older patients with SAA.

Exosomes derived from human umbilical cord blood mesenchymal stem cells stimulate regenerative wound healing via transforming growth factor-ß receptor inhibition.

BACKGROUND: Scar formation is a common consequence of skin wound healing, and no effective treatment exists. Umbilical cord blood mesenchymal stem cells (UCB-MSCs) can improve wound healing; however, the role of UCB-MSCs remains unclear and whether they can ameliorate scar formation has not been fully elucidated. METHODS: To determine the function of UCB-MSCs, we examined and compared the therapeutic effects of UCB-MSCs and UCB-MSC-derived exosomes (UCB-MSC-exo) on skin healing in rats. Moreover, UCB-MSC-exo-specific miRNAs were identified and their effects in inhibiting the human dermal fibroblast (HDF) differentiation into myofibroblasts were investigated. RESULTS: Both UCB-MSCs and UCB-MSC-exo accelerated wound closure; reduced scar formation; improved the regeneration of skin appendages, nerves, and vessels; and regulated the natural distribution of collagen fibers in wound healing. Additionally, UCB-MSC-exo suppressed the excessive formation of myofibroblasts and collagen I and increased the proliferation and migration of skin cells in vivo and in vitro. Functional analysis showed that UCB-MSC-derived miRNAs were closely related to the transforming growth factor-ß (TGF-ß) signaling pathway, which could induce myofibroblast differentiation. We identified abundant miRNAs that were highly expressed in UCB-MSC-exo. miR-21-5p and miR-125b-5p were predicted to contribute to TGF-ß receptor type II (TGFBR2) and TGF-ß receptor type I (TGFBR1) inhibition, respectively. Using miRNA mimics, we found that miR-21-5p and miR-125b-5p were critical for anti-myofibroblast differentiation in the TGF-ß1-induced HDF. CONCLUSION: The effect of UCB-MSCs in stimulating regenerative wound healing might be achieved through exosomes, which can be, in part, through miR-21-5p- and miR-125b-5p-mediated TGF-ß receptor inhibition, suggesting that UCB-MSC-exo might represent a novel strategy to prevent scar formation during wound healing.

Case Report: Metagenomic Next-Generation Sequencing in Diagnosis of Legionella pneumophila Pneumonia in a Patient After Umbilical Cord Blood Stem Cell Transplantation.

We report a case of hospital-acquired Legionella pneumonia that was detected by metagenomic next-generation sequencing (mNGS) of blood from a 7-year-old girl after umbilical cord blood stem cell transplantation (UCBT) with myelodysplastic syndrome. UCBT is traditionally associated with an increased risk of infection, particularly during the first 3 months after transplantation. Controlling interstitial pneumonia and severe infection is the key to reducing patient mortality from infection. Legionella pneumophila can cause a mild cough to rapidly fatal pneumonia. After mNGS confirmed that the pathogen was L. pneumophila, azithromycin, cefoperazone sulbactam, and posaconazole were used for treatment, and the patient's temperature decreased and remained normal. The details of this case highlight the benefits of the timely use of metagenomic NGS to identify pathogens for the survival of immunocompromised patients.

Células madre mesenquimatosas y sus diferentes usos / Mesenchymal stem cells and their different uses

Introducción: las células madre mesenquimatosas (CMM) se diferencian de diversos tipos celulares para la regeneración de tejidos, esta característica sumada con la versatilidad del antígeno leucocitario humano (HLA) representan una eficaz alternativa para el tratamiento de enfermedades con tejidos deteriorados. Se pueden obtener a partir de médula ósea, cordón umbilical (CU) y sangre fetal. Objetivo: analizar los tipos de diferenciación de las CMM, sus métodos de extracción y su relación con bancos de sangre de cordón umbilical (BSCU), a fin de demostrar la eficacia de las CMM, en patologías que impliquen alteración de algún tejido u órgano. Metodología: se revisaron varias publicaciones en español e inglés en Pubmed, Clinicalkey y Science Direct; desde 2013 hasta 2020. Se usaron los términos sangre fetal, células madre mesenquimatosas, trasplante de Células Madre de Sangre del Cordón Umbilical y bancos de sangre. Con dicha información se redactó un panorama amplio sobre las células mesenquimales y como estas participan en diversas áreas de la salud, con un énfasis importante en sus usos terapéuticos y lo referente a de donde provienen. Conclusión: a través de la pluripotencialidad de las CMM, se han podido emplear en múltiples patologías pues reestablece tejidos o líneas celulares exitosamente. Así mismo, los recursos para su obtención son claves en la tolerancia de los pacientes, por lo cual una gran opción para su obtención es el CU, que actualmente cuenta con bancos exclusivos para esto. (AU)

Introduction: mesenchymal stem cells (MSC) differentiate into multiple cell types for tissue regeneration, this characteristic added with the versatility of human leukocyte antigen (HLA) represent an effective alternative for the treatment of diseases with damaged tissues. They can be obtained from bone marrow, umbilical cord (UC), and fetal blood. Objetive: analyze the types of differentiation of MSC, their extraction methods and their relationship with umbilical cord blood banks (UCBB), in order to demonstrate the efficacy of MSC, in pathologies that involve alteration of a tissue or organ. Methodology: several publications in Spanish and English in Pubmed, Clinicalkey and Science Direct were reviewed; from 2013 to 2020. The terms fetal blood, mesenchymal stem cells, Umbilical Cord Blood Stem Cell transplantation and blood banks were used. With this information, a broad overview of mesenchymal cells and how they participate in various areas of health was drawn up, with an important emphasis on their therapeutic uses and where they come from. Conclusion: through the pluripotentiality of MSC, they have been used in multiple pathologies as it successfully re-establishes tissues or cell lines. Also, the resources for obtaining it are key in the tolerance of patients, which is why a great option for obtaining it is the UC, which currently has exclusive banks for this.

Women's attitude towards umbilical cord blood banking in Poland.

Umbilical cord blood (UCB) is considered as a valuable potential source of hematopoietic stem and progenitor cells. A process of collecting and storing UCB in the immediate period after the birth is called UCB banking. The study was conducted in order to determine women's knowledge, awareness, preferences and attitude towards UCB banking in Poland, considering the sociodemographic and obstetric factors. A cross-sectional, self-administered, online questionnaire-based study including mostly multiple choice questions concerning attitude and awareness regarding UCB banking was conducted entirely online among Facebook female users in Poland. A total of 1077 participants correctly completed the survey. Most participants (n = 911, 84.6%) were aware of the possibility of UCB banking. Social media were considered as the main source of information (47.5%). However, the participants mostly indicated the doctor as their preferred source of reliable information (86.8%). The majority of women (61.8%) assessed their level of knowledge of UCB banking as still insufficient. Among the participants who supported UCB banking (70%), the following reasons were considered as the most vital: potential possibility of helping their child (93.9%) and helping other relatives (64.4%). More than half of the respondents (66.9%), who have not stored and are not willing to store their children's UCB, indicated the high cost of UCB banking as the main reason of this decision. The knowledge and awareness of UCB storage and banking possibilities amongst women in Poland could be improved. The professional medical personnel should be a source of reliable information.

Beneficial Effects of Human Umbilical Cord Blood Mononuclear Cells on Persistent Erectile Dysfunction After Treatment of 5-Alpha Reductase Inhibitor in Rats.

BACKGROUND: Effects of human umbilical cord blood (HUCB) as a valuable source for stem cell-based therapies have not been studied in persistent post-5-alpha reductase inhibitors (5ARI) erectile dysfunction (PPED). AIM: To determine the effect of intracavernosal injection of HUCB mononuclear cells (MNCs) on ED associated with dutasteride treatment. METHODS: Twenty five adult male Sprague-Dawley rats were divided into 5 groups (n = 5 per group): (i) control, (ii) 8-week dutasteride (0.5 mg/kg/day, in drinking water), (iii) 12-week dutasteride, (iv) 8-week dutasteride+HUCB-MNCs (1 × 106) and (v) 12-week dutasteride+HUCB-MNCs. HUCB-MNCs were administered intracavernosally after eight weeks of dutasteride treatment. Experiments were performed at 4 weeks following the injection of HUCB-MNCs. Erectile responses and isometric tension of corpus cavernosum (CC) were measured. The protein expressions of phosphodiesterase type 5 (PDE5), endothelial nitric oxide synthase (eNOS), neuronal NOS (nNOS), hypoxia-inducible factor (HIF)-1α and smooth muscle/collagen contents in penile tissue were evaluated by Western blotting, immunohistochemistry, and Masson's trichrome staining, respectively. MAIN OUTCOME: In vivo erectile function, in vitro relaxant and contractile responses of CC, protein expression and localization of PDE5, eNOS, nNOS, HIF-1α, and smooth muscle content in penile tissue. RESULTS: Erectile responses in the dutasteride-treated groups were significantly decreased compared with controls (P < .001), persisting after 4-wk of washout. HUCB-MNCs restored diminished intracavernosal pressure responses, acetylcholine-, sodium nitroprusside-, sildenafil-induced relaxations, and increased phenylephrine and electrical field stimulation (EFS)-induced contractions. Decreased EFS-induced relaxations in dutasteride-treated groups were not restored by HUCB-MNCs. Increased PDE5 and reduced nNOS expressions in dutasteride groups were restored by HUCB-MNCs in the 12-week dutasteride group. eNOS and HIF-1α protein expression and serum total and free testosterone  levels were similar among groups. HUCB-MNCs reversed the decreased smooth muscle/collagen ratio in dutasteride-treated tissues. There was a significant increase in PDE5 and HIF-1α staining in 8-week dutasteride animals. CLINICAL TRANSLATION: This study demonstrates the corrective potential of HUCB-MNCs on some persistent structural and functional deterioration caused by 5ARI treatment in rats, which may encourage further evaluation of HUCB-MNCs in men with PPED. STRENGTHS AND LIMITATIONS: Therapeutic application of intracavernosal HUCB-MNCs is a novel approach for the rat model of post-5ARI ED. Lack of serum and tissue dihydrotestosterone measurements, vehicle injections and characterization of the cells remain limitations of our study. CONCLUSION: The persistent ED after prolonged administration of dutasteride in rats is reversed by HUCB-MNC treatment, which holds promise as a realistic therapeutic modality for this type of ED. Oztekin CV, Yilmaz-Oral D, Kaya-Sezginer E, et al. Beneficial Effects of Human Umbilical Cord Blood Mononuclear Cells on Persistent Erectile Dysfunction After Treatment of 5-Alpha Reductase Inhibitor in Rats. J Sex Med 2021;18:889-899.

Humanized NOD/SCID/IL2rγnull mice exhibit functionally augmented human regulatory T cells associated with enzymatic up-regulation of H3K27me3 in comparison with humans.

Humanized non-obese diabetic/severe combined immunodeficiency/interleukin-2 receptor-γ-null (NOD/SCID/IL2rγnull ) [humanized (huNSG)] mice engrafted with human hematopoietic cells have been used for investigations of the human immune system. However, the epigenetic features of the human regulatory T (Treg ) cells of huNSG mice have not been studied. The objective of this study was to clarify the characteristics of human Treg cells in huNSG mice, especially in terms of the epigenetic aspects. We compared the populations, inhibitory molecule expression and suppressive capacity of human Treg cells in spleens harvested from the huNSG mice 120 days after the engraftment of human umbilical cord blood CD34+ cells with human peripheral blood mononuclear cells (PBMCs). Histone modifications and enhancer of zeste homolog 2 (Ezh2), an H3K27 methyltransferase, of human Treg cells were quantified in huNSG mice and human PBMCs. The effect of Ezh2 inhibitor on human Treg cells exposed to interleukin (IL)-6 was also compared between them. Human Treg cells in the spleens of huNSG mice showed an increased proportion among CD4+ T cells, higher expressions of forkhead box protein 3 (FoxP3), cytotoxic T lymphocyte antigen 4 (CTLA-4) and glucocorticoid-induced tumor necrosis factor-related protein (GITR), a higher production of IL-10 and enhanced suppressive capacity when compared with those in human PBMCs. H3K27me3 and Ezh2 were specifically up-regulated in human Treg cells of huNSG mice in comparison with those of human PBMCs. The decrease in Treg cells induced by IL-6 exposure was attenuated in huNSG mice when compared with human PBMCs, while the difference between them was cancelled by addition of Ezh2 inhibitor. In conclusion, huNSG mice exhibit functionally augmented human Treg cells owing to enzymatic up-regulation of H3K27me3.

Human Umbilical Cord Mesenchymal Stem Cells Over Platelet Rich Fibrin Scaffold for Mandibular Cartilage Defects Regenerative Medicine

ABSTRACT Objective: To evaluate the regeneration of mandibular cartilage defect after implantation of human umbilical cord mesenchymal stem cells (hUCMSC) over platelet rich fibrin (PRF) as scaffold. Material and Methods: 20 male Wistar rats were randomly divided into four experimental groups consisting of: a control group featuring untreated mandibular defects (C), experimental groups whose mandibular defects were implanted with hUCMSC (E1), mandibular defects implanted with PRF (E2), mandibular defects implanted with hUCMSC and PRF scaffold (E3). The subjects were sacrificed after six weeks of observation for immunohistochemical examination in order to evaluate the expression of Ki67, Sox9, FGF 18, type 2 collagen, and aggrecan, in addition to histology examination to evaluate chondrocyte number and cartilage thickness. Data was analyzed with univariate analysis (ANOVA). Results: The implantation of hUCMSC and PRF scaffold proved capable of regenerating mandibular cartilage defect through the expression of FGF 18, Sox9, Ki67, chondrosis counts, type 2 collagen, aggrecan, and cartilage thickness. The regeneration were significantly higher in group E3. Conclusion: Human umbilical cord mesenchymal stem cells in platelet rich fibrin scaffold proved capable of regenerating mandibular cartilage defect.

Effect of allogeneic HCT from unrelated donors in AML patients with intermediate- or poor-risk cytogenetics: a retrospective study from the Japanese Society for HCT.

This study aimed to analyze the factors associated with outcomes of bone marrow transplantation (UR-BMT) or cord blood stem cell transplantation from unrelated donors (UR-CBT). We assessed the time from diagnosis to transplantation among acute myeloid leukemia (AML) patients with intermediate- or poor-risk cytogenetics to identify the potential clinical efficacy of transplantation. We retrospectively analyzed 5331 patients who received UR-BMT or UR-CBT between 2008 and 2017. Patients were divided into four groups according to time from diagnosis to transplantation: (1) UR-BMT and > 5 months (n = 2353), (2) UR-BMT and ≤ 5 months (n = 379), (3) UR-CBT and > 5 months (n = 1494), and (4) UR-CBT and ≤ 5 months (n = 1106). There was no difference in overall survival (OS) for transplantation at ≤5 months and > 5 months in patients with first complete remission for both UR-BMT and UR-CBT, but OS in patients with primary induction failure (PIF) and transplantation at ≤ 5 months was significantly higher in the UR-CBT group compared with that at >5 months (P < 0.001). Multivariate Cox regression analysis also showed that transplantation at >5 months in patients with PIF was an independent predictor of poorer OS. Therefore, UR-CBT at ≤ 5 months after diagnosis is an alternative option for AML patients with PIF.