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Treatment trends for newly diagnosed multiple myeloma (NDMM) are not fully evaluated in real-world settings in the Japanese population. Triple-class exposed (TCE) patients with relapsed or refractory MM have a poor prognosis and limited treatment options. To clarify characteristics, treatment trends, and TCE status in Japanese patients with MM, we conducted a retrospective, non-interventional study. Data from patients with MM were extracted from a Japanese claims database between 2015 and 2022: this study identified patients with NDMM prescribed daratumumab (D), lenalidomide (R), and/or bortezomib (V) as 1st-line treatment. The patient characteristics and treatment trends were analyzed for non-transplant and transplant groups. Of 1,784 patients, non-transplant patients (n = 1,656, median age 75 years [range: 37–94]) received R+dexamethasone (Rd) (24.7%), Vd (23.8%), and RVd (15.6%) and transplant patients (n = 128, median age 61 years [range: 35–73]) received RVd (49.5%), Vd (18.7%), and DVd (8.4%) in 1st line. In the non-transplant group, the commonly prescribed treatment regimens were Rd for patients aged ≥75 years, Vd for patients aged 65–74 years, and RVd for patients aged <65 years. Patients with renal or cardiac dysfunction commonly received Vd or Rd, respectively. In the transplant group, 107 (83.6%) and 20 (15.6%) patients received transplantation in the 1st and 2nd lines, respectively. The top three regimens as induction therapy before stem cell transplantation were RVd (49.5%), Vd (18.7%), or DVd (8.4%) in 1st line. Cumulative TCE patients by 5th line were 351 (21.2%) and 56 (43.8%) for non-transplant and transplant patients, respectively. TCE ratio at each line gradually increased from 1st to 5th line (11.1–69.2% in the non-transplant group and 21.1–100% in the transplant group, respectively). Of 184 TCE patients in the non-transplant group, 89.7% received sequencing treatments including DRd, RVd, and DVd, and 10.3% received D-RVd in 1st line. [ABSTRACT FROM AUTHOR]

Multiple myeloma is a haematological malignancy typically characterised by neoplastic plasma cell infiltration of the bone marrow. Treatment for multiple myeloma consists of multi-line chemotherapy with or without autologous stem cell transplantation and has been rapidly evolving in recent years. However, clinical trials are unable to provide patients and clinicians with long-term prognostic information nor policymakers with the full body of evidence needed to perform economic evaluation of new therapies or make reimbursement decisions. To address these limitations of the available evidence, this study aimed to develop and validate the EpiMAP Myeloma model, a discrete-event simulation model of multiple myeloma disease outcomes and treatment pathways. Risk equations were estimated using the Australian and New Zealand Myeloma & Related Diseases Registry after multiple imputation of missing data. Risk equation coefficients were combined with multiple myeloma patients at diagnosis from the Registry to perform the simulation. The model was validated with 100 bootstraps of an out-of-sample prediction analysis using a 70/30 split of the 4,121 registry patients diagnosed between 2009 and 2023, resulting in 2,884 and 1,237 patients in the training and validation cohorts, respectively. For 90% of the 120 months in the 10-year post-diagnosis period, there was no significant difference in overall survival between the validation and simulated cohorts. These results highlight that the EpiMAP Myeloma model is robust at predicting multiple myeloma disease outcomes and treatment pathways in Australia & New Zealand. In the future, clinicians will be able to use the EpiMAP Myeloma model to provide personalised estimates of life expectancy to patients based on their specific characteristics, disease stage, and response to treatment. Policymakers will also be able to use the model to perform economic evaluation, to forecast the number of patients receiving treatment at different stages, and to determine the downstream impact of listing new, effective therapies. [ABSTRACT FROM AUTHOR]

Background: To identify childhood cancer survivors (CCSs) at risk of premature ovarian insufficiency (POI) and impaired fertility is important given its impact on quality of life. The aim of this study was to assess ovarian markers and fertility outcomes in adult female CCSs. We used the Swedish and the PanCareLIFE classifications for infertility risk grouping. Methods: 167 CCSs, at median age 34.6 years (19.3–57.8) with a median follow-up time of 25.4 years (11.6–41.3), and 164 healthy matched controls were included in this cross-sectional study. We assessed anti-Müllerian hormone (AMH) levels, antral follicle count (AFC), ovarian volume (OV), and fertility outcomes. Based on gonadotoxic treatments given, CCSs were categorized into infertility risk groups. Results: The median levels of AMH, AFC and OV were lower in CCSs (1.9 vs. 2.1 ng/ml, 12.0 vs. 13.0, 6.8 vs. 8.0 cm3) compared with controls, although statistically significant only for OV (p = 0.021). AMH levels in CCSs <40 years were lower for those classified as high-risk (p = 0.034) and very high-risk (p<0.001) for infertility, based on the Swedish risk classification. Similarly, AFC was reduced in the high-risk (p<0.001) and the very high-risk groups (p = 0.003). CCSs of all ages showed a trend towards impaired fertility, especially in the very high-risk group. POI was diagnosed in 22/167 CCSs, of whom 14 were in the high- and very high-risk groups. The results according to the PanCareLIFE classification were similar. Conclusion: Both the Swedish and the PanCareLIFE infertility risk classifications are reliable tools for identifying those at risk of reduced ovarian markers and fertility, as well as POI. We recommend fertility preservation counselling for patients receiving highly gonadotoxic treatments (i.e., Cyclophosphamide Equivalent Dose ≥6 g/m2, radiotherapy exposure to ovaries or stem cell transplantation) with follow-up at a young reproductive age due to the risk of a shortened reproductive window. [ABSTRACT FROM AUTHOR]

Xenogenesis has been recognized as a prospective method for producing channel catfish, Ictalurus punctatus ♀ × blue catfish, I. furcatus ♂ hybrids. The xenogenesis procedure can be achieved by transplanting undifferentiated stem cells derived from a donor fish into a sterile recipient. Xenogenesis for hybrid catfish embryo production has been accomplished using triploid channel catfish as a surrogate. However, having a surrogate species with a shorter maturation period, like white catfish (Ameiurus catus), would result in reduced feed costs, labor costs, and smaller body size requirements, making it a more suitable species for commercial applications where space is limited, and as a model species. Hence, the present study was conducted to assess the effectiveness of triploid white catfish as a surrogate species to transplant blue catfish stem cells (BSCs) and channel catfish stem cells (CSCs). Triploid white catfish fry were injected with either BSCs or CSCs labeled with PKH 26 fluorescence dye from 0 to 12 days post hatch (DPH). No significant differences in weight and length of fry were detected among BSCs and CSCs injection times (0 to 12 DPH) when fry were sampled at 45 and 90 DPH (P > 0.05). The highest survival was reported when fry were injected between 4.0 to 5.5 DPH (≥ 81.2%). At 45 and 90 DPH, cell and cluster area increased for recipients injected from 0 to 5.2 DPH, and the highest cluster area values were reported between 4.0 to 5.2 DPH. Thereafter, fluorescent cell and cluster area in the host declined with no further decrease after 10 DPH. At 45 DPH, the highest percentage of xenogens were detected when fry were injected with BSCs between 4.0 to 5.0 and CSCs between 3.0 to 5.0 DPH. At 90 DPH, the highest number of xenogens were detected from 4.0 to 6.0 DPH when injected with either BSCs or CSCs. The current study demonstrated the suitability of white catfish as a surrogate species when BSCs and CSCs were transplanted into triploid white catfish between 4.0 to 6.0 DPH (27.4 ± 0.4°C). Overall, these findings allow enhanced efficiency of commercializing xenogenic catfish carrying gametes of either blue catfish or channel catfish. [ABSTRACT FROM AUTHOR]

Hematopoietic stem cell transplantation is a common life-saving treatment for hematologic malignancies, though can lead to long-term functional impairment, fatigue, muscle atrophy, with decreased quality of life. Although traditional exercise has helped reduce these effects, it is inconsistently recommended and infrequently maintained, and most patients remain sedentary during and after treatment. There is need for alternative rehabilitation strategies, like neuromuscular electrical stimulation, that may be more amenable to the capabilities of hematopoietic stem cell transplant recipients. Patients receiving autologous HCT are being enroled in a randomized controlled trial with 1:1 (neuromuscular electrical stimulation:sham) design stratified by diagnosis and sex. Physical function, body composition, quality of life, and fatigue are assessed prior to hematopoietic stem cell transplant (prior to initiating preparatory treatment) and 24±5 days post hematopoietic stem cell transplant (Follow-up 1); physical function and quality of life are also assessed 6-months post hematopoietic stem cell transplant (Follow-up 2). The primary outcome is between-group difference in the 6-minute walk test change scores (Follow-up 1—Pre-transplant; final enrolment goal N = 23/group). We hypothesize that 1) neuromuscular electrical stimulation will attenuate hematopoietic stem cell transplant-induced adverse effects on physical function, muscle mass, quality of life, and fatigue compared to sham at Follow-up 1, and 2) Pre-transplant physical function will significantly predict fatigue and quality of life at Follow-up 2. We will also describe feasibility and acceptability of neuromuscular electrical stimulation during hematopoietic stem cell transplant. This proposal will improve rehabilitative patient care and quality of life by determining efficacy and feasibility of a currently underutilized therapeutic strategy aimed at maintaining daily function and reducing the impact of a potent and widely used cancer treatment. This trial is registered with clinicaltrials.gov (NCT04364256). [ABSTRACT FROM AUTHOR]

Bacterial bloodstream infections (BSI) are a common threat among patients with haematological malignancies (HM) and hematopoietic stem cell transplant recipients (HSCT). The purpose of this research was to describe clinical and microbiological aspects of BSI caused by carbapenem-resistant Klebsiella pneumoniae (CRKp) and assess risk factors associated with 30-day mortality in a 10-year cohort of haematological patients. A total of 65 CRKp-BSI episodes occurring in HM patients and HSCT recipients and CRKp-BSI between January 2010 and December 2019 were retrospectively studied. Acute leukemias were the most frequently observed underlying disease (87.7%) and 18 patients (27.7%) received HSCT. Mucosal barrier injury in the gastrointestinal tract was the primary cause of bacteremia (86.1%). Also, 14 individuals (21.6%) had an Invasive Fungal Disease (IFD) throughout the episode. Regarding treatment, in 31 patients (47.7%) empirical therapy was deemed appropriate, whereas 33 (50.8%) patients received a combination therapy. Microbiological data revealed that the majority of isolates (53–58%) had the Polymyxin B co-resistance phenotype, while amikacin resistance was less common (16 samples, or 24.7%). The mortality rates at 14 and 30 days were 32.3% and 36.9%, respectively. In a multivariate Cox regression analysis, prompt appropriate antibiotic administration within three days was associated with a better outcome (Adjusted Hazard Ratio [aHR]: 0.33; 95% Confidence Interval [CI]: 0.14–0.76; p = 0.01), whereas hypotension at presentation (aHR: 3.88; 95% CI: 1.40–10.74; p = 0.01) and concurrent IFD (aHR: 2.97; 95% CI: 1.20–7.37; p = 0.02) were independently associated with death within 30 days. Additionally, a favorable correlation between combination therapy and overall survival was found (aHR: 0.18; 95%CI: 0.06–0.56; p = 0.002). In conclusion, 30-day mortality CRKp-BSI was elevated and most of the isolates were polymyxin B resistant. Early appropriate antimicrobial treatment and the use of combination therapy were linked to a better outcome. [ABSTRACT FROM AUTHOR]

Introduction: Pre-emptive therapy for cytomegalovirus (CMV) reactivation has been used in allogeneic hematopoietic stem cell transplantation (allo-HSCT). It is unclear if this strategy has poorer clinical outcomes in CMV-endemic areas and if more aggressive prophylaxis is required. Methods: We retrospectively analyzed the patterns and survival after CMV reactivation in patients undergoing pre-emptive therapy following allo-HSCT and assessed high-risk patients who could benefit from aggressive CMV prophylaxis in endemic areas. Results: Of the 292 patients who underwent allo-HSCT, 70.5% (donor+ or recipient+) were CMV seropositive. CMV reactivation occurred in 139 patients (47.6%), with a median of 31.5 days from day 0 of allo-HSCT. The overall survival of patients with CMV reactivation who received pre-emptive therapy did not differ from those without reactivation. Of the 139 patients with CMV reactivation, 78 (56.1%) underwent ≥2 rounds of pre-emptive therapy. In multivariate analysis, the risk of CMV reactivation was higher in patients with multiple myeloma, with CMV seropositivity of the recipient and donor, administered with a higher dose of anti-thymocyte globulin (ATG), and with acute graft-versus-host disease (aGVHD) ≥ grade 2. Conclusion: Although half of the patients with allo-HSCT were administered with pre-emptive therapy for CMV, CMV reactivation did not affect their survival, indicating the advantages of pre-emptive therapy, even in CMV-endemic areas. The cost-effectiveness of more aggressive CMV prophylaxis should be re-evaluated in patients at a high risk for CMV reactivation. [ABSTRACT FROM AUTHOR]

Medication non-adherence rates in children range between 50% and 80% in the United States. Due to multifaceted outpatient routines, children receiving hematopoietic stem cell transplant (HCT) are at especially high risk of non-adherence, which can be life-threatening. Although digital health interventions have been effective in improving non-adherence in many pediatric conditions, limited research has examined their benefits among families of children receiving HCT. To address this gap, we created the BMT4me© mobile health app, an innovative intervention serving as a "virtual assistant" to send medication-taking reminders for caregivers and to track, in real-time, the child's medication taking, barriers to missed doses, symptoms or side effects, and other notes regarding their child's treatment. In this randomized controlled trial, caregivers will be randomized to either the control (standard of care) group or the intervention (BMT4me© app) group at initial discharge post-HCT. Both groups will receive an electronic adherence monitoring device (i.e., medication event monitoring system "MEMS" cap, Medy Remote Patient Management "MedyRPM" medication adherence box) to store their child's immunosuppressant medication. Caregivers who agree to participate will be asked to complete enrollment, weekly, and monthly parent-proxy measures of their child's medication adherence until the child reaches Day 100 or complete taper from immunosuppression. Caregivers will also participate in a 15 to 30-minute exit interview at the conclusion of the study. Descriptive statistics and correlations will be used to assess phone activity and use behavior over time. Independent samples t-tests will examine the efficacy of the intervention to improve adherence monitoring and reduce readmission rates. The primary expected outcome of this study is that the BMT4me© app will improve the real-time monitoring and medication adherence in children receiving hematopoietic stem cell transplant following discharge, thus improving clinical outcomes. [ABSTRACT FROM AUTHOR]

Background: Autologous stem cell transplant is a common procedure for people with haematological malignancies. While effective at improving survival, autologous stem cell transplant recipients may have a lengthy hospital admission and experience debilitating side-effects such as fatigue, pain and deconditioning that may prolong recovery. Prehabilitation comprising exercise and nutrition intervention before stem cell transplant aims to optimise physical capacity before the procedure to enhance functional recovery after transplant. However, few studies have evaluated prehabilitation in this setting. We aim to explore preliminary efficacy of improving physical capacity of prehabilitation for people undergoing autologous stem cell transplant. Methods: The PIRATE study is a single-blinded, parallel two-armed pilot randomised trial of multidisciplinary prehabilitation delivered prior to autologous stem cell transplantation. Twenty-two patients with haematological malignancy waitlisted for transplant will be recruited from a tertiary haematology unit. The intervention will include up to 8 weeks of twice-weekly, supervised tailored exercise and fortnightly nutrition education delivered via phone, in the lead up to autologous stem cell transplant. Blinded assessments will be completed at week 13, approximately 4 weeks after transplant and health service measures collected at week 25 approximately 12 weeks after transplant. The primary outcome is to assess changes in physical capacity using the 6-minute walk test. Secondary measures are time to engraftment, C-reactive protein, physical activity (accelerometer), grip strength, health-related quality of life (EORTC QLQ-C30 and HDC29 supplement), self-efficacy and recording of adverse events. Health service data including hospital length of stay, hospital readmissions, emergency department presentations and urgent symptom clinic presentation at will also be recorded. Discussion: This trial will inform design of a future definitive randomised controlled trial and implementation of prehabilitation for people receiving autologous stem cell transplant by providing data on efficacy and safety. Trial registration: The PIRATE Trial has been approved by the Eastern Health Human Research Ethics Committee (E20/003/61055) and is funded by the Eastern Health Foundation. This trial is registered with the Australian New Zealand Clinical Trials Registry ACTRN12620000496910. Registered April 20, 2020. [ABSTRACT FROM AUTHOR]

Multiple myeloma therapy has made remarkable progress with the advent of new drugs. We explored the treatment pattern and outcomes in Japanese patients with multiple myeloma using the Medical Data Vision database. Patients were categorized as per the initial diagnosis period (2003–2015 and 2016–2020), considering the adoption of these new agents and then based on stem cell transplantation. Overall, 6438 patient data were extracted as eligible for data analysis, and the median age at the index diagnosis date was 72.0 years. Bortezomib/dexamethasone was the most common regimen for induction therapy in patients requiring stem cell transplantation from 2003–2015, and the use of bortezomib/lenalidomide/dexamethasone increased from 2016–2020. Lenalidomide/dexamethasone was the most commonly used post-transplant therapy. In the non-stem cell transplantation group, bortezomib/dexamethasone was mainly used for both periods, while lenalidomide/dexamethasone was primarily used from 2016–2020. There was a trend toward shorter first-line treatment duration and a shift to additional treatment patterns with new drugs at the following lines. The time to inpatient death period suggested an improvement between the two periods. Thus, this study revealed that recent diversification of treatment options is preferred and contributes to improved outcomes in the clinical practice of multiple myeloma in Japan. [ABSTRACT FROM AUTHOR]

Introduction: High-dose chemotherapy followed by autologous stem cell transplant is the mainstay of treatment for multiple myeloma (MM). The purpose of this study was to evaluate the ability of MRI-derived indices to predict mobilized hematopoietic stem cell yield. Materials and methods: In this exploratory pilot work, we retrospectively analyzed 38 mobilization procedures for MM. Successful mobilization procedure was defined as a total yield of >4.0×106 CD34+ cells/kg. Univariate and multivariate analyses were performed to identify factors with a significant effect on successful mobilization from among clinical characteristics including number of prior lines of therapy, period from diagnosis to harvest, type of monoclonal protein (M protein); and radiological characteristics including total diffusion volume (tDV), median apparent diffusion coefficient (ADC) of tDV, and mean fat fraction of bone marrow calculated by MRI. Results: Univariate analyses showed that relatively poor mobilization was significantly associated with M protein of Bence-Jones type and with median ADC of tDV (P = 0.02 and P = 0.004, respectively). Multivariate analyses using these two indices showed that median ADC of tDV was a significant predictive factor for adequate mobilization (P = 0.01), with an area under the curve of 0.784 (cutoff value, 1.18×10−3 mm2/s; sensitivity, 72.7%; specificity, 87.5%). Conclusion: The present data indicate that median ADC of tDV is a predictive factor for relatively poor mobilization of hematopoietic stem cells in MM patients undergoing autologous stem cell transplant. [ABSTRACT FROM AUTHOR]

Non-infectious pulmonary complications including idiopathic pneumonia syndrome (IPS) and bronchiolitis obliterans syndrome (BOS), which are clinical and diagnostic manifestations of lung chronic graft-versus-host disease (GVHD), cause significant mortality after allogeneic stem cell transplantation (SCT). Increasing evidence suggests that alloantigen reactions in lung tissue play a central role in the pathogenesis of IPS and BOS; however, the mechanism is not fully understood. Several clinical and experimental studies have reported that intra-bone marrow (IBM)-SCT provides high rates of engraftment and is associated with a low incidence of acute GVHD. In the present study, allogeneic SCT was conducted in mouse models of IPS and BOS, to compare intravenous (IV)-SCT with IBM-SCT. Allogeneic IBM-SCT improved the clinical and pathological outcomes of pulmonary complications compared to those of IV-SCT. The mechanisms underlying the reductions in pulmonary complications in IBM-SCT mice were explored. The infiltrating lung cells were mainly CD11b+ myeloid and CD3+ T cells, in the same proportions as in transplanted donor cells. In an in vivo bioluminescence imaging, a higher proportion of injected donor cells was detected in the lung during the early phase (1 h after IV-SCT) than after IBM-SCT (16.7 ± 1.1 vs. 3.1 ± 0.7 × 105 photons/s/animal, IV-SCT vs. IBM-SCT, P = 1.90 × 10−10). In the late phase (5 days) after SCT, there were also significantly more donor cells in the lung after IV-SCT than after IBM-SCT or allogeneic-SCT (508.5 ± 66.1 vs. 160.1 ± 61.9 × 106 photons/s/animal, IV-SCT vs. IBM-SCT, P = 0.001), suggesting that the allogeneic reaction induces sustained donor cell infiltration in the lung during the late phase. These results demonstrated that IBM-SCT is capable of reducing injected donor cells in the lung; IBM-SCT decreases donor cell infiltration. IBM-SCT therefore represents a promising transplantation strategy for reducing pulmonary complications, by suppressing the first step in the pathophysiology of chronic GVHD. [ABSTRACT FROM AUTHOR]

Background: Stem cell transplantation therapy is a potential approach for the repair of spinal cord injuries and other neurodegenerative diseases, but its effectiveness is hampered by the low rate of targeted migration of cells to the area of injury. The aim of this study was to investigate the effects of miR-31 on the migration of bone marrow mesenchymal stem cells (BMSCs) and the regulation of MMP-2 and CXCR4 expression in vitro and in vivo. Methods: eGFP-expressing BMSCs were isolated and cultured for subsequent experiments. The experiments were divided into three groups: control group, miR-31agomir group, and miR-31antagomir group. Proliferation was analyzed using CCK-8 and flow cytometry; cell migration in vitro was analyzed using wound-healing and transwell assays. The mouse SCI model was prepared by the impact method, and cells were transplanted (3 groups, 12 per group). Relevant inflammatory factors were detected by ELISA. The BMS score was used to evaluate the functional recovery of the mouse spinal cord and the frozen section was used to analyze the cell migration ability in vivo. The in vitro and in vivo expression levels of MMP-2 and CXCR4 were evaluated by Western blot and immunohistochemical staining. Results: In vitro experiments showed that cells in the miR-31agomir group exhibited enhanced cell proliferation (P<0.05, P<0.001) and migration (P<0.001) and upregulated protein expression levels of CXCR4 (P<0.01) and MMP-2 (P<0.001) compared with cells in the control group. The results of in vivo experiments showed that the expression of pro-inflammatory factors was reduced after cell transplantation treatment. Cells in the miR-31agomir group showed enhanced cell-targeted migration ability (P<0.001), improved the function of damaged tissues (P<0.001), and upregulated CXCR4 and MMP-2 expression compared to the control group (P<0.001). Conclusion: Our experiment demonstrated that miR-31 could promote the migration of BMSCs and miR-31 could repair and improve the function of damaged tissues in SCI. [ABSTRACT FROM AUTHOR]

Transcranial electrically stimulated motor-evoked potentials (tcMEPs) are widely used to evaluate motor function in humans and animals. However, the relationship between tcMEPs and the recovery of paralysis remains unclear. We previously reported that transplantation of mesenchymal stem cells to a spinal cord injury (SCI) rat model resulted in various degrees of recovery from paraplegia. As a continuation of this work, in the present study, we aimed to establish the longitudinal electrophysiological changes in this SCI rat model after mesenchymal stem cell transplantation. SCI rats were established using the weight-drop method. The model rats were transvenously transplanted with two types of mesenchymal stem cells (MSCs), one derived from rat cranial bones and the other from the bone marrow of the femur and tibia bone, 24 h after SCI. A phosphate-buffered saline (PBS) group that received only PBS was also created for comparison. The degree of paralysis was evaluated over 28 days using the Basso–Beattie–Bresnahan (BBB) scale and inclined plane task score. Extended tcMEPs were recorded using a previously reported bone-thinning technique, and the longitudinal electrophysiological changes in tcMEPs were investigated. In addition, the relationship between the time course of recovery from paralysis and reappearance of tcMEPs was revealed. The appearance of the tcMEP waveform was earlier in MSC-transplanted rats than in PBS-administered rats (earliest date was 7 days after SCI). The MEP waveforms also appeared at approximately the same level on the BBB scale (average score, 11 points). Ultimately, this study can help enhance our understanding of the relationship between neural regeneration and tcMEP recording. Further application of tcMEP in regenerative medicine research is expected. [ABSTRACT FROM AUTHOR]

Introduction: This study aimed to validate hematopoietic stem cell transplantation (HSCT) treatment via a tailored nutritional pathway in myeloablative conditioning (MAC), determine its efficacy in terms of remission, and explore associations between clinical outcomes and nutritional indicators. Methods: We included patients who underwent MAC for HSCT at the Shizuoka Cancer Center Stem Cell Transplantation between 2015 and 2019. We evaluated outcomes from the day before treatment initiation (transplant date: day 0) to day 42. Results: Among the 40 MAC cases (participant characteristics: 20/40 males, mean age of 52 years, and mean body mass index of 21.9 kg/m2), we found that the percent loss of body weight and loss of skeletal muscle mass were correlated with the basal energy expenditure rate (BEE rate; r = 0.70, p<0.001 and r = 0.49, p<0.01, respectively). Based on the receiver operating characteristics curves, the cutoff value for the BEE rate in terms of weight loss was 1.1. Salivary amylase levels did not significantly change during the treatment course. Continuous variables, including oral caloric intake and performance status, showed statistically significant correlations with nutrition-related adverse events during treatment (r = −0.93, p<0.01 and r = 0.91, p<0.01, respectively). Skeletal muscle mass before treatment initiation was an independent predictive variable for reduced 2-year survival (p = 0.04). Conclusion: Our results support the validity of a safe nutritional pathway with a BEE rate of 1.1 for HSCT patients pretreated with MAC. Specifically, we found that this pathway could prevent weight loss in response to nutrition-related adverse events. Skeletal muscle mass before treatment was identified as an independent risk factor for reduced 2-year survival. [ABSTRACT FROM AUTHOR]

To assess morbidity and mortality of parainfluenza virus (PIV) infections in immunocompromised patients, we analysed PIV infections in a hematology and stem cell transplantation (SCT) unit over the course of three years. Isolated PIV strains were characterized by sequence analysis and nosocomial transmission was assessed including phylogenetic analysis of viral strains. 109 cases of PIV infection were identified, 75 in the setting of SCT. PIV type 3 (n = 68) was the most frequent subtype. PIV lower respiratory tract infection (LRTI) was observed in 47 patients (43%) with a mortality of 19%. Severe leukopenia, prior steroid therapy and presence of co-infections were significant risk factors for development of PIV-LRTI in multivariate analysis. Prolonged viral shedding was frequently observed with a median duration of 14 days and up to 79 days, especially in patients after allogeneic SCT and with LRTI. Nosocomial transmission occurred in 47 patients. Phylogenetic analysis of isolated PIV strains and combination with clinical data enabled the identification of seven separate clusters of nosocomial transmission. In conclusion, we observed significant morbidity and mortality of PIV infection in hematology and transplant patients. The clinical impact of co-infections, the possibility of long-term viral shedding and frequent nosocomial transmission should be taken into account when designing infection control strategies. [ABSTRACT FROM AUTHOR]

Objectives: To assess the usability of German hospital administrative claims data (GHACD) to determine inpatient management patterns, healthcare resource utilization, and quality-of-care in patients with multiple myeloma (PwMM). Methods: Based on German tertiary hospital's claims data (2015–2017), PwMM aged >18 years were included if they had an International Classification of Diseases, Tenth Revision, code of C90.0 or received anti-MM therapy. Subgroup analysis was performed on stem cell transplantation (SCT) patients. Results: Of 230 PwMM, 59.1% were men; 56.1% were aged ≥65 years. Hypertension and infections were present in 50% and 67.0%, respectively. Seventy percent of PwMM received combination therapy. Innovative drugs such as bortezomib and lenalidomide were given to 36.1% and 10.9% of the patients, respectively. Mean number of admissions and mean hospitalization length/patient were 3.69 (standard deviation (SD) 2.71 (1–16)) and 12.52 (SD 9.55 (1–68.5)) days, respectively. In-hospital mortality was recorded in 12.2%. Seventy-two percent of SCT patients (n = 88) were aged ≤65 years, 22.7% required second transplantation, and 89.8% received platelet transfusion at a mean of 1.42(SD 0.63 (1–3)). Conclusion: GHACD provided relevant information essential for healthcare studies about PwMM from routine care settings. Data fundamental for quality-of-care assessment were also captured. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) is one of the deadly cancers. Chemotherapy is the first-line treatment and the only curative intervention is stem cell transplantation which are intolerable for aged and comorbid patients. Therefore, finding complementary treatment is still an active research area. For this, empirical knowledge driven search for therapeutic agents have been carried out by long and arduous wet lab processes. Nonetheless, currently there is an accumulated bioinformatics data about natural products that enabled the use of efficient and cost effective in silico methods to find drug candidates. In this work, therefore, we set out to computationally investigate the phytochemicals from Brucea antidysentrica to identify therapeutic phytochemicals for AML. We performed in silico molecular docking of compounds against AML receptors IDH2, MCL1, FLT3 and BCL2. Phytochemicals were docked to AML receptors at the same site where small molecule drugs were bound and their binding affinities were examined. In addition, random compounds from PubChem were docked with AML targets and their docking score was compared with that of phytochemicals using statistical analysis. Then, non-covalent interactions between phytochemicals and receptors were identified and visualized using discovery studio and Protein-Ligand Interaction Profiler web tool (PLIP). From the statistical analysis, most of the phytochemicals exhibited significantly lower (p-value ≤ 0.05) binding energies compared with random compounds. Using cutoff binding energy of less than or equal to one standard deviation from the mean of the phytochemicals' binding energies for each receptor, 12 phytochemicals showed considerable binding affinity. Especially, hydnocarpin (-8.9 kcal/mol) and yadanzioside P (-9.4 kcal/mol) exhibited lower binding energy than approved drugs AMG176 (-8.6 kcal/mol) and gilteritinib (-9.1 kcal/mol) to receptors MCL1 and FLT3 respectively, indicating their potential to be lead molecules. In addition, most of the phytochemicals possessed acceptable drug-likeness and absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties. Based on the binding affinities as exhibited by the molecular docking studies supported by the statistical analysis, 12 phytochemicals from Brucea antidysentrica (1,11-dimethoxycanthin-6-one, 1-methoxycanthin-6-one, 2-methoxycanthin-6-one, beta-carboline-1-propionic acid, bruceanol A, bruceanol D, bruceanol F, bruceantarin, bruceantin, canthin-6-one, hydnocarpin, and yadanzioside P) can be considered as candidate compounds to prevent and manage AML. However, the phytochemicals should be further studied using in vivo & in vitro experiments on AML models. Therefore, this study concludes that combination of empirical knowledge, in silico molecular docking and ADMET profiling is useful to find natural product-based drug candidates. This technique can be applied to other natural products with known empirical efficacy. [ABSTRACT FROM AUTHOR]

Objectives: Caregivers of allogeneic hematopoietic stem cell transplant (HCT) cancer patients experience high caregiver burden and carry a significant amount of responsibility. Mindfulness has the potential to lessen caregiver burden by aiding in stress management. To date, no studies have examined the efficacy of mindfulness in reducing caregiver burden in this population. Based on our pilot study demonstrating initial feasibility and acceptability of FOCUS (Focusing On mindfulness for Caregivers Under Stress), this 3-arm randomized controlled trial aims to examine the efficacy of a 6-week mindfulness-based stress management program for allogeneic HCT caregivers. Hypotheses include that the FOCUS condition will have lower post-treatment caregiver burden and that patients of these caregivers will have better patient health outcomes compared to other treatment conditions. Method: Eligible caregivers will be randomly assigned to one of three treatment conditions: FOCUS, Healthy Living (HL; active control), and Enhanced Care (EC; usual care). Caregivers in FOCUS and HL will participate in 6-week weekly individual treatment sessions and will be sent brief daily momentary interventions/messages. Caregivers in all conditions will complete daily diaries over the course of treatment. Patients of enrolled caregivers will be enrolled for assessments only. Participants will complete assessments at baseline, end of treatment, 2- and 6-months post-treatment. Biomarker data will be collected via hair cortisol concentrations from caregivers at baseline and 6 months post-treatment. Results: Recruitment is ongoing. Conclusions: The data collected from this study will provide evidence on the efficacy of mindfulness in alleviating HCT caregiver stress and impacting patient health outcomes. Trial registration: The current study is registered in clinicaltrials.gov (NCT05078229); see https://clinicaltrials.gov/ct2/show/NCT05078229?term=christine+vinci&draw=2&rank=1. [ABSTRACT FROM AUTHOR]

Previously, we showed silicone nerve conduits containing a vascular bundle and decellularized allogenic basal laminae (DABLs) seeded with bone marrow-derived mesenchymal stem cells (BMSCs) demonstrated successful nerve regeneration. Nerve conduits should be flexible and biodegradable for clinical use. In the current study, we used nerve conduits made of polyglycoric acid (PGA) fiber mesh, which is flexible, biodegradable and capillary-permeable. DABLs were created using chemical surfactants to remove almost all cell debris. In part 1, capillary infiltration capability of the PGA tube was examined. Capillary infiltration into regenerated neural tissue was compared between the PGA tube with blood vessels attached extratubularly (extratubularly vascularized tube) and that containing blood vessels intratubularly (intratubularly vascularized tube). No significant difference was found in capillary formation or nerve regeneration between these two tubes. In part 2, a 20 mm gap created in a rat sciatic nerve model was bridged using the extratubularly vascularized PGA tube containing the DABLs with implantation of isogenic cultured BMSCs (TubeC+ group), that containing the DABLs without implantation of the BMSCs (TubeC- group), and 20 mm-long fresh autologous nerve graft (Auto group). Nerve regeneration in these three groups was assessed electrophysiologically and histomorphometrically. At 24 weeks, there was no significant difference in any electrophysiological parameters between TubeC+ and Auto groups, although all histological parameters in Auto group were significantly greater than those in TubeC+ and TubeC- groups, and TubeC+ group demonstrated significant better nerve regeneration than TubeC- group. The transplanted DABLs showed no signs of immunological rejection and some transplanted BMSCs were differentiated into cells with Schwann cell-like phenotype, which might have promoted nerve regeneration within the conduit. This study indicated that the TubeC+ nerve conduit may become an alternative to nerve autograft. [ABSTRACT FROM AUTHOR]

Background: Hematopoietic stem cell transplantation (HSCT) is the current mainstay treatment for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). However, tyrosine kinase inhibitors (TKI) also play a significant role in the treatment of these patients. We conducted this systematic review and meta-analysis to compare the efficacy of allogeneic (allo-) HSCT, autologous (auto-) HSCT, and chemotherapy (CMT) alone–all in combination with TKIs in adult Ph+ ALL patients. Materials and methods: This systematic review identified studies from the EMBASE and MEDLINE databases from inception to April 2021 using search terms related to "ALL" and "HSCT." Eligible studies could be randomized controlled trials or cohort studies that included adult Ph+ ALL patients who received a TKI and either allo-HSCT, auto-HSCT, or CMT alone, and that reported the number of patients in each group for each of our primary outcomes of interest: overall survival (OS) or disease-free survival (DFS). Point estimates and associated 95% confidence intervals (CI) from each study were combined using the Hantel-Maenszel method. Results: After two rounds of review, 26 cohort studies were determined to be eligible for the meta-analysis. Adult Ph+ ALL patients who received HSCT had better survival outcomes than those who did not receive any HSCT (pooled odds ratio [OR] for OS of 1.61, 95%CI: 1.08–2.40; I2 = 59%, and for DFS of 3.23, 95%CI: 2.00–5.23; I2 = 62% for allo-HSCT; and, pooled OR for OS of 7.04, 95%CI: 1.97–25.15; I2 = 0%, and for DFS of 5.78, 95%CI: 1.04–32.19; I2 = 42% for auto-HSCT). Allo-HSCT recipients had comparable OS and DFS, but lower relapse rate compared to auto-HSCT recipients. Funnel plot generally demonstrated no presence of publication bias. Conclusions: This systematic review and meta-analysis demonstrated superior results of HSCT in Ph+ ALL patients compared to CMT alone. Moreover, auto-HSCT could be implemented with comparable survival outcomes to allo-HSCT in patients with no available donor or when haploidentical HSCT is not feasible. [ABSTRACT FROM AUTHOR]

Background: Allogeneic hematopoietic stem cell transplantation (HCT) is an often curative intent treatment, however it is associated with significant gastrointestinal (GI) toxicity and treatment related mortality. Graft-versus-host disease is a significant contributor to transplant-related mortality. We performed a phase 2 trial of the somatostatin analog pasireotide to prevent gastrointestinal toxicity and GVHD after myeloablative allogeneic HCT. Methods: Patients received 0.9mg pasireotide every 12 hours from the day prior to conditioning through day +4 after HCT (or a maximum of 14 days). The primary outcomes were grade 3–4 gastrointestinal toxicity through day 30 and acute GVHD. Secondary outcomes were chronic GVHD, overall survival and relapse free survival at one year. Stool and blood samples were collected from before and after HCT for analyses of stool microbiome, local inflammatory markers, and systemic inflammatory and metabolic markers. Results were compared with matched controls. Results: Twenty-six patients received pasireotide and were compared to 52 matched contemporaneous controls using a 1–2 match. Grade 3–4 GI toxicity occurred in 21 (81%) patients who received pasireotide and 35 (67%) controls (p = 0.33). Acute GVHD occurred in 15 (58%) patients in the pasireotide group and 28 (54%) controls (p = 0.94). Chronic GVHD occurred in 16 patients in the pasireotide group (64%) versus 22 patients in the control group (42%) (p = 0.12). Overall survival at 1 year in the pasireotide group was 63% (95% CI: 47%,86%) versus 82% (95% CI: 72%, 93%) in controls (log-rank p = 0.006). Relapse-free survival rate at one year was 40% (95% CI: 25%, 65%) in the pasireotide group versus 78% (95% CI: 68%, 91%) in controls (log-rank p = 0.002). After controlling for the effect of relevant covariates, patients in the pasireotide group had attenuated post-HCT loss of microbial diversity. Analysis of systemic inflammatory markers and metabolomics demonstrated feasibility of such analyses in patients undergoing allogeneic HCT. Baseline level and pre-to-post transplant changes in several inflammatory markers (including MIP1a, MIP1b, TNFa, IL8Pro, and IL6) correlated with likelihood of survival. Conclusions: Pasireotide did not prevent gastrointestinal toxicity or acute GVHD compared to contemporaneous controls. Pasireotide was associated with numerically higher chronic GVHD and significantly decreased OS and RFS compared to contemporaneous controls. Pasireotide may provide a locally protective effect in the stool microbiome and in local inflammation as measured by stool calprotectin, stool beta-defensin, and stool diversity index. [ABSTRACT FROM AUTHOR]

Asherman's Syndrome is characterized by intrauterine adhesions or fibrosis resulting as a consequence of damage to the basal layer of endometrium and is associated with infertility due to loss of normal endometrium. We have previously shown that bone marrow derived stem cells (BMDSCs) engraft the endometrium in mice and humans and Ischemia/reperfusion injury of uterus promoted BMDSCs migration to the endometrium; however, the role of BMDSCs in Asherman's syndrome has not been characterized. Here a murine model of Asherman's syndrome was created by traumatizing the uterus. We evaluate stem cell recruitment and pregnancy after BMDSCs transplantation in a model of Asherman's syndrome. In the Asheman's syndrome model, after BMDSC transplant, the Y chromosome bearing CD45-cells represented less than 0.1% of total endometrial cells. Twice the number of Y+CD45- cells was identified in the damaged uterus compared to the uninjured controls. There was no significant difference between the damaged and undamaged uterine horns in mice that received injury to a single horn. In the BMDSC transplant group, 9 of the 10 mice conceived, while only 3 of 10 in the non-transplanted group conceived (Chi-Square p = 0.0225); all mice in an uninjured control group conceived. The time to conception and mean litter size were not different between groups. Taken together, BMDSCs are recruited to endometrium in response to injury. Fertility improves after BMDSC transplant in Asherman's Syndrome mice, demonstrating a functional role for these cells in uterine repair. BMDSC transplantation is a potential novel treatment for Asherman's Syndrome and may also be useful to prevent Asherman's syndrome after uterine injury.

Purpose: While early adjunctive corticosteroid therapy (EACST) has been proven effective in HIV patients with Pneumocystis Jirovecii Pneumonia (PJP), data remains controversial concerning non-HIV oncology or haematology patients. Methods: This retrospective study included cancer patients without HIV and with diagnosis of PJP admitted in a cancer referral centre, from January-1-2010 to March-31-2017. We compared 30-day and 1-year mortality rate, change in the respiratory item of the Sequential Organ Failure Assessment score(SOFA-resp worsening), use of tracheal intubation between day-1 and day-5 of anti-pneumocystis therapy and occurrence of coinfections between patients with EACST and those with no or late corticosteroid therapy, using an inverse probability weighting propensity score-based (IPW) analysis. Results: 133 non-HIV oncology or haematology PJP patients were included (EACST n = 58, others n = 75). The main underlying conditions were haematological malignancies (n = 107, 80,5%), solid tumour (n = 27, 20,3%) and allogeneic stem cell transplantation (n = 17, 12,8%). Overall 30-day and 1-year mortality rate was 24,1% and 56,4%, respectively. IPW analysis found no difference on 30-day (HR = 1.45, 95% CI [0.7–3.04], p = 0.321) and 1-year (HR = 1.25, CI 95% [0.75–2.09], p = 0.39) mortality rate between groups. Conclusion: No difference in SOFA-resp worsening, tracheal intubation and coinfections was found between groups. Combination of EACST with anti-pneumocystis therapy in non-HIV onco-haematology PJP-patients was not associated with clinical improvement. [ABSTRACT FROM AUTHOR]

Many human viruses, including Epstein-Barr virus (EBV), do not infect mice, which is challenging for biomedical research. We have previously reported that EBV infection induces erosive arthritis, which histologically resembles rheumatoid arthritis, in humanized NOD/Shi-scid/IL-2Rγnull (hu-NOG) mice; however, the underlying mechanisms are not known. Osteoclast-like multinucleated cells were observed during bone erosion in this mouse model, and therefore, we aimed to determine whether the human or mouse immune system activated bone erosion and analyzed the characteristics and origin of the multinucleated cells in hu-NOG mice. Sections of the mice knee joint tissues were immunostained with anti-human antibodies against certain osteoclast markers, including cathepsin K and matrix metalloproteinase-9 (MMP-9). Multinucleated cells observed during bone erosion stained positively for human cathepsin K and MMP-9. These results indicate that human osteoclasts primarily induce erosive arthritis during EBV infections. Human osteoclast development from hematopoietic stem cells transplanted in hu-NOG mice remains unclear. To confirm their differentiation potential into human osteoclasts, we cultured bone marrow cells of EBV-infected hu-NOG mice and analyzed their characteristics. Multinucleated cells cultured from the bone marrow cells stained positive for human cathepsin K and human MMP-9, indicating that bone marrow cells of hu-NOG mice could differentiate from human osteoclast progenitor cells into human osteoclasts. These results indicate that the human immune response to EBV infection may induce human osteoclast activation and cause erosive arthritis in this mouse model. Moreover, this study is the first, to our knowledge, to demonstrate human osteoclastogenesis in humanized mice. We consider that this model is useful for studying associations of EBV infections with rheumatoid arthritis and human bone metabolism. [ABSTRACT FROM AUTHOR]

Human embryonic and induced pluripotent stem cells (hESC/hiPSC) are promising cell sources for the derivation of large numbers of specific cell types for tissue engineering and cell therapy applications. We have describe a directed differentiation protocol that generates fibroblasts from both hESC and hiPSC (EDK/iPDK) that support the repair and regeneration of epithelial tissue in engineered, 3D skin equivalents. In the current study, we analyzed the secretory profiles of EDK and iPDK cells to investigate the production of factors that activate and promote angiogenesis. Analysis of in vitro secretion profiles from EDK and iPDK cells demonstrated the elevated secretion of pro-angiogenic soluble mediators, including VEGF, HGF, IL-8, PDGF-AA, and Ang-1, that stimulated endothelial cell sprouting in a 3D model of angiogenesis in vitro. Phenotypic analysis of EDK and iPDK cells during the course of differentiation from hESCs and iPSCs revealed that both cell types progressively acquired pericyte lineage markers NG2, PDGFRβ, CD105, and CD73 and demonstrated transient induction of pericyte progenitor markers CD31, CD34, and Flk1/VEGFR2. Furthermore, when co-cultured with endothelial cells in 3D fibrin-based constructs, EDK and iPDK cells promoted self-assembly of vascular networks and vascular basement membrane deposition. Finally, transplantation of EDK cells into mice with hindlimb ischemia significantly reduced tissue necrosis and improved blood perfusion, demonstrating the potential of these cells to stimulate angiogenic responses in vivo. These findings demonstrate that stable populations of pericyte-like angiogenic cells can be generated with high efficiency from hESC and hiPSC using a directed differentiation approach. This provides new cell sources and opportunities for vascular tissue engineering and for the development of novel strategies in regenerative medicine.

The dynamics of recovery of cytomegalovirus (CMV)-specific cell-mediated immunity (CMI) and its impact on controlling clinically significant CMV infections following hematopoietic stem cell transplant (HSCT) are rarely reported in pediatric HSCT recipients. In this study, dynamics of recovery of CMV-specific CMI and its clinical significance in controlling CMV viremia and clinically significant CMV infections were assessed in pediatric allogeneic HSCT recipients. All subjects underwent CMV pp65- and IE1-specific enzyme-linked immune absorbent spot (ELISPOT) assays just before transplantation and then monthly until the detection of CMV-specific CMI with ≥ 5 spot-forming cells (SFC) / 2.0 × 105 cells. Clinically significant CMV infections were defined as CMV diseases, prolonged CMV infections, recurrent CMV infections or late onset CMV infections. Among 52 recipients, 88.5% of recipients recovered CMV-specific CMI with ≥ 5 SFC/ 2.0 × 105 cells at a median of 34 days (interquartile range [IQR]: 29–95 days) following HSCT, 55.8% at 30 days following HSCT, and 73.1% at 90 days following HSCT. The presence of CMV-specific CMI before HSCT was the significant factors for the reconstitution of CMV specific CMI after HSCT (adjusted odds ratio [aOR] = 13.33; 95% confidence interval [CI] = 1.21–142.86). After HSCT, 30 recipients experienced CMV viremia, of which 20 were clinically significant CMV infections. The full recovery of CMV-specific CMI with ≥ 50 SFC / 2.0 × 105 cells after HSCT was the protective factor for the development of clinically significant CMV infections (aOR = 0.13; 95% CI = 0.22–0.71). In the haploidentical HSCT recipients, 82.1% recovered CMV-specific CMI at a median of 65 days after HSCT (IQR: 34–118 days) with a tendency to recover their CMV-specific CMI later than did those from non-haploidentical donors (65 days vs. 30 days; P = 0.001). Clinically significant CMV infections tended to occur more frequently in the haploidentical HSCT recipients compared to those with matched donor HSCT (46.4% vs. 29.2%; P = 0.205). The full recovery of CMV-specific CMI with ≥ 50 SFC/2.0 × 105 cells after HSCT also lowered the risk of development of clinically significant CMV infections (aOR = 0.08; 95% CI = 0.01–0.90). However, transplantation from haploidentical donors was a significant risk factor hampering recovery of CMV-specific CMI (aOR = 0.08; 95% CI = 0.01–0.86) and full recovery of CMV-specific CMI (aOR = 0.05; 95% CI = 0.01–0.50). Pre-transplant CMV-specific CMI influenced the recovery of CMV-specific CMI, and the full recovery of CMV-specific CMI could be a surrogate marker for preventing clinically significant CMV infections in pediatric HSCT recipients. Immunologic monitoring using ELISPOT assay before and after HSCT helps in identifying patients with a high risk of CMV infection and in controlling CMV infection. [ABSTRACT FROM AUTHOR]

There is limited data on iron reduction therapy (IRT) after successful allogeneic haematopoietic stem cell transplantation (aHSCT) for patients with thalassemia major (TM). We present the long term outcome of IRT in 149 patients with TM who underwent aHSCT during January, 2001-December, 2012. The median age was 7 years (range:1–18) and 92 (61.7%) belonged to Pesaro class 3 with a median ferritin at aHSCT of 2480ng/ml (range:866–8921). IRT was reinitiated post-aHSCT at a median of 14 months (range:5–53) post aHSCT with phlebotomy alone in 10 (6.7%) patients or iron chelation alone in 60 (40.3%) patients while 79 (53%) were treated with the combination. Reduction in serum ferritin/month [absolute quantity (ng/ml/month) was as follows: 87 (range:33–195), 130 (range:17–1012) and 147 (range:27.7–1427) in the phlebotomy, chelation and combination therapy groups, respectively (p = 0.038). With a median follow up of 80 months (range:37–182), target ferritin level of <300ng/ml was achieved in 59(40%) while a level <500ng/ml was achieved in 88 patients (59%) in a median duration of 41 months of IRT (range: 3–136). Patients in class III risk category and higher starting serum ferritin levels (>2500ng/ml) were associated with delayed responses to IRT. Our data shows that IRT may be needed for very long periods in ex-thalassaemics to achieve target ferritin levels and should therefore be carefully planned and initiated as soon as possible after aHSCT. A combination of phlebotomy and iron chelators is more effective in reducing iron overload. [ABSTRACT FROM AUTHOR]

Background: Multiple Myeloma (MM) is a heterogeneous, hematological neoplasm that accounts 2% of all cancers. Although, autologous stem cell transplantation and chemotherapy are currently the most effective therapy, it carries a notable hazards, in addition for being non curative. Recently, the Clustered Regular Interspaced Short Palindromic Repeats (CRISPR-cas9) has been successfully tried at the experimental level, for the treatment of several hematological malignancies. Objectives: We aimed to investigate the in-vitro effect of CRISPR-cas9-mediated knock-out of V-set pre B-cell surrogate light chain 1"VPREB1" gene on the malignant proliferation of primary cultured myeloma cells. Methods: Bioinformatics' analysis was performed to explore the gene expression profile of MM, and the VPREB1 gene was selected as a target gene for this study. We knocked-out the VPREB1 gene in primary cultured myeloma cells using CRISPR-cas9, the VPREB1 gene editing efficacy was verified by determining VPREB1 gene expression at both the mRNA and protein levels by qPCR and immunofluorescence, respectively. Furthermore, the cytotoxic effect on primary myeloma cells proliferation was evaluated using cytotoxicity assay. Results: There was a statistically significant reduction of both VPREB1 mRNA and protein expression levels (p<0.01). knock-out of VPREB1 gene in myeloma cell line resulted in a statistically significant reduction of myeloma cell proliferation. Conclusion: CRISPR-cas9-mediated knock-out of VPREB1 gene is effective for inhibiting the proliferation of primary myeloma cells. This would provide a basis for a promising therapeutic strategy for patients with multiple myeloma. [ABSTRACT FROM AUTHOR]

Ischemia-reperfusion injury is an important contributor to acute kidney injury and a major factor affecting early functional recovery after kidney transplantation. We conducted this experiment to investigate the protective effect of induced multipotent stem cell transplantation on renal ischemia-reperfusion injury. Forty rabbits were divided into four groups of 10 rabbits each. Thirty rabbits were used to establish the renal ischemia-reperfusion injury model, and ten rabbits served as the model group and were not treated. Among the 30 rabbits with renal ischemia-reperfusion injury, 10 rabbits were treated with induced peripheral blood mononuclear cells (PBMCs), and 10 other rabbits were treated with noninduced PBMCs. After three weekly treatments, the serum creatinine levels, urea nitrogen levels and urine protein concentrations were quantified. The kidneys were stained with hematoxylin-eosin (HE), periodic acid-Schiff (PAS) and Masson's trichrome and then sent for commercial metabolomic testing. The kidneys of the rabbits in the model group showed different degrees of pathological changes, and the recovery of renal function was observed in the group treated with induced cells. The results indicate that PBMCs differentiate into multipotent stem cells after induction and exert a therapeutic effect on renal ischemia-reperfusion injury. [ABSTRACT FROM AUTHOR]

BackgroundEndogenous cardiac progenitor cells are a promising option for cell-therapy for myocardial infarction (MI). However, obtaining adequate numbers of cardiac progenitors after MI remains a challenge. Cardiospheres (CSs) have been proposed to have cardiac regenerative properties; however, their cellular composition and how they may be influenced by the tissue milieu remains unclear.Methodology/principal findingUsing "middle aged" mice as CSs donors, we found that acute MI induced a dramatic increase in the number of CSs in a mouse model of MI, and this increase was attenuated back to baseline over time. We also observed that CSs from post-MI hearts engrafted in ischemic myocardium induced angiogenesis and restored cardiac function. To determine the role of Sca-1(+)CD45(-) cells within CSs, we cloned these from single cell isolates. Expression of Islet-1 (Isl1) in Sca-1(+)CD45(-) cells from CSs was 3-fold higher than in whole CSs. Cloned Sca-1(+)CD45(-) cells had the ability to differentiate into cardiomyocytes, endothelial cells and smooth muscle cells in vitro. We also observed that cloned cells engrafted in ischemic myocardium induced angiogenesis, differentiated into endothelial and smooth muscle cells and improved cardiac function in post-MI hearts.Conclusions/significanceThese studies demonstrate that cloned Sca-1(+)CD45(-) cells derived from CSs from infarcted "middle aged" hearts are enriched for second heart field (i.e., Isl-1(+)) precursors that give rise to both myocardial and vascular tissues, and may be an appropriate source of progenitor cells for autologous cell-therapy post-MI.

Cardiac stem cells (CSCs) can home to the infarcted area and regenerate myocardium. Stromal cell-derived factor-1α/C-X-C chemokine receptor type 4 (SDF-1α/CXCR4) axis is pivotal in inducing CSCs migration. However, the mechanisms remain unclear. This study set out to detect if SDF-1α promotes migration and engraftment of CSCs through the CXCR4/PI3K (phosphatidylinositol 3-kinase) pathway. In the in vitro experiment, c-kit+ cells were isolated from neonatal mouse heart fragment culture by magnetic cell sorting. Fluorescence-activated cell sorting results demonstrated that a few c-kit+ cells expressed CD45 (4.54%) and Sca-1 (2.58%), the hematopoietic stem cell marker. Conditioned culture could induce c-kit+ cells multipotent differentiation, which was confirmed by cardiac troponin I (cTn-I), α-smooth muscle actin (α-SMA), and von Willebrand factor (vWF) staining. In vitro chemotaxis assays were performed using Transwell cell chambers to detect CSCs migration. The results showed that the cardiomyocytes infected with rAAV1-SDF-1α-eGFP significantly increased SDF-1α concentration, 5-fold more in supernatant than that in the control group, and subsequently attracted more CSCs migration. This effect was diminished by administration of AMD3100 (10 µg/ml, CXCR4 antagonist) or LY294002 (20 µmol/L, PI3K inhibitor). In myocardial infarction mice, overexpression of SDF-1α in the infarcted area by rAAV1-SDF-1α-eGFP infection resulted in more CSCs retention to the infarcted myocardium, a higher percentage of proliferation, and reduced infarcted area which was attenuated by AMD3100 or ly294002 pretreatment. These results indicated that overexpression of SDF-1α enhanced CSCs migration in vitro and engraftment of transplanted CSCs and reduced infarcted size via CXCR4/PI3K pathway.

BackgroundMutation in the ubiquitously expressed cytoplasmic superoxide dismutase (SOD1) causes an inherited form of Amyotrophic Lateral Sclerosis (ALS). Mutant synthesis in motor neurons drives disease onset and early disease progression. Previous experimental studies have shown that spinal grafting of human fetal spinal neural stem cells (hNSCs) into the lumbar spinal cord of SOD1(G93A) rats leads to a moderate therapeutical effect as evidenced by local α-motoneuron sparing and extension of lifespan. The aim of the present study was to analyze the degree of therapeutical effect of hNSCs once grafted into the lumbar spinal ventral horn in presymptomatic immunosuppressed SOD1(G93A) rats and to assess the presence and functional integrity of the descending motor system in symptomatic SOD1(G93A) animals.Methods/principal findingsPresymptomatic SOD1(G93A) rats (60-65 days old) received spinal lumbar injections of hNSCs. After cell grafting, disease onset, disease progression and lifespan were analyzed. In separate symptomatic SOD1(G93A) rats, the presence and functional conductivity of descending motor tracts (corticospinal and rubrospinal) was analyzed by spinal surface recording electrodes after electrical stimulation of the motor cortex. Silver impregnation of lumbar spinal cord sections and descending motor axon counting in plastic spinal cord sections were used to validate morphologically the integrity of descending motor tracts. Grafting of hNSCs into the lumbar spinal cord of SOD1(G93A) rats protected α-motoneurons in the vicinity of grafted cells, provided transient functional improvement, but offered no protection to α-motoneuron pools distant from grafted lumbar segments. Analysis of motor-evoked potentials recorded from the thoracic spinal cord of symptomatic SOD1(G93A) rats showed a near complete loss of descending motor tract conduction, corresponding to a significant (50-65%) loss of large caliber descending motor axons.Conclusions/significanceThese data demonstrate that in order to achieve a more clinically-adequate treatment, cell-replacement/gene therapy strategies will likely require both spinal and supraspinal targets.

BackgroundCardiovascular progenitor cells (CPCs) have been identified within the developing mouse heart and differentiating pluripotent stem cells by intracellular transcription factors Nkx2.5 and Islet 1 (Isl1). Study of endogenous and induced pluripotent stem cell (iPSC)-derived CPCs has been limited due to the lack of specific cell surface markers to isolate them and conditions for their in vitro expansion that maintain their multipotency.Methodology/principal findingsWe sought to identify specific cell surface markers that label endogenous embryonic CPCs and validated these markers in iPSC-derived Isl1(+)/Nkx2.5(+) CPCs. We developed conditions that allow propagation and characterization of endogenous and iPSC-derived Isl1(+)/Nkx2.5(+) CPCs and protocols for their clonal expansion in vitro and transplantation in vivo. Transcriptome analysis of CPCs from differentiating mouse embryonic stem cells identified a panel of surface markers. Comparison of these markers as well as previously described surface markers revealed the combination of Flt1(+)/Flt4(+) best identified and facilitated enrichment for Isl1(+)/Nkx2.5(+) CPCs from embryonic hearts and differentiating iPSCs. Endogenous mouse and iPSC-derived Flt1(+)/Flt4(+) CPCs differentiated into all three cardiovascular lineages in vitro. Flt1(+)/Flt4(+) CPCs transplanted into left ventricles demonstrated robust engraftment and differentiation into mature cardiomyocytes (CMs).Conclusion/significanceThe cell surface marker combination of Flt1 and Flt4 specifically identify and enrich for an endogenous and iPSC-derived Isl1(+)/Nkx2.5(+) CPC with trilineage cardiovascular potential in vitro and robust ability for engraftment and differentiation into morphologically and electrophysiologically mature adult CMs in vivo post transplantation into adult hearts.

BackgroundInherited and acquired retinal degenerations are frequent causes of visual impairment and photoreceptor cell replacement therapy may restore visual function to these individuals. To provide a source of new retinal neurons for cell based therapies, we developed methods to derive retinal progenitors from human ES cells.Methodology/physical findingsIn this report we have used a similar method to direct induced pluripotent stem cells (iPS) from human fibroblasts to a retinal progenitor fate, competent to generate photoreceptors. We also found we could purify the photoreceptors derived from the iPS cells using fluorescence activated cell sorting (FACS) after labeling photoreceptors with a lentivirus driving GFP from the IRBP cis-regulatory sequences. Moreover, we found that when we transplanted the FACS purified iPSC derived photoreceptors, they were able to integrate into a normal mouse retina and express photoreceptor markers.ConclusionsThis report provides evidence that enriched populations of human photoreceptors can be derived from iPS cells.

Background: Autologous stem cell transplantation (ASCT) remains the standard of care for young multiple myeloma (MM) patients; indeed, at-home ASCT has been positioned as an appropriate therapeutic strategy. However, despite the use of prophylactic antibiotics, neutropenic fever (NF) and hospital readmissions continue to pose as the most important limitations in the outpatient setting. It is possible that the febrile episodes may have a non-infectious etiology, and engraftment syndrome could play a more significant role. The aim of this study was to analyze the impact of both G-CSF withdrawal and the addition of primary prophylaxis with corticosteroids after ASCT. Methods: Between January 2002 and August 2018, 111 MM patients conditioned with melphalan were managed at-home beginning +1 day after ASCT. Three groups were established: Group A (n = 33) received standard G-CSF post-ASCT; group B (n = 32) avoided G-CSF post-ASCT; group C (n = 46) avoided G-CSF yet added corticosteroid prophylaxis post-ASCT. Results: The incidence of NF among the groups was reduced (64%, 44%, and 24%; P<0.001), with a non-significant decrease in hospital readmissions as well (12%, 6%, and 2%; P = 0.07). The most important variables identified for NF were: HCT-CI >2 (OR 6.1; P = 0.002) and G-CSF avoidance plus corticosteroids (OR 0.1; P<0.001); and for hospital readmission: age ≥60 years (OR 14.6; P = 0.04) and G-CSF avoidance plus corticosteroids (OR 0.07; P = 0.05). Conclusions: G-CSF avoidance and corticosteroid prophylaxis post ASCT minimize the incidence of NF in MM patients undergoing at-home ASCT. This approach should be explored in a prospective randomized clinical trial. [ABSTRACT FROM AUTHOR]

Herpes simplex virus 1 (HSV) is a ubiquitous human virus resident in a majority of the global population as a latent infection. Acyclovir (ACV), is the standard of care drug used to treat primary and recurrent infections, supplemented in some patients with intravenous immunoglobulin (IVIG) treatment to suppress infection and deleterious inflammatory responses. As many diverse medications have recently been shown to change composition of the gut microbiome, we used Illumina 16S rRNA gene sequencing to determine the effects of ACV and IVIG on the gut bacterial community. We found that HSV, ACV and IVIG can all independently disrupt the gut bacterial community in a sex biased manner when given to uninfected C57BL/6 mice. Treatment of HSV infected mice with ACV or IVIG alone or together revealed complex interactions between these drugs and infection that caused pronounced sex biased dysbiosis. ACV reduced Bacteroidetes levels in male but not female mice, while levels of the Anti-inflammatory Clostridia (AIC) were reduced in female but not male mice, which is significant as these taxa are associated with protection against the development of graft versus host disease (GVHD) in hematopoietic stem cell transplant (HSCT) patients. Gut barrier dysfunction is associated with GVHD in HSCT patients and ACV also decreased Akkermansia muciniphila, which is important for maintaining gut barrier functionality. Cumulatively, our data suggest that long-term prophylactic ACV treatment of HSCT patients may contribute to GVHD and also potentially impact immune reconstitution. These data have important implications for other clinical settings, including HSV eye disease and genital infections, where ACV is given long-term. [ABSTRACT FROM AUTHOR]

Simple limbal epithelial transplantation (SLET) and cultivated limbal epithelial transplantation (CLET) are proven techniques for treating limbal stem cell deficiency (LSCD). However, the precise regions that are most suitable for preparing explants for transplantation have not been identified conclusively. Accordingly, this in vitro study aimed at determining ideal sites to be selected for tissue harvest for limbal stem cell culture and transplantation. We evaluated cell outgrowth potential and the expression of stem cell markers in cultures from 48 limbal explants from five cadaveric donors. The limbal explants were generated from the three specific sites: Lcor (located innermost and adjacent to the cornea), Lm (middle limbus), and Lconj (located outermost adjacent to the conjunctiva). We found that explants from the Lconj and Lm sites exhibited higher growth potential than those from the Lcor site. Transcript encoding the stem cell marker and p63 isoform, ΔNp63, was detected in cells from Lm and Lconj explants; expression levels were slightly, though significantly (p-value < 0.05), higher in Lm than in Lconj, although expression of ΔNp63α protein was similar in cells from all explants. Differential expression of ATP-Binding Cassette Subfamily G Member 2 (ABCG2) did not reach statistical significance. Immunohistochemistry by indirect immunofluorescence analysis of limbus tissue revealed that the basal layer in explant tissue from Lconj and Lm contained markedly more stem cells than found in Lcor explant tissue; these findings correlate with a higher capacity for growth. Collectively, our findings suggest that explants from the Lconj and Lm sites should be selected for limbal cell expansion for both CLET and SLET procedures. These new insights may guide surgeons toward specific limbal sites that are most suitable for stem cell culture and transplantation and may ultimately improve treatment outcomes in the patients with LSCD. [ABSTRACT FROM AUTHOR]

Autologous transplantation of spermatogonial stem cells is a promising new avenue to restore fertility in infertile recipients. Expansion of the initial spermatogonial stem cell pool through cell culturing is a necessary step to obtain enough cells for effective repopulation of the testis after transplantation. Since in vitro propagation can lead to (epi-)genetic mutations and possibly malignant transformation of the starting cell population, we set out to investigate genome-wide DNA methylation status in uncultured and cultured primary testicular ITGA6+ sorted cells and compare them with germ cell tumor samples of the seminoma subtype. Seminomas displayed a severely global hypomethylated profile, including loss of genomic imprinting, which we did not detect in cultured primary testicular ITGA6+ cells. Differential methylation analysis revealed altered regulation of gamete formation and meiotic processes in cultured primary testicular ITGA6+ cells but not in seminomas. The pivotal POU5F1 marker was hypomethylated in seminomas but not in uncultured or cultured primary testicular ITGA6+ cells, which is reflected in the POU5F1 mRNA expression levels. Lastly, seminomas displayed a number of characteristic copy number variations that were not detectable in primary testicular ITGA6+ cells, either before or after culture. Together, the data show a distinct DNA methylation patterns in cultured primary testicular ITGA6+ cells that does not resemble the pattern found in seminomas, but also highlight the need for more sensitive methods to fully exclude the presence of malignant cells after culture and to further study the epigenetic events that take place during in vitro culture. [ABSTRACT FROM AUTHOR]

Objectives: Large studies are needed to update risk factors of bronchiolitis hospitalization. We performed a nationwide analysis of hospitalization rates for bronchiolitis over four consecutive bronchiolitis seasons to identify underlying medical disorders at risk of bronchiolitis hospitalization and assess their frequency. Methods: Data were retrieved from the French National Hospital Discharge database. Of all infants discharged alive from maternity wards from January 2008 to December 2013 in France (N = 3,884,791), we identified four consecutive cohorts at risk of bronchiolitis during the seasons of 2009–2010 to 2012–2013. The main outcome was bronchiolitis hospitalization during a season. Individual risk factors were collected. Results: Among infants, 6.0% were preterm and 2.0% had ≥1 chronic condition including 0.2% bronchopulmonary dysplasia (BPD) and 0.2% hemodynamically significant congenital heart disease (HS-CHD). Bronchiolitis hospitalization rates varied between seasons (min: 1.26% in 2010–2011; max: 1.48% in 2012–2013; p<0.001). Except omphalocele, the following conditions were associated with an increased risk for bronchiolitis hospitalization: solid organ (9.052; 95% CI, 4.664–17.567) and stem cell transplants (6.012; 95% CI, 3.441–10.503), muscular dystrophy (4.002; 95% CI, 3.1095–5.152), cardiomyopathy (3.407; 95% CI, 2.613–4.442), HS-CHD (3.404; 95% CI, 3.153–3.675), congenital lung disease and/or bronchial abnormalities, Down syndrome, congenital tracheoesophageal fistula, diaphragmatic hernia, pulmonary hypertension, chromosomal abnormalities other than Down syndrome, hemodynamically non-significant CHD, congenital abnormalities of nervous system, cystic fibrosis, cleft palate, cardiovascular disease occurring during perinatal period, and BPD. Conclusion: Besides prematurity, BPD, and HS–CHD, eighteen underlying conditions were associated with a significant increased risk for bronchiolitis hospitalization in a nationwide population. [ABSTRACT FROM AUTHOR]

Non-implanted central vascular catheters (CVC) are frequently required for therapy in hospitalized patients with hematological malignancies or solid tumors. However, CVCs may represent a source for bloodstream infections (central line-associated bloodstream infections, CLABSI) and, thus, may increase morbidity and mortality of these patients. A retrospective cohort study over 3 years was performed. Risk factors were determined and evaluated by a multivariable logistic regression analysis. Healthcare costs of CLABSI were analyzed in a matched case-control study. In total 610 patients got included with a CLABSI incidence of 10.6 cases per 1,000 CVC days. The use of more than one CVC per case, CVC insertion for conditioning for stem cell transplantation, acute myeloid leukemia, leukocytopenia (≤ 1000/μL), carbapenem therapy and pulmonary diseases were independent risk factors for CLABSI. Hospital costs directly attributed to the onset of CLABSI were 8,810 € per case. CLABSI had a significant impact on the overall healthcare costs. Knowledge about risk factors and infection control measures for CLABSI prevention is crucial for best clinical practice. [ABSTRACT FROM AUTHOR]

Introduction: Haematopoietic stem cell transplantation (HSCT) recipients are at increased risk for severe infections. This study examined the associations of common oral infections with survival and infectious complications in HSCT recipients. Materials and methods: All autologous and allogeneic HSCT recipients transplanted in the University Hospital of Basel, Switzerland, between 2008 and 2016 and referred to oral infection control pre-HSCT were included in this retrospective case-control study. All patients had a clinical and a panoramic radiological dental examination taken immediately prior to HSCT. Presence of acute or chronic oral foci of infections, decayed, missing or filled tooth index (DMFT) and radiological attachment loss (RAL) were examined. Survival and infections of the subjects were followed up for 6 months post-HSCT. Results: Altogether 341 allogeneic and 125 autologous HSCT recipients were included in the study. Within 6 months post-HSCT, 47 (14%) of the allogeneic and 4 (3%) of the autologous recipients died. Oral foci of infections (acute or chronic), DMFT or periodontitis pre-HSCT were not associated with survival 6 months post-HSCT. Oral foci of infections were also not associated with hospital treated infectious diseases or blood culture positive bacteremia during the 6 month follow-up period. Untreated oral foci of infections were not associated with survival or severe infectious complications within 6 months post-HSCT. Conclusion: The results of this study suggest that radical dental interventions to chronic oral infections could be postponed until post-HSCT. [ABSTRACT FROM AUTHOR]

Introduction: Under the hypothesis that early natural killer cell infusion (NKI) following haploidentical stem cell transplantation (haplo-SCT) will reduce relapse in the early post-transplant period, we conducted a pilot study to evaluate the safety and feasibility of NKI following haplo-SCT in children with recurrent neuroblastoma who failed previous tandem high-dose chemotherapy and autologous SCT. Methods: We used the high-dose 131I-metaiodobenzylguanidine and cyclophosphamide/fludarabine/anti-thymocyte globulin regimen for conditioning and infused 3 × 107/kg of ex-vivo expanded NK cells derived from a haploidentical parent donor on days 2, 9, and 16 post-transplant. Interleukin-2 was administered (1 × 106 IU/m2/day) subcutaneously to activate infused donor NK cells on days 2, 4, 6, 9, 11, 13, 16, 18, and 20 post-transplant. Results: Seven children received a total of 19 NKIs, and NKI-related acute toxicities were fever (n = 4) followed by chills (n = 3) and hypertension (n = 3); all toxicities were tolerable. Grade ≥II acute GVHD and chronic GVHD developed in two and five patients, respectively. Higher amount of NK cell population was detected in peripheral blood until 60 days post-transplant than that in the reference cohort. Cytomegalovirus and BK virus reactivation occurred in all patients and Epstein-Barr virus in six patients. Six patients died of relapse/progression (n = 5) or treatment-related mortality (n = 1), and one patient remained alive. Conclusion: NKI following haplo-SCT was relatively safe and feasible in patients with recurrent neuroblastoma. Further studies to enhance the graft-versus-tumor effect without increasing GVHD are needed. [ABSTRACT FROM AUTHOR]

Autologous hematopoietic stem cell transplantation (auto-HSCT) provides a potentially curative treatment option for relapsed and refractory lymphomas. Obesity displays an emerging epidemic risk factor for global mortality and is associated with an increased mortality in cancer patients. To date, the impact of obesity on the outcome of lymphoma patients undergoing auto-HSCT is understudied. We conducted a retrospective single-center study assessing 119 lymphoma patients who underwent auto-HSCT. Overall survival (OS) served as the primary endpoint whereas progression free survival (PFS), cumulative incidence of non-relapse related mortality (NRM) and cumulative incidence of relapse were analyzed as secondary endpoints. Obese patients (Body mass index, BMI≥30) had significantly lower OS (45.3% vs. 77.9%; p = 0.005) and PFS (29.8% vs. 67.2%; p<0.001) compared to non-obese patients at 48 months post-transplantation. The cumulative incidence of NRM displayed no significant differences while the cumulative incidence of relapse was significantly increased in patients with BMI≥30 (66.2% vs. 21.5%; p<0.001). Patients with a BMI<25 and overweight patients (BMI 25–30; 76.1% vs. 80.9%; p = 0.585), showed no significant difference in OS, whereas patients with BMI≥30 exhibited significant lower OS when compared to either of both groups (76.1% vs. 45.3%; p =.0.021 and 80.9% vs. 45.3%; p = 0.010). Furthermore, in a multivariate analysis, obesity was identified as an independent risk factor for death (Hazard ratio 2.231; 95% CI 1.024 to 4.860; p = 0.043). Further studies are needed to evaluate the reasons for the higher relapse rate causing higher mortality in obese patients. [ABSTRACT FROM AUTHOR]

Sickle cell disease (SCD) is a monogenic red cell disorder associated with multiple vascular complications, microvessel injury and wound-healing deficiency. Although stem cell transplantation with bone marrow-derived mesenchymal stem cells (BMSC) can promote wound healing and tissue repair in SCD patients, therapeutic efficacy is largely dependent on the paracrine activity of the implanted BM stromal cells. Since in vitro expansion and culture conditions are known to modulate the innate characteristics of BMSCs, the present study investigated the effects of normoxic and hypoxic cell-culture preconditioning on the BMSC secretome, in addition to the expression of paracrine molecules that induce angiogenesis and skin regeneration. BMSCs derived from SCD patients were submitted to culturing under normoxic (norCM) and hypoxic (hypoCM) conditions. We found that hypoxically conditioned cells presented increased expression and secretion of several well-characterized trophic growth factors (VEGF, IL8, MCP-1, ANG) directly linked to angiogenesis and tissue repair. The hypoCM secretome presented stronger angiogenic potential than norCM, both in vitro and in vivo, as evidenced by HUVEC proliferation, survival, migration, sprouting formation and in vivo angiogenesis. After local application in a murine wound-healing model, HypoCM showed significantly improved wound closure, as well as enhanced neovascularization in comparison to untreated controls. In sum, the secretome of hypoxia-preconditioned BMSC has increased expression of trophic factors involved in angiogenesis and skin regeneration. Considering that these preconditioned media are easily obtainable, this strategy represents an alternative to stem cell transplantation and could form the basis of novel therapies for vascular regeneration and wound healing in individuals with sickle cell disease. [ABSTRACT FROM AUTHOR]

The Epstein-Barr virus (EBV) induces B-cell proliferation with high efficiency through expression of latent proteins and microRNAs. This process takes place in vivo soon after infection, presumably to expand the virus reservoir, but can also induce pathologies, e.g. an infectious mononucleosis (IM) syndrome after primary infection or a B-cell lymphoproliferation in immunosuppressed individuals. In this paper, we investigated the growth characteristics of EBV-infected B-cells isolated from transplant recipients or patients with IM. We found that these cells grew and withstood apoptosis at highly variable rates, suggesting that the expansion rate of the infected B-cells widely varies between individuals, thereby influencing the size of the B-cell reservoir and the ability to form tumors in infected individuals. All viruses investigated were type 1 and genetically close to western strains. EBV-infected B-cells expressed the transforming EBV latent genes and microRNAs (miRNAs) at variable levels. We found that the B-cell growth rates positively correlated with the BHRF1 miRNA levels. Comparative studies showed that infected B-cells derived from transplant recipients with iEBVL on average expressed higher levels of EBV miR-BHRF1 miRNAs and grew more rapidly than B-cells from IM patients, suggesting infection by more transforming viruses. Altogether, these findings suggest that EBV infection has a highly variable impact on the B-cell compartment that probably reflects the genetic diversity of both the virus and the host. It also demonstrates the unexpected finding that B-cells from different individuals can grow at different speed under the influence of the same virus infection. [ABSTRACT FROM AUTHOR]

Since their appearance, humanized mice carrying human immune system seemed promising tools to study the crosstalk between cancer and immunity. The NOD-scidIL2Rgammanull (NSG) mice engrafted with human cord blood (hCB)-CD34+ cells have been proposed to be a valuable tool to reproduce human immune system in mouse. However, the lack of solid evidences on the functionality of their human immune components limits their usage in immune-oncology. We report that (hCB)-CD34+ cells lose their ability to propagate and originate bone marrow-derived human immune cells after two serial transplantations in NSG mice. We demonstrate that transplants of bone marrow patient-derived acute myeloid leukemias (hAMLs) grow very similarly in the humanized (hCB)-CD34+ NSG and parental NSG mice. The similar extent of engraftment and development of leukemias in (hCB)-CD34+ NSG and controls suggests a poor human immune response against not compatible hAMLs. Our findings suggest that (hCB)-CD34+ NSG mice are transient and/or incomplete carriers of the human immune system and, therefore, represent a suboptimal tool to study the interaction between tumor and immune cells. [ABSTRACT FROM AUTHOR]

Purpose: In a retrospective cohort study, we report the current epidemiology of patients with multiple myeloma (MM) and analyze the real-world clinical outcomes of bortezomib-based therapy. Materials and methods: This retrospective study was mainly designed to evaluate the characteristics, treatment outcomes, and prognostic factors of patients with MM who received bortezomib-based therapy. We identified 5,726 patients in Taiwan with MM newly diagnosed between 2007 and 2015. Confidential data from the National Health Insurance Research Database (NHIRD) was used under strict guidelines, as it was made available in an electronic format for research purposes. In addition, we analyzed 96 patients who have been diagnosed with MM and were treated at the Tri-Service General Hospital (TSGH) between January 1, 2002, and December 31, 2018. Results: Patients receiving first-line treatment with bortezomib had longer overall survival (OS) compared to those who received non-first-line treatment (p<0.001). In addition, the statistically lowest risk of mortality was when patients received first-line bortezomib followed by an autologous hematopoietic stem cell transplant (adjusted hazard ratio = 0.39, p<0.001). In the TSGH study, the patients were enrolled between January 1, 2002, and December 31, 2018, with an initial diagnosis of MM; there were 96 individuals treated with bortezomib. There was no statistically significant difference in the OS or progression-free survival (PFS) according to the gender, myeloma type, International Staging System stage, or treatment regimen. There was a significant difference in the PFS in patients receiving first-line bortezomib treatment with transplantation compared to those without transplantation (p = 0.021). Conclusions: Bortezomib as a first-line treatment extended the OS in four-year mortality tracking and lowered the mortality risk according to the NHIRD analysis. In the TSGH analysis, the results indicated that the initial conditions of patients with MM have a lower influence on the OS and PFS after bortezomib-based therapy was administered. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is characterized by demyelinated lesions in the central nervous system. Destruction of myelin and secondary damage to axons and neurons leads to significant disability, particularly in people with progressive MS. Accumulating evidence suggests that the potential for myelin repair exists in MS, although for unclear reasons this process fails. The cells responsible for producing myelin, the oligodendrocytes, and their progenitors, oligodendrocyte precursor cells (OPCs), have been identified at the site of lesions, even in adults. Their presence suggests the possibility that endogenous remyelination without transplantation of donor stem cells may be a mechanism for myelin repair in MS. Strategies to develop novel therapies have focused on induction of signaling pathways that stimulate OPCs to mature into myelin-producing oligodendrocytes that could then possibly remyelinate lesions. We have been investigating pharmacological approaches to enhance OPC differentiation, and have identified that the combination of two agents, triiodothyronine (T3) and quetiapine, leads to an additive effect on OPC differentiation and consequent myelin production via both overlapping and distinct signaling pathways. While the ultimate production of myelin requires cholesterol biosynthesis, we identified that quetiapine enhances gene expression in this pathway more potently than T3. Two blockers of cholesterol production, betulin and simvastatin, reduced OPC differentiation into myelin producing oligodendrocytes. Elucidating the nature of agents that lead to complementary and additive effects on oligodendrocyte differentiation and myelin production may pave the way for more efficient induction of remyelination in people with MS. [ABSTRACT FROM AUTHOR]

The beneficial effect of mesenchymal stem cells (MSCs) on wound healing is mostly attributed to a trophic effect that promotes angiogenesis. Whether MSCs can contribute to the formation of new blood vessels by direct differentiation is still controversial. Pelvic floor dysfunction (PFD) is a group of disorders that negatively affect the quality of women’s lives. Traditional vaginal surgical repair provides disappointing anatomical outcome. Stem cell transplantation may be used to supplement surgery and improve its outcome. Here we aimed to examine the engraftment, survival, differentiation and angiogenic effect of transplanted MSCs in a vaginal injury rat model. MSCs were obtained from the bone marrow of Sprague Drawley (SD) rats, expanded and characterized in vitro. The MSCs expressed CD90 and CD29, did not express CD45, CD34, CD11b and CD31 and could differentiate into osteogenic, chondrogenic and adipogenic lineages. Cells were labeled with either PKH-26 or GFP and transplanted systemically or locally to female SD rats, just after a standardized vaginal incision was made. Engraftment after local transplantation was less efficient at all-time points compared to systemic administration. In the systemically transplanted animal group, MSCs migrated to the injury site and were present in the healed vagina for at least 30 days. Both systemic and local MSCs transplantation promoted host angiogenesis. Systemically transplanted MSCs created new vascular-like structures by direct differentiation into endothelium. These findings pave the way to further studies of the potential role of MSCs transplantation in improving surgical outcome in women with PFD. [ABSTRACT FROM AUTHOR]