Bone Marrow Transplantation For Treatment Research Articles

Survival Prediction of Children after Bone Marrow Transplant Using Machine Learning Algorithms

Bone marrow is the source of many blood-related diseases, such as blood cancers, and Bone Marrow Transplantation (BMT), also known as Hematopoietic Stem Cell Transplantation (HSCT), is a life-saving surgical procedure. However, this treatment is associated with a high risk of mortality. Predicting survival after BMT is therefore essential for effective and accurate treatment. BMT is considered a treatment-related mortality due to several primary causes of death such as infections, toxicity, and Graft-versus-Host Disease (GvHD) that occur after treatment. In addition, several risk factors affect the success of BMT and long-term survival after treatment. Therefore, there is a need for a prediction system based on machine learning techniques that can predict whether the patient will survive after BMT or not, which will definitely help the physicians to make the right decisions before performing the surgery for the patient. In this paper, using a publicly available BMT dataset from the University of California, Irvine ML repository (UCI ML repository), different machine learning models were investigated to predict the survival status of children undergoing BMT treatment. In particular, Random Forest (RF), Bagging Classifier, Extreme Gradient Boost (XGBoost), Adaptive Boosting (AdaBoost), Decision Tree (DT), Gradient Boost (GB), and K-Nearest Neighbors (KNN) were trained on the given dataset. The dataset consists of 45 variables after applying a series of preprocessing steps and removing the multicollinearity features based on the correlation heat map. Then, a feature engineering and modelling step was applied to identify the most significant features, followed by the use of machine learning models to simplify the overall classification process. It’s important to note that the most important features obtained by DT and those obtained by GB were the most suitable for training the Bagging classifier and the KNN model, respectively. In addition to that, hyper-parameters optimization using Grid Search Cross-Validation (GSCV) was applied to both approaches to improve the accuracy of the survival prediction. RF, AdaBoost, GB, and Bagging techniques have achieved the best accuracy of 97.37%

TMI-Based Dose-Escalated Bone Marrow Transplantation Can Help Preserve the Bone Marrow Microenvironment and Reduce Cellular Senescence in Old Mice

Introduction:Senescence is one of the hallmarks of aging and age-related conditions, including but not limited to, inflammaging, frailty, and various age-related diseases. It has been well-established that radiation and chemotherapy can accelerate senescence. While myeloablative conditioning-based allogeneic hematopoietic cell transplant (HCT) is a curative treatment for patients with leukemia. The dose of total body irradiation (TBI) conditioning has to be reduced in older patients to reduce potential high treatment-related mortality, which may still cause accelerated senescence in aged individuals, resulting in poor survival outcomes. We initiated the testing of a novel total marrow irradiation (TMI) based myeloablative conditioning in older patients to enhance the anti-leukemia effect and overall survival. We hypothesize that this new radiation preconditioning strategy may also reduce radiation-induced senescence in aged individuals compared to TBI to reduce treatment-associated side effects and improve the outcomes of allogeneic HCT. We tested this hypothesis in the present study and further investigated the mechanisms of the effects of TMI-based myeloablative and dose-escalated bone marrow transplantation (BMT) on old mice by examining the changes in expression of various senescence markers and senescence-associated secretory phenotype (SASP) in the bone marrow (BM) and selected organs. Method: The radiation treatment regimens were: TMI (12:4), TMI (16:4) and TBI (12:12), and TBI (16:16), were developed as described (Zuro et al., 2021); i.e. (12:4) means the radiation dose to the BM was 12 Gy and the dose to the organs was 4 Gy. The young (8 weeks old) and aged mice (90 weeks old) of host C57BL/6j (JAX000664, CD45.2) were irradiated in 2 fractions 24h apart, and 25 million whole BM cells from donor (JAX002014, CD45.1) were transplanted by i.v. at 24 h after irradiation. For the hematopoietic stem and progenitor cell (HSPC) population study, more mature hematopoietic progenitors (Lin − Sca-1 −c-Kit + or LK cells) and HSPCs (Lin − Sca-1 + c-Kit + or LSK cells) were examined in BM by flow analysis. Cultured bone marrow mesenchymal stem cells (MSCs) were analyzed for the gene expression of the senescence marker CDNK1a (or p21) and SASP factors MMP13 and CXCL12 by qPCR. For senescence study in organs such as the liver, gut, and spleen, senescence-associated beta-galactosidase (SA-β-gal) staining was performed and expression of the CDNK2a (or p16) was analyzed by qPCR. Results: TMI or TBI treatment with young donor BMT repopulated the BM HSPC population without significant bone damage in aged mice (data not shown). While the BM LK and LSK populations significantly reduced in aged mice after TMI or TBI with young donor BMT compared to aged control mice ( Fig 1A), these populations were not different from young mice groups ( Fig 1B). In addition, TMI or TBI treatment with young donor BMT reduced MSC senescence. Cultured MSCs analysis showed the reduction of p21, MMP13, and CXCL12 expression ( Fig 1C-E) after TMI or TBI with young donor BMT in aged compared to aged control without radiation and BMT. However, while TMI treatment and BMT reduced senescence in the organs, mice receiving TBI treatment and BMT showed a higher senescence burden. In the liver, the aged control mice showed a significant increase in SA-β-gal staining, which was decreased in TMI (12:4) and TMI (16:4) mice ( Fig 1F). In contrast, this effect was not observed in aged mice after TBI (12:12) or (16:16) ( Fig 1G). Moreover, the senescence marker p16 expression in the liver and gut was reduced only in TMI (12:4) and TMI (16:4), not in TBI (12:12) or (16:16) ( Fig 1H, I), whereas the p16 expression in the hematopoietic tissue, spleen was decreased in all treatment groups TMI vs. TBI ( Fig 1J). Conclusion: TMI-based dose escalates with young donor BMT in aged mice preserved BM microenvironment and reduced senescence of organs while TBI treatment causes senescence of the organs. Young donor BMT, which combined with TMI or TBI treatment, preserved bone structure and reduced senescence of HSPC and MSC. However, TMI treatment decreased the SA-β-gal staining and p16 expression significantly in organs such as the liver and gut, but not by TBI treatment. This study showed the senescence reduction in both bone marrow and organs after young donor BMT and TMI treatment. For further study, we have a plan to study the mechanism and signaling pathway of senescence reduction.

Quantitative Evaluation of the Reduced Capacity of Skeletal Muscle Hypertrophy after Total Body Irradiation in Relation to Stem/Progenitor Cells.

The effects of total body irradiation (TBI) to the capacity of skeletal muscle hypertrophy were quantified using the compensatory muscle hypertrophy model. We additionally assessed the responses of stem and/or progenitor cells in the muscles. A single TBI of 9.0, 5.0 and 2.5 Gy was delivered to C57BL/6 mice. Bone marrow stromal cells were obtained from GFP-Tg mice, and were injected into the tail vein of the recipient mice (1 × 106 cells/mouse), for bone marrow transplantation (BMT). Five weeks after TBI, the mean GFP-chimerism in the blood was 96 ± 0.8% in the 9 Gy, 83 ± 3.9% in the 5 Gy, and 8.4 ± 3.4% in the 2.5 Gy groups. This implied that the impact of 2.5 Gy is quite low and unavailable as the BMT treatment. Six weeks after the TBI/BMT procedure, muscle hypertrophy was induced in the right plantaris muscle by surgical ablation (SA) of the synergist muscles (gastrocnemius and soleus), and the contralateral left side was preserved as a control. The muscle hypertrophy capacity significantly decreased by 95% in the 9 Gy, 48% in the 5 Gy, and 36% in the 2.5 Gy groups. Furthermore, stem/progenitor cells in the muscle were enzymatically isolated and fractionated into non-sorted bulk cells, CD45-/34-/29+ (Sk-DN), and CD45-/34+ (Sk-34) cells, and myogenic capacity was confirmed by the presence of Pax7+ and MyoD+ cells in culture. Myogenic capacity also declined significantly in the Bulk and Sk-DN cell groups in all three TBI conditions, possibly implying that skeletal muscles are more susceptible to TBI than bone marrow. However, interstitial Sk-34 cells were insusceptible to TBI, retaining their myogenic/proliferative capacity.

Gosha-Jinki-Gan Recovers Spermatogenesis in Mice with Busulfan-Induced Aspermatogenesis.

Busulfan is an anti-cancer chemotherapeutic drug and is often used as conditioning regimens prior to bone marrow transplant for treatment of chronic myelogenous leukemia. Male infertility, including spermatogenesis disturbance, is known to be one of the side effects of anticancer drugs. While hormone preparations and vitamin preparations are used for spermatogenesis disturbance, their therapeutic effects are low. Some traditional herbal medicines have been administered to improve spermatogenesis. In the present study, we administered Gosha-jinki-gan (TJ107; Tsumura Co., Ltd., Tokyo, Japan) to mice suffering from severe aspermatogenesis after busulfan treatment to determine whether TJ107 can recover spermatogenesis. Male 4-week-old C57BL/6J mice were administered a single intraperitoneal injection of busulfan, and they were then fed a normal diet for 60 days and then a TJ107 diet or TJ107-free normal diet for another 60 days. After busulfan treatment, the weight of the testes and the epididymal sperm count progressively decreased in the normal diet group. On the other hand, in the TJ107 group, these variables dramatically recovered at 120 days. These results suggest that busulfan-induced aspermatogenesis is irreversible if appropriate treatment is not administered. Supplementation of TJ107 can completely recover the injured seminiferous epithelium via normalization of the macrophage migration and reduction of the expressions of Tool-like receptor (TLR) 2 and TLR4, suggesting that TJ107 has a therapeutic effect on busulfan-induced aspermatogenesis.

Synergistic actions of FGF2 and bone marrow transplantation mitigate radiation-induced intestinal injury

Unwanted radiological or nuclear exposure remains a public health risk for which effective therapeutic countermeasures are lacking. Here, we evaluated the efficacy of fibroblast growth factor-2 (FGF2) in treating radiation-induced gastrointestinal syndrome (RIGS) incurred by lethal whole-body irradiation (WBI) when administered in conjunction with bone marrow transplantation (BMT). In vitro experiments indicated FGF2 treatment increased proliferation, reduced apoptosis, and upregulated AKT–GSK3β/β–catenin signaling in irradiated IEC-6 cells. We next established and analyzed mice cohorts consisting of sham irradiation (Group Sh); 12 Gy WBI (Group A); WBI with BMT (Group B); WBI with FGF2 treatment (Group F); and WBI with BMT and FGF2 treatment (Group BF). At 2 weeks post-irradiation, Group BF showed a dramatic increase in survival over all other groups. Intestinal epithelium of Group BF, but not Group B or F, showed augmented proliferation, decreased apoptosis, and preserved crypt numbers and morphology. Furthermore, Group BF maintained intestinal barrier function with minimal inflammatory disturbances in a manner comparable to Group Sh. In accordance, transcriptomic analyses showed significant upregulation of intestinal barrier and stem cell markers in Group BF relative to Groups A and B. Taken together, parenteral FGF2 synergizes with BMT to confer potent mitigation against RIGS.

Developing Hand Therapy Interventions based on ICF Framework for Epidermolysis Bullosa, the “Worst Skin Disease You Have Never Heard Of*”: An Observational Case Series

Study Design-Case series. Epidermolysis Bullosa (EB) is a rare congenital condition, characterized by skin which erupts with blisters, creating deformities in the upper limb from shoulders to fingers, to a “mitten hand.” Care for this population requires a collaborative multidisciplinary team working with the person and their family. Participation in life is limited due to the skin fragility and loss of dexterity is impacted early in life, impairing childhood development, and growth into productive young adults. The University of Minnesota is the only center in the world performing Bone Marrow Transplant (BMT) for a small subset of those with the recessive form of Dystrophic EB (RDEB). While many who attend the EB Center may not be candidates for BMT treatment, all are provided comprehensive care of the EB multispecialty team, of which hand therapy is a part. Patients come from multiple countries as well as the USA, for extended stays. Since 2015 persons with hand deformities related to EB have been referred to hand therapy by multiple departments, toddlers to young adults. Intervention focuses on correction or prevention of finger/hand/wrist/elbow deformities including finger webbing, contracture, and hypermobility, depending on the EB disease type and the hand deformity. There are 4 major subtypes of EB, each with their own severity levels: EB Simplex, Junctional EB, Dystrophic EB (DEB) and Kindler’s Syndrome. The purpose of this case series is to increase the understanding of hand therapy intervention for EB, share lessons learned, and initiate a clinical pathway aligned with the International Classification of Functioning, Disability and Health (ICF).

Gene Therapy for Epidermolysis Bullosa: Sticky Business

Despite efforts to promote development of therapies for rare diseases, the number of available treatments remains low and progress is too slow to have a significant impact on patients. This does not necessarily reflect a lack of interest in rare disease research, and significant efforts have been made toward the development and clinical testing of molecular therapies for these diseases. The intrinsic challenges of understanding the mechanisms underlying rare diseases render the design of efficacious therapies laborious.

Brain atrophy after bone marrow transplantation for treatment of multiple sclerosis

Background: A cohort of patients with poor-prognosis multiple sclerosis (MS) underwent chemotherapy-based immune ablation followed by immune reconstitution with an autologous hematopoietic stem cell transplant (IA/aHSCT). This eliminated new focal inflammatory activity, but resulted in early acceleration of brain atrophy. Objective: We modeled the time course of whole-brain volume in 19 patients to identify the baseline predictors of atrophy and to estimate the average rate of atrophy after IA/aHSCT. Methods: Percentage whole-brain volume changes were calculated between the baseline and follow-up magnetic resonance imaging (MRI; mean duration: 5 years). A mixed-effects model was applied using two predictors: total busulfan dose and baseline volume of T1-weighted white-matter lesions. Results: Treatment was followed by accelerated whole-brain volume loss averaging 3.3%. Both the busulfan dose and the baseline lesion volume were significant predictors. The atrophy slowed progressively over approximately 2.5 years. There was no evidence that resolution of edema contributed to volume loss. The mean rate of long-term atrophy was −0.23% per year, consistent with the rate expected from normal aging. Conclusion: Following IA/aHSCT, MS patients showed accelerated whole-brain atrophy that was likely associated with treatment-related toxicity and degeneration of “committed” tissues. Atrophy eventually slowed to that expected from normal aging, suggesting that stopping inflammatory activity in MS can reduce secondary degeneration and atrophy.

Rationale for Bone Marrow Transplantation in Treatment of Various Intractable Diseases

In this article, we provide evidence that bone marrow transplantation (BMT) can be used to treat various otherwise intractable diseases. We also show which currently incurable diseases could be treated using our novel BMT methods.

The Current Status of Bone Marrow Transplantation in Treatment of Patients with Hemophilia

Background Bone marrow transplantation (BMT)is nowadays used in various hematological disorders including leukemias. Hemophilia A & B are sex linked bleeding disorders in which there are various genetic abnormalities in factor VIII & IX genes. Among various hematological disorders, bleeding disorders mainly hemophilia in now widely treated using plasma derived and recombinant factor VIII & IX concentrates. Day to day transfusion of coagulation factor VIII & IX in current lifelong disorder is a burden for the patients and decrease their quality of life. Although infection of coagulation products with blood-borne viruses that was major concern in treatment of hemophilia has been eliminated nearly complete at the present time, but appearance of factor VIII & IX inhibitors are huge burdens in treatment of hemophilia for both clinicians and patients. In this day and age BMT has gathered new insight and acceptable treatment for many hematological and non-hematological disorders. If BMT will be successful in treatment of hemophilia, it will improve quality of life (by nearly permanent treatment without necessary of daily treatment) and decrease mortality rate (by providing continuous coagulation factor level in blood system). The aim of current study was to determine current role of BMT in treatment of hemophilia A & B and evaluate current usage of BMT for treatment of hemophilia A & B. Methods literature review was done using following key words: “bone marrow transplantation & hemophilia”, “stem cells transplantation & hemophilia”, BMT & hemophilia” in PubMed search engine without any time restriction. In addition the literature search limited to English languages papers. Results After complete search, abstracts of 24 original papers obtained and among them full text of 18 full text of papers accessed. The review of current papers showed that although BMT has been used in a rare cases with hemophilia (mainly hemophilia with another blood disorder), it does not use commonly and currently in treatment of patients with hemophilia A at present time. Literature review showed that scientists now focused on bone marrow transplantation in mouse model of hemophilia. Conclusion The literature review showed that BMT at present time is not common medical procedure and it is now in animal models, stage. Key Words: Bone marrow transplantation, Hemophilia, Treatment.

The effect of bone marrow transplantation on oxidative stress in X-linked adrenoleukodystrophy

Oxidative stress plays an important role in the pathophysiology of neurodegenerative diseases, including X-linked adrenoleukodystrophy (X-ALD). In the present work, we evaluated lipid (malondialdehyde [MDA] content) and protein (sulfhydryl and carbonyl contents) oxidative damage parameters in plasma from X-ALD patients before and after bone marrow transplant (BMT), in order to verify if this treatment is capable to alter the oxidative parameters studied. We also evaluated the plasma concentration of hexacosanoic acid (C26:0) from X-ALD patients and correlated it with the oxidative damage parameters investigated. We observed that MDA content was significantly increased in plasma of X-ALD patients before BMT and after BMT when compared to controls, and that it was significantly reduced in plasma of X-ALD after BMT when compared to the before BMT group. These results indicate that lipid peroxidation is stimulated in X-ALD patients but there is a significant reduction of lipid peroxidation after BMT. Next, we observed a significant reduction of sulfhydryl content in plasma of X-ALD patients before BMT compared to controls indicating protein oxidative damage and that this measurement was increased in these patients after BMT as compared to before BMT. We found no significant differences in plasma carbonyl content in X-ALD patients before and after BMT as compared to controls. However, we observed a significant reduction in this parameter in X-ALD patients after BMT compared to before BMT. Finally, C26:0 plasma concentration was significantly reduced in X-ALD patients after BMT when compared to before BMT. We found no significant correlations between MDA and carbonyl values with C26:0 levels of the patients before BMT and after BMT, but a significant inverse correlation between sulfhydryl content and C26:0 levels was detected. In conclusion, the present study reinforces the hypothesis that lipid peroxidation and protein damage are induced in plasma of X-ALD patients and, in addition, demonstrates that BMT treatment is capable to reduce this pathogenic process. Taken together, the data obtained from plasma of X-ALD patients before and after BMT showing induction and protection, respectively, of oxidative stress, allowed to suggest that BMT, when well succeeded and under the recommendations, is effective to reduce C26:0 plasma levels and the increased lipid and protein oxidative damage in X-ALD.

Autoimmune Dysregulation and Purine Metabolism in Adenosine Deaminase Deficiency

Genetic defects in the adenosine deaminase (ADA) gene are among the most common causes for severe combined immunodeficiency (SCID). ADA-SCID patients suffer from lymphopenia, severely impaired cellular and humoral immunity, failure to thrive, and recurrent infections. Currently available therapeutic options for this otherwise fatal disorder include bone marrow transplantation (BMT), enzyme replacement therapy with bovine ADA (PEG-ADA), or hematopoietic stem cell gene therapy (HSC-GT). Although varying degrees of immune reconstitution can be achieved by these treatments, breakdown of tolerance is a major concern in ADA-SCID. Immune dysregulation such as autoimmune hypothyroidism, diabetes mellitus, hemolytic anemia, and immune thrombocytopenia are frequently observed in milder forms of the disease. However, several reports document similar complications also in patients on long-term PEG-ADA and after BMT or GT treatment. A skewed repertoire and decreased immune functions have been implicated in autoimmunity observed in certain B-cell and/or T-cell immunodeficiencies, but it remains unclear to what extent specific mechanisms of tolerance are affected in ADA deficiency. Herein we provide an overview about ADA-SCID and the autoimmune manifestations reported in these patients before and after treatment. We also assess the value of the ADA-deficient mouse model as a useful tool to study both immune and metabolic disease mechanisms. With focus on regulatory T- and B-cells we discuss the lymphocyte subpopulations particularly prone to contribute to the loss of self-tolerance and onset of autoimmunity in ADA deficiency. Moreover we address which aspects of immune dysregulation are specifically related to alterations in purine metabolism caused by the lack of ADA and the subsequent accumulation of metabolites with immunomodulatory properties.

Neuroprotective and Angiogenic Effects of Bone Marrow Transplantation Combined With Granulocyte Colony-Stimulating Factor in a Mouse Model of Amyotrophic Lateral Sclerosis.

Bone marrow (BM) cells from amyotrophic lateral sclerosis (ALS) patients show significantly reduced expression of several neurotrophic factors. Monotherapy with either wild-type (WT) BM transplantation (BMT) or granulocyte colony-stimulating factor (GCSF) has only a small clinical therapeutic effect in an ALS mouse model, due to the phenomenon of neuroprotection. In this study, we investigated the clinical benefits of combination therapy using BMT with WT BM cells, plus GCSF after disease onset in ALS mice [transgenic mice expressing human Cu/Zn superoxide dismutase (SOD1) bearing a G93A mutation]. Combined treatment with BMT and GCSF delayed disease progression and prolonged the survival of G93A mice, whereas BMT or GCSF treatment alone did not. Histological study of the ventral horns of lumbar cords from G93A mice treated with BMT and GCSF showed a reduction in motor neuron loss coupled with induced neuronal precursor cell proliferation, increased expression of neurotrophic factors (glial cell line-derived neurotrophic factor, brain-derived neurotrophic factor, vascular endothelial growth factor and angiogenin), and neovascularization compared with controls (vehicle only). Compared with G93A microglial cells, most BM-derived WT cells differentiated into microglial cells and strongly expressed neurotrophic factors, combined BMT and GCSF treatment led to the replacement of G93A microglial cells with BM-derived WT cells. These results indicate combined treatment with BMT and GCSF has potential neuroprotective and angiogenic effects in ALS mice, induced by the replacement of G93A microglial cells with BM-derived WT cells. Furthermore, this is the first report showing the effects of combined BMT and GCSF treatment on blood vessels in ALS.

Unresponsiveness to a Kidney Graft After a Fully Matched Allogenic Bone Marrow Transplantation Combined With Low-Dose Tacrolimus Therapy: A Case Report

We present the case of a patient with past medical history of acute mieloblastic leukemia treated with a related, fully match alogenic bone marrow transplantation (BMT). He presented after BMT treatment graft versus host disease (GVHD) and thrombotic thrombocytopenic purpura. He also developed end-stage renal disease that required renal replacement therapy. A preemptive kidney transplant was performed. The haematopoiesis were in complete chimera and the patient developed tolerance to the kidney graft, requiring only minimal immunossupression because of his GVHD.

Regulatory dendritic cell mediated allo-antigen specific tolerance for acute graft versus host disease in young and older mice (169.42)

Abstract Graft-versus-host disease (GVHD) occurring after allogeneic bone marrow transplant (BMT) is often fatal. When compared to younger recipients, older BMT recipients experience increased morbidity and mortality. Following BMT, in our model, older (≥14 month) and young (3-4 month) mice succumb to GVHD, but older mice experience faster onset of weight loss and earlier mortality. Prophylactic treatment with syngeneic regulatory DC (DCreg) has been shown to decrease mortality of GHVD and maintain the graft vs. tumor response. DCreg were generated as previously described from age-matched bone marrow. In vitro analysis of young and older DCreg revealed no difference in co-stimulatory or inhibitory marker expression following culture. Following BMT and DCreg treatment most young DCreg treated BMT mice exhibited a brief period of weight loss and survived at least 45 days post-BMT with no evidence of GVHD; older mice had increased morbidity and decreased long-term survival than young mice. Analysis of inhibitory molecules on DCreg one day following adoptive transfer showed significantly lower expression of PD-L1 and PIR B on older DCreg than younger. To assess the donor immune system’s capacity to respond to infection while remaining free of GVHD, DCreg treated BMT mice were challenged with influenza. DCreg treated BMT mice displayed similar morbidity to control mice and GVHD relapse was not observed. Future studies will continue to investigate the mechanisms of DCreg mediated tolerance.

Therapy for skin disease using bone marrow cells

Attempts to treat congenital protein deficiencies using bone marrow-derived cells have been reported. These efforts have been based on the concepts of stem cell plasticity. We aimed to clarify whether bone marrow transplantation (BMT) treatment can rescue epidermolysis bullosa (EB) caused by defects in keratinocyte structural proteins. BMT treatment of adult collagen XVII (Col17) knockout mice induced donor-derived keratinocytes and Col17 expression associated with the recovery of hemidesmosomal structure and better skin manifestations, as well improving the survival rate. Furthermore, human cord blood CD34+ cells also differentiated into keratinocytes and expressed human skin component proteins in transplanted immunocompromised mice. The current conventional BMT techniques have significant potential as a systemic therapeutic approach for the treatment of human EB.

Treatment of Ocular Graft-Versus-Host Disease With Topical Cyclosporine 0.05%

To evaluate the efficacy of topical cyclosporine-A 0.05% (CsA) in the treatment of dry eye syndrome in ocular graft-versus-host disease after bone marrow transplantation (BMT) of hematopoietic stem cells. One-hundred five patients were enrolled in a retrospective, comparative, interventional case series. Eighty-one patients received topical CsA starting 1 month before BMT (treatment group), and 24 patients did not receive CsA until at least 6 months after the transplantation (control group). Mean follow-up time was 17.5 ± 11.0 months (range: 6.0-49.0 months). Clinical history, ocular surface disease index questionnaire, slit-lamp examination, lissamine green and fluorescein staining of the ocular surface, tear breakup time, and Schirmer test with topical anesthesia were obtained to create a composite dry eye-grading score. Dry eye symptoms were significantly more severe in the control group at 3 months, 1 year, and 2 years (P < 0.05). There was no correlation with type of stem cell transplant (related vs. unrelated donor), presenting indication for BMT, or concurrent systemic immunosuppressive medications. Pre-BMT initiation of topical CsA may reduce the inflammatory response in the lacrimal glands that may be responsible for the development of post-BMT keratitis sicca.

Comparison of Outcomes after Transplantation of G-CSF–Stimulated Bone Marrow Grafts versus Bone Marrow or Peripheral Blood Grafts from HLA-Matched Sibling Donors for Patients with Severe Aplastic Anemia

We compared outcomes of patients with severe aplastic anemia (SAA) who received granulocyte-colony stimulating factor (G-CSF)-stimulated bone marrow (G-BM) (n = 78), unstimulated bone marrow (BM) (n= 547), or peripheral blood progenitor cells (PBPC) (n = 134) from an HLA-matched sibling. Transplantations occurred in 1997 to 2003. Rates of neutrophil and platelet recovery were not different among the 3 treatment groups. Grade 2-4 acute graft-versus-host disease (aGVHD) (relative risk [RR] = 0.82, P = .539), grade 3-4 aGVHD (RR = 0.74, P = .535), and chronic GVHD (cGVHD) (RR = 1.56, P = .229) were similar after G-BM and BM transplants. Grade 2-4 aGVHD (RR = 2.37, P = .012) but not grade 3-4 aGVHD (RR = 1.66, P = .323) and cGVHD (RR = 5.09, P < .001) were higher after PBPC transplants compared to G-BM. Grade 2-4 (RR = 2.90, P < .001), grade 3-4 (RR = 2.24, P = .009) aGVHD and cGVHD (RR = 3.26, P < .001) were higher after PBPC transplants compared to BM. Mortality risks were lower after transplantation of BM compared to G-BM (RR = 0.63, P = .05). These data suggest no advantage to using G-BM and the observed higher rates of aGVHD and cGVHD in PBPC recipients warrants cautious use of this graft source for SAA. Taken together, BM is the preferred graft for HLA-matched sibling transplants for SAA.

Bone marrow transplantation restores epidermal basement membrane protein expression and rescues epidermolysis bullosa model mice

Attempts to treat congenital protein deficiencies using bone marrow-derived cells have been reported. These efforts have been based on the concepts of stem cell plasticity. However, it is considered more difficult to restore structural proteins than to restore secretory enzymes. This study aims to clarify whether bone marrow transplantation (BMT) treatment can rescue epidermolysis bullosa (EB) caused by defects in keratinocyte structural proteins. BMT treatment of adult collagen XVII (Col17) knockout mice induced donor-derived keratinocytes and Col17 expression associated with the recovery of hemidesmosomal structure and better skin manifestations, as well improving the survival rate. Both hematopoietic and mesenchymal stem cells have the potential to produce Col17 in the BMT treatment model. Furthermore, human cord blood CD34(+) cells also differentiated into keratinocytes and expressed human skin component proteins in transplanted immunocompromised (NOD/SCID/gamma(c)(null)) mice. The current conventional BMT techniques have significant potential as a systemic therapeutic approach for the treatment of human EB.

Bayesian semiparametric modeling for stochastic precedence, with applications in epidemiology and survival analysis

We propose a prior probability model for two distributions that are ordered according to a stochastic precedence constraint, a weaker restriction than the more commonly utilized stochastic order constraint. The modeling approach is based on structured Dirichlet process mixtures of normal distributions. Full inference for functionals of the stochastic precedence constrained mixture distributions is obtained through a Markov chain Monte Carlo posterior simulation method. A motivating application involves study of the discriminatory ability of continuous diagnostic tests in epidemiologic research. Here, stochastic precedence provides a natural restriction for the distributions of test scores corresponding to the non-infected and infected groups. Inference under the model is illustrated with data from a diagnostic test for Johne's disease in dairy cattle. We also apply the methodology to the comparison of survival distributions associated with two distinct conditions, and illustrate with analysis of data on survival time after bone marrow transplantation for treatment of leukemia.