Effect Of Bone Marrow Transplantation Research Articles

Bone marrow versus peripheral blood allogeneic haematopoietic stem cell transplantation for haematological malignancies in adults.

Allogeneic haematopoietic stem cell transplantation (allo-HSCT) is an established treatment option for many malignant and non-malignant haematological disorders. Peripheral blood stem cells represent the main stem cell source in malignant diseases due to faster engraftment and practicability issues compared with bone marrow stem cells. Since the early 2000s, there have been many developments in the clinical field. Allo-HSCT using haploidentical family donors (haplo-HSCT) has emerged as an alternative for people who do not have human leukocyte antigen (HLA)-matched siblings or unrelated donors. In addition, the introduction of new methods and strategies in allo-HSCT, such as the use of post-transplant cyclophosphamide (PT-Cy), better donor selection, the more frequent administration of anti-thymocyte globulins (ATGs), but also improved management of side effects such as graft-versus-host disease (GvHD) and infection, have impacted outcomes after allo-HSCT. In addition, as transplant indications and strategies continue to adapt in line with novel research findings, the effect of the stem cell source on post-transplant outcomes is unclear. For our analysis, we considered peripheral blood stem cells as the standard graft source for adults with haematological malignancies. This is an update of a review first published in 2014. To assess the effect of bone marrow transplantation versus peripheral blood stem cell transplantation in adults with haematological malignancies with regard to overall survival, disease-free survival, incidence of non-relapse or transplant-related mortality, incidence of extensive chronic graft-versus-host disease (GvHD), incidence of acute GvHD grades III to IV, incidence of overall chronic GvHD, and quality of life. For this update we searched CENTRAL, MEDLINE, Embase, and two trials registries on 2 November 2022 with no language restrictions. We included randomised controlled trials (RCTs) comparing bone marrow transplantation (BMT) with peripheral blood stem cell transplantation (PBSCT) in adults (aged ≥ 18 years) with haematological malignancies. Two review authors independently selected studies and extracted data. We evaluated risk of bias using the original Cochrane risk of bias tool (RoB 1), and we evaluated the certainty of the evidence using the GRADE approach. The updated search identified no new studies for inclusion. We found two additional reports relating to a previously included study; they provided new data on quality of life and infection rates after transplantation. As these are clinically relevant outcomes, quality of life was added to the summary of findings table (replacing acute GvHD II to IV), and rate of infection was added to our list of secondary outcomes. We included nine RCTs with a total of 1521 participants. Overall, the risk of bias in the included studies was low. Median participant age across studies ranged from 21 to 45 years, and studies took place in Canada, the USA, New Zealand, Brazil, Australia, Egypt, and across Europe. Bone marrow transplantation (BMT) compared with peripheral blood stem cell transplantation (PBSCT) likely results in little to no difference in overall survival (hazard ratio (HR) for all-cause death 1.07, 95% CI 0.91 to 1.25; 6 studies, 1330 participants; moderate-certainty evidence). There may be little to no difference between BMT and PBSCT in terms of disease-free survival (HR for disease recurrence or all-cause death 1.04, 95% CI 0.89 to 1.21; 6 studies, 1225 participants; low-certainty evidence) and non-relapse or transplant-related mortality (HR 0.98, 95% CI 0.76 to 1.28; 3 studies, 758 participants; low-certainty evidence). BMT compared with PBSCT likely results in lower rates of extensive chronic GvHD (HR 0.69, 95% CI 0.54 to 0.90; 4 studies, 765 participants; moderate-certainty evidence) and overall chronic GvHD (HR 0.72, 95% CI 0.61 to 0.85; 4 studies, 1121 participants; moderate-certainty evidence). BMT compared with PBSCT may reduce the incidence of acute GvHD grades III to IV, although the 95% CI of the HR is also compatible with no effect (HR 0.75, 95% CI 0.55 to 1.02; 3 studies, 925 participants; moderate-certainty evidence). Evidence from two trials that used different quality of life assessment instruments suggests that BMT compared with PBSCT may be associated with higher quality of life five years after transplantation. Moderate-certainty evidence suggests little to no difference in overall survival following allo-HSCT using bone marrow versus peripheral blood stem cells (the current clinical standard stem cell source). Low-certainty evidence suggests little to no difference between the stem cell sources in terms of disease-free survival and non-relapse or transplant-related survival. BMT likely reduces the risk of extensive chronic GvHD and overall chronic GvHD compared with PBSCT. Evidence from two RCTs suggests that BMT compared with PBSCT may result in higher long-term quality of life, possibly due to the lower chronic GvHD incidence. With this update, we aimed to supply the most recent data on the choice of stem cell source for allo-HSCT in adults by including new evidence published up to November 2022. We identified no new ongoing studies and no new RCTs with published results. Further research in this field is warranted.

Reversal of obesity development in Ceacam1-/- male mice by bone marrow transplantation or introduction of the human CEACAM1 gene.

ObjectiveAlthough Ceacam1 −/− male mice become obese on normal chow, the effect of bone marrow transplantation or introduction of the carcinoembryonic antigen‐related cell adhesion molecule 1 (CEACAM1) gene has not been studied, to the knowledge of the authors.MethodsThis study analyzed Ceacam1 −/− mice on normal diet or high‐fat diet (HFD), including effects of bone marrow transplantation or introduction of the CEACAM1 gene.ResultsMale Ceacam1 −/− mice on normal diet versus HFD for 24 weeks gained significantly more weight than controls, and Ceacam1 −/− mice aged up to 2 years had a high frequency of liver cancer. Transplantation of wild‐type bone marrow into Ceacam1 −/− mice or introduction of the human CEACAM1 gene fully or partially reversed the obesity phenotype. Liver lipidomics on Ceacam1 −/− versus wild‐type controls on an HFD revealed a significant increase in diacyl glycerides. An increase in fatty acid transporter CD36 levels further suggests that loss of Ceacam1 leads to a major dysregulation of free fatty acid uptake.ConclusionsCEACAM1 expression in both the liver and immune cells regulates obesity and lipid storage pathways in the liver. Bone marrow reconstitution of the immune system or introduction of the human CEACAM1 gene can fully or partially reverse the phenotype.

Effect of Bone Marrow Transplantation on the Fetal Skeleton of Maternally Irradiated Pregnant Rats.

Prenatal exposure to ionizing radiation can interfere with embryonic and fetal growth depending on the dose and gestational age. The present study was completed to evaluate the effect of transplanted bone marrow on the fetal skeleton of pregnant rats exposed to gamma radiation. Experimental animals were separated into 5 groups: C group, R7 group, R7+BM group, R14 group and R14+BM group. All pregnant rats were sacrificed on day 20 days of gestation and the skeletal systems of the fetuses were examined and photographed. This study focused on skull, upper and lower jaw, occipital region, sacral and caudal region, fore and hind limbs. Gamma rays caused any disturbance in the ossification process of the skull bones, upper and lower jaws, occipital bones, it caused the loss of some ossification centers in metacarpal bones, metatarsal bones but bone marrow transplantation greatly reduced the injury that happened because of γ-radiation. This study showed that transplantation of bone marrow post-irradiation in pregnant rats could reduce the hazards of gamma-irradiation in the different regions of the fetal skeleton.

Final Height of Patients Who Underwent Bone Marrow Transplantation for Hematological Disorders During Childhood: A Study by the Working Party for Late Effects-EBMT

AbstractFew data are available on the long-term effect of bone marrow transplantation (BMT) on growth. This study examines those factors that play a role in the final height outcome of patients who underwent BMT during childhood. Data on 181 of 230 patients with aplastic anemia, leukemias, and lymphomas who had BMT before puberty (mean age, 9.8 ± 2.6 years) and who had reached their final height were analyzed. An overall decrease in final height standard deviation score (SDS) value was found compared with the height at BMT (P < 107) and with the genetic height (P < 107). Girls did better than boys, and the younger in age the person was at time of BMT, the greater the loss in height. Previous cranial irradiation + single-dose total body irradiation (TBI) caused the greatest negative effect on final height achievement (P < 104). Fractionation of TBI reduces this effect significantly and conditioning with busulfan and cyclophosphamide seems to eliminate it. The type of transplantation, graft-versus-host disease, growth hormone, or steroid treatment did not influence final height. Irradiation, male gender and young age at BMT were found to be major factors for long-term height loss. Nevertheless, the majority of patients (140/181) have reached adult height within the normal range of the general population.

The Effect of Bone Marrow Transplantation on Oocyte-Granulosa Cell Interaction and Follicular Development of Cisplatin-Induced Ovarian Failure in Rat

Introduction: Chemotherapy has cytotoxic effect that induces follicular damage and abnormal folliculogenesis leads to ovarian failure. Two crucial growth factors in abnormal folliculogenesis, Growth Differentiation Factor-9 (GDF-9) and Kit-Ligand, will be disrupted and affect follicular development. In this study, we evaluate whether bone marrow transplantation (BMT) has a role on oocyte-granulosa cell interaction by analyzing GDF-9 and Kit-Ligand expressions and also follicular development by analyzing primordial, primary, secondary and graafian follicles of cisplatin-induced ovarian failure in rat. Material and method: Forty eight rats were divided into three groups: control, cisplatin and cisplatin + BMT. Ovarian failure was induced by administration of intraperitoneal cisplatin 5 mg/kg body weight for 1 week. BMT 2 x107 cells were injected through rat tail vein after cisplatin administration. Bone marrow was isolated from rat femur and characterized by CD44(+), CD45(-), CD105(+). Immunohistochemistry examinations for ovarian GDF-9, Kit-Ligand and follicle development evaluation were performed after 2 weeks of BMT injection. Results: The expressions of Kit-ligand among three groups by ANOVA were significant different (p=0.00), whereas by Post Hoc: cisplatin group lower than control group (p=0.00); cisplatin + BMT group higher than cisplatin group (p=0.00); and no significant different between control group and cisplatin + BMT group (p=0.955). The expressions of GDF-9 by Kruskal Wallis showed significant different (p=0.00) among three groups whereas cisplatin + BMT group higher than cisplatin group and control group. In cisplatin + BMT group the number of primordial, primary, secondary and graafian follicles were higher than those in cisplatin group; but were lower than those in control group (p=0.000). Positive Paul Kart Horan (PKH) labeling was seen in cisplatin + BMT group only. Conclusion: In cisplatin-induced ovarian failure in rat, bone marrow transplantation may improve oocytegranulosa cell interaction and follicular development.

Stable Neurocognitive Function with Improvement in Processing Speed Following Haploidentical Bone Marrow Transplant with Post-Transplant Cytoxan in Children and Adolescents with Sickle Cell Disease

Background: Children and adolescents with sickle cell disease (SCD) are at significant risk for cerebral infarction and neurocognitive deficits. In a quantitative meta-analysis, Prussien et al. (2019) showed that school-aged children with SCD display significant deficits in full scale IQ, verbal reasoning, perceptual reasoning, executive function, and processing speed relative to the normative mean in sibling and healthy controls, with mean standard scores ranging from 82.38 to 87.51. Quantitative reviews have also shown that deficits in cognitive function in this population also increase with age (Prussien et al., 2019; Schatz et al., 2002). Few studies have investigated whether therapeutic interventions to prevent cerebral infarction impact progressive neurocognitive benefits in individuals with SCD. Four studies to date have assessed the effect of bone marrow transplantation (BMT) on cognition in SCD, and findings show that full scale IQ remained stable after transplant (Neha Bhatnagar et al, 2011; Bockenmeyer et al., 2013; King et al., 2019; Woodard et al., 2005). King et al., also found that verbal IQ and performance IQ also remain stable. However, these findings are based on very small samples, and replication is necessary across multiple domains of cognition including various transplant approaches. We hypothesize that successful related haploidentical BMT (haplo-BMT) in individuals with SCD will result in stable to improved neurocognitive function. Method: In a select cohort of patients who underwent reduced intensity conditioning haplo-BMT with post-transplant cytoxan for SCD as part of an international learning collaborative. Neurocognitive assessments were conducted 2-3 months prior and 12 months post-transplant. All participants were administered age-appropriate Wechsler scale of intelligence (i.e., Wechsler Intelligence Scale for Children - Fourth Edition for children ages 6 to 16 years and the Wechsler Adult Intelligence Scale - Fourth Edition for adolescents over age 18 years). The transplant data base was used to assess baseline demographics and transplant related outcomes. Descriptive statistics was used to evaluate pre- and post-transplant cognitive function. Only participants who completed both pre- and post-transplant cognitive assessments were included for analysis. Results: All sixteen patients had sickle cell anemia (Hb SS), and completed both pre- and post-transplant cognitive assessments. Indication for transplant included stroke 56% (9/16), silent infarcts 63% (10/16) and both in 50% (8/16) (Table 1). Results show that despite disease severity, the current sample of adolescents demonstrated greater scores in verbal reasoning, perceptual reasoning, and executive function relative to prior meta-analytic findings for school-aged children (Prussien et al., 2019). Findings from repeated measures t tests (Table 2), showed no significant difference in mean scores pre- and post-transplant in verbal reasoning (pre = 91.44, post = 90.69, d = .09, p = .641), perceptual reasoning (pre = 91.56, post = 86.12, d = .57, p = .066), working memory (pre = 93.56, post = 86.19, d = .46, p = .158), and full scale IQ (pre = 84.50, post = 86.00, d = .20, p = .694); however, mean scores for processing speed were significantly greater post-transplant relative to pre-transplant (pre = 79.81, post = 86.31, d = .49, p = .023). Conclusions: Neurocognitive function outcomes are stable to improved following haplo-BMT with post-transplant cytoxan in children and adolescents with SCD. Future studies should evaluate long-term neurocognitive function outcomes in SCD patients undergoing haplo-BMT compared to age-matched cohorts on best supportive care. Disclosures No relevant conflicts of interest to declare.

Abstract 5155: Increased longevity of continuous bone marrow cultures and radioresistance of bone marrow stromal cells from SOD193A ALS (Amyotrophic Lateral Sclerosis) mice

Abstract Introduction: The SOD1G93A mouse model of ALS, demonstrates hind limb paralysis beginning at 90 - 100 days of age with stage 4 paralysis at 125 days of age and progressive neuromuscular loss. Materials and Methods: To determine whether deficiency of functional SOD1 influenced parameters of hematopoiesis, long-term bone marrow cultures were established from ALS and control mice. Bone marrow stromal cell lines derived from LTBMCs were tested for clonogenic radiation survival. We tested the effect of bone marrow transplant after total body irradiation on delay of paralysis. Results: SOD1G93A marrow cultures demonstrated significant increase in production of hematopoietic progenitor cells (p &amp;lt; 0.0001) and overall longevity of production of hematopoietic cells (p = 0.0354), and bone marrow stromal cell lines were significantly radioresistant (D0 = 1.33 ± 0.09, and ñ = 8.57 ± 1.8) compared to control C57BL/6J mice (D0 = 1.59 ± 0.11, p = 0.117; and ñ = 3.4 ± 0.4, p= 0.0466). Total body irradiation and bone marrow transplantation with GFP+ donor marrow demonstrated a significant increase in paralysis free interval from 129.2 ± 3.0 to 240.7 ± 21.1 days (p = 0.0010), normalization of blood/brain barrier permeability, and increase in M2 marrow origin microglial cells in proximity to degenerating anterior horn cell/motor neurons. Isolated brain and spinal cord irradiation did not prolong the paralysis free interval (129.0 ± 2.7 days, p = 0.7748). Conclusions: The results of hematopoiesis in LTBMCs in the absence of functional SOD1 showed improved LTBMC longevity and radioresistance of marrow stromal cells both unexpected pleiotropic effects of the SOD1G93A genotype. Marrow transplant after TBI prolonged the paralysis free interval in ALS mice. Citation Format: Andrew Henderson, Michael W. Epperly, Renee Fisher, Donna Shields, Lora Rigatti, Christopher Donnelly, Simon Watkins, Joel S. Greenberger. Increased longevity of continuous bone marrow cultures and radioresistance of bone marrow stromal cells from SOD193A ALS (Amyotrophic Lateral Sclerosis) mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5155.

Kidney Injury in Murine Models of Hematopoietic Stem Cell Transplantation.

Acute graft-versus-host disease (GVHD) affects different organs, including the skin, liver, and gastrointestinal tract. Although kidneys are not among the organs commonly known to be the target of acute GVHD, kidney damage is frequently reported after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We have studied the effect of bone marrow transplantation (BMT) on the kidneys in different murine models of GVHD. We found that glomerular damage in the kidneys is a common pathological finding in mice after BMT. The histopathological features of glomeruli damage included mesengiolysis, mesangial proliferation and edema, subendothelial and endothelial thickening, splitting of capillary walls in glomeruli, narrowing and collapsing of capillary lumens, fibrinoid necrosis of afferent arterioles, intimal hyperplasia, and microthrombi. These pathological features are similar to those detected in kidneys of patients with thrombotic microangiopathy (TMA) after allo-HSCT. We previously showed that activation of the complement system plays a role in GVHD-induced tissue injury in mice. Here we report the presence of complement activation products in the kidney specimens of mice after BMT. We also report that complement deficiency reduced the extent and severity of post-BMT glomerular damage in mice. We conclude that BMT in mice is associated with glomerular injury and tubulointerstitial nephritis, and that kidney damage is at least partially mediated by activation of the complement system.

Airway management in patients with mucopolysaccharidoses: The progression toward difficult intubation.

Patients with mucopolysaccharidoses (MPS) have physical changes to their airways over time. Due to the natural progression of their disease, these patients become more difficult to intubate as they get older. The aims of this study were to evaluate the difficulty of airway management in MPS patients over time, and to evaluate the effect of bone marrow transplant and/or enzyme replacement therapy on airway difficulty. A retrospective review of MPS patients presenting for surgery from January 2012 to May 2018 was performed. Patients were assigned to groups based on their ages at the time of surgery, number of intubation attempts, equipment used for intubation, difficulty of mask ventilation, and difficulty of laryngeal mask airway placement. The same designations were applied to patients with a history of a bone marrow transplant (BMT) and/or enzyme replacement therapy, and they were compared to patients of similar ages who had received no treatment. Logistic regression was used to determine the odds of difficult intubation. One hundred and twenty-eight anesthetic records were reviewed. In 27 cases, the patient had a BMT and in 54 cases, the patient had received enzyme replacement therapy. Adults (18years and older) had the highest likelihood of difficult intubation (OR 13.44, CI 1.45-124.86, P=0.022). Mask ventilation and laryngeal mask airway placement were not significantly more difficult in any age groups. Bone marrow transplant did not improve airway management. A history of enzyme replacement therapy was associated with an increased risk of difficult intubation in patients under the age of 12. As patients with MPS get older, there is a progression toward difficult intubation. Mask ventilation and laryngeal mask airway placement does not become more difficult with age. Bone marrow transplantation did not affect airway difficulty in our population, while enzyme replacement therapy was associated with difficult intubations in younger patients.

Increased Longevity of Continuous Bone Marrow Cultures and Radioresistance of Bone Marrow Stromal Cells from SOD193A ALS (Amyotrophic Lateral Sclerosis) Mice

Introduction: The SOD1G93A mouse model of ALS, demonstrates hind limb paralysis beginning at 90 - 100 days of age with stage 4 paralysis at 125 days of age and progressive neuromuscular loss.Materials & Methods: To determine whether deficiency of functional SOD1 influenced parameters of hematopoiesis, long-term bone marrow cultures were established from ALS and control mice. Bone marrow stromal cell lines derived from LTBMCs were tested for clonogenic radiation survival. We tested the effect of bone marrow transplant after total body irradiation on delay of paralysis.Results: SOD1G93A marrow cultures demonstrated significant increase in production of hematopoietic progenitor cells (p < 0.0001) and overall longevity of production of hematopoietic cells (p = 0.0354), and bone marrow stromal cell lines were significantly radioresistant (D0 = 1.33 ± 0.09, and ñ = 8.57 ± 1.8) compared to control C57BL/6J mice (D0 = 1.59 ± 0.11, p = 0.117; and ñ = 3.4 ± 0.4, p= 0.0466).Total body irradiation and bone marrow transplantation with GFP+ donor marrow demonstrated a significant increase in paralysis free interval from 129.2 ± 3.0 to 240.7 ± 21.1 days (p = 0.0010), normalization of blood/brain barrier permeability, and increase in M2 marrow origin microglial cells in proximity to degenerating anterior horn cell/motor neurons. Isolated brain and spinal cord irradiation did not prolong the paralysis free interval (129.0 ± 2.7 days, p = 0.7748).Conclusions: The results showing increased longevity of hematopoiesis in LTBMCs of marrow from mice displaying an absence of SOD1 and the radioresistance of derived bone marrow stromal cell lines represent two unexpected pleiotrophic effects of the SOD1 G93A genotype. Further studies will be required to determine how marrow transplant after TBI prolonged the paralysis free interval in these ALS mice. DisclosuresNo relevant conflicts of interest to declare.

Polyphenolic Compounds Alter Stress-Induced Patterns of Global DNA Methylation in Brain and Blood.

Stress is a known contributor to various forms of disease in humans and animals, although mechanisms are still unknown. In animals, psychosocial stress-induced depression/anxiety phenotypes are coincidental with increased inflammation in both brain and blood. The authors recently showed that a novel treatment with a select bioactive polyphenol preparation promotes resilience to stress-mediated depression/anxiety phenotypes mice. Moreover, selective bioactive phenolic compounds within the polyphenol preparation are identified that are effective in mitigating the behavioral effects of bone marrow transplantation from stressed mice. Here, an animal model of adult stress and bone marrow transplantation is used to identify an epigenetic signature of repeated social defeat stress (RSDS) that is passed through bone marrow hematopoietic progenitor cells to naïve mice, revealing the maintenance of epigenetic memory following stress both centrally and peripherally. Further, polyphenols are administered to naïve and stress-susceptible mice, demonstrating that polyphenol treatment in mice from both susceptible and naïve donors alters global DNA methylation in the central nervous system and periphery and likewise has an effect on human blood cells after immune challenge. Findings highlight the enduring molecular memory of stress and the possible mechanism by which select bioactive polyphenols may promote resiliency to stress. Polyphenols may be an efficacious alternative to traditional pharmacological treatments in psychiatry.

Ameliorating Effects of Bone Marrow Transplantation and Zinc Supplementation on Physiological and Immunological Changes in γ-Irradiated Rats.

The present study was carried out to determine the prophylactic impact of zinc sulphate administration to irradiated rats treated with bone marrow transplantation (BMT) as indicated by the hematological and immunologic response as well as oxidative stress. Rats were injected orally with zinc sulphate, 10 mg/ Kg body wt, daily for 2 weeks before whole body 5Gy gamma irradiation and intravenous injection of bone marrow cells, one hour post irradiation. The results revealed a significant decrease in red blood cells (RBC), white blood cells (WBC), glutathione (GSH) and zinc superoxide dismutase (Zn /SOD), splenocyte count as well as bone marrow lymphocyte count and viability of irradiated rats. Regarding immunological data: tumor necrosis factor alpha (TNF-α) and interleukin 2 (IL-2) recorded a significant decrease while interleukin 6 (IL-6) and lipid peroxidation product (MDA) in the serum and spleen were conversely elevated. Zn supplementation before irradiation and BMT and showed significant decrease of serum and tissue MDA compared to the irradiated group. Lymphocytes, bone marrow viability percentage, splenocytes percentage, IL-2, IL-6 and GSH were significantly elevated compared to irradiated group. Conclusion: Protection with Zn, enforcing significant innate response, could trigger and augment adaptive immune response by BMT which suggests its use to protect against radiation hazards.

BubR1 Insufficiency Results in Decreased Macrophage Proliferation and Attenuated Atherogenesis in Apolipoprotein E-Deficient Mice.

In the article by Tanaka et al, “BubR1 Insufficiency Results in Decreased Macrophage Proliferation and Attenuated Atherogenesis in Apolipoprotein E‐Deficient Mice,” which published online on September 24, 2016, and appeared in the September 2016 issue of the journal ( J Am Heart Assoc . 2016

Role of Bone Marrow Transplantation in Reducing the Dangerous Effect of Multi-Walled Carbon Nanotubes or / and Gamma Rays on Male Rats

Aim of the work: this study evaluated the efficacy of bone marrow (BM) transplantation to protect male rats from dangerous effect of multi-walled carbon nanotubes (MWCNTs) or/and γ-irradiation on the hematopoietic and lung tissues. Materials and methods: experimental animals were divided into 8 groups each consist of 6 male albino rats. Control group, BM-injected group, MWCNTs-injected group, 5Gy γ-irradiated group, 5Gy γ-irradiated+ MWCNTs-injected group, MWCNTs-injected+ BM-injected group, 5Gy γ-irradiated+ BM-injected group and 5Gy of γ-irradiated+ MWCNTs-injected + BM-injected group. All the treated animal groups were sacrificed after 28 days of the treatments. Blood components, MDA and GSH levels in the lung tissue were analyzed. The histopathological study in the lung tissue was also recorded. Results: exposure to MWCNTs or/and γ-radiation induced a significant decrease in certain blood components (WBCs, RBCs, Hb content, HCT value and PLT count). Furthermore, a significant elevation in MDA level and a significant decrease in GSH content were detected in the lung tissue. The histopathological changes after exposure of rats to MWCNTs recorded perivasculitis, atelectasis and interstitial pneumonia. Also, γ-radiation represented more collapsed and thickened walls in the alveoli, thickened bronchiolar walls with partial epithelial lining and foci of pulmonary hemorrhage in the lung tissue. The effect of BM transplantation after MWCNTs or/and γ-radiation ameliorated the values of blood components, MDA and GSH levels in the lung tissue. The improvement occurred by BM transplantation in rats treated with MWCNTs or/and exposed to γ-radiation were also recorded. The lung tissue showed numerous alveoli with thin interalveolar septa, alveolar sacs and terminal bronchioles with highly folded mucosa. Conclusion: treatment with BM transplantation improved the most deleterious parameters obtained in the blood and lung tissue of MWCNTs exposed or/and γ-irradiated rats.

Bone marrow transplantation improves proximal tubule dysfunction in a mouse model of Dent disease

Dent disease is a rare X-linked tubulopathy caused by mutations in the endosomal chloride-proton exchanger (ClC-5) resulting in defective receptor-mediated endocytosis and severe proximal tubule dysfunction. Bone marrow transplantation has recently been shown to preserve kidney function in cystinosis, a lysosomal storage disease causing proximal tubule dysfunction. Here we test the effects of bone marrow transplantation in Clcn5Y/- mice, a faithful model for Dent disease. Transplantation of wild-type bone marrow in Clcn5Y/- mice significantly improved proximal tubule dysfunction, with decreased low-molecular-weight proteinuria, glycosuria, calciuria, and polyuria four months after transplantation, compared to Clcn5Y/- mice transplanted with ClC-5 knockout bone marrow. Bone marrow-derived cells engrafted in the interstitium, surrounding proximal tubule cells, which showed a rescue of the apical expression of ClC-5 and megalin receptors. The improvement of proximal tubule dysfunction correlated with Clcn5 gene expression in kidneys of mice transplanted with wild-type bone marrow cells. Coculture of Clcn5Y/- proximal tubule cells with bone marrow-derived cells confirmed rescue of ClC-5 and megalin, resulting in improved endocytosis. Nanotubular extensions between the engrafted bone marrow-derived cells and proximal tubule cells were observed invivo andinvitro. No rescue was found when the formation of the tunneling nanotubes was prevented by actin depolymerization or when cells were physically separated by transwell inserts. Thus, bone marrow transplantation may rescue the epithelial phenotype due to an inherited endosomal defect. Direct contacts between bone marrow-derived cells and diseased tubular cells play a key role in the rescue mechanism.

Experiences and Decision Making for Bone Marrow Transplant in Sickle Cell Disease: Patients and Caregivers Perspective

Background:Bone marrow transplantation (BMT) is currently the only curative treatment option available for patients with sickle cell disease (SCD). There are very limited data available on the patients and caregivers perspective on decision making for BMT and their overall experiences with the BMT process. The objective of this study was to determine patients and caregivers knowledge of BMT, the factors that influenced families to consider BMT as a treatment option and their experiences during and after transplantation.Methods:At Children's Healthcare of Atlanta, we conducted 22 qualitative interviews involving patient-caregiver dyads using a semi-structured interview guide. The questions focused on patient and caregiver decision-making and their experience with bone marrow transplant for SCD. All interviews were recorded and transcribed verbatim. Transcripts were then double-coded. Content analysis was performed using NVivo 10.Results: Eleven patients (n=6; Females) and 11 caregivers (n=10, Mothers) participated. At the time of interview, patient's age range was 11-32 years with a median value of 20 years; at the time of transplant, patient's age range was 6 to 17 years with a median value of 11 years. Time from transplant ranged from 0-17 years with a median value of 2 years. Analysis revealed that most patients' and caregivers' were presented with BMT as a treatment option based on the severity of patient's clinical situations. Six participants, patients and caregivers combined, described minimal knowledge and understanding of the BMT process and/or the associated risks/benefits involved with transplant before consultation with the BMT team. Both patients and caregivers reported that the decision to move forward with BMT was strongly influenced by the progression of sickle cell related complications. All patients were either suffering from chronic pain or had been on chronic transfusions for several years. Given the effects of BMT on the entire family, 7 patients and 5 caregivers reported the need to involve the entire family in the decision-making process. Other factors that played a significant role in the decision-making process for patients and caregivers included: information and education received from the BMT team, having an HLA-matched sibling or unrelated donor, and spirituality. A few patients and caregivers stated that hearing from other families would have provided them a more realistic understanding of the transplant process and further aided in their decision-making. Of the 7 patients and caregivers asked about fertility issues and its impact on transplant decision making, 3 patients, and 3 caregivers conveyed that it was the "least of their concerns" and did not feel the need to proceed with fertility preservation. One caregiver voiced concerns about fertility issues, but after consultation with a fertility specialist decided to proceed with BMT. About 95% of patients and caregivers described transplant day as a "re-birth day" or "new birthday". Most patients conveyed that having to deal with chemotherapy-related side effects, such as hair loss, the need for nasogastric tubes, and being isolated from family and friends was all "worth it" because they no longer have sickle cell disease. For 8 caregivers, prayers and family support played a prominent role in helping to cope with the fears and stress involved with BMT. Eight patients indicated that prayers and distractions such as watching movies, playing video games and doing school work helped with coping. Despite having to deal with the arduous transplant process and transplant-related complications, patients and caregivers alike were satisfied with their decision and expressed no decisional regret.While this study included some patients who had severe complications including chronic GVHD, we did not interview caregivers of any patient who had died following BMT.Conclusion: Decision making for bone marrow transplant as a treatment option for those with sickle cell disease is a complex process. Most patients and caregivers have limited knowledge about bone marrow transplant being a curative treatment for sickle cell disease, and the need to educate patients and families is crucial. Gaining an understanding of factors that influence decision making for this population and their experiences with the transplant process will generate crucial insights that will impact the care of future patients and research studies. DisclosuresNo relevant conflicts of interest to declare.

Assessment of Myocardial Function in Children before and after Autologous Peripheral Blood Stem Cell Transplantation.

Increased interest is focused on the long-term adverse effects of bone marrow transplantation. Subclinical cardiac involvement appears common in adults, but only a few reports have examined pediatric patients. A prospective case-control study of 19 children with normal cardiac function undergoing autologous hematopoietic stem cell transplantation (HSCT) was performed. Tissue Doppler imaging (TDI) and echocardiographic measurements were obtained according to the guidelines of the American Society of Echocardiography before and 3 months after HSCT. Lateral mitral annulus before HSCT showed significant reduced mitral systolic annular velocity (P < 0.0001), early diastolic annular velocity (P < 0.0001), late diastolic annular velocity (P = 0.02) and prolonged isovolumetric relaxation time (IRT) (P < 0.0001) compared with control. Significant reduced mitral systolic annular velocity (P < 0.0001), early diastolic annular velocity (P = 0.0005) and Em/Am ratio (P = 0.004), with higher late diastolic annular velocity (P = 0.02) and prolonged isovolumetric contraction time (ICT) (P = 0.003) and IRT (P = 0.002) after HSCT, were observed. Investigation of lateral tricuspid annulus showed nearly similar results as the lateral mitral annulus. LV and RV Tei indices were higher before HSCT compared with control and remained high after HSCT. TDI detected subtle abnormalities in systolic and diastolic functions before and after HSCT, which suggests that a conditioning regimen may affect cardiac function.

Quantifying initial cellular events of mouse radiation lymphomagenesis and its tumor prevention in vivo by positron emission tomography and magnetic resonance imaging

Radiation-induced thymic lymphoma (RITL) in mice is induced by fractionated whole-body X-irradiation (FX) and has served as a useful model for studying radiation carcinogenesis. In this model, the initial postirradiation cellular events in the thymus and bone marrow (BM) are critically important for tumorigenesis, and BM transplantation (BMT) prevents RITL. However, direct assessment of these events is so far restricted by the lack of noninvasive monitoring techniques. Here, we have developed positron emission tomography (PET) and magnetic resonance imaging (MRI) methods to quantify the events critical for RITL development and the effects of BMT in living animals. Apparent diffusion coefficients (ADCs) were calculated from diffusion-weighted MRI to evaluate the changes in the BM of mice receiving FX. ADC values dramatically changed in the irradiated BM, corresponding to pathological findings of the irradiated BM, returning to normal levels following BMT sooner than with spontaneous recovery. PET with 4ʹ-[methyl-11C]thiothymidine, a novel tracer for cell proliferation, revealed that the irradiated thymus showed significantly higher tracer uptake than the unirradiated thymus 1 week after FX. Interestingly, its increased uptake was completely abolished by BMT, even with very few donor-derived cells in the thymus. Thereafter, the thymus receiving BMT had significantly increased tracer uptake. These findings suggest that BMT first suppresses FX-induced aberrant thymocyte proliferation and then accelerates thymic regeneration. This study demonstrates the feasibility of using PET and MRI for noninvasive monitoring of tumorigenic cellular processes in an animal model of radiation-induced cancer.

Information theory of ageing: Studying the effect of bone marrow transplantation on the life span of mice

In this paper the method of life span extension of multicellular organisms (human) using the reservation of stem cells followed by autotransplantation has been proposed. As the efficiency of this method results from the information theory of ageing, it is important to verify it experimentally testing the basic concepts of the theory. Taking it into consideration, the experiment on the bone marrow transplantation to old mice from young closely-related donors of the inbred line was carried out. It has been shown, that transplanted animals exhibited a survival advantage, a mean life span increased by 34% as compared to the control. This result not only demonstrates the efficiency of the proposed method for life span extension of multicellular organisms, but also confirms the basis of the information theory of ageing.

The effect of bone-marrow transplantation on decidua formation in pseudopregnant rats

A main cause of failed pregnancy is insolvency of the decidual reaction of endometrial cells. It is believed that bone-marrow cells (BMCs) are a partial source of decidual cells in endometrial tissue. In the present work, the effect is studied of transplantation of BMCs on the desidualization processes using the model of pseudopregnancy in rats. BMCs were flushed from rat femurs and tibias. On the fifth day of pseudopregnancy, a suspension of single BMCs was injected into one of the uterine horns. PBS injection into the contralateral horn without cells served as control. Rats were sacrificed on the 11th day of pseudopregnancy. The diameter in the meso-antimesometral direction in the experimental uterine horn increased by 1.5–2 times compared to the control horn. The weight of decidual tissue in the experimental horn was three times greater than the weight of the control horn. The presence of transplanted BMCs in decidual tissue was documented by preliminary double-staining of BMCs with membrane dye PKH26 Red and nuclear dye Hoechst 33342. Histological analysis of decidua sections after transplantation did not reveal any alterations in cell differentiation or tissue structure. We concluded that transplantation of BMCs stimulated decidualization in animals.