Chronic Injury of Mice Bone Marrow Multipotent Hematopoietic Progenitor Cells Induced by Ionizing Radiation / 中国实验血液学杂志

OBJECTIVE@#To explore the chronic injury and its possible mechanism of ionizing radiation on multipotent hematopoietic progenitor cells (MPPs) by determining the related indicators of MPPs in bone marrow of mice post-radiation.@*METHODS@#Sixteen C57BL/6 adult mice were randomly divided into normal control and irradiation groups, 8 mice in each group. The mice in irradiation group were exposed to 6 Gy X-ray. The proportion of bone marrow MPPs, their apoptosis and proliferation 2 months after irradiation were detected by flow cytometry. Mitochondrial activity and levels of reactive oxygen species (ROS) in each MPPs population were detected by Mitotracker Red and DCFDA probes, and the senescent state of MPPs in the bone marrow was analyzed.@*RESULTS@#Ionizing radiation could reduce the proportion of MPPs in mouse bone marrow. The proportions and numbers of MPP1, MPP3 and MPP4 in the bone marrow were significantly decreased after whole-body irradiation with 6 Gy X-ray (P<0.05). In addition, radiation significantly reduced the colony-forming capacity of MPPs in bone marrow (P<0.05), the proportions of apoptotic cells in the MPP1 and MPP4 cell populations increased significantly in the bone marrow (P<0.05). The activity of mitochondria was significantly reduced in the bone marrow MPP2, MPP3 and MPP4 cell populations compared with that of the control group (P<0.05). It was also found that the radiation could significantly increase the ROS levels of MPPs in bone marrow, and the content of ROS in the MPP2, MPP3 and MPP4 cell population of the bone marrow was significantly increased(P<0.05). The senescent cells ratios of MPP1, MPP3 and MPP4 cells in the bone marrow after irradiation were significantly higher than those in the control group (P<0.05).@*CONCLUSION@#Ionizing radiation can cause chronic MPPs damage in mice, which is closely associated with persistent oxidative stress, cells apoptosis, and cellular senescence.

Trasplante de progenitores hematopoyéticos alogénico haploidéntico en aplasia medular, reporte del primer caso en Cuba / Allogenic hematopoietic stem-cell transplantation in marrow aplasia: the first case report in cuba

Introducción: La aplasia medular adquirida grave es una enfermedad hematológica infrecuente caracterizada por una disminución o ausencia de precursores hematopoyéticos en la médula ósea, lo cual se expresa con distintos grados de citopenias. Varios factores, infecciosos o no, pueden incidir en su origen. Su manejo es complejo y puede incluir tratamiento inmunosupresor y trasplante de progenitores hematopoyéticos alogénico. Objetivo: Demostrar la utilidad de la realización del trasplante de progenitores hematopoyéticos alogénico haploidéntico en pacientes con aplasia medular grave. Caso clínico: Paciente masculino de 21 años de edad, con antecedentes de salud, que en octubre del 2018 debutó con íctero, pancitopenia, lesiones purpúrico hemorrágicas en piel y mucosas, en el curso de una hepatitis aguda seronegativa. La biopsia de médula ósea mostró aplasia medular severa. Se inició tratamiento inmunosupresor con globulina antitimocίtica, ciclosporina A y metilprednisolona. Al cabo de los 6 meses mantenía trombocitopenia severa con necesidades transfusionales y en octubre de 2019 se decide realizar trasplante de progenitores hematopoyéticos alogénico con donante haploidéntico y empleando como tratamiento acondicionante globulina antitimocίtica, fludarabina, ciclofosfamida y bajas dosis de irradiación corporal total. En evaluación clίnica de julio de 2020 (dίa + 280 del trasplante) el paciente estaba asintomático y con parámetros hematológicos normales. Conclusiones: Se demostró que el trasplante de progenitores hematopoyéticos alogénico haploidéntico es un proceder realizable y útil en pacientes con aplasia medular grave, lo cual corrobora el beneficio clínico que puede aportar su ejecución en pacientes con esta enfermedad(AU)

Introduction: Acquired severe marrow aplasia is a rare hematological disease characterized by decrease or absence of hematopoietic precursors in bone marrow, which is expressed with different degrees of cytopenias. Several factors, infectious or not, can influence its origin. Its management is complex and may include immunosuppressive treatment and allogeneic hematopoietic stem-cell transplantation. Objective: To demonstrate the usefulness of performing haploidentical allogeneic hematopoietic stem-cell transplantation in patients with severe medullary aplasia. Clinical case: A 21-year-old male patient, with medical history, who first presented, in October 2018, with icterus, pancytopenia, as well as purpuric hemorrhagic lesions on the skin and mucosa, in the course of acute seronegative hepatitis. The bone marrow biopsy showed severe marrow aplasia. Immunosuppressive treatment was started with antithymocytic globulin, cyclosporine A, and methylprednisolone. After six months, he maintained severe thrombocytopenia under transfusion requirements and, in October 2019, the decision was to perform allogeneic hematopoietic stem-cell transplantation with a haploidentical donor and using antithymocyte globulin, fludarabine, cyclophosphamide, and low doses of total body irradiation as conditioning treatment. In the clinical assessment carried out in July 2020 (day +280 after transplantation), the patient was asymptomatic and with normal hematological parameters. Conclusions: Transplantation of haploidentic allogeneic hematopoietic progenitors was shown to be a feasible and useful procedure in patients with severe marrow aplasia, which corroborates the clinical benefit that its execution can bring in patients with this disease(AU)

Impact of pediatric hematopoietic stem-cell transplantation on craniofacial growth

OBJECTIVES: To assess the craniofacial skeletal growth in pediatric hematopoietic stem-cell transplantation (HSCT) survivors in comparison with age-sex matched-paired controls. METHODS: A case-controlled retrospective comparison of the craniofacial growth in 25 HSCT children and 25 matched-paired controls was conducted. Craniofacial growth was quantitatively assessed by linear and angular measurements in panoramic radiographic images using ImageJ¯. Stature growth and body weight were obtained through physical examination. Cancer diagnosis, myeloablative conditioning, and HSCT were retrieved from medical records. RESULTS: Patients aged 12.2 years (±3.8; 16 male, 9 female). Radiographic images were obtained on an average of 2.43 (±2.0) years after HSCT. The main malignant diagnosis was acute lymphoblastic leukemia (56%), followed by acute myeloid leukemia (36%) and myelodysplastic syndromes (8%). Total body irradiation was associated with chemotherapy at 80%. Mean age at transplantation was 10 (±4.7) years. HSCT survivors showed reduced a vertical growth of the mandibular ramus (p=0.003). This persisted among individuals below 12 years of age (p=0.017). The HSCT group showed delayed dental eruption, though there was no statistically significant difference (p=0.3668). The HSCT group showed stature deficit, increased weight, and body mass index (Z-score stature: -0.28; Z-score weight: 0.38, respectively). CONCLUSIONS: Pediatric HSCT has decreased vertical craniofacial growth compared to their matched controls. There might be an association between reduced craniofacial vertical growth and reduced estature growth. Further studies to quantitatively investigate the impact of different myeloablative regimens in craniofacial skeletal growth and development.

Tetramethylpyrazine promotes bone marrow repair in a C57 mouse model of X-rayinduced immune-mediated bone marrow failure / 南方医科大学学报

OBJECTIVE@#To observe the therapeutic effect of tetramethylpyrazine on immune-mediated bone marrow failure (BMF) induced by different doses of X-ray exposure in C57 mice.@*METHODS@#C57BL6 mice were randomized into 4 groups, including a blank control group and 3 X-ray exposure groups with X-ray exposure at low (5.0 Gy), moderate (5.75 Gy), and high (6.5 Gy) doses. After total body irradiation with 0.98 Gy/min X-ray. The mice as recipient received injections of 4×10 lymphocytes from DBA/2 mice via the tail vein within 4 h. The survival rate of the recipient mice, peripheral blood cell counts, bone marrow nucleated cell count, and bone marrow pathology were examined at 14 days after the exposure. In the subsequent experiment, C57 mice were exposed to 5.0 Gy X-ray and treated with intraperitoneal injection of tetramethylpyrazine at the low (5 mg/mL), moderate (10 mg/mL), or high (20 mg/mL) doses (12 mice in each group) for 14 consecutive days, and the changes in BMF were observed.@*RESULTS@#X-ray exposure, especially at the high dose, resulted in significantly lowered survival rate in the mouse models of BMF at 14 days. As the X-ray dose increased, the mice showed significantly reduced peripheral blood counts of red blood cells, white blood cells, platelets and lowered bone marrow nucleated cell counts with obvious bone marrow congestion and reduction of nucleated cells ( < 0.05 or 0.001). In the mice exposed to 5.0 Gy X-ray, tetramethylpyrazine at the high dose most obviously increased bone marrow nucleated cells ( < 0.01) and red blood cells ( < 0.001), and even at the low dose, tetramethylpyrazine significantly increased the counts of white blood cells ( < 0.05) and platelets ( < 0.01) following the exposure. Tetramethylpyrazine dose-dependently alleviated bone marrow hyperemia, increased bone marrow nucleated cell counts, and lowered Fas protein expression in the bone marrow.@*CONCLUSIONS@#X-ray irradiation at 5.0 Gy is suitable for establish mouse models of immune-mediated BMF. Tetramethylpyrazine promotes bone marrow repair by regulating Fas cell apoptosis signals, which further expands the traditional Chinese medicine theory of "removing blood stasis to create new."

Recovery of Spermatogenesis Following Cancer Treatment with Cytotoxic Chemotherapy and Radiotherapy

The survival rates of boys and men with cancer have increased due to advances in cancer treatments; however, maintenance of quality of life, including fertility preservation, remains a major issue. Fertile male patients who receive radiation and/or chemotherapy face temporary, long-term, or permanent gonadal damage, particularly with exposure to alkylating agents and whole-body irradiation, which sometimes induce critical germ cell damage. These cytotoxic treatments have a significant impact on a patient's ability to have their own biological offspring, which is of particular concern to cancer patients of reproductive age. Therefore, various strategies are needed in order to preserve male fertility. Sperm cryopreservation is an effective method for preserving spermatozoa. Advances have also been achieved in pre-pubertal germ cell storage and research to generate differentiated male germ cells from various types of stem cells, including embryonic stem cells, induced pluripotent stem cells, and spermatogonial stem cells. These approaches offer hope to many patients in whom germ cell loss is associated with sterility, but are still experimental and preliminary. This review examines the current understanding of the effects of chemotherapy and radiation on male fertility.

Outcome and prognostic factors of children with Philadelphia chromosome-positive acute lymphoblastic leukemia treated with imatinib followed by allogeneic hematopoietic cell transplantation in first remission

BACKGROUND: Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) is a subset of ALL with poor prognosis. Here, we analyzed the outcomes and prognostic factors of children with Ph+ ALL who received imatinib and chemotherapy followed by allogeneic hematopoietic cell transplantation (HCT) in first complete remission (CR). METHODS: Thirty-one Ph+ ALL patients (female 10) diagnosed from January 2005 to December 2016 were included in the study. All patients were treated with imatinib and chemotherapy before HCT. Bone marrow (BM) evaluations included real-time quantitative polymerase chain reaction (RQ-PCR) study of the BCR-ABL1 fusion transcript. All patients received HCT with total body irradiation (TBI)-based conditioning at a median of 6.4 (range, 4.2–47.1) months from diagnosis. RESULTS: Compared to values at diagnosis, the median decrement of RQ-PCR value post-consolidation, and prior to HCT was −3.7 Log and −4.8 Log, respectively. The 5-year event-free survival (EFS) and overall survival of the patients were 64.5±9.4% (20/31) and 75.0±8.3% (23/31) respectively. Events included relapse (N=5) and death in CR post-HCT (N=6). The 5-year incidence of molecular relapse was 30.9±9.1% (9/31). An RQ-PCR decrement of at least −4 Log post-consolidation significantly predicted lower incidence of molecular relapse: 7.7±7.7% for ≥−4 Log decrement, 50.0±13.8% for <−4 Log decrement (P=0.027). CONCLUSION: Decrement in RQ-PCR for the BCR-ABL1 transcript that was determined after consolidation was the only significant prognostic factor for incidence of molecular relapse. In the post-induction TKI initiation setting, steadfast imatinib treatment during consolidation may allow for optimum post-HCT outcomes.

MMP Inhibitor Ilomastat Improves Survival of Mice Exposed to γ-Irradiation / 生物医学与环境科学（英文）

There is still a need for better protection against or mitigation of the effects of ionizing radiation following conventional radiotherapy or accidental exposure. The objective of our current study was to investigate the possible roles of matrix metalloproteinase inhibitor, ilomastat, in the protection of mice from total body radiation (TBI), and the underlying protective mechanisms. Ilomastat treatment increased the survival of mice after TBI. Ilomastat pretreatment promoted recovery of hematological and immunological cells in mice after 6 Gy γ-ray TBI. Our findings suggest the potential of ilomastat to protect against or mitigate the effects of radiation.

Myeloablative Hematopoietic Stem Cell Transplantation with a Non-total Body Irradiation Regimen for Treating Pediatric Acute Lymphoblastic Leukemia / 임상소아혈액종양

BACKGROUND: Total body irradiation (TBI) has been traditionally used as a conditioning regimen prior to hematopoietic stem cell transplantation (HSCT) in patients with pediatric leukemia. However, TBI can cause late sequelae such as growth impairment, cataract, hormone abnormalities, infertility, neurocognitive effects, and secondary malignancy in pediatric patients. METHODS: This single center retrospective study included 22 patients with acute lymphoblastic leukemia who were aged <18 years and underwent HSCT between May 1999 and December 2014; seven patients received a TBI-based regimen and 15 received a non-TBI regimen. RESULTS: The overall survival and event-free survival rates in the TBI group were not significantly different from those in the non-TBI group (overall survival rate 71% vs. 73%, respectively; P=0.906; event-free survival rate 71% vs. 73%, respectively P=0.923). CONCLUSION: Our results indicate that non-TBI conditioning regimens can be an alternative treatment option of the treatment of pediatric acute lymphoblastic leukemia undergoing HSCT.

Factors associated with pulmonary toxicity after myeloablative conditioning using fractionated total body irradiation

PURPOSE: Pulmonary toxicities, including infectious pneumonia (IP) and idiopathic pneumonia syndrome (IPS), are serious side effects of total body irradiation (TBI) used for myeloablative conditioning. This study aimed to evaluate clinical factors associated with IP and IPS following TBI. MATERIALS AND METHODS: Fifty-eight patients with hematologic malignancies who underwent TBI before allogeneic hematopoietic stem cell transplantation between 2005 and 2014 were reviewed. Most patients (91%) received 12 Gy in 1.5 Gy fractions twice a day. Pulmonary toxicities were diagnosed based on either radiographic evidence or reduced pulmonary function, and were subdivided into IP and IPS based on the presence or absence of concurrent infection. RESULTS: Pulmonary toxicities developed in 36 patients (62%); 16 (28%) had IP and 20 (34%) had IPS. IP was significantly associated with increased treatment-related mortality (p = 0.028) and decreased survival (p = 0.039). Multivariate analysis revealed that the risk of developing IPS was significantly higher in patients who received stem cells from a matched unrelated donor than from a matched sibling donor (p = 0.021; hazard ratio [HR] = 12.67; 95% confidence interval [CI], 1.46–110.30). Combining other conditioning agents with cyclophosphamide produced a higher tendency to develop IP (p = 0.064; HR = 6.19; 95% CI, 0.90–42.56). CONCLUSION: IP and IPS involve different risk factors and distinct pathogeneses that should be considered when planning treatments before and after TBI.

Factors associated with pulmonary toxicity after myeloablative conditioning using fractionated total body irradiation

PURPOSE: Pulmonary toxicities, including infectious pneumonia (IP) and idiopathic pneumonia syndrome (IPS), are serious side effects of total body irradiation (TBI) used for myeloablative conditioning. This study aimed to evaluate clinical factors associated with IP and IPS following TBI. MATERIALS AND METHODS: Fifty-eight patients with hematologic malignancies who underwent TBI before allogeneic hematopoietic stem cell transplantation between 2005 and 2014 were reviewed. Most patients (91%) received 12 Gy in 1.5 Gy fractions twice a day. Pulmonary toxicities were diagnosed based on either radiographic evidence or reduced pulmonary function, and were subdivided into IP and IPS based on the presence or absence of concurrent infection. RESULTS: Pulmonary toxicities developed in 36 patients (62%); 16 (28%) had IP and 20 (34%) had IPS. IP was significantly associated with increased treatment-related mortality (p = 0.028) and decreased survival (p = 0.039). Multivariate analysis revealed that the risk of developing IPS was significantly higher in patients who received stem cells from a matched unrelated donor than from a matched sibling donor (p = 0.021; hazard ratio [HR] = 12.67; 95% confidence interval [CI], 1.46–110.30). Combining other conditioning agents with cyclophosphamide produced a higher tendency to develop IP (p = 0.064; HR = 6.19; 95% CI, 0.90–42.56). CONCLUSION: IP and IPS involve different risk factors and distinct pathogeneses that should be considered when planning treatments before and after TBI.

Effect of Coenzyme Q10 on Radiation Nephropathy in Rats

The kidney is one of the most radiosensitive organs in the abdominal cavity and is the dose-limiting structure in cancer patients receiving abdominal or total body irradiation. In the present study, the effect of coenzyme Q10 (CoQ10) on radiation nephropathy was evaluated in rats. A total of 72 rats were equally randomized into 4 groups: Control, CoQ10, irradiation with 10 Gy (RT) + placebo, or RT + CoQ10. The 2 RT groups received single 10 Gy of abdominal irradiation. The 2 CoQ10 groups were supplemented daily with 1 mL of soybean oil containing 10 mg/kg of CoQ10. The RT + placebo and control groups received same dose of soybean oil. After 24 weeks, laboratory and histopathologic findings were compared. The 2 RT groups showed significant increases in blood urea nitrogen (BUN) and creatinine levels and significant pathologic changes such as glomerulosclerosis and tubulointerstitial fibrosis. CoQ10 supplementation resulted in significant reductions of BUN and creatinine levels compared with the RT + placebo group (P < 0.001 and P = 0.038, respectively). CoQ10 treatment significantly attenuated glomerular and tubular changes of irradiated kidney in semiquantitative analysis (P < 0.001 for both). Administration of CoQ10 can alleviate the radiation-induced nephropathy.

Comparison of Total Body Irradiation (TBI) Conditioning with Non-TBI for Autologous Stem Cell Transplantation in Newly Diagnosed or Relapsed Mature T- and NK-Cell Non-Hodgkin Lymphoma / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: This retrospective study was conducted for comparison of survival outcomes and toxicities of autologous stem cell transplantation (ASCT) based on the use of total body irradiation (TBI) as a part of the conditioning regimen in patients with mature T- and natural killer (NK)-cell lymphomas. MATERIALS AND METHODS: Patients who underwent ASCT in the upfront or salvage setting between January 2000 and December 2013 were analyzed. Patients were dichotomized according to the TBI group (n=38) and non-TBI group (n=60) based on the type of conditioning regimen for ASCT. RESULTS: Patients with responsive disease underwent upfront ASCT (TBI, n=16; non-TBI, n=29) whereas patients with refractory disease (TBI, n=9; non-TBI, n=12) or relapsed disease (TBI, n=13; non-TBI, n=19) underwent ASCT after salvage treatment. Hematologic and non-hematologic toxicities were manageable, and the median cumulative toxicity score according to Seattle criteria was estimated as 2 (range, 0 to 7) in both groups. No significant difference in 100-day mortality was observed between the TBI (13%, 5/38) and non-TBI (12%, 12/60) groups, and most deaths were related to disease progression. There was no difference in overall and progression-free survival; however, the TBI group showed a trend of better survival in upfront and salvage ASCT than the non-TBI group. However, patients with refractory disease showed the worst outcome regardless of the use of TBI. Patients who showed complete response before ASCT showed better progression-free survival than thosewho showed partial response. CONCLUSION: TBI could be used as an effective part of conditioning for ASCT in patients with mature T- and NK-cell lymphomas.

Myeloablative Hematopoietic Stem Cell Transplantation with a Non-total Body Irradiation Regimen for Treating Pediatric Acute Lymphoblastic Leukemia / 임상소아혈액종양

BACKGROUND: Total body irradiation (TBI) has been traditionally used as a conditioning regimen prior to hematopoietic stem cell transplantation (HSCT) in patients with pediatric leukemia. However, TBI can cause late sequelae such as growth impairment, cataract, hormone abnormalities, infertility, neurocognitive effects, and secondary malignancy in pediatric patients.METHODS: This single center retrospective study included 22 patients with acute lymphoblastic leukemia who were aged <18 years and underwent HSCT between May 1999 and December 2014; seven patients received a TBI-based regimen and 15 received a non-TBI regimen.RESULTS: The overall survival and event-free survival rates in the TBI group were not significantly different from those in the non-TBI group (overall survival rate 71% vs. 73%, respectively; P=0.906; event-free survival rate 71% vs. 73%, respectively P=0.923).CONCLUSION: Our results indicate that non-TBI conditioning regimens can be an alternative treatment option of the treatment of pediatric acute lymphoblastic leukemia undergoing HSCT.

Fertility preservation for patients with hematologic malignancies: The Korean Society for Fertility Preservation clinical guidelines / 대한생식의학회지

Although the survival rate of hematologic malignancies in young patients is very high, cytotoxic therapies such as chemotherapy and total body irradiation therapy can significantly reduce a patient's reproductive capacity and cause irreversible infertility. Early ovarian failure also commonly occurs following additional cancer treatment, bone marrow transplantation, or autologous transplantation. Because the risk of early ovarian failure depends on the patient's circumstances, patients with a hematologic malignancy must consult health professionals regarding fertility preservation before undergoing treatments that can potentially damage their ovaries. While it is widely known that early menopause commonly occurs following breast cancer treatment, there is a lack of reliable study results regarding fertility preservation during hematologic malignancy treatment. Therefore, an in-depth discussion between patients and health professionals about the pros and cons of the various options for fertility preservation is necessary. In this study, we review germ cell toxicity, which occurs during the treatment of hematologic malignancies, and propose guidelines for fertility preservation in younger patients with hematologic malignancies.

Acute Hyperglycemia Associated with Anti-Cancer Medication

Hyperglycemia during chemotherapy occurs in approximately 10% to 30% of patients. Glucocorticoids and L-asparaginase are well known to cause acute hyperglycemia during chemotherapy. Long-term hyperglycemia is also frequently observed, especially in patients with hematologic malignancies treated with L-asparaginase-based regimens and total body irradiation. Glucocorticoid-induced hyperglycemia often develops because of increased insulin resistance, diminished insulin secretion, and exaggerated hepatic glucose output. Screening strategies for this condition include random glucose testing, hemoglobin A1c testing, oral glucose loading, and fasting plasma glucose screens. The management of hyperglycemia starts with insulin or sulfonylurea, depending on the type, dose, and delivery of the glucocorticoid formulation. Mammalian target of rapamycin (mTOR) inhibitors are associated with a high incidence of hyperglycemia, ranging from 13% to 50%. Immunotherapy, such as anti-programmed death 1 (PD-1) antibody treatment, induces hyperglycemia with a prevalence of 0.1%. The proposed mechanism of immunotherapy-induced hyperglycemia is an autoimmune process (insulitis). Withdrawal of the PD-1 inhibitor is the primary treatment for severe hyperglycemia. The efficacy of glucocorticoid therapy is not fully established and the decision to resume PD-1 inhibitor therapy depends on the severity of the hyperglycemia. Diabetic patients should achieve optimized glycemic control before initiating treatment, and glucose levels should be monitored periodically in patients initiating mTOR inhibitor or PD-1 inhibitor therapy. With regard to hyperglycemia caused by anti-cancer therapy, frequent monitoring and proper management are important for promoting the efficacy of anti-cancer therapy and improving patients' quality of life.

Therapeutic Effect of Combined Cytokines on Nonhuman Primate Model of Severe Haemopoietic Acute Radiation Sickness / 中国实验血液学杂志

<p><b>OBJECTIVE</b>To evaluate the therapeutic effects of combined administration of recombinant human granulocyte colony-stimulating factor (rhG-CSF), recombinant human thrombopoietin (rhTPO) and recombinant human interleukin-2 (rhIL-2) on radiation-induced severe haemopoietic acute radiation sickness (ARS) in rhesus monkeys, so as to provide experimental evidences for the effective clinical treatment.</p><p><b>METHODS</b>Seventeen rhesus monkeys were exposed to 7.0 Gy (60)Co γ-ray total body irradiation (TBI) to establish severe haemopoietic ARS model, and were randomly divided into supportive care group, rhG-CSF+rhTPO treatment group and rhG-CSF+rhTPO+rhIL-2 treatment group. Survival time, general signs such as bleeding and infections, and peripheral blood cell counts in each group were monitored. Bone marrow cells were cultivated to examine the colony formation ability. The histomorphology changes of bone marrow were observed at 45 d post irradiation.</p><p><b>RESULTS</b>After 7.0 Gy (60)Co γ-ray TBI, monkeys of supportive care group underwent tarry stool and emesis, then died in 12~18 d. The overall survival rate in this group was 16.7%. Gastrointestinal reactions of monkeys in two combined-cytokines treatment groups were inapparent. Combined-cytokines treatment induced 100% survival. Complete blood cells declined sharply after irradiation in each group, but two combined-cytokines treatment schemes could elevate the nadir of all blood cells, shorten the duration of pancytopenia and accelerate the recovery of hemogram. Compared with rhG-CSF+ rhTPO treatment, rhG-CSF+ rhTPO+ rhIL-2 treatment could increase the counts of lymphocytes and monocytes. The colony-formation rate of haemopoietic stem/progenitor cells in bone marrow dropped markedly at 2 d after irradiation. Combined-cytokines treatment promoted the ability of colony formation on day 29. Hematopoietic cells mostly disappeared in bone marrow of animals in supportive care group, but hematopoietic functions were recovered after cytokines were administrated.</p><p><b>CONCLUSION</b>rhG-CSF+ rhTPO and rhG-CSF+ rhTPO+ rhIL-2 treatment can significantly promote hematopoiesis recovery, improve the quantity of life, simplify the supportive therapy, and enhance the survival rate of rhesus monkeys with severe haemopoietic ARS induced by 7.0 Gy (60)Co γ-ray exposure. Especially the application of rhIL-2 can accelerate the recovery of lymphocytes and monocytes and restore the immunological function. Thus, combination of rhG-CSF, rhTPO and rhIL-2 on the basis of supportive care is an efficient strategy to treat severe haemopoietic ARS.</p>

Hepatic veno-occlusive disease may develop in secondary iron overloaded mice after allogeneic hematopoietic stem cell transplantation with total body irradiation

BACKGROUND: The outcome of hematopoietic stem cell transplantation (HSCT) is poor in patients with secondary iron overload (SIO). We evaluated the relationship between SIO and veno-occlusive disease (VOD) in an animal model with radiation for HSCT. METHODS: We used a 6-week-old female BDF1 (H-2b/d) and a male C57/BL6 (H-2b) as recipient and donor, respectively. Recipient mice were injected intraperitoneally with 10 mg of iron dextran (cumulative doses of 50 mg, 100 mg, and 200 mg). All mice received total body irradiation for HSCT. We obtained peripheral blood for alanine transaminase (ALT) and liver for pathologic findings, lipid hyperoxide (LH) as reactive oxygen species (ROS), and liver iron content (LIC) on post-HSCT day 1 and day 7. The VOD score was assessed by pathologic findings. RESULTS: ALT levels increased depending on cumulative iron dose, with significant differences between days 1 and 7 for mice loaded with 200 mg of iron (P<0.01). LH levels significantly increased in mice loaded with 200 mg of iron compared to those in other groups (P<0.01). For mice loaded with 100 mg of iron, the LH level depended on the radiation dose (P<0.01). There was a statistically significant relationship among ALT, LH, and LIC parameters (P<0.05). Pathologic scores for VOD correlated with LIC (P<0.01). CONCLUSION: Livers with SIO showed high ROS levels depending on cumulative iron dose, and correlations with elevated liver enzyme and LIC. The pathologic score for VOD was associated with the LIC. Our results suggest that SIO may induce VOD after HSCT with irradiation.

Study of biological markers for radiation pretreatment of hematopoietic stem cell transplant recipients / 中华血液学杂志

<p><b>OBJECTIVE</b>To study the early biological parameter changes of blood and immune systems of mice after 60Co γ-ray irradiation in order to find sensitive and reliable biological dose markers for radiation pretreatment of hematopoietic stem cell transplant recipients.</p><p><b>METHODS</b>Pure strain BALB/c male mice were randomly divided into control group and three irradiation groups and absorbed doses of total body irradiation by ⁶⁰Co γ-ray were 0, 2, 4, 6 Gy, respectively. In 24h after irradiation, WBC counts and lymphocyte percentages of peripheral blood were determined by blood cell counting; polychromatic erythrocyte micronucleus（mn- PCE） of peripheral blood and bone marrow were observed by microscope after Giemsa staining; apoptosis rates of bone marrow, spleen, thymus cells were assayed by flow cytometry using Annexin Ⅴ and PI double staining.</p><p><b>RESULTS</b>Compared with the control group, WBC counts and lymphocyte percentages of peripheral blood in the irradiated groups significantly decreased with the increase of radiation doses（P<0.01），and their regression equations were E=0.1750D2-1.7440D+5.2020 and E=84.9390-3.4255D respectively. The mn-PCE of peripheral blood and bone marrow in the irradiated groups significantly increased with the increase of radiation doses（P<0.01）, bone marrow mn-PCE was positively correlated with the radiation dose with regression equation as E=3.9725D+2.9700. The early apoptosis rates of bone marrow cells, spleen and thymus cells significantly increased with the increase of radiation doses（P<0.01）, which were positively correlated with radiation doses, and their regression equations were E=3.42D + 8.36, E=3.0645D + 3.1840 and E=2.5620D + 2.5090 respectively.</p><p><b>CONCLUSION</b>Peripheral blood lymphocyte count and bone marrow mn-PCE rate were linearly correlated to radiation doses, which could be used as sensitive and reliable early biological markers of the radiation pretreatment recipients, and the doses of the radiation pretreatment recipients could be accurately judged according to their regression equations. The early apoptosis rates of bone marrow, spleen and thymus cells were positive linear correlation with the radiation doses, and their regression equations could be used to judge the degree of inhibition of the immune system for radiation pretreatment recipients.</p>

Rapamycin decreases irradiation-induced hematopoietic system damage / 中华血液学杂志

<p><b>OBJECTIVE</b>To explore the protection function of rapamycin in hematopoietic system damage induced by irradiation.</p><p><b>METHODS</b>Six to eight week old C57BL/6J male mice were used for experiment. Mice received 4 mg/kg rapamycin by i.p.injection every other day for 5 times. The day after the last injection, mice were exposed to a dose (5 Gy) of total body irradiation (TBI). Peripheral blood was measured by a complete blood count at 0.5, 1, 2, 3, 5, 7, 40, 70 days after TBI. The hematoxylin-eosin staining was used to observe the pathologic changes in sternum obtained from mice at day 5 after TBI. CFU-S of spleen was measured by immerging in Tellyesniczky solution for 24 h at day 5 after TBI.</p><p><b>RESULTS</b>Before TBI, WBC and LYM decreased in rapamycin-treated mice compared with control (P<0.01); RBC and HGB increased (P<0.05); there was no difference in PLT; HE staining of bone marrow from rapamcin-treated and control mice before irradiation showed no difference in marrow cellularity. After TBI, WBC and LYM decreased significantly, with no difference at 0.5 d to 7 d between rapamycin-treated and control. The counts of WBC and LYM in rapamycin-treated mice restored to normal at 40 d and 70 d. RBC and HGB decreased at irradiation group at 3 d to 7 d, but rapamycin stimulated them to a higher level, both of them tended to normal at 40 d and 70 d. HE staining of bone marrow after 5 day of 5 Gy irradiation, nucleated cells in control decreased significantly, but restored in rapamycin-treated mice. CFU-S results showed the colony number in rapamycin-treated mice was much higher than control mice after 5 Gy irradiation, with 40.00±12.86 and 13.20±2.31 (P=0.035), respectively.</p><p><b>CONCLUSION</b>Administration of rapamycin to mice before irradiation protected the mice from hematopoietic damage induced by irradiation by maintaining the bone marrow nucleated cells, slowing down decrease and promoting the restoration of peripheral blood cells and protecting hematopoitic stem/progenitor cells in spleen.</p>

Evaluation of a novel decorporation approach to prevent radioactivity uptake by using acidosis in experimental animals.

With an aim to devise a prophylactic and/or therapeutic approach for preventing internalization of radiothallium (201Tl), and more importantly by implication, its chemical analogue radiocesium (137Cs) during any nuclear emergency, different ex vivo and in vivo animal models were created to determine the role of pH in absorption of 201Tl across jejunum/muscle tissue and whole body retention of 201Tl respectively. Movement of Tl+ under simulated pH conditions proved that pH had direct influence on its absorption. Oral intake of acidified water or parenteral administration of lactic acid was able to reduce the body burden of 201Tl by up to 12 and 50% respectively. The results indicate that acidification of gut, within physiological range may be used as an option for decorporation/inhibition of incorporation of radiothallium and radiocesium, particularly in cases of mass casualty.