bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adjustment of Immonosuppressants Based on T Lymphocyte Chimerism Following Allogeneic Hematopoietic Stem Cell Transplantation.
Authors: Wang Chun , Wan Liping , Yan Shike , Jiang Jieling , Yang Jun , Qin Youwen 
Published: October 2019

Abstract
Twenty-eight patients with a median age of 38 (15~54) years received allogeneic peripheral blood stem cell transplantation (allo-HSCT). Diagnoses included AML (n=7), ALL (n=2), CML (n=13), MM (n=4), MDS (n=1) and advanced ovarian cancer (n=1). Thirteen patients of them had progressive diseases. Myeloablative conditioning was given to 12 patients and non-myeloablative conditioning to 16 patients. FACS sorted granulocytes, T lymphocytes, B lymphocytes and NK cells from peripheral blood of all patients were analyzed for PCR amplification of short tandem repeats. The purity of sorted cells was above 96%. On day 7 posttransplant, the chimerism of NK cells was the highest in 88.5% patients, indicating that NK cells were the earliest engrafting cells. The subpopulations of granulocytes, B lymphocytes and NK cells reached complete chimerism (CC) on a median of day 14 posttransplant, while T lymphocytes were the latest subpopulation to reach CC in both myeloablative and non-myeloablative transplant on a median of day 21 and day 28 posttransplant, respectively. Seven patients with myeloid malignancy had molecular omen of graft rejection or disease relapse. Three patients of them had chimerism of donor T cells shifting from CC to MC only, while other subpopulation of cells remained CC. T cell chimerism in 2 patients of them remained lowest level among all subpopulation of cells. Recipient T cells had decreasing MC in 5 cases after discontinuance of immunosuppressant and donor lymphocyte infusion, 3 of them achieved CC again. Eight cases developed acute GVHD in 19 stable CC patients. Seven of them had GVHD after CC was achieved by all cell subsets. None of the patients in unstable CC group developed GVHD before they had graft rejection or relapse. The rate of acute GVHD of CC group was higher than MC group(χ2=4.25, P<0.05). We conclude that donor T lymphocytes are the earliest subpopulation of cells to subside during the course of graft rejection and disease relapse in myeloid malignancy. Patients responding to adjustment of immunosuppressants and/or DLI could achieve CC of T lymphocyte fraction again. CC of T lymphocyte could be a marker of stable engraftment of donor cells. Progressive MC of T cell is the omen of graft rejection and disease relapse. Immunosuppressant dosage should be adjusted according to T lymphocyte chimerism for different patients. GVHD prevention should be preferred in patients who reach CC in T cell fraction in one month after transplant. Therefore we suggest the patients might be given higher dose and longer period of immunosuppressants in 3 months posttransplant. In order to promote the engraftment of donor cell and avoid disease recurrence, the immunosuppressants might be tapered in the patients who do not reach CC in T cell fraction in one month after transplant and the patients with progressive MC in T cell.
Polymorphisms of MBL2, Encoding Mannan-Binding Lectin, Influences the Risk of Sepsis in Multiple Myeloma Patients during Autologous Stem Cell Transplantation (ASCT).
Authors: Molle Ingolf , Peterslund Niels A. , Steffensen Rudi , Thiel Steffen 
Published: October 2019

Abstract
Polymorphisms of various immune defence genes interfere with the risk of severe infections in critically ill patients. This includes studies on autologous and allogeneic stem cell transplantation (ASCT).
Mannan-binding lectin (MBL) is a plasma protein which is able to recognize carbohydrate structures forming pathogen associated molecular patterns on the surface of bacteria and viruses. When binding to pathogens occur the complement system is activated leading killing of the microorganisms. Lack of MBL may lower the ability to resist infections.
The gene MBL2, encoding mannan-binding lectin (MBL), contains three well-characterized single nucleotide polymorphisms B (G54D), C (G57E), and D (R52C) (collectively termed O in contrast to the wild-type A). The presence of O variants greatly reduces the effector functions of MBL.
We examined the impact of the polymorphisms on the occurrence of severe infections related to ASCT in patients with multiple myeloma. Patients were genotyped with PCR techniques using aliquots of peripheral stem cells from apheresis. Infectious complications were recorded retrospectively from clinical records and database extractions from the Department of Microbiology. One hundred and thirteen consecutive patients were studied. During ASCT 71 patients (63%) had fever above 38.5°C despite prophylactic antibiotics. Eleven (10%) patients had proven sepsis. MBL2 analyses: 4/71 patients with AA genotype had sepsis versus 7/41 with AO/OO genotype (p=0.09). Two lethal cases of sepsis were seen in the AO/OO patients, none in the AA patients. In multivariate analyses the risk of sepsis was significantly lower in AA patients: OR 0.15 (95% CI: 0.03–0.74), p=0.02. Wild-type MBL2, associated with a high function of mannose-binding lectin, probably reduces the risk of sepsis in myeloma patients during ASCT. Myeloma patients with variant MBL2 may be candidates for future MBL replacement trials.
Single Center Analysis of Risk Factors for Puberty Disorders in Children after Allogeneic Haematopoietic Stem Cell Transplantation (HSCT).
Authors: Wojcik Dorota M. , Barg Ewa , Niedzielska Ewa , Kalwak Krzysztof , Ussowicz Marek , Doroszko Adrian , Chybicka Alicja 
Published: October 2019

Abstract
Background
Preparative regimen consisting of high dose chemotherapy HDC/T and/or cranial irradiation (CI) in combination with prolonged steroid therapy may cause abnormal gonadal function.
Objective
Evaluate puberty disorders in children occurring after HSCT as single center experience.
Material and methods
The study group consisting of 21 patients (13 girls and 8 boys) age 10–20 years at grafting (median 14 years) was prospectively evaluated post grafting. The indications for HSCT were: ALL (5), AML (4), CML (5), MDS (2) and NHL, JMML, SAA, Blackfan Diamond anemia, RMS. According to donor availability 11 children had mached sib donors (MSD), 7 matched unrelated donors (MUD) and 3 patients HLA-mismatched related donors. The preparative regimens consisted of HDC/T usually BU/MEL (2pts); BU/CY/VP (5pts); BU/CY/ATG (4pts) and total body irradiation (TBI) received 3 patients with 12 Gy. CI prior to grafting was delivered to 5 children: 18 Gy (4) and 24 Gy (1). Prolonged high doses steroids (beyond day +28) received 7 children prior to- and 10 children after grafting. Endocrine function after allo-HSCT was evaluated from 10 to 42 (median 26 months). Analysis of LH, FSH, PRL, oestradiol and testosterone levels, fT3, fT4, aTPO, TRH test and LHRH test was performed in all study patients. Bone age according to Pyle-Grulich method was estimated.
Results:
Abnormal gonadal function was present in 12/21 children (9 girls, 3 boys) in average 28 months after HSCT Primary amenorrhea occurred in 3, secondary amenorrhea in 6 girls. Delayed bone age was documented in 2 children in average 30 mths post grafting. No significant correlation was found between children’s age during allo-HSCT and occurrence of puberty disorders. Gender of children had no effect on evalated variables. Time elapsing from HSCT did not influence the occurrence of abnormal gonadal function. No association was found between abnormal gonadal function and TBI, prolonged high doses steroids prior to- and after HSCT. Occurrence of puberty disorders was statistically significantly blunted by conditioning regimen containing Cyclophosphamide (p=0,019) and Busulfan (p=0,0179) while Melfalan did not turn out such a risk factor. PRL levels and thyroid function do not have any determination on occurrence of abnormal gonadal function after HSCT.
Conclusion:
Abnormal gonadal function as late effect frequently occure after HSCT. High-dose Cyclophoshamide and Busulphan tretaed children often had blunted puberty. Melfalan and TBI, however, did not cause such an effect reported by others. Endocrinological care for patients after HSCT is necessary in order to: - Discover the impaired endocrine function - Initiate correct hormonal substitution therapy - Significantly improve the quality of life after allo- HSCT and - Secondary prevent treatment related complications.
Campath-1H-Containing Reduced Intensity Regimen Followed by Unrelated Allogeneic Stem Cell Transplantation in Patients with Advanced Hematologic Malignancies.
Authors: Magalhaes-Silverma Margarida , Carter Thomas , Schlueter Annette , Gingrich Roger 
Published: October 2019

Abstract
BACKGROUND: Graft versus host disease (GVHD) remains a major cause of mortality after unrelated transplants. Reduced intensity conditioning regimens (RIC) followed by allogeneic stem cell transplantation (SCT) with in vivo T-cell depletion using Campath-1H have been shown to decrease the incidence of GVHD. We report our experience with such an approach in 19 patients (pts) with advanced hematologic malignacies who undergone unrelated SCT.
PATIENTS AND METHODS: Between October 2001 and June 2003, 19 pts with a median age of 56 years (range 18–70) not eligible for ablative SCT received Campath-1H 20 mg/m2, fludarabine 25 mg/m2 × 5 days and either cyclophosphamide 1 g/m2 × 2 days (n=16pts), melphalan 140mg/m2 (1 pt) or busulfan 0.8 mg/m2 × 8 doses (n=2pts) followed by G-CSF stimulated peripheral blood (n=13) or unmanipulated bone marrow (n=6). GVHD prophylaxis consisted of cyclosporin at least until T+60 and mycophenolate mofetil through T+30. DLI was allowed for residual disease/progressive disease or mixed chimerism after T+ 60, in the absence of acute GVHD. Seven pts had a previous autologous transplant. Ten pts had myeloid diseases (AML=6, CML Ph negative=1, CML accelerated phase =1, therapy related MDS=1, myelofibrosis=1); 9 pts lymphoid (HD=3, NHD=5, PLL=1); Only 5 pts were in CR at transplant. Six pts received bone marrow witha median CD34+ cells infused of 3.7 × 106/Kg, and 13 pts received peripheral blood with a median of 4.5 × 106/Kg CD34+ cells infused.
RESULTS:19 pts achieved ANC>0.5 × 106/L within a median of 12 days (range 8–16); 2 pts rejected the graft and 1 had autologous reconstitutuion; 10/19 pts achieved sustained platelet engraftment at a median of 16 days (range7–27). 2/17 pts with sustained engraftment developed acute GVHD (grade IV T+30 and grade III T+53); 7/14 at risk pts had CMV reactivation; TRM at T+100 was 16% (disease progression in 2 and GVHD in 1). Nine pts received DLI (5 for mixed chimerism and 4 pts for persistent/progressive disease). After DLI, 5 pts had GVHD limited to skin. None of the pts receiving DLI for persistent/progressive disease responded. Response to transplant was as follows: CR in 3/6 AML pts, CR in 1/1 pt with myelofibrosis, CR in 3/3 HD pts, CR in 3/5 NHL pts. Five pts (26%) remain alive in CR at T+ 36, 42, 50, 56 and 66 months. Causes of death include disease progression/relapse in 7 pts, CMV disease in 1 pt, sepsis in 2 pts, GVHD in 3 pts (2 underwent a second transplant), other malignancy in 1 pt.
CONCLUSION: These results confirm that unrelated SCT with in vivo T -cell depletion using Campath-1H is well tolerated. This approach is associated with low TRM even in pts with advanced disease, and some can achieve long-term disease control. Disease progression/relapse remains a major impediment to this approach.
Submyeloablative Cord Blood Transplant Corrects Clinical Defects Seen in IPEX Syndrome.
Authors: Lucas Kenneth G. , Comito Melanie A. , Ungar David R. , Groh Brandt P. 
Published: October 2019

Abstract
IPEX syndrome (immune dysfunction, polyendocrinopathy, enteropathy, X-linked) is a disorder of regulatory T cell function caused by mutations in the FOXP3 gene. This disorder is generally associated with a fatal outcome early in life from complications related to bleeding, infection, or enteritis. Allogeneic stem cell transplant (SCT) can be curative for this disorder, but pre-transplant disease-related complications may preclude a full myeloablative conditioning regimen. We report a seven year old boy with IPEX whose pre-transplant course was complicated by recurrent laryngeal papillomas and severe airway obstruction, frequent pulmonary infections, and recurrent gastrointestinal hemorrhage. Due to these problems he underwent a submyeloablative conditioning regimen consisting of fludarabine 30 mg/m2/day for 6 days, Busulfan 0.8 mg/kg/dose every 6 hours for 2 days, then anti-thymocyte globulin 2.5 mg/kg/dose for 4 days. Mycophenylate and cyclosporine were used for graft versus host disease (GVHD) prophylaxis. This patient received an HLA 5/6 matched (A,B,DR) unrelated donor cord blood transplant with 1.1 ×108 total nucleated cells/kg and 3 × 105 CD34+ cells/kg. His diarrhea and airway issues resolved following the conditioning regimen. The patient achieved myeloid engraftment on day 14, and was platelet and red cell transfusion independent by day 29 and 56, respectively. He had 81% and 98% donor chimerism at 2 and 9 months post-transplant, respectively. While tapering cylcosporine he developed graft versus host disease of the lower GI tract, which was sucessfully treated with a course of corticosteroids. He also experienced reactivation of EBV and was treated with 4 weekly doses (375 mg/m2) of anti-CD20 monoclonal antibody. This patient has had full resolution of his clinical symptoms and is currently 17 months post-transplant, with no signs of GVHD. For those children who do not respond or have only partial improvement following immunosuppressive therapy, allogeneic SCT using a submyeloablative approach can be well tolerated and result in sustained donor chimerism.
HSV ICP0 Inhibits TLR-Mediated NF-κB Response to TLR Signaling.
Authors: Tolba Khaled A. , Bowers William , Tan Yaohong , Daubeuf Sandrine , Federoff Howard J. , Rosenblatt Joseph D. 
Published: October 2019

Abstract
HSV infection activates a robust innate response through engagement of multiple pattern recognition receptors (PRR) including both TLR (TLR2 and TLR9) as well as non-TLR. Signaling events downstream of these receptors activate NF-κB and IRF3 responsive genes and initiate an innate inflammatory response aimed at controlling viral replication and spread. In this work, we studied immune suppressive activity of a replication-defective HSV virus and identified the immediate early protein ICP0 as a negative regulator of both NF-κB and IRF3 signaling. ICP0 possesses an ubiquitin E3 ligase function through its NH2 RING domain, as well as de-ubiquitinating activity through its association with the cellular de-ubiquitinating enzyme USP7 (HAUSP). We show that these two domains of ICP0 function independently to suppress IRF3 and NF-κB signaling, respectively and, in the process, effectively shut down host innate immunity to HSV infection. Although ICP0 inhibition of IRF3 has been reported, inhibition of TLR-mediated NF-κB response has not been previously described. We show that ICP0 globally inhibits NF-κB response to all TLR receptors as well as IL-1R. ICP0 exerts this activity by associating with USP7 and altering its cellular localization from a nuclear to cytoplasmic protein. In the cytosol, USP7 associates with and de-ubiquitinates TRAF6 and IKK-γ (NEMO), two signaling components of the TLR-mediated NF-κB pathway that are poly-ubiquitinated upon TLR activation. ICP-0 expression vectors harboring point mutations/deletions that target the RING domain E3 ligase function or compromise ICP-0 ability to bind USP7 would selectively inhibit its ability to interfere with either IRF3 or NF-kB signaling, respectively. In support of this, knockdown of endogenous USP7 by RNAi severely impaired ICP0-mediated inhibition of NF-κB response while leaving its capacity to inhibit IRF3 intact. In contrast, over-expression of USP-7 was sufficient to inhibit TLR-mediated NF-κB response. Ability of ICP-0 to inhibit both IRF3 and NF-κB signaling pathways, the former through its E3 ligase function and the latter through its association with USP-7, affords HSV comprehensive protection from host immunity during repeated cycles of lytic infection and reactivation from latency. The work also identifies a rare example of how two seemingly contradictory biologic functions resident within ICP0, namely ubiquitin E3 ligase activity at the NH2 terminus RING domain and de-ubiquitinating activity through association with USP-7, could cooperate to inhibit multiple signaling pathways necessary for efficient silencing of innate immunity. Finally, the work also identifies a previously unknown function for USP7 in regulating innate signaling beyond its known function as a regulator of p53.
The Prevalence of Anemia in Older Nursing Facility (NF) Residents with Chronic Kidney Disease (CKD).
Authors: Tangalos Eric G. , Erwin Gary , Stuart Bruce , Molotsky Sandra , Dybicz Sharon , Barlev Arie , Sciarra Angela , Audhya Paul 
Published: October 2019

Abstract
Anemia and CKD contribute to poor outcomes in the elderly. An understanding of chronic health conditions which may affect older NF residents, such as anemia and CKD, are important to providing optimal care to these residents. The objective of this study was to determine the proportion of NF residents who had CKD, anemia, and anemia associated with CKD, and to evaluate the use of anemia therapies in residents with CKD and Hb < 11 g/dL. ALTER (Anemia and associated outcomes in Long-TErm care Residents) was conducted in a representative sample of 24 NFs with Minimum Data Set (MDS) and prescription claims data available for the 1-year period before chart abstraction. Eligibility criteria included: ≥ 65 years of age, ≥ 1 hemoglobin (Hb) documentation, available records to estimate glomerular filtration rates (eGFR), not receiving dialysis, and not comatose. The first record to estimate GFR was used to analyze CKD status and the first subsequent Hb record was used to assess anemia status. CKD was conservatively defined as eGFR < 60mL/min/1.73m2 (MDRD equation). Anemia was defined according to the WHO criteria of < 13 g/dL for men and < 12 g/dL for women. Treatment was evaluated for residents with CKD and a Hb < 11g/dL (NKF/KFDOQI Guidelines, 2003). A total of 1501 residents were eligible: 80.5% were white, 75.1% were female and the mean (SD) age was 84.1 (8.1) years. Anemia was identified in 54.7% (784/1434) of the residents and CKD was identified in 45.7% (686/1501) of the residents. Both CKD and anemia were diagnosed in 31.8% (210/661) of the residents. Only 15.6% (26/210) and 7.2% (12/210) of residents with CKD and Hb < 11 g/dL received iron therapy and erythropoiesis-stimulating protein treatment, respectively. The prevalence of select co-morbid conditions, which may also be associated with anemia, in residents with CKD and Hb < 11 g/dL were: diabetes, 43.1%; heart failure, 43.1%; and chronic infection, 25.7%. In summary, anemia associated with CKD is highly prevalent in older NF residents. Conventional treatment to correct anemia in residents with CKD was uncommon.
Hyperglycemia in Patients with Acute Myeloid Leukemia Is Associated with Increased Hospital Mortality.
Authors: Ali Naeem A. , O’Brien James M. , Blum William , Klisovic Rebecca B. , Marcucci Guido , Phillips Gary , Marsh Clay B. , Lemeshow Stanley , Byrd John C. , Grever Michael R. 
Published: October 2019

Abstract
Patients with acute myeloid leukemia (AML) who receive therapy for their disease are at significant risk for infections. One risk factor for infections is hyperglycemia which can often be observed in medically ill patients. In post-operative critically ill patients, intensive insulin therapy has been shown to reduce the incidence of nosocomial infections. (Van den Berghe, 2001) In one study of patients with acute lymphoblastic leukemia, hyperglycemia during induction therapy was associated with more infections and shorter disease free survival. (Weiser, 2004) We hypothesized that hyperglycemia is associated with worse outcomes in AML due to increased incidence and severity of infectious complications. We performed a retrospective cohort study to determine if there was an association between hyperglycemia and hospital mortality in hospitalized patients with AML. Four-hundred and sixty-four adult patients were identified through a search of our administrative databases as having the diagnosis of acute myeloid leukemia over a three year period. These individuals experienced 1,004 admissions to the hospital. The occurrence of increasing hyperglycemia, defined as the proportion of glucose assessments above normal (>110 mg/dL), during all hospital days was associated with increased odds of hospital mortality [OR 1.24, 95% CI 1.13–1.36, p<0.001) after adjusting for co-variates like age, gender, diabetes and other co-morbidities. In addition, the odds of developing sepsis [OR 1.08, 95% CI 1.02–1.14, p=0.007], severe sepsis [OR 1.16, 95% CI 1.08–1.26, p<0.001), respiratory [OR 1.23, 95% CI 1.07–1.40, p=0.003] or renal failure [OR 1.14, 95% CI 1.01–1.30, p=0.04] were increased with increasing hyperglycemia. Because duration of neutropenia is known to increase the risk of infectious complications, we included leukopenia (WBC<1000) as a possible mediator in the risk-adjusting models. Independently, leukopenia was associated with the development of severe sepsis, however inclusion of this co-variate did not appreciably change the relationship between hyperglycemia and sepsis [OR 1.07, 95% CI 1.01–1.16, p=0.01], severe sepsis [OR 1.18, 95% CI 1.09–1.28, p<0.001] or mortality [OR 1.24, 95% CI 1.12–1.35, p<0.001]. Finally, after adjusting for the diagnosis of severe sepsis, hyperglycemia remained significantly associated with mortality, but the point estimate was reduced (OR from 1.24 to 1.16) suggesting that the association between abnormal glucose regulation and hospital mortality may be partially mediated by the development of severe sepsis. Based on these findings we are performing a more formal analysis of the relationship between hyperglycemia and the morbidity and mortality associated with treatment of patients with AML in a prospective study.