bluuebunny/crossref_metadata_2025_split huggingface dataset:
Stem Cell Transplantation in 281 Patients over 60 Years in Onco Hematologic Malignancies: A Single Center Experience.
Authors: Stoppa Anne-Marie , Vey N. , Faucher C. , Bouabdallah R. , Viret F. , Chabannon C. , Ladaique P. , Coso D. , Charbonnier A. , Schiano J.M. , Viens P. , Gastaut J.A. , Maraninchi D. , Blaise D. 
Published: October 2019

Abstract
From 06/1982 to 12/2003, 281 patients (163 male) received autologous (AuSCt) and/or allogeneic (AlloSCT) transplantations as part of first line treatment (61%) second line treatment(21%) or salvage therapy (17%). There were 140 multiple myelomas (including 3 amyloidosis), 62 lymphomas, 51 acute myeloid leukemias, 24 solid tumors and 4 chronic myeloid leukemias.Two hundred and sixty nine patients-median age: 64 y(60–77) - received Au SCT (28/261 received a second Au SCT in med of 2–7 months), 1patient (71 y) received a double syngeneic transplant,12 patients -median age: 62(60–68) received AlloSCT. Conditionning regimen (Cond reg) for the first Au SCT included Melphalan 140 mg/m² n=168; BEAM n=41; Melphalan 200mg/m² n=29; Mel Busulfan (8 to 16 mg/kg) or Mel TBI 8 grays n=18; Cytoxan 200mg/kg Melphalan1 40 n=9: TBI 8 Grays n=7; BCNU 600mg/m² n=3. Cond reg for the second Au SCT included Mel 200 n=20; Mel 140 n=4; BCU 600 n=4. Cond reg for the double syngeneic transplant were Mel 140 and Bu 8 Mel 140.Cond reg for the AlloSCT were Fludarabin/Busulfan/ATG (FBS) based reduced intensity regimen (RIC) in 11 cases. Ninety percent of the patients received peripheral blood stem cells-med 5,3.10*6CD34/kg (2–40)- 10% of the patients transplanted before 1994 received bone marrow cells. Tolerance was good with only 9/281 transplant related deaths: 5 sepsis/MOF in aplasia (D11–D21) 2 ARDS (D30–D80) 1 AGVH (D 60) 1 CGVH (3 years). Theses deaths occured in 4 ref MM( 2 renal instability,1 cardiac amyloidosis), 2 CR2 NHL, 1 OR1 MM, 1 stable MDS after FBS in 2 pts, BEAM in 2 pts, Mel 140 in 4 pts, Mel 200 (second transplant) in 1 pt. With a median follow up of 20 months from transplant,7/281 second cancers had occured: 1AML, 1ALL, 2 NSC pulmonary carcinoma, 1 colon cancer, 1uterin carcinoma, 1 melanoma; 2 of these 7 patients had died. One hundred and fifty eight patients had relapsed in a median of 11 months (1–92). Median survival for the 281 patients is 37 months without diference between pts older or younger than 65. Median survival for MM, NHL/HL, AML or ST are 40 months, 45 months, 18 months and 23 months respectively
Targeted Radiotherapy to the Skeleton Using 166Ho-DOTMP with Autologous Stem Cell Transplantation for Patients with Bone-Only Metastatic Breast Cancer.
Authors: Champlin Richard , Booser Daniel , Rondon Gabriela , Williams Patricia , Wendt Richard , Hortobagyi Gabriel , Ueno Naoto , Podoloff Donald 
Published: October 2019

Abstract
The skeleton is the most frequent site of metastatic disease in breast cancer, involving cortical and trabecular bone with or without extension into adjacent bone marrow. A subset of breast cancer patients develop bone dominant disease without metastases to other organs over a prolonged period of time. An attractive strategy is to utilize bone targeted radiotherapy to address this site of disease with minimal systemic toxicity. This study was designed to determine the safety and preliminary efficacy of 166Ho-DOTMP, which localizes to bone providing radiation to adjacent marrow and malignant cells. The limiting toxicity is myelosuppression, which can be overcome by autologous stem cell transplantation. We studied this strategy in subjects with breast cancer metastatic to confined to the bone.
Treatment occurred between 1997 and 1999. Subjects were eligible if they were <65 years of age, had bone only disease, had an estrogen receptor negative tumor or had failed hormonal therapy. A 30 mCi tracer dose was administered to assess targeting and to allow the therapeutic dose to be calculated.
If uptake was adequate, a therapeutic dose was to be administered in one of 2 dose levels, receiving 22 Gy (n=3) or 28 Gy (n=3). Treatment was followed by autologous stem cell transplantation when the ongoing radiation dose to marrow was <1 cGy/hour. The 6 subjects received a median of 1548 mCi (range 870 2065 mCi) of 166Ho DOTMP. There was selective uptake in the bone, particularly in sites of osteoblastic metastases, with unbound drug cleared into the urine. The most common toxicities seen during active treatment were mild nausea and vomiting. None of the patients experienced grade >3 acute toxicity aside from the expected profound myelosuppression. All subjects treated in the trial had prompt trilineage hematologic recovery post transplant. Two patients developed hemorrhagic cystitis at approximately two years following therapy which resolved in both patients. One of these patients also had GI bleeding and pseudomembranous colitis unrelated to the 166Ho DOTMP treatment. One subject developed MDS, but was found to have a pre-existing trisomy 8 by FISH analysis from the peripheral blood stem cell product collected prior to treatment on this study. Two patients achieved complete remission and remain progression-free over 5 years following study entry. Four relapsed and died of progressive disease; all recurred in extraosseous sites with two also having disease in the bone marrow. Median time to progression was 10 months.
Conclusions: Treatment with 166Ho DOTMP delivers targeted radiotherapy to the skeleton with an acceptable toxicity profile. Two of 6 patients with bone-only metastases achieved sustained complete responses. Further studies are warranted to evaluate this strategy for treatment of bone metastases.
Dendritic Cells Tranfected with CML-28 cDNA Induce CML28-Specific Cytotoxic T Cells.
Authors: Zhou Hongsheng , Zhang Donghua , Wang Yaya , Xiao Yi , Huang Wei , Li Dengju 
Published: October 2019

Abstract
Dendritic cells (DC) are the most potent antigen-presenting cells known; the use of DC loaded with tumor antigen is one of the most promising approaches to induce specific immune response. CML28 is an attractive candidate. According to the published article and our following study, CML28 is a broadly immunogenic antigen, which is overexpessed in leukemia cells, including acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL) and chronic myelogenous leukemia (CML); but not in normal hematopoietic tissues or other normal tissue, with the exception of testis. In our study, DCs were generated from peripheral blood mononuclear cells (PBMC) by culture with GM-CSF, IL-4 and TNF-α. The full CML28 cDNA was amplified from K562 cell and then cloned into plasmid pcDNA3.1 HisA. Load DC with the constructed plasmid pcDNA3.1 HisA-CML28 by electroporation. The results of FACS analysis and Western Blot respectively demonstrate that the plasmid transfected DC retain immunophenotypical characteristics and can express the fusion protein CML28-His. Cytotoxic T lymphocytes (CTL) were generated from autologous PBMC stimulated by the transfected DCs. Cytoxicity assay in vitro revealed that CTL can recognize and lyse CML28-expressing target cells, such as the transfected DCs but not normal autologous DCs, which show that the plasmid pcDNA 3.1 HisA-CML28 transfected DC can induce CML28-specific CTL. Our studies demonstrate that CML28 can be a promising target of tumor antigen for leukemia-specific immunotherapy and DC loaded with CML28 tumor antigen can be a promising tool to induce specific anti-leukemia immune response.
MLL Rearranged Infant Acute Lymphoblastic Leukemia Is Characterized by Silencing of the Putative Tumor Suppressor Gene FHIT.
Authors: Stam Ronald W. , Den Boer Monique L. , Passier Monique , Sallan Stephen E. , Armstrong Scott A. , Pieters Pieters 
Published: October 2019

Abstract
MLL gene rearranged acute lymphoblastic leukemia (MLL) is an aggressive type of acute lymphoblastic leukemia (ALL) with a relatively poor response to treatment, predominantly occurring in infants (<1 years of age). Since conventional chemotherapy is failing in >50% of these patients, identification of novel therapeutic targets to direct therapy against is demanded. For this, understanding this disease and finding biological and molecular features characterizing MLL may be crucial. Here we report that infant MLL is characterized by silencing of the putative tumor suppressor fragile histidine triad (FHIT) gene.
Gene expression profiling showed that FHIT expression is significantly reduced in MLL patients (n=20) as compared to patients diagnosed with conventional ALL (n=24) bearing germ line MLL genes. Using quantitative real-time PCR we confirmed FHIT mRNA expression to be low in MLL gene rearranged infant ALL (infant MLL) as compared to both infants and older children (non-infants) not carrying chromosomal abnormalities involving the MLL gene. Infant MLL patients (n=35) significantly (p<0.001) expressed ~15-fold less FHIT mRNA compared to infant ALL patients (n=8) and 11-fold less than non-infant ALL patients (n=22).
Methylation specific PCR (MSP) analysis demonstrated that the FHIT promoter region is hypermethylated in all of the 36 infant MLL cases tested, resulting in strongly reduced FHIT mRNA as well as FHIT protein expression. In contrast, the incidence of FHIT promoter methylation in both infant and non-infant ALL patients carrying germ line MLL genes was markedly lower, with a frequency of 63% (5/8) and 56% (24/43) respectively. Suppression of FHIT expression could be reversed by exposing leukemia cells bearing MLL gene rearrangements to the demethylating drug 5′-aza-2′-deoxycytidine.
These findings imply that MLL rearranged ALL is characterized by FHIT promoter hypermethylation. Currently experiments are being conducted to determine the biological significance of FHIT silencing in this type of cancer.
An Novel Approach in Protective Gene Therapy: Recombinant Adeno-Associated Virus 2-Mediated Transfer of the Human Superoxide-Dismutase Gene.
Authors: Veldwijk Marlon R. , Herskind Carsten , Laufs Stephanie , Stiefelhagen Marius , Zeller W. Jens , Fruehauf Stefan , Wenz Frederik 
Published: October 2019

Abstract
Background and purpose: The success rate of any therapeutic approach depends on the therapeutic window, which can be increased by either raising the resistance of the normal tissue such as hematopoietic cells without protecting the tumor cells or by sensitizing the tumor cells but not the normal cells. Two promising candidate genes for normal tissue protection against superoxide-induced damage may be the copper-zinc (CuZnSOD) and manganese superoxide-dismutase genes (MnSOD). Oxidative stress-induced apoptosis plays a role in both radiation- and chemotherapy-induced tissue damage. Relevant cytostatic drugs for which oxidative stress as one mechanism of action has been described are e.g. anthracyclins, platinum analogues, etoposide and ara-C. For gene therapeutic approaches, recombinant adeno-associated virus 2 (rAAV-2)-based vectors offer attractive advantages over other vector systems: low immunogenicity, possibility of in vivo application, ability to infect dividing and non-dividing tissues and a low chance of insertional mutagenesis, due to extra-chromosomal localization. Here, we report the production and testing of novel rAAV-2-SOD vectors with the goal of normal tissue protection.
Material and methods: Various rAAV-2 vectors containing CuZnSOD, MnSOD and fusion proteins of both with the enhanced green fluorescent protein (eGFP) gene were cloned and vector stocks were produced. Human cervix carcinoma (HeLa-RC) cells were chosen for their susceptibility to rAAV-2. Cells were seeded and transduced with the rAAV-2-SOD vectors. Gene transfer and transgene expression were investigated using FACS and an SOD-activity assay.
Results: Over 70% of all HeLa cells expressed SOD and significant amounts of functional SOD protein were detected (table 1).
Conclusion: These results forms the basis to evaluate the radio- and chemoprotective effects of AAV-mediated SOD gene therapy in hematopoietic and non-hematopoietic (e.g. mucosal) cells.
Vector % GFP+ cells SOD activity (U/mg) Mock control - 435 ± 37 rAAV-2-CuZnSOD N/A 965 ± 112 rAAV-2-CuZnSOD/eGFP 78 ± 2 1093 ± 178 rAAV-2-MnSOD N/A 1516 ± 191 rAAV-2-MnSOD/eGFP 77 ± 3 1204 ± 124
Simultaneous Silencing of Two Independent Signaling Pathways Essential for Angiogenesis Using Bispecific, Tetravalent Intra-Diabodies.
Authors: Jendreyko Nina , Popkov Mikhail , Rader Christoph , Barbas Carlos F. , Gaedicke Gerhard 
Published: October 2019

Abstract
Vascular endothelial growth factor and its receptors (VEGF-R) have been implicated in promoting tumor growth and metastasis. Emerging evidence suggest that angiogenesis also play an important role in the growth of leukemias and lymphomas. Antiangiogenic therapies that interfere with the VEGF/VEGF-R pathways represent novel approaches to effective treatment for certain leukemia, such as myeloid leukemias. But not all types of tumors respond to interruption of the VEGF/VEGF-R pathway. This suggest that alternative pathways for vascular growth exist and can drive tumor angiogenesis. Intrabodies have been used to specifically target intracellular proteins and manipulate biological processes,as well as for the generation of phenotypic knockouts in vivo by surface depletion of extracellular or transmembrane proteins. In order to generate a precise tool for the simultaneous silencing ot two independent signaling pathways essential for angiogenesis, we developed an endoplasmatic-reticulum (ER) targeted bispecific, tetravalent intrabody format, targeting VEGF-R2 and Tie-2. Comparison of the ER-targeted intradiabody with the corresponding conventional ER-targeted single-chain antibody fragment (scFv) intrabodies showed that the intradiabody is significantly more efficient with respect to efficiency and duration of surface depletion of VEGF-R2 and Tie-2. In vitro and in vivo data demonstrate the development of a very effective antiangiogenic intrabody format for the simultaneous functional knockout of two cell surface receptors using an adenovirus-mediated gene delivery system. Our findings suggest that simultaneous interference with the VEGF and the Tie-2 receptor pathway results in at least additive antiangiogenic effects. Our study provides a novel antiangiogenic therapeutic tool for the silencing of two independent signaling pathways involved in angiogenesis.
Bone Marrow Biopsy Needle Design Influences the Bone Content of Recovered Specimens.
Authors: Goldenberg Alec , Kelley Priscilla , Liu Cynthia , Sen Filiz , Ibrahim Sherif 
Published: October 2019

Abstract
Introduction: The integrity and composition of bone marrow core biopsies may be influenced by many parameters including patient age, sex, bone density, operator experience, needle selection and biopsy technique. Biopsy needle design impacts on a needle’s performance and the quality of recovered specimens. We studied the effect of modifying the Snarecoil bone marrow biopsy needle tip on the recovery of trabecular bone in core specimens.
Methods: 7 patients, ages 35–92, M/F = 4/3, (2 leukemias, 1 lymphoma, 1 cytopenia, 1 anemia, 2 other) underwent a bone marrow biopsy using a 8 gauge Snarecoil needle with a new needle tip (TPNSP). The tip has a twin peak point and more distal Snarecoil position. As a control group, 7 patients biopsied with a standard 8 gauge Snarecoil needle (NTP) were retrospectively identified and matched for age and sex and were ages 37–87, M/F = 5/2, (3 cytopenias, 2 leukemias, 1 lymphoma, 1 other). All biopsies were completed using a minimally manipulative technique from the left posterior superior iliac spine with 2% lidocaine. The length of the specimen and attached clot was measured. The specimens were decalcified for 90 minutes and otherwise processed in the standard fashion. The percentage of bone per core biopsy was determined with computer-assisted morphometry using a BioGenex iVision V3.5 system.
Results: The study and control groups were comparable, as the mean age and M/F distribution of the two groups and the mean lengths of the recovered specimens were not statistically significantly different. (TPNSP vs. NTP, 63.8±7.1 vs. 64.7± 6.4 p=0.93, 4/3 vs.5/2 p= 0.57, 2.32± 0.26cm vs. 2.21± 0.26cm p=0.761, respectively).
Needle Age M/F Specimen Length % Bone TPNSP 63.8±7.1 4/3 2.32±0.26 (1.2–3.3) 16.3±1.5 (12.1–21.8) NTP 64.7±6.4 5/2 2.21±0.26 (1.3–2.9) 6.8±1.4 (2.9–12.5)
However, the mean percentage of bone in the specimens recovered by the new TPNSP needle was greater than that recovered with the NTP needle. (16.3±1.5% vs. 6.8±1.4%, p= 0.0008). Grossly, the TPNSP specimens had a more linear edge than those of the NTP specimens. Also, more (5/7) of the NTP specimens had > 0.5 cm of attached clot then did the TPNSP specimens (0/7), p=0.005 suggesting that the twin peak needle produced less tissue hemorrhage.
Conclusions: 1. 8 gauge Snarecoil needles having a sharper tip and more distal Snarecoil recover specimens with as much as 2.5 fold more bone for histopathologic study. 2. The twin peak needle may produce less tissue hemorrhage and disruption.
Long-Term Follow-Up of Recombinant Human Erythropoietin (epoetin)Induced Pure Red Cell Aplasia (PRCA): A Comparison of Data Collected through Active and Passive Pharmacovigilance Efforts.
Authors: Bennett Charles L. , Carson Kenneth R. , McKoy June M. , Belknap Steven M. , Klinge Stephen A. , Evens Andrew M. , Raisch Dennis W. , Yarnold Paul R. , Kim Benjamin , Lyons Elizabeth A. , Kuzel Timothy K. , Tallman Martin S. 
Published: October 2019

Abstract
Background: Follow-up reports describing the long-term prognosis of 47 patients with epoetin induced PRCA have been confined to a single study from France, England, and Germany, investigated through active surveillance efforts. There is concern that reporting quality may differ between active versus voluntary reporting efforts.
Methods: Investigators from the Research on Adverse Drug reactions And Reports (RADAR) program compared clinical findings for epoetin-associated PRCA cases reported by voluntary surveillance efforts (n= 47) versus active surveillance (n= 47). (Verhelst et at, Lancet 2004). Recovery from PRCA was defined as transfusion independence, normalized reticulocyte count, and/or disappearance of anti-erythropoietin antibody.
Results: Baseline characteristics of age and gender were similar in both the MEDWatch and active surveillance groups. The two groups were similar with respect to median age similar (67 years) and gender (70%) and follow-up duration for patients who recovered (mean of 3 months). Median follow-up was shorter for passive surveillance patients who did not recover (6 versus 11 months). Recovery rates with immunosuppression differed (39.5% for MedWatch versus 21.6% for active surveillance).
Conclusions: Follow-up of active versus passive pharmacovigilance differed markedly for epoetin-associated PRCA cases in France, Germany, and the UK, in part due to differences in follow-up time. Active pharmacovigilance efforts should be supported by national health authorities.
Surveillance of Rx’ed patients Active N=37 (%) Passive N=38 (%) Patients with known follow-up (%) 100 100 Recovered w/transplant 16.2 18.4 Recovered w/Immunosuppression 62.2 42.1 No recovery 21.6 39.5
Active Site-Inactivated Recombinant Factor VIIa Blocks Shiga Toxin-Induced Upregulation of Tissue Factor Activity on Human Glomerular Endothelial Cells and Human Proximal Tubular Epithelial Cells.
Authors: Nestoridi Eirini , Kushak Rafail , Ingelfinger Julie R. , Grabowski Eric F. 
Published: October 2019

Abstract
Post-diarrheal hemolytic uremic syndrome (HUS), the leading cause of acute renal failure in children, is most often caused by Shiga toxin (Stx)-producing Escherichia coli infection. The most widely recognized tissue damage in HUS occurs within the kidney, most prominently with local thrombosis and platelet-fibrin accumulation, suggesting activation of the coagulation cascade. We have shown that human proximal tubular epithelial cells (HK-2 cells) exposed to Stx-1 augment their constitutive surface tissue factor (TF) activity by 3.2-fold, and that Stx-1 treatment following TNF-alpha exposure enhances TF activity by 2.7-fold on human glomerular endothelial cells (HGECs). We investigated the possibility of modulating this cellular response to Stx-1 by blocking the TF pathway with active site-inactivated recombinant factor VIIa (irFVIIa), which retains the ability to bind TF, but is enzymatically inactive, thereby inhibiting thrombin formation. Moreover, its action is limited to exposed, functional TF and does not significantly prolong the bleeding time in vivo. Monolayers of both HK-2 cells and TNF-alpha-activated HGECs were incubated at 37°C with Stx-1. Functional TF was determined chromogenically as the production rate of factor Xa. The use of 60 nM irFVIIa completely abrogated the enhanced activity of TF caused by 4 hours incubation with 10 pM Stx-1 of TNF-alpha-activated HGECs (N = 4; Figure 1). On HK-2 cells, irFVIIa (60 – 200 nM) also effectively reversed the observed TF upregulation after exposure to 1 nM Stx-1 for 22 hours as well as blocked the constitutive TF expression which is seen with this cell type (N = 3; Figure 2). The TF pathway may prove to be of major importance in the pathogenesis of HUS, and direct targeting of this pathway with irFVIIa might provide a novel therapeutic approach to this disease.