bluuebunny/crossref_metadata_2025_split huggingface dataset:
Breast Nodules: First Manifestation of LLA.
Authors: Avila Estela Est. , Macias Mirian Mir , De Salvo cardullo Luigi Lui , Nunez Alonso Alo , Romero Esmeira Esm. , Weir Jesus Jes , Hassanieh Angelina Ang 
Published: April 2020

Abstract
INTRODUCTION: Malignant hematological process that affects breast are infrequent in lymphoma and leukemia, only 0.25%, being most common in non Hodgkin lymphoma (NHL), acute myeloid leukemia (AML), and very rare in acute lymphoblastic leukemia (ALL), with very few cases reported. The infiltration of breast due to leukemia cells may occur initially, during relapse, after bone marrow transplantation (ABMT) or after radiotherapy in cancer. Affect young people presenting single or multiple mass, with diffuse increment of breast, unilateral or bilateral. The following report belongs to one case of ALL with initial presentation of nodules in breast.
DESCRIPTION: 35 years old female patient who presented increased volume in breasts, intermittent fever and generalized weakness. The echogram showed solid nodules in both breasts. The needle biopsy reported diffuse infiltration of lymphoid cells, being confirmed by biopsy and inmunohistochemical study, which results were: bcl-2, cd99, cd10, cd34, cd43 and cd45ro positives in neoplastic lymphocytes. The diagnosis of ALL/lymphoblastic lymphoma was made. The Oncologist referred the case to the Hematology Service and blood peripheral studies were made: Hemoglobin: 9.4grs/dl, hematocrit 29%, WBC; 86000 dl., 80% of blasts. Bone marrow was infiltrated by immature lymphoid cells. It was confirmed by morphology and flow cytometry studies. The diagnosis was ALL L1 CALLA positive. Cytogenetic studies revealed t(2:7)(q11:q11), t(9:22)(q34:q11) [20] Philadelphia chromosome positive. The patient was treated with chemotherapy without remission, allogenic bone marrow transplant with recidive in breasts, including the scalp and bone marrow by lymphoid blasts and confirmed by inmunophenotype. The patient received Imatinib Mesylato and Hyper CVAD as reinduction. She, eventually, died.
CONCLUSION: The importance of this case is the atypical and unusual presentation of ALL Ph (+) and the association of Philadelphia chromosome with balanced translocation t(2:7)(q11:q11), which has been rarely reported in hematological malignances. The biopsy of nodules allowed the early diagnosis. This is the first case reported in Venezuela.
Post-Transplant Lymphoproliferative Diseases after Renal Transplantation. Long Term Experience over 35 Years in Peru.
Authors: Beltran Brady , Morales Domingo , Malaga Jose , Carrasco-Yalan Antonio A. 
Published: April 2020

Abstract
BACKGROUND: Post-transplant lymphoproliferative diseases (PTLD) are a combination of diseases characterized by the proliferation of lymphoid cells that occur in the context of post-transplant immunosuppression. Primary infection by Epstein Barr Virus (EBV) is the main risk factor for the development of PTLD. A total of 11% of all the cancers recorded in renal transplant recipients are PTLD.
OBJECTIVE: To determine prevalence of PTLD in renal transplant recipients.
PATIENTS AND METHODS: We retrospectively reviewed the records of 1038 renal transplant recipients who received allograft transplants between 1972 and 2007 and recorded the incidence and types of de novo malignancies that developed in these patients. The study was carried out from two centers in Peru.
RESULTS: Forty-seven neoplasms were diagnosed in 43 recipients. 26 were men and 16 women, mean age was 46.0, range (17–67 years). Malignancy was diagnosed 2 to 240 months after transplantation. The tumors included Kaposi’s sarcoma (KS) in ten patients, squamous cell carcinoma (SCC) in seven, basal cell carcinoma (BCC) in six, cervix cancer in four, colon and breast cancer in three and hepatocarcinoma in two .Also were reported one case of small intestine cancer, osteosarcoma, pancreatic cancer, lung cancer, bladder cancer, schwanoma, melanoma, tongue cancer, pelvis renal cancer and carcinomatosis from unknown primary. PTLD were 4.2% (two cases) from all neoplasm found in renal transplant patients. First case corresponds a female 53 years old with four year from renal transplant. ATG, ALG OKT3 were not used in the patient during transplant induction. She was receiving cyclosporin and azatrioprine as inmunosupresors. She had a bulky diffuse large B cell lymphoma primary from retroperitoneal node, stage IVB, IPI high risk and bone marrow involved. She received CHOP-21 regimen for four cycles with progressive disease. She died from meningeal involvement, six months after from diagnosis. Second case was a male, 74 years old with ten years from renal transplant. He has a diffuse large B cell lymphoma from neck skin, stage IB. ATG, ALG OKT3 were not used in the patient during transplant induction. He was receiving cyclosporine and azathioprine as inmunosupresors, currently the patient continues CHOP-21 regimen with good response.
Conclusions: A low incidence of PTLD after renal transplantation occurred in Peru.
RASSF8 Overexpression Expands KLS Cells in Vitro and Blocks Murine Hematopoietic Stem Cells in a Primitive Phenotype.
Authors: Schoemans Helene M. , Snoeckx Rikkert , Buckley Shannon , Mimiola Elda , Schouteden Sarah , Verfaillie Catherine M. 
Published: April 2020

Abstract
A recent transcriptome analysis of human umbilical cord blood and bone marrow (BM) CD34+CD33−CD38−ckit+Rholo (Rholo) vs. CD34+CD33−CD38−ckit+Rhohi (Rhohi) cells identified the gene RASSF8, to be more highly expressed in the hematopoietic stem cell (HSC) rich compartment (Rholo) versus committed progenitor cells (Rhohi). In a subsequent screen for the function of differentially expressed genes in hematopoiesis, the knockdown of RASSF8 using morpholinos in zebrafish embryos resulted in decreased blood formation and reduced expression of early (scl and gata1) and late (hbae1 and lcp1) hematopoietic markers. To test the function of RASSF8 in mammalian hematopoiesis, we overexpressed RASSF8 cDNA in lineage depleted murine bone marrow cells (Lin−) by retroviral transduction using the MSCV-RASSF8-IRES-GFP vector (rMIG-RASSF8). Sorted transduced GFP+ cells were cultured in serum-free medium (supplemented with SCF, TPO, Flt3L and Il-3) for three to five days. No significant differences were seen in overall cell expansion, cell death (7-AAD staining) or cell proliferation (thymidine incorporation assay and propidium iodide staining) between rMIG-RASSF8 transduced cells and cells transduced with the control vector (rMIG). However, we noted a significant accumulation of the stem cell enriched cKit+Lin−Sca1+ (KLS) population in rMIG-RASSF8 transduced cells (43+/−9%) compared to control cells transduced with rMIG (13+/−8%, p=0.003; n=4) after five days. The total number of colony forming cells (CFCs) produced by 750 rMIG-RASSF8 transduced Lin− cells (24+/−7) was significantly lower than in rMIG transduced cells (54+/−8, p=0.008; n=3). CFCs from rMIG-RASSF8 transduced cells were morphologically smaller and more compact, consistent with the morphology of primitive blast-forming colonies. Competitive repopulation assays using 25 000 rMIG-RASSF8 or rMIG transduced C57/Bl6 CD45.1 Lin- cells versus 100 000 C57/Bl6 CD45.2 mononuclear BM cells were performed to evaluate HSC engraftment potential. Four weeks after transplantation only 1+/−0.96% CD45.1 cells were found in the peripheral blood (PB) of the animals receiving rMIG-RASSF8 transduced cells vs. 23+/−12% CD45.1 cells in animals that had received rMIG transduced cells (p&lt; 0.05; n=3). Likewise, PB analysis at 3 months demonstrated nearly no reconstitution of rMIG-RASSF8 transduced CD45.1 cells (1+/−1.7%) vs 30+/−23% rMIG transduced CD45.1 cells (p=0.02). In conclusion, constitutive overexpression of RASSF8 increases the retention/expansion of KLS cells in vitro, blocks differentiation of progenitors giving rise to CFC and inhibits engraftment of HSC. These studies thus suggest that short term overexpression of RASSF8 might ultimately lead to new methods of HSC expansion.
A Phase II Trial of Darinaparsin in Advanced Lymphomas: Report on Safety and Activity.
Authors: Craig Michael , Shah Sandip , Tallman Martin , Patil Poonam , Easow Jose , Buck Jill , Shah Sachin , Lewis Jonathan , Lossos Izidore S. 
Published: April 2020

Abstract
Darinaparsin (ZIO-101) is a novel organic arsenic molecule that has a mechanism of action mediated by targeted disruption of mitochondrial function, modified signal transduction, and antiangiogenesis. It is active against diverse cancers in vitro. This Phase II multi-center trial is being conducted in patients diagnosed with advanced lymphomas that have received at least 1 prior therapy and require additional treatment. Patients receive 300 mg/m2 of darinaparsin intravenously for 5 consecutive days every 28 days (1 cycle) and are then evaluated for efficacy and safety by standard criteria. Treatment continues until toxicity or progression. To date the study has accrued 22 patients (15 non-Hodgkin’s [NHL], 7 Hodgkin’s); 12 are male and 10 are female. Median age at baseline was 60.5 years (range: 28–80), ECOG performance status was ≤2, and median number of prior therapies was 4 (range 2–6). Thirteen subjects have received at least 2 cycles of darinaparsin and are evaluable for efficacy. Of these, 1 (diagnosed with PTCL) has achieved a complete response (CR) and 3 (diagnosed with marginal zone transformed to diffuse large B-cell, marginal zone, and Hodgkin’s nodular sclerosis, respectively) have achieved partial responses (PRs). These patients had been heavily pretreated (PTCL: CHOP, ICE, and EPOCH; marginal zone transformed to diffuse B-cell: RCHOP, RICE, RT and autologous bone marrow transplantation; marginal zone: rituximab, RCVP, and gemcitabine; and Hodgkin’s: ICE, CBV, gemcitabine+ MDX-060, and stem cell transplant). In the patient with transformed diffuse large B-cell lymphoma who achieved PR, no evidence for macroscopic disease was present, but microscopic low-grade marginal zone lymphoma was detectable in random biopsies from normal-appearing gastric mucosa. In addition, 2 patients (diagnosed with PTCL and Hodgkin’s, respectively) have achieved stable disease (SD). The only Grade 3 adverse event (AE) considered drug-related was wheezing. A total of 12 subjects have reported 37 serious adverse events (SAEs) while on study. Of these, only 2 had SAEs that were considered drug-related (neutropenic fever, fall). In conclusion, darinaparsin has been very well tolerated and has demonstrated promising activity in heavily pretreated patients diagnosed with advanced lymphoma. Initial responses (1 CR, 3 PRs, 2 SDs) have been observed among 13 evaluable patients. Accrual continues; additional safety and efficacy data will be reported.
Disruption of T Cell Suppression in Chronic Lymphocytic Leukemia by CD200 Blockade.
Authors: Pallasch Christian P , Ulbrich Susanne , Brinker Reinhild , Uger Robert A , Hallek Michael , Wendtner Clemens- Martin 
Published: April 2020

Abstract
Suppression of patients’ T-cells is a key event in CLL pathogenesis and was demonstrated to be mediated by direct cell-cell contact of malignant CLL cells with T-cells. CD200 plays a critical role in regulating the immune system and has been shown to be up-regulated on the surface of different tumors including CLL. In this study we addressed the effects of CD200 over-expression on CLL cells on autologous T cells in a mixed lymphocyte reaction system. We used native and CD40 ligand (CD40L)- stimulated CLL cells as antigen-presenting cells (APCs) to expand autologous T cells of 14 patients. T-cell proliferation was analyzed over 3 weeks of in vitro culture. A functional anti- CD200 antibody (1B9) was added to reveal CD200-mediated immunosuppression in the autologous system. Expansion of patient T-cells was assessed by flow cytometry including intracellular staining of FOXP3. Specificity towards CLL-specific antigens was monitored applying fibromodulin derived peptides for detection of specific T-cells by ELISPOT analysis. T-cell proliferation over 3 weeks of in vitro culture was significantly enhanced compared to control cells when using CD40L-stimulated APCs and an anti-CD200 antibody (p=0.0004). CD200 blockade was further shown to stimulate antigen-specific T-cell responses towards the F2 and F4 peptides of the CLL-associated antigen fibromodulin (p=0.04). Finally, the number of CD4+/CD25high/FOXP3+ T cells (Treg) was significantly decreased in CD200 treated mixed lymphocyte reaction (p=0.04). In summary, CD200 blockade may provide therapeutic benefits in CLL by
enhancing T-cell expansion, augmenting an antigen-specific T cell response with suppression of regulatory T cells.
CD200 seems to be an important immunosuppressive molecule in CLL: by CD200 blockade immune suppression can be overcome by altering tolerance to tumor antigens and deregulation of regulatory T cells. This combination of an immune induction paralleled by a disruption of immunosuppressive factors makes anti-CD200 mAb a powerful tool for future treatment of CLL, possibly in combination with other B cell cytotoxic or immunostimulatory approaches.
Payer Costs of Autologous Stem Cell Transplant: Results from a U.S. Claims Data Analysis
Authors: Pelletier Elise M , Smith Paula J , Dembek Carole J 
Published: April 2020

Abstract
Objectives: Autologous stem cell transplant (ASCT) includes costly pre-transplant care which must be considered in the overall cost of treatment. The objective of this study was to evaluate total costs of an ASTC, from mobilization/apheresis through 100 days following transplant, in U.S. managed care plans.
Methods: Patients 18+ years of age with evidence of an ASCT between January 1, 2000 and December 31, 2006 were identified from a nationally-representative database of medical and pharmacy claims from over 90 U.S. managed care health plans. Patients were required to have a claim for apheresis within 60 days prior to the ASCT and have a history of multiple myeloma, non-Hodgkin’s lymphoma, or Hodgkin’s disease. Patients were included in the study only if they were continuously enrolled in one health plan for a minimum of 90 days before to 100 days following the ASCT; patients with evidence of a prior ASCT were excluded. Costs were calculated for 4 phases of ASCT:
Mobilization/Apheresis: 5 days prior to the first G-CSF administration through the last apheresis claim, Conditioning: 1 day after the last apheresis claim to 1 day prior to ASCT, Transplant: ASCT through 30 days post-transplant, and Follow-up: 31 to 100 days following transplant.
Paid claims (payer perspective) were used as a proxy for medical costs and were expressed in 2006 US$, adjusted as necessary using the medical care component of the U.S. Consumer Price Index.
Results: A total of 249 ASCT patients were identified; the mean age was 50 years and 57% were male. Total costs from mobilization to 100 days post-transplant averaged $146,890 per patient (median $134,878). Mobilization and apheresis costs comprised 27% of the total costs (mean $38,803), while conditioning therapy represented 43% of the total costs (mean $63,369). Transplant costs (mean $22,032) and follow-up costs (mean $22,686) each accounted for approximately 15% of the total costs.
Conclusion: ASCTs are costly procedures with mean payer costs of almost $150,000. This study reviewed recent U.S. managed care health plan claims data to determine the component costs of ASCT. Conditioning therapy and mobilization/apheresis were identified as the main cost drivers, comprising 43% and 27% of the total costs, respectively. Delineating these ASCT-related costs is important in evaluating the overall economic burden of ASCT on the healthcare system and in estimating the benefit of new therapies that could provide greater efficiency and reduce cost in these areas.
Total Medical Costs from Mobilization through 100 Days Post-ASCT in ASCT Patients (N=249).
Mean (SD) % of Total Costs Total Costs from Mobilization through 100 Days Post-ASCT $146,890 (87,628) -- Mobilization/Apheresis $38,803 (31,060) 26.5% Conditioning $63,369 (70,836) 43.1% Transplant $22,032 (30,960) 15.0% Follow-up $22,686 (38,129) 15.4%
nPKC Epsilon Negatively Regulates Platelet Functional Responses
Authors: Bynagari Yamini Saraswathy , Nagy Bela , Bhavaraju Kamala , Woulfe Donna , Kim Soochong , Kunapuli Satya P. 
Published: April 2020

Abstract
Protein Kinase C (PKC) are family of serine threonine kinases, known to regulate various platelet functional responses. Among them novel class of PKC isoforms (nPKC) including delta(δ), theta(𝛉), eta(η), and epsilon(ε) are expressed in platelets. Although, the role of nPKC ε and η in platelets is fairly understood, not much is known about nPKC ε and η in platelets. In this study, we investigated the role of nPKC ε in platelet functional responses using ADP-induced signaling as our stereotype. ADP causes platelet activation via Gq-coupled P2Y1 receptor and Gi-coupled P2Y12 receptor. Thus, we primarily studied the role of P2Y1 receptor in nPKC ε activation. ADP activated nPKC ε in time- and concentration- dependent manner. In the presence of P2Y1 receptor antagonist MRS-2179 and in P2Y1 knockout (KO) murine platelets ADP failed to activate nPKC ε, suggesting that ADP activates nPKC ε via P2Y1 receptor. We further investigated the functional role of nPKC ε using specific nPKC ε inhibitory RACK peptide (ε V1-2). ε V1-2 is a peptide designed to compete with native nPKC ε to bind ε-Receptors for activated C Kinase (ε-RACK) and thereby inhibits nPKC ε catalytic activity due to decreased substrate accessibility. ADP-induced thromboxane generation in human platelets pretreated with ε V1-2 peptide was more compared to the platelets pretreated with control peptide. Similarly, ADP-induced thromboxane generation in platelets derived from nPKC ε KO mouse was more compared to the wild type (WT) littermates. However, ADP- induced alpha granule secretion and aggregation in aspirin treated platelets derived from PKC ε KO mice was not significantly different from platelets derived from wild type littermates. These data suggest that nPKC e regulates an unknown pathway, which primarily regulates thromboxane generation with minimal effects on aggregation and alpha granule secretion. Furthermore, we also investigated the role of nPKC ε in PAR- and GPVI- mediated platelet aggregation and dense granule secretion. Interestingly, in both aspirin-treated and non-aspirin-treated platelets PAR- and GPVI- mediated platelet aggregation and dense granule secretion were potentiated. Consistent with ex vivo studies, FeCl3-induced arterial thrombosis was enhanced in nPKC ε KO mice compared to WT littermates.
The Frequency, Manifestations and Duration of Prolonged Cytopenias after First Line Fludarabine-Combination Chemotherapy for Chronic Lymphocytic Leukemia and Non-Hodgkin Lymphoma
Authors: Gill Saar I. , Carney Dennis , Ritchie David S. , Wolf Max , Westerman David , Prince H. Miles , Januszewicz Henry , Seymour John F. 
Published: April 2020

Abstract
The combination of fludarabine with other cytotoxic agents or rituximab is established in the treatment of lymphoid malignancies, with well-recognised efficacy and short-term toxicity. However, the presence and significance of prolonged cytopenias after completion of treatment have not been thoroughly described. In addition, recent guidelines on the management of chronic lymphocytic leukemia (CLL) highlight the importance of delineating the cause of post-treatment cytopenias. In order to address this important and under-reported aspect of treatment outcome, we evaluated 61 patients with indolent non-Hodgkin lymphoma or chronic lymphocytic leukemia treated in our institution with fludarabine with or without other agents as their first-line cytotoxic therapy. Post-treatment cytopenias (defined as hemoglobin &lt; 130 g/L, neutrophils &lt; 2.0 × 109/L or platelets &lt; 140 × 109/L) persisting longer than 3 months were found in 43% of patients. Increasing patient age was found to be the only predictive factor (p= 0.02), whereas the presence of pre-treatment cytopenias, dose delivered, and requirement for dose delay during treatment were not. Patients failing to achieve complete count recovery by 3 months were more likely to experience post-treatment complications (infection, transfusion requirement, and bleeding) (p=0.03). The median time to resolution of anaemia, neutropenia and thrombocytopenia was 7, 9, and 10 months respectively, and the median hemoglobin, neutrophil count and platelet count were 94 g/L, 0.94 × 109/L and 86 × 109/L, respectively. Persistent cytopenias at 3 months did not impact on overall survival at 36 months. Bone marrow biopsies revealed residual disease infiltration and autoimmune aetiology in only 4% and 11% of patients, respectively, and there was no typical morphological appearance in the remaining 85%. After the completion of first-line fludarabine-based combination therapy for CLL and NHL, persistent cytopenias are frequent and clinically significant. Although cytopenias tend to resolve over time, treating physicians should be aware of these factors when considering fludarabine combination chemotherapy and when documenting post-treatment response status in CLL.
Reprogrammed Murine Fibroblasts Differentiated into Hematopoietic Progenitors Are Able to Successfully Engraft and Repopulate the Bone Marrow
Authors: Alipio Zaida , Xu Dan , Yang Jianchang , Fink Louis M. , Xu Wilson , Ward David C , Ma Yupo 
Published: April 2020

Abstract
Cellular therapy using embryonic stem cells has always been an area of great interest due to the pluripotent characteristics of stem cells. In 2006, Takahashi and Yamanaka (Cell 126, 663–676) demonstrated that somatic cells can be reprogrammed into a stem cell-like state, termed induced pluripotent stem (iPS) cells, by ectopic expression of Oct4, Sox2, Klf4 and c Myc. A later report (Nakagawa et al. Nat. Biotechnol.26:101–106, 2008) showed that iPS cells can be produced in the absence of the c Myc oncogene. We have used this latter strategy to successfully reprogram somatic cells derived from C57BL/6 mouse tail fibroblast to iPS cells. Retrovirus infected fibroblasts exhibited stem cell-like morphology by 14 days post infection. These iPS cells were then infected with a retrovirus that expressed HOXB4. Recombinant leukemia inhibitor factor (LIF) supplement was removed from media at this time and the cells allowed to differentiate into embryoid bodies. These cells were screened for specific differentiation stem cell markers, such as Oct4, Nanog, Sall4 and SSEA-1. iPS cells were converted into embryonic bodies and then infected with retroviruses expressing HOXB4. Embryoid bodies stably expressing HOXB4 were induced to hematopoietic differentiation by treatment of thrombopoietin (TPO), stem cell factor (SCF), vascular endothelial growth factor (VEGF), interferon gamma (IFNg) and fms-like tyrosine kinase (FLT3 ligand). Evaluation of iPS-derived hematopoietic cells on smears show strikingly similarity in morphology to the W4 mouse embryonic stem (ES) cells differentiated into hematopoietic cells as a control. Flow cytometry analysis of iPS-derived hematopoietic cells after 1 week exposure to cytokines revealed 7% B220+ cells (B cells), 11% Ter119+ cells (erythroid), and 13% Gr-1+ cells (granulocytes) similar to W4 ES cells. The iPS-derived hematopoietic cells were transplanted into irradiated immunodeficient mice via lateral tail vein injection. Transplantation of these iPS-derived hematopoietic progenitors tagged with GFP into irradiated SCID mice revealed that the hematopoietic progenitors were able to home to the bone marrow after 1 week of transplantation. Importantly, after 1 month, GFP+ engrafted cells remained in the bone marrow suggesting a long-term engraftment. This long term engraftment of the iPS-derived hematopoietic cells to the bone marrow constitutes an important step toward potential therapy of numerous patient-specific blood based diseases.