bluuebunny/crossref_metadata_2025_split huggingface dataset:
Platelet, CD40/CD40L, MPS-Cells: Partners in Crime
Authors: Corinaldesi Giorgio , Corinaldesi Christian 
Published: April 2020

Abstract
Several suggestions showed a strong correlation of platelet and CD40/40L; CD40/40L is a member of TNF superfamily, the genes is located on chromosome X, and it is expressed on endothelial cells, SMC, fibroblast and activated platelet and plays a pivotal role in inflammatory and expression of adhesion molecules, and it stimulates the release of cytokines. It helps identifing patients with atherosclerosis and an increased risk of thrombosis, peripheral and cardiovascular disease (CAD and CHF). CD40/40L was measured by flow cytometry, and s-CD40L by ELISA. In platelet activation CD40L is translocated to the platelet surface and it is accompanied by the release of sCD40L and RONS (reactive ossigen and nitrogen species) and this contributes to atherothrombotic disease and inflammatory process by forming (CD40-40L/GPIIb-IIIa, CD40-40L/Pselectin- PSGL) complex strictly correlated with levels of ICAM-1 and VCAM-1, induced TF-expression and release of MMPs. Activated platelets release chemokines, enhance adhesion and aggregation cytochine like-factors and coagulation factors. Patients with thrombotic events had more platelet-monocyte aggregate (36.8 +/− 12.4 %) than controls (14.2 +/− 2.1 %) and sCD40L above 4.5 ng/l, ICAM-1 levels 248 +/− 10.8 ng/ml vs 168 +/− 5.4 ng/ml, VCAM-1 764 +/− 18.6 ng/ml vs 532 +/− 8.6 ng/ml. The interaction of platelet and MPS-cells were enhanced by activation of P-Selectin 38.6 +/− 12.4 ng/ml vs 20.4 +/− 4.4 ng/ml, and MCP-1 286 +/−10.4 pg/ ml vs 132 +/− 5.8 pg/ml which are one of the major promoter of inflammation. This finding demonstrated that the development and progression of atherosclerosis is critically dependent on these molecules; this may propose new therapeutic target for future therapies.
The Effect of Omega-3 as a Dietary Supplement in a Mouse Model of Stem Cell Transplantation (SCT)
Authors: Al-Hashmi Sulaiman Ali , Sadeghi Behnam , Hassan Zuzana , Lindskog Magnus , Hassan Moustapha 
Published: April 2020

Abstract
Introduction: Several studies reported the importance of nutrition on SCT outcome. Many food components have been shown to affect the immune system and to interact with a number of drugs used in conditioning and in prophylactic treatment during SCT. Omega-3 fatty acids have immuno-modulatory effects via improving endothelial function, protection against oxidative DNA damage and by suppressing CD4+ T-cell function and proliferation. In the present study we examined the effects of omega-3 on the immune system in mice undergoing SCT.
Method: Female BALB/c mice, 8 – 12 weeks, were randomised to receive either diet enriched with menhaden fish oil (omega-3) or, corn oil (rich in omega-6). Both groups were fed for two weeks prior to conditioning (Day 0 was set to be the day of transplantation). Both groups injected intra-peritoneally with 80mg/kg busulfan (Bu) for four days (day –7 to day –4) followed by 200mg/kg cyclophosphamide (Cy) for two days (days –3 & -2). At day 0, half of the mice of both groups were killed and bone marrow, spleen and thymus were harvested and analysed with FACS to evaluate the lymphoid and myeloid cell phenotype. Serum was collected for analysis of cytokines. The remaining mice in both groups were transplanted with allogeneic bone marrow from 8 – 12 weeks male C57BL/6 mice (2.0 × 107 bone marrow cells and 3.0 × 107 spleen cells).
Results: Mice fed an omega 3-rich diet showed significant decrease in bone marrow and spleen cellularity compared to that observed in the corn oil group. In particular, the splenic B-cell population was severely affected, showing a 50% decrease in the omega-3 group compared to that seen in corn oil group. The T-cell populations of omega-3 fed mice were also affected, with a significant decrease by 10 to 20 % in the number of CD4+ cells. In contrast, no difference was observed for CD8+ cells, compared to corn oil-fed mice. In the thymus, the number of activated T-cells was decreased by 50% in the omega-3 compared to that observed in corn oil group. NK cells were decreased by 50% in the spleens of omega-3 fed mice. In bone marrow, the myeloid cells (CD11b+) were significantly lower in omega-3 fed mice compared to corn oil-fed controls. All transplanted mice that had received an omega-3 enriched diet died within the first week. These data can be compared to our previous results where more than 60% of mice receiving standard diet survive during the first week and of which at least 20% reach day+21.
Conclusion: Omega-3 administration as a dietary supplement for two weeks prior to conditioning regimen showed significant effects on the immune system in terms of a pronounced alteration in the balance of different cells lineages in both bone marrow and spleen. Rapid death of omega-3 fed animals after allogeneic transplantation was observed. Further studies are warranted to investigate the role of omega-3 on the outcome of stem cell transplantation.
Anti-CD3 Preconditioning Separates GVL from GVHD Via Modulating Host Dendritic and Donor T Cell Migration in TBI-Conditioned Recipients
Authors: Li Nainong , Chen Ying , He Wei , Yi Tangsheng , Zhao Dongchang , Zhang Chunyan , Lin Chia-Lei , Forman Stephen , Zeng Defu 
Published: April 2020

Abstract
Host dendritic cells (DCs) play a critical role in initiating graft versus host disease (GVHD) and graft versus leukemia (GVL), and separation of GVL from GVHD remains a major challenge in the treatment of hematological malignancies by allogeneic hematopoietic cell transplantation (HCT). Here, we show that preconditioning with anti- CD3 mAb before conditioning with total body irradiation prevents GVHD but retains GVL in a HCT model of MHC-mismatched C57BL/6 donor to BALB/c host. Prevention of GVHD is associated with inhibition of donor T expression of homing and chemokine receptors and inhibition of GVHD target tissue expression of chemokines. Furthermore, inhibition of donor T expression of gut homing a4b7 and chemokine receptor CCR9 by anti-CD3 preconditioning results from reduction of CD103+ DCs in draining mesenteric lymph nodes, which is associated with downregulation of DC expression of CCR7, a receptor required for tissue DC migration to draining LN. These results indicate that anti-CD3 preconditioning reduces not only tissue release of chemokines but also prevents tissue DC migration to draining LN and subsequently reduces draining LN DC’s capacity in imprinting donor T tissue tropism. Therefore, modulation of host DCs by anti-CD3 preconditioning before HCT represents a new approach for separating GVL from GVHD. (Li and Chen contribute equally.
Association Between Acute Graft Versus Host Disease and Lung Injury after Allogenic Hematopoietic Stem Cell Transplantation
Authors: Liu Qifa , Luo Xiaodan , Ning Juan , Xu Dan , Fan Zhiping , Sun Jing , Zhang Yu , Xu Bing , Wei Yongqiang 
Published: April 2020

Abstract
To investigate the characteristics of chest computed tomography (CT) and pathogenesis of acute graft versus host disease(GVHD)-induced lung injury after allogenic hematopoietic stem cell transplantation. In 47 patients with acute GVHD of grade II–IV, CT showed abnormalities in 20 patients in which 17 cases were suspected of acute GVHD-induced lung injury. Of 17 patients, CT revealed diffused interstitial infiltrate in 5 cases, diffused interstitial and alveolar infiltrate in 7 cases,diffused interstitial and segmental lobar alveolar infiltrate in 5 cases. The levels of serum IFNγ and TNFα in patients were higher than those of the healthy group. The histopathology of lung showed disorganization, epithelial cell damage, interstitial fibroplasias and interstitial T cell or macrophage infiltrate. In 24 patients who survived more than 6 months, 3 cases each in cases with and without lung injury developed late-onset noninfectious lung injury; 11 patients had abnormal pulmonary function including 7 patients in 9 patients with lung injury and 4 patients in 15 patients without lung injury. We concluded that T cell, macrophage, IFNγ and TNFα might play a role in the pathogenesis of acute GVHD-induced lung injury. Acute GVHD-induced lung injury might progress to late-onset noninfectious lung injury.
Construction and Pre-Clinical Evaluation of An Anti-CD19 Chimeric Antigen Receptor
Authors: Kochenderfer James , Feldman Steven , Zhao Yangbing , Xu Hui , Black Mary , Morgan Richard , Dudley Mark , Wilson Wyndham , Rosenberg Steven 
Published: April 2020

Abstract
Adoptive T cell immunotherapy can cause regression of established malignancy. One promising approach is to transfer genes encoding chimeric antigen receptors (CARs) that specifically recognize tumor-associated antigens to T cells before the T cells are adoptively transferred to patients. We have constructed a CAR that consists of an anti-CD19 single chain variable region (scFv) that is coupled to a portion of the CD28 costimulatory molecule and the signaling component of the CD3-zeta chain. CD19 is a promising target for immunotherapy because most malignant B cell express CD19, but the only normal cells that express CD19 are B cells, B cell precursors, and perhaps follicular dendritic cells. We have demonstrated that gamma-retroviruses encoding the anti-CD19 CAR can be used to transduce human T cells and that these transduced T cells specifically recognize CD19+ targets. To transduce T cells, we stimulated T cells with the anti-CD3 monoclonal antibody OKT3 on day 0 then conducted sequential retroviral transductions on day 2 and on day 3. Transductions were performed by spin-loading retroviruses onto RetroNectin (Takara) coated culture plates followed by overnight incubation of the OKT3- stimulated T cells on the plates. Forty-five to sixty-seven percent of T cells expressed the anti-CD19 CAR as measured by flow cytometry 7–8 days after transduction (n=8). Anti-CD19-CAR-transduced CD8+ and CD4+ T cells produced IFNg and IL-2 specifically in response to stimulation with CD19+ target cells. The transduced T cells specifically killed primary chronic lymphocytic leukemia (CLL) cells. T cells from CLL patients that were either untreated or previously treated with fludarabine plus rituximab could be transduced and induced to proliferate sufficiently to provide enough cells for clinical adoptive T cell transfer. In addition, we adapted this protocol for use in CLL patients with very high peripheral blood leukemia cell counts by depleting CD19+ cells using magnetic bead sorting prior to OKT3 stimulation. In preparation for a clinical trial that will enroll patients with advanced B cell malignancies, we have generated a producer cell clone that produces GALV (Gibbon ape leukemia virus)-enveloped gamma-retroviruses encoding the anti-CD19 CAR, and we have produced sufficient retroviral supernatant for the proposed clinical trial under good manufacturing practice (GMP) conditions.
Murine Leukemias with Insertional Mutations at Lmo2 Are Highly Predicitive of Leukemias Induced Following Gene Therapy in SCID-X1 Patients
Authors: Dave Utpal P. , Akagi Keiko , Tripathi Rati , Cleveland Susan , Thompson Mary , Yi Ming , Stephens Robert , Downing James R. , Jenkins Nancy , Copeland Neal G. 
Published: April 2020

Abstract
Five SCID-X1 patients successfully treated with autologous bone marrow stem cells infected ex vivo with an IL2RG-containing retrovirus subsequently developed T-cell leukemia and four contained insertional mutations at LMO2, a known T cell oncogene. Indirect genetic evidence suggests a role for deregulated IL2RG expressed from the retroviral vector in tumor formation, although this remains controversial. Here we show that the genes and signaling pathways deregulated in murine leukemias with retroviral insertions at Lmo2 are strikingly similar to those in human leukemias with deregulated LMO2 and are highly predictive of the leukemias induced following gene therapy in SCID-X1 patients. We also provide genetic evidence suggesting that deregulated IL2RG and LMO2 expression cooperate to induce leukemia but are not sufficient and require additional cooperating mutations. The highly concordant nature of the genetic events giving rise to mouse and human leukemias with mutations at Lmo2 are an encouraging sign to those wanting to use mice to model human cancer and may help in designing safer methods for retroviral gene therapy.
Lipid Emulsion as Antisense Oligonucleotides Vector That Inhibits P-Glycoprotein Expression in a Sarcoma Cell Line through LDL Receptor
Authors: Levy Debora , Debes Adriana Aguiar , Celestino Andrea Turbuck , Schreier Shirley , Maranhão Raul , Bydlowski Sergio Paulo 
Published: April 2020

Abstract
It is well known that antisense oligonucleotides (OAS) are able to inhibit gene expression in a sequence-specific way. The potencial use of an artificial lipid nanoemulsion (LDE) as a vector to carry OAS has been described. LDE was shown to bind 3’-cholesteryl- OAS (C-OAS) and to be internalized into cells through LDL receptors. Here we further explore these findings by examining the capacity of this complex to inhibit MDR-1 gene expression in a sarcoma cell line (MES-DX), which express P-glycoprotein. LDE was prepared as described (Bydlowski et al. ,1995). The capacity of LDE to bind C-OAS was examined by fluorescence spectra analysis using a Hitachi F4500 fluorimeter. Human plasma was obtained from healthy blood donors and LDL, HDL and lipoprotein free serum (LPDS) were separated by sequencial ultracentrifugation. C-OAS/LDE complex was incubated with HDL (apoE donor) before cell experiments were performed. Binding of [3H] LDE/C-OAS complex to LDL receptors from MES-DX cells was studied by competition assay. Two different C-OASs, both complementary to regions flanking the AUG initiation codon were used. Inhibition of MDR-1 gene expression was evaluated by RT-PCR. The binding constant for C-OAS/LDE was 4,2 × 10−3M−1 indicating a high specific capacitiy of conjugation.The C-OAS/LDE complex was shown, by the competition assays and confocal microscopy, to bind to LDL receptors and then to be internalized into cells. Both C-OAS/ LDE complexes strongly inhibited (70% inhibition) the MDR-1 gene expression after 48 hours of cell incubation. This inhibition was not observed when LDE was used alone or complexed with scrambled OAS sequences. The results show that this nanoemulsion binds to cholesteryl-OASs. Moreover, this nanoparticle is an efficient carrier for OAS to target cells expressing LDL receptors. This complex is able to internalize oligonucleotides into cells specifically through the LDL receptor-mediated pathway. The internalized ODN was able to act on nucleic acid sequences as determined by the inhibition of MDR-1 gene expression. Therefore, LDE/C-OAS is promissing nanoparticle complex to be used in gene therapy studies.
Bone Loss Study in Type 1 Gaucher Disease by Two Different Technologies
Authors: Roca Mercedes , Latre Paz , Alfonso Pilar , Irun Pilar , Civeira Ignacio , Meriño Erardo , Pocovi Miguel , Giraldo Pilar 
Published: April 2020

Abstract
Background: Bone disease is the most important source of disability in type 1 Gaucher disease (GD1). High percentage of patients present generalized osteopenia and osteoporosis with reduced bone mass. It is important to know the risk of bone mass lost in order to avoid the bone resorption. The standard technique to evaluate bone disease is Dual-Energy X-ray Absorptiometry (DEXA) that measures bone density in the axial skeleton. Nevertheless other procedure to exam bone density using ultrasound (US) can measure the amount of mechanical energy transmitted by the bone, as well as their speed of transmission (BUA).
Aims: In order to evaluate bone disease indicators in GD1, we have planned a comparative analysis in GD1 by both techniques to exam individual variability in bone mineral density and to study the response to therapy.
Patients and Methods: 24 adults GD1 patients diagnosed in last 5 years and 15 healthy controls stratified by age and gender were analyzed. Bone marrow changes have been evaluated by a semi quantitative score (S-MRI, Roca et al 2006 Eur J Radiol). To analyse the bone density we have used the Z-score quantification in L5 and femur head, calcaneus US was performed simultaneously determined BUA and bone density, in addition GBA genotype, clinical characteristics and subrogate biomarkers profile included chitotriosidase, CCL-18, MIP- 1b were analyzed. The advantages/disadvantages of each procedure and the correlation of results with the clinical characteristics, S-MRI, response to therapy, have been analyzed.
Results: Osteopenia in GD is present in 85% of cases, it progresses with age and has been correlated with the severity of the disease and response to therapy. BMD evaluation by DEXA in GD1 is well documented but the special physio-pathological characteristics of GD make the use of US feasible and BUA results provide more information about the risk of skeletal complications.
Comments: More experience is needed in order to precisely define the role of bone US exam in the management of GD patients. This work has been partially sponsored by FIS 07/90938 and CIBERER U-752
Dose Delay Amongst Cancer Patients Undergoing Chemotherapy
Authors: Wu Ying , Aravind Suresh , Nalysnyk Luba , Ranganathan Gayatri 
Published: April 2020

Abstract
Background. Cancer patients often have their chemotherapy dose delayed or reduced to mitigate chemotherapy-induced side effects such as thrombocytopenia, neutropenia, anemia, etc. In situations where the patient is responding to the chemotherapy, such dose delay and dose reduction may minimize the effectiveness of the chemotherapy and lead to poorer clinical outcomes. In this study, we analyzed the characteristics of dose delay among cancer patients on chemotherapy in the US.
Methods. Pooled data over the period 2000–07 from a large electronic database of 15 community and 3 hospital-based outpatient oncology clinics in the US were analyzed. Adult patients with a cancer diagnosis were grouped as: lung, breast, ovarian, H&N, colorectal, other solid cancers, hematologic and mixed cancers. Chemotherapies used were grouped into platinum, anthracycline, gemcitabine, taxane-based and other regimens. Among patients with complete chemotherapy plan information, each subsequent cycle of the chemotherapy regimen after the first cycle was examined. The planned cycle duration was compared to the actual duration between the start of one cycle and start of the next. Any delay of more than 7 days was defined as a cycle delay. Demographic and clinical characteristics of patients with delays were further analyzed.
Results. The dataset included 47,159 cancer patients (mean age 61, male 42%) and 75,243 chemotherapy regimens. A total of 26,317 patients (113,175 chemo cycles) had complete chemotherapy plan information in the database. Of these, 5,961 patients (22.7%) experienced chemo delays. A total of 9,293 chemotherapy cycles (8.2%) were delayed. The average chemo delay was 17 days (SD, 8 days; median, 14 days). 25% of the delays were more than 3 weeks. Tumor types of the 5,961 patients with cycle delays included, colorectal cancer 20.3%, NSCLC 18.6%, breast cancer 15.2%, ovarian 4.4%, and H&N 2.9%. The reasons for delaying chemo were not specified in the database. However, 60% of these patients experienced anemia (Hb&lt;11g/dL) and 62% had thrombocytopenia (&lt;150,000/μl) at some point during their chemotherapy. Baseline and clinical characteristics of patients with chemo delays were similar to the overall population in the database.
Conclusions. Chemotherapy cycle delays were relatively common in this large group of cancer patients. While the decision to delay therapy was multi-factorial, further research is needed to investigate the reasons, preventable measures, clinical and cost outcomes of such delays.
Measurements of Heterogeneity of Bone Marrow Cellularity
Authors: Goldenberg Alec , Haglof Karen , Kelley Priscilla , Davis Geri , Liu Cynthia , Ibrahim Sherif 
Published: April 2020

Abstract
Introduction: Quantifying cellularity is an integral component of bone marrow examinations. Estimates of marrow cellularity may influence the diagnostic interpretation of bone marrow samples. The accuracy of cellularity estimates may be influenced by the variable distribution of cellular elements within the marrow space. To better understand the degree of heterogeneity of bone marrow cellularity, we undertook a study to quantify the variable distribution of bone marrow cells in bone marrow core biopsies.
Method: 8 gauge bone marrow core biopsies of 20 patients were retrospectively reviewed by 2 hematopathologists (SI,CL). The specimens were recovered from the posterior superior iliac crest using standard technique with 8G Snarecoil biopsy needles by 3 operators (KH, PK, GD). The percent cellularity was determined in sequential 0.2 X 0.4 cm portions of the core biopsies by each of the hematopathologists. Cellularities were recorded in 10% increments.
Results: The mean age of the patients was 73.2 ± 1.8 years. There were 12 males and 8 females. 5 patients had monoclonal gammopathies. Anemia, multiple myeloma and thrombocytopenia were each diagnosed in three patients. 2 patients demonstrated myelodysplasia and 1 patient each had acute leukemia, leukocytosis, non-Hodgkin’s lymphoma and thrombocytosis. The mean white blood cell count, hemoglobin and platelet count were 8.7 (range 3.8–42.8), 12.2 (range 10.1–15.3), and 233 (range 91–226), respectively. The mean length of the core biopsies was 1.78 ± 0.09 cm (range 1.4–3.3) and the median number of 0.2 × 0.4 cm portions examined per core biopsy was 8 (range 5–12). In total, 165 portions were examined by each hematopathologist independently. The cellularity of 12 and 11 portions could not be determined by each of the hematopathologists, respectively, as a result of biopsy artifacts. No core biopsy showed a consistent cellularity within the examined portions, each core demonstrating a range of cellularities. Only 2/20 and 1/20 of the core biopsies, as examined by each hematopathologist, respectively, demonstrated 2 consistent cellularities. A median of 4 different cellularities were identified in each core. The mean range of cellularities of each core’s portions was 43 ± 4.6 %, and 46.5 ± 4.9 %, as determined by the 2 hematopathologists, respectively, which was statistically equivalent (paired t-test p=0.349).
Conclusions:
Bone marrow cellularity is heterogeneous. Cellularities of different portions of core biopsies vary significantly. Average differences between minimal and maximal portional cellularities may be as high as 46%. The accuracy of bone marrow cellularity measurements is related to the size of the biopsy specimen.