bluuebunny/crossref_metadata_2025_split huggingface dataset:
Use of RNA Interference to Inhibit Integrin Subunit alphaV-Mediated Angiogenesis.
Authors: Graef Thorsten T. , Steidl Ulrich U. , Fenk Roland R. , Rohr Ulrich U. , Nedbal Wolfgang W. , Haas Rainer R. , Kronenwett Ralf R. 
Published: April 2020

Abstract
Inhibition of angiogenesis is a promising approach for the treatment of solid tumors, inflammatory diseases and different hematological malignancies such as multiple myeloma. One of the central molecules in capillary formation during angiogenesis is the integrin alphaVbeta3 (aVb3), therefore aVb3 is a potential target molecule to inhibit angiogenesis. The aim of this study was to inhibit alphaV-mediated angiogenesis in vitro using RNA interference (RNAi) technology as well as antisense oligodeoxyribonucleotides (asON). We used synthetic small interfering RNAs (siRNA) and asON directed against the alphaV chain of aVb3 to inhibit integrin expression. Five siRNAs were selected on the basis of a systematic alignment of computer-predicted secondary structures of target mRNA and on the basis of current recommendations for siRNA oligonucleotide design. In parallel, 3 asON were examined. They had the sequence of the antisense sequence of 3 of the siRNAs molecules, respectively. SiRNAs, asON and respective control sequences were transfected into human umbilical vein endothelials cells (HUVEC) using lipofection. Following stimulation by phorbol 12-myristate 13-acetate (PMA), two siRNAs showed a dose- and time dependent inhibition of PMA-induced aV-mRNA and -protein upregulation as assessed by real-time RT-PCR and flow cytometry. At a concentration of 25 nM a 100% (SD: 4.9%) inhibition of aV upregulation was observed, whereas transfection of the respective asON sequences resulted in a 63% (SD: 6.1%) inhibition of aV upregulation at 25nM. To evaluate the anti-angiogenic potential of siRNAs in comparison to asON a cell culture model of human angiogenesis based on the co-cultivation of endothelial cells and dermal fibroblasts was used. Transfection of the most efficient siRNA sequence at a concentration of 50nM resulted in an inhibition of total length of capillary-like tubules by 48.7% (SD: 3.6%) in comparison to 21.8% (SD: 9.8%) by the respective asON sequence treated cultures.
In conclusion, siRNAs can successfully be selected on the basis of computer-predicted secondary structures. In comparison with asON having the same sequence as the antisense strand of the respective siRNA the siRNA-mediated inhibition of aV expression showed a stronger inhibition of capillary tube formation in an angiogenesis in vitro assay. Therefore, siRNAs are useful tools for functional aV knock-down experiments and might be a therapeutic alternative for antagonists which bind directly to the integrins aVb3 or aVb5.
Prevalence of Antiphospholipid Anitbodies in Idiopathic Venous Thromboembolism.
Authors: Paramsothy Koushi , Wells Philip S. 
Published: April 2020

Abstract
The presence of antiphospholipid antibodies (APLA), which include lupus anticoagulant (LA) and anticardiolipin antibodies (ACA), increases the risk of venous thromboembolism (VTE). Although, the association demonstrated between LA and VTE is strong, that between ACA and VTE is weak with the exception of high titers. This suggestion has been that this may be related to the induction of ACA by acute illness. This may be the explanation for the widely varying frequency of ACA positivity in patients with acute VTE in the current medical literature. The prevalence of LA in patients with acute VTE is more consistent but the value of testing for ACA and LA at presentation of acute VTE remains unknown. We routinely test all idiopathic VTE patients at presentation for LA and ACA. It had been our impression that most positive results revert to normal with subsequent testing. We sough to test this hypothesis. The objective was to determine the prevalence of abnormal LA and ACA results and the frequency of subsequent normalization in patients presenting with a first idiopathic venous thromboembolic event. A retrospective chart review was conducted at the Thrombosis Unit at the Ottawa Hospital. 278 charts of unrelated, consecutive patients with idiopathic VTE were reviewed. 232 patients with single idiopathic venous thromboembolic events with documented LA and ACA results were included. The patients were divided into two groups based on the time between the acute VTE and initial APLA test. The frequency of abnormal LA and ACA on initial and repeat tests was determined in each group. 170 and 177 patients were screened for LA and ACA within one month of the acute VTE. On initial tests, LA and ACA were detected in 14.1% and 7.9% of patients, respectively. However, LA and ACA were present in only 1.2% and 1.7% of patients, respectively, on subsequent tests. In patients screened more than one month after an acute VTE 3.8% of the 52 patients had evidence of LA on initial testing and all were positive on repeat tests. ACA were present in 8% of patients on initial tests and in 6% (75% of the initial positive results) of patients on subsequent tests. A high frequency of positive LA and ACA tests results is observed when these tests are performed at the time of presentation of acute VTE. Repeat testing beyond one month from presentation demonstrates most of the results return to normal suggesting false positive results are common at presentation. However, when the tests are performed one month or longer after the acute VTE, the frequency of positive APLA test is much lower and false positives are uncommon. Screening for APLA should not be performed until at least one month after the diagnosis of idiopathic.
Effect of Chemotherapy on the Distress and Quality of Life of Cancer Patients.
Authors: Hussain Mirsa B. , Sarita Gangadharan P. , Devi Nandakumar , Thomas Bejoy C. , Rita Krishnan , Ramdas Kunnambath , Rajan Balakrishna , Pandey Manoj , Narayanan Geetha N. 
Published: April 2020

Abstract
Introduction: The deteriorating effects of chemotherapy on cancer patients are well documented, as is the need and impact of psychosocial interventions in improving quality of life (QOL). In India, cancer centres have a very high patient load and providing quality treatment and achieving good survival is still the first priority. Published studies from India on QOL in cancer patients are far and few, current ongoing studies are even fewer. The present study is on effect of chemotherapy on QOL, and prevalence of psychological morbidity in the Indian context.
Patients and Methods: The study sample consisted of 117 cancer patients undergoing chemotherapy with curative intent as single modality or as part of the multi modality regimen. Nearly 30% of the sample had lymphoproliferative disease, 17% had haematological malignancies, 45% had solid tumours, and the rest had multiple myeloma. The assessments were carried out using the Distress Inventory for cancer version 2 (DIC V2), Functional Assessment of Cancer Therapy-General (FACT-G), and the Hospital Anxiety and Depression scales (HADS).
Results: Older patients (&gt;=47 years) had significantly greater spiritual distress, and difficulties in activities of daily living, but had better emotional well being compared to younger patients (&lt;47 years). Patients from lower income strata had significantly greater distress levels and poorer QOL than those in the upper income category. Those with advanced disease had significantly poorer scores on most of the QOL subscales. More than 20% of the patients were found to have significant psychological morbidity ranging from mood disturbances (12%), to anxiety (3%) and depression (5%). Though chemotherapy did not significantly influence anxiety and depression, it was noted that male patients had significantly higher depression rates than females.
Conclusions: The study was intended to measure the existence of psychological morbidity within the cancer patients. Older patients, those from lower incomes groups, and those with advanced disease had significantly greater levels of distress and significantly poorer QOL scores. Depression rates were significantly higher in male patients than in female patients. This shows the need to have psychiatric assessment and intervention among patients undergoing cancer chemotherapy.
Hematopoietic Growth Factors Reduce Side Effects of Cancer Treatment: Results of Two Comprehensive Meta-Analyses.
Authors: Bohlius Julia , Engert Andreas 
Published: April 2020

Abstract
Background: Hematopoietic growth factors such as G-CSF/GM-CSF and erythropoietin (EPO) are used in clinical practice to reduce side effects of cancer treatment but also to improve tumour response and overall survival. We conducted two meta-analyses on the effects of hematopoietic growth factors in the treatment of malignant diseases a) to determine the effectiveness of G-CSF and GM-CSF to i) prevent infection, ii) improve tumor response and overall survival in lymphoma patients undergoing standard chemotherapy and b) to assess the effectiveness of EPO to i) prevent anemia, ii) improve tumor response and overall survival in cancer patients.
Methods: The Cochrane Library, Medline, Embase and smaller databases were searched. Randomized controlled trials comparing G-CSF/GM-CSF or EPO versus placebo/no treatment were included in the reviews. Both study arms had to receive identical antineoplastic treatment and identical additional supportive care. We included full-text and abstract publications as well as unpublished data. Data were meta-analysed using fixed and random effects models.
Results: Twenty one trials with 2,794 adults were included in the EPO meta-analysis. Use of EPO significantly reduced the relative risk of red blood cell transfusions (RR 0.67; 95% CI 0.62 to 0.73). For participants with baseline hemoglobin below 10 g/dL hematological response was observed more often in participants receiving EPO (RR 3.60; 95% CI 3.07 to 4.23). There was inconclusive evidence whether EPO improves tumour response (random effects: RR 1.21; 95% CI 0.92–1.59) and overall survival (unadjusted data: HR 0.84; 95% CI 0.69 to 1.02). 12 trials with 1,823 randomized patients were included in the G-CSF/GM-CSF meta-analysis. Compared with no prophylaxis, G-CSF/GM-CSF significantly reduced the relative risk for infections (RR 0.74; 95% CI 0.64–0.85). There was no evidence for G-CSF/GM-CSF to decrease infection related mortality (RR 1.37; 95% CI 0.66–2.32), to improve complete response (RR 1.02; 95% CI 0.94–1.11) or overall survival (HR 1.00; 95% CI 0.86–1.16).
Conclusions: There is consistent evidence that the administration of EPO and G-CSF/GM-CSF reduces the side effects of antineoplastic therapy, such as risk for blood transfusions (EPO) and infections (G-CSF/GM-CSF). However, there is inconclusive evidence whether the administration of hematopoietic growth factors in these clinical settings also improve tumor response and overall survival.
Detection of Cytokeratin-19 in Peripheral Blood of Breast Cancer Patients: Results from a Systematic Review/Meta-Analysis.
Authors: Soares Heloisa P. , Santucci Rodrigo , Kumar Ambuj , Djulbegovic Benjamin , Glasberg Joao , Del Giglio Auro 
Published: April 2020

Abstract
Background: The identification of occult micrometastatic disease is potentially important in management of breast cancer (BC) patients. Therefore, detection of cytokeratin 19 (CK-19) and others molecular markers using reverse transcriptase polymerase chain reaction (RT-PCR)-based techniques to detect micrometastases could have significant implications in prevention, early detection and treatment of breast cancer.
Objective: To assess the diagnostic specificity and sensitivity of detection of CK-19 in the peripheral blood (PB) of BC patients as well as to assess its relation to prognostic factors and implication on survival.
Methods: We conducted a systematic review/meta-analysis of all studies that analyzed CK-19 in the PB of BC patients. We searched MEDLINE, LILACS and Cochrane Database of Systematic Reviews (last search June 2004). Studies that had at least 10 BC patients and controls and evaluated the presence of CK-19 in PB using RT-PCR were included in this review. Diagnostic sensitivity was defined as the percentage of detection of CK-19 in patients with histological proven diagnosis of breast cancer. The specificity was defined as the percentage of negative tests for CK-19 in the control group (healthy individuals or non breast cancer patients).
Results: Out of 1842 relevant studies that were identified, 26 met our inclusion criteria, enrolling 2398 patients (1176 treatment and 1222 controls). Results showed that PCR had an overall diagnostic sensitivity of 0.39 (95% CI: 0.36–0.42) and diagnostic specificity of 0.83 (95% CI: 0.76–0.87) regardless of the breast cancer stage. Six studies researched the association between CK-19 and well established prognostic factors (i.e. positive axillary lymph nodes, hormonal receptors, tumor size); however data were not available for quantitative synthesis. Survival was poorly reported making impossible to generate any conclusion about the implication of detection of CK-19 on prognosis. When studies were critically appraised, we also identified many methodological weaknesses in the design, conduct and the analysis of these studies (e.g. use of multiple control arms, use of non-consecutive patients, different timing of sample collection, inclusion of all stages of breast cancer and differential work-up in the study & control groups) hence resulting in biased findings due to selection, verification, detection and spectrum bias.
Conclusion: The existing body of evidence regarding the assessment and prognostic value of CK-19 using RT-PCR techniques is poor and needs ample improvement before the initiation of its clinical application.
The Role of Race on Survival after Alternative Donor Hematopoietic Progenitor Cell Transplant for Pediatric Acute Leukemia: Provocative Single Center Data.
Authors: Margolis David A. , Eapen Mary , Carreras Jeanette , Talano Julie-An , Browning Meghen , Casper James 
Published: April 2020

Abstract
Allogeneic blood or bone marrow transplant (BMT) can be a curative treatment for many children and adolescents with acute leukemia. With advances in unrelated donor transplant, others and we have shown that unrelated donor BMT can have similar survival to matched sibling BMT. There are several reports describing outcomes after matched related donor transplantation among various ethnic groups. Thus far, there are no published studies comparing outcomes among ethnic groups after alternative donor transplantation. Anecdotally, however, there have been concerns regarding outcomes among racial and ethnic groups, especially African-Americans. In order to address this question, we utilized our institutional database to analyze survival among children and adolescents receiving an alternative donor BMT at Children’s Hospital of Wisconsin from 1988-present. We compared survival in Caucasians and African-Americans undergoing unrelated donor and mismatched related donor transplantation (including haploidentical donors). One hundred and twenty four Caucasians underwent matched and mismatched unrelated donor transplantation compared to 11 African Americans. The 2-year probabilities of overall survival were significantly better for Caucasians at 53% (95% CI 44–62) than for African Americans, 18% (95% CI 2–45), p=0.01. Fifty-four Caucasians and 9 African Americans received mismatched family donor transplantation. Corresponding probabilities of overall 2-year survival were 38% (95% CI 25–51) and 30% (95% CI 5–64), respectively. Interestingly, our data show no statistically significant difference in survival after mismatched related donor transplantation between the Caucasian and African-American cohorts. Our data should be interpreted cautiously as the number of African Americans transplanted at our institution is few. Additionally, our analysis is limited by our inability to adjust for disease status at transplantation, HLA disparity and other known risk factors that may impact survival. Nevertheless these observations from a single institution cannot be ignored and warrant further analysis in a larger cohort such that outcomes after transplantation may be adjusted appropriately for relevant risk factors. We believe that a national database/registry study will have the numbers necessary to answer the questions that need to be asked regarding outcomes with alternative donor transplantation in the African-American population. We also believe that as cell processing and supportive care technologies improve mismatched family member transplantation outcomes, these advances could have a significant impact in improving leukemia-free survival for African-American children and adolescents.
Third Autotransplant for the Management of 98 Patients among 1358 Who Had Received Prior Tandem Autotransplants: Benefit Apparent When 2nd to 3rd Transplant Interval Exceeds 3 Years.
Authors: Lee Choon Kee , Barlogie Bart , Fassas Athanasios , Anaissie Elias , Zangari Maurizio , Rasmussen Erik , Tricot Guido 
Published: April 2020

Abstract
Tandem autotransplants have recently been reported in the IFM 94 randomized trial to confer more durable event-free survival (EFS) and overall survival (OS) than a single transplant. In the Arkansas program, scheduled tandem transplants have been part of Total Therapy 1 (TT 1) and Total Therapy 2 (TT 2) protocols since 1989 for newly diagnosed patients; this strategy was also applied for the management of previously treated patients. Among a total of 1358 patients receiving two prior autologous transplants at our institution (median interval from 1st to 2nd transplant, 4 mos), 98 received a further autologous transplant. In a search for features associated with favorable post 3rd autotransplant survival, pre-transplant 1, 2 and 3 features, especially the presence of cytogenetic abnormalities (CA) and standard laboratory features such as, B2M, CRP, LDH, albumin, hemoglobin and creatinine were examined along with the time interval from 2nd to 3rd transplant and whether a 3rd transplant was applied to rescue TT 1 or TT 2 front line or other patients receiving tandem transplants as salvage therapy. Remarkably, the presence of CA at any of the indicated time points had no impact on survival after a 3rd autotransplant usually with melphalan 200mg/m2. According to multivariate analysis, the 2nd to 3rd transplant interval (time-dependent covariate analysis) (HR 8.8, p=.002) and hypoalbuminemia &lt; 3.0g/dL (HR 3.2, p&lt;.0001) were independently important. Thus, post 3rd tx survival was superior among the 41 patients with a post-2nd tx survival &gt;3 yr and albumin ≥ 3.0g/dL (median, 21 mos; 5 yr OS 20%), with an intermediate outcome noted for the 34 patients with one of these favorable features present (median, 10 mos; 3 yr 20%) while the worst outcome was noted in the 13 patients who were both hypoalbuminemic and had received their 3rd transplant within 3 yrs of the 2nd transplant (median, 3 mos, no survival beyond 12 mos). Our data indicate that meaningful survival can be obtained with a 3rd autotransplant maneuver in approximately 50% of patients who have derived meaningful survival from a 2nd transplant of at least 3 years and have a preserved albumin concentration as an indication of their overall performance status.
Figure Figure
Expression of Endomucin, a CD34-Like Sialomucin, Marks Definitive Hematopoietic Stem Cells throughout Development.
Authors: Maeda Azusa , Iwama Atsushi , Eto Koji , Ema Hideo , Kitamura Toshio , Vestweber Dietmar , Nakauchi Hiromitsu 
Published: April 2020

Abstract
In order to identify cell surface molecules specific to hematopoietic stem cells (HSCs), a modified signal sequence trap was applied to mouse bone marrow (BM) CD34− c-Kit+ sca-1+ lineage− (CD34−KSL) cells which is highly enriched for HSCs. Among the identified genes, mRNA expression of Endomucin, an endothelium-specific gene encoding a CD34-like sialomucin, appeared highly specific to CD34-KSL HSCs.
To further investigate the expression of Endomucin, we generated two rat anti-mouse Endomucin monoclonal antibodies that recognize different epitopes (AE2D4, AE7F2). Taking advantage of these and another monoclonal antibody, V7c7 (1999, Blood, 93; 1; 165), detailed expression analysis was performed. Endomucin expression was largely confined to lineage markers-negative (Lin−) cells. Approximately 7 % of Lin− cells were Endomucin-positive. Cells strongly expressing Endomucin represented 30% of c-kit+ sca-1+ cells. Gating out CD34+ cells from Lin− Endomucin+ population resulted in high yield of KSL cells. High correlation between Lin− Endomucin+CD34− cells and KSL cells was confirmed by in vivo bone marrow transplantation. When Lin− cells were fractionated by their expression of CD34 and Endomucin, only Lin− Endomucin+CD34− cells contributed to long-term repopulation (LTR), and as few as 100 cells were enough to obtain engraftment. Furthermore, the majority of CD34−KSL cells were Endomucin+, and again, only CD34−KSL-Endomucin+ cells had LTR activity. These data indicate two facts: 1) A single positive marker, Endomucin can substitute for c-kit+ sca-1+, 2) All LTR -HSCs express Endomucin.
We then analyzed the expression of Endomucin during embryonic development of the hematopoietic system. Definitive HSCs arise from the hemogenic endothelium lining the wall of the dorsal aorta in embryonic aorta-gonads-mesonephros (AGM) region, then seed to the fetal liver. E10.5 AGM CD45− cells were segregated into subpopulations by their expression of Endomucin and CD41, an early marker of embryonic hematopoiesis. In vitro coculture system with a stromal cell line, OP9, was applied to detect the ability of hematopoietic potential. Hematopoietic activity was exclusively found in the CD41+Endomucin+ population, that represents 24% of CD41+ cells. Taken together, these data indicate that Endomucin marks both embryonic and adult HSCs, providing a novel useful cell surface marker for definitive HSCs throughout development.
Figure Figure
Significant Differences in the IGVH and BCL6 Mutation Status in Aggressive B-Cell Lymphomas with and without MYC Breakpoints.
Authors: Pott Christiane , Trautmann Heiko , Harder Lana , Kneba Michael , Siebert Reiner ,   on behalf of the MMML-Network
Published: April 2020

Abstract
Somatically mutated IGVH regions are a hallmark of germinal center (GC) B-cells. Moreover, aberrant somatic hypermutation (SHM) of oncogenes, like changes in the 5′ non-coding region of the BCL6 gene occurring in 75% of DLBCL, are a mechanism of oncogene activation independently of chromosomal translocations.
Large scale mutational screening using DHPLC and direct sequencing was applied to determine the somatic hypermutation status of clonal IGVH as well as several oncogenes like BCL6 and MYC in a series of more than 250 aggressive B-cell lymphomas included in the Deutsche Krebshilfe funded network “Molecular Mechanisms in Malignant Lymphoma”. Mutation patterns were correlated with the results of molecular cytogenetic analyses. MYC breakpoints detected by FISH clearly differentiated two groups of aggressive B-NHL with significantly different VH mutation status. MYC-positive lymphomas by FISH carried VH genes with a mutation frequency significantly lower compared to aggressive lymphomas lacking these features (median 4.8% vs.11.,0%, p&lt;0.0001). Similarly, the mutation frequency of BCL6 was significantly lower in MYC-positive than in MYC-negative lymphomas (median 0.13% vs 0.25% p=0,020). We observed a bias in VH gene usage in both groups with an overrepresentation of VH4 (40% in both groups) and VH3 gene (24% in MYC-positive, 40% in MYC-negative). The group of MYC-positive lymphomas was heterogeneous with regard to the pattern of chromosomal aberrations. (IGH, MYC, BCL2, BCL6, MALT1 and REL loci). Lymphomas with IG-MYC fusion lacking breakpoints in BCL2, BCL6, MALT1 or REL loci as well as non-MYC associated IGH translocations displayed a median IGVH mutation frequency of 4,8% vs. 12,2% in those cases with additional chromosomal translocations (p=0.0060).
Molecular classification of aggressive B-cell lymphomas according to MYC breakpoints distinguishes subgroups with significant differences in the VH and BCL6 mutation frequencies.