bluuebunny/crossref_metadata_2025_split huggingface dataset:
Regulation of Dendritic Cell Function by Histone Deacetylase Inhibitors.
Authors: Beck Julia , Nencioni Alessio , Grünebach Frank , Bringmann Anita , Kanz Lothar , Patrone Franco , Ballestrero Alberto , Brossart Peter 
Published: April 2020

Abstract
Histone deacetylases (HDACs) modulate gene transcription and chromatin assembly by modifying histones at the post-transcriptional level. HDAC inhibitors have promising antitumor activity and are presently explored in clinical studies for malignancies of different histology. Preliminary evidence in animal models of immune disorders also suggests immunosuppressive properties for these small molecules, although the underlying mechanisms remain at present poorly understood. Here, we show that two HDAC inhibitors of clinical use, sodium valproate and MS-275, profoundly affect cytokine-induced differentiation of human monocytes to dendritic cells (DCs), and impair DC phenotypic maturation in response to the Toll-like receptor (TLR) ligand polyinosinic:polycytidylic acid (poly I:C) characterized by a reduced expression of HLA- and costimulatory molecules. HDAC inhibitors reduce cytokine secretion important for T-cell activation like IL-12 and immunostimulatory capacity in DCs and inhibit DC migratory capacity toward the chemoattractant CCL19/MIP-3β. The observed defects in DC function upon exposure to HDAC inhibitors were not due to an increased rate of apoptosis or production of IL-10. We finally investigated the effects of HDAC inhibition on intracellular signalling pathways that play a key role in controlling DC differentiation and function. HDAC inhibitors have been reported to cause a downregulation of the hematopoietic transcription factor PU.1, which contributes to the development of thymic and myeloid dendritic cells and of Langerhans cells in the mouse. We evaluated herein whether PU.1 expression was affected by VPA in monocyte-derived DCs, however, no significant reduction in protein levels could be detected. Therefore, our data rule out PU.1 shortening as a mechanism responsible for the functional defects observed in DCs that were exposed to HDAC inhibitors. Similarly, no significant effect of HDAC inhibitors was detected on Bcl-6, another known target of HDAC inhibitors that, besides its role in lymphomas, has also been linked to the regulation of cytokine and chemokine release in macrophages. In contrast, addition of VPA blocked RelB nuclear relocalization in response to poly I:C in a concentration-dependent manner. Interestingly, IRF-3 and IRF-8, which have been involved in DC differentiation, IL-12 production and DC migration, were also affected by HDAC inhibitors, since their nuclear levels were reduced by VPA in unstimulated as well as in poly I:C-activated DCs. On the other hand, IRAK-1 downregulation in response to poly I:C was not affected by VPA, suggesting that the effects of HDAC inhibition on RelB, IRF-3 and IRF-8 are probably mediated downstream of MyD88 and IRAK-1.
In conclusion, HDAC inhibitors exhibit strong immunomodulatory properties on human DCs. Our results support the evaluation of HDAC inhibitors in inflammatory and autoimmune disorders.
Comparison of 7-Day Storage of Buffy-Coat Derived Platelet Concentrates in an Osmotically Balanced, Interface Stabilizing Platelet Storage Solution and in Plasma.
Authors: Zhang Jerry G. , Culibrk Brankica , Devine Dana D.V. , Hoang Lien , Hunter Faith , Kerr Ian , Levin Elena , Scammell Ken , Stewart Tamiko , Weiss Sandra , Gyongyossy-Issa Maria I.C. 
Published: April 2020

Abstract
The use of platelet additive solutions (PAS) for the storage of buffy-coat derived platelet concentrates (PC) could conserve plasma resources and reduce post-transfusion reactions. However, PASs are difficult to handle in a production environment where their relative low viscosity produces an unstable interface between the platelet rich plasma and the red cell pellet. In the current study, a comparison is drawn between buffy-coat derived PCs (4 buffy-coats per pool) stored over 7 days either in plasma or in a novel Viscous PAS that contains 26 % plasma as a by-product of the buffy-coat pooling process. The increased viscosity (1.18 cp at 37°C) of the PAS results in a stable interface during processing. Similar, though more consistent platelet recoveries from buffy-coat pools (BCP) are achieved by the Viscous PAS (77.0 ± 2.6%) as compared to plasma (73.7 ± 5.9 %). These are significantly higher (p&lt;0.05) than recoveries using conventional PASs (64.5 ± 2.1 %). On day 7, platelet concentration, mean platelet volume (MPV), and soluble protein concentration in PCs stored using Viscous PAS (782 ± 87 x 109 cells/L, 9.1 ± 0.5fL, 15.0 ± 1.6 mg/L, respectively) and plasma (840 ± 104 x 109 cells/L, 9.0 ± 0.7fL, 56.09 ± 9.2 mg/L, respectively) were not significantly different from their corresponding day 1 parameters (837 ± 84 x 109 cells/L, 9.1 ± 0.3 fL, 13.5 ± 0.2 mg/L) respectively for Viscous PAS and (830 ± 73 x 109 cells/L, 8.3 ± 0.5 fL, 56.6 ± 6.5 mg/mL) and for plasma. This indicates that Viscous PAS and plasma maintain platelet integrity to a similar degree during 7-day storage. Both storage media maintain pH around 7.20 until day 7. However, the rate of glucose consumption and lactate production of PCs stored in Viscous PAS (0.3365 mmol/L.day, and 0.7591 mmol/L.day) was roughly half that of the rate exhibited by PCs stored in plasma (0.8447 mmol/L.day, and 1.4258 mmol/L.day). As lactate production and glucose consumption are correlated with in vivo platelet recovery (Goodrich et al., 2006) this augurs well for platelets stored in Viscous PAS. Monitoring the extent of shape change (ESC) and morphology scores for PCs in either of the storage media showed no significant difference on day 7. However, CD62 surface expression and the hypotonic shock response (HSR) were significantly better at day 7 (p&lt;0.05) for platelets stored in the Viscous PAS (37.43 ± 3.31% and 75.76 ± 10.95%, respectively) than stored in plasma (58.37 ± 11.71% and 49.79 ± 15.34%, respectively). We have developed a PAS that is easy to handle in a production environment and because of its osmotic balance and realtive viscosity exhibits equivalent or better storage parameters over a 7 day period than does plasma.
High Definition Contrast-Enhanced MR Imaging in Paroxysmal Nocturnal Hemoglobinuria (PNH) Suggests a High Frequency of Subclinical Thrombosis.
Authors: Hill Anita , Reid Scott A. , Rother Russell P. , Gladwin Mark T. , Collinson Paul O. , Gaze David C. , Lowe Angela , Guthrie Ashley , Sivananthan Mohan U. , Hillmen Peter 
Published: April 2020

Abstract
Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired disorder characterized by intravascular hemolysis and venous thrombosis. Thrombosis is the most feared complication in PNH and is reported to occur in &gt;40% of patients. Proposed mechanisms of thrombosis include depletion of the coagulation regulator nitric oxide (NO) by intravascular hemolysis and increased sensitivity of PNH platelets to activation. The occurrence of subclinical thrombosis in PNH patients has not been previously studied using modern imaging techniques. In order to evaluate for subclincal thrombosis we evaluated PNH patients with a comprehensive state-of-the-art MRI protocol (which included the use of both blood pool and conventional Gadolinium based contrast agents) for the detection of subclinical thromboses and its sequelae. The detailed protocol consisted of:
lung perfusion and pulmonary MRA, cardiac MR - including quantitative studies of both ventricles, right heart flow dynamics and delayed enhancement for the detection of left ventricular damage, and abdominal MR for the assessment of hepatic and portal venous systems and kidneys.
10 PNH patients (median age 31.5 yrs) with large PNH clones but without previous clinical evidence of venous or arterial thrombosis underwent imaging. Five (50%) of the patients were on primary anticoagulant prophylaxis with warfarin. There was evidence of significant renal hemosiderosis, which was distributed throughout the cortices, in 8/10 patients. Two patients had small myocardial scars suggestive of previous unsuspected ischemic damage. Six patients had sub-segmental perfusion defects mainly distributed in the peripheries of the lung fields indicative of previous small pulmonary emboli. No such subclinical thromboses would be anticipated in an age-matched control population. 8 patients had mildly reduced right ventricular ejection fractions (mean 42.2±1.8%; normal range 48–63%). The plasma B-type natriuretic peptide (BNP) level was high in all 10 patients (median 29.4pmol/l; range 18.7–373.90; normal subjects 4.89±1.00pmol/l). BNP has been shown to increase in proportion to right ventricular dysfunction in pulmonary hypertenstion. No intraabdominal defects were identified with the current protocol. In summary, we identified abnormalities suggestive of previous subclinical thromboses in 6 of 10 hemolytic PNH patients by high-resolution MR imaging, including in patients on primary prophylaxis with warfarin. Effective prevention of thrombosis is an important aspect of the therapy in PNH.
A Prospective Trial of Radiation Alone vs Combination Chemotherapy Alone for Early-Stage Hodgkin’s Disease: Implications of 25-Year Follow-Up to Current Combined Modality Therapy.
Authors: Longo Dan L. , Glatstein Eli , Duffey Patricia L. , Young Robert C. , Fiem Shelby , Jaffe Elaine S. , Camphausen Kevin , Wilson Wyndham , DeVita Vincent T. 
Published: April 2020

Abstract
We conducted a prospective randomized trial comparing radiation therapy to MOPP chemotherapy in patients with stages IA through IIIA Hodgkin’s disease (HD). Patients with peripheral stage IA disease received radiation therapy without randomization. Median follow-up is now 25 years. Among the 30 patients with peripheral stage IA disease, all achieved complete response, 4 relapsed (13%), 8 died [27%; 2 from HD, 1 suicide, 1 myocardial infarction (MI), and 4 from second malignancies). Among the 51 patients randomized to receive radiation, 49 (96%) achieved complete response, 19 relapsed (39%), 18 died (35%; 10 from HD, 1 AIDS, 1 anorexia nervosa, 1 pulmonary fibrosis, 3 congestive heart failure, and 2 from second malignancies). In addition, 7 other second cancers have been observed in 6 patients treated with radiation who are alive and significant treatment toxicities affect the lives of 5 others. Among the 54 patients randomized to receive MOPP chemotherapy, 52 (96%) achieved complete response, 7 relapsed (13%), 10 died [18%; 5 from HD, 2 MI (1 in cycle 1), 1 from Pneumocystis pneumonia during treatment, and 2 from second malignancies]. Two other patients are alive with a second cancer and one has AIDS. Disease-free survival is 87% for MOPP and 61% for radiation in the randomized arms at 25 years (p=0.0034). Overall survival is 81% for MOPP and 63% for radiation in the randomized arms at 25 years (p=0.048). When the peripheral IA patients are added to the randomized radiation-treated patients, disease-free survival is 70% (p=0.36 vs MOPP) and overall survival is 67% (p=0.07 vs MOPP). The design of the study permits an analysis of the late effects associated with the administration of radiation alone or MOPP alone as a substantial fraction of patients achieved complete response and remained in their initial remission. Among all patients treated with radiation, 11 died in first remission (5 from a second cancer, 2 from CHF, 1 MI, 1 pulmonary fibrosis, 1 AIDS, 1 suicide). Among all patients treated with MOPP, 3 died in first remission (2 from a second cancer, 1 MI). The difference in survival after achieving initial CR (93% for MOPP, 78% for radiation) is significant (p=0.054). The current standard practice of using combined modality therapy might be expected to incur the toxicities associated with both chemotherapy and radiation therapy. Furthermore, synergistic toxicities associated with the combination have been described. Thus, efforts should be made to define the substantial fraction of patients whose disease can be controlled with a single modality and reserve combined modality therapy for the subset that requires it for disease control.
HD12 Randomised Trial Comparing 8 Dose-Escalated Cycles of BEACOPP with 4 Escalated and 4 Baseline Cycles in Patients with Advanced Stage Hodgkin Lymphoma (HL): An Analysis of the German Hodgkin Lymphoma Study Group (GHSG), University of Cologne, D-50924 Cologne, Germany.
Authors: Engert Andreas , Franklin Jeremy , Mueller Rolf-Peter , Eich Hans-Theodor , Gossmann Axel , Mueller-Hermelink Hans Konrad , Cerny Thomas , Markova Jana , Ho Anthony D. , Kanz Lothar , Greil Richard , Hiddemann Wolfgang , Pfistner Beate , Diehl Volker 
Published: April 2020

Abstract
The preceding trial HD9 had shown a significant superiority for escalated BEACOPP (EB) for failure-free survival (FFTF) and overall survival (OS) over COPP/ABVD or baseline BEACOPP (BB) (each 8 cycles). HD12 aimed to de-escalate chemotherapy by comparing 8 cycles EB with 4 cycles EB plus 4 cycles BB, with or without consolidatory 30 Gy radiation (RT) to initial bulky and residual disease. A total of 1661 patients aged 16–65 with HL in stage IIB (large mediastinal mass and/or E-lesions) or stage III-IV were randomised from 9/1999-1/2003 according to a factorial design between: 8EB + RT, 8EB no RT, 4EB+4BB + RT, 4EB+4BB no RT. A central diagnostic panel reviewed CT images after completion of chemotherapy independent of randomisation arm, and prescribed RT in selected cases. In the fifth analysis of HD12 (5/2006), 94% of all 1593 eligible randomised patients were evaluable, including 1498 for the chemotherapy comparison and 1449 for the radiotherapy comparison. Patient characteristics were very similar for all 4 arms. Radiation was given in arms with planned RT in 65%, in arms with no planned RT in 10%. 93% of all patients reached a complete remission, 2.2% suffered early progression, 4.6% relapsed and 8.2% died with a median folllow-up time of 48 months. Death due to acute toxicity was 3.2% (sepsis, cardiac, pulmonary, infection), with 21 such deaths in the 8EB arms and 27 in the 4EB+4BB arms. Secondary neoplasias were observed in 55 patients (3.7%): 14 AML/MDS, 12 NHL and 29 solid tumors/others. Four-year Kaplan-Meier estimates for arm pairs according to the factorial design were:
4 year rates, %(95% CI) 8EB vs. 4EB+4BB with RT vs. without RT FFTF 88(86–91) 86(83–89) 91(89–93) 88(86–91) OS 93(91–95) 91(89–93)
No significant differences were observed when comparing treatments according to the sequential analysis plan (N.B. 10% received RT in arms ‘without RT’). The final analysis, scheduled when 80% of patients have 5 years follow-up, must be awaited before final conclusions can be drawn.
Cancer Risks in Fanconi Anemia: Experience of the German Fanconi Anemia (GEFA) Registry.
Authors: Rosenberg Philip S. , Alter Blanche P. , Ebell Wolfram 
Published: April 2020

Abstract
OBJECTIVE: Acute Myeloid Leukemia (AML) and solid tumors (ST) occur frequently in Fanconi Anemia (FA). Our objective was to characterize the age of onset of cancer and identify any neoplasms occurring in excess.
METHODS: We analyzed data from the German Fanconi Anemia (GEFA) Registry, a retrospective cohort. For competing adverse events of bone marrow failure (BMF), AML, and ST, we determined cause-specific hazards and cumulative incidence curves. We calculated the ratio of observed to expected cancers (O/E ratio) in GEFA compared to age- and sex-matched persons from the general North American population. We studied outcomes after bone marrow transplantation (BMT) using survival analysis.
RESULTS: In GEFA, 182 patients contributed 2548 person-years of observation prior to BMT; 63 had BMF as the first adverse event, 15 had AML, and 10 had ST. The cumulative incidence by age 50 was 48% for BMF and 29% for ST. The cumulative incidence by age 20 was 9% for AML. The hazard of BMF peaked at 4%/y at age 10. The hazard of AML increased to 1.6%/y at age 20. The hazard of ST increased from 1%/y at age 20, to 5%/y at age 40, to ~10%/y at age 50. The O/E ratio was 45 for all cancers, 24 for all solid tumors, and 926 for AML; these increased risks were statistically significant. Significantly elevated O/E ratios were observed for esophagus (6346), vulva (2436), oral cavity and pharynx (121), breast (34), and brain (23) cancers. Forty-eight patients had BMT prior to cancer. Subsequently, there were 20 deaths and 3 malignancies in 216 person-years. The 3 malignancies (tongue, liver, and esophagus) occurred 2, 16, and 17 years after mismatched, matched, and matched transplant at ages 13, 23, and 34, respectively. The age-specific hazard of ST was 3.8-fold higher in transplanted versus untransplanted patients; this increased risk was not significant (P = 0.11). During 2000–2004, none of 5 patients with matched, and 3 of 18 patients with mismatched donors, died during the period from 0 – 6 months. In patients with matched donors, acute and chronic GVH were significant risk factors for death beyond 6 months.
CONCLUSIONS: Absolute and relative risks of cancer in GEFA are quantitatively similar to previously reported estimates from the North American Survey. Outcomes after transplantation in GEFA are comparable to the Hôpital St Louis Cohort. Our prior observation that FA patients who survive BMF are at extraordinary risk of specific ST has been replicated.
OFD1-Mediated T Cell Responses in MGUS Patients: Implications for Immunotherapy.
Authors: Blotta Simona , Prabhala Rao , Pelluru Dheeraj , Tetsuro Sasada , Franco Brunella , Tagliaferri Pierosandro , Tassone Pierfranceso , Anderson Kenneth C. , Munshi Nikhil C. 
Published: April 2020

Abstract
We have identified a panel of 11 novel antigens with induced antibody response in patients with Monoclonal Gammopathy of Undetermined Significance (MGUS) by screening a Multiple Myeloma (MM) cDNA library with patient serum using Serological Analysis of Recombinant Expression cloning (SEREX). Among these antigens, a specific antibody response against OFD1 protein was observed in 6/29 (20.6%) MGUS patients, while 0/12 newly diagnosed, 1/11 (8.3%) relapsed and 3/11 (27.2%) post-transplant MM patients in complete or partial remission showed an antibody response against this protein. Interestingly, in 1 of these patients the antibody response appeared only after autologous transplantation. No responses were observed in 25 healthy donors. OFD1 is widely expressed in embryonic stage with important role in organogenesis; however its expression decreases significantly in adult tissues. Moreover, OFD1 that is involved in the functional regulation of the Hedgehog-pathway, is dysregulated in solid tumors, suggesting a potential role in the tumorigenesis. We have observed the OFD1 expression at high levels in all 11 MM cell lines and 4 primary MM patient cells tested as compared with low or no expression in PBMC and normal bone marrow stromal cells. Specific sequences, derived from three clones corresponding to three different parts of OFD1 protein, were used to identify 15 peptides with potential binding to HLA-A*0201 and selected two peptides (3 and 8) on the basis of their high binding affinity. We observed presence of OFD1 specific CD8+ T cells, as measured by HLA-A2+ pentamers, on all 6 HLA2-A2+ MGUS patients tested. Presence of these cells was also observed in 5 MM patients. However, T cell proliferation following incubation with OFD1 peptides for 7days was observed only in MGUS (=6) while T cell proliferation was not observed in MM (n=5) patients indicating intact OFD1-specific responses in MGUS as compared with MM. These results highlight a possible role of OFD1 in the immune regulation in MGUS and provide the framework for further evaluation of OFD1 as a new potential target for immunotherapeutic approaches in both MGUS and MM.
Activation of the JNK Pathway Mediates Chemoresistance in T-Cell Acute Lymphoblastic Leukemia by Phosphorylation and Proteosomal Degradation of BimEL.
Authors: Leung Kam Tong , Li Karen Kwai Har , Sun Samuel Sai Ming , Chan Paul Kay Sheung , Wong Yum Shing , Ooi Vincent Eng Choon , Chiu Lawrence Chi Ming 
Published: April 2020

Abstract
Despite progress in the development of effective treatments against T-cell acute lymphoblastic leukemia (T-ALL), about 20% of patients still exhibit poor response to the current chemotherapeutic regimens and the cause of treatment failure in these patients remains largely unknown. In this study, we aimed at finding mechanisms that drive T-ALL cells resistant to chemotherapeutic agents. By screening etoposide sensitivity of a panel of T-ALL cell lines using DNA content and PARP cleavage as apoptosis markers, we identified an apoptosis-resistant cell line, Sup-T1. Western blot analysis and caspase activity assay showed that Sup-T1 cells were deficient in etoposide-induced activation of caspase-3 and caspase-9. In addition, mitochondrial cytochrome c release was not evident in etoposide-treated Sup-T1 cells. However, addition of exogenous cytochrome c in cell-free apoptosis reactions induced prominent caspase-3 activation, indicating that the chemoresistance observed in Sup-T1 cells was due to its insusceptibility to the drug-induced mitochondrial alterations. Analysis of the basal expression of the Bcl-2 family proteins revealed that the levels of Bcl-2 was higher in Sup-T1 cells, while Bax and BimEL levels were lower, when compared to etoposide-sensitive T-ALL cell lines. Gene silencing using antisense oligonucleotide to Bcl-2 and overexpression of Bax did not resensitize cells to etoposide-induced apoptosis. On the contrary, transient transfection of BimEL into Sup-T1 cells significantly restored etoposide sensitivity. Further experiments revealed that the lack of BimEL expression in Sup-T1 cells was due to the rapid degradation of newly-synthesized BimEL by the proteosomal pathway, as treatment of Sup-T1 cells with a proteosome inhibitor significantly restored the protein level of BimEL. Moreover, treatment with proteosome inhibitor resulted in mobility shift of BimEL, which was sensitive to phosphatase digestion. Furthermore, treatment of Sup-T1 cells with JNK inhibitor resulted in accumulation of BimEL, and pretreatment with JNK inhibitor restored sensitivity of Sup-T1 cells to etoposide-induced apoptosis, indicating that constitutive activation of the JNK pathway in Sup-T1 cells was responsible for promoting BimEL phosphorylation, and this may serve as a signal targeting BimEL to the proteosome for degradation. Altogether, our findings provide the first evidence that JNK activation correlates inversely with BimEL level by promoting its phosphorylation and degradation. This, in turn, reduces the sensitivity of T-ALL cells to chemotherapeutic agents.