bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bortezomid-Induced Sweet Syndrome.
Authors: Schmidt-Tanguy Aline A. , Avenel-Audran Martine M. , Lissandre Séverine S. , Dib Mammoun M. , Croue Anne A. , Moles Marie-Pierre M.P. , Ifrah Norbert N. , Hunault-Berger Mathilde M. 
Published: April 2020

Abstract
Bortezomid (VELCADE®) is a potent proteasome inhibitor used in patients with relapsed and/or refractory multiple myeloma (MM). Numerous undesirable effects are known including thrombocytopenia, neuropathy, various gastrointestinal disorders, fatigue, or rare pulmonary complications. Cutaneous complications have also been described. We reported here a case of Bortezomid-induced Sweet syndrome. A 72-year-old man received Bortezomid for a second relapse of MM previously treated with VAD (vincristine, adriamycin, dexamethasone), double high dose melphalan and autologous transplant, and thalidomide. Bortezomid was given at the dose of 1.3 mg/m2 on days 1, 4, 8, and 11 every 21 days. Dexamethasone was associated with the first cycle at the dose of 20mg/d given on days 1, 2, 4, 5, 8, and 9. On day 11 of the third cycle, a partial response was observed. However, the patient presented a painful skin eruption without any fever. Centimetric erythematous, oedematous papulo-nodular plaques were observed on his back and a periorbital oedema. Spontaneous partial regression was noted on the first day of the following cycle but major analgesic drug were necessary. These cutaneous lesions on the back and the dorsal of fingers recurred on the fourth and fifth cycles with a maximum on day 11. Histopathological examination of a lesion showed oedeme of the dermis and a perivascular polymorphic dermal infiltrate of lymphocytes, neutrophils and eosinophils with some leukocytoclasia, but without parietal necrosis or vasculitis. This findings were consistent with neutrophilic dermatosis. During the sixth Bortezomid cycle, the administration of dexamethasone 20 mg/d on days 1, 2, 4, 5, 8, 9, 11, and 12 prevents the reoccurrence of the skin lesions but the periorbital oedema persists. A variety of cutaneous manifestations has been described in MM. Sweet syndrome has been described in two untreated MM or in some patients receiving granulocyte-colony stimulating factor. Bortezomid has been associated with rash, pruritus, erythema, periorbital oedema, urticaria, alopecia, skin nodules. Few cases of non-necrotising cutaneous vasculitis with perivascular lymphocytic infiltrates have also been reported. Bortezomid-induced Sweet syndrome has been reported in three other patients at the second and third injection of the second cycle for two of them while the eruption occurred after the first injection in the third case. The recurring skin lesions after each bortezomid cycle strongly suggests Bortezomid responsibility’s in the occurrence of Sweet syndrome. Unlike classic hypersensitivity type reactions, this vasculitis rash may not necessary prompt cessation of drug as the administration of dexamethasone prevents its recurrence.
Engineering Mesenchymal Cells with Interleukin 7 Gene: In Vitro Effects on Naive T Cell Population.
Authors: Sportoletti Paolo , Del Papa Beatrice , De Ioanni Mariangela , Moretti Lorenzo , Bonifacio Elisabetta , Fettucciari Katia , Zei Tiziana , Falzetti Franca , Di Ianni Mauro , Tabilio Antonio 
Published: April 2020

Abstract
T cell homeostasis is regulated by several molecules among which Interleukin 7 (IL-7) plays an essential role for survival and homeostatic proliferation of peripheral naive T cells. In a previous study we demonstrated whether human mesenchymal cells could be engineered with IL-7 gene to produce functional level of this cytokine. Now we analysed the impact of different quantities of IL-7 produced by mesenchymal cells on survival and proliferation of a negative immunoselected naive (CD3+/CD45RA+) T cell population. Co-cultivation of peripheral naive T cells with mesenchymal cells producing low (16 pg/ml) or high (1000 pg/ml) IL-7 levels or in presence of exogenous IL-7 (0,01 ng/ml and 100 ng/ml) maintained the CD3+/CD45RA+ naive T cell phenotype. The chemokine receptor CCR7+ expression was also maintained among this T cell population. Naive T cell molecular characteristics were maintained as assessed by the Vβ spectratyping complexity score which shows the maintenance of a broad T cell repertoire. No Th1 or Th2 differentiation was observed as assessed by IFNγ or IL-4 accumulation. In contrast only mesenchymal cells producing high IL-7 amount caused increases in the activation (CD25 31.2%±12 vs 10%±3.5, p&lt;0.05), proliferation (CD71 17.8±7% vs 9.3%±3, p&lt;0.05), apoptosis (assessed by annexin V: 18.6%±5 vs 14.9%±2.6, p&gt;0.05) and phase S cell cycle (15% vs 6.9%, p&gt;0.05). Exogenous IL-7 did not exert any significant effect. In conclusion, we demonstrated that IL-7 produced by mesenchymal cells has a dose-independent effect on naive T cell survival while exerts a dose-dependent effect on activation/proliferation. Due to continuous production of IL-7 by engineered cells, our system emerge as more efficacious than the exogenous IL-7.
Degranulation of T-Cells Specific for the CMV-Proteins pp65 and IE-1 in Allogeneic Stem Cell Recipients.
Authors: Ganepola Susanne S. , Fuhrmann Stephan S. , Uharek Lutz L. , Thiel Eckhard E. , Volk Hans Dieter H.D. , Kern Florian F. 
Published: April 2020

Abstract
Infection and disease with human cytomegalovirus (HCMV) is still an important cause for morbidity and mortality after allogeneic stem cell transplantation (allo SCT). Specific T-cells (CTL) are crucial for the control of CMV infection. In addition to cytokine production, degranulation is an interesting marker of T-cell function. Recent studies in patients after solid organ transplantation revealed that high levels of IE-1-specific CTL correlate with a protection from CMV disease. However, the functionality of these cells is less clear. As demonstrated in AIDS suffering patients, CTL activity is more related to a protection than to a cytokine secretion. Here we address the question, whether CD4 and CD8 T-cells have different abilities to degranulate or to produce cytokines depending on the type of immunosuppression and the CMV target protein.
Material and Methods: T-cells from 6 healthy CMV exposed donors and 16 allografted patients (11 AML, 3 ALL, 1 NHL, 1 MPS) were stimulated with peptide pools representing the pp65 (UL83) and IE-1 (UL123) proteins. Mobilized CD107 (marker of CTL activity), TNF, IFN-g, and IL-2 production was analyzed by 8-color flowcytometry. Immunosuppression consisted of CSA/MMF (n=4), CSA alone (n=4) and CSA/MTX (n=8), 4/8 patients additionally received ATG for GvHD-prophylaxis as part of the conditioning regimen. In all transplanted patients CMV antigenemia was assessed twice a week.
Results and Conclusion: The responding T-cell population mainly demonstrated an effector phenotype with a low expression of CD28. Frequency of reactive CTL did not correlate with CMV antigenemia. Interestingly, there was no impairment of degranulation or cytokine production found in any of the allogeneic transplanted patients compared with healthy CMV exposed controls, showing that immunosuppression does not target the function of the specific CTL.
The Role of SDF-1/CXCR4 in the Procession of Auto-Stem Cell Transplantation of Multiply Myeloma Patients.
Authors: Li Caixia , Wu De Pei , Zhang Xue Guang 
Published: April 2020

Abstract
CXCR4, receptor of the chemokine stromal derived factor-1 (SDF-1), is expressed on CD34+ cells, and has been implicated in the process of CD34+ cell migration and homing. We studied the mobilization of CD34/CXCR4 cells and the plasma levels of SDF-1 and sgp130 in 22 patients, 11 acute Leukemia, 5 non-Hodgkin’s lymphoma, and 6 multiply myloma respectably, receiving cyclophosphamide (Cy) and plus G-CSF, or Mitoxantrone(Mit) and Cytarabine plus G-CSF for peripheral blood stem cell (PBSC) mobilization and autotransplantation. We observed lower plasma levels of SDF-1 in PBSCs compared with premobilized PB and bone marrow samples. The average levels of SDF-1 and sgp130 were 24.67±5.58ng/ml and 106.2±16.4ng/ml respectively while the level of SDF-1 as well as sgp130 decreased to 14659±2.11ng/ml(p&lt;0.05)and 58.8±29.1ng/ml(p&lt;0.05) respectively on day when PBSC was collected after mobilization. SDF-1 levels in the apheresis collections of the “good mobilizers” (patients who collected a minimum of 2 × 106 CD34+ cells/kg in one to three PBSC collections) were significantly lower than the apheresis collections of the “poor mobilizers” (&lt;2 × 106 CD34+ cells/kg in the three cycles of PBSC collections; 14.82 ± 7.08 ng/ml versus 27.2 ± 8.13 ng/ml; p&lt;0.01). The mean percentage of CD34+ cells expressing CXCR4 in the apheresis collections was decreased in the PBSC collections compared with premobilization values ranging from 32.09±5.39% to 22.4±5.92%. But the mean CXCR4 expression on CD34+ cells of the good mobilizers was not different from the expression on CD34+ cells of poor mobilizers. Furthermore, the levels of sgp130 closely correlated with SDF-1 levels (r = 0.87; p &lt; 0.001); the plasma level of SDF-1 and expression of CXCR4 on the CD34+ cells were gradually decreased in the PB of patients during the procession of mobilization; low plasma levels of SDF-1 turned out with good mobilization outcome, and the levels of SDF-1 correlated with sgp130, suggesting an association of these cytokines in mobilization of CD34+ cells.
Prophylaxis Against Cytomegalovirus Infections with Oral Maribavir in Allogeneic Stem Cell Transplant Recipients: Results of a Randomized, Double-Blind, Placebo-Controlled Trial.
Authors: Winston Drew , van Burik Jo-Anne , Pullarkat Vinod , Papanicolaou Genovefa , Vij Ravi , Vance Estil , Alangaden George , Chemaly Roy , Petersen Finn , Chao Nelson , Klein Jared , Sprague Kellie , Dougherty Carolyn , Villano Stephen , Boeckh Michael 
Published: April 2020

Abstract
Cytomegalovirus (CMV) remains a major threat to recipients of allogeneic stem cell transplants (SCT). Potential toxicities of currently available anti-CMV agents complicate their use in this population. Maribavir (MBV) is an oral antiviral drug with a unique mechanism of action against CMV and a promising safety profile in early clinical studies. This randomized, double-blind, multicenter, dose-ranging study enrolled adult CMV-seropositive recipients of allogeneic SCT. After engraftment, patients were randomized to receive CMV prophylaxis with placebo or MBV at one of three doses for up to 12 weeks. CMV surveillance was performed weekly with both CMV pp65 antigenemia and plasma CMV DNA PCR assays. If CMV was detected, study drug was stopped and preemptive anti-CMV therapy started as per standard practice at each center. A total of 111 patients were enrolled (median age 47 years; 70% myeloablative SCT; 53% related donor). Incidence of CMV infection or disease in the first 100 days post-SCT are shown in the table. The safety profile of maribavir was favorable in this patient population; most adverse events occurred at similar rates in placebo and MBV groups. There was no adverse impact of MBV on neutrophil counts or other laboratory or ECG parameters. Consistent with prior clinical studies, the most notable events that appeared to be associated with MBV were mild-moderate taste disturbance, nausea, and diarrhea. In conclusion, maribavir prophylaxis reduced the rate of CMV infection compared to placebo, with a favorable safety profile in this complex patient population. Phase 3 studies of maribavir in stem cell and solid organ transplant recipients are being planned.
Placebo MBV 100 mg BID MBV 400 mg QD MBV 400 mg BID N evaluable 28 27 27 26 p values represent comparison to placebo (stratified by myeloablative or nonmyeloablative SCT) CMV infection or disease based on:     pp65 antigenemia 11 (39%) 4 (15%) 5 (19%) 4 (15%) p=0.046 p=0.116 p=0.053     plasma CMV DNA PCR 13 (46%) 2 (7%) 3 (11%) 5 (19%) p=0.001 p=0.007 p=0.038 Use of preemptive anti-CMV Rx 16 (57%) 4 (15%) 8 (30%) 4 (15%) p=0.001 p=0.051 p=0.002 CMV disease only 3 (11%) 0 0 0 p=0.089 p=0.084 p=0.091
MK-0457, a Novel Multikinase Inhibitor, Inhibits BCR-ABL Activity in Patients with Chronic Myeloid Leukemia (CML) and Acute Lymphocytic Leukemia (ALL) with the T315I BCR-ABL Mutation.
Authors: Bergstrom Donald A. , Clark Jason B. , Xiao Alan , Griffiths Matthew , Falcon Susannah , Pollard John , Freedman Steven J. , Giles Francis 
Published: April 2020

Abstract
Background. MK-0457 (VX-680) is a small-molecule inhibitor of Aurora kinases A, B, and C, FLT3, and JAK-2 with nanomolar level broad spectrum pre-clinical anti-tumor activity. The T315I BCR-ABL mutation mediates high level resistance to imatinib, dasatinib and nilotinib. A Phase I study of MK-0457 is being conducted in patients with refractory hematologic malignancies. The study regime is a 5 day continuous IV regimen given every 2 to 3 weeks.
Methods. Fifteen CML patients received MK-0457 dosed at 8, 12, 16, 20, 24, 28, and 32 mg/m2/hr (11/15 had detectable BCR-ABL T315I). Peripheral blood for biomarker studies was available from patients at the 12 mg/m2/hr dose and above. Specimens were drawn prior to initiation of the infusion and at the end of the infusion (Day 5) during Cycle 1. Patient specimens have been analyzed using flow cytometry assays to measure BCR-ABL inhibition (phospho-CRKL), FLT3 and JAK-2 inhibition (phospho-STAT5) and Aurora kinase inhibition (phospho-histone H3).
Results. MK-0457 has in vitro activity against cells expressing wild-type or mutated BCR-ABL, including the T315I BCR-ABL mutation. In CML and ALL patients with the T315I BCR-ABL mutation, MK-0457 is capable of inhibiting BCR-ABL as measured by the phospho-CRKL assay. The observed decrease in BCR-ABL activity trends with plasma exposure to MK-0457. At dose levels less than 20 mg/m2/hr, plasma exposure of MK-0457 typically does not exceed 1 micromolar and inhibition of BCR-ABL has not been observed. At exposures that exceed 1 micromolar, MK-0457 inhibits BCR-ABL, with pCRKL abundance falling below the lower limit of detection in one patient dosed at 24 mg/m2/hr and decreasing compared to baseline in several other patients. There is also a trend correlating degree of BCR-ABL inhibition as measured by the pCRKL biomarker and clinical response to MK-0457.
Conclusions. MK-0457 inhibits BCR-ABL activity in CML and ALL patients with the BCR-ABL T315I mutation. Objective responses have been observed in patients without demonstrable BCR-ABL inhibition, suggesting that inhibition of Aurora kinase may also contribute to the clinical efficacy of MK-0457 in CML and ALL patients with the BCR-ABL T315I mutation.
Fibrin(ogen) Exacerbates Inflammatory Joint Disease Via a Mechanism Linked to Its αMβ2 Binading Motif.
Authors: Flick Matthew J. , La Jeunesse Christine M. , Talmage Kathryn E. , Witte David P. , Palumbo Joseph , Pinkerton Malinda D. , Thornton Sherry , Degen Jay L. 
Published: April 2020

Abstract
Activation of the hemostatic system is a common pathological feature of severe inflammatory processes. In the context of inflammatory joint disease, articular fibrin deposition is a prominent feature that has been hypothesized to contribute to the derangements in immune/inflammatory processes and tissue reorganization that lead to debilitating and irreversible damage within arthritic joints. We directly examined the role of fibrin(ogen) in the progression of inflammatory joint disease using the well-established experimental setting of collagen-induced arthritis (CIA). Mice with genetically-imposed fibrinogen deficiency (Fib−/−) were found to exhibit significantly reduced macroscopic arthritic disease incidence, progression, and severity in the paws relative to littermate controls throughout the evaluation period. Consistent with the macroscopic observations, qualitative and quantitative histological analysis of distal- and knee-joint sections revealed a significant decrease in all joint disease parameters (e.g., inflammatory cell infiltrates, synovial hyperplasia, edema, and cartilage/bone loss) in Fib−/− mice as compared to fibrinogen-sufficient controls. Fibrin(ogen) has been shown to promote pro-inflammatory activity through engagement of the leukocyte integrin receptor αMβ2 (Mac-1). To determine if fibrinogen/αMβ2 interactions promote the pathogenesis of arthritis, we compared CIA progression in mice expressing fibrinogen that lacks the leukocyte integrin receptor αMβ2 binding motif (i.e., Fibγ390–396A mice). We observed decreased gross and histological inflammatory joint disease in Fibγ390–396A mice relative to control animals. This diminution in arthritic disease severity was comparable to that observed in Fib−/− mice despite the maintenance of normal clotting function in Fibγ390–396A animals. In comparison, CIA studies in mice expressing a mutant form of fibrinogen lacking the platelet integrin receptor αIIbβ3 binding motif showed that this feature of fibrinogen was not an essential driver of arthritis. The reduction in macroscopic and histological arthritic disease observed in CIA-challenged Fibγ390–396A mice was accompanied by reduced local mRNA levels of the pro-inflammatory cytokines TNF α, IL-6, and IL-1β in paws relative to paws from control animals. This data suggests that fibrin(ogen) may function upstream of local production of these critical inflammatory mediators. Consistent with this hypothesis, fibrinogen deficiency did not diminish arthritic disease driven by TNFα-overexpression. Together, these data support the view that local fibrin deposition is an important determinant of inflammatory joint disease and that one mechanism by which fibrin promotes arthritic disease is through leukocyte activation events downstream of αMβ2 engagement.
GATA1 Mutations in Newborns with Down Syndrome.
Authors: Sandoval Claudio , Pine Sharon R. , Druschel Charlotte , Jayabose Somasundaram , Guo Qianxu , Yin Changhong 
Published: April 2020

Abstract
Somatic mutations of the GATA1 gene have been detected in almost all cases of Down syndrome (DS)-associated acute megakaryoblastic leukemia (AMKL) and transient leukemia (TL). There is emerging evidence that the protein product of GATA1 mutations, GATA1s, directly contributes to leukemogenesis. Although an in utero origin of GATA1 mutations is established, a comprehensive study using a large number of cases is required to determine the overall incidence and clinical relevance of GATA1 mutations in DS newborns. We screened 575 DS infants born between January 1997 and December 1999 for GATA1 exon 2 mutations by single-strand conformation polymorphism analysis of PCR products. We used Gunthrie cards obtained from the New York Congenital Malformation Registry. Registry data was blinded until after the GATA1 mutation analyses were completed. Twenty-eight (4.9%) infants were identified as having a GATA1 mutation. There was no significant difference in the frequency of GATA1 mutations based on gender or maternal average age (p = 0.93 and 0.31, respectively). There was no significant difference in the GATA1 mutation frequency between those classified as black, white, or Asian, but Hispanics had a borderline non-significant increase in frequency of GATA1 mutations compared to non-Hispanics (8.5% compared to 4.0%, p=0.06). Based on data from the New York Cancer Registry reviewed in 2005, two of the patients with a GATA1 mutation subsequently developed leukemia; one patient developed AMKL and the other had a leukemia of unspecified phenotype. Out of the 547 GATA1-negative patients, there was only one case of leukemia, but it was AML excluding AMKL. These results confirm a pre-natal origin of GATA1 mutations in DS patients. The frequency in this study was lower than the 10 percent previously reported (2 of 21 DS blood spots). Obtaining Gunthrie card blood spots for GATA1 mutation analysis serves as a relatively non-invasive screening approach. The presence of a GATA1 mutation at the time of birth might serve as a biomarker for an increased risk of developing DS-related AMKL.
Alpha Hemoglobin Stabilizing Protein (AHSP) Optimizes Hemoglobin A Synthesis by Maintaining a Pool of Viable Alpha Globin Subunits.
Authors: Yu Xiang , Kong Yi , Dore Louis C. , Katein Anne M. , Choi John K. , Gow Andrew J. , Weiss Mitchell J. 
Published: April 2020

Abstract
AHSP binds alpha hemoglobin (Hb) to maintain its structure and limit its prooxidant activities. In addition, AHSP binds and stabilizes apo-alpha globin, which lacks heme. Previously, we demonstrated that Ahsp−/− mice exhibit hemolytic anemia with Hb precipitation in erythroid cells. Through interbreeding of mutant strains, we also showed that loss of AHSP exacerbates beta thalassemia. Together, these studies indicate that AHSP participates in Hb homeostasis and may act to neutralize potentially toxic excess alpha globin that is known to accumulate in normal erythroid precursors, and to a greater extent, in beta thalassemic ones. However, additional functions for AHSP may exist. In particular, AHSP-alpha globin complexes may also promote HbA synthesis. To test this, we depleted the pool of excess alpha globin in Ahsp−/− mice by interbreeding with alpha thalassemic ones. Compared to mice with either mutation alone, compound mutants missing both AHSP and one alpha globin allele (genotype Ahsp−/− //alpha globin*α/αα) exhibited more severe erythroid defects, including worsened anemia, hypochromia, Hb instability and ineffective erythropoiesis. Pulse-labeling of double-mutant reticulocytes showed that alpha to beta globin synthetic ratios were unaffected by loss of AHSP, but precipitation of both alpha and beta nascent chains into cell membranes was strongly enhanced. These data indicate that AHSP is important for erythropoiesis and Hb production even when alpha globin is not produced in excess. In vitro translation studies using wheat germ extracts showed that recombinant AHSP present during the synthesis of alpha globin improved its ability to become incorporated into HbA. Moreover, AHSP conferred protease resistance to nascent alpha globin, suggesting enhanced folding into the native state. Further supporting this interpretation, circular dichroism studies showed that AHSP accelerated refolding of purified denatured alpha Hb. Finally, through pulse labeling of reticulocytes followed by isoelectric focusing of soluble cytosolic fractions, we identified transient pools of free alpha Hb and AHSP-alpha Hb in vivo and showed that Ahsp gene ablation fully depleted both pools. Together, our studies indicate that AHSP acts as a molecular chaperone to promote alpha globin folding and stability prior to its incorporation into HbA. In addition, it is possible that alterations in AHSP gene function or expression could modulate alpha thalassemia severity in patients.