bluuebunny/crossref_metadata_2025_split huggingface dataset:
Subclinical progression of systemic sclerosis-related cardiomyopathy
Authors: Stronati Giulia , Manfredi Lucia , Ferrarini Alessia , Zuliani Lucia , Fogante Marco , Schicchi Nicolò , Capucci Alessandro , Giovagnoni Andrea , Russo Antonio Dello , Gabrielli Armando , Guerra Federico 
Published: April 2020

Aims
Cardiac involvement in patients with systemic sclerosis (SSc) is frequent and represents a negative prognostic factor. Recent studies have described subclinical heart involvement of both the right ventricle (RV) and left ventricle (LV) via speckle-tracking-derived global longitudinal strain (GLS). It is currently unknown if SSc-related cardiomyopathy progresses through time. Our aim was to assess the progression of subclinical cardiac involvement in patients with SSc via speckle-tracking-derived GLS.

Methods
This was a prospective longitudinal study enrolling 72 consecutive patients with a diagnosis of SSc and no structural heart disease nor pulmonary hypertension. A standard echocardiographic exam and GLS calculations were performed at baseline and at follow-up.

Results
Traditional echocardiographic parameters did not differ from baseline to 20-month follow-up. LV GLS, despite being already impaired at baseline, worsened significantly during follow-up (from –19.8 ± 3.5% to –18.7 ± 3.5%, p = .034). RV GLS impairment progressed through the follow-up period (from –20.9 ± 6.1% to –18.7 ± 5.4%, p = .013). The impairment was more pronounced for the endocardial layers of both LV (from –22.5 ± 3.9% to –21.4 ± 3.9%, p = .041) and RV (–24.2 ± 6.2% to –20.6 ± 5.9%, p = .001). A 1% worsening in RV GLS was associated with an 18% increased risk of all-cause death or major cardiovascular event (p = .03) and with a 55% increased risk of pulmonary hypertension (p = .043).

Conclusion
SSC-related cardiomyopathy progresses over time and can be detected by speckle-tracking GLS. The highest progression towards reduced deformation was registered for the endocardial layers, which supports the hypothesis that microvascular dysfunction is the main determinant of heart involvement in SSc patients and starts well before overt pulmonary hypertension.
Major Cytogenetic Responses to BMS-354825 in Patients with Chronic Myeloid Leukemia Are Associated with a One to Two Log Reduction in BCR-ABL Transcript.
Authors: Shah Neil P. , Branford Susan , Hughes Timothy P. , Nicoll John M. , Decillis Arthur P. , Sawyers Charles L. 
Published: April 2020

Abstract
The success of imatinib for the treatment of chronic myeloid leukemia (CML) has created a need for a sensitive and accurate method of monitoring disease response and burden. Quantitative PCR (Q-PCR) has been previously shown to correlate well with cytogenetic response in patients treated with imatinib, whereby a one-log reduction in BCR-ABL transcript level corresponded well with attainment of a major cytogenetic response (MCyR) and a two-log reduction correlated with a complete cytogenetic response (CCyR) (Branford et al, Leukemia17:2401, 2003). BMS-354825 is a novel orally bioavailable SRC/ABL kinase inhibitor with impressive activity against imatinib-resistant BCR-ABL mutant isoforms in vitro (Shah et al, Science305:399, 2004). The compound is presently undergoing evaluation in phase I clinical trials (see Sawyers et al, Talpaz et al, abstracts submitted for this meeting). We sought to address whether cytogenetic responses in patients treated with BMS-354825 correlated with reduction in BCR-ABL transcript levels as determined by Q-PCR. Of 13 evaluable imatinib-resistant/intolerant patients with chronic phase CML treated at UCLA, four have attained a MCyR. Achievement of MCyR corresponded with a one to two-log reduction in BCR-ABL transcript as assessed by Q-PCR. In the majority of cases, a substantial reduction in BCR-ABL transcript was detected four weeks after initiation of BMS-354825. Overall, the median reduction in BCR-ABL transcript level after four weeks of therapy was 32%. Three of these patients had developed resistance to imatinib, and two harbored the common imatinib-resistant M351T mutation. Of the nine patients who have failed to achieve a MCyR, none have achieved a one log reduction in BCR-ABL transcript level. We conclude that similar to imatinib, BMS-354825-associated MCyR in chronic phase CML is highly associated with a one to two-log reduction in BCR-ABL transcript level. Furthermore, Q-PCR offers a rapid and reliable method to assess for disease response in this setting, which promises to be of significant clinical value. Although the maximal tolerated dose of BMS-354825 has yet to be determined, the compound is clearly capable of substantially reducing disease burden in patients with imatinib-resistant CML. Updated Q-PCR data from all chronic, accelerated, and blast crisis-phase patients on study at UCLA will be presented.
Single Daily Dose of I.V. Busulfan (BU) in Pediatric Patients. Feasibility, Pharmacokinetics (PK) and Toxicity.
Authors: Kletzel Morris , Jacobsohn David , Tse William , Duerst Reggie 
Published: April 2020

Abstract
Administration of oral BU is a challenge in pediatric patients. The I.V preparation can improve compliance and eliminate variability in absorption. The metabolism and clearance of BU is age dependant. A prospective trial using a single daily dose of I.V. BU as part of a reduced Intensity Regimen was undertaken. Patients were enrolled after proper informed consent was signed... The regimen consisted of a test dose of BU (0.8mg/kg as a 2 hr infusion) on day -10, Fludarabine 25mg/m2/day from day-10 to -5, BU 3.2 mg/Kg/Day on days -5 ,-4.and rabbit ATG 2mg/kg daily on days -4 to-1. Cells were infused on day 0. The stem cell source were UCB (n=4), MUD (n=7) and MSD (n=1). PK samples (2, 4, 6,8,12 hrs) were obtained and submitted to the Seattle Cancer Care Alliance for determination of the Area Under the Curve (AUC) and clearance for BU. Twelve patients were enrolled (8F, 4M), median age 8 (0.5–16), median weight 22.6 kg (4.3–58.8) with the following diagnoses: Neuroblastoma (n=3), ALL (n=3), CML (n=2), Aplastic Anemia and X linked Lymphoprolipherative Disease, Ommen’s syndrome, Severe Combined Immune Deficiency. An AUC of 800–1200 and 3200–4800 uMol*min were targeted for the test dose and the single daily dose respectively. The median AUC for the test dose was 1003 uMol*min (804–1315), and the median clearance was 3.1 (ml/min)/Kg (2.4–7.3). The median AUC for the single daily dose was 3512 uMol*min (1511–4097) and the clearance 3.4 (ml/min)/kg (2.8–6.8). After the test dose 4 patients had their dose adjusted (2 patients lower and 2 patients higher). In the very young patients (&lt; 1 year of age) the AUC of the single daily dose could not be predicted due to abnormal clearance. No instances of VOD or seizures were observed. Full donor chimerism was achieved in 8 patients in a median of 23 days (14–53), 2 patients developed graft failure, 1 patient was not evaluable for engraftment due to early TRM from pre-existing CMV pneumonia and 1 patient is too early. In conclusion, a single daily dose of I.V. BU is feasible, a test dose can be a predictor of the single daily dose AUC except in the very young, No regimen related toxicity was observed and engraftment was prompt and complete in 8 evaluable patients.
A Genomic and Proteomic Research for the Regulatory Networks of ATRA-Induced Differentiation of Acute Promyelocytic Leukemia Cells.
Authors: Huang Qiu-Hua , Zhang Qun-Ye , Shen Shu-Hong , Zheng Pei-Zheng , Lu Jing , Jing Yi , Zhang Ji , Wang Kan-Kan , Chen Sai-Juan , Chen Zhu 
Published: April 2020

Abstract
The treatment of acute promyelocytic leukemia (APL) with all trans retinoic acid (ATRA) has set a model for the differentiation induction-based new therapy. Although a substantial body of data related to ATRA-induced differentiation mechanisms has been obtained, the molecular events down stream of RA receptor complexes remain obscure. With the goal to get further insights into regulatory networks underlying ATRA-induced differentiation in APL, we applied 2DG, MS and cDNA microarray combined with bioinformatics analysis such as self-organizing map(SOM) to profile NB4 cells treated with ATRA over 3 time points (0h, 12h, 48h). Our results showed that cell cycle was arrested and proliferation was suppressed. For instance, ;the Origin recognition complex subunit 3 involved in initiating DNA replication that make the cell switch to S phase was downregulated significantly at protein (67.55 times) and mRNA levels; Breast cancer type 2 susceptibility protein (BRCA2) that can interact with BRAF335 as the checkpoint of G2 / M phase was upregulated while mRNA expression unchanged. Our results showed that the expression of many proteins associated with Ca2+ signal pathway such as IP3 receptor isoform 1 and phospholipase C-β changed upon induction with ATRA, implying that Ca2+ signal pathways may play an important role during ATRA-induced APL cell differentiation. Our results also indicated that the cell apoptosis was inhibited in the process of ATRA-induced differentiation. For example, BFL1, one of the BCL-2 family and the main apoptosis repressor in neutrophils, was upregulated at protein and mRNA levels. BCL2-like13 is one of the BCL-2 families and its overexpression initiated the cell apoptosis pathway by activating caspase-3. It was downregulated at protein level. Our results revealed that the phosphopentose pathway and ribonucleotide synthesis were repressed obviously. The protein expressions of the key enzyme of phosphopentose pathway - Glucose-6-phosphate dehydrogenase and rate-limiting enzyme of purine nucleotide de novo synthesis - AICAR methylferase and adenylosuccinate synthetase were all downregulated remarkably. Moreover, the protein expression of nitricoxide synthase 2A was upregulated 236 times after 12 hours of treatment with ATRA. The dramatic changes imply that the effect of NO on the differentiation induced by ATRA deserves more investigation. In brief, the data presented above indicated the expression of a large number of genes and proteins is modulated upon effect of ATRA during ATRA-induced APL cell differentiation, resulting in a complex and well-organized network to ensured cell reprogramming.
The Follicular Lymphoma International Prognostic Index (FLIPI) as Part of a Proposed Prognostic Model for Follicular Lymphoma Patients Undergoing Autologous Hematopoietic Stem Cell Transplantation (ASCT).
Authors: Keeney Grant E. , Gooley Theodore A. , Press Oliver W. , Pagel John M. , Petersdorf Stephen H. , Maloney David G. , Gopal Ajay K. 
Published: April 2020

Abstract
The FLIPI has recently been demonstrated to correlate with survival in patients (pts) with newly diagnosed follicular lymphoma (FL). No such index has been developed or evaluated to predict outcome for FL pts in the setting of myeloablative therapy and ASCT, despite data suggesting that ASCT may improve overall and progression-free survival (PFS). We examined the factors that contribute to the FLIPI as well as other factors assessed at time of transplant for their association with overall survival (OS) in 189 pts undergoing ASCT for FL. Baseline characteristics included: median age = 47 years (range, 24 – 64), stage III–IV = 94%, &gt;4 nodal areas = 7.7%, elevated LDH = 30%, &gt;5 cm maximal bulk of disease = 18%, chemoresistant disease = 13%, median number of prior chemotherapy regimens = 2. The FL histologies included: Grade 1 (49%), Grade 2 (31%), Grade 3 (13%), and transformation to diffuse large B-cell lymphoma (6%). Patients were conditioned with chemotherapy-only (21%), chemo+TBI (45%), or radioimmunotherapy +/− chemo (34%). Among all pts, the five-year estimated OS and PFS are 58% and 39%, respectively, with a median follow-up among surviving pts of 8 years (range, 1 – 18). The five factors that were found to be most significantly associated with OS include two FLIPI factors [age, hazard ratio for death (HR) = 1.37 per ten-year increase in age; elevated LDH, HR = 1.57] and three other clinical factors [&gt;1 maximal extranodal site of disease, HR = 1.67; ≥2 prior chemotherapy regimens, HR = 1.99; chemoresistant disease, HR = 2.8]. Patients with 0 – 1 adverse factors (with age dichotomized as &lt; 45 vs. ≥ 45) had an estimated 5-year OS of 79%, those with 2 factors 50%, 3 factors 41%, 4 or 5 factors 13% (Figure). Although prospective validation of this proposed model is required, this approach may be used to counsel FL pts regarding expected outcome following ASCT, to compare data between trials, and to design future studies.
Figure Figure
Ferritin Heavy Chain, a Repressor of the Human β-Globin Gene That Binds a Conserved Cagtgc Motif, Is Bound to the Repressed β-Globin Promoter In Vivo in K562 Cells and Specifically Binds an Analogous Site in the Mouse βMajor-Globin Promoter.
Authors: Broyles Robert H. , Belegu Visar , Stewart Charles A. , Pye Quentin N. , Roth Austin C. , Harris Katharine M. , Floyd Robert A. , Jani Klodianna , Trudel Marie 
Published: April 2020

Abstract
Ferritin heavy chain (FH), an embryonically-expressed protein in the erythroid lineage, localizes to the nucleus and represses the human adult β-globin promoter in transient expression assays (Broyles et al., PNAS98: 9145, 2001). Recently, we have performed chromatin immunoprecipitation (ChIP) assays with cross-linked chromatin of K562 cells in which the β-globin gene is repressed, using anti-FH polyclonal antisera. These results strongly indicate that FH occupies the repression site (a CAGTGC motif) in vivo. Binding to this -150 site has been previously demonstrated to be required for β-promoter repression in co-transfections. EMSA assays (competitive gel shifts) have revealed that the mouse βMajor-globin promoter has an analogous CAGTGN motif at -160 bp from the cap site that competes specifically with the human CAGTGC site for FH binding. The mouse βMinor-globin promoter lacks the -150/-160 CAGTGN motif and, therefore, the FH binding site. Thus, a human FH transgenic mouse, in which the FH gene is driven by a truncated β-promoter lacking the CAGTGN motif, should express human FH in definitive erythroid cells where the FH would be predicted to repress βMajor-globin but not βMinor-globin. Such a mouse would be predicted to survive but be born with a mild β-thalassemia due to the decreased βMajor/βMinor ratio in its definitive erythroid cells. Preliminary results from the litters of F1 generation FH-tg mice indicate that such is indeed the case, i.e., that human FH functions as a βMajor-globin repressor in vivo.
A Multi-Institutional Study of Extracorporeal Photoimmune Therapy with UVADEX® for the Prevention of Acute GVHD in Patients Undergoing Standard Myeloablative Conditioning and Allogeneic Hematopoietic Stem Cell Transplantation.
Authors: Shaughnessy Paul J. , Bolwell Brian J. , Abhyankar Sunil , van Besien Koen , Mistrik Martin , Grigg Andrew , Dodds Anthony , Prince H. Miles , Machado Alexandra , Thienel Ulrich , Wang Jim , Foss Francine , Apperley Jane 
Published: April 2020

Abstract
Acute graft-versus-host disease (aGVHD) is partly mediated by host antigen presenting cells (APCs) that activate donor T-cells. Extracorporeal photoimmune therapy with UVADEX® (ECP) has shown benefit in some patients (pts) with GVHD, which was associated with decreased host APCs. We report preliminary results of the first multi-institutional phase II study examining ECP with a standard myeloablative preparative regimen prior to allogeneic hematopoietic stem cell transplantation (ASCT). ECP was given on two consecutive days between D-10 and D-6, followed by cyclophosphamide 60 mg/kg/day for 2 days and TBI 1200 cGy over 3 days. GVHD prophylaxis was Cyclosporine 3–5 mg/kg IV daily beginning D-1, and latter switched to PO, adjusted to keep levels 200–600 ng/ml, and methotrexate 10 mg/m2 on D1, 3, 6, and 11 for pts who had matched unrelated donors (MUD) or HLA class 1 one-antigen mismatched related donors (MMRD), or 10 mg/m2 on D1 and 5 mg/m2 on D3, 6, and 11 for pts who had matched related donors (MRD). Enrollment has been completed and data are available on 61 of 65 pts. The median age was 39 (20–60) years and 40 (66%) pts were male. Diagnoses included AML/MDS (n=20), ALL (n=14), CML (n=16), lymphoma (n=5), CLL (n=3), and other (n=3). Pts who received bone marrow (n=28) engrafted at a median of 20 (9–30) days, and pts who received peripheral blood (n=33) engrafted at a median of 15 (10–32) days. Grade II–IV and III/IV aGVHD occurred in 11 (38%) and 2 (7%) pts, respectively, who received MRD transplants (n=29), and in 16 (52%) and 10 (32%) pts, respectively, who received MUD transplants (n=31). No aGVHD occurred in 1 pt who received a MMRD transplant. Mild reversible hypotension related to ECP occurred in 1 pt who was able to continue on study. Chronic GVHD occured in 23 (42%) of 54 evaluable pts; limited in 15, extensive in 6, and unknown in 2 pts. There are 49 (80%) pts alive at a median follow up of 272 (23–560) days. Actuarial estimates of survival at one year are 93% for pts who received MRD transplants and 69% for pts who received MUD or MMRD transplants. Causes of death include relapse (n=4), aGVHD (n=3), multi-organ-system-failure (n=2), and 1 each of infection, interstitial pneumonitis, and neurologic toxicity. Preliminary results of this study reveal no adverse affects of ECP in combination with conventional preparative regimens or on engraftment after a standard myeloablative ASCT. Data correlating measurement of APCs with the incidence and severity of acute and chronic GVHD is pending. The overall survival of pts in this trial is encouraging and warrants further study.
ABO Incompatibility Is a Risk Factor for Intestinal Thrombotic Microangiopathy (TMA) after Allogeneic Stem Cell Transplantation.
Authors: Matsumoto Kimikazu , Hirabayashi Norio , Kato Koji , Matsuyama Takaharu 
Published: April 2020

Abstract
Intestinal thrombotic microangiopathy (TMA) after allogeneic stem cell transplantation is emerging as a major clinical issue, which is different from aGVHD in pathogenesis and clinical management. We performed a retrospective analysis of 140 pediatric patients with acute leukemia (82 ALL and 58 AML) who underwent allogeneic stem cell transplantation in Japanese Red Cross Nagoya First Hospital from 1991 to 2003 (69 from HLA matched sibling, 13 from HLA mismatched family donors and 58 from unrelated volunteer donors). Blood type was matched in 78 patients and mismatched in 62 patients (25 in minor , 26 in major and 11 in bidirectional). Seventeen patients developed intestinal TMA with a cumulative incidence of 13%. The median time to onset was 28 days (range, 10–104 days). Intestinal TMA was defined histopathologically by colonoscopic biopsies in 7 patients and bloody diarrhea and laboratory findings. Intestinal TMA occured in 28% of ABO minor mismatched transplantation, 32.5% of bidirectional, 14.4% of major mismatched and 5.8% in matched transplantation (p&lt;0.01)(Fig1)p. In multivariate analysis, ABO minor mismatched transplants (HR=5.3, 95%CI 1.4–19.7, p=0.01), HLA mismatched related donors (HR=16.6, 95%CI 1.6–173.3, p=0.02 ) and unrelated donors (HR=16.4, 95%CI 2.0–130.6, p&lt;0.01 ) were significantly associsted with the risk of intestinal TMA. The estimated 5-year overall survival (OS) was 47.1% in intestinal TMA patients compared with 56.7% in patients with no intestinal TMA (p=0.18). Intensified immunosuppressants for the treatment of intestinal TMA (n=5) lead to poor OS (20%). Seven out of 12patients (58%) who had reduced immunosuppressant were still alive with a median follow-up of 24 months (p=0.29). Our findings suggest that ABO mismatched transplantation, especially ABO minor mismatch, is a risk factor for developing intestinal TMA. Successful treatment for intestinal TMA by diminishing immunosuppressive drugs is warranted.
Figure Figure Figure Figure
Classification of Familial Hemophagocytic Lymphohistiocytosis Based on Genetic and Immunologic Analyses.
Authors: Ishii Eiichi , Ueda Ikuyo , Yamamoto Ken , Ohga Shouichi , Furuno Kenji , Morimoto Akira , Imayoshi Miyoko , Sako Masahiro , Takada Hidetoshi , Hara Toshiro , Imashuku Shinsaku , Sasazuki Takehiko , Yasukawa Masaki 
Published: April 2020

Abstract
Background: Familial hemophagocytic lymphohistiocytosis (FHL) is a disorder with an autosomal recessive mode of inheritance in infancy. Recently, mutations of the perforin (PRF1) and MUNC13–4 genes have been identified in FHL patients. Since natural killer (NK) cells and cytotoxic T lymphocytes (CTLs) involve mechanisms to kill virus-infected and malignant cells via perforin/granzyme-mediated granule exocytosis pathway, cytotoxic functions of NK cells and CTLs are impaired in FHL. In the present study, we analyzed the correlation between clinical features, genetic abnormalites and cytotoxic functions of CTLs in patients with different FHL subtypes.
FHL families: In Japan HLH Study Group, total 57 Japanese patients fulfilled the diagnostic criteria of FHL and their family members were registered and the clinical data were collected from each family. Since the majority of FHL patients in Japan were registered in our study, it is thought that our data reflect the epidemiology of FHL in Japanese.
Results: Among 57 patients registered in this study, PRF1 mutations were detected in 11 patients (FHL2), whereas 8 showed mutations of MUNC13–4 gene (FHL3). When the clinical findings were compared, the FHL2 patients with PRF1nonsense mutation showed early onset, while the onset of those with both PRF1 missense mutation and MUNC13–4 mutation was late. Alloantigen-specific CD8+ CTL lines were established from the FHL patients and their healthy parents. The degrees of cytotoxicity mediated by CTL lines generated from the patients with various FHL subtypes were compared. CTLs generated from the FHL2 patients with PRF1 nonsense mutation exerted no antigen-specific cytotoxicity. The cytotoxicity of CTLs from the patients with MUNC13–4 mutation was low but still remained, whereas cytotoxicity of CTLs from those with PRF1 missence mutation appeared to be moderate. By Western blot analysis, the missense mutant PRF1 gene also produced full length protein, but the active mature form was markedly reduced, indicating that the proteolytic cleavage of perforin is inhibited in these patients.
Conclusion: The present study demonstrates that the subtypes of FHL can be classified by the patterns of genetic mutation and dysfunction of CTLs responsible for the pathogenesis of FHL. Although it has been established that allogeneic hematopoietic stem cell transplantation (HSCT) is a sole curative therapy for FHL, early identification of genetic defects and cytotoxic activity of CTLs may confirm whether HSCT should be really needed in each patient.