bluuebunny/crossref_metadata_2025_split huggingface dataset:
hTERT, the Catalytic Component of Telomerase, Is Down-Regulated in the Hematopoietic Stem Cells of Patients with Chronic Myeloid Leukemia.
Authors: Campbell Lisa J. , Eagleton Helen , Littlewood Tim J. , Peniket Andy , Kusec Rajko , Gal Shira , Fidler Carrie , Wainscoat James S. , Boutlwood Jacqueline 
Published: April 2020

Abstract
Telomere shortening and increased telomerase activity is associated with disease progression in chronic myeloid leukemia (CML). In order to gain insight into the biology of telomerase and its regulation in CML we have evaluated the expression levels of the components of telomerase, its regulators, and several telomeric associated proteins in the hematopoietic stem cells (HSC)/leukemic blast cells of 21 patients with this disorder, as compared to the HSC population of a group of healthy individuals, using quantitative real time PCR. In this study we have made the surprising observation that hTERT, the catalytic component of telomerase, is down-regulated in the CD34+/blast cells of the majority of CML patients in chronic phase (CP) (7 out of 9, p=0.0339) relative to CD34+ cells from normal controls. Furthermore hTERT was found to be significantly down-regulated in 2 out of 3 patients in accelerated phase (AP) and in 9 out of 9 patients in blast crisis (BC) relative to normal controls (p=0.0003). The expression levels of hTR, the telomerase RNA template, and the telomeric- associated proteins TEP1, TRF1, TRF2 and tankyrase were all up-regulated in the CD34+/blast cells of the majority of the CML patients in CP and AP, relative to normal control CD34+ cells. With the exception of TEP1, the expression levels of all these factors were highest in CP CML and, in the majority of patients, decreased during disease progression. We speculate that the up-regulation of tankyrase (positive regulator of telomere length) and TRF2 (protects critically shortened telomeres) may contribute to telomere maintenance in CML. The expression levels of hTERT and c-myc, a positive regulator of hTERT expression, correlate in all stages of CML (R2=0.623). The expression levels of c-myc decreased with disease progression, falling below the levels observed in normal CD34+ cells in the majority of patients in BC. The expression levels of hTERT were increased in the CD34+ cells of three additional CP CML patients in remission following successful treatment with imatinib, relative to both untreated CP CML patients (p=0.0126) and to normal individuals, reflecting a restoration of haematopoiesis towards normal. In CML the turnover of all types of Ph+ stem and progenitor cells is known to be increased. We suggest that the reduced (and presumably inadequate) expression levels of hTERT in CML CD34+/blast cells, and the consequent telomere shortening with each division, is the direct cause of the shortened telomeres frequently observed in CML patients. These data challenge the widely accepted view that hTERT expression is always increased in tumorigenesis. It is possible that the Bcr-Abl fusion product may play a role in the down-regulation of hTERT observed in the HSC of CML patients in this study.
The DCC Heterozygote Reduces the Latency Period and Changes the Disease Phenotype of Myeloproliferative Disease in p230BCR/ABL-Expressing Mice.
Authors: Inokuchi Koiti , Inami Mituharu , Wang Yazhu , Watanabe Ayako , Yamaguchi Hiroki , Tanosaki Sakae , Shimada Takashi , Dan Kazuo 
Published: April 2020

Abstract
Chronic neutrophilic leukemia (CNL) is a distinct disease form with less aggressive phenotype mimicking chronic myelogenous leukemia (CML). CNL sometimes has a unique p230BCR/ABL gene abnormality, as does Philadelphia-positive myeloproliferative disease (MPD) mimicking essential thrombocythemia (Ph+ET). The reason of the phenotypic difference between CNL and Ph+ET remains unclear. Recently, we have generated the p230BCR/ABL-transgenic mice, whose disease phenotype is MPD mimicking ET, to study the disease phenotype. In studies of human leukemia cells, loss of DCC (deleted colorectal carcinoma) gene expression is reported in about 20% of CML cases.
To investigate whether loss of DCC expression plays a role in the disease phenotype of p230BCR/ABL-expressing MPD, we crossmated p230BCR/ABL-transgenic (BCR/ABLTg/−) mice with DCC-heterogenous (DCC+/−) mice, thereby generating p230BCR/ABL-transgenic, DCC-heterogenous (BCR/ABLTg/− DCC+/−) mice.
BCR/ABLTg/− DCC+/− mice have a short latency (9 to 12 months) compared with BCR/ABLTg/− DCC+/+ mice (17 to 20 months) for developing overt MPD. Less thrombocytosis (91–140x104/mm3) was found in the BCR/ABLTg/− DCC+/− transgenic littermates compared with the BCR/ABLTg/− DCC+/+ transgenic littermates (115–170 x 104/mm3). Leukocytosis and the percentage of granulocytes in BCR/ABLTg/− DCC+/− mice were greatly increased compared with BCR/ABLTg/− DCC+/+ transgenic littermates (6.1–13.5 x 103/mm3 vs 5.0–11.2 x 103/mm3; 42–68 % vs 23–49 %). However, blasts, which were detected in the blastic crisis, were not found in the peripheral blood of either mouse line.
Thus, the DCC-heterozygote, in cooperation with p230BCR/ABL cDNA, shortened the latency period of overt MPD, and changed the disease phenotype from MPD mimicking ET to MPD mimicking CNL. However, pathological analysis of the bone marrow, spleen, liver, etc. did not reveal any difference between the BCR/ABLTg/− DCC+/− transgenic littermates and the BCR/ABLTg/− DCC+/+ transgenic littermates.
Promoter Methylation of RASSFIA, SHP1 and SOCS1 Genes in Acute Myeloid Leukaemia (AML) and Myelodysplastic Syndromes (MDS).
Authors: Johan M. Farid , Goodeve Anne C. , Bowen David T. , Reilly John T. 
Published: April 2020

Abstract
Mutations in the receptor tyrosine kinase (RTK)/RAS signalling pathway frequently provide a proliferative signal in AML, especially those with inv(16) and t(15;17). We have reported, for example, that approximately 70% of AML and inv(16) have mutations in FLT3, c-KIT and RAS. However, the role of RASSFIA, SHP1 and SOCS1, negative regulators of RTK/RAS signalling, has not been extensively investigated in AML. RASSFIA is a tumour suppressor gene that serves as a RAS effector that inhibits cell cycle progression and mediates apoptotic cell death, while SHP1 and SOCS1 are negative regulators of the Jak/STAT pathway. In many cancers, the CpG islands of RASSFIA, SHP1 and SOCS1 are aberrantly hypermethylated, resulting in gene inactivation due to repression of transcription. In this study, methylation-specific polymerase chain reaction (MS-PCR) was employed to determine if aberrant promoter methylation of these negative regulators are involved in the pathogenesis of AML and MDS. Patients with MDS (n=107), AML (n=154), JMML (n=5) were studied, together with 15 normal controls. Primers were located in the promoter region of each gene as well as within exon 2 of SOCS1 as previously reported. Methylation of RASSFIA was found in five of 55 (11%) MDS patients, but in none of 57 AML cases. RASSFIA methylation was present in one case (20%) of JMML, which lacked a RAS, NF1 or PTPN11 mutation, a finding that strengthens the concept of mutual exclusivity of genetic and epigenetic changes in this disorder. SHP1 methylation was identified in 13 of 121 (11%) AML cases, including 3 AML with inv(16) and c-KIT 419 mutations. In contrast, none of the 65 MDS or 5 JMML cases showed SHP1 methylation. MS-PCR for SOCS1 promoter and exon 2 gave discrepant results. Promoter analysis was negative in the 15 controls whereas 2 controls showed exon 2 positivity. SOCS1 promoter methylation was seen in eight of 74 (11%) MDS patients, but not in the five JMML cases. Methylation of RASSFIA and SOCS1 promoters in MDS were mutually exclusive. No case of AML showed SOCS1 promoter methylation whereas 19 of 47 (40%) cases exhibited exon 2 methylation. In conclusion, promoter methylation may lead to epigenetic silencing of RASSFIA and SOCS1 in MDS but not in AML, whereas SHP1 gene silencing may be important in the pathogenesis of AML. SHP1 methylation studies suggest that some patients with inv(16) AML and RTK mutations possess additional epigenetic events. Finally, SOCS1 exon 2 methylation does not appear to be pathogenetically important, since methylation may occur in normal samples and results do not correlate with promoter methylation.
Prevention of Murine Acute Graft-versus-Host Disease by Recipient-Derived TGFβ1-Treated Dendritic Cells.
Authors: Mou Haibo , Lin Maofang , Cen Hong , Huang He , Cai Zhen 
Published: April 2020

Abstract
Acute graft-versus-host disease (GVHD) remains the major barrier of allogeneic bone marrow transplantation (allo-BMT). In the current view, GVHD fundamentally depends on donor T cells interaction with host derived dendritic cells (DC) leading to their activation, proliferation, and differentiation. We and others have demonstrated that transforming growth factor β1 (TGF-β1) treated DC (TGFβ-DC) have regulatory characteristic and could induce allogeneic specific immune tolerance in vitro. In the current study, we focused on the effects of recipient-derived TGFβ-DC in a murine GVHD model. After total body irradiation, 5.0×106 recipient-derived TGFβ-DC were injected into C57BL/6 (H-2b) with bone marrow-splenocyte grafts from major histocompatibility complex (MHC) disparate BALB/c mice (H-2d). Survival analysis showed TGFβ-DC co-transplantation resulted in significant prolongation of allograft survival and mean survival time (MST) was 44.3±4.5 days (p&lt;0.01), whereas MST of untreated BMT recipient was 9.5±0.6 days (p&lt;0.01). However, mature DC aggravated the GVHD and the MST was 6.6±0.6 days (p&lt;0.01). In addition, donor-derived or the third party-C3H mice derived TGFβ-DC could not enhance the survival rate indicating that the protection effect of TGFβ-DC was recipient-specific. Consistent with clinical outcomes, the histopathologic studies showed no or mild GVHD evidences were found in recipient-derived TGFB-DC co-transplantation mice, while specific severe GVHD alternations occurred in the liver, skin and intestine in other groups. Flow cytometry analysis of TGFβ-DC labeled with 5,6-carboxyfluorescein diacetate succinimidyl ester (CFSE) showed approximately 5% of TGFβ-DC in spleen mononuclear cells the next day after transplantation and half-life of the injected TGFβ-DC was around 20 days after transplantation. Furthermore, serum Th1 type cytokines of IFN-γ, IL-12 and IL-18 levels in TGFβ-DC co-transplantation mouse reduced compared with untreated BMT mouse, while serum IL-10 level was not changed. Taken together, these preliminary results indicate that TGFβ-DC co-transplantation may induce MHC-specific tolerance and attenuate the severity of GVHD by suppressing Th1 responses. Further research should be carried out to explore the optimal transplantation regimen and elucidate the mechanism.
Cologne High-Dose Sequential Chemotherapy in Relapsed and Refractory Hodgkin Lymphoma - Results of a Large Multicenter Study of the German Hodgkin Lymphoma Study Group (GHSG).
Authors: Josting Andreas , Rudolph Christian , Mapara Markus , Glossmann Jan-Peter , Sieber Markus , Kirchner Hartmut H. , Dörken Bernd , Hossfeld Dieter K. , Kisro Jens , Metzner Bernd , Berdel Wolfgang E. , Diehl Volker , Engert Andreas 
Published: April 2020

Abstract
Purpose: Combination chemotherapy can cure patients (pts) with Hodgkin lymphoma (HD), but those with treatment failure or relapse still have a poor prognosis. We thus, designed a dose- and time-intensified high-dose sequential chemotherapy regimen with a final myeloablative course.
Patients and Methods: Eligibility criteria included age 18–65 years, histologically proven primary progressive (PD) or relapsed HD. Treatment consists of two cycles DHAP (dexamethasone 40mg d1-4, high-dose cytarabin 2g/m2 12q d2, cisplatinum 100mg/m2 d1); pts with partial (PR) or complete remission (CR) received cyclophosphamide 4g/m2, followed by peripheral blood stem cell (PBSC) harvest; methotrexate 8g/m2 plus vincristine 1,4mg/m2; and etoposide 2g/m2. The final myeloblative course was BEAM followed by PBSCT.
Results: 102 pts (median age 34 years, range 18–64) were enrolled. The response rate (RR) at the final evaluation (100 days posttransplantation) was 80% (72% CR, 8% PR). PBSC harvest was succesful in 96% of pts. Toxicity was tolerable. With a median follow-up of 30 months (range 3–61 months) freedom from second failure (FF2F) and overall survival (OS) were 59% and 78% for all patients, respectively. FF2F and OS for patients with early relapse were 62% and 81%, for late relapse 65% and 81%; for PD: 41% and 48% and for multiple relapse 39% and 48%, respectively. In multivariate analysis response after 2 cycles of DHAP (p &lt; 0.0001) and duration of first remission (PD and multiple relapse vs. early and late relapse; p = 0.0127) were prognostic factors for FF2F. Response after DHAP (p &lt; 0.0081), duration of first remission (p = 0.0017) and anemia (p = 0.019) were identified as prognostic factors for OS.
Conclusion: We conclude that this regimen is feasible, tolerable and highly effective in poor risk patients with relapsed and refractory HD. Based on these results a prospective randomized european intergoup study was started comparing this intensified regimen with two courses of DHAP followed by BEAM (HD-R2 protocol). First results of the second interim analysis of this study will be presented.
MAL Is Expressed in a Subset of Hodgkin Lymphomas and Identifies a Population of Patients with Poor Prognosis.
Authors: Hsi Eric D. , Sup Stephen J. , Alemany Carlos , Tso Elisa , Skacel Marek , Elson Paul , Alonso Miguel A. , Pohlman Brad 
Published: April 2020

Abstract
Recent evidence suggests that classical Hodgkin lymphoma (cHL) and primary mediastinal diffuse large B-cell lymphoma (PMLBL) have similarities that span clinical, histopathologic, and molecular genetic features. MAL is a gene that encodes a protein associated with lipid rafts in T-cells and epithelial cells. In T-cells, it is involved in the reorganization of lipid rafts during T-cell receptor activation and signaling. MAL is overexpressed in PMLBL and in a minority of cHL cases; however, data on its expression in a large series of cHL with clinical follow-up is lacking. In order to determine whether there might be some clinical significance associated with MAL expression, we evaluated MAL expression in a series of cHL by immunohistochemistry. Clinical information including age, sex, stage, bulky tumors (≥ 1/3 of the thoracic diameter or mass ≥ 10cm), hemoglobin, WBC, lymphocyte count, albumin, and outcome were collected for the cHL patients. Tissue microarrays containing diffuse large B-cell lymphoma (n=33), PMLBL (n=41), and cHL (n=87) were stained for MAL. 54% of PBLBL, 17% of cHL, and 3% of non-mediastinal diffuse large B-cell lymphomas were found to express MAL. Focussing on cHL, MAL expression correlated with the nodular sclerosis histologic subtype (P=0.03, Fisher exact). Overall, 22 HL patients have failed (relapse or death) and 15 patients have died. Median follow-up of patients alive and free of disease is 6.7 years (range 1.0–16.9 years). The 5-year failure-free and overall survival are 75 +/− 5% and 85 +/−4%, respectively. Using P&lt;0.1 as significant, univariable analysis (Wilcoxon rank sum) showed that the following factors were associated with shorter failure free survival and overall survival: age ≥ 45 (P=0.01 and P&lt;0.001, respectively), stage III/IV (P=0.09 and P=0.03, respectively), and MAL expression (P=0.05 and P=0.01, respectively). Cox proportional hazards modeling showed that the following were independent predictors of both time to treatment failure and overall survival: age (P=0.03 and 0.01, respectively), stage (P=0.06 and 0.04, respectively), and MAL expression (P=0.06 and 0.02, respectively). These data suggest that MAL expression in cHL identifies a biologically different subset of cHL compared to those cases that lack MAL and that MAL expression is a predictor of adverse outcome.
Epstein-Barr Virus Infection Is Not the Sole Cause of High Prevalence for Hodgkin’s Lymphoma in Saudi Arabia.
Authors: Al-Kuraya Khawla S. , Narayanappa Rajeswari , Al-Dayel Fouad , El-Solh Hassan , Ezzat Adnan , Ismail Hoda , Belgaumi Asim , Atizado Valerie , Bhatia Kishor , Sauter Guido , Simon Ronald 
Published: April 2020

Abstract
Age adjusted incidence of Hodgkin’s Lymphoma (HL) is markedly higher in Saudi Arabia than in the United States. For example, HL accounts for 10.5% of all neoplasia in children 15 years and younger in Saudi Arabia. EBV virus infection, which can induce HL transformation has been suspected to cause high HL incidence in developing countries. To investigate the role of EBV for the high frequency of HL in Saudi Arabia, we analyzed 265 HL from Saudi Arabia and 58 HL from Europe for EBV infection by in situ hybridization with fluoresce in-conjugated Epstein-Barr virus (EBER) on tissue microarray (TMA) sections. All Saudi and European HL were analyzed in one staining run under identical conditions. Unexpectedly, our data show only minor, statistically insignificant differences in EBV infection rates between Saudi (64 out of 150 informative cases; 42.6%) and European HL (11 out of 30 informative cases; 33%; p=0.5). Within the Arabian population, EBV positivity was more frequent in 79 children (53%) than among 133 adults (36%; p=0.015). EBV positivity was also linked to high stage with EBV positivity in 36% of 69 stage I/II and 64% of 73 stage III/IV tumors (p=0.009). EBV infection was most frequently seen in mixed cellularity HL (63% of 27 cases). This was significantly more frequent than in nodular sclerosing HL (39% of 136; p=0.02). Interestingly, EBV positivity was associated with good prognosis in Saudi childhood HL (p=0.016) but with poor prognosis in Saudi adulthood HL (p=0.0048). In conclusion, our data strongly suggest that EBV is not the main cause for the high prevalence of HL in Middle East countries. Among others, this would be consistent with a major role of genetic susceptibility genes for HL in these populations. Saudi Arabia with high consanguinity and large families would be ideal to search for HL susceptibility genes.
Immunohistochemical Markers Can Be of Predictive Value in Hodgkin’s Lymphoma Response to Treatment. A Preliminary Study of 23 Cases.
Authors: Canioni Danielle , Deau Benedicte , Taupin Pierre , Delarue Richard , Vasiliu Viorel , Brousse Nicole , Hermine Olivier 
Published: April 2020

Abstract
Hodgkin’s lymphoma (HL) belongs to the most curable tumor diseases in adults and about 80% of patients can be cured with modern treatment strategies. However, some HL are primary refractory to usual treatments including a first line of anthracyclins based regimen and have more than 50% of residual disease after treatment. Currently, clinical parameters are considered as main relevant factors for prognosis. Herein, in order to predict value of some other factors on treatment response, we evaluate immunohistochemical markers of apoptosis, proliferation and of environmental non neoplastic cells in HL. A retrospective study was performed on pre-treatment biopsy specimen of 23 patients presenting with HL treated with the same anthracyclin based regimen, 8 primary refractory HL (non responders or relapse occurring within one year) and 15 good responders (free of disease for 2 or 3 years) to chemotherapy. These patients ranged in age from 23 to 52 years old (median= 36.5 years) for refractory HL and from 21 to 75 years old (median= 37.9 years) for good responders (n.s). All refractory HL, except one for whom histological type could not be defined because of a too small biopsy, had a nodular sclerosis (NS) histological type. The histological type was NS in 13 responding patients and mixed cellularity for the 2 others (n.s). The semi-quantitative immunohistochemical study used bcl2, p53, Ki67, TiA1 and c-kit antibodies. The results were statistically evaluated using a Wilcoxon sum rank test. Ki67 was strongly expressed on Hodgkin (Hg) and Reed-Sternberg (RS) cells whatever patients were refractory or responders to chemotherapy. By contrast, p53 and bcl2 had a significantly higher expression on Hg or RS cells in refractory patients (median= 90%&60%) compared to responding HL (median= 42.5 & 8%)( p=0.0001 & p=0.026 respectively). The cytotoxic marker TiA1 stained a significantly higher number of small lymphocytes in refractory HL (median= 53 per high power field (hpf)) compared to responding patients (median= 24/hpf)(p=0.0003). C-kit antibody was negative on Hg or RS cells but stained significantly more mastocytes in refractory HL (median= 13/hpf) comparing to responders (median= 3.8/hpf) (p=0.001). These results indicate that some immunohistochemical markers may be useful for predicting the response to therapy of HL. A high expression of bcl2 and p53 in refractory HL supports the notion that an intact apoptosis cascade is essential for killing effect of chemotherapy. The increase of TiA1 and c-kit positive cells emphasizes the importance of the environmental non neoplastic cells in HL. A larger study is mandatory to confirm these preliminary results.
Regulation of NKT Cell Development by Sap, the Adaptor Mutated in X-Linked Lymphoproliferative Disease.
Authors: Nichols Kim E. , Hom Jamie , Ganguly Arupa , Ma Cindie S. , Tangye Stuart G. , Cannons Jennifer L. , Schwartzberg Pamela L. , Koretzky Gary A. , Stein Paul L. 
Published: April 2020

Abstract
The adaptor molecule SAP is expressed in T and natural killer (NK) cells, where it regulates cytokine production and cytotoxicity. Here we demonstrate that SAP also plays a critical role during NKT cell development. Sap−/− mice lack thymic and peripheral NKT cells and fail to produce cytokines in response to the NKT cell stimulus alpha-galactosyl ceramide. Infection of Sap−/− bone marrow cells with retroviruses expressing wild-type SAP permits NKT cell development after transfer into irradiated recipients. X-linked lymphoproliferative disease (XLP) patients, who harbor germline mutations in the gene encoding SAP, also lack NKT cells. Furthermore, a female XLP carrier demonstrates completely skewed X chromosome inactivation within peripheral blood NKT cells, but not T or B cells. Thus, SAP is a critical regulator of NKT cell ontogeny in humans and in mice. The absence of this cell lineage may contribute to the phenotypes of XLP, including abnormal anti-viral and anti-tumor immunity and hypogammaglobulinemia.