bluuebunny/crossref_metadata_2025_split huggingface dataset:
Protein Phosphatase1 gamma (PP1cγ) Is Required for Thrombin-Induced Integrin αIIbβ3 Activation.
Authors: Gushiken Francisca C. , Patel Vimal , Rambuat Rolando , Varmuza Susannah , Vijayan K. Vinod 
Published: October 2019

Abstract
Integrin αIIbβ3 activation is critical for platelet physiology and is controlled by agonists- induced signal transduction through kinases and phosphatases. Compared to kinases, a role of phosphatases in platelet integrin αIIbβ3 signaling and activation is less understood. We have previously demonstrated that the catalytic subunit of protein phosphatase 1 (PP1c) associates constitutively with the integrin αIIbβ3 and regulates myosin light chain phosphorylation. Platelets express three isoforms of PP1c namely PP1cα, PP1cβ/δ and PP1cγ1, however their role in platelet physiology is unclear. In this study, we explored a role for the PP1cγ in integrin αIIbβ3 activation using the PP1cγ null mice that lacks both PP1cγ1 and PP1cγ2 splice variants. Deletion of PP1cγ did not alter the expression of PP1cα and PP1cβ/δ in platelets. Compared to the wild type mice, PP1cγ null mice had significantly (P=0.03) more platelets but not other blood cells and increased megakaryocytes in an in vitro bone marrow culture system, suggesting that PP1cγ may regulate platelet production. Compared to the wild type platelets, PP1cγ null platelets exhibited a ∼50% decreased activation (P=0.007) of integrin αIIbβ3 in response to low doses of thrombin as measured by the binding of soluble Alexa-flour 488-conjugated fibrinogen or Jon/A, an antibody to high affinity integrin αIIbβ3. Consistent with this observation, PP1cγ null platelets showed decreased aggregation in response to thrombin or protease activated receptor activating peptide. Soluble fibrinogen binding and aggregation to ADP, collagen and cross linked collagen -related peptide was not different between the PP1cγ null and wild type platelets. Surface expression of integrin αIIbβ3 was comparable in the PP1cγ null platelets indicating that the decreased activation of αIIbβ3 in PP1cγ platelets was not due to decreased integrin expression. These studies suggest that PP1cγ is required for thrombin-induced αIIbβ3 inside-out signaling process. In contrast, αIIbβ3 outside-in signaling process was not altered in PP1cγ null mice as revealed by normal adhesion to immobilized fibrinogen. Intravital microscopy revealed that the thrombus formation induced by a light/dye injury in the cremaster muscle venules was significantly (P=0.03) delayed in PP1cγ null mice compared to wild type mice. These studies illustrates that PP1cγ is an essential component of thrombin signaling that is downstream of protease activated receptors and promotes thrombus formation in part by supporting soluble fibrinogen binding and platelet aggregation.
Nongastric Marginal Zone B-Cell Lymphoma: A Prognostic Model from a Retrospective Multicenter Study.
Authors: Oh Sung Yong , Kwon Hyuk-Chan , Kim Won Seog , Park Yeon Hee , Kim Kihyun , Kim Sung-Hyun , Kim Hyun Jung , Kwon Jung Mi , Lee Jeeyun , Ko Young Hye , Ahn Yong Chan , Oh Suk Joong , Lee Soon Il , Bang Soo Mee , Kim Jung Han , Park Jinny , Ryoo Baek-Yeol , Lee Seung-Sook , Kim Ho Young , Kim Hyo-Jin 
Published: October 2019

Abstract
Purpose: The International Prognostic Index (IPI) and Follicular Lymphoma Prognostic Index (FLIPI) are used as prognostic indices for NHL and indolent lymphoma. However, marginal zone B-cell Lymphoma (MZL) evidences a distinctive clinical presentation and a natural course; thus, in this study, we attempted to devise an adequate prognostic index for MZL.
Patients and method: From 1990 to 2005, 205 patients diagnosed with MZL were retrospectively reviewed. After analysis of the prognostic factors, progression free survival (PFS) and overall survival (OS), we constructed a prognostic index of MZL (MZLPI) via the summation of each factor. We then compared PFS and OS with IPI, FLIPI, and MZLPI.
Results: According to our multivariate analysis of PFS and OS of MZL, nodal MZL, ECOG performance ≥ 2 and advanced stage were composed of MZLPI. MZLPI was grouped as follows: score 0 as a low risk group, score 1 as an intermediate risk group, and score ≥2 as a high risk group. The PFS curve, according to MZLPI results, evidenced a more discriminated pattern than IPI and FLIPI, and this was especially true in the intermediate risk group. In OS, MZLPI (P=0.0007) evidenced a more discriminated pattern than IPI (P=NS) or FLIPI (P=0.0044).
Conclusion: MZLPI, which is constructed of relatively simple factors, may represent a useful prognostic index for the prediction of PFS and OS in MZL, and may also be used as a substitute for IPI or FLIPI.
Phase I/II Study of Rituxan (R) in Combination with Doxil (D) in Patients (pts) with Relapsing or Refractory B-Cell Lymphoma: Clinical Efficacy without Cardiac Toxicity.
Authors: Czuczman Myron S. , Skipper Marion , Mohr Alice , Bernstein Zale P. , Hernandez-Ilizaliturri Francisco J. , Chanan-Khan Asher A. 
Published: October 2019

Abstract
In the past, the most common initial combination chemotherapy regimen used by most oncologists to treat B-cell lymphoma was the CHOP regimen. Although doxorubicin (DOX) is a major component of CHOP, it is associated with myelosuppression, alopecia, and potential cardiotoxicity. In vitro data has demonstrated synergistic activity between rituximab and certain drugs, including DOX. Because of D’s unique liposomal encapsulation, delivery, and toxicity profile, it may prove to be a more effective, less toxic anthracycline to combine with R. A formal Phase I/II trial to evaluate the safety and efficacy of R+D in pts with relapsing B-cell lymphoma was undertaken. R (375 mg/m2/dose) was given on day 1 and D (30 mg/m2/dose) on day 3 on q 21 day cycles for 6 cycles. Thirty-six of 42 pts have been enrolled to date. Four pts (n=3 with aggressive histologies) progressed while on treatment and did not complete the planned 6 cycles of therapy; 1 pt has not completed therapy, but is a PR mid-treatment. Demographics: 19M:17F; Median age = 63 (range 35–83); Follicular lymphoma (FL) grade 1 or 2 (n=14); FL, grade 3 (n=7); SLL (n=5); de novo DLBCL (n=3); Transformed NHL (n=6); Mantle cell lymphoma (n=1); Median number of prior treatments = 2 (range 1–8); prior anthracycline exposure (n=24; 67%). Overall, R + D was very well-tolerated. Reversible grade 3 (n=8) or grade 4 (n=4) neutropenia was seen and responded to growth factor support. Reversible grade 3 thrombocytopenia was seen in 2 pts. Of note, grade 3 palmar/plantar erythrodysesthesia occurred only in 3 pts whom were non-compliant with instructions given to avoid this side-effect associated with D therapy. Overall response rate (ITT) = 64% (42% CR, 22% PR); responses were equally distributed between both indolent and aggressive histologies. Median time-to-progression (TTP) = 12 months (range 1M to 57+M); mean TTP = 17 months. Median TTP in CRs = 14 months (range 4M to 57+M); Median TTP in PRs = 5 months (range 1M to 17M). Fifteen of 24 (63%) pts with prior anthracycline exposure demonstrated objective responses (9 CR; 6 PR). No clinical cardiac toxicity has been seen and comparison of pre-Rx to post-Rx LVEF remained >50% in all pts completing therapy. D + R immunochemotherapy is a unique, well-tolerated, non-cardiotoxic and effective salvage therapy for pts with either indolent or aggressive relapsed B-cell lymphoma. An update of the completed database will be presented at the annual ASH meeting.
RNA Based Cancer Vaccines - Clinical Trials in Patients with Prostate Cancer and Malignant Melanoma.
Authors: Kvalheim Gunnar , Aamdal Steinar , Gaudernack Gustav 
Published: October 2019

Abstract
Anti-tumour vaccines targeting the entire tumour antigen repertoire represent an attractive immunotherapeutic approach. This repertoire is present in the total mRNA isolated from the tumour. The mRNA from each cancer patient may be amplified and thus overcome the problem of limitation of material that has hampered the development of individualized vaccines. We have developed immuno-gene-therapy for malignant melanoma and prostate cancer. Monocyte-derived dendritic dells are transfected with autologous melanoma-mRNA or mRNA from three prostate cancer cell lines (DU-145, LN-CaP and PC-3). The vaccines may generate T cell responses against a broad repertoire of tumor-associated epitopes, and the melanoma approach moreover target patient-specific tumor antigens. Effective protocols were established for mRNA-transfection by square wave electroporation and for generation of clinical grade dendritic cells. A full scale preclinical evaluation demonstrated in vitro T cell responses in 6/6 advanced melanoma patients. The responses were specific to antigens encoded by the transfected tumor-mRNA. Recently, we have conducted two phase I/II trials, in advanced malignant melanoma and androgen-resistant prostate cancer. Successful vaccine preparations were obtained for all 41 patients elected. No serious adverse effects were observed. Specific T cell responses (T cell proliferation and/or IFNγ ELISPOT) were demonstrated in 9/19 evaluable melanoma patients and in 12/19 prostate cancer patients. The response rates were higher for patients receiving intradermal vaccination, compared to intranodal injection. Thirteen prostate cancer patients developed a decrease in log-slope PSA. The PSA-response was significantly related to the T cell response (p=0,002). We conclude that the tumour mRNA based DC-vaccine is feasible and safe, and that T cell responses are elicited in about 50% of patients. In the next generation clinical protocols, patients will undergo Treg depletion by chemotherapy (Temozolomide) prior to DC vaccination. Subsequently, T cells will be expanded ex vivo using the Dynabeads Clin Ex Vivo system before re-infusion into the patients.
The Clinical Outcomes of Autologous Stem Cell Transplantation in Peripheral T Cell Lymphoma: from Retrospective Multicenter Study in Korea.
Authors: Yang Deok-Hwan , Kim Won Seog , Kim Seok Jin , Bae Sung Hwa , Kim Sung Hyun , Kim In Ho , Mun Yeung-Chul , Shin Ho-Jin , Chae Yee Soo , Kwak Jae-Yong , Kim Hawk , Kim Min Kyoung , Kim Jin Seok , Baek Jin Ho , Suh Cheol Won , Park16 Hee Sook 
Published: October 2019

Abstract
Peripheral T cell lymphoma (PTCL) is a heterogenous group of aggressive lymphoma, which T-cell phenotype itself associated with unfavorable prognostic factors when compare to patients with B-cell phenotype lymphoma. High-dose chemotherapy (HDT) followed by autologous stem cell transplantation (ASCT) has represented a rescue option from poor prognosis. We retrospectively investigated the clinical outcomes of ASCT in 139 Korean patients with PTCL between December 1994 and June 2007. The overall survival (OS) and progression-free survival (PFS) were measured from the date of transplantation and were estimated using the Kaplan-Meier method. The median age at transplantation was 41 years. The histological subtypes had 45.3% PTCL-unspecified, 13.7% anaplastic large cell (ALK +/−: 15.7/57.8%), 10.8% angioimmunoblastic T cell, 21.6% extranodal NK/T cell, and 8.6% others. Disease status at transplantation consisted of 54 patients (38.8%) with first complete response (CR)/partial response (PR), 58 patients (41.7%) with chemosensitive-relapsed CR/PR, 15 patients (10.8%) with refractory CR/PR and 12 patients (8.6%) with progressive or refractory. At a median follow-up of 29.3 months, the 5-year probability of OS and PFS was 42.3±4.9% and 42.2±5.9%, respectively. The 5-year OS and PFS rates in patients with 1st CR/PR were 64.9±7.2% and 61.1±7.6%, compared to those in patients with chemosensitive-relapsed and refractory CR/PR were 33.5±6.8% and 33.2±8.3%, respectively. Early transplant-related mortality was 10.1%. Histological subtypes, bulky (≥10cm), prognostic index for PTCL (PIT) at diagnosis (0–2 vs 3–4), age-adjusted IPI at diagnosis, disease status at transplantation, the transplant timing (front-line vs second-line) and conditioning regimen were significant differences of survivals in univariate analysis. PIT, the transplant timing and the achievement of CR before transplantation were the variable prognostic for OS and PIT, bulky, and the achievement of CR provided significant independent factors for PFS in multivariate analysis. Our data showed that patients with PTCL who had low PIT and achieved CR before ASCT improved the OS and PFS regardless of the transplant timing and front-line ASCT of primary chemosensitive patients was effective in the OS.
Figure Figure
Effect of Thrombotic Events on Overall Survival in Patients with Newly Diagnosed Myeloma: Analysis from a Randomized Phase III Trial of Thalidomide Plus Dexamethasone Versus Dexamethasone in Newly Diagnosed Multiple Myeloma (E1A00).
Authors: Kumar Shaji , Zhang Lijun , Greipp Philip R. , Rajkumar S. Vincent 
Published: October 2019

Abstract
Background: Patients with newly diagnosed multiple myeloma is at increased risk of thrombotic events, primarily venous thrombosis. The risk is significantly increased in patients receiving certain therapeutic regimens such as the combination of thalidomide and dexamethasone. Deep vein thrombosis, especially if complicated by pulmonary embolism, can result in death. It is not clear if venous thrombotic events can result in compromised survival in this group of patients.
Methods: We studied patients enrolled in the Eastern Co-operative Group trial (E1A00) that randomized patients with newly diagnosed myeloma to single agent dexamethasone or thalidomide and dexamethasone. Patients with grade 3 or greater thrombotic events (DVT, or myocardial ischemia, or stroke) were identified. Wilcoxon rank sum test (for continuous variables) or Fisher’s exact test (for categorical variables) was used to compare age, baseline M-protein, hemoglobin, WBC, platelets count, creatinine, beta2-microglobulin, or ECOG PS between patients with and without thrombotic events.
Results: Among the 207 patients enrolled, 36 patients (17.4%) had grade 3 or greater thrombotic events with any treatment attribution, of whom, 27 patients had DVT, 3 patients had an MI and 6 pts had a stroke. However, in only 31 of these patients were the event considered treatment-related (possible, probable, or definite) and among these 24 had a DVT. The baseline characteristics did not differ between the patients with thrombosis and those without, irrespective of its relationship to treatment. Similarly, the baseline characteristics did not diff for those with venous or arterial thrombosis. The overall survival was similar among the patients developing a DVT compared to those without a thrombotic event, when all DVT events were considered irrespective of the treatment attribution (Figure). However, majority of the patients with an arterial event (3 patients with MI and 6 with stroke) had a short overall survival.
Conclusion: Venous thrombosis remains a common complication in patients with myeloma, especially when treated with thalidomide and dexamethasone. While occurrence of thrombosis clearly contributes to morbidity and often leads to dose reductions and missed doses, it does not appear to have an adverse impact on the overall survival of these patients.
Figure Figure
Anti-CD3 Activated T Cells from Cord Blood Can Be Expanded Ex Vivo and Armed with Bispecific Antibodies To Lyse Her2/Neu + and CD20+ Targets: A Strategy for Providing Anti-Tumor/Lymphoma Effects after Cord Blood Transplant.
Authors: Sorenson Carly B. , Frandsen Thomas D. , Dorr Suanne , Ratanatharathorn Voravit , Uberti Joseph P. , Lum Lawrence G. 
Published: October 2019

Abstract
Our previous studies showed that anti-CD3 activated T cells (ATC) from peripheral blood mononuclear cells could be expanded in interleukin-2 (IL-2) for 14 days and armed with anti-CD3 x anti-Her2/neu (Her2Bi)[J Hemat & Stem Cell Res10:247,2001], anti-CD3 x anti-CD20 (CD20Bi)[Exp Hemat33:452,2005], or anti-CD3 x anti-EGFR [Clin Cancer Res12:183,2006] bispecific antibody (BiAb)and can kill Her2/neu, CD20, and EGFR+ tumor targets, respectively. In this study, we asked whether anti-CD3 activated cord blood T cells (CBATC) could be expanded and targeted with Her2Bi and CD20Bi to tumors or hematologic malignancies for infusions after cord blood stem cell transplant (CBSCT). CB mononuclear cells were activated with anti-CD3 (20 ng/ml) and expanded for 14 days in IL-2 (100 IU/ml). CBATC were armed with Her2Bi or CD20Bi and tested for specific cytotoxicity directed SK-BR-3, Raji, or B9C targets and cytokine secretion or IFNγ EliSpots after binding to tumor cells. Our results show the mean expansion of CBATC to be 43-fold (n=8) after 14 days of culture. By the end of culture, the proportions of CD8+ and CD4+ were 82% and 18%, respectively. The proportion of cells expressing CD19 or CD20 did not exceed 6.3%, CD56+ cells were <3.6% and CD3-CD16+CD56+ cells was <0.7%. Cells positive for CD4+CD25+ or CD8+ CD25+ were 4.2% or 7.1%, respectively (n=2). Specific cytotoxicity was optimized when CBATC were armed with 50 ng/106 cells of Her2Bi or CD20Bi (arming dose ranged from 5, 50, and 500 ng/106 cells); arming significantly increased cytotoxicity of the armed CBATC over that seen for unarmed CBATC. Cytotoxicity peaked between days 12 and 14 for both BiAbs. The ability of CD20Bi armed ATC to produce Elispots for IFNγ were tested by arming ATC the CD20Bi after 0, 8, 11, and 13 days of culture peaked on day 8. Only CD20+ targets induced Elispots and day 8 armed ATC exhibited peak numbers (2,200 Elispots(ranged from 1,700 to 1,800 on day 8)/106 armed ATC plated). At an effector/target ratio (E:T) of 25:1, the mean cytotoxicity of CBATC armed with Her2Bi or CD20Bi was 60% (n=4) and 35% (n=1), respectively. In an extended culture to day 47, mean cytotoxicity for Her2Bi-armed CBATC was 36% at an E/T of 25:1 compared to 4.35% for unarmed CBATC. Unarmed CBATC did not kill Daudi targets. Armed CBATC mediated both specific cytotoxicity and secreted IFN-γ as measured by ELISA or EliSpots. Both fresh and frozen CB could be used in the assays. In a clinical application, specific cytotoxicity of armed CBATC could be used to augment anti-tumor and anti-lymphoma effects after CBSCT.
Onset of Cardiac Iron Loading in Pediatric Patients.
Authors: Wood John C. , Origa Raffaella , Agus Annalisa , Matta Gildo , Coates Thomas D. , Galanello Renzo 
Published: October 2019

Abstract
Patients with thalassemia major develop life threatening cardiac complications in their teens and twenties from iron overload. Cardiac MRI allows us to diagnosis preclinical cardiac iron deposition, but it is not known at what age T2* screening should be initiated. Historical data and pilot MRI studies suggest that patients must reach a critical transfusional exposure prior to cardiac iron uptake. This study was a two-institution characterization of the prevalence of cardiac iron overload in 77 pediatric patients.
Methods: Study was performed at the Ospedale Regionale Microcitemie in Cagliari and the Childrens Hospital Los Angeles (CHLA). Retrospective review of medical records was authorized by the IRB for pediatric patients undergoing cardiac MRI prior to July of 2007. Subjects at both institutions had assessment of cardiac T2* and cardiac function using validated techniques on a 1.5 T General Electric CVi scanner; patients at CHLA also underwent MRI-based liver iron measurements. Complete transfusional iron burden was measured in the Italian patients. Serial MRI data was recorded in 30 patients, but associations between cardiac T2* and age were determined using linear and logistic regression using only results from the first patient MRI scan.
Results: Patient ages ranged from 8.0 to 18 years of age at Cagliari (n=36) and 2.5 to 17.9 years of age at CHLA (n=41), reflecting the use of MRI to monitor liver iron in patients < 8 years of age. Patients were moderately iron loaded with hepatic iron concentrations of 12.7 ± 9.8 (CHLA) and ferritin values of 2329 ± 1162 (Cagliari). Median cardiac T2* was 30.2 and ranged from 3.4 to 72.8. Cardiac T2* and its reciprocal were uncorrelated with liver iron (CHLA) and ferritin levels (Cagliari). Figure 1 demonstrates the decrease in cardiac T2* with increasing chronologic age. Serial data are connected by lines. Although linear regression was weakly positive (r2 = 0.06, p = 0.03), the relationship was fundamentally nonlinear. No patient below the age of 9.5 years of age demonstrated an abnormal cardiac T2* (< 20 ms) while 36% of patients between the ages of 15–18 years had detectable cardiac iron. Figure 2 demonstrates the logistic regression curve modeling the prevalence of detectable cardiac iron as a function of age (r2= 0.13, p< 0.002). Chronologic age was highly correlated (r2 = 0.88) with both transfusional iron burden and with duration of transfusion therapy, making it impossible to separate the relative importance of these three variables.
Conclusion: Thalassemia major patients did not accumulate cardiac iron until early in their second decade of life. Consequently, cardiac iron monitoring can be safely deferred until children are able undergo MRI examination without sedation.
Figure Figure Figure Figure
Improved Outcome of Adult Acute Lymphoblastic Leukemia Treated with a Pediatric Protocol: Results of a Pilot Study.
Authors: Haiat Stephanie , Vekhoff Anne , Marzac Christophe , Calendini OrsAnton , Lapusan Simona , Marjanovic Zora , Rio Bernard , Marie Jean-Pierre , Legrand Ollivier 
Published: October 2019

Abstract
Adult ALL still have poor outcome compared with childhood ALL, with an expected OS of less than 40%. Recent retrospective studies have shown that adolescents and young adults (<30 yo) treated with pediatric protocol have a better prognosis than those treated with adult protocols. The aim of this pilot study was to assess the feasibility and efficacy of the French pediatric protocol FRALLE 2000 to treat 28 oldest adult ALL aged from 16 to 57 years.
Methods: 28 consecutive adults Philadelphia negative ALL aged from 16 to 57 years, with a median follow-up of alive patients of 35 months, received treatment courses according to FRALLE 2000 from 2001 to 2007. After a prednisone prephase and a four-drugs induction (prednisone, daunorubicin, vincristine and 9 infusions of L-asparaginase), patients in CR received a consolidation course, two delayed intensifications with L-asparaginase separated by an interphase, and a maintenance chemotherapy during two years. Results were compared with the outcome from 20 consecutive patients treated in our institution with the historic EORTC ALL-4 adults protocol from 1998 to 2001.
Results: All the clinical (age, WHO performance status, gender) and biological (WBC, phenotype, cytogenetic) parameters of patients treated in FRALLE protocol were statistically similar with those of patients treated in ALL-4 adults protocol. CR rate was achieved in 82% of patients after FRALLE induction, and 100% after a salvage therapy with high doses cytarabine. The good early response was evaluated by cortico-sensitivity and chemo-sensitivity (after 14 days of chemotherapy). All patients who achieved cortico and chemo-sensitivity were alive in persistant CR, with a better survival than other patients (p=0.008) (fig1). When we compared patients treated by FRALLE or ALL-4 protocol, the 4-years DFS and OS are 90% +/−6% vs 47%+/−12%, (p= 0,01) and 83%+/−9% vs 35%+/−16%, (p=0,05) respectively (figures 2 and 3). This better outcome is not explained by significant differences in patients characteristics nor by a better CR rate but rather by a lower relapse rate in the pediatric treatment group. This indicates a major role of the dose intensity, especially for L-asparaginase, corticosteroid, methotrexate, and purinethol. No treatment related mortality and no severe side effect, except one pulmonary embolism, were observed during treatment with supportive cares including parenteral nutrition, granular growth factor, infectious prophylaxis, and antithrombine III infusions. This pilot study shows that adults up to 57 years with Ph negative-ALL have a dramatically better outcome when there are treated with childhood ALL protocol without any major side effect. This therapeutic strategy has to be confirmed by the current prospective study performed by the EORTC/HOVON group.
Figure Figure