bluuebunny/crossref_metadata_2025_split huggingface dataset:
Myeloma Cell-Derived Factors Retard the Differentiation and Function of Dendritic Cells.
Authors: Yi Qing , Wang Siqing , Xie Jin , Qian Jianfei , Yang Jin , Freeman Muta E. , Barlogie Bart 
Published: October 2019

Abstract
Multiple myeloma (MM) is a B-cell malignancy often associated with a suppressed immune system. The mechanisms for the immunosuppression are largely unknown. In this study, we examined, using the murine 5T33 myeloma model, the effects of tumor cell or its-derived factors on the differentiation and function of bone marrow-derived dendritic cells (BMDCs). Our results showed that differentiation of BMDCs was retarded in the presence of 10% of tumor-derived supernatant (TSN). This is evident by, compared with control cells, the downregulated expression of surface molecules including CD40, CD86 and MHC class II; secretion of higher levels of IL-10 and lower levels of IL-12; and a poor T-cell response in an allogeneic mixed lymphocyte reaction induced by TSN-treated cells. The same phenomenon was also observed when the bone marrow progenitor cells were cocultured, either in direct contact or separated by transwell membrane, with myeloma cells. The treatment downregulated the expression of phosphorylated extracellular signal-related kinase (ERK) and mitogen-induced extracellular kinase (MEK), and upregulated the expression of phosphorylated p38 mitogen-activated protein kinase (p38 MAPK) and signal transducer and activator of transcription-3 (STAT3) in the cells. As a high level of interleukin (IL)-10, IL-6, vascular endothelial growth factor (VEGF) and transforming growth factor (TGF)-b can be detected in TSN, we examined whether these cytokines were responsible. Our results showed that addition of TGF-b, IL-10 and/or IL-6 could largely replace TSN in retarding the differentiation of BMDCs, and neutralizing antibodies against these cytokines, especially in combination, were able to block the effects of TSN or tumor cells on BMDCs. Finally, our results showed that inhibiting p38 MAPK or STAT3 restored the differentiation and function of these cells. Hence, our study not only sheds light on the mechanisms of tumor-induced immune evasion in MM and but also provides one of the solutions to overcome the problems.
Identification and Characterization of an ALK Inhibitor That Attenuates the Proliferation and Survival of Anaplastic Large Cell Lymphoma-Derived Cell Lines and ALK Dependent Cell Lines.
Authors: Cheng Mangeng , Wan Weihua , Albom Mark , Weinberg Linda , Angeles Thelma , Quail Matthew , Lu Lihui , Underiner Ted , Hudkins Robert , Ator Mark , Ruggeri Bruce 
Published: October 2019

Abstract
Anaplastic large cell lymphomas (ALCLs) are a unique subgroup of high grade non-Hodgkin lymphomas. Approximately 60% to 70% of ALCLs contain a t (2:5) (p23; q35) chromosomal rearrangement, generating the nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) fusion protein. NPM-ALK encodes a constitutively activated tyrosine kinase that has been demonstrated to be directly involved in the pathogenesis of ALCLs. Currently there is no optimal therapeutic regimen for ALK positive ALCLs. Even with high dose CHOP (cyclophophamide, doxorubicin, vincristine and prednisone)-based chemotherapy, a substantial number of patients with ALK positive ALCLs have very poor outcome, either failing to enter remission or relapsing within a few months from the start of treatment. This prompted a search for small molecule ALK inhibitors as potential therapeutic agents for these patients. In this report, we describe the identification and characterization of a potent small molecule ALK inhibitor, cmpd-1. Cmpd-1 inhibited the ALK kinase activity in an in vitro enzymatic assay with an IC50 value of 4 nM. In NPM-ALK transfected BaF3 cells and ALCL-derived cell lines, cmpd-1 potently inhibited the tyrosine phosphorylation of NPM-ALK with a cellular IC50 value of 10–30 nM. Treatment with cmpd-1 inhibited IL-3 independent proliferation of BaF3 cells expressing constitutively active NPM-ALK (more than 95% inhibition at 100 nM) and the addition of IL-3 rescued the growth of these cells, while cmpd-1 had little effect on the parental BaF3 cells. Inhibition of NPM-ALK activity by cmpd-1 in ALK positive ALCL-derived cell lines, Karpas-299, Sudhl-1, Sup-M2 and Sr-786, resulted in inhibition of cell proliferation (50–90% inhibition at 100–300 nM) and induction of apoptotic cell death, while having marginal effects on the proliferation and survival of K562, an ALK negative leukemia cell line. These data suggest that the inhibition of cell proliferation and induction of apoptosis by cmpd-1 is an ALK-dependent event. Several putative downstream targets of NPM-ALK, including ERK1/2, Stat3 and Akt, were hypo- or unphosphorylated when the ALK positive cells were treated with cmpd-1. With the potent ALK inhibitory activity, cmpd-1 can be used as a molecular and pharmacological tool to study the biological roles of ALK and to dissect ALK-mediated signaling pathways in ALCLs and possibly other tumor types in which ALK is implicated in their pathogenesis.
Preliminary Safety and Efficacy Report of a Randomized Trial of Alemtuzumab vs Chlorambucil as Front-Line Therapy in 297 Patients with Progressive B-Cell Chronic Lymphocytic Leukemia.
Authors: Hillmen Peter , Skotnicki Aleksander B. , Robak Tadeusz , Mayer Jiri , Jaksic Branimir , Vukovic Vojo , Weitman Steven 
Published: October 2019

Abstract
CAM307, a Phase III, open-label, international, randomized trial comparing the efficacy and safety of alemtuzumab (CAMPATH®, MABCAMPATH®) with chlorambucil in B-CLL. Untreated Rai stage I-IV B-CLL patients with evidence of progressive disease were randomized 1:1 to intravenous alemtuzumab 30 mg three times a week for a maximum of 12 weeks or oral chlorambucil 40 mg/m2 once every 28 days, up to a maximum of 12 cycles. Patients with autoimmune thrombocytopenia, prior bone marrow transplant, active infection, positive CMV by quantitative PCR assay, secondary malignancy or CNS involvement were excluded. All alemtuzumab patients received prophylaxis with cotrimoxazole (trimethoprim/ sulfamethoxazole DS) and famciclovir during treatment and after completion of therapy until CD4+ counts were ≥200 cells/μL. The primary endpoint for the trial is progression free survival; secondary endpoints include safety, overall survival and response rate. Patient recruitment has been completed, and demographic data are available for 297 patients (213 males, 84 females; median age 60 years; 67% Rai I/II; 33% Rai III/IV). AEs occurring in >10% of alemtuzumab patients included pyrexia, rigors, dermatitis, urticaria, headache, hypertension, hypotension (“infusion reactions”), CMV antigen reactivation, nausea and neutropenia. In chlorambucil patients, AEs occurring in >10% of patients included nausea and vomiting. A total of 7 deaths have been reported, 2 in the alemtuzumab arm and 5 in the chlorambucil arm. Two deaths in the chlorambucil arm were related to study drug. Symptomatic CMV reactivations have been tracked by investigator reports. Preliminary analysis indicates that 22 of 149 (15%) patients treated with alemtuzumab developed symptomatic CMV reactivation. In 14 of 22 (64%) cases, mild to moderate fever was the only clinical symptom. All symptomatic CMV reactivations resolved promptly with ganciclovir and most patients were able to complete alemtuzumab therapy per protocol. No symptomatic CMV reactivations have been reported in the chlorambucil arm. No deaths due to CMV have been reported. Preliminary efficacy results on approximately 100 patients that have completed 12 months of follow-up following start of treatment and were reviewed by an independent committee will be presented at the meeting. This randomized Phase III trial demonstrates that alemtuzumab as first line therapy has an acceptable toxicity profile compared to chlorambucil. Therefore, this trial will address whether treatment with alemtuzumab as front line therapy results in greater disease reduction than conventional treatment in B-CLL and whether this strategy confers a survival advantage compared to standard approaches.
MLL Partner Gene Domains Contribute Critical Functional Specificity to Immortalization and Differentiation of Hematopoietic Progenitors.
Authors: Santillan Donna A. , Ryan Amanda S. , Zeleznik-Le Nancy J. 
Published: October 2019

Abstract
The in-frame fusion of MLL (mixed-lineage-leukemia) to CBP (CREB binding protein) has been cloned from several patients with therapy-related AML with a t(11;16)(q23;p13). In a murine retroviral transduction model of MLL-CBP, the mice develop a preleukemic phase which evolves to myeloid leukemia, reminiscent of what is seen in patients with the t(11;16). From this work, it was determined that the amino terminus of MLL fused to the bromodomain and HAT domain of CBP are minimally necessary for transformation. To better understand the role of the CBP bromodomain and HAT domain in determining the characteristics of the leukemia, we have undertaken domain-swapping experiments. In the context of the MLL-CBP (bromodomain + HAT domain) fusion, we have replaced the bromodomain of CBP with either the bromodomain from PCAF or the double bromodomain from TAFII250. The HAT domain of CBP has been replaced with either the HAT domain from PCAF or that from GCN5. We are studying the immortalization and differentiation potential of retrovirally transduced hematopoietic precursors in vitro and in vivo. We have observed differences in the ability of the various domain-swapped constructs to immortalize murine bone marrow progenitors in vitro. The PCAF HAT domain can substitute for the CBP HAT domain such that bone marrow progenitor cells have an enhanced proliferative capacity when grown under myeloid differentiation conditions. In contrast, bromodomain-swapped constructs do not grow under these same conditions. In vivo, mice reconstituted with hematopoietic precursors that were transduced with the bromodomain swapped are developing a disease that is different from that seen in mice reconstituted with MLL-CBP transduced hematopoietic precursors. However, mice reconstituted with cells retrovirally transduced with the HAT domain swapped appear to be developing a disease similar to that seen with MLL-CBP. These results suggest an important role for the bromodomain of CBP in determining the phenotype of MLL-CBP related leukemia. Additionally, MLL-CBP (bromodomain + HAT domain) cell lines undergo a phenotypic change when grown in vitro on stromal cells that promote B cell differentiation. This result implies that immortalized cells are not completely restricted in their differentiation potential.
Fatal Pulmonary Embolism and Cancer - a Post Mortem Study.
Authors: Cohen Alexander T. , Weston Gabriel J. , Tasker Andrew J. , Fellows Greg A. , Wilmott Rosalind 
Published: October 2019

Abstract
Introduction: During the period of 1965–1990 and 1991–2000, two separate analyses were carried out at King’s College Hospital, London, taking a retrospective review of all autopsy reports during this time. The initial aims of these reviews were to determine the number of deaths from autopsy-confirmed fatal pulmonary embolism (FPE) in hospitalised patients, and the clinical characteristics of these patients.
Methodology: Cases for inclusion were identified and data derived from manually examining copies of post-mortem reports. The data form recorded the patient gender, age, race, height, weight and surgical status. In addition, evidence of DVT, myocardial infarction (MI), stroke, chronic obstructive pulmonary disease (COPD), cardiac failure, infection or cancer was recorded from the autopsy report. Cases of fatal PE were classified as occurring in either surgical (if death occurred within 8 weeks of surgery), or non-surgical patients. The outcome of fatal pulmonary embolism was recorded as the cause of death only when the post-mortem stated that embolism was the main or contributing cause of death and identified emboli present either in the main pulmonary trunk or in the proximal right or left pulmonary arteries formed from the bifurcation of the main trunk. Emboli found in the distal pulmonary arteries after further division of the right and left pulmonary arteries were not included. Emboli derived from bone marrow, fat, tumour, or amniotic fluid were also excluded from the analysis. Ethical approval for the study was obtained from the local research ethics committee. The identity of deceased patients was protected by the use of code numbers on the data forms.
Results: Over the 35 year period there were 45,575 hospital deaths and 16,862 (37%) post-mortems. FPE was recorded as cause of death in 1,040 (6.2%) adult patients. Of these 85% (n=885) were in non-surgical patients, and 15% (n=155) in post-operative patients. Of the fatal pulmonary emboli, 347 of 1040 (33%) had either cancer (active malignancy) or a past history of cancer. Of this cancer group, 93% (n= 323) had an active malignancy, with 7% (n= 24) giving a past history of cancer. Cancer sites were gastro-intestinal in 34% (n= 119), lung 24% (n= 82), urological 10% (n= 33), gynaecological 8% (n= 29) and breast 8% (n= 28), 5% haematological (n= 17) endocrine 5% (n= 16), and dermatological 1% (n= 3). The majority of active cancers were found within the peritoneal cavity (60%, n= 194). Infection was the additional risk factor that was most prevalent in all those with FPE occurring in 32% (n=334), 76.3% (n=808) had one or more additional risk factors.
Conclusions: Most fatal pulmonary emboli occur in non-surgical patients, cancer is a very common association (33%). Active cancer is seen in 93% of all FPE deaths associated with cancer. Intra-peritoneal cavity tumours are the commonest type to be associated with FPE. Infection is a common associated risk factor.
Improved Leukemia-Free Survival after Post-Consolidation Treatment with Histamine Dihydrochloride and Interleukin-2 in AML: A Randomized Phase III Trial.
Authors: Brune Mats , Castaigne Sylvie , Catalano John , Gehlsen Kurt , Hofmann Wolf-Karsten , Ho Anthony , Hogge Donna , Nilsson Bo , Or Reuven , Rowe Jacob , Simonsson Bengt , Spearing Ruth , Stadtmauer Edward , Szer Jeff , Wallhult Elisabeth , Hellstrand Kristoffer 
Published: October 2019

Abstract
Background: Histamine dihydrochloride (HDC) potentiates immune-based therapies by protecting pivotal anti-neoplastic lymphocytes from phagocyte-induced suppression. Previous results in AML indicated that post-consolidation treatment with HDC and low-dose interleukin-2 (IL-2) is safe and feasible, and that the combination may prolong leukemia-free survival (LFS).
Aims: The primary objective was to determine if post-consolidation treatment with IL-2 and HDC could improve LFS for AML pts in complete remission (CR). Secondary objectives included overall survival (OS), LFS in CR1 and CR>1 subgroups, and safety.
Methods: This international, randomized, open-label, phase III study was conducted at 92 centers. From June 1998 to October 2000, 320 AML pts [148 females, 172 males, median age 57 (18–84) yrs] were enrolled in CR after completion of standard consolidation therapy. Pts were stratified by CR1 or CR>1 and randomized to either treatment (n=160) or no treatment (control, n=160) arms. The treatment was self-administered at home and included 10 cycles of low-dose IL-2 (aldesleukin, Chiron Corp) 18 000 U/kg, sc bid plus HDC (Maxim Pharmaceuticals) 0.5 mg sc bid. For cycles 1–3, each cycle comprised 3 wks of treatment and 3 wks of rest, whereas in cycles 4–10 the rest periods were 6 wks. The study arms were well balanced with respect to age, sex, karyotype-based risk, time from CR to inclusion and frequency of secondary leukemia. Pts were followed for relapse and survival using an identical assessment schedule until 3 yrs after last enrollment. All efficacy analyses were intent-to-treat.
Results: The median follow-up of living pts was 46 months. For the primary endpoint, treatment with HDC/IL-2 increased LFS in the entire study population (CR1/CR>1, n=320, p=0.026 stratified log-rank test). There was no significant difference in OS (p=0.33). In the analysis of pre-stratified subgroups, one pt was excluded. For CR1 pts (n=262), HDC/IL-2 significantly improved LFS (p=0.011, log-rank test), with 3-year Kaplan-Meier estimates of 26% (control group) and 40% (treatment group). The difference in OS did not reach significance (p=0.16). For CR>1 pts (n=57), outcome was not affected by treatment. Side effects attributable to IL-2 included fever and local inflammatory reactions. HDC treatment induced symptoms of transient vasodilatation. Serious adverse events occurred in approximately 20% of pts in both groups. There were no treatment-related deaths.
Conclusions: For AML pts in CR, post-consolidation therapy with HDC and IL-2 was safe and significantly improved LFS compared to standard of care. The benefit observed of HDC/IL-2 treatment appears to be explained by a reduction of relapses in CR1 pts.
Human Atheromatous Plaques Stimulate Thrombus Formation by Activating Platelet Glycoprotein VI.
Authors: Reininger Armin J. , Brandl Richard , Penz Sandra , Goyal Pankaj , Rabie Tamer , Rother Enno , Goetz Christine , Engelmann Bernd , Farndale Richard , Nieswandt Bernhard , Siess Wolfgang 
Published: October 2019

Abstract
Lipid-rich atherosclerotic plaques are vulnerable, and upon disruption trigger intraarterial thrombus formation. Tissue factor activating blood coagulation is viewed as the major prothrombotic stimulus within the plaque. We isolated lipid-rich atheromatous plaques from 50 patients with carotid artery stenosis and identified morphologically diverse collagenous structures within in the plaques. They stimulated platelet adhesion, dense granule secretion and aggregation, and triggered thrombus formation in hirudin-anticoagulated blood under arterial flow conditions. Even in fully anticoagulated flowing blood, i.e. in the absence of tissue factor-mediated coagulation, plaques were able to activate platelets. Thrombus formation was more rapid and stable when blood was anticoagulated with a low concentration of heparin, but, although fibrin was detectable within the thrombus, the initial step was always single platelet adhesion and not fibrin formation. In contrast, absence or inhibition of the platelet collagen receptor glycoprotein VI prevented platelet adhesion to atheromatous plaques and thrombus formation. We thus identified platelet glycoprotein VI as being essential and sufficient to mediate plaque-induced thrombus formation. Our study suggests a novel anti-thrombotic strategy to prevent and treat atherothrombosis in patients with vulnerable atherosclerotic plaques.
Figure Figure
Cannabinoids Inhibit the CXCL12-Induced Migration of T Lymphocytes.
Authors: Ghosh Sharmistha , Ganju Ramesh K. , Groopman Jerome E. 
Published: October 2019

Abstract
Cannabinoids are both exogenous compounds produced by Cannabis sativa, known for their psychoactive properties, and a family of related endogenous ligands whose functions have been recently characterized. The reported effects of cannabinoids on the immune system include inhibition of T lymphocyte proliferation, altered production of cytokines by T helper cells and decreased antibody formation by B cells. Cannabinoid receptors have been detected in several immune cells, including monocytes, macrophages, basophils and B and T lymphocytes. CB2 (Cannabinoid Receptor 2) appears to be the predominant cannabinoid receptor in the immune system, while the CB1 receptor is found primarily in the brain. We observed high levels of CB2 expression in the Jurkat T lymphocyte cell line, while others have reported expression of the CB2 receptor in CD8+ T lymphocytes. Here, we studied the ability of synthetic and endogenous cannabinoids to modulate a key function of T lymphocytes: chemotactic migration in response to the chemokine CXCL12 (also known as stromal cell-derived factor-1). We observed a 40–50% inhibition of CXCL12-induced chemotaxis in Jurkat T cells with the endogenous cannabinoid anandamide (at 15 μM concentration) and with the synthetic cannabinoids CP55,940 and Win-55,212–2 (each at 10 μM concentration). Inhibition occurred in a dose-dependent manner, indicating that it is a regulated, receptor-mediated process. Further studies showed that the inhibition of migration involved, in part, significant down-regulation of the CXCL12 receptor, CXCR4. We are currently elucidating the signaling cascade whereby endogenous cannabinoids may limit T cell migration in response to CXCL12. Thus, cannabinoids may be novel mediators of immunosuppression when clinically desired.
Stromal Cell-Derived Factor (SDF-1) Mediates Stem Cell Mobilization and Homing to the Kidney after Acute Renal Failure.
Authors: Toegel Florian E. , Isaac Jorge , Hu Zhuma , Weiss Kathy , Westenfelder Christof 
Published: October 2019

Abstract
The chemokine stromal cll-derived factor-1 (SDF-1) and its receptor CXCR4, expressed by hematopoietic stem cells (HSC) and other cells, represents a major mediator-system for G-CSF-induced hematopoietic stem cell (HSC) mobilization and stem cell (SC) homing to the bone marrow (BM) after BM transplantation. HSC have been shown to contribute to repair processes in kidneys damaged by ischemia and HSC as well as endothelial progenitor cells (EPC) are mobilized in response to kidney damage. The signals mediating this process are currently unknown. We tested the hypothesis that SDF-1 mediates both mobilization and homing of SCs into the kidney with acute renal failure (ARF) and may thus be crucial to SC-mediated organ repair. SDF-1 is expressed in normal kidneys and upregulated in ischemically injured (60 min bi- or unilateral renal pedicle clamp) mouse kidneys (FVB strain) as evaluated by immunohistochemistry, in-situ hybridization, quantitative RT-PCR and ELISA. Post ARF SDF-1 was upregulated in sublethally injured proximal tubular cells (PTC), peripheral blood levels of SDF-1 rose, and circulating CD34+ and Colony-forming Units of Cell numbers as well as EPCs increased significantly. In vitro chemotaxis of SC from the top of transwell inserts towards the bottom well, containing cultured PTC that exhibited augmented SDF-1 expression post partial ATP depletion, increased significantly, a response that was abolished when SC cells were preincubated with CXCR4 antibody. Injected, CFDA-labeled, BM cells were only recruited to ischemic kidneys (bi- or unilateral), a response that was also blocked after SC pre-incubation with CXCR4 antibody. Our data show that there is increased renal SDF-1 expression after ARF and secretion into the circulation, which, in turn, stimulates HSC and EPC-mobilization into the circulation and directs homing into the post-ischemic kidney. Therefore, both circulating and administered SC and other CXCR4-expressing cells can be recruited to the injured kidney, where they, as we showed previously, are able to greatly support effective tissue repair, functional recovery and animal survival following ARF.