bluuebunny/crossref_metadata_2025_split huggingface dataset:
The MyD88 Adapter-Like (Mal) Protein Variant Leu 180, a Candidate Polymorphism for Protection Against Graft Versus Host Disease.
Authors: Holtick Udo , Middleton Peter G. , Harrold Jane L. , Holler Ernst , Gluckman Eliane , Hromadnikova Ilona , Dickinson Anne M. , Collin Matthew P. 
Published: October 2019

Abstract
The involvement of mediators of the innate immune response in immunological processes after allogeneic haematopoietic stem cell transplantation (HSCT) has been an important finding. Toll-like receptor (TLR) signalling plays a key role in the innate response to pathogens. The MyD88 adapter-like (Mal) protein is involved in TLR 2, 4 and 9 signalling. A polymorphism leading to a non functional variant (Ser → Leu 180) has been reported to be protective in cerebral malaria due to a reduced inflammatory response (O’Neill LA, ASH 2005). A dominant negative form of Mal inhibits NFκB activation by TLR-4 and LPS (Fitzgerald KA, Nature 2001). As bacterial products like LPS are believed to contribute to initiation and maintenance of graft versus host disease (GvHD), we hypothesised that one or two non functional Mal variants (Ser → Leu 180) present in donor or recipient cells might reduce the incidence of GvHD and improve survival after allogeneic HSCT.
163 donor recipient sibling pairs transplanted with full or reduced intensity conditioning without T depletion were identified from the Eurobank database. DNA was amplified using allele specific PCR primers: allele 1 (Ser)5′ CACCATCCCCCTGCTGTC; allele 2 (Leu) 5′ CACCATCCCCCTGCTGTT; reverse 5′ TGACGAAAGCCATCAG. The allele frequency was: allele 1 (Ser) 0.84; allele 2 (Leu) 0.16. There were no significant differences between the cohorts in age, gender mismatch, immunosuppression, conditioning or transplant center. The overall incidence of acute and chronic GvHD was reduced (83 vs 75% and 63 vs 52% respectively), when both donor and recipient possessed allele 2 (p=0.247 and p=0.155). A similar trend could be seen when the donor alone had at least one uncommon allele. The 5 year projected survival was not different for patient/donor pairs for any given combination of alleles.
To further test the functional relevance of the Mal polymorphism, PBMCs from 33 Donor/Recipient pairs were stimulated with LPS or PHA and TNFα levels were analysed after 24h and 72h respectively. After LPS stimulation the median TNFα levels were lower when one or two uncommon alleles were present (1871 vs 1774 vs 988 pg/ml; p=0.9 and p=0.178). PHA stimulated cells also showed lower median TNFα levels, approaching statistical significance for the combined group carrying at least one uncommon allele (6656 vs 5173 pg/ml, p=0.085) and being statistically significant when two uncommon alleles were present (6656 vs 1495 pg/ml, p=0.031).
We conclude that the presence of a non-functional Mal variant especially in donor cells may reduce the incidence of acute and chronic GvHD, although this did not reach statistical significance in this group of patients. There was no impact on survival. A larger cohort is currently being investigated.
High Alloreactive Potential of Central Memory T-Lymphocytes Expressing a Suicide Gene for the Cure of Hematologic Malignancies.
Authors: Kaneko Shin , Mastaglio Sara , Bondanza Attilio , Ponzoni Maurilio , Aldrighetti Luca , Toma Salvatore , Radrizzani Marina , La Seta Catamancio Simona , Ciceri Fabio , Nagasawa Toshiro , Bordignon Claudio , Bonini Chiara 
Published: October 2019

Abstract
Alloantigen targeting adoptive immunotherapy is a powerful therapeutic approach for the treatment of hematologic malignancies. A compelling example is represented by donor lymphocyte infusions after allogeneic hematopoietic stem cell transplantation. The clinical efficacy of T-cell based therapy relies not only on the ability of T cells to mediate a direct anti-tumor effect (GvT) and a protective immune response against pathogens, but also in their capacity to persist and expand in vivo, providing a long-term protection from disease relapse. Despite undeniable efficacy, the extensive exploitation of donor lymphocytes is limited by the risk of a severe and potentially life-threatening complication: Graft-versus-host disease (GvHD). To solve this double bind, we investigated the therapeutic potential of donor lymphocytes retrovirally transduced to express the suicide gene thymidine kinase of Herpes Simplex virus (TK) in patients affected by hematologic malignancies, and showed that the suicide machinery controls severe GvHD. To maximize the extent and persistence of GvT activity mediated by TK cells, we exploited the positive effects of IL-7 in maintaining the homeostasis of memory lymphocytes. We observed that while stimulation with anti-CD3 antibodies and culture in the presence of high doses of IL-2 generates mainly CD45RA−CD62L− effector memory (EM) TK cells with a limited ability to engraft and persist in vivo, stimulation with anti-CD3/CD28 conjugated cell sized beads and culture with low doses of IL-7 result in the generation of CD45RA−/CD62L+ TK cells with central memory (CM) functional phenotype, producing high levels of IL-2 upon stimulation, and expressing persistent high levels of IL-2R alpha and IL-7R alpha, a molecule associated to activation and long term survival memory T-cells, respectively. In mixed lymphocytes cultures (MLR), CM TK cells showed higher proliferative potential and lower sensitivity to apoptosis than EM TK cells, and such alloreactive CM TK cells kept CCR7 and IL-7R alpha expression even after 2ndary MLR. Accordingly, CM cells were more potent than EM cells in mediating allogeneic GvHD, after infusion in NOD/Scid mice, previously transplanted with allogeneic human skin. Newly developed homeostatic CM TK cells combine a high alloreactive potential with the selective sensitivity to GCV-mediated cell death, providing a tool for maximal anti-tumor activity with control of GvHD.
Pulmonary Embolism in Cancer Patients Is Associated with Lower Severity of Illness and Lower Mortality Rates with Increasing Use of CT Scans.
Authors: Villaruz Liza C. , Dang Qianyu , Ragni Margaret V. 
Published: October 2019

Abstract
Pulmonary embolism (PE) is a major cause of morbidity and mortality in patients with cancer (CA). However, predicting which CA patients will develop PE is not possible and thromboprophylaxis is infrequently used. In order to define the incidence and clinical characteristics of CA patients with PE, we analyzed discharge data from all patients with PE collected by the Pennsylvania Health Care Cost Containment Council (PHC4) from 1997–2001. The analyses included all PE discharges with ICD-9 codes 415.11 and 415.19, excluding pregnant patients and all second or later PE admissions. Cancer diagnoses were enumerated by ICD-9 codes 140–239 and diagnostic procedures by revenue codes for computerized tomographic (CT) (including spiral CT) scans. Of 33,036 PE patients identified in this period, one-quarter had cancer, among whom PE incidence increased marginally, from 1,589 (24.0%) in 1997 to 2,262 (25.4%) in 2001, p = 0.072. CA patients were more likely to be Caucasian, OR 1.22, p<0.001, greater than 70 years of age, OR 1.16, p<0.001, and male, OR 1.19, p<0.001. CA of the lung was the most common CA type associated with PE, 1150 (17.7%), followed by CA of the digestive tract, 1150 (17.4%); genitourinary tract, 832 (12.6%); and lymphatic/hematopoetic tissues, 771 (11.7%). CT scans were performed with increasing frequency in CA PE patients, from 27.7% in 1997 to 50.0% in 2001, p < 0.001, and more frequently in Caucasians than in blacks, OR =1.61, p<0.001, and in those 70 years or younger, OR =1.91, p<0.001. At the same time, MediQual Atlas severity of illness scores decreased over time, from a mean 2.6 in 1997 to 2.3 in 2001, p<0.001, with a significant decrease in the two higher categories, 65.8% vs. 38.1%, and an increase in the three lowest categories, 34.2% to 61.9%, p<0.001. CA patients were less likely than non-CA patients to have other risk factors for PE, i.e. trauma, 3.7% vs. 8.1%, p< 0.001, or congestive heart failure, 12.9% vs. 20.8%, p<0.001. Although CA patients had higher mortality rates than non-CA PE patients, OR 1.86, p<0.001, these rates decreased from 23.3% in 1997 to 18.6% in 2001, p<0.001. In conclusion, patients with cancer account for one fourth of all PE, and they are typically elderly Caucasian males with cancer of the lung or digestive tract. The increasing use of CT scans in this group is associated with lower severity of illness scores and decreasing mortality rates, which suggest PE may be diagnosed earlier. Consideration of early thromboprophylaxis among CA patients at risk for PE may improve health outcomes.
Inflammatory Disease Associated Gene Polymorphisms Detected in Patients with Chronic Graft-vs-Host Disease.
Authors: Shimada Masako , Onizuka Makoto , Oba Taku , Ogawa Yosiaki , Kawada Hiroshi , Miyamura Koichi , Hotta Tomomitsu , Kodera Yosihisa , Inoko Hidetoshi , Ando Kiyoshi 
Published: October 2019

Abstract
Chronic graft-vs-host disease (cGVHD) is the most serious and common long-term complication of allogeneic hematopoietic stem cell transplantation(HSCT). Incidence of cGVHD is 20% to 70% of recipient surviving more than 100days after HSCT. cGVHD most commonly affects the skin, liver, eyes, lung, or the mouth, while multiple other sites may also be affected. Similarities of clinical features of cGVHD and several inflammatory diseases and auto-immune diseases have been commonly observed. Autoantibody formation has also been noted in experimental models of cGVHD, although the pathogenetic role of antibodies in cGVHD is still poorly defined. Both donor and host factors contribute to the pathogenesis of GVHD. While the most important determinant is the compatibility of HLA, non HLA genetic associations with cGVHD have not been extensively studied. Therefore we investigated a relationship between cGVHD and well known inflammatory disease associated gene polymorphisms. We analyzed 100 pairs of Japanese HLA-matched sibling recipients and donors who underwent HSCT in Japanese Red-cross Nagoya First hospital(1990–2001). We examined SNPs, Fc receptor-like3 (FCRL3), programmed cell death 1(PDCD1), peptidyl arginine deiminase(PADI4), solute carrier family 22 memberA4(Slc22A4), and DLG5 by PCR-SSO methods or TaqMan assays, and analyzed correlation between these gene polymorphisms and clinical feature of cGVHD. Statistical analysis were done by using Fisher’s exact probability test.
So far FCRL3-169T allele has been correlated with high incidence of cGVHD(p=0.017). Especially, 18 patients out of 37 who has been occurred extensive cGVHD have -169T/T genotype. On the other hand, there is no relationship between cGVHD and FCRL3 SNP in donors. Our result is FCRL3 -169T allele has been correlated with incidence of cGVHD. FCRL3 is one of a new family genes of FCγ receptor II/III, and is located at chromosome 1q21-23 which is the regions implicated in susceptibility to multiple autoimmune disease. FCRL3 has high structural homology with classical FCγreceptor, although it’s ligands and function are not yet known. Contrary to our result, FCRL3 -169C allele is disease-susceptible allele to inflammatory disease. Since the expression of FCRL3 are detected in the germinal center in spleen and tonsils, residual host B cells or other types of cells expressing the gene might be involved in pathogenesis of cGVHD. This study is the first to report the relationship between cGVHD and inflammatory disease associated gene polymorphisms in hosts.
Bronchiolitis Obliterans Syndrome after Hematopoietic Stem Cell Transplantation: A Retrospective Multicenter Survey of the Late Effect Working Party EBMT.
Authors: Arat Mutlu , Socié Gérard , Passweg Jacob R. , Caballero Dolores , Ljungman Per T. , Bonifazi Francesca , Kumbasar Ozlem O. , Fernandez A.O. , Broeters D. , Guidi Stefano , Greil J. , Zander Axel R. , Tichelli Andre , Bekassy Albert N. 
Published: October 2019

Abstract
Aim and Scope: Substantial morbidity and mortality is caused by respiratory complications in 40–60% of patients after HSCT. Bronchiolitis obliterans syndrome (BOS) is reported in 2–13% of patients, occurring within 6–12 months post transplant. The LEWP launched a retrospective survey in 2003 to document the incidence, current practice for the diagnosis, clinical work-up and treatment of BOS after allogeneic HSCT.
Patients&Method: Between 2003 – 2005, 31 centers reported 226 patients with BOS. Adjusted BOS criteria were accepted (normal spirometry pretransplant, respiratory symptoms in the absence of an infection and combination of 3/4 items at onset: FEV1 <80% predicted/measured; FEV1/FVC <80% and MMFR <50% predicted/measured and residual volume >120%; HR CAT scan of the thorax. FOB and BAL were used in 60% of centers, but open lung bx.was not recommended by 75%.
Results: The median age of the patients was 30.9 years (1–62) and 19% was pediatric. The donors were 64.6% siblings. HSCT indication was hematological malignancy in 92.3% (37% AL, 21% CL). The graft source was BM in 60% and PBSC in 39%. The preparative regimen was myeloablation in 85.8%. The majority of the patients had antecedent GVHD (acute 66%, chronic 89%). The median interval from transplant to onset of BOS was 11.7 mo.s (1–260). Two third of the patients are still alive (22% in remission and 70% still receiving therapy). Median survival is 39.5 mo.s (1–277). The main reasons for high mortality rate are BOS (69%), relapse (15%) and GVHD (14%). The results of the univariate analysis on KM curves are summarized in Table 1.
Conclusion: Univariate data showed a negative impact of male gender, early onset (<11.7 mo.s) and MUD transplants. BOS is still an important cause of non-relapse late morbidity and mortality. Diagnosis and treatment are difficult and heterogeneous. The final analysis with multivariate methods should validate current results.
Variables tested in univariate analyses Variables Med. OS, months (95% CI) P NR: not reached Sibling/MUD NR 75.9 (28.1–123.6) 043 Male/Female 72.5 (47.6–97.4) NR 0.038 Onset: Early/Late 59 (33.3–84.8) NR 0.00001 Ablative/Non Ablative 102.8 (67.7–137.9) NR 0.191
AKT Kinase Addiction in Multiple Myeloma.
Authors: Bardeleben Carolyne , Yan Huajun , Frost Patrick , Hoang Bao , Shi Yijiang , Sharma Sanjai , Lichtenstein Alan 
Published: October 2019

Abstract
Cancer cells with activating kinase mutations are singularly hypersensitive to drugs that target these kinases, a phenomenon referred to as kinase or oncogene addiction. Although the AKT kinase is not known to be mutated in multiple myeloma (MM), it is frequently hyperactivated due to mutations in upstream signaling proteins. Previous work indicated that MM cells with heightened AKT activity were hypersensitive to drugs targeted to mTOR, a downstream substrate of AKT, suggesting an addiction to this pathway. “Kinase addiction” would theortically render the cell dependent on the kinase for growth. This dependency implies that other cascades of viability and/or proliferation may become downregulated subsequent to kinase activation. To test for AKT kinase addiction in MM we stably transfected the U266 MM cell line that is known to be protected against apoptosis by an autocrine Il-6/IL6R pathway (Caitlett-Falcone et al., Immunity 10, 105–115, 1999) with a constitutively active AKT construct (U266-AKT). AKT-transfected MM cells were protected against fas-induced apoptosis even when the autocrine IL-6 protective pathway was paralyzed by anti-IL6 and anti-IL6 receptor antibodies. However, as expected for an AKT addicted cell line, the U266-AKT cell line was more sensitive to agents that target the PI3/AKT/mTOR pathway, including two AKT inhibitors and the PI3K inhibitors LY294002 and wortmanin in terms of increased level of apoptosis and/or growth inhibition in comparison to the control U266 cell line. This “kinase-addicted” state was associated with down regulation of several components of the autocrine anti-apoptotic pathway of U266 cells. Expression of IL6, the IL6 receptor subunits gp80 and gp130 and STAT3 were all markedly silenced following AKT transfection. This down regulation of the survival pathway was relatively specific as expression of the fas receptor and VEGF receptors were relatively unaffected. The decrease in protein expression was also reflected in the decrease of mRNA for the receptor subunits, suggesting a transcriptional mechanism for down regulation. As expected from the decrease in autocrine IL-6 signaling, AKT-transfected cells also demonstrated a marked inhibition of Jak1 and MAPK 42/44 phosphorylation and enzymatic activity. In summary, over expression of activated AKT results in an AKT-addicted state whereby the MM cell becomes dependent on AKT for survival as other growth-promoting and anti-apoptotic cascades become paralyzed. These data support AKT as an important target for therapeutic intervention of MM and suggest such therapy would be most successful in patients whose MM cells contain the highest amount of activated AKT.
Biological Pathways and In Vivo Anti-Tumor Activity Induced by Atiprimod in Multiple Myeloma (MM).
Authors: Neri Paola , Tassone Pierfrancesco , Shammas Masood , Yasui Hiroshi , Schipani Ernestina , Batchu Ramesh B. , Blotta Simona , Prabhala Rao , Catley Laurence , Hamasaki Makoto , Hideshima Teru , Chauhan Dharminder , Jacob Gary S. , Picker Donald , Venuta Salvatore , Anderson Kenneth C. , Munshi Nikhil C. 
Published: October 2019

Abstract
Atiprimod (N-N-diethl-8, 8-dipropyl-2-azaspiro [4.5] decane-2-propanamine) is a novel orally bio-available agent with anti-inflammatory properties. Although its in vitro anti-MM activity have been previously reported, here we have investigated molecular changes induced by Atiprimod as well as its in vivo activity in murine models of MM. Atiprimod inhibits in vitro growth and survival of IL-6 dependent as well as independent MM cell-lines in a time- and dose-dependent manner. Evaluation of changes in gene expression profile following treatment with Atiprimod identified down-regulation of genes involved in adhesion, cell-signalling, cell-cycle and BMP pathways and up-regulation of genes implicated in apoptosis and bone metabolism. The signalling pathway analysis identified the integrin, TGF-beta and FGF signaling as well as Wnt/b-catenin, IGF1 and cell cycle regulation networks as being most modulated by Atiprimod treatment. Next, we evaluated its in vivo activity in three different murine models of MM. A xenograft model bearing subcutaneous MM cells confirmed in vivo the anti-MM activity of Atiprimod and established its dose-response activity; a model based on engraftment of human fetal bone chip implanted in SCID mice (SCID-hu) with INA-6 cells, confirmed its ability to overcome the protective effects of the bone marrow milieu on MM cell growth, survival and drug resistance; and a SCID-hu model engrafted with primary patient MM cells confirmed its activity in the context of primary human disease recapitulating the clinical condition. Finally, we observed reduced number of osteoclasts, following Atiprimod treatment, compared to control bone samples confirming its beneficial effects on bone remodelling. Taken together, these data demonstrate the in vitro and in vivo anti-tumor activity of Atiprimod and delineate potential molecular targets triggered by this agent, providing a preclinical rational for its clinical evaluation in MM.
Eradication of Tumors in Pre-Clinical Models of Multiple Myeloma by Anti-CS1 Monoclonal Antibody HuLuc63: Mechanism of Action Studies.
Authors: Rice Audie , Dillon Myles , van Abbema Anne , Jesaitis Lynne , Wong Melanie , Lawson Stacey , Liu Gao , Zhang Yin , Powers David , Rhodes Susan , Caras Ingrid , Law Debbie , Afar Daniel 
Published: October 2019

Abstract
Introduction: We have recently shown that CS1 (CD2 subset 1, CRACC, SLAMF7), a cell surface glycoprotein of the CD2 family, is uniformly expressed on myeloma cells from multiple myeloma (MM) patients. Based on its high expression in MM and limited expression in normal cells, we propose CS1 as a novel and specific antibody target for the treatment of MM.
Methods: A panel of monoclonal anti-CS1 antibodies (mAbs) was generated to identify a potential therapeutic candidate. MAb clones MuLuc63 and MuLuc90 were selected for testing in CS1 positive MM xenograft models in vivo in severe combined immunodeficient mice. HuLuc63, a humanized IgG1 version of MuLuc63, was generated as the potential therapeutic candidate for the treatment of MM. HuLuc63 and Fc-modified versions of HuLuc63 were tested for anti-tumor activity in mouse models vivo. In vitro antibody-dependent cellular cytotoxicity (ADCC) assays were performed to define the potential mechanism of action for HuLuc63.
Results: Both MuLuc63 and MuLuc90 exhibited significant in vivo anti-tumor activity compared to isotype control antibodies in the L363 MM xenograft model. MuLuc63 was significantly more potent, resulting in rapid tumor eradication in most of the animals for the length of the study (~4 months). Based on these results, MuLuc63 was humanized to generate HuLuc63, which exhibited similar affinity for CS1 when compared to the mouse parent antibody. In two different MM xenograft models, L363 and OPM2, HuLuc63 exhibited significant anti-tumor activity resulting in tumor eradication in a high proportion of animals. To investigate the mechanism of action, two modified versions of HuLuc63 were tested in xenograft models. One version, HuLuc63-Ala,Ala, exhibits a mutation in the Fc region that decreases the ability to interact with the Fc receptor on natural killer (NK) cells. The second version, HuLuc63-LF, exhibits low levels of fucosylation in the Fc region that would result in increased binding to the Fc receptor. Compared to HuLuc63, the LF version exhibited significantly better in vivo anti-tumor activity towards, while the Ala,Ala mutant exhibited no anti-tumor activity. These data indicate that the Fc region of HuLuc63 is critical for its anti-tumor activity, and suggest ADCC as a possible mechanism of action. In vitro, HuLuc63 exhibits substantial ADCC towards L363 and OPM2 cells. The activity was dose-dependent, with increasing cytotoxicity being observed with concentrations ranging from 0.01μg/mL to10 μg/mL.
Conclusions: These pre-clinical data support HuLuc63 as a new therapeutic for the treatment of MM and suggest that ADCC is part of the mechanism of action. HuLuc63 will be entering a phase I clinical study for multiple myeloma.