bluuebunny/crossref_metadata_2025 huggingface dataset:
QT interval prolongation in patients with acute ischemic stroke: a report in northwest China
Authors: Wu Jine , Nizhamuding Dilimulati , Liu Peng , Jiang Yongrong , Qiang Hua , Sun Chaofeng , Dai Chongliang , Yin Yanrong
Published: October 2019

Aims

QT interval prolongation is common in patients with stroke and increases the risk of malignant arrhythmia and sudden death. Our aim was to analyze differences in the QT interval and electrocardiogram abnormalities between acute ischemic stroke patients and controls.

Methods

We retrospectively collected data from 273 patients with acute ischemic stroke from the neurological intensive care unit and 495 controls from other departments. A standard 12-lead electrocardiogram was recorded within 24 hours of hospitalization. Clinical information, the QT interval corrected for heart rate (QTc), and the incidence of electrocardiogram abnormalities were compared between groups.

Results

There was no difference in age, sex, or the prevalence of hypertension or diabetes mellitus between the acute ischemic stroke group and controls. Acute ischemic stroke patients showed a significantly longer QTc and a higher incidence of both sinus bradycardia and ST-T changes compared with controls. We also showed that the changes in electrocardiogram results observed in acute ischemic stroke might be transient.

Conclusion

Acute ischemic stroke patients may have a longer QT interval and a higher incidence of electrocardiogram abnormalities. In clinical practice, careful attention should be paid to acute ischemic stroke patients to prevent malignant arrhythmia.
Mapping the Landscape of Behavioral Theories: Systematic Literature Review
Authors: Kwon Heeseo Rain , Silva Elisabete A.
Published: October 2019

The term “behavioral” has become a hot topic in recent years in various disciplines; however, there is yet limited understanding of what theories can be considered behavioral theories and what fields of research they can be applied to. Through a cross-disciplinary literature review, this article identifies sixty-two behavioral theories from 963 search results, mapping them in a diagram of four groups (factors, strategies, learning and conditioning, and modeling), and points to five discussion points: understanding of terms, classification, guidance on the use of appropriate theories, inclusion in data-driven research and agent-based modeling, and dialogue between theory-driven and data-driven approaches.
An experimental study on adhesion, flexibility, interlaminar shear strength, and damage mechanism of jute/rubber-based flexible “green” composite
Authors: Mahesh Vishwas , Joladarashi Sharnappa , Kulkarni Satyabodh M
Published: October 2019

Determining the interlaminar shear strength (ILSS) of the composite laminates is vital for deciding their usage in any engineering applications. The matrix used and its curing characteristics are vital in deciding the ILSS of the composite. Present work deals with an experimental study on adhesive behavior, degree of flexibility, ILSS, and damage mechanism of the novel jute/rubber-based flexible “green” composite. The proposed flexible composites were prepared in three different stacking sequences, namely jute/rubber/jute (JRJ), jute/rubber/rubber/jute (JRRJ), and jute/rubber/jute/rubber/jute (JRJRJ), using compression molding technique. After determining the optimal curing characteristics of the proposed rubber-based matrix, the constituents are tested for their adhesive strength with the matrix which showed that rubber matrix system is compatible with jute fabric and natural rubber sheet. Composites are prepared and degree of flexibility for each stacking sequence is found out. Results pertaining to ILSS show that JRJRJ has better ILSS compared to JRJ and JRRJ. Fractographic analysis using scanning electron microscope reveals the mode of failure of the composites and the mechanism governing their failure. Fourier transform infrared spectroscopic study reveals the bonding between the constituents is good enough to be used in composites with flexibility.
Non-uniformly loaded row of moving shear cracks in magnetoelectroelastic media
Authors: Tupholme GE
Published: October 2019

Derivations and discussions are obtained in detail of the closed-form representations of the components of the deformation fields at a general point created by a moving row of smart magnetoelectroelastic shear cracks that are subjected to non-uniform mechanical, electric, and magnetic loadings. The creative analysis exploits a generalization of the basic dislocation layer method. Near a crack tip, their angular variations and the corresponding stress, electric displacement and magnetic induction intensity factors are deduced. Graphical displays of some illustrative numerical data are presented. As a particular case, the results for an analogous stationary row of non-constantly loaded magnetoelectroelastic cracks are derived. The correctness and validity of the results of this novel analysis are examined by the verification of their agreement with those previously presented for various limiting particular cases.
Effect of Seasonal Variation on Bacterial Inhabitants and Diversity in Drinking Water of an Office Building, Delhi
Authors: Yadav Neha , Singh Sradhanjali , Goyal Sanjeev K
Published: October 2019

The work reported in this article raises some serious concern about the drinking water quality and its standards. Mere presence or absence of an indicator organism does not assure that the water is safe for drinking purposes. Instead of infecting directly, many pathogens pass through a host and retrieve their virulent properties by causing diseases/infections in humans. Pathogenic bacteria which exist in aquatic habitats show a unique and peculiar pattern of appearing or reappearing in different microenvironments. Several factors that prevail in the water system make a safe house for the growth, proliferation, and colonization of microorganisms. In our case, 6 different microenvironments inside the premises of an office building were taken as the sampling sites to study the effect of seasonal variations (summer, monsoon, and post-monsoon/winter) on bacterial diversity and inhabitants. Results suggested that the presence of total and thermotolerant coliforms were highest in the monsoon followed by summer and post-monsoon/winter seasons. To know the bacterial diversity and pattern of appearance/reappearance prevailing in the water system, bacterial strains were analyzed by 16S rRNA sequencing which showed Pseudomonas putida to be the predominant identified bacterial strain occurring about 38% to 77% in all 3 seasons. This was followed by Lelliottia nimipressuralis (6%-21%), Escherichia coli (4%-18%), Salmonella typhimurium and Aeromonas dhakensis (4%-10% each), and Klebsiella pneumoniae (5%-6%). Despite the absence of other opportunistic bacteria, P putida was reported to be present as a single organism in water coolers and dispensers. This might be due to the persistent nature of P putida in low-nutrient environments and capable of colonizing by forming a rigid biofilm inside the water cooler/dispenser which makes a conducive environment for it.
I resent society's irrational fear of sex: An intersectional inquiry into youth sexuality in two Indian states
Authors: Manian Sunita
Published: October 2019

This research investigates attitudes about sex, sexuality and sexual pleasure, as well as awareness regarding reproductive and sexual health among Indian youth. The study takes place against the backdrop of a sea change in India in the last few decades brought about by economic liberalization, accompanied by rapid commercialization and consumerism. This has in turn been accompanied by changes in sexual mores especially among youth in India. Most of the young people I interviewed were either sexually active or would like to be sexually active, outside of the socially prescribed conjugal context. Some of the young men shared with great candor their immense frustration at being unable to find sexual pleasure with a partner. Others had the freedom to explore various aspects of their sexuality; however their sexual behavior was often dangerous because of their lack of knowledge about safe-sex. The experiences of young women were shaped both by their gender and their families' class status. The young people I interviewed, regardless of whether they were sexually active, had one thing in common—namely a profound ignorance about issues related to sex, sexuality and sexual health. Girls and young women in most cases were either denied sexual education or found their ability to access information about sex highly curtailed. However, the narratives presented in this article also problematize easy categorizations of India as being homophobic and intolerant of non-heteronormative sexualities.
Consuming takeaway food: Convenience, waste and Chinese young people’s urban lifestyle
Authors: Liu Chen , Chen Jiaxi
Published: October 2019

Considering food consumption as an important daily practice, this article explores how and why Chinese young people consume takeaway food – a typical type of convenience food – and whether this food practice creates a wasteful urban lifestyle, drawing on a qualitative analysis. The key finding of this research suggests that Chinese young people have normalised takeaway food consumption and have their own strategies to reduce food/food-related waste after consumption. Such a dynamic process of takeaway food consumption reflects young people’s lifestyle in urban China: an individualised or self-centred, technology-dependent and fast-paced lifestyle. Moreover, this research suggests that social studies on household food practices should take household sizes and patterns into more considerations. This research can be read as a contribution to the existing body of literature on convenience food and its environmental consequences within and beyond the family space from a non-Western perspective.
Solving robotic distributed flowshop problem using an improved iterated greedy algorithm
Authors: Li Wenhan , Li Junqing , Gao Kaizhou , Han Yuyan , Niu Ben , Liu Zhengmin , Sun Qun
Published: October 2019

In this study, we propose an improved iterated greedy algorithm for solving the distributed permutation flowshop problem, where there is a single robot in each factory and the makespan needs to be minimized. In the problem considered, the robot is used to transfer each job from the predecessor machine to the successor machine. A blocking constraint between machines is considered, thus jobs should remain on the completed machine while waiting for the robot. The loading and unloading times are considered and different for all of the jobs conducted by the robot, and the deteriorating time is also considered. In the proposed algorithm, first, four types of neighborhood structures are developed. Then, the simulated annealing algorithm is embedded in the proposed algorithm to enhance the exploration abilities. Furthermore, a problem-specific destruction and construction strategies are investigated. Finally, several realistic instances were generated to test the proposed algorithm, and its competitive performance was verified based on detailed experimental comparisons.
The EU and its Arctic spirit: Solving Arctic climate change from home?
Authors: Chuffart Romain , Raspotnik Andreas
Published: October 2019

Dealing with climate change and developing the Arctic sustainably are often seen as both binary and contradictory sets of challenges. The EU is in a unique position in Arctic affairs: unlike non-Arctic states, it is part of and linked to the region. However, the EU is at risk of missing the opportunity to be a leader in setting standards for a coherent and sustainable approach for the region. The Arctic is often used as a symbol for global climate change and, conversely, climate change is also used as a reason for more Arctic engagement. Yet, the roots of global heating—greenhouse gas emissions—mostly originate from outside the region. This article asks whether the path towards more EU–Arctic involvement should start closer to home.
Common risk factors for major noncommunicable disease, a systematic overview of reviews and commentary: the implied potential for targeted risk reduction
Authors: Peters Ruth , Ee Nicole , Peters Jean , Beckett Nigel , Booth Andrew , Rockwood Kenneth , Anstey Kaarin J.
Published: October 2019

Noncommunicable disease now contributes to the World Health Organization top 10 causes of death in low-, middle- and high-income countries. Particular examples include stroke, coronary heart disease, dementia and certain cancers. Research linking clinical and lifestyle risk factors to increased risk of noncommunicable disease is now well established with examples of confirmed risk factors, including smoking, physical inactivity, obesity and hypertension. However, despite a need to target our resources to achieve risk reduction, relatively little work has examined the overlap between the risk factors for these main noncommunicable diseases. Our high-level review draws together the evidence in this area. Using a systematic overview of reviews, we demonstrate the likely commonality of established risk factors having an impact on multiple noncommunicable disease outcomes. For example, systematic reviews of the evidence on physical inactivity and poor diet found each to be associated with increased risk of cancers, coronary heart disease, stroke, diabetes mellitus and dementia. We highlight the potential for targeted risk reduction to simultaneously impact multiple noncommunicable disease areas. These relationships now need to be further quantified to allow the most effective development of public health interventions in this area.
Physical activity may drive healthy microvascular ageing via downregulation of p66Shc
Authors: Streese Lukas , Khan Abdul W , Deiseroth Arne , Hussain Shafaat , Suades Rosa , Tiaden Andre , Kyburz Diego , Hanssen Henner , Cosentino Francesco
Published: October 2019

Background

Narrower retinal arterioles and wider venules are linked to adverse cardiovascular outcomes. The mitochondrial adaptor p66Shc is a major source of ageing-induced generation of reactive oxygen species. Promoter DNA methylation inhibits p66Shc gene transcription. This cross-sectional study was designed to investigate the link between physical activity, retinal vessel diameters and p66Shc expression in active and sedentary ageing subjects.

Design/methods

Altogether 158 subjects were included in the study (mean age 59.4 ± 7.0 years). Thirty-eight subjects were healthy active, 36 were healthy sedentary and 84 were sedentary with ≥2 cardiovascular risk factors. Retinal arteriolar and venular diameters were measured by means of a retinal vessel analyser. As a marker of oxidative stress, plasma 3-nitrotyrosine was determined by enzyme-linked immunosorbent assay. Gene expression of p66Shc and DNA methylation were assessed in mononuclear cells by real-time quantitative polymerase chain reaction and methylated-DNA capture (MethylMiner Enrichment kit) coupled with quantitative polymerase chain reaction, respectively.

Results

Wider retinal arterioles (179 ± 14 vs 172 ± 11 and 171 ± 14 µm; p < 0.05 and narrower venules (204 ± 17 vs 209 ± 11 and 218 ± 16 µm; p < 0.001) were observed in healthy active subjects compared with healthy sedentary subjects and sedentary subjects with ≥2 cardiovascular risk factors, respectively. Furthermore, healthy active subjects had blunted p66Shc expression and lower 3-nitrotyrosine plasma levels compared with healthy sedentary and sedentary subjects with ≥2 cardiovascular risk factors. Accordingly, hypomethylation of p66Shc promoter observed in healthy sedentary and sedentary subjects with ≥2 cardiovascular risk factors was not found in healthy active subjects.

Conclusion

Long-term physical activity-induced DNA methylation of p66Shc may represent a putative mechanistic link whereby active lifestyle promotes healthy microvascular ageing.
Chinese version of the Rotator Cuff Quality of Life questionnaire: Cross-cultural adaptation and validation in rotator cuff-impaired patients in Hong Kong
Authors: Li Ho-ming , Chau Jackie YM , Woo SB , Lai J , Chan WL
Published: October 2019

Purpose:

To adapt the Rotator Cuff Quality of Life (RC-QOL) questionnaire into traditional Chinese (Chi-RC-QOL) and to evaluate the validity and reliability in patients suffering from rotator cuff pathologies in Hong Kong.

Methods:

The Chi-RC-QOL will be constructed using the forward-translation followed by the backward-translation method. Thirty consecutive patients with clinically and radiologically confirmed rotator cuff pathology were recruited. Descriptive statistics will be followed by validity assessment using comparison with the Constant Shoulder (CS) score, University of California Los Angeles (UCLA) Shoulder Rating Scale, and Western Ontario Rotator Cuff (WORC) score. Parametric data will be tested using Pearson’s correlation coefficient for the total scores. Reliability was assessed using a test–retest interval of 30 min. The Cronbach’s α and intraclass correlation coefficient were calculated.

Results:

Cronbach’s α and internal consistency scores were high for all parts of the Chi-RC-QOL, with Cronbach’s α ranging between 0.89 and 0.98. Internal consistency scores range from 0.82 to 0.92, which can be regarded as an excellent correlation. Test–retest reliability was excellent for all parts of the Chi-RC-QOL with good absolute reliability. Chi-RC-QOL correlates well with the CS score, UCLA Shoulder Rating Scale, and the WORC score, with all being statistically significant.

Conclusions:

The current study adapted the RC-QOL to traditional Chinese version. The analysis confirmed the validity and reliability of the Chi-RC-QOL questionnaire.

Level of Evidence:

III.
Inherited Disorders of the Ras-MAPK Pathway
Authors: Kratz Christian P. , Zenker Martin
Published: October 2019

RASopathies are a group of rare congenital diseases in which dysregulated signaling through the RAS-MAPK signaling cases is the critical pathogenetic mechanism. This definition excludes postnatally acquired conditions (e.g. RAS-MAPK driven neoplasms) and PIK3-AKT pathway related disorders as well as conditions with only ancillary RAS pathway involvement (e.g. KAT6B-, RAP1A/B-related disorders). The definition, however, includes the following categories: (1) Noonan syndrome and related disorders, specifically Noonan syndrome (NS), NS with multiple lentigines, NS-like disorder with loose anagen hair, CBL syndrome, cardiofaciocutaneous syndrome, and Costello syndrome); (2) Neurofibromatosis type 1 and the related disorders Neurofibromatosis-Noonan syndrome and Legius syndrome; (3) Mosaic RASopathies including a rapidly growing group of mainly (neuro)cutaneous disorders with "oncogenic" mutations in a somatic mosaic state; (4) RAS-MAPK pathway dysregulation without a NS-like phenotype including non-syndromic intellectual disability due to SYNGAP1mutations and capillary malformation-arteriovenous malformation/Parkes-Weber syndrome; (5) RAS-MAPK pathway defects without overactivation such as metachondromatosis. Germline mutations leading to Ras-MAPK dysregulation typically lead to a characteristic pattern of craniofacial anomalies, heart defects, shorts stature, and variable neurodevelopmental deficits as seen in NS and other RASopathies of category 1. Confirmed genes leading to RASopathies from this category include BRAF,CBL, HRAS, KRAS, MAP2K1, MAP2K1, NRAS, PTPN11, RAF1, RIT1, SHOC2, SOS1, LZTR1, and PPP1CB. Newer genes include SOS2, MRAS, RRAS, and RASA2. For some individual RASopathy disease entities, specific genotype associations exist, for others, this correlation is not tight. The cancer risk in many patients with RASopathies is only moderately increased, however, for a subgroup of patients the cancer risk is very high. These include patients with Costello syndrome (HRAS) who develop rhabdomyosarcoma, neuroblastoma and bladder cancer, patients with NF1 who develop juvenile myelomonocytic leukemia (JMML), neurofibroma/-fibrosarcoma, and brain tumors, and patients and with CBL syndrome who develop JMML. New clinical studies explore the use of RAS-MAPK Pathway inhibitors in this unique population. Various animal and in vitro models have been described, which (partially) recapitulate the human RASopathy phenotype and phenotypic rescue by manipulating RAS-MAPK signal flow has been demonstrated.

Disclosures

No relevant conflicts of interest to declare.
PKM2 Expression Is Associated with Favorable Outcome in Patients with Diffuse Large B-Cell Lymphoma
Authors: Wei Yongqiang , Wei Xiaolei , Song Jialin , Huang Weimin , Zeng Hong , Zheng Jingxia , Wei Qi , Feng Ru
Published: October 2019

Pyruvate kinase muscle isoenzyme 2 (PKM2) is a key enzyme in aerobic glycolysis and thought to contribute to cancer cell metabolic reprogramming. The aim of this study was to evaluate whether PKM2 expression by immunohistochemical was a potential prognostic biomarker in diffuse large B-cell lymphoma (DLBCL) patients. Herein, we explore the expression of PKM2 by immunohistochemistry in all 87 patients diagnosed as de novo DLBCL according to WHO classification. Among all the 87 patients, high expression of PKM2 was observed in 20 cases (23.0%). There was no significant difference in gender, age, B symptoms, performance status, LDH, stage and IPI score between patients with high and low PKM2 expression(P>0.05). Patients with high PKM2 expression showed significant superiorevent-free survival, but only a tendency in overall survival compared with low PKM2 expression patients (p=0.047 and p=0.465, respectively). Multivariate analysis showed that high expression of PKM2, independent of the international prognostic index, implied a favorable event-free survival (HR=0.363; 95% CI=0.109-0.927, p=0.038), but not overall survival (HR=0.646; 95% CI= 0.185-2.254, p=0.493). In conclusion, these data suggest that the expression of PKM2 may implied a good outcome in DLBCL patients treated with R-CHOP.

Disclosures

No relevant conflicts of interest to declare.
Adipocyte Differentiation of SOD2−/− Mouse Bone Marrow Stromal Cells Is Associated with Decreased Antioxidant Reserves and Is Reversed by the Antioxidant WR2721 (Amifostine).
Authors: Epperly Michael W. , Lechpammer Stanislav , Nie Suhua , Glowacki Julie , Greenberger Joel S.
Published: October 2019

Cell lines from homozygous deletion recombinant negative manganese superoxide dismutase (SOD2 −/−) mice have intrinsic ionizing radiation sensitivity that is reversed by expression of the transgene for human SOD2 (Radiation Research154:365, 2000). This study tests whether redox status influences adipocyte differentiation potential of bone marrow stromal cells by comparing the differentiation potential of SOD2−/− and SOD2 +/+ bone marrow stromal cell lines. Cells were cultured in basal medium (Dulbecco’s Modified Eagle’s Medium, 1% fetal bovine serum (FBS), 100 U/ml penicillin and 100 μg/mL streptomycin +/− adipocytogenic supplements (10 μg/ml insulin, 1 μM dexamethasone, 100 mM indomethacin)). Adipocytogenesis was assessed by spectrophotometric content of oil red-O dye and by RT-PCR for peroxisome proliferator-activated receptor-gamma (PPARγ) and lipoprotein lipase (LPL). Glutathione peroxidase (GPX) activity or glutathione (GSH) levels were measured by a Glutathione Peroxidase, Cellular Assay Kit or Glutathione Assay Kit, respectively, by Calbiochem, Inc. SOD2+/+ cells developed adipocytes only when treated with adipocytogenic supplements and expressed PPARγ and LPL at day 5. SOD2−/− cells cultured in basal conditions demonstrated constitutive adipocytogenesis. The level of GPX activity in SOD2−/− cells (43.2 ± 3.5 mU/ml) was 52.7% (p<0.001) of that in SOD2+/+ cells (82.0 ± 2.3). The level of GSH in SOD2−/− cells (173 ± 2 μM) was 78.6% (p=0.0089) of that in SOD2+/+ cells (220 ± 4 μM). Three day treatment of SOD2−/−with 4 mM WR2721 resulted in 22% reduction in oil red-O content. In addition, in SOD2−/− cells cultured in adipocytogenic medium, 3-day treatment in 4 mM WR2721 resulted in 46% reduction in oil red-O content and undetectable expression of PPARγ and LPL. In conclusion, WR2721 limits constitutive adipocytogenesis and inhibits induced adipocytogenesis in SOD2−/− cells. These data provide evidence for the involvement of the cellular redox pathway in adipocyte differentiation of bone marrow stromal cells.
Targeting IKK Inhibits Multiple Myeloma (MM) Cell Growth in the Bone Marrow Microenvironment.
Authors: Hideshima Teru , Tassone Pierfrancesco , Chauhan Dharminder , Ishitsuka Kenji , Mitsiades Constantine , Raje Noopur , Kumar Shaji , Hamasaki Makoto , Hideshima Hiromasa , Munshi Nikhil C. , Richardson Paul G. , Schenkein David , Anderson Kenneth C.
Published: October 2019

NF-κB is a transcriptional factor promoting tumor cell growth and inhibition of apoptosis via regulating expression of proteins modulating cell cycle and anti-apoptosis. NF-κB is constitutively associated with an inhibitor (IκB), which is phosphorylated by IκB kinase (IKK) upon cell stimulation (ie, TNFα) and subsequently degraded by ubiquitin-proteasome pathway, thereby allowing NF-κB to translocate to nucleus. We have previously shown that an IKK inhibitor PS-1145 partially (20–50%) inhibits MM cell proliferation; however, it inhibits both IL-6 secretion from BMSCs triggered by MM cell adhesion and proliferation of MM cells adherent to BMSCs. Targeting IKKβ is therefore a possible therapeutic option for inhibition of MM cell growth in the bone marrow microenvironment by downregulating NF-κB activity.

In this study, we further delineated the biologic significance of IKK inhibition in MM cells using IKKβ specific inhibitor MLN120B (Millennium Pharmaceuticals, Cambridge, MA). MLN120B induced 60–90% growth inhibition in cells from the MM cell lines RPMI8226, RPMI/Dox40, RPMI/LR5, U266, and INA-6; on the other hand, it induced only 25–30% inhibition in MM.1S and MM.1R cells, assessed by 72 h tritiated-thymidine uptake. Importantly, neither IL-6 nor IGF-1 overcomes the growth inhibitory effect of MLN120B in both MM.1S and U266 cells. Interestingly, MLN120B significantly augmented TNFα-induced cytotoxicity in MM.1S cells. We next examined whether MLN120B could enhance the cytotoxicity of other agents. MLN120B augmented growth inhibition triggered by doxorubicin and melphalan in RPMI8226 and IL-6 dependent INA-6 cell line. We therefore studied growth inhibitory effect of MLN120B in the presence of bone marrow stromal cells (BMSCs). MLN120B inhibited 70–80% of constitutive IL-6 secretion from BMSCs, without toxicity. Importantly, MLN120B almost completely blocked stimulation of MM.1S, U266 and INA-4 cell growth and IL-6 secretion from BMSCs induced by binding of tumor cells to BMSCs. Finally, MLN120B overcame the protective effect of BMSCs, cell adhesion mediated drug resistance, against dexamethasone in MM.1S cells. Taken together, our data demonstrate that an IKKβ inhibitor induces cytotoxicity in MM cells in the BM milieu, providing the framework for clinical trials of these novel agents to improve patient outcome in MM.
Multiple B Cell Clones Producing Antibodies Directed to the Spacer and Disintegrin/TSR1 Domains of ADAMTS13 in a Patient with Acquired TTP.
Authors: Luken Brenda M. , Kaijen Paul H.P. , Turenhout Ellen A.M. , Fijnheer Rob , Voorberg Jan
Published: October 2019

Thrombotic thrombocytopenic purpura (TTP) is associated with a severe deficiency of the von Willebrand factor-cleaving protease ADAMTS13. In plasma of the majority of patients with acquired TTP, antibodies that inhibit ADAMTS13 activity have been detected. In this study we have used phage display to isolate anti-ADAMTS13 antibodies from the total immunoglobulin repertoire of a patient with acquired TTP. The immunoglobulin G variable heavy chain (VH) gene repertoire was amplified from CD19 positive B cells and combined with a variable light chain (VL) gene repertoire. The resulting library consisted of 3.4 x 108 individual clones. Combined VH and VL segments, expressed as single-chain Fv fragments (scFv) on the surface of filamentous phage, were selected for binding to an ADAMTS13 fragment consisting of the disintegrin/ first thrombospondin type 1 repeat (TSR1)/ cysteine-rich/ spacer domains. After three rounds of selection, six different scFv antibody clones were identified that were assigned to four groups based on the use of VH germline gene segments. ScFv 9, 10, and 27, all use the VH1–69 germline gene segments, possess the same CDR3, and show a similar pattern of somatic hypermutation. These results suggest that scFv 9, 10 and 27 are derived from a common B cell precursor. ScFv 26 also belongs to the VH1 family, but uses germline gene segment VH1–02 instead. Clones 16 and 41 are both part of the VH3 family and are derived from germline gene segments VH3–07 and VH3–09 respectively. The affinity of the scFv for the ADAMTS13 disintegrin/ TSR1/ cysteine-rich/ spacer fragment was determined by surface plasmon resonance analysis. Purified disintegrin/ TSR1/ cysteine-rich/ spacer fragment was immobilized on an activated CM5-sensor chip and subsequently different concentrations of purified scFv were added. Binding and dissociation of scFv was followed for 2 minutes and the affinity of the different scFv for the immobilized ADAMTS13 fragment was calculated from the obtained binding curves. ScFv 9 binds with high affinity to the disintegrin/ TSR1/ cysteine-rich/ spacer fragment (Kd 3.6 ± 0.8 nM); whereas scFv 10, 16, 26, 27 and 41 displayed a somewhat lower affinity (Kd ranging from 20–200 nM). Epitope mapping using several smaller ADAMTS13 fragments in the disintegrin/ TSR1/ cysteine-rich/ spacer region revealed that scFv 9, 10, and 41, bind specifically to the ADAMTS13 spacer domain. The epitope of scFv 16 however, resides in the disintegrin/ TSR1 domains. Our results indicate that multiple B cell clones that produce antibodies recognizing epitopes in the spacer and disintegrin/ TSR1 domains of ADAMTS13 are present in the immunoglobulin repertoire of a patient with acquired TTP.
Safety and Efficacy of Bortezomib (Velcade) for the Treatment of Relapsed Classical Hodgkin’s Disease.
Authors: Younes Anas , Pro Barbara , Romaguera Jorge , Dang Nam
Published: October 2019

The proteasome inhibitor bortezomib has demonstrated clinical activity in patients with multiple myeloma and different types of non-Hodgkin’s lymphoma. Its activity in patients with Hodgkin’s disease (HD) is unknown. We have recently reported that bortezomib had a significant activity against HD-derived cell lines in vitro (Zheng et al, Clin Cancer Res 2004), In four HD-derived cell lines, bortezomib induced cell cycle arrest and apoptosis in a dose and time dependent manner, irrespective of IkB gene mutations. Furthermore, bortezomib enhanced the activity of chemotherapy and TRAIL in these cell lines. Based on these encouraging preclinical results, we initiated a pilot study of single agent bortezomib in patients with relapsed classical HD. Eligibility: (1) relapsed classical HD with a measurable disease (2) At least 2 prior treatment regimens; (3) Patients with prior autologous stem cell transplant (ASCT) are eligible (4) platelet counts > 50,000/uL and ANC counts of > 1,500/uL (5) no HIV infection, or CNS involvement with HD, (6) bilirubin < 2mg/dL and creatinine < 2.5 mg/dL. Patients were treated with 1.3 mg/m2 bortezomib intravenously on days 1, 4, 8, 11 of 21-day cycles in an outpatient setting. Treatment was delayed if the Platelet counts on the day of therapy was < 30,000/mm3. After 3 cycles of bortezomib therapy patients were evaluated for treatment response. If there was no evidence of disease progression after 3 cycles of therapy, patients were allowed to receive a maximum of 6 cycles. To date, 11 patients are enrolled (6 men and 5 women), with a median age of 28 years (range: 21 to 68 years). All patients were heavily pretreated, with a median number of 5 prior treatment regimens (range 2 to 7 regimens), and all patients have previously failed ASCT. The median pretreatment platelet count was 126, 000/uL (range 66,000 – 339,000/uL). All patients received at least one dose of bortezomib and are evaluable for treatment toxicity. Treatment was reasonably well tolerated with the majority of toxic effects were of grade 1 and 2. Two patients had grade 3 dyspnea and one patient had grade 3 neutropenic fever. Progressive thrombocytopenia was the most common hematologic toxicity, which frequently caused delays in therapy. Nadir platelet count below 30,000/uL was observed in 3/11 patients during the first cycle, in 4/10 during the second cycle, and in 4/6 during the third cycle. Nadir ANC below 1000/uL was observed in 1/11 pts during cycle 1, in 2/10 during cycle 2, and in 1/6 during cycle 3. Eight patients completed the planned 3 cycles and are evaluable for treatment response. One patient achieved a partial remission and one had a minimal response. Our preliminary data demonstrate encouraging clinical activity of bortezomib in this heavily pretreated patients with classical HD, and warrants studying bortezomib in less heavily pretreated patients either as a single agent or in combination with chemotherapy.
Liposomal Cytarabine (DepoCyte™Injection) Is Cost-Effective Compared with Standard Cytarabine for the Intrathecal Treatment of Patients with Lymphomatous Meningitis.
Authors: Moeremans Karen , Annemans Lieven , Morris James
Published: October 2019

Background and Objective : The clinical benefit of liposomal cytarabine (DepoCyteTM injection) for the intrathecal treatment of lymphomatous meningitis has been demonstrated in a randomised controlled trial (Glantz M. et al. J Clin Oncol 1999;3110-3116 ). Liposomal cytarabine has recently become available in the UK at a cost considerably above that of standard cytarabine (1,250GBP per dose compared to 4GBP). A cost-utility analysis (CUA) comparing liposomal cytarabine versus standard cytarabine was conducted from the perspective of the UK National Health Service to determine whether or not liposomal cytarabine is a cost-effective treatment option for patients with lymphomatous meningitis.

Methods: Using data from the clinical trial, each patient’s survival time was partitioned according to the presence of progressive neurological disease. Utility estimates for two health states, progression and non-progression, were derived from clinical experts using a time-tradeoff exercise and assigned to each patient according to the period of time they remained in each health state. Observed response rates from the clinical trial were used to model expected quality adjusted life year (QALY) estimates for each treatment arm. Health care costs were estimated using resource data from the clinical trial and unit costs from the literature. Probabilistic analyses were used to estimate the expected cost per QALY gained with liposomal cytarabine, taking into account the uncertainty surrounding model input parameters.

Results: From a total of 33 randomised patients, response status was available for 29. 13 of 16 patients treated with liposomal cytarabine responded to treatment compared to 3 of 13 patients treated with standard cytarabine (81 vs. 23%; p=0.003). The mean total expected healthcare cost per patient was estimated to be 8,275GBP (+/−796) for patients treated with liposomal cytarabine and 3,238GBP (+/−494) for those treated with standard cytarabine. Patients treated with liposomal cytarabine accrued on average 0.27 (+/−0.027) QALYs compared to 0.15 (+/−0.025) QALYs in the standard cytarabine arm. The mean expected incremental cost per QALY gained with liposomal cytarabine was 47,764GBP (95%CI = 22,921–95,676). This estimate of cost-effectiveness was particularly sensitive to the health state utilities for progression and non-progression.

Conclusion : The results of this analysis suggest that liposomal cytarabine is a cost-effective treatment option for patients with lymphomatous meningitis. Although the incremental cost-effectiveness ratio (ICER) is close to the probable willingness-to-pay threshold, the results of this analysis should be evaluated in the context of a severe disease with few effective treatment options. Further research into patient preferences for the health states modelled here would be valuable given the sensitivity of QALY estimates to this variable.
Imatinib Interim Therapy Has Favorable Impact on the Outcome of Patients with Ph+ ALL Treated with Allogeneic SCT.
Authors: Seok Lee , Kim Yoo-Jin , Min Chang-Ki , Kim Hee-Je , Eom Ki-Sung , Kim Dong-Wook , Lee Jong-Wook , Min Woo-Sung , Kim Chun-Choo
Published: October 2019

Recently, we demonstrated the feasibility of first-line imatinib interim therapy (400~600 mg/day for 4 weeks) prior to allogeneic stem cell transplantation (SCT) in newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) (Blood, 2003;102:3068). Here, we report on the updated results of this strategy in 29 adult patients who completed induction chemotherapy and intended to undergo allogeneic SCT. In addition, we compared these results with those in 31 historic patients who proceeded to allogeneic SCT without imatinib therapy. There were no significant differences between the two groups with respect to presenting clinical and biologic characteristics. At the time of enrollment, 23 of the 29 patients (79.3%) had achieved a complete remission (CR) in the imatinib group, and the CR rate was not significantly different from the historic rate (26/31, 81.8%). In contrast, the relapse rate was significantly lower in the imatinib group during the post-remission treatment phase prior to SCT (3.5% vs 42.3%, p=0.002). Furthermore, 3 of the 6 refractory patients achieved a CR after the imatinib interim therapy. This study also found that the kinetics of the BCR-ABL transcript correlated well with the patients’ clinical course. Overall, the BCR-ABL/ABL ratios were decreased in 25 (86.2%) and increased in 4 (13.8%) patients after the imatinib interim therapy. A total of 57 patients (28 imatinib group, 29 historic group) underwent allogeneic SCT, and among them, 25 and 16 patients had sustained CR at the time of transplantation, respectively. The remaining 3 patients (1 imatinib group, 2 historic group) died of their disease progression before SCT. This has translated into lower relapse (4.8±4.7% vs 45.3±10.7%, p=0.004) and superior disease-free survival (75.8±12.9% vs 37.9±9.0%, p=0.001) for the imatinib group. Acute transplant-related toxicity and mortality were not different in the two groups. Considering the high frequency of relapse or refractoriness to chemotherapy-alone prior to SCT, imatinib interim therapy might provide a higher curative possibility for Ph+ ALL patients.
Durable Remission after Prophylactic Donor Lymphocyte Transfusion Following Allogeneic Stem Cell Transplantation with Reduced Conditioning for High-Risk AML and MDS.
Authors: Schleuning Michael , Schmid Christoph , Ledderose Georg , Tischer Johanna , Humann Meike , Ullmann Johanna , Schwerdtfeger Rainer , Kolb Hans-Jochem
Published: October 2019

Prophylactic transfusion of donor lymphocytes (pDLT) is an attractive form of maintenance therapy after allogeneic stem cell transplantation in patients with high risk of relapse. However, clinical experience is limited, and disease response is often achieved at the expense of severe graft-versus-host disease (GvHD). We here report our data on pDLT in high-risk AML and MDS. Cells were given within a prospective protocol that contained a sequence of chemotherapy, reduced intensity conditioning for allogeneic transplantation, and pDLT (FLAMSA-regimen). For pDLT, patients had to be in CR at least 120 days from transplantation, off immunosuppression for 30 days, and free of GvHD. 22/86 patients alive at day +120 fulfilled the criteria for pDLT. They had been transplanted for refractory or relapsed leukemia (n=9 each) or in CR1 because of unfavorable cytogenetics (n=4). 14 patients had an unfavorable karyotype, 8 with complex aberrations. Reasons for withholding pDLT in 64 patients included cGvHD or prolonged immunosuppression (n=38), refractory or relapsed leukemia (n=15), refusal of patient or donor (n=4 each), a history of grade IV acute GvHD (n=2), and chronic infections (n=3). The median time from transplant to first pDLT was 167 days (range 120–297). Median follow up of transfused patients is 696 days (range 209–1341). Ten patients received 1, 6 patients received 2, and 6 patients received 3 transfusions in escalating doses, containing a median of 1x106, 5x106 and 1x107 CD3+ cells/kg at pDLT 1, 2 and 3, respectively. Reasons for giving less than 3 transfusions were GvHD, relapse or refusal of the patient. Induction of GvHD was the main complication; grade III acute GvHD developed in 1, and chronic GvHD in 7 patients. So far, 5 patients have relapsed despite pDLT. One died of refractory leukemia, whereas 2 achieved secondary CR following adoptive immunotherapy. Two patients are currently under treatment. At present, 18/22 patients are alive and in CR at a median of 423 days post DLT. The current leukemia free survival at two years from first pDLT is 79%. Nineteen patients were complete chimeras at time of pDLT. pDLT converted mixed into complete bone marrow chimerism in 1, but failed in 2 cases. In our experience, pDLT is safe after allogeneic transplantation for high risk AML, when given at low doses and to a selected group of patients. Results are encouraging, and long term survival can be achieved. However, further studies need to define more precisely the contribution of pDLT to the therapeutic effect of the entire procedure.
The Use of TCR Vβ Spectratype Analysis in Allogeneic Blood and Marrow Transplantation.
Authors: Friedman Thea M. , Hopely Deborah D. , Stern Joshua L. , Filicko Joanne , Mookerjee Bijoyesh , Grosso Delores , Flomenberg Neal , Korngold Robert
Published: October 2019

The major complications of allogeneic blood and marrow transplantation (BMT) include graft failure, opportunistic infections, leukemic relapse and graft-versus-host disease (GVHD). The incidence of the first three complications is diminished by the presence of mature donor T cells in the transplant inoculum. Unfortunately, the transplantation of mature alloreactive donor T cells also directly induces the latter complication of acute GVHD, which can be directed against either HLA or minor histocompatibilty antigen (miHA) disparities. Efforts to deplete donor marrow inoculum of T cells have been successful in minimizing the development of disease but have been associated with increased leukemic relapse. Thus, one approach to solve this problem would be to identify and then selectively deplete alloreactive donorT cells while allowing the residual T cells to provide protection against infection and to mediate a leukemia-specific GVL response. In this regard, TCR Vβ repertoire analysis by CDR3-size spectratyping can be a powerful tool to characterize the alloreactive T cell response. As an initial test of this capability, we studied lethal GVHD in the B6->CXB-2 MHC-matched murine model, expressing multiple miHA differences. Herein, we determined the correlation between the in vitro alloreactive-specific CD8+ T cell response and their actual involvement in the development of GVHD. The results indicated a high correlation in the Vβ CDR3-size skewing patterns between the in vitro and in vivo spectratype histograms, and laid the foundation for the potential clinical application of this approach. We proceeded to test the predictive value of the in vitro spectratyping assays of donor anti-host mixed lymphocyte reactions with GVHD outcome in the clinical BMT setting. The results again indicated a high association of overlapping CDR3-size skewing. Thus, in vitro spectratyping analysis may be useful in guiding the manipulation of the donor T cell inoculum in order to provide improved BMT outcomes.
Immune Tolerance Induction (ITI) in Hemophilia A and Inhibitors using VWF Containing Factor VIII Concentrates.
Authors: Kreuz Wolfhart , Ettingshausen Carmen Escuriola , Auerswald Guenter K.H. , Brackmann Hans Herrmann , Klingebiel Thomas
Published: October 2019

Immune tolerance induction using the Bonn protocol (ITI) is the most successful approach to eliminate inhibitors in hemophilia A patients. The influence of the type of concentrate, particularly the content of von-Willebrand-Factor (VWF) used for ITI is under discussion and has never been investigated comparatively.

A longitudinal study at the Frankfurt center on the influence of VWF on ITI using the Bonn protocol (low responder: 50–100 IU FVIII/kg bw daily or every other day; high responder: 100–150 IU FVIII/kg bw every 12 hours; according to the bleeding tendency concomitant treatment with FEIBA®/Baxter) showed a significantly decreased success rate since the introduction of high purity plasma derived (pd) and recombinant (rec) F VIII products (success rate with pd VWF-F VIII 91% vs ultrapure F VIII 29%). Similar observations have been reported by the Bonn and Bremen centers (success rate with pd VWF-F VIII 87% vs ultrapure F VIII 54%). A meta-analysis of different ITI studies revealed a higher success rate with the use of VWF-FVIII concentrates (88% using VWF-FVIII and 63% using rec and pd/monoclonal purified F VIII).

The change to VWF-FVIII concentrates during ITI in inhibitor patients who showed an unsatisfactory treatment course with ultrapure F VIII concentrates (n=12 high responders) led to success in 10 out of 12 patients after a median treatment period of 17 months (5–36 months). Successful IT after changing to VWF-F VIII concentrates was evaluated by a questionnaire in another 10 high responders who had unsatisfactory treatment courses with ultrapure F VIII concentrates.

These observations indicate that VWF has a major impact on the success of ITI.
Loss of EBV-Specific CD4+T Cells during Progression to EBV-Related AIDS Non-Hodgkin Lymphoma: Restoration by Highly Active Antiretroviral Therapy (HAART).
Authors: Piriou Erwan R. , Jansen Christine , van Dort Karel , De Cuyper Iris , Nanlohy Nening M. , Lange Joep M. , Miedema Frank , Van Oers Marinus H.J. , van Baarle Debbie
Published: October 2019

Objective: EBV-specific CD8+ T cells have been extensively studied in various settings, and appear to play a major role in the control of EBV-related malignancies. In contrast, it is still unclear whether EBV-specific CD4+ T cells play a role in vivo. To study this question, an assay was developed to measure the CD4+ T-cell response towards two EBV antigens, in both healthy (n=14) and HIV-infected subjects (n=23). In addition, both HAART-treated (n=12) and untreated HIV+ individuals (n=14) - including progressors to EBV-related lymphoma - were studied longitudinally.

Methods: EBV-specific CD4+ T cells were stimulated with peptide pools from latent protein EBNA1 and lytic protein BZLF1, and detected by measurement of IFNg-production.

Results: After direct ex vivo stimulation, EBNA1 or BZLF1-specific IFNg- (and/or IL2) producing CD4+ T cell numbers were low, and measurable in less than half of the subjects studied (either HIV- and HIV+). Therefore, PBMC were cultured for 12 days in the presence of peptides and IL2 (from day 3), and then restimulated with peptides, allowing specific and reproducible expansion of EBV-specific CD4+ T cells, independent of HLA type and ex vivo antigen processing. Interestingly, numbers of EBV-specific CD4+ T cells inversely correlated with EBV viral load, implying an important role for EBV-specific CD4+ T cells in the control of EBV in vivo. Untreated HIV-infected individuals had a lower CD4+ T cell response to EBNA1 and BZLF1 as compared to healthy EBV carriers and HAART-treated HIV+ subjects. In longitudinal samples, EBNA1-specific, but not BZLF1-specific T-cell numbers increased after HAART, while EBV load was not affected by treatment. In all the progressors to EBV-related lymphoma, EBV-specific CD4+ T cells were lost at least 24 months before lymphoma diagnosis.

Conclusions: Both cross-sectional and longitudinal data suggest an important role for EBV-specific CD4+ T cells in the control of EBV-related malignancies. Furthermore, it seems that HAART treatment leads to recovery of EBNA1-specific, but not BZLF1-specific CD4+ T-cell responses, implying changes in the latency pattern of EBV, despite an unaltered cell-associated EBV DNA load. Thus, early HAART treatment might prevent loss of specific CD4+ T-cell help and progression to NHL.