bluuebunny/crossref_metadata_2025 huggingface dataset:
Adoptable strategic approaches to improve outcomes of allogeneic peripheral blood stem cell transplantations from unrelated donors
Authors: Sohn Sang Kyun , Moon Joon Ho
Published: November 2013

While previous studies have shown comparable clinical results for related and unrelated bone marrow transplantation (BMT), the transplantation outcomes for related and unrelated peripheral blood stem cell transplantation (PBSCT) may not follow the same pattern due to a higher incidence of graft‐versus‐host disease (GVHD)‐related morbidity and mortality in the case of long‐term survival after unrelated PBSCT. Thus, given the higher possibility of an impaired quality of life due to severe GVHD in long‐term survivors who receive unrelated PBSCT, the selection of the stem cell source needs to be decided very carefully. In addition, strategic approaches, such as the extended use of immunosuppressant as a GVHD prophylaxis, the use of antithymocyte globulins (ATGs), choosing a younger donor, and optimizing the CD34+ cell dose, need to be adopted to improve the transplantation outcomes by minimizing GVHD‐related morbidity and mortality in an unrelated PBSCT setting. This review article provides a comparison of BMT and PBSCT, and related and unrelated PBSCT, plus introduces several adoptable strategies to improve the outcomes of unrelated PBSCT.
The effects of unpaved roads on suspended sediment concentration at varying spatial scales – a case study fromSouthernBrazil
Authors: Thomaz Edivaldo L. , Vestena Leandro R. , Ramos Scharrón Carlos E.
Published: November 2013

Unpaved roads may induce adverse effects on downstream water resources by increasing suspended sediment concentration (SSC). This study documents the localized impacts on streamSSCof six unpaved road–stream crossings in the ruralGuabirobaRiverCatchment, in southernBrazil. Results demonstrated thatSSCvalues downstream of road–stream crossings was between 3.5 and 10 times higher than upstreamSSCat all third‐ and fourth‐order stream locations. However, downstream values were statistically undistinguishable from those collected upstream of road–stream crossings at fifth‐order sampling sites. These findings suggest that localized road effects on streamSSCsare scale‐dependent in that these are important for low‐order headwater streams yet undetectable for their higher order counterparts. Findings point to the importance of low‐order stream crossings in increasingSSCand the need to further explore the role of unpaved roads as agents of water quality degradation in agriculturally active rural settings.
Subcategories of singularity categories via tensor actions
Authors: Stevenson Greg
Published: November 2013

We obtain, via the formalism of tensor actions, a complete classification of the localizing subcategories of the stable derived category of any affine scheme that has hypersurface singularities or is a complete intersection in a regular scheme; in particular, this classifies the thick subcategories of the singularity categories of such rings. The analogous result is also proved for certain locally complete intersection schemes. It is also shown that from each of these classifications one can deduce the (relative) telescope conjecture.
Estimating nonrigid motion from inconsistent intensity with robust shape features
Authors: Liu Wenyang , Ruan Dan
Published: November 2013

Purpose:

To develop a nonrigid motion estimation method that is robust to heterogeneous intensity inconsistencies amongst the image pairs or image sequence.

Methods:

Intensity and contrast variations, as in dynamic contrast enhanced magnetic resonance imaging, present a considerable challenge to registration methods based on general discrepancy metrics. In this study, the authors propose and validate a novel method that is robust to such variations by utilizing shape features. The geometry of interest (GOI) is represented with a flexible zero level set, segmented via well‐behaved regularized optimization. The optimization energy drives the zero level set to high image gradient regions, and regularizes it with area and curvature priors. The resulting shape exhibits high consistency even in the presence of intensity or contrast variations. Subsequently, a multiscale nonrigid registration is performed to seek a regular deformation field that minimizes shape discrepancy in the vicinity of GOIs.

Results:

To establish the working principle, realistic 2D and 3D images were subject to simulated nonrigid motion and synthetic intensity variations, so as to enable quantitative evaluation of registration performance. The proposed method was benchmarked against three alternative registration approaches, specifically, optical flow, B‐spline based mutual information, and multimodality demons. When intensity consistency was satisfied, all methods had comparable registration accuracy for the GOIs. When intensities among registration pairs were inconsistent, however, the proposed method yielded pronounced improvement in registration accuracy, with an approximate fivefold reduction in mean absolute error (MAE = 2.25 mm, SD = 0.98 mm), compared to optical flow (MAE = 9.23 mm, SD = 5.36 mm), B‐spline based mutual information (MAE = 9.57 mm, SD = 8.74 mm) and mutimodality demons (MAE = 10.07 mm, SD = 4.03 mm). Applying the proposed method on a real MR image sequence also provided qualitatively appealing results, demonstrating good feasibility and applicability of the proposed method.

Conclusions:

The authors have developed a novel method to estimate the nonrigid motion of GOIs in the presence of spatial intensity and contrast variations, taking advantage of robust shape features. Quantitative analysis and qualitative evaluation demonstrated good promise of the proposed method. Further clinical assessment and validation is being performed.
Two Y Genes Can Replace the Entire Y Chromosome for Assisted Reproduction in the Mouse
Authors: Yamauchi Yasuhiro , Riel Jonathan M. , Stoytcheva Zoia , Ward Monika A.
Published: November 2013

Why, Oh Y?

The mammalian Y chromosome is a symbol of maleness and encodes genes important for male reproduction. Various deletions of the Y chromosome result in sperm defects and infertility. When haploid male germ cells were injected directly into oocytes,

Yamauchi
et al.

(p.
69
, published online 21 November; see the Perspective by

Capel

) found that living offspring could be derived from male mice whose Y chromosome contribution was limited to only two genes. These two genes are the testis determinant factor
Sry
and the spermatogonial proliferation factor
Eif2s3y
.
Genetic and Molecular Basis of Drug Resistance and Species-Specific Drug Action in Schistosome Parasites
Authors: Valentim Claudia L. L. , Cioli Donato , Chevalier Frédéric D. , Cao Xiaohang , Taylor Alexander B. , Holloway Stephen P. , Pica-Mattoccia Livia , Guidi Alessandra , Basso Annalisa , Tsai Isheng J. , Berriman Matthew , Carvalho-Queiroz Claudia , Almeida Marcio , Aguilar Hector , Frantz Doug E. , Hart P. John , LoVerde Philip T. , Anderson Timothy J. C.
Published: November 2013

Blood Fluke Resistance

The larval stages of the blood fluke
Schistosoma mansoni
are disseminated via a replicative cycle in freshwater snails. When people come into contact with contaminated water, the larvae attach to and penetrate the skin. The resulting disease, bilharzia or schistosomiasis, afflicts approximately 67 million people in Africa and South America. Unfortunately, the parasite is showing resistance to one of the available therapeutic drugs, oxamniquine, which means that schistosome control relies on a single drug, praziquantel.

Valentim
et al.

(p.
1385
, published online 21 November) analyzed the genetic and molecular basis of resistance to oxamniquine through a combination of genetic linkage mapping, genome sequencing, functional genomics analysis, and x-ray crystallography.
Complete Genome Sequence of Channel Catfish Gastrointestinal Septicemia Isolate Edwardsiella tarda C07-087
Authors: Tekedar Hasan C. , Karsi Attila , Williams Michele L. , Vamenta Stefanie , Banes Michelle M. , Duke Mary , Scheffler Brian E. , Lawrence Mark L.
Published: November 2013

Edwardsiella tarda
is a Gram-negative facultative anaerobe causing disease in animals and humans. Here, we announce the complete genome sequence of the channel catfish isolate
E. tarda
strain C07-87, which was isolated from an outbreak of gastrointestinal septicemia on a commercial catfish farm.
Whole-Genome Sequencing of Lactobacillus shenzhenensis Strain LY-73
T
Authors: Lin Zhe , Liu Zhaoshan , Yang Rentao , Zou Yuanqiang , Wan Daiwei , Chen Jing , Guo Min , Zhao Jiao , Fang Chengxiang , Yang Ruifu , Liu Feng
Published: November 2013

Lactobacillus shenzhenensis
strain LY-73
T
is a novel species which was first isolated from fermented goods. Here, we report the draft genome sequence of
Lactobacillus shenzhenensis
LY-73
T
.
Repeated seizures in an elderly patient with alcohol dependence and mild cognitive impairment
Authors: Ishii Nobuyoshi , Terao Takeshi , Araki Yasuo , Hatano Koji
Published: November 2013

A 69-year-old man with alcohol dependence and mild cognitive impairment (MCI) suffered from repeated tonic–clonic seizures. The seizures typically occurred several hours after his last alcohol intake at home (early withdrawal seizure) and 22 days after his last intake of alcohol (14 days after the last dose of diazepam substituting for alcohol: late withdrawal seizure) on the ward. Psychiatrists in charge of this patient found it difficult to attribute his seizures to alcohol withdrawal syndrome (AWS) because of the atypical onset. The patient responded to diazepam resumption and valproate combination. This case highlights the need to always consider AWS as a possible cause of seizures and to gradually decrease diazepam as a substitute for alcohol. Moreover, in this patient, MCI may have induced vulnerability in the brain for AWS and the patients’ older age might have decreased liver function leading to delayed onset of the seizures after diazepam withdrawal.
Central gender theoretical concepts in health research: the state of the art
Authors: Hammarström Anne , Johansson Klara , Annandale Ellen , Ahlgren Christina , Aléx Lena , Christianson Monica , Elwér Sofia , Eriksson Carola , Fjellman-Wiklund Anncristine , Gilenstam Kajsa , Gustafsson Per E , Harryson Lisa , Lehti Arja , Stenberg Gunilla , Verdonk Petra
Published: November 2013

Despite increasing awareness of the importance of gender perspectives in health science, there is conceptual confusion regarding the meaning and the use of central gender theoretical concepts. We argue that it is essential to clarify how central concepts are used within gender theory and how to apply them to health research. We identify six gender theoretical concepts as central and interlinked—but problematic and ambiguous in health science: sex, gender, intersectionality, embodiment, gender equity and gender equality. Our recommendations are that: the conceptssexandgendercan benefit from a gender relational theoretical approach (ie, a focus on social processes and structures) but with additional attention to the interrelations between sex and gender;intersectionalityshould go beyond additive analyses to study complex intersections between the major factors which potentially influence health and ensure that gendered power relations and social context are included; we need to be aware of the various meanings given toembodiment, which achieve an integration of gender and health and attend to different levels of analyses to varying degrees; and appreciate thatgender equalityconcerns absence of discrimination between women and men whilegender equityfocuses on women's and men's health needs, whether similar or different. We conclude that there is a constant need to justify and clarify our use of these concepts in order to advance gender theoretical development. Our analysis is an invitation for dialogue but also a call to make more effective use of the knowledge base which has already developed among gender theorists in health sciences in the manner proposed in this paper.
A CRITICAL HISTORY OF RENORMALIZATION
Authors: HUANG KERSON
Published: November 2013

The history of renormalization is reviewed with a critical eye, starting with Lorentz's theory of radiation damping, through perturbative QED with Dyson, Gell-Mann and Low, and others, to Wilson's formulation and Polchinski's functional equation, and applications to "triviality," and dark energy in cosmology.
POSITION OPERATORS AND CENTER-OF-MASS: NEW PERSPECTIVES
Authors: AGUILAR P. , CHRYSSOMALAKOS C. , CORONADO H. HERNANDEZ , OKON E.
Published: November 2013

After reviewing the work of Pryce on Center-of-Mass (CoM) definitions in special relativity, and that of Jordan and Mukunda on position operators for relativistic particles with spin, we propose two new criteria for a CoM candidate: associativity, and compatibility with the Poisson bracket structure. We find that they are not satisfied by all of Pryce's definitions, and they also rule out Dixon's CoM generalization to the curved space–time case. We also emphasize that the various components of the CoM position do not commute among themselves, in the general case, and thus provide a natural entry point to the arena of noncommutative space–time, without the ad-hoc assumptions of the standard paradigm.
INVARIANTS OF HANDLEBODY-KNOTS VIA YOKOTA'S INVARIANTS
Authors: MIZUSAWA ATSUHIKO , MURAKAMI JUN
Published: November 2013

We construct quantum [Formula: see text] type invariants for handlebody-knots in the 3-sphere S3. A handlebody-knot is an embedding of a handlebody in a 3-manifold. These invariants are linear sums of Yokota's invariants for colored spatial graphs which are defined by using the Kauffman bracket. We give a table of calculations of our invariants for genus 2 handlebody-knots up to six crossings. We also show our invariants are identified with special cases of the Witten–Reshetikhin–Turaev invariants.
4-MOVES AND THE DABKOWSKI–SAHI INVARIANT FOR KNOTS
Authors: BRITTENHAM MARK , HERMILLER SUSAN , TODD ROBERT G.
Published: November 2013

We study the 4-move invariant [Formula: see text] for links in the 3-sphere developed by Dabkowski and Sahi, which is defined as a quotient of the fundamental group of the link complement. We develop techniques for computing this invariant and show that for several classes of knots it is equal to the invariant for the unknot; therefore, in these cases the invariant cannot detect a counterexample to the 4-move conjecture.
CONSTRUCTING DOUBLY-POINTED HEEGAARD DIAGRAMS COMPATIBLE WITH (1,1) KNOTS
Authors: ORDING PHILIP
Published: November 2013

A (1,1) knot K in a 3-manifold M is a knot that intersects each solid torus of a genus 1 Heegaard splitting of M in a single trivial arc. Choi and Ko developed a parametrization of this family of knots by a four-tuple of integers, which they call Schubert's normal form. This paper presents an algorithm for constructing a genus 1 doubly-pointed Heegaard diagram compatible with K, given a Schubert's normal form for K. The construction, coupled with results of Ozsváth and Szabó, provides a practical way to compute knot Floer homology groups for (1,1) knots. The construction uses train tracks, and its method is inspired by the work of Goda, Matsuda, and Morifuji.
CAUSALITY CONSTRAINT ON NONCRITICAL EINSTEIN–WEYL GRAVITY
Authors: SHU FU-WEN , GONG YUNGUI
Published: November 2013

We explore, in the context of AdS/CFT correspondence, the causality constraints on the Noncritical Einstein–Weyl (NEW) gravity model in five dimensions. The scalar and shear channels are considered as small metric perturbations around an AdS black brane background. Our results show that the causality analysis on the propagation of these two channels imposes a new bound on the coupling of the Weyl-squared term in the NEW gravity. This new bound imposes more stringent restrictions than those by the tachyon-free condition, improving the predictive power of the theory.
AN INTRODUCTION TO LOGICAL ENTROPY AND ITS RELATION TO SHANNON ENTROPY
Authors: ELLERMAN DAVID
Published: November 2013

The logical basis for information theory is the newly developed logic of partitions that is dual to the usual Boolean logic of subsets. The key concept is a "distinction" of a partition, an ordered pair of elements in distinct blocks of the partition. The logical concept of entropy based on partition logic is the normalized counting measure of the set of distinctions of a partition on a finite set — just as the usual logical notion of probability based on the Boolean logic of subsets is the normalized counting measure of the subsets (events). Thus logical entropy is a measure on the set of ordered pairs, and all the compound notions of entropy (join entropy, conditional entropy, and mutual information) arise in the usual way from the measure (e.g. the inclusion-exclusion principle) — just like the corresponding notions of probability. The usual Shannon entropy of a partition is developed by replacing the normalized count of distinctions (dits) by the average number of binary partitions (bits) necessary to make all the distinctions of the partition.
Folded Variscan thrusts in the Herrera Unit of the Iberian Range (NE Spain)
Authors: Calvín-Ballester Pablo , Casas Antonio
Published: November 2013

The Variscan structure of the Herrera unit (Iberian Chain, NE Spain) is characterized by a system of NNW–SSE-striking, east-verging, foreland-dipping thrusts, generated in a thin-skinned context, whose formation was favoured by the presence of two main detachment levels (Precambrian and Silurian shales). During the formation of the thrust system (first phase of deformation, D
1
), the thrust sheets were deformed internally, mainly by asymmetrical folds with axial surface cleavage and east-verging thrusts; the normal evolution of the thrust system and the emplacement of an underlying thrust sheet resulted in progressive tilting and stacking, thus generating a foreland-dipping thrust system. These structures were folded and tilted by the emplacement of the Datos thrust (second phase of deformation, D
2
), generating an associated deformation characterized by subvertical folds with axial surface cleavage, with slight east vergence. These structures can obliterate the previous D
1
structures in the sector near the Datos thrust. D
1
and D
2
structures have not been observed in the same outcrops, but the relationship between bedding and cleavage as well as cleavage relationship with other structures allows discrimination between the two cleavage sets. Based on the features of Palaeozoic rocks of the Iberian Range and the Iberian Massif, we support the idea that the Herrera unit belongs to the Cantabrian Zone.
Increase in tendon protein synthesis in response to insulin-like growth factor-I is preserved in elderly men
Authors: Nielsen Rie Harboe , Holm Lars , Malmgaard-Clausen Nikolaj Mølkjær , Reitelseder Søren , Heinemeier Katja Maria , Kjaer Michael
Published: November 2013

Insulin-like growth factor-I (IGF-I) is known to be an anabolic factor in tendon, and the systemic levels are reduced with aging. However, it is uncertain how tendon fibroblasts are involved in tendon aging and how aging cells respond to IGF-I. The purpose of this study was to investigate the in vivo IGF-I stimulation of tendon protein synthesis in elderly compared with young men. We injected IGF-I in the patellar tendons of young ( n = 11, 20–30 yr of age) and old ( n = 11, 66–75 yr of age) men, and the acute fractional synthesis rate (FSR) of tendon protein was measured with the stable isotope technique and compared with the contralateral side (injected with saline as control). We found that tendons injected with IGF-I had significantly higher protein FSR compared with controls (old group: 0.018 ± 0.015 vs. 0.008 ± 0.008, young group: 0.016 ± 0.009 vs. 0.009 ± 0.006%/h, mean ± SE, P < 0.01). This increase in protein synthesis was seen in both young and old men, with no differences between age groups. The old group had markedly lower serum IGF-I levels compared with young (165 ± 17 vs. 281 ± 27 ng/ml, P < 0.01). In conclusion, local IGF-I stimulated tendon protein synthesis in both young and old men, despite lower systemic IGF-I levels in the old group. This could indicate that the changed phenotype in aging tendon is not caused by decreased fibroblast function.
What a Tangled Web We Weave: Emerging Resistance Mechanisms to Inhibition of the Phosphoinositide 3-Kinase Pathway
Authors: Klempner Samuel J. , Myers Andrea P. , Cantley Lewis C.
Published: November 2013

The phosphoinositide 3-kinase (PI3K) pathway is one of the most frequently mutated pathways in cancer, and is actively being pursued as a therapeutic target. Despite the importance of the PI3K pathway in cancer, durable responses to PI3K pathway-targeted therapies are uncommon with monotherapy. Several in vitro and xenograft models have elucidated compensatory signaling and genomic changes which may limit the therapeutic effectiveness of PI3K inhibitors in the clinic. Future clinical trials with prospective evaluation of tumor signaling and genomic changes are likely to identify novel resistance mechanisms as well as subsets of patients who may derive maximal benefit from PI3K pathway inhibitors.

Significance: There are multiple ongoing clinical trials targeting the PI3K pathway members in several malignancies. This review summarizes the known mechanisms of resistance to targeting the PI3K pathway. Understanding of resistance mechanisms will help to inform more rational clinical trial design to optimize the clinical impact of targeting the PI3K pathway in cancer. Cancer Discov; 3(12); 1345–54. ©2013 AACR.
The Genetic Landscape of Clinical Resistance to RAF Inhibition in Metastatic Melanoma
Authors: Van Allen Eliezer M. , Wagle Nikhil , Sucker Antje , Treacy Daniel J. , Johannessen Cory M. , Goetz Eva M. , Place Chelsea S. , Taylor-Weiner Amaro , Whittaker Steven , Kryukov Gregory V. , Hodis Eran , Rosenberg Mara , McKenna Aaron , Cibulskis Kristian , Farlow Deborah , Zimmer Lisa , Hillen Uwe , Gutzmer Ralf , Goldinger Simone M. , Ugurel Selma , Gogas Helen J. , Egberts Friederike , Berking Carola , Trefzer Uwe , Loquai Carmen , Weide Benjamin , Hassel Jessica C. , Gabriel Stacey B. , Carter Scott L. , Getz Gad , Garraway Levi A. , Schadendorf Dirk
Published: November 2013

Most patients with BRAFV600-mutant metastatic melanoma develop resistance to selective RAF kinase inhibitors. The spectrum of clinical genetic resistance mechanisms to RAF inhibitors and options for salvage therapy are incompletely understood. We performed whole-exome sequencing on formalin-fixed, paraffin-embedded tumors from 45 patients with BRAFV600-mutant metastatic melanoma who received vemurafenib or dabrafenib monotherapy. Genetic alterations in known or putative RAF inhibitor resistance genes were observed in 23 of 45 patients (51%). Besides previously characterized alterations, we discovered a “long tail” of new mitogen-activated protein kinase (MAPK) pathway alterations (MAP2K2, MITF) that confer RAF inhibitor resistance. In three cases, multiple resistance gene alterations were observed within the same tumor biopsy. Overall, RAF inhibitor therapy leads to diverse clinical genetic resistance mechanisms, mostly involving MAPK pathway reactivation. Novel therapeutic combinations may be needed to achieve durable clinical control of BRAFV600-mutant melanoma. Integrating clinical genomics with preclinical screens may model subsequent resistance studies.

Significance: The use of RAF inhibitors for BRAFV600-mutant metastatic melanoma improves patient outcomes, but most patients demonstrate early or acquired resistance to this targeted therapy. We reveal the genetic landscape of clinical resistance mechanisms to RAF inhibitors from patients using whole-exome sequencing, and experimentally assess new observed mechanisms to define potential subsequent treatment strategies. Cancer Discov; 4(1); 94–109. ©2013 AACR.

See related commentary by Solit and Rosen, p. 27

This article is highlighted in the In This Issue feature, p. 1
Acquired Resistance and Clonal Evolution in Melanoma during BRAF Inhibitor Therapy
Authors: Shi Hubing , Hugo Willy , Kong Xiangju , Hong Aayoung , Koya Richard C. , Moriceau Gatien , Chodon Thinle , Guo Rongqing , Johnson Douglas B. , Dahlman Kimberly B. , Kelley Mark C. , Kefford Richard F. , Chmielowski Bartosz , Glaspy John A. , Sosman Jeffrey A. , van Baren Nicolas , Long Georgina V. , Ribas Antoni , Lo Roger S.
Published: November 2013

BRAF inhibitors elicit rapid antitumor responses in the majority of patients with BRAFV600-mutant melanoma, but acquired drug resistance is almost universal. We sought to identify the core resistance pathways and the extent of tumor heterogeneity during disease progression. We show that mitogen-activated protein kinase reactivation mechanisms were detected among 70% of disease-progressive tissues, with RAS mutations, mutant BRAF amplification, and alternative splicing being most common. We also detected PI3K–PTEN–AKT–upregulating genetic alterations among 22% of progressive melanomas. Distinct molecular lesions in both core drug escape pathways were commonly detected concurrently in the same tumor or among multiple tumors from the same patient. Beyond harboring extensively heterogeneous resistance mechanisms, melanoma regrowth emerging from BRAF inhibitor selection displayed branched evolution marked by altered mutational spectra/signatures and increased fitness. Thus, melanoma genomic heterogeneity contributes significantly to BRAF inhibitor treatment failure, implying upfront, cotargeting of two core pathways as an essential strategy for durable responses.

Significance: This study provides critical insights into how human BRAF-mutant melanoma, a malignancy with marked mutational burden, escapes from BRAF inhibitors. Understanding the core resistance pathways as well as tumor heterogeneity, fitness, and mutational patterns, which emerge under drug selection, lays a foundation to rationalize clinical studies and investigate mechanisms of disease progression. Cancer Discov; 4(1); 80–93. ©2013 AACR.

See related commentary by Solit and Rosen, p. 27

This article is highlighted in the In This Issue feature, p. 1
Ex Vivo Assays of Dendritic Cell Activation and Cytokine Profiles as Predictors of In Vivo Effects in an Anti-Human CD40 Monoclonal Antibody ChiLob 7/4 Phase I Trial
Authors: Chowdhury F. , Johnson P.W. , Glennie M.J. , Williams A.P.
Published: November 2013

Immunostimulatory antibodies entering the clinic create challenge in terms of not only pharmacodynamics for monitoring anticipated mechanisms but also predetermining cytotoxicity. We show the use of ex vivo whole-blood samples to predict the activation requirements, cytokine signature, and adverse events of an anti-human-CD40 chimeric IgG1 antibody, ChiLob 7/4. Assessments were initially undertaken on human myeloid (mDC1) and plasmacytoid (pDC) dendritic cells, in which an absolute need for cross-linking was shown through the upregulation of activation markers CD83 and CCR7. Subsequent cytokine secretion evaluations of ex vivo whole blood showed the cross-linked antibody-induced increases in MIP1β, interleukin (IL)-8, IL-12, TNFα, and IL-6. This cytokine signature compared favorably with the Toll-like receptor (TLR) ligand lipopolysaccharide (LPS), in which levels of TNFα and IL-6 were significantly higher, suggesting a less intense proinflammatory response and possible modified cytokine release syndrome when used in human trials. Following first-in-human use of this agent within a dose escalation study, in vivo evaluations of dendritic cell activation and secreted cytokines closely matched the predetermined immunomonitoring endpoints. Patients showed a comparable pattern of MIP1β, IL-8, and IL-12 secretion, but no TNFα and IL-6 were identified. Mild symptoms relating to a cytokine release syndrome were seen at an equivalent dosage to that observed for dendritic cell activation and cytokine release. In summary, ChiLob 7/4 induces a distinctive pattern of dendritic cell activation and cytokine secretion in ex vivo assays that can be predictive of in vivo responses. Such preclinical approaches to monoclonal antibody evaluation may inform both the starting dosages and the anticipated cytokine release events that could occur, providing a valuable adjunct for future first-in-human assessments of immunostimulatory antibodies. Cancer Immunol Res; 2(3); 229–40. ©2013 AACR.
Outcome of Single Pediatric Deceased Donor Renal Transplantation to Adult Kidney Transplant Recipients
Authors: Friedersdorff Frank , Fuller Tom Florian , Werthemann Peter , Cash Hannes
Published: November 2013

Introduction: In times of organ shortage more kidneys were transplanted in ‘expanded criteria kidney' programs. This study examines the outcome of adult kidney recipients from pediatric donors. Materials and Methods: This single-center retrospective analysis evaluated eight adult patients who received a kidney from a deceased pediatric donor (age 5-17) between 06/2000 and 09/2011. Results: The median donor age was 14 years (range 5-17). The median recipient age was 49 years (range 25-57). The median cold ischemia time was 13.3 h (range 4.3-20.1), while the median warm ischemia time was 53 min (range 42-60). The median follow-up was 35.8 months (range 7-142). Acute rejection was observed in 50.0% of cases. The median HLA mismatch was 2.0. The median 1-year creatinine level was 0.95 mg/dl, the uncensored 1-year graft survival was 75.0% and the 3-year graft survival 62.5%, respectively. No recipient died within the follow-up period. As severe surgical complications, one stenosis of the renal artery and one lymphocele needing surgical revision were observed. Conclusions: Renal transplantation of a deceased single pediatric donor to an adult recipient can be performed safely and shows a good outcome. Wherever feasible, single pediatric kidney transplantation can double the number of recipients over an ‘en-bloc' transplantation. The price for a single pediatric kidney transplant may be a higher vascular complication rate and a higher rejection risk. Despite the higher risks, transplantation of a single pediatric donor kidney should be performed when accomplishable.
Clinical and Histological Features of Different Types of Budd-Chiari Syndrome: A Comparison of 4 Cases
Authors: Nishida Naoshi , Iwamura Shinichi , Ida Hiroshi , Hagiwara Satoshi , Kagioka Yoshinori , Minami Yasunori , Maetani Yoji , Itoh Kyo , Kudo Masatoshi
Published: November 2013

Budd-Chiari syndrome (BCS) is a rare condition characterized by hepatic venous outflow obstruction. In this report, we present 4 cases of BCS with complete and incomplete obstruction of the inferior vena cava (IVC) and hepatic vein (HV). Each case showed different and unique features of liver damage, which were attributed to the site and degree of obstruction. Interestingly, improved liver functions such as increased serum albumin levels, decreased hyaluronic acid levels and a normal indocyanine green clearance test were evident within 1 month of the balloon angioplasty. Pericellular fibrosis and hypervascular regenerative nodules were also reversible after obstruction removal. Therefore, it is very important to manage this rare disease before it progresses to liver cirrhosis.
Autoimmune Hepatitis and Immunoglobulin G4-Associated Autoimmune Hepatitis
Authors: Yada Norihisa , Kudo Masatoshi , Chung Hobyung , Watanabe Tomohiro
Published: November 2013

Autoimmune hepatitis (AIH) is a disease that is characterized by the presence of autoantibodies and elevated levels of serum immunoglobulin G (IgG) and hepatic enzymes. Its characteristic findings in the liver include interface hepatitis, infiltration of lymphocytes and plasma cells, and rosette formation, and is treated with immunosuppressive drugs. Autoimmune pancreatitis, a pancreatic disease caused by an autoimmune mechanism, is associated with elevated levels of serum IgG4 and the infiltration of IgG4-positive cells into the pancreatic parenchyma, and it is occasionally accompanied by systemic features. This systemic inflammatory disease characterized by the infiltration of IgG4-positive plasma cells and elevated serum IgG4 levels was recently classified as an IgG4-related disease. A few studies have reported AIH cases with infiltrated IgG4-positive plasma cells in the liver, suggesting the involvement of IgG4 in the pathogenesis of AIH. This feature was called IgG4-associated AIH and only two studies have been published. However, the diagnostic criteria of IgG4-associated AIH has not been defined and the epidemiology and clinical features remain uncertain. The degree of IgG4-positive plasma cell infiltration in the liver was different in each article. The serum IgG4 level was not elevated in one study, whereas it was severely elevated in the other. Corticosteroid therapy normalized liver enzymes in both studies. Further studies are needed to define the epidemiological features or diagnostic criteria.
Outcome of Double-Filtration Plasmapheresis plus Interferon Treatment in Nonresponders to Pegylated Interferon plus Ribavirin Combination Therapy
Authors: Sugimoto Kayo , Kim Soo Ryang , El-Shamy Ahmed , Imoto Susumu , Fujioka Haruma , Kim Ke Ih , Tanaka Yasuhito , Yano Yoshihiko , Kim Soo Ki , Hasegawa Yutaka , Fujinami Aya , Ohta Mitsuhiro , Hatae Takashi , Hotta Hak , Hayashi Yoshitake , Kudo Masatoshi
Published: November 2013

Objectives: We assessed the outcome of double-filtration plasmapheresis (DFPP) combined with pegylated interferon (PEG-IFN) and ribavirin (RBV) therapy in patients infected with hepatitis C virus (HCV)-1b whose HCV had not disappeared during PEG-IFN/RBV combination therapy, or who had relapsed after the end of the therapy. Additionally, we investigated factors predictive of sustained virological response (SVR), including host and viral genetic factors, to DFPP plus IFN/RBV therapy. Methods: A total of 40 patients infected with HCV-1b whose HCV virus had not been eradicated by previous PEG-IFN/RBV therapy were enrolled for treatment by DFPP plus IFN/RBV. Rapid virological response (RVR) and SVR were assessed, and pretreatment factors associated with SVR - the interleukin (IL)28B gene, the IFN/RBV resistance-determining region (IRRDR) and the IFN sensitivity-determining region (ISDR) - were analyzed. Results: Of the 40 patients, 9 (23%) achieved RVR and 10 (25%) achieved SVR. The significant factors associated with SVR were IL28B major and RVR, as assessed by multivariate analysis (p = 0.0182, p = 0.0005). Conclusion: Patients whose HCV is not eradicated by previous PEG-IFN/RBV would be good candidates for combined DFPP and IFN/RBV retreatment provided they demonstrate IL28B major and have achieved RVR.
Oxidative Stress and Epigenetic Instability in Human Hepatocarcinogenesis
Authors: Nishida Naoshi , Kudo Masatoshi
Published: November 2013

Hepatocellular carcinoma (HCC) is a major cause of cancer death, and its development is influenced by the status of inflammation and oxidative stress in the liver. Although oxidative stress might induce genetic changes and play a role in HCC development, many epigenetic alterations have also been reported in this type of tumor, suggesting the importance of epigenetic instability in hepatocarcinogenesis. Epigenetic instability results in 2 types of DNA alterations: hypermethylation of the promoter of tumor suppressor genes (TSGs), and hypomethylation of nonpromoter CpG, such as repetitive elements and satellite DNA. The former causes transcriptional inactivation of TSGs, while the latter reportedly induces chromosomal instability and an abnormal activation of oncogenes as well as mobile genetic elements. Oxidative stress could induce epigenetic instability and inactivate TSGs through the recruitment of the polycomb repressive complex to the promoter sequence carrying DNA damage induced by oxidation. Inflammatory cytokines from immune cells also reportedly induce expression of several histone and DNA modulators. On the other hand, DNA oxidation could lead to activation of DNA repair pathways and affect the binding of methyl cytosine-binding protein to DNA, which could cause DNA hypomethylation. The decrease of the level of methyl group donors also contributes to the alteration in the methylation status. These mechanisms should act in concert and induce epigenetic instability, leading to HCC.
Hypovascular Hepatic Nodules Showing Hypointense on the Hepatobiliary-Phase Image of Gd-EOB-DTPA-Enhanced MRI to Develop a Hypervascular Hepatocellular Carcinoma: A Nationwide Retrospective Study on Their Natural Course and Risk Factors
Authors: Inoue Tatsuo , Hyodo Tomoko , Murakami Takamichi , Takayama Yukihisa , Nishie Akihiro , Higaki Atsushi , Korenaga Keiko , Sakamoto Azusa , Osaki Yukio , Aikata Hiroshi , Chayama Kazuaki , Suda Takeshi , Takano Toru , Miyoshi Kennichi , Koda Masahiko , Numata Kazushi , Tanaka Hironori , Iijima Hiroko , Ochi Hironori , Hirooka Masashi , Imai Yasuharu , Kudo Masatoshi
Published: November 2013

Objective: We aimed to investigate the natural outcome of nonhypervascular lesions detected in the hepatobiliary phase of gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced MRI by performing a longitudinal study retrospectively enrolled in a nationwide manner. Methods: Between February 2008 and March 2011, 224 patients with 504 nodules that were diagnosed as nonhypervascular by imaging were recruited from institutions that participated in the present study. We examined the natural outcome of nonhypervascular lesions and evaluated the risk factors. Results: Of the 504 nodules, 173 (34.3%) showed hypervascular transformation. The overall cumulative incidence of hypervascular transformation was 14.9% at 12 months and 45.8% at 24 months. Multivariate analysis using the Cox regression model revealed previous treatment history for hepatocellular carcinoma (HCC; relative risk = 1.498; p = 0.036, 95% CI 1.03-2.19) and hyperintensity on T2-weighted images (relative risk = 1.724; p = 0.015, 95% CI 1.11-2.67) were identified as independent factors for hypervascular transformation. Conclusions: Patients who have a previous treatment history for HCC and with hypointense nodules showing hyperintensity on T2-weighted images need careful follow-up because of the high incidence of hypervascular transformation.
Hepatocellular Carcinoma in Child-Pugh C Cirrhosis: Prognostic Factors and Survival Benefit of Nontransplant Treatments
Authors: Kudo Masatoshi , Osaki Yukio , Matsunaga Takashi , Kasugai Hiroshi , Oka Hiroko , Seki Toshihito ,   for the Osaka Liver Cancer Study Group
Published: November 2013

A retrospective multicenter study was conducted to clarify the survival benefit of nontransplant treatments for patients with hepatocellular carcinoma (HCC) associated with Child-Pugh C cirrhosis. Data on 436 patients, including 203 treated patients with HCC, were collected from 20 institutions in Japan. Cox's proportional hazards model corrected for bias by propensity score analysis clearly showed the following as significant independent prognostic factors, including all four nontransplant treatments examined: transarterial chemoembolization, hepatic arterial infusion chemotherapy, percutaneous ethanol injection therapy, radiofrequency ablation, hepatitis B virus, number of tumors, log α-fetoprotein, encephalopathy, ascites and prothrombin time. The cumulative survival rate was significantly higher in the treated group than in the untreated group. The present findings suggest that prognosis can be improved by nontransplant treatments in patients with low Child-Pugh scores. Since this study was retrospective, the possibility of selection bias cannot be ruled out. Therefore, verification by a prospective controlled study is warranted.
Metformin for the Treatment of Hyperandrogenism in Adolescents with Type 1 Diabetes Mellitus
Authors: Codner Ethel , Iñíguez Germán , López Patricia , Mujica Verónica , Eyzaguirre Francisca C. , Asenjo Sylvia , Torrealba Isabel , Cassorla Fernando
Published: November 2013

Background: A high prevalence of hyperandrogenism has been reported in women with type 1 diabetes (T1D). Metformin has been used as a therapeutic agent in patients with polycystic ovarian syndrome and in T1D patients without hyperandrogenism. This study sought to determine the effect of metformin on hyperandrogenism and ovarian function in adolescents with T1D. Methods: We recruited 24 girls with T1D. The participants had hyperandrogenism and displayed suboptimal metabolic control. The patients were enrolled in a randomized, double-blind, placebo-controlled trial. One group received metformin (850 mg bid) and the other group received a placebo. Treatment was administered for 9 months. Ovulation, steroids and gonadotropin levels were evaluated. Results: Metformin treatment was associated with decreases in testosterone, free androgen index, androstenedione, 17-OH progesterone and estradiol levels. The girls who were treated with placebo showed stable steroid, gonadotropin and sex hormone-binding globulin levels during the analysis. No differences were observed in the Ferriman-Gallwey scores, ovulation rates, HbA1c levels or daily insulin doses of the girls treated with metformin compared with the placebo group. Conclusion: Treating hyperandrogenic T1D adolescents with metformin significantly decreased the serum androgens compared to the placebo, but metformin therapy did not significantly affect clinical parameters, such as hirsutism, ovulation and metabolic control.
De novo Reciprocal Translocation t(5;6)(q13;q34) in Cattle: Cytogenetic and Molecular Characterization
Authors: De Lorenzi L. , Rossi E. , Gimelli S. , Parma P.
Published: November 2013

The cytogenetic analysis of a phenotypically normal bull from the Marchigiana breed revealed the presence of an abnormal karyotype due to the presence of a very long chromosome. This finding, identified in all the metaphases observed, was associated with the 2n = 60, XY karyotype, suggesting the presence of a reciprocal translocation. RBG- banding analyses identified a de novo reciprocal translocation involving BTA5 and BTA6, t(5;6)(q13;q34), while FISH analyses using cattle-specific BACs as probes enabled the confirmation and narrowed down the breakpoint regions. Array-CGH analysis also established that neither deletions nor duplications were present in the regions including the breakpoints, nor were they present elsewhere in the genome, confirming the balanced state of the translocation.
Metastatic Germ Cell Tumour Following Renal Transplantation
Authors: Graham Donna M. , Plant William D. , Mayer Nick J. , Power Derek G.
Published: November 2013

Background: Treatment of germ cell tumours with cisplatin-based chemotherapy results in cure for the majority of patients. There is, however, a small but significant mortality rate, reported to be higher in patients with multiple co-morbidities. Case Report: We report our management of a renal transplant patient with spina bifida, who was diagnosed with stage IIIC, poor-risk, non-seminomatous germ cell carcinoma. A marker-negative partial response, which has been maintained more than 2 years following completion of treatment, was seen following chemotherapy with cisplatin and etoposide. Performance status has been preserved at pre-treatment levels. Conclusion: Administration of cisplatin-based chemotherapy is feasible for treatment of renal transplant patients with advanced non-seminomatous germ cell tumours. Treatment strategies require careful planning and monitoring. Dose modifications may be required. This case highlights a favourable outcome in spite of multiple obstacles to ideal management.
HIV, Inflammation, and Calcium in Atherosclerosis
Authors: Shrestha Sadeep , Irvin Marguerite R. , Grunfeld Carl , Arnett Donna K.
Published: November 2013

Atherosclerosis is consistently higher among the HIV-positive patients, with or without treatment, than among the HIV-negative population. Risk factors linked to atherosclerotic cardiovascular disease in HIV infection are both traditional and HIV specific although the underlying mechanisms are not fully delineated. Three key sequential biological processes are postulated to accelerate progression of atherosclerosis in the context of HIV: (1) inflammation, (2) transformation of monocytes to macrophages and then foam cells, and (3) apoptosis of foam cells leading to plaque development through Ca
2+
-dependent endoplasmic reticulum stress. These proatherogenic mechanisms are further affected when HIV interacts with the genes involved in various phases within this network.
C-Reactive Protein Predicts Hematoma Growth in Intracerebral Hemorrhage
Authors: Di Napoli Mario , Parry-Jones Adrian R. , Smith Craig J. , Hopkins Stephen J. , Slevin Mark , Masotti Luca , Campi Veronica , Singh Puneetpal , Papa Francesca , Popa-Wagner Aurel , Tudorica Valerica , Godoy Daniel Agustin
Published: November 2013

Background and Purpose—

Early hematoma growth (EHG) occurs in about one third of patients with spontaneous intracerebral hemorrhage. The main aim of this study was to investigate the potential of plasma C-reactive protein (CRP) for predicting EHG after acute spontaneous intracerebral hemorrhage.

Methods—

Plasma CRP was measured within 6 hours of onset (median, 120 minutes) in 399 patients with primary or vitamin K antagonist–associated spontaneous intracerebral hemorrhage and without recent infection. Computed tomography brain scans were performed at baseline and repeated within 24 hours (median, 22 hours). The primary outcome was EHG, defined as absolute growth >12.5 cm
3
or relative growth >33%. Secondary outcomes included early neurological worsening (ENW) using the Glasgow Coma Scale and 30-day mortality. Multivariable regression analyses were used to evaluate associations of CRP concentration and outcomes. Kaplan–Meier analysis was used for survival.

Results—

EHG occurred in 25.8%, ENW in 19.3%, and mortality was 31.8% at 30 days. Thirty-day mortality was significantly higher in patients with ENW (hazard ratio, 3.21; 95% confidence interval, 2.00–5.17;
P
<0.0001) and in patients with EHG (hazard ratio, 2.13; 95% confidence interval, 1.42–3.18;
P
<0.0001, log-rank test). Median CRP was 12 mg/L (interquartile range, 10–17) in the EHG group and 7 mg/L (interquartile range, 4–12.1) in those without EHG (
P
<0.0001). In multivariable analyses, plasma CRP>10 mg/L independently predicted EHG (odds ratio, 4.71; 95% confidence interval, 2.75–8.06;
P
<0.0001) and ENW (odds ratio, 2.70; 95% confidence interval, 1.50–4.84;
P
=0.0009).

Conclusions—

CRP>10 mg/L is independently predictive of EHG and ENW, both of which are associated with increased mortality. Inflammation may be important in contributing to EHG and warrants further investigation.