bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of Genes Upregulated in ALK-Positive and EGFR/KRAS/ALK-Negative Lung Adenocarcinomas
Authors: Okayama Hirokazu , Kohno Takashi , Ishii Yuko , Shimada Yoko , Shiraishi Kouya , Iwakawa Reika , Furuta Koh , Tsuta Koji , Shibata Tatsuhiro , Yamamoto Seiichiro , Watanabe Shun-ichi , Sakamoto Hiromi , Kumamoto Kensuke , Takenoshita Seiichi , Gotoh Noriko , Mizuno Hideaki , Sarai Akinori , Kawano Shuichi , Yamaguchi Rui , Miyano Satoru , Yokota Jun 
Published: November 2011

Abstract
Activation of the EGFR, KRAS, and ALK oncogenes defines 3 different pathways of molecular pathogenesis in lung adenocarcinoma. However, many tumors lack activation of any pathway (triple-negative lung adenocarcinomas) posing a challenge for prognosis and treatment. Here, we report an extensive genome-wide expression profiling of 226 primary human stage I–II lung adenocarcinomas that elucidates molecular characteristics of tumors that harbor ALK mutations or that lack EGFR, KRAS, and ALK mutations, that is, triple-negative adenocarcinomas. One hundred and seventy-four genes were selected as being upregulated specifically in 79 lung adenocarcinomas without EGFR and KRAS mutations. Unsupervised clustering using a 174-gene signature, including ALK itself, classified these 2 groups of tumors into ALK-positive cases and 2 distinct groups of triple-negative cases (groups A and B). Notably, group A triple-negative cases had a worse prognosis for relapse and death, compared with cases with EGFR, KRAS, or ALK mutations or group B triple-negative cases. In ALK-positive tumors, 30 genes, including ALK and GRIN2A, were commonly overexpressed, whereas in group A triple-negative cases, 9 genes were commonly overexpressed, including a candidate diagnostic/therapeutic target DEPDC1, that were determined to be critical for predicting a worse prognosis. Our findings are important because they provide a molecular basis of ALK-positive lung adenocarcinomas and triple-negative lung adenocarcinomas and further stratify more or less aggressive subgroups of triple-negative lung ADC, possibly helping identify patients who may gain the most benefit from adjuvant chemotherapy after surgical resection. Cancer Res; 72(1); 100–11. ©2011 AACR.
Metastasis Suppressor NM23-H1 Promotes Repair of UV-Induced DNA Damage and Suppresses UV-Induced Melanomagenesis
Authors: Jarrett Stuart G. , Novak Marian , Dabernat Sandrine , Daniel Jean-Yves , Mellon Isabel , Zhang Qingbei , Harris Nathan , Ciesielski Michael J. , Fenstermaker Robert A. , Kovacic Diane , Slominski Andrzej , Kaetzel David M. 
Published: November 2011

Abstract
Reduced expression of the metastasis suppressor NM23-H1 is associated with aggressive forms of multiple cancers. Here, we establish that NM23-H1 (termed H1 isoform in human, M1 in mouse) and two of its attendant enzymatic activities, the 3′–5′ exonuclease and nucleoside diphosphate kinase, are novel participants in the cellular response to UV radiation (UVR)–induced DNA damage. NM23-H1 deficiency compromised the kinetics of repair for total DNA polymerase–blocking lesions and nucleotide excision repair of (6–4) photoproducts in vitro. Kinase activity of NM23-H1 was critical for rapid repair of both polychromatic UVB/UVA-induced (290–400 nm) and UVC-induced (254 nm) DNA damage, whereas its 3′–5′ exonuclease activity was dominant in the suppression of UVR-induced mutagenesis. Consistent with its role in DNA repair, NM23-H1 rapidly translocated to sites of UVR-induced (6–4) photoproduct DNA damage in the nucleus. In addition, transgenic mice hemizygous-null for nm23-m1 and nm23-m2 exhibited UVR-induced melanoma and follicular infundibular cyst formation, and tumor-associated melanocytes displayed invasion into adjacent dermis, consistent with loss of invasion-suppressing activity of NM23 in vivo. Taken together, our data show a critical role for NM23 isoforms in limiting mutagenesis and suppressing UVR-induced melanomagenesis. Cancer Res; 72(1); 133–43. ©2011 AACR.
Costimulatory Protein 4IgB7H3 Drives the Malignant Phenotype of Glioblastoma by Mediating Immune Escape and Invasiveness
Authors: Lemke Dieter , Pfenning Philipp-Niclas , Sahm Felix , Klein Ann-Catherine , Kempf Tore , Warnken Uwe , Schnölzer Martina , Tudoran Ruxandra , Weller Michael , Platten Michael , Wick Wolfgang 
Published: November 2011

Abstract
Purpose: Recent work points out a role of B7H3, a member of the B7-family of costimulatory proteins, in conveying immunosuppression and enforced invasiveness in a variety of tumor entities. Glioblastoma is armed with effective immunosuppressive properties resulting in an impaired recognition and ineffective attack of tumor cells by the immune system. In addition, extensive and diffuse invasion of tumor cells into the surrounding brain tissue limits the efficacy of local therapies. Here, 4IgB7H3 is assessed as diagnostic and therapeutic target for glioblastoma.
Experimental Design: To characterize B7H3 in glioblastoma, we conduct analyses not only in glioma cell lines and glioma-initiating cells but also in human glioma tissue specimens.
Results: B7H3 expression by tumor and endothelial cells correlates with the grade of malignancy in gliomas and with poor survival. Both soluble 4IgB7H3 in the supernatant of glioma cells and cell-bound 4IgB7H3 are functional and suppress natural killer cell–mediated tumor cell lysis. Gene silencing showed that membrane and soluble 4IgB7H3 convey a proinvasive phenotype in glioma cells and glioma-initiating cells in vitro. These proinvasive and immunosuppressive properties were confirmed in vivo by xenografted 4IgB7H3 gene silenced glioma-initiating cells, which invaded significantly less into the surrounding brain tissue in an orthotopic model and by subcutaneously injected LN-229 cells, which were more susceptible to natural killer cell–mediated cytotoxicity than unsilenced control cells.
Conclusions: Because of its immunosuppressive and proinvasive function, 4IgB7H3 may serve as a therapeutic target in the treatment of glioblastoma. Clin Cancer Res; 18(1); 105–17. ©2011 AACR.
A qualitative study of how mothers and teenage daughters negotiate sex-related risk and independence
Authors: Salmon Debra 
Published: November 2011

Concern across more economically developed nations has focused on the role of parental communication and monitoring in predicting risk-taking behaviour and health outcomes. However, explorations of how mothers and daughters negotiate risk remain under-researched. This paper presents the findings of a qualitative study examining mothers’ and teenage daughters’ perceptions of risk-related health concerns around sexual behaviour and the implications for health policy, nursing practice and future research. A purposive sample of seven young women aged 14–16 years and their mothers ( n = 14) were recruited from low-income families living in the south-west of England. Data were collected through longitudinal in-depth interviews and were analysed for thematic content using constant comparative methods. Findings highlighted how mothers and daughters understand risks associated with sex and relationships and their implications for safety. Mothers’ concerns focused on their daughters’ vulnerability to the risk of sexual threat, particularly after alcohol consumption. Within relationships mothers did not advocate abstinence but developed harm minimisation approaches to minimise the impact of risk taking and maximise opportunities for independence. Strategies based on trust and openness were preferred to expectations of rigid adherence in rule negotiation. Clinical significance lies in building on maternal expertise to develop community-based initiatives that have the potential to improve health and clinical outcomes for young women.
Transcriptome analysis of orange-spotted grouper (Epinephelus coioides) spleen in response to Singapore grouper iridovirus
Authors: Huang Youhua , Huang Xiaohong , Yan Yang , Cai Jia , Ouyang Zhengliang , Cui Huachun , Wang Peiran , Qin Qiwei 
Published: November 2011

Abstract

Background
Orange-spotted grouper (Epinephelus coioides) is an economically important marine fish cultured in China and Southeast Asian countries. The emergence of infectious viral diseases, including iridovirus and betanodavirus, have severely affected food products based on this species, causing heavy economic losses. Limited available information on the genomics of E. coioides has hampered the understanding of the molecular mechanisms that underlie host-virus interactions. In this study, we used a 454 pyrosequencing method to investigate differentially-expressed genes in the spleen of the E. coioides infected with Singapore grouper iridovirus (SGIV).

Results
Using 454 pyrosequencing, we obtained abundant high-quality ESTs from two spleen-complementary DNA libraries which were constructed from SGIV-infected (V) and PBS-injected fish (used as a control: C). A total of 407,027 and 421,141 ESTs were produced in control and SGIV infected libraries, respectively. Among the assembled ESTs, 9,616 (C) and 10,426 (V) ESTs were successfully matched against known genes in the NCBI non-redundant (nr) database with a cut-off E-value above 10-5. Gene ontology (GO) analysis indicated that "cell part", "cellular process" and "binding" represented the largest category. Among the 25 clusters of orthologous group (COG) categories, the cluster for "translation, ribosomal structure and biogenesis" represented the largest group in the control (185 ESTs) and infected (172 ESTs) libraries. Further KEGG analysis revealed that pathways, including cellular metabolism and intracellular immune signaling, existed in the control and infected libraries. Comparative expression analysis indicated that certain genes associated with mitogen-activated protein kinase (MAPK), chemokine, toll-like receptor and RIG-I signaling pathway were alternated in response to SGIV infection. Moreover, changes in the pattern of gene expression were validated by qRT-PCR, including cytokines, cytokine receptors, and transcription factors, apoptosis-associated genes, and interferon related genes.

Conclusion
This study provided abundant ESTs that could contribute greatly to disclosing novel genes in marine fish. Furthermore, the alterations of predicted gene expression patterns reflected possible responses of these fish to the virus infection. Taken together, our data not only provided new information for identification of novel genes from marine vertebrates, but also shed new light on the understanding of defense mechanisms of marine fish to viral pathogens.
A Mad Mayor of Fremantle: The Mysterious Illness of Edward Davies
Authors: Martyr Philippa , Janca Aleksandar 
Published: November 2011

Objective: The aim of this paper is to illustrate how a person's standing in a small, close-knit community can distort local medical and legal attitudes to their diagnosis. We examined various historical texts describing Edward Davies (1855–1904), Mayor of Fremantle, and the medical, legal and family responses to his illness. Conclusions: When Davies developed an apparently serious mental illness, his family was able to keep this behaviour hidden for some time. However, when evidence of his illness finally erupted into the public eye, it led to a ground-breaking 1903 case in the WA Supreme Court in Lunacy. It is clear that Davies' defenders wanted him to be diagnosed and treated as an alcoholic, when in fact he may have had late onset psychosis, complicated by alcohol abuse. With the increasing amount of historical material available through Australian digitized newspaper collections, new scope is opening up for retrospective diagnosis.
Inducible CD4+LAP+Foxp3− Regulatory T Cells Suppress Allergic Inflammation
Authors: Duan Wei , So Takanori , Mehta Amit K. , Choi Heonsik , Croft Michael 
Published: November 2011

Abstract
Regulatory T cells (Tregs) play a critical role in the maintenance of airway tolerance. We report that inhaled soluble Ag induces adaptive Foxp3+ Tregs, as well as a regulatory population of CD4+ T cells in the lungs and lung-draining lymph nodes that express latency-associated peptide (LAP) on their cell surface but do not express Foxp3. Blocking the cytokine IL-10 or TGF-β prevented the generation of LAP+ Tregs and Foxp3+ Tregs in vivo, and the LAP+ Tregs could also be generated concomitantly with Foxp3+ Tregs in vitro by culturing naive CD4+ T cells with Ag and exogenous TGF-β. The LAP+ Tregs strongly suppressed naive CD4+ T cell proliferation, and transfer of sorted OVA-specific LAP+ Tregs in vivo inhibited allergic eosinophilia and Th2 cytokine expression in the lung, either when present at the time of Th2 sensitization or when injected after Th2 cells were formed. Furthermore, inflammatory innate stimuli from house dust mite extract, nucleotide-binding oligomerization domain containing 2 ligand, and LPS, which are sufficient for blocking airway tolerance, strongly decreased the induction of LAP+ Tregs. Taken together, we concluded that inducible Ag-specific LAP+ Tregs can suppress asthmatic lung inflammation and constitute a mediator of airway tolerance together with Foxp3+ Tregs.
Elongation Factor-2, a Th1 Stimulatory Protein of Leishmania donovani, Generates Strong IFN-γ and IL-12 Response in Cured Leishmania-Infected Patients/Hamsters and Protects Hamsters against Leishmania Challenge
Authors: Kushawaha Pramod K. , Gupta Reema , Sundar Shyam , Sahasrabuddhe Amogh A. , Dube Anuradha 
Published: November 2011

Abstract
In visceral leishmaniasis, Th1 types of immune responses correlate with recovery from and resistance to disease, and resolution of infection results in lifelong immunity against the disease. Leishmanial Ags that elicit proliferative and cytokine responses in PBMCs from cured/exposed/Leishmania patients have been characterized through proteomic approaches, and elongation factor-2 is identified as one of the potent immunostimulatory proteins. In this study, we report the cloning and expression of Leishmania donovani elongation factor-2 protein (LelF-2) and its immunogenicity in PBMCs of cured/exposed Leishmania-infected patients and hamsters (Mesocricetus auratus). Leishmania-infected cured/exposed patients and hamsters exhibited significantly higher proliferative responses to recombinant Lelf-2 (rLelF-2) than those with L. donovani-infected hosts. The soluble L. donovani Ag stimulated PBMCs of cured/exposed and Leishmania patients to produce a mixed Thl/Th2-type cytokine profile, whereas rLelF-2 stimulated the production of IFN-γ, IL-12, and TNF-α but not IL-4 or IL-10. Further, rLelF-2 downregulated LPS-induced IL-10 as well as soluble L. donovani Ag-induced IL-4 production by Leishmania patient PBMCs. The immunogenicity of rLelF-2 was also checked in hamsters in which rLelF-2 generates strong IL-12– and IFN-γ–mediated Th1 immune response. This was further supported by a remarkable increase in IgG2 Ab level. We further demonstrated that rLelF-2 was able to provide considerable protection (∼65%) to hamsters against L. donovani challenge. The efficacy was supported by the increased inducible NO synthase mRNA transcript and Th1-type cytokines IFN-γ, IL-12, and TNF-α and downregulation of IL-4, IL-10, and TGF-β. Hence, it is inferred that rLelF-2 elicits a Th1 type of immune response exclusively and confers considerable protection against experimental visceral leishmaniasis.
Dengue Virus-Induced Autoantibodies Bind to Plasminogen and Enhance Its Activation
Authors: Chuang Yung-Chun , Lei Huan-Yao , Lin Yee-Shin , Liu Hsiao-Sheng , Wu Hua-Lin , Yeh Trai-Ming 
Published: November 2011

Abstract
Dengue virus infection can lead to life-threatening dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS) in patients. Abnormal activation of the coagulation and fibrinolysis system is one of the hallmarks associated with DHF/DSS patients. However, the mechanisms that cause pathology in DHF/DSS patients are still unclear. Because conversion of plasminogen (Plg) to plasmin (Plm) is the first step in the activation of fibrinolysis, Abs against Plg found in DHF/DSS patients may be important. Therefore, to investigate the specificity, function, and possible origin of these Abs, we generated several Plg cross-reactive mAbs from DENV-immunized mice. An IgG mAb, 6H11, which recognizes an epitope associated with a dengue envelope protein, demonstrated a high level of cross-reactivity with Plg. The 6H11 Ab was further characterized with regard to its effect on Plg activation. Using Plm-specific chromogenic substrate S-2251, we found that mAb 6H11 demonstrated serine protease activity and could convert Plg directly to Plm. The serine protease activity of mAb 6H11 was further confirmed using serine protease chromogenic substrate S-2288. In addition, we found several Plg cross-reactive mAbs that could enhance urokinase-induced Plg activation. Lastly, mAb 6H11 could induce Plm activity and increase the level of D-dimer (a fibrin degradation product) in both human and mouse platelet-poor plasma. Taken together, these data suggest DENV-induced Plg cross-reactive Abs may enhance Plg conversion to Plm, which would be expected to contribute to hyperfibrinolysis in DHF/DSS patients.
Regulation of TCRβ Allelic Exclusion by Gene Segment Proximity and Accessibility
Authors: Kondilis-Mangum Hrisavgi D. , Shih Han-Yu , Mahowald Grace , Sleckman Barry P. , Krangel Michael S. 
Published: November 2011

Abstract
Ag receptor loci are regulated to promote allelic exclusion, but the mechanisms are not well understood. Assembly of a functional TCR β-chain gene triggers feedback inhibition of Vβ-to-DJβ recombination in double-positive (DP) thymocytes, which correlates with reduced Vβ chromatin accessibility and a locus conformational change that separates Vβ from DJβ gene segments. We previously generated a Tcrb allele that maintained Vβ accessibility but was still subject to feedback inhibition in DP thymocytes. We have now further analyzed the contributions of chromatin accessibility and locus conformation to feedback inhibition using two novel TCR alleles. We show that reduced Vβ accessibility and increased distance between Vβ and DJβ gene segments both enforce feedback inhibition in DP thymocytes.
Cutting Edge: Activation of Virus-Specific CD4 T Cells throughout γ-Herpesvirus Latency
Authors: Freeman Michael L. , Burkum Claire E. , Lanzer Kathleen G. , Jensen Meghan K. , Ahmed Mushtaq , Yager Eric J. , Flaño Emilio , Winslow Gary M. , Woodland David L. , Blackman Marcia A. 
Published: November 2011

Abstract
CD4 T cells are essential for immune control of γ-herpesvirus latency. We previously identified a murine MHC class II-restricted epitope in γ-herpesvirus-68 gp150 (gp15067–83I-Ab) that elicits CD4 T cells that are maintained throughout long-term infection. However, it is unknown whether naive cells can be recruited into the antiviral CD4 T cell pool during latency. In this study, we generate a mouse transgenic for a gp150-specific TCR and show epitope-specific activation of transgenic CD4 T cells during acute and latent infections. Furthermore, although only dendritic cells can stimulate virus-specific CD8 T cells during latency, we show that both dendritic cells and B cells stimulate transgenic CD4 T cells. These studies demonstrate that naive CD4 T cells specific for a viral glycoprotein can be stimulated throughout infection, even during quiescent latency, suggesting that CD4 T cell memory is maintained in part by the continual recruitment of naive cells.
Computed tomography scanning facilitates the diagnosis of sacroiliitis in patients with suspected spondylarthritis: Results of a prospective multicenter French cohort study
Authors: Devauchelle‐Pensec Valérie , D'Agostino Maria Antonietta , Marion Julien , Lapierre Marie , Jousse‐Joulin Sandrine , Colin Danielle , Chary‐Valckenaere Isabelle , Marcelli Christian , Loeuille Damien , Aegerter Philippe , Guis Sandrine , Gaudin Philippe , Breban Maxime , Saraux Alain ,   Study Group of Spondylarthritis
Published: November 2011

AbstractObjectiveTo assess the performance of computed tomography (CT) scanning for ascertaining sacroiliitis in patients with suspected spondylarthritis (SpA).MethodsThe Echography in Spondylarthritis French cohort consists of 489 patients with suspected SpA. At baseline, all patients underwent clinical examination, HLA–B typing, and pelvic radiography. Pelvic CT scanning was performed if sacroiliitis on radiography was considered uncertain or if patients presented with buttock pain duration of >6 months. A set of 100 paired radiographs and CT scans was read in a blinded manner by 2 radiologists, and the kappa coefficient was used to assess their interreader reliability. One of the radiologists read the 173 available pairs of radiographs and CT scans performed at baseline.ResultsAfter training, interreader reliability was moderate for sacroiliitis grading on radiographs (κ = 0.59), excellent on CT scans (κ = 0.91), and excellent for ascertaining sacroiliitis on both radiographs (κ = 1) and CT scans (κ = 0.96). The first and second readers considered the quality of imaging to be excellent in 66% and 67%, respectively, of the radiographs (κ = 0.88) and in 93% and 92%, respectively, of the CT scans (κ = 0.93). Concordance between radiographs and CT scans was low for sacroiliitis grading (κ = 0.08) or ascertainment (κ = 0.16). Definite sacroiliitis was ascertained on radiographs in 6 patients (3.5%) (confirmed by CT scans in 4 patients) and on CT scans in 32 patients (18.5%). A history of uveitis was associated with definite sacroiliitis on radiographs (P = 0.04) and CT scans (P < 0.0001).ConclusionDefinite sacroiliitis was underestimated by radiography, as compared to CT scanning. CT scanning should facilitate the diagnosis of ankylosing spondylitis in patients with suspected SpA.
Neuropathology of sporadic Parkinson's disease: Evaluation and changes of concepts
Authors: Jellinger Kurt A. 
Published: November 2011

AbstractParkinson's disease (PD), one of the most frequent neurodegenerative disorders, is no longer considered a complex motor disorder characterized by extrapyramidal symptoms, but a progressive multisystem or—more correctly—multiorgan disease with variegated neurological and nonmotor deficiencies. It is morphologically featured not only by the degeneration of the dopaminergic nigrostriatal system, responsible for the core motor deficits, but by multifocal involvement of the central, peripheral and autonomic nervous system and other organs associated with widespread occurrence of Lewy bodies and dystrophic Lewy neurites. This results from deposition of abnormal α‐synuclein (αSyn), the major protein marker of PD, and other synucleinopathies. Recent research has improved both the clinical and neuropathological diagnostic criteria of PD; it has further provided insights into the development and staging of αSyn and Lewy pathologies and has been useful in understanding the pathogenesis of PD. However, many challenges remain, for example, the role of Lewy bodies and the neurobiology of axons in the course of neurodegeneration, the relation between αSyn, Lewy pathology, and clinical deficits, as well as the interaction between αSyn and other pathologic proteins. Although genetic and experimental models have contributed to exploring the causes, pathomechanisms, and treatment options of PD, there is still a lack of an optimal animal model, and the etiology of this devastating disease is far from being elucidated. © 2011 Movement Disorder Society