bluuebunny/crossref_metadata_2025_split huggingface dataset:
Divergent Immune Responses to Mycobacterium avium subsp. paratuberculosis Infection Correlate with Kinome Responses at the Site of Intestinal Infection
Authors: Määttänen Pekka , Trost Brett , Scruten Erin , Potter Andrew , Kusalik Anthony , Griebel Philip , Napper Scott 
Published: May 2013

ABSTRACT

Mycobacterium avium
subsp.
paratuberculosis
is the causative agent of Johne's disease (JD) in cattle.
M. avium
subsp.
paratuberculosis
infects the gastrointestinal tract of calves, localizing and persisting primarily in the distal ileum. A high percentage of cattle exposed to
M. avium
subsp.
paratuberculosis
do not develop JD, but the mechanisms by which they resist infection are not understood. Here, we merge an established
in vivo
bovine intestinal segment model for
M. avium
subsp.
paratuberculosis
infection with bovine-specific peptide kinome arrays as a first step to understanding how infection influences host kinomic responses at the site of infection. Application of peptide arrays to
in vivo
tissue samples represents a critical and ambitious step in using this technology to understand host-pathogen interactions. Kinome analysis was performed on intestinal samples from 4 ileal segments subdivided into 10 separate compartments (6
M. avium
subsp.
paratuberculosis
-infected compartments and 4 intra-animal controls) using bovine-specific peptide arrays. Kinome data sets clustered into two groups, suggesting unique binary responses to
M. avium
subsp.
paratuberculosis
. Similarly, two
M. avium
subsp.
paratuberculosis
-specific immune responses, characterized by different antibody, T cell proliferation, and gamma interferon (IFN-γ) responses, were also observed. Interestingly, the kinomic groupings segregated with the immune response groupings. Pathway and gene ontology analyses revealed that differences in innate immune and interleukin signaling and particular differences in the Wnt/β-catenin pathway distinguished the kinomic groupings. Collectively, kinome analysis of tissue samples offers insight into the complex cellular responses induced by
M. avium
subsp.
paratuberculosis
in the ileum and provides a novel method to understand mechanisms that alter the balance between cell-mediated and antibody responses to
M. avium
subsp.
paratuberculosis
infection.
Enteric disease on Operation HERRICK
Authors: Connor Patrick , Hutley E , Mulcahy H E , Riddle M S 
Published: May 2013

BackgroundIt is increasingly recognised that diarrhoeal disease is an important contributor to disease non-battle injury (DNBI) rates on operations. Current data collection methods (J97/EPINATO) rely on self-presentation of patients to medical care, which is likely to under-record the true incidence of diarrhoea in theatre. Along with this, the data recording itself is less than adequate, with acknowledged issues in classification of diarrhoeal disease within J97/EPINATO categories.MethodsTwo post-tour diarrhoeal disease questionnaire surveillance exercises were carried out at the end of Operation HERRICK 6 (H6) and 10 (H10), respectively.ResultsCrude diarrhoeal disease attack rates were similar across the two surveillance periods with approximately 40% of troops questioned reporting at least one diarrhoeal illness episode. The severity of illness increased from H6 to H10 as measured by disease-related symptomatology and days ill and/or off work. Mission burden was substantial and increased in H10 compared with H6.ConclusionsDiarrhoeal disease is a significant cause of DNBI on operations. Current data collection methodologies underestimate its incidence and true operational burden.
Tumor Promotion by Intratumoral Plasmacytoid Dendritic Cells Is Reversed by TLR7 Ligand Treatment
Authors: Le Mercier Isabelle , Poujol Dominique , Sanlaville Amélien , Sisirak Vanja , Gobert Michael , Durand Isabelle , Dubois Bertrand , Treilleux Isabelle , Marvel Jacqueline , Vlach Jaromir , Blay Jean-Yves , Bendriss-Vermare Nathalie , Caux Christophe , Puisieux Isabelle , Goutagny Nadège 
Published: May 2013

Abstract
Plasmacytoid dendritic cells (pDC) are key regulators of antiviral immunity. In previous studies, we reported that pDC-infiltrating human primary breast tumors represent an independent prognostic factor associated with poor outcome. To understand this negative impact of tumor-associated pDC (TApDC), we developed an orthotopic murine mammary tumor model that closely mimics the human pathology, including pDC and regulatory T cell (Treg) infiltration. We showed that TApDC are mostly immature and maintain their ability to internalize antigens in vivo and to activate CD4+ T cells. Most importantly, TApDC were specifically altered for cytokine production in response to Toll-like receptor (TLR)–9 ligands in vitro while preserving unaltered response to TLR7 ligands (TLR7L). In vivo pDC depletion delayed tumor growth, showing that TApDC provide an immune-subversive environment, most likely through Treg activation, thus favoring tumor progression. However, in vivo intratumoral administration of TLR7L led to TApDC activation and displayed a potent curative effect. Depletion of pDC and type I IFN neutralization prevented TLR7L antitumoral effect. Our results establish a direct contribution of TApDC to primary breast tumor progression and rationalize the application of TLR7 ligands to restore TApDC activation in breast cancer. Cancer Res; 73(15); 4629–40. ©2013 AACR.
Evaluation of LDH-A and Glutaminase Inhibition In Vivo by Hyperpolarized 13C-Pyruvate Magnetic Resonance Spectroscopy of Tumors
Authors: Dutta Prasanta , Le Anne , Vander Jagt David L. , Tsukamoto Takashi , Martinez Gary V. , Dang Chi V. , Gillies Robert J. 
Published: May 2013

Abstract
Hyperpolarized 13C magnetic resonance spectroscopy provides a unique opportunity to detect real-time metabolic fluxes as a means to measure metabolic treatment responses in vivo. Here, we show that pharmacologic inhibition of lactate dehydrogenase-A suppressed the conversion of hyperpolarized 13C-pyruvate to lactate in murine xenografts of P493 human lymphoma. In contrast, a glutaminase inhibitor reduced conversion of 13C-pyruvate to alanine without affecting conversion of pyruvate to lactate. These results illustrate the ability to monitor biomarkers for responses to antimetabolic therapy in real-time, paving the way for clinical development of imaging biomarkers to monitor metabolic pharmacodynamics. Cancer Res; 73(14); 4190–5. ©2013 AACR.
Therapeutic Potential of HSP90 Inhibition for Neurofibromatosis Type 2
Authors: Tanaka Karo , Eskin Ascia , Chareyre Fabrice , Jessen Walter J. , Manent Jan , Niwa-Kawakita Michiko , Chen Ruihong , White Cory H. , Vitte Jeremie , Jaffer Zahara M. , Nelson Stanley F. , Rubenstein Allan E. , Giovannini Marco 
Published: May 2013

Abstract
Purpose: The growth and survival of neurofibromatosis type 2 (NF2)–deficient cells are enhanced by the activation of multiple signaling pathways including ErbBs/IGF-1R/Met, PI3K/Akt, and Ras/Raf/Mek/Erk1/2. The chaperone protein HSP90 is essential for the stabilization of these signaling molecules. The aim of the study was to characterize the effect of HSP90 inhibition in various NF2-deficient models.
Experimental Design: We tested efficacy of the small-molecule NXD30001, which has been shown to be a potent HSP90 inhibitor. The antiproliferative activity of NXD30001 was tested in NF2-deficient cell lines and in human primary schwannoma and meningioma cultures in vitro. The antitumor efficacy of HSP90 inhibition in vivo was verified in two allograft models and in one NF2 transgenic model. The underlying molecular alteration was further characterized by a global transcriptome approach.
Results: NXD30001 induced degradation of client proteins in and suppressed proliferation of NF2-deficient cells. Differential expression analysis identified subsets of genes implicated in cell proliferation, cell survival, vascularization, and Schwann cell differentiation whose expression was altered by NXD30001 treatment. The results showed that NXD30001 in NF2-deficient schwannoma suppressed multiple pathways necessary for tumorigenesis.
Conclusions: HSP90 inhibition showing significant antitumor activity against NF2-related tumor cells in vitro and in vivo represents a promising option for novel NF2 therapies. Clin Cancer Res; 19(14); 3856–70. ©2013 AACR.
Leukemia Cell-Rhabdovirus Vaccine: Personalized Immunotherapy for Acute Lymphoblastic Leukemia
Authors: Conrad David P. , Tsang Jovian , Maclean Meaghan , Diallo Jean-Simon , Le Boeuf Fabrice , Lemay Chantal G. , Falls Theresa J. , Parato Kelley A. , Bell John C. , Atkins Harold L. 
Published: May 2013

Abstract
Purpose: Acute lymphoblastic leukemia (ALL) remains incurable in most adults. It has been difficult to provide effective immunotherapy to improve outcomes for the majority of patients. Rhabdoviruses induce strong antiviral immune responses. We hypothesized that mice administered ex vivo rhabdovirus-infected ALL cells [immunotherapy by leukemia-oncotropic virus (iLOV)] would develop robust antileukemic immune responses capable of controlling ALL.
Experimental Design: Viral protein production, replication, and cytopathy were measured in human and murine ALL cells exposed to attenuated rhabdovirus. Survival following injection of graded amounts of ALL cells was compared between cohorts of mice administered γ-irradiated rhabdovirus-infected ALL cells (iLOV) or multiple control vaccines to determine key immunotherapeutic components and characteristics. Host immune requirements were assessed in immunodeficient and bone marrow–transplanted mice or by adoptive splenocyte transfer from immunized donors. Antileukemic immune memory was ascertained by second leukemic challenge in long-term survivors.
Results: Human and murine ALL cells were infected and killed by rhabdovirus; this produced a potent antileukemia vaccine. iLOV protected mice from otherwise lethal ALL by developing durable leukemia-specific immune-mediated responses (P &lt; 0.0001), which required an intact CTL compartment. Preexisting antiviral immunity augmented iLOV potency. Splenocytes from iLOV-vaccinated donors protected 60% of naïve recipients from ALL challenge (P = 0.0001). Injecting leukemia cells activated by, or concurrent with, multiple Toll-like receptor agonists could not reproduce the protective effect of iLOV. Similarly, injecting uninfected irradiated viable, apoptotic, or necrotic leukemia cells with/without concurrent rhabdovirus administration was ineffective.
Conclusion: Rhabdovirus-infected leukemia cells can be used to produce a vaccine that induces robust specific immunity against aggressive leukemia. Clin Cancer Res; 19(14); 3832–43. ©2013 AACR.
Functional Profiling of Receptor Tyrosine Kinases and Downstream Signaling in Human Chondrosarcomas Identifies Pathways for Rational Targeted Therapy
Authors: Zhang Yi-Xiang , van Oosterwijk Jolieke G. , Sicinska Ewa , Moss Samuel , Remillard Stephen P. , van Wezel Tom , Bühnemann Claudia , Hassan Andrew B. , Demetri George D. , Bovée Judith V.M.G. , Wagner Andrew J. 
Published: May 2013

Abstract
Purpose: Chondrosarcomas are notoriously resistant to cytotoxic chemotherapeutic agents. We sought to identify critical signaling pathways that contribute to their survival and proliferation, and which may provide potential targets for rational therapeutic interventions.
Experimental Design: Activation of receptor tyrosine kinases (RTK) was surveyed using phospho-RTK arrays. S6 phosphorylation and NRAS mutational status were examined in chondrosarcoma primary tumor tissues. siRNA or small-molecule inhibitors against RTKs or downstream signaling proteins were applied to chondrosarcoma cells and changes in biochemical signaling, cell cycle, and cell viability were determined. In vivo antitumor activity of BEZ235, a phosphoinositide 3-kinase (PI3K)/mTOR inhibitor, was evaluated in a chondrosarcoma xenograft model.
Results: Several RTKs were identified as critical mediators of cell growth, but the RTK dependencies varied among cell lines. In exploration of downstream signaling pathways, strong S6 phosphorylation was found in 69% of conventional chondrosarcomas and 44% of dedifferentiated chondrosarcomas. Treatment with BEZ235 resulted in dramatic reduction in the growth of all chondrosarcoma cell lines. Tumor growth was similarly inhibited in a xenograft model of chondrosarcoma. In addition, chondrosarcoma cells with an NRAS mutation were sensitive to treatment with a mitogen-activated protein kinase/extracellular signal–regulated kinase kinase (MEK) inhibitor. Functional NRAS mutations were found in 12% of conventional central chondrosarcomas.
Conclusions: RTKs are commonly activated in chondrosarcoma, but because of their considerable heterogeneity, targeted inhibition of the PI3K/mTOR pathway represents a rational therapeutic strategy. Chondrosarcomas with NRAS mutations may benefit from treatment with MEK inhibitors. Clin Cancer Res; 19(14); 3796–807. ©2013 AACR.
Cyclin D1 Downregulation Contributes to Anticancer Effect of Isorhapontigenin on Human Bladder Cancer Cells
Authors: Fang Yong , Cao Zipeng , Hou Qi , Ma Chen , Yao Chunsuo , Li Jingxia , Wu Xue-Ru , Huang Chuanshu 
Published: May 2013

Abstract
Isorhapontigenin (ISO) is a new derivative of stilbene compound that was isolated from the Chinese herb Gnetum Cleistostachyum and has been used for treatment of bladder cancers for centuries. In our current studies, we have explored the potential inhibitory effect and molecular mechanisms underlying isorhapontigenin anticancer effects on anchorage-independent growth of human bladder cancer cell lines. We found that isorhapontigenin showed a significant inhibitory effect on human bladder cancer cell growth and was accompanied with related cell cycle G0–G1 arrest as well as downregulation of cyclin D1 expression at the transcriptional level in UMUC3 and RT112 cells. Further studies identified that isorhapontigenin downregulated cyclin D1 gene transcription via inhibition of specific protein 1 (SP1) transactivation. Moreover, ectopic expression of GFP-cyclin D1 rendered UMUC3 cells resistant to induction of cell-cycle G0–G1 arrest and inhibition of cancer cell anchorage-independent growth by isorhapontigenin treatment. Together, our studies show that isorhapontigenin is an active compound that mediates Gnetum Cleistostachyum's induction of cell-cycle G0–G1 arrest and inhibition of cancer cell anchorage-independent growth through downregulating SP1/cyclin D1 axis in bladder cancer cells. Our studies provide a novel insight into understanding the anticancer activity of the Chinese herb Gnetum Cleistostachyum and its isolate isorhapontigenin. Mol Cancer Ther; 12(8); 1492–503. ©2013 AACR.
Tumor Suppressor Functions of miR-133a in Colorectal Cancer
Authors: Dong Yujuan , Zhao Junhong , Wu Chung-Wah , Zhang Lijing , Liu Xiaodong , Kang Wei , Leung Wing-Wah , Zhang Ning , Chan Francis K.L. , Sung Joseph J.Y. , Ng Simon S.M. , Yu Jun 
Published: May 2013

Abstract
Dysregulated microRNA (miRNA) expression was profiled through a miRNA array comparison between human colorectal cancer tumors and their adjacent normal tissues. Specifically, using laser capture micro-dissection, miR-133a was shown to be significantly downregulated in primary colorectal cancer specimens compared with matched adjacent normal tissue. Ectopic expression of miR-133a significantly suppressed colorectal cancer cell growth in vitro and in vivo. Cell-cycle analysis revealed that miR-133a induced a G0/G1-phase arrest, concomitant with the upregulation of the key G1-phase regulator p21Cip1. We further revealed that miR-133a markedly increased p53 protein and induced p21Cip1 transcription. Studies in silico revealed that the 3′UTR of the ring finger and FYVE-like domain containing E3-ubiquitin protein ligase (RFFL), which regulates p53 protein, contains an evolutionarily conserved miR-133a binding site. miR-133a repressed RFFL-3′UTR reporter activity and reduced RFFL protein levels, indicating that miR-133a directly bound to RFFL mRNA and inhibited RFFL translation. Moreover, miR-133a sensitized colon cancer cells to doxorubicin and oxaliplatin by enhancing apoptosis and inhibiting cell proliferation. These data add weight to the significance of miR-133a in the development of CRC.
Implications: miR-133a serves as a potential tumor suppressor upstream of p53 in colorectal cancer and may sensitize cells to therapeutics. Mol Cancer Res; 11(9); 1051–60. ©2013 AACR.
A Novel
APOB
Mutation Identified by Exome Sequencing Cosegregates With Steatosis, Liver Cancer, and Hypocholesterolemia
Authors: Cefalù Angelo B. , Pirruccello James P. , Noto Davide , Gabriel Stacey , Valenti Vincenza , Gupta Namrata , Spina Rossella , Tarugi Patrizia , Kathiresan Sekar , Averna Maurizio R. 
Published: May 2013

Objective—
In familial hypobetalipoproteinemia, fatty liver is a characteristic feature, and there are several reports of associated cirrhosis and hepatocarcinoma. We investigated a large kindred in which low-density lipoprotein cholesterol, fatty liver, and hepatocarcinoma displayed an autosomal dominant pattern of inheritance.

Approach and Results—

The proband was a 25-year-old female with low plasma cholesterol and hepatic steatosis. Low plasma levels of total cholesterol and fatty liver were observed in 10 more family members; 1 member was affected by liver cirrhosis, and 4 more subjects died of either hepatocarcinoma or carcinoma on cirrhosis. To identify the causal mutation in this family, we performed exome sequencing in 2 participants with hypocholesterolemia and fatty liver. Approximately 22 400 single nucleotide variants were identified in each sample. After variant filtering, 300 novel shared variants remained. A nonsense variant, p.K2240X, attributable to an A>T mutation in exon 26 of
APOB
(c.6718A>T) was identified, and this variant was confirmed by Sanger sequencing. The gentotypic analysis of 16 family members in total showed that this mutation segregated with the low cholesterol trait. In addition, genotyping of the
PNPLA3
p.I148M did not show significant frequency differences between carriers and noncarriers of the c.6718A>T
APOB
gene mutation.

Conclusions—

We used exome sequencing to discover a novel nonsense mutation in exon 26 of
APOB
(p.K2240X) responsible for low cholesterol and fatty liver in a large kindred. This mutation may also be responsible for cirrhosis and liver cancer in this family.
Beneficial Effect of Mechanical Stimulation on the Regenerative Potential of Muscle-Derived Stem Cells Is Lost by Inhibiting Vascular Endothelial Growth Factor
Authors: Beckman Sarah A. , Chen William C.W. , Tang Ying , Proto Jonathan D. , Mlakar Logan , Wang Bing , Huard Johnny 
Published: May 2013

Objective—
We previously reported that mechanical stimulation increased the effectiveness of muscle-derived stem cells (MDSCs) for tissue repair. The objective of this study was to determine the importance of vascular endothelial growth factor (VEGF) on mechanically stimulated MDSCs in a murine model of muscle regeneration.

Approach and Results—

MDSCs were transduced with retroviral vectors encoding the
LacZ
reporter gene (lacZ-MDSCs), the soluble VEGF receptor
Flt1
(sFlt1-MDSCs), or a short hairpin RNA (shRNA) targeting messenger RNA of VEGF (shRNA_VEGF MDSCs). Cells were subjected to 24 hours of mechanical cyclic strain and immediately transplanted into the gastrocnemius muscles of
mdx/scid
mice. Two weeks after transplantation, angiogenesis, fibrosis, and regeneration were analyzed. There was an increase in angiogenesis in the muscles transplanted with mechanically stimulated lacZ-MDSCs compared with nonstimulated lacZ-MDSCs, sFlt1-MDSCs, and shRNA _VEGF MDSCs. Dystrophin-positive myofiber regeneration was significantly lower in the shRNA_VEGF-MDSC group compared with the lacZ-MDSC and sFlt1-MDSC groups. In vitro proliferation of MDSCs was not decreased by inhibition of VEGF; however, differentiation into myotubes and adhesion to collagen were significantly lower in the shRNA_VEGF-MDSC group compared with the lacZ-MDSC and sFlt1-MDSC groups.

Conclusions—
The beneficial effects of mechanical stimulation on MDSC-mediated muscle repair are lost by inhibiting VEGF.
Elevated Prothrombin Promotes Venous, but Not Arterial, Thrombosis in Mice
Authors: Aleman Maria M. , Walton Bethany L. , Byrnes James R. , Wang Jian-Guo , Heisler Matthew J. , Machlus Kellie R. , Cooley Brian C. , Wolberg Alisa S. 
Published: May 2013

Objective—
Individuals with elevated prothrombin, including those with the prothrombin G20210A mutation, have increased risk of venous thrombosis. Although these individuals do not have increased circulating prothrombotic biomarkers, their plasma demonstrates increased tissue factor–dependent thrombin generation in vitro. The objectives of this study were to determine the pathological role of elevated prothrombin in venous and arterial thrombosis in vivo, and distinguish thrombogenic mechanisms in these vessels.

Approach and Results—
Prothrombin was infused into mice to raise circulating levels. Venous thrombosis was induced by electrolytic stimulus to the femoral vein or inferior vena cava ligation. Arterial thrombosis was induced by electrolytic stimulus or ferric chloride application to the carotid artery. Mice infused with prothrombin demonstrated increased tissue factor–triggered thrombin generation measured ex vivo, but did not have increased circulating prothrombotic biomarkers in the absence of vessel injury. After venous injury, elevated prothrombin increased thrombin generation and the fibrin accumulation rate and total amount of fibrin ≈3-fold, producing extended thrombi with increased mass. However, elevated prothrombin did not accelerate platelet accumulation, increase the fibrin accumulation rate, or shorten the vessel occlusion time after arterial injury.

Conclusions—
These findings reconcile previously discordant findings on thrombin generation in hyperprothrombinemic individuals measured ex vivo and in vitro, and show elevated prothrombin promotes venous, but not arterial, thrombosis in vivo.
Androgen Receptor Promotes Sex-Independent Angiogenesis in Response to Ischemia and Is Required for Activation of Vascular Endothelial Growth Factor Receptor Signaling
Authors: Yoshida Sumiko , Aihara Ken-ichi , Ikeda Yasumasa , Sumitomo-Ueda Yuka , Uemoto Ryoko , Ishikawa Kazue , Ise Takayuki , Yagi Shusuke , Iwase Takashi , Mouri Yasuhiro , Sakari Matomo , Matsumoto Takahiro , Takeyama Ken-ichi , Akaike Masashi , Matsumoto Mitsuru , Sata Masataka , Walsh Kenneth , Kato Shigeaki , Matsumoto Toshio 
Published: May 2013

Background—

Hypoandrogenemia is associated with an increased risk of ischemic diseases. Because actions of androgens are exerted through androgen receptor (AR) activation, we studied hind-limb ischemia in
AR
knockout mice to elucidate the role of AR in response to ischemia.

Methods and Results—

Both male and female
AR
knockout mice exhibited impaired blood flow recovery, more cellular apoptosis, and a higher incidence of autoamputation after ischemia. In ex vivo and in vivo angiogenesis studies, AR-deficient vascular endothelial cells showed reduced angiogenic capability. In ischemic limbs of
AR
knockout mice, reductions in the phosphorylation of the Akt protein kinase and endothelial nitric oxide synthase were observed despite a robust increase in hypoxia-inducible factor 1α and vascular endothelial cell growth factor (
VEGF
) gene expression. In in vitro studies, siRNA-mediated ablation of AR in vascular endothelial cells blunted VEGF-stimulated phosphorylation of Akt and endothelial nitric oxide synthase. Immunoprecipitation experiments documented an association between AR and kinase insert domain protein receptor that promoted the recruitment of downstream signaling components.

Conclusions—
These results document a physiological role of AR in sex-independent angiogenic potency and provide evidence of novel cross-talk between the androgen/AR signaling and VEGF/kinase insert domain protein receptor signaling pathways.