bluuebunny/crossref_metadata_2025_split huggingface dataset:
Expression of the interleukin-21 and phosphorylated extracellular signal regulated kinase 1/2 in Kimura disease
Authors: Chen Qing-li , Li Chen-xi , Shao Bo , Gong Zhong-cheng , Liu Hui , Ling Bin , Abasi Keremu , Hu Lu-lu , Wang Bing , Yin Xiao-peng 
Published: January 2017

ObjectiveTo investigate the expressions of interleukin (IL)-21 and phosphorylated extracellular signal regulated kinase 1/2 (pERK1/2) in Kimura disease (KD) and to correlate the findings with clinical and prognostic variables.MethodsImmunohistochemical analysis of IL-21 and pERK1/2 was performed in 18 cases of KD and five gender- and age-matched control samples. Clinical data were extracted and patients followed up for a mean period of 32.1 months.ResultsAfter a mean follow-up period of 32.1 months (range 1–102 months), recurrence was diagnosed as the end point for seven patients—that is, a 44% (7/16) cumulative recurrence rate. In comparison with gender- and age-matched controls, patients showed strong in situ expressions of IL-21 and pERK1/2, respectively (p<0.05). Patients with strong IL-21 staining intensity and overexpression of pERK1/2 had a lower recurrence rate than those with moderate staining intensity (p=0.049, p=0.019, respectively). However, differences were not statistically significant by gender, age, eosinophils, location, multiplicity, laterality, size, duration and primary outbreak. pERK1/2 was the independent prognostic factor (p=0.020), while age, gender, eosinophils, multiplicity, laterality, size, duration, primary outbreak and expression of IL-21 were not.ConclusionsThis study suggests that the IL-21/pERK1/2 pathway is activated in KD, and pERK1/2 might be considered as a potential prognostic indicator in KD.
Relay-balloon technique for recanalization of acute symptomatic proximal internal carotid artery occlusion with short balloon-tipped guiding catheter landing zone
Authors: Lee Sang Hun , Lee Dong Geun , Kwon Sun U , Lee Deok Hee 
Published: January 2017

BackgroundEndovascular recanalization of a completely occluded proximal internal carotid artery (ICA) with underlying stenosis may be challenging owing to a possible thrombotic component. This is especially true when the landing zone for a balloon-tipped guiding catheter (BGC) at the bulb portion is insufficient. Sequential application of the balloons of a BGC and an angioplasty catheter may prevent thromboembolism during revascularization. This study analyzed the safety and effectiveness of this relay-balloon technique.MethodsTen consecutive patients with acute symptomatic proximal ICA occlusion were treated by the relay-balloon technique. Outcomes analyzed included technical success rate, procedure-related complications, and short-term clinical outcomes.ResultsSuccessful revascularization was achieved in all 10 patients. One patient experienced a post-procedural infarct extension, but there was no change in National Institutes of Health Stroke Scale (NIHSS) score. Mean NIHSS score decreased from 12.0±5.6 (range 0–18) initially to 6.8±5.4 (range 0–18) at discharge.ConclusionsThe relay-balloon technique is safe and effective in the endovascular revascularization of acute symptomatic proximal ICA occlusions, which are at high risk of distal thromboembolism due to insufficient landing zone for the BGC.
Right heart function during simulated altitude in patients with pulmonary arterial hypertension
Authors: Seccombe Leigh M , Chow Vincent , Zhao Wei , Lau Edmund M T , Rogers Peter G , Ng Austin C C , Veitch Elizabeth M , Peters Matthew J , Kritharides Leonard 
Published: January 2017

ObjectivePatients with pulmonary arterial hypertension (PAH) are often recommended supplemental oxygen for altitude travel due to the possible deleterious effects of hypoxia on pulmonary haemodynamics and right heart function. This includes commercial aircraft travel; however, the direct effects and potential risks are unknown.MethodsDoppler echocardiography and gas exchange measures were investigated in group 1 patients with PAH and healthy patients at rest breathing room air and while breathing 15.1% oxygen, at rest for 20 min and during mild exertion.ResultsThe 14 patients with PAH studied were clinically stable on PAH-specific therapy, with functional class II (n=11) and III (n=3) symptoms when tested. Measures of right ventricular size and function were significantly different in the PAH group at baseline as compared to 7 healthy patients (p<0.04). There was no evidence of progressive right ventricular deterioration during hypoxia at rest or under exertion. Pulmonary arterial systolic pressure (PASP) increased in both groups during hypoxia (p<0.01). PASP in hypoxia correlated strongly with baseline PASP (p<0.01). Pressure of arterial oxygen correlated with PASP in hypoxia (p<0.03) but not at baseline, with three patients with PAH experiencing significant desaturation. The duration and extent of hypoxia in this study was tolerated well despite a mild increase in symptoms of breathlessness (p<0.01).ConclusionsNon-invasive measures of right heart function in group 1 patients with PAH on vasodilator treatment demonstrated a predictable rise in PASP during short-term simulated hypoxia that was not associated with a deterioration in right heart function.
SDHDPromoter Mutations Ablate GABP Transcription Factor Binding in Melanoma
Authors: Zhang Tongwu , Xu Mai , Makowski Matthew M. , Lee Christine , Kovacs Michael , Fang Jun , Willems Esther , Trent Jeffrey M. , Hayward Nicholas K. , Vermeulen Michiel , Brown Kevin M. 
Published: January 2017

AbstractSDHD encodes subunit D of the succinate dehydrogenase complex, an integral membrane protein. Across cancer types, recurrent SDHD promoter mutations were reported to occur exclusively in melanomas, at a frequency of 4% to 5%. These mutations are predicted to disrupt consensus ETS transcription factor–binding sites and are correlated with both reduced SDHD gene expression and poor prognosis. However, the consequence of these mutations on SDHD expression in melanoma is still unclear. Here, we found that expression of SDHD in melanoma correlated with the expression of multiple ETS transcription factors, particularly in SDHD promoter wild-type samples. Consistent with the predicted loss of ETS transcription factor binding, we observed that recurrent hotspot mutations resulted in decreased luciferase activity in reporter assays. Furthermore, we demonstrated specific GABPA and GABPB1 binding to probes containing the wild-type promoter sequences, with binding disrupted by the SDHD hotspot promoter mutations in both quantitative mass spectrometry and band-shift experiments. Finally, using siRNA-mediated knockdown across multiple melanoma cell lines, we determined that loss of GABPA resulted in reduced SDHD expression at both RNA and protein levels. These data are consistent with a key role for GABPA/B1 as the critical ETS transcription factors deregulating SDHD expression in the context of highly recurrent promoter mutations in melanoma and warrant a detailed search for other recurrent promoter mutations that create or disrupt GABPA consensus sequences. Cancer Res; 77(7); 1649–61. ©2017 AACR.
Bone Marrow Adipocytes Facilitate Fatty Acid Oxidation Activating AMPK and a Transcriptional Network Supporting Survival of Acute Monocytic Leukemia Cells
Authors: Tabe Yoko , Yamamoto Shinichi , Saitoh Kaori , Sekihara Kazumasa , Monma Norikazu , Ikeo Kazuho , Mogushi Kaoru , Shikami Masato , Ruvolo Vivian , Ishizawa Jo , Hail Numsen , Kazuno Saiko , Igarashi Mamoru , Matsushita Hiromichi , Yamanaka Yasunari , Arai Hajime , Nagaoka Isao , Miida Takashi , Hayashizaki Yoshihide , Konopleva Marina , Andreeff Michael 
Published: January 2017

Abstract
Leukemia cells in the bone marrow must meet the biochemical demands of increased cell proliferation and also survive by continually adapting to fluctuations in nutrient and oxygen availability. Thus, targeting metabolic abnormalities in leukemia cells located in the bone marrow is a novel therapeutic approach. In this study, we investigated the metabolic role of bone marrow adipocytes in supporting the growth of leukemic blasts. Prevention of nutrient starvation–induced apoptosis of leukemic cells by bone marrow adipocytes, as well as the metabolic and molecular mechanisms involved in this process, was investigated using various analytic techniques. In acute monocytic leukemia (AMoL) cells, the prevention of spontaneous apoptosis by bone marrow adipocytes was associated with an increase in fatty acid β-oxidation (FAO) along with the upregulation of PPARγ, FABP4, CD36, and BCL2 genes. In AMoL cells, bone marrow adipocyte coculture increased adiponectin receptor gene expression and its downstream target stress response kinase AMPK, p38 MAPK with autophagy activation, and upregulated antiapoptotic chaperone HSPs. Inhibition of FAO disrupted metabolic homeostasis, increased reactive oxygen species production, and induced the integrated stress response mediator ATF4 and apoptosis in AMoL cells cocultured with bone marrow adipocytes. Our results suggest that bone marrow adipocytes support AMoL cell survival by regulating their metabolic energy balance and that the disruption of FAO in bone marrow adipocytes may be an alternative, novel therapeutic strategy for AMoL therapy. Cancer Res; 77(6); 1453–64. ©2017 AACR.
Differential PI3Kδ Signaling in CD4+ T-cell Subsets Enables Selective Targeting of T Regulatory Cells to Enhance Cancer Immunotherapy
Authors: Ahmad Shamim , Abu-Eid Rasha , Shrimali Rajeev , Webb Mason , Verma Vivek , Doroodchi Atbin , Berrong Zuzana , Samara Raed , Rodriguez Paulo C. , Mkrtichyan Mikayel , Khleif Samir N. 
Published: January 2017

Abstract
To modulate T-cell function for cancer therapy, one challenge is to selectively attenuate regulatory but not conventional CD4+ T-cell subsets [regulatory T cell (Treg) and conventional T cell (Tconv)]. In this study, we show how a functional dichotomy in Class IA PI3K isoforms in these two subsets of CD4+ T cells can be exploited to target Treg while leaving Tconv intact. Studies employing isoform-specific PI3K inhibitors and a PI3Kδ-deficient mouse strain revealed that PI3Kα and PI3Kβ were functionally redundant with PI3Kδ in Tconv. Conversely, PI3Kδ was functionally critical in Treg, acting there to control T-cell receptor signaling, cell proliferation, and survival. Notably, in a murine model of lung cancer, coadministration of a PI3Kδ-specific inhibitor with a tumor-specific vaccine decreased numbers of suppressive Treg and increased numbers of vaccine-induced CD8 T cells within the tumor microenvironment, eliciting potent antitumor efficacy. Overall, our results offer a mechanistic rationale to employ PI3Kδ inhibitors to selectively target Treg and improve cancer immunotherapy. Cancer Res; 77(8); 1892–904. ©2017 AACR.
Somatic Ephrin Receptor Mutations Are Associated with Metastasis in Primary Colorectal Cancer
Authors: Mathot Lucy , Kundu Snehangshu , Ljungström Viktor , Svedlund Jessica , Moens Lotte , Adlerteg Tom , Falk-Sörqvist Elin , Rendo Verónica , Bellomo Claudia , Mayrhofer Markus , Cortina Carme , Sundström Magnus , Micke Patrick , Botling Johan , Isaksson Anders , Moustakas Aristidis , Batlle Eduard , Birgisson Helgi , Glimelius Bengt , Nilsson Mats , Sjöblom Tobias 
Published: January 2017

Abstract
The contribution of somatic mutations to metastasis of colorectal cancers is currently unknown. To find mutations involved in the colorectal cancer metastatic process, we performed deep mutational analysis of 676 genes in 107 stages II to IV primary colorectal cancer, of which half had metastasized. The mutation prevalence in the ephrin (EPH) family of tyrosine kinase receptors was 10-fold higher in primary tumors of metastatic colorectal than in nonmetastatic cases and preferentially occurred in stage III and IV tumors. Mutational analyses in situ confirmed expression of mutant EPH receptors. To enable functional studies of EPHB1 mutations, we demonstrated that DLD-1 colorectal cancer cells expressing EPHB1 form aggregates upon coculture with ephrin B1 expressing cells. When mutations in the fibronectin type III and kinase domains of EPHB1 were compared with wild-type EPHB1 in DLD-1 colorectal cancer cells, they decreased ephrin B1–induced compartmentalization. These observations provide a mechanistic link between EPHB receptor mutations and metastasis in colorectal cancer. Cancer Res; 77(7); 1730–40. ©2017 AACR.
Prostate Cancer Patients with Late Radiation Toxicity Exhibit Reduced Expression of Genes Involved in DNA Double-Strand Break Repair and Homologous Recombination
Authors: van Oorschot Bregje , Uitterhoeve Lon , Oomen Ilja , ten Cate Rosemarie , Medema Jan Paul , Vrieling Harry , Stalpers Lukas J.A. , Moerland Perry D. , Franken Nicolaas A.P. 
Published: January 2017

Abstract
Severe late damage to normal tissue is a major limitation of cancer radiotherapy in prostate cancer patients. In a recent retrospective study, late radiation toxicity was found to relate to a decreased decay of γ-H2AX foci and reduced induction of DNA double-strand break repair genes. Here, we report evidence of prognostic utility in prostate cancer for γ-H2AX foci decay ratios and gene expression profiles derived from ex vivo–irradiated patient lymphocytes. Patients were followed ≥2 years after radiotherapy. Clinical characteristics were assembled, and toxicity was recorded using the Common Terminology Criteria (CTCAE) v4.0. No clinical factor was correlated with late radiation toxicity. The γ-H2AX foci decay ratio correlated negatively with toxicity grade, with a significant difference between grade ≥3 and grade 0 patients (P = 0.02). A threshold foci decay ratio, determined in our retrospective study, correctly classified 23 of 28 patients with grade ≥3 toxicity (sensitivity 82%) and 9 of 14 patients with grade 0 toxicity (specificity 64%). Induction of homologous recombination (HR) repair genes was reduced with increasing toxicity grade. The difference in fold induction of the HR gene set was most pronounced between grade 0 and grade ≥3 toxicity (P = 0.008). Notably, reduced responsiveness of HR repair genes to irradiation and inefficient double-strand break repair correlated with severe late radiation toxicity. Using a decay ratio classifier, we correctly classified 82% of patients with grade ≥3 toxicity, suggesting a prognostic biomarker for cancer patients with a genetically enhanced risk for late radiation toxicity to normal tissues after radiotherapy. Cancer Res; 77(6); 1485–91. ©2017 AACR.
Biomarker Dynamics in B-cell Lymphoma: A Longitudinal Prospective Study of Plasma Samples Up to 25 Years before Diagnosis
Authors: Späth Florentin , Wibom Carl , Krop Esmeralda J.M. , Johansson Ann-Sofie , Bergdahl Ingvar A. , Vermeulen Roel , Melin Beatrice 
Published: January 2017

AbstractThe B-cell activation markers CXCL13, sCD23, sCD27, and sCD30 are associated with future lymphoma risk. However, a lack of information about the individual dynamics of marker–disease association hampers interpretation. In this study, we identified 170 individuals who had donated two prediagnostic blood samples before B-cell lymphoma diagnosis, along with 170 matched cancer-free controls from the Northern Sweden Health and Disease Study. Lymphoma risk associations were investigated by subtype and marker levels measured at baseline, at the time of the repeated sample, and with the rate of change in the marker level. Notably, we observed strong associations between CXCL13, sCD23, sCD27, and sCD30 and lymphoma risk in blood samples collected 15 to 25 years before diagnosis. B-cell activation marker levels increased among future lymphoma cases over time, while remaining stable among controls. Associations between slope and risk were strongest for indolent lymphoma subtypes. We noted a marked association of sCD23 with chronic lymphocytic leukemia (ORSlope = 28, Ptrend = 7.279 × 10−10). Among aggressive lymphomas, the association between diffuse large B-cell lymphoma risk and slope was restricted to CXCL13. B-cell activation seemed to play a role in B-cell lymphoma development at early stages across different subtypes. Furthermore, B-cell activation presented differential trajectories in future lymphoma patients, mainly driven by indolent subtypes. Our results suggest a utility of these markers in predicting the presence of early occult disease and/or the screening and monitoring of indolent lymphoma in individual patients. Cancer Res; 77(6); 1408–15. ©2017 AACR.
Disease Characteristics and Prognostic Implications of Cell-Surface FLT3 Receptor (CD135) Expression in Pediatric Acute Myeloid Leukemia: A Report from the Children's Oncology Group
Authors: Tarlock Katherine , Alonzo Todd A. , Loken Michael R. , Gerbing Robert B. , Ries Rhonda E. , Aplenc Richard , Sung Lillian , Raimondi Susana C. , Hirsch Betsy A. , Kahwash Samir B. , McKenney Amy , Kolb E. Anders , Gamis Alan S. , Meshinchi Soheil 
Published: January 2017

Abstract
Purpose: The FLT3 cell-surface receptor tyrosine kinase (CD135) is expressed in a majority of both acute lymphoid leukemia (ALL) and myeloid leukemia (AML). However, the prognostic significance of CD135 expression in AML remains unclear. We therefore evaluated the association between FLT3 surface expression and disease characteristics and outcomes in pediatric patients with AML.
Experimental Design: We analyzed FLT3 receptor expression on AML blasts by multi-dimensional flow cytometry and its association with disease characteristics, clinical outcomes, and FLT3 transcript level in 367 children with AML treated on the Children's Oncology Group trial AAML0531.
Results: There was high variability in blast CD135 cell-surface expression across specimens. CD135 expression measured by flow cytometry was not correlated with FLT3 transcript expression determined by quantitative RT-PCR. Overall, CD135 expression was not significantly different for patients with FLT3/WT, FLT3/ITD, or FLT3/ALM (P = 0.25). High cell-surface CD135 expression was associated with FAB M5 subtype (P &lt; 0.001), KMT2A rearrangements (P = 0.009), and inversely associated with inv(16)/t(16;16) (P &lt; 0.001). Complete remission rate, overall survival, disease-free survival, and relapse rates were not significantly different between patients with low and high CD135 expression.
Conclusions: FLT3 cell-surface expression did not vary by FLT3 mutational status, but high FLT3 expression was strongly associated with KMT2A rearrangements. Our study found that there was no prognostic significance of FLT3 cell surface expression in pediatric AML. Clin Cancer Res; 23(14); 3649–56. ©2017 AACR.
Bispecific Antibodies and Antibody–Drug Conjugates (ADCs) Bridging HER2 and Prolactin Receptor Improve Efficacy of HER2 ADCs
Authors: Andreev Julian , Thambi Nithya , Perez Bay Andres E. , Delfino Frank , Martin Joel , Kelly Marcus P. , Kirshner Jessica R. , Rafique Ashique , Kunz Arthur , Nittoli Thomas , MacDonald Douglas , Daly Christopher , Olson William , Thurston Gavin 
Published: January 2017

Abstract
The properties of cell surface proteins targeted by antibody–drug conjugates (ADCs) have not been fully exploited; of particular importance are the rate of internalization and the route of intracellular trafficking. In this study, we compared the trafficking of HER2, which is the target of the clinically approved ADC ado-trastuzumab emtansine (T-DM1), with that of prolactin receptor (PRLR), another potential target in breast cancer. In contrast to HER2, we found that PRLR is rapidly and constitutively internalized, and traffics efficiently to lysosomes, where it is degraded. The PRLR cytoplasmic domain is necessary to promote rapid internalization and degradation, and when transferred to HER2, enhances HER2 degradation. In accordance with these findings, low levels of cell surface PRLR (∼30,000 surface receptors per cell) are sufficient to mediate effective killing by PRLR ADC, whereas cell killing by HER2 ADC requires higher levels of cell surface HER2 (∼106 surface receptors per cell). Noncovalently cross-linking HER2 to PRLR at the cell surface, using a bispecific antibody that binds to both receptors, dramatically enhances the degradation of HER2 as well as the cell killing activity of a noncompeting HER2 ADC. Furthermore, in breast cancer cells that coexpress HER2 and PRLR, a HER2xPRLR bispecific ADC kills more effectively than HER2 ADC. These results emphasize that intracellular trafficking of ADC targets is a key property for their activity and, further, that coupling an ADC target to a rapidly internalizing protein may be a useful approach to enhance internalization and cell killing activity of ADCs. Mol Cancer Ther; 16(4); 681–93. ©2017 AACR.
Inflammatory Molecule, PSGL-1, Deficiency Activates Macrophages to Promote Colorectal Cancer Growth through NFκB Signaling
Authors: Li Jiangchao , Zhou Zeqi , Zhang Xiaohan , Zheng Li , He Dan , Ye Yuxiang , Zhang Qian-Qian , Qi Cui-Ling , He Xiao-Dong , Yu Chen , Shao Chun-kui , Qiao Liang , Wang Lijing 
Published: January 2017

Abstract
P-selectin glycoprotein ligand 1 (SELPLG/PSGL-1) is an inflammatory molecule that is functionally related to immune cell differentiation and leukocyte mobilization. However, the role of PSGL-1 in tumor development remains unknown. Therefore, this study investigates the mechanistic role of PSGL-1 in the development of intestinal tumors in colorectal cancer. ApcMin/+ mice are highly susceptible to spontaneous intestinal adenoma formation, and were crossbred with PSGL1-null mice to generate compound transgenic mice with a ApcMin/+;PSGL-1−/− genotype. The incidence and pathologic features of the intestinal tumors were compared between the ApcMin/+ mice and ApcMin/+;PSGL-1−/− mice. Importantly, PSGL-1–deficient mice showed increased susceptibility to develop intestinal tumors and accelerated tumor growth. Mechanistically, increased production of the mouse chemokine ligand 9 (CCL9/MIP-1γ) was found in the PSGL-1–deficient mice, and the macrophages are likely the major source of macrophage inflammatory protein-1 gamma (MIP-1γ). Studies in vitro demonstrated that macrophage-derived MIP-1γ promoted colorectal cancer tumor cell growth through activating NFκB signaling. Conversely, restoration of the PSGL-1 signaling via bone marrow transplantation reduced MIP-1γ production and attenuated the ability of ApcMin/+;PSGL-1−/− mice to generate intestinal tumors. In human colorectal cancer clinical specimens, the presence of PSGL-1–positive cells was associated with a favorable tumor–node–metastasis staging and decreased lymph node metastasis.
Implications: PSGL-1 deficiency and inflammation render intestinal tissue more vulnerable to develop colorectal tumors through a MIP-1γ/NFκB signaling axis. Mol Cancer Res; 15(4); 467–77. ©2017 AACR.
Macropinocytosis of Nab-paclitaxel Drives Macrophage Activation in Pancreatic Cancer
Authors: Cullis Jane , Siolas Despina , Avanzi Antonina , Barui Sugata , Maitra Anirban , Bar-Sagi Dafna 
Published: January 2017

AbstractPancreatic cancer is a devastating disease that is largely refractory to currently available treatment strategies. Therapeutic resistance is partially attributed to the dense stromal reaction of pancreatic ductal adenocarcinoma tumors that includes a pervasive infiltration of immunosuppressive (M2) macrophages. Nab-paclitaxel (trade name Abraxane) is a nanoparticle albumin-bound formulation of paclitaxel that, in combination with gemcitabine, is currently the first-line treatment for pancreatic cancer. Here, we show that macrophages internalized nab-paclitaxel via macropinocytosis. The macropinocytic uptake of nab-paclitaxel induced macrophage immunostimulatory (M1) cytokine expression and synergized with IFNγ to promote inducible nitric oxide synthase expression in a TLR4-dependent manner. Nab-paclitaxel was internalized by tumor-associated macrophages in vivo, and therapeutic doses of nab-paclitaxel alone, and in combination with gemcitabine, increased the MHCII+CD80+CD86+ M1 macrophage population. These data revealed an unanticipated role for nab-paclitaxel in macrophage activation and rationalized its potential use to target immune evasion in pancreatic cancer. Cancer Immunol Res; 5(3); 182–90. ©2017 AACR.