bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mitochondria-Targeted Analogues of Metformin Exhibit Enhanced Antiproliferative and Radiosensitizing Effects in Pancreatic Cancer Cells
Authors: Cheng Gang , Zielonka Jacek , Ouari Olivier , Lopez Marcos , McAllister Donna , Boyle Kathleen , Barrios Christy S. , Weber James J. , Johnson Bryon D. , Hardy Micael , Dwinell Michael B. , Kalyanaraman Balaraman 
Published: May 2016

Abstract
Metformin (Met) is an approved antidiabetic drug currently being explored for repurposing in cancer treatment based on recent evidence of its apparent chemopreventive properties. Met is weakly cationic and targets the mitochondria to induce cytotoxic effects in tumor cells, albeit not very effectively. We hypothesized that increasing its mitochondria-targeting potential by attaching a positively charged lipophilic substituent would enhance the antitumor activity of Met. In pursuit of this question, we synthesized a set of mitochondria-targeted Met analogues (Mito-Mets) with varying alkyl chain lengths containing a triphenylphosphonium cation (TPP+). In particular, the analogue Mito-Met10, synthesized by attaching TPP+ to Met via a 10-carbon aliphatic side chain, was nearly 1,000 times more efficacious than Met at inhibiting cell proliferation in pancreatic ductal adenocarcinoma (PDAC). Notably, in PDAC cells, Mito-Met10 potently inhibited mitochondrial complex I, stimulating superoxide and AMPK activation, but had no effect in nontransformed control cells. Moreover, Mito-Met10 potently triggered G1 cell-cycle phase arrest in PDAC cells, enhanced their radiosensitivity, and more potently abrogated PDAC growth in preclinical mouse models, compared with Met. Collectively, our findings show how improving the mitochondrial targeting of Met enhances its anticancer activities, including aggressive cancers like PDAC in great need of more effective therapeutic options. Cancer Res; 76(13); 3904–15. ©2016 AACR.
Antagonizing Integrin β3 Increases Immunosuppression in Cancer
Authors: Su Xinming , Esser Alison K. , Amend Sarah R. , Xiang Jingyu , Xu Yalin , Ross Michael H. , Fox Gregory C. , Kobayashi Takayuki , Steri Veronica , Roomp Kirsten , Fontana Francesca , Hurchla Michelle A. , Knolhoff Brett L. , Meyer Melissa A. , Morgan Elizabeth A. , Tomasson Julia C. , Novack Joshua S. , Zou Wei , Faccio Roberta , Novack Deborah V. , Robinson Stephen D. , Teitelbaum Steven L. , DeNardo David G. , Schneider Jochen G. , Weilbaecher Katherine N. 
Published: May 2016

Abstract
Integrin β3 is critical for tumor invasion, neoangiogenesis, and inflammation, making it a promising cancer target. However, preclinical and clinical data of integrin β3 antagonists have demonstrated no benefit or worse outcomes. We hypothesized that integrin β3 could affect tumor immunity and evaluated tumors in mice with deletion of integrin β3 in macrophage lineage cells (β3KOM). β3KOM mice had increased melanoma and breast cancer growth with increased tumor-promoting M2 macrophages and decreased CD8+ T cells. Integrin β3 antagonist, cilengitide, also enhanced tumor growth and increased M2 function. We uncovered a negative feedback loop in M2 myeloid cells, wherein integrin β3 signaling favored STAT1 activation, an M1-polarizing signal, and suppressed M2-polarizing STAT6 activation. Finally, disruption of CD8+ T cells, macrophages, or macrophage integrin β3 signaling blocked the tumor-promoting effects of integrin β3 antagonism. These results suggest that effects of integrin β3 therapies on immune cells should be considered to improve outcomes. Cancer Res; 76(12); 3484–95. ©2016 AACR.
The Tumor-Associated Glycosyltransferase ST6Gal-I Regulates Stem Cell Transcription Factors and Confers a Cancer Stem Cell Phenotype
Authors: Schultz Matthew J. , Holdbrooks Andrew T. , Chakraborty Asmi , Grizzle William E. , Landen Charles N. , Buchsbaum Donald J. , Conner Michael G. , Arend Rebecca C. , Yoon Karina J. , Klug Christopher A. , Bullard Daniel C. , Kesterson Robert A. , Oliver Patsy G. , O'Connor Amber K. , Yoder Bradley K. , Bellis Susan L. 
Published: May 2016

Abstract
The glycosyltransferase ST6Gal-I, which adds α2-6–linked sialic acids to substrate glycoproteins, has been implicated in carcinogenesis; however, the nature of its pathogenic role remains poorly understood. Here we show that ST6Gal-I is upregulated in ovarian and pancreatic carcinomas, enriched in metastatic tumors, and associated with reduced patient survival. Notably, ST6Gal-I upregulation in cancer cells conferred hallmark cancer stem-like cell (CSC) characteristics. Modulating ST6Gal-I expression in pancreatic and ovarian cancer cells directly altered CSC spheroid growth, and clonal variants with high ST6Gal-I activity preferentially survived in CSC culture. Primary ovarian cancer cells from patient ascites or solid tumors sorted for α2-6 sialylation grew as spheroids, while cells lacking α2-6 sialylation remained as single cells and lost viability. ST6Gal-I also promoted resistance to gemcitabine and enabled the formation of stably resistant colonies. Gemcitabine treatment of patient-derived xenograft tumors enriched for ST6Gal-I–expressing cells relative to pair-matched untreated tumors. ST6Gal-I also augmented tumor-initiating potential. In limiting dilution assays, subcutaneous tumor formation was inhibited by ST6Gal-I knockdown, whereas in a chemically induced tumor initiation model, mice with conditional ST6Gal-I overexpression exhibited enhanced tumorigenesis. Finally, we found that ST6Gal-I induced expression of the key tumor-promoting transcription factors, Sox9 and Slug. Collectively, this work highlighted a previously unrecognized role for a specific glycosyltransferase in driving a CSC state. Cancer Res; 76(13); 3978–88. ©2016 AACR.
Rho GTPase Transcriptome Analysis Reveals Oncogenic Roles for Rho GTPase-Activating Proteins in Basal-like Breast Cancers
Authors: Lawson Campbell D. , Fan Cheng , Mitin Natalia , Baker Nicole M. , George Samuel D. , Graham David M. , Perou Charles M. , Burridge Keith , Der Channing J. , Rossman Kent L. 
Published: May 2016

Abstract
The basal-like breast cancer (BLBC) subtype accounts for a disproportionately high percentage of overall breast cancer mortality. The current therapeutic options for BLBC need improvement; hence, elucidating signaling pathways that drive BLBC growth may identify novel targets for the development of effective therapies. Rho GTPases have previously been implicated in promoting tumor cell proliferation and metastasis. These proteins are inactivated by Rho-selective GTPase-activating proteins (RhoGAP), which have generally been presumed to act as tumor suppressors. Surprisingly, RNA-Seq analysis of the Rho GTPase signaling transcriptome revealed high expression of several RhoGAP genes in BLBC tumors, raising the possibility that these genes may be oncogenic. To evaluate this, we examined the roles of two of these RhoGAPs, ArhGAP11A (also known as MP-GAP) and RacGAP1 (also known as MgcRacGAP), in promoting BLBC. Both proteins were highly expressed in human BLBC cell lines, and knockdown of either gene resulted in significant defects in the proliferation of these cells. Knockdown of ArhGAP11A caused CDKN1B/p27-mediated arrest in the G1 phase of the cell cycle, whereas depletion of RacGAP1 inhibited growth through the combined effects of cytokinesis failure, CDKN1A/p21-mediated RB1 inhibition, and the onset of senescence. Random migration was suppressed or enhanced by the knockdown of ArhGAP11A or RacGAP1, respectively. Cell spreading and levels of GTP-bound RhoA were increased upon depletion of either RhoGAP. We have established that, via the suppression of RhoA, ArhGAP11A and RacGAP1 are both critical drivers of BLBC growth, and propose that RhoGAPs can act as oncogenes in cancer. Cancer Res; 76(13); 3826–37. ©2016 AACR.
FAP Promotes Immunosuppression by Cancer-Associated Fibroblasts in the Tumor Microenvironment via STAT3–CCL2 Signaling
Authors: Yang Xuguang , Lin Yuli , Shi Yinghong , Li Bingji , Liu Weiren , Yin Wei , Dang Yongjun , Chu Yiwei , Fan Jia , He Rui 
Published: May 2016

Abstract
Cancer-associated fibroblasts (CAF) are components of the tumor microenvironment whose contributions to malignant progression are not fully understood. Here, we show that the fibroblast activation protein (FAP) triggers induction of a CAF subset with an inflammatory phenotype directed by STAT3 activation and inflammation-associated expression signature marked by CCL2 upregulation. Enforcing FAP expression in normal fibroblasts was sufficient to endow them with an inflammatory phenotype similar to FAP+CAFs. We identified FAP as a persistent activator of fibroblastic STAT3 through a uPAR-dependent FAK–Src–JAK2 signaling pathway. In a murine liver tumor model, we found that FAP+CAFs were a major source of CCL2 and that fibroblastic STAT3–CCL2 signaling in this setting promoted tumor growth by enhancing recruitment of myeloid-derived suppressor cells (MDSC). The CCL2 receptor CCR2 was expressed on circulating MDSCs in tumor-bearing subjects and FAP+CAF-mediated tumor promotion and MDSC recruitment was abrogated in Ccr2-deficient mice. Clinically, we observed a positive correlation between stromal expression of FAP, p-STAT3, and CCL2 in human intrahepatic cholangiocarcinoma, a highly aggressive liver cancer with dense desmoplastic stroma, where elevated levels of stromal FAP predicted a poor survival outcome. Taken together, our results showed how FAP–STAT3–CCL2 signaling in CAFs was sufficient to program an inflammatory component of the tumor microenvironment, which may have particular significance in desmoplasia-associated cancers. Cancer Res; 76(14); 4124–35. ©2016 AACR.
Clonotypic Diversification of Intratumoral T Cells Following Sipuleucel-T Treatment in Prostate Cancer Subjects
Authors: Sheikh Nadeem , Cham Jason , Zhang Li , DeVries Todd , Letarte Simon , Pufnock Jeff , Hamm David , Trager James , Fong Lawrence 
Published: May 2016

Abstract
Sipuleucel-T is an autologous cellular therapy for asymptomatic, or minimally symptomatic, metastatic castrate-resistant prostate cancer, designed to stimulate an immune response against prostate cancer. In a recent clinical trial (NCT00715104), we found that neoadjuvant sipuleucel-T increased the number of activated T cells within the tumor microenvironment. The current analysis examined whether sipuleucel-T altered adaptive T-cell responses by expanding pre-existing T cells or by recruiting new T cells to prostate tissue. Next-generation sequencing of the T-cell receptor (TCR) genes from blood or prostate tissue was used to quantitate and track T-cell clonotypes in these treated subjects with prostate cancer. At baseline, there was a significantly greater diversity of circulating TCR sequences in subjects with prostate cancer compared with healthy donors. Among healthy donors, circulating TCR sequence diversity remained unchanged over the same time interval. In contrast, sipuleucel-T treatment reduced circulating TCR sequence diversity versus baseline as measured by the Shannon index. Interestingly, sipuleucel-T treatment resulted in greater TCR sequence diversity in resected prostate tissue in sipuleucel-T–treated subjects versus tissue of nonsipuleucel-T–treated subjects with prostate cancer. Furthermore, sipuleucel-T increased TCR sequence commonality between blood and resected prostate tissue in treated versus untreated subjects with prostate cancer. The broadening of the TCR repertoire within the prostate tissue supports the hypothesis that sipuleucel-T treatment facilitates the recruitment of T cells into the prostate. Our results highlight the importance of assessing T-cell response to immunotherapy both in the periphery and in tumor tissue. Cancer Res; 76(13); 3711–8. ©2016 AACR.
Adipocyte Exosomes Promote Melanoma Aggressiveness through Fatty Acid Oxidation: A Novel Mechanism Linking Obesity and Cancer
Authors: Lazar Ikrame , Clement Emily , Dauvillier Stéphanie , Milhas Delphine , Ducoux-Petit Manuelle , LeGonidec Sophie , Moro Cédric , Soldan Vanessa , Dalle Stéphane , Balor Stéphanie , Golzio Muriel , Burlet-Schiltz Odile , Valet Philippe , Muller Catherine , Nieto Laurence 
Published: May 2016

Abstract
Malignant progression results from a dynamic cross-talk between stromal and cancer cells. Recent evidence suggests that this cross-talk is mediated to a significant extent by exosomes, nanovesicles secreted by most cell types and which allow the transfer of proteins, lipids, and nucleic acids between cells. Adipocytes are a major component of several tumor microenvironments, including that of invasive melanoma, where cells have migrated to the adipocyte-rich hypodermic layer of the skin. We show that adipocytes secrete exosomes in abundance, which are then taken up by tumor cells, leading to increased migration and invasion. Using mass spectrometry, we analyzed the proteome of adipocyte exosomes. Interestingly, these vesicles carry proteins implicated in fatty acid oxidation (FAO), a feature highly specific to adipocyte exosomes. We further show that, in the presence of adipocyte exosomes, FAO is increased in melanoma cells. Inhibition of this metabolic pathway completely abrogates the exosome-mediated increase in migration. Moreover, in obese mice and humans, both the number of exosomes secreted by adipocytes as well as their effect on FAO-dependent cell migration are amplified. These observations might in part explain why obese melanoma patients have a poorer prognosis than their nonobese counterparts. Cancer Res; 76(14); 4051–7. ©2016 AACR.
Anti-EGFR Targeted Monoclonal Antibody Isotype Influences Antitumor Cellular Immunity in Head and Neck Cancer Patients
Authors: Trivedi Sumita , Srivastava Raghvendra M. , Concha-Benavente Fernando , Ferrone Soldano , Garcia-Bates Tatiana M. , Li Jing , Ferris Robert L. 
Published: May 2016

Abstract
Purpose: EGF receptor (EGFR) is highly overexpressed on several cancers and two targeted anti-EGFR antibodies which differ by isotype are FDA-approved for clinical use. Cetuximab (IgG1 isotype) inhibits downstream signaling of EGFR and activates antitumor, cellular immune mechanisms. As panitumumab (IgG2 isotype) may inhibit downstream EGFR signaling similar to cetuximab, it might also induce adaptive immunity.
Experimental Design: We measured in vitro activation of cellular components of the innate and adaptive immune systems. We also studied the in vivo activation of components of the adaptive immune system in patient specimens from two recent clinical trials using cetuximab or panitumumab.
Results: Both monoclonal antibodies (mAb) primarily activate natural killer (NK) cells, although cetuximab is significantly more potent than panitumumab. Cetuximab-activated neutrophils mediate antibody-dependent cellular cytotoxicity (ADCC) against head and neck squamous cell carcinomas (HNSCC) tumor cells, and interestingly, this effect was FcγRIIa- and FcγRIIIa genotype–dependent. Panitumumab may activate monocytes through CD32 (FcγRIIa); however, monocytes activated by either mAb are not able to mediate ADCC. Cetuximab enhanced dendritic cell (DC) maturation to a greater extent than panitumumab, which was associated with improved tumor antigen cross-presentation by cetuximab compared with panitumumab. This correlated with increased EGFR-specific cytotoxic CD8+ T cells in patients treated with cetuximab compared with those treated with panitumumab.
Conclusions: Although panitumumab effectively inhibits EGFR signaling to a similar extent as cetuximab, it is less effective at triggering antitumor, cellular immune mechanisms which may be crucial for effective therapy of HNSCC. Clin Cancer Res; 22(21); 5229–37. ©2016 AACR.
Inverted U-Shaped Relation Between the Risk of Sudden Cardiac Death and Maximal Left Ventricular Wall Thickness in Hypertrophic Cardiomyopathy
Authors: O’Mahony Constantinos , Jichi Fatima , Monserrat Lorenzo , Ortiz-Genga Martin , Anastasakis Aristides , Rapezzi Claudio , Biagini Elena , Gimeno Juan Ramon , Limongelli Giuseppe , McKenna William J. , Omar Rumana Z. , Elliott Perry M. 
Published: May 2016

Background—
Hypertrophic cardiomyopathy is associated with sudden cardiac death (SCD). Some studies have shown an association between risk of sudden death and left ventricular maximal wall thickness (MWT), but there are few data in patients with extreme hypertrophy. The aim of this study was to determine the relation between MWT and the risk of SCD.

Methods and Results—
This is a multicenter, retrospective, longitudinal cohort study of 3673 adult (≥16 years) patients, previously used to develop and validate a risk prediction model for SCD (HCM Risk-SCD [hypertrophic cardiomyopathy risk-SCD]). There was an inverted U-shaped relation between MWT and the estimated 5-year risk of SCD. In patients with MWT≥35 mm (n=47; mean age, 33 years; 81% men), there was a single SCD end point (annual rate, 0.2%; 95% confidence interval, 0.03–1.60) and 3 additional cardiovascular events during a median follow-up of 9.5 years. Compared with patients with MWT≤14 mm, those with MWT≥35 mm did not have a higher risk for SCD (hazard ratio, 0.22; 95% confidence interval, 0.03–1.65), cardiovascular death (hazard ratio, 0.66; 95% confidence interval, 0.26–1.67), or all-cause mortality (hazard ratio, 0.73; 95% confidence interval, 0.32–1.69).

Conclusions—
The risk of SCD has a complex, nonlinear relationship to MWT. The pathophysiological mechanisms behind this observation require further study but implantable cardioverter defibrillator implantation should not be guided solely on the severity of left ventricular hypertrophy.
Global Comparisons of Regional Life Cycle Properties and Motion of Multiday Convective Systems: Tropical and Midlatitude Land and Ocean
Authors: Vant-Hull Brian , Rossow William , Pearl Cindy 
Published: May 2016

Abstract
Tracking of convective cloud systems (cloud-top temperature &lt;245 K) in geosynchronous satellite images at 3-h intervals is used to determine life cycle statistics of convective systems in four regimes: tropical land and ocean and midlatitude land and ocean, including seasonal comparisons. The ISCCP tracking dataset covers the period 1984–2006. Only systems with lifetimes greater than or equal to 1 day that were moving predominantly eastward or westward are considered, with splits and merges combined into larger extended convective systems. The life cycle variables are lifetime (duration), maximum area, and minimum cloud-top temperature. These are compared to each other and to the speed of longitudinal motion. Distributions and relationships between the life cycle variables are similar to previous studies based on single-day lifetimes, but the current study is globally extensive (all longitudes at lower and middle latitudes) and multidecadal, which allows extension of such results to rarer, larger, and longer-lived convective systems than previous work. Velocity distributions were monomodal with tails skewed in the direction of the zonal mean wind, being almost purely eastward in the midlatitudes but nearly symmetric in both directions with a small westward bias in the tropics. Representative life cycles for each geographical region are formed by averaging together systems with similar lifetimes. These composite life cycles show that, except for the first and last days, the daily evolution of most system variables exhibits little variation during the average multiday convective life cycle, although the cloud area goes through one cycle of expansion and contraction in a lifetime.
Radiometric Comparison of 1.6-μm CO2 Absorption Band of Greenhouse Gases Observing Satellite (GOSAT) TANSO-FTS with Suomi-NPP VIIRS SWIR Band
Authors: Uprety Sirish , Cao Changyong 
Published: May 2016

AbstractAn atmospheric CO2 increase has become a progressively important global concern in recent past decades. Since the 1950s, the Keeling curve has documented the atmospheric CO2 increase as well as seasonal variations, which also intrigued scientists to develop new methods for global CO2 measurements from satellites. One of the dedicated satellite missions is the CO2 measurement in the 1.6-μm shortwave infrared spectra by the Greenhouse Gases Observing Satellite (GOSAT) Thermal and Near Infrared Sensor for Carbon Observations–Fourier Transform Spectrometer (TANSO-FTS) instrument. While this spectral region has unique advantages in detecting lower-trophosphere CO2, there are many challenges because it relies on accurate measurements of reflected solar radiance from Earth’s surface. Therefore, the calibration of the TANSO-FTS CO2 has a direct impact on the CO2 retrievals and its long-term trends. Coincidently, the Suomi-NPP Visible Infrared Imaging Radiometer Suite (VIIRS) 1.6-μm band spectrally overlaps with the TANSO-FTS CO2 band, and both satellites are in orbit with periodical simultaneous nadir overpass measurements. This study performs an intercomparison of VIIRS and the TANSO-FTS CO2 band in an effort to evaluate and improve the radiometric consistency. Understanding the differences provides feedback on how well the GOSAT TANSO-FTS is performing over time, which is critical to ensure a well-calibrated, stable, and bias-free CO2 product.
Calprotectin is a potential prognostic marker for polycystic ovary syndrome
Authors: Chen Shouzhen , Jiang Mei , Ding Tao , Wang Junmei , Long Ping 
Published: May 2016

Background Calprotectin is an antimicrobial, calcium and zinc-binding heterocomplex protein and has been proposed as a marker to rule out inflammatory conditions. The aim of this study was to evaluate the role of calprotectin in the diagnosis of polycystic ovary syndrome and to investigate the association between calprotectin and insulin resistance. Methods A total of 41 females with polycystic ovary syndrome and 54 age-matched without polycystic ovary syndrome were eligible for the study. Serum concentration of calprotectin was determined using enzyme-linked immunosorbent assay. Clinical characteristics, hormone and metabolic parameters were evaluated in each subject. The predictive value of serum calprotectin was assessed using receiver operating characteristic curves. Correlations between the serum calprotectin concentrations and insulin resistance were examined using Spearman’s correlation. Results We found that the serum calprotectin concentrations were significantly higher in polycystic ovary syndrome compared with the non-polycystic ovary syndrome group ( P < 0.001). The area under the receiver operating characteristic curve assay yielded a satisfactory result of 0.88 (95% confidence interval 0.81–0.95; P < 0.001). The optimum cut-off was 2.4  µg/mL with a 85.2% specificity and 75.6% sensitivity for polycystic ovary syndrome diagnosis. A significant positive correlation was found between the serum calprotectin and insulin resistance. Conclusions These results suggest that calprotectin might be a useful adjunct in the diagnosis of polycystic ovary syndrome, especially those with insulin resistance.