bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization of the Activity of the PI3K/mTOR Inhibitor XL765 (SAR245409) in Tumor Models with Diverse Genetic Alterations Affecting the PI3K Pathway
Authors: Yu Peiwen , Laird A. Douglas , Du Xiangnan , Wu Jianming , Won Kwang-Ai , Yamaguchi Kyoko , Hsu Pin Pin , Qian Fawn , Jaeger Christopher T. , Zhang Wentao , Buhr Chris A. , Shen Paula , Abulafia Wendy , Chen Jason , Young Jenny , Plonowski Arthur , Yakes F. Michael , Chu Felix , Lee Michelle , Bentzien Frauke , Lam Sanh Tan , Dale Stephanie , Matthews David J. , Lamb Peter , Foster Paul 
Published: March 2014

Abstract
Activation of the PI3K (phosphoinositide 3-kinase) pathway is a frequent occurrence in human tumors and is thought to promote growth, survival, and resistance to diverse therapies. Here, we report pharmacologic characterization of the pyridopyrimidinone derivative XL765 (SAR245409), a potent and highly selective pan inhibitor of class I PI3Ks (α, β, γ, and δ) with activity against mTOR. Broad kinase selectivity profiling of &gt;130 protein kinases revealed that XL765 is highly selective for class I PI3Ks and mTOR over other kinases. In cellular assays, XL765 inhibits the formation of PIP3 in the membrane, and inhibits phosphorylation of AKT, p70S6K, and S6 phosphorylation in multiple tumor cell lines with different genetic alterations affecting the PI3K pathway. In a panel of tumor cell lines, XL765 inhibits proliferation with a wide range of potencies, with evidence of an impact of genotype on sensitivity. In mouse xenograft models, oral administration of XL765 results in dose-dependent inhibition of phosphorylation of AKT, p70S6K, and S6 with a duration of action of approximately 24 hours. Repeat dose administration of XL765 results in significant tumor growth inhibition in multiple human xenograft models in nude mice that is associated with antiproliferative, antiangiogenic, and proapoptotic effects. Mol Cancer Ther; 13(5); 1078–91. ©2014 AACR.
Hedgehog Pathway Inhibition in Chondrosarcoma Using the Smoothened Inhibitor IPI-926 Directly Inhibits Sarcoma Cell Growth
Authors: Campbell Veronica T. , Nadesan Puviindran , Ali S. Amanda , Wang Chang Ye Yale , Whetstone Heather , Poon Raymond , Wei Qingxia , Keilty John , Proctor Jennifer , Wang Lauren W. , Apte Suneel S. , McGovern Karen , Alman Benjamin A. , Wunder Jay S. 
Published: March 2014

Abstract
Hedgehog (Hh) pathway inhibition in cancer has been evaluated in both the ligand-independent and ligand-dependent settings, where Hh signaling occurs either directly within the cancer cells or within the nonmalignant cells of the tumor microenvironment. Chondrosarcoma is a malignant tumor of cartilage in which there is ligand-dependent activation of Hh signaling. IPI-926 is a potent, orally delivered small molecule that inhibits Hh pathway signaling by binding to Smoothened (SMO). Here, the impact of Hh pathway inhibition on primary chondrosarcoma xenografts was assessed. Mice bearing primary human chondrosarcoma xenografts were treated with IPI-926. The expression levels of known Hh pathway genes, in both the tumor and stroma, and endpoint tumor volumes were measured. Gene expression profiling of tumors from IPI-926–treated mice was conducted to identify potential novel Hh target genes. Hh target genes were studied to determine their contribution to the chondrosarcoma neoplastic phenotype. IPI-926 administration results in downmodulation of the Hh pathway in primary chondrosarcoma xenografts, as demonstrated by evaluation of the Hh target genes GLI1 and PTCH1, as well as inhibition of tumor growth. Chondrosarcomas exhibited autocrine and paracrine Hh signaling, and both were affected by IPI-926. Decreased tumor growth is accompanied by histopathologic changes, including calcification and loss of tumor cells. Gene profiling studies identified genes differentially expressed in chondrosarcomas following IPI-926 treatment, one of which, ADAMTSL1, regulates chondrosarcoma cell proliferation. These studies provide further insight into the role of the Hh pathway in chondrosarcoma and provide a scientific rationale for targeting the Hh pathway in chondrosarcoma. Mol Cancer Ther; 13(5); 1259–69. ©2014 AACR.
Protein Kinase D as a Potential Chemotherapeutic Target for Colorectal Cancer
Authors: Wei Ning , Chu Edward , Wipf Peter , Schmitz John C. 
Published: March 2014

Abstract
Protein kinase D (PKD) signaling plays a critical role in the regulation of DNA synthesis, proliferation, cell survival, adhesion, invasion/migration, motility, and angiogenesis. To date, relatively little is known about the potential role of PKD in the development and/or progression of human colorectal cancer. We evaluated the expression of different PKD isoforms in colorectal cancer and investigated the antitumor activity of PKD inhibitors against human colorectal cancer. PKD2 was the dominant isoform expressed in human colon cancer cells. PKD3 expression was also observed but PKD1 expression, at both the RNA and protein levels, was not detected. Suppression of PKD using the small molecule inhibitors CRT0066101 and kb-NB142-70 resulted in low micromolar in vitro antiproliferative activity against multiple human colorectal cancer cell lines. Drug treatment was associated with dose-dependent suppression of PKD2 activation. Incubation with CRT0066101 resulted in G2–M phase arrest and induction of apoptosis in human colorectal cancer cells. Further studies showed that CRT0066101 treatment gave rise to a dose-dependent increase in expression of cleaved PARP and activated caspase-3, in addition to inhibition of AKT and ERK signaling, and suppression of NF-κB activity. Transfection of PKD2-targeted siRNAs resulted in similar effects on downstream pathways as observed with small molecule inhibitors. Daily administration of CRT0066101 resulted in significant inhibition of tumor growth in HCT116 xenograft nude mice. Taken together, our studies show that PKD plays a significant role in mediating growth signaling in colorectal cancer and may represent a novel chemotherapeutic target for the treatment of colorectal cancer. Mol Cancer Ther; 13(5); 1130–41. ©2014 AACR.
Metallothionein 1G and Zinc Sensitize Human Colorectal Cancer Cells to Chemotherapy
Authors: Arriaga Juan M. , Greco Angela , Mordoh José , Bianchini Michele 
Published: March 2014

Abstract
Metallothioneins (MT) are a family of low molecular weight proteins that are silenced during colorectal cancer progression, mainly through epigenetic mechanisms, and this loss is associated with poor survival. In this article, we show that overexpression of the MT1G isoform sensitizes colorectal cell lines to the chemotherapeutic agents oxaliplatin (OXA) and 5-fluorouracil (5-FU), in part through enhancing p53 and repressing NF-κB activity. Despite being silenced, MTs can be reinduced by histone deacetylase inhibitors such as trichostatin A and sodium butyrate. In fact, this induction contributes to the cytotoxicity of these agents, given that silencing of MTs by siRNAs reduces their growth-inhibitory activities. Zinc ions also potently enhance MT expression and are cytotoxic to cancer cells. We show for the first time that OXA and 5-FU induce higher levels of intracellular labile zinc, as measured using the fluorescent probe FLUOZIN-3, and that such zinc contributes to the activation of p53 and repression of NF-κB. Addition of zinc enhanced growth inhibition by OXA and 5-FU, and was also capable of resensitizing 5-FU–resistant cell lines to levels comparable with sensitive cell lines. This effect was MT independent because silencing MTs did not affect zinc cytotoxicity. In conclusion, we show that MT induction and zinc administration are novel strategies to sensitize colorectal cancer cells to presently utilized chemotherapeutic agents. Mol Cancer Ther; 13(5); 1369–81. ©2014 AACR.
Nuclear Epidermal Growth Factor Receptor Is a Functional Molecular Target in Triple-Negative Breast Cancer
Authors: Brand Toni M. , Iida Mari , Dunn Emily F. , Luthar Neha , Kostopoulos Kellie T. , Corrigan Kelsey L. , Wleklinski Matthew J. , Yang David , Wisinski Kari B. , Salgia Ravi , Wheeler Deric L. 
Published: March 2014

AbstractTriple-negative breast cancer (TNBC) is a subclass of breast cancers (i.e., estrogen receptor–negative, progesterone receptor–negative, and HER2-negative) that have poor prognosis and very few identified molecular targets. Strikingly, a high percentage of TNBCs overexpresses the EGF receptor (EGFR), yet EGFR inhibition has yielded little clinical benefit. Over the last decade, advances in EGFR biology have established that EGFR functions in two distinct signaling pathways: (i) classical membrane-bound signaling and (ii) nuclear signaling. Previous studies have demonstrated that nuclear EGFR (nEGFR) can enhance resistance to anti-EGFR therapies and is correlated with poor overall survival in breast cancer. On the basis of these findings, we hypothesized that nEGFR may promote intrinsic resistance to cetuximab in TNBC. To examine this question, a battery of TNBC cell lines and human tumors were screened and found to express nEGFR. Knockdown of EGFR expression demonstrated that TNBC cell lines retained dependency on EGFR for proliferation, yet all cell lines were resistant to cetuximab. Furthermore, Src Family Kinases (SFKs) influenced nEGFR translocation in TNBC cell lines and in vivo tumor models, where inhibition of SFK activity led to potent reductions in nEGFR expression. Inhibition of nEGFR translocation led to a subsequent accumulation of EGFR on the plasma membrane, which greatly enhanced sensitivity of TNBC cells to cetuximab. Collectively, these data suggest that targeting both the nEGFR signaling pathway, through the inhibition of its nuclear transport, and the classical EGFR signaling pathway with cetuximab may be a viable approach for the treatment of patients with TNBC. Mol Cancer Ther; 13(5); 1356–68. ©2014 AACR.
ERBB3/HER2 Signaling Promotes Resistance to EGFR Blockade in Head and Neck and Colorectal Cancer Models
Authors: Zhang Li , Castanaro Carla , Luan Bo , Yang Katie , Fan Liangfen , Fairhurst Jeanette L. , Rafique Ashique , Potocky Terra B. , Shan Jing , Delfino Frank J. , Shi Ergang , Huang Tammy , Martin Joel H. , Chen Gang , MacDonald Douglas , Rudge John S. , Thurston Gavin , Daly Christopher 
Published: March 2014

Abstract
EGFR blocking antibodies are approved for the treatment of colorectal cancer and head and neck squamous cell carcinoma (HNSCC). Although ERBB3 signaling has been proposed to limit the effectiveness of EGFR inhibitors, the underlying molecular mechanisms are not fully understood. To gain insight into these mechanisms, we generated potent blocking antibodies against ERBB3 (REGN1400) and EGFR (REGN955). We show that EGFR and ERBB3 are coactivated in multiple HNSCC cell lines and that combined blockade of EGFR and ERBB3 inhibits growth of these cell lines more effectively than blockade of either receptor alone. Blockade of EGFR with REGN955 strongly inhibited activation of ERK in HNSCC cell lines, whereas blockade of ERBB3 with REGN1400 strongly inhibited activation of Akt; only the combination of the 2 antibodies blocked both of these essential downstream pathways. We used a HER2 blocking antibody to show that ERBB3 phosphorylation in HNSCC and colorectal cancer cells is strictly dependent on association with HER2, but not EGFR, and that neuregulin 1 activates ERBB3/HER2 signaling to reverse the effect of EGFR blockade on colorectal cancer cell growth. Finally, although REGN1400 and REGN955 as single agents slowed the growth of HNSCC and colorectal cancer xenografts, the combination of REGN1400 plus REGN955 caused significant tumor regression. Our results indicate that activation of the Akt survival pathway by ERBB3/HER2 limits the effectiveness of EGFR inhibition, suggesting that REGN1400, which is currently in a phase I clinical trial, could provide benefit when combined with EGFR blocking antibodies. Mol Cancer Ther; 13(5); 1345–55. ©2014 AACR.
Hospital Variation in Noninvasive Positive Pressure Ventilation for Acute Decompensated Heart Failure
Authors: Kulkarni Vivek T. , Kim Nancy , Dai Ying , Dharmarajan Kumar , Safavi Kyan C. , Bikdeli Behnood , Lindenauer Peter K. , Testani Jeffrey , Dries Daniel L. , Krumholz Harlan M. 
Published: March 2014

Background—
Although noninvasive positive pressure ventilation (NIPPV) for patients with acute decompensated heart failure was introduced almost 20 years ago, the variation in its use among hospitals remains unknown. We sought to define hospital practice patterns of NIPPV use for acute decompensated heart failure and their relationship with intubation and mortality.

Methods and Results—

We conducted a cross-sectional study using a database maintained by Premier, Inc., that includes a date-stamped log of all billed items for hospitalizations at >400 hospitals. We examined hospitalizations for acute decompensated heart failure in this database from 2005 to 2010 and included hospitals with annual average volume of >25 such hospitalizations. We identified 384 hospitals that encompassed 524 430 hospitalizations (median annual average volume: 206). We used hierarchical logistic regression models to calculate hospital-level outcomes: risk-standardized NIPPV rate, risk-standardized intubation rate, and in-hospital risk-standardized mortality rate. We grouped hospitals into quartiles by risk-standardized NIPPV rate and compared risk-standardized mortality rates and risk-standardized intubation rates across quartiles. Median risk-standardized NIPPV rate was 6.2% (interquartile range, 2.8%–9.3%; 5th percentile, 0.2%; 95th percentile, 14.8%). There was no clear pattern of risk-standardized mortality rates across quartiles. The bottom quartile of hospitals had higher risk-standardized intubation rate (11.4%) than each of the other quartiles (9.0%, 9.7%, and 9.1%;
P
<0.02 for all comparisons).

Conclusions—
Substantial variation exists among hospitals in the use of NIPPV for acute decompensated heart failure without evidence for differences in mortality. There may be a threshold effect in relation to intubation rates, with the lowest users of NIPPV having higher intubation rates.
Echocardiographic Diagnosis of Constrictive Pericarditis
Authors: Welch Terrence D. , Ling Lieng H. , Espinosa Raul E. , Anavekar Nandan S. , Wiste Heather J. , Lahr Brian D. , Schaff Hartzell V. , Oh Jae K. 
Published: March 2014

Background—
Constrictive pericarditis is a potentially reversible cause of heart failure that may be difficult to differentiate from restrictive myocardial disease and severe tricuspid regurgitation. Echocardiography provides an important opportunity to evaluate for constrictive pericarditis, and definite diagnostic criteria are needed.

Methods and Results—
Patients with surgically confirmed constrictive pericarditis (n=130) at Mayo Clinic (2008–2010) were compared with patients (n=36) diagnosed with restrictive myocardial disease or severe tricuspid regurgitation after constrictive pericarditis was considered but ruled out. Comprehensive echocardiograms were reviewed in blinded fashion. Five principal echocardiographic variables were selected based on prior studies and potential for clinical use: (1) respiration-related ventricular septal shift, (2) variation in mitral inflow E velocity, (3) medial mitral annular e' velocity, (4) ratio of medial mitral annular e' to lateral e', and (5) hepatic vein expiratory diastolic reversal ratio. All 5 principal variables differed significantly between the groups. In patients with atrial fibrillation or flutter (n=29), all but mitral inflow velocity remained significantly different. Three variables were independently associated with constrictive pericarditis: (1) ventricular septal shift, (2) medial mitral e', and (3) hepatic vein expiratory diastolic reversal ratio. The presence of ventricular septal shift in combination with either medial e'≥9 cm/s or hepatic vein expiratory diastolic reversal ratio ≥0.79 corresponded to a desirable combination of sensitivity (87%) and specificity (91%). The specificity increased to 97% when all 3 factors were present, but the sensitivity decreased to 64%.

Conclusions—
Echocardiography allows differentiation of constrictive pericarditis from restrictive myocardial disease and severe tricuspid regurgitation. Respiration-related ventricular septal shift, preserved or increased medial mitral annular e' velocity, and prominent hepatic vein expiratory diastolic flow reversals are independently associated with the diagnosis of constrictive pericarditis.
Diastolic Dysfunction in Women With Signs and Symptoms of Ischemia in the Absence of Obstructive Coronary Artery Disease
Authors: Nelson Michael D. , Szczepaniak Lidia S. , Wei Janet , Haftabaradaren Afsaneh , Bharadwaj Meghan , Sharif Behzad , Mehta Puja , Zhang Xiao , Thomson Louise E. , Berman Daniel S. , Li Debiao , Bairey Merz C. Noel 
Published: March 2014

Background—
Angina, in the absence of obstructive coronary artery disease, is more common in women, is associated with adverse cardiovascular morbidity and mortality, and is a major burden to the healthcare system. Although advancements have been made to understand the mechanistic underpinning of this disease, the functional consequence remains unclear.

Methods and Results—

Cardiac magnetic resonance imaging was performed to assess left ventricular function in 20 women with signs and symptoms of ischemia, but no obstructive coronary artery disease (cases), and 15 age- and body mass index–matched reference controls. Functional imaging included standard cinematic imaging to assess left ventricular morphology and global function, along with tissue tagging to assess left ventricular tissue deformation. Systolic function was preserved in both cases and controls, with no differences in ejection fraction (mean±SE: 63.1±8% versus 65±2%), circumferential strain (−20.7±0.6% versus −21.9±0.5%), or systolic circumferential strain rate (−105.9±6.1% versus −109.0±3.8% per second). In contrast, we observed significant differences between cases and controls in diastolic function, as demonstrated by reductions in both diastolic circumferential strain rate (153.8±8.9% versus 191.4±8.9% per second;
P
<0.05) and peak rate of left ventricular untwisting (−99.4±8.0° versus −129.4±12.8° per second;
P
<0.05).

Conclusions—
Diastolic function is impaired in women with signs and symptoms of ischemia in the absence of coronary artery disease, as assessed by cardiac magnetic resonance tissue tagging. These results are hypothesis-generating. Larger studies are needed to define the exact mechanism(s) responsible and to establish viable treatment strategies.
Temporal Relationship Between Subclinical Atrial Fibrillation and Embolic Events
Authors: Brambatti Michela , Connolly Stuart J. , Gold Michael R. , Morillo Carlos A. , Capucci Alessandro , Muto Carmine , Lau Chu P. , Van Gelder Isabelle C. , Hohnloser Stefan H. , Carlson Mark , Fain Eric , Nakamya Juliet , Mairesse Georges H. , Halytska Marta , Deng Wei Q. , Israel Carsten W , Healey Jeff S. 
Published: March 2014

Background—
Among patients with implantable pacemakers and defibrillators, subclinical atrial fibrillation (SCAF) is associated with an increased risk of stroke; however, there is limited understanding of their temporal relationship.

Methods and Results—
The Asymptomatic Atrial Fibrillation and Stroke Evaluation in Pacemaker Patients and the Atrial Fibrillation Reduction Atrial Pacing Trial (ASSERT) enrolled 2580 pacemaker and defibrillator patients aged ≥65 years with a history of hypertension but without a history of atrial fibrillation. Pacemakers and implantable cardioverter-defibrillators precisely logged the time and duration of all episodes of SCAF and recorded electrograms that were adjudicated by experts. We examined the temporal relationship between SCAF >6 minutes in duration and stroke or systemic embolism. Of 51 patients who experienced stroke or systemic embolism during follow-up, 26 (51%) had SCAF. In 18 patients (35%), SCAF was detected before stroke or systemic embolism. However, only 4 patients (8%) had SCAF detected within 30 days before stroke or systemic embolism, and only 1 of these 4 patients was experiencing SCAF at the time of the stroke. In the 14 patients with SCAF detected >30 days before stroke or systemic embolism, the most recent episode occurred at a median interval of 339 days (25th to 75th percentile, 211–619) earlier. Eight patients (16%) had SCAF detected only after their stroke, despite continuous monitoring for a median duration of 228 days (25th to 75th percentile, 202–719) before their event.

Conclusions—
Although SCAF is associated with an increased risk of stroke and embolism, very few patients had SCAF in the month before their event.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00256152.
Notes on Early Land Plants Today. 48. Drepanolejeunea longifolia, a new synonym of Drepanolejeunea angustifolia (Marchantiophyta, Lejeuneaceae)
Authors: HE QIONG , ZHU RUI-LIANG 
Published: March 2014

Drepanolejeunea (Spruce 1884: 186) Stephani (1891: 209), with about 110 currently accepted species, is the fourth largest genus of Lejeuneaceae (following Cololejeunea (Spruce 1884: 291) Stephani (1891: 208), Lejeunea Libert (1820: 373), and Cheilolejeunea (Spruce 1884: 251) Stephani (1890: 284) (He et al. 2012). Although Drepanolejeunea is a diverse pantropical genus, it is characterized and easily distinguished from other related genera by the 1) erect to widely divergent lobes of underleaves without a basal disc, 2) transverse section of stem with 7 cortical cells and 3 medullary cells, 3) presence of ocelli at least at base of leaf lobe), 4) proximal hyaline papilla, 5) pycnolejeuneoid leaf sequence of gynoecial innovation (if present), 6) inflated perianths usually with various projections near apex, and 7) asexual reproduction by means of cladia or caducous leaves (Zhu & So 2001; He et al. 2012; Pócs et al., 2013). The genus has been classified in a separate subtribe, Drepanolejeuneinae Gradstein (2013: 14), together with Vitalianthus Schuster & Giancotti (1993: 447).
Factors Affecting Outcomes of Alternating Chemoradiotherapy for Nasopharyngeal Cancer
Authors: Ueno Takayoshi , Endo Kazuhira , Kondo Satoru , Wakisaka Naohiro , Murono Shigeyuki , Ito Makoto , Yoshizaki Tomokazu 
Published: March 2014

Objective: Nasopharyngeal cancer (NPC) is radiosensitive and chemosensitive. We evaluated the efficacy of alternating chemoradiotherapy in patients with advanced NPC. Methods: Alternating chemoradiotherapy was initiated in 30 patients with NPC, and 27 patients with cancer stages II (n = 6), III (n = 8), IVA (n = 9), and IVB (n = 4) were retrospectively analyzed. Chemotherapy was initially administered followed by radiotherapy, and chemotherapy, radiotherapy, and chemotherapy were alternately administered. Of the 27 patients, 22 patients received cisplatin (50 mg/m2/day, days 6 and 7) and 5-fluorouracil (5-FU; 800 mg/m2/day, days 1-5), whereas 5 patients received carboplatin (AUC 4-5, day 6) and 5-FU. Results: Of the 27 patients, 19 (70%) received 3 chemotherapy courses. The total duration of alternating chemoradiotherapy was 81 to 101 days (median, 90 days). At a median follow-up of 53 months, the 5-year progression-free survival (PFS) was 71%. Multivariate analysis showed that weight loss and the number of chemotherapy courses had a significant effect on PFS. Conclusion: Alternating chemoradiotherapy led to similar or higher survival rates compared with concurrent chemoradiotherapy, which was characterized by good compliance and adaptable intensity.