bluuebunny/crossref_metadata_2025_split huggingface dataset:
Analysis of emergency physicians' Twitter accounts
Authors: Lulic Ileana , Kovic Ivor 
Published: May 2012

BackgroundTwitter is one of the fastest growing social media networks for communication between users via short messages. Technology proficient physicians have demonstrated enthusiasm in adopting social media for their work.ObjectiveTo identify and create the largest directory of emergency physicians on Twitter, analyse their user accounts and reveal details behind their connections.MethodsSeveral web search tools were used to identify emergency physicians on Twitter with biographies completely or partially written in English. NodeXL software was used to calculate emergency physicians' Twitter network metrics and create visualisation graphs.ResultsThe authors found 672 Twitter accounts of self-identified emergency physicians. Protected accounts were excluded from the study, leaving 632 for further analysis. Most emergency physicians were located in USA (55.4%), had created their accounts in 2009 (43.4%), used their full personal name (77.5%) and provided a custom profile picture (92.2%). Based on at least one published tweet in the last 15 days, there were 345 (54.6%) active users on 31 December 2011. Active users mostly used mobile devices based on the Apple operating system to publish tweets (69.2%). Visualisation of emergency physicians' Twitter network revealed many users with no connections with their colleagues, and a small group of most influential users who were highly interconnected.ConclusionsOnly a small proportion of registered emergency physicians use Twitter. Among them exists a smaller inner network of emergency physicians with strong social bonds that is using Twitter's full potentials for professional development.
PTEN deletion is rare but often homogeneous in gastric cancer
Authors: Mina Sormeh , Bohn Benjamin A , Simon Ronald , Krohn Antje , Reeh Matthias , Arnold Dirk , Bokemeyer Carsten , Sauter Guido , Izbicki Jakob R , Marx Andreas , Stahl Phillip R 
Published: May 2012

Background and aimGastric carcinoma is the second most frequent cause of cancer-related death worldwide. As PTEN is a potential modifier of tumour response to trastuzumab, a recently approved therapy in metastatic HER2 positive gastric cancer, the existence of PTEN deletions in primary gastric cancer was investigated.Methods230 primary gastric cancers were analysed in a tissue microarray format by dual labelling fluorescence in situ hybridisation for PTEN deletion. HER2 analysis was also performed. To study PTEN deletion heterogeneity, all available large tissue sections from primary cancer and corresponding metastases were analysed in seven patients.ResultsEight of 180 interpretable primary gastric cancer spots showed PTEN deletions (4.4%), including seven hemizygous and one homozygous deletion. PTEN deletion was correlated with nodal (8 of 122 cases (6.6%); p=0.041) and distant metastases (4 of 19 (21.1%); p<0.001). Large section validation showed a homogeneous distribution of PTEN deletion. HER2 positivity was seen in one PTEN deleted case.ConclusionGenomic PTEN deletion is a rare event in gastric adenocarcinoma but correlates with metastatic disease. The homogeneous distribution pattern indicates that this alteration occurs early in tumour development.
Twisted gastrulation expression in cholangiocellular and hepatocellular carcinoma
Authors: Johnston Jolene , Al-Bahrani Redha , Abuetabh Yasser , Chiu Brian , Forsman Cynthia L , Nagamori Seishi , Leng Roger , Petryk Anna , Sergi Consolato 
Published: May 2012

AimsTo assess the expression of Twisted gastrulation (TWSG1) protein, which regulates the activity of bone morphogenetic proteins (BMPs) in the extracellular space in malignant epithelial tumours of the liver.MethodsThirteen hepatocellular carcinoma (HCC) samples and 12 intrahepatic cholangiocellular carcinoma (CCA) samples were compiled into diagnosis-specific tissue microarrays. Sections were immunostained with a monoclonal antibody against TWSG1 and a polyclonal antibody against BMP4. Human cell lines were also used, including one HCC cell line (HepG2), three CCA cell lines (OZ, Huh-28, HuCCT-1) and a Papova-immortalised normal hepatocyte cell line (THLE-3) for western blot analysis (WBA).ResultsImmunostaining and WBA showed a stronger TWSG1 expression in CCA than in HCC. The difference in expression was significant (p<0.05), and the immunohistochemical signal was particularly evident in the malignant epithelial areas close to desmoplastic stroma in CCA and in the areas of glandular differentiation in HCC. No expression was seen in normal hepatocytes. Interestingly, BMP4 was fully expressed in CCA and only partly in HCC. WBA showed a band for BMP4 in both CCA and HCC cell lines.ConclusionsTWSG1 is expressed in both malignant epithelial carcinomas, although the level of expression is higher in CCA than in HCC and seems to correlate at least partially with BMP4 expression.
Use of matrix assisted laser desorption ionisation–time of flight mass spectrometry in a paediatric clinical laboratory for identification of bacteria commonly isolated from cystic fibrosis patients
Authors: Desai Ankita Patel , Stanley Theresa , Atuan Maria , McKey Jonelle , Lipuma John J , Rogers Beverly , Jerris Robert 
Published: May 2012

BackgroundMatrix-assisted laser desorption ionisation–time of flight mass spectrometry (MALDI-TOF MS) has been described as a rapid, accurate method for bacterial identification.AimsTo investigate the ability of the technique, using the unamended database supplied with the system, to identify bacteria commonly isolated in cystic fibrosis (CF) patients.MethodsOrganisms commonly isolated from CF patients identified by MALDI-TOF MS were compared to conventional phenotypic and genotypic analyses. For MALDI-TOF MS, the direct colony technique was used routinely with one extraction procedure performed on a mucoidPseudomonas aeruginosa. For 24 unique CF specimens, workload comparison and time to identification were assessed.ResultsOf 464 tested isolates, conventional (phenotypic and genotypic) identification compared to MALDI-TOF MS showed complete genus, species agreement in 92%, with genus agreement in 98%. This included 29 isolates within theBurkholderia cepaciacomplex. All 29 were correctly identified to the genus level and 24 of these were speciated. Time to identification with 47 bacterial isolates from 24 CF patients showed identification of 85% of isolates by MALDI-TOF MS at 48 h of incubation, compared to only 34% with conventional methods.ConclusionsUsing the unamended database supplied with the system, MALDI-TOF MS provides rapid and reliable identification of bacteria isolated from CF specimens. Time to identification studies showed that the use of same day, same method for organism identification will decrease time to result and optimise microbiology workflow.
Trends of stage, grade, histology and tumour necrosis in renal cell carcinoma in a European centre surgical series from 1984 to 2010
Authors: Pichler Martin , Hutterer Georg C , Chromecki Thomas F , Jesche Johanna , Kampel-Kettner Karin , Eberhard Katharina , Hoefler Gerald , Pummer Karl , Zigeuner Richard 
Published: May 2012

AimsTo analyse renal cell carcinoma (RCC) stage, grade, histology and necrosis migration in a large European centre series over the last 27 years.MethodsThe pathology reports of 2739 consecutive patients with RCC who underwent nephrectomy from 1984 to 2010 at the institution of the authors were systematically re-evaluated. Patients were pooled into five time groups according to the date of surgery: group 1: 1984–1989, group 2: 1990–1994, group 3: 1995–1999, group 4: 2000–2004 and group 5: 2005–2010, respectively. Changes in pT categories according to WHO 2010 classification, tumour grade, histological subtype and presence of tumour necrosis (TN) were evaluated.ResultsSmall pT1a tumours were found in 62/485 (12.8%) and 312/639 (48.8%) patients in groups 1 and 5, respectively (p<0.001). Advanced tumour stages (pT3a-4) were found in 306/485 (63.1%) and 171/639 (26.8%) patients in groups 1 and 5, respectively (p<0.001). The number of grade 3/4 tumours increased from 62/485 (12.7%) and 130/639 (20.3%) in groups 1 and 5, respectively, whereas the number of grade 1 tumours decreased over time (p<0.001). There has been a significant histological migration for the chromophobe subtype from 1.1% to 4.3% (p=0.002). The frequency of the presence TN decreased from 41.7% in group 1 to 32.7% in group 5 (p<0.001).ConclusionsIn contrast to data from Australia but similar to data from US cohorts, a statistically significant stage migration towards small RCCs was observed in this European cohort. Significant changes in tumour grade, histological subtype and TN were also observed.
CCR5 Antagonist Blocks Metastasis of Basal Breast Cancer Cells
Authors: Velasco-Velázquez Marco , Jiao Xuanmao , De La Fuente Marisol , Pestell Timothy G. , Ertel Adam , Lisanti Michael P. , Pestell Richard G. 
Published: May 2012

Abstract
The roles of the chemokine CCL5 and its receptor CCR5 in breast cancer progression remain unclear. Here, we conducted microarray analysis on 2,254 human breast cancer specimens and found increased expression of CCL5 and its receptor CCR5, but not CCR3, in the basal and HER-2 genetic subtypes. The subpopulation of human breast cancer cell lines found to express CCR5 displayed a functional response to CCL5. In addition, oncogene transformation induced CCR5 expression, and the subpopulation of cells that expressed functional CCR5 also displayed increased invasiveness. The CCR5 antagonists maraviroc or vicriviroc, developed to block CCR5 HIV coreceptor function, reduced in vitro invasion of basal breast cancer cells without affecting cell proliferation or viability, and maraviroc decreased pulmonary metastasis in a preclinical mouse model of breast cancer. Taken together, our findings provide evidence for the key role of CCL5/CCR5 in the invasiveness of basal breast cancer cells and suggest that CCR5 antagonists may be used as an adjuvant therapy to reduce the risk of metastasis in patients with the basal breast cancer subtype. Cancer Res; 72(15); 3839–50. ©2012 AACR.
Wnt/Snail Signaling Regulates CytochromecOxidase and Glucose Metabolism
Authors: Lee Su Yeon , Jeon Hyun Min , Ju Min Kyung , Kim Cho Hee , Yoon Gyesoon , Han Song Iy , Park Hye Gyeong , Kang Ho Sung 
Published: May 2012

AbstractWnt signaling plays a critical role in embryonic development, and its deregulation is closely linked to the occurrence of a number of malignant tumors, including breast and colon cancer. The pathway also induces Snail-dependent epithelial-to-mesenchymal transition (EMT), which is responsible for tumor invasion and metastasis. In this study, we show that Wnt suppresses mitochondrial respiration and cytochrome C oxidase (COX) activity by inhibiting the expression of 3 COX subunits, namely, COXVIc, COXVIIa, and COXVIIc. We found that Wnt induced a glycolytic switch via increased glucose consumption and lactate production, with induction of pyruvate carboxylase (PC), a key enzyme of anaplerosis. In addition, Wnt-induced mitochondrial repression and glycolytic switching occurred through the canonical β-catenin/T-cell factor 4/Snail pathway. Short hairpin RNA–mediated knockdown of E-cadherin, a regulator of EMT, repressed mitochondrial respiration and induced a glycolytic switch via Snail activation, indicating that EMT may contribute to Wnt/Snail regulation of mitochondrial respiration and glucose metabolism. Together, our findings provide a new function for Wnt/Snail signaling in the regulation of mitochondrial respiration (via COX gene expression) and glucose metabolism (via PC gene expression) in tumor growth and progression. Cancer Res; 72(14); 3607–17. ©2012 AACR.
A Phase I First-in-Human Trial of Bardoxolone Methyl in Patients with Advanced Solid Tumors and Lymphomas
Authors: Hong David S. , Kurzrock Razelle , Supko Jeffrey G. , He Xiaoying , Naing Aung , Wheler Jennifer , Lawrence Donald , Eder Joseph Paul , Meyer Colin J. , Ferguson Deborah A. , Mier James , Konopleva Marina , Konoplev Sergej , Andreeff Michael , Kufe Donald , Lazarus Hillard , Shapiro Geoffrey I. , Dezube Bruce J. 
Published: May 2012

Abstract
Purpose: Bardoxolone methyl, a novel synthetic triterpenoid and antioxidant inflammation modulator, potently induces Nrf2 and inhibits NF-κB and Janus-activated kinase/STAT signaling. This first-in-human phase I clinical trial aimed to determine the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), and appropriate dose for phase II studies; characterize pharmacokinetic and pharmacodynamic parameters; and assess antitumor activity.
Experimental Design: Bardoxolone methyl was administered orally once daily for 21 days of a 28-day cycle. An accelerated titration design was employed until a grade 2–related adverse event occurred. A standard 3 + 3 dose escalation was then employed until the MTD was reached. Single dose and steady-state plasma pharmacokinetics of the drug were characterized. Assessment of Nrf2 activation was examined in peripheral blood mononuclear cells (PBMC) by measuring NAD(P)H:quinone oxidoreductase (NQO1) mRNA levels. Immunohistochemical assessment of markers of inflammation, cell cycle, and apoptosis was carried out on tumor biopsies.
Results: The DLTs were grade 3 reversible liver transaminase elevations. The MTD was established as 900 mg/d. A complete tumor response occurred in a mantle cell lymphoma patient, and a partial response was observed in an anaplastic thyroid carcinoma patient. NQO1 mRNA levels increased in PBMCs, and NF-κB and cyclin D1 levels decreased in tumor biopsies. Estimated glomerular filtration rate (eGFR) was also increased.
Conclusions: Bardoxolone methyl was well tolerated with an MTD of 900 mg/d. The increase in eGFR suggests that bardoxolone methyl might be beneficial in chronic kidney disease. Objective tumor responses and pharmacodynamic effects were observed, supporting continued development of other synthetic triterpenoids in cancer. Clin Cancer Res; 18(12); 3396–406. ©2012 AACR.
Sustained Remission of Multicentric Castleman Disease in Children Treated with Tocilizumab, an Anti-Interleukin-6 Receptor Antibody
Authors: Galeotti Caroline , Boucheron Adeline , Guillaume Séverine , Koné-Paut Isabelle 
Published: May 2012

Abstract
Multicentric Castleman Disease (MCD) is an idiopathic lymphoproliferative disorder, reported exceptionally in children and generally believed to be an autoinflammatory disease resulting in an increase of interleukin-6 secretion. Previous studies in adult patients suggested a beneficial role of the anti-interleukin-6 receptor antibody tocilizumab on the clinical and biologic disease manifestations of MCD. Here, we describe the efficacy and safety of tocilizumab in two children with MCD, which was diagnosed on the basis of clinical and histologic findings. In both cases, tocilizumab was administered intravenously at a dose of 8 mg/kg every 2 weeks. The tocilizumab treatment alleviated fever and restored growth rate in both patients. The patients' hypergammaglobulinemia, high C-reactive protein, and high erythrocyte sedimentation rates normalized simultaneously. Nevertheless, splenomegaly persisted in the first patient, and a secondary hepatic node appeared in the second patient. The side effects, essentially sustained thrombocytopenia, were mild in both cases. For the first patient, following an initial 10-month period, the interval between infusions was increased. This patient benefited from sustained remission for a period of 3 years. Tocilizumab was effective and safe in these two children with MCD. Mol Cancer Ther; 11(8); 1623–6. ©2012 AACR.
Early to Intermediate Steps of Tumor Embolic Formation Involve Specific Proteolytic Processing of E-Cadherin Regulated by Rab7
Authors: Ye Yin , Gao Jian-Xin , Tian Honglin , Yearsley Kurtis , Lange Alicia R. , Robertson Fredika M. , Barsky Sanford H. 
Published: May 2012

Abstract
The lymphovascular embolus is an enigmatic entity adept at metastatic dissemination and chemotherapy resistance. Using MARY-X, a human breast cancer xenograft that exhibits florid lymphovascular emboli in mice and spheroids in vitro, we established a model where the in vitro transition stages from minced tumoral aggregates to well-formed spheroids served as a surrogate for in vivo emboli formation. MARY-X well-formed spheroids and emboli exhibited strong similarity of expression. The aggregate-to-spheroid transition stages were characterized by increased ExoC5, decreased Hgs and Rab7, increased calpains, increased full-length E-cadherin (E-cad/FL), and the transient appearance of E-cad/NTF2, a 95 kDa E-cadherin fragment and increased Notch3icd (N3icd), the latter two fragments produced by increased γ-secretase. Both transient and permanent knockdowns of Rab7 in MCF-7 cells increased protein but not transcription of E-cad/FL and resulted in the de novo appearance of E-cad/NTF2, the presence of nuclear E-cad/CTF2, and increased Notch1icd (N1icd). Overexpression of Rab7 conversely decreased E-cad/FL, γ-secretase (PS1/NTF), and E-cad/NTF2. Overexpression of calpains did not alter PS1/NTF but decreased E-cad/FL and E-cad/NTF2 and increased N1icd. Well-formed spheroids showed increased Rab7, absent E-cad/NTF2, decreased PS1/NTF, increased E-cad/NTF1, and increased N3icd, the latter two fragments being the direct and indirect consequences, respectively, of increased calpains (calpain 1 and calpain 2). Inhibition of calpains decreased E-cad/NTF1 but increased E-cad/NTF2 showing that calpains compete with γ-secretase (PS1) for closely located cleavage/binding sites on E-cadherin and that increased calpains can shuttle even decreased levels of γ-secretase to Notch 3, resulting in increased Notch 3 signaling in the well-formed spheroids. Mol Cancer Res; 10(6); 713–26. ©2012 AACR.
State of the Science: An Update on Renal Cell Carcinoma
Authors: Jonasch Eric , Futreal P. Andrew , Davis Ian J. , Bailey Sean T. , Kim William Y. , Brugarolas James , Giaccia Amato J. , Kurban Ghada , Pause Armin , Frydman Judith , Zurita Amado J. , Rini Brian I. , Sharma Pam , Atkins Michael B. , Walker Cheryl L. , Rathmell W. Kimryn 
Published: May 2012

Abstract
Renal cell carcinomas (RCC) are emerging as a complex set of diseases that are having a major socioeconomic impact and showing a continued rise in incidence throughout the world. As the field of urologic oncology faces these trends, several major genomic and mechanistic discoveries are altering our core understanding of this multitude of cancers, including several new rare subtypes of renal cancers. In this review, these new findings are examined and placed in the context of the well-established association of clear cell RCC (ccRCC) with mutations in the von Hippel-Lindau (VHL) gene and resultant aberrant hypoxia inducible factor (HIF) signaling. The impact of novel ccRCC-associated genetic lesions on chromatin remodeling and epigenetic regulation is explored. The effects of VHL mutation on primary ciliary function, extracellular matrix homeostasis, and tumor metabolism are discussed. Studies of VHL proteostasis, with the goal of harnessing the proteostatic machinery to refunctionalize mutant VHL, are reviewed. Translational efforts using molecular tools to elucidate discriminating features of ccRCC tumors and develop improved prognostic and predictive algorithms are presented, and new therapeutics arising from the earliest molecular discoveries in ccRCC are summarized. By creating an integrated review of the key genomic and molecular biological disease characteristics of ccRCC and placing these data in the context of the evolving therapeutic landscape, we intend to facilitate interaction among basic, translational, and clinical researchers involved in the treatment of this devastating disease, and accelerate progress toward its ultimate eradication. Mol Cancer Res; 10(7); 859–80. ©2012 AACR.
A Central Role for RAF→MEK→ERK Signaling in the Genesis of Pancreatic Ductal Adenocarcinoma
Authors: Collisson Eric A. , Trejo Christy L. , Silva Jillian M. , Gu Shenda , Korkola James E. , Heiser Laura M. , Charles Roch-Philippe , Rabinovich Brian A. , Hann Byron , Dankort David , Spellman Paul T. , Phillips Wayne A. , Gray Joe W. , McMahon Martin 
Published: May 2012

Abstract
KRAS mutation is a hallmark of pancreatic ductal adenocarcinoma (PDA) but remains an intractable pharmacologic target. Consequently, defining RAS effector pathway(s) required for PDA initiation and maintenance is critical to improve treatment of this disease. Here, we show that expression of BRAFV600E, but not PIK3CAH1047R, in the mouse pancreas leads to pancreatic intraepithelial neoplasia (PanIN) lesions. Moreover, concomitant expression of BRAFV600E and TP53R270H result in lethal PDA. We tested pharmacologic inhibitors of RAS effectors against multiple human PDA cell lines. Mitogen-activated protein (MAP)/extracellular signal–regulated (ERK) kinase (MEK) inhibition was highly effective both in vivo and in vitro and was synergistic with AKT inhibition in most cell lines tested. We show that RAF→MEK→ERK signaling is central to the initiation and maintenance of PDA and to rational combination strategies in this disease. These results emphasize the value of leveraging multiple complementary experimental systems to prioritize pathways for effective intervention strategies in PDA.
Significance: PDA is difficult to treat, in large part, due to recurrent mutations in the KRAS gene. Here, we define rational treatment approaches for the disease achievable today with existing drug combinations by thorough genetic and pharmacologic dissection of the major KRAS effector pathways, RAF→MEK→ERK and phosphoinositide 3′-kinase (PI3′K)→AKT. Cancer Discov; 2(8); 685–93. ©2012 AACR.
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Layered Activation of Epicardial Scar in Arrhythmogenic Right Ventricular Dysplasia
Authors: Haqqani Haris M. , Tschabrunn Cory M. , Betensky Brian P. , Lavi Nimrod , Tzou Wendy S. , Zado Erica S. , Marchlinski Francis E. 
Published: May 2012

Background—
Ventricular tachycardia ablation in arrhythmogenic right ventricular dysplasia (ARVD) is more successful when including epicardial ablation. Scarring may cause independent, layered epicardial activation and promote epicardially confined ventricular tachycardia circuits. We aimed to characterize transmural right ventricular activation in ARVD patients and to compare this with reference patients without structural heart disease.

Methods and Results—

Eighteen ARVD patients underwent detailed endocardial and epicardial sinus rhythm electroanatomic mapping. Bipolar activation was annotated at the sharpest intrinsic deflection including late potentials and compared with 6 patients with normal hearts. Total scar area was larger on the epicardium (97±78 cm
2
) than the endocardium (57±44 cm
2
;
P
=0.04), with significantly more isolated potentials. Total epicardial activation time was longer than endocardial (172±54 versus 99±27 ms;
P
<0.01), and both were longer than in reference patients. Earliest endocardial site was the right ventricular anteroseptum in 17 of 18 ARVD patients versus 5 of 6 controls (
P
=0.446), and latest endocardial site was in the outflow tract in 13 of 18 ARVD patients versus 4 of 6 controls and tricuspid annulus in 5 of 18 ARVD patients versus 2 of 6 controls (
P
=1.00). In reference patients, epicardial activation directly opposite endocardial sites occurred in 5.2±1.9 ms, suggesting direct transmural activation. In contrast, ARVD patients had major activation delay to the epicardium with laminar central scar activation from the scar border, not by direct transmural spread from the endocardium.

Conclusions—
Transmural right ventricular activation is modified by ARVD scarring with a delayed epicardial activation sequence suggestive of independent rather than direct transmural activation. This may predispose ventricular tachycardia circuits contained entirely within the epicardium in ARVD and explains observations on the need for direct epicardial ablation to eliminate ventricular tachycardia.