bluuebunny/crossref_metadata_2025_split huggingface dataset:
New Challenges in Endpoints for Drug Development in Advanced Melanoma
Authors: Ribas Antoni , Hersey Peter , Middleton Mark R. , Gogas Helen , Flaherty Keith T. , Sondak Vernon K. , Kirkwood John M. 
Published: December 2011

Abstract
During the past 3 decades, the field of clinical research for the treatment of advanced melanoma lacked significant advances. Available drugs had low antitumor activity and no proven benefit in overall survival. Recently, new drugs developed based on an in-depth understanding of the biology of this disease have shown significant benefit, with ipilimumab and vemurafenib having recently shown a positive impact in overall survival in patients with metastatic melanoma leading to approval in this indication by the U.S. Food and Drug Administration. This rapid introduction of new active agents is likely to challenge current notions on how to develop future agents for the treatment of melanoma. The strong evidence of benefit for initial agents that modulate immune regulatory checkpoints or target driver oncogenes has spurred great interest in developing other similarly acting agents. However, this will pose problems in the choice of endpoints for the future definitive clinical trials, and the hurdles for achieving these endpoints will be higher given the similar activity for comparator agents or the availability of competing agents for salvage therapy. This new reality will likely require tailoring registrational clinical trial endpoints to the patient benefits shown in early clinical testing. In this perspective article, we illustrate the challenges in the choice of endpoints for registrational trials in metastatic melanoma and that, with an improved understanding of the agent being developed, the design of the registrational programs can be informed by earlier mechanistic studies to define the assumptions for definitive clinical testing. Clin Cancer Res; 18(2); 336–41. ©2011 AACR.
Ganetespib, a Unique Triazolone-Containing Hsp90 Inhibitor, Exhibits Potent Antitumor Activity and a Superior Safety Profile for Cancer Therapy
Authors: Ying Weiwen , Du Zhenjian , Sun Lijun , Foley Kevin P. , Proia David A. , Blackman Ronald K. , Zhou Dan , Inoue Takayo , Tatsuta Noriaki , Sang Jim , Ye Shuxia , Acquaviva Jamie , Ogawa Luisa Shin , Wada Yumiko , Barsoum James , Koya Keizo 
Published: December 2011

AbstractTargeted inhibition of the molecular chaperone Hsp90 results in the simultaneous blockade of multiple oncogenic signaling pathways and has, thus, emerged as an attractive strategy for the development of novel cancer therapeutics. Ganetespib (formerly known as STA-9090) is a unique resorcinolic triazolone inhibitor of Hsp90 that is currently in clinical trials for a number of human cancers. In the present study, we showed that ganetespib exhibits potent in vitro cytotoxicity in a range of solid and hematologic tumor cell lines, including those that express mutated kinases that confer resistance to small-molecule tyrosine kinase inhibitors. Ganetespib treatment rapidly induced the degradation of known Hsp90 client proteins, displayed superior potency to the ansamycin inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG), and exhibited sustained activity even with short exposure times. In vivo, ganetespib showed potent antitumor efficacy in solid and hematologic xenograft models of oncogene addiction, as evidenced by significant growth inhibition and/or regressions. Notably, evaluation of the microregional activity of ganetespib in tumor xenografts showed that ganetespib was efficiently distributed throughout tumor tissue, including hypoxic regions &gt;150 μm from the microvasculature, to inhibit proliferation and induce apoptosis. Importantly, ganetespib showed no evidence of cardiac or liver toxicity. Taken together, this preclinical activity profile indicates that ganetespib may have broad application for a variety of human malignancies, and with select mechanistic and safety advantages over other first- and second-generation Hsp90 inhibitors. Mol Cancer Ther; 11(2); 475–84. ©2011 AACR.
Long-Term Effects of Changes in Cardiorespiratory Fitness and Body Mass Index on All-Cause and Cardiovascular Disease Mortality in Men
Authors: Lee Duck-chul , Sui Xuemei , Artero Enrique G. , Lee I-Min , Church Timothy S. , McAuley Paul A. , Stanford Fatima C. , Kohl Harold W. , Blair Steven N. 
Published: December 2011

Background—
The combined associations of changes in cardiorespiratory fitness and body mass index (BMI) with mortality remain controversial and uncertain.

Methods and Results—
We examined the independent and combined associations of changes in fitness and BMI with all-cause and cardiovascular disease (CVD) mortality in 14 345 men (mean age 44 years) with at least 2 medical examinations. Fitness, in metabolic equivalents (METs), was estimated from a maximal treadmill test. BMI was calculated using measured weight and height. Changes in fitness and BMI between the baseline and last examinations over 6.3 years were classified into loss, stable, or gain groups. During 11.4 years of follow-up after the last examination, 914 all-cause and 300 CVD deaths occurred. The hazard ratios (95% confidence intervals) of all-cause and CVD mortality were 0.70 (0.59–0.83) and 0.73 (0.54–0.98) for stable fitness, and 0.61 (0.51–0.73) and 0.58 (0.42–0.80) for fitness gain, respectively, compared with fitness loss in multivariable analyses including BMI change. Every 1-MET improvement was associated with 15% and 19% lower risk of all-cause and CVD mortality, respectively. BMI change was not associated with all-cause or CVD mortality after adjusting for possible confounders and fitness change. In the combined analyses, men who lost fitness had higher all-cause and CVD mortality risks regardless of BMI change.

Conclusions—
Maintaining or improving fitness is associated with a lower risk of all-cause and CVD mortality in men. Preventing age-associated fitness loss is important for longevity regardless of BMI change.
Mitochondrial Thioredoxin Reductase Is Essential for Early Postischemic Myocardial Protection
Authors: Horstkotte Jan , Perisic Tamara , Schneider Manuela , Lange Philipp , Schroeder Melanie , Kiermayer Claudia , Hinkel Rabea , Ziegler Tilman , Mandal Pankaj K. , David Robert , Schulz Sabine , Schmitt Sabine , Widder Julian , Sinowatz Fred , Becker Bernhard F. , Bauersachs Johann , Naebauer Michael , Franz Wolfgang M. , Jeremias Irmela , Brielmeier Markus , Zischka Hans , Conrad Marcus , Kupatt Christian 
Published: December 2011

Background—
Excessive formation of reactive oxygen species contributes to tissue injury and functional deterioration after myocardial ischemia/reperfusion. Especially, mitochondrial reactive oxygen species are capable of opening the mitochondrial permeability transition pore, a harmful event in cardiac ischemia/reperfusion. Thioredoxins are key players in the cardiac defense against oxidative stress. Mutations in the mitochondrial thioredoxin reductase (thioredoxin reductase-2, Txnrd2) gene have been recently identified to cause dilated cardiomyopathy in patients. Here, we investigated whether mitochondrial thioredoxin reductase is protective against myocardial ischemia/reperfusion injury.

Methods and Results—

In mice, α-MHC-restricted Cre-mediated Txnrd2 deficiency, induced by tamoxifen (
Txnrd2-/-ic
), aggravated systolic dysfunction and cardiomyocyte cell death after ischemia (90 minutes) and reperfusion (24 hours).
Txnrd2-/-ic
was accompanied by a loss of mitochondrial integrity and function, which was resolved on pretreatment with the reactive oxygen species scavenger N-acetylcysteine and the mitochondrial permeability transition pore blocker cyclosporin A. Likewise, Txnrd2 deletion in embryonic endothelial precursor cells and embryonic stem cell-derived cardiomyocytes, as well as introduction of Txnrd2-shRNA into adult HL-1 cardiomyocytes, increased cell death on hypoxia and reoxygenation, unless N-acetylcysteine was coadministered.

Conclusions—
We report that Txnrd2 exerts a crucial function during postischemic reperfusion via thiol regeneration. The efficacy of cyclosporin A in cardiac Txnrd2 deficiency may indicate a role for Txnrd2 in reducing mitochondrial reactive oxygen species, thereby preventing opening of the mitochondrial permeability transition pore.
Quiet Desperation
Authors: Wollard Karen Kelly 
Published: December 2011

The Problem. Employee engagement continues to capture the interest of practitioners and scholars, yet estimates are that between 50%and 70% of workers are not engaged. Disengagement has implications for profitability, productivity, safety, mental health, turnover, and employee theft. The Solution. The article builds on Kahn’s concept of disengagement and presents a consolidated view of the research regarding the process of disengagement. A call to action is presented, as a plea to organizations to address cognitive, emotional and behavioral/physical needs of the majority of workers who are less than fully engaged. The Stakeholders. Human resource development (HRD) researcher and practitioners who work in organizations where engagement is low, turnover is high, or morale is plummeting.
BH3-only protein Noxa regulates apoptosis in activated B cells and controls high-affinity antibody formation
Authors: Wensveen Felix M. , Derks Ingrid A. M. , van Gisbergen Klaas P. J. M. , de Bruin Alex M. , Meijers Joost C. M. , Yigittop HaciAli , Nolte Martijn A. , Eldering Eric , van Lier René A. W. 
Published: December 2011

Abstract
The efficiency of humoral immune responses depends on the selective outgrowth of B cells and plasmacells that produce high affinity antibodies. The factors responsible for affinity maturation of B cell clones in the germinal center (GC) have been well established but selection mechanisms that allow clones to enter the GC are largely unknown. Here we identify apoptosis, regulated by the proapoptotic BH3-only member Noxa (Pmaip1), as a critical factor for the selection of high-affinity clones during B cell expansion after antigen triggering. Noxa is induced in activated B cells, and its ablation provides a survival advantage both in vitro and in vivo. After immunization or influenza infection, Noxa−/− mice display enlarged GCs, in which B cells with reduced antigen affinity accumulate. As a consequence, Noxa−/− mice mount low affinity antibody responses compared with wild-type animals. Importantly, the low affinity responses correlate with increased immunoglobulin diversity, and cannot be corrected by booster immunization. Thus, normal elimination of low affinity cells favors outgrowth of the remaining high-affinity clones, and this is mandatory for the generation of proper antibody responses. Manipulation of this process may alter the breadth of antibody responses after immunization.
TFPIβ is the GPI-anchored TFPI isoform on human endothelial cells and placental microsomes
Authors: Girard Thomas J. , Tuley Elodee , Broze George J. 
Published: December 2011

AbstractTissue factor pathway inhibitor (TFPI) produces factor Xa-dependent feedback inhibition of factor VIIa/tissue factor-induced coagulation. Messages for 2 isoforms of TFPI have been identified. TFPIα mRNA encodes a protein with an acidic N-terminus, 3 Kunitz-type protease inhibitor domains and a basic C-terminus that has been purified from plasma and culture media. TFPIβ mRNA encodes a form in which the Kunitz-3 and C-terminal domains of TFPIα are replaced with an alternative C-terminus that directs the attachment of a glycosylphosphatidylinositol (GPI) anchor, but whether TFPIβ protein is actually expressed is not clear. Moreover, previous studies have suggested that the predominant form of TFPI released from cells by phosphatidylinositol-specific phospholipase C (PIPLC) treatment is TFPIα, implying it is bound at cell surfaces to a separate GPI-anchored coreceptor. Our studies show that the form of TFPI released by PIPLC treatment of cultured endothelial cells and placental microsomes is actually TFPIβ based on (1) migration on SDS-PAGE before and after deglycosylation, (2) the lack of a Kunitz-3 domain, and (3) it contains a GPI anchor. Immunoassays demonstrate that, although endothelial cells secrete TFPIα, greater than 95% of the TFPI released by PIPLC treatment from the surface of endothelial cells and from placental microsomes is TFPIβ.
A co-ordinated interaction between CTCF and ER in breast cancer cells
Authors: Ross-Innes Caryn S , Brown Gordon D , Carroll Jason S 
Published: December 2011

Abstract

Background
CCCTC-binding factor (CTCF) is a conserved zinc finger transcription factor that is involved in both intra- and interchromasomal looping. Recent research has shown a role for CTCF in estrogen receptor (ER) biology, at some individual loci, but a multi-context global analysis of CTCF binding and transcription activity is lacking.

Results
We now map CTCF binding genome wide in breast cancer cells and find that CTCF binding is unchanged in response to estrogen or tamoxifen treatment. We find a small but reproducible set of CTCF binding events that overlap with both the nuclear receptor, estrogen receptor, and the forkhead protein FOXA1. These overlapping binding events are likely functional as they are biased towards estrogen-regulated genes, compared to regions lacking either CTCF or ER binding. In addition we identify cell-line specific CTCF binding events. These binding events are more likely to be associated with cell-line specific ER binding events and are also more likely to be adjacent to genes that are expressed in that particular cell line.

Conclusion
The evolving role for CTCF in ER biology is complex, but is likely to be multifunctional and possibly influenced by the specific genomic locus. Our data suggest a positive, pro-transcriptional role for CTCF in ER-mediated gene expression in breast cancer cells. CTCF not only provides boundaries for accessible and 'protected' transcriptional blocks, but may also influence the actual binding of ER to the chromatin, thereby modulating the estrogen-mediated gene expression changes observed in breast cancer cells.
Role and expression of FRS2 and FRS3 in prostate cancer
Authors: Valencia Tania , Joseph Ajay , Kachroo Naveen , Darby Steve , Meakin Susan , Gnanapragasam Vincent J 
Published: December 2011

Abstract

Background
FGF receptor substrates (FRS2 and FRS3) are key adaptor proteins that mediate FGF-FGFR signalling in benign as well as malignant tissue. Here we investigated FRS2 and FRS3 as a means of disrupting global FGF signalling in prostate cancer.

Methods
FRS2 and FRS3 manipulation was investigated in vitro using over-expression, knockdown and functional assays. FRS2 and FRS3 expression was profiled in cell lines and clinical tumors of different grades.

Results
In a panel of cell lines we observed ubiquitous FRS2 and FRS3 transcript and protein expression in both benign and malignant cells. We next tested functional redundancy of FRS2 and FRS3 in prostate cancer cells. In DU145 cells, specific FRS2 suppression inhibited FGF induced signalling. This effect was not apparent in cells stably over-expressing FRS3. Indeed FRS3 over-expression resulted in enhanced proliferation (p = 0.005) compared to control cells. Given this functional redundancy, we tested the therapeutic principle of dual targeting of FRS2 and FRS3 in prostate cancer. Co-suppression of FRS2 and FRS3 significantly inhibited ERK activation with a concomitant reduction in cell proliferation (p < 0.05), migration and invasion (p < 0.05). Synchronous knockdown of FRS2 and FRS3 with exposure to cytotoxic irradiation resulted in a significant reduction in prostate cancer cell survival compared to irradiation alone (p < 0.05). Importantly, this synergistic effect was not observed in benign cells. Finally, we investigated expression of FRS2 and FRS3 transcript in a cohort of micro-dissected tumors of different grades as well as by immunohistochemistry in clinical biopsies. Here, we did not observe any difference in expression between benign and malignant biopsies.

Conclusions
These results suggest functional overlap of FRS2 and FRS3 in mediating mitogenic FGF signalling in the prostate. FRS2 and FRS3 are not over-expressed in tumours but targeted dual inhibition may selectively adversely affect malignant but not benign prostate cells.
STAT3 activation in monocytes accelerates liver cancer progression
Authors: Wu Wen-Yong , Li Jun , Wu Zheng-Sheng , Zhang Chang-Le , Meng Xiang-Ling 
Published: December 2011

Abstract

Background
Signal transducer and activator of transcription 3 (STAT3) is an important transcription factor ubiquitously expressed in different cell types. STAT3 plays an essential role in cell survival, proliferation, and differentiation. Aberrantly hyper-activated STAT3 signaling in cancer cells and in the tumor microenvironment has been detected in a wide variety of human cancers and is considered an important factor for cancer initiation, development, and progression. However, the role of STAT3 activation in monocytes in the development of HCC has not been well understood.

Methods
Immunohistochemical analysis of phosphorylated STAT3 was performed on tissue microarray from HCC patients. Using a co-culture system in vivo, HCC cell growth was determined by the MTT assay. In vivo experiments were conducted with mice given diethylinitrosamine (DEN), which induces HCC was used to investigate the role of STAT3 expression in monocytes on tumor growth. Real-time PCR was used to determine the expression of cell proliferation and cell arrest associated genes in the tumor and nontumor tissue from liver.

Results
Phosphorylated STAT3 was found in human hepatocellular carcinoma tissue samples and was expressed in tumor cells and also in monocytes. Phosphorylated STAT3 expression in monocyte was significantly correlated to advanced clinical stage of HCC and a poor prognosis. Using a co-culture system in vivo, monocytes promoted HCC cell growth via the IL-6/STAT3 signaling pathway. The STAT3 inhibitor, NSC 74859, significantly suppressed tumor growth in vivo in mice with diethylinitrosamine (DEN)-induced HCC. In this animal model, blockade of STAT3 with NSC 74859 induced tumor cell apoptosis, while inhibiting both tumor cells and monocytes proliferation. Furthermore, NSC 74859 treatment suppressed cancer associated inflammation in DEN-induce HCC.

Conclusion
Our data suggest constitutively activated STAT3 monocytes promote liver tumorigenesis in clinical patients and animal experiments. Thus, STAT3 in tumor infiltrating inflammatory cells may an attractive target for liver cancer therapy.
M2 macrophages exhibit higher sensitivity to oxLDL-induced lipotoxicity than other monocyte/macrophage subtypes
Authors: Isa Suleiman A , Ruffino José S , Ahluwalia Maninder , Thomas Andrew W , Morris Keith , Webb Richard 
Published: December 2011

Abstract

Background
In obesity, phenotypic switches occur in macrophage populations such that the predominantly M2-polarised anti-inflammatory state seen in lean individuals changes to a predominantly M1-polarised pro-inflammatory state in those who are obese. However, the mechanisms by which these phenotypic shifts occur have not yet been fully elucidated.

Results
The effects of oxLDL (1-40 μg/ml; 24 h) on several parameters relevant to the Unfolded Protein Response (UPR)-mediated lipotoxic effects of oxLDL (disruption of ER Ca2+ handling; activation of the UPR transcription factor XBP-1; upregulation of the UPR target genes BiP and CHOP; apoptosis; cell viability) were investigated in human primary monocyte-derived macrophages, and also in monocyte-macrophages derived from the THP-1 monocytic cell line. A consistent pattern was observed: M2-polarised macrophages were more sensitive to the lipotoxic effects of oxLDL than either non-polarised macrophages or non-differentiated monocytic cells. Specifically, M2-polarised macrophages were the only cell type to undergo significantly increased apoptosis (Primary cells: 1.23 ± 0.01 basal; THP-1-derived: 1.97 ± 0.12 basal; P < 0.05 in both cases) and decreased cell viability (Primary cells: 0.79 ± 0.04 basal; THP-1-derived: 0.67 ± 0.02 basal; P < 0.05 in both cases) when exposed to oxLDL levels similar to those seen in overweight individuals (ie. 1 μg/ml).

Conclusions
We propose that the enhanced susceptibility of M2-polarised macrophages to lipotoxicity seen in the present in vitro study could, over time, contribute to the phenotypic shift seen in obese individuals in vivo. This is because a higher degree of oxLDL-induced lipotoxic cell death within M2 macrophages could contribute to a decrease in numbers of M2 cells, and thus a relative increase in proportion of non-M2 cells, within macrophage populations. Given the pro-inflammatory characteristics of a predominantly M1-polarised state, the data presented here may constitute a useful contribution to our understanding of the origin of the pro-inflammatory nature of obesity, and of the pathogenesis of obesity-associated inflammatory disorders such as Type 2 Diabetes and atherosclerosis.
Laparoscopic low anterior resection for hematogenous rectal metastasis from gastric adenocarcinoma: A Case Report
Authors: Lim Sang Woo , Huh Jung Wook , Kim Young Jin , Kim Hyeong Rok 
Published: December 2011

AbstractBackgroundGastric cancer is one of the most common malignancies in the world and is the second most common cause of cancer-related death in Korea. Colorectal metastases from gastric adenocarcinoma are known to be very rare. We report an unusual case of rectal metastasis of gastric adenocarcinoma.Case presentationWe report a case of a 43-year-old female patient with gastric cancer who first presented with epigastric pain. The endoscopic and radiologic findings were suggestive of Borrmann type III advanced gastric cancer with linitis plastica. Radical total gastrectomy with D2 lymph node dissection was performed. The pathology report was AJCC TNM Stage II gastric adenocarcinoma (T3N0M0). On follow up at 34 months after surgery, the patient complained of difficulty in defecation. On colonoscopy, a hard, indurated extraluminal mass was detected 7 cm proximal to the anal verge. The biopsy demonstrated chronic nonspecific colitis. Abdominal CT, rectal MRI and PET-CT revealed rectal metastasis from gastric cancer. Laparoscopic ultralow anterior resection with diverting ileostomy was performed. The pathology report was metastatic adenocarcinoma, and this diagnosis was identical to the gastric pathology reported in the previous pathology report. The patient was discharged after the 11thpostoperative day with no adverse events.ConclusionRectal metastasis from gastric cancer is known to be very rare. However, metastatic gastric adenocarcinoma should be considered as a differential diagnosis for patients presenting with a colorectal mass and a past history of gastric cancer.