bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I/II Trial of Orteronel (TAK-700)—an Investigational 17,20-Lyase Inhibitor—in Patients with Metastatic Castration-Resistant Prostate Cancer
Authors: Dreicer Robert , MacLean David , Suri Ajit , Stadler Walter M. , Shevrin Daniel , Hart Lowell , MacVicar Gary R. , Hamid Omid , Hainsworth John , Gross Mitchell E. , Shi Yuanjun , Webb Iain J. , Agus David B. 
Published: January 2014

Abstract
Purpose: The androgen receptor pathway remains active in men with prostate cancer whose disease has progressed following surgical or medical castration. Orteronel (TAK-700) is an investigational, oral, nonsteroidal, selective, reversible inhibitor of 17,20-lyase, a key enzyme in the production of androgenic hormones.
Experimental Design: We conducted a phase I/II study in men with progressive, chemotherapy-naïve, metastatic castration-resistant prostate cancer, and serum testosterone &lt;50 ng/dL. In the phase I part, patients received orteronel 100 to 600 mg twice daily or 400 mg twice a day plus prednisone 5 mg twice a day. In phase II, patients received orteronel 300 mg twice a day, 400 mg twice a day plus prednisone, 600 mg twice a day plus prednisone, or 600 mg once a day without prednisone.
Results: In phase I (n = 26), no dose-limiting toxicities were observed and 13 of 20 evaluable patients (65%) achieved ≥50% prostate-specific antigen (PSA) decline from baseline at 12 weeks. In phase II (n = 97), 45 of 84 evaluable patients (54%) achieved a ≥50% decline in PSA and at 12 weeks, substantial mean reductions from baseline in testosterone (−7.5 ng/dL) and dehydroepiandrosterone-sulfate (−45.3 μg/dL) were observed. Unconfirmed partial responses were reported in 10 of 51 evaluable phase II patients (20%). Decreases in circulating tumor cells were documented. Fifty-three percent of phase II patients experienced grade ≥3 adverse events irrespective of causality; most common were fatigue, hypokalemia, hyperglycemia, and diarrhea.
Conclusions: 17,20-Lyase inhibition by orteronel was tolerable and results in declines in PSA and testosterone, with evidence of radiographic responses. Clin Cancer Res; 20(5); 1335–44. ©2014 AACR.
Strain Improves Risk Prediction Beyond Ejection Fraction in Chronic Systolic Heart Failure
Authors: Zhang Kathleen W. , French Benjamin , May Khan Abigail , Plappert Ted , Fang James C. , Sweitzer Nancy K. , Borlaug Barry A. , Chirinos Julio A. , St. John Sutton Martin , Cappola Thomas P. , Ky Bonnie 
Published: January 2014

Background
The utility of longitudinal, circumferential, and radial strain and strain rate in determining prognosis in chronic heart failure is not well established.

Methods and Results

In 416 patients with chronic systolic heart failure, we performed speckle‐tracking analyses of left ventricular longitudinal, circumferential, and radial strain and strain rate on archived echocardiography images (30 frames per second). Cox regression models were used to determine the associations between strain and strain rate and risk of all‐cause mortality, cardiac transplantation, and ventricular‐assist device placement. The area under the time‐dependent
ROC
curve (
AUC
) was also calculated at 1 year and 5 years. Over a maximum follow‐up of 8.9 years, there were 138 events (33.2%). In unadjusted models, all strain and strain rate parameters were associated with adverse outcomes (
P
<0.001). In multivariable models, all parameters with the exception of radial strain rate (
P
=0.11) remained independently associated, with patients in the lowest tertile of strain or strain rate parameter having a ≈2‐fold increased risk of adverse outcomes compared with the reference group (
P
<0.05). Addition of strain to ejection fraction (
EF
) led to a significantly improved
AUC
at 1 year (0.697 versus 0.633,
P
=0.032) and 5 years (0.700 versus 0.638,
P
=0.001). In contrast, strain rate did not provide incremental prognostic value to
EF
alone.

Conclusions

Longitudinal and circumferential strain and strain rate, and radial strain are associated with chronic heart failure prognosis. Strain provides incremental value to
EF
in the prediction of adverse outcomes, and with additional study may be a clinically relevant prognostic tool.
Trends in Incidence, Management, and Outcomes of Cardiogenic Shock Complicating ST‐Elevation Myocardial Infarction in the United States
Authors: Kolte Dhaval , Khera Sahil , Aronow Wilbert S. , Mujib Marjan , Palaniswamy Chandrasekar , Sule Sachin , Jain Diwakar , Gotsis William , Ahmed Ali , Frishman William H. , Fonarow Gregg C. 
Published: January 2014

Background

Limited information is available on the contemporary and potentially changing trends in the incidence, management, and outcomes of cardiogenic shock complicating
ST
‐elevation myocardial infarction (
STEMI
).

Methods and Results

We queried the 2003–2010 Nationwide Inpatient Sample databases to identify all patients ≥40 years of age with
STEMI
and cardiogenic shock. Overall and age‐, sex‐, and race/ethnicity‐specific trends in incidence of cardiogenic shock, early mechanical revascularization, and intra‐aortic balloon pump use, and inhospital mortality were analyzed. From 2003 to 2010, among 1 990 486 patients aged ≥40 years with
STEMI
, 157 892 (7.9%) had cardiogenic shock. The overall incidence rate of cardiogenic shock in patients with
STEMI
increased from 6.5% in 2003 to 10.1% in 2010 (
P
trend
<0.001). There was an increase in early mechanical revascularization (30.4% to 50.7%,
P
trend
<0.001) and intra‐aortic balloon pump use (44.8% to 53.7%,
P
trend
<0.001) in these patients over the 8‐year period. Inhospital mortality decreased significantly, from 44.6% to 33.8% (
P
trend
<0.001; adjusted
OR
, 0.71; 95%
CI
, 0.68 to 0.75), whereas the average total hospital cost increased from $35 892 to $45 625 (
P
trend
<0.001) during the study period. There was no change in the average length of stay (
P
trend
=0.394). These temporal trends were similar in patients <75 and ≥75 years of age, men and women, and across each racial/ethnic group.

Conclusions

The incidence of cardiogenic shock complicating
STEMI
has increased during the past 8 years together with increased use of early mechanical revascularization and intra‐aortic balloon pumps. There has been a concomitant decrease in risk‐adjusted inhospital mortality, but an increase in total hospital costs during this period.
Percutaneous balloon kyphoplasty for the treatment of vertebral compression fractures
Authors: Yu Chia-Wei , Hsieh Ming-Kai , Chen Lih-Huei , Niu Chi-Chien , Fu Tsai-Sheng , Lai Po-Liang , Chen Wen-Jer , Chen Wen-Chien , Lu Meng-Ling 
Published: January 2014

AbstractBackgroundVertebral compression fractures (VCFs) constitute a major health care problem, not only because of their high incidence but also because of their direct and indirect negative impacts on both patients’ health-related quality of life and costs to the health care system. Two minimally invasive surgical approaches were developed for the management of symptomatic VCFs: balloon kyphoplasty and vertebroplasty. The purpose of this study was to evaluate the effectiveness and safety of balloon kyphoplasty in the treatment of symptomatic VCFs.MethodsBetween July 2011 and June 2012, one hundred and eighty-seven patients with two hundred and fifty-one vertebras received balloon kyphoplasty in our hospital. There were sixty-five male and one hundred and twenty-two female patients with an average age of 74.5 (range, 61 to 95 years). The pain symptoms and quality of life, were measured before operation and at one day, three months, six months and one year following kyphoplasty. Radiographic data including restoration of kyphotic angle, anterior vertebral height, and any leakage of cement were defined.ResultsThe mean visual analog pain scale decreased from a preoperative value of 7.7 to 2.2 at one day (p < .05) following operation and the Oswestry Disability Index improved from 56.8 to 18.3 (p < .05). The kyphotic angle improved from a mean of 14.4° before surgery to 6.7° at one day after surgery (p < .05). The mean anterior vertebral height increased significantly from 52% before surgery to 74.5% at one day after surgery (p < .05) and 70.2% at one year follow-up. Minor cement extravasations were observed in twenty-nine out of two hundred and fifty-one procedures, including six leakage via basivertebral vein, three leakage via segmental vein and twenty leakage through a cortical defect. None of the leakages were associated with any clinical consequences.ConclusionsBalloon kyphoplasty not only rapidly reduced pain and disability but also restored sagittal alignment in our patients at one-year follow-up. The treatment of osteoporotic vertebral compression fractures with balloon kyphoplasty is a safe, effective, and minimally invasive procedure that provides satisfactory clinical results.
HIV-1 Vif N-terminal Motif is required for recruitment of Cul5 to Suppress APOBEC3
Authors: Evans Sean L , Schön Arne , Gao Qimeng , Han Xue , Zhou Xiaohong , Freire Ernesto , Yu Xiao-Fang 
Published: January 2014

Abstract

Background
HIV-1 Vif promotes the degradation of host anti-retroviral factor family, APOBEC3 proteins via the recruitment of a multi-subunit E3 ubiquitin ligase complex. The complex is composed of a scaffold protein, Cullin 5 (Cul5), RING-box protein (Rbx), a SOCS box binding protein complex, Elongins B/C (Elo B/C), as well as newly identified host co-factor, core binding factor beta (CBF-β). Cul5 has previously been shown to bind amino acids within an HCCH domain as well as a PPLP motif at the C–terminus of Vif; however, it is unclear whether Cul5 binding requires additional regions of the Vif polypeptide.

Results
Here, we provide evidence that an amino terminal region of full length Vif is necessary for the Vif-Cul5 interaction. Single alanine replacement of select amino acids spanning residues 25–30 (25VXHXMY30) reduced the ability for Vif to bind Cul5, but not CBF-β or Elo B/C in pull-down experiments. In addition, recombinant Vif mutants had a reduced binding affinity for Cul5 compared to wild-type as measured by isothermal titration calorimetry. N-terminal mutants that demonstrated reduced Cul5 binding were also unable to degrade APOBEC3G as well as APOBEC3F and were unable to restore HIV infectivity, in the presence of APOBEC3G. Although the Vif N-terminal amino acids were necessary for Cul5 interaction, the mutation of each residue to alanine induced a change in the secondary structure of the Vif-CBF-β-Elo B/C complex as suggested by results from circular dichroism spectroscopy and size-exclusion chromatography experiments. Surprisingly, the replacement of His108 to alanine also contributed to the Vif structure. Thus, it is unclear whether the amino acids contribute to a direct interaction with Cul5 or whether the amino acids are responsible for the structural organization of the Vif protein that promotes Cul5 binding.

Conclusions
Taken together, we propose a novel Vif N-terminal motif that is responsible for Vif recruitment of Cul5. Motifs in Vif that are absent from cellular proteins represent attractive targets for future HIV pharmaceutical design.
The D-amino acid peptide D3 reduces amyloid fibril boosted HIV-1 infectivity
Authors: Widera Marek , Klein Antonia Nicole , Cinar Yeliz , Funke Susanne Aileen , Willbold Dieter , Schaal Heiner 
Published: January 2014

Abstract

Background
Amyloid fibrils such as Semen-Derived Enhancer of Viral Infection (SEVI) or amyloid-β-peptide (Aβ) enhance HIV-1 attachment and entry. Inhibitors destroying or converting those fibrils into non-amyloidogenic aggregates effectively reduce viral infectivity. Thus, they seem to be suitable as therapeutic drugs expanding the current HIV-intervening repertoire of antiretroviral compounds.

Findings
In this study, we demonstrate that the small D-amino acid peptide D3, which was investigated for therapeutic studies on Alzheimer’s disease (AD), significantly reduces both SEVI and Aβ fibril boosted infectivity of HIV-1.

Conclusions
Since amyloids could play an important role in the progression of AIDS dementia complex (ADC), the treatment of HIV-1 infected individuals with D3, that inhibits Aβ fibril formation and converts preformed Aβ fibrils into non-amyloidogenic and non-fibrillar aggregates, may reduce the vulnerability of the central nervous system of HIV patients for HIV associated neurological disorders.
DLC1 suppresses NF-κB activity in prostate cancer cells due to its stabilizing effect on adherens junctions
Authors: Tripathi Veenu , Popescu Nicholas C , Zimonjic Drazen B 
Published: January 2014

Abstract
DLC1 (Deleted in Liver Cancer 1) gene encodes a RhoGTPase-activating protein (RhoGAP), which exerts most of its tumor suppressor functions through suppression of small Rho GTPases proteins RhoA, RhoB, RhoC and to some degree Cdc42, but not Rac. RhoGTPases are implicated in NF-κB activation in highly invasive prostate carcinoma (PCA), with consequences on cell proliferation, survival and metastatic capacity. Here we demonstrate that DLC1 transduction in two androgen-independent (AI) and highly metastatic PCA cell lines negatively regulates NF-κB activity in a GAP- and α-catenin-dependent manner. Expressed DLC1 protein suppresses the phosphorylation of NF-κB inhibitor, IκBα, causes its relocation from membrane ruffles into cytoplasm and attenuates its ubiquitination and subsequent degradation. DLC1-mediated NF-kB suppression and its effects are comparable to NF-κB inhibition using either shRNA knockdown or peptide inhibitor. Expression of transduced DLC1 suppressed the expression of NF-κB mediated genes. Such effects were found to be reliant on presence of calcium, indicating that the observed modifications are dependent on, and enabled by DLC-mediated stabilization of adherens junctions. These results expand the multitude of DLC1 interactions with other genes that modulate its oncosuppressive function, and may have potential therapeutic implications.
Multiple sclerosis lesion detection with local multimodal Markovian analysis and cellular automata ‘GrowCut’
Authors: Biediger Daniel , Collet Christophe , Armspach Jean‐Paul 
Published: January 2014

Abstract
Multiple sclerosis affect over 2.5 million people world‐wide. This autoimmune disease of the central nervous system causes damage to the insulating myelin sheaths around the axons in the brain. The disease progresses at different rates in different people and can have periods of remission and relapse. A fast and accurate method for evaluating the number and size of MS lesions in the brain is a key component in evaluating the progress of the disease and the efficacy of treatments. Manual segmentation is slow and difficult and the results can be somewhat subjective. It requires a physician to consider several MRI slices across multiple modalities. The power and speed of computer systems provide an obvious avenue to help. While many automated methods exist, they have not reached human‐level accuracy of the segmentation results. There exists a need for a robust, fast and accurate method to improve the results of automatic MS lesion segmentation methods. We propose a post‐processing stage to improve the segmentation results of an existing system. It uses two different strategies to improve the segmentation results of an automated system based on whole‐brain tissue classification and lesion detection. The first strategy leverages the current processing system at a granularity finer than the whole brain to detect lesions at a local level. This reflects the way that a physician considers only a part of the brain at a time. It then combines the series of local results to produce a whole‐brain segmentation. This approach better captures the local lesion properties and produces encouraging results, with a general improvement in the detection rate of lesions. The second method dives deeper and looks at the individual voxel level. Just as a physician might look more closely at a lesion, it considers the local neighborhood around a lesion detection. The method selects seed points from the existing results and uses a region growing method based on cellular automata. It grows the lesion areas based on a local neighborhood similarity in intensity. Over the eleven patients examined, some results improved over the base case and show the efficiency of the proposed approach.
Randomized Controlled Trial of a Cognitive-Behavioral Therapy Plus Hypnosis Intervention to Control Fatigue in Patients Undergoing Radiotherapy for Breast Cancer
Authors: Montgomery Guy H. , David Daniel , Kangas Maria , Green Sheryl , Sucala Madalina , Bovbjerg Dana H. , Hallquist Michael N. , Schnur Julie B. 
Published: January 2014

Purpose The objective of this study was to test the efficacy of cognitive-behavioral therapy plus hypnosis (CBTH) to control fatigue in patients with breast cancer undergoing radiotherapy. We hypothesized that patients in the CBTH group receiving radiotherapy would have lower levels of fatigue than patients in an attention control group. Patients and Methods Patients (n = 200) were randomly assigned to either the CBTH (n = 100; mean age, 55.59 years) or attention control (n = 100; mean age, 55.97 years) group. Fatigue was measured at four time points (baseline, end of radiotherapy, 4 weeks, and 6 months after radiotherapy). Fatigue was measured using the Functional Assessment of Chronic Illness Therapy (FACIT) –Fatigue subscale and Visual Analog Scales (VASs; Fatigue and Muscle Weakness). Results The CBTH group had significantly lower levels of fatigue (FACIT) at the end of radiotherapy (z, 6.73; P < .001), 4-week follow-up (z, 6.98; P < .001), and 6-month follow-up (z, 7.99; P < .001) assessments. Fatigue VAS scores were significantly lower in the CBTH group at the end of treatment (z, 5.81; P < .001) and at the 6-month follow-up (z, 4.56; P < .001), but not at the 4-week follow-up (P < .07). Muscle Weakness VAS scores were significantly lower in the CBTH group at the end of treatment (z, 9.30; P < .001) and at the 6-month follow-up (z, 3.10; P < .02), but not at the 4-week follow-up (P < .13). Conclusion The results support CBTH as an evidence-based intervention to control fatigue in patients undergoing radiotherapy for breast cancer. CBTH is noninvasive, has no adverse effects, and its beneficial effects persist long after the last intervention session. CBTH seems to be a candidate for future dissemination and implementation.
Optimal Duration and Timing of Adjuvant Chemotherapy After Definitive Surgery for Ductal Adenocarcinoma of the Pancreas: Ongoing Lessons From the ESPAC-3 Study
Authors: Valle Juan W. , Palmer Daniel , Jackson Richard , Cox Trevor , Neoptolemos John P. , Ghaneh Paula , Rawcliffe Charlotte L. , Bassi Claudio , Stocken Deborah D. , Cunningham David , O'Reilly Derek , Goldstein David , Robinson Bridget A. , Karapetis Christos , Scarfe Andrew , Lacaine Francois , Sand Juhani , Izbicki Jakob R. , Mayerle Julia , Dervenis Christos , Oláh Attila , Butturini Giovanni , Lind Pehr A. , Middleton Mark R. , Anthoney Alan , Sumpter Kate , Carter Ross , Büchler Markus W. 
Published: January 2014

Purpose Adjuvant chemotherapy improves patient survival rates after resection for pancreatic adenocarcinoma, but the optimal duration and time to initiate chemotherapy is unknown. Patients and Methods Patients with pancreatic ductal adenocarcinoma treated within the international, phase III, European Study Group for Pancreatic Cancer–3 (version 2) study were included if they had been randomly assigned to chemotherapy. Overall survival analysis was performed on an intention-to-treat basis, retaining patients in their randomized groups, and adjusting the overall treatment effect by known prognostic variables as well as the start time of chemotherapy. Results There were 985 patients, of whom 486 (49%) received gemcitabine and 499 (51%) received fluorouracil; 675 patients (68%) completed all six cycles of chemotherapy (full course) and 293 patients (30%) completed one to five cycles. Lymph node involvement, resection margins status, tumor differentiation, and completion of therapy were all shown by multivariable Cox regression to be independent survival factors. Overall survival favored patients who completed the full six courses of treatment versus those who did not (hazard ratio [HR], 0.516; 95% CI, 0.443 to 0.601; P < .001). Time to starting chemotherapy did not influence overall survival rates for the full study population (HR, 0.985; 95% CI, 0.956 to 1.015). Chemotherapy start time was an important survival factor only for the subgroup of patients who did not complete therapy, in favor of later treatment (P < .001). Conclusion Completion of all six cycles of planned adjuvant chemotherapy rather than early initiation was an independent prognostic factor after resection for pancreatic adenocarcinoma. There seems to be no difference in outcome if chemotherapy is delayed up to 12 weeks, thus allowing adequate time for postoperative recovery.
Patterns of Recurrence After Surgery Alone Versus Preoperative Chemoradiotherapy and Surgery in the CROSS Trials
Authors: Oppedijk Vera , van der Gaast Ate , van Lanschot Jan J.B. , van Hagen Pieter , van Os Rob , van Rij Caroline M. , van der Sangen Maurice J. , Beukema Jannet C. , Rütten Heidi , Spruit Patty H. , Reinders Janny G. , Richel Dick J. , van Berge Henegouwen Mark I. , Hulshof Maarten C.C.M. 
Published: January 2014

Purpose To analyze recurrence patterns in patients with cancer of the esophagus or gastroesophageal junction treated with either preoperative chemoradiotherapy (CRT) plus surgery or surgery alone. Patients and Methods Recurrence pattern was analyzed in patients from the previously published CROSS I and II trials in relation to radiation target volumes. CRT consisted of five weekly courses of paclitaxel and carboplatin combined with a concurrent radiation dose of 41.4 Gy in 1.8-Gy fractions to the tumor and pathologic lymph nodes with margin. Results Of the 422 patients included from 2001 to 2008, 418 were available for analysis. Histology was mostly adenocarcinoma (75%). Of the 374 patients who underwent resection, 86% were allocated to surgery and 92% to CRT plus surgery. On January 1, 2011, after a minimum follow-up of 24 months (median, 45 months), the overall recurrence rate in the surgery arm was 58% versus 35% in the CRT plus surgery arm. Preoperative CRT reduced locoregional recurrence (LRR) from 34% to 14% (P < .001) and peritoneal carcinomatosis from 14% to 4% (P < .001). There was a small but significant effect on hematogenous dissemination in favor of the CRT group (35% v 29%; P = .025). LRR occurred in 5% within the target volume, in 2% in the margins, and in 6% outside the radiation target volume. In 1%, the exact site in relation to the target volume was unclear. Only 1% had an isolated infield recurrence after CRT plus surgery. Conclusion Preoperative CRT in patients with esophageal cancer reduced LRR and peritoneal carcinomatosis. Recurrence within the radiation target volume occurred in only 5%, mostly combined with outfield failures.