bluuebunny/crossref_metadata_2025_split huggingface dataset:
A First-Time-in-Human Study of GSK2636771, a Phosphoinositide 3 Kinase Beta-Selective Inhibitor, in Patients with Advanced Solid Tumors
Authors: Mateo Joaquin , Ganji Gopinath , Lemech Charlotte , Burris Howard A. , Han Sae-Won , Swales Karen , Decordova Shaun , DeYoung M. Phillip , Smith Deborah A. , Kalyana-Sundaram Shanker , Wu Jiuhua , Motwani Monica , Kumar Rakesh , Tolson Jerry M. , Rha Sun Young , Chung Hyun Cheol , Eder Joseph P. , Sharma Sunil , Bang Yung-Jue , Infante Jeffrey R. , Yan Li , de Bono Johann S. , Arkenau Hendrik-Tobias 
Published: June 2017

Abstract
Background: The PI3K/protein kinase B (AKT) pathway is commonly activated in several tumor types. Selective targeting of p110β could result in successful pathway inhibition while avoiding the on- and off-target effects of pan-PI3K inhibitors. GSK2636771 is a potent, orally bioavailable, adenosine triphosphate-competitive, selective inhibitor of PI3Kβ.
Methods: We evaluated the safety, pharmacokinetics, pharmacodynamics and antitumor activity of GSK2636771 to define the recommended phase II dose (RP2D). During the dose-selection and dose-escalation stages (parts 1 and 2), patients with PTEN-deficient advanced solid tumors received escalating doses of GSK2636771 (25–500 mg once daily) using a modified 3+3 design to determine the RP2D; tumor type-specific expansion cohorts (part 3) were implemented to further assess tumor responses at the RP2D.
Results: A total of 65 patients were enrolled; dose-limiting toxicities were hypophosphatemia and hypocalcemia. Adverse events included diarrhea (48%), nausea (40%), and vomiting (31%). Single- and repeat-dose exposure increased generally dose proportionally. GSK2636771 400 mg once daily was the RP2D. Phospho/total AKT ratio decreased with GSK2636771 in tumor and surrogate tissue. A castrate-resistant prostate cancer (CRPC) patient harboring PIK3CB amplification had a partial response for over a year; an additional 10 patients derived durable (≥24 weeks) clinical benefit, including two other patients with CRPC with PIK3CB alterations (≥34 weeks). GSK2636771 400 mg once daily orally induced sufficient exposure and target inhibition with a manageable safety profile.
Conclusions: Genomic aberrations of PIK3CB may be associated with clinical benefit from GSK2636771. Clin Cancer Res; 23(19); 5981–92. ©2017 AACR.
Mutational Heterogeneity in APC and KRAS Arises at the Crypt Level and Leads to Polyclonality in Early Colorectal Tumorigenesis
Authors: Gausachs Mireia , Borras Ester , Chang Kyle , Gonzalez Sara , Azuara Daniel , Delgado Amador Axel , Lopez-Doriga Adriana , San Lucas F. Anthony , Sanjuan Xavier , Paules Maria J. , Taggart Melissa W. , Davies Gareth E. , Ehli Erik A. , Fowler Jerry , Moreno Victor , Pineda Marta , You Y. Nancy , Lynch Patrick M. , Lazaro Conxi , Navin Nicholas E. , Scheet Paul A. , Hawk Ernest T. , Capella Gabriel , Vilar Eduardo 
Published: June 2017

Abstract
Purpose: The majority of genomic alterations causing intratumoral heterogeneity (ITH) in colorectal cancer are thought to arise during early stages of carcinogenesis as a burst but only after truncal mutations in APC have expanded a single founder clone. We have investigated if the initial source of ITH is consequent to multiple independent lineages derived from different crypts harboring distinct truncal APC and driver KRAS mutations, thus challenging the prevailing monoclonal monocryptal model.
Experimental Design: High-depth next-generation sequencing and SNP arrays were performed in whole-lesion extracts of 37 familial adenomatous polyposis colorectal adenomas. Also, ultrasensitive genotyping of hotspot mutations of APC and KRAS was performed using nanofluidic PCRs in matched bulk biopsies (n = 59) and crypts (n = 591) from 18 adenomas and seven carcinomas and adjacent normal tissues.
Results: Multiple co-occurring truncal APC and driver KRAS alterations were uncovered in whole-lesion extracts from adenomas and subsequently confirmed to belong to multiple clones. Ultrasensitive genotyping of bulk biopsies and crypts revealed novel undetected APC mutations that were prominent among carcinomas, whereas abundant wild-type APC crypts were detected in adenomas. KRAS mutational heterogeneity within crypts was evident in both adenomas and carcinomas with a higher degree of concordance between biopsy and crypt genotyping in carcinomas. Nonrandom heterogeneity among crypts was also observed.
Conclusions: The striking degree of nonrandom intercrypt heterogeneity in truncal and driver gene mutations observed in adenomas and carcinomas is consistent with a polycryptal model derived from multiple independent initiation linages as the source of early ITH in colorectal carcinogenesis. Clin Cancer Res; 23(19); 5936–47. ©2017 AACR.
Repeated Measurements of Cardiac Biomarkers in Atrial Fibrillation and Validation of the ABC Stroke Score Over Time
Authors: Hijazi Ziad , Lindahl Bertil , Oldgren Jonas , Andersson Ulrika , Lindbäck Johan , Granger Christopher B. , Alexander John H. , Gersh Bernard J. , Hanna Michael , Harjola Veli‐Pekka , Hylek Elaine M. , Lopes Renato D. , Siegbahn Agneta , Wallentin Lars 
Published: June 2017

Background

Cardiac biomarkers are independent risk markers in atrial fibrillation, and the novel biomarker–based
ABC
stroke score (age, biomarkers, and clinical history of prior stroke) was recently shown to improve the prediction of stroke risk in patients with atrial fibrillation. Our aim was to investigate the short‐term variability of the cardiac biomarkers and evaluate whether the
ABC
stroke risk score provides a stable short‐term risk estimate.

Methods and Results

According to the study protocol, samples were obtained at entry and also at 2 months in 4796 patients with atrial fibrillation followed for a median of 1.8 years in the
ARISTOTLE
(Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial. Cardiac troponin I, cardiac troponin T, and N‐terminal pro‐B‐type natriuretic peptide were measured with high‐sensitivity immunoassays. Associations with outcomes were evaluated by Cox regression. C indices and calibration plots were used to evaluate the
ABC
stroke score at 2 months. The average changes in biomarker levels during 2 months were small (median change cardiac troponin T +2.8%, troponin I +2.0%, and N‐terminal pro‐B‐type natriuretic peptide +13.5%) and within‐subject correlation was high (all ≥0.82). Repeated measurement of cardiac biomarkers provided some incremental prognostic value for mortality but not for stroke when combined with clinical risk factors and baseline levels of the biomarkers. Based on 8702 person‐years of follow‐up and 96 stroke/systemic embolic events, the
ABC
stroke score at 2 months achieved a similar C index of 0.70 (95% CI, 0.65–0.76) as compared with 0.70 (95% CI, 0.65–0.75) at baseline. The
ABC
stroke score remained well calibrated using predefined risk classes.

Conclusions

In patients with stable atrial fibrillation, the variability of the cardiac biomarkers and the biomarker‐based
ABC
stroke score during 2 months are small. The prognostic information by the
ABC
stroke score remains consistent and well calibrated with similar good predictive performance if patients are retested after 2 months.

Clinical Trial Registration

URL:
http://www.clinicaltrials.gov
. Unique identifier:
NCT
00412984.
Angiopoietin‐Like Protein 4 Is a High‐Density Lipoprotein (HDL) Component for HDL Metabolism and Function in Nondiabetic Participants and Type‐2 Diabetic Patients
Authors: Yang Long‐Yan , Yu Cai‐Guo , Wang Xu‐Hong , Yuan Sha‐Sha , Zhang Li‐Jie , Lang Jia‐Nan , Zhao Dong , Feng Ying‐Mei 
Published: June 2017

Background

ANGPTL
4 (angiopoietin‐like protein 4) is a LPL (lipoprotein lipase) inhibitor and is present in high‐density lipoprotein (
HDL
). However, it is not defined whether
ANGPTL
4 in
HDL
s could affect
HDL
metabolism and function in type 2 diabetes mellitus (T2
DM
).

Methods and Results

ANGPTL
4 levels in the circulation and
HDL
s were quantified in nondiabetic participants (n=201, 68.7% females) and T2
DM
patients (n=185, 66.5% females).
HDL
s were isolated from nondiabetic controls and T2
DM
patients to assess cholesterol efflux
or
subjected to endothelial lipase (
EL
)‐overexpressed
HEK
293 cells for
EL
hydrolysis in vitro. The association between
ANGPTL
4 in
HDL
s and
HDL
components and function was analyzed in nondiabetic participants or diabetic patients, respectively. Plasma or
HDL
s of
ANGPTL
4+/+ and
ANGPTL
4−/− mice was subjected for cholesterol efflux or
EL
hydrolysis, respectively.
ANGPTL
4 levels in the plasma and
HDL
s were 1.7‐ and 2.0‐fold higher in T2
DM
patients than nondiabetic controls, respectively (
P
<0.0001). Multivariable analysis demonstrated that per 1 doubling increase of
ANGPTL
4 levels in
HDL
s, the changes amounted to +0.27% cholesterol efflux (
P
=0.03), +0.06 μg/mL apolipoprotein A‐I (
P
=0.09) and −9.41 μg/L serum amyloid A (
P
=0.02) in nondiabetic controls. In T2
DM
patients, the corresponding estimates were −0.06% cholesterol efflux (
P
=0.10), −0.06 μg/mL apolipoprotein A‐I (
P
=0.38), and +3.64 μg/L serum amyloid A (
P
=0.72).
HDL
s isolated from
ANGPTL
4−/− mice showed accelerated hydrolysis by
EL
and reduced cholesterol efflux compared with
ANGPTL
4+/+ littermates.

Conclusions

Physically,
ANGPTL
4 in
HDL
s protected
HDL
s from hydrolysis. Resulting from increased circulating
ANGPTL
4 levels in T2
DM
,
ANGPTL
4 levels in
HDL
s were elevated but with compromised inhibitory effect on
EL
, leading to increased
HDL
hydrolysis and dysfunction.
Partnerships for active elementary schools: Physical education outcomes after 4 months of a 2-year pilot study
Authors: Weaver R. Glenn , Webster Collin , Egan Catherine , Campos Carolina , Michael Robert D , Crimarco Anthony 
Published: June 2017

Objective: This study assessed the impact of Partnerships for Active Children in Elementary Schools (PACES) on children’s moderate-to-vigorous physical activity (MVPA) during physical education (PE) and teachers’ incorporation of physical activity promotion strategies after one academic semester (i.e. 4 months) of the intervention. Design: Single group pre–post pilot study. Setting: Three elementary schools in one southeastern metropolitan city in the USA. Methods: Using principles of community-based participatory-research, researchers worked with teachers to identify contextually appropriate physical activity promotion strategies aligned with prevailing recommendations, principles and theories. Outcome measures included accelerometer-derived percent of time children ( N = 150) engaged in MVPA. The System for Observing Fitness Instruction Time+ assessed changes in teachers’ incorporation of physical activity promotion strategies. Multi-level mixed-effects linear regression estimated differences over time. Results: MVPA increased for girls (22.7%–26.6%) and boys (33.2%–39.0%). Small-sided games (1.0%–9.0%) and teachers’ verbal promotion of physical activity (6.4%–13.5%) increased while student’s off-task behaviour (6.0%–2.0%) decreased. Lines (20.2%–8.4%) and elimination games (21.6%–13.3%) decreased, but these changes were not statistically significant. Conclusion: PACES shows promise for increasing the percent of time children spend in MVPA during PE but requires further evaluation.
Developing a practical readability tool for assessing written oral health promotion material for people with low literacy
Authors: de Silva Andrea M , Martin-Kerry Jacqueline M , Van Kelly , Hegde Shalika , Heilbrunn-Lang Adina 
Published: June 2017

Objective: Oral health promotion resources need to be simple, useful, accessible and understandable to be effective. The importance of this is magnified for population groups who are at increased risk of poor oral health, have low literacy or language barriers. Consultation with health service providers identified the need for a readability tool to assist them to assess and develop appropriate oral health promotion resources to ensure they were written using language that was easy to understand by those with high oral health needs and low literacy levels. The objective of this study was to identify and adapt existing health literacy and readability tools and pilot the tool to determine its appropriateness for use in oral health promotion targeting those with high oral health needs and low literacy levels. Design: This paper reports the development of an oral health readability tool. Methods: Existing readability tools were identified through electronic searching and reviewed for suitability. In parallel, written oral health resources used in Australia specifically targeting refugee and asylum seeker population were identified through discussions with oral health service providers and an online grey literature search. Results: No single tool was identified which could be readily used to screen and assess written oral health resources. Two existing tools, the Fry readability formula and a suitability checklist, were therefore adapted and integrated into one tool. This new readability tool was then piloted by screening 10 written oral health resources currently in use in the public oral health sector for refugee and asylum seeker populations. Of the 10 written oral health resources assessed, only 4 were of an appropriate reading level for clients with low literacy. Conclusion: This study developed and tested an oral health readability tool to assess and develop oral health promotion resources.
Peroneal Sheath Volumes in Patients with Peroneal Tendon Injuries
Authors: Miller Christopher , Smith Stacy , Goodman Eric , Fisk Erica , Smith Jeremy , Chiodo Christopher , Ciurylo William , Dicarlo Hunter , Bluman Eric 
Published: June 2017

Category: Sports Introduction/Purpose: Peroneal tendinopathy is a common condition of the ankle and may lead to substantial pain and disability. Low lying peroneus brevis (PB) muscle belly, accessory tendons and bony abnormalities have been implicated in peroneal tendon pathology. To date, studies have reported the presence of these variants or the distal extent of a muscle belly with the presumption that this reflects an increased intra-sheath volume. The goal of this study was to perform volumetric measurements of MR images of peroneal tendons in patients with peroneal pathology requiring surgical intervention and those without. Methods: Two fellowship trained musculoskeletal radiologists evaluated MR images of patients with and without peroneal tendon pathology. The volume of the peroneal tendon sheath and its contents were measured from the level of the tibial plafond down to the peroneal tubercle. The volumes were measured using the Vital Images 3D Vitoria program. The program allows calculation of volumes based on selected area outlines on each axial slice and then compiles each slice into a stacked volume. The presence of a peroneus quartus (PQ), synovitis and peroneal tendon tears were also recorded. Results: Fifty-one patients with peroneal pathology and 15 control patients were included. The mean distance of the PB muscle belly to the tip of the fibula was 5.55 ± 2.5 mm and 11.79 ± 4.07 mm for the groups with and without pathology, respectively (p=0.017). The mean total sheath volume was 7.06 ± 0.95 cc and 5.12 ± 0.53 cc (p=0.001), respectively. The mean PB and PQ combined volume was 1.31 ± 0.29 and 0.86 ± 0.24 cc (p=0.023), respectively. In isolation, the peroneal muscle volume was 0.87 ± 0.25 cc and 0.80 ± 0.25 cc (p=0.733), respectively. Conclusion: The volume of the peroneal tendon sheath and its contents are greater in the patients with peroneal tendinopathy that required surgery compared to controls. Despite the lower position of the muscle belly in the peroneal tendinopathy group, which is similar to previous studies, this was not reflected in increased volumetric measurements. However, when the PQ tendon was included this combined volume was significantly greater. Volumetric measurements are a more accurate way to assess the peroneal sheath in patients with peroneal pathology.
The Association of Perioperative Glycemic Control with Postoperative Surgical Site Infection Following Elective Foot Surgery in Patients with Diabetes
Authors: Cancienne Jourdan , Cooper Minton , Werner Brian 
Published: June 2017

Category: Midfoot/Forefoot Introduction/Purpose: Diabetes mellitus has been associated with an increased risk for postoperative surgical site infection (SSI) following foot and ankle surgery; however, among patients with diabetes, the level of perioperative glycemic control may affect the risk of postoperative SSI. There remains little evidence to support a perioperative hemoglobin A1c (HbA1c) level that could serve as a threshold for a significantly increased risk of postoperative SSI following foot surgery. The primary goal of the present study was to evaluate the association of perioperative glycemic control as demonstrated by hemoglobin a1c (HbA1c) in patients with diabetes with the incidence of postoperative SSI following elective foot surgery. Our secondary objective was to calculate a threshold level of HbA1c above which the risk of postoperative SSI after foot surgery increases significantly in patients with diabetes. Methods: A national administrative database was queried for patients who underwent common elective foot surgeries, including hallux valgus corrections, hallux rigidus correction and hammertoe corrections among others. Patients who underwent more complex procedures and patients with concomitant hindfoot procedures were excluded. Patients with diabetes mellitus who had a perioperative HbA1c level recorded within 3 months of surgery were identified; and were then stratified into thirteen mutually exclusive groups based on their hemoglobin a1c in 0.5 mg/dl increments from < 5.49 mg/dl to > 11.5 mg/dl. The incidence of SSI was determined by either a diagnosis or procedure for SSI within 1 year postoperatively using CPT and ICD-9 codes, and was calculated for each HbA1c patient group. A receiver operating characteristic (ROC) analysis was performed to determine an optimal threshold value of the HbA1c above which the risk of postoperative SSI was significantly increased. Results: 4,744 patients who underwent forefoot surgery with diabetes and a perioperative HbA1c recorded within 3 months of surgery in the database were included in the study. The rate of deep SSI requiring irrigation and debridement within one year postoperatively stratified by HbA1c is pictured in Figure 1, which ranged from a low of 2.5% to a high of 11.8% and was significantly correlated with increasing HbA1c levels (P < 0.0001). The results of ROC analysis determined that the inflection point of the ROC curve corresponded to an HbA1c level above 7.5 mg/dL (P < 0.0001, AUC = 0.622, spec. = 75%, sens. = 44%). Conclusion: The risk of postoperative SSI following elective foot surgery in patients with diabetes mellitus increases significantly as the perioperative HbA1c increases. ROC analysis determined that a perioperative HbA1c above 7.5 mg/dL could serve as a threshold for a significantly increased risk of postoperative SSI following elective foot surgery.
Attitudes and preferences of home mechanical ventilation users from four European countries: an ERS/ELF survey
Authors: Masefield Sarah , Vitacca Michele , Dreher Michael , Kampelmacher Michael , Escarrabill Joan , Paneroni Mara , Powell Pippa , Ambrosino Nicolino 
Published: June 2017

Home mechanical ventilation is increasingly used by people with chronic respiratory failure. However, there are few reports on attitudes towards treatment.A web-based survey in eight languages was disseminated across 11 European countries to evaluate the perception of home mechanical ventilation provision in ventilator-assisted individuals and caregivers.Out of 787 responders from 11 European countries, 687 were patients and 100 were caregivers. 95% of patients and 94% of caregivers were from only 4 countries (Germany, the Netherlands, Italy, Spain). The majority of respondents were male and aged 46–65 years. Obstructive lung diseases were proportionally more represented among respondent patients (46%), and neuromuscular diseases (65%) were more represented among patients of respondent caregivers. About 20% of respondent patients and caregivers were not sure of the modality of ventilation. Different interfaces were used, with a minority of respondents in all countries using invasive home mechanical ventilation by tracheostomy.These results may be useful for healthcare providers and policy makers to improve the quality of patients' daily lives.
Pneumothoraces in collagen VI-related dystrophy: a case series and recommendations for management
Authors: Fraser Kristin L. , Wong Scott , Foley A. Reghan , Chhibber Sameer , Bönnemann Carsten G. , Lesser Daniel J. , Grosmann Carla , Rutkowski Anne 
Published: June 2017

Collagen VI-related dystrophy (collagen VI-RD) is a rare neuromuscular condition caused by mutations in theCOL6A1,COL6A2orCOL6A3genes. The phenotypic spectrum includes early-onset Ullrich congenital muscular dystrophy, adult-onset Bethlem myopathy and an intermediate phenotype. The disorder is characterised by distal hyperlaxity and progressive muscle weakness, joint contractures and respiratory insufficiency. Respiratory insufficiency is attributed to chest wall contractures, scoliosis, impaired diaphragmatic function and intercostal muscle weakness. To date, intrinsic parenchymal lung disease has not been implicated in the inevitable respiratory decline of these patients.This series focuses on pneumothorax, an important but previously under-recognised disease manifestation of collagen VI-RD.We describe two distinct clinical presentations within collagen VI-RD patients with pneumothorax. The first cohort consists of neonates and children with a single pneumothorax in the setting of large intrathoracic pressure changes. The second group is made up of adult patients with recurrent pneumothoraces, associated with chest computed tomography scan evidence of parenchymal lung disease. We describe treatment challenges in this unique population with respect to expectant observation, tube thoracostomy and open pleurodesis.Based on this experience, we offer recommendations for early identification of lung disease in collagen VI-RD and definitive intervention.