bluuebunny/crossref_metadata_2025_split huggingface dataset:
Long-term study of the impact of methotrexate on serum cytokines and lymphocyte subsets in patients with active rheumatoid arthritis: correlation with pharmacokinetic measures
Authors: Kremer Joel M , Lawrence David A , Hamilton Robert , McInnes Iain B 
Published: June 2016

ObjectiveTo describe changes in immune parameters observed during long-term methotrexate (MTX) therapy in patients with active rheumatoid arthritis (RA) and explore correlations with simultaneously measured MTX pharmacokinetic (PKC) parameters.DesignProspective, open-label, long-term mechanism of action study.SettingUniversity clinic.MethodsMTX was initiated at a single weekly oral dose of 7.5 mg and dose adjusted for efficacy and toxicity for the duration of the study. Standard measures of disease activity were performed at baseline and every 6–36 months. Serum cytokine measurements in blood together with lymphocyte surface immunophenotypes and stimulated peripheral blood mononuclear cell (PBMC) cytokine production were assessed at each clinical evaluation.ResultsCytokine concentrations exhibited multiple significant correlations with disease activity measures over time. The strongest correlations observed were for interleukin (IL)-6 (r=0.45, p<0.0001 for swollen joints and r=0.32, p=0.002 for tender joints) and IL-8 (r=0.25, p=0.01 for swollen joints). Significant decreases from baseline were observed in serum IL-1B, IL-6 and IL-8 concentrations. The most significant changes were observed for IL-6 (p<0.001). Significant increases from baseline were observed in IL-2 release from PBMCs ex vivo (p<0.01). In parallel, multiple statistically significant correlations were observed between MTX PKC measures and immune parameters. The change in swollen joint count correlated inversely with the change in area under the curve (AUC) for MTX (r=−0.63, p=0.007).ConclusionsMTX therapy of patients with RA is accompanied by a variety of changes in serum cytokine expression, which in turn correlate strongly with clinical disease activity and MTX pharmacokinetics (PKCs). These data strongly support the notion that MTX mediates profound and functionally relevant effects on the immunological hierarchy in the RA lesion.
(Z)-3,5,4′-Trimethoxystilbene Limits Hepatitis C and Cancer Pathophysiology by Blocking Microtubule Dynamics and Cell-Cycle Progression
Authors: Nguyen Charles B. , Kotturi Hari , Waris Gulam , Mohammed Altaf , Chandrakesan Parthasarathy , May Randal , Sureban Sripathi , Weygant Nathaniel , Qu Dongfeng , Rao Chinthalapally V. , Dhanasekaran Danny N. , Bronze Michael S. , Houchen Courtney W. , Ali Naushad 
Published: June 2016

Abstract
Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths worldwide. Chronic hepatitis C virus (HCV) infection causes induction of several tumors/cancer stem cell (CSC) markers and is known to be a major risk factor for development of HCC. Therefore, drugs that simultaneously target viral replication and CSC properties are needed for a risk-free treatment of advanced stage liver diseases, including HCC. Here, we demonstrated that (Z)-3,5,4′-trimethoxystilbene (Z-TMS) exhibits potent antitumor and anti-HCV activities without exhibiting cytotoxicity to human hepatocytes in vitro or in mice livers. Diethylnitrosamine (DEN)/carbon tetrachloride (CCl4) extensively induced expression of DCLK1 (a CSC marker) in the livers of C57BL/6 mice following hepatic injury. Z-TMS exhibited hepatoprotective effects against DEN/CCl4-induced injury by reducing DCLK1 expression and improving histologic outcomes. The drug caused bundling of DCLK1 with microtubules and blocked cell-cycle progression at G2–M phase in hepatoma cells via downregulation of CDK1, induction of p21cip1/waf1 expression, and inhibition of Akt (Ser473) phosphorylation. Z-TMS also inhibited proliferation of erlotinib-resistant lung adenocarcinoma cells (H1975) bearing the T790M EGFR mutation, most likely by promoting autophagy and nuclear fragmentation. In conclusion, Z-TMS appears to be a unique therapeutic agent targeting HCV and concurrently eliminating cells with neoplastic potential during chronic liver diseases, including HCC. It may also be a valuable drug for targeting drug-resistant carcinomas and cancers of the lungs, pancreas, colon, and intestine, in which DCLK1 is involved in tumorigenesis. Cancer Res; 76(16); 4887–96. ©2016 AACR.
Survival of Patients with Gastrointestinal Cancers Can Be Predicted by a Surrogate microRNA Signature for Cancer Stem–like Cells Marked by DCLK1 Kinase
Authors: Weygant Nathaniel , Ge Yang , Qu Dongfeng , Kaddis John S. , Berry William L. , May Randal , Chandrakesan Parthasarathy , Bannerman-Menson Edwin , Vega Kenneth J. , Tomasek James J. , Bronze Michael S. , An Guangyu , Houchen Courtney W. 
Published: June 2016

Abstract
Doublecortin-like kinase 1 (DCLK1) is a gastrointestinal (GI) tuft cell kinase that has been investigated as a biomarker of cancer stem–like cells in colon and pancreatic cancers. However, its utility as a biomarker may be limited in principle by signal instability and dilution in heterogeneous tumors, where the proliferation of diverse tumor cell lineages obscures the direct measurement of DCLK1 activity. To address this issue, we explored the definition of a miRNA signature as a surrogate biomarker for DCLK1 in cancer stem–like cells. Utilizing RNA/miRNA-sequencing datasets from the Cancer Genome Atlas, we identified a surrogate 15-miRNA expression signature for DCLK1 activity across several GI cancers, including colon, pancreatic, and stomach cancers. Notably, Cox regression and Kaplan–Meier analysis demonstrated that this signature could predict the survival of patients with these cancers. Moreover, we identified patient subgroups that predicted the clinical utility of this DCLK1 surrogate biomarker. Our findings greatly strengthen the clinical significance for DCLK1 expression across GI cancers. Further, they provide an initial guidepost toward the development of improved prognostic biomarkers or companion biomarkers for DCLK1-targeted therapies to eradicate cancer stem–like cells in these malignancies. Cancer Res; 76(14); 4090–9. ©2016 AACR.
Lenalidomide Induces Interleukin-21 Production by T Cells and Enhances IL21-Mediated Cytotoxicity in Chronic Lymphocytic Leukemia B Cells
Authors: Browning Rebekah L. , Byrd William H. , Gupta Nikhil , Jones Jeffrey , Mo Xiaokui , Hertlein Erin , Yu Lianbo , Muthusamy Natarajan , Byrd John C. 
Published: June 2016

Abstract
The immunomodulatory drug lenalidomide has demonstrated efficacy in patients with chronic lymphocytic leukemia (CLL), despite a lack of direct cytotoxic effects in vitro. The mechanism of lenalidomide efficacy in vivo is thought to occur via a combination of enhanced immune activity and an alteration of tumor cell–microenvironment interactions. We demonstrate in whole blood from patients with CLL that lenalidomide significantly depletes malignant B cells. Lenalidomide also induced production of interleukin-21 (IL21) and its mRNA in T cells from patients with CLL. In addition, lenalidomide enhanced upregulation of functional IL21 receptor (IL21R) on the cell surface and increased receptor mRNA in vitro. The in vitro combination of IL21 and lenalidomide enhanced IL21-mediated cytotoxicity toward CLL cells through a variety of mechanisms. We show association of cell death with upregulation of Bid by IL21, enhanced upregulation of Bid by the combination therapy, and diminished Lck and downstream BCR signaling activation of Syk and PLCG2. Collectively, we demonstrated an immune cell–tumor cell interaction through lenalidomide-mediated induction of IL21 and IL21R, with enhanced IL21-mediated cytotoxicity, which provides justification for this combination in clinical trials for patients with CLL. Cancer Immunol Res; 4(8); 698–707. ©2016 AACR.
Dysfunction of the Voltage‐Gated K
+
Channel β2 Subunit in a Familial Case of Brugada Syndrome
Authors: Portero Vincent , Le Scouarnec Solena , Es‐Salah‐Lamoureux Zeineb , Burel Sophie , Gourraud Jean‐Baptiste , Bonnaud Stéphanie , Lindenbaum Pierre , Simonet Floriane , Violleau Jade , Baron Estelle , Moreau Eléonore , Scott Carol , Chatel Stéphanie , Loussouarn Gildas , O'Hara Thomas , Mabo Philippe , Dina Christian , Le Marec Hervé , Schott Jean‐Jacques , Probst Vincent , Baró Isabelle , Marionneau Céline , Charpentier Flavien , Redon Richard 
Published: June 2016

Background

The Brugada syndrome is an inherited cardiac arrhythmia associated with high risk of sudden death. Although 20% of patients with Brugada syndrome carry mutations in

SCN
5A

, the molecular mechanisms underlying this condition are still largely unknown.

Methods and Results

We combined whole‐exome sequencing and linkage analysis to identify the genetic variant likely causing Brugada syndrome in a pedigree for which

SCN
5A

mutations had been excluded. This approach identified 6 genetic variants cosegregating with the Brugada electrocardiographic pattern within the pedigree. In silico gene prioritization pointed to 1 variant residing in

KCNAB
2

, which encodes the voltage‐gated K
+
channel β2‐subunit (Kvβ2‐R12Q). Kvβ2 is widely expressed in the human heart and has been shown to interact with the fast transient outward K
+
channel subunit Kv4.3, increasing its current density. By targeted sequencing of the

KCNAB
2

gene in 167 unrelated patients with Brugada syndrome, we found 2 additional rare missense variants (L13F and V114I). We then investigated the physiological effects of the 3

KCNAB
2

variants by using cellular electrophysiology and biochemistry. Patch‐clamp experiments performed in
COS
‐7 cells expressing both Kv4.3 and Kvβ2 revealed a significant increase in the current density in presence of the R12Q and L13F Kvβ2 mutants. Although biotinylation assays showed no differences in the expression of Kv4.3, the total and submembrane expression of Kvβ2‐R12Q were significantly increased in comparison with wild‐type Kvβ2.

Conclusions
Altogether, our results indicate that Kvβ2 dysfunction can contribute to the Brugada electrocardiographic pattern.
Relationship Between Low‐Density Lipoprotein Cholesterol, Free Proprotein Convertase Subtilisin/Kexin Type 9, and Alirocumab Levels After Different Lipid‐Lowering Strategies
Authors: Rey Jacques , Poitiers Franck , Paehler Tobias , Brunet Aurélie , DiCioccio A. Thomas , Cannon Christopher P. , Surks Howard K. , Pinquier Jean‐Louis , Hanotin Corinne , Sasiela William J. 
Published: June 2016

Background

Alirocumab undergoes target‐mediated clearance via binding of proprotein convertase subtilisin/kexin type 9 (
PCSK
9). Statins increase
PCSK
9 levels; the effects of nonstatin lipid‐lowering therapies are unclear. Every‐4‐weeks dosing of alirocumab may be appropriate for some patients in absence of background statin but is not yet approved.

Methods and Results

Low‐density lipoprotein cholesterol (
LDL
‐C),
PCSK
9, and alirocumab levels were assessed in subjects (
LDL
‐C >130 mg/dL, n=24/group) after a 4‐week run‐in taking oral ezetimibe, fenofibrate, or ezetimibe placebo, when alirocumab 150 mg every 4 weeks (days 1, 29, and 57) was added. Maximal mean
LDL
‐C reductions from day −1 baseline (prealirocumab) occurred on day 71 in all groups: alirocumab plus placebo, 47.4%; alirocumab plus ezetimibe, 56.6%; and alirocumab plus fenofibrate, 54.3%.
LDL
‐C reductions were sustained through day 85 with alirocumab plus placebo (47.0%); the duration of effect was slightly diminished at day 85 versus day 71 with ezetimibe (49.6%) or fenofibrate combinations (43.2%). Free
PCSK
9 concentrations were lowest at day 71 in all groups, then increased over time; by day 85, free
PCSK
9 concentrations were higher, and alirocumab levels lower, with alirocumab plus fenofibrate, and to a lesser extent alirocumab plus ezetimibe, versus alirocumab plus placebo.

Conclusions

Alirocumab 150 mg every 4 weeks produced maximal
LDL
‐C reductions of 47% in combination with placebo and 54% to 57% in combination with ezetimibe or fenofibrate. The oral lipid‐lowering therapies appear to increase
PCSK
9 levels, leading to increased alirocumab clearance. Although the duration of effect was modestly diminished with alirocumab plus ezetimibe/fenofibrate versus placebo, the effect was less than observed in trials with background statins, and it would not preclude the use of alirocumab every 4 weeks in patients taking these nonstatin lipid‐lowering therapies concomitantly.

Clinical Trial Registration

URL
:
http://www.Clinicaltrials.gov
. Unique identifier:
NCT
01723735.
Utility of the Highly Articulated Flex Robotic System for Head and Neck Procedures
Authors: Newsome Hillary , Mandapathil Magis , Koh Yoon Woo , Duvvuri Umamaheswar 
Published: June 2016

Objective: Robotic head and neck surgery potentially reduces the morbidity associated with traditional open procedures. This study’s goal was to employ a novel highly articulated robotic system (Flex Robotic System) for head and neck procedures, including a postauricular facelift approach thyroidectomy, submandibular gland (SMG) removal, and cervical lymphadenectomy. Study Design: It was hypothesized that the Medrobotics Flex Robotic System could be used for transcervical head and neck surgical procedures. Methods: Three fresh upper body human cadavers were used. The Flex Robotic System was used to complete a thyroidectomy, neck dissection, and SMG removal on each cadaver. Results: A postauricular incision and flap was manually raised. The robotic system was positioned on the right side of the cadaver’s head. The system’s manually controlled flexible instruments and highly shapeable, robot-assisted scope were used to perform a thyroid lobectomy. Neck dissection and SMG removal were also performed. Conclusions: Although a promising technology, the current robotic system (Intuitive Surgical Inc, Sunnyvale, California, USA) has limitations due to its rigid and large configuration, which decreases exposure and access. The new system’s shapeable, computer-assisted scope seeks to reduce some of these difficulties and may be better adapted for transcervical approaches to the neck operations.
Esophageal Swallowing Timing Measures in Healthy Adults During Videofluoroscopy
Authors: Miles Anna , Clark Stacie , Jardine Marie , Allen Jacqui 
Published: June 2016

Objectives: Establishing the range of normal esophageal bolus transit times (ETT) is valuable when distinguishing pathology from normal variance, especially in elderly patients, and has not been documented for paste or pill. The aim of this study was to measure esophageal transit of liquid, paste, and pill during upright videofluoroscopy. Methods: One hundred eighteen healthy adults (mean age 54; range 20-98 years; SD = 21.40) with no complaints of dysphagia completed a videofluoroscopy with esophageal visualization including 20 ml liquid barium, 5 ml paste, and pill. Results: Mean ETTs were: 20 ml fluid, 10.7 seconds (SD = 13.6, median = 5.76, IQR = 4.33, range, 2.0-60.0); pill, 25.3 seconds (SD = 24.0, median = 12.70, IQR = 49.81, range, 1.0-60.0); paste, 28.6 seconds (SD = 23.31, median = 17.47, IQR = 53, range, 4.0-60.0). Age was significantly associated with increasing 20 ml fluid ETT ( P < .001) but not pill ( P = .58) or paste ETT ( P = .12). Fluid ETT over 10 seconds occurred in 10% of participants between 20 and 59 years, in comparison to 35% over 60 years ( P < .001). Conclusions: These normative values provide a standardized protocol and guidance in interpretation when completing esophageal visualization as part of videofluoroscopy. While measuring fluid ETT may support referral for further specialist investigations, slower paste and pill ETT may be normal findings. Age-related slowing in fluid ETT was seen in healthy adults. Further investigation of ETT is needed in both normal and dysphagic subjects.
Men’s physical activity and dietary behaviours on Kangaroo Island, South Australia
Authors: Drummond Murray , Elliott Sam , Drummond Claire , Lewis Felicity 
Published: June 2016

Background: Men’s health has been subjected to diverse approaches to research over the past two decades. Much of the literature has focused on specific medical and health issues. Other contributions have focused more broadly on masculinities and its relationship to health. It is arguable that there has not been a lot of attention paid to Australian rural men’s health and even less on their understanding of health as it relates to physical activity and dietary behavior. Objectives: To gain a better understanding of these issues this paper provides rich, descriptive qualitative data from men living on Kangaroo Island, which is 13.5 kilometres off the South Australian mainland and is regarded as a rural and remote area. Methods: Qualitative data is used to develop greater understanding of the men’s attitudes and behaviours as they relate to physical activity and dietary behaviours. The semistructured interviews and focus groups were conducted with 40 men aged between 23–64. Conclusions: The results indicated that the locality in which the men lived provided them with an excellent opportunity to be physically active and eat fresh, locally produced, foods. However, it was identified that many of the men did not have a comprehensive understanding of health and seemingly displayed low levels of health knowledge. As a result for many of these men, their physical health was left to chance. There was little evidence of any planned health promotion to assist them with making improvements to their nutrition and physical activity levels as they aged. Recommendations and population-based strategies are provided to assist men living in remote rural settings to enhance not only their health ultimately their health knowledge. This will positively impact community health.
The current state of research on ayahuasca: A systematic review of human studies assessing psychiatric symptoms, neuropsychological functioning, and neuroimaging
Authors: dos Santos Rafael G , Balthazar Fermanda M , Bouso José C , Hallak Jaime EC 
Published: June 2016

Rationale: In recent decades, the use of ayahuasca (AYA) – a β-carboline- and dimethyltryptamine-rich hallucinogenic botanical preparation traditionally used by Northwestern Amazonian tribes for ritual and therapeutic purposes – has spread from South America to Europe and the USA, raising concerns about its possible toxicity and hopes of its therapeutic potential. Thus, it is important to analyze the acute, subacute, and long-term effects of AYA to assess its safety and toxicity. Objectives: The purpose of this study was to conduct a systematic review of human studies assessing AYA effects on psychiatric symptoms, neuropsychological functioning, and neuroimaging. Methods: Papers published until 16 December 2015 were included from PubMed, LILACS and SciELO databases following a comprehensive search strategy and pre-determined set of criteria for article selection. Results: The review included 28 full-text articles. Acute AYA administration was well tolerated, increased introspection and positive mood, altered visual perceptions, activated frontal and paralimbic regions and decreased default mode network activity. It also improved planning and inhibitory control and impaired working memory, and showed antidepressive and antiaddictive potentials. Long-term AYA use was associated with increased cortical thickness of the anterior cingulate cortex and cortical thinning of the posterior cingulate cortex, which was inversely correlated to age of onset, intensity of prior AYA use, and spirituality. Subacute and long-term AYA use was not associated with increased psychopathology or cognitive deficits, being associated with enhanced mood and cognition, increased spirituality, and reduced impulsivity. Conclusions: Acute, subacute, and long-term AYA use seems to have low toxicity. Preliminary studies about potential therapeutic effects of AYA need replication due to their methodological limitations.
Patellar position in weight-bearing radiographs compared with non-weight-bearing: significance for the detection of osteoarthritis
Authors: Skou Nikolaj , Egund Niels 
Published: June 2016

Background Diagnosis and treatment of patellofemoral disorders including osteoarthritis are currently often based on imaging and clinical assessment with patients in the supine position. Purpose To evaluate differences in patellar position in the trochlear groove and to assess the detection of medial and lateral patellofemoral (PF) osteoarthritis (OA) on axial radiographs in supine and standing positions, respectively. Material and Methods Thirty-five women and 23 men (mean age, 56 years; age range, 18–87 years) referred for routine radiographic examinations of the knees were included. Axial radiographs of the PF joint in both supine non-weight-bearing and standing weight-bearing position in 30° knee flexion were obtained of 111 knees. Measurements performed on the radiographs: patellar tilt, patellar displacement, joint space width, and grade of OA according to Ahlbäck. Results From supine to standing position the patella moved medially and medial joint space width and lateral patellar tilt angle decreased ( P < 0.0001 for the three measured parameters). In the standing position, medial PF OA was observed in 19 knees compared to three knees in the supine position. Fourteen knees had lateral PF OA with almost unchanged grade of OA irrespective of position. Conclusion In weight-bearing positions, the patella is positioned medially in the trochlear groove compared to supine non-weight-bearing positions. Therefore, this study suggests that the common occurrence of medial PF OA can generally not be detected on axial radiographs in supine non-weight-bearing positions and confirms the importance of imaging the PF joint in standing weight-bearing positions.
OnabotulinumtoxinA improves quality of life and reduces impact of chronic migraine over one year of treatment: Pooled results from the PREEMPT randomized clinical trial program
Authors: Lipton Richard B , Rosen Noah L , Ailani Jessica , DeGryse Ronald E , Gillard Patrick J , Varon Sepideh F 
Published: June 2016

Background Chronic migraine (CM) is associated with high impact and reduced health-related quality of life (HRQoL). Methods Patients with CM from PREEMPT (Phase 3 REsearch Evaluating Migraine Prophylaxis Therapy) were randomized (1:1) to receive onabotulinumtoxinA or placebo for two 12-week cycles in the double-blind (DB) phase, followed by three 12-week cycles of open-label (OL) onabotulinumtoxinA (onabotulinumtoxinA/onabotulinumtoxinA (O/O) and placebo/onabotulinumtoxinA (P/O) groups, respectively). HRQoL endpoints were assessed over 56 weeks using the Headache Impact Test (HIT-6) and the Migraine-Specific Quality of Life Questionnaire (MSQ). HIT-6 score reductions ≥2.3 and ≥5 denoted between-group minimally important difference and within-patient clinically meaningful response, respectively. Results A total of 1236 participants (O/O, n = 607; P/O, n = 629) participated in both phases. The DB phase showed significantly reduced HIT-6 and MSQ for onabotulinumtoxinA versus placebo (all p < 0.001). The OL phase showed significantly reduced HIT-6 for O/O versus P/O at weeks 28, 36, and 48, but not 56. All three MSQ domains showed improved HRQoL relative to baseline, but only the role restrictive domain showed a significant difference between O/O and P/O at week 56. Conclusions Benefits of onabotulinumtoxinA on HRQoL versus baseline persisted throughout the OL phase. Statistical superiority in favor of O/O was demonstrated for HIT-6 through 48 weeks and for MSQ (role restrictive) at 56 weeks.