bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of CYP Inducers/Inhibitors on Topiramate Concentration: Clinical Value of Therapeutic Drug Monitoring
Authors: Yamamoto Yoshiaki , Takahashi Yukitoshi , Imai Katsumi , Kagawa Yoshiyuki , Inoue Yushi 
Published: December 2016

Background:This study investigated the pharmacokinetic interactions between topiramate (TPM) and concomitant antiepileptic drugs and evaluated the therapeutic concentration range of TPM and the effect of the achieved plasma concentration on the retention rate of TPM therapy.Methods:A total of 1217 plasma samples obtained from 610 patients were retrospectively investigated, and the concentration-to-dose ratio (CD ratio) of TPM was compared among patients on various antiepileptic drug regimens. In addition, the therapeutic concentration of TPM was reviewed in patients on long-term therapy, and factors influencing the retention rate of TPM were analyzed by the Kaplan–Meier method.Results:Among patients using hepatic enzyme inducers (phenytoin, phenobarbital, and carbamazepine), the CD ratio was reduced by 45.4% in adults and 33.3% in children. Patients taking phenytoin concomitantly had a significantly lower CD ratio than patients taking phenobarbital or carbamazepine. Among noninducers, concomitant use of stiripentol increased the CD ratio. In 276 patients who remained on TPM therapy for more than 2 years, the mean therapeutic concentration was 5.1 mcg/mL (15.0 μmol/L). The estimated retention day was significantly higher for patients with a TPM concentration >5 mcg/mL than that for patients with a concentration <5 mcg/mL (945 versus 802 days;P= 0.007 by the log-rank test). Also, patients without hepatic enzyme inducers had a significantly higher retention rate than patients using such inducers (P= 0.002).Conclusions:Concomitant use of hepatic enzyme inducers markedly reduced the plasma TPM concentration and can decrease its antiepileptic effect. A therapeutic concentration of >5 mcg/mL TPM was significantly associated with continuation of therapy, and therapeutic drug monitoring can be helpful.
Treatment strategies for endometrial cancer: current practice and perspective
Authors: Lee Yeh C. , Lheureux Stephanie , Oza Amit M. 
Published: December 2016

Purpose of review
Endometrial cancer incidence is increasing in North America and is a major cause of morbidity and mortality in women. We review recent literature published on treatment of endometrial cancer and highlight areas of active interest.

Recent findings
There has been movement toward minimal invasive surgery at diagnosis; lymph node staging remains controversial and continues to be investigated. Progress has been made to establish consensus on endometrial cancer risk classification to promote consistency for future trial design. Molecular characterization of endometrial cancer and its integration into clinicopathological profiling to develop predictive biomarkers for treatment selection are active areas of research. Optimal adjuvant treatment strategy in high-risk endometrial cancer remains to be defined with recognition of treatment-related toxicity. Despite encouraging results in drug development for treatment of advanced/recurrent endometrial cancer, no targeted therapies beyond hormonal therapy are approved. There is an urgent need for scientifically validated therapy with predictive biomarkers.

Summary
Our understanding of endometrial cancer has evolved through improvements in molecular biology, allowing improved definition of target-specific therapies. The precise role and sequence of conventional and targeted therapies, including immunotherapy, will require careful attention to the design of clinical trials with translational emphasis to allow the discovery, validation, and implementation of predictive biomarkers into clinical care.
Molecular characterization of endometrial cancer and therapeutic implications
Authors: Uppendahl Locke , Mullany Sally A. , Winterhoff Boris 
Published: December 2016

Purpose of review
This article reviews the emerging comprehensive genomic classification of endometrial carcinoma and discusses the therapeutic implications of these subgroups.

Recent findings
Comprehensive, multiplatform evaluation of endometrial cancers by the Cancer Genome Atlas stratified the molecular aberrations into four distinct subtypes: POLE mutations, microsatellite instability, copy-number low/microsatellite stable, and copy-number high/‘serous-like.’ POLE-mutant tumors have a favorable prognosis and may often be overtreated. Microsatellite instability hypermutated tumors commonly have alterations in the phosphatidylinositide 3-kinases/AKT/mechanistic target of rapamycin pathway and limiting targeted therapy to this group may lead to greater response rates. Copy-number low/microsatellite stable tumors represent the majority of grade 1 and grade 2 endometrioid cancers and have an intermediate prognosis, few TP53 mutations, but frequent mutations in genes involved with Wingless-related integration site signaling. Approximately 25% of high-grade endometrioid tumors have mutational profiles that classify as copy-number high/‘serous-like’ and might benefit from treatment approaches similar to those for serous tumors.

Summary
Molecular characterization of endometrial cancer classifies tumors into prognostically significant subtypes with a broad range of therapeutic implications.
Comparison of Topical Low-Molecular-Weight Heparin–Taurocholate and Bevacizumab for Treatment and Prevention of Corneal Neovascularization
Authors: Moon Chan Hee , Moon Byung Gil , Kim Jae Yong , Kim Myoung Joon , Tchah Hungwon 
Published: December 2016

Purpose:
To compare the therapeutic and preventive effects of topically administered 7-taurocholic acid–conjugated low-molecular-weight heparin (LHT7) and bevacizumab in experimentally induced corneal neovascularization (CoNV).

Methods:
CoNV was induced using sutures in the right eyes of 24 mice. To investigate the therapeutic effects, CoNV was allowed to develop for 1 week before treatment. To ascertain the preventive effects, the treatments were applied immediately after the suture. In each experiment, 12 eyes were divided into 3 groups and treated topically using bevacizumab (bevacizumab group), LHT7 (LHT7 group), and normal saline (control group). The treatments were instilled 3 times daily for 2 weeks. The CoNV area was measured before instillation and after 1 and 2 weeks after instillation.

Results:
In the investigation of therapeutic effects, the CoNV area had decreased significantly 1 week after treatment in the bevacizumab group (1.58–0.75 mm2; P = 0.036) and LHT7 group (1.38–0.74 mm2; P = 0.018). Two weeks after treatment, the CoNV area was significantly smaller in the bevacizumab groups (0.60 mm2; P = 0.005) and LHT7 group (0.64 mm2; P = 0.015) than in the control group (1.68 mm2), but the bevacizumab group did not differ significantly from the LHT7 group. In the experiment addressing the preventive effects, CoNV was less developed in the bevacizumab group (0.70 mm2; P = 0.003) and LHT7 group (0.54 mm2; P = 0.003) than in the control group (1.75 mm2), and the CoNV area was smaller in the LHT7 group than in the bevacizumab group (P = 0.021).

Conclusions:
The effects of LHT7 on CoNV regression are comparable to those of bevacizumab. Topical administration of LHT7 prevents CoNV more effectively than bevacizumab.
Autologous Blood Versus Fibrin Glue in Pterygium Excision With Conjunctival Autograft Surgery
Authors: Nadarajah Gaayathri , Ratnalingam Vanitha Hema , Mohd Isa Hazlita 
Published: December 2016

Purpose:
To evaluate graft stability and recurrence rate between fibrin glue and autologous blood in pterygium conjunctival autograft surgery.

Methods:
A prospective, randomized, single-blinded clinical trial to assess the efficacy of autologous blood in place of fibrin glue in pterygium surgery. A total of 120 eyes of 111 patients were randomized according to pterygium morphology, to undergo pterygium surgery with autografting using either autologous blood or fibrin glue. All patients were operated by a single surgeon; 58 eyes were operated using fibrin glue and 62 eyes had a conjunctival autograft with autologous blood. Patients were seen on postoperative day 1, 1 week, 1 month, 6 months, and 1 year after surgery. Graft stability and pterygium recurrence were graded by an independent observer who was masked to the method of treatment.

Results:
All 120 eyes completed the 1-year follow-up. Graft loss was seen only in the autologous blood group. Of the 62 eyes in this group, a total of 15 (24.2%) grafts dislodged. Recurrence was calculated after excluding grafts that were dislodged. Of the 105 patients, there were a total of 7 recurrences, 2 (3.4%) from the fibrin adhesive method and 5 (10.6%) from the autologous blood method. This was not statistically significant (P = 0.238).

Conclusions:
Autologous blood does not exhibit similar graft stability seen with fibrin glue. Although the recurrence rate may not be significant, careful patient selection and a standard method needs to be laid out before the use of this method is widely accepted.
Ten-Year Clinical Outcome of the First Patient Undergoing Descemet Membrane Endothelial Keratoplasty
Authors: Baydoun Lamis , Müller Thomas , Lavy Itay , Parker Jack , Rodriguez-Calvo-de-Mora Marina , Liarakos Vasilios S. , Dapena Isabel , Melles Gerrit R. J. 
Published: December 2016

Purpose:
To describe the 10-year clinical outcome of the first patient worldwide who underwent Descemet membrane endothelial keratoplasty (DMEK).

Methods:
In 2006, a 63-year-old man presented at the Melles Cornea Clinic, Rotterdam, with bilateral Fuchs endothelial dystrophy and cataract. After phacoemulsification, in vivo DMEK was performed in the left eye and 10 months later in the right eye. Best spectacle-corrected visual acuity (BSCVA), endothelial cell density, pachymetry, and complications were recorded every 6 months over a 10-year period.

Results:
BSCVA in the left eye improved from 20/60 (0.3) before surgery to 20/17 (1.2) at 1 month, and remained stable over 10 years, ranging from 20/20 (1.0) to 20/13 (1.5). BSCVA in the right eye improved from 20/50 (0.4) preoperative and 20/60 (0.3) at 1 month to 20/25 (0.8) at 3 months and 20/17 (1.2) at 6 months, ranging from 20/25 (0.8) to 20/17 (1.2) over 9 years. Both eyes underwent YAG-laser-capsulotomy to manage posterior capsule opacification at 5 and 4 years after DMEK, respectively. Endothelial cell density in the right and left eyes, respectively, decreased by 43% and 45% at 1 year, 52% and 59% at 5 years, and 72% and 68% at 10/9 years, respectively. No intraoperative or postoperative complications occurred; at the last follow-up, both corneas were clear.

Conclusions:
The first DMEK patient worldwide may show all short and long-term characteristics of this endothelial keratoplasty technique: outstanding patient satisfaction, quick visual recovery, low incidence of complications, and graft longevity. Published studies in the past decade would suggest that this case was the start of a new era in corneal transplantation.
Adjunctive Brexpiprazole as a Novel Effective Strategy for Treating Major Depressive Disorder
Authors: Yoon Seoyoung , Jeon Sang Won , Ko Young-Hoon , Patkar Ashwin A. , Masand Prakash S. , Pae Chi-Un , Han Changsu 
Published: December 2016

Abstract

Purpose/Background
Brexpiprazole was approved for adjunctive treatment of major depressive disorder (MDD) in 2015. Because only a small number of randomized controlled trials have investigated the use of brexpiprazole in MDD, we performed a meta-analysis.

Methods/Procedures
We systematically searched literatures in PubMed, Cochrane Library database, EMBASE, Google Scholar, and clinicaltrials.gov up to January 2016. The primary efficacy measure was the mean change in total Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline. Secondary efficacy measures were the mean change in total Hamilton Rating Scale for Depression (17 items) score from baseline and the response (≥50% reduction in MADRS total score) and remission (MADRS total score ≤ 10 with ≥50% reduction) rates.

Findings/Results
Four studies fulfilled the inclusion criteria and were included in the analysis. Brexpiprazole showed superior efficacy over placebo with effect sizes (mean differences) of −1.76 (95% confidence interval [CI], −2.45 to −1.07) for MADRS and −1.21 (95% CI, −1.71 to −0.72) for the 17-item Hamilton Rating Scale for Depression. The risk ratios for response and remission were 1.57 (95% CI, 1.29–1.91) and 1.55 (95% CI, 1.22–1.96), respectively. The incidences of discontinuation due to adverse events, akathisia, and weight increase were higher in the brexpiprazole group than in the placebo group, with risk ratios of 3.44 (95% CI, 1.52–7.80), 3.39 (95% CI, 2.08–5.51), and 4.36 (95% CI, 2.45–7.77), respectively, and the incidence of akathisia was related to the brexpiprazole dose.

Implications/Conclusions
Although our results suggest that brexpiprazole could be an effective adjunctive agent for MDD, they should be cautiously translated into clinical practice because the meta-analysis was based on only a handful of randomized controlled trials.
Influence Of Desire To Belong And Feelings Of Loneliness On Emotional Prosody Perception In Schizophrenia
Authors: Mitchell Rachel , Gamez Krystal , Kohler Christian , Calkins Monica E. , Turetsky Bruce I. , Leitman David I. 
Published: December 2016

ABSTRACTObjective: Humans are social creatures, with desires to connect or belong, producing loneliness when isolated. Individuals with schizophrenia are often more isolated than healthy adults and demonstrate profound social communication impairments such as vocal affect perception (prosody). Loneliness, levels of desire for social connectedness (need to belong, NTB), and their relationship to perception of social communications have not been investigated in schizophrenia.Method: In a sample of 69 individuals (36 SZ), we measured endorsements of loneliness and NTB, and evaluated their putative relationships to clinical symptoms and social communication abilities, as indexed by emotional prosody and pitch perception.Results: Loneliness endorsement was highly variable but particularly so in patients, whilst patients endorsed NTB at levels equivalent to healthy controls. In schizophrenia, pitch and prosody acuity were reduced, and prosody perception correlated with NTB. Loneliness, but not desire for social connectedness, correlated with negative symptoms.Conclusion: Loneliness and negative symptoms likely exert bidirectional effects on each other. Loneliness and desire to form interpersonal attachments may be pivotal in shaping and stimulating social interactions and, subsequently, the ability to perceive social intent through prosody. Intact NTB levels in patients augurs well for cognitive remediation which, target vocal-communication processing to improve social skills.Significant OutcomesPatients with schizophrenia endorsed higher levels of loneliness than controls, but ratings of desire for social connectedness were at normal levels.Pitch acuity and prosody perception were correlated, confirming the importance of basic sensory processing in recognizing prosodic emotions.Socio-cognitive perceptual ability (emotional prosody perception) correlated with increased desire for social connections, implying that they may still be motivated to find social interactions reinforcing. Thus interventions to improve perceptual deficits could still be an effective means of improving social function.LimitationsCausal relationships between desire for social connections, loneliness, and emotional prosody perception cannot be inferred through correlations and cross-sectional studies alone.Subjective endorsements of loneliness through self-report are not the same thing as objective indices of loneliness. New and more extensive tools for measuring desire for both loneliness and social connectedness may be needed.Direct experimental comparison of the interrelations between desire for social connectedness, loneliness, pitch acuity and emotional prosody perception in patients with schizophrenia and other populations such as autism will enable a more accurate comparison of the likely success of remediating socio-cognitive perceptual impairment in neuropsychiatric disorders.
A Resource for Assessing Information Processing in the Developing Brain Using EEG and Eye Tracking
Authors: Langer Nicolas , Ho Erica J. , Alexander Lindsay M. , Xu Helen Y. , Jozanovic Renee K. , Henin Simon , Cohen Samantha , Marcelle Enitan T. , Parra Lucas C. , Milham Michael P. , Kelly Simon P. 
Published: December 2016

AbstractWe present a dataset combining electrophysiology and eye tracking intended as a resource for the investigation of information processing in the developing brain. The dataset includes high-density task-based and task-free EEG, eye tracking, and cognitive and behavioral data collected from 126 individuals (ages: 6–44). The task battery spans both the simple/complex and passive/active dimensions to cover a range of approaches prevalent in modern cognitive neuroscience. The active task paradigms facilitate principled deconstruction of core components of task performance in the developing brain, whereas the passive paradigms permit the examination of intrinsic functional network activity during varying amounts of external stimulation. Alongside these neurophysiological data, we include an abbreviated cognitive test battery and questionnaire-based measures of psychiatric functioning. We hope that this dataset will lead to the development of novel assays of neural processes fundamental to information processing, which can be used to index healthy brain development as well as detect pathologic processes.
Hoxa1 and TALE proteins display cross-regulatory interactions and form a combinatorial binding code on Hoxa1 targets
Authors: De Kumar Bony , Parker Hugo J. , Paulson Ariel , Parrish Mark E. , Pushel Irina , Slaughter Brian D. , Unruh Jay R. , Zeitlinger Julia , Krumlauf Robb 
Published: December 2016

AbstractHoxa1has diverse functional roles in differentiation and development. We have identified and characterized properties of regions bound by Hoxa1 on a genome-wide basis in differentiating mouse ES cells. Hoxa1 bound regions are enriched for clusters of consensus binding motifs for Hox, Pbx and Meis and many display co-occupancy of Pbx and Meis. Pbx and Meis are members of the TALE family and genome-wide analysis of multiple TALE members (Pbx, Meis, TGIF, Prep1 and Prep2) show that nearly all Hoxa1 targets display occupancy of one or more TALE members. The combinatorial binding patterns of TALE proteins defines distinct classes of Hoxa1 targets and indicates a role as cofactors in modulating the specificity of Hox proteins. We also discovered extensive auto- and cross-regulatory interactions among the Hoxa1 and TALE genes. This study provides new insight into a regulatory network involving combinatorial interactions between Hoxa1 and TALE proteins.
Tracking the embryonic stem cell transition from ground state pluripotency
Authors: Kalkan Tüzer , Olova Nelly , Roode Mila , Mulas Carla , Lee Heather J. , Nett Isabelle , Marks Hendrik , Walker Rachael , Stunnenberg Hendrik G. , Lilley Kathryn S. , Nichols Jennifer , Reik Wolf , Bertone Paul , Smith Austin 
Published: December 2016

SummaryMouse embryonic stem (ES) cells are locked into self-renewal by shielding from inductive cues. Release from this ground state in minimal conditions offers a system for delineating developmental progression from naive pluripotency. Here we examined the initial transition of ES cells. The population behaves asynchronously. We therefore exploited a short-half-lifeRex1::GFPreporter to isolate cells either side of exit from naive status. Extinction of ES cell identity in single cells is acute. It occurs only after near-complete elimination of naïve pluripotency factors, but precedes appearance of lineage specification markers. Cells newly departed from the ES cell state exhibit global transcriptome features consistent with features of early post-implantation epiblast and distinct from primed epiblast. They also exhibit a genome-wide increase in DNA methylation, intermediate between early and late epiblast. These findings are consistent with the proposition that naïve cells transition to a discrete formative phase of pluripotency preparatory to lineage priming.HighlightsThe Rex1 destabilized GFP reporter demarcates naive pluripotency.Exit from the naive state is asynchronous in the population.Transition is relatively acute in individual cells and precedes lineage priming.Transcriptome and DNA methylome reflect events in the pre-gastrulation embryo.
Flux through lipid synthesis dictates bacterial cell size
Authors: Vadia Stephen , Tse Jessica L. , Wang Jue D. , Levin Petra Anne 
Published: December 2016

AbstractNutrients—and by extension biosynthetic capacity—positively impact cell size in organisms throughout the tree of life. In bacteria, cell size is reduced three-fold in response to nutrient starvation or accumulation of the alarmone ppGpp, a global inhibitor of biosynthesis. However, whether biosynthetic capacity as a whole determines cell size or if particular anabolic pathways are more important than others remains an open question. Utilizing a top-down approach, here we identify flux through lipid synthesis as the primary biosynthetic determinant ofEscherichia colicell size. Altering flux through lipid synthesis recapitulated the impact of altering nutrients on cell size and morphology, while defects in other biosynthetic pathways either did not impact size or altered size in a lipid-dependent manner. Together our findings support a model in which lipid availability dictates cell envelope capacity and ppGpp functions as a linchpin linking surface area expansion with cytoplasmic volume to maintain cellular integrity.