bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacokinetics and pharmacodynamics of intrathecally administered Xen2174, a synthetic conopeptide with norepinephrine reuptake inhibitor and analgesic properties
Authors: Okkerse Pieter , Hay Justin L. , Sitsen Elske , Dahan Albert , Klaassen Erica , Houghton William , Groeneveld Geert Jan 
Published: December 2016

AimXen2174 is a synthetic 13‐amino acid peptide that binds specifically to the norepinephrine transporter, which results in inhibition of norepinephrine uptake. It is being developed as a possible treatment for moderate to severe pain and is delivered intrathecally. The current study was performed to assess the pharmacodynamics (PD) and the cerebrospinal fluid (CSF) pharmacokinetics (PK) of Xen2174 in healthy subjects.MethodsThis was a randomized, blinded, placebo‐controlled study in healthy subjects. The study was divided into three treatment arms. Each group consisted of eight subjects on active treatment and two or three subjects on placebo. The CSF was sampled for 32 h using an intrathecal catheter. PD assessments were performed using a battery of nociceptive tasks (electrical pain, pressure pain and cold pressor tasks).ResultsTwenty‐five subjects were administered Xen2174. CSF PK analysis showed a higher area under the CSF concentration–time curve of Xen2174 in the highest dose group than allowed by the predefined safety margin based on nonclinical data. The most common adverse event was post‐lumbar puncture syndrome, with no difference in incidence between treatment groups. Although no statistically significant differences were observed in the PD assessments between the different dosages of Xen2174 and placebo, pain tolerability in the highest dose group was higher than in the placebo group [contrast least squares mean pressure pain tolerance threshold of Xen2174 2.5 mg–placebo (95% confidence interval), 22.2% (−5.0%, 57.1%); P = 0.1131].ConclusionsAt the Xen2174 dose level of 2.5 mg, CSF concentrations exceeded the prespecified exposure limit based on the nonclinical safety margin. No statistically significant effects on evoked pain tests were observed.
Metabolic Response to Olanzapine in Healthy Chinese Subjects with rs7093146 Polymorphism in Transcription Factor 7‐like 2 Gene (TCF7L2): A Prospective Study
Authors: Li Qing , Guo Dong , Yang Hong , Ye Zhi , Huang Jin , Shu Yan 
Published: December 2016

AbstractOlanzapine is a widely used atypical antipsychotic with significant weight gain and other metabolic side effects. The locus of the transcription factor 7‐like 2 (TCF7L2) gene is strongly associated with type 2 diabetes (T2D). The goal of this study was to determine whether polymorphic TCF7L2 is involved in the susceptibility to the metabolic changes associated with the atypical antipsychotic agents (AAPs). In this study, a parallel clinical study with 3‐day consecutive administration of olanzapine (10 mg/day) was conducted in 17 healthy subjects with a genotype of TCF7L2 rs7903146 CC (N = 10) or CT (N = 7). Olanzapine caused rapid metabolic changes including body‐weight gain, increased triglycerides level and reduced HDL‐cholesterol level in the healthy subjects. rs7093146 T carriers (CT) were found to have greater AUC0–2 hr of insulin during OGTT compared to those (CC) bearing only reference alleles before and after olanzapine treatment. However, the triglyceride level in the subjects with the CT genotype was found to be significantly lower than that in the subjects with CC genotype. Moreover, a significant interaction between the effect by genotype and that by olanzapine treatment on triglyceride level was identified. Acute olanzapine treatment also significantly caused total protein, albumin and haemoglobin decrease and uric acid increase in the healthy subjects. In conclusion, even acute olanzapine treatment induces significant and rapid metabolic changes, and TCF7L2 polymorphism is a genetic risk factor of olanzapine‐associated metabolic side effects.
TP53 mutations predict decitabine‐induced complete responses in patients with myelodysplastic syndromes
Authors: Chang Chun‐Kang , Zhao You‐Shan , Xu Feng , Guo Juan , Zhang Zheng , He Qi , Wu Dong , Wu Ling‐Yun , Su Ji‐Ying , Song Lu‐Xi , Xiao Chao , Li Xiao 
Published: December 2016

SummaryTo identify the molecular signatures that predict responses to decitabine (DAC), we examined baseline gene mutations (28 target genes) in 109 myelodysplastic syndrome (MDS) patients at diagnosis. We determined that TP53 mutations predicted complete response (CR), as 10 of 15 patients (66·7%) who possessed TP53 mutations achieved a CR. Univariate and multivariate analyses showed that TP53 mutations are the only molecular signatures predictive of a CR to DAC in MDS. Among the ten patients with TP53 mutations who achieved a CR, nine presented with complex karyotypes due to abnormalities involving chromosome 5 and/or chromosome 7, and eight possessed monosomies. Although TP53 mutations were associated with a higher frequency of CRs, they were not associated with improved survival. Poor outcomes were attributed to early relapses and transformation to acute myeloid leukaemia after CR. Post‐DAC therapy patient gene mutation profiles showed that most CR patients exhibited fewer gene mutations after achieving a CR. It seems that suppression of these gene mutations was facilitated by DAC, resulting in a CR. In summary, TP53 mutations might predict decitabine‐induced complete responses in patients with MDS. DAC‐induced responses may result from partial suppression of malignant clones containing mutated TP53 genes.
Interim assessment of liver damage in patients with sickle cell disease using new non‐invasive techniques
Authors: Drasar Emma , Fitzpatrick Emer , Gardner Kate , Awogbade Moji , Dhawan Anil , Bomford Adrian , Suddle Abid , Thein Swee L. 
Published: December 2016

SummaryWe explored transient elastography (TE) and enhanced liver fibrosis (ELF™) score with standard markers of liver function to assess liver damage in 193 well patients with sickle cell disease (SCD). Patients with HbSS or HbSβ0 thalassaemia (sickle cell anaemia, SCA; N = 134), had significantly higher TE results and ELF scores than those with HbSC (N = 49) disease (TE, 6·8 vs. 5·3, P < 0·0001 and ELF, 9·2 vs. 8·6 P < 0·0001). In SCA patients, TE and ELF correlated significantly with age and all serum liver function tests (LFTs). Additionally, (weak) positive correlation was found with lactate dehydrogenase (TE: r = 0·24, P = 0·004; ELF: r = 0·26 P = 0·002), and (weak) negative correlation with haemoglobin (TE: r = −0·25, P = 0·002; ELF: r = −0·25 P = 0·004). In HbSC patients, correlations were weaker or not significant between TE or ELF, and serum LFTs. All markers of iron loading correlated with TE values when corrected for sickle genotype (serum ferritin, β = 0·25, P < 0·0001, total blood transfusion units, β = 0·25, P < 0·0001 and LIC β = 0·32, P = 0·046). The exploratory study suggests that, while TE could have a role, the utility of ELF score in monitoring liver damage in SCD, needs further longitudinal studies.
Genomic characterization of paediatric acute lymphoblastic leukaemia: an opportunity for precision medicine therapeutics
Authors: Tasian Sarah K. , Hunger Stephen P. 
Published: December 2016

SummaryMajor advances in genetic and epigenetic profiling of acute lymphoblastic leukaemia (ALL) have enhanced the understanding of key biological subsets of de novo and relapsed ALL, which has led to improved risk stratification of patients. These achievements have further defined critical leukaemia‐associated pathways and somatic alterations that may be preferentially sensitive to treatment with kinase inhibitors, epigenetic therapy or other novel agents. Therapeutic success in childhood ALL currently relies upon refined risk stratification of patients based on (i) underlying biological and clinical characteristics, and (ii) depth of initial treatment response with appropriate modulation of chemotherapy intensity. This review describes the current mutational landscape of childhood ALL and discusses opportunities for substantial improvements in survival with implementation of molecularly targeted therapies.
The survival outcome of patients with relapsed/refractory peripheral T‐cell lymphoma‐not otherwise specified and angioimmunoblastic T‐cell lymphoma
Authors: Chihara Dai , Fanale Michelle A. , Miranda Roberto N. , Noorani Mansoor , Westin Jason R. , Nastoupil Loretta J. , Hagemeister Fredrick B. , Fayad Luis E. , Romaguera Jorge E. , Samaniego Felipe , Turturro Francesco , Lee Hun J. , Neelapu Sattva S. , Rodriguez M. Alma , Wang Michael , Fowler Nathan H. , Davis Richard E. , Medeiros L. Jeffrey , Hosing Chitra , Nieto Yago L. , Oki Yasuhiro 
Published: December 2016

SummarySurvival outcome of patients with peripheral T‐cell lymphoma‐not otherwise specified (PTCL‐NOS) and angioimmunoblastic T‐cell lymphoma (AITL) who experience disease progression/relapse remains very poor. A total of 321 patients, newly diagnosed with PTCL‐NOS (n = 180) or AITL (n = 141) between 1999 and 2015, were analysed. Failure‐free survival (FFS) and overall survival (OS) were calculated from the time of first disease progression (FFS1, OS1), from second disease progression (FFS2, OS2) and from third progression (FFS3, OS3). With a median follow‐up duration of 52 months, 240 patients (135 PTCL‐NOS, 105 AITL) experienced progression/relapse. In patients with PTCL‐NOS, the median durations of FFS1, FFS2 and FFS3 were 3·1, 2·5 and 2·1 months, respectively. In patients with AITL, they were 5·5, 2·9 and 2·3 months, respectively. There was no improvement in FFS1 and OS1 by the time of recurrence during this period (1999–2004, 2005–2009 and 2010–2015). The median FFS after pralatrexate and romidepsin was only 3·0 and 2·5 months, respectively. The 5‐year OS rates after salvage autologous and allogeneic transplant were 32% and 52%, respectively; while the 5‐year OS rates for patients who did not undergo transplant was 10%. Further research for novel therapeutic approaches with higher efficacy and better safety profile are needed.
Bendamustine, lenalidomide and dexamethasone (BRd) has high activity as 2nd‐line therapy for relapsed and refractory multiple myeloma – a phase II trial
Authors: Mey Ulrich J. M. , Brugger Wolfram , Schwarb Heike , Pederiva Stefanie , Schwarzer Andreas , Dechow Tobias , Jehner Paul , Rauh Jacqueline , Taverna Christian J. , Schmid Mathias , Schmidt‐Hieber Martin , Doerfel Steffen , Fischer Natalie , Ruefer Axel , Ziske Carsten , Knauf Wolfgang , Cathomas Richard , von Moos Roger , Hitz Felicitas , Sauter Rafael , Hiendlmeyer Elke , Cantoni Nathan , Bargetzi Mario , Driessen Christoph 
Published: December 2016

SummaryThe combination of lenalidomide (Revlimid®, R) and dexamethasone (d) is a standard regimen for patients with relapsed/refractory multiple myeloma (rrMM). With this regimen, only a small fraction of patients will achieve high quality responses [≥ very good partial response (VGPR)]. The combination of bendamustine (B), lenalidomide and dexamethasone (BRd) has shown high efficacy in patients with advanced rrMM. However, dose‐limiting haematotoxicity restricted its use in extensively pre‐treated patient populations. This prospective, multicentre Phase II study evaluated the efficacy and safety of BRd in rrMM patients with one prior line of therapy. Fifty patients were enrolled (median age 68·5 years [range 46–83]) and were treated with B 75 mg/m2 days 1, 2; R 25 mg days 1–21 and d (40/20 mg) days 1, 8, 15 and 22, for 6 28‐day induction cycles, followed by 12 cycles with Rd alone. Pegfilgrastim was administered according to protocol‐defined criteria. The study aimed to demonstrate a complete response (CR)/VGPR rate of >40% after induction therapy. Of 45 evaluable patients, 23 (51%) achieved a CR/VGPR. Grade 4 neutropenia or thrombocytopenia occurred in 17 (34%) and 8 (16%) of patients, respectively. BRd is a safe and efficacious regimen as a second line treatment for rrMM, leading to high quality responses in a considerable proportion of patients.
Importance and outcome relevance of central pathology review in prostatectomy specimens: data from the SAKK 09/10 randomized trial on prostate cancer
Authors: Ghadjar Pirus , Hayoz Stefanie , Genitsch Vera , Zwahlen Daniel R. , Hölscher Tobias , Gut Philipp , Guckenberger Matthias , Hildebrandt Guido , Müller Arndt‐Christian , Putora Paul M. , Papachristofilou Alexandros , Stalder Lukas , Biaggi‐Rudolf Christine , Sumila Marcin , Kranzbühler Helmut , Najafi Yousef , Ost Piet , Azinwi Ngwa C. , Reuter Christiane , Bodis Stephan , Khanfir Kaouthar , Budach Volker , Aebersold Daniel M. , Thalmann George N. ,   the Swiss Group for Clinical Cancer Research (SAKK)
Published: December 2016

ObjectiveTo conduct a central pathology review within a randomized clinical trial on salvage radiation therapy (RT) in the presence of biochemical recurrence after prostatectomy to assess whether this results in changes in histopathological prognostic factors, such as Gleason score.Patients and MethodsA total of 350 patients were randomized and specimens from 279 patients (80%) were centrally reviewed by a dedicated genitourinary pathologist. Gleason score, tumour classification and resection margin status were reassessed and compared with the results of local pathology review. Agreement was assessed using contingency tables and Cohen's kappa coefficient. The association between other histopathological features (e.g. largest diameter of carcinoma) and rapid biochemical progression (up to 6 months after salvage RT) was also investigated.ResultsThere was good concordance between central and local pathology review for seminal vesicle invasion (pT3b: 91%; κ = 0.95 [95% confidence interval {CI} 0.89, 1.00]), extraprostatic extension (pT3a/b: 94%; κ = 0.82 [95% CI 0.75, 0.89]) and positive surgical margin (PSM) status (87%; κ = 0.7 [95% CI 0.62, 0.79]). The rate of agreement was lower for Gleason score (78%; κ = 0.61 [95% CI 0.52, 0.70]). The median (range) largest diameter of carcinoma was 16 (3–38) mm. A total of 49 patients (18%) experienced rapid biochemical progression after salvage RT. Largest diameter of carcinoma (odds ratio [OR] 2.04 [95% CI 1.30, 3.20]; P = 0.002), resection margin status (OR 0.36 [95% CI 0.18, 0.72]; P = 0.004) and Gleason score (OR 1.55 [95% CI 1.00, 2.42]; P = 0.05) remained associated with rapid progression after salvage RT after backward selection.ConclusionThe results of the central pathology analyses showed concordance between central and local pathology review with regard to seminal vesicle invasion, extraprostatic extension and PSM status, but a lower rate of agreement for Gleason score. Largest diameter of carcinoma was found to be a potential prognostic factor for rapid biochemical progression after salvage RT.
Hurricane Sandy Exposure Alters the Development of Neural Reactivity to Negative Stimuli in Children
Authors: Kessel Ellen M. , Nelson Brady D. , Kujawa Autumn , Hajcak Greg , Kotov Roman , Bromet Evelyn J. , Carlson Gabrielle A. , Klein Daniel N. 
Published: December 2016

This study examined whether exposure to Hurricane Sandy‐related stressors altered children's brain response to emotional information. An average of 8 months (Mage = 9.19) before and 9 months after (Mage = 10.95) Hurricane Sandy, 77 children experiencing high (n = 37) and low (n = 40) levels of hurricane‐related stress exposure completed a task in which the late positive potential, a neural index of emotional reactivity, was measured in response to pleasant and unpleasant, compared to neutral, images. From pre‐ to post‐Hurricane Sandy, children with high stress exposure failed to show the same decrease in emotional reactivity to unpleasant versus neutral stimuli as those with low stress exposure. Results provide compelling evidence that exposure to natural disaster‐related stressors alters neural emotional reactivity to negatively valenced information.
The “Batman Effect”: Improving Perseverance in Young Children
Authors: White Rachel E. , Prager Emily O. , Schaefer Catherine , Kross Ethan , Duckworth Angela L. , Carlson Stephanie M. 
Published: December 2016

This study investigated the benefits of self‐distancing (i.e., taking an outsider's view of one's own situation) on young children's perseverance. Four‐ and 6‐year‐old children (N = 180) were asked to complete a repetitive task for 10 min while having the option to take breaks by playing an extremely attractive video game. Six‐year‐olds persevered longer than 4‐year‐olds. Nonetheless, across both ages, children who impersonated an exemplar other—in this case a character, such as Batman—spent the most time working, followed by children who took a third‐person perspective on the self, or finally, a first‐person perspective. Alternative explanations, implications, and future research directions are discussed.
Utility of ultrasound for body fat assessment: validity and reliability compared to a multicompartment criterion
Authors: Smith‐Ryan Abbie E. , Blue Malia N. M. , Trexler Eric T. , Hirsch Katie R. 
Published: December 2016

SummaryMeasurement of body composition to assess health risk and prevention is expanding. Accurate portable techniques are needed to facilitate use in clinical settings. This study evaluated the accuracy and repeatability of a portable ultrasound (US) in comparison with a four‐compartment criterion for per cent body fat (%Fat) in overweight/obese adults. Fifty‐one participants (mean ± SD; age: 37·2 ± 11·3 years; BMI: 31·6 ± 5·2 kg m−2) were measured for %Fat using US (GE Logiq‐e) and skinfolds. A subset of 36 participants completed a second day of the same measurements, to determine reliability. US and skinfold %Fat were calculated using the seven‐site Jackson–Pollock equation. The Wang 4C model was used as the criterion method for %Fat. Compared to a gold standard criterion, US %Fat (36·4 ± 11·8%; P = 0·001; standard error of estimate [SEE] = 3·5%) was significantly higher than the criterion (33·0 ± 8·0%), but not different than skinfolds (35·3 ± 5·9%; P = 0·836; SEE = 4·5%). US resulted in good reliability, with no significant differences from Day 1 (39·95 ± 15·37%) to Day 2 (40·01 ± 15·42%). Relative consistency was 0·96, and standard error of measure was 0·94%. Although US overpredicted %Fat compared to the criterion, a moderate SEE for US is suggestive of a practical assessment tool in overweight individuals. %Fat differences reported from these field‐based techniques are less than reported by other single‐measurement laboratory methods and therefore may have utility in a clinical setting. This technique may also accurately track changes.
Effects of supine rest duration on ultrasound measures of the vastus lateralis
Authors: Arroyo Eliott , Stout Jeffrey R. , Beyer Kyle S. , Church David D. , Varanoske Alyssa N. , Fukuda David H. , Hoffman Jay R. 
Published: December 2016

SummaryIntroductionDue to the potential for intramuscular fluid shifts from changing body position, researchers often utilize a 10‐ to 15‐min period of supine rest as a standardizing procedure prior to ultrasound assessment of the lower limbs. However, no previous research has observed the changes in muscle morphological characteristics via ultrasonography of the lower limbs depending on the length of time of supine rest to determine whether 10–15 min of supine rest is necessary. The aim of this study was to examine changes in muscle morphology of the vastus lateralis (VL) at various time‐points over the course of 15 min of supine rest.MethodsMuscle thickness (MT), cross‐sectional area (CSA) and echo intensity (EI) of the VL were assessed in 24 adults at four time‐points including the following: immediately upon moving from a standing to supine position (T0), after 5 (T5), 10 (T10) and 15 min (T15) of lying in a supine position.ResultsCSA significantly decreased from T0 to T10 (P = 0·001) and T15 (P<0·001), with no difference between any other time‐points (P = 0·055–0·666). However, the reported changes in CSA did not exceed the standard error of the measurement for this procedure. No significant differences between any time‐points for MT (P = 0·726–0·966) or EI (P = 0·061–0·783) were observed.DiscussionThese findings suggest extended periods of supine rest may not be needed to obtain consistent muscle morphological measurements of the VL using ultrasonography.
TRPM1 (melastatin) expression is an independent predictor of overall survival in clinical AJCC stage I and II melanoma patients
Authors: Brożyna Anna A. , Guo Huazhang , Yang Sun‐Eun , Cornelius Lynn , Linette Gerald , Murphy Michael , Sheehan Christine , Ross Jeffrey , Slominski Andrzej , Carlson J. Andrew 
Published: December 2016

BackgroundThe expression of TRPM1 (melastatin) mRNA is an independent marker, as measured by radioactive in situ hybridization (RISH), of disease‐free survival in primary cutaneous melanoma (PM). The aim of the study was to determine if chromogenic in situ hybridization (CISH) can reproduce results examining diagnostic and prognostic utility of TRPM1 mRNA expression in melanocytic proliferations as measured by RISH.
Methods
The expression of TRPM1 mRNA was detected by CISH in melanocytic nevi (MN, n = 61), PM (n = 145) and metastatic melanomas (MMs, n = 15).ResultsA progressive loss of TRPM1 was found moving from MN to PM to MM. The histologic stepwise model of melanoma progression revealed that loss of TRPM1 occurred at the transition of RGP PM to VGP PM. As a diagnostic marker, TRPM1 gradient loss showed 93.8% sensitivity and 52.4% specificity for PM. Loss of TRPM1 mRNA correlated with melanoma aggressiveness markers and was independent predictor of disease‐free and overall survival. The corresponding survival curves for degree of melanoma pigmentation matched those for degree of loss of TPRM1 mRNA.ConclusionLoss of TRPM1 mRNA expression appears to be a crucial event in the progression of melanoma to a more malignant, metastatic phenotype.
Scissor‐type knife significantly improves self‐completion rate of colorectal endoscopic submucosal dissection: Single‐center prospective randomized trial
Authors: Yamashina Takeshi , Takeuchi Yoji , Nagai Kengo , Matsuura Noriko , Ito Takashi , Fujii Mototsugu , Hanaoka Noboru , Higashino Koji , Uedo Noriya , Ishihara Ryu , Iishi Hiroyasu 
Published: December 2016

Background and AimColorectal endoscopic submucosal dissection (C‐ESD) is recognized as a difficult procedure. Recently, scissors‐type knives were launched to reduce the difficulty of C‐ESD. The aim of this study was to evaluate the efficacy and safety of the combined use of a scissors‐type knife and a needle‐type knife with a water‐jet function (WJ needle‐knife) for C‐ESD compared with using the WJ needle‐knife alone.MethodsThis was a prospective randomized controlled trial in a referral center. Eighty‐five patients with superficial colorectal neoplasms were enrolled and randomly assigned to undergo C‐ESD using a WJ needle‐knife alone (Flush group) or a scissor‐type knife‐supported WJ needle‐knife (SB Jr group). Procedures were conducted by two supervised residents. Primary endpoint was self‐completion rate by the residents.ResultsSelf‐completion rate was 67% in the SB Jr group, which was significantly higher than that in the Flush group (39%, P = 0.01). Even after exclusion of four patients in the SB Jr group in whom C‐ESD was completed using the WJ needle‐knife alone, the self‐completion rate was significantly higher (63% vs 39%; P = 0.03). Median procedure time among the self‐completion cases did not differ significantly between the two groups (59 vs 51 min; P = 0.14). No fatal adverse events were observed in either group.ConclusionsIn this single‐center phase II trial, scissor‐type knife significantly improved residents’ self‐completion rate for C‐ESD, with no increase in procedure time or adverse events. A multicenter trial would be warranted to confirm the validity of the present study.