bluuebunny/crossref_metadata_2025 huggingface dataset:
Incremental changes verses a technological quantum leap: The additional value of intensity‐modulated radiotherapy beyond image‐guided radiotherapy for prostate irradiation
Authors: Ratnayake Gishan , Martin Jarad , Plank Ashley , Wong Winnie
Published: February 2014

Introduction

Both intensity‐modulated radiotherapy (IMRT) and image‐guided radiotherapy (IGRT) have been shown to independently reduce late rectal toxicity for men with prostate cancer (PC) treated with radiotherapy. We explore whether IMRT offers further reductions in late rectal toxicity for men already being managed with IGRT and compare this with more gradual changes over time.

Methods

Between 2007 and 2009, 103 patients with PC were treated with three‐dimensional conformal radiotherapy (3D‐CRT n = 52) or IMRT (n = 51) with doses of 74–78 Gy at 2 Gy per fraction. All men had daily IGRT using intra‐prostatic gold fiducials. The primary endpoint was incidence of grade ≥2 late rectal toxicity as graded by the Radiation Therapy Oncology Group scale.

Results

The relative risk of late grade ≥2 rectal toxicity in patients treated with IMRT was 68% less than seen with image‐guided 3D‐CRT at 36 months post‐treatment (7% versus 22%; hazard ratio = 0.32, P = 0.03). IMRT remained a significant protective factor in a multivariate analysis. A discriminant analysis showed that the relative volume of rectal wall exposed to doses over 50 Gy was most strongly associated with late rectal toxicity. Controlling for duration of follow‐up, a later year of treatment was the strongest clinical predictor of late rectal toxicity in multivariate modelling (P = 0.03).

Conclusion

For men with PC managed to doses of 74–78 Gy with IGRT, IMRT leads to reduced rectal toxicity compared with 3D‐CRT. Incremental improvements in treatment delivery over time also appear to have an independently strong beneficial effect.
Favorable response to icotinib in a lung cancer patient with a special mutation at exon 19 of epidermal growth factor receptor
Authors: Zheng Hua , Wang Qunhui , Shi Heling , Zhang Hongmei , Hu Fanbin , Li Baolan
Published: February 2014

Many studies have illustrated that two types of mutation – deletions in exon 19 and a point mutation in exon 21 (L858R) – have been reported to comprise up to 90% of all activating epidermal growth factor receptor (EGFR) mutations. A point mutation at exon 19 is a rare mutation, and to date there have been no reports investigating the sensitivities of EGFR‐tyrosine kinase inhibitors (TKIs) to the mutation. In this case report, we have demonstrated a special mutation, a point mutation at c.2279T>C (p.L760P) in exon 19 of EGFR, which has responded favorably to icotinib in a lung adenocarcinoma patient with brain metastasis. Icotinib is a new type of oral EGFR‐TKI developed in China and is the first EGFR‐TKI in Asia. Icotinib has the potential to improve the prognosis of lung adenocarcinoma patients and with less toxic‐effect.
Knee surgery recovery: Post‐operative Quality of Recovery Scale comparison of age and complexity of surgery
Authors: ROYSE C. F. , WILLIAMS Z. , YE G. , WILKINSON D. , DE STEIGER R. , RICHARDSON M. , NEWMAN S.
Published: February 2014

Background

Initial validation and feasibility for the Post‐operative Quality of Recovery Scale (PQRS) was published in 2010. Ongoing validation includes studies to determine whether this scale can discriminate differences in recovery between cohorts.

Methods

A prospective cohort study included 61 patients, 18–40 years, and 61 patients, aged ≥ 65 years, undergoing knee arthroscopy under general anaesthesia; and 13 patients, aged ≥ 65 years, undergoing total knee replacement under general anaesthesia. Patients were assessed using the PQRS. Assessments were performed pre‐surgery, at 15 and 40 min, 1 and 3 days, and 3 months after surgery.

Results

The effect of age was assessed by comparing young versus older arthroscopy patients. There were minimal differences in recovery profiles, other than for the nociceptive domain, where pain recovery was significantly better in the older arthroscopy patients (P < 0.001). The effect of surgery was assessed by comparing older patients undergoing knee arthroscopy with knee replacement patients. Recovery was significantly worse for the knee replacement group for cognition (P = 0.015), nociception (pain and nausea, P < 0.001), activities of daily living (P < 0.001), emotive recovery (P = 0.029), and all‐domains recovery (P < 0.001). Despite differences in quality of recovery, satisfaction was high in all cohorts.

Conclusions

Knee replacement had a large effect on recovery compared with knee arthroscopy. Age had minimal effect on recovery after knee arthroscopy. The study showed the ability of the PQRS to discriminate recovery in different domains.
The Validity of Phosphatidylethanol in Dried Blood Spots of Newborns for the Identification of Prenatal Alcohol Exposure
Authors: Bakhireva Ludmila N. , Leeman Lawrence , Savich Renate D. , Cano Sandra , Gutierrez Hilda , Savage Daniel D. , Rayburn William F.
Published: February 2014

Background

Accurate identification of prenatal alcohol exposure (PAE) in the newborn period offers an opportunity for early identification of children at risk of future neurocognitive problems and the implementation of interventional approaches earlier in life. PAE newborn screening by measuring phosphatidylethanol in dried blood spot (PEth‐DBS) cards is feasible, logistically easier, and more cost‐efficient compared with other biomarkers. However, the sensitivity and specificity of this method have yet to be established.

Methods

This prospective cohort study examined validity of PEth‐DBS among 28 infants with PAE and 32 controls relative to maternal self‐report and other biomarkers. Pregnant women were recruited from a University of New Mexico clinic and followed to early postpartum period. The composite index, which was based on self‐reported measures of alcohol use and allowed to classify subjects into PAE and control groups, was the criterion measure used to estimate sensitivity and specificity of PEth‐DBS.

Results

The study included large proportions of patients representing ethnic minorities (7.4% American Indian, 81.7% Hispanic/Latina), low education (54.2% <high school), and unplanned pregnancy (90.0%). No differences in sociodemographic characteristics, smoking or illicit drug use were observed among the study groups. The sensitivity of maternal biomarkers (gamma glutamyltranspeptidase [GGT], % carbohydrate‐deficient transferrin [%CDT], urine ethyl glucuronide [UEtG], urine ethyl sulfate [UEtS]) was low (<15%) reflecting a moderate chronic or intermittent binge pattern of drinking in this cohort. PEth‐DBS demonstrated 100% specificity and the highest sensitivity (32.1%) compared with other biomarkers. A battery consisting of maternal direct ethanol metabolites (UEtG, UEtS, PEth) and newborn PEth‐DBS increased sensitivity to 50% without a substantial drop in specificity (93.8%).

Conclusions

Newborn PEth‐DBS is a highly specific biomarker and can facilitate accurate detection of PAE in conjunction with other biomarkers. Minimal invasiveness, ease of storage and transportation of DBS cards, absence of postcollection synthesis, cost savings, and potential integration with routine newborn screening are all unique advantages of this method.
Association Between Copy Number Variation Losses and Alcohol Dependence Across African American and European American Ethnic Groups
Authors: Ulloa Alvaro E. , Chen Jiayu , Vergara Victor M. , Calhoun Vince , Liu Jingyu
Published: February 2014

Background

Copy number variations (CNVs) are structural genetic mutations consisting of segmental gains or losses in DNA sequence. Although CNVs contribute substantially to genomic variation, few genetic and imaging studies report association of CNVs with alcohol dependence (AD). Our purpose is to find evidence of this association across ethnic populations and genders. This work is the first AD–CNV study across ethnic groups and the first to include the African American (AA) population.

Methods

This study considers 2 CNV data sets, one for discovery (2,345 samples) and the other for validation (239 samples), both including subjects with AD and healthy controls of European and African ancestry. Our analysis assesses the association between AD and CNV losses across ethnic groups and gender by examining the effect of overall losses across the whole genome, collective losses within individual cytogenetic bands, and specific losses in CNV regions.

Results

Results from the discovery data set showed an association between CNV losses within 16q12.2 and AD diagnosis (p = 4.53 × 10−3). An overlapping CNV region from the validation data set exhibited the same direction of effect with respect to AD (p = 0.051). This CNV region affects the genes CES1p1 and CES1, which are members of the carboxylesterase (CES) family. The enzyme encoded by CES1 is a major liver enzyme that typically catalyzes the decomposition of ester into alcohol and carboxylic acid and is involved in drug or xenobiotics, fatty acid, and cholesterol metabolisms. In addition, the most significantly associated CNV region was located at 9p21.2 (p = 1.9 × 10−3) in our discovery data set. Although not observed in the validation data set, probably due to small sample size, this result might hold potential connection to AD given its connection with neuronal death. In contrast, we did not find any association between AD and the overall total losses or the collective losses within individual cytogenetic bands.

Conclusions

Overall, our study provides evidence that the specific CNVs at 16q12.2 contribute to the development of alcoholism in AA and European American populations.
Turning up the heat on the provenance debate: Testing the ‘local is best’ paradigm under heatwave conditions
Authors: Hancock Nola , Hughes Lesley
Published: February 2014

A key aspect of successful restoration projects is the sourcing of propagation material suited to the environmental and biotic conditions of the proposed planting site. Traditionally, the use of propagules collected locally has been advocated for revegetation on the assumption that this material is better adapted to local conditions. A rapidly changing climate, however, is challenging the assumption that the use of local genetic stock will provide the best restoration outcome in the long term. We tested the ‘local is best’ paradigm using open top chambers to simulate the predicted summer temperatures for 2050 in western Sydney, Australia. We compared the establishment success of Eucalyptus tereticornis and Themeda australis, dominant species in Cumberland Plain Woodland, grown from local versus non‐local seed. All plants survived an exceptional summer heatwave and few differences between temperature treatments were found. No evidence of local superiority was found for survival or growth of non‐reproductive tissues of either species. However, local provenance plants of E. tereticornis suffered significantly greater herbivory in the ambient temperature treatment than one non‐local provenance, and local provenance plants of T. australis demonstrated significant superiority to most non‐local provenances in all categories of reproductive growth. For both species, the provenances from warmer climates demonstrated comparable, and often better, growth performance than the local provenance plants.
Institutional review of patients presenting with suspected appendicitis
Authors: Teo Andrew Teck Kwee , Lefter Liviu Paul , Zarrouk Ali Jafar Mohamad , Merrett Neil Donald
Published: February 2014

Background

Appendicitis is a common gastrointestinal surgical emergency. Treatment balances the risks of negative appendicectomy (NA) against potential complicated appendicitis in determining clinical priority. This study reviewed the population characteristics, results of the diagnostic modalities and Alvarado score (AlvS) of patients with suspected appendicitis.

Methods

A clinical audit of emergency appendicectomies was performed. Generalized linear models with a binomial distribution were used to evaluate the association between the age groups, gender, white cell count (WCC), neutrophil count (NC) and C‐reactive protein (CRP) levels versus NAs and the different types of appendicitis. The utilization and accuracy of preoperative ultrasound and computed tomography (CT) and a preliminary analysis of AlvS were also evaluated.

Results

Patients 17 to 24 years old had significantly higher odds of NA but lower odds of complicated appendicitis compared with patients above 40 years. Adult women and men had significantly higher odds of NA and suppurative appendicitis (SA), respectively. Only adults with SA and acute appendicitis had significantly higher odds of raised WCC, NC and CRP. The sensitivity of CT for adult females was high (100%). Patients who had CT and an AlvS of more than 7 did not have NAs.

Conclusion

Elevated WCC, NC and CRP were all associated with acute appendicitis and SA in adults only. CT is useful for refining the diagnosis in adult females. A combination of inflammatory markers, ultrasound and AlvS may be used selectively to complement or maximize the advantages of CT.
Extracellular calcium regulates keratinocyte proliferation and HPV 16 E6 RNA expression in vitro
Authors: Turunen Aaro , Syrjänen Stina
Published: February 2014

Human papillomaviruses (HPV) are known to immortalize oral keratinocytes in vitro, but the underlying mechanisms causing the following resistance to differentiation remain unclear. We investigated the effect of extracellular calcium on the proliferation of HPV16‐positive keratinocytes and on the mRNA expression of the viral E6‐oncogene. HPV16‐positive hypopharyngeal carcinoma cells (UD‐SCC‐2), spontaneously immortalized‐ (HMK) and HPV16 E6/E7‐immortalized human gingival keratinocytes (IHGK) were grown for 3, 6 and 9 days in Keratinocyte Serum‐free Medium with calcium concentrations ranging from 0 mM to 6 mM. Calcium concentrations up to 0.09 mM increased cellular proliferation, which decreased at higher concentrations. A shift of calcium concentration from 0 to 4 mM increased E6 expression in UD‐SCC‐2 cells 2.4‐fold by day 9. Simultaneously, E2 expression increased. The most significant upregulation of E6 and E2 expressions was observed at day 9, grown in high‐calcium media and the increase in E6 expression coincided with an increase in involucrin expression, likely indicating cell differentiation. Despite this, HPV‐positive cells continued to proliferate even at high‐calcium media in contrast to HPV‐negative cells. Overexpression of E6 mRNA may be an important feature of HPV16‐positive cells to resist the natural calcium gradient in differentiating keratinocytes allowing cell proliferation.
Dilated intercellular space diameter as marker of reflux‐related mucosal injury in children with chronic cough and gastro‐oesophageal reflux disease
Authors: Borrelli O. , Mancini V. , Thapar N. , Ribolsi M. , Emerenziani S. , de'Angelis G. , Bizzarri B. , Lindley K. J. , Cicala M.
Published: February 2014

Background

The diagnostic corroboration of the relationship between gastro‐oesophageal reflux disease (GERD) and chronic cough remains challenging.

Aims

To compare oesophageal mucosal intercellular space diameter (ISD) in children with GERD, children with gastro‐oesophageal reflux (GER)‐related cough (GrC) and a control group, and to explore the relationship between baseline impedance levels and dilated ISD in children with GER‐related cough.

Methods

Forty children with GERD, 15 children with GrC and 12 controls prospectively underwent oesophagogastroduodenoscopy (EGD) with oesophageal biopsies taken 2–3 cm above squamocolumnar junction. ISD were quantified using transmission electron microscopy. Impedance‐pH monitoring with evaluation of baseline impedance in the most distal impedance channel was performed in both patient groups.

Results

A significant difference in mean ISD values was found between GrC patients (0.9 ± 0.2 μm) and controls (0.5 ± 0.2 μm, P < 0.001), whereas there was no difference between GrC and GERD group (1 ± 0.3 μm, NS). No difference was found in the mean ISD between GrC children with or without pathological oesophageal acid exposure time (1 ± 0.3 vs. 0.9 ± 0.2 μm), and there was no correlation between ISD and any reflux parameter. Finally, there was no correlation between ISD and distal baseline impedance values (r:−0.35; NS).

Conclusions

In children with reflux‐related cough, dilated intercellular space diameter appears to be an objective and useful marker of oesophageal mucosal injury regardless of acid exposure, and its evaluation should be considered for those patients where the diagnosis is uncertain. In children with reflux‐related cough, baseline impedance levels have no role in identifying reflux‐induced oesophageal mucosal ultrastructural changes.
Nine scoring models for short‐term mortality in alcoholic hepatitis: cross‐validation in a biopsy‐proven cohort
Authors: Papastergiou V. , Tsochatzis E. A. , Pieri G. , Thalassinos E. , Dhar A. , Bruno S. , Karatapanis S. , Luong T. V. , O'Beirne J. , Patch D. , Thorburn D. , Burroughs A. K.
Published: February 2014

Background

Several prognostic models have emerged in alcoholic hepatitis (AH), but lack of external validation precludes their universal use.

Aim

To validate the Maddrey Discriminant Function (DF); Glasgow Alcoholic Hepatitis Score (GAHS); Mayo End‐stage Liver Disease (MELD); Age, Bilirubin, INR, Creatinine (ABIC); MELD‐Na, UK End‐stage Liver Disease (UKELD), and three scores of corticosteroid response at 1 week: an Early Change in Bilirubin Levels (ECBL), a 25% fall in bilirubin, and the Lille score.

Methods

Seventy‐one consecutive patients with biopsy‐proven AH, admitted between November 2007‐September 2011, were evaluated. The clinical and biochemical parameters were analysed to assess prognostic models with respect to 30‐ and 90‐day mortality.

Results

There were no significant differences in the areas under the receiver operating characteristics curve (AUROCs) relative to 30‐day/90‐day mortality: MELD 0.79/0.84, DF 0.71/0.74, GAHS 0.75/0.78, ABIC 0.71/0.78, MELD‐Na 0.68/0.76, UKELD 0.56/0.68. One‐week rescoring yielded a trend towards improved predictive accuracies (30‐day/90‐day AUROCs: 0.69–0.84/0.77–0.86). In patients with admission DF ≥32 (n = 31), response to corticosteroids according to ECBL, 25% fall in bilirubin and the Lille model yielded AUROCs of 0.73/0.73, 0.78/0.72 and 0.81/0.82 for a 30‐day/90‐day outcome respectively. All models showed excellent negative predictive values (NPVs; range: 86–100%), while the positive ones were low (range: 17–50%).

Conclusions

MELD, DF, GAHS, ABIC and scores of corticosteroid response proved to be valid in an independent cohort of biopsy‐proven alcoholic hepatitis. MELD modifications incorporating sodium did not confer any prognostic advantage over classical MELD. Based on excellent NPVs, the models are best to identify patients at low risk of death.
Land grabbing as a driver of environmental change
Authors: Lazarus Eli D
Published: February 2014

A worldwide increase in large‐scale land acquisitions over the past decade has been described as a global land rush for access to natural resources. ‘Land grabbing’ is a dynamic of land‐use change that can enable especially rapid environmental transformations across vast spatial scales. New scholarship is beginning to address these land deals in terms of their implications for social and political systems, but exploitative land uses also leave legacies of change in physical landscapes. Historical precedents from around the world, including various examples of frontier expansion, reflect the kinds of environmental responses that modern land grabbing could induce. Insights into land grabbing as a mechanism of abrupt, large‐scale transitions in human–environmental systems is a research opportunity and a pressing grand challenge for Earth‐surface science.
‘Wiping New Berlin off the map’: political economy and the de‐Germanisation of the toponymic landscape in First World War USA
Authors: Post Chris W , Alderman Derek H
Published: February 2014

Within critical place name studies, the perspectives of ‘toponym‐as‐commodity’ and ‘toponym‐as‐nationalistic symbol’ have tended to be studied separately, but they are not necessarily mutually exclusive. Using a case study of toponymic change from First World War USA, specifically the renaming of New Berlin, Ohio, to North Canton, we illustrate that this effort to de‐Germanise the landscape cannot be adequately understood without considering how seemingly nationalistically‐driven toponymic changes took place within, and facilitated, local industrial and commercial momentum. While the toponymic literature has tended to emphasise the role of government elites in controlling and contesting place names, our Ohio case demonstrates the powerful role of a corporation, namely the WH Hoover and Hoover Suction Sweeper companies, in shaping place naming debates and changes. We interpret the New Berlin name change via three themes: symbolic capital and place re‐branding, symbolic annihilation and fetishisation, and the toponymic rescaling of economic linkages.
Tracing absence: enduring methods, empirical research and a quest for the first neon sign in the USA
Authors: DeLyser Dydia
Published: February 2014

In this paper I review approaches to absence in geography to argue that, while apprehending absence requires creative and varied approaches, actually tracing absence may demand traditional, methodical and time‐intensive empirical research. Without undermining the value of novel methods or expanded understandings of the empirical, I demonstrate how sometimes only exhaustive empirical research (archival in this case) can address our research questions – as much as we may favour the new, sometimes we must rely on the methods that endure. To make this point I present my quest for evidence of the much‐lauded first neon sign in the USA. The story of the 1922–3 Earle C. Anthony ‘Packard’ sign had not been questioned by print or Internet source – but neither had any primary evidence (such as photographs or media coverage) been presented of its existence. That lack of evidence became a six‐month quest to trace the sign's absence, one that reveals how exhaustive archival research, utilising sources previously not consulted (or perhaps even known), could upset previous histories of neon signs in the USA.
Antithyroid drug‐related hepatotoxicity in hyperthyroidism patients: a population‐based cohort study
Authors: Wang Meng‐Ting , Lee Wan‐Ju , Huang Tien‐Yu , Chu Che‐Li , Hsieh Chang‐Hsun
Published: February 2014

Aims

The evidence of hepatotoxicity of antithyroid drugs (ATDs) is limited to case reports or spontaneous reporting. This study aimed to quantify the incidence and comparative risks of hepatotoxicity for methimazole (MMI)/carbimazole (CBM) vs. propylthiouracil (PTU) in a population‐based manner.

Methods

We conducted a cohort study of hyperthyroidism patients initially receiving MMI/CBM or PTU between 1 January 2004 and 31 December 2008 using the Taiwan National Health Insurance Research Database. The examined hepatotoxicity consisted of cholestasis, non‐infectious hepatitis, acute liver failure and liver transplant, with the incidences and relative risks being quantified by Poisson exact methods and Cox proportional hazard models, respectively.

Results

The study cohort comprised 71 379 ATD initiators, with a median follow‐up of 196 days. MMI/CBM vs. PTU users had a higher hepatitis incidence rate (3.17/1000 vs. 1.19/1000 person‐years) but a lower incidence of acute liver failure (0.32/1000 vs. 0.68/1000 person‐years). The relative risk analysis indicated that any use of MMI/CBM was associated with a 2.89‐fold (95% CI 1.81, 4.60) increased hepatitis risk compared with PTU, with the risk increasing to 5.08‐fold for high dose MMI/CBM (95% CI 3.15, 8.18). However, any MMI/CBM use vs. PTU was not related to an increased risk of cholestasis (adjusted hazard ratio [HR] 1.14, 95% CI 0.40, 3.72) or acute liver failure (adjusted HR 0.54, 95% CI 0.24, 1.22).

Conclusions

MMI/CBM and PTU exert dissimilar incidence rates of hepatotoxicity. Compared to PTU, MMI/CBM are associated in a dose‐dependent manner with an increased risk for hepatitis while the risks are similar for acute liver failure and cholestasis.
Pharmacogenomics – how close/far are we to practising individualized medicine for children?
Authors: Sing Chor‐Wing , Cheung Ching‐Lung , Wong Ian C. K.
Published: February 2014

The translation of pharmacogenomics into clinical practice is a key approach for practising individualized medicine, which aims to maximize drug efficacy and minimize drug toxicity. Since the completion of both the Human Genome Project and the International HapMap project, the development of pharmacogenomics has been greatly facilitated. However, progress in translating pharmacogenomics into clinical practice, especially in paediatric medicine, is unexpectedly slow. Many challenges from different areas remain. This paper discusses the existing applications and the limitations to the implementation of paediatric pharmacogenomics, as well as possible solutions for overcoming these limitations and challenges.
Impact of statin adherence on cardiovascular disease and mortality outcomes: a systematic review
Authors: De Vera Mary A. , Bhole Vidula , Burns Lindsay C. , Lacaille Diane
Published: February 2014

Aims

While suboptimal adherence to statin medication has been quantified in real‐world patient settings, a better understanding of its impact is needed, particularly with respect to distinct problems of medication taking. Our aim was to synthesize current evidence on the impacts of statin adherence, discontinuation and persistence on cardiovascular disease and mortality outcomes.

Methods

We conducted a systematic review of peer‐reviewed studies using a mapped search of Medline, Embase and International Pharmaceutical Abstracts databases. Observational studies that met the following criteria were included: defined patient population; statin adherence exposure; defined study outcome [i.e. cardiovascular disease (CVD), mortality]; and reporting of statin‐specific results.

Results

Overall, 28 studies were included, with 19 studies evaluating outcomes associated with statin adherence, six with statin discontinuation and three with statin persistence. Among adherence studies, the proportion of days covered was the most widely used measure, with the majority of studies reporting increased risk of CVD (statistically significant risk estimates ranging from 1.22 to 5.26) and mortality (statistically significant risk estimates ranging from 1.25 to 2.54) among non‐adherent individuals. There was greater methodological variability in discontinuation and persistence studies. However, findings of increased CVD (statistically significant risk estimates ranging from 1.22 to 1.67) and mortality (statistically significant risk estimates ranging from 1.79 to 5.00) among nonpersistent individuals were also consistently reported.

Conclusions

Observational studies consistently report an increased risk of adverse outcomes associated with poor statin adherence. These findings have important implications for patients and physicians and emphasize the importance of monitoring and encouraging adherence to statin therapy.
Avoiding obsolescence in advanced prostate cancer management: a guide for urologists
Authors: Shore Neal D. , Karsh Lawrence , Gomella Leonard G. , Keane Thomas E. , Concepcion Raoul S. , Crawford E. David
Published: February 2014

Prostate cancer is one of the most common cancers diagnosed in men in the USA and 20–30% of men treated for localised prostate cancer will fail therapy and develop advanced prostate cancer. More drugs have been approved for the treatment of advanced prostate cancer in the past 3 years than in the past three decades, and each drug has its own mechanism of action and, often, unique monitoring requirements. As the treatment landscape for men with advanced prostate cancer is undergoing significant expansion, the roles of both oncologists and urologists are shifting, and the decision for the urologist to treat vs refer requires early assessment to identify which patients are candidates for these novel treatments and the monitoring of patients for tolerability, response, and potential side‐effects. Given these rapid changes, the authors of this review met in January 2013 and again in April 2013 to discuss the current challenges facing urologists in adopting these new treatments into their own practices. Here, we provide a brief overview of advanced prostate cancer medical therapies approved in the past decade, the necessary monitoring procedures and early detection methods needed to safely and effectively manage patients receiving these therapies, and our recommendations for applying these new therapies within different models of urology practice, such that urologists can remain an integral component of their patient's care once he has transitioned into advanced prostate cancer
Investigating the molecular mechanisms through which FTY720‐P causes persistent S1P1 receptor internalization
Authors: Sykes David A , Riddy Darren M , Stamp Craig , Bradley Michelle E , McGuiness Neil , Sattikar Afrah , Guerini Danilo , Rodrigues Ines , Glaenzel Albrecht , Dowling Mark R , Mullershausen Florian , Charlton Steven J
Published: February 2014

Background and Purpose

The molecular mechanism underlying the clinical efficacy of FTY720‐P is thought to involve persistent internalization and enhanced degradation of the S1P1 receptor subtype (S1P1R). We have investigated whether receptor binding kinetics and β‐arrestin recruitment could play a role in the persistent internalization of the S1P1R by FTY720‐P.

Experimental Approach

[3H]‐FTY720‐P and [33P]‐S1P were used to label CHO‐S1P1/3Rs for binding studies. Ligand efficacy was assessed through [35S]‐GTPγS binding and β‐arrestin recruitment. Metabolic stability was evaluated using a bioassay measuring intracellular Ca2+ release. CHO‐S1P1/3R numbers were determined, following FTY720‐P treatment using flow cytometry.

Key Results

The kinetic off‐rate of [3H]‐FTY720‐P from the S1P1R was sixfold slower than from the S1P3R, and comparable to [33P]‐S1P dissociation from S1P1/3Rs. S1P and FTY720‐P stimulated [35S]‐GTPγS incorporation to similar degrees, but FTY720‐P was over 30‐fold less potent at S1P3Rs. FTY720‐P stimulated a higher level of β‐arrestin recruitment at S1P1Rs, 132% of the total recruited by S1P. In contrast, FTY720‐P was a weak partial agonist at S1P3R, stimulating just 29% of the total β‐arrestin recruited by S1P. Internalization experiments confirmed that cell surface expression of the S1P1R but not the S1P3R was reduced following a pulse exposure to FTY720‐P, which is metabolically stable unlike S1P.

Conclusions and Implications

FTY720‐P and S1P activation of the S1P1R results in receptor internalization as a consequence of an efficient recruitment of β‐arrestin. The combination of slow off‐rate, efficacious β‐arrestin recruitment and metabolic stability all contribute to FTY720‐P's ability to promote prolonged S1P1R internalization and may be critical factors in its efficacy in the clinic.
Signalling profiles of H3 relaxin, H2 relaxin and R3(BΔ23–27)R/I5 acting at the relaxin family peptide receptor 3 (RXFP3)
Authors: Kocan M , Sarwar M , Hossain M A , Wade J D , Summers R J
Published: February 2014

Background and Purpose

Relaxin family peptide receptor 3 (RXFP3) is expressed in brain areas important for processing sensory information and feeding, suggesting that it may be a target for anti‐anxiety and anti‐obesity drugs. We examined the effects of H3 relaxin, the biased agonist H2 relaxin and the antagonist, R3(BΔ23–27)R/I5, on RXFP3 signalling to establish their suitability as tools to assess the physiological roles of RXFP3.

Experimental Approach

The signalling profile of the RXFP3 ligands was determined using reporter gene assays, multiplexed signalling assays and direct examination of receptor–G protein and receptor–β‐arrestin interactions using BRET.

Key Results

H2 relaxin activated p38MAPK and ERK1/2 with lower efficacy than H3 relaxin, but had similar efficacy for JNK1/2 phosphorylation. H2 or H3 relaxin activation of p38MAPK, JNK1/2 or ERK1/2 involved Pertussis toxin‐sensitive G‐proteins. R3(BΔ23–27)R/I5 blocked H3 relaxin AP‐1 reporter gene activation, but not H2 relaxin AP‐1 activation or H3 relaxin NF‐κB activation. R3(BΔ23–27)R/I5 activated the SRE reporter, but did not inhibit either H2 or H3 relaxin SRE activation. R3(BΔ23–27)R/I5 blocked H3 relaxin‐stimulated p38MAPK and ERK1/2 phosphorylation, but was a weak partial agonist for p38MAPK and ERK1/2 signalling. p38MAPK activation by R3(BΔ23–27)R/I5 was G protein‐independent. H3 relaxin‐activated RXFP3 interacts with Gαi2, Gαi3, GαoA and GαoB whereas H2 relaxin or R3(BΔ23–27)R/I5 induce interactions only with Gαi2 or GαoB. Only H3 relaxin promoted RXFP3/β‐arrestin interactions that were blocked by R3(BΔ23–27)R/I5.

Conclusion and Implications

Understanding signalling profile of drugs acting at RXFP3 is essential for development of therapies targeting this receptor.
GSK‐3β inhibition promotes early engraftment of ex vivo‐expanded haematopoietic stem cells
Authors: Dolnikov A. , Xu N. , Shen S. , Song E. , Holmes T. , Klamer G. , O'Brien T. A.
Published: February 2014

Objectives

Umbilical cord blood (UCB) is a source of stem cells used for allogeneic transplantation, in addition to bone marrow and peripheral blood. Limited numbers of stem cells in a single UCB unit is associated with slow haematopoietic recovery and high risk of graft failure, particularly in adult patients. UCB stem cells can be expanded ex vivo; however, rapid differentiation reduces their regenerative potential. We have recently shown that Wnt/β‐catenin signalling is down‐regulated in ex vivo‐expanded stem cells; therefore, we propose that re‐activation of Wnt signalling using GSK‐3β inhibition may act to improve regenerative potential of these ex vivo‐expanded stem cells.

Materials and methods

Immunocompromised mice were employed in transplantation studies to determine stem‐cell engraftment. Flow cytometry was used to phenotype the engrafted human cells. Retroviral gene transfer was used to examine the role of Myc gene up‐regulated by GSK‐3β inhibition, in ex vivo‐expanded stem cells.

Results

Treatment with GSK‐3β inhibitor, 6‐bromoindirubin 3′‐oxime (BIO) improved early human cell engraftment in the mice and elevated the numbers of myeloid progenitor cells in cytokine‐stimulated culture. BIO up‐regulated β‐catenin and c‐myc in ex vivo‐expanded stem cells. Ectopic expression of Myc acted to increase clonogenic potential and to delay differentiation of haematopoietic progenitor cells, suggesting the potential mechanism to improve regenerative potential of ex vivo‐expanded grafts.

Conclusions

Pharmacological inhibition of GSK‐3β provided a novel approach to improve early engraftment of ex vivo‐expanded haematopoietic progenitor cells.
Cutaneous lymphatic malformation characterized by swelling of digits: a report of six cases
Authors: Wang Lei , Gao Tianwen , Wang Gang
Published: February 2014

Background

Cutaneous lymphatic malformations represent a group of heterogeneous diseases. In clinical practice, some cases of cutaneous lymphatic malformation have been found to differ from the well‐characterized entities, and are difficult to classify.

Objective

To report the clinical, histopathological and immunohistochemical characteristics of six cases of lymphatic malformation characterized by swelling of the digits.

Methods

Six patients with swelling of the digits were included in this study. Histopathological examination and immunohistochemical staining of CD31, D2‐40, Prox1, Wilms tumor 1 (WT‐1) and human herpesvirus‐8 (HHV‐8) were performed for all cases.

Results

All cases were congenital lesions and presented as swelling of single or multiple digits. Histopathologically, the lesions showed proliferation of small‐to‐medium‐sized vessels in the dermis and subcutaneous tissue. These abnormal vessels were positive for CD31, D2‐40 and Prox1, and negative for WT‐1 and HHV‐8.

Conclusion

The six cases reported herein represent a specific cutaneous lymphatic malformation different from previously reported entities.
Vemurafenib‐induced interface dermatitis manifesting as radiation‐recall and a keratosis pilaris‐like eruption
Authors: Braunstein Inbal , Gangadhar Tara C. , Elenitsas Rosalie , Chu Emily Y.
Published: February 2014

Vemurafenib is a specific inhibitor of the V600E mutated BRAF protein kinase used for the treatment of unresectable or metastatic melanoma harboring this mutation. Multiple predictable side effects have been described with use of this targeted therapy, and implicate BRAF and mitogen activated protein kinase (MAPK) signaling pathways in their pathogenesis. Herein, we report the novel finding of an interface dermatitis in radiation recall and a keratosis pilaris‐like clinical reaction in a patient treated with vemurafenib.
Role of selective peroxisome proliferator‐activated receptor modulators in managing cardiometabolic disease: tale of a roller‐coaster
Authors: Sahebkar A. , Watts G. F.
Published: February 2014

Atherogenic dyslipidaemia is a hypertriglyceridaemic phenotype, associated with increased plasma concentrations of small, dense low‐density lipoprotein (sdLDL) particles, triglyceride‐rich lipoproteins (TRLs) and non‐high‐density lipoprotein cholesterol (non‐HDL‐C), and low HDL particles. Atherogenic dyslipidaemia commonly accompanies several metabolic disorders including type 2 diabetes, metabolic syndrome, non‐alcoholic fatty liver disease (NAFLD) and obesity, and increases the risk of cardiovascular disease (CVD). Statins significantly lower plasma LDL‐cholesterol and CVD risk, but their efficacy in correcting hypertriglyceridaemia is limited. Untreated hypertriglyceridaemia may partly account for residual risk of CVD in patients on statin treatment. Activators of peroxisome proliferator‐activated receptor (PPAR) α are more effective in correcting TRL and HDL metabolism than statins. A dual PPARα/δ agonist (GFT‐505) may have additional benefits on hepatic insulin sensitivity, steatosis and fibrosis. Selective PPAR modulators (SPPARMs) have the potential of increasing therapeutic specificity, while reducing unwanted off‐target effects. This review provides a summary of findings from randomized controlled trials of the efficacy of fenofibrate (as the most widely used PPARα agonist) and novel selective PPARα (ABT‐335 and k‐877), PPARα/δ (GFT‐505), PPARδ (MBX‐8025 and GW501516) and PPARγ (INT131) agonists in the treatment of atherogenic dyslipidaemia and NAFLD.
Role of 18F‐FDG‐PET/CT in the management of Burkitt lymphoma
Authors: Carrillo‐Cruz Estrella , Marín‐Oyaga Víctor A. , Rodríguez María Solé , Borrego‐Dorado Isabel , de la Cruz Vicente Fátima , Quiroga Cantero Eduardo , Pérez Marina Manzanares , Capote Francisco J. , Ramírez Sánchez María J. , Espigado Tocino Ildefonso , Pérez‐Vega Herminia , Vázquez‐Albertino Ricardo , Pérez‐Simón Jose A.
Published: February 2014

Burkitt lymphoma (BL) is highly FDG‐avid even though its usefulness in the management of these patients is still controversial.

Aim

We analyzed the role of positron emission tomography/computerized tomography (PET/CT) in staging newly diagnosed patients with BL and evaluating disease after first‐line chemotherapy.

Methods

Fifty‐two PET/CTs were performed in 32 patients (20 at diagnosis, 27 after treatment, five to monitor residual disease). Involved areas were retrospectively compared with those observed in contrast‐enhanced CT.

Results

Discrepancies were found in 64.7% of patients for whom results of both tests at diagnosis were available (n = 17), most of them involving extranodal sites. Regarding response assessment, discrepancies were observed in 38% of patients with both tests (5/13): residual masses detected by CT with negative PET/CT. Of 27 patients with post‐treatment PET/CT, 22 were in complete remission whereas one true‐positive and four false‐positive lesions (two nodal and two extranodal) were detected. With a median follow‐up of 27 months, 22 patients with negative PET/CT did not relapse. Thus, negative predictive value (NPV) was 100%. With respect to positive predictive value (PPV), one of five patients with positive assays after treatment died due to progression while the remaining four had false‐positive lesions. Nevertheless, for these four patients, mean SUVmax at nodal sites was 4.1 vs. 14.9 at diagnosis, while mean SUVmax at extranodal sites was 3.8 vs. 12.1. Thus, with a cutoff value for SUVmax <66% of that observed at diagnosis, PPV was also 100%.

Conclusion

More accurate staging can be achieved using PET/CT. NPV reaches 100%, and using a ΔSUV <66%, a high PPV is also observed.
Screening of major depression in epilepsy: The Neurologic Depression Disorders Inventory in Epilepsy‐Spanish version (Argentina)
Authors: Thomson Alfredo E. , Calle Analía , Fontela María E. , Yepez Luis , Muñoz Giacomelli Francisco , Jáuregui Agustín , Racosta Juan M. , Kanner Andrés M.
Published: February 2014

Objectives

To validate and translate the English version of the Neurologic Depression Disorders Inventory in Epilepsy (NDDI‐E) into Spanish as a screening instrument for major depressive episodes (MDE) for patients with epilepsy from Argentina and Uruguay.

Methods

One hundred fifty‐five consecutive outpatients with epilepsy participated in this study. The module of MDE of the MINI International Neuropsychiatric Instrument (MINI Plus version) was used as the gold standard against which the translated version of the NDDI‐E was validated.

Results

Among the 155 patients, 25 (16%) met Diagnostic and Statistical Manual, Fourth Edition (DSM‐IV) criteria for MDE according to the MINI. With a total score of >15, The NDDI‐E identified MDE with an 80% sensitivity, 90% specificity, 60% positive predictive value, and 95.5% negative predictive value.

Significance

These data indicate that the Spanish version of the NDDI‐E can reliably identify MDE in patients with epilepsy from Argentina and Uruguay.
Developmental brain abnormalities in tuberous sclerosis complex: A comparative tissue analysis of cortical tubers and perituberal cortex
Authors: Ruppe Véronique , Dilsiz Pelin , Reiss Carol Shoshkes , Carlson Chad , Devinsky Orrin , Zagzag David , Weiner Howard L. , Talos Delia M.
Published: February 2014

Objective

Genetic loss of Tsc1/Tsc2 function in tuberous sclerosis complex (TSC) results in altered mammalian target of rapamycin (mTOR) signaling and abnormal brain development. Although earlier studies have focused on characterization of cortical tubers, in this study we sought to examine the unique cellular and molecular features of the perituberal cortex in order to better understand its contribution to epileptogenesis, cognitive dysfunction, and autism.

Methods

Standard histologic and immunohistochemical labeling was used to assess structural abnormalities and cell‐specific pattern of mTORC1 activation in surgically resected cortical tubers and perituberal cortex. Western blotting was performed to quantify the expression of the mTORC1 and mTORC2 biomarkers phospho‐S6 (Ser235/236), phospho‐S6 (Ser240/244), and phospho‐Akt (Ser473), in addition to evaluating the differential expression levels of several neuronal and glial‐specific proteins in tubers and peritubers, as compared to non‐TSC epilepsy specimens.

Results

Tubers demonstrated mild to severe disruption of cortical lamination, the presence of pS6‐positive dysplastic neurons and giant cells, an overall increase in mTORC1 and a decrease in mTORC2 activity, increased axonal connectivity and growth, and hypomyelination. Perituberal cortex presented similar histologic, immunohistochemical, and molecular features; however, they were overall milder. Axonal growth was specific for TSC and was negatively correlated with deficient myelination.

Significance

Our results show an extension of cellular dysplasia and dysregulated mTOR signaling in the perituberal tissue, and demonstrate for the first time aberrant connectivity in human TSC brain. This study provides new insights into the pathophysiology of neurologic dysfunction associated with TSC and supports the intrinsic epileptogenicity of normal‐appearing perituberal cortex.

A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.
Combined influence of expertise and fatigue on riding strategy and horse–rider coupling during the time course of endurance races
Authors: Viry S. , De Graaf J. B. , Frances J.‐P. , Berton E. , Laurent M. , Nicol C.
Published: February 2014

Reasons for performing study

The relationship between the biomechanical horse–rider interaction and endurance race performance requires further investigation.

Objectives

To characterise, both quantitatively and qualitatively, elite and advanced horse–rider dyads on the basis of the biomechanical horse–rider interaction during endurance races.

Study design

Five elite and 5 advanced horse–rider dyads were recorded duringCEI*/CEI** endurance races using 2 synchronised triaxial accelerometers each placed close to horse and rider centres of mass.

Methods

For each horse–rider dyad, analyses focused on the vertical displacements of horse and rider per stride. This allowed quantification of the proportional use of each gait and riding technique per loop. The quality of the biomechanical horse–rider interaction was examined through the relative phases (RP) of their respective vertical displacement minima. Instantaneous speed and rider heart rates were recorded using a global positioning system device/heart rate monitor.

Results

All dyads predominantly used 2 riding techniques per gait. The 2‐point trot proportion was limited in both groups (11%). Throughout the race, the advanced horse–rider dyads showed a global stability in speed, in the proportion of 4 combinations of gait and riding techniques and in meanRP. However, the elite horse–rider dyads initially had higher meanRPvalues (P<0.01), and from mid‐race to the end an increasing proportion of sitting canter, with associated increases in racing speed (P<0.001) and in mean heart rate (P<0.01). IntradyadRPvariability in 2‐point canter increased in both groups (P<0.01).

Conclusions

Accelerometers are a valuable tool to follow the quantitative and qualitative trends of the biomechanical horse–rider interaction during international endurance races. The overall results emphasise the influence of the level of expertise on the adopted gait and riding techniques, thus influencing the racing speed. It remains to be established whether fatigue and/or strategy underlie our observations.
Stochastic galactokinase expression underlies GAL gene induction in a GAL3 mutant of Saccharomyces cerevisiae
Authors: Kar Rajesh Kumar , Qureshi Mohd. Tanvir , DasAdhikari Akshay Kumar , Zahir Taiyeb , Venkatesh Kareenhalli V. , Bhat Paike Jayadeva
Published: February 2014

GAL1 and GAL3 are paralogous signal transducers that functionally inactivate Gal80p to activate the Gal4p‐dependent transcriptional activation of GAL genes in Saccharomyces cerevisiae in response to galactose. Unlike a wild‐type strain, the gal3∆ strain shows delayed growth kinetics as a result of the signaling function of GAL1. The mechanism ensuring that GAL1 is eventually expressed to turn on the GAL switch in the gal3∆ strain remains a paradox. Using galactose and histidine growth complementation assays, we demonstrate that 0.3% of the gal3∆ cell population responds to galactose. This is corroborated by flow cytometry and microscopic analysis. The galactose responders and nonresponders isolated from the galactose‐adapted population attain the original bimodal state and this phenotype is found to be as hard wired as a genetic trait. Computational analysis suggests that the log‐normal distribution in GAL4 synthesis can lead to bimodal expression of GAL80, resulting in the bimodal expression of GAL genes. Heterozygosity at the GAL80 but not at the GAL1, GAL2 or GAL4 locus alters the extent of bimodality of the gal3∆ cell population. We suggest that the asymmetric expression pattern between GAL1 and GAL3 results in the ability of S. cerevisiae to activate the GAL pathway by conferring nongenetic heterogeneity.