bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adjuvant radiotherapy in node positive prostate cancer patients: a debate still on. when, for whom?
Authors: Marvaso Giulia , Montesano Marianna , Corrao Giulia , De Angelis Simone P. , Gandini Sara , Mazzola Giovanni C. , Augugliaro Matteo , Franzetti Jessica , Zerini Dario , Pepa Matteo , Luzzago Stefano , Mistretta Francesco A. , Musi Gennaro , Nolè Franco , De Cobelli Ottavio , Orecchia Roberto , Jereczek‐Fossa Barbara A. 
Published: September 2020

ObjectiveTo evaluate the impact of adjuvant radiotherapy (aRT) in patients with prostate cancer (PCa) found to have pathological positive lymph nodes (pN1s) after radical prostatectomy (RP) and extended pelvic lymph node dissection (ePLND) with regard to distant recurrence‐free survival (RFS), according to both main tumour pathological characteristics and number of positive lymph nodes. Biochemical RFS, local RFS, overall survival (OS) and acute and late toxicity were assessed as secondary endpoints.Patients and MethodsA retrospective cohort of 187 consecutive patients with pN1 PCa were treated with aRT at the IEO, European Institute of Oncology IRCCS, Milan, Italy. aRT on the tumour bed and pelvis was administered within 6 months of RP. Androgen deprivation therapy was administered according to the guidelines. Univariate and multivariate Cox regression analyses predicting biochemical RFS, local RFS, distant RFS and OS rates were performed to assess whether the number of pN1s represented an independent prognostic factor. The Youden index was computed to find the optimal threshold for the number of pN1s able to discriminate between patients with or without biochemical and clinical relapse.ResultsAt 5 years, local RFS, distant RFS, biochemical RFS and OS were 68%, 71%, 56% and 94%, respectively. The median follow‐up was 49 months. The number of pN1s was significantly associated with biochemical RFS, local RFS and distant RFS. The best threshold for discriminating between patients with or without biochemical and clinical relapse was five pN1s. In multivariate analyses, the number of pN1s was confirmed to be an independent predictor of biochemical RFS, local RFS and distant RFS, but not of OS. Multivariate analyses also showed an increased risk of biochemical relapse for increasing values of initial prostate‐specific antigen and for patients with tumour vascular invasion. Local and distant RFS were also inversely correlated with significantly reduced risk for International Society of Urological Pathology grade group <3 (group 1 or 2 compared to group 3).ConclusionsOur data confirmed the encouraging outcomes of patients with pN1 PCa treated with adjuvant treatments and the key role represented by the number of pN1s in predicting biochemical RFS, clinical RFS and distant RFS. Large prospective cohort studies and randomized clinical trials are needed to confirm these results and to identify the subgroup of patients with pN1 PCa who would most benefit from aRT.
Palaeoenvironmental conditions during MIS 6/MIS 5 transition recorded in speleothems from the Tatra Mountains
Authors: Pawlak Jacek , Błaszczyk Marcin , Hercman Helena , Matoušková Šárka 
Published: September 2020

We present 100‐ka multiproxy palaeoenvironmental records from three stalagmites collected in different caves located in the Tatra Mountains on the Polish/Slovakian border. A combination of three records from one mountain region helps to estimate local factors controlling the recorded proxies and separate them from regional/global patterns. The studied stalagmites react to the same environmental changes in different ways due to the differences in their local settings. Furthermore, the analysed records show environmental changes from relatively cold and dry climates to interglacial conditions of MIS 5e. One episode of a colder climate during the MIS 6/MIS 5e transition similar to Dryas periods is observed in all studied stalagmites. The δ18O record from the MAG‐1 stalagmite is most similar to the GRIP record. During the MIS 5e, the δ18O record from the MAG‐1 stalagmite e xhibits a pattern similar to the records from the western part of the European continent. This finding suggests that the Atlantic Ocean was an important source of moisture for the region. The observed rapid change of δ18O, δ13C, Sr and Si proxies from the MAG‐1 and Dz‐1 stalagmites after 109 ka are potentially related to a drier and colder climate.
Rho kinase inhibitor fasudil reduces l‐DOPA‐induced dyskinesia in a rat model of Parkinson's disease
Authors: Lopez‐Lopez Andrea , Labandeira Carmen M. , Labandeira‐Garcia Jose L. , Muñoz Ana 
Published: September 2020

Background and PurposeRho kinase (ROCK) activation is involved in neuroinflammatory processes leading to progression of neurodegenerative diseases such as Parkinson's disease. Furthermore, ROCK plays a major role in angiogenesis. Neuroinflammation and angiogenesis are mechanisms involved in developing l‐DOPA‐induced dyskinesias (LID). However, it is not known whether ROCK plays a role in LID and whether ROCK inhibitors may be useful against LID.Experimental ApproachIn rats, we performed short‐ and long‐term dopaminergic lesions using 6‐hydroxydopamine and developed a LID model. Effects of dopaminergic lesions and LID on the RhoA/ROCK levels were studied by western blot, real‐time PCR analyses and ROCK activity assays in the substantia nigra and striatum. The effects of the ROCK inhibitor fasudil on LID were particularly investigated.Key ResultsShort‐term 6‐hydroxydopamine lesions increased nigrostriatal RhoA/ROCK expression, apparently related to the active neuroinflammatory process. However, long‐term dopaminergic denervation (completed and stabilized lesions) led to a decrease in RhoA/ROCK levels. Rats with LID showed a significant increase of RhoA and ROCK expression. The development of LID was reduced by the ROCK inhibitor fasudil (10 and 40 mg·kg−1), without interfering with the therapeutic effect of l‐DOPA. Interestingly, treatment of 40 mg·kg−1 of fasudil also induced a significant reduction of dyskinesia in rats with previously established LID.Conclusion and ImplicationsThe present results suggest that ROCK is involved in the pathophysiology of LID and that ROCK inhibitors such as fasudil may be a novel target for preventing or treating LID. Furthermore, previous studies have revealed neuroprotective effects of ROCK inhibitors.
What skeletal muscle has to say in amyotrophic lateral sclerosis: Implications for therapy
Authors: Manzano Raquel , Toivonen Janne Markus , Moreno‐Martínez Laura , de la Torre Miriam , Moreno‐García Leticia , López‐Royo Tresa , Molina Nora , Zaragoza Pilar , Calvo Ana Cristina , Osta Rosario 
Published: September 2020

Amyotrophic lateral sclerosis (ALS) is an adult onset disorder characterized by progressive neuromuscular junction (NMJ) dismantling and degeneration of motor neurons leading to atrophy and paralysis of voluntary muscles responsible for motion and breathing. Except for a minority of patients harbouring genetic mutations, the origin of most ALS cases remains elusive. Peripheral tissues, and particularly skeletal muscle, have lately demonstrated an active contribution to disease pathology attracting a growing interest for these tissues as therapeutic targets in ALS. In this sense, molecular mechanisms essential for cell and tissue homeostasis have been shown to be deregulated in the disease. These include muscle metabolism and mitochondrial activity, RNA processing, tissue‐resident stem cell function responsible for muscle regeneration, and proteostasis that regulates muscle mass in adulthood. This review aims to compile scientific evidence that demonstrates the role of skeletal muscle in ALS pathology and serves as reference for development of novel therapeutic strategies targeting this tissue to delay disease onset and progression.LINKED ARTICLESThis article is part of a themed issue on Recent advances in ALS pathogenesis and therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.6/issuetoc
Glycogen synthase kinase‐3β participates in acquired resistance to gemcitabine in pancreatic cancer
Authors: Uehara Masahiro , Domoto Takahiro , Takenaka Satoshi , Bolidong Dilireba , Takeuchi Osamu , Miyashita Tomoharu , Minamoto Toshinari 
Published: September 2020

AbstractAcquisition of resistance to gemcitabine is a challenging clinical and biological hallmark property of refractory pancreatic cancer. Here, we investigated whether glycogen synthase kinase (GSK)‐3β, an emerging therapeutic target in various cancer types, is mechanistically involved in acquired resistance to gemcitabine in human pancreatic cancer. This study included 3 gemcitabine‐sensitive BxPC‐3 cell‐derived clones (BxG30, BxG140, BxG400) that acquired stepwise resistance to gemcitabine and overexpressed ribonucleotide reductase (RR)M1. Treatment with GSK3β‐specific inhibitor alone attenuated the viability and proliferation of the gemcitabine‐resistant clones, while synergistically enhancing the efficacy of gemcitabine against these clones and their xenograft tumors in rodents. The gemcitabine‐resensitizing effect of GSK3β inhibition was associated with decreased expression of RRM1, reduced phosphorylation of Rb protein, and restored binding of Rb to the E2 transcription factor (E2F)1. This was followed by decreased E2F1 transcriptional activity, which ultimately suppressed the expression of E2F1 transcriptional targets including RRM1, CCND1 encoding cyclin D1, thymidylate synthase, and thymidine kinase 1. These results suggested that GSK3β participates in the acquisition of gemcitabine resistance by pancreatic cancer cells via impairment of the functional interaction between Rb tumor suppressor protein and E2F1 pro‐oncogenic transcription factor, thereby highlighting GSK3β as a promising target in refractory pancreatic cancer. By providing insight into the molecular mechanism of gemcitabine resistance, this study identified a potentially novel strategy for pancreatic cancer chemotherapy.
Epigenetic methylation in Eosinophilic Esophagitis: Molecular ageing and novel biomarkers for treatment response
Authors: Jensen Elizabeth T. , Langefeld Carl D. , Zimmerman Kip D. , Howard Timothy D. , Dellon Evan S. 
Published: September 2020

AbstractBackgroundTreatment failure in eosinophilic esophagitis (EoE) is common. We hypothesize that DNA methylation differs between patients by treatment response to topical steroids (oral viscous budesonide), thus offering the potential to inform targeting therapies.ObjectiveWe sought to identify differentially methylated sites and affiliated genes in pre‐treatment oesophageal cells between responders and non‐responders and test for accelerated epigenetic ageing in oesophageal cells of EoE patients.MethodsDNA was extracted from prospectively collected and biobanked oesophageal biopsies from 36 Caucasian treatment naïve EoE patients at diagnosis. Methylation assays were completed using the Infinium HumanMethylation450 BeadChip. Normalizedβvalues for each CpG site were tested (t test) for differential methylation. Further, 353 CpG probes were used to estimate epigenetic age for each patient and a linear regression model tested whether chronologic age and epigenetic age differed. Epigenetic age results were confirmed in an independent cohort of healthy controls.ResultsEighteen CpG sites were differentially methylated by treatment response (P < .00001). The mean epigenetic age and chronological age were 56.1 ± 11.1 and 36.7 ± 12.3 years, a mean age difference of 19.3 ± 5.2 years (P < .0001); accelerated ageing was not observed in the oesophageal cells of healthy controls.Conclusions and clinical relevanceEoE patients that respond versus do not respond to treatment have differences in their methylation profile, including enrichment of genes in pathways consistent with cellular injury and repair due to environmental stress and cell adhesion and barrier integrity. EoE also appears to accelerate cellular ageing. Whether treatment can arrest or reverse accelerated epigenetic ageing and the implications for long‐term disease progression is important areas for future research.
Efficacy, safety, and tolerability of adjunctive perampanel in patients from China with focal seizures or generalized tonic‐clonic seizures: Post hoc analysis of phase III double‐blind and open‐label extension studies
Authors: Weiping Liao , Dong Zhou , Zhen Hong , Patten Anna , Dash Amitabh , Malhotra Manoj 
Published: September 2020

Abstract
AimsThis post hoc analysis assessed the efficacy and safety/tolerability of adjunctive perampanel in patients from China (aged ≥12 years) with focal seizures (FS), with/without focal to bilateral tonic‐clonic seizures (FBTCS), or generalized tonic‐clonic seizures (GTCS).MethodsStudy centers in China were identified using data from five double‐blind, randomized, phase III studies of adjunctive perampanel (2‐12 mg/day) and their open‐label extensions (OLEx). Efficacy assessments included median percent reduction in seizure frequency per 28 days, and 50% and 75% responder and seizure‐freedom rates. Safety/tolerability assessments included monitoring of treatment‐emergent adverse events (TEAEs).ResultsOverall, 277 patients (placebo, n = 79; perampanel, n = 198) were included in the double‐blind safety analysis set. The full analysis set comprised 274 patients (FS, n = 238 [placebo, n = 60; perampanel, n = 178]; FBTCS, n = 120 [placebo, n = 31; perampanel, n = 89]; GTCS, n = 36 [placebo, n = 18; perampanel, n = 18]). Median percent reductions in seizure frequency for placebo vs perampanel were as follows: 16.6% vs 32.4% (FS; P < 0.05) and 39.1% vs 48.2% (FBTCS; not significant [NS]) at 4‐12 mg/day, and 37.9% vs 82.6% (GTCS; NS) at 8 mg/day; 50% responder rates were 31.7% vs 37.4% (FS; NS), 48.4% vs 51.9% (FBTCS; NS), and 33.3% vs 61.1% (GTCS; NS), respectively. Seizure‐freedom rates were 1.7% vs 9.2%, 16.1% vs 25.3%, and 16.7% vs 44.4%, respectively (all NS). Overall, 262 patients entered the OLEx (FS, n = 228; GTCS, n = 34). Perampanel was efficacious for up to four years for FS and FBTCS and up to two years for GTCS. Across the double‐blind and OLEx studies, TEAEs were reported in 65.7% and 81.3% of perampanel‐treated patients, respectively; the most common was dizziness. Efficacy and safety/tolerability outcomes were generally similar between Chinese and non‐Chinese patients.ConclusionAdjunctive perampanel (up to 12 mg/day) may be a suitable treatment for Chinese patients with FS, with/without FBTCS, or GTCS, with similar efficacy and safety/tolerability compared to non‐Chinese patients.
Treatment of faecal incontinence with autologous expanded mesenchymal stem cells: results of a pilot study
Authors: de la Portilla Fernando , Guerrero José Luis , Maestre Maria Victoria , Leyva Laura , Mera Santiago , García‐Olmo Damián , Rodríguez Antonio , Mata Rosario , Lora Fabiola 
Published: September 2020

AbstractAimManagement of faecal incontinence (FI) remains challenging because no definitive optimal treatment for this condition has yet been determined. Regenerative medicine could be an attractive therapeutic alternative for treating FI. Here, we aimed to determine the safety and feasibility of autologous expanded mesenchymal stem cells derived from adipose tissue (AdMSCs) in the treatment of patients diagnosed with structural FI.MethodThis was a randomized, multicentre, triple‐blinded, placebo‐controlled pilot study conducted at four sites in Spain with 16 adults with FI and a sphincter defect. Autologous AdMSCs were obtained from patients from surgically excised adipose tissue. These patients were intralesionally infused with a single dose of 4 × 107 AdMSCs or a placebo while under anaesthesia. We assessed the safety and feasibility of the treatment as the cumulative incidence of adverse events and the treatment efficacy using the Cleveland Clinic Faecal Incontinence Score, Faecal Incontinence Quality of Life score and Starck criteria to classify sphincter defects and anorectal physiology outcomes.ResultsAdipose tissue extraction, cell isolation and intralesional infusion procedures were successful in all the patients. There was only one adverse event connected to adipose tissue extraction (a haematoma), and none was associated with the injection procedure. There were no significant differences in any of the assessed clinical, manometric or ultrasonographic parameters.ConclusionThis study indicates that this infusion procedure in the anal sphincter is feasible and safe. However, it failed to demonstrate efficacy to treat patients with structural FI.
Associations between socio‐environmental factors and landscape‐scale biodiversity recovery in naturally regenerating tropical and subtropical forests
Authors: Crouzeilles Renato , Maurenza Daniel , Prieto Pablo V. , Barros Felipe S. M. , Jakovac Catarina , Ferreira Mariana S. , Chazdon Robin L. , Lindenmayer David B. , Brancalion Pedro H. S. , Ceccon Eliane , Adams Cristina , Lazos‐Chavero Elena , Monteiro Lara , Junqueira André B. , Strassburg Bernardo B. N. , Guariguata Manuel R. 
Published: September 2020

AbstractNatural regeneration is key for large‐scale forest restoration, yet it may lead to different biodiversity outcomes depending on socio‐environmental context. We combined the results of a global meta‐analysis to quantify how biodiversity recovery in naturally regenerating forests deviates from biodiversity values in reference old‐growth forests, with structural equation modeling, to identify direct and indirect associations between socioeconomic, biophysical and ecological factors and deviation in biodiversity recovery at a landscape scale. Low deviation within a landscape means higher chances of multiple sites in naturally regenerating forests successfully recovering biodiversity compared to reference forests. Deviation in biodiversity recovery was directly negatively associated with the percentage of cropland, forest cover, and positively associated with the percentage of urban areas in the surrounding landscape. These three factors mediated the indirect associations with rural population size, recent gross deforestation, time since natural regeneration started, mean annual temperature, mean annual water deficit, road density, land opportunity cost, percentage cover of strictly protected forest areas, and human population variation in the surrounding landscape. We suggest that natural forest restoration should be prioritized in landscapes with both low socioeconomic pressures on land use conversion to pasturelands and urban areas, and high percentage of forest cover.
Entwicklung und Evaluation eines interprofessionellen Lehrkonzepts zum modernen Wundmanagement
Authors: Bergendahl Lukas , Werner Felix , Schmidt Anita , Ronicke Moritz , Renner Regina , Erfurt‐Berge Cornelia 
Published: September 2020

ZusammenfassungHintergrund und ZielsetzungZiel dieser Arbeit war die Konzeptionierung und Evaluation einer neuartigen interprofessionellen Lehrveranstaltung zum Thema Wundmanagement.MethodenNach einer Überprüfung der Ist‐Situation mittels Befragung von Studierenden der Humanmedizin in der Hauptvorlesung Dermatologie wurde ein 150 Minuten umfassendes Lehrkonzept mit praktischen Inhalten zum Thema Wundmanagement erstellt und innerhalb der bereits etablierten studentischen Übungseinrichtung interprofessionell angeboten. Die Kursteilnehmer wurden vor und nach Kursteilnahme mit Hilfe von Fragebögen hinsichtlich ihres subjektiven Kenntnisstandes befragt.ErgebnisseDie Befragung an 190 Studierenden ergab einen deutlichen Wunsch nach praktischer Wissensvermittlung zum Thema Wundmanagement. Bislang konnten 120 Teilnehmer (54,8 % Studierende der Humanmedizin, 45,2 % Auszubildende zum/zur Gesundheits‐ und Krankenpfleger/in) an dem neuen interprofessionellen Kursangebot teilnehmen. Es fand sich eine hohe Nachfrage des angebotenen Konzeptes sowohl von Studierenden als auch Auszubildenden. In allen Bereichen (Diagnostik, Therapie, Anwendung von Wundauflagen, Wunddebridement) konnte ein signifikanter Wissenszuwachs durch die Kursteilnahme erreicht werden.SchlussfolgerungenDie Versorgung von Patienten mit chronischen Wunden ist aufgrund der hohen Relevanz für die spätere Praxis für alle Medizinstudierenden von Bedeutung. Gerade der Fachbereich Dermatologie kann für ein besseres Verständnis und auch praktische Kenntnisse in der Wundversorgung sorgen, indem den Bedürfnissen der Studierenden nachgekommen wird und neue Lehrangebote geschaffen werden. Die Thematik bietet dabei beste Voraussetzungen für ein interprofessionelles Lernen.
Weak relationships of parasite infection with sexual and life‐history traits in wild‐caught Texas field crickets (Gryllus texensis)
Authors: Worthington Amy M. , Kelly Clint D. , Proctor Heather 
Published: September 2020

Sex differences in immune investment and infection rate are predicted due to the divergent life histories of males and females, where females invest more toward immunity due to the fitness consequences of a reduced lifespan and males allocate less toward immunity due to increased resource investment in traits critical to sexual selection. Consequently, males are expected to fight infection less adeptly, resulting in higher parasite loads relative to females across all taxa.
Wild animals rarely face a single parasite within their given environment, yet nearly all studies on sex‐biased infection rates have focused on a single host–parasite relationship. Here, we investigate how simultaneous natural infections of ecto‐ and endosymbionts (i.e. both parasitic and phoretic taxa) correlate with sex biases in host immune response and reproductive investment in a field‐caught cricket, Gryllus texensis.
Our comprehensive analysis found no significant sex differences in two measures of immune response (melanization and nodulation), and found no strong evidence of a sex bias in the prevalence or intensity of parasitism by the three most common parasites infecting wild G. texensis field crickets (Eutrombidiidae, gregarines, and nematodes).
Two traits related to female fitness, egg number and egg size, showed no relation to parasitic infection; however, males having wider heads and poorer body condition were significantly more infected by eutrombidiid mites, gregarines, and nematodes.
Despite frequent predictions of male‐biased parasitism in the literature, our results concur with many other studies indicating that the divergent life histories of males and females alone are not sufficient to explain natural infection rates in wild insects.
The positive attitude approach for teaching in higher education: An untrodden path for policy and practice
Authors: Miočić Ivana , Brajdić Vuković Marija , Ledić Jasminka 
Published: September 2020

AbstractThis article reports on a study in which a new conceptual framework for fostering a positive attitude towards teaching in higher education (PATTHE) was developed. The PATTHE framework builds on a holistic four‐dimensional theoretical concept and is not limited by the specificity of teaching within a particular discipline or national higher education context. The four dimensions of PATTHE pertain to (a) emotional dimension, (b) professional development, (c) constructivist approaches to teaching, and (d) the teaching and research nexus; all of which are relevant for empowering quality teaching at personal, institutional and/or national higher education policy levels. The purpose of our study was to test and analyse this conceptual framework. Creative qualitative research methods were used including identification of keywords, evoking participant opinions through visual materials, reactions to vignettes, and by documenting discussions regarding the proposed PATTHE conceptual framework. A purposive and critically informed approach was used for the selection of twelve higher education experts as research participants. Responses from the selected education developers were collected through an online protocol system. Research results revealed that participant reflections on a positive attitude towards teaching showed a high level of agreement with the proposed conceptual framework; the proposed theoretical concept is thereby deemed well‐constructed and acceptable with minimal extensions.