bluuebunny/crossref_metadata_2025_split huggingface dataset:
Early results of localised, high-risk prostate cancer treated by moderate hypo-fractionation (70 Gy at 2·5 Gy per fraction): 5-year experiences of a moderate hypo-fractionation regimen
Authors: Tharavichitkul Ekkasit , Chakrabandhu Somvilai , Klunklin Pitchayaponne , Onchan Wimrak , Jia-Mahasap Bongkot , Meungwong Pooriwat , Nobnop Wannapha , Tippanya Damrongsak , Sripun Patumrat , Galalae Razvan M. , Chitapanarux Imjai 
Published: November 2019

AbstractBackground:Radiotherapy is one of the treatments used to treat prostate cancer, and dose escalation to 74–78 Gy in conventional fractionation is the standard regimen. Currently, according to the hypothesis of low alpha/beta ratio in prostate cancer cells, using hypo-fractionation has been reported in many publications with promising results. This retrospective study was designed to evaluate the implementation of a moderate hypo-fractionation regimen in high-risk prostate cancer in our division.Materials and Methods:Between 2012 and 2017, 40 patients with high-risk, localised prostate cancer were treated by a moderate hypo-fractionation regimen (70 Gy at 2·5 Gy per fraction) with intensity-modulated radiation therapy. The data related to treatment outcomes and toxicities were evaluated.Results:The mean PSA at diagnosis was 86·2 ng/mL (95% CI 49·9–122·4). Thirty-eight patients received long-term hormonal therapy. Fifty-two percent had a Gleason score of 8–10, and 65% had an initial PSA >20 ng/mL. The mean doses (in EQD2) to the D50% of PTV, D2% of organs at risk (bladder, rectum and bowels) were 80, 78·3, 76·4, and 50·2 Gy, respectively. Two patients had biochemical recurrence during the follow-up period.Conclusion:A moderate hypo-fractionation regimen (70 Gy at 2·5 Gy per fraction) is feasible. Our experience found that this regimen yields tolerable, acceptable toxicity profiles in high-risk, localised prostate cancer patients.
MOTIVATED PROOFS: WHAT THEY ARE, WHY THEY MATTER AND HOW TO WRITE THEM
Authors: MORRIS REBECCA LEA 
Published: November 2019

AbstractMathematicians judge proofs to possess, or lack, a variety of different qualities, including, for example, explanatory power, depth, purity, beauty and fit. Philosophers of mathematical practice have begun to investigate the nature of such qualities. However, mathematicians frequently draw attention to another desirable proof quality: being motivated. Intuitively, motivated proofs contain no “puzzling” steps, but they have received little further analysis. In this article, I begin a philosophical investigation into motivated proofs. I suggest that a proof is motivated if and only if mathematicians can identify (i) the tasks each step is intended to perform; and (ii) where each step could have reasonably come from. I argue that motivated proofs promote understanding, convey new mathematical resources and stimulate new discoveries. They thus have significant epistemic benefits and directly contribute to the efficient dissemination and advancement of mathematical knowledge. Given their benefits, I also discuss the more practical matter of how we can produce motivated proofs. Finally I consider the relationship between motivated proofs and proofs which are explanatory, beautiful and fitting.
Dynamic Accretion Beneath a Slow‐Spreading Ridge Segment: IODP Hole 1473A and the Atlantis Bank Oceanic Core Complex
Authors: Dick H. J. B. , MacLeod C. J. , Blum P. , Abe N. , Blackman D. K. , Bowles J. A. , Cheadle M. J. , Cho K. , Ciazela J. , Deans J. R. , Edgcomb V. P. , Ferrando C. , France L. , Ghosh B. , Ildefonse B. , John B. , Kendrick M. A. , Koepke J. , Leong J. A. M. , Liu C. , Ma Q. , Morishita T. , Morris A. , Natland J. H. , Nozaka T. , Pluemper O. , Sanfilippo A. , Sylvan J. B. , Tivey M. A. , Tribuzio R. , Viegas G. 
Published: November 2019

Abstract809 deep IODP Hole U1473A at Atlantis Bank, SWIR, is 2.2 km from 1,508‐m Hole 735B and 1.4 from 158‐m Hole 1105A. With mapping, it provides the first 3‐D view of the upper levels of a 660‐km2 lower crustal batholith. It is laterally and vertically zoned, representing a complex interplay of cyclic intrusion, and ongoing deformation, with kilometer‐scale upward and lateral migration of interstial melt. Transform wall dives over the gabbro‐peridotite contact found only evolved gabbro intruded directly into the mantle near the transform. There was no high‐level melt lens, rather the gabbros crystallized at depth, and then emplaced into the zone of diking by diapiric rise of a crystal mush followed by crystal‐plastic deformation and faulting. The residues to mass balance the crust to a parent melt composition lie at depth below the center of the massif—likely near the crust‐mantle boundary. Thus, basalts erupted to the seafloor from >1,550 mbsf. By contrast, the Mid‐Atlantic Ridge lower crust drilled at 23°N and at Atlantis Massif experienced little high‐temperature deformation and limited late‐stage melt transport. They contain primitive cumulates and represent direct intrusion, storage, and crystallization of parental MORB in thinner crust below the dike‐gabbro transition. The strong asymmetric spreading of the SWIR to the south was due to fault capture, with the northern rift valley wall faults cutoff by a detachment fault that extended across most of the zone of intrusion. This caused rapid migration of the plate boundary to the north, while the large majority of the lower crust to spread south unroofing Atlantis Bank and uplifting it into the rift mountains.
Partly Cloudy With a Chance of Lava Flows: Forecasting Volcanic Eruptions in the Twenty‐First Century
Authors: Poland Michael P. , Anderson Kyle R. 
Published: November 2019

AbstractA primary goal of volcanology is forecasting hazardous eruptive activity. Despite much progress over the last century, however, volcanoes still erupt with no detected precursors, lives and livelihoods are lost to eruptive activity, and forecasting the onsets of eruptions remains fraught with uncertainty. Long‐term forecasts are generally derived from the geological and historical records, from which recurrence intervals and styles of activity can be inferred, while shorter‐term forecasts are derived from patterns in monitoring data. Information from geology and monitoring data can be evaluated and combined using statistical analysis, expert elicitation, and conceptual and or mathematical models. Integrative frameworks, such as event trees, combine this diversity of information to produce probabilistic forecasts that can inform the style and scale of the societal response to a potential future eruption. Several developments show promise to revolutionize the utility and accuracy of these forecasts. These include growth in the quantity and quality of multidisciplinary monitoring data, coupled with increases in computing power; machine learning algorithms, which will allow far better utilization of this growing volume of data; and new physiochemical volcano models and data assimilation algorithms, which take advantage of a wide range of monitoring data and realistic physics to better predict the evolution of a given physical state. Although eruption forecasts may never be as generally reliable as weather forecasts, and great caution must be exercised when attempting to predict highly complex volcanic behavior, these and other innovations—particularly when combined in integrative, fully probabilistic forecasting frameworks—should help volcanologists to better issue warnings of volcanic activity on societally relevant time frames.
Anisotropy of Magnetic Susceptibility (AMS) of Sediments From Holes U1480E and U1480H, IODP Expedition 362: Sedimentary or Artificial Origin and Implications for Paleomagnetic Studies
Authors: Yang Tao , Zhao Xixi , Petronotis Katerina , Dekkers Mark J. , Xu Huiru 
Published: November 2019

AbstractRecognition of coring‐induced disturbance, which is essential for magnetic fabric and paleomagnetic studies of poorly lithified sediments, is generally not straightforward. Here, we report on anisotropy of magnetic susceptibility (AMS) and paleomagnetic data of the sediments from Holes U1480E and U1480H, IODP Expedition 362, west of the Sumatra subduction zone. AMS is characterized by steep minimum principal axes (Kmin) in undisturbed sediments. However, a considerable portion of the recovered sediments are affected by significant coring‐induced disturbance. In these cases, we observed three AMS patterns: (1) AMS principal axes are randomly distributed for sediments with mingling and distortion of beds, (2) Kmin axes of sediments with upward‐arching beds are deflected out of the splitting face of the working half, and (3) suck‐in sediments are characterized by vertical Kmax axes. These deformation‐dependent AMS patterns can be attributed to the realignment of mineral particles caused by the coring process and subsequent sampling procedures. Besides a low‐coercivity, vertical, drilling‐induced overprint, we observed a high‐coercivity component that is likely a composite of the primary magnetization with a demagnetization‐resistant portion of the drilling overprint. After accounting for the disturbed intervals, several polarity transitions can be identified in the undisturbed sediments which correlate well with the Pleistocene geomagnetic polarity timescale. These observations demonstrate that great caution is required when attributing geological significance to AMS and paleomagnetic data obtained from soft sediment cores, which are highly susceptible to coring‐induced disturbance. In addition, AMS measurements provide a potential tool for identifying core deformation for further paleomagnetic studies.
Magma Flow Rates and Temporal Evolution of the 2012–2014 Post‐Eruptive Intrusions at El Hierro, Canary Islands
Authors: Benito‐Saz Maria Angeles , Sigmundsson Freysteinn , Charco Maria , Hooper Andrew , Parks Michelle 
Published: November 2019

AbstractThe 2011–2014 volcanic activity at El Hierro (Canary Islands) was characterized by a 5‐month long submarine eruption as well as a series of magmatic intrusions occurring between 5 months and 2 years after the eruption, as revealed by seismic swarms and ground deformation. We study the temporal evolution of the six post‐eruptive magmatic intrusions, using Global Navigation Satellite System and Interferometric Synthetic Aperture Radar observations complemented with relocated earthquakes. Magma volumes and magma supply rates are determined from inversion of the geodetic data using a Bayesian approach. The intrusions last between ~3 and 20 days and are inferred to be sill‐like, thin compared with their lateral extent and emplaced in the ~13–16 km depth range. Initial magma flow rates of ~300 m3/s decay exponentially with time. The two largest intrusions occurred in June–July 2012 and March–April 2013. During each of these events, magma migrated laterally, and >120 ×106 m3 of magma was intruded beneath the island. The shortest events, <1 week‐long, intruded ~(24hyphen;44) ×106 m3 of magma beneath the volcano. We suggest that all intrusions originated from an overpressure in a deep magma body located beneath the center of El Hierro. The crust/mantle boundary and the previous intrusion that fed the 2011–2012 submarine eruption may have discouraged the ascent of the post‐eruptive intrusions to the surface and forced them to migrate laterally away from the island as sill‐like sources.
Which out-of-office measurement technique should be used for diagnosing hypertension in prehypertensives?
Authors:   on behalf of the Turkish Society of Hypertension and Renal Diseases, Ulusoy Şükrü , Özkan Gülsüm , Arıcı Mustafa , Derici Ülver , Akpolat T. , Şengül Şule , Yılmaz Rahmi , Ertürk Şehsuvar , Erdem Yunus 
Published: November 2019

AbstractHypertension (HT) is diagnosed with high office blood pressure (BP), although confirmation with the addition of out-of-office measurements is currently recommended. However, insufficient data are available concerning the use of out-of-office BP measurement techniques for the diagnosis of HT in the prehypertensive population. The aim of the present study was to determine which out-of-office measurements yielded earlier and more frequent detection of development of HT in prehypertensive patients. Two hundred seven prehypertensive patients under monitoring in the Cappadocia cohort were included in the study. Office BP was measured five times at 1-min intervals, followed by 24-h ambulatory BP monitoring (24-h ABPM). Home BP measurement (HBPM) was performed five times, at the same times in the morning and evening, at 1-min intervals for 1 week. The same procedure was carried out at 4–6-month intervals for ~2 years. HT was diagnosed in 25.6% of subjects, masked HT in 11.1%, and white coat HT in 2.9%, while 23.7% remained prehypertensive and 36.7% became normotensive. Briefly, 56.6% of the patients with HT were diagnosed with office plus 24-h ABPM, 13.2% with office plus HBPM, and 30.2% with office plus HBPM and 24-h ABPM. Office with 24-h ABPM yielded statistically significantly more diagnoses (p < 0.001). In conclusion, our prospective observational study evaluated the usefulness of out-of-office BP measurements in confirming diagnosis of HT in prehypertensive patients. The findings show that 24-h ABPM detected HT earlier and more frequently in this high-risk population.
Long-read sequencing reveals the complex splicing profile of the psychiatric risk gene CACNA1C in human brain
Authors: Clark Michael B. , Wrzesinski Tomasz , Garcia Aintzane B. , Hall Nicola A. L. , Kleinman Joel E. , Hyde Thomas , Weinberger Daniel R. , Harrison Paul J. , Haerty Wilfried , Tunbridge Elizabeth M. 
Published: November 2019

AbstractRNA splicing is a key mechanism linking genetic variation with psychiatric disorders. Splicing profiles are particularly diverse in brain and difficult to accurately identify and quantify. We developed a new approach to address this challenge, combining long-range PCR and nanopore sequencing with a novel bioinformatics pipeline. We identify the full-length coding transcripts ofCACNA1Cin human brain.CACNA1Cis a psychiatric risk gene that encodes the voltage-gated calcium channel CaV1.2. We show thatCACNA1C’s transcript profile is substantially more complex than appreciated, identifying 38 novel exons and 241 novel transcripts. Importantly, many of the novel variants are abundant, and predicted to encode channels with altered function. The splicing profile varies between brain regions, especially in cerebellum. We demonstrate that human transcript diversity (and thereby protein isoform diversity) remains under-characterised, and provide a feasible and cost-effective methodology to address this. A detailed understanding of isoform diversity will be essential for the translation of psychiatric genomic findings into pathophysiological insights and novel psychopharmacological targets.
Paying attention to attention in depression
Authors: Keller Arielle S. , Leikauf John E. , Holt-Gosselin Bailey , Staveland Brooke R. , Williams Leanne M. 
Published: November 2019

AbstractAttention is the gate through which sensory information enters our conscious experiences. Oftentimes, patients with major depressive disorder (MDD) complain of concentration difficulties that negatively impact their day-to-day function, and these attention problems are not alleviated by current first-line treatments. In spite of attention’s influence on many aspects of cognitive and emotional functioning, and the inclusion of concentration difficulties in the diagnostic criteria for MDD, the focus of depression as a disease is typically on mood features, with attentional features considered less of an imperative for investigation. Here, we summarize the breadth and depth of findings from the cognitive neurosciences regarding the neural mechanisms supporting goal-directed attention in order to better understand how these might go awry in depression. First, we characterize behavioral impairments in selective, sustained, and divided attention in depressed individuals. We then discuss interactions between goal-directed attention and other aspects of cognition (cognitive control, perception, and decision-making) and emotional functioning (negative biases, internally-focused attention, and interactions of mood and attention). We then review evidence for neurobiological mechanisms supporting attention, including the organization of large-scale neural networks and electrophysiological synchrony. Finally, we discuss the failure of current first-line treatments to alleviate attention impairments in MDD and review evidence for more targeted pharmacological, brain stimulation, and behavioral interventions. By synthesizing findings across disciplines and delineating avenues for future research, we aim to provide a clearer outline of how attention impairments may arise in the context of MDD and how, mechanistically, they may negatively impact daily functioning across various domains.
Molecular and cellular mechanisms underlying the antidepressant effects of ketamine enantiomers and its metabolites
Authors: Yang Chun , Yang Jianjun , Luo Ailin , Hashimoto Kenji 
Published: November 2019

AbstractAlthough the robust antidepressant effects of the N-methyl-d-aspartate receptor (NMDAR) antagonist ketamine in patients with treatment-resistant depression are beyond doubt, the precise molecular and cellular mechanisms underlying its antidepressant effects remain unknown. NMDAR inhibition and the subsequent α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) activation are suggested to play a role in the antidepressant effects of ketamine. Although (R)-ketamine is a less potent NMDAR antagonist than (S)-ketamine, (R)-ketamine has shown more marked and longer-lasting antidepressant-like effects than (S)-ketamine in several animal models of depression. Furthermore, non-ketamine NMDAR antagonists do not exhibit robust ketamine-like antidepressant effects in patients with depression. These findings suggest that mechanisms other than NMDAR inhibition play a key role in the antidepressant effects of ketamine. Duman’s group demonstrated that the activation of mammalian target of rapamycin complex 1 (mTORC1) in the medial prefrontal cortex is reportedly involved in the antidepressant effects of ketamine. However, we reported that mTORC1 serves a role in the antidepressant effects of (S)-ketamine, but not of (R)-ketamine, and that extracellular signal-regulated kinase possibly underlie the antidepressant effects of (R)-ketamine. Several lines of evidence have demonstrated that brain-derived neurotrophic factor (BDNF) and its receptor, tyrosine kinase receptor B (TrkB), are crucial in the antidepressant effects of ketamine and its two enantiomers, (R)-ketamine and (S)-ketamine, in rodents. In addition, (2R,6R)-hydroxynormetamine [a metabolite of (R)-ketamine] and (S)-norketamine [a metabolite of (S)-ketamine] have been shown to exhibit antidepressant-like effects on rodents through the BDNF–TrkB cascade. In this review, we discuss recent findings on the molecular and cellular mechanisms underlying the antidepressant effects of enantiomers of ketamine and its metabolites. It may be time to reconsider the hypothesis of NMDAR inhibition and the subsequent AMPAR activation in the antidepressant effects of ketamine.
Cannabidiol promotes apoptosis via regulation of XIAP/Smac in gastric cancer
Authors: Jeong Soyeon , Jo Min Jee , Yun Hye Kyeong , Kim Dae Yeong , Kim Bo Ram , Kim Jung Lim , Park Seong Hye , Na Yoo Jin , Jeong Yoon A , Kim Bu Gyeom , Ashktorab Hassan , Smoot Duane T. , Heo Jun Young , Han Jeongsu , Il Lee Sun , Do Kim Han , Kim Dae Hyun , Oh Sang Cheul , Lee Dae-Hee 
Published: November 2019

AbstractAccording to recent studies, Cannabidiol (CBD), one of the main components of Cannabis sativa, has anticancer effects in several cancers. However, the exact mechanism of CBD action is not currently understood. Here, CBD promoted cell death in gastric cancer. We suggest that CBD induced apoptosis by suppressing X-linked inhibitor apoptosis (XIAP), a member of the IAP protein family. CBD reduced XIAP protein levels while increasing ubiquitination of XIAP. The expression of Smac, a known inhibitor of XIAP, was found to be elevated during CBD treatment. Moreover, CBD treatment increased the interaction between XIAP and Smac by increasing Smac release from mitochondria to the cytosol. CBD has also been shown to affect mitochondrial dysfunction. Taken together, these results suggest that CBD may have potential as a new therapeutic target in gastric cancer.
p53 mitotic centrosome localization preserves centrosome integrity and works as sensor for the mitotic surveillance pathway
Authors: Contadini Claudia , Monteonofrio Laura , Virdia Ilaria , Prodosmo Andrea , Valente Davide , Chessa Luciana , Musio Antonio , Fava Luca L. , Rinaldo Cinzia , Di Rocco Giuliana , Soddu Silvia 
Published: November 2019

AbstractCentrosomal p53 has been described for three decades but its role is still unclear. We previously reported that, in proliferating human cells, p53 transiently moves to centrosomes at each mitosis. Such p53 mitotic centrosome localization (p53-MCL) occurs independently from DNA damage but requires ATM-mediated p53Ser15 phosphorylation (p53Ser15P) on discrete cytoplasmic p53 foci that, through MT dynamics, move to centrosomes during the mitotic spindle formation. Here, we show that inhibition of p53-MCL, obtained by p53 depletion or selective impairment of p53 centrosomal localization, induces centrosome fragmentation in human nontransformed cells. In contrast, tumor cells or mouse cells tolerate p53 depletion, as expected, and p53-MCL inhibition. Such tumor- and species-specific behavior of centrosomal p53 resembles that of the recently identified sensor of centrosome-loss, whose activation triggers the mitotic surveillance pathway in human nontransformed cells but not in tumor cells or mouse cells. The mitotic surveillance pathway prevents the growth of human cells with increased chance of making mitotic errors and accumulating numeral chromosome defects. Thus, we evaluated whether p53-MCL could work as a centrosome-loss sensor and contribute to the activation of the mitotic surveillance pathway. We provide evidence that centrosome-loss triggered by PLK4 inhibition makes p53 orphan of its mitotic dock and promotes accumulation of discrete p53Ser15P foci. These p53 foci are required for the recruitment of 53BP1, a key effector of the mitotic surveillance pathway. Consistently, cells from patients with constitutive impairment of p53-MCL, such as ATM- and PCNT-mutant carriers, accumulate numeral chromosome defects. These findings indicate that, in nontransformed human cells, centrosomal p53 contributes to safeguard genome integrity by working as sensor for the mitotic surveillance pathway.