bluuebunny/crossref_metadata_2025_split huggingface dataset:
Figure and ground: how the visual cortex integrates local cues for global organization
Authors: von der Heydt Rüdiger , Zhang Nan R. 
Published: July 2018

Inferring figure-ground organization in two-dimensional images may require different complementary strategies. For isolated objects, it has been shown that mechanisms in visual cortex exploit the overall distribution of contours, but in images of cluttered scenes where the grouping of contours is not obvious, that strategy would fail. However, natural scenes contain local features, specifically contour junctions, that may contribute to the definition of object regions. To study the role of local features in the assignment of border ownership, we recorded single-cell activity from visual cortex in awake behaving Macaca mulatta. We tested configurations perceived as two overlapping figures in which T- and L-junctions depend on the direction of overlap, whereas the overall distribution of contours provides no valid information. While recording responses to the occluding contour, we varied direction of overlap and variably masked some of the critical contour features to determine their influences and their interactions. On average, most features influenced the responses consistently, producing either enhancement or suppression depending on border ownership. Different feature types could have opposite effects even at the same location. Features far from the receptive field produced effects as strong as near features and with the same short latency. Summation was highly nonlinear: any single feature produced more than two-thirds of the effect of all features together. These findings reveal fast and highly specific organization mechanisms, supporting a previously proposed model in which “grouping cells” integrate widely distributed edge signals with specific end-stopped signals to modulate the original edge signals by feedback.NEW & NOTEWORTHY Seeing objects seems effortless, but defining objects in a scene requires sophisticated neural mechanisms. For isolated objects, the visual cortex groups contours based on overall distribution, but this strategy does not work for cluttered scenes. Here, we demonstrate mechanisms that integrate local contour features like T- and L-junctions to resolve clutter. The process is fast, evaluates widely distributed features, and gives any single feature a decisive influence on figure-ground representation.
Differential effects of radiant and mechanically applied thermal stimuli on human C-tactile afferent firing patterns
Authors: Ackerley Rochelle , Wiklund Fernström Katarina , Backlund Wasling Helena , Watkins Roger H. , Johnson Richard D. , Vallbo Åke , Wessberg Johan 
Published: July 2018

C-tactile (CT) afferents respond to gentle tactile stimulation, but only a handful of studies in humans and animals have investigated whether their firing is modified by temperature. We describe the effects of radiant thermal stimuli, and of stationary and very slowly moving mechanothermal stimuli, on CT afferent responses. We find that CT afferents are primarily mechanoreceptors, as they fired little during radiant thermal stimuli, but they exhibited different patterns of firing during combined mechano-cool stimulation compared with warming. CTs fired optimally to gentle, very slowly moving, or stationary mechanothermal stimuli delivered at neutral temperature (~32°C, normal skin temperature), but they responded with fewer spikes (median 67% decrease) and at significantly lower rates (47% decrease) during warm (~42°C) tactile stimuli. During cool tactile stimuli (~18°C), their mean instantaneous firing frequency significantly decreased by 35%, but they often fired a barrage of afterdischarge spikes at a low frequency (~5 Hz) that outlasted the mechanical stimulus. These effects were observed under a variety of stimulus conditions, including during stationary and slowly moving touch (0.1 cm/s), and we complemented these tactile approaches using a combined electrical-thermal stimulation experiment where we found a suppression of spiking during warming. Overall, CT afferents are exquisitely sensitive to tactile events, and we show that their firing is modulated with touch temperatures above and below neutral skin temperature. Warm touch consistently decreased their propensity to fire, whereas cool touch produced lower firing rates but afterdischarge spiking. NEW & NOTEWORTHY C-tactile (CT) afferents are thought to underpin pleasant touch, and previous work has shown that they respond optimally to a slow caress delivered at typical (neutral) skin temperature. Here, we show that, although CTs are primarily mechanoreceptive afferents, they are modified by temperature: warm touch decreases their firing, whereas cool touch produces lower firing rates but long-lasting spiking, frequently seen as afterdischarges. This has implications for the encoding of affective sensory events in human skin.
Phase I Trial of ALT-803, A Novel Recombinant IL15 Complex, in Patients with Advanced Solid Tumors
Authors: Margolin Kim , Morishima Chihiro , Velcheti Vamsidhar , Miller Jeffrey S. , Lee Sylvia M. , Silk Ann W. , Holtan Shernan G. , Lacroix Andreanne M. , Fling Steven P. , Kaiser Judith C. , Egan Jack O. , Jones Monica , Rhode Peter R. , Rock Amy D. , Cheever Martin A. , Wong Hing C. , Ernstoff Marc S. 
Published: July 2018

Abstract
Purpose: IL15 induces the activation and proliferation of natural killer (NK) and memory CD8+ T cells and has preclinical antitumor activity. Given the superior activity and favorable kinetics of ALT-803 (IL15N72D:IL15RαSu/IgG1 Fc complex) over recombinant human IL15 (rhIL15) in animal models, we performed this first-in-human phase I trial of ALT-803 in patients with advanced solid tumors.
Patients and Methods: Patients with incurable advanced melanoma, renal cell, non–small cell lung, and head and neck cancer were treated with ALT-803 0.3 to 6 μg/kg weekly intravenously or 6 to 20 μg/kg weekly subcutaneously for 4 consecutive weeks, every 6 weeks. Immune correlates included pharmacokinetics, immunogenicity, and lymphocyte expansion and function. Clinical endpoints were toxicity and antitumor activity.
Results: Twenty-four patients were enrolled; 11 received intravenous and 13 received subcutaneous ALT-803. Of these patients, nine had melanoma, six renal, three head and neck, and six lung cancer. Although total lymphocyte and CD8+ T-cell expansion were modest, NK cell numbers rose significantly. Neither anti–ALT-803 antibodies nor clinical activity were observed. Overall, ALT-803 was well tolerated, with adverse effects including fatigue and nausea most commonly with intravenous administration, whereas painful injection site wheal was reported most commonly with subcutaneous ALT-803.
Conclusions: Subcutaneous ALT-803 produced the expected NK cell expansion and was well tolerated with minimal cytokine toxicities and a strong local inflammatory reaction at injection sites in patients with advanced cancer. These data, together with compelling evidence of synergy in preclinical and clinical studies, provide the rationale for combining ALT-803 with other anticancer agents. Clin Cancer Res; 24(22); 5552–61. ©2018 AACR.
Cotargeting the Cell-Intrinsic and Microenvironment Pathways of Prostate Cancer by PI3Kα/β/δ Inhibitor BAY1082439
Authors: Zou Yongkang , Qi Zhi , Guo Weilong , Zhang Liuzhen , Ruscetti Marcus , Shenoy Tanu , Liu Ningshu , Wu Hong 
Published: July 2018

Abstract
Targeting the PI3K pathway is a promising strategy for treating prostate cancers with PTEN-loss. However, current anti-PI3K therapies fail to show long lasting in vivo effects. We find that not only the PI3Kα- and PI3kβ-isoforms, but also PI3Kδ, are associated with the epithelial–mesenchymal transition (EMT), a critical process distinguishing indolent from aggressive prostate cancer. This suggests that cotargeting PI3Kα/β/δ could preempt the rebound activation of the parallel pathways induced by α- or β-isoform–selective inhibitor and prevent EMT. Indeed, BAY1082439, a new selective PI3Kα/β/δ inhibitor, is highly effective in vivo in inhibiting Pten-null prostate cancer growth and preventing EMT in the mutant Pten/Kras metastatic model. The anti-PI3Kδ property of BAY1082439 further blocks B-cell infiltration and lymphotoxin release, which are tumor microenvironment factors that promote castration-resistant growth. Together, our data suggest a new approach for the treatment of prostate cancer by targeting both tumor cells and tumor microenvironment with PI3Kα/β/δ inhibitor. Mol Cancer Ther; 17(10); 2091–9. ©2018 AACR.
SHP2 Inhibition Prevents Adaptive Resistance to MEK Inhibitors in Multiple Cancer Models
Authors: Fedele Carmine , Ran Hao , Diskin Brian , Wei Wei , Jen Jayu , Geer Mitchell J. , Araki Kiyomi , Ozerdem Ugur , Simeone Diane M. , Miller George , Neel Benjamin G. , Tang Kwan Ho 
Published: July 2018

Abstract
Adaptive resistance to MEK inhibitors (MEKi) typically occurs via induction of genes for different receptor tyrosine kinases (RTK) and/or their ligands, even in tumors of the same histotype, making combination strategies challenging. SHP2 (PTPN11) is required for RAS/ERK pathway activation by most RTKs and might provide a common resistance node. We found that combining the SHP2 inhibitor SHP099 with a MEKi inhibited the proliferation of multiple cancer cell lines in vitro. PTPN11 knockdown/MEKi treatment had similar effects, whereas expressing SHP099 binding–defective PTPN11 mutants conferred resistance, demonstrating that SHP099 is on-target. SHP099/trametinib was highly efficacious in xenograft and/or genetically engineered models of KRAS-mutant pancreas, lung, and ovarian cancers and in wild-type RAS-expressing triple-negative breast cancer. SHP099 inhibited activation of KRAS mutants with residual GTPase activity, impeded SOS/RAS/MEK/ERK1/2 reactivation in response to MEKi, and blocked ERK1/2-dependent transcriptional programs. We conclude that SHP099/MEKi combinations could have therapeutic utility in multiple malignancies.
Significance: MEK inhibitors show limited efficacy as single agents, in part because of the rapid development of adaptive resistance. We find that SHP2/MEK inhibitor combinations prevent adaptive resistance in multiple cancer models expressing mutant and wild-type KRAS. Cancer Discov; 8(10); 1237–49. ©2018 AACR.
See related commentary by Torres-Ayuso and Brognard, p. 1210.
This article is highlighted in the In This Issue feature, p. 1195
Pharmacokinetic Study on Protocatechuic Aldehyde and Hydroxysafflor Yellow A of Danhong Injection in Rats with Hyperlipidemia
Authors: Zhou Jing , Li Min , Jin Weifeng , Li Xiaohong , Fan Hongjin , Zhang Yuyan 
Published: July 2018

<b><i>Background:</i></b> Protocatechuic aldehyde (PAL) and hydroxysafflor yellow A (HSYA) are 2 effective ingredients of Danhong Injection, which is extensively used for the clinical treatment of cardio-cerebrovascular diseases. This study aims to investigate the pharmacokinetic differences between single and combined medication of PAL and HSYA and analyze the interaction of the above effective components in hyperlipidemia rats. <b><i>Methods:</i></b> Thirty male SD rats were randomly divided into the control group (<i>n</i> = 6) and the model group (<i>n </i>= 24). The hyperlipidemia model was established by feeding with superfatted forage. The successful model rats were then randomly divided into the PAL group (16 mg/kg), the HSYA group (10 mg/kg), and the combination group (16 mg/kg + 10 mg/kg). Administration through tail-vein, and orbital blood was sampled at different time points. The mass concentration of PAL and HSYA was determined by high performance liquid chromatography (HPLC-DAD). Analysis of pharmacokinetic parameters was conducted by using DAS 3.2.6 software and SPSS 19.0 statistical analysis software. <b><i>Results:</i></b> According to the parameters of statistical moment of non-compartmental model, there was a significant difference in plasma clearance (CL) between the PAL group and the drug combination group (<i>p</i> &#x3c; 0.01), as well as in the area under the first moment of the plasma concentration-time curve and the elimination half-life (t<sub>1/2</sub>) between the HSYA group and the drug combination group (<i>p</i> &#x3c; 0.01) but no obvious differences about the blood concentration time curve area, the average dwell time (MRT), and the peak concentration (C<sub>max;</sub> <i>p</i> &#x3e; 0.05). <b><i>Conclusion:</i></b> The combined medication of PAL and HSYA could increase the plasma CL significantly and have a great influence on the absorption of HSYA in rats with hyperlipidemia.
КЛІНІЧНА ЕФЕКТИВНІСТЬ ЗАСТОСУВАННЯ ФІТОПРЕПАРАТУ «РЕСВЕРАЗИН» В КОМПЛЕКСНОМУ ЛІКУВАННІ ГЕНЕРАЛІЗОВАНОГО ПАРОДОНТИТУ
Authors: Hevkalyuk N. O. 
Published: July 2018

Захворювання пародонта – сьогодні одне із найпоширеніших уражень організму людини. За даними ВООЗ (1990), від 55 до 98 % дорослого населення планети має патологію пародонта, найвищий рівень захворюваності зареєстровано в осіб 15–19 років (55–89 %) та 35–44 років (65–98 %) [1, 3, 6]. Висока поширеність, несприятливий вплив вогнищ пародонтальної інфекції на стан порожнини рота та організм у цілому, високий рівень ускладнень, пов’язаних із функціональними та морфологічними порушеннями внаслідок втрати зубів, – все це визначає актуальність даної проблеми.Мета дослідження – оцінити клінічну ефективність препарату “Ресверазин” у складі комплексного лікування генералізованого пародонтиту.Матеріали і методи. У дослідженні взяли участь 43 пацієнти, хворі на хронічний генералізований пародонтит. Оцінку стану пародонта проводили за клінічними ознаками. Для оцінки гігієнічного стану порожнини рота використовували індекси Green–Wermillion, ОНІ-S, Silness–Loe, Stallard, пародонтологічні індекси: РМА, ПІ, індекс кровоточивості за Мuhlleman. Визначення і підрахунок індексів проводили за загальноприйнятими методиками. Пацієнтам основної групи в комплексній терапії призначали препарат “Ресверазин” по 1 капсулі 2 рази на добу. Курс лікування становив 2 місяці.Результати дослідження та їх обговорення. Дані клінічних досліджень, які ми отримали, послугували обґрунтуванням для впровадження в медичну стоматологічну практику лікування генералізованого пародонтиту (ГП) фітопрепаратом “Ресверазин”. Включення до комплексної терапії хворих на пародонтит препарату “Ресверазин” сприяло підвищенню ефективності проведеного етіотропного, патогенетичного та симптоматичного лікування хворих, що забезпечило клінічно виражені ознаки стабілізації пародонтиту та швидший перехід ГП у стадію ремісії. Позитивний клінічний результат отриманий за основними критеріями ефективності, які заключались у зменшенні симптомів запалення – гіперемії, набряку та кровоточивості міжзубних сосочків і маргінальної частини ясен. Тенденція до зменшення ознак запалення за клінічними, суб’єктивними даними, підтвердилась позитивною динамікою показника поширеності запаленнятканин пародонта (РМА). Зниження значення інтегративного пародонтального індексу відбувається переважно за рахунок зменшення тяжкості симптоматичного гінгівіту та глибини пародонтальних кишень. У результаті проведеного лікування настає нормалізація функціональних адаптаційно-компенсаторних реакцій, що підтверджується нормалізацією показників – гігієнічними індексами Green–Wermillion, ОНІ-S, Silness–Loe, Stallard та пародонтальними індексами: папілярно-маргінально-альвеолярним (РМА), індексом кровоточивості за Muhlleman, пародонтальним індексом (ПІ).Висновки. Результати клінічного дослідження свідчать про необхідність застосування фітопрепаратів, зокрема фітопрепарату “Ресвератрол”, із протизапальною, антиангіогенною, імунотропною, антиоксидантною дією в комплексному лікуванні хворих на генералізований пародонтит.
Distribution patterns and population dynamics of the pandalid shrimp Plesionika izumiae (Decapoda, Caridea) in a unique semi-enclosed deep-water bay environment
Authors: Ohtomi J. , Ahamed F. , Rahman M. Mosaddequr , Fukushima H. 
Published: July 2018

Abstract
The pandalid shrimp Plesionika izumiae Omori, 1971 has a wide bathymetric distribution in the coastal waters and the upper continental slope of west Pacific regions. The distribution patterns and population dynamics of P. izumiae were studied in a unique semi-enclosed deep-water bay, Kagoshima Bay, southern Japan, with very steep slopes on both sides. Plesionika izumiae shows a wide spatial distribution in the bay with the majority of the individuals inhabiting the channel area with sediments of almost equal portions of silt and sand, as well as in the bay head with a silty sediment. There were no significant relationships between bottom water temperature or salinity and the distribution patterns of this shrimp, but the sediment characteristics and water depth might appear to influence the distribution patterns of P. izumiae. The distribution patterns with progression of age reveal the dynamics of the P. izumiae population, which was studied by selecting one cohort from each sex and tracing them throughout their life cycle, resulting in similar patterns being shown for both sexes. Juveniles (at the age of 5.7 months) occurred throughout the distribution areas; however, there was a low catch per unit effort (CPUE) even in the main spawning grounds, probably from due to the ongoing recruitment process. The substantial increment in CPUE at the age of 8.4 months throughout the distribution areas likely indicate the stock to be fully recruited by then. A clear shift in CPUE of these cohorts was observed at the ages of 11.6 months and 14.3 months, from the deeper areas towards the shallower areas of the bay, possibly suggesting spawning migration. Individuals approaching their maximum size and longevity were found mostly in the deeper waters. A marked seasonal pattern in CPUE was noted with higher values recorded in summer and lower in winter, which could possibly be related to the life history of the shrimp.
Colloquium 4 Commentary on Ewegen
Authors: Forte J.M. 
Published: July 2018

Abstract
This commentary begins by analyzing two textual selections about death in the Gorgias (486a7–b4 and 526e4–527a4) in order to expand upon Ewegen’s portrayal of Socrates. I close by briefly giving voice to another, perhaps more familiar side of Socrates’ rhetorical approach in the dialogue in order to provide some further perspective about Ewegen’s claims.
Does Clarithromycin Cause Hearing Loss? A 12-Year Review of Clarithromycin Therapy for Nontuberculous Mycobacterial Lymphadenitis in Children
Authors: Heffernan Colleen B. , McKeon Mallory G. , Molony Sasha , Kawai Kosuke , Stiles Derek J. , Lachenauer Catherine S. , Kenna Margaret A. , Watters Karen 
Published: July 2018

Objective(s): The objective was to describe the characteristics of hearing losses documented in patients treated with clarithromycin alone for nontuberculous mycobacterial NTM lymphadenitis in a pediatric tertiary care center over a 12-year period. Methods: An institutional review board (IRB) approval was obtained. A database search was performed using the ICD-10 diagnosis codes 31.0, 31.1, and 31.8 between January 2004 and January 2017. A REDCap database was created to record variables. Patients were included if they received clarithromycin alone and had, at the minimum, a baseline audiology assessment, and 1 further evaluation during treatment. Fisher’s exact test was used to analyze categorical variables, and Wilcoxon rank sum test was used to analyze continuous variables. Results: A total of 167 patients with cervicofacial NTM were identified. Of them, 42 patients fulfilled inclusion criteria. Three children (7%) developed a hearing loss (HL) between 25 and 63 days after starting treatment. HL was unilateral in 2 children. HL persisted in 1 child following cessation of treatment. However, this patient had Rubinstein Taybi syndrome, limiting our ability to attribute the HL solely to clarithromycin. Conclusion: We noted a 7% hearing loss rate in our series. Confounding issues, such as 1 patient with a syndrome potentially contributing to HL, and limitations to this study, including retrospective design and loss to follow-up, temper our ability to conclude that clarithromycin was the sole cause of these HL. However, enough supporting data for a role in clarithromycin causing HL exist that testing should be considered for patients undergoing long-term clarithromycin treatment.
Association between Antidepressant Use during Pregnancy and Infants Born Small for Gestational Age
Authors: Ramos Élodie , St-André Martin , Bérard Anick 
Published: July 2018

Objective To measure the association between the class of antidepressant (AD) used according to trimester of exposure during pregnancy and infants born small for gestational age (SGA). Methods A case–control study was performed using data from the Quebec Pregnancy Registry, which includes 152 107 pregnant women between January 1, 1998, and December 31, 2002. For this study, eligible women were aged 15 to 45 years on the first day of gestation, had drug plan coverage from the Régie de l'Assurance Maladie du Québec for 12 months or more prior to and during pregnancy, had at least 1 psychiatric disorder diagnosis before pregnancy, used ADs for at least 30 days in the year prior to pregnancy, and delivered a live singleton. AD exposure during pregnancy was defined according to trimester of use and class (selective serotonin reuptake inhibitors [SSRIs], tricyclic antidepressants, or other ADs). SGA cases were defined as newborns with a birth weight of less than the 10th percentile according to Canadian charts. Relative risks, adjusted for potential confounders, were estimated using modified Poisson regression. Results Among the 938 eligible pregnancies, 128 (13.6%) infants were born SGA. Other ADs, mainly venlafaxine, used by women during the second trimester were associated with an increased risk of infants born SGA, compared with nonusers of ADs (adjusted relative risk = 2.41; 95% CI 1.07 to 5.43). Regardless of the trimester of use, no association was found between SSRIs or tricyclics and the risk of SGA. Conclusions This study suggests that use of venlafaxine during the second trimester of pregnancy may increase the risk of infants born SGA.