bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interaction between TRPV1-expressing neurons in the hypothalamus
Authors: Molinas Adrien J. R. , Desmoulins Lucie D. , Hamling Brooke V. , Butcher Sierra M. , Anwar Imran J. , Miyata Kayoko , Enix Courtney L. , Dugas Courtney M. , Satou Ryousuke , Derbenev Andrei V. , Zsombok Andrea 
Published: November 2018

Transient receptor potential vanilloid type 1 (TRPV1) is a ligand-gated ion channel expressed in the peripheral and central nervous systems. TRPV1-dependent mechanisms take part in a wide range of physiological and pathophysiological pathways including the regulation of homeostatic functions. TRPV1 expression in the hypothalamus has been described as well as evidence that TRPV1-dependent excitatory inputs to hypothalamic preautonomic neurons are diminished in diabetic conditions. Here we aimed to determine the functional expression of TRPV1 in two hypothalamic nuclei known to be involved in the central control of metabolism and to test the hypothesis that TRPV1-expressing neurons receive TRPV1-expressing inputs. A mouse model (TRPV1Cre/tdTom) was generated to identify TRPV1-expressing cells and determine the cellular properties of TRPV1-expressing neurons in adult mice. Our study demonstrated the functional expression of TRPV1 in the dorsomedial hypothalamic nucleus and paraventricular nucleus in adult mice. Our findings revealed that a subset of TRPV1Cre/tdTom neurons receive TRPV1-expressing excitatory inputs, indicating direct interaction between TRPV1-expressing neurons. In addition, astrocytes likely play a role in the modulation of TRPV1-expressing neurons. In summary, this study identified specific hypothalamic regions where TRPV1 is expressed and functional in adult mice and the existence of direct connections between TRPV1Cre/tdTom neurons. NEW & NOTEWORTHY Transient receptor potential vanilloid type 1 (TRPV1) is expressed in the hypothalamus, and TRPV1-dependent regulation of preautonomic neurons is decreased in hyperglycemic conditions. Our study demonstrated functional expression of TRPV1 in two hypothalamic nuclei involved in the control of energy homeostasis. Our results also revealed that a subset of TRPV1-expressing neurons receive TRPV1-expressing excitatory inputs. These findings suggest direct interaction between TRPV1-expressing neurons.
Causal inference for spatial constancy across whole body motion
Authors: Perdreau Florian , Cooke James R. H. , Koppen Mathieu , Medendorp W. Pieter 
Published: November 2018

The brain uses self-motion information to internally update egocentric representations of locations of remembered world-fixed visual objects. If a discrepancy is observed between this internal update and reafferent visual feedback, this could be either due to an inaccurate update or because the object has moved during the motion. To optimally infer the object’s location it is therefore critical for the brain to estimate the probabilities of these two causal structures and accordingly integrate and/or segregate the internal and sensory estimates. To test this hypothesis, we designed a spatial updating task involving passive whole body translation. Participants, seated on a vestibular sled, had to remember the world-fixed position of a visual target. Immediately after the translation, the reafferent visual feedback was provided by flashing a second target around the estimated “updated” target location, and participants had to report the initial target location. We found that the participants’ responses were systematically biased toward the position of the second target position for relatively small but not for large differences between the “updated” and the second target location. This pattern was better captured by a Bayesian causal inference model than by alternative models that would always either integrate or segregate the internally updated target location and the visual feedback. Our results suggest that the brain implicitly represents the posterior probability that the internally updated estimate and the visual feedback come from a common cause and uses this probability to weigh the two sources of information in mediating spatial constancy across whole body motion. NEW & NOTEWORTHY When we move, egocentric representations of object locations require internal updating to keep them in register with their true world-fixed locations. How does this mechanism interact with reafferent visual input, given that objects typically do not disappear from view? Here we show that the brain implicitly represents the probability that both types of information derive from the same object and uses this probability to weigh their contribution for achieving spatial constancy across whole body motion.
Functional brain stem circuits for control of nose motion
Authors: Kurnikova Anastasia , Deschênes Martin , Kleinfeld David 
Published: November 2018

Rodents shift their nose from side to side when they actively explore and lateralize odors in the space. This motor action is driven by a pair of muscles, the deflector nasi. We studied the premotor control of this motion. We used replication-competent rabies virus to transsynaptically label inputs to the deflector nasi muscle and find putative premotor labeling throughout the parvocellular, intermediate, and gigantocellular reticular formations, as well as the trigeminal nuclei, pontine reticular formation, midbrain reticular formation, red nucleus, and superior colliculus. Two areas with extensive labeling were analyzed for their impact on nose movement. One area is in the reticular formation caudal to the facial motor nucleus and is denoted the nose retrofacial area. The second is in the caudal part of the intermediate reticular region near the oscillator for whisking (the nose IRt). Functionally, we find that optogenetic activation of glutamatergic cells in both areas drives deflection of the nose. Ablation of cells in the nose retrofacial area, but not the nose IRt, impairs movement of the nose in response to the presentation of odorants but otherwise leaves movement unaffected. These data suggest that the nose retrofacial area is a conduit for a sensory-driven orofacial motor action. Furthermore, we find labeling of neurons that are immediately upstream of premotor neurons in the preBötzinger complex that presumably synchronizes a small, rhythmic component of nose motion to breathing. NEW & NOTEWORTHY We identify two previously undescribed premotor areas in the medulla that control deflection of the nose. This includes a pathway for directed motion of the nose in response to an odorant.
Dentate spikes and learning: disrupting hippocampal function during memory consolidation can improve pattern separation
Authors: Lensu Sanna , Waselius Tomi , Penttonen Markku , Nokia Miriam S. 
Published: November 2018

Hippocampal dentate spikes (DSs) are short-duration, large-amplitude fluctuations in hilar local field potentials and take place while resting and sleeping. During DSs, dentate gyrus granule cells increase firing while CA1 pyramidal cells decrease firing. Recent findings suggest DSs play a significant role in memory consolidation after training on a hippocampus-dependent, nonspatial associative learning task. Here, we aimed to find out whether DSs are important in other types of hippocampus-dependent learning tasks as well. To this end, we trained adult male Sprague-Dawley rats in a spatial reference memory task, a fixed interval task, and a pattern separation task. During a rest period immediately after each training session, we either let neural activity to take place as usual, timed electrical stimulation of the ventral hippocampal commissure (vHC) to immediately follow DSs, or applied the vHC stimulation during a random neural state. We found no effect of vHC stimulation on performance in the spatial reference memory task or in the fixed interval task. Surprisingly, vHC stimulation, especially contingent on DSs, improved performance in the pattern separation task. In conclusion, the behavioral relevance of hippocampal processing and DSs seems to depend on the task at hand. It could be that in an intact brain, offline memory consolidation by default involves associating neural representations of temporally separate but related events. In some cases this might be beneficial for adaptive behavior in the future (associative learning), while in other cases it might not (pattern separation). NEW & NOTEWORTHY The behavioral relevance of dentate spikes seems to depend on the learning task at hand. We suggest that dentate spikes are related to associating neural representations of temporally separate but related events within the dentate gyrus. In some cases this might be beneficial for adaptive behavior in the future (associative learning), while in other cases it might not (pattern separation).
Intersegmental coordination patterns are differently affected in Parkinson’s disease and cerebellar ataxia
Authors: Israeli-Korn Simon D. , Barliya Avi , Paquette Caroline , Franzén Erika , Inzelberg Rivka , Horak Fay B. , Flash Tamar 
Published: November 2018

The law of intersegmental coordination (Borghese et al. 1996) may be altered in pathological conditions. Here we investigated the contribution of the basal ganglia (BG) and the cerebellum to lower limb intersegmental coordination by inspecting the plane’s orientation and other parameters pertinent to this law in patients with idiopathic Parkinson’s disease (PD) or cerebellar ataxia (CA). We also applied a mathematical model that successfully accounts for the intersegmental law of coordination observed in control subjects (Barliya et al. 2009). In the present study, we compared the planarity index (PI), covariation plane (CVP) orientation, and CVP orientation predicted by the model in 11 PD patients, 8 CA patients, and two groups of healthy subjects matched for age, height, weight, and gender to each patient group (Ctrl_PD and Ctrl_CA). Controls were instructed to alter their gait speed to match those of their respective patient group. PD patients were examined after overnight withdrawal of anti-parkinsonian medications (PD-off-med) and then on medication (PD-on-med). PI was above 96% in all gait conditions in all groups suggesting that the law of intersegmental coordination is preserved in both BG and cerebellar pathology. However, the measured and predicted CVP orientations rotated in PD-on-med and PD-off-med compared with Ctrl_PD and in CA vs. Ctrl_CA. These rotations caused by PD and CA were in opposite directions suggesting differences in the roles of the BG and cerebellum in intersegmental coordination during human locomotion. NEW & NOTEWORTHY Kinematic and muscular synergies may have a role in overcoming motor redundancies, which may be reflected in intersegmental covariation. Basal ganglia and cerebellar networks were suggested to be involved in crafting and modulating synergies. We thus compared intersegmental coordination in Parkinson’s disease and cerebellar disease patients and found opposite effects in some aspects. Further research integrating muscle activities as well as biomechanical and neural control modeling are needed to account for these findings.
Combined Mineral Intakes and Risk of Colorectal Cancer in Postmenopausal Women
Authors: Swaminath Samyukta , Um Caroline Y. , Prizment Anna E. , Lazovich DeAnn , Bostick Roberd M. 
Published: November 2018

Abstract

Background:
Despite considerable biological plausibility, other than for calcium, there are few reported epidemiologic studies on mineral intake–colorectal cancer associations, none of which investigated multiple minerals in aggregate.

Methods:
Accordingly, we incorporated 11 minerals into a mineral score and investigated its association with incident colorectal cancer in the Iowa Women's Health Study, a prospective cohort study of 55- to 69-year-old women who completed a food frequency questionnaire in 1986. In the analytic cohort (n = 35, 221), 1,731 incident colorectal cancer cases were identified via the State Health Registry of Iowa. Participants' calcium, magnesium, manganese, zinc, selenium, potassium, and iodine intakes were ranked 1 to 5, with higher ranks indicating higher, potentially anticarcinogenic, intakes, whereas for iron, copper, phosphorus, and sodium intakes, the rankings were reversed to account for their possible procarcinogenic properties. The rankings were summed to create each woman's mineral score. The mineral score–incident colorectal cancer association was estimated using multivariable Cox proportional hazards regression.

Results:
There was decreasing risk with an increasing score (Ptrend = 0.001). The hazard ratios and 95% confidence intervals (CI) for those in mineral score quintiles 2 to 5 relative to those in the lowest were 0.91 (CI, 0.88–1.08), 0.85 (CI, 0.75–0.95), 0.86 (CI, 0.75–0.97), and 0.75 (CI, 0.71–0.95), respectively.

Conclusions:
Our findings suggest that a predominance of putative anti- relative to pro-colorectal carcinogenic mineral intakes may be inversely associated with colorectal cancer risk.

Impact:
These results support further investigation of colorectal cancer etiology using composite mineral intake scores.
Trends in Pediatric Central Nervous System Tumor Incidence in the United States, 1998–2013
Authors: Withrow Diana R. , de Gonzalez Amy Berrington , Lam Clara J.K. , Warren Katherine E. , Shiels Meredith S. 
Published: November 2018

Abstract

Background:
Brain and other central nervous system (CNS) cancers are the leading cause of U.S. pediatric cancer mortality. Incidence trends can provide etiologic insight. We report trends in incidence rates of pediatric malignant CNS cancers and pilocytic astrocytoma (nonmalignant but historically registered) in the United States.

Methods:
Age-standardized incidence rates and annual percent changes (APC) in rates during 1998 to 2013 were calculated for children aged 0 to 19, stratified by subtype, age, sex, and for gliomas, histology and location. We estimated the absolute change in number of cases diagnosed U.S.-wide during 2013 compared with the expected number of cases had 1998 rates remained stable.

Results:
Rates of all pediatric malignant CNS cancer combined (n = 18,612) did not change [APC: 0.16; 95% confidence interval (CI): −0.21–0.53]. There were statistically significant changes in several subtypes; however, glioma incidence (n = 10,664) increased by 0.77% per year (95% CI: 0.29–1.26), embryonal cancer rates (n = 5,423) decreased by 0.88% per year (95% CI: −1.33 to −0.43), and pilocytic astrocytoma rates (n = 6,858) increased by 0.89% per year (95% CI: 0.21–1.58). Of the 1,171 malignant tumors and 450 pilocytic astrocytomas diagnosed in U.S. children in 2013, we estimated 120 excess gliomas, 94 excess pilocytic astrocytomas, and 72 fewer embryonal CNS tumors than would be expected had 1998 rates remained stable.

Conclusions:
The gradual changes in incidence we observed for specific types of pediatric CNS cancers are likely due to a combination of changes in classification and diagnosis and true changes in CNS cancer.

Impact:
Continued surveillance of pediatric CNS tumors should remain a priority, given their significant contribution to pediatric cancer–related deaths.
Cancer-associated Fibroblast–promoted LncRNA DNM3OS Confers Radioresistance by Regulating DNA Damage Response in Esophageal Squamous Cell Carcinoma
Authors: Zhang Hongfang , Hua Yuhui , Jiang Zhenzhen , Yue Jing , Shi Ming , Zhen Xiaoli , Zhang Xiaoyan , Yang Ling , Zhou Rongjing , Wu Shixiu 
Published: November 2018

Abstract

Purpose:
Our study aimed to investigate whether CAF (cancer-associated fibroblasts) were involved in long noncoding RNAs (lncRNA)-regulated radioresponse in esophageal squamous cell carcinoma (ESCC).
Experimental Design: By use of lncRNAs PCR array, 38 lncRNAs were screened in esophageal cancer cells and in normal esophageal epithelial cells Het-1A. LncRNA DNM3OS was detected in tumor tissues of patients with ESCC and in matched normal esophageal epithelial tissues by qRT-PCR analysis and in situ hybridization assay. The association of DNM3OS and tumor radioresistance was investigated in vitro and in vivo. The influences of DNM3OS on DNA damage response (DDR) was investigated by Western blotting, immunofluorescence imaging, and comet assay. The mechanisms by which CAFs promoted DNM3OS expression was investigated by kinase inhibitors' screening, luciferase assay, and chromatin immunoprecipitation.

Results:
Among the 38 lncRNAs tested, DNM3OS was found to have a much higher expression level in esophageal cancer cells than in Het-1A. In tumor tissues of 16 patients with ESCC, the expression level of DNM3OS showed an average increase of 6.3429-fold compared with that in matched normal tissues. DNM3OS conferred significant radioresistance in vitro and in vivo by regulating DDR. CAFs promoted the expression of DNM3OS with a 39.2554-fold and 38.3163-fold increase in KYSE-30 and KYSE-140, respectively. CAFs promoted the expression of DNM3OS in a PDGFβ/PDGFRβ/FOXO1 signaling pathway–dependent manner. FOXO1, a transcription factor downstream of PDGFβ/PDGFRβ signaling pathway, initiated the transcription of DNM3OS by binding to DNM3OS promoter.

Conclusions:
Our study highlighted CAF-promoted DNM3OS as an attractive target to reverse tumor radioresistance in ESCC.
Biological Consequences of MHC-II Expression by Tumor Cells in Cancer
Authors: Axelrod Margaret L. , Cook Rebecca S. , Johnson Douglas B. , Balko Justin M. 
Published: November 2018

AbstractImmunotherapy has emerged as a key pillar of cancer treatment. To build upon the recent successes of immunotherapy, intense research efforts are aimed at a molecular understanding of antitumor immune responses, identification of biomarkers of immunotherapy response and resistance, and novel strategies to circumvent resistance. These studies are revealing new insight into the intricacies of tumor cell recognition by the immune system, in large part through MHCs. Although tumor cells widely express MHC-I, a subset of tumors originating from a variety of tissues also express MHC-II, an antigen-presenting complex traditionally associated with professional antigen-presenting cells. MHC-II is critical for antigen presentation to CD4+ T lymphocytes, whose role in antitumor immunity is becoming increasingly appreciated. Accumulating evidence demonstrates that tumor-specific MHC-II associates with favorable outcomes in patients with cancer, including those treated with immunotherapies, and with tumor rejection in murine models. Herein, we will review current research regarding tumor-enriched MHC-II expression and regulation in a range of human tumors and murine models, and the possible therapeutic applications of tumor-specific MHC-II.
First CAR to Pass the Road Test: Tisagenlecleucel's Drive to FDA Approval
Authors: Geyer Mark B. 
Published: November 2018

Abstract
In August 2017, the FDA took historic action in granting the first approval of gene therapy to tisagenlecleucel. This landmark step brought CAR T-cell therapy to the commercial space and heralded a new era in managing refractory B-cell malignancies and FDA oversight of gene-modified therapies.
See related article by O'Leary et al., p. 1142
Activation of AXL as a Preclinical Acquired Resistance Mechanism Against Osimertinib Treatment inEGFR-Mutant Non–Small Cell Lung Cancer Cells
Authors: Namba Kei , Shien Kazuhiko , Takahashi Yuta , Torigoe Hidejiro , Sato Hiroki , Yoshioka Takahiro , Takeda Tatsuaki , Kurihara Eisuke , Ogoshi Yusuke , Yamamoto Hiromasa , Soh Junichi , Tomida Shuta , Toyooka Shinichi 
Published: November 2018

AbstractOsimertinib (AZD9291) has an efficacy superior to that of standard EGFR-tyrosine kinase inhibitors for the first-line treatment of patients with EGFR-mutant advanced non–small cell lung cancer (NSCLC). However, patients treated with osimertinib eventually acquire drug resistance, and novel therapeutic strategies to overcome acquired resistance are needed. In clinical or preclinical models, several mechanisms of acquired resistance to osimertinib have been elucidated. However, the acquired resistance mechanisms when osimertinib is initially used for EGFR-mutant NSCLC remain unclear. In this study, we experimentally established acquired osimertinib-resistant cell lines from EGFR-mutant NSCLC cell lines and investigated the molecular profiles of resistant cells to uncover the mechanisms of acquired resistance. Various resistance mechanisms were identified, including the acquisition of MET amplification, EMT induction, and the upregulation of AXL. Using targeted next-generation sequencing with a multigene panel, no secondary mutations were detected in our resistant cell lines. Among three MET-amplified cell lines, one cell line was sensitive to a combination of osimertinib and crizotinib. Acquired resistance cell lines derived from H1975 harboring the T790M mutation showed AXL upregulation, and the cell growth of these cell lines was suppressed by a combination of osimertinib and cabozantinib, an inhibitor of multiple tyrosine kinases including AXL, both in vitro and in vivo. Our results suggest that AXL might be a therapeutic target for overcoming acquired resistance to osimertinib.Implications:Upregulation of AXL is one of the mechanisms of acquired resistance to osimertinib, and combination of osimertinib and cabozantinib might be a key treatment for overcoming osimertinib resistance.
Interaction Between Susceptibility Loci in MAVS and TRAF3 Genes, and High-risk HPV Infection on the Risk of Cervical Precancerous Lesions in Chinese Population
Authors: Xiao Di , Liu Dandan , Wen Zihao , Huang Xiuxia , Zeng Chengli , Zhou Zixing , Han Yajing , Ye Xiaohong , Wu Jing , Wang Yao , Guo Congcong , Ou Meiling , Huang Shiqi , Huang Chuican , Wei Xiangcai , Yang Guang , Jing Chunxia 
Published: November 2018

Abstract
Persistent high-risk HPV infection is considered as a major cause of cervical cancer. Nevertheless, only some infected individuals actually develop cervical cancer. The RIG-I pathway in innate immunity plays an important role in antivirus response. Here, we hypothesized that altered function of mitochondrial antiviral signaling protein (MAVS) and mitochondrial TNF receptor–associated factor 3(TRAF3), key molecules downstream of the viral sensors RIG-I, may impair their ability of clearing HPV and thereby influence the risk for cervical precancerous lesions. To investigate the effects of MAVS and TRAF3 polymorphisms on susceptibility to cervical precancerous lesions, 8 SNPs were analyzed in 164 cervical precancerous lesion cases and 428 controls. Gene–environment interactions were also calculated. We found that CA genotype of rs6052130 in MAVS gene were at 1.48 times higher risk of developing cervical precancerous lesion than individuals with CC genotype (CA vs. CC: ORadjusted = 1.48, 95% CI, 1.02–2.16). In addition, a significant synergetic interaction between high-risk HPV infection and rs6052130 was found on an additive scale. A significantly decreased risk of cervical precancerous lesions for the TC genotype of rs12435483 in the TRAF3 gene (ORadjusted = 0.67, 95% CI, 0.45–0.98) was also found. Moreover, MDR analysis identified a significant three-locus interaction model, involving high-risk HPV infection, TRAF3 rs12435483 and number of full-term pregnancies. Our results indicate that the MAVS rs6052130 and TRAF3 rs12435483 confer genetic susceptibility to cervical precancerous lesions. Moreover, MAVS rs6052130–mutant individuals have an increased vulnerability to high-risk HPV-induced cervical precancerous lesions.