bluuebunny/crossref_metadata_2025_split huggingface dataset:
Low-threshold mechanoreceptors play a frequency-dependent dual role in subjective ratings of mechanical allodynia
Authors: Löken Line S. , Duff Eugene P. , Tracey Irene 
Published: September 2017

In the setting of injury, myelinated primary afferent fibers that normally signal light touch are thought to switch modality and instead signal pain. In the absence of injury, touch is perceived as more intense when firing rates of Aβ afferents increase. However, it is not known if varying the firing rates of Aβ afferents have any consequence to the perception of dynamic mechanical allodynia (DMA). We hypothesized that, in the setting of injury, the unpleasantness of DMA would be intensified as the firing rates of Aβ afferents increase. Using a stimulus-response protocol established in normal skin, where an increase in brush velocity results in an increase of Aβ afferent firing rates, we tested if brush velocity modulated the unpleasantness of capsaicin-induced DMA. We analyzed how changes in estimated low-threshold mechanoreceptor firing activity influenced perception and brain activity (functional MRI) of DMA. Brushing on normal skin was perceived as pleasant, but brushing on sensitized skin produced both painful and pleasant sensations. Surprisingly, there was an inverse relationship between Aβ firing rates and unpleasantness such that brush stimuli that produced low firing rates were most painful and those that elicited high firing rates were rated as pleasant. Concurrently to this, we found increased cortical activity in response to low Aβ firing rates in regions previously implicated in pain processing during brushing of sensitized skin, but not normal skin. We suggest that Aβ signals do not merely switch modality to signal pain during injury. Instead, they exert a high- and low-frequency-dependent dual role in the injured state, with respectively both pleasant and unpleasant consequences. NEW & NOTEWORTHY We suggest that Aβ signals do not simply switch modality to signal pain during injury but play a frequency-dependent and dual role in the injured state with both pleasant and unpleasant consequences. These results provide a framework to resolve the apparent paradox of how touch can inhibit pain, as proposed by the Gate Control Theory and the existence of dynamic mechanical allodynia.
Calcium Promotes Human Gastric Cancer via a Novel Coupling of Calcium-Sensing Receptor and TRPV4 Channel
Authors: Xie Rui , Xu Jingyu , Xiao Yufeng , Wu Jilin , Wan Hanxing , Tang Bo , Liu Jingjing , Fan Yahan , Wang Suming , Wu Yuyun , Dong Tobias Xiao , Zhu Michael X. , Carethers John M. , Dong Hui , Yang Shiming 
Published: September 2017

Abstract
Although dietary calcium intake has long been recommended for disease prevention, the influence of calcium in development of cancer in the upper gastrointestinal tract has not been explored. Here, we assess the roles of calcium and calcium-sensing receptor (CaSR) in gastric cancer development. CaSR expression was enhanced in gastric cancer specimens, which positively correlated with serum calcium concentrations, tumor progression, poor survival, and male gender in gastric cancer patients. CaSR and transient receptor potential cation channel subfamily V member 4 (TRPV4) were colocalized in gastric cancer cells, and CaSR activation evoked TRPV4-mediated Ca2+ entry. Both CaSR and TRPV4 were involved in Ca2+-induced proliferation, migration, and invasion of gastric cancer cells through a Ca2+/AKT/β-catenin relay, which occurred only in gastric cancer cells or normal cells overexpressing CaSR. Tumor growth and metastasis of gastric cancer depended on CaSR in nude mice. Overall, our findings indicate that calcium may enhance expression and function of CaSR to potentially promote gastric cancer, and that targeting the novel CaSR/TRPV4/Ca2+ pathway might serve as preventive or therapeutic strategies for gastric cancer. Cancer Res; 77(23); 6499–512. ©2017 AACR.
Mechanisms of Acquired Resistance to BRAF V600E Inhibition in Colon Cancers Converge on RAF Dimerization and Are Sensitive to Its Inhibition
Authors: Yaeger Rona , Yao Zhan , Hyman David M. , Hechtman Jaclyn F. , Vakiani Efsevia , Zhao HuiYong , Su Wenjing , Wang Lu , Joelson Andrew , Cercek Andrea , Baselga Jose , de Stanchina Elisa , Saltz Leonard , Berger Michael F. , Solit David B. , Rosen Neal 
Published: September 2017

Abstract
BRAF V600E colorectal cancers are insensitive to RAF inhibitor monotherapy due to feedback reactivation of receptor tyrosine kinase signaling. Combined RAF and EGFR inhibition exerts a therapeutic effect, but resistance invariably develops through undefined mechanisms. In this study, we determined that colorectal cancer progression specimens invariably harbored lesions in elements of the RAS–RAF–MEK–ERK pathway. Genetic amplification of wild-type RAS was a recurrent mechanism of resistance in colorectal cancer patients that was not seen in similarly resistant melanomas. We show that wild-type RAS amplification increases receptor tyrosine kinase-dependent activation of RAS more potently in colorectal cancer than in melanoma and causes resistance only in the former. Currently approved RAF inhibitors inhibit RAF monomers but not dimers. All the drug-resistant lesions we identified activate BRAF V600E dimerization directly or by elevating RAS-GTP. Overall, our results show that mechanisms of resistance converge on formation of RAF dimers and that inhibiting EGFR and RAF dimers can effectively suppress ERK-driven growth of resistant colorectal cancer. Cancer Res; 77(23); 6513–23. ©2017 AACR.
Modeling Cytostatic and Cytotoxic Responses to New Treatment Regimens for Ovarian Cancer
Authors: Falcetta Francesca , Bizzaro Francesca , D'Agostini Elisa , Bani Maria Rosa , Giavazzi Raffaella , Ubezio Paolo 
Published: September 2017

Abstract
The margin for optimizing polychemotherapy is wide, but a quantitative comparison of current and new protocols is rare even in preclinical settings. In silico reconstruction of the proliferation process and the main perturbations induced by treatment provides insight into the complexity of drug response and grounds for a more objective rationale to treatment schemes. We analyzed 12 treatment groups in trial on an ovarian cancer xenograft, reproducing current therapeutic options for this cancer including one-, two-, and three-drug schemes of cisplatin (DDP), bevacizumab (BEV), and paclitaxel (PTX) with conventional and two levels (“equi” and “high”) of dose-dense schedules. All individual tumor growth curves were decoded via separate measurements of cell death and other antiproliferative effects, gaining fresh insight into the differences between treatment options. Single drug treatments were cytostatic, but only DDP and PTX were also cytotoxic. After treatment, regrowth stabilized with increased propensity to quiescence, particularly with BEV. More cells were killed by PTX dose-dense-equi than with PTX conventional, but with the addition of DDP, cytotoxicity was similar and considerably less than expected from that of individual drugs. In the DDP/PTX dose-dense-high scheme, both cell death and regrowth impairment were intensified enough to achieve complete remission, and addition of BEV increased cell death in all schemes. The results support the option for dose-dense PTX chemotherapy with active single doses, showing the relative additional contribution of BEV, but also indicate negative drug interactions in concomitant DDP/PTX treatments, suggesting that sequential schedules could improve antitumor efficacy. Cancer Res; 77(23); 6759–69. ©2017 AACR.
PHGDH as a Key Enzyme for Serine Biosynthesis in HIF2α-Targeting Therapy for Renal Cell Carcinoma
Authors: Yoshino Hirofumi , Nohata Nijiro , Miyamoto Kazutaka , Yonemori Masaya , Sakaguchi Takashi , Sugita Satoshi , Itesako Toshihiko , Kofuji Satoshi , Nakagawa Masayuki , Dahiya Rajvir , Enokida Hideki 
Published: September 2017

Abstract
Continuous activation of hypoxia-inducible factor (HIF) is important for progression of renal cell carcinoma (RCC) and acquired resistance to antiangiogenic multikinase and mTOR inhibitors. Recently, HIF2α antagonists PT2385 and PT2399 were developed and are being evaluated in a phase I clinical trial for advanced or metastatic clear cell RCC (ccRCC). However, resistance to HIF2α antagonists would be expected to develop. In this study, we identified signals activated by HIF2α deficiency as candidate mediators of resistance to the HIF2α antagonists. We established sunitinib-resistant tumor cells in vivo and created HIF2α-deficient variants of these cells using CRISPR/Cas9 technology. Mechanistic investigations revealed that a regulator of the serine biosynthesis pathway, phosphoglycerate dehydrogenase (PHGDH), was upregulated commonly in HIF2α-deficient tumor cells along with the serine biosynthesis pathway itself. Accordingly, treatment with a PHGDH inhibitor reduced the growth of HIF2α-deficient tumor cells in vivo and in vitro by inducing apoptosis. Our findings identify the serine biosynthesis pathway as a source of candidate therapeutic targets to eradicate advanced or metastatic ccRCC resistant to HIF2α antagonists. Cancer Res; 77(22); 6321–9. ©2017 AACR.
Genomic Landscape of Atypical Adenomatous Hyperplasia Reveals Divergent Modes to Lung Adenocarcinoma
Authors: Sivakumar Smruthy , Lucas F. Anthony San , McDowell Tina L. , Lang Wenhua , Xu Li , Fujimoto Junya , Zhang Jianjun , Futreal P. Andrew , Fukuoka Junya , Yatabe Yasushi , Dubinett Steven M. , Spira Avrum E. , Fowler Jerry , Hawk Ernest T. , Wistuba Ignacio I. , Scheet Paul , Kadara Humam 
Published: September 2017

AbstractThere is a dearth of knowledge about the pathogenesis of premalignant lung lesions, especially for atypical adenomatous hyperplasia (AAH), the only known precursor for the major lung cancer subtype adenocarcinoma (LUAD). In this study, we performed deep DNA and RNA sequencing analyses of a set of AAH, LUAD, and normal tissues. Somatic BRAF variants were found in AAHs from 5 of 22 (23%) patients, 4 of 5 of whom had matched LUAD with driver EGFR mutations. KRAS mutations were present in AAHs from 4 of 22 (18%) of patients. KRAS mutations in AAH were only found in ever-smokers and were exclusive to BRAF-mutant cases. Integrative analysis revealed profiles expressed in KRAS-mutant cases (UBE2C, REL) and BRAF-mutant cases (MAX) of AAH, or common to both sets of cases (suppressed AXL). Gene sets associated with suppressed antitumor (Th1; IL12A, GZMB) and elevated protumor (CCR2, CTLA-4) immune signaling were enriched in AAH development and progression. Our results reveal potentially divergent BRAF or KRAS pathways in AAH as well as immune dysregulation in the pathogenesis of this premalignant lung lesion. Cancer Res; 77(22); 6119–30. ©2017 AACR.
Inflammatory Monocytes Promote Perineural Invasion via CCL2-Mediated Recruitment and Cathepsin B Expression
Authors: Bakst Richard L. , Xiong Huizhong , Chen Chun-Hao , Deborde Sylvie , Lyubchik Anna , Zhou Yi , He Shizhi , McNamara William , Lee Sei-Young , Olson Oakley C. , Leiner Ingrid M. , Marcadis Andrea R. , Keith James W. , Al-Ahmadie Hikmat A. , Katabi Nora , Gil Ziv , Vakiani Efsevia , Joyce Johanna A. , Pamer Eric , Wong Richard J. 
Published: September 2017

Abstract
Perineural invasion (PNI) is an ominous event strongly linked to poor clinical outcome. Cells residing within peripheral nerves collaborate with cancer cells to enable PNI, but the contributing conditions within the tumor microenvironment are not well understood. Here, we show that CCR2-expressing inflammatory monocytes (IM) are preferentially recruited to sites of PNI, where they differentiate into macrophages and potentiate nerve invasion through a cathepsin B–mediated process. A series of adoptive transfer experiments with genetically engineered donors and recipients demonstrated that IM recruitment to nerves was driven by CCL2 released from Schwann cells at the site of PNI, but not CCL7, an alternate ligand for CCR2. Interruption of either CCL2–CCR2 signaling or cathepsin B function significantly impaired PNI in vivo. Correlative studies in human specimens demonstrated that cathepsin B–producing macrophages were enriched in invaded nerves, which was associated with increased local tumor recurrence. These findings deepen our understanding of PNI pathogenesis and illuminate how PNI is driven in part by corruption of a nerve repair program. Further, they support the exploration of inhibiting IM recruitment and function as a targeted therapy for PNI. Cancer Res; 77(22); 6400–14. ©2017 AACR.
Multiscale Modeling of Inflammation-Induced Tumorigenesis Reveals Competing Oncogenic and Oncoprotective Roles for Inflammation
Authors: Guo Yucheng , Nie Qing , MacLean Adam L. , Li Yanda , Lei Jinzhi , Li Shao 
Published: September 2017

Abstract
Chronic inflammation is a serious risk factor for cancer; however, the routes from inflammation to cancer are poorly understood. On the basis of the processes implicated by frequently mutated genes associated with inflammation and cancer in three organs (stomach, colon, and liver) extracted from the Gene Expression Omnibus, The Cancer Genome Atlas, and Gene Ontology databases, we present a multiscale model of the long-term evolutionary dynamics leading from inflammation to tumorigenesis. The model incorporates cross-talk among interactions on several scales, including responses to DNA damage, gene mutation, cell-cycle behavior, population dynamics, inflammation, and metabolism-immune balance. Model simulations revealed two stages of inflammation-induced tumorigenesis: a precancerous state and tumorigenesis. The precancerous state was mainly caused by mutations in the cell proliferation pathway; the transition from the precancerous to tumorigenic states was induced by mutations in pathways associated with apoptosis, differentiation, and metabolism-immune balance. We identified opposing effects of inflammation on tumorigenesis. Mild inflammation removed cells with DNA damage through DNA damage-induced cell death, whereas severe inflammation accelerated accumulation of mutations and hence promoted tumorigenesis. These results provide insight into the evolutionary dynamics of inflammation-induced tumorigenesis and highlight the combinatorial effects of inflammation and metabolism-immune balance. This approach establishes methods for quantifying cancer risk, for the discovery of driver pathways in inflammation-induced tumorigenesis, and has direct relevance for early detection and prevention and development of new treatment regimes. Cancer Res; 77(22); 6429–41. ©2017 AACR.
FGF19 Protects Hepatocellular Carcinoma Cells against Endoplasmic Reticulum Stress via Activation of FGFR4–GSK3β–Nrf2 Signaling
Authors: Teng Yong , Zhao Huakan , Gao Lixia , Zhang Wenfa , Shull Austin Y. , Shay Chloe 
Published: September 2017

Abstract
The tumor microenvironment induces endoplasmic reticulum (ER) stress in tumor cells, an event that can promote progression, but it is unknown how tumor cells adapt to this stress. In this study, we show that the fibroblast growth factor FGF19, a gene frequently amplified in hepatocellular carcinoma (HCC), facilitates a survival response to ER stress. Levels of FGF19 expression were increased in stressed HCC cells in culture and in a mouse xenograft model. Induction of ER stress required the transcription factor ATF4, which directly bound the FGF19 promoter. In cells where ER stress was induced, FGF19 overexpression promoted HCC cell survival and increased resistance to apoptosis, whereas FGF19 silencing counteracted these effects. Mechanistic investigations implicated glycogen synthase kinase-3β (GSK3β) in regulating nuclear accumulation of the stress-regulated transcription factor Nrf2 activated by FGF19. Our findings show how FGF19 provides a cytoprotective role against ER stress by activating a FGFR4–GSK3β–Nrf2 signaling cascade, with implications for targeting this signaling node as a candidate therapeutic regimen for HCC management. Cancer Res; 77(22); 6215–25. ©2017 AACR.
Degalactotigonin, a Natural Compound from Solanum nigrum L., Inhibits Growth and Metastasis of Osteosarcoma through GSK3β Inactivation–Mediated Repression of the Hedgehog/Gli1 Pathway
Authors: Zhao Zhiqiang , Jia Qiang , Wu Man-Si , Xie Xianbiao , Wang Yongqian , Song Guohui , Zou Chang-Ye , Tang Qinglian , Lu Jinchang , Huang Gang , Wang Jin , Lin De-Chen , Koeffler H. Phillip , Yin Jun-Qiang , Shen Jingnan 
Published: September 2017

Abstract
Purpose: Agents extracted from natural sources with antitumor property have attracted considerable attention from researchers and clinicians because of their safety, efficacy, and immediate availability. Degalactotigonin (DGT), extracted from Solanum nigrum L., has anticancer properties without serious side effects. Here, we explored whether DGT can inhibit the growth and metastasis of osteosarcoma.
Experimental Design: MTT, colony formation, and apoptosis assays were performed to analyze the effects of DGT on osteosarcoma cell viability in vitro. The migration and invasion abilities were measured using a Transwell assay. Animal models were used to assess the roles of DGT in both tumor growth and metastasis of osteosarcoma. Gli1 expression and function were measured in osteosarcoma cells and clinical samples. After DGT treatment, Gli1 activation and the phosphorylation status of multiple cellular kinases were measured with a luciferase reporter and phospho-kinase antibody array.
Results: DGT inhibited proliferation, induced apoptosis, and suppressed migration and invasion in osteosarcoma cells. DGT, injected intraperitoneally after tumor inoculation, significantly decreased the volume of osteosarcoma xenografts and dramatically diminished the occurrence of osteosarcoma xenograft metastasis to the lungs. Mechanistically, DGT inhibited osteosarcoma growth and metastasis through repression of the Hedgehog/Gli1 pathway, which maintains malignant phenotypes and is involved in the prognosis of osteosarcoma patients. DGT decreased the activity of multiple intracellular kinases that affect the survival of osteosarcoma patients, including GSK3β. In addition, DGT represses the Hedgehog/Gli1 pathway mainly through GSK3β inactivation.
Conclusions: Our studies provide evidence that DGT can suppress the growth and metastasis of human osteosarcoma through modulation of GSK3β inactivation–mediated repression of the Hedgehog/Gli1 pathway. Clin Cancer Res; 24(1); 130–44. ©2017 AACR.
Short-Term Outcome and Hemodynamic Performance of Next-Generation Self-Expanding Versus Balloon-Expandable Transcatheter Aortic Valves in Patients With Small Aortic Annulus
Authors: Mauri Victor , Kim Won K. , Abumayyaleh Mohammad , Walther Thomas , Moellmann Helge , Schaefer Ulrich , Conradi Lenard , Hengstenberg Christian , Hilker Michael , Wahlers Thorsten , Baldus Stephan , Rudolph Volker , Madershahian Navid , Rudolph Tanja K. 
Published: September 2017

Background—
Surgical aortic valve replacement in patients with small annular dimensions is challenging because they are at increased risk for prosthesis–patient mismatch and impaired outcomes. Transcatheter aortic valve replacement might be a good alternative; however, comparative data on different transcatheter heart valves are missing.

Methods and Results—

This multicenter, propensity score–matched study compared hemodynamics and early clinical outcomes in 246 patients with an aortic annulus area <400 mm
2
undergoing transcatheter aortic valve replacement with either a self-expanding transcatheter heart valve (Symetis ACURATE neo, n=129) or a balloon-expandable transcatheter heart valve (Edwards SAPIEN 3, n=117). The 1:1 propensity score matching resulted in 92 matched pairs. For ACURATE neo versus SAPIEN 3-treated patients, 30-day mortality (0.0% versus 1.0%), 1-year mortality (8.3% versus 13.3%), incidence of stroke (3.3% versus 2.2%), life-threatening bleeding (1.1% versus 1.1%), and major vascular complications (2.2% versus 6.5%), as well as pacemaker implantation rate (12.0% versus 15.2%), were similar. Paravalvular regurgitation ≥moderate was rare in both groups (4.5% versus 3.6%). The ACURATE neo presented lower mean transvalvular gradients (9.3 versus 14.5 mm Hg;
P
<0.001), larger indexed effective orifice areas (0.96 versus 0.80 cm
2
/m
2
;
P
=0.003), and lower rates of severe prosthesis–patient mismatch (3% versus 22%;
P
=0.004). Hemodynamics were sustained at 1-year follow-up.

Conclusions—
Albeit a similar safety profile with low clinical event rates, transcatheter aortic valve replacement with the ACURATE neo valve resulted in lower transvalvular gradients and consequently less prosthesis–patient mismatch compared with the SAPIEN 3 in patients with small annulus. These results emphasize the need of careful prosthesis selection in each individual patient.
Isentropic Analysis on the Intensification of Hurricane Edouard (2014)
Authors: Fang Juan , Pauluis Olivier , Zhang Fuqing 
Published: September 2017

Abstract
An isentropic analysis technique is adopted in this study to investigate the intensification of Hurricane Edouard (2014) predicted by an experimental real-time convection-permitting hurricane analysis and forecast system. This technique separates the vertical mass transport in terms of equivalent potential temperature θe for the rising air parcels at high entropy from the subsiding air at low entropy. It is found that as Edouard intensifies the vertical circulation becomes wider via the expansion of upward (downward) mass flux to higher (lower) θe. In the early developing stages, the asymmetric convection dominates the vertical circulation and leads to a remarkable upward mass flux maximum center in the upper troposphere. When Edouard becomes intense, the axisymmetric convection becomes important to the upper-level vertical mass transport while the asymmetric convection still dominates the low-level vertical mass transport. Development of the warm core in the eye leads to double maxima along the θe axis for both the isentropic-mean relative humidity and tangential velocity. The isentropic-mean properties such as the mid- to upper-level relative humidity, vertical velocity, and radial outflow decrease considerably while the mid- to upper-level vorticity enhances on the high-θe side before the onset of rapid intensification. The isentropic analysis also reveals that as Edouard intensifies the eye characterized by warm and dry core first forms in the low to middle troposphere and then gradually expands upward. The abovementioned results indicate that the isentropic framework may have the advantages of binning common variables with θe that could reflect the changes of the tropical cyclone structure in the inner-core region without a prior specification of the location of the storm center.