bluuebunny/crossref_metadata_2025_split huggingface dataset:
A deep subglacial embayment adjacent to the grounding line of Institute Ice Stream, West Antarctica
Authors: Jeofry Hafeez , Ross Neil , Corr Hugh F. J. , Li Jilu , Gogineni Prasad , Siegert Martin J. 
Published: June 2017

Abstract
The Institute Ice Stream (IIS) in West Antarctica may be increasingly vulnerable to melting at the grounding line through modifications in ocean circulation. Understanding such change requires knowledge of grounding-line boundary conditions, including the topography on which it rests. Here, we discuss evidence from new radio-echo sounding (RES) data on the subglacial topography adjacent to the grounding line of the IIS. In doing so, we reveal a previously unknown subglacial embayment immediately inland of the IIS grounding zone which is not represented in the Bedmap2 compilation. We discuss whether there is an open-water connection between the embayment and the ice-shelf cavity. The exact location of the grounding line over the embayment has been the subject of considerable uncertainty, with several positions being proposed recently. From our compilation of data, we are able to explain which of these grounding lines is most likely and, in doing so, highlight the need for accurate bed topography in conjunction with satellite observations to fully comprehend ice-sheet processes in this region and other vulnerable locations at the grounded margin of Antarctica.
Comparison of the VTA and LC response to methylphenidate: a concomitant behavioral and neuronal study of adolescent male rats
Authors: Karim Tahseen J. , Reyes-Vazquez Cruz , Dafny Nachum 
Published: June 2017

Methylphenidate (MPD), also known as Ritalin, is a psychostimulant used to treat attention deficit hyperactivity disorder. However, it is increasingly being misused by normal adolescents for recreation and academic advantage. Therefore, it is important to elucidate the behavioral and neurophysiological effects of MPD in normal subjects. MPD inhibits the reuptake of catecholamines, mainly found in the ventral tegmental area (VTA) and locus coeruleus (LC). The VTA and LC normally mediate attention, motivation, and drug reward behaviors. Selective neuronal connections between the VTA and LC have been identified implicating regular interaction between the structures. The objective of this study was to compare the neuronal responses of the VTA and LC to MPD in normal adolescent rats. Animals were implanted with permanent electrodes in the VTA and LC, and neuronal units were recorded following acute and repetitive (chronic) saline or 0.6, 2.5, or 10.0 mg/kg MPD exposure. Animals displayed either behavioral sensitization or tolerance to all three doses of MPD. Acute MPD exposure elicited excitation in the majority of all VTA and LC units. Chronic MPD exposure elicited a further increase in VTA and LC neuronal activity in animals exhibiting behavioral sensitization and an attenuation in VTA and LC neuronal activity in animals exhibiting behavioral tolerance, demonstrating neurophysiological sensitization and tolerance, respectively. The similar pattern in VTA and LC unit activity suggests that the two structures are linked in their response to MPD. These results may help determine the exact mechanism of action of MPD, resulting in optimized treatment of patients. NEW & NOTEWORTHY The same dose of 0.6, 2.5, and 10 mg/kg methylphenidate (MPD) elicits either behavioral sensitization or tolerance in adolescent rats. There is a direct correlation between the ventral tegmental area (VTA) and locus coeruleus (LC) neuronal response to chronic MPD exposure. Both the VTA and LC are involved in the behavioral and neurophysiological effects of chronic MPD.
High-frequency epidural stimulation across the respiratory cycle evokes phrenic short-term potentiation after incomplete cervical spinal cord injury
Authors: Gonzalez-Rothi Elisa J. , Streeter Kristi A. , Hanna Marie H. , Stamas Anna C. , Reier Paul J. , Baekey David M. , Fuller David D. 
Published: June 2017

C2 spinal hemilesion (C2Hx) paralyzes the ipsilateral diaphragm, but recovery is possible through activation of “crossed spinal” synaptic inputs to ipsilateral phrenic motoneurons. We tested the hypothesis that high-frequency epidural stimulation (HF-ES) would potentiate ipsilateral phrenic output after subacute and chronic C2Hx. HF-ES (300 Hz) was applied to the ventrolateral C4 or T2 spinal cord ipsilateral to C2Hx in anesthetized and mechanically ventilated adult rats. Stimulus duration was 60 s, and currents ranged from 100 to 1,000 µA. Bilateral phrenic nerve activity and ipsilateral hypoglossal (XII) nerve activity were recorded before and after HF-ES. Higher T2 stimulus currents potentiated ipsilateral phasic inspiratory activity at both 2 and 12 wk post-C2Hx, whereas higher stimulus currents delivered at C4 potentiated ipsilateral phasic phrenic activity only at 12 wk ( P = 0.028). Meanwhile, tonic output in the ipsilateral phrenic nerve reached 500% of baseline values at the high currents with no difference between 2 and 12 wk. HF-ES did not trigger inspiratory burst-frequency changes. Similar responses occurred following T2 HF-ES. Increases in contralateral phrenic and XII nerve output were induced by C4 and T2 HF-ES at higher currents, but the relative magnitude of these changes was small compared with the ipsilateral phrenic response. We conclude that following incomplete cervical spinal cord injury, HF-ES of the ventrolateral midcervical or thoracic spinal cord can potentiate efferent phrenic motor output with little impact on inspiratory burst frequency. However, the substantial increases in tonic output indicate that the uninterrupted 60-s stimulation paradigm used is unlikely to be useful for respiratory muscle activation after spinal injury. NEW & NOTEWORTHY Previous studies reported that high-frequency epidural stimulation (HF-ES) activates the diaphragm following acute spinal transection. This study examined HF-ES and phrenic motor output following subacute and chronic incomplete cervical spinal cord injury. Short-term potentiation of phrenic bursting following HF-ES illustrates the potential for spinal stimulation to induce respiratory neuroplasticity. Increased tonic phrenic output indicates that alternatives to the continuous stimulation paradigm used in this study will be required for respiratory muscle activation after spinal cord injury.
An Immunosuppressive Dendritic Cell Subset Accumulates at Secondary Sites and Promotes Metastasis in Pancreatic Cancer
Authors: Kenkel Justin A. , Tseng William W. , Davidson Matthew G. , Tolentino Lorna L. , Choi Okmi , Bhattacharya Nupur , Seeley E. Scott , Winer Daniel A. , Reticker-Flynn Nathan E. , Engleman Edgar G. 
Published: June 2017

Abstract
Pancreatic ductal adenocarcinoma (PDAC) after complete surgical resection is often followed by distant metastatic relapse for reasons that remain unclear. In this study, we investigated how the immune response at secondary sites affects tumor spread in murine models of metastatic PDAC. Early metastases were associated with dense networks of CD11b+CD11c+MHC-II+CD24+CD64lowF4/80low dendritic cells (DC), which developed from monocytes in response to tumor-released GM-CSF. These cells uniquely expressed MGL2 and PD-L2 in the metastatic microenvironment and preferentially induced the expansion of T regulatory cells (Treg) in vitro and in vivo. Targeted depletion of this DC population in Mgl2DTR hosts activated cytotoxic lymphocytes, reduced Tregs, and inhibited metastasis development. Moreover, blocking PD-L2 selectively activated CD8 T cells at secondary sites and suppressed metastasis, suggesting that the DCs use this particular pathway to inhibit CD8 T-cell–mediated tumor immunity. Phenotypically similar DCs accumulated at primary and secondary sites in other models and in human PDAC. These studies suggest that a discrete DC subset both expands Tregs and suppresses CD8 T cells to establish an immunosuppressive microenvironment conducive to metastasis formation. Therapeutic strategies to block the accumulation and immunosuppressive activity of such cells may help prevent PDAC progression and metastatic relapse after surgical resection. Cancer Res; 77(15); 4158–70. ©2017 AACR.
Smurf2-Mediated Stabilization of DNA Topoisomerase IIα Controls Genomic Integrity
Authors: Emanuelli Andrea , Borroni Aurora P. , Apel-Sarid Liat , Shah Pooja A. , Ayyathan Dhanoop Manikoth , Koganti Praveen , Levy-Cohen Gal , Blank Michael 
Published: June 2017

Abstract
DNA topoisomerase IIα (Topo IIα) ensures genomic integrity and unaltered chromosome inheritance and serves as a major target of several anticancer drugs. Topo IIα function is well understood, but how its expression is regulated remains unclear. Here, we identify the E3 ubiquitin ligase Smurf2 as a physiologic regulator of Topo IIα levels. Smurf2 physically interacted with Topo IIα and modified its ubiquitination status to protect Topo IIα from the proteasomal degradation in dose- and catalytically dependent manners. Smurf2-depleted cells exhibited a reduced ability to resolve DNA catenanes and pathological chromatin bridges formed during mitosis, a trait of Topo IIα–deficient cells and a hallmark of chromosome instability. Introducing Topo IIα into Smurf2-depleted cells rescued this phenomenon. Smurf2 was a determinant of Topo IIα protein levels in normal and cancer cells and tissues, and its levels affected cell sensitivity to the Topo II–targeting drug etoposide. Our results identified Smurf2 as an essential regulator of Topo IIα, providing novel insights into its control and into the suggested tumor-suppressor functions of Smurf2. Cancer Res; 77(16); 4217–27. ©2017 AACR.
Targeting SRC Coactivators Blocks the Tumor-Initiating Capacity of Cancer Stem-like Cells
Authors: Rohira Aarti D. , Yan Fei , Wang Lei , Wang Jin , Zhou Suoling , Lu Andrew , Yu Yang , Xu Jianming , Lonard David M. , O'Malley Bert W. 
Published: June 2017

Abstract
Tumor-initiating cells (TIC) represent cancer stem-like cell (CSC) subpopulations within tumors that are thought to give rise to recurrent cancer after therapy. Identifying key regulators of TIC/CSC maintenance is essential for the development of therapeutics designed to limit recurrence. The steroid receptor coactivator 3 (SRC-3) is overexpressed in a wide range of cancers, driving tumor initiation, cell proliferation, and metastasis. Here we report that SRC-3 supports the TIC/CSC state and induces an epithelial-to-mesenchymal transition (EMT) by driving expression of the master EMT regulators and stem cell markers. We also show that inhibition of SRC-3 and SRC-1 with SI-2, a second-generation SRC-3/SRC-1 small-molecule inhibitor, targets the CSC/TIC population both in vitro and in vivo. Collectively, these results identify SRC coactivators as regulators of stem-like capacity in cancer cells and that these coactivators can serve as potential therapeutic targets to prevent the recurrence of cancer. Cancer Res; 77(16); 4293–304. ©2017 AACR.
β-Catenin Is a Candidate Therapeutic Target for Myeloid Neoplasms with del(5q)
Authors: Li Liping , Sheng Yue , Li Wenshu , Hu Chao , Mittal Nupur , Tohyama Kaoru , Seba Amber , Zhao You-Yang , Ozer Howard , Zhu Tongyu , Qian Zhijian 
Published: June 2017

Abstract
Deletion of the chromosome 5q [del(5q)] is one of the most common cytogenetic abnormalities observed in patients with de novo myelodysplastic syndromes (MDS) and therapy-related MDS or acute myeloid leukemia (t-MDS/tAML). Emerging evidence indicates that activation of the Wnt/β-catenin pathway contributes to the development of myeloid neoplasms with del(5q). Whether β-catenin is a potential therapeutic target for myeloid neoplasms with del(5q) has yet to be evaluated. Here, we report that genetic deletion of a single allele of β-catenin rescues ineffective hematopoiesis in an Apc haploinsufficient mouse model, which recapitulates several characteristic features of the preleukemic stage of myeloid neoplasms with a −5/del(5q). In addition, loss of a single allele of β-catenin reversed the defective self-renewal capacity of Apc-haploinsufficient hematopoietic stem cells and reduced the frequency of apoptosis induced by Apc haploinsufficiency. Suppression of β-catenin by indomethacin or β-catenin shRNA reduced proliferation and survival of human leukemia cell lines with del(5q) but not of control leukemia cell lines in vitro; β-catenin inactivation also inhibited leukemia progression in vivo in xenograft mice reconstituted with del(5q) leukemia cell lines. Inhibition of β-catenin also stunted growth and colony-forming abilities of primary bone marrow cells from del(5q) AML patients in vitro. Overall, our data support the idea that β-catenin could serve as a therapeutic target for the treatment of myeloid neoplasms with del(5q). Cancer Res; 77(15); 4116–26. ©2017 AACR.
Phase I Dose-Escalation and -Expansion Study of the BRAF Inhibitor Encorafenib (LGX818) in Metastatic BRAF-Mutant Melanoma
Authors: Delord Jean-Pierre , Robert Caroline , Nyakas Marta , McArthur Grant A. , Kudchakar Ragini , Mahipal Amit , Yamada Yasuhide , Sullivan Ryan , Arance Ana , Kefford Richard F. , Carlino Matteo S. , Hidalgo Manuel , Gomez-Roca Carlos , Michel Daniela , Seroutou Abdelkader , Aslanis Vassilios , Caponigro Giordano , Stuart Darrin D. , Moutouh-de Parseval Laure , Demuth Tim , Dummer Reinhard 
Published: June 2017

Abstract
Purpose: Encorafenib, a selective BRAF inhibitor (BRAFi), has a pharmacologic profile that is distinct from that of other clinically active BRAFis. We evaluated encorafenib in a phase I study in patients with BRAFi treatment-naïve and pretreated BRAF-mutant melanoma.
Experimental Design: The pharmacologic activity of encorafenib was first characterized preclinically. Encorafenib monotherapy was then tested across a range of once-daily (50–700 mg) or twice-daily (75–150 mg) regimens in a phase I, open-label, dose-escalation and -expansion study in adult patients with histologically confirmed advanced/metastatic BRAF-mutant melanoma. Study objectives were to determine the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D), characterize the safety and tolerability and pharmacokinetic profile, and assess the preliminary antitumor activity of encorafenib.
Results: Preclinical data demonstrated that encorafenib inhibited BRAF V600E kinase activity with a prolonged off-rate and suppressed proliferation and tumor growth of BRAF V600E–mutant melanoma models. In the dose-escalation phase, 54 patients (29 BRAFi-pretreated and 25 BRAFi-naïve) were enrolled. Seven patients in the dose-determining set experienced dose-limiting toxicities. Encorafenib at a dose of 300 mg once daily was declared the RP2D. In the expansion phase, the most common all-cause adverse events were nausea (66%), myalgia (63%), and palmar–plantar erythrodysesthesia (54%). In BRAFi-naïve patients, the overall response rate (ORR) and median progression-free survival (mPFS) were 60% and 12.4 months [95% confidence interval (CI), 7.4–not reached (NR)]. In BRAFi-pretreated patients, the ORR and mPFS were 22% and 1.9 months (95% CI, 0.9–3.7).
Conclusions: Once-daily dosing of single-agent encorafenib had a distinct tolerability profile and showed varying antitumor activity across BRAFi-pretreated and BRAFi-naïve patients with advanced/metastatic melanoma. Clin Cancer Res; 23(18); 5339–48. ©2017 AACR.
Clinical and Genome-Wide Analysis of Cisplatin-Induced Peripheral Neuropathy in Survivors of Adult-Onset Cancer
Authors: Dolan M. Eileen , El Charif Omar , Wheeler Heather E. , Gamazon Eric R. , Ardeshir-Rouhani-Fard Shirin , Monahan Patrick , Feldman Darren R. , Hamilton Robert J. , Vaughn David J. , Beard Clair J. , Fung Chunkit , Kim Jeri , Fossa Sophie D. , Hertz Daniel L , Mushiroda Taisei , Kubo Michiaki , Einhorn Lawrence H. , Cox Nancy J. , Travis Lois B. 
Published: June 2017

AbstractPurpose: Our purpose was to characterize the clinical influences, genetic risk factors, and gene mechanisms contributing to persistent cisplatin-induced peripheral neuropathy (CisIPN) in testicular cancer survivors (TCSs).Experimental Design: TCS given cisplatin-based therapy completed the validated EORTC QLQ-CIPN20 questionnaire. An ordinal CisIPN phenotype was derived, and associations with age, smoking, excess drinking, hypertension, body mass index, diabetes, hypercholesterolemia, cumulative cisplatin dose, and self-reported health were examined for 680 TCS. Genotyping was performed on the Illumina HumanOmniExpressExome chip. Following quality control and imputation, 5.1 million SNPs in 680 genetically European TCS formed the input set. GWAS and PrediXcan were used to identify genetic variation and genetically determined gene expression traits, respectively, contributing to CisIPN. We evaluated two independent datasets for replication: Vanderbilt's electronic health database (BioVU) and the CALGB 90401 trial.Results: Eight sensory items formed a subscale with good internal consistency (Cronbach α = 0.88). Variables significantly associated with CisIPN included age at diagnosis (OR per year, 1.06; P = 2 × 10−9), smoking (OR, 1.54; P = 0.004), excess drinking (OR, 1.83; P = 0.007), and hypertension (OR, 1.61; P = 0.03). CisIPN was correlated with lower self-reported health (OR, 0.56; P = 2.6 × 10−9) and weight gain adjusted for years since treatment (OR per Δkg/m2, 1.05; P = 0.004). PrediXcan identified lower expressions of MIDN and RPRD1B, and higher THEM5 expression as associated with CisIPN (P value for each &lt; 5 × 10−6) with replication of RPRD1B meeting significance criteria (Fisher combined P = 0.0089).Conclusions: CisIPN is associated with age, modifiable risk factors, and genetically determined expression level of RPRD1B. Further study of implicated genes could elucidate the pathophysiologic underpinnings of CisIPN. Clin Cancer Res; 23(19); 5757–68. ©2017 AACR.
Dendritic Cell/Cytokine-Induced Killer Cell Immunotherapy Combined with S-1 in Patients with Advanced Pancreatic Cancer: A Prospective Study
Authors: Jiang Ni , Qiao Guoliang , Wang Xiaoli , Morse Michael A. , Gwin William R. , Zhou Lei , Song Yuguang , Zhao Yanjie , Chen Feng , Zhou Xinna , Huang Lefu , Hobeika Amy , Yi Xin , Xia Xuefeng , Guan Yanfang , Song Jin , Ren Jun , Lyerly H. Kim 
Published: June 2017

AbstractPurpose: Advanced pancreatic cancer has remained challenging to treat effectively. This study aimed to investigate the clinical effects and safety of immunotherapy with dendritic cells and cytokine-induced killer cells (DC-CIK) administered with the chemotherapy (CT) S-1 in this malignancy.Experimental Design: Consecutive patients (n = 47) with advanced pancreatic cancer were treated with either DC-CIK + S-1, DC-CIK alone, S-1 alone, or best supportive care.Results: DC-CIK plus S-1 produced significantly longer median OS and PFS (212 and 136 days) compared with DC-CIK (128 and 85 days), CT (141 and 92 days), or supportive care only (52 and 43 days; P &lt; 0.001). After adjusting for competing risk factors, DC-CIK combined with S-1 and receipt of 2 or more cycles of DC-CIK treatment remained independent predictors of disease-free and overall survival (P &lt; 0.05). Phenotypic analysis of PBMCs demonstrated that the CD3+, CD3+/CD4+, and CD8+/CD28+ T-cell subsets were elevated (P &lt; 0.05), while the CD3+/CD8+, CD3+/CD16+/CD56+ and CD4+/CD25+ cell subsets were significantly decreased after DC-CIK cell therapy (P &lt; 0.05). There were no grade 3 or 4 toxicities. In addition, the mutational frequency in cell-free tumor DNA (cfDNA) declined in 4 of 14 patients who received DC-CIK, and was associated with a more favorable survival.Conclusions: Treatment of advanced pancreatic cancer with combined DC-CIK infusions and S-1 was safe, resulted in favorable PFS and OS, and modulated the peripheral blood immune repertoire. Clin Cancer Res; 23(17); 5066–73. ©2017 AACR.
U.S. Food and Drug Administration Approval Summary: Atezolizumab for Metastatic Non–Small Cell Lung Cancer
Authors: Weinstock Chana , Khozin Sean , Suzman Daniel , Zhang Lijun , Tang Shenghui , Wahby Sakar , Goldberg Kirsten B. , Kim Geoffrey , Pazdur Richard 
Published: June 2017

Abstract
On October 18, 2016, the FDA approved atezolizumab (TECENTRIQ; Genentech, Inc.) for treatment of patients with metastatic non–small cell lung cancer (mNSCLC) whose disease progressed during or following platinum-containing chemotherapy. Approval was based on demonstration of clinically meaningful improvements in overall survival (OS) and an acceptable safety profile in two randomized clinical trials (OAK and POPLAR). Median OS in OAK, a phase III trial, was 13.8 months [95% confidence interval (CI), 11.8–15.7] in the atezolizumab arm compared with 9.6 months (95% CI, 8.6–11.2) in the docetaxel arm [hazard ratio (HR) = 0.74; 95% CI, 0.63–0.87; P = 0.0004]. Median OS in POPLAR, a phase II trial, was 12.6 months (95% CI, 9.7–16.0) and 9.7 months (95% CI, 8.6–12.0; HR = 0.69; 95% CI, 0.52–0.92) for the atezolizumab and docetaxel arms, respectively. In patients treated with atezolizumab, the most common (≥20%) adverse reactions were fatigue, decreased appetite, dyspnea, cough, nausea, musculoskeletal pain, and constipation; the most common (≥2%) grade 3 to 4 adverse events were dyspnea, pneumonia, hypoxia, hyponatremia, fatigue, anemia, musculoskeletal pain, aspartate aminotransferase increase, alanine aminotransferase increase, dysphagia, and arthralgia. Clinically significant immune-related adverse events for patients receiving atezolizumab included 1.4% incidence each of grade 3 to 4 pneumonitis, hepatitis, colitis, and thyroid disease. Clin Cancer Res; 23(16); 4534–9. ©2017 AACR.
An In Vivo Functional Screen Identifies JNK Signaling As a Modulator of Chemotherapeutic Response in Breast Cancer
Authors: Ashenden Matthew , van Weverwijk Antoinette , Murugaesu Nirupa , Fearns Antony , Campbell James , Gao Qiong , Iravani Marjan , Isacke Clare M. 
Published: June 2017

Abstract
Chemotherapy remains the mainstay of treatment for advanced breast cancer; however, resistance is an inevitable event for the majority of patients with metastatic disease. Moreover, there is little information available to guide stratification of first-line chemotherapy, crucial given the common development of multidrug resistance. Here, we describe an in vivo screen to interrogate the response to anthracycline-based chemotherapy in a syngeneic metastatic breast cancer model and identify JNK signaling as a key modulator of chemotherapy response. Combining in vitro and in vivo functional analyses, we demonstrate that JNK inhibition both promotes tumor cell cytostasis and blocks activation of the proapoptotic protein Bax, thereby antagonizing chemotherapy-mediated cytotoxicity. To investigate the clinical relevance of this dual role of JNK signaling, we developed a proliferation-independent JNK activity signature and demonstrate high JNK activity to be enriched in triple-negative and basal-like breast cancer subtypes. Consistent with the dual role of JNK signaling in vitro, high-level JNK pathway activation in triple-negative breast cancers is associated both with poor patient outcome in the absence of chemotherapy treatment and, in neoadjuvant clinical studies, is predictive of enhanced chemotherapy response. These data highlight the potential of monitoring JNK activity as early biomarker of response to chemotherapy and emphasize the importance of rational treatment regimes, particularly when combining cytostatic and chemotherapeutic agents. Mol Cancer Ther; 16(9); 1967–78. ©2017 AACR.