bluuebunny/crossref_metadata_2025_split huggingface dataset:
HPV self-sampling in CIN2+ detection: sensitivity and specificity of different RLU cut-off of HC2 in specimens from 786 women
Authors: Bottari F , Igidbashian S , Boveri S , Tricca A , Gulmini C , Sesia M , Spolti N , Sideri M , Landoni F , Sandri M T 
Published: September 2016

AimsMortality for cervical cancer varies between the different regions of the world, with high rates in low-income countries where screening programmes are not present and organised. However, increasing screening coverage is still a priority in all countries: one way to do that is to base screening on self-sampled screening. The success of a self-sampling screening strategy depends on capacity to recruit unscreened women, on the performance and acceptability of the device and on the clinical performance of the high-risk human papillomavirus (HPV) test.MethodsThis study based on 786 enrolled women investigates the best cut-off value of Hybrid Capture 2 HPV test (HC2) for self-sampled specimens in terms of sensitivity and specificity.ResultsIn this population, we found that the sensitivity and the specificity for cervical intraepithelial neoplasia grade 2 or more detection of HC2 performed on self-sampled specimens were 82.5% and 82.8%, respectively considering the relative light units (RLU) cut-off value of 1. Increasing the cut-off value the sensitivity decreases and the specificity raises and the best area under the curve for the RLU cut-off value is 1.ConclusionsOur results confirm that the cut-off value of 1 suggested by Qiagen for PreservCyt specimen is the best cut-off value also for self-sampled specimens.
Vasopressin analog terlipressin attenuates kidney injury in hemorrhagic shock
Authors: Cardoso de Castro Letícia Urbano , Ida Keila Kazue , Otsuki Denise Aya , Sanches Talita Rojas , Volpini Rildo A , Borges Emilyn da Silva , Malbouisson Luiz-Marcelo Sá , Andrade Lúcia 
Published: September 2016

BackgroundIn hemorrhagic shock (HS), volume replacement with crystalloid solution can restore the hemodynamic status and decrease mortality. However, it can also lead to tissue edema and pulmonary congestion, as well as increasing vascular permeability. Here, we analyzed the effects that resuscitation with lactated Ringer's solution (LRS) or administration of the vasopressin analog terlipressin has on renal function in a porcine model of HS.MethodsUsing pressure-controlled bleeding, we induced pigs to HS, maintaining mean arterial pressure (MAP) at 40 mm Hg for 30 min. Animals were divided into 4 groups: sham (anesthesia only); shock-only (HS induction); shock+LRS (HS induction and subsequent resuscitation with LRS at 3 times the volume of blood removed); and shock+Terli (HS induction and subsequent bolus administration of 2 mg of terlipressin). Parameters were evaluated at baseline, then at 30, 60, and 120 min after treatment (T30, T60, and T120, respectively). Animals were euthanized at T60 or T120.ResultsBoth treatments restored MAP to baseline values. At T30 and T60, creatinine clearance was highest in shock+LRS pigs, whereas it was highest in shock+Terli pigs at T120. Both treatments initially induced hyponatremia, although urinary excretion of all ions was higher in shock+LRS pigs at T30. Both treatments restored Na–K–2Cl cotransporter expression, whereas only terlipressin restored aquaporin 2 expression. Both treatments also prevented HS-induced acute tubular necrosis. Expression of the vasopressin receptors V1a and V2 was highest in shock-only pigs. At T120, V1a expression was lowest in shock+LRS pigs.DiscussionTerlipressin might be useful for preventing HS-induced acute kidney injury.
Occurrence and development of folding related to normal faulting within a mechanically heterogeneous sedimentary sequence: a case study from Inner Moray Firth, UK
Authors: Lăpădat A. , Imber J. , Yielding G. , Iacopini D. , McCaffrey K. J. W. , Long J. J. , Jones R. R. 
Published: September 2016

Abstract

Folds associated with normal faults are potential hydrocarbon traps and may impact the connectivity of faulted reservoirs. Well-calibrated seismic reflection data that image a normal fault system from the Inner Moray Firth basin, offshore Scotland, show that folding was preferentially localized within the mechanically incompetent Lower–Middle Jurassic pre-rift interval, comprising interbedded shales and sandstones, and within Upper Jurassic syn-rift shales. Upward propagation of fault tips was initially inhibited by these weak lithologies, generating fault propagation folds with amplitudes of
c.
50 m. Folds were also generated, or amplified, by translation of the hanging wall over curved, convex-upward fault planes. These fault bends resulted from vertical fault segmentation and linkage within mechanically incompetent layers. The relative contributions of fault propagation and fault-bend folding to the final fold amplitude may vary significantly along the strike of a single fault array. In areas where opposite-dipping, conjugate normal faults intersect, the displacement maxima are skewed upwards towards the base of the syn-rift sequence (i.e. the free surface at the time of fault initiation) and significant fault propagation folding did not occur. These observations can be explained by high compressive stresses generated in the vicinity of conjugate fault intersections, which result in asymmetric displacement distributions, skewed towards the upper tip, with high throw gradients enhancing upward fault propagation. Our observations suggest that mechanical interaction between faults, in addition to mechanical stratigraphy, is a key influence on the occurrence of normal fault-related folding, and controls kinematic parameters such as fault propagation/slip ratios and displacement rates.
Coupled THM modelling of engineered barriers for the final disposal of spent nuclear fuel isolation
Authors: Toprak Erdem , Olivella Sebastia , Pintado Xavier 
Published: September 2016

Abstract
This paper describes the thermohydromechanical (THM) simulation of engineered barrier systems (EBS) for the final disposal of nuclear spent fuel in Finland. The bentonite barriers were simulated with the Barcelona Basic Model and the model was calibrated from laboratory tests. The evolution of gap closure and the presence of a fracture intersecting the disposal were analysed. The simulations were performed in 2D axisymmetrical geometries. Full 3D simulations were carried out in order to check the effect of the third dimension. The time required for the barriers to reach full saturation, the maximum temperature, deformations and displacements at the buffer–backfill interface and the homogenization of components both locally and globally are the main interests. The effect of rock fracture and the hydraulic conductivity of the rock are subjected to 2D sensitivity analyses.
Polycyclic scoria cones of the Antofagasta de la Sierra basin, Southern Puna plateau, Argentina
Authors: Báez Walter , Carrasco Nuñez Gerardo , Giordano Guido , Viramonte José G. , Chiodi Agostina 
Published: September 2016

Abstract
Despite a number of published papers focusing on the geodynamic implications of the recent Southern Puna mafic magmatism, there have been fewer studies of the volcanology and stratigraphy of this outstanding volcanism. This paper presents a detailed map of two well-preserved Quaternary scoria cones showing their complex stratigraphy. Complementary morphometric, morpho-structural, petrographic and geochemical data were used to reconstruct the evolution of both volcanoes. The occurrence of more than one eruption at each volcano was inferred by the recognition of temporal hiatuses using morpho-stratigraphic criteria. The polycyclic nature of both scoria cones could be related to a combination of a high input magma in response to lithospheric delamination, a favourable regional stress field and the interaction of rising magma with pre-existing faults. The youngest eruptions in both volcanoes were complex, with shifts in the eruptive style from violent strombolian to hawaiian/strombolian phases, and probably lasted for a few years. The explosive activity was accompanied by the emission of lava flows from lateral vents. Phreatomagmatic activity was triggered during the waning stages of the eruptions. The occurrence of more than one eruption in a single scoria cone and the changes in the eruptive style during long-lasting eruptions are important topics for volcanic hazard assessment in the Southern Puna.
Neogene monogenetic volcanism from the Northern Puna region: products and eruptive styles
Authors: Maro Guadalupe , Caffe Pablo J. 
Published: September 2016

Abstract

The Neogene mafic volcanism of the Northern Puna region in the Central Andes is represented by scoria cones and lava flows dispersed over a wide region (
c.
9150 km
2
) as isolated or poorly clustered centres. Although all the products are basaltic andesites to andesites, the behaviour of these magmatic systems resembles that seen in basaltic monogenetic fields. These centres were studied with the aim of defining the main volcanic lithofacies and evaluating the eruptive styles. The results suggest that the eruptions developed under a dry strombolian dynamic, with brief periods of lava fountaining and hydrovolcanism, the latter usually restricted to the early stages of cone construction. Changes in eruptive style are thought to be caused by variations in both the internal (e.g. magma ascent) and external (e.g. surficial water availability) conditions. The transitions do not reflect compositional changes, as evidenced by the small chemical differences observed among the products of the studied eruptive centres. Stratigraphic analysis, in addition to a few pre-existing radiometric dates, suggests that this volcanic activity occurred during the Late Miocene to Early Pliocene. This information supports the inference that these eruptions occurred before the peak of Southern Puna mafic volcanism and that they were coeval with eruptions of some of the most important silicic calderas of the Altiplano-Puna Volcanic Complex. The good preservation of volcanic edifices reveals that erosion rates were extremely low, in agreement with the high aridity conditions that have prevailed in the Puna region since the Mid- to Late Miocene.
FGF2 from Marrow Microenvironment Promotes Resistance to FLT3 Inhibitors in Acute Myeloid Leukemia
Authors: Traer Elie , Martinez Jacqueline , Javidi-Sharifi Nathalie , Agarwal Anupriya , Dunlap Jennifer , English Isabel , Kovacsovics Tibor , Tyner Jeffrey W. , Wong Melissa , Druker Brian J. 
Published: September 2016

Abstract
Potent FLT3 inhibitors, such as quizartinib (AC220), have shown promise in treating acute myeloid leukemia (AML) containing FLT3 internal tandem duplication (ITD) mutations. However, responses are not durable and resistance develops within months. In this study, we outline a two-step model of resistance whereby extrinsic microenvironmental proteins FLT3 ligand (FL) and fibroblast growth factor 2 (FGF2) protect FLT3-ITD+ MOLM14 cells from AC220, providing time for subsequent accumulation of ligand-independent resistance mechanisms. FL directly attenuated AC220 inhibition of FLT3, consistent with previous reports. Conversely, FGF2 promoted resistance through activation of FGFR1 and downstream MAPK effectors; these resistant cells responded synergistically to combinatorial inhibition of FGFR1 and FLT3. Removing FL or FGF2 from ligand-dependent resistant cultures transiently restored sensitivity to AC220, but accelerated acquisition of secondary resistance via reactivation of FLT3 and RAS/MAPK signaling. FLT3-ITD AML patients treated with AC220 developed increased FGF2 expression in marrow stromal cells, which peaked prior to overt clinical relapse and detection of resistance mutations. Overall, these results support a strategy of early combination therapy to target early survival signals from the bone marrow microenvironment, in particular FGF2, to improve the depth of response in FLT3-ITD AML. Cancer Res; 76(22); 6471–82. ©2016 AACR.
Spatial Proximity to Fibroblasts Impacts Molecular Features and Therapeutic Sensitivity of Breast Cancer Cells Influencing Clinical Outcomes
Authors: Marusyk Andriy , Tabassum Doris P. , Janiszewska Michalina , Place Andrew E. , Trinh Anne , Rozhok Andrii I. , Pyne Saumyadipta , Guerriero Jennifer L. , Shu Shaokun , Ekram Muhammad , Ishkin Alexander , Cahill Daniel P. , Nikolsky Yuri , Chan Timothy A. , Rimawi Mothaffar F. , Hilsenbeck Susan , Schiff Rachel , Osborne Kent C. , Letai Antony , Polyak Kornelia 
Published: September 2016

Abstract
Using a three-dimensional coculture model, we identified significant subtype-specific changes in gene expression, metabolic, and therapeutic sensitivity profiles of breast cancer cells in contact with cancer-associated fibroblasts (CAF). CAF-induced gene expression signatures predicted clinical outcome and immune-related differences in the microenvironment. We found that fibroblasts strongly protect carcinoma cells from lapatinib, attributable to its reduced accumulation in carcinoma cells and an elevated apoptotic threshold. Fibroblasts from normal breast tissues and stromal cultures of brain metastases of breast cancer had similar effects as CAFs. Using synthetic lethality approaches, we identified molecular pathways whose inhibition sensitizes HER2+ breast cancer cells to lapatinib both in vitro and in vivo, including JAK2/STAT3 and hyaluronic acid. Neoadjuvant lapatinib therapy in HER2+ breast tumors lead to a significant increase of phospho-STAT3+ cancer cells and a decrease in the spatial proximity of proliferating (Ki67+) cells to CAFs impacting therapeutic responses. Our studies identify CAF-induced physiologically and clinically relevant changes in cancer cells and offer novel approaches for overcoming microenvironment-mediated therapeutic resistance. Cancer Res; 76(22); 6495–506. ©2016 AACR.
Shifts in the Fecal Microbiota Associated with Adenomatous Polyps
Authors: Hale Vanessa L. , Chen Jun , Johnson Stephen , Harrington Sean C. , Yab Tracy C. , Smyrk Thomas C. , Nelson Heidi , Boardman Lisa A. , Druliner Brooke R. , Levin Theodore R. , Rex Douglas K. , Ahnen Dennis J. , Lance Peter , Ahlquist David A. , Chia Nicholas 
Published: September 2016

Abstract
Background: Adenomatous polyps are the most common precursor to colorectal cancer, the second leading cause of cancer-related death in the United States. We sought to learn more about early events of carcinogenesis by investigating shifts in the gut microbiota of patients with adenomas.
Methods: We analyzed 16S rRNA gene sequences from the fecal microbiota of patients with adenomas (n = 233) and without (n = 547).
Results: Multiple taxa were significantly more abundant in patients with adenomas, including Bilophila, Desulfovibrio, proinflammatory bacteria in the genus Mogibacterium, and multiple Bacteroidetes species. Patients without adenomas had greater abundances of Veillonella, Firmicutes (Order Clostridia), and Actinobacteria (family Bifidobacteriales). Our findings were consistent with previously reported shifts in the gut microbiota of colorectal cancer patients. Importantly, the altered adenoma profile is predicted to increase primary and secondary bile acid production, as well as starch, sucrose, lipid, and phenylpropanoid metabolism.
Conclusions: These data hint that increased sugar, protein, and lipid metabolism along with increased bile acid production could promote a colonic environment that supports the growth of bile-tolerant microbes such as Bilophilia and Desulfovibrio. In turn, these microbes may produce genotoxic or inflammatory metabolites such as H2S and secondary bile acids, which could play a role in catalyzing adenoma development and eventually colorectal cancer.
Impact: This study suggests a plausible biological mechanism to explain the links between shifts in the microbiota and colorectal cancer. This represents a first step toward resolving the complex interactions that shape the adenoma–carcinoma sequence of colorectal cancer and may facilitate personalized therapeutics focused on the microbiota. Cancer Epidemiol Biomarkers Prev; 26(1); 85–94. ©2016 AACR.
The Association between Alcohol Consumption and Breast Density: A Systematic Review and Meta-analysis
Authors: Ziembicki Stephanie , Zhu Jie , Tse Elizabeth , Martin Lisa J. , Minkin Salomon , Boyd Norman F. 
Published: September 2016

Abstract
Background: Percent breast density (PBD) is a strong risk factor for breast cancer that is influenced by several other risk factors for the disease. Alcohol consumption is associated with an increased risk of breast cancer with an uncertain association with PBD. We have carried out a systematic review and meta-analysis to examine the association of alcohol consumption with PBD.
Methods: We searched nine databases to identify all relevant studies on the association between alcohol intake and breast density. Two independent investigators evaluated and selected 20 studies that were included in our analyses. We divided the studies into three groups according to the methods used to measure and analyze the association of breast density with alcohol consumption.
Results: Meta-analysis of the 11 studies that used quantitative methods to measure and analyze PBD as a continuous variable found a statistically significant difference in PBD when comparing the highest with the lowest alcohol level [β = 0.84; 95% confidence interval (CI), 0.12–1.56]. Three studies that used quantitative methods to measure PBD and categories of PBD for analysis had a summary OR = 1.81 (95% CI, 1.07–3.04). Five studies that used categories to classify PBD and analyze their association with alcohol intake had a summary OR = 1.78 (95% CI, 0.90–3.51).
Conclusions: These results suggest that there is a positive association between alcohol intake and PBD.
Impact: Alcohol may increase the risk of breast cancer associated with PBD. Cancer Epidemiol Biomarkers Prev; 26(2); 170–8. ©2016 AACR.
Development of a Novel Antibody–Drug Conjugate for the Potential Treatment of Ovarian, Lung, and Renal Cell Carcinoma Expressing TIM-1
Authors: Thomas Lawrence J. , Vitale Laura , O'Neill Thomas , Dolnick Ree Y. , Wallace Paul K. , Minderman Hans , Gergel Lauren E. , Forsberg Eric M. , Boyer James M. , Storey James R. , Pilsmaker Catherine D. , Hammond Russell A. , Widger Jenifer , Sundarapandiyan Karuna , Crocker Andrea , Marsh Henry C. , Keler Tibor 
Published: September 2016

AbstractT-cell immunoglobulin and mucin domain 1 (TIM-1) is a type I transmembrane protein that was originally described as kidney injury molecule 1 (KIM-1) due to its elevated expression in kidney and urine after renal injury. TIM-1 expression is also upregulated in several human cancers, most notably in renal and ovarian carcinomas, but has very restricted expression in healthy tissues, thus representing a promising target for antibody-mediated therapy. To this end, we have developed a fully human monoclonal IgG1 antibody specific for the extracellular domain of TIM-1. This antibody was shown to bind purified recombinant chimeric TIM-1-Fc protein and TIM-1 expressed on a variety of transformed cell lines, including Caki-1 (human renal clear cell carcinoma), IGROV-1 (human ovarian adenocarcinoma), and A549 (human lung carcinoma). Internalization studies using confocal microscopy revealed the antibody was rapidly internalized by cells in vitro, and internalization was confirmed by quantitative imaging flow cytometry. An antibody–drug conjugate (ADC) was produced with the anti-TIM-1 antibody covalently linked to the potent cytotoxin, monomethyl auristatin E (MMAE), and designated CDX-014. The ADC was shown to exhibit in vitro cytostatic or cytotoxic activity against a variety of TIM-1–expressing cell lines, but not on TIM-1–negative cell lines. Using the Caki-1, IGROV-1, and A549 xenograft mouse models, CDX-014 showed significant antitumor activity in a clinically relevant dose range. Safety evaluation in nonhuman primates has demonstrated a good profile and led to the initiation of clinical studies of CDX-014 in renal cell carcinoma and potentially other TIM-1–expressing tumors. Mol Cancer Ther; 15(12); 2946–54. ©2016 AACR.
AXL Inhibition Suppresses the DNA Damage Response and Sensitizes Cells to PARP Inhibition in Multiple Cancers
Authors: Balaji Kavitha , Vijayaraghavan Smruthi , Diao Lixia , Tong Pan , Fan Youhong , Carey Jason P.W. , Bui Tuyen N. , Warner Steve , Heymach John V. , Hunt Kelly K. , Wang Jing , Byers Lauren Averett , Keyomarsi Khandan 
Published: September 2016

Abstract
Epithelial to mesenchymal transition (EMT) is associated with a wide range of changes in cancer cells, including stemness, chemo- and radio-resistance, and metastasis. The mechanistic role of upstream mediators of EMT has not yet been well characterized. Recently, we showed that non–small cell lung cancers (NSCLC) that have undergone EMT overexpress AXL, a receptor tyrosine kinase. AXL is also overexpressed in a subset of triple-negative breast cancers (TNBC) and head and neck squamous cell carcinomas (HNSCC), and its overexpression has been associated with more aggressive tumor behavior and linked to resistance to chemotherapy, radiotherapy, and targeted therapy. Because the DNA repair pathway is also altered in patient tumor specimens overexpressing AXL, it is hypothesized that modulation of AXL in cells that have undergone EMT will sensitize them to agents targeting the DNA repair pathway. Downregulation or inhibition of AXL directly reversed the EMT phenotype, led to decreased expression of DNA repair genes, and diminished efficiency of homologous recombination (HR) and RAD51 foci formation. As a result, AXL inhibition caused a state of HR deficiency in the cells, making them sensitive to inhibition of the DNA repair protein, PARP1. AXL inhibition synergized with PARP inhibition, leading to apoptotic cell death. AXL expression also associated positively with markers of DNA repair across TNBC, HNSCC, and NSCLC patient cohorts.
Implications: The novel role for AXL in DNA repair, linking it to EMT, suggests that AXL can be an effective therapeutic target in combination with targeted therapy such as PARP inhibitors in several different malignancies. Mol Cancer Res; 15(1); 45–58. ©2016 AACR.