bluuebunny/crossref_metadata_2025_split huggingface dataset:
Seismic slip on the west flank of the Upper Rhine Graben (France–Germany): evidence from tectonic morphology and cataclastic deformation bands
Authors: Shipton Zoe K. , Meghraoui Mustapha , Monro Louise 
Published: September 2016

Abstract

The Upper Rhine Graben (URG) is a seismically active tectonic structure in intraplate Europe. Large and moderate earthquakes have occurred along the URG in the past but no coseismic surface faulting has been reported so far. We investigated active faulting along the western edge of the northern URG and identified the 25 km-long linear Riedseltz–Landau normal fault scarp as a major tectonic structure affecting late Pleistocene and Holocene deposits. The fault zone is exposed in the Riedseltz quarry where it affects Pliocene sand and gravels and overlying late Pleistocene (Wurm) units. These units have not been buried deeper than a few tens of metres and yet the fault zone contains cataclastic deformation textures. Cataclasis is demonstrated by spalling and transgranular fractures in quartz grains concentrated in deformation bands with reduced grain size. The observed microstructures suggest multiple phases of deformation with cataclasis followed by emplacement of a prominent Fe-oxide matrix into deformation bands, and later emplacement of a clay-rick matrix into fractures. Previous geological and geophysical studies along the fault show late Pleistocene (Wurm) loess deposits (
c.
24–10 ka before present) and early Holocene sand–silty deposits with individual or cumulative 1.5 and 0.7 m surface slip, respectively. Field observations and previous results from shallow geophysics provide a minimum 0.15 mm a
−1
time-averaged slip rate. The Riedseltz fault parameters integrated in a dislocation model suggest a minimum Mw 6.6 earthquake as a plausible scenario in the northern URG. The observations of cataclasis in shallowly buried sediments coupled with observations of the late Quaternary fault scarp call for palaeoseismic studies that may document the occurrence of a larger earthquake on the western edge of URG. Surface faulting of young, shallowly buried sediments associated with cataclasis provides new evidence for assessing the occurrence of large earthquakes and seismic hazard assessment in the northern URG.
Insight into the structures below the Deccan Trap-covered region of Maharashtra, India from geopotential data
Authors: Rajaram Mita , Anand S. P. , Erram V. C. , Shinde B. N. 
Published: September 2016

Abstract
Ground magnetic data collected at an average data spacing of 5 km over the Deccan Traps in Maharashtra, India are studied. In conjunction with a magnetic anomaly map generated from ground, aero and marine magnetic data, seven lineaments are identified below the Deccan Traps: six NW–SE-trending lineaments (Ln1 to Ln6) and a NE–SW-oriented lineament, Ln7. From the filtered Bouguer gravity data the sources at different depths are studied. From combined analysis we find that Ln1 coincides with the continuation of Bababudan Nallur Shear zone. The boundary between the Western and Eastern Dharwar cratons, the Chitradurg Boundary Shear, merges with Ln2. Ln3 is part of the Peninsular Lineament identified earlier. Ln4 coincides in part with the Bhima River, while Ln5 and Ln6 are possibly related to Godavari rifting. The region between Ln4 and Ln5 relates to the Kurudwadi Lineament Zone. The Kaladgi and Bhima sediments and the schist belts continue northwards below the Deccan Traps and are constrained to lie to the south of NE–SW-oriented Ln7. With the exception of Ln3 (the Peninsular Lineament) the other six lineaments below the Deccan Traps are identified for the first time. The crustal structure below the Deccan Traps that we derive from 2D modelling of combined gravity and magnetic data supports the presence of the identified lineaments.
Commentary on Almassalha et al., “The Greater Genomic Landscape: The Heterogeneous Evolution of Cancer”
Authors: Lynch Henry T. , Rendell Marc , Shaw Trudy G. , Silberstein Peter , Ngo Binh T. 
Published: September 2016

Abstract
In this issue of Cancer Research, Almassalha and colleagues have proposed a new concept of the development of malignancy, that of the greater genomic landscape. They propose a stressor-related exploration of intracellular genomic sites as a response mechanism. This process can express sites with beneficial or deleterious effects, among them those that promote cell proliferation. They point out that their conception is broader, although certainly inclusive, of the process of gene induction. The authors view the physical process of chromatin reorganization as central to the exploration of the genomic landscape. Accordingly, they advocate the development of agents to limit chromatin structural modification as a chemotherapeutic approach in cancer. We found their theory relevant to understand the phenotypic heterogeneity of malignancy, particularly in familial cancer syndromes. For example, the familial atypical multiple mole melanoma (FAMMM) syndrome, related to a gene mutation, is characterized by a diversity of melanocytic lesions, only some of which become malignant melanoma. This new conceptualization can do much to increase understanding of the diversity of malignancy in families with hereditary cancer. Cancer Res; 76(19); 5602–4. ©2016 AACR.
Mutant p53 Together with TGFβ Signaling Influence Organ-Specific Hematogenous Colonization Patterns of Pancreatic Cancer
Authors: Zhong Yi , Macgregor-Das Anne , Saunders Tyler , Whittle Martin C. , Makohon-Moore Alvin , Kohutek Zachary A. , Poling Justin , Herbst Brian T. , Javier Breanna M. , Cope Leslie , Leach Steven D. , Hingorani Sunil R. , Iacobuzio-Donahue Christine A. 
Published: September 2016

Abstract
Purpose: TP53 and the TGFβ pathway are major mediators of pancreatic cancer metastasis. The mechanisms by which they cause hematogenous metastasis have not been fully explored.
Experimental Design: KPC (LSL-KRASG12D/+;LSL-Trp53R172H/+; Ptf1aCre/+) mice were generated, and the frequency and morphology of organ-specific hematogenous metastases compared with that seen in KPTC and KTC littermates (Tgfbr2+/−). Key findings were validated in primary cells from each genotype and samples of human pancreatic cancer liver metastases.
Results: The frequency of hematogenous metastasis in KPTC mice was significantly lower than for KPC mice (41% vs. 68%, P &lt; 0.05), largely due to a reduction in liver metastases. No differences were found between KPC and KPTC lung metastases, whereas liver metastases in KPTC mice showed a profound extravasation deficiency characterized by sinusoidal growth and lack of desmoplastic stroma. Analogous findings were confirmed in liver samples from patients indicating their clinical relevance. Portal vein colonization as a direct mode of access to the liver was observed in both mice and humans. Secretome analyses of KPC cells revealed an abundance of secreted prometastatic mediators including Col6A1 and Lcn2 that promoted early steps of metastatic colonization. These mediators were overexpressed in primary tumors but not metastases, suggesting that the ability to colonize is, in part, developed within the primary site, a phenomenon we refer to as the “Cinderella effect.”
Conclusions: These findings establish a novel paradigm for understanding pancreatic cancer metastasis and the observed clinical latencies of liver versus lung metastases specifically. Clin Cancer Res; 23(6); 1607–20. ©2016 AACR.
The Human CD38 Monoclonal Antibody Daratumumab Shows Antitumor Activity and Hampers Leukemia–Microenvironment Interactions in Chronic Lymphocytic Leukemia
Authors: Matas-Céspedes Alba , Vidal-Crespo Anna , Rodriguez Vanina , Villamor Neus , Delgado Julio , Giné Eva , Roca-Ho Heleia , Menéndez Pablo , Campo Elías , López-Guillermo Armando , Colomer Dolors , Roué Gaël , Wiestner Adrian , Parren Paul W.H.I. , Doshi Parul , van Bueren Jeroen Lammerts , Pérez-Galán Patricia 
Published: September 2016

Abstract
Purpose: To establish a proof-of-concept for the efficacy of the anti-CD38 antibody daratumumab in the poor prognosis CD38+ chronic lymphocytic leukemia (CLL) subtype.
Experimental Design: The mechanism of action of daratumumab was assessed in CLL primary cells and cell lines using peripheral blood mononuclear cells to analyze antibody-dependent cell cytotoxicity (ADCC), murine and human macrophages to study antibody-dependent cell phagocytosis (ADCP), or human serum to analyze complement-dependent cytotoxicity (CDC). The effect of daratumumab on CLL cell migration and adhesion to extracellular matrix was characterized. Daratumumab activity was validated in two in vivo models.
Results: Daratumumab demonstrated efficient lysis of patient-derived CLL cells and cell lines by ADCC in vitro and ADCP both in vitro and in vivo whereas exhibited negligible CDC in these cells. To demonstrate the therapeutic effect of daratumumab in CLL, we generated a disseminated CLL mouse model with the CD38+ MEC2 cell line and CLL patient–derived xenografts (CLL-PDX). Daratumumab significantly prolonged overall survival of MEC2 mice, completely eliminated cells from the infiltrated organs, and significantly reduced disease burden in the spleen of CLL-PDX. The effect of daratumumab on patient-derived CLL cell dissemination was demonstrated in vitro by its effect on CXCL12-induced migration and in vivo by interfering with CLL cell homing to spleen in NSG mice. Daratumumab also reduced adhesion of CLL cells to VCAM-1, accompanied by downregulation of the matrix metalloproteinase MMP9.
Conclusions: These unique and substantial effects of daratumumab on CLL viability and dissemination support the investigation of its use in a clinical setting of CLL. Clin Cancer Res; 23(6); 1493–505. ©2016 AACR.
Antitumor and Antiangiogenic Effects of Aspirin-PC in Ovarian Cancer
Authors: Huang Yan , Lichtenberger Lenard M. , Taylor Morgan , Bottsford-Miller Justin N. , Haemmerle Monika , Wagner Michael J. , Lyons Yasmin , Pradeep Sunila , Hu Wei , Previs Rebecca A. , Hansen Jean M. , Fang Dexing , Dorniak Piotr L. , Filant Justyna , Dial Elizabeth J. , Shen Fangrong , Hatakeyama Hiroto , Sood Anil K. 
Published: September 2016

Abstract
To determine the efficacy of a novel and safer (for gastrointestinal tract) aspirin (aspirin-PC) in preclinical models of ovarian cancer, in vitro dose–response studies were performed to compare the growth-inhibitory effect of aspirin-PC versus aspirin on three human (A2780, SKOV3ip1, and HeyA8) and a mouse (ID8) ovarian cancer cell line over an 8-day culture period. In the in vivo studies, the aspirin test drugs were studied alone and in the presence of a VEGF-A inhibitor (bevacizumab or B20), due to an emerging role for platelets in tumor growth following antiangiogenic therapy, and we examined their underlying mechanisms. Aspirin-PC was more potent (vs. aspirin) in blocking the growth of both human and mouse ovarian cancer cells in monolayer culture. Using in vivo model systems of ovarian cancer, we found that aspirin-PC significantly reduced ovarian cancer growth by 50% to 90% (depending on the ovarian cell line). The efficacy was further enhanced in combination with Bevacizumab or B20. The growth-inhibitory effect on ovarian tumor mass and number of tumor nodules was evident, but less pronounced for aspirin and the VEGF inhibitors alone. There was no detectable gastrointestinal toxicity. Both aspirin and aspirin-PC also inhibited cell proliferation, angiogenesis, and increased apoptosis of ovarian cancer cells. In conclusion, PC-associated aspirin markedly inhibits the growth of ovarian cancer cells, which exceeds that of the parent drug, in both cell culture and in mouse model systems. We also found that both aspirin-PC and aspirin have robust antineoplastic action in the presence of VEGF-blocking drugs. Mol Cancer Ther; 15(12); 2894–904. ©2016 AACR.
Alkylating Agent–Induced NRF2 Blocks Endoplasmic Reticulum Stress–Mediated Apoptosis via Control of Glutathione Pools and Protein Thiol Homeostasis
Authors: Zanotto-Filho Alfeu , Masamsetti V. Pragathi , Loranc Eva , Tonapi Sonal S. , Gorthi Aparna , Bernard Xavier , Gonçalves Rosângela Mayer , Moreira José C.F. , Chen Yidong , Bishop Alexander J.R. 
Published: September 2016

AbstractAlkylating agents are a commonly used cytotoxic class of anticancer drugs. Understanding the mechanisms whereby cells respond to these drugs is key to identify means to improve therapy while reducing toxicity. By integrating genome-wide gene expression profiling, protein analysis, and functional cell validation, we herein demonstrated a direct relationship between NRF2 and Endoplasmic Reticulum (ER) stress pathways in response to alkylating agents, which is coordinated by the availability of glutathione (GSH) pools. GSH is essential for both drug detoxification and protein thiol homeostasis within the ER, thus inhibiting ER stress induction and promoting survival, an effect independent of its antioxidant role. NRF2 accumulation induced by alkylating agents resulted in increased GSH synthesis via GCLC/GCLM enzyme, and interfering with this NRF2 response by either NRF2 knockdown or GCLC/GCLM inhibition with buthionine sulfoximine caused accumulation of damaged proteins within the ER, leading to PERK-dependent apoptosis. Conversely, upregulation of NRF2, through KEAP1 depletion or NRF2-myc overexpression, or increasing GSH levels with N-acetylcysteine or glutathione-ethyl-ester, decreased ER stress and abrogated alkylating agents–induced cell death. Based on these results, we identified a subset of lung and head-and-neck carcinomas with mutations in either KEAP1 or NRF2/NFE2L2 genes that correlate with NRF2 target overexpression and poor survival. In KEAP1-mutant cancer cells, NRF2 knockdown and GSH depletion increased cell sensitivity via ER stress induction in a mechanism specific to alkylating drugs. Overall, we show that the NRF2-GSH influence on ER homeostasis implicates defects in NRF2-GSH or ER stress machineries as affecting alkylating therapy toxicity. Mol Cancer Ther; 15(12); 3000–14. ©2016 AACR.
Restoring Retinoic Acid Attenuates Intestinal Inflammation and Tumorigenesis in APCMin/+ Mice
Authors: Penny Hweixian Leong , Prestwood Tyler R. , Bhattacharya Nupur , Sun Fionna , Kenkel Justin A. , Davidson Matthew G. , Shen Lei , Zuniga Luis A. , Seeley E. Scott , Pai Reetesh , Choi Okmi , Tolentino Lorna , Wang Jinshan , Napoli Joseph L. , Engleman Edgar G. 
Published: September 2016

Abstract
Chronic intestinal inflammation accompanies familial adenomatous polyposis (FAP) and is a major risk factor for colorectal cancer in patients with this disease, but the cause of such inflammation is unknown. Because retinoic acid (RA) plays a critical role in maintaining immune homeostasis in the intestine, we hypothesized that altered RA metabolism contributes to inflammation and tumorigenesis in FAP. To assess this hypothesis, we analyzed RA metabolism in the intestines of patients with FAP as well as APCMin/+ mice, a model that recapitulates FAP in most respects. We also investigated the impact of intestinal RA repletion and depletion on tumorigenesis and inflammation in APCMin/+ mice. Tumors from both FAP patients and APCMin/+ mice displayed striking alterations in RA metabolism that resulted in reduced intestinal RA. APCMin/+ mice placed on a vitamin A–deficient diet exhibited further reductions in intestinal RA with concomitant increases in inflammation and tumor burden. Conversely, restoration of RA by pharmacologic blockade of the RA-catabolizing enzyme CYP26A1 attenuated inflammation and diminished tumor burden. To investigate the effect of RA deficiency on the gut immune system, we studied lamina propria dendritic cells (LPDC) because these cells play a central role in promoting tolerance. APCMin/+ LPDCs preferentially induced Th17 cells, but reverted to inducing Tregs following restoration of intestinal RA in vivo or direct treatment of LPDCs with RA in vitro. These findings demonstrate the importance of intestinal RA deficiency in tumorigenesis and suggest that pharmacologic repletion of RA could reduce tumorigenesis in FAP patients. Cancer Immunol Res; 4(11); 917–26. ©2016 AACR.
Weight Gain Trajectories Associated With Elevated C‐Reactive Protein Levels in Chinese Adults
Authors: Thompson Amanda L. , Koehler Elizabeth , Herring Amy H. , Paynter Lauren , Du Shufa , Zhang Bing , Popkin Barry , Gordon‐Larsen Penny 
Published: September 2016

Background

Recent longitudinal work suggests that weight change is an important risk factor for inflammation across the full range of
BMI
. However, few studies have examined whether the risk of inflammation differs by patterns of weight gain over time. Using latent class trajectory analysis, we test whether patterns of weight gain are associated with elevated high‐sensitivity C‐reactive protein (hs‐
CRP
2–10 mg/L).

Methods and Results

Data come from China Health and Nutrition Survey (
CHNS
) participants (n=5536), aged 18 at baseline to 66 years in 2009, with measured weight over 18 years. Latent class trajectory analysis was used to identify weight‐change trajectories in 6 age and sex strata. Multivariable general linear mixed‐effects models fit with a logit link were used to assess the risk of elevated hs‐
CRP
across weight trajectory classes. Models were fit within age and sex strata, controlling for baseline weight, adult height, and smoking, and included random intercepts to account for community‐level correlation. Steeper weight‐gain trajectories were associated with greater risk of elevated hs‐
CRP
compared to more moderate weight‐gain trajectories in men and women. Initially high weight gain followed by weight loss was associated with lower risk of elevated hs‐
CRP
in women aged 18 to 40.

Conclusions
Latent class trajectory analysis identified heterogeneity in adult weight change associated with differential risk of inflammation independently of baseline weight and smoking. These results suggest that trajectories of weight gain are an important clinical concern and may identify those at risk for inflammation and the development of cardiometabolic disease.
Cumulative Exposure to Ideal Cardiovascular Health and Incident Diabetes in a Chinese Population: The Kailuan Study
Authors: Liu Xiaoxue , Cui Liufu , Wang Anxin , Wang Xizhu , Song Qiaofeng , Li Shanshan , Shi Jihong , Zhao Xiaohong , Chen Shuohua , Du Xin , Ji Chunpeng , Huxley Rachel , Guo Yuming , Wu Shouling 
Published: September 2016

Background

It is unclear whether ideal cardiovascular health (
CVH
), and particularly cumulative exposure to ideal
CVH
(cum
CVH
), is associated with incident diabetes. We aimed to fill this research gap.

Methods and Results

The Kailuan Study is a prospective cohort of 101 510 adults aged 18 to 98 years recruited in 2006–2007 and who were subsequently followed up at 2‐ (Exam 2), 4‐ (Exam 3), and 6 (Exam 4)‐year intervals after baseline. The main analysis is restricted to those individuals with complete follow‐up at all 4 examinations and who had no history of diabetes until Exam 3. Cumulative exposure to ideal
CVH
(cum
CVH
) was calculated as the summed
CVH
score for each examination multiplied by the time between the 2 examinations (score×year). Logistic regression models were used to assess the association between cum
CVH
and incident diabetes. In fully adjusted models, compared with the lowest quintile of cum
CVH
, individuals in the highest quintile had ~68% (95% confidence interval [
CI
] 60‐75) lower risk for incident diabetes (compared with 61% [95%
CI
52‐69] lower risk when using baseline
CVH
). Every additional year lived with a 1‐unit increase in ideal
CVH
was associated with a 24% (95%
CI
21‐28) reduction in incident diabetes.

Conclusions

Ideal
CVH
is associated with a reduced incidence of diabetes, but the association is likely to be underestimated if baseline measures of
CVH
exposure are used. Measures of cumulative exposure to ideal
CVH
are more likely to reflect lifetime risk of diabetes and possibly other health outcomes.

Clinical Trial Registration

URL
:
https://www.chictr.org
. Unique identifier: Chi
CTRTNC
‐11001489.
Effect of dietary modification by calorie restriction on cholesterol levels in lipoprotein(a) and other lipoprotein classes
Authors: Hirowatari Yuji , Manita Daisuke , Kamachi Keiko , Tanaka Akira 
Published: September 2016

Background Dietary habits are associated with obesity which is a risk factor for coronary heart disease. The objective is to estimate the change of lipoprotein(a) and other lipoprotein classes by calorie restriction with obesity index and Framingham risk score. Methods Sixty females (56 ± 9 years) were recruited. Their caloric intakes were reduced during the six-month period, and the calorie from fat was not more than 30%. Lipoprotein profiles were estimated at baseline and after the six-month period of calorie restriction. Cholesterol levels in six lipoprotein classes (HDL, LDL, IDL, VLDL, chylomicron and lipoprotein(a)) were analysed by anion-exchange liquid chromatography. The other tests were analysed by general methods. Additionally, Framingham risk score for predicting 10-year coronary heart disease risk was calculated. Results Body mass index, waist circumference, insulin resistance, Framingham risk score, total cholesterol, LDL-cholesterol and IDL-cholesterol were significantly decreased by the calorie restriction, and the protein and cholesterol levels of lipoprotein(a) were significantly increased. The change of body mass index was significantly correlated with those of TC, VLDL-cholesterol and chylomicron-cholesterol, and that of waist circumference was significantly correlated with that of chylomicron-cholesterol. The change of Framingham risk score was significantly correlated with the change of IDL-C. Conclusion Obesity indexes and Framingham risk score were reduced by the dietary modification. Lipoprotein profile was improved with the reduction of obesity indexes, but lipoprotein(a) was increased. The changes of obesity indexes and Framingham risk score were related with those of triglyceride-rich lipoproteins, e.g. IDL, VLDL and CM.
Antiphospholipid and antioangiogenic activity in females with recurrent miscarriage and antiphospholipid syndrome
Authors: Pelusa Hector F , Pezzarini Eleonora , Basiglio Cecilia L , Musuruana Jorge , Bearzotti Mariela , Svetaz María J , Daniele Stella M , Bottai Hebe , Arriaga Sandra MM 
Published: September 2016

Background Antiphospholipid syndrome is an autoimmune disease characterized by thrombosis, fetal losses and thrombocytopenia associated to antiphospholipid antibodies. They are directed to phospholipids, such as cardiolipins (anticardiolipin) and lupus anticoagulant or to complexes formed by phospholipids and protein cofactors, such as β2 glycoprotein 1 (a-β2GP1) and annexin V (a-annexin V). These auto-antibodies may be considered as a family of antibodies involved in thrombotic events and antiphospholipid activity. On the other hand, some proangiogenic factors are involved in the normal development of placental vasculature, such as the vascular endothelial growth factor. Overexpression of vascular endothelial growth factor receptor in its soluble form (sVEGFR-1) has been associated to a higher antiangiogenic activity. Our aim was to analyse the association between anticardiolipin, lupus anticoagulant, a-β2GP1, a-annexin V and sVEGFR-1 with recurrent miscarriage before week 10 of gestation in females with antiphospholipid syndrome. Methods We studied 24 females (primary or secondary antiphospholipid syndrome), who were divided into two groups: females with recurrent miscarriage before week 10 of gestation (M; n = 12) and females with no history of fetal loss (NM; n = 12). Anticardiolipin, a-β2GP1, a-annexin V and sVEGF-R1 concentrations were assessed by ELISA, while lupus anticoagulant was assessed by screening and confirmatory tests. Results A significant association was observed between the number of positive biomarkers and the belonging group ( P < 0.05). Besides, a positive result for lupus anticoagulant and a-β2GP1 was found to be significantly associated to the M group ( P < 0.05). Conclusions Lupus anticoagulant and a-β2GP1 may be implicated in pregnancies complicated by recurrent miscarriage in females with antiphospholipid syndrome.