bluuebunny/crossref_metadata_2025_split huggingface dataset:
Recurrent RARB Translocations in Acute Promyelocytic Leukemia Lacking RARA Translocation
Authors: Osumi Tomoo , Tsujimoto Shin-ichi , Tamura Moe , Uchiyama Meri , Nakabayashi Kazuhiko , Okamura Kohji , Yoshida Masanori , Tomizawa Daisuke , Watanabe Akihiro , Takahashi Hiroyuki , Hori Tsukasa , Yamamoto Shohei , Hamamoto Kazuko , Migita Masahiro , Ogata-Kawata Hiroko , Uchiyama Toru , Kizawa Hiroe , Ueno-Yokohata Hitomi , Shirai Ryota , Seki Masafumi , Ohki Kentaro , Takita Junko , Inukai Takeshi , Ogawa Seishi , Kitamura Toshio , Matsumoto Kimikazu , Hata Kenichiro , Kiyokawa Nobutaka , Goyama Susumu , Kato Motohiro 
Published: June 2018

Abstract
Translocations of retinoic acid receptor-α (RARA), typically PML–RARA, are a genetic hallmark of acute promyelocytic leukemia (APL). However, because a small fraction of APL lack translocations of RARA, we focused here on APL cases without RARA translocation to elucidate the molecular etiology of RARA-negative APL. We performed whole-genome sequencing, PCR, and FISH for five APL cases without RARA translocations. Four of five RARA-negative APL cases had translocations involving retinoic acid receptor-β (RARB) translocations, and TBL1XR1–RARB was identified as an in-frame fusion in three cases; one case had an RARB rearrangement detected by FISH, although the partner gene could not be identified. When transduced in cell lines, TBL1XR1–RARB homodimerized and diminished transcriptional activity for the retinoic acid receptor pathway in a dominant-negative manner. TBL1XR1–RARB enhanced the replating capacity of mouse bone marrow cells and inhibited myeloid maturation of human cord blood cells as PML–RARA did. However, the response of APL with RARB translocation to retinoids was attenuated compared with that of PML–RARA, an observation in line with the clinical resistance of RARB-positive APL to ATRA. Our results demonstrate that the majority of RARA-negative APL have RARB translocations, thereby forming a novel, distinct subgroup of APL. TBL1XR1–RARB as an oncogenic protein exerts effects similar to those of PML–RARA, underpinning the importance of retinoic acid pathway alterations in the pathogenesis of APL.
Significance: These findings report a novel and distinct genetic subtype of acute promyelocytic leukemia (APL) by illustrating that the majority of APL without RARA translocations harbor RARB translocations. Cancer Res; 78(16); 4452–8. ©2018 AACR.
Cancer-Associated Fibroblasts Affect Intratumoral CD8+ and FoxP3+ T Cells Via IL6 in the Tumor Microenvironment
Authors: Kato Takuya , Noma Kazuhiro , Ohara Toshiaki , Kashima Hajime , Katsura Yuki , Sato Hiroaki , Komoto Satoshi , Katsube Ryoichi , Ninomiya Takayuki , Tazawa Hiroshi , Shirakawa Yasuhiro , Fujiwara Toshiyoshi 
Published: June 2018

Abstract
Purpose: Cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME) play a central role in tumor progression. We investigated whether CAFs can regulate tumor-infiltrating lymphocytes (TILs) and their role in tumor immunosuppression.
Experimental Design: A total of 140 cases of esophageal cancer were analyzed for CAFs and CD8+ or forkhead box protein 3 (FoxP3+) TILs by IHC. We analyzed cytokines using murine or human fibroblasts and cancer cells. Murine-derived fibroblasts and cancer cells were also inoculated into BALB/c or BALB/c-nu/nu mice and the tumors treated with recombinant IL6 or anti-IL6 antibody.
Results: CD8+ TILs and CAFs were negatively correlated in intratumoral tissues (P &lt; 0.001), whereas FoxP3+ TILs were positively correlated (P &lt; 0.001) in esophageal cancers. Cocultured Colon26 cancer cells and fibroblasts resulted in accelerated tumor growth in BALB/c mice, along with decreased CD8+ and increased FoxP3+ TILs, compared with cancer cells alone. In vitro, IL6 was highly secreted in both murine and human cancer cell/fibroblast cocultures. IL6 significantly increased Colon26 tumor growth in immune-competent BALB/c (P &lt; 0.001) with fewer CD8+ TILs than untreated tumors (P &lt; 0.001), whereas no difference in BALB/c-nu/nu mice. In contrast, FoxP3+ TILs increased in IL6-treated tumors (P &lt; 0.001). IL6 antibody blockade of tumors cocultured with fibroblasts resulted not only in regression of tumor growth but also in the accumulation of CD8+ TILs in intratumoral tissues.
Conclusions: CAFs regulate immunosuppressive TIL populations in the TME via IL6. IL6 blockade, or targeting CAFs, may improve preexisting tumor immunity and enhance the efficacy of conventional immunotherapies. Clin Cancer Res; 24(19); 4820–33. ©2018 AACR.
Prognostic Value of Methylator Phenotype in Stage III Colon Cancer Treated with Oxaliplatin-based Adjuvant Chemotherapy
Authors: Gallois Claire , Taieb Julien , Le Corre Delphine , Le Malicot Karine , Tabernero Josep , Mulot Claire , Seitz Jean-François , Aparicio Thomas , Folprecht Gunnar , Lepage Côme , Mini Enrico , Van Laethem Jean-Luc , Emile Jean-François , Laurent-Puig Pierre 
Published: June 2018

Abstract
Purpose: There are conflicting results concerning the prognostic value of the CpG island methylator phenotype (CIMP) in patients with nonmetastatic colon cancer. We studied this phenotype in stage III colon cancer characterized for mismatch repair (MMR), RAS, and BRAF status, and treated with adjuvant FOLFOX-based regimen.
Experimental Design: Tumor samples of 1,907 patients enrolled in the PETACC-8 adjuvant phase III trial were analyzed. The method used was methylation-specific PCR, where CIMP+ status was defined by methylation of at least 3 of 5 following genes: IGF2, CACNA1G, NEUROG1, SOCS1, and RUNX3. Association between CIMP status and overall survival (OS), disease-free survival (DFS), and survival after recurrence (SAR), was assessed by Cox model adjusted for prognostic factors and treatment arm (FOLFOX4 ± cetuximab).
Results: CIMP status was successfully determined in 1,867 patients (97.9%): 275 (14.7%) tumors were CIMP+. Compared with CIMP− patients, CIMP+ patients were more frequently older (P = 0.002), females (P = 0.04), with right-sided (P &lt; 0.0001), grade 3–4 (P &lt; 0.0001), pN2 (P = 0.001), dMMR (P &lt; 0.0001), BRAF mutated (P &lt; 0.0001), and RAS wild-type (P &lt; 0.0001) tumors. In multivariate analysis, CIMP+ status was associated with shorter OS [HR, 1.46; 95% confidence interval (CI), 1.02–1.94; P = 0.04] and SAR [HR, 1.76; 95% CI, 1.20–2.56; P &lt; 0.0004]; but not DFS [HR, 1.15; 95% CI, 0.86–1.54; P = 0.34]. A nonsignificant trend of detrimental effect of cetuximab was observed in patients with CIMP+ tumors for OS, DFS, and SAR.
Conclusions: In a large cohort of well-defined patients with stage III colon cancer, CIMP+ phenotype is associated with a shorter OS and SAR but not to DFS. Clin Cancer Res; 24(19); 4745–53. ©2018 AACR.
Aromatase Acetylation Patterns and Altered Activity in Response to Sirtuin Inhibition
Authors: Molehin Deborah , Castro-Piedras Isabel , Sharma Monica , Sennoune Souad R. , Arena Daphne , Manna Pulak R. , Pruitt Kevin 
Published: June 2018

Abstract
Aromatase, a cytochrome P450 member, is a key enzyme involved in estrogen biosynthesis and is dysregulated in the majority of breast cancers. Studies have shown that lysine deacetylase inhibitors (KDI) decrease aromatase expression in cancer cells, yet many unknowns remain regarding the mechanism by which this occurs. However, advances have been made to clarify factors involved in the transcriptional regulation of the aromatase gene (CYP19A1). Yet, despite aromatase being a primary target for breast cancer therapy, its posttranslational regulation has been virtually unexplored. Acetylation is a posttranslational modification (PTM) known to alter the activity and stability of many oncoproteins, and given the role of KDIs in regulating aromatase expression, we postulate that aromatase acetylation acts as a novel posttranslational regulatory mechanism that impacts aromatase expression and/or activity in breast cancer. Liquid chromatography–tandem mass spectrometry (LC-MS/MS) analysis revealed that aromatase is basally acetylated on several lysine residues (108, 169, 242, 262, 334, 352, and 354) in MCF-7 cells, and treatment with a SIRT-1 inhibitor induced additional acetylation (376, 390, 440, and 448). These acetylated lysine residues are in regions critical for aromatase activity. Site-directed mutagenesis and overexpression studies demonstrated that K108R/Q or K440R/Q mutations significantly altered aromatase activity in breast cancer cells without altering its subcellular localization.
Implications: These findings demonstrate a novel posttranslational regulation of aromatase and uncover novel anticancer effects of deacetylase inhibitors, thus providing new insight for ongoing development of deacetylase inhibitors as cancer therapeutics. Mol Cancer Res; 16(10); 1530–42. ©2018 AACR.
Exploração de rochas metacarbonáticas na região centro-sul do estado do Rio de Janeiro
Authors: Parente Marcelo Lyra , Almeida Cícera Neysi de , Nunes Rodrigo Peternel Machado 
Published: June 2018

A atividade mineral no estado do Rio de Janeiro tem, essencialmente, importância local, pois, de maneira geral, não produz bens minerais que sejam cotados em bolsas de valores como commodities (excluindo os hidrocarbonetos). De tal modo, o presente artigo teve por objetivo avaliar se ainda existe potencial para o aproveitamento econômico das rochas metacarbonáticas no centro-sul do estado do Rio de Janeiro. Para tanto, a metodologia utilizada para o desenvolvimento do presente estudo incluiu revisão bibliográfica; compilação de dados inventariados juntamente com os dados dos trabalhos de campo, das análises químicas e mineralógicas; e confecção de um mapa temático, cujo principal objetivo foi indicar áreas potenciais para pesquisas geológicas. O resultado desta pesquisa indicou uma anomalia bastante moderada para a ocorrência de mármores impuros no centro-sul do Rio de Janeiro. No entanto, as características dos corpos, no que diz respeito às suas dimensões e enquadramento geológico, não são favoráveis para a existência de um grande depósito de rocha metacarbonática na área de estudo.
Geoquímica e geocronologia da Suíte Paciência: implicações para o fim da evolução riaciana do Bloco Itacambira-Monte Azu
Authors: Bersan Samuel Moreira , Danderfer Filho André , Abreu Francisco , Lana Cristiano 
Published: June 2018

Diversos corpos plutônicos alcalinos de alto potássio paleoproterozoicos ocorrem no embasamento do cráton São Francisco, bem como no embasamento dos orógenos que o bordejam. Localizado no bordo oeste do cráton São Francisco, o bloco Itacambira-Monte Azul integra o embasamento do orógeno Araçuaí, em partes retrabalhado pelo evento tectonometamórfico Brasiliano. Nesse bloco, os plutonitos Paciência, Morro do Quilombo e Serra Branca, constituídos de rochas alcalinas, são englobados na Suíte Paciência. Os resultados petrográficos para a Suíte Paciência mostram o predomínio de monzonitos e sienitos, equigranulares a porfiríticos, com ocorrência de enclaves máficos. As análises químicas indicam altas concentrações de álcalis, bem como o enriquecimento de óxidos ferromagnesianos e alto Mg# (número de magnésio). Essas rochas são dominantemente metaluminosas, alcalinas a alcalino-cálcicas e magnesianas, enriquecidas em Ba, Sr e Rb e depletadas em Nb, P, Ti e em elementos incompatíveis. Mostram altos conteúdos em elementos terras raras (ETR) com fracionamento dos ETR leves sobre os pesados e anomalias de Eu que variam de negativas a fracamente positivas. As características geoquímicas dessas rochas são similares às de granitoides potássicos originados tardiamente em eventos orogênicos associados à subducção, com fonte mantélica metassomatizada e enriquecida em elementos incompatíveis e participação de crosta arqueana na geração desse magma. A idade de cristalização em 2053 ± 6.3 Ma indica que as rochas da Suíte Paciência se relacionam aos estágios tardios da orogênese Transamazônica, possivelmente associados com a evolução de um extenso arco magmático desenvolvido ao final do Riaciano. Dessa forma, a Suíte Paciência e também as demais suítes alcalinas paleoproterozoicas presentes no embasamento do orógeno Araçuaí registram um período de estabilização do paleocontinente São Francisco-Congo na transição Riaciano-Orosiriano.
Small GTP-Binding Protein GDP Dissociation Stimulator Prevents Thoracic Aortic Aneurysm Formation and Rupture by Phenotypic Preservation of Aortic Smooth Muscle Cells
Authors: Nogi Masamichi , Satoh Kimio , Sunamura Shinichiro , Kikuchi Nobuhiro , Satoh Taijyu , Kurosawa Ryo , Omura Junichi , Elias-Al-Mamun Md. , Abdul Hai Siddique Mohammad , Numano Kazuhiko , Kudo Shun , Miyata Satoshi , Akiyama Masatoshi , Kumagai Kiichiro , Kawamoto Shunsuke , Saiki Yoshikatsu , Shimokawa Hiroaki 
Published: June 2018

Background:
Thoracic aortic aneurysm (TAA) and dissection are fatal diseases that cause aortic rupture and sudden death. The small GTP-binding protein GDP dissociation stimulator (SmgGDS) is a crucial mediator of the pleiotropic effects of statins. Previous studies revealed that reduced force generation in aortic smooth muscle cells (AoSMCs) causes TAA and thoracic aortic dissection.

Methods:

To examine the role of SmgGDS in TAA formation, we used an angiotensin II (1000 ng·min
−1
·kg
−1
, 4 weeks)–induced TAA model.

Results:

We found that 33% of
Apoe
−/−
SmgGDS
+/−
mice died suddenly as a result of TAA rupture, whereas there was no TAA rupture in
Apoe
−/−
control mice. In contrast, there was no significant difference in the ratio of abdominal aortic aneurysm rupture between the 2 genotypes. We performed ultrasound imaging every week to follow up the serial changes in aortic diameters. The diameter of the ascending aorta progressively increased in
Apoe
−/−
SmgGDS
+/−
mice compared with
Apoe
−/−
mice, whereas that of the abdominal aorta remained comparable between the 2 genotypes. Histological analysis of
Apoe
−/−
SmgGDS
+/−
mice showed dissections of major thoracic aorta in the early phase of angiotensin II infusion (day 3 to 5) and more severe elastin degradation compared with
Apoe
−/−
mice. Mechanistically,
Apoe
−/−
SmgGDS
+/−
mice showed significantly higher levels of oxidative stress, matrix metalloproteinases, and inflammatory cell migration in the ascending aorta compared with
Apoe
−/−
mice. For mechanistic analyses, we primary cultured AoSMCs from the 2 genotypes. After angiotensin II (100 nmol/L) treatment for 24 hours,
Apoe
−/−
SmgGDS
+/−
AoSMCs showed significantly increased matrix metalloproteinase activity and oxidative stress levels compared with Apoe
−/−
AoSMCs. In addition, SmgGDS deficiency increased cytokines/chemokines and growth factors in AoSMCs. Moreover, expressions of fibrillin-1 (
FBN1
), α-smooth muscle actin (
ACTA2
), myosin-11 (
MYH11
),
MYLLK
, and
PRKG1
, which are force generation genes, were significantly reduced in
Apoe
−/−
SmgGDS
+/−
AoSMCs compared with Apoe
−/−
AoSMCs. A similar tendency was noted in AoSMCs from patients with TAA compared with those from control subjects. Finally, local delivery of the SmgGDS gene construct reversed the dilation of the ascending aorta in
Apoe
−/−
SmgGDS
+/−
mice.

Conclusions:
These results suggest that SmgGDS is a novel therapeutic target for the prevention and treatment of TAA.
Scholarly Frameworks for Reading Irenaeus: The Question of Theophanies
Authors: Bucur Bogdan G. 
Published: June 2018

Abstract
Irenaeus’ understanding of Old Testament theophanies and their exegesis is one of the loci of marked disagreement in scholarship. After a detailed survey of the various scholarly positions, this article argues against the oft-repeated judgment that Irenaeus’ treatment of theophanies would set forth a theological corrective to, or even an explicit rebuttal of, Justin of Neapolis’ Logos-theology, and shows that Irenaeus’ exesis of theophanies is also consistent with that of authors who have read Adv. haer. (Tertullian, Clement of Alexandria, and Origen). If the bishop of Lyons participated fully in the tradition of interpreting Old Testament theophanies as “Christophanies,” it follows that some strands of scholarship are severe misreadings of Irenaeus.
The Monastic Paradox: Desert Ascetics as Founders, Fathers, and Benefactors in Early Christian Historiography
Authors: Westergren Andreas 
Published: June 2018

Abstract
This is a study of three literary sources from the late fourth and early fifth centuries CE that depict the rise of monasticism, the anonymous History of the Monks of Egypt, the History of the Monks of Syria by Theodoret of Cyrrhus, and Sozomen’s Church History. Although each of these texts conveys what Peter Brown has termed the “myth of the desert,” i.e. a portrayal of monks as being part of another world, I argue that the same texts also reflect a “myth of the city,” in which the monastic movement is depicted as a civic institution with regard to its foundation, regulation, and influence in the world. What these texts reflect is an attempt from the side of Christian authors to make sense of the multifaceted phenomenon that was monasticism, creating a conceptual space where different ascetic expressions come together as one, as ‘monasticism’ or as a desert city.
The Human Spirit and Its Appropriation
Authors: Giddy Patrick 
Published: June 2018

Abstract
The reductionist conclusions of some evolutionary theorists are countered by appealing to the transformation of feeling-traces from our evolutionary origins. Presupposed to the science of evolutionary biology is the capacity to get at the truth of things, and to live by values, which Rahner terms “spirit”; its appropriation comes about through the process of moral and intellectual “conversion” (Lonergan), extended into the realm of feelings and the psyche (Doran). This allows a non-supernaturalistic way of understanding the saving interpersonal transaction at the heart of Christian belief; framed as a personal journey, it implies a less conceptual and more imaginal approach to faith.
Nearly Synchronous Multidecadal Oscillations of Surface Air Temperature in Punta Arenas and the Atlantic Multidecadal Oscillation Index
Authors: Kayano Mary Toshie , Setzer Alberto W. 
Published: June 2018

AbstractThe Atlantic multidecadal oscillation (AMO) signature in southern South America (SA) is examined using the surface air temperature (T-air) of Punta Arenas, Chile (53.0°S, 70.85°W), during the 1888–2016 period. The T-air shows multidecadal oscillations with a significant positive correlation of 0.77 to the AMO index. The relations of the Punta Arenas T-air time series with the AMO-related global sea surface temperature (SST) and regional circulation anomaly patterns are discussed. During the warm (cold) AMO phase, a cold (warm) center in southwestern Atlantic waters induces low-level anticyclonic (cyclonic) anomalies in the region, which together with the cyclonic (anticyclonic) anomalies in the southeastern Pacific channel the northerly (southerly) flow over southern SA. This meridional flow transports warm (cold) air from lower (higher) latitudes into the Punta Arenas region. Therefore, the temperature horizontal advection at the low level is the main thermodynamic process that alters the Punta Arenas T-air in a multidecadal time scale. The use of a relation between a long T-air surface sensor series in southern SA with the AMO presents a novel approach in climate monitoring and modeling.
Adjoint-Based Observation Impact Estimation with Direct Verification Using Forward Calculation
Authors: Ishibashi Toshiyuki 
Published: June 2018

Abstract
The adjoint-based observation impact estimation method has been providing essential information to improve data assimilation systems (DASs) in numerical weather prediction (NWP). This paper has two purposes. The first is to verify the four approximations used in the method: iterative construction of the Kalman gain adjoint operator, the tangent linear (TL) approximation of a forecast model, ignoring cross terms of observation impacts, and approximations for incremental DASs. The second is to add new information to our knowledge of observation impacts. For the verification of the adjoint-based method, we use the TL-based observation impact estimation method that can calculate the same quantity as the adjoint-based method without adjoint calculations. Results of these verifications and observation impact estimations performed on the global NWP system of the Japan Meteorological Agency are as follows. First, observation impacts calculated using the adjoint-based method agree well with those from the TL-based method, with the correlation coefficient between them exceeding 0.97. Second, estimated observation impacts are consistent with previous studies in many aspects. There are also system-dependent properties, such as relatively small impacts from GPS radio occultation data above 13 km. Furthermore, new aspects of observation impacts are found: 1) the probability density function of the observation impact agrees well with the scalar theory when giving the experimental value of the observation and the forecast error standard deviations; 2) later observations in the data assimilation window have larger positive impacts; and 3) impacts of AMSU-A in the Southern Hemisphere are more than double those in the Northern Hemisphere.
Suboptimal rise in awakening-induced cortisol is an accurate marker of cortisol insufficiency in patients with normal renal function (eGFR >60 mL/min)
Authors: Ramachandran Radha , Alaghband-Zadeh Jamshid , Sankaralingam Arun , Khan Shahid A , Tavabie Marianne , Fernyhough Catrin , Sabry Mustafa , Maghsoodi Negar , McGowan Barbara , Carroll Paul V , Wierzbicki Anthony S 
Published: June 2018

Background The insulin tolerance test is the gold standard for diagnosis of cortisol insufficiency. However, it is cumbersome, invasive, requires supervised hospital facilities and has unpleasant side-effects. A non-invasive outpatient-based test will be useful. We hypothesized that free cortisol concentrations in multiple spot urine samples can be used to diagnose cortisol insufficiency in patients with normal renal function (eGFR > 60 mL/min). Method Patients and controls provided urine samples at bedtime (S1), and first (S2) and second (S3) void the next day. Cortisol and creatinine were measured in all three samples, and cortisol:creatinine ratio (S1, S2 and S3) was used for further analysis. The sum of S1 + S2 + S3 was used to calculate total cortisol secretion (T). Variation (V) in cortisol secretion in response to circadian rhythm was calculated as the modulus of the difference between S1 and S2 and S2 and S3. Results Samples were collected from 96 controls and 11 patients. S1 was significantly lower vs . S2 and S3 in controls ( P < 0.0001) but not in patients. S2, S3, T and V were significantly lower in patients vs . controls ( P < 0.0001). ROC curve analysis using insulin tolerance test as gold standard showed that S2, S3, T and V were all equally accurate diagnostic markers for cortisol insufficiency (AUC: 0.87, NPV: 100%). The best balance of sensitivity and specificity was achieved using T (sensitivity: 100%, specificity: 58%). Conclusion Multiple spot urine samples test is an accurate, relatively inexpensive, non-invasive, convenient outpatient-based screening test for exclusion of cortisol insufficiency.