bluuebunny/crossref_metadata_2025_split huggingface dataset:
SMAD4 Loss in Colorectal Cancer Patients Correlates with Recurrence, Loss of Immune Infiltrate, and Chemoresistance
Authors: Wasserman Isaac , Lee Lik Hang , Ogino Shuji , Marco Michael R. , Wu Chao , Chen Xi , Datta Jashodeep , Sadot Eran , Szeglin Bryan , Guillem Jose G. , Paty Philip B. , Weiser Martin R. , Nash Garrett M. , Saltz Leonard , Barlas Afsar , Manova-Todorova Katia , Uppada Srijaya Prakash Babu , Elghouayel Arthur E. , Ntiamoah Peter , Glickman Jonathan N. , Hamada Tsuyoshi , Kosumi Keisuke , Inamura Kentaro , Chan Andrew T. , Nishihara Reiko , Cercek Andrea , Ganesh Karuna , Kemeny Nancy E. , Dhawan Punita , Yaeger Rona , Sawyers Charles L. , Garcia-Aguilar Julio , Giannakis Marios , Shia Jinru , Smith J. Joshua 
Published: December 2018

Abstract

Purpose:
SMAD4 has shown promise in identifying patients with colorectal cancer at high risk of recurrence or death.
Experimental Design: A discovery cohort and independent validation cohort were classified by SMAD4 status. SMAD4 status and immune infiltrate measurements were tested for association with recurrence-free survival (RFS). Patient-derived xenografts from SMAD4-deficient and SMAD4-retained tumors were used to examine chemoresistance.

Results:
The discovery cohort consisted of 364 patients with stage I–IV colorectal cancer. Median age at diagnosis was 53 years. The cohort consisted of 61% left-sided tumors and 62% stage II/III patients. Median follow-up was 5.4 years (interquartile range, 2.3–8.2). SMAD4 loss, noted in 13% of tumors, was associated with higher tumor and nodal stage, adjuvant therapy use, fewer tumor-infiltrating lymphocytes (TIL), and lower peritumoral lymphocyte aggregate (PLA) scores (all P &lt; 0.04). SMAD4 loss was associated with worse RFS (P = 0.02). When stratified by SMAD4 and immune infiltrate status, patients with SMAD4 loss and low TIL or PLA had worse RFS (P = 0.002 and P = 0.006, respectively). Among patients receiving 5-fluorouracil (5-FU)-based systemic chemotherapy, those with SMAD4 loss had a median RFS of 3.8 years compared with 13 years for patients with SMAD4 retained. In xenografted mice, the SMAD4-lost tumors displayed resistance to 5-FU. An independent cohort replicated our findings, in particular, the association of SMAD4 loss with decreased immune infiltrate, as well as worse disease-specific survival.

Conclusions:
Our data show SMAD4 loss correlates with worse clinical outcome, resistance to chemotherapy, and decreased immune infiltrate, supporting its use as a prognostic marker in patients with colorectal cancer.
Epigenetic Silencing of miRNA-338-5p and miRNA-421 Drives SPINK1-Positive Prostate Cancer
Authors: Bhatia Vipul , Yadav Anjali , Tiwari Ritika , Nigam Shivansh , Goel Sakshi , Carskadon Shannon , Gupta Nilesh , Goel Apul , Palanisamy Nallasivam , Ateeq Bushra 
Published: December 2018

Abstract

Purpose:
Serine peptidase inhibitor, Kazal type-1 (SPINK1) overexpression defines the second most recurrent and aggressive prostate cancer subtype. However, the underlying molecular mechanism and pathobiology of SPINK1 in prostate cancer remains largely unknown.

Experimental Design:
miRNA prediction tools were employed to examine the SPINK1-3′UTR for miRNA binding. Luciferase reporter assays were performed to confirm the SPINK1-3′UTR binding of shortlisted miR-338-5p/miR-421. Furthermore, miR-338-5p/-421–overexpressing cancer cells (SPINK1-positive) were evaluated for oncogenic properties using cell-based functional assays and a mouse xenograft model. Global gene expression profiling was performed to unravel the biological pathways altered by miR-338-5p/-421. IHC and RNA in situ hybridization were carried out on prostate cancer patients' tissue microarray for SPINK1 and EZH2 expression, respectively. Chromatin immunoprecipitation assay was performed to examine EZH2 occupancy on the miR-338-5p/-421–regulatory regions. Bisulfite sequencing and methylated DNA immunoprecipitation were performed on prostate cancer cell lines and patients' specimens.

Results:
We established a critical role of miRNA-338-5p/-421 in posttranscriptional regulation of SPINK1. Ectopic expression of miRNA-338-5p/-421 in SPINK1-positive cells abrogates oncogenic properties including cell-cycle progression, stemness, and drug resistance, and shows reduced tumor burden and distant metastases in a mouse model. Importantly, we show that patients with SPINK1-positive prostate cancer exhibit increased EZH2 expression, suggesting its role in epigenetic silencing of miRNA-338-5p/-421. Furthermore, presence of CpG dinucleotide DNA methylation marks on the regulatory regions of miR-338-5p/-421 in SPINK1-positive prostate cancer cells and patients' specimens confirms epigenetic silencing.

Conclusions:
Our findings revealed that miRNA-338-5p/-421 are epigenetically silenced in SPINK1-positive prostate cancer, although restoring the expression of these miRNAs using epigenetic drugs or synthetic mimics could abrogate SPINK1-mediated oncogenesis.
See related commentary by Bjartell, p. 2679
Enhancing Chemosensitivity of Breast Cancer Stem Cells by Downregulating SOX2 and ABCG2 Using Wedelolactone-encapsulated Nanoparticles
Authors: Das Sreemanti , Mukherjee Pritha , Chatterjee Ranodeep , Jamal Zarqua , Chatterji Urmi 
Published: December 2018

Abstract
A major caveat in the treatment of breast cancer is disease recurrence after therapeutic regime at both local and distal sites. Tumor relapse is attributed to the persistence of chemoresistant cancer stem cells (CSC), which need to be obliterated along with conventional chemotherapy. Wedelolactone, a naturally occurring coumestan, demonstrates anticancer effects in different cancer cells, although with several limitations, and is mostly ineffective against CSCs. To enhance its biological activity in cancer cells and additionally target the CSCs, wedelolactone-encapsulated PLGA nanoparticles (nWdl) were formulated. Initial results indicated that nanoformulation of wedelolactone not only increased its uptake in breast cancer cells and the CSC population, it enhanced drug retention and sustained release within the cells. Enhanced drug retention was achieved by downregulation of SOX2 and ABCG2, both of which contribute to drug resistance of the CSCs. In addition, nWdl prevented epithelial-to-mesenchymal transition, suppressed cell migration and invasion, and reduced the percentage of breast cancer stem cells (BCSC) in MDA-MB-231 cells. When administered in combination with paclitaxel, which is known to be ineffective against BCSCs, nWdl sensitized the cells to the effects of paclitaxel and reduced the percentage of ALDH+ BCSCs and mammospheres. Furthermore, nWdl suppressed growth of solid tumors in mice and also reduced CD44+/CD24−/low population. Taken together, our data imply that nWdl decreased metastatic potential of BCSCs, enhanced chemosensitivity through coordinated regulation of pluripotent and efflux genes, and thereby provides an insight into effective drug delivery specifically for obliterating BCSCs.
Blood Interactions, Pharmacokinetics, and Depth-Dependent Ablation of Rat Mammary Tumors with Photoactivatable, Liposomal Doxorubicin
Authors: Carter Kevin A. , Luo Dandan , Geng Jumin , Stern Stephan T. , Lovell Jonathan F. 
Published: December 2018

Abstract
Photosensitizers can be integrated with drug delivery vehicles to develop chemophototherapy agents with antitumor synergy between chemo- and photocomponents. Long-circulating doxorubicin (Dox) in porphyrin–phospholipid (PoP) liposomes (LC-Dox-PoP) incorporates a phospholipid-like photosensitizer (2 mole %) in the bilayer of Dox-loaded stealth liposomes. Hematological effects of endotoxin-minimized LC-Dox-PoP were characterized via standardized assays. In vitro interaction with erythrocytes, platelets, and plasma coagulation cascade were generally unremarkable, whereas complement activation was found to be similar to that of commercial Doxil. Blood partitioning suggested that both the Dox and PoP components of LC-Dox-PoP were stably entrapped or incorporated in liposomes. This was further confirmed with pharmacokinetic studies in Fischer rats, which showed the PoP and Dox components of the liposomes both had nearly identical, long circulation half-lives (25–26 hours). In a large orthotopic mammary tumor model in Fischer rats, following intravenous dosing (2 mg/kg Dox), the depth of enhanced Dox delivery in response to 665 nm laser irradiation was over 1 cm. LC-Dox-PoP with laser treatment cured or potently suppressed tumor growth, with greater efficacy observed in tumors 0.8 to 1.2 cm, compared with larger ones. The skin at the treatment site healed within approximately 30 days. Taken together, these data provide insight into nanocharacterization and photo-ablation parameters for a chemophototherapy agent.
TSR-033, a Novel Therapeutic Antibody Targeting LAG-3, Enhances T-Cell Function and the Activity of PD-1 BlockadeIn VitroandIn Vivo
Authors: Ghosh Srimoyee , Sharma Geeta , Travers Jon , Kumar Sujatha , Choi Justin , Jun H. Toni , Kehry Marilyn , Ramaswamy Sridhar , Jenkins David 
Published: December 2018

AbstractProgressive upregulation of checkpoints on tumor-infiltrating lymphocytes promotes an immunosuppressive tumor microenvironment, severely compromising tumor immunity. Lymphocyte activation gene-3 (LAG-3) is a coinhibitory receptor associated with impaired T-cell function and is frequently coexpressed with programmed cell death protein-1 (PD-1) in the context of human cancers. Targeting LAG-3 in conjunction with PD-1 thus represents a strategy to amplify and broaden the therapeutic impact of PD-1 blockade alone. We have generated a high affinity and selective humanized monoclonal IgG4 antibody, TSR-033, which binds human LAG-3 and serves as a functional antagonist, enhancing in vitro T-cell activation both in mixed lymphocyte reactions and staphylococcal enterotoxin B-driven stimulation assays. In a humanized mouse non–small cell lung carcinoma model, TSR-033 boosted the antitumor efficacy of PD-1 monotherapy, with a concomitant increase in immune activation. Analogous studies in a murine syngeneic tumor model using surrogate antibodies demonstrated significant synergy between LAG-3 and PD-1 blockade—combination treatment led to a marked improvement in therapeutic efficacy, increased T-cell proliferation, IFNγ production, and elicited durable immunologic memory upon tumor rechallenge. Taken together, the pharmacologic activity of TSR-033 demonstrates that it is a potent anti-LAG-3 therapeutic antibody and supports its clinical investigation in cancer patients.
Interactions with Muscle Cells Boost Fusion, Stemness, and Drug Resistance of Prostate Cancer Cells
Authors: Uygur Berna , Leikina Evgenia , Melikov Kamran , Villasmil Rafael , Verma Santosh K. , Vary Calvin P.H. , Chernomordik Leonid V. 
Published: December 2018

AbstractPoorly understood interactions with nonmalignant cells within the tumor microenvironment play an important role in cancer progression. Here, we explored interactions between prostate cancer and muscle cells that surround the prostate. We found that coculturing of prostate cancer cells with skeletal or smooth muscle cells expands the subpopulations of cancer cells with features characteristic of cancer stem-like cells, including anchorage-independent growth, elevated CD133 expression, and drug resistance. These changes in the properties of cancer cells depend on: (i) the muscle cell–induced increases in the concentrations of interleukins 4 and 13; (ii) the cytokine-induced upregulation of the expression of syncytin 1 and annexin A5; and (iii) cancer cell fusion. In human prostate cancer tissues, expression of syncytin 1 and annexin A5, proteins that we found to be required for the cell fusion, positively correlated with the cancer development suggesting that these proteins can be used as biomarkers to evaluate cancer progression and potential therapeutic targets.Implications:The discovered effects of muscle cells on prostate cancer cells reveal a novel and specific pathway by which muscle cells in the microenvironment of prostate cancer cells promote cell fusion and cancer progression.
Ovarian Cancer Cells Commonly Exhibit Defective STING Signaling Which Affects Sensitivity to Viral Oncolysis
Authors: de Queiroz Nina Marí Gual Pimenta , Xia Tianli , Konno Hiroyasu , Barber Glen N. 
Published: December 2018

Abstract

Ovarian cancer is the sixth most prevalent cancer in women and the most lethal of the gynecologic malignancies. Treatments have comprised the use of immunotherapeutic agents as well as oncolytic viruses, with varying results for reasons that remain to be clarified. To better understand the mechanisms that may help predict treatment outcome, we have evaluated innate immune signaling in select ovarian cancer cell lines, governed by the Stimulator of Interferon Genes (STING), which controls self or viral DNA–triggered cytokine production. Our results indicate that STING-dependent signaling is habitually defective in majority of ovarian cancer cells examined, frequently through the suppression of STING and/or the cyclic dinucleotide (CDN) enzyme Cyclic GMP-AMP synthase (cGAS) expression, by epigenetic processes. However, STING-independent, dsRNA-activated innate immune cytokine production, which require RIG-I/MDA5, were largely unaffected. Such defects enabled ovarian cancer cells to avoid DNA damage–mediated cytokine production, which would alert the immunosurveillance system. Loss of STING signaling also rendered ovarian cancer cells highly susceptible to viral oncolytic γ34.5 deleted-HSV1 (Herpes simplex virus) infection in vitro and in vivo.

Implications:
STING signaling evaluation in tumors may help predict disease outcome and possibly dictate the efficacy of oncoviral and other types of cancer therapies.
A literatura marginal brasileira no atual contexto francês
Authors: Coutinho Priscilla 
Published: December 2018

Qual seria o lugar da literatura marginal brasileira no atual cenário internacional ? A voz oriunda das periferias seria uma nova forma de expressão literária em desenvolvimento, ou apenas a repetição de um clichê historicamente atribuído à sociedade brasileira ? Numa conversa franca, Paula Anacaona nos revela seu ponto de vista sobre o assunto, compartilhando sua experiência profissional no meio editorial francês.
Fundadora das edições Anacaona, seu projeto foi motivado por um desejo pessoal de difundir a produção literária das minorias e suas diversidades. Suas publicações privilegiam as narrativas consideradas marginais, sendo, em sua maioria, oriundas das periferias urbanas ou dos distantes espaços rurais brasileiros. Mas ao trazer à tona esses espaços « esquecidos » e essas vozes silenciadas, estaríamos nós contribuindo para a disseminação de um singular movimento literário, ou estaríamos uma vez mais caindo na armadilha do esperado « exotismo » brasileiro? Eis algumas questões que, através dessa entrevista, buscamos refletir.
Considerações sobre o caráter sombrio na música
Authors: Martinez Gandhi De Oliveira , Piedade Acácio Tadeu de Camargo 
Published: December 2018

Atualmente há uma forte presença do caráter sombrio nas artes, literatura e entretenimento. Este artigo busca investigar o sombrio como tópica musical através de um levantamento preliminar do campo do sombrio na música. Iniciamos discutindo questões como a luminosidade e suas associações com o medo, o diabólico e o grotesco. Após comentar o expressionismo no cinema e o movimento gótico dos anos 1980, apresentaremos um histórico do sombrio como tópica musical a partir de figuras de retórica do período barroco e tópicas posteriores como ombrae das unheimliche. Na conclusão, tentaremos argumentar que o sombrio é uma tópica musical contemporânea levando em conta toda essa trajetória histórica e sua intensificação pela arquitetura simbólica da indústria do entretenimento.
On the reproductive biology of Salacia fruticosa Wall. ex M.A. Lawson - an endemic medicinal plant of the Western Ghats, india
Authors: Subin K. , Jose P. A. , Sarath T. V. 
Published: December 2018

Salacia fruticosa Wall. ex M.A. Lawson, an endemic species was studied for the reproductive biology as this species showed reduced fruit set and natural regeneration. The stigma-anther proximity, an extremely low number of pollen grains, a short period of pollen viability, a sparse incidence of pollinators, protandrous and facultative autogamous nature of the flowers and a low percent in fruit set were identified as biological constraints for the species. The incidence of seed pest was added to the poor seed and seedling bank and accelerated rarity process of the species.
Photographic evidence of Striped Hyena Hyaena hyaena (Mammalia: Carnivora: Hyaenidae) in Ramnagar forest division, Uttarakhand, India
Authors: Maurya Vipul , Singh Jai Pratap , Naseem Kahkashan , Mehra Surender , Dhakate Parag M. , Verma Neha , Ansari A. G. 
Published: December 2018

Striped Hyena Hyaena hyaena is a large carnivorous mammal found in parts of Africa, the Middle East, and India. Though the mammal is largely distributed across the globe, it is listed under the Near Threatened category by IUCN Red List. Uttarakhand is one of the states in India that is highly rich in biodiversity. The last reported evidence of the Striped Hyena in Ramnagar Division, Uttarakhand, was in a working plan in 1977. All India tiger estimations through camera traps conducted in 2010, 2012, 2014, and 2016 failed to record the species in the area. The current study conducted in March–December 2015 utilized opportunistic sampling methods to confirm the presence of hyenas in Ramnagar Forest Division of Uttarakhand. The study presents photographic evidence of the Striped Hyena in the area.
On the diversity of the vertebrate fauna (excluding fishes) of Panchet Hill (Garh Panchkot), Purulia, West Bengal, India
Authors: Chattopadhyay Sanjib , Dey Somenath , Roy Utpal Singha 
Published: December 2018

The present study was conducted at Panchet Hill (Garh Panchkot), Purulia, West Bengal between June 2013 and May 2015. Multiple methods were used for making a consolidated checklist and comments on the relative abundance of vertebrate diversity, excluding fishes. The methods included hand capturing, extensive searches in micro habitats, opportunistic spotting and information collection from the local people. A total of 106 different vertebrate species were recorded during the study span of two years. Aves was recorded as the Class with the highest diversity (63 species) while Amphibia was recorded as the Class with the lowest diversity (9 species). Most of the species recorded during the present study belong to ‘Least Concern’ category as designated by IUCN. The Black-headed Ibis Threskiornis melanocephalus and Striped Hyaena Hyaena hyaena belong to ‘Near Threatened’ category while the White-rumped Vulture Gyps bengalensis belongs to ‘Critically Endangered’ category. The present study location is facing pressures from the usual anthropogenic interventions and needs attention from the concerned authorities.
Dietary preference and feeding patterns of the urban Rhesus Macaque Macaca mulatta (Mammalia: Primates: Cercopithecidae) in Asola-Bhatti Wildlife Sanctuary in India
Authors: Ganguly Ishita , Chauhan Netrapal Singh 
Published: December 2018

We studied the feeding patterns and discrete spatio-temporal food habitsof16 groups of the urban Rhesus Macaque Macaca mulatta following their relocation in Asola-Bhatti Wildlife Sanctuary near Delhi, India. We observed that the macaques fed on 31 plant species, with Prosopis juliflora and P. cineraria appearing in most scans. We classified the food consumed by the species into six main categories the species and recorded the average time spent on each of these throughout the year. The maximum time was spent on supplementary feeding provided by the forest department and the minimum on natural plant resources. There was a significant difference in the consumption of different food categories from morning to evening but there were no significant seasonal variations. This study showed that Rhesus Macaque adopted different foraging strategies based on the availability of resources in their new environment and that variety in food resources buffered seasonality in their diet. Information on their feeding patterns and food habits will help in developing management protocols for the primates in urban environments.
Human Monocyte Heterogeneity as Revealed by High-Dimensional Mass Cytometry
Authors: Hamers Anouk A.J. , Dinh Huy Q. , Thomas Graham D. , Marcovecchio Paola , Blatchley Amy , Nakao Catherine S. , Kim Cheryl , McSkimming Chantel , Taylor Angela M. , Nguyen Anh T. , McNamara Coleen A. , Hedrick Catherine C. 
Published: December 2018

Objective—
Three distinct human monocyte subsets have been identified based on the surface marker expression of CD14 and CD16. We hypothesized that monocytes were likely more heterogeneous in composition.

Approach and Results—

We used the high dimensionality of mass cytometry together with the FlowSOM clustering algorithm to accurately identify and define monocyte subsets in blood of healthy human subjects and those with coronary artery disease (CAD). To study the behavior and functionality of the newly defined monocyte subsets, we performed RNA sequencing, transwell migration, and efferocytosis assays. Here, we identify 8 human monocyte subsets based on their surface marker phenotype. We found that 3 of these subsets fall within the CD16
+
nonclassical monocyte population and 4 subsets belong to the CD14
+
classical monocytes, illustrating significant monocyte heterogeneity in humans. As nonclassical monocytes are important in modulating atherosclerosis in mice, we studied the functions of our 3 newly identified nonclassical monocytes in subjects with CAD. We found a marked expansion of a Slan
+
CXCR6
+
nonclassical monocyte subset in CAD subjects, which was positively correlated with CAD severity. This nonclassical subset can migrate towards CXCL16 and shows an increased efferocytosis capacity, indicating it may play an atheroprotective role.

Conclusions—
Our data demonstrate that human nonclassical monocytes are a heterogeneous population, existing of several subsets with functional differences. These subsets have changed frequencies in the setting of severe CAD. Understanding how these newly identified subsets modulate CAD will be important for CAD-based therapies that target myeloid cells.