bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inverse Correlation of STAT3 and MEK Signaling Mediates Resistance to RAS Pathway Inhibition in Pancreatic Cancer
Authors: Nagathihalli Nagaraj S. , Castellanos Jason A. , Lamichhane Purushottam , Messaggio Fanuel , Shi Chanjuan , Dai Xizi , Rai Priyamvada , Chen Xi , VanSaun Michael N. , Merchant Nipun B. 
Published: August 2018

Abstract
Major contributors to therapeutic resistance in pancreatic ductal adenocarcinoma (PDAC) include Kras mutations, a dense desmoplastic stroma that prevents drug delivery to the tumor, and activation of redundant signaling pathways. We have previously identified a mechanistic rationale for targeting STAT3 signaling to overcome therapeutic resistance in PDAC. In this study, we investigate the molecular mechanisms underlying the heterogeneous response to STAT3 and RAS pathway inhibition in PDAC. Effects of JAK/STAT3 inhibition (STAT3i) or MEK inhibition (MEKi) were established in Ptf1acre/+; LSL-KrasG12D/+; and Tgfbr2flox/flox (PKT) mice and patient-derived xenografts (PDX). Amphiregulin (AREG) levels were determined in serum from human patients with PDAC, LSL-KrasG12D/+;Trp53R172H/+;Pdx1Cre/+ (KPC), and PKT mice. MEKi/STAT3i–treated tumors were analyzed for integrity of the pancreas and the presence of cancer stem cells (CSC). We observed an inverse correlation between ERK and STAT3 phosphorylation. MEKi resulted in an immediate activation of STAT3, whereas STAT3i resulted in TACE-induced, AREG-dependent activation of EGFR and ERK. Combined MEKi/STAT3i sustained blockade of ERK, EGFR, and STAT3 signaling, overcoming resistance to individual MEKi or STAT3i. This combined inhibition attenuated tumor growth in PDX and increased survival of PKT mice while reducing serum AREG levels. Furthermore, MEKi/STAT3i altered the PDAC tumor microenvironment by depleting tumor fibrosis, maintaining pancreatic integrity, and downregulating CD44+ and CD133+ CSCs. These results demonstrate that resistance to MEKi is mediated through activation of STAT3, whereas TACE-AREG-EGFR–dependent activation of RAS pathway signaling confers resistance to STAT3 inhibition. Combined MEKi/STAT3i overcomes these resistances and provides a novel therapeutic strategy to target the RAS and STAT3 pathway in PDAC.
Significance: This report describes an inverse correlation between MEK and STAT3 signaling as key mechanisms of resistance in PDAC and shows that combined inhibition of MEK and STAT3 overcomes this resistance and provides an improved therapeutic strategy to target the RAS pathway in PDAC.
Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/21/6235/F1.large.jpg. Cancer Res; 78(21); 6235–46. ©2018 AACR.
A Mutant p53-Dependent Embryonic Stem Cell Gene Signature Is Associated with Augmented Tumorigenesis of Stem Cells
Authors: Koifman Gabriela , Shetzer Yoav , Eizenberger Shay , Solomon Hilla , Rotkopf Ron , Molchadsky Alina , Lonetto Giuseppe , Goldfinger Naomi , Rotter Varda 
Published: August 2018

Abstract
Mutations in the tumor suppressor p53 are the most frequent alterations in human cancer. These mutations include p53-inactivating mutations as well as oncogenic gain-of-function (GOF) mutations that endow p53 with capabilities to promote tumor progression. A primary challenge in cancer therapy is targeting stemness features and cancer stem cells (CSC) that account for tumor initiation, metastasis, and cancer relapse. Here we show that in vitro cultivation of tumors derived from mutant p53 murine bone marrow mesenchymal stem cells (MSC) gives rise to aggressive tumor lines (TL). These MSC-TLs exhibited CSC features as displayed by their augmented oncogenicity and high expression of CSC markers. Comparative analyses between MSC-TL with their parental mutant p53 MSC allowed for identification of the molecular events underlying their tumorigenic properties, including an embryonic stem cell (ESC) gene signature specifically expressed in MSC-TLs. Knockout of mutant p53 led to a reduction in tumor development and tumorigenic cell frequency, which was accompanied by reduced expression of CSC markers and the ESC MSC-TL signature. In human cancer, MSC-TL ESC signature–derived genes correlated with poor patient survival and were highly expressed in human tumors harboring p53 hotspot mutations. These data indicate that the ESC gene signature–derived genes may serve as new stemness-based prognostic biomarkers as well as novel cancer therapeutic targets.
Significance: Mesenchymal cancer stem cell-like cell lines express a mutant p53-dependent embryonic stem cell gene signature, which can serve as a potential prognostic biomarker and therapeutic target in cancer. Cancer Res; 78(20); 5833–47. ©2018 AACR.
PTTG and PBF Functionally Interact with p53 and Predict Overall Survival in Head and Neck Cancer
Authors: Read Martin L. , Modasia Bhavika , Fletcher Alice , Thompson Rebecca J. , Brookes Katie , Rae Peter C. , Nieto Hannah R. , Poole Vikki L. , Roberts Sally , Campbell Moray J. , Boelaert Kristien , Turnell Andrew S. , Smith Vicki E. , Mehanna Hisham , McCabe Christopher J. 
Published: August 2018

Abstract
Head and neck squamous cell carcinoma (HNSCC) is the 6th most common cancer worldwide and poses a significant health burden due to its rising incidence. Although the proto-oncogene pituitary tumor–transforming gene 1 (PTTG) predicts poor patient outcome, its mechanisms of action are incompletely understood. We show here that the protein PBF modulates PTTG function, is overexpressed in HNSCC tumors, and correlates with significantly reduced survival. Lentiviral shRNA attenuation of PTTG or PBF expression in HNSCC cells with either wild-type or mutant p53, and with and without HPV infection, led to dysregulated expression of p53 target genes involved in DNA repair and apoptosis. Mechanistically, PTTG and PBF affected each other's interaction with p53 and cooperated to reduce p53 protein stability in HNSCC cells independently of HPV. Depletion of either PTTG or PBF significantly repressed cellular migration and invasion and impaired colony formation in HNSCC cells, implicating both proto-oncogenes in basic mechanisms of tumorigenesis. Patients with HNSCC with high tumoral PBF and PTTG had the poorest overall survival, which reflects a marked impairment of p53-dependent signaling.
Significance: These findings reveal a complex and novel interrelationship between the expression and function of PTTG, PBF, and p53 in human HNSCC that significantly influences patient outcome. Cancer Res; 78(20); 5863–76. ©2018 AACR.
Clinical Proteomics of Breast Cancer Reveals a Novel Layer of Breast Cancer Classification
Authors: Yanovich Gali , Agmon Hadar , Harel Michal , Sonnenblick Amir , Peretz Tamar , Geiger Tamar 
Published: August 2018

AbstractBreast cancer classification has been the focus of numerous worldwide efforts, analyzing the molecular basis of breast cancer subtypes and aiming to associate them with clinical outcome and to improve the current diagnostic routine. Genomic and transcriptomic profiles of breast cancer have been well established, however the proteomic contribution to these profiles has yet to be elucidated. In this work, we utilized mass spectrometry–based proteomic analysis on more than 130 clinical breast samples to demonstrate intertumor heterogeneity across three breast cancer subtypes and healthy tissue. Unsupervised analysis identified four proteomic clusters, among them, one that represents a novel luminal subtype characterized by increased PI3K signaling. This subtype was further validated using an independent protein-based dataset, but not in two independent transcriptome cohorts. These results demonstrate the importance of deep proteomic analysis, which may affect cancer treatment decision making.Significance: These findings utilize extensive proteomics to identify a novel luminal breast cancer subtype, highlighting the added value of clinical proteomics in breast cancer to identify unique features not observable by genomic approaches. Cancer Res; 78(20); 6001–10. ©2018 AACR.
Ribonucleotide Excision Repair Is Essential to Prevent Squamous Cell Carcinoma of the Skin
Authors: Hiller Björn , Hoppe Anja , Haase Christa , Hiller Christina , Schubert Nadja , Müller Werner , Reijns Martin A.M. , Jackson Andrew P. , Kunkel Thomas A. , Wenzel Jörg , Behrendt Rayk , Roers Axel 
Published: August 2018

Abstract
Because of imperfect discrimination against ribonucleoside triphosphates by the replicative DNA polymerases, large numbers of ribonucleotides are incorporated into the eukaryotic nuclear genome during S-phase. Ribonucleotides, by far the most common DNA lesion in replicating cells, destabilize the DNA, and an evolutionarily conserved DNA repair machinery, ribonucleotide excision repair (RER), ensures ribonucleotide removal. Whereas complete lack of RER is embryonically lethal, partial loss-of-function mutations in the genes encoding subunits of RNase H2, the enzyme essential for initiation of RER, cause the SLE-related type I interferonopathy Aicardi-Goutières syndrome. Here, we demonstrate that selective inactivation of RER in mouse epidermis results in spontaneous DNA damage and epidermal hyperproliferation associated with loss of hair follicle stem cells and hair follicle function. The animals developed keratinocyte intraepithelial neoplasia and invasive squamous cell carcinoma with complete penetrance, despite potent type I interferon production and skin inflammation. These results suggest that compromises to RER-mediated genome maintenance might represent an important tumor-promoting principle in human cancer.
Significance: Selective inactivation of ribonucleotide excision repair by loss of RNase H2 in the murine epidermis results in spontaneous DNA damage, type I interferon response, skin inflammation, and development of squamous cell carcinoma. Cancer Res; 78(20); 5917–26. ©2018 AACR.
Intensive Surveillance with Biannual Dynamic Contrast-Enhanced Magnetic Resonance Imaging Downstages Breast Cancer in BRCA1 Mutation Carriers
Authors: Guindalini Rodrigo Santa Cruz , Zheng Yonglan , Abe Hiroyuki , Whitaker Kristen , Yoshimatsu Toshio F. , Walsh Tom , Schacht David , Kulkarni Kirti , Sheth Deepa , Verp Marion S. , Bradbury Angela R. , Churpek Jane , Obeid Elias , Mueller Jeffrey , Khramtsova Galina , Liu Fang , Raoul Akila , Cao Hongyuan , Romero Iris L. , Hong Susan , Livingston Robert , Jaskowiak Nora , Wang Xiaoming , Debiasi Marcio , Pritchard Colin C. , King Mary-Claire , Karczmar Gregory , Newstead Gillian M. , Huo Dezheng , Olopade Olufunmilayo I. 
Published: August 2018

Abstract

Purpose:
To establish a cohort of high-risk women undergoing intensive surveillance for breast cancer.
Experimental Design: We performed dynamic contrast-enhanced MRI every 6 months in conjunction with annual mammography (MG). Eligible participants had a cumulative lifetime breast cancer risk ≥20% and/or tested positive for a pathogenic mutation in a known breast cancer susceptibility gene.

Results:
Between 2004 and 2016, we prospectively enrolled 295 women, including 157 mutation carriers (75 BRCA1, 61 BRCA2); participants' mean age at entry was 43.3 years. Seventeen cancers were later diagnosed: 4 ductal carcinoma in situ (DCIS) and 13 early-stage invasive breast cancers. Fifteen cancers occurred in mutation carriers (11 BRCA1, 3 BRCA2, 1 CDH1). Median size of the invasive cancers was 0.61 cm. No patients had lymph node metastasis at time of diagnosis, and no interval invasive cancers occurred. The sensitivity of biannual MRI alone was 88.2% and annual MG plus biannual MRI was 94.1%. The cancer detection rate of biannual MRI alone was 0.7% per 100 screening episodes, which is similar to the cancer detection rate of 0.7% per 100 screening episodes for annual MG plus biannual MRI. The number of recalls and biopsies needed to detect one cancer by biannual MRI were 2.8 and 1.7 in BRCA1 carriers, 12.0 and 8.0 in BRCA2 carriers, and 11.7 and 5.0 in non-BRCA1/2 carriers, respectively.

Conclusions:
Biannual MRI performed well for early detection of invasive breast cancer in genomically stratified high-risk women. No benefit was associated with annual MG screening plus biannual MRI screening.
See related commentary by Kuhl and Schrading, p. 1693
Exome Analysis Reveals Genomic Markers Associated with Better Efficacy of Nivolumab in Lung Cancer Patients
Authors: Richard Corentin , Fumet Jean-David , Chevrier Sandy , Derangère Valentin , Ledys Fanny , Lagrange Aurélie , Favier Laure , Coudert Bruno , Arnould Laurent , Truntzer Caroline , Boidot Romain , Ghiringhelli François 
Published: August 2018

Abstract

Purpose:
Immune checkpoint inhibitors revolutionized the treatment of non-small cell lung cancer (NSCLC). However, only one-quarter of patients benefit from these new therapies. PD-L1 assessment and tumor mutational burden (TMB) are available tools to optimize use of checkpoint inhibitors but novel tools are needed. Exome sequencing could generate many variables but their role in identifying predictors of response is unknown.

Experimental Design:
We performed somatic and constitutional exome analyses for 77 patients with NSCLC treated with nivolumab. We studied: one-tumor-related characteristics: aneuploidy, CNA clonality, mutational signatures, TMB, mutations in WNT, AKT, MAPK, and DNA repair pathways, and two-immunologic characteristics: number of intratumoral TCR clones, HLA types, and number of neoantigens; and six clinical parameters.

Results:
A high TMB per Mb, a high number of neoantigens, mutational signatures 1A and 1B, mutations in DNA repair pathways, and a low number of TCR clones are associated with greater PFS. Using a LASSO method, we established an exome-based model with nine exome parameters that could discriminate patients with good or poor PFS (P &lt; 0.0001) and overall survival (P = 0.002). This model shows better ability to predict outcomes compared with a PD-L1 clinical model with or without TMB. It was externally validated on two cohorts of patients with NSCLC treated with pembrolizumab or with nivolumab and ipilimumab as well as in urothelial tumors treated with atezolizumab.

Conclusions:
Altogether, these data provide a validated biomarker that predicts the efficacy of nivolumab or pembrolizumab in patients with NSCLC. Our biomarker seems to be superior to PD-L1 labeling and TMB models.
SD-101 in Combination with Pembrolizumab in Advanced Melanoma: Results of a Phase Ib, Multicenter Study
Authors: Ribas Antoni , Medina Theresa , Kummar Shivaani , Amin Asim , Kalbasi Anusha , Drabick Joseph J. , Barve Minal , Daniels Gregory A. , Wong Deborah J. , Schmidt Emmett V. , Candia Albert F. , Coffman Robert L. , Leung Abraham C.F. , Janssen Robert S. 
Published: August 2018

Abstract
PD-1 inhibitors are approved for treating advanced melanoma, but resistance has been observed. This phase Ib trial evaluated intratumoral SD-101, a synthetic CpG oligonucleotide that stimulates Toll-like receptor 9 (TLR9), in combination with pembrolizumab in patients with unresectable or metastatic malignant melanoma. The most common adverse events related to SD-101 were injection-site reactions and transient, mild-to-moderate “flu-like” symptoms. Among the 9 patients naïve to anti–PD-1 therapy, the overall response rate (ORR) was 78%. The estimated 12-month progression-free survival rate was 88%, and the overall survival rate was 89%. Among 13 patients having prior anti–PD-1 therapy, the ORR was 15%. RNA profiling of tumor biopsies demonstrated increased CD8+ T cells, natural killer cells, cytotoxic cells, dendritic cells, and B cells. The combination of intratumoral SD-101 and pembrolizumab was well tolerated and induced broad immune activation in the tumor microenvironment with durable tumor responses in both peripheral and visceral lesions.
Significance: These early data demonstrate that the combination of pembrolizumab with intratumoral SD-101 is well tolerated and can induce immune activation at the tumor site. Combining an intratumoral TLR9 innate immune stimulant with PD-1 blockade can potentially increase clinical efficacy with minimal additional toxicity relative to PD-1 blockade alone. Cancer Discov; 8(10); 1250–7. ©2018 AACR.
This article is highlighted in the In This Issue feature, p. 1195
In Situ Vaccination with a TLR9 Agonist and Local Low-Dose Radiation Induces Systemic Responses in Untreated Indolent Lymphoma
Authors: Frank Matthew J. , Reagan Patrick M. , Bartlett Nancy L. , Gordon Leo I. , Friedberg Jonathan W. , Czerwinski Debra K. , Long Steven R. , Hoppe Richard T. , Janssen Robert , Candia Albert F. , Coffman Robert L. , Levy Ronald 
Published: August 2018

Abstract
This multicenter phase I/II clinical trial evaluated intratumoral SD-101, a TLR9 agonist, and low-dose radiation in patients with untreated indolent lymphoma. Twenty-nine enrolled patients received 4 Gy of radiation followed by 5 weekly intratumoral injections of SD-101 at a single tumor site. No treatment-related grade 4 or serious adverse events occurred. Nearly all patients had tumor reduction at their treated site. More importantly, 24 patients had tumor reduction at their nontreated sites, with 5 patients achieving a partial response and one achieving a complete response. Treatment-related increases of CD8+ and CD4+ effector T cells and decreases of T follicular helper and T regulatory cells (Treg) were observed in the tumor microenvironment. Low pretreatment levels of CD4+ Tregs, proliferating CD8+ T cells, and Granzyme B+ CD8+ T cells were associated with favorable outcomes. Intratumoral SD-101 in combination with low-dose radiation is well tolerated and results in regression of both treated and untreated sites of disease.
Significance: In situ vaccination with the TLR9 agonist SD-101, along with low-dose radiation, was safe and induced systemic responses in patients with indolent lymphoma. Low levels of CD4+ Tregs, proliferating CD8+ T cells, and Granzyme B+ CD8+ T cells in the tumor microenvironment predicted favorable response to treatment. Cancer Discov; 8(10); 1258–69. ©2018 AACR.
This article is highlighted in the In This Issue feature, p. 1195
GITR Agonism Enhances Cellular Metabolism to Support CD8+ T-cell Proliferation and Effector Cytokine Production in a Mouse Tumor Model
Authors: Sabharwal Simran S. , Rosen David B. , Grein Jeff , Tedesco Dana , Joyce-Shaikh Barbara , Ueda Roanna , Semana Marie , Bauer Michele , Bang Kathy , Stevenson Christopher , Cua Daniel J. , Zúñiga Luis A. 
Published: August 2018

Abstract
GITR is a costimulatory receptor currently undergoing phase I clinical trials. Efficacy of anti-GITR therapy in syngeneic mouse models requires regulatory T-cell depletion and CD8+ T-cell costimulation. It is increasingly appreciated that immune cell proliferation and function are dependent on cellular metabolism. Enhancement of diverse metabolic pathways leads to different immune cell fates. Little is known about the metabolic effects of GITR agonism; thus, we investigated whether costimulation via GITR altered CD8+ T-cell metabolism. We found activated, GITR-treated CD8+ T cells upregulated nutrient uptake, lipid stores, glycolysis, and oxygen consumption rate (OCR) in vitro. Using MEK, PI3Kδ, and metabolic inhibitors, we show increased metabolism is required, but not sufficient, for GITR antibody (DTA-1)-induced cellular proliferation and IFNγ production. In an in vitro model of PD-L1–induced CD8+ T-cell suppression, GITR agonism alone rescued cellular metabolism and proliferation, but not IFNγ production; however, DTA-1 in combination with anti–PD-1 treatment increased IFNγ production. In the MC38 mouse tumor model, GITR agonism significantly increased OCR and IFNγ and granzyme gene expression in both tumor and draining lymph node (DLN) CD8+ T cells ex vivo, as well as basal glycolysis in DLN and spare glycolytic capacity in tumor CD8+ T cells. DLN in GITR-treated mice showed significant upregulation of proliferative gene expression compared with controls. These data show that GITR agonism increases metabolism to support CD8+ T-cell proliferation and effector function in vivo, and that understanding the mechanism of action of agonistic GITR antibodies is crucial to devising effective combination therapies. Cancer Immunol Res; 6(10); 1199–211. ©2018 AACR.
Evald Ilyenkov’s ‘Creative Marxism’
Authors: Maidansky Andrey , Pavlov Evgeni V. 
Published: August 2018

AbstractThe latest book by Russian philosopher Sergey Mareev consists of two parts: recollections of his teacher Evald Ilyenkov, and reflections on some of the key themes of Ilyenkov’s philosophical heritage. The author traces several polemical lines related to the problem of the ideal (Ilyenkov versus Losev and Lifschitz), dialectics of the abstract and the concrete, the principle of historicism, as well as Ilyenkov’s interpretation of Spinoza and Hegel.
Social Class in China Today
Authors: Westra Richard 
Published: August 2018

AbstractThis article looks anew at questions of social class in China. It does this through the prism of three recent books on China dealing with class. Key problems regarding social class in China treated in the article are those of the constitution of the working class given the fact that China’s workforce is largely composed of a ‘floating population’ of migrants, and of the position of the peasantry which had emerged as the revolutionary agent of the Mao years.
Going and Coming Home in Diasporan Pilgrimage: The Case of Philo’s Ἱεροποµποί and Diaspora-Homeland Relations in Alexandrian Jewish Perspective
Authors: Trotter Jonathan 
Published: August 2018

AbstractThis article focuses on how community-sanctioned pilgrimage to Jerusalem could be employed to establish both the homeland and the diaspora as places of belonging. As a case study, I will analyze Philo’s portrayal of the ἱεροποµποί—a term unique to Philo used to describe those chosen to carry offerings, especially the annual half-shekels—from the diaspora to the Jerusalem temple. I will argue that, according to Philo, the ἱεροποµποί (1) were elected community leaders who functioned as representatives of their communities, (2) enabled those who did not travel to Jerusalem to participate vicariously in sacrifice and pilgrimage, and (3) established both the homeland and the diaspora as places of belonging for their community through providing a context for participating in and perpetuating the collective memory of the Jewish nation, in general, and the Alexandrian Jewish community, in particular.
Nestling begging calls increase predation risk by corvids
Authors: Husby Magne 
Published: August 2018

Abstract
Despite nest predation being the most common cause of breeding failure in open-nesting birds, we have little insight into the cues used by nest predators when they search for nests. So far we have assumed that nest-predating birds are visually oriented while mammal predators to a large extent use scent and auditory cues like nestling begging calls. To evaluate how important nestling begging calls are for corvid nest predators searching for nests, I used artificial nests, which made it possible to find the real costs of the begging without mitigation by parental and nestling behavior. I used paired artificial nests, one with and one without nestling begging call playback. Within 10 days, 62.9% of the nests were predated. The analyses showed that nests with begging calls suffered a significantly higher predation rate than nests without begging calls, especially when the nests were placed close to corvid nests. Moreover, nests with begging calls were predated significantly earlier than nests without begging calls. In artificial nest pairs with both nests predated but on different days, nests with begging calls were predated first. In nest pairs with only one predated nest, nests with begging calls were predated most often. This experiment shows that nestling begging calls imply a cost in terms of increased and earlier nest predation, and that corvids use nestling begging calls as a cue to find and depredate bird nests, challenging earlier expectations.