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Κυριακή 1 Απριλίου 2018

No association between circulating concentrations of vitamin D and risk of lung cancer: An analysis in 20 prospective studies in the Lung Cancer Cohort Consortium (LC3)

Abstract
Background
There is observational evidence suggesting that high vitamin D concentrations may protect against lung cancer. To investigate this hypothesis in detail, we measured circulating vitamin D concentrations in pre-diagnostic blood from 20 cohorts participating in the Lung Cancer Cohort Consortium (LC3).
Patients and methods
The study included 5,313 lung cancer cases and 5,313 controls selected from. Blood samples for the cases were collected, on average, 5 years prior to lung cancer diagnosis. Controls were individually matched to the cases by cohort, sex, age, race/ethnicity, date of blood collection, and smoking status in 5 categories. Liquid chromatography coupled with tandem mass spectrometry was used to separately analyze 25-hydroxyvitamin D2 (25(OH)D2) and 25-hydroxyvitamin D3 (25(OH)D3) and their concentrations were combined to give an overall measure of 25(OH)D. We used conditional logistic regression to calculate odds ratios (OR) and 95% confidence intervals (CI) for 25(OH)D as both a continuous and categorical variable.
Results
Overall, no apparent association between 25(OH)D and risk of lung cancer was observed (multivariable adjusted OR for a doubling in concentration: 0.98, 95% confidence interval: 0.91, 1.06). Similarly, we found no clear evidence of interaction by cohort, sex, age, smoking status, or histology.
Conclusion
This study did not support an association between vitamin D concentrations and lung cancer risk.

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A Small-Molecule Splicing Modulator Targets Spliceosome-Mutant Cells [Splicing]

The small molecule H3B-8800 binds to and modulates the SF3b complex to kill spliceosome-mutant cells.



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By the Numbers: Novel Drugs Approved by the FDA, 2011-2017 [News in Brief]

In 2017, the FDA approved 12 novel cancer drugs. The agency also approved two chimeric antigen receptor T-cell therapies for blood cancers.



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Lutetium Lu 177 Dotatate Approved by FDA [News in Brief]

The FDA recently approved the radiopharmaceutical lutetium Lu 177 dotatate to treat patients with somatostatin receptor–positive gastroenteropancreatic neuroendocrine tumors. The approval was based on results of the phase III NETTER-1 trial.



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The Pancreatic Cancer Microbiome Promotes Oncogenesis by Induction of Innate and Adaptive Immune Suppression [Research Briefs]

We found that the cancerous pancreas harbors a markedly more abundant microbiome compared with normal pancreas in both mice and humans, and select bacteria are differentially increased in the tumorous pancreas compared with gut. Ablation of the microbiome protects against preinvasive and invasive pancreatic ductal adenocarcinoma (PDA), whereas transfer of bacteria from PDA-bearing hosts, but not controls, reverses tumor protection. Bacterial ablation was associated with immunogenic reprogramming of the PDA tumor microenvironment, including a reduction in myeloid-derived suppressor cells and an increase in M1 macrophage differentiation, promoting TH1 differentiation of CD4+ T cells and CD8+ T-cell activation. Bacterial ablation also enabled efficacy for checkpoint-targeted immunotherapy by upregulating PD-1 expression. Mechanistically, the PDA microbiome generated a tolerogenic immune program by differentially activating select Toll-like receptors in monocytic cells. These data suggest that endogenous microbiota promote the crippling immune-suppression characteristic of PDA and that the microbiome has potential as a therapeutic target in the modulation of disease progression.

Significance: We found that a distinct and abundant microbiome drives suppressive monocytic cellular differentiation in pancreatic cancer via selective Toll-like receptor ligation leading to T-cell anergy. Targeting the microbiome protects against oncogenesis, reverses intratumoral immune tolerance, and enables efficacy for checkpoint-based immunotherapy. These data have implications for understanding immune suppression in pancreatic cancer and its reversal in the clinic. Cancer Discov; 8(4); 403–16. ©2018 AACR.

See related commentary by Riquelme et al., p. 386.

This article is highlighted in the In This Issue feature, p. 371



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NIH Offers Funding for Genome-Editing Projects [News in Brief]

The NIH is launching a new funding program for genome-editing technologies. The agency will award $190 million for projects including new delivery methods for genome editors, new editing technologies, and preclinical models to test their safety.



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Umbralisib Inhibits PI3K{delta} with Less Toxicity Than Previous Inhibitors [Clinical Trials]

Umbralisib is well tolerated and has activity against relapsed or refractory hematologic cancers.



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Drug Combo Bests Sunitinib in RCC [News in Brief]

The phase III IMmotion151 trial found that the combination of atezolizumab and bevacizumab boosts progression-free survival compared with sunitinib in patients with advanced or metastatic renal cell carcinoma. The increase was 2.8 months in all patients and 3.5 months in patients with PD-L1–positive tumors.



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Immunotherapy for Pancreatic Cancer: More Than Just a Gut Feeling [In the Spotlight]

Summary: Development of pancreatic cancer in spontaneous murine models is associated with enrichment of specific strains of gut and intratumoral bacteria that induce a tolerogenic immunosuppressive microenvironment favoring cancer progression and resistance to immunotherapies. Ablation of the microbiome with antibiotics reshapes the tumor microenvironment, inducing T-cell activation, improving immune surveillance, and increasing sensitivity to immunotherapy in established tumors. Cancer Discov; 8(4); 386–8. ©2018 AACR.

See related article by Pushalkar et al., p. 403.



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BMI Can Underestimate Breast Cancer Risk [News in Brief]

New findings suggest that postmenopausal women with high levels of body fat are at increased risk of ER-positive breast cancer, even if their body mass index is within the normal range. If confirmed, these results would put many more women at elevated risk for breast cancer than was previously thought, with implications for the way that healthy-weight women should be counseled to reduce their health risks.



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BRD4 Profiling Identifies Critical Chronic Lymphocytic Leukemia Oncogenic Circuits and Reveals Sensitivity to PLX51107, a Novel Structurally Distinct BET Inhibitor [Research Articles]

Bromodomain and extra-terminal (BET) family proteins are key regulators of gene expression in cancer. Herein, we utilize BRD4 profiling to identify critical pathways involved in pathogenesis of chronic lymphocytic leukemia (CLL). BRD4 is overexpressed in CLL and is enriched proximal to genes upregulated or de novo expressed in CLL with known functions in disease pathogenesis and progression. These genes, including key members of the B-cell receptor (BCR) signaling pathway, provide a rationale for this therapeutic approach to identify new targets in alternative types of cancer. Additionally, we describe PLX51107, a structurally distinct BET inhibitor with novel in vitro and in vivo pharmacologic properties that emulates or exceeds the efficacy of BCR signaling agents in preclinical models of CLL. Herein, the discovery of the involvement of BRD4 in the core CLL transcriptional program provides a compelling rationale for clinical investigation of PLX51107 as epigenetic therapy in CLL and application of BRD4 profiling in other cancers.

Significance: To date, functional studies of BRD4 in CLL are lacking. Through integrated genomic, functional, and pharmacologic analyses, we uncover the existence of BRD4-regulated core CLL transcriptional programs and present preclinical proof-of-concept studies validating BET inhibition as an epigenetic approach to target BCR signaling in CLL. Cancer Discov; 8(4); 458–77. ©2018 AACR.

This article is highlighted in the In This Issue feature, p. 371



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Axitinib plus Pembrolizumab Is Effective in Renal Cell Carcinoma [Clinical Trials]

Axitinib plus pembrolizumab has a 73% response rate in previously untreated advanced renal cell carcinoma.



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Tumorigenic Colonic Bacteria May Promote Early Neoplasia [Microbiome]

Colonic biofilms may accelerate tumorigenesis in patients with familial adenomatous polyposis (FAP).



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The PI3K{alpha} Inhibitor Alpelisib Has Activity in PIK3CA-altered Tumors [Clinical Trials]

The PI3Kα inhibitor alpelisib achieved a 58.2% disease control rate in PIK3CA-altered solid tumors.



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Medulloblastoma Circulating Tumor Cells Form Leptomeningeal Metastases [Metastasis]

NCAM+CD45+ medulloblastoma cells were shown to be medulloblastoma circulating tumor cells (CTC).



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AR Inhibition Achieves Responses in AR+ Triple-Negative Breast Cancer [Clinical Trials]

The AR inhibitor enzalutamide achieved responses in patients with advanced TNBC in a phase II trial.



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Natural Killer Cells Recruit Dendritic Cells to Promote Antitumor Immunity [Immunology]

Natural killer (NK) cells recruit conventional type 1 dendritic cells (cDC1) to the tumor microenvironment.



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SLFN11 Blocks DNA Replication Independently of ATR Activity [DNA Repair]

SLFN11 inhibits replication in response to DNA damage or cell cycle checkpoint inhibition.



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Plasma DNA and Metastatic Castration-Resistant Prostate Cancer: The Odyssey to a Clinical Biomarker Test [In the Spotlight]

Summary: Comprehensive plasma DNA analysis identifies clinically actionable genomic aberrations. Cancers harboring disruption of TP53 or BRCA2 or ATM detected in plasma have significantly worse outcomes on novel AR targeting. Cancer Discov; 8(4); 392–4. ©2018 AACR.

See related article by Annala et al., p. 444.



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TGF{beta} Promotes Immune Evasion to Limit the Efficacy of Anti-PD-1/PD-L1 [Immunotherapy]

The TGFβ-activated stroma induces T-cell exclusion to suppress antitumor immunity.



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Combined BRAF, EGFR, and MEK Inhibition in Patients with BRAFV600E-Mutant Colorectal Cancer [Research Articles]

Although BRAF inhibitor monotherapy yields response rates >50% in BRAFV600-mutant melanoma, only approximately 5% of patients with BRAFV600E colorectal cancer respond. Preclinical studies suggest that the lack of efficacy in BRAFV600E colorectal cancer is due to adaptive feedback reactivation of MAPK signaling, often mediated by EGFR. This clinical trial evaluated BRAF and EGFR inhibition with dabrafenib (D) + panitumumab (P) ± MEK inhibition with trametinib (T) to achieve greater MAPK suppression and improved efficacy in 142 patients with BRAFV600E colorectal cancer. Confirmed response rates for D+P, D+T+P, and T+P were 10%, 21%, and 0%, respectively. Pharmacodynamic analysis of paired pretreatment and on-treatment biopsies found that efficacy of D+T+P correlated with increased MAPK suppression. Serial cell-free DNA analysis revealed additional correlates of response and emergence of KRAS and NRAS mutations on disease progression. Thus, targeting adaptive feedback pathways in BRAFV600E colorectal cancer can improve efficacy, but MAPK reactivation remains an important primary and acquired resistance mechanism.

Significance: This trial demonstrates that combined BRAF + EGFR + MEK inhibition is tolerable, with promising activity in patients with BRAFV600E colorectal cancer. Our findings highlight the MAPK pathway as a critical target in BRAFV600E colorectal cancer and the need to optimize strategies inhibiting this pathway to overcome both primary and acquired resistance. Cancer Discov; 8(4); 428–43. ©2018 AACR.

See related commentary by Janku, p. 389.

See related article by Hazar-Rethinam et al., p. 417.

This article is highlighted in the In This Issue feature, p. 371



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People Use Emotion to Persuade, Even When It Could Backfire

We intuitively use more emotional language to enhance our powers of persuasion, according to research published in Psychological Science, a journal of the Association for Psychological Science. The research shows that people tend toward appeals that aren't simply more positive or negative but are infused with emotionality, even when they're trying to sway an audience that may not be receptive to such language.

"Beyond simply becoming more positive or negative, people spontaneously shift toward using more emotional language when trying to persuade," says researcher Matthew D. Rocklage of The Kellogg School of Management at Northwestern University.

We might imagine that people would use very positive words such as "excellent" or "outstanding" to bring others around to their point of view, but the findings showed that people specifically used terms that convey a greater degree of emotion, such as "exciting" and "thrilling."

Understanding the components that make for a persuasive message is a critical focus of fields ranging from advertising to politics and even public health. Rocklage and colleagues wanted to look at the question from a different angle, exploring how we communicate with others when we are the ones trying to persuade.

"It's possible that to be seen as rational and reasonable, people might remove emotion from their language when attempting to persuade," says Rocklage. Drawing from attitudes theory and social-function theories of emotion, however, Rocklage and colleagues Derek D. Rucker and Loran F. Nordgren hypothesized that people would go the other way, tapping into emotional language as a means of social influence.

In one online study, the researchers showed 1,285 participants a photo and some relevant details for a particular product available from Amazon.com. They asked some participants to write a five-star review that would persuade readers to purchase that product, while they asked others to write a five-star review that simply described the product's positive features.

Using an established tool for quantitative linguistic analysis, the Evaluative Lexicon, the researchers then quantified how emotional, positive or negative, and extreme the reviews were.

Although the reviews were equally positive in their language, the data showed that reviewers used more emotional language when they were trying to persuade readers to buy a product compared with when they were writing a five-star review without intending to persuade. Participants' persuasive reviews also had more emotional language compared with actual five-star reviews for the same products published on Amazon.com.

Importantly, the shift toward more emotional language appeared to be automatic rather than deliberative. Participants still used more emotional descriptors in persuasive reviews when they were simultaneously trying to remember an 8-digit number, a competing task that made strategizing very difficult.

The tendency to use more emotional language emerged even when participants were attempting to persuade a group of "rational" thinkers.

"Past research indicates that emotional appeals can backfire when an audience prefers unemotional appeals," says Rocklage. "Our findings indicate that there is a strong enough connection between persuasion and emotion in people's minds that they continue to use emotion even in the face of an audience where that approach can backfire."

Indeed, additional evidence indicated a connection between emotion and persuasion in memory. The researchers found that the more emotional a word was, the more likely participants were to associate it with persuasion and the quicker they did so.

An interesting avenue for future research, says Rocklage, is to investigate whether the association transfers across various contexts.

"For instance, would people use less emotion if they were in a boardroom meeting or if they were writing a formal letter of recommendation?" he wonders.

The design and analysis plans for Experiment 4 were preregistered at the Open Science Framework. The complete Open Practices Disclosure for this article is available online. This article has received the badge for Preregistration.



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Myeloma Cells Are Activated in Bone Marrow Microenvironment by the CD180/MD-1 Complex, Which Senses Lipopolysaccharide

Multiple myeloma (MM) cells acquire dormancy and drug resistance via interaction with bone marrow stroma cells (BMSC) in a hypoxic microenvironment. Elucidating the mechanisms underlying the regrowth of dormant clones may contribute to further improvement of the prognosis of MM patients. In this study, we find that the CD180/MD-1 complex, a noncanonical lipopolysaccharide (LPS) receptor, is expressed on MM cells but not on normal counterparts, and its abundance is markedly upregulated under adherent and hypoxic conditions. Bacterial LPS and anti-CD180 antibody, but not other Toll-like receptor ligands, enhanced the growth of MM cells via activation of MAP kinases ERK and JNK in positive correlation with expression levels of CD180. Administration of LPS significantly increased the number of CD180/CD138 double-positive cells in a murine xenograft model when MM cells were inoculated with direct attachment to BMSC. Knockdown of CD180 canceled the LPS response in vitro and in vivo. Promoter analyses identified IKZF1 (Ikaros) as a pivotal transcriptional activator of the CD180 gene. Both cell adhesion and hypoxia activated transcription of the CD180 gene by increasing Ikaros expression and its binding to the promoter region. Pharmacological targeting of Ikaros by the immunomodulatory drug lenalidomide ameliorated the response of MM cells to LPS in a CD180-dependent manner in vitro and in vivo. Thus, the CD180/MD-1 pathway may represent a novel mechanism of growth regulation of MM cells in a BM milieu and may be a therapeutic target of preventing the regrowth of dormant MM cells.Significance: This study describes a novel mechanism by which myeloma cells are regulated in the bone marrow, where drug resistance and dormancy can evolve after treatment, with potential therapeutic implications for treating this often untreatable blood cancer. Cancer Res; 78(7); 1766–78. ©2018 AACR.

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Integrative Genomic Analysis Predicts Causative Cis-Regulatory Mechanisms of the Breast Cancer-Associated Genetic Variant rs4415084

Previous genome-wide association studies (GWAS) have identified several common genetic variants that may significantly modulate cancer susceptibility. However, the precise molecular mechanisms behind these associations remain largely unknown; it is often not clear whether discovered variants are themselves functional or merely genetically linked to other functional variants. Here, we provide an integrated method for identifying functional regulatory variants associated with cancer and their target genes by combining analyses of expression quantitative trait loci, a modified version of allele-specific expression that systematically utilizes haplotype information, transcription factor (TF)–binding preference, and epigenetic information. Application of our method to a breast cancer susceptibility region in 5p12 demonstrates that the risk allele rs4415084-T correlates with higher expression levels of the protein-coding gene mitochondrial ribosomal protein S30 (MRPS30) and lncRNA RP11-53O19.1. We propose an intergenic SNP rs4321755, in linkage disequilibrium (LD) with the GWAS SNP rs4415084 (r2 = 0.988), to be the predicted functional SNP. The risk allele rs4321755-T, in phase with the GWAS rs4415084-T, created a GATA3-binding motif within an enhancer, resulting in differential GATA3 binding and chromatin accessibility, thereby promoting transcription of MRPS30 and RP11-53O19.1. MRPS30 encodes a member of the mitochondrial ribosomal proteins, implicating the role of risk SNP in modulating mitochondrial activities in breast cancer. Our computational framework provides an effective means to integrate GWAS results with high-throughput genomic and epigenomic data and can be extended to facilitate rapid functional characterization of other genetic variants modulating cancer susceptibility.Significance: Unification of GWAS results with information from high-throughput genomic and epigenomic profiles provides a direct link between common genetic variants and measurable molecular perturbations. Cancer Res; 78(7); 1579–91. ©2018 AACR.

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In Silico Evaluation of Pharmacokinetic Optimization for Antimitogram-Based Clinical Trials

Antimitograms are prototype in vitro tests for evaluating chemotherapeutic efficacy using patient-derived primary cancer cells. These tests might help optimize treatment from a pharmacodynamic standpoint by guiding treatment selection. However, they are technically challenging and require refinements and trials to demonstrate benefit to be widely used. In this study, we performed simulations aimed at exploring how to validate antimitograms and how to complement them by pharmacokinetic optimization. A generic model of advanced cancer, including pharmacokinetic–pharmacodynamic monitoring, was used to link dosing schedules with progression-free survival (PFS), as built from previously validated modules. This model was used to explore different possible situations in terms of pharmacokinetic variability, pharmacodynamic variability, and antimitogram performance. The model recapitulated tumor dynamics and standalone therapeutic drug monitoring efficacy consistent with published clinical results. Simulations showed that combining pharmacokinetic and pharmacodynamic optimization should increase PFS in a synergistic fashion. Simulated data were then used to compute required clinical trial sizes, which were 30% to 90% smaller when pharmacokinetic optimization was added to pharmacodynamic optimization. This improvement was observed even when pharmacokinetic optimization alone exhibited only modest benefit. Overall, our work illustrates the synergy derived from combining antimitograms with therapeutic drug monitoring, permitting a disproportionate reduction of the trial size required to prove a benefit on PFS. Accordingly, we suggest that strategies with benefits too small for standalone clinical trials could be validated in combination in a similar manner.Significance: This work offers a method to reduce the number of patients needed for a clinical trial to prove the hypothesized benefit of a drug to progression-free survival, possibly easing opportunities to evaluate combinations. Cancer Res; 78(7); 1873–82. ©2018 AACR.

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Pyruvate Dehydrogenase PDH-E1{beta} Controls Tumor Progression by Altering the Metabolic Status of Cancer Cells

Downregulation of pyruvate dehydrogenase (PDH) is critical for the aberrant preferential activation of glycolysis in cancer cells under normoxic conditions. Phosphorylation-dependent inhibition of PDH is a relevant event in this process, but it is not durable as it relies on PDH kinases that are activated ordinarily under hypoxic conditions. Thus, it remains unclear how PDH is durably downregulated in cancer cells that are not hypoxic. Building on evidence that PDH activity depends on the stability of a multi-protein PDH complex, we found that the PDH-E1β subunit of the PDH complex is downregulated to inhibit PDH activity under conditions of prolonged hypoxia. After restoration of normoxic conditions, reduced expression of PDH-E1β was sustained such that glycolysis remained highly activated. Notably, PDH-E1β silencing in cancer cells produced a metabolic state strongly resembling the Warburg effect, but inhibited tumor growth. Conversely, enforced exogenous expression of PDH-E1β durably increased PDH activity and promoted the malignant growth of breast cancer cells in vivo. Taken together, our results establish the specific mechanism through which PDH acts as an oncogenic factor by tuning glycolytic metabolism in cancer cells.Significance: This seminal study offers a mechanistic explanation for why glycolysis is aberrantly activated in normoxic cancer cells, offering insights into this long-standing hallmark of cancer termed the Warburg effect. Cancer Res; 78(7); 1592–603. ©2018 AACR.

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Fc-Mediated Anomalous Biodistribution of Therapeutic Antibodies in Immunodeficient Mouse Models

A critical benchmark in the development of antibody-based therapeutics is demonstration of efficacy in preclinical mouse models of human disease, many of which rely on immunodeficient mice. However, relatively little is known about how the biology of various immunodeficient strains impacts the in vivo fate of these drugs. Here we used immunoPET radiotracers prepared from humanized, chimeric, and murine mAbs against four therapeutic oncologic targets to interrogate their biodistribution in four different strains of immunodeficient mice bearing lung, prostate, and ovarian cancer xenografts. The immunodeficiency status of the mouse host as well as both the biological origin and glycosylation of the antibody contributed significantly to the anomalous biodistribution of therapeutic monoclonal antibodies in an Fc receptor-dependent manner. These findings may have important implications for the preclinical evaluation of Fc-containing therapeutics and highlight a clear need for biodistribution studies in the early stages of antibody drug development.Significance: Fc/FcγR-mediated immunobiology of the experimental host is a key determinant to preclinical in vivo tumor targeting and efficacy of therapeutic antibodies. Cancer Res; 78(7); 1820–32. ©2018 AACR.

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Polyol Pathway Links Glucose Metabolism to the Aggressiveness of Cancer Cells

Cancer cells alter their metabolism to support their malignant properties. In this study, we report that the glucose-transforming polyol pathway (PP) gene aldo-keto-reductase-1-member-B1 (AKR1B1) strongly correlates with epithelial-to-mesenchymal transition (EMT). This association was confirmed in samples from lung cancer patients and from an EMT-driven colon cancer mouse model with p53 deletion. In vitro, mesenchymal-like cancer cells showed increased AKR1B1 levels, and AKR1B1 knockdown was sufficient to revert EMT. An equivalent level of EMT suppression was measured by targeting the downstream enzyme sorbitol-dehydrogenase (SORD), further pointing at the involvement of the PP. Comparative RNA sequencing confirmed a profound alteration of EMT in PP-deficient cells, revealing a strong repression of TGFβ signature genes. Excess glucose was found to promote EMT through autocrine TGFβ stimulation, while PP-deficient cells were refractory to glucose-induced EMT. These data show that PP represents a molecular link between glucose metabolism, cancer differentiation, and aggressiveness, and may serve as a novel therapeutic target.Significance: A glucose-transforming pathway in TGFβ-driven epithelial-to-mesenchymal transition provides novel mechanistic insights into the metabolic control of cancer differentiation. Cancer Res; 78(7); 1604–18. ©2018 AACR.

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STAT3/PIAS3 Levels Serve as “Early Signature” Genes in the Development of High-Grade Serous Carcinoma from the Fallopian Tube

The initial molecular events that lead to malignant transformation of the fimbria of the fallopian tube (FT) through high-grade serous ovarian carcinoma (HGSC) remain poorly understood. In this study, we report that increased expression of signal transducer and activator of transcription 3 (pSTAT3 Tyr705) and suppression or loss of protein inhibitor of activated STAT3 (PIAS3) in FT likely drive HGSC. We evaluated human tissues-benign normal FT, tubal-peritoneal junction (TPJ), p53 signature FT tissue, tubal intraepithelial lesion in transition (TILT), serous tubal intraepithelial carcinoma (STIC) without ovarian cancer, and HGSC for expression of STAT3/PIAS3 (compared with their known TP53 signature) and their target proliferation genes. We observed constitutive activation of STAT3 and low levels or loss of PIAS3 in the TPJ, p53 signature, TILT, and STIC through advanced stage IV (HGSC) tissues. Elevated expression of pSTAT3 Tyr705 and decreased levels of PIAS3 appeared as early as TPJ and the trend continued until very advanced stage HGSC (compared with high PIAS3 and low pSTAT3 expression in normal benign FT). Exogenous expression of STAT3 in FT cells mediated translocation of pSTAT3 and c-Myc into the nucleus. In vivo experiments demonstrated that overexpression of STAT3 in FT secretory epithelial cells promoted tumor progression and metastasis, mimicking the clinical disease observed in patients with HGSC. Thus, we conclude that the STAT3 pathway plays a role in the development and progression of HGSC from its earliest premalignant states.Significance: Concomitant gain of pSTAT3 Tyr705 and loss of PIAS3 appear critical for initiation and development of high-grade serous carcinoma. Cancer Res; 78(7); 1739–50. ©2018 AACR.

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Keratin 19 Expression in Hepatocellular Carcinoma Is Regulated by Fibroblast-Derived HGF via a MET-ERK1/2-AP1 and SP1 Axis

Keratin (KRT) 19 is a poor prognostic marker for hepatocellular carcinoma (HCC); however, regulatory mechanisms underlying its expression remain unclear. We have previously reported the presence of fibrous tumor stroma in KRT19-positive HCC, suggesting that cross-talk between cancer-associated fibroblasts (CAF) and tumor epithelial cells could regulate KRT19 expression. This was investigated in this study using an in vitro model of paracrine interaction between HCC cell lines (HepG2, SNU423) and hepatic stellate cells (HSC), a major source of hepatic myofibroblasts. HSCs upregulated transcription and translation of KRT19 in HCC cells via paracrine interactions. Mechanistically, hepatocyte growth factor (HGF) from HSCs activated c-MET and the MEK–ERK1/2 pathway, which upregulated KRT19 expression in HCC cells. Furthermore, AP1 (JUN/FOSL1) and SP1, downstream transcriptional activators of ERK1/2, activated KRT19 expression in HCC cells. In clinical specimens of human HCC (n = 339), HGF and KRT19 protein expression correlated with CAF levels. In addition, HGF or MET protein expression was associated with FOSL1 and KRT19 expression and was found to be a poor prognostic factor. Analysis of data from The Cancer Genome Atlas also revealed KRT19 expression was closely associated with CAF and MET-mediated signaling activities. These results provide insights into the molecular background of KRT19-positive HCC that display an aggressive phenotype.Significance: These findings reveal KRT19 expression in hepatocellular carcinoma is regulated by cross-talk between cancer-associated fibroblasts and HCC cells, illuminating new therapeutic targets for this aggressive disease. Cancer Res; 78(7); 1619–31. ©2018 AACR.

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TRIM59 Promotes Gliomagenesis by Inhibiting TC45 Dephosphorylation of STAT3

Aberrant EGFR signaling is a common driver of glioblastoma (GBM) pathogenesis; however, the downstream effectors that sustain this oncogenic pathway remain unclarified. Here we demonstrate that tripartite motif-containing protein 59 (TRIM59) acts as a new downstream effector of EGFR signaling by regulating STAT3 activation in GBM. EGFR signaling led to TRIM59 upregulation through SOX9 and enhanced the interaction between TRIM59 and nuclear STAT3, which prevents STAT3 dephosphorylation by the nuclear form of T-cell protein tyrosine phosphatase (TC45), thereby maintaining transcriptional activation and promoting tumorigenesis. Silencing TRIM59 suppresses cell proliferation, migration, and orthotopic xenograft brain tumor formation of GBM cells and glioma stem cells. Evaluation of GBM patient samples revealed an association between EGFR activation, TRIM59 expression, STAT3 phosphorylation, and poor prognoses. Our study identifies TRIM59 as a new regulator of oncogenic EGFR/STAT3 signaling and as a potential therapeutic target for GBM patients with EGFR activation.Significance: These findings identify a novel component of the EGFR/STAT3 signaling axis in the regulation of glioma tumorigenesis. Cancer Res; 78(7); 1792–804. ©2018 AACR.

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MBD2 Ablation Impairs Lymphopoiesis and Impedes Progression and Maintenance of T-ALL

Aberrant DNA methylation patterns in leukemia might be exploited for therapeutic targeting. In this study, we employed a genetically deficient mouse model to explore the role of the methylated DNA binding protein MBD2 in normal and malignant hematopoiesis. MBD2 ablation led to diminished lymphocytes. Functional defects of the lymphoid compartment were also observed after in vivo reconstitution of MBD2-deficient hematopoietic stem cells (HSC). In an established model of Notch1-driven T-cell acute lymphoblastic leukemia (T-ALL), MBD2 ablation impeded malignant progression and maintenance by attenuating the Wnt signaling pathway. In clinical specimens of human T-ALL, Wnt signaling pathway signatures were significantly enhanced and positively correlated with the expression and function of MBD2. Furthermore, a number of typical Wnt signaling inhibitory genes were abnormally hypermethylated in primary human T-ALL. Abnormal activation of Wnt signaling in T-ALL was switched off by MBD2 deletion, partially by reactivating epigenetically silenced Wnt signaling inhibitors. Taken together, our results define essential roles for MBD2 in lymphopoiesis and T-ALL and suggest MBD2 as a candidate therapeutic target in T-ALL.Significance: This study highlights a methylated DNA binding protein as a candidate therapeutic target to improve the treatment of T-cell acute lymphoblastic leukemias, as a new starting point for developing epigenetic therapy in this and other lymphoid malignancies. Cancer Res; 78(7); 1632–42. ©2018 AACR.

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Selective mTORC2 Inhibitor Therapeutically Blocks Breast Cancer Cell Growth and Survival

Small-molecule inhibitors of the mTORC2 kinase (torkinibs) have shown efficacy in early clinical trials. However, the torkinibs under study also inhibit the other mTOR-containing complex mTORC1. While mTORC1/mTORC2 combined inhibition may be beneficial in cancer cells, recent reports describe compensatory cell survival upon mTORC1 inhibition due to loss of negative feedback on PI3K, increased autophagy, and increased macropinocytosis. Genetic models suggest that selective mTORC2 inhibition would be effective in breast cancers, but the lack of selective small-molecule inhibitors of mTORC2 have precluded testing of this hypothesis to date. Here we report the engineering of a nanoparticle-based RNAi therapeutic that can effectively silence the mTORC2 obligate cofactor Rictor. Nanoparticle-based Rictor ablation in HER2-amplified breast tumors was achieved following intratumoral and intravenous delivery, decreasing Akt phosphorylation and increasing tumor cell killing. Selective mTORC2 inhibition in vivo, combined with the HER2 inhibitor lapatinib, decreased the growth of HER2-amplified breast cancers to a greater extent than either agent alone, suggesting that mTORC2 promotes lapatinib resistance, but is overcome by mTORC2 inhibition. Importantly, selective mTORC2 inhibition was effective in a triple-negative breast cancer (TNBC) model, decreasing Akt phosphorylation and tumor growth, consistent with our findings that RICTOR mRNA correlates with worse outcome in patients with basal-like TNBC. Together, our results offer preclinical validation of a novel RNAi delivery platform for therapeutic gene ablation in breast cancer, and they show that mTORC2-selective targeting is feasible and efficacious in this disease setting.Significance: This study describes a nanomedicine to effectively inhibit the growth regulatory kinase mTORC2 in a preclinical model of breast cancer, targeting an important pathogenic enzyme in that setting that has been undruggable to date. Cancer Res; 78(7); 1845–58. ©2018 AACR.

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Forkhead Box F2 Suppresses Gastric Cancer through a Novel FOXF2-IRF2BPL-{beta}-Catenin Signaling Axis

DNA methylation has been identified as a hallmark of gastric cancer (GC). Identifying genes that are repressed by DNA promoter methylation is essential in providing insights into the molecular pathogenesis of gastric cancer. Using genome-wide methylation studies, we identified that transcription factor forkhead box F2 (FOXF2) was preferentially methylated in gastric cancer. We then investigated the functional significance and clinical implication of FOXF2 in gastric cancer. FOXF2 was silenced in gastric cancer cell lines and cancer tissues by promoter methylation, which was negatively associated with mRNA expression. Ectopic expression of FOXF2 inhibited proliferation, colony formation, G1–S cell-cycle transition, induced apoptosis of gastric cancer cell lines, and suppressed growth of xenograft tumors in nude mice; knockdown of FOXF2 elicited opposing effects. FOXF2 inhibited Wnt signaling by inducing β-catenin protein ubiquitination and degradation independently of GSK-3β. FOXF2 directly bound the promoter of E3 ligase interferon regulatory factor 2-binding protein-like (IRF2BPL) and induced its transcriptional expression. IRF2BPL in turn interacted with β-catenin, increasing its ubiquitination and degradation. Multivariate Cox regression analysis identified FOXF2 hypermethylation as an independent prognostic factor of poor survival in early-stage gastric cancer patients. In conclusion, FOXF2 is a critical tumor suppressor in gastric carcinogenesis whose methylation status serves as an independent prognostic factor for gastric cancer patients.Significance: FOXF2-mediated upregulation of the E3 ligase IRF2BPL drives ubiquitylation and degradation of β-catenin in gastric cancer, blunting Wnt signaling and suppressing carcinogenesis. Cancer Res; 78(7); 1643–56. ©2018 AACR.

https://ift.tt/2GNOntx

Highlights from Recent Cancer Literature



https://ift.tt/2GNOq8H

CCR5 Governs DNA Damage Repair and Breast Cancer Stem Cell Expansion

The functional significance of the chemokine receptor CCR5 in human breast cancer epithelial cells is poorly understood. Here, we report that CCR5 expression in human breast cancer correlates with poor outcome. CCR5+ breast cancer epithelial cells formed mammospheres and initiated tumors with >60-fold greater efficiency in mice. Reintroduction of CCR5 expression into CCR5-negative breast cancer cells promoted tumor metastases and induced DNA repair gene expression and activity. CCR5 antagonists Maraviroc and Vicriviroc dramatically enhanced cell killing mediated by DNA-damaging chemotherapeutic agents. Single-cell analysis revealed CCR5 governs PI3K/Akt, ribosomal biogenesis, and cell survival signaling. As CCR5 augments DNA repair and is reexpressed selectively on cancerous, but not normal breast epithelial cells, CCR5 inhibitors may enhance the tumor-specific activities of DNA damage response–based treatments, allowing a dose reduction of standard chemotherapy and radiation.Significance: This study offers a preclinical rationale to reposition CCR5 inhibitors to improve the treatment of breast cancer, based on their ability to enhance the tumor-specific activities of DNA-damaging chemotherapies administered in that disease. Cancer Res; 78(7); 1657–71. ©2018 AACR.

https://ift.tt/2EfTr4I

miR-508 Defines the Stem-like/Mesenchymal Subtype in Colorectal Cancer

Colorectal cancer includes an invasive stem-like/mesenchymal subtype, but its genetic drivers, functional, and clinical relevance are uncharacterized. Here we report the definition of an altered miRNA signature defining this subtype that includes a major genomic loss of miR-508. Mechanistic investigations showed that this miRNA affected the expression of cadherin CDH1 and the transcription factors ZEB1, SALL4, and BMI1. Loss of miR-508 in colorectal cancer was associated with upregulation of the novel hypoxia-induced long noncoding RNA AK000053. Ectopic expression of miR-508 in colorectal cancer cells blunted epithelial-to-mesenchymal transition (EMT), stemness, migration, and invasive capacity in vitro and in vivo. In clinical colorectal cancer specimens, expression of miR-508 negatively correlated with stemness and EMT-associated gene expression and positively correlated with patient survival. Overall, our results showed that miR-508 is a key functional determinant of the stem-like/mesenchymal colorectal cancer subtype and a candidate therapeutic target for its treatment.Significance: These results define a key functional determinant of a stem-like/mesenchymal subtype of colorectal cancers and a candidate therapeutic target for its treatment. Cancer Res; 78(7); 1751–65. ©2018 AACR.

https://ift.tt/2GM5BY9

Antiestrogen Therapy Increases Plasticity and Cancer Stemness of Prolactin-Induced ER{alpha}+ Mammary Carcinomas

Although antiestrogen therapies are successful in many patients with estrogen receptor alpha-positive (ERα+) breast cancer, 25% to 40% fail to respond. Although multiple mechanisms underlie evasion of these treatments, including tumor heterogeneity and drug-resistant cancer stem cells (CSC), further investigations have been limited by the paucity of preclinical ERα+ tumor models. Here, we examined a mouse model of prolactin-induced aggressive ERα+ breast cancer, which mimics the epidemiologic link between prolactin exposure and increased risk for metastatic ERα+ tumors. Like a subset of ERα+ patient cancers, the prolactin-induced adenocarcinomas contained two major tumor subpopulations that expressed markers of normal luminal and basal epithelial cells. CSC activity was distributed equally across these two tumor subpopulations. Treatment with the selective estrogen receptor downregulator (SERD), ICI 182,780 (ICI), did not slow tumor growth, but induced adaptive responses in CSC activity, increased markers of plasticity including target gene reporters of Wnt/Notch signaling and epithelial–mesenchymal transition, and increased double-positive (K8/K5) cells. In primary tumorsphere cultures, ICI stimulated CSC self-renewal and was able to overcome the dependence of self-renewal upon Wnt or Notch signaling individually, but not together. Our findings demonstrate that treatment of aggressive mixed lineage ERα+ breast cancers with a SERD does not inhibit growth, but rather evokes tumor cell plasticity and regenerative CSC activity, predicting likely negative impacts on patient tumors with these characteristics.Significance: This study suggests that treatment of a subset of ERα+ breast cancers with antiestrogen therapies may not only fail to slow growth but also promote aggressive behavior by evoking tumor cell plasticity and regenerative CSC activity. Cancer Res; 78(7); 1672–84. ©2018 AACR.

https://ift.tt/2J9zyzX

Metformin-Induced Reduction of CD39 and CD73 Blocks Myeloid-Derived Suppressor Cell Activity in Patients with Ovarian Cancer

Metformin is a broadly prescribed drug for type 2 diabetes that exerts antitumor activity, yet the mechanisms underlying this activity remain unclear. We show here that metformin treatment blocks the suppressive function of myeloid-derived suppressor cells (MDSC) in patients with ovarian cancer by downregulating the expression and ectoenzymatic activity of CD39 and CD73 on monocytic and polymononuclear MDSC subsets. Metformin triggered activation of AMP-activated protein kinase α and subsequently suppressed hypoxia-inducible factor α, which was critical for induction of CD39/CD73 expression in MDSC. Furthermore, metformin treatment correlated with longer overall survival in diabetic patients with ovarian cancer, which was accompanied by a metformin-induced reduction in the frequency of circulating CD39+CD73+ MDSC and a concomitant increase in the antitumor activities of circulating CD8+ T cells. Our results highlight a direct effect of metformin on MDSC and suggest that metformin may yield clinical benefit through improvement of antitumor T-cell immunity by dampening CD39/CD73-dependent MDSC immunosuppression in ovarian cancer patients.Significance: The antitumor activity of an antidiabetes drug is attributable to reduced immunosuppressive activity of myeloid-derived tumor suppressor cells. Cancer Res; 78(7); 1779–91. ©2018 AACR.

https://ift.tt/2GLluxS

Downregulation of Membrane Trafficking Proteins and Lactate Conditioning Determine Loss of Dendritic Cell Function in Lung Cancer

Restoring antigen presentation for efficient and durable activation of tumor-specific CD8+ T-cell responses is pivotal to immunotherapy, yet the mechanisms that cause subversion of dendritic cell (DC) functions are not entirely understood, limiting the development of targeted approaches. In this study, we show that bona fide DCs resident in lung tumor tissues or DCs exposed to factors derived from whole lung tumors become refractory to endosomal and cytosolic sensor stimulation and fail to secrete IL12 and IFNI. Tumor-conditioned DC exhibited downregulation of the SNARE VAMP3, a regulator of endosomes trafficking critical for cross-presentation of tumor antigens and DC-mediated tumor rejection. Dissection of cell-extrinsic suppressive pathways identified lactic acid in the tumor microenvironment as sufficient to inhibit type-I IFN downstream of TLR3 and STING. DC conditioning by lactate also impacted adaptive function, accelerating antigen degradation and impairing cross-presentation. Importantly, DCs conditioned by lactate failed to prime antitumor responses in vivo. These findings provide a new mechanistic viewpoint to the concept of DC suppression and hold potential for future therapeutic approaches.Significance: These findings provide insight into the cell-intrinsic and cell-extrinsic mechanisms that cause loss of presentation of tumor-specific antigens in lung cancer tissues. Cancer Res; 78(7); 1685–99. ©2018 AACR.

https://ift.tt/2EfTq0E

PHD3 Controls Lung Cancer Metastasis and Resistance to EGFR Inhibitors through TGF{alpha}

Lung cancer is the leading cause of cancer-related death worldwide, in large part due to its high propensity to metastasize and to develop therapy resistance. Adaptive responses to hypoxia and epithelial–mesenchymal transition (EMT) are linked to tumor metastasis and drug resistance, but little is known about how oxygen sensing and EMT intersect to control these hallmarks of cancer. Here, we show that the oxygen sensor PHD3 links hypoxic signaling and EMT regulation in the lung tumor microenvironment. PHD3 was repressed by signals that induce EMT and acted as a negative regulator of EMT, metastasis, and therapeutic resistance. PHD3 depletion in tumors, which can be caused by the EMT inducer TGFβ or by promoter methylation, enhanced EMT and spontaneous metastasis via HIF-dependent upregulation of the EGFR ligand TGFα. In turn, TGFα stimulated EGFR, which potentiated SMAD signaling, reinforcing EMT and metastasis. In clinical specimens of lung cancer, reduced PHD3 expression was linked to poor prognosis and to therapeutic resistance against EGFR inhibitors such as erlotinib. Reexpression of PHD3 in lung cancer cells suppressed EMT and metastasis and restored sensitivity to erlotinib. Taken together, our results establish a key function for PHD3 in metastasis and drug resistance and suggest opportunities to improve patient treatment by interfering with the feedforward signaling mechanisms activated by PHD3 silencing.Significance: This study links the oxygen sensor PHD3 to metastasis and drug resistance in cancer, with implications for therapeutic improvement by targeting this system. Cancer Res; 78(7); 1805–19. ©2018 AACR.

https://ift.tt/2JaZriF

Tumor-Stroma IL1{beta}-IRAK4 Feedforward Circuitry Drives Tumor Fibrosis, Chemoresistance, and Poor Prognosis in Pancreatic Cancer

Targeting the desmoplastic stroma of pancreatic ductal adenocarcinoma (PDAC) holds promise to augment the effect of chemotherapy, but success in the clinic has thus far been limited. Preclinical mouse models suggest that near-depletion of cancer-associated fibroblasts (CAF) carries a risk of accelerating PDAC progression, underscoring the need to concurrently target key signaling mechanisms that drive the malignant attributes of both CAF and PDAC cells. We previously reported that inhibition of IL1 receptor–associated kinase 4 (IRAK4) suppresses NFκB activity and promotes response to chemotherapy in PDAC cells. In this study, we report that CAF in PDAC tumors robustly express activated IRAK4 and NFκB. IRAK4 expression in CAF promoted NFκB activity, drove tumor fibrosis, and supported PDAC cell proliferation, survival, and chemoresistance. Cytokine array analysis of CAF and microarray analysis of PDAC cells identified IL1β as a key cytokine that activated IRAK4 in CAF. Targeting IRAK4 or IL1β rendered PDAC tumors less fibrotic and more sensitive to gemcitabine. In clinical specimens of human PDAC, high stromal IL1β expression associated strongly with poor overall survival. Together, our studies establish a tumor–stroma IL1β-IRAK4 feedforward signal that can be therapeutically disrupted to increase chemotherapeutic efficacy in PDAC.Significance: Targeting the IL1β-IRAK4 signaling pathway potentiates the effect of chemotherapy in pancreatic cancer. Cancer Res; 78(7); 1700–12. ©2018 AACR.

https://ift.tt/2GNOm8X

What We're Reading: Article Recommendations from Our Deputy and Senior Editors



https://ift.tt/2H2BWYz

Re(de)fining Innate Lymphocyte Lineages in the Face of Cancer

Innate lymphocytes play critical roles in maintaining tissue homeostasis and integrity of the host at steady state and during pathogenic insults. The successive identification of new innate lymphocyte subsets has revealed an incredible diversity within the family. While this heterogeneous population can be grouped based on their cytotoxic potential into exclusively cytokine-producing helpers and cytolytic killers, the exact developmental relationships between the subsets are not fully understood. The former group is enriched at mucosal surfaces, whereas innate lymphocytes with cytotoxic potential can be identified in a wider array of tissues, including tumors. Although their cytotoxicity suggests an antitumor role, the nature of tumor-elicited innate lymphocyte responses has only begun to be investigated, and the identities of participating subsets still remain contentious. In this review, we provide a brief overview of innate lymphocyte biology, review the current knowledge on their ontogeny, and discuss their roles in tumor immunosurveillance. Cancer Immunol Res; 6(4); 372–7. ©2018 AACR.



https://ift.tt/2EcsJtG

Quantitative Analysis of Immune Infiltrates in Primary Melanoma

Novel methods to analyze the tumor microenvironment (TME) are urgently needed to stratify melanoma patients for adjuvant immunotherapy. Tumor-infiltrating lymphocyte (TIL) analysis, by conventional pathologic methods, is predictive but is insufficiently precise for clinical application. Quantitative multiplex immunofluorescence (qmIF) allows for evaluation of the TME using multiparameter phenotyping, tissue segmentation, and quantitative spatial analysis (qSA). Given that CD3+CD8+ cytotoxic lymphocytes (CTLs) promote antitumor immunity, whereas CD68+ macrophages impair immunity, we hypothesized that quantification and spatial analysis of macrophages and CTLs would correlate with clinical outcome. We applied qmIF to 104 primary stage II to III melanoma tumors and found that CTLs were closer in proximity to activated (CD68+HLA-DR+) macrophages than nonactivated (CD68+HLA-DR) macrophages (P < 0.0001). CTLs were further in proximity from proliferating SOX10+ melanoma cells than nonproliferating ones (P < 0.0001). In 64 patients with known cause of death, we found that high CTL and low macrophage density in the stroma (P = 0.0038 and P = 0.0006, respectively) correlated with disease-specific survival (DSS), but the correlation was less significant for CTL and macrophage density in the tumor (P = 0.0147 and P = 0.0426, respectively). DSS correlation was strongest for stromal HLA-DR+ CTLs (P = 0.0005). CTL distance to HLA-DR macrophages associated with poor DSS (P = 0.0016), whereas distance to Ki67 tumor cells associated inversely with DSS (P = 0.0006). A low CTL/macrophage ratio in the stroma conferred a hazard ratio (HR) of 3.719 for death from melanoma and correlated with shortened overall survival (OS) in the complete 104 patient cohort by Cox analysis (P = 0.009) and merits further development as a biomarker for clinical application. Cancer Immunol Res; 6(4); 481–93. ©2018 AACR.



https://ift.tt/2H33UmJ

Identification of Tumoricidal TCRs from Tumor-Infiltrating Lymphocytes by Single-Cell Analysis

T-cell receptor (TCR) gene therapy is a promising next-generation antitumor treatment. We previously developed a single–T-cell analysis protocol that allows the rapid capture of paired TCRα and β cDNAs. Here, we applied the protocol to analyze the TCR repertoire of tumor-infiltrating lymphocytes (TIL) of various cancer patients. We found clonally expanded populations of T cells that expressed the same clonotypic TCR in 50% to 70% of CD137+CD8+ TILs, indicating that they responded to certain antigens in the tumor environment. To assess the tumor reactivity of the TCRs derived from those clonally expanded TILs in detail, we then analyzed the CD137+CD8+ TILs from the tumor of B16F10 melanoma cells in six C57BL/6 mice and analyzed their TCR repertoire. We also found clonally expanded T cells in 60% to 90% of CD137+CD8+ TILs. When the tumor reactivity of dominant clonotypic TCRs in each mouse was analyzed, 9 of 13 TCRs induced the secretion of IFN in response to, and showed killing of, B16F10 cells in vitro, and 2 of them showed strong antitumor activity in vivo. Concerning their antigen specificity, 7 of them reacted to p15E peptide of endogenous murine leukemia virus-derived envelope glycoprotein 70, and the rest reacted to tumor-associated antigens expressed on EL4 lymphoma as well as B16 melanoma cells. These results show that our strategy enables us to simply and rapidly obtain the tumor-specific TCR repertoire with high fidelity in an antigen- and MHC haplotype–independent manner from primary TILs. Cancer Immunol Res; 6(4); 378–88. ©2018 AACR.



https://ift.tt/2Ed67ZM

NK Cell-Specific CDK8 Deletion Enhances Antitumor Responses

Cyclin-dependent kinase 8 (CDK8) is a member of the transcription-regulating CDK family. CDK8 activates or represses transcription by associating with the mediator complex or by regulating transcription factors. Oncogenic activity of CDK8 has been demonstrated in several cancer types. Targeting CDK8 represents a potential therapeutic strategy. Because knockdown of CDK8 in a natural killer (NK) cell line enhances cytotoxicity and NK cells provide the first line of immune defense against transformed cells, we asked whether inhibiting CDK8 would improve NK-cell antitumor responses. In this study, we investigated the role of CDK8 in NK-cell function in vivo using mice with conditional ablation of CDK8 in NKp46+ cells (Cdk8fl/flNcr1Cre). Regardless of CDK8 expression, NK cells develop and mature normally in bone marrow and spleen. However, CDK8 deletion increased expression of the lytic molecule perforin, which correlated with enhanced NK-cell cytotoxicity in vitro. This translates into improved NK cell–mediated tumor surveillance in vivo in three independent models: B16F10 melanoma, v-abl+ lymphoma, and a slowly developing oncogene-driven leukemia. Our results thereby define a suppressive effect of CDK8 on NK-cell activity. Therapies that target CDK8 in cancer patients may enhance NK-cell responses against tumor cells. Cancer Immunol Res; 6(4); 458–66. ©2018 AACR.



https://ift.tt/2GLprCI

Targeting Cytokine Therapy to the Pancreatic Tumor Microenvironment Using PD-L1-Specific VHHs

Cytokine-based therapies for cancer have not achieved widespread clinical success because of inherent toxicities. Treatment for pancreatic cancer is limited by the dense stroma that surrounds tumors and by an immunosuppressive tumor microenvironment. To overcome these barriers, we developed constructs of single-domain antibodies (VHHs) against PD-L1 fused with IL-2 and IFN. Targeting cytokine delivery in this manner reduced pancreatic tumor burden by 50%, whereas cytokines fused to an irrelevant VHH, or blockade of PD-L1 alone, showed little effect. Targeted delivery of IL-2 increased the number of intratumoral CD8+ T cells, whereas IFN reduced the number of CD11b+ cells and skewed intratumoral macrophages toward the display of M1-like characteristics. Imaging of fluorescent VHH–IFN constructs, as well as transcriptional profiling, demonstrated targeting of IFN to the tumor microenvironment. Many tumors and tumor-infiltrating myeloid cells express PD-L1, rendering them potentially susceptible to this form of targeted immunotherapy. Cancer Immunol Res; 6(4); 389–401. ©2018 AACR.



https://ift.tt/2Iorjif

Neurotoxicity Associated with a High-Affinity GD2 CAR--Response



https://ift.tt/2H4BNUn

Durable Clinical Benefit in Metastatic Renal Cell Carcinoma Patients Who Discontinue PD-1/PD-L1 Therapy for Immune-Related Adverse Events

The current standard of care for treatment of metastatic renal cell carcinoma (mRCC) patients is PD-1/PD-L1 inhibitors until progression or toxicity. Here, we characterize the clinical outcomes for 19 mRCC patients who experienced an initial clinical response (any degree of tumor shrinkage), but after immune-related adverse events (irAE) discontinued all systemic therapy. Clinical baseline characteristics, outcomes, and survival data were collected. The primary endpoint was time to progression from the date of treatment cessation (TTP). Most patients had clear cell histology and received anti–PD–1/PD-L1 therapy as second-line or later treatment. Median time on PD-1/PD-L1 therapy was 5.5 months (range, 0.7–46.5) and median TTP was 18.4 months (95% CI, 4.7–54.3) per Kaplan–Meier estimation. The irAEs included arthropathies, ophthalmopathies, myositis, pneumonitis, and diarrhea. We demonstrate that 68.4% of patients (n = 13) experienced durable clinical benefit off treatment (TTP of at least 6 months), with 36% (n = 7) of patients remaining off subsequent treatment for over a year after their last dose of anti–PD-1/PD-L1. Three patients with tumor growth found in a follow-up visit, underwent subsequent surgical intervention, and remain off systemic treatment. Nine patients (47.4%) have ongoing irAEs. Our results show that patients who benefitted clinically from anti–PD-1/PD-L1 therapy can experience sustained beneficial responses, not needing further therapies after the initial discontinuation of treatment due to irAEs. Investigation of biomarkers indicating sustained benefit to checkpoint blockers are needed. Cancer Immunol Res; 6(4); 402–8. ©2018 AACR.



https://ift.tt/2Ebt8fV

Low-Density Lipoprotein Uptake Inhibits the Activation and Antitumor Functions of Human V{gamma}9V{delta}2 T Cells

V9V2 T cells, the main subset of T lymphocytes in human peripheral blood, are endowed with antitumor functions such as cytotoxicity and IFN production. These functions are triggered upon T-cell receptor–dependent activation by non-peptidic prenyl pyrophosphates ("phosphoantigens") that are selective agonists of V9V2 T cells, and which have been evaluated in clinical studies. Because phosphoantigens have shown interindividual variation in V9V2 T-cell activities, we asked whether metabolic resources, namely lipids such as cholesterol, could affect phosphoantigen-mediated V9V2 T-cell activation and function. We show here that V9V2 T cells express the LDL receptor upon activation and take up LDL cholesterol. Resulting changes, such as decreased mitochondrial mass and reduced ATP production, correlate with downregulation of V9V2 T-cell activation and functionality. In particular, the expression of IFN, NKG2D, and DNAM-1 were reduced upon LDL cholesterol treatment of phosphoantigen-expanded V9V2 T cells. As a result, their capacity to target breast cancer cells was compromised both in vitro and in an in vivo xenograft mouse model. Thus, this study describes the role of LDL cholesterol as an inhibitor of the antitumor functions of phosphoantigen-activated V9V2 T cells. Our observations have implications for therapeutic applications dependent on V9V2 T cells. Cancer Immunol Res; 6(4); 448–57. ©2018 AACR.



https://ift.tt/2H41DaW

Interleukin 33 Signaling Restrains Sporadic Colon Cancer in an Interferon-{gamma}-Dependent Manner

Interleukin 33 (IL33) is an inflammatory cytokine released during necrotic cell death. The epithelium and stroma of the intestine express large amounts of IL33 and its receptor St2. IL33 is therefore continuously released during homeostatic turnover of the intestinal mucosa. Although IL33 can prevent colon cancer associated with inflammatory colitis, the contribution of IL33 signaling to sporadic colon cancer remains unknown. Here, we utilized a mouse model of sporadic colon cancer to investigate the contribution of IL33 signaling to tumorigenesis in the absence of preexisting inflammation. We demonstrated that genetic ablation of St2 enhanced colon tumor development. Conversely, administration of recombinant IL33 reduced growth of colon cancer cell allografts. In reciprocal bone marrow chimeras, the concurrent loss of IL33 signaling within radioresistant nonhematopoietic, and the radiosensitive hematopoietic, compartments was associated with increased tumor burden. We detected St2 expression within the radioresistant mesenchymal cell compartment of the colon whose stimulation with IL33 induced expression of bona fide NF-B target genes. Mechanistically, we discovered that St2 deficiency within the nonhematopoietic compartment coincided with increased abundance of regulatory T cells and suppression of an IFN gene expression signature, whereas IL33 administration triggered IFN expression by tumor allograft-infiltrating T cells. The decrease of this IFN gene expression signature was associated with more aggressive disease in human colon cancer patients, suggesting that lack of IL33 signaling impaired the generation of a potent IFN-mediated antitumor immune response. Collectively, our data reveal that IL33 functions as a tumor suppressor in sporadic colon cancer. Cancer Immunol Res; 6(4); 409–21. ©2018 AACR.



https://ift.tt/2EcYi6s

Intrinsic Functional Potential of NK-Cell Subsets Constrains Retargeting Driven by Chimeric Antigen Receptors

Natural killer (NK) cells hold potential as a source of allogeneic cytotoxic effector cells for chimeric antigen receptor (CAR)-mediated therapies. Here, we explored the feasibility of transfecting CAR-encoding mRNA into primary NK cells and investigated how the intrinsic potential of discrete NK-cell subsets affects retargeting efficiency. After screening five second- and third-generation anti-CD19 CAR constructs with different signaling domains and spacer regions, a third-generation CAR with the CH2-domain removed was selected based on its expression and functional profiles. Kinetics experiments revealed that CAR expression was optimal after 3 days of IL15 stimulation prior to transfection, consistently achieving over 80% expression. CAR-engineered NK cells acquired increased degranulation toward CD19+ targets, and maintained their intrinsic degranulation response toward CD19 K562 cells. The response of redirected NK-cell subsets against CD19+ targets was dependent on their intrinsic thresholds for activation determined through both differentiation and education by killer cell immunoglobulin-like receptors (KIR) and/or CD94/NKG2A binding to self HLA class I and HLA-E, respectively. Redirected primary NK cells were insensitive to inhibition through NKG2A/HLA-E interactions but remained sensitive to inhibition through KIR depending on the amount of HLA class I expressed on target cells. Adaptive NK cells, expressing NKG2C, CD57, and self-HLA–specific KIR(s), displayed superior ability to kill CD19+, HLA low, or mismatched tumor cells. These findings support the feasibility of primary allogeneic NK cells for CAR engineering and highlight a need to consider NK-cell diversity when optimizing efficacy of cancer immunotherapies based on CAR-expressing NK cells. Cancer Immunol Res; 6(4); 467–80. ©2018 AACR.



https://ift.tt/2H7XUcN

TNF{alpha} and Radioresistant Stromal Cells Are Essential for Therapeutic Efficacy of Cyclic Dinucleotide STING Agonists in Nonimmunogenic Tumors

The cGAS–STING cytosolic DNA sensing pathway may play an integral role in the initiation of antitumor immune responses. Studies evaluating the immunogenicity of various cyclic dinucleotide (CDN) STING agonists administered by intratumoral (i.t.) injection showed potent induction of inflammation, tumor necrosis, and, in some cases, durable tumor-specific adaptive immunity. However, the specific immune mechanisms underlying these responses remain incompletely defined. The majority of these studies have focused on the effect of CDNs on immune cells but have not conclusively interrogated the role of stromal cells in the acute rejection of the CDN-injected tumor. Here, we revealed a mechanism of STING agonist-mediated tumor response that relied on both stromal and immune cells to achieve tumor regression and clearance. Using knockout and bone marrow chimeric mice, we showed that although bone marrow–derived TNFα was necessary for CDN-induced necrosis, STING signaling in radioresistant stromal cells was also essential for CDN-mediated tumor rejection. These results provide evidence for crosstalk between stromal and hematopoietic cells during CDN-mediated tumor collapse after i.t. administration. These mechanistic insights may prove critical in the clinical development of STING agonists. Cancer Immunol Res; 6(4); 422–33. ©2018 AACR.



https://ift.tt/2ImOtWj

Neurotoxicity Associated with a High-Affinity GD2 CAR--Letter



https://ift.tt/2H33TPH

Macrophages and CD8+ T Cells Mediate the Antitumor Efficacy of Combined CD40 Ligation and Imatinib Therapy in Gastrointestinal Stromal Tumors

Tyrosine kinase inhibition of gastrointestinal stromal tumors (GIST) is effective but typically culminates in resistance and is rarely curative. Immunotherapy has potential application to GIST, as we previously showed that T-cell checkpoint blockade increases the antitumor effects of imatinib. Here, we showed that ligation of CD40 using an agonistic antibody (anti-CD40) activated tumor-associated macrophages (TAMs) in vivo in a knock-in mouse model of GIST harboring a germline mutation in Kit exon 11. Activated TAMs had greater TNFα production and NFB signaling and directly inhibited tumor cells in vitro. Anti-CD40 required concomitant therapy with imatinib for efficacy and depended on TAMs, and to a lesser extent CD8+ T cells, but not on CD4+ T cells or B cells. In an analysis of 50 human GIST specimens by flow cytometry, we found that CD40 was expressed on human TAMs and tumor cells yet was downregulated after response to imatinib. CD40 ligation did not have a direct inhibitory effect on human GIST cells. Our findings provide the rationale for combining anti-CD40 and tyrosine kinase inhibition to treat human GIST. Cancer Immunol Res; 6(4); 434–47. ©2018 AACR.



https://ift.tt/2ImOpG3

Correction: Comprehensive Meta-analysis of Key Immune-Related Adverse Events from CTLA-4 and PD-1/PD-L1 Inhibitors in Cancer Patients



https://ift.tt/2GNn2rq

Adaptive threshold hunting for the effects of transcranial direct current stimulation on primary motor cortex inhibition

Abstract

Primary motor cortex excitability can be modulated by anodal and cathodal transcranial direct current stimulation (tDCS). These neuromodulatory effects may, in part, be dependent on modulation within gamma-aminobutyric acid (GABA)-mediated inhibitory networks. GABAergic function can be quantified non-invasively using adaptive threshold hunting paired-pulse transcranial magnetic stimulation (TMS). The previous studies have used TMS with posterior–anterior (PA) induced current to assess tDCS effects on inhibition. However, TMS with anterior–posterior (AP) induced current in the brain provides a more robust measure of GABA-mediated inhibition. The aim of the present study was to assess the modulation of corticomotor excitability and inhibition after anodal and cathodal tDCS using TMS with PA- and AP-induced current. In 16 young adults (26 ± 1 years), we investigated the response to anodal, cathodal, and sham tDCS in a repeated-measures double-blinded crossover design. Adaptive threshold hunting paired-pulse TMS with PA- and AP-induced current was used to examine separate interneuronal populations within M1 and their influence on corticomotor excitability and short- and long-interval inhibition (SICI and LICI) for up to 60 min after tDCS. Unexpectedly, cathodal tDCS increased corticomotor excitability assessed with AP (P = 0.047) but not PA stimulation (P = 0.74). SICIAP was reduced after anodal tDCS compared with sham (P = 0.040). Pearson's correlations indicated that SICIAP and LICIAP modulation was associated with corticomotor excitability after anodal (P = 0.027) and cathodal tDCS (P = 0.042). The after-effects of tDCS on corticomotor excitability may depend on the direction of the TMS-induced current used to make assessments, and on modulation within GABA-mediated inhibitory circuits.



https://ift.tt/2ImgQns

Two cases of unidentified acute compartment syndrome

Acute compartment syndrome (ACS) is a surgical emergency that requires urgent fasciotomy to prevent irreversible sequelae. We report two cases of unidentified ACS, which did not result from traumatic injuries such as fractures or crush injury, iatrogenic injury or diseases such as haematological malignancies. Both patients complained of severe pain and swelling of their extremity. No bite marks, blisters or skin necrosis was noted. They also complained of marked symptoms of third cranial nerve injury, including divergent squint and diplopia. The diagnosis of ACS was made following continuous intracompartmental pressure measurement, and both patients underwent urgent fasciotomy with partial incision. Considering the season and location of the injuries, together with the rapid progression of signs and symptoms that included thrombocytopaenia, acute renal failure, rhabdomyolysis and especially that of third cranial nerve injury, we postulate that these two cases may have developed following mamushi (Gloydiusblomhoffii) bites.



https://ift.tt/2GtAFZj

Immunomodulatory Effects of Momordica charantia Extract in the Prevention of Oral Cancer

In recent times, bitter melon extract (BME) has gained significant attention for its anticancer efficacy against various malignancies. In this issue, Sur and colleagues show that BME prevents the development of 4-nitronitroquinoline 1-oxide–induced oral dysplasia and squamous cell carcinoma (SCC) in an immunocompetent mouse model. Importantly, gene ontology and pathway analyses revealed an elevated expression of s100a9, IL23a, IL1β, and PDCD1/PD1 of immune system during oral cancer development, which was significantly suppressed by BME. Overall, this study demonstrates the potential clinical benefits of BME in preventing and delaying the progression of oral dysplasia to SCC. Cancer Prev Res; 11(4); 185–6. ©2018 AACR.

See related article by Sur et al., p. 191



https://ift.tt/2pYIWh3

Genome-Wide Gene Expression Changes in the Normal-Appearing Airway during the Evolution of Smoking-Associated Lung Adenocarcinoma

Smoking perpetuates in cytologically normal airways a molecular "field of injury" that is pertinent to lung cancer and early detection. The evolution of airway field changes prior to lung oncogenesis is poorly understood largely due to the long latency of lung cancer in smokers. Here, we studied airway expression changes prior to lung cancer onset in mice with knockout of the Gprc5a gene (Gprc5a–/–) and tobacco carcinogen (NNK) exposure and that develop the most common type of lung cancer, lung adenocarcinoma, within 6 months following exposure. Airway epithelial brushings were collected from Gprc5a–/– mice before exposure and at multiple times post-NNK until time of lung adenocarcinoma development and then analyzed by RNA sequencing. Temporal airway profiles were identified by linear models and analyzed by comparative genomics in normal airways of human smokers with and without lung cancer. We identified significantly altered profiles (n = 926) in the NNK-exposed mouse normal airways relative to baseline epithelia, a subset of which were concordantly modulated with smoking status in the human airway. Among airway profiles that were significantly modulated following NNK, we found that expression changes (n = 22) occurring as early as 2 months following exposure were significantly associated with lung cancer status when examined in airways of human smokers. Furthermore, a subset of a recently reported human bronchial gene classifier (Percepta; n = 56) was enriched in the temporal mouse airway profiles. We underscore evolutionarily conserved profiles in the normal-appearing airway that develop prior to lung oncogenesis and that comprise viable markers for early lung cancer detection in suspect smokers. Cancer Prev Res; 11(4); 237–48. ©2018 AACR.



https://ift.tt/2Grsktk

Pioglitazone Inhibits Periprostatic White Adipose Tissue Inflammation in Obese Mice

Obesity is associated with an increased incidence of high-grade prostate cancer and poor prognosis for prostate cancer patients. Recently, we showed that obesity-related periprostatic white adipose tissue (WAT) inflammation, characterized by crown-like structures (CLS) consisting of dead or dying adipocytes surrounded by macrophages, was associated with high-grade prostate cancer. It is possible, therefore, that agents that suppress periprostatic WAT inflammation will alter the development or progression of prostate cancer. Pioglitazone, a ligand of PPAR, is used to treat diabetes and possesses anti-inflammatory properties. Here, our main objectives were to determine whether pioglitazone inhibited obesity-related periprostatic WAT inflammation in mice and then to elucidate the underlying mechanism. Treatment with pioglitazone reduced the density of CLS in periprostatic fat and suppressed levels of TNFα, TGFβ, and the chemokine monocyte chemoattractant protein-1 (MCP-1). Importantly, the ability of pioglitazone to suppress periprostatic WAT inflammation was abrogated in MCP-1 knockout mice. Pioglitazone caused dose-dependent induction of both adiponectin, an anti-inflammatory adipokine, and its receptor AdipoR2 in cultured 3T3-L1 cells and in periprostatic WAT of obese mice. Pioglitazone blocked TNFα-mediated induction of MCP-1 in 3T3-L1 cells, an effect that was attenuated when either adiponectin or AdipoR2 were silenced. Taken together, pioglitazone-mediated induction of adiponectin suppressed the elevation in MCP-1 levels, thereby attenuating obesity-related periprostatic WAT inflammation. These findings strengthen the rationale for future efforts to determine whether targeting the PPAR–adiponectin–MCP-1 axis will decrease periprostatic adipose inflammation and thereby reduce the risk of high-grade prostate cancer or improve outcomes for men with prostate cancer. Cancer Prev Res; 11(4); 215–26. ©2017 AACR.



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The Conundrum of Omega-3 Fatty Acids in Cancer Prevention Studies: Which One? How Much? What Biomarkers?

Marine omega-3 fatty acids promote resolution of inflammation and have potential to reduce risk of obesity-related breast cancer. For prevention trials in obese women, inflammatory cytokines, aromatase, and measures of breast immune cell infiltration are logical, as are biomarkers of growth factor, adipokine, and estrogen signaling. Where best to look for marker change: in the circulation (easiest), in benign breast tissue (most relevant), or in visceral adipose (inflammation often most marked)? A null biomarker modulation trial may reflect limitations in design, source and dose of fatty acids, or biomarkers and should not lead to premature abandonment of marine omega-3 fatty acids for cancer prevention. Cancer Prev Res; 11(4); 187–90. ©2018 AACR.

See related article by Gucalp et al., p. 203



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Accelerating the Pace of Cancer Prevention- Right Now

As a nation, we underinvest in prevention and fail to implement strategies that ensure all population groups equitably share in the return on investment in prevention research and the benefits of prevention effectiveness. There is significant evidence indicating that by applying knowledge that we already have to reduce tobacco, inactivity, and obesity (known modifiable causes of cancer), we can prevent more than 50% of cancers. Vaccination against HPV, aspirin and selective estrogen receptor modulators, and screening programs further reduce risk. Evidence-based prevention strategies are inconsistently implemented across the United States. Substantial variation across States indicates that there is much room for improvement in implementation of prevention. Implementation science applies innovative approaches to identifying, understanding, and developing strategies for overcoming barriers to the adoption, adaptation, integration, scale-up, and sustainability of evidence-based interventions, tools, policies, and guidelines that will prevent cancer through application of evidence-based interventions. When we get implementation of prevention programs right and at scale, we achieve substantial population benefits. Although many efforts are underway to maximize our knowledge about the causes and treatments of cancer, we can achieve reductions in the cancer burden right now by doing what we already know. The time to start is now. Cancer Prev Res; 11(4); 171–84. ©2018 AACR.



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Bitter Melon Prevents the Development of 4-NQO-Induced Oral Squamous Cell Carcinoma in an Immunocompetent Mouse Model by Modulating Immune Signaling

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, and tobacco is one of the most common factors for HNSCC of the oral cavity. We have previously observed that bitter melon (Momordica charantia) extract (BME) exerts antiproliferative activity against several cancers including HNSCC. In this study, we investigated the preventive role of BME in 4-nitroquinoline 1-oxide (4-NQO) carcinogen-induced HNSCC. We observed that BME feeding significantly reduced the incidence of 4-NQO–induced oral cancer in a mouse model. Histologic analysis suggested control 4-NQO–treated mouse tongues showed neoplastic changes ranging from moderate dysplasia to invasive squamous cell carcinoma, whereas no significant dysplasia was observed in the BME-fed mouse tongues. We also examined the global transcriptome changes in normal versus carcinogen-induced tongue cancer tissues, and following BME feeding. Gene ontology and pathway analyses revealed a signature of biological processes including "immune system process" that is significantly dysregulated in 4-NQO–induced oral cancer. We identified elevated expression of proinflammatory genes, s100a9, IL23a, IL1β and immune checkpoint gene PDCD1/PD1, during oral cancer development. Interestingly, BME treatment significantly reduced their expression. Enhancement of MMP9 ("ossification" pathway) was noted during carcinogenesis, which was reduced in BME-fed mouse tongue tissues. Our study demonstrates the preventive effect of BME in 4-NQO–induced carcinogenesis. Identification of pathways involved in carcinogen-induced oral cancer provides useful information for prevention strategies. Together, our data strongly suggest the potential clinical benefits of BME as a chemopreventive agent in the control or delay of carcinogen-induced HNSCC development and progression. Cancer Prev Res; 11(4); 191–202. ©2017 AACR.

See related editorial by Rao, p. 185



https://ift.tt/2pYTw7E

Adiposity, Inflammation, and Breast Cancer Pathogenesis in Asian Women

Obesity is associated with white adipose tissue (WAT) inflammation in the breast, elevated levels of the estrogen biosynthetic enzyme, aromatase, and systemic changes that predispose to breast cancer development. We examined whether WAT inflammation and its associated systemic effects correlate with body fat levels in an Asian population where body mass index (BMI) is not an accurate assessment of obesity and cancer risk. We also investigated whether biologic differences could account for the greater proportion of premenopausal estrogen receptor (ER)–positive breast cancer in Asian versus Western countries. Breast WAT and fasting blood were prospectively collected from Taiwanese women undergoing mastectomy for breast cancer treatment. Body composition was measured in a subgroup using bioelectrical impedance analysis. WAT inflammation was defined by the presence of crown-like structures of the breast, which are composed of dead or dying adipocytes surrounded by macrophages. Findings were compared with U.S. Caucasian women. In the Taiwanese cohort (n = 72), breast WAT inflammation was present in 31 (43%) women and was associated with elevated BMI (P < 0.01) and increased levels of body fat (P < 0.01), C-reactive protein (P = 0.02), triglycerides (P < 0.01), insulin resistance scores (P = 0.04), and lower HDL cholesterol (P < 0.01). ER+ tumors were associated with greater body fat versus other subtypes (P = 0.03). Compared with U.S. Caucasians (n = 267), Taiwanese women had larger breast adipocytes despite lower BMI after adjusting for BMI and menopausal status (P = 0.01). A subclinical inflammatory state associated with increased adiposity and metabolic dysfunction could contribute to breast cancer pathogenesis in Asian women. Cancer Prev Res; 11(4); 227–36. ©2017 AACR.



https://ift.tt/2JewmTE

A Randomized Multicenter Phase II Study of Docosahexaenoic Acid in Patients with a History of Breast Cancer, Premalignant Lesions, or Benign Breast Disease

Obesity, a cause of subclinical inflammation, is a risk factor for the development of postmenopausal breast cancer and is associated with poorer cancer outcomes. Docosahexaenoic acid (DHA), an omega-3 fatty acid, possesses anti-inflammatory properties. We hypothesized that treatment with DHA would reduce the expression of proinflammatory genes and aromatase, the rate-limiting enzyme for estrogen biosynthesis, in benign breast tissue of overweight/obese women. A randomized, placebo-controlled, double-blind phase II study of DHA given for 12 weeks to overweight/obese women with a history of stage I–III breast cancer, DCIS/LCIS, Paget's disease, or proliferative benign breast disease was carried out. In this placebo controlled trial, the primary objective was to determine whether DHA (1,000 mg by mouth twice daily) reduced breast tissue levels of TNFα. Secondary objectives included evaluation of the effect of DHA on breast tissue levels of COX-2, IL1β, aromatase, white adipose tissue inflammation, and gene expression by RNA-seq. Red blood cell fatty acid levels were measured to assess compliance. From July 2013 to November 2015, 64 participants were randomized and treated on trial (32 women per arm). Increased levels of omega-3 fatty acids in red blood cells were detected following treatment with DHA (P < 0.001) but not placebo. Treatment with DHA did not alter levels of TNFα (P = 0.71), or other biomarkers including the transcriptome in breast samples. Treatment with DHA was overall well-tolerated. Although compliance was confirmed, we did not observe changes in the levels of prespecified biomarkers in the breast after treatment with DHA when compared with placebo. Cancer Prev Res; 11(4); 203–14. ©2018 AACR.

See related editorial by Fabian and Kimler, p. 187



https://ift.tt/2pYTvR8

Correction: Whole-Genome Sequencing of Salivary Gland Adenoid Cystic Carcinoma



https://ift.tt/2Jahk1a

CXCL1 and CXCR2 as potential markers for vital reactions in skin contusions

Abstract

Detection of the vitality of wounds is one of the most important issues in forensic practice. This study investigated mRNA and protein levels of CXCL1 and CXCR2 in skin wounds in mice and humans. Western blot analysis of CXCL1 and CXCR2 protein levels showed no difference between wounded and intact skin. However, mRNA levels demonstrated higher expression of CXCL1 and CXCR2 in contused mouse and human skin, compared with intact skin. At postmortem there were no remarkable changes in CXCL1 and CXCR2 mRNA levels in contused mouse skin. Increased mRNA expression was observed in contused mouse skin up to 96 h and 72 h after death for CXCL1 and CXCR2 respectively. In human samples of wounded skin, increased CXCL1 mRNA levels were detected up to 48 h after autopsy in all 5 cases, while increased CXCR2 mRNA levels were observed 48 h after autopsy in 4 of 5 cases. These findings suggest that the levels of CXCL1 and CXCR2 mRNA present in contused skin can be used as potential markers for a vital reaction in forensic practice.



https://ift.tt/2Ii4Fru

Lymph node cancer of the mediastinum with a putative necrotic primary lesion in the lung: a case report

Abstract

Background

Although mediastinal lymph node cancer is presumed to originate in the lung, the primary site is usually unidentified, so the pathological course remains unclear. We recently encountered a case of mediastinal lymph node cancer having a putative primary lesion remaining in the lung as a necrotic focus.

Case presentation

The patient was a 56-year-old man who visited our department because computed tomography screening had revealed a nodular shadow in the lingular segment. However, on positron emission tomography, fluorine-18 deoxyglucose accumulation was detected in a subcarinal lymph node and not in the nodule in the lingular segment. Biopsy of the lung tumor and the lymph node was performed via minimal thoracotomy. Intraoperative pathologic examination showed necrosis alone and no malignant findings in the lung tumor. By contrast, carcinoma was detected in the lymph node. Additional subcarinal lymph node dissection was performed. Results of postoperative histopathologic examination indicated poorly differentiated adenocarcinoma of the subcarinal lymph node. Meanwhile, the nodule in the lingular segment was speculated to be a spontaneously resolved primary focus of lung cancer.

Conclusions

In this case, the primary lung cancer focus resolved spontaneously after lymph node metastasis, explaining the pathogenesis underlying mediastinal lymph node cancer of unknown primary site. For similar cases of malignancy, aggressive treatment, including surgery, is effective.



https://ift.tt/2Jacili

Guest Post – Down with STEMI – The OMI Manifesto by Pendell Meyers

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Down with STEMI

EMCrit Project by Pendell Meyers.



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Plasticity and biological diversity of myeloid derived suppressor cells

Kerem Ben-Meir | Nira Twaik | Michal Baniyash

https://ift.tt/2IixYKQ

Luteinizing Hormone/Human Chorionic Gonadotropin Receptor Immunohistochemical Score Associated with Poor Prognosis in Endometrial Cancer Patients

The aim of this study was to develop a scoring system of the immunohistochemical (IHC) expression of luteinizing hormone/human chorionic gonadotropin receptor (LHCG-R) in endometrial cancer (EC) patients. Nonconsecutive hysterectomy specimens containing EC collected from April 2013 to October 2015 were selected. Hematoxylin-eosin stained sections from each case were reviewed and representative sections from each tumor were selected. IHC staining was performed for the detection of LHCG-R. The percentage of stained cells and the staining intensity were assessed in order to develop an immunohistochemical score. Moreover, we examined the correlation of the score with grading and lymphovascular space invasion (LVSI). There was a statistically significant positive correlation between grading and IHC scoring () and a statistically significant positive correlation between LVSI and IHC score (). In conclusion, we suggest that the immunohistochemical score presented here could be used as a marker of bad prognosis of EC patients. Nevertheless, further studies are needed in order to validate it. The study was registered in the Careggi Hospital public trials registry with the following number: 2013/0011391.

https://ift.tt/2Gp7872

BRAF 1799T>A Mutation Frequency in Mexican Mestizo Patients with Papillary Thyroid Cancer

Thyroid cancer is the most frequent endocrine malignancy, and its incidence and prevalence are increasing worldwide. Despite its generally good prognosis, the observed mortality rates are higher in the less-developed regions. This indicates that timely diagnosis and appropriate initial management of this disease are important to achieve a positive outcome. We performed an observational study in order to describe the frequency of the BRAF 1799T>A mutation in Mexican mestizo patients with thyroid nodules, a scarcely studied ethnic group with large populations. Competitive allele-specific Taqman PCR was performed in 147 samples of thyroid tissue DNA obtained from patients histologically diagnosed with papillary thyroid cancer (PTC), colloid goiters, and follicular adenomas. The BRAF 1799T>A mutation frequency was 61.1% in PTC samples ( = 4.99 × 10−11). Potential diagnostic values were as follows: sensitivity, 61.1%; specificity, 96%; PPV, 94.2%; NPV, 69.5%; accuracy, 77.9%. Taking into account the fact that this mutation is not frequently found in cytologically indeterminate nodules, we suggest that the BRAF mutational analysis should be implemented in the clinical setting along with other diagnostic criteria such as USG, in order to contribute to diagnosis and to surgical decision-making during the initial management of thyroid nodules in Mexican public hospitals.

https://ift.tt/2GtiYcu

How to feed patients with gastrointestinal mucositis

Purpose of review Gastrointestinal mucositis is a frequent side effect of systemic anticancer treatment and radiotherapy. The occurrence endangers body resources by decreasing food intake and absorption. This review highlights new developments in treatment and prevention. Recent findings Recent clinical practice guidelines recommend supplying adequate amounts of energy and nutrients to cancer patients undergoing anticancer treatments. This requires repeated screening for risk of malnutrition and in at-risk patients, assessment of food intake and nutritional status, followed by nutritional interventions targeted at individual deficiencies and tolerance to oral, enteral or parenteral feeding. Recent preclinical data report beneficial effects of stimulating the sensor for cell damage signals TRPA1, blocking histamine H2 receptors or supplying probiotics. In a recent clinical trial, amifostine reduced gastrointestinal symptoms and was well tolerated. Probiotics are studied in ongoing clinical trials and glucagon-like peptide 2 analogues are considered for future trials. Due to limited options available today, it has been suggested to also consider several plant-based complementary therapies. Summary Although options for prevention and treatment of chemotherapy or radiotherapy-induced gastrointestinal mucositis today are still limited, inadequate energy and nutrient intake should trigger nutritional interventions, including counselling, oral nutritional supplements, tube feeding and parenteral nutrition. To prevent gastrointestinal mucositis, several new agents have shown promising results in preclinical trials. Correspondence to Jann Arends, MD, Medizinische Klinik I, Universitätsklinikum Freiburg, Hugstetter Strasse 55, Freiburg 79106, Germany. Tel: +49 761 270 31284/34010; e-mail: jann.arends@uniklinik-freiburg.de Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

https://ift.tt/2uDir6f

Editorial for pain: nonmalignant diseases in 2018

No abstract available

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Editorial for pain: cancer in 2018

No abstract available

https://ift.tt/2uG6pcc

Hello World – Welcome to The Tox and The Hound

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We are excited to launch a new endeavor in collaboration with the EMCrit collective. The Tox and The Hound. A toxicology blog written by toxicologists.

EMCrit Project by Tox & Hound.



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Hello from The Dantastic Mr. Tox &Howard Show

https://ift.tt/2JdAlzF   Join the Dantastic Mr. Tox (@drusyniak) &Howard (@heshiegreshie) as they interview leading scientists and raconteurs about, what else, toxicology. Like a middle linebacker, they tackle the latest topics and controversies. Throw in fake ads and a house band and you get a podcast that the New York Times exclaimed "Mueller probe narrows in […]

EMCrit Project by Tox & Hound.



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Clinical Predictors of Survival and Functional Outcome of Stroke Patients Admitted to Critical Care

Objectives: To determine the predictive value of commonly used clinical variables upon ICU admission for long-term all-cause mortality and functional outcome of adult stroke patients admitted to the ICU. Design: Retrospective observational cohort study. Setting: General and neurosurgical ICUs of the University College London Hospitals in North Central London. Patients: All adult ICU patients with a clinical diagnosis of acute stroke admitted between February 2010 and May 2012. Interventions: None. Measurements and Main Results: Demographic and clinical data concerning the first 24 hours after ICU admission were obtained. Patients were followed until February 2016 to assess long-term survival. Functional outcome was determined using the modified Rankin Scale. We evaluated 131 critically ill stroke patients, with a median (interquartile range) age of 70 years (55–78 yr). One-year mortality rate was 52.7%. Surviving patients were followed up over a median (interquartile range) period of 4.3 years (4.0–4.8 yr). The multivariable model that best predicted long-term all-cause mortality indicated that mortality of critically ill stroke patients was predicted by high Acute Physiology and Chronic Health Evaluation II score, impaired consciousness (Glasgow Coma Scale score ≤ 8) as reason for ICU admission, low Glasgow Coma Scale sum score after 24 hours, and absence of brainstem reflexes. Long-term independent functional status occurred in 30.9% of surviving patients and was predicted by low Acute Physiology and Chronic Health Evaluation II score, high Glasgow Coma Scale sum score at ICU admission, and absence of mass effect on CT scan. Conclusions: Mortality in critically ill stroke patients is high and occurs most often shortly after the event. Less than one in three surviving patients is able to function independently after 1 year. This study has identified several clinical variables that predict long-term all-cause mortality and functional outcome among critically ill stroke patients and found that mainly acute physiologic disturbance and absolute values of neurologic clinical assessment are predictive. This work was performed at University College London Hospitals NHS Trust, London, United Kingdom. Data for this study were collected for quality audit purposes. The study was exempt from approval per the local ethics committee as this study was retrospective and part of an audit of the stroke care pathway. This study is a publication of the results of this trust audit. Trial registration: This study was registered at https://ift.tt/HkCGY7 as ISRCTN13328713. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (https://ift.tt/29S62lw). The authors have disclosed that they do not have any potential conflicts of interest. Address requests for reprints to: Mariel van Valburg, MD, Department of Anaesthesiology, University Medical Centre Utrecht P.O. Box 85500, Mail stop Q.04.2.313, 3508 GA Utrecht, The Netherlands. E-mail: m.k.vanvalburg@umcutrecht.nl Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

https://ift.tt/2GvJMsk

Using Brain Activation (nir-HEG/Q-EEG) and Execution Measures (CPTs) in a ADHD Assessment Protocol

This work presents a new protocol for the assessment of Attention Deficit Hyperactivity Disorder (ADHD) by providing a more objective diagnostic procedure for this developmental disorder based on the use of innovative tools. It also analyzes the relationship between activation measures and executive function measures.

https://ift.tt/2IlvUlj

Grafting Multiwalled Carbon Nanotubes with Polystyrene to Enable Self-Assembly and Anisotropic Patchiness

A procedure for the synthesis of polystyrene-grafted multiwalled carbon nanotubes using successive chemical modification steps to selectively introduce the polymer chains to the sidewalls and their self-assembly via anisotropic patchiness is presented.

https://ift.tt/2EbffOV

Effect of Long-Term Sodium Salicylate Administration on Learning, Memory, and Neurogenesis in the Rat Hippocampus

Tinnitus is thought to be caused by damage to the auditory and nonauditory system due to exposure to loud noise, aging, or other etiologies. However, at present, the exact neurophysiological basis of chronic tinnitus remains unknown. To explore whether the function of the limbic system is disturbed in tinnitus, the hippocampus was selected, which plays a vital role in learning and memory. The hippocampal function was examined with a learning and memory procedure. For this purpose, sodium salicylate (NaSal) was used to create a rat animal model of tinnitus, evaluated with prepulse inhibition behavior (PPI). The acquisition and retrieval abilities of spatial memory were measured using the Morris water maze (MWM) in NaSal-treated and control animals, followed by observation of c-Fos and delta-FosB protein expression in the hippocampal field by immunohistochemistry. To further identify the neural substrate for memory change in tinnitus, neurogenesis in the subgranular zone of the dentate gyrus (DG) was compared between the NaSal group and the control group. The results showed that acquisition and retrieval of spatial memory were impaired by NaSal treatment. The expression of c-Fos and delta-FosB protein was also inhibited in NaSal-treated animals. Simultaneously, neurogenesis in the DG was also impaired in tinnitus animals. In general, our data suggest that the hippocampal system (limbic system) may play a key role in tinnitus pathology.

https://ift.tt/2GqrMQe

Natural Products for the Prevention and Treatment of Chronic Inflammatory Diseases: Integrating Traditional Medicine into Modern Chronic Diseases Care



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Malignant Gliomas as Second Neoplasms in Pediatric Cancer Survivors: Neuropathological Study

This study presents a unique series of malignant supratentorial gliomas in children previously cured from non-CNS primary cancer. On neuroimaging these tumors were not specific, so the patients were suspected of cerebral recurrence of their primary neoplasm: leukemia in four children and sarcoma in one child. Histologically, the group contained four glioblastomas and one anaplastic astrocytoma. Three patients underwent neurosurgical resection, while the other two underwent stereotactic diagnostic biopsy only. Despite combined oncological treatment, four children died during 20 months, and only one glioblastoma patient continued to live for another twelve years. Microscopically, the neoplasms consisted of small cells with some morphologic features of astrocytic lineage, having scanty or prominent processes. Microvascular proliferation and focal or diffuse necrosis were encountered in four cases. The GFAP reactivity in neoplastic cells was low or nil, together with the expression of Olig2, vimentin, and nestin. In two cases a subpopulation of synaptophysin-positive cells was present. Molecular immunohistochemical profiling revealed the expression of phosphorylated forms of PI3Kp110 and AKT, in parallel to a strong PTEN and p53 positivity. The tumors were of IDH1R132H-wild type and immunoreactive for ATRX, HER3, and EGFR. Secondary malignant gliomas in pediatric cancer survivors pose a diagnostic challenge. The present study shows that these tumors are of IDH wild type, PI3K/AKT-activated, having no PTEN and EGFR mutations. Therefore, the biopsy of brain tumors in such patients is crucial both for accurate diagnosis and material preservation for molecular typing.

https://ift.tt/2Gsvqcy

Antioxidative Potential of a Streptomyces sp. MUM292 Isolated from Mangrove Soil

Mangrove derived microorganisms constitute a rich bioresource for bioprospecting of bioactive natural products. This study explored the antioxidant potentials of Streptomyces bacteria derived from mangrove soil. Based on 16S rRNA phylogenetic analysis, strain MUM292 was identified as the genus Streptomyces. Strain MUM292 showed the highest 16S rRNA gene sequence similarity of 99.54% with S. griseoruber . Furthermore, strain MUM292 was also characterized and showed phenotypic characteristics consistent with Streptomyces bacteria. Fermentation and extraction were performed to obtain the MUM292 extract containing the secondary metabolites of strain MUM292. The extract displayed promising antioxidant activities, including DPPH, ABTS, and superoxide radical scavenging and also metal-chelating activities. The process of lipid peroxidation in lipid-rich product was also retarded by MUM292 extract and resulted in reduced MDA production. The potential bioactive constituents of MUM292 extract were investigated using GC-MS and preliminary detection showed the presence of pyrazine, pyrrole, cyclic dipeptides, and phenolic compound in MUM292 extract. This work demonstrates that Streptomyces MUM292 can be a potential antioxidant resource for food and pharmaceutical industries.

https://ift.tt/2IiDVHu

Reviews of Interleukin-37: Functions, Receptors, and Roles in Diseases

Interleukin-37 (IL-37) is an IL-1 family cytokine discovered in recent years and has 5 different isoforms. As an immunosuppressive factor, IL-37 can suppress excessive immune response. IL-37 plays a role in protecting the body against endotoxin shock, ischemia-reperfusion injury, autoimmune diseases, and cardiovascular diseases. In addition, IL-37 has a potential antitumor effect. IL-37 and its receptors may serve as novel targets for the study, diagnosis, and treatment of immune-related diseases and tumors.

https://ift.tt/2H3NI52