tbuckley/cabot-search huggingface dataset:
Anthelmintic Niclosamide Disrupts the Interplay of p65 and FOXM1/β-catenin and Eradicates Leukemia Stem Cells in Chronic Myelogenous Leukemia
Authors: Bei Jin, Chengyan Wang, Juan Li, Xin Du, Ke Ding, Jingxuan Pan
Journal: Clinical Cancer Research (2016)

Leukemia stem cells (LSC), which are insensitive to tyrosine kinase inhibitors (TKI), are an important source of TKI resistance and disease relapse in chronic myelogenous leukemia (CML). Obstacles to eradicating LSCs include limited understanding of the regulation network of LSCs. The current study aimed to examine the interplay between NF-κB and FOXM1/β-catenin, and the effect of its chemical intervention on CML LSCs.The interplay between NF-κB and FOXM1/β-catenin was analyzed by reciprocal coimmunoprecipitation (co-IP) and chromatin immunoprecipitation (ChIP) assay in CML cells. The effect of disturbing NF-κB and FOXM1/β-catenin by niclosamide on the self-renewal capacity and survival of LSCs was evaluated in vitro in human primary CML CD34+ cells and in vivo in CML mice.Reciprocal co-IP experiments showed physical interaction of p65 and FOXM1. p65 promoted transcription of FOXM1 gene. ChIP assay revealed recruitment of p65 on the promoter of FOXM1 gene. Conversely, FOXM1 and β-catenin positively regulated the nuclear translocation and transcriptional activity of NF-κB in CML cells. Niclosamide disrupted the positive feedback loop between NF-κB and FOXM1/β-catenin, thereby impairing the self-renewal capacity and survival of CML LSCs. Niclosamide decreased the long-term engraftment of human CML LSCs in NOD-SCID IL2Rγ chain-deficient (NOG) mice, and prolonged the survival of CML mice.Interaction of p65 with FOXM1/β-catenin is critical in CML and its disruption by niclosamide eradicates LSCs. These findings may improve the understanding of a self-renewal regulatory mechanism of LSCs and offer a rationale-based approach to eliminate LSCs in CML. Clin Cancer Res; 23(3); 789-803. ©2016 AACR.
Juniors’ “reduced” hours are more intense
Authors: Kieran P Nunn
Journal: BMJ (2016)

Thank you for an interesting retrospective on junior work. There is no straightforward solution.

Not so long ago, treatment for many conditions was rest, as treatment options were limited. Today, smaller hospitals have only those inpatients who need active, often complex, intervention. Therefore, all patients covered by juniors are really sick. Reduced hours are intense hours.

Reduced hours …
Abstract 492: Automated circulating cell-free DNA purification from large volume draws
Authors: Robert Ray, Mark Bratz, Doug Wieczorek, Douglas White, Douglas Horejsh, Eric Vincent, Trista Schagat
Journal: Cancer Research (2016)

Abstract Circulating, cell-free DNA (ccfDNA) has emerged as an important tool in molecular oncology research. Because it is highly fragmented, present in small quantities, and highly susceptible to degradation, purification of ccfDNA poses unique challenges to researchers. While plasma is the main focus of many researchers for ccfDNA, recent work has shown that it is present in other biological fluids. Promega has developed a unique chemistry to selectively purify ccfDNA from plasma. The Maxwell RSC ccfDNA Plasma system is a completely automated system that allows purification of ccfDNA from 1ml of plasma. To add flexibility, we adapted the chemistry to automated platforms in 24-well configurations. These platforms include the Hamilton Microlab STAR series and the KingFisher Flex Processor. Because the biomarkers in ccfDNA can be of very low frequency, many researchers prefer to process volumes of samples &amp;gt;1ml which can exceed the capacity of many purification systems. Using a sequential bind strategy, we demonstrate that ccf DNA can be purified from at least 8ml sample draw using a fully automated method. Liquid draws tested include plasma and urine. DNA quantity was assessed by qPCR using an autosomal target, and quality was assessed using an internal PCR control. This study shows the flexibility and robustness of the Maxwell RSC ccfDNA chemistry. We successfully adapted it for purification from relatively large volume liquids in a fully automated manner making this a convenient option for early biomarker research. Citation Format: Robert Ray, Mark Bratz, Doug Wieczorek, Douglas White, Douglas Horejsh, Eric Vincent, Trista Schagat. Automated circulating cell-free DNA purification from large volume draws. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 492.
Abstract LB-161: Exploiting non-canonical heterochromatin-mediated telomere protection mechanisms in human cells
Authors: Tracy T. Chow, Elizabeth H. Blackburn
Journal: Cancer Research (2016)

Abstract Mammalian telomeres are inherently heterochromatic. While enhanced telomere maintenance is evident in malignant cancers, some cancers appear to maintain telomeres by neither the common telomerase nor the alternative telomere repeat recombination mechanisms. Specifically, the roles of epigenetic modifications in telomere protection are largely unknown in human cancers. I have combined newly developed cellular and molecular approaches to show that in some cancer cell types, experimentally enhanced heterochromatinization localized specifically at telomeres reduced damage-induced foci at telomeres, suggesting augmentation of telomere stability. These results lead to the intriguing hypothesis that manipulating the epigenetic status at telomeres may be exploited to elicit damage at the telomeres of cancer cells as a novel approach to fight cancer. My current work in progress focuses on identifying novel chromatin modifiers that weaken telomere protection by modulating telomere compaction. It is especially urgent to understand the plasticity and modes of telomere protection by which some human cancers escape the requirement of telomerase activation to sustain immortalization. Results from this work can potentially advance the development of novel combinatorial telomere-directed cancer treatments. Citation Format: Tracy T. Chow, Elizabeth H. Blackburn. Exploiting non-canonical heterochromatin-mediated telomere protection mechanisms in human cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-161.
Abstract 1926: Hippo pathway effectors YAP/TAZ integrate tissue mechanics and Wnt signaling to regulate microRNA biogenesis
Authors: Siyang Han, Celeste M. Nelson
Journal: Cancer Research (2016)

Abstract Although mechanical cues including extracellular matrix (ECM) stiffness are known to regulate cell and tissue behavior, it remains unclear how these mechanical cues integrate with biochemical signals to control these processes. The Hippo pathway and its transcriptional coactivators YAP and TAZ, which have emerged as major regulators of organ size, proliferation and cancer development, are thought to be involved in this integration. In addition to being regulated by the canonical Hippo pathway, YAP/TAZ have been found to mediate responses to both biochemical and mechanical signals including ECM stiffness and Wnt signaling. Moreover, recent studies have shown that microRNAs (miRNAs) are sensitive to mechanical cues and YAP/TAZ may regulate miRNA biogenesis through mechanotransduction. Although misregulation of YAP/TAZ and miRNA expression are frequently observed in multiple cancers, which appears to be associated with the altered mechanics of the tumor microenvironment, the signaling mechanisms controlling these processes remain poorly understood and controversial. Here we examine how YAP/TAZ integrate biochemical and mechanical signals to regulate miRNA biogenesis. We found that Wnt3A and stiff ECM synergistically lead to nuclear accumulation and activation of YAP/TAZ. Surprisingly, ECM stiffness induces miRNA-18a expression while Wnt3A signaling has an opposite effect on miRNA-18a expression depending on the stiffness of the cellular microenvironment. Thus, YAP/TAZ activity may define a mechanism by which cells respond to ECM stiffness and Wnt signaling to control miRNA biogenesis. Citation Format: Siyang Han, Celeste M. Nelson. Hippo pathway effectors YAP/TAZ integrate tissue mechanics and Wnt signaling to regulate microRNA biogenesis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1926.
Abstract 3658: A novel microtubule associated RNA binding protein matrin 3 act as a tumor suppressor by regulating mitotic spindle organizing proteins in triple negative breast cancers
Authors: Panneerdoss Subbarayalu, Subapriya Rajamanickam, Suryavathi Viswanadhapalli, Benjamin C. Onyeagucha, Vijay K. Eedunuri, Nicholas Dybdal-Hargreaves, Santosh Timilsina, Hima Bansal, Sanjay Bansal, Tabrez Mohammad, Yidong Chen, John C. Herr, Susan L. Mooberry, Manjeet K. Rao
Journal: Cancer Research (2016)

Abstract Microtubule-targeting drugs are widely used as cancer chemotherapeutic agents and they have been shown to inhibit mitotic progression and interphase signaling. Despite their use as a first line treatment for cancer, many patients develop resistance to microtubule-targeting drugs leading to early relapse and shorter survival. Moreover, the quality of life for patients who do survive is often substantially reduced due to the toxicity associated with these drugs. Therefore, identification of new factors that determine the effectiveness of microtubule-targeting agents will not only facilitate a better understanding of the mechanisms of acquired drug resistance but will also be amenable to therapeutic interventions. We discovered a novel microtubule associated protein “Matrin 3 (MATR3)” that is known to bind to RNA and play a critical role in RNA transport and RNA stabilization. Our results revealed that MATR3 acts as a potent tumor suppressor as it inhibits long-term growth, migration, invasion as well as tumor growth of triple negative breast cancer (TNBC) cells in vivo. We demonstrated that MATR3 overexpression induced cell cycle arrest and apoptosis in TNBC cells. Furthermore, analysis of breast cancer samples showed a significantly lower expression of MATR3 when compared to normal adjacent tissues. Importantly, our RNA immunoprecipitation (RIP)-seq analysis showed that MATR3 controls expression of several mitotic spindle organizing proteins by binding to their RNA. Interestingly, we found that these MATR3 regulated proteins were highly altered in breast cancer patients. In conclusion, we identified a novel RNA-binding protein that inhibits breast cancer growth and progression suppressor by regulating microtubule dynamics. Citation Format: Panneerdoss Subbarayalu, Subapriya Rajamanickam, Suryavathi Viswanadhapalli, Benjamin C. Onyeagucha, Vijay K. Eedunuri, Nicholas Dybdal-Hargreaves, Santosh Timilsina, Hima Bansal, Sanjay Bansal, Tabrez Mohammad, Yidong Chen, John C. Herr, Susan L. Mooberry, Manjeet K. Rao. A novel microtubule associated RNA binding protein matrin 3 act as a tumor suppressor by regulating mitotic spindle organizing proteins in triple negative breast cancers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3658.
The Prediction of Clinical Outcome in Hepatocellular Carcinoma Based on a Six-Gene Metastasis Signature
Authors: Shengxian Yuan, Jie Wang, Yuan Yang, Jin Zhang, Hui Liu, Juanjuan Xiao, Qingguo Xu, Xinhui Huang, Bangde Xiang, Shaoliang Zhu, Lequn Li, Jingfeng Liu, Lei Liu, Weiping Zhou
Journal: Clinical Cancer Research (2016)

The dismal outcome of hepatocellular carcinoma (HCC) is largely attributed to its early recurrence and venous metastases. We aimed to develop a metastasis-related model to predict hepatocellular carcinoma prognosis.Using microarrays, sequencing, and RT-PCR, we measured the expression of mRNAs and lncRNAs in a training set of 94 well-defined low-risk (LRM) and high-risk metastatic (HRM) HCC patients from a Shanghai cohort. We refined a metastasis signature and established a corresponding model using logistic regression analysis. The validation set consisted of 567 HCC patients from four-center cohorts. Survival analysis was performed according to the metastasis model.Using relative expression of tumor to para-tumor tissues, we refined the metastasis signature of five mRNAs and one lncRNA. A generalized linear model was further established to predict the probability of metastasis (MP). Using MP cutoff of 0.7 to separate LRM and HRM in Shanghai cohort, the specificity and sensitivity of the model were 96% [95% confidence interval (CI), 85%-99%] and 74% (95% CI, 58%-86%), respectively. Furthermore, HRM patients showed a significantly shorter overall and recurrence-free survival in validation cohorts (P < 0.05 for each cohort). Early HCC patients also have a poorer outcome for multicenter HRM patients. Finally, Cox regression analysis indicated that continuous MP was an independent risk factor and associated with the recurrence and survival of HCC patients after resection (HR 2.98-16.6, P < 0.05).We developed an applicable six-gene metastasis signature, which is robust and reproducible in multicenter cohorts for HCC prognosis. Clin Cancer Res; 23(1); 289-97. ©2016 AACR.
Circulating Tumor DNA as an Early Indicator of Response to T-cell Transfer Immunotherapy in Metastatic Melanoma
Authors: Liqiang Xi, Trinh Hoc-Tran Pham, Eden C. Payabyab, Richard M. Sherry, Steven A. Rosenberg, Mark Raffeld
Journal: Clinical Cancer Research (2016)

Abstract Purpose: Adoptive transfer of activated autologous tumor-infiltrating lymphocytes (TIL) can mediate complete, durable regressions in patients with metastatic melanoma. Responding patients generally do not have significant changes in noncutaneous RECIST targets before 30 to 60 days following TIL infusion, and complete responses are often not confirmed for 1 to 2 years. There is a critical need for a biomarker that can provide early information regarding the likelihood and duration of a response to enable rational decisions about altering therapy. We wished to evaluate the role of circulating tumor DNA (ctDNA) in separating responding from nonresponding patients. Experimental Design: We studied BRAF V600E ctDNA levels by a sensitive allele-specific PCR assay in 388 serum samples from 48 patients who received TIL immunotherapy at the NCI and correlated differences in the dynamic patterns of their ctDNA measurements with response outcomes. Results: A strong correlation was found between the presence or absence of an early serum peak of V600E ctDNA, and the likelihood of an objective response. Furthermore, patients that developed an early ctDNA peak and cleared their serum of V600E ctDNA were highly likely to achieve a complete response over the next 1 to 2 years. Patients that showed no peak of V600E ctDNA failed to achieve an objective response, with one exception. Conclusions: We show that the dynamic changes occurring in BRAF V600E ctDNA levels within the first month following T-cell transfer immunotherapy in metastatic melanoma can be used to rapidly identify responding from nonresponding patients, potentially allowing clinicians to make critical treatment-related decisions in a more timely manner. These data also suggest that the majority of tumor killing by TIL occurs very early after the initiation of therapy. Clin Cancer Res; 22(22); 5480–6. ©2016 AACR.
Anti-tumor efficacy and PD-L1 expression in the tumor microenvironment after poxvirus-based active immunotherapy and PD-1 blockade.
Authors: Stefanie J Mandl, Susan P Foy, Barbara Sennino, Tracy dela Cruz, Evan Gordon, Felicia Kemp, Veronica Xavier, Ryan B Rountree, Alex Franzusoff
Journal: Journal of Clinical Oncology (2015)

3079 Background: Treatment with poxvirus-based active immunotherapies shows evidence of robust immune responses against a variety of tumor-associated antigens in preclinical and clinical studies. These active immunotherapies are in clinical trials to treat tumors expressing PSA (PROSTVAC/Phase 3), CEA and MUC-1 (CV-301/Phase 2), HER-2 (MVA-BN-HER2), and Brachyury (MVA-BN-Brachyury). Because these immunotherapies drive IFNγ-producing T cells to the tumor, we hypothesized that the tumors would upregulate PD-L1 in an attempt to evade the immune response. Thus, combination treatment of poxvirus-based immunotherapy with PD-1 axis blockade has the potential to yield therapeutic synergy against tumors in preclinical and clinical regimens. Methods: In therapeutic MC38-CEA and CT26-HER2 tumor models, mice were treated with CV-301 or MVA-BN-HER2, respectively, in combination with anti-PD-1 antibody. PD-L1 expression was evaluated in the tumor microenvironment by immunofluorescence and FACS. Results: Poxvirus-based immunotherapies induced activation and trafficking of antigen specific T cells that produce high levels of IFNγ in the tumor microenvironment.TumorPD-L1 expression was upregulated following CV-301 and MVA-BN-HER2 immunotherapy in vivo as measured by immunofluorescence. The PD-L1 expression was significantly elevated on tumor cells (p < 0.01) and infiltrating immune cells (p < 0.05) as measured by FACS. Combining poxvirus-based immunotherapy with PD-1 blockade in therapeutic mouse tumor models demonstrated synergistic anti-tumor efficacy. Conclusions: In preclinical studies, CV-301 and MVA-BN-HER2 poxvirus-based immunotherapies drive a robust, tumor-infiltrating T cell response that provokes tumor PD-L1 expression. Synergistic anti-tumor efficacy in mice resulted from combining active immunotherapy with PD-1 immune checkpoint inhibition. The potential of active immunotherapy to drive productive antigen specific T cell immunity could provide patients with PD-L1neg/low tumors an opportunity to benefit from PD-1/PD-L1 axis blockade when given in combination with poxvirus-based immunotherapies.
MondoA coordinately regulates skeletal myocyte lipid homeostasis and insulin signaling
Authors: Byungyong Ahn, Mangala M. Soundarapandian, Hampton Sessions, Satyamaheshwar Peddibhotla, Gregory P. Roth, Jian-Liang Li, Eliot Sugarman, Ada Koo, Siobhan Malany, Miao Wang, Kyungmoo Yea, Jeanne Brooks, Teresa C. Leone, Xianlin Han, Rick B. Vega, Daniel P. Kelly
Journal: Journal of Clinical Investigation (2016)

Intramuscular lipid accumulation is a common manifestation of chronic caloric excess and obesity that is strongly associated with insulin resistance. The mechanistic links between lipid accumulation in myocytes and insulin resistance are not completely understood. In this work, we used a high-throughput chemical biology screen to identify a small-molecule probe, SBI-477, that coordinately inhibited triacylglyceride (TAG) synthesis and enhanced basal glucose uptake in human skeletal myocytes. We then determined that SBI-477 stimulated insulin signaling by deactivating the transcription factor MondoA, leading to reduced expression of the insulin pathway suppressors thioredoxin-interacting protein (TXNIP) and arrestin domain–containing 4 (ARRDC4). Depleting MondoA in myocytes reproduced the effects of SBI-477 on glucose uptake and myocyte lipid accumulation. Furthermore, an analog of SBI-477 suppressed TXNIP expression, reduced muscle and liver TAG levels, enhanced insulin signaling, and improved glucose tolerance in mice fed a high-fat diet. These results identify a key role for MondoA-directed programs in the coordinated control of myocyte lipid balance and insulin signaling and suggest that this pathway may have potential as a therapeutic target for insulin resistance and lipotoxicity.
DNMT3A and TET2 compete and cooperate to repress lineage-specific transcription factors in hematopoietic stem cells
Authors: Xiaotian Zhang, Jianzhong Su, Mira Jeong, Myunggon Ko, Yun Huang, Hyun Jung Park, Anna Guzman, Yong Lei, Yung-Hsin Huang, Anjana Rao, Wei Li, Margaret A Goodell
Journal: Nature Genetics (2016)
A systematic review and meta-analysis of bone metabolism in prostate adenocarcinoma.
Authors: M. Tobias-Machado, A. Serpa Neto, F. L. Fonseca, M. L. Wroclawski, M. D. Senra, M. A. Esteves, A. C. Pompeo, A. Del Giglio
Journal: Journal of Clinical Oncology (2010)

e15149 Background: Osteoporosis could be associated with the hormone therapy for metastatic prostate carcinoma (PCa) and with PCa per se. The objective of the study is to clarify the relationship of prostate cancer and/or androgen deprivation therapy (ADT) with osteoporosis. Methods: The Medline, Embase, Cancerlit, and American Society of Clinical Oncology Abstract databases were searched for published studies on prostate cancer and bone metabolism. The outcomes assessed were: fracture, osteoporosis and osteopenia. Results: Thirty-one articles (78,753 participants) were included in the meta-analysis. PCa patients under ADT had a higher risk of osteoporosis (RR, 1.30; p < 0.00001) and a higher risk of fractures (RR, 1.10; p < 0.00001) as compared to patients not under ADT. The total bone mineral density was lower in patients under ADT when compared with patients not under ADT (p = 0.031) but it was similar to bone mineral density found in healthy controls (p = 0.895). The time of androgen deprivation therapy correlated negatively with lumbar spine and total hip bone mineral density (Spearman's rho = - 0.490 and - 0.773; p = 0.028 and 0.001, respectively) and with total hip t score (Spearman's rho = - 0.900; p = 0.037). Conclusions: We found consistent evidence that the use of androgen deprivation therapy in patients with PCa reduces bone mineral density, increasing the risk of fractures in these patients. No significant financial relationships to disclose.