tbuckley/cabot-search huggingface dataset:
Abstract NTOC-110: UNEXPECTED ROLES FOR KDM4A: PROTEIN SYNTHESIS AND MTOR INHIBITOR SENSITIVITY
Authors: Capucine Van Rechem, Joshua C. Black, Patricia Greninger, Yang Zhao, Myriam Boukhali, Carlos Donado, Martin J. Aryee, Paul d. Burrowes, Brendon Ladd, Susanne Gräslund, Wilhelm Haas, David C. Christiani, Cyril H. Benes, Johnathan R. Whetstine
Journal: Clinical Cancer Research (2017)

Abstract Single nucleotide polymorphisms (SNPs) occur within chromatin-modulating factors; however, little is known about how these variants within the coding sequence impact cancer progression or treatment. Therefore, there is a need to establish their biochemical and/or molecular contribution, their use in sub-classifying patients and their impact on therapeutic response. We demonstrate that coding SNP-A482 within the lysine tri-demethylase KDM4A/JMJD2A associates with differential outcome in cancer patients and promotes KDM4A protein turnover. Interestingly, homozygous SNP-482 cells have increased mTOR inhibitor sensitivity. mTOR inhibitors significantly reduce SNP-A482 protein levels, which parallels the increased drug sensitivity observed with KDM4A depletion. Furthermore, we demonstrate that KDM4A interacts with the translation initiation complex and impacts the distribution of translation initiation factors within polysome fractions. Upon KDM4A depletion, protein synthesis was reduced and there was enhanced protein synthesis suppression with mTOR inhibitors, which paralleled an increased sensitivity to these drugs. Lastly, we demonstrate that JIB-04, a JmjC demethylases inhibitor, suppresses translation initiation and enhances mTOR inhibitor sensitivity. These data highlight an unexpected role for KDM4A in regulating protein synthesis, in modulating mTOR inhibitor sensitivity and suggest potential novel therapeutic applications for this class of enzyme. Citation Format: Capucine Van Rechem, Joshua C. Black, Patricia Greninger, Yang Zhao, Myriam Boukhali, Carlos Donado, Martin J. Aryee, Paul d. Burrowes, Brendon Ladd, Susanne Gräslund, Wilhelm Haas, David C. Christiani, Cyril H. Benes and Johnathan R. Whetstine. UNEXPECTED ROLES FOR KDM4A: PROTEIN SYNTHESIS AND MTOR INHIBITOR SENSITIVITY [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr NTOC-110.
Case 17-2017
Authors: Ryan W. Carroll, Michelle L. Katz, Elahna Paul, Harald Jüppner
Journal: New England Journal of Medicine (2017)

A 14-year-old boy was seen in the emergency department because he had a fear of choking while swallowing that had lasted for 2 days. On examination, he was alert and appeared to be anxious, with involuntary burping and drooling. Diagnostic tests were performed.
18F-FES PET Has Added Value in Staging and Therapy Decision Making in Patients With Disseminated Lobular Breast Cancer
Authors: Clasina Venema, Erik de Vries, Andor Glaudemans, Boelo Poppema, Geke Hospers, Carolina Schröder
Journal: Clinical Nuclear Medicine (2017)

Lobular breast cancer is the second most common type of invasive breast cancer. Lobular breast cancer lesions are often difficult to detect with conventional imaging because they tend to grow less cohesively than ductal cancer. These images represent 3 lobular breast cancer cases, in whom confirmation of metastatic disease would make the crucial difference between curative or noncurative treatment. Staging with conventional imaging, however, yielded equivocal results, and a biopsy was not feasible. In contrast, FES (16α-[F]fluoro-17β-estradiol) PET provided a decisive contribution to clinical decision making in these patients. This indicates that FES PET may have added value in relation to conventional staging.
Macrophage Migration Inhibitory Factor Induces Inflammation and Predicts Spinal Progression in Ankylosing Spondylitis
Authors: Vidya Ranganathan, Francesco Ciccia, Fanxing Zeng, Ismail Sari, Guiliana Guggino, Janogini Muralitharan, Eric Gracey, Nigil Haroon
Journal: Arthritis & Rheumatology (2017)

Objective To investigate the role of macrophage migration inhibitory factor (MIF) in the pathogenesis of ankylosing spondylitis (AS). Methods Patients who met the modified New York criteria for AS were recruited for the study. Healthy volunteers, rheumatoid arthritis patients, and osteoarthritis patients were included as controls. Based on the annual rate of increase in modified Stoke AS Spine Score (mSASSS), AS patients were classified as progressors or nonprogressors. MIF levels in serum and synovial fluid were quantitated by enzyme‐linked immunosorbent assay. Predictors of AS progression were evaluated using logistic regression analysis. Immunohistochemical analysis of ileal tissue was performed to identify MIF‐producing cells. Flow cytometry was used to identify MIF‐producing subsets, expression patterns of the MIF receptor (CD74), and MIF‐induced tumor necrosis factor (TNF) production in the peripheral blood. MIF‐induced mineralization of osteoblast cells (SaOS‐2) was analyzed by alizarin red S staining, and Western blotting was used to quantify active β‐catenin levels. Results Baseline serum MIF levels were significantly elevated in AS patients compared to healthy controls and were found to independently predict AS progression. MIF levels were higher in the synovial fluid of AS patients, and MIF‐producing macrophages and Paneth cells were enriched in their gut. MIF induced TNF production in monocytes, activated β‐catenin in osteoblasts, and promoted the mineralization of osteoblasts. Conclusion Our findings indicate an unexplored pathogenic role of MIF in AS and a link between inflammation and new bone formation.
Choice of treatment and adherence to international ESO-ESMO (ABC) guidelines in HR+/HER2-ve metastatic breast cancer (MBC) patients (pts).
Authors: Marina Elena Cazzaniga, Giorgio Mustacchi, Emanuela Romagnoli, Filippo Montemurro, Paola Caporello, Michele De Laurentiis, Ferdinando Riccardi, Anna Turletti, Claudia De Angelis, Vincenzo Graziano, Lorenzo Livi, Lucia Del Mastro, Alessandra Beano, Ornella Garrone, Laura Biganzoli, Paolo Pronzato, Sabino De Placido
Journal: Journal of Clinical Oncology (2017)

1057 Background: ESO/ESMO recently developed consensus guidelines for MBC treatment, potentially applicable worldwide. Aim of the present analysis is to verify the adherence to ABC recommendations for HR+ve MBC in the context of the AMBRA study. Methods: AMBRA is a longitudinal cohort study, aiming to describe the choice of first and subsequent lines of treatment in HER2-ve MBC pts receiving at least one Chemotherapy (CHT) (SABCS 2016, P5-15-07 &amp; P5-14-09). For the present analysis, we selected 6 statements from the ABC1 &amp; ABC2 Conferences, comparing them with the clinical choices of 1 st -line therapy in all evaluable cases. Results: So far, 791/1500 pts have been registered into the study, 673 of them (85%) with HR+ MBC. Main characteristics are: N+=422 (62.2%), adjuvant chemotherapy=288 (42.4%), median DFI=70 months. 26 pts were excluded due to change into HR-ve (26; 3.8%). Endocrine Therapy (ET) was the 1 st -line of treatment in 187/647 (27.8%), CHT in 310 (47.9%) and CHT followed by ET in 135 (20.8%). Viscera was the main site of disease in 328 pts (48.7%): 56 (17%) received ET, 209 (63.7%) CHT alone, the remaining CHT followed by ET. Median DFI was similar in all the 3 groups. Selected recommendations and percentages of adherence are reported in the table below. Conclusions: The adherence to clinical recommendation about the use of ET as 1 st -line treatment in HR+ pts is very low; a potential bias could be due to the selection of the study population. Visceral disease appears to be often a key factor for selecting CHT as 1 st -line treatment. In pts receiving ET, the recommendation to use AIs, TAM or F is transposed in almost all the cases. [Table: see text]
Pharmaceutical industry payments and oncologist drug selection.
Authors: Aaron Philip Mitchell, Aaron Winn, Stacie Dusetzina
Journal: Journal of Clinical Oncology (2017)

6510 Background: Financial relationships between physicians and the pharmaceutical industry are common, and have the potential to influence clinical practice in potentially inappropriate ways. Oncology may be an ideal setting to study the influence of industry payments on physician drug choice given the high levels of competition for market share and high prices commanded by orally administered oncologic drugs. Methods: We linked the Open Payments database of industry-physician financial transactions with the Medicare Part D Prescriber file by physician name and practice location. We used McFadden’s conditional logit model to determine whether receipt of industry payments was associated with higher odds of using a drug manufactured by the same company. We applied this model to clinical scenarios in which oncologists may choose between multiple, on-patent drugs: metastatic renal cell cancer (mRCC) (sunitinib, sorafenib, and pazopanib) and chronic myeloid leukemia (CML) (imatinib, dasatinib, and nilotinib). The primary, binary independent variable was receipt of payments from a manufacturer of one of these drugs in 2013; the primary dependent variable was choosing that manufacturer’s drug in 2014. We divided industry payments into two categories, research payments and non-research “general” payments (including meals, travel, lodging, and speaking/consulting fees), and analyzed each payment type separately. Results: Physicians who received general payments from a manufacturer had increased odds of prescribing that manufacturer’s drug for both mRCC (OR: 1.78, 95%CI 1.23-2.57, mean payments $566) and CML (OR: 1.29, 95%CI 1.13-1.48, mean payments $166). Research payments were associated with an increased odds of manufacturer drug use for mRCC (OR: 2.13, 95%CI 1.13-4.00, mean payments $33,391) but not CML (OR: 1.10, 95%CI 0.83-1.45, mean payments $185,763). Conclusions: Receipt of general payments from pharmaceutical companies is associated with increased prescribing of those companies’ drugs. An association between research payments and prescribing was less consistent. This study suggests that conflicts of interest with the pharmaceutical industry may influence oncologists in high-stakes treatment decisions for patients with cancer.
NKTR-102, a novel PEGylated-irinotecan, has a superior acute safety and tolerability profile compared to irinotecan in rats and dogs
Authors: Heather Persson, Tamra Barker, Michael Eldon, Ronald Wolff
Journal: Cancer Research (2008)

5742  Purpose: NKTR-102, a novel PEGylated-irinotecan, is currently in Phase 2 clinical development as a second-line colorectal cancer therapy. Prior non-clinical studies demonstrate that adding a PEG moiety to irinotecan results in sustained tumor growth inhibition that is associated with an increase in SN38 exposure secondary to extended disposition and metabolism of NKTR-102. The purpose of these studies was to evaluate the acute single dose toxicity of NKTR 102 compared to irinotecan in rats and dogs.  Methods: Groups of 6 to 12 rats were administered 30-minute intravenous infusions of either NKTR-102 (PEG-irinotecan) or irinotecan at a target dose range of 30 to 120 mg/kg. Endpoints included mortality, clinical observations, clinical chemistry, hematology and histopathology. Groups of 2 dogs were given 30- to 60-minute intravenous infusions at target dose ranges from 6 to 60 mg/kg NKTR-102 (irinotecan equivalents) or 6 to 30 mg/kg irinotecan.  Results: In rats, the maximum tolerated dose (MTD) was 90 mg/kg for NKTR-102 and 60 mg/kg for irinotecan. Within the dose ranges evaluated, no neutropenia was noted for either NTKR-102 or irinotecan. Diarrhea was not observed for NKTR-102, whereas diarrhea occurred in 50% of rats receiving irinotecan at 90 or 120 m/kg. In dogs, the MTD was 40 mg/kg for NKTR-102 and 20 mg/kg for irinotecan. Leukopenia occurred at 6 mg/kg irinotecan, but only at doses of 30 mg/kg and greater of NKTR-102. Severe (bloody) diarrhea occurred at 30 mg/kg irinotecan, but only at doses of 60 mg/kg and greater of NKTR-102.  Conclusions: The MTD of NKTR-102 was 33% and 50% greater than that of irinotecan in rats and dogs, respectively. In dogs, the onset of neutropenia was at a five-fold higher dose of NKTR-102 relative to irinotecan. Similarly, the onset of severe diarrhea in dogs was at a two-fold higher dose of NKTR-102 relative to irinotecan. The findings in rats were consistent with the improved acute safety profile for NKTR-102 relative to irinotecan observed in dogs.
Identification and validation of N-acetyltransferase 2 as an insulin sensitivity gene
Authors: Joshua W. Knowles, Weijia Xie, Zhongyang Zhang, Indumathi Chennamsetty, Themistocles L. Assimes, Jussi Paananen, Ola Hansson, James Pankow, Mark O. Goodarzi, Ivan Carcamo-Orive, Andrew P. Morris, Yii-Der I. Chen, Ville-Petteri Mäkinen, Andrea Ganna, Anubha Mahajan, Xiuqing Guo, Fahim Abbasi, Danielle M. Greenawalt, Pek Lum, Cliona Molony, Lars Lind, Cecilia Lindgren, Leslie J. Raffel, Philip S. Tsao, Eric E. Schadt, Jerome I. Rotter, Alan Sinaiko, Gerald Reaven, Xia Yang, Chao A. Hsiung, Leif Groop, Heather J. Cordell, Markku Laakso, Ke Hao, Erik Ingelsson, Timothy M. Frayling, Michael N. Weedon, Mark Walker, Thomas Quertermous
Journal: Journal of Clinical Investigation (2016)
Oxymatrine Induces Apoptosis in Human Myeloma Cells By Cell Cycle Arrest and Activation of Caspase-Dependent Apoptosis
Authors: Wenjun Wu, Cai Wu, Fuming Zi, Yi Li, Li Yang, Jingsong He, Donghua He, Yang Yang, Yi Zhao, Xiaoyan Han, Gaofeng Zheng, He Huang, Zhen Cai
Journal: Blood (2014)
Tenascin-C Is Highly Expressed in T-Cell Non-Hodgkin Lymphomas and Represents an Attractive Target for Radioimmunotherapy
Authors: Giuseppe Gritti, Andrea Gianatti, Fiorella Petronzelli, Cristina Boschini, Riccardo Rossi, Rosangela Trezzi, Andrea Rossi, Anna Maria Barbui, Alessandro Rambaldi
Journal: Blood (2016)
The role of hepatokines in NAFLD-related extrahepatic diseases: culprit or accomplice?
Authors: Ri-Yue Jiang, Ling Yang
Journal: Gut (2017)

We recently read with great interest a review by Adams et al 1 showing that non-alcoholic fatty liver disease (NAFLD) has a profound impact on the onset of extrahepatic diseases, such as cardiovascular diseases and kidney diseases. We fully agree with this conclusion, and the authors have fully elucidated the relationship between NAFLD and extrahepatic diseases. We think that hepatokines produced and secreted by liver may play a critical role in NAFLD-related extrahepatic diseases, which would deepen the understanding of this disease.

Fibroblast growth factor 21 (FGF21), a hepatokine that is mainly secreted by the liver, has beneficial effects for improving metabolic …
<i>PRSS1</i> copy number variants and promoter polymorphisms in pancreatitis: common pathogenetic mechanism, different genetic effects
Authors: Emmanuelle Masson, Jian-Min Chen, David N Cooper, Claude Férec
Journal: Gut (2017)

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Heme oxygenase‐1 directly binds <scp>STAT</scp>3 to control the generation of pathogenic Th17 cells during neutrophilic airway inflammation
Authors: X. L. Lin, J. J. Lv, J. Lv, C. X. Di, Y. J. Zhang, T. Zhou, J. L. Liu, Z. W. Xia
Journal: Allergy (2017)

Abstract Background Specific JAK / STAT pathways play a critical role in the functional differentiation of distinct Th subsets. Previously, we showed that HO ‐1, a stress‐inducible protein, inhibits Th17 cell differentiation and alleviates neutrophilic airway inflammation, but the responsible molecular basis remains unclear. Methods We employed Th17‐skewing differentiation and NEA mouse models to study the role of HO ‐1 in regulating IL ‐6‐ STAT 3‐ ROR γt/ SOCS 3 signaling pathway to control Th17 cell‐mediated neutrophilic airway inflammation. The levels of cytokines and expressions of relative signaling molecules were measured by ELISA , western blot, and qPCR , respectively. Frequency of CD 4 + IL ‐17A + , CD 4 + IL ‐6R + , and CD 4 + IL ‐23R + cells was analyzed by FCM . The interaction between HO ‐1 and signaling pathway‐related proteins was determined by co‐immunoprecipitation and western blot. Results Here, we show that hemin‐induced HO ‐1 overexpression is required to mediate this process. Specifically, HO ‐1 decreased STAT 3 phosphorylation but not IL ‐6R/ IL ‐23R expression or JAK 1/ JAK 2 activation in CD 4 + T cells. The effect was accompanied by co‐inhibition of SOCS 3, a negative feedback factor of STAT 3 activation. HO ‐1 bound to three domains on STAT 3 ( DNA ‐binding, linker, and transactivation domains) to directly regulate STAT 3 activation. Conversely, either forced expression of a constitutively active STAT 3 mutant or application of small‐interfering RNA (si RNA ) for HO ‐1 reversed these effects. Conclusions Our data suggest that HO ‐1 exerts its inhibitory effect on Th17 cell differentiation by directly associating and blocking STAT 3 phosphorylation. We speculate that hemin may be a potential therapeutic candidate for the treatment of other types of immune and pulmonary inflammatory‐related diseases.
Abstract IS02: BCAM-AKT2 FUSION GENE LEADS TO A CONSTITUTIVELY ACTIVATED AKT2 FUSION KINASE IN HGSC
Authors: Laising Yen
Journal: Clinical Cancer Research (2017)

Abstract High-grade serous ovarian cancer (HGSC) is among the most lethal forms of cancer in women. Excessive genomic rearrangements, which are expected to create fusion oncogenes, are the hallmark of this cancer. Using high-throughput RNAseq, we identify a cancer-specific gene fusion between BCAM, a membrane adhesion molecule, and AKT2, a key kinase in the PI3K signaling pathway. This fusion is present in 7% of patient cancers tested, a significant frequency considering the highly heterogeneous nature of this malignancy. We provide direct evidence that BCAM-AKT2 is translated into an in-frame fusion protein in the patient's tumor. The resulting AKT2 fusion kinase is membrane-associated, constitutively phosphorylated, and activated as a functional kinase in cells, suggesting a new mechanism of AKT2 kinase activation in HGSC. This recurrent genomic alteration is a potential therapeutic target and marker of a clinically relevant subtype for tailored therapy of HGSC. Citation Format: Laising Yen. BCAM-AKT2 FUSION GENE LEADS TO A CONSTITUTIVELY ACTIVATED AKT2 FUSION KINASE IN HGSC [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr IS02.
Diosgenin inhibits Akt-mediated signaling in breast cancer cells
Authors: Sowmyalakshmi Srinivasan, Srinivas Koduru, Raj Kumar, Gary Gairola, Damodaran Chendil
Journal: Cancer Research (2008)

632  Constitutive over expression of Akt has been implicated in de novo resistance to current treatments in many cancer types including breast cancer. Akt mediates a variety of biological responses and is associated with a poor prognosis in breast carcinoma resulting in resistance to hormone -, radiation- and chemo-therapy. Our research is focused on exploring the role of a natural dietary compound, Diosgenin (a major constituent of fenugreek) in Akt signaling and its ability to sensitize breast cancer cells in vitro and in vivo models. Inhibition of Akt kinase activation resulted in the downregulation of its downstream targets (Raf, MEK and ERK) in breast cancer cells. Also, inactivation of NFκB and downregulation of Bcl-2 resulted in an induction of caspase activation in breast cancer cells. The complete inhibition of pro-survival signaling by disogenin resulted in cell cycle arrest and induction of apoptosis in breast cancer cells. Additional studies revealed a downregulation in G1 cell cycle regulatory proteins - cyclin D1 and cdk-4 following treatment with Diosgenin in a time dependent fashion. Interestingly, diosgenin had minimal toxicity in normal breast epithelial cells, MCF-10A, showing that it specifically targets cancer cells sparing the normal cells. In vivo studies suggested that diosgenin significantly inhibited tumor growth in both MCF-7 and MDA-231 xenografts in nude mice. Our results suggest that diosgenin can be used as a potential chemopreventive or chemotherapeutic agent for breast cancer.
Junior doctors hesitate to speak up over unprofessional behaviour, study finds
Authors: Matthew Limb
Journal: BMJ (2017)

New doctors are less likely to speak up about a colleague’s unprofessional behaviour than they are about traditional threats to patients’ safety, even when they perceive high potential for harm to patients, a US study has found.

The study found that junior doctors reported “fear of conflict” as a barrier to speaking up about unprofessional behaviour. The authors said that their findings, published in BMJ Quality and Safety ,1 showed “important safety deficits” and the need to provide more supportive clinical environments to foster open communication.

The research involved 837 interns (doctors in the first year of postgraduate training) and residents (those in second year or above of postgraduate training) at six US academic medical centres …
Abstract 151: A Polymorphic T-Rich Element in ATP1B1 Is Associated with Blood Pressure and Regulates Alternative Polyadenylation
Authors: Megana Prasad, Kavita Bhalla, Zhenhua Pan, Jeffrey R O'Connell, Zhe Ji, Alan Weder, Aravinda Chakravarti, Bin Tian, Yen-Pei C Chang
Journal: Circulation Research (2012)

Genome-wide linkage and association studies of hypertension (HTN) aim to uncover loci that are involved in blood pressure (BP) regulation and the pathophysiology of HTN. However, even when such loci are successfully identified, the mechanism by which the implicated genes increase HTN susceptibility is not well understood. ATP1B1, which encodes the beta subunit of Na+, K+ ATPase, a co-transporter involved in multiple BP-regulating physiological processes, is located within a well-established BP linkage peak. Although a single nucleotide polymorphism (rs12079745) in the 3’UTR of ATP1B1 has previously been shown to be associated with BP levels, the molecular mechanism underlying this association is unknown. We identified a multi-allelic T-rich element (TRE) in the 3’UTR of ATP1B1 that varies in length and sequence composition (T22-27 and T12GT3GT6). The 3’UTR of ATP1B1 contains 2 functional polyadenylation signals and the TRE is downstream of the proximal site (A2). Because U-rich elements (UREs) in 3’UTRs are known to play a role in the cleavage and polyadenylation of mRNA, and ATP1B1 transcripts with shorter 3’UTRs are translationally more efficient, we hypothesized that alleles of this TRE might influence ATP1B1 expression by regulating alternative polyadenylation. Consistent with our hypothesis, the A2-polyadenylated mRNA isoform was more abundant in human kidneys with at least one copy of T12GT3GT6 than in those homozygous for the T22-27 alleles. Functionally, in vitro, we demonstrated that the T12GT3GT6 allele has greater luciferase activity than the T22 allele and that the T12GT3GT6 allele shows increased polyadenylation at the A2 site than the T22 allele. In addition, the TRE element is associated with systolic BP in European Americans of the GenNet network of the NHLBI Family Blood Pressure Program, with the T12GT3GT6 allele being associated with higher BP (effect size = 2.4 mmHg SBP, P = 0.003). Sharing strong linkage disequilibrium with rs12079745, this TRE is likely the functional site underlying the original association. In summary, we have identified a novel multi-allelic TRE in the 3’UTR of ATP1B1. Alleles at this site are associated with HTN and may mediate their effect on BP by regulating polyadenylation of the ATP1B1 mRNA.
Histopathologic features of melanoma in difficult-to-diagnose lesions: A case-control study
Authors: Manuel Lora Gonzalez, Eric D. Young, James Bush, Katelyn McKenzie, Edgar Hunt, Viseslav Tonkovic-Capin, Melissa Jacobs, Michael Kucenic, Garth R. Fraga
Journal: Journal of the American Academy of Dermatology (2017)