tbuckley/cabot-search huggingface dataset:
Abstract 424: Urine cf-DNA SNPs as early biomarkers of prostate cancer
Authors: Amrita Datta, Hogyoung Kim, Allison Feibus, Melody Badoo, Adedoyin Johnson, Ahmed Moustafa, Jonathan Silberstein, Krishnarao Moparty, Raju Thomas, Asim B. Abdel-Mageed
Journal: Cancer Research (2016)

Abstract Background: The current strategies of prostate cancer (PC) detection, such as serum PSA, digital rectal examination (DRE) and prostate biopsy have been hampered by many limitations, including the degree of aggressiveness, invasiveness, non-specificity to PCa, over diagnosis and over treatment. Recent studies have proposed the use of cell-free circulating DNA (cf-DNA) as non-invasive biomarkers for cancer diagnosis, prediction of tumor burden and prognosis. We hypothesize that a selective subset of PC associated Single Nucleotide Polymorphisms (SNPs) in urine cf-DNA detects PCa with high specificity and sensitivity. Aim: To identify PC specific SNPs in urine cf-DNA from prostate cancer (PC) patients and further validate their clinical utilities as non-invasive biomarkers for early detection of PC in comparison to other genitourinary conditions, such as benign prostate hyperplasia (BPH) and prostatitis. Method and Results: A protocol was optimized for collection, processing and storage of urine samples and isolation of urine cf-DNA. Our discovery dataset was constructed by comparative Illumina HiSeq next generation sequencing (NGS) of urine cf-DNA from three different cohorts of patients presenting with PC (Gleason score 6), benign prostatic hyperplasia (BPH) or prostatitis. The data was analyzed by SNAPE-pooled and annotated using ANNOVAR; revealing 24 PC-specific non-synonymous SNPs. The selective detection of urine cf-DNAs in PC patients was verified by conventional PCR using primers flanking their genomic sites. Our validation analysis was performed in patients (n = 50/group) diagnosed with PC (Gleason score ≤ 3+4), Gleason score ≥ than 4 + 3, or patients deemed as “no cancer seen”. This was performed by Droplet Digital PCR (ddPCR) targeting wild-type versus variant (SNP) DNA in each patient sample. The results have revealed detection of two PC specific SNPs in urine cf-DNA (&amp;gt;60% for SNP1 and &amp;gt;75% SNP2 in 91 patients; patent pending). Conclusion: Our study brings forth the potential clinical utility for two novel urine cf-DNA SNPs as early biomarkers for prostate cancer. Citation Format: Amrita Datta, Hogyoung Kim, Allison Feibus, Melody Badoo, Adedoyin Johnson, Ahmed Moustafa, Jonathan Silberstein, Krishnarao Moparty, Raju Thomas, Asim B. Abdel-Mageed. Urine cf-DNA SNPs as early biomarkers of prostate cancer. [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 424.
Abstract 1841: Dissecting gene expression programs that define tumor aggression and patient outcome in pancreatic cancer
Authors: Danielle J. Fassler, Luisa F. Escobar-Hoyos, Kenneth R. Shroyer
Journal: Cancer Research (2016)

Abstract By the year 2020, pancreatic cancer (PDAC) is projected to be the second leading cause of cancer deaths in the United States. Current systemic therapies offer limited survival advantages in subgroups of patients, suggesting underlying biological differences in this deadly cancer. Our lab has recently identified keratin-17 (K17) gene expression as a prognostic and predictive biomarker in PDAC. Furthermore, we found that K17 acts as an oncoprotein by promoting degradation of tumor suppressor p27KIP1, while knockdown of K17 limits tumor size and sensitizes cancer cells to chemotherapy agents. Together, these findings suggest that targeting K17 expression in PDACs may increase patient survival and response to treatment. The factors that lead to increased K17 gene expression in only a subset of PDAC cases, however, are unknown. K17 is expressed in embryonic ectoderm and aberrantly induced in keratinocytes from psoriasis patients through paracrine signaling from the microenvironment. To determine how K17 gene expression is upregulated in PDAC, we tested the effects of two major contributing factors in PDAC pathogenesis: driver mutations and inflammatory mediators present in tumor microenvironment. Using in vitro and in vivo loss- and gain-of function approaches, we modulated oncogene expression in and performed acute cytokine treatments on cells to test for changes in K17 gene expression. K17 expression was evaluated by qRT-PCR and western blot. We found that forced expression of oncogenes like KRASG12D, Q61K or TP53R248W significantly increase K17 expression, yet these cell-autonomous factors are not sufficient to explain K17 gene expression in PDACs. In addition, we found that pro-inflammatory cytokines, typically released by helper T cells, induce a strong increase in K17 gene expression. Together these findings suggest that K17 gene expression across otherwise clinically identical PDAC cases may be explained by early transformation events and maintained by positive feedback loops associated with patient specific adaptive immune response. Ongoing studies are seeking to test the combined effects of genetic and paracrine events in K17 expression, and understand the signaling pathways and transcription factors downstream of these inducing factors. Ultimately, insight into the mechanisms that mediate K17 overexpression in PDACs could help guide future research to develop K17 as a potential therapeutic target. Citation Format: Danielle J. Fassler, Luisa F. Escobar-Hoyos, Kenneth R. Shroyer. Dissecting gene expression programs that define tumor aggression and patient outcome in pancreatic cancer. [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 1841.
Disruption of Gpr45 causes reduced hypothalamic POMC expression and obesity
Authors: Jing Cui, Yi Ding, Shu Chen, Xiaoqiang Zhu, Yichen Wu, Mingliang Zhang, Yaxin Zhao, Tong-Ruei R. Li, Ling V. Sun, Shimin Zhao, Yuan Zhuang, Weiping Jia, Lei Xue, Min Han, Tian Xu, Xiaohui Wu
Journal: Journal of Clinical Investigation (2016)

A rise in the occurrence of obesity has driven exploration of its underlying genetic basis and potential targets for intervention. GWAS studies have identified obesity susceptibility pathways involving several neuropeptides that control energy homeostasis, suggesting that variations in the genes that regulate food intake and energy expenditure may contribute to obesity. In this study, we identified 5 additional obesity loci, including a neuronal orphan GPCR called Gpr45, in a forward genetic screen of mutant mice generated by piggyBac insertional mutagenesis. Disruption of Gpr45 led to increased adiposity at the time of weaning and increases in body mass, fat content, glucose intolerance, and hepatic steatosis with advancing age. Mice with disruptions in Gpr45 also displayed a reduction in expression of the metabolic regulator POMC and less energy expenditure prior to the onset of obesity. Mechanistically, we determined that GPR45 regulates POMC expression via the JAK/STAT pathway in a cell-autonomous manner. Consistent with this finding, intraventricular administration of melanotan-2, an analog of the POMC derivative α-MSH, suppressed adult obesity in Gpr45 mutants. These results reveal that GPR45 is a regulator of POMC signaling and energy expenditure, which suggests that it may be a potential intervention target to combat obesity.
Autophagy inhibition (AI) as a novel treatment strategy in bladder cancer (BC).
Authors: Petros Grivas, Valeria Visconte, Mark L. Day, Kathleen C. Day, Monica Liebert, Phillip Lee Palmbos, Scott A. Tomlins, Jennifer Carew
Journal: Journal of Clinical Oncology (2016)

449 Background: BC response to chemotherapy has reached a plateau; novel treatment targets are needed. Autophagy is an important protein degradation mechanism that may be involved in chemotherapy response/resistance. AI was shown to overcome drug resistance in preclinical studies, but has not been well studied in BC. We conducted comprehensive gene expression analysis in BC cell lines to define their autophagy pathway expression signatures. We then investigated the anti-tumor activity and pharmacodynamics (PD) of our novel autophagy inhibitor ROC-325 (superior to hydroxychloroquine) in preclinical BC models with high baseline autophagy levels. Methods: Baseline expression of autophagy-related genes was evaluated by RNASeq in 21 BC cell lines. Gene and protein expression of selected autophagy-related genes was confirmed by qRT-PCR and immunoblot. PD effects of ROC-325 on lysosomal protease cathepsin D (CTSD) were assessed in 2 selected BC cell lines: UM-UC-3 (mesenchymal), UM-UC-6 (epithelial). The ability of ROC-325 (72 hour treatment) to augment gemcitabine (G) and cisplatin (C) activity in the 2 cell lines was evaluated by MTT assay and combination index analyses, t- test with 2-sided comparison was used, experiments were in triplicate. Results: RNASeq showed significant heterogeneity in baseline expression of early and late autophagy-related genes among BC cell lines; elevated expression of multiple autophagy-related genes was a prevalent phenomenon. CTSD level was elevated in multiple cell lines. PD analysis showed dose-dependent increase of CTSD expression in UM-UC-3 cells after ROC-325 (1-10uM) treatment correlating with reduced cell viability. The activity of G and C was greater in UM-UC-6 vs UM-UC-3 cells. Both cell lines were sensitive to ROC-325. The addition of ROC-325 to G or C yielded additive benefit in both cell lines. In UM-UC-6, ROC-325 addition significantly increased the activity of GC combination vs GC alone (p = 0.0049). Conclusions: AI merits further investigation as new treatment strategy in BC. Evaluation of in vitro and in vivo efficacy/safety of ROC-325 with/without other agents, and assessment of putative predictive biomarkers is being pursued in BC models with genomic and transcriptomic annotation.
Still Life: Room 8005
Authors: Brenda Butka
Journal: Annals of Internal Medicine (2016)

Ad Libitum19 July 2016Still Life: Room 8005Brenda Butka, MDBrenda Butka, MDFrom Nashville, Tennessee.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/M16-1034 Audio Reading - “Still Life: Room 8005” Audio. Michael A. LaCombe, MD, Annals Associate Editor, reads "Still Life: Room 8005" by B. Butka. Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail the room is always still in northern lightplastic bags, one small, one large, danglefrom the crosspiece of the IV polebacklit, brilliant, shining, a banana, the waterpitcher, the edges of the breakfast tray,a medicine cup, two white pills like pearlsa jumble of handbags and jackets on the windowsillsome mornings it's her mother, motionlessa silhouette, arms crossed, looking out towards townsometimes the husband, innocent, bewilderedthey have heard everything we have to say many timesand the light caught ... Author, Article, and Disclosure InformationAffiliations: From Nashville, Tennessee.Current Author Address: Brenda Butka, MD; e-mail, brenda.[email protected]edu. PreviousarticleNextarticle Advertisement Audio Reading - “Still Life: Room 8005” Audio. Michael A. LaCombe, MD, Annals Associate Editor, reads "Still Life: Room 8005" by B. Butka. Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ FiguresReferencesRelatedDetails Metrics 19 July 2016Volume 165, Issue 2Page: 152KeywordsBoneOxygenShoulders ePublished: 19 July 2016 Issue Published: 19 July 2016 Copyright & PermissionsCopyright © 2016 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Abstract 4768: Determination of Rab GTPase-mediated pathways critical for the antimyeloma activity of Rab GGTase inhibitors
Authors: Kaitlyn M. Dykstra, Cheryl L. Allen, Sarah A. Holstein
Journal: Cancer Research (2016)

Abstract Multiple myeloma (MM) is a plasma cell malignancy characterized by the production of high levels of monoclonal protein (MP). This leads to an increased protein folding burden in the endoplasmic reticulum (ER) in MM cells, resulting in a constitutively upregulated unfolded protein response (UPR) and a lower threshold for ER stress-mediated apoptosis. We have previously shown that inhibitors of Rab GGTase, the enzyme responsible for Rab GTPase geranylgeranylation, disrupt MP trafficking in MM cells, leading to an accumulation of MP in the ER and induction of the UPR and apoptosis. There are over 60 different Rab GTPases in mammalian cells involved in regulating a wide range of membrane trafficking events including exocytic, endocytic, and lysosomal pathways. In this study, we aimed to further define how disruption of RabGTPase function in MM cells leads to apoptosis by knocking down individual Rab proteins. Given the accumulation of MP and induction of UPR, our initial focus was on secretory Rabs. Knockdown of Rab1A/B (&amp;gt;50%) using siRNA in RPMI 8226 cells lead to moderate increases in intracellular lambda light chain in Rab1A/B knockdowns after 72 hours (∼120-140% of control levels by ELISA). However, despite the increase in intracellular MP, no increases in UPR or apoptosis markers were seen by western blot analysis or annexin-V/propidium iodide flow cytometry. Extended time course experiments (up to 120 hours) also did not exhibit any increase in UPR or apoptosis. Knockdown of Rab6A (&amp;gt;60%), another RabGTPase associated with the secretory pathway, did not lead to increases in intracellular lambda light chain or induction of apoptosis. These results suggest that although individual knockdown of Rab1 is sufficient to partially disrupt MP trafficking, either more complete knockdown of the individual Rabs or knockdown of multiple Rabs is necessary for induction of the UPR and apoptosis. Additional optimization of the knockdowns will be performed in order to verify these results. These studies support the further development of Rab GGTase inhibitors that globally effect Rab GTPase geranylgeranylation as a novel anti-myeloma strategy. Citation Format: Kaitlyn M. Dykstra, Cheryl L. Allen, Sarah A. Holstein. Determination of Rab GTPase-mediated pathways critical for the antimyeloma activity of Rab GGTase inhibitors. [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 4768.
Improving hospital care for patients with non-Hodgkin's lymphomas.
Authors: Rosella Hermens, Jozette Stienen, Han van Krieken, Nicole Blijlevens, P. B. Ottevanger
Journal: Journal of Clinical Oncology (2016)

6593 Background: Previous studies showed suboptimal quality of hospital care for patients with non-Hodgkin’s lymphoma (NHL). We aimed to assess effectiveness and feasibility of a multifaceted strategy compared to a standard strategy, towards improvement of NHL guideline adherence and patient-reported outcomes and experiences (PROs and PREs) . Methods: In a cluster randomized controlled trial (c-RCT), 19 Dutch hospitals were randomly assigned to either a standard strategy of audit and feedback (N = 10), or a multifaceted strategy (N = 9), with in addition tools adapted to barriers perceived by patients and professionals of current NHL care (e.g. patient e-tool, standardized forms for diagnostics and NHL care pathway overview). Effectiveness and feasibility were evaluated by questionnaires and medical record data. Outcomes for effectiveness were scores on 20 quality indicators (QIs) of optimal NHL care (N = 835 patients), extracted from international NHL guidelines, added with PROs and PREs. We used multilevel logistic regression analyses to calculate differences between before and after the implementation period. Outcome measures for feasibility were experiences with the different elements of both implementation strategies. Results: Most QIs measured before the start of the implementation period, showed much room for improvement; the five lowest scores ranged from 14-43%. After implementation of both strategies a significant improvement in guideline adherence was found in both study groups for the use of multidisciplinary team consultations (41 - > 49% standard strategy; 41 - > 64% tailored strategy), besides other small improvements. No superior effect was found for the multifaceted strategy. Professionals evaluated the feedback report as the best tool to improve guideline adherence, patients were very satisfied about the e-tool. PROs measuring anxiety and depression, physical well being and general health status showed no differences between the two strategies. However, PREs with NHL care were slightly better in the multifaceted strategy. Conclusions: This trial demonstrates that feedback resulted in slightly improved guideline adherence. Effectiveness of the multifaceted strategy was not superior compared to the standard one. Clinical trial information: ID.NCT01562509.
Abstract POSTER-THER-1413: Targeting constitutively-activated STAT3 in hypoxic ovarian cancer
Authors: Georgia A McCann, Adam ElNaggar, Shan Naidu, Kellie S Rath, Brent J Tierney, Adrian Suarez, David E Cohn, Karuppaiyah Selvendiran
Journal: Clinical Cancer Research (2015)

Abstract Background: Tumor hypoxia, a feature of many solid tumors including ovarian cancer, is associated with resistance to therapies. We previously demonstrated that hypoxic exposure results in increased expression of phosphorylated signal transducer and activator of transcription 3 (pSTAT3). We hypothesized that the activation of STAT3 could lead to chemotherapeutic resistance in ovarian cancer cells in hypoxic conditions. Methods: The increase of pSTAT3 Tyr705 in the hypoxic regions of human epithelial ovarian cancer (EOC) specimens was determined by HIF-1α and CD-31 staining. In vitro mutagenesis studies of pSTAT3 Tyr705 were used to demonstrate the necessity for cell survival and proliferation under hypoxic conditions. In addition, S1PR1, a regulator of STAT3 transcription via the JAK/STAT pathway, is highly expressed in hypoxic ovarian cancer cells (HOCCs). This association was evaluated with knock down of S1PR1 in HOCCs. HOCCs were treated with our novel STAT3 inhibitor, HO-3867. Results: pSTAT3 Tyr705 is increased in the hypoxic regions of EOC specimens. In vitro mutagenesis studies proved that pSTAT3 Tyr705 is necessary for cell survival and proliferation under hypoxic conditions. Knock down of S1PR1 in HOCCs reduced pSTAT3 Tyr705 levels and was associated with decreased cell survival. Treatment of HOCCs with the STAT3 inhibitor HO-3867 resulted in a rapid and dramatic decrease in pSTAT3 Tyr705 levels as a result of ubiquitin proteasome degradation. There was decreased expression of the STAT3-target proteins Bcl-xL, cyclin D2, and VEGF in all HO-3867 treated cells. Conclusions: These findings suggest that activation of STAT3 Tyr705 promotes cell survival and proliferation in HOCCs, and that S1PR1 is involved in the initiation of STAT3 activation. Therefore, targeting hypoxia-mediated STAT3 activation represents a therapeutic option for ovarian cancer and other solid tumors. Citation Format: Georgia A McCann, MD, Adam ElNaggar, MD, Shan Naidu, MS; Kellie S Rath, MD; Brent J Tierney, MD; Adrian Suarez, MD; David E Cohn, MD; Karuppaiyah Selvendiran, PhD. Targeting constitutively-activated STAT3 in hypoxic ovarian cancer [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-THER-1413.
IgM and IgD Receptors Differentially Contribute to CLL Survival and Chemokine Secretion: Implications for CLL Biology and Treatment
Authors: Elisa ten Hacken, Mariela Sivina, Li Ping, Susan O'Brien, William G. Wierda, Alessandra Ferrajoli, Zeev Estrov, Michael J. Keating, Cristina Scielzo, Paolo Ghia, Federico Caligaris-Cappio, Jan A. Burger
Journal: Blood (2015)
IKKβ-mediated inflammatory myeloid cell activation exacerbates experimental autoimmune encephalomyelitis by potentiating Th1/Th17 cell activation and compromising blood brain barrier
Authors: Min Jung Lee, So Jin Bing, Jonghee Choi, Minhee Jang, Gihyun Lee, Hyunkyoung Lee, Byung Soo Chang, Youngheun Jee, Sung Joong Lee, Ik-Hyun Cho
Journal: Molecular Neurodegeneration (2016)

The inflammatory myeloid cell activation is one of the hallmarks of experimental autoimmune encephalomyelitis (EAE), yet the in vivo role of the inflammatory myeloid cell activation in EAE has not been clearly resolved. It is well-known that IKK/NF-κB is a key signaling pathway that regulates inflammatory myeloid activation. We investigated the in vivo role of inflammatory myeloid cell activation in myelin oligodendrocyte glycoprotein (MOG) peptides-induced EAE using myeloid cell type-specific ikkβ gene conditional knockout-mice (LysM-Cre/Ikkβ F/F ). In our study, LysM-Cre/Ikkβ F/F mice had alleviated clinical signs of EAE corresponding to the decreased spinal demyelination, microglial activation, and immune cell infiltration in the spinal cord, compared to the wild-type mice (WT, Ikkβ F/F ). Myeloid ikkβ gene deletion significantly reduced the percentage of CD4+/IFN-γ+ (Th1) and CD4+/IL-17+ (Th17) cells but increased the percentages of CD4+/CD25+/Foxp3+ (Treg) cells in the spinal cord and lymph nodes, corresponding to the altered mRNA expression of IFN-γ, IL-17, IL-23, and Foxp3 in the spinal cords of LysM-Cre/Ikkβ F/F EAE mice. Also, the beneficial effect of myeloid IKKβ deletion in EAE corresponded to the decreased permeability of the blood brain barrier (BBB). Our findings strongly suggest that IKK/NF-kB-induced myeloid cell activation exacerbates EAE by activating Th1 and Th17 responses and compromising the BBB. The development of NF-κB inhibitory agents with high efficacy through specific targeting of IKKβ in myeloid cells might be of therapeutic potential in MS and other autoimmune disorders.