tbuckley/cabot-search huggingface dataset:
Abstract LB-342: HDAC inhibition promotes tubulin-independent cancer cell migration
Authors: Lindsay K. Hessler, Amanda E. Boggs, Rebecca A. Whipple, Michele I. Vitolo, Kristi R. Chakrabarti, Lekhana Bhandary, Keyata N. Thompson, Stuart S. Martin
Journal: Cancer Research (2016)

Abstract Breast cancer remains the most common cancer and second-leading cause of cancer-related death in women, with metastatic disease carrying a particularly poor prognosis. Despite advances with chemotherapeutic drugs aimed at tumor growth, we do not fully understand the effects of these drugs on the metastatic process. Histone deacetylase inhibitors (HDACi) are novel epigenetic therapies that induce cancer cell death through various mechanisms, including apoptosis, cell-cycle arrest and antiangiogenesis. Clinical trials investigating HDACi use in solid tumors are ongoing but have yielded mixed results. To date, very few studies have examined how HDACi influence the metastatic potential of breast tumor cells. Since HDAC enzymes act on both histone and non-histone targets, HDACi drugs cause dramatic increases in non-histone protein acetylation, including acetylation of alpha-tubulin. A well-known marker of stable microtubules, tubulin acetylation increases in metastatic breast tumors and predicts poor patient survival. However, the effects of HDACi on tubulin-related cytoskeletal dynamics of tumor cells have not been previously examined. The current study investigates whether the use of HDACi in breast cancer cells could promote metastatic phenotypes. Clinically-relevant HDAC pan-inhibitors that target multiple Class I HDAC enzymes (Entinostat) or both Class I and Class II (FDA-approved Vorinostat) yielded strong and rapid increases in the migration of both MCF-7 and Bt-549 breast cancer cells. In addition, Vorinostat and Entinostat were each able to strongly induce histone acetylation, while only Vorinostat induced tubulin acetylation. To determine if the increased tubulin acetylation induced by HDACi drugs was sufficient to induce tumor cell migration, we used an isotype-specific HDACi (Tubastatin) that selectively targets the Class II HDAC6 and therefore can increase tubulin acetylation. At doses which strongly induce tubulin acetylation, Tubastatin did not increase tumor cell migration or other tubulin-dependent cancer cell processes, including reattachment and microtentacle formation. Vorinostat and Entinostat therefore induce tumor cell migration through a tubulin-independent mechanism, indicating that more precise targeting of HDAC enzymes could help avoid therapeutic approaches that induce metastatic phenotypes. Citation Format: Lindsay K. Hessler, Amanda E. Boggs, Rebecca A. Whipple, Michele I. Vitolo, Kristi R. Chakrabarti, Lekhana Bhandary, Keyata N. Thompson, Stuart S. Martin. HDAC inhibition promotes tubulin-independent cancer cell migration. [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-342.
Evaluation of CTL antigen 4 (CTLA-4) expression as prognostic factor in non-small cell lung cancer (NSCLC).
Authors: F. Grossi, S. Salvi, F. Merlo, E. Margallo, S. Boccardo, A. Morabito, S. Laurent, E. Rijavec, G. Barletta, C. Genova, M. Mora, M. Mannucci, G. B. Ratto, P. Pronzato, M. Truini, M. P. Pistillo
Journal: Journal of Clinical Oncology (2011)

e21157 Background: CTLA-4, a close homologue to CD28, is a vital negative regulator of T-cell activation and proliferation. We previously reported that CTLA-4 is expressed by NSCLC cell lines providing evidence of its involvement in apoptosis induction upon engagement with soluble CTLA-4 ligands (Contardi E, Int J Cancer 2005). The present study examined the expression of CTLA-4 on tumor tissues of patients (pts) with radically resected stage I-IIIA NSCLC. Methods: Tumor tissue samples from 82 pts who underwent surgery between 7/2005-3/2007 were analyzed for expression of CTLA-4 using immunohistochemistry (IHC). Viable tumor was sampled in triplicate for tissue microarray analysis, and slides were stained by IHC with 14D3 mAb (eBioscence, San Diego, CA, USA). All tissue arrays were independently scored by two observers (M.T. and S.S.), blinded to the patients. CTLA-4 score was calculated using the following formula: (1 + I) x PC, where I is the staining intensity and PC the percentage of tumor cells that stained at each intensity, respectively. The score median value was a priori chosen as the cutoff point for classifying tumors as CTLA-4-negative (score ≤ 20) and positive (>20). Results: The median follow-up time was 41 months (range 28-54), and 27 deaths were observed. CTLA-4 expression was positive in 48% of tumors and similar in males and females (47 vs 47%), age ≤ 70 and > 70 (46 vs 49%), ex-never smokers and current smokers (46 vs 47%), whereas was higher in non-squamous than in squamous carcinoma (53 vs 36%). Cox's multiple regression analysis identified stage and CTLA-4 expression as the only variables associated with survival. The hazard ratio (HR) was 2.76, (95%CI, 0.9-8.3; p= 0.07) and 6.61 (95%CI, 2.6-16.8; p≤ 0.001 ) for tumor stage II and III compared to stage I respectively, and 0.39 (95%CI, 0.2-0.9; p= 0.03) for CTLA-4 score >20. Conclusions: Our results demonstrate an association between CTLA-4 expression and increased overall survival in NSCLC pts suggesting a prognostic role for CTLA-4 in NSCLC. An increased CTLA-4 expression may contribute to NSCLC progression by modulating the interaction of microscopic disease with CTLA-4 ligand-expressing cells leading to NSCLC cell death.
Mechanistically distinct cancer-associated mTOR activation clusters predict sensitivity to rapamycin
Authors: Jianing Xu, Can G. Pham, Steven K. Albanese, Yiyu Dong, Toshinao Oyama, Chung-Han Lee, Vanessa Rodrik-Outmezguine, Zhan Yao, Song Han, David Chen, Daniel L. Parton, John D. Chodera, Neal Rosen, Emily H. Cheng, James J. Hsieh
Journal: Journal of Clinical Investigation (2016)

Genomic studies have linked mTORC1 pathway-activating mutations with exceptional response to treatment with allosteric inhibitors of mTORC1 called rapalogs. Rapalogs are approved for selected cancer types, including kidney and breast cancers. Here, we used sequencing data from 22 human kidney cancer cases to identify the activating mechanisms conferred by mTOR mutations observed in human cancers and advance precision therapeutics. mTOR mutations that clustered in focal adhesion kinase targeting domain (FAT) and kinase domains enhanced mTORC1 kinase activity, decreased nutrient reliance, and increased cell size. We identified 3 distinct mechanisms of hyperactivation, including reduced binding to DEP domain-containing MTOR-interacting protein (DEPTOR), resistance to regulatory associated protein of mTOR-mediated (RAPTOR-mediated) suppression, and altered kinase kinetics. Of the 28 mTOR double mutants, activating mutations could be divided into 6 complementation groups, resulting in synergistic Rag- and Ras homolog enriched in brain-independent (RHEB-independent) mTORC1 activation. mTOR mutants were resistant to DNA damage-inducible transcript 1-mediated (REDD1-mediated) inhibition, confirming that activating mutations can bypass the negative feedback pathway formed between HIF1 and mTORC1 in the absence of von Hippel-Lindau (VHL) tumor suppressor expression. Moreover, VHL-deficient cells that expressed activating mTOR mutants grew tumors that were sensitive to rapamycin treatment. These data may explain the high incidence of mTOR mutations observed in clear cell kidney cancer, where VHL loss and HIF activation is pathognomonic. Our study provides mechanistic and therapeutic insights concerning mTOR mutations in human diseases.
Abstract 1719: CD133 attenuates ROS accumulation via a steady increase in the expression of the cystine/glutamate transporter xCT: Consequence on chemoresistance in hepatocellular carcinoma
Authors: Haengran Seo
Journal: Cancer Research (2016)

Abstract CD133+ cells in hepatocellular carcinoma (HCC) exhibit cancer stem cell (CSC)-like properties as well as resistance to chemotherapeutic agents and ionizing radiation; however, their function remains unknown. In this study, we tried to define new target and compound for enhancement of chemotherapy efficiency in HCC through elucidation of mechanism of CD133-induced chemoresistance. Here, we show that CD133+ HCC cells exhibit strong resistance to reactive oxygen species (ROS) via persistent maintenance of the ROS-induced increase in xCT expression that upregulates glutathione (GSH) levels, and thereby play a central role in resistance to liver cancer therapy. ROS are generally known to act as mediators of apoptosis induced by various anti-cancer drugs. We found that increased CD133 expression enhanced the capacity for ROS defense by enhancing cellular GSH levels, and ablation of CD133 attenuated not only the capacity for defense against ROS, but also chemoresistance, in HCC. Sulfasalazine, a potent xCT inhibitor, impaired the ROS defense system and increased the therapeutic efficacy of anticancer therapies in CD133+ HCC but not CD133−HCC in vivo and in vitro. Furthermore, we found that CD133 sustained the ROS stress-induced increase in the expression of xCT, a cystine/glutamate transporter that plays an important role in maintaining GSH levels, and thereby in preventing cell death via anticancer therapies. These results strongly indicate functional roles for CD133 in ROS defense and in evading anticancer therapies in HCC, and suggest that sulfasalazine, administered in combination with conventional chemotherapy, might be an effective treatment for CD133-targeted liver cancer therapy. Citation Format: Haengran Seo. CD133 attenuates ROS accumulation via a steady increase in the expression of the cystine/glutamate transporter xCT: Consequence on chemoresistance in hepatocellular carcinoma. [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 1719.
Abstract 3375: Activation of the acid sphingomyelinase pathway as a potential mechanism of chemotherapy-induced normal tissue vasculature damage
Authors: Aviram Mizrachi
Journal: Cancer Research (2016)

Abstract Background: Several classes of chemotherapy confer substantial risk for late-term vascular morbidity. We aimed to investigate the mechanisms of chemotherapy-induced vascular toxicity in normal tissues. Methods: The effect of Doxorubicin and Cisplatin has been studied in-vitro using bovine aortic endothelial cells (BAEC) as a model of normal tissue vascular endothelium. Specifically, we investigated activation of the acid sphingomyelinase (ASMase) pathway, which may lead to endothelial dysfunction (vasoconstriction) and apoptosis following incubation with different concentrations of Doxorubicin and Cisplatin. ASMase activity was measured using radioenzymatic assay with [N-methyl-14C] sphingomyelin. Cellular Reactive Oxygen Species (ROS) production was assessed using the 2’,7’-dichlorofluorescin diacetate (DCFDA) detection assay kit (Abcam®). Endothelial apoptosis was quantified using the 3,5-bis-benzamide assay (Sigma-Aldrich®). For the in-vivo studies, mouse femoral arterial blood flow was measured in real-time during and after Doxorubicin (8 mg/kg intravenously) or Cisplatin (8 mg/kg) administration. Visualization of ovarian and femoral microvasculature was obtained by fluorescence optical imaging system, equipped with a confocal fiber microscope (Cell-viZio). Results: Incubation of BAEC with Doxorubicin (0.25 μM or 0.50 μM) resulted in increased ASMase activity, production of ROS and induction of apoptosis in a dose-dependent fashion. Cisplatin (25 μM or 50 μM) generated significantly reduced effects in BAEC yet apoptosis and ROS were notable. In-vivo endoscopic fibered confocal microscopy following chemotherapy administration revealed a differential pattern between the two agents. While post Doxorubicin injection, there was a marked reduction in fluorescent signal in small vessels (&amp;lt;15 μM) indicating vessel constriction and disintegration of vessel's wall in larger vessels, Cisplatin treatment resulted in very minor vascular changes. Conclusions: These findings suggest that chemotherapy-induced vascular damage in normal tissues may represent different modes of toxicity in vivo and in vitro, while is mediated via activation of the ASMase pathway in response to Doxorubicin and to a lesser extent in response to Cisplatin. Citation Format: Aviram Mizrachi. Activation of the acid sphingomyelinase pathway as a potential mechanism of chemotherapy-induced normal tissue vasculature damage. [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 3375.
Screening for Lipid Disorders in Children and Adolescents
Authors: Kirsten Bibbins-Domingo, David C. Grossman, Susan J. Curry, Karina W. Davidson, John W. Epling, Francisco A. R. García, Matthew W. Gillman, Alex R. Kemper, Alex H. Krist, Ann E. Kurth, C. Seth Landefeld, Michael LeFevre, Carol M. Mangione, Douglas K. Owens, William R. Phillips, Maureen G. Phipps, Michael P. Pignone, Albert L. Siu
Journal: JAMA (2016)

<h3>Importance</h3> Elevations in levels of total, low-density lipoprotein, and non–high-density lipoprotein cholesterol; lower levels of high-density lipoprotein cholesterol; and, to a lesser extent, elevated triglyceride levels are associated with risk of cardiovascular disease in adults. <h3>Objective</h3> To update the 2007 US Preventive Services Task Force (USPSTF) recommendation on screening for lipid disorders in children, adolescents, and young adults. <h3>Evidence Review</h3> The USPSTF reviewed the evidence on screening for lipid disorders in children and adolescents 20 years or younger—1 review focused on screening for heterozygous familial hypercholesterolemia, and 1 review focused on screening for multifactorial dyslipidemia. <h3>Findings</h3> Evidence on the quantitative difference in diagnostic yield between universal and selective screening approaches, the effectiveness and harms of long-term treatment and the harms of screening, and the association between changes in intermediate outcomes and improvements in adult cardiovascular health outcomes are limited. Therefore, the USPSTF concludes that the balance of benefits and harms cannot be determined. <h3>Conclusions and Recommendation</h3> The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for lipid disorders in children and adolescents 20 years or younger. (I statement)
Case 22-1978
Authors: Richard C. Cabot, Robert E. Scully, James J. Galdabini, Betty U. McNeely, Michael N. Margolies, James J. Galdabini
Journal: New England Journal of Medicine (1978)

Presentation of CaseA 55-year-old woman was admitted to the hospital because of abdominal pain and vomiting.Since childhood the patient had had portal hypertension caused by cavernous transformation of the portal vein. She was repeatedly admitted to the hospital because of variceal bleeding, which was treated with blood transfusions, splenectomy, esophageal-balloon tamponade, injection of esophageal varices, transthoracic and thoracoabdominal ligation of esophageal varices and a mesocaval shunt. There was no evidence of hepatic decompensation at any time. Seven months before admission she returned to the hospital because of another episode of hematemesis and melena. An upper gastrointestinal series ( . . .
Abstract 1519: Myb-regulated gene networks and signaling pathways in pancreatic cancer
Authors: Shafquat Azim, Sanjeev K. Srivastava, Arun Bhardwaj, Haseeb Zubair, Mohammad Aslam Khan, Seema Singh, Ajay P. Singh
Journal: Cancer Research (2016)

Abstract The MYB proto-oncogene (a cellular progenitor of v-Myb oncogene) encodes an oncogenic transcription factor that regulates the expression of a wide array of genes responsible for different cellular functions. We have recently identified MYB as a key driver of pancreatic cancer (PC) pathogenesis. Our findings demonstrated that MYB was overexpressed in majority of PC tissues and cell lines, while remained undetectable in normal pancreatic cells. In addition, MYB overexpression was shown to be associated with pancreatic tumor growth and metastasis. To gain further insight into the molecular mechanisms involved in MYB-potentiated effects in PC cells, we conducted Next-Generation Sequencing of transcriptome of control and MYB-silenced MiaPaCa cells on an Illumina HiSeq 2500 platform. By keeping a cut-off of fold change &amp;gt; 1.5 and p ≤ 0.05, we identified a total of 774 genes to be differentially expressed in MYB-altered MiaPaCa cells. Out of these, 485 genes were downregulated, while 289 genes exhibited upregulated expression. The differentially-regulated genes were subsequently analyzed for functions and cellular pathways alterations using Ingenuity Pathway Analysis (IPA) software. The top three networks to be affected in MYB knockdown PC cells included i) RNA post-transcriptional modifications, molecular transport, RNA trafficking, ii) cellular assembly and organization, cancer, and, iii) cell cycle, DNA replication, recombination and repair. These networks are centered on splicing factors, EGFR and NF-κB complex, respectively. IPA predicted pancreatic adenocarcinoma signaling as one of the most significantly affected canonical pathway upon MYB-silencing. Altogether, our findings identify novel MYB-regulated gene networks and signaling pathways in PC and thus suggest potential molecular mechanisms involved in mediating MYB action in pancreatic tumorigenesis. Citation Format: Shafquat Azim, Sanjeev K. Srivastava, Arun Bhardwaj, Haseeb Zubair, Mohammad Aslam Khan, Seema Singh, Ajay P. Singh. Myb-regulated gene networks and signaling pathways 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 1519.
Abstract 1818: Coregulation of progesterone receptor and O-GlcNAc in breast cancer
Authors: Gloria Trinca, Merit Goodman, Lauren Workman, Jason Carroll, Clive D’Santos, Chad Slawson, Christy R. Hagan
Journal: Cancer Research (2016)

Abstract Progesterone receptor (PR) activity is highly regulated by post-translational modifications. Rapid immunoprecipitation mass spectrometry of endogenous protein (RIME) analysis identified O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT) as a PR-interacting protein. OGT catalyzes the addition of N-acetylglucosamine sugar moieties to serine/threonine residues in order to coordinate several cellular processes—including transcription, metabolism, and cell fate. Further investigation revealed that PR is O-GlcNAcylated, and enhanced OGT activity subsequently decreases PR protein stability. Interestingly, PR-expressing breast cancer cells display lower OGT levels in comparison to PR-null counterparts, suggesting that PR may govern its own O-GlcNAcylation or that of other key regulatory proteins. Our lab previously identified a phosphorylation site at Ser-81 in PR that potentiates the expression of PR proliferative target genes. Phosphorylation and O-GlcNAcylation are known to compete for the same residue substrates; and our preliminary data suggests that PR O-GlcNAcylation may also alter its transcriptional activity for a subset of target genes. While the role of PR in breast cancer progression is well characterized, the overall effect of protein O-GlcNAcylation within these tumors remains highly controversial. Collectively, our data supports a potential regulatory mechanism wherein OGT serves to restrain PR function in early PR+ tumors; whereas those that have lost PR expression may exhibit the elevated pro-tumorigenic OGT activity previously associated with more advanced breast cancers. As such, the continued study of O-GlcNAcylation with respect to PR stability, phosphorylation, and transcriptional activity may lead to a clearer understanding of these effectors and their contribution to breast cancer progression. Citation Format: Gloria Trinca, Merit Goodman, Lauren Workman, Jason Carroll, Clive D’Santos, Chad Slawson, Christy R. Hagan. Coregulation of progesterone receptor and O-GlcNAc in breast 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 1818.
Part 2: Ethical Issues
Journal: Circulation (2005)

The goals of emergency cardiovascular care are to preserve life, restore health, relieve suffering, limit disability, and reverse clinical death. CPR decisions are often made in seconds by rescuers who may not know the patient or know if an advance directive exists. As a result, administration of CPR may sometimes conflict with a patient’s desires or best interests.1 This section provides guidelines to healthcare providers for making the difficult decision to provide or withhold emergency cardiovascular care.

Ethical and cultural norms must be considered when beginning and ending a resuscitation attempt. Although physicians must play a role in resuscitation decision making, they should be guided by scientifically proven data and patient preferences.

### Principle of Patient Autonomy

Patient autonomy is generally respected both ethically and legally. It assumes that a patient can understand what an intervention involves and consent to or refuse it. Adult patients are presumed to have decision-making capability unless they are incapacitated or declared incompetent by a court of law. Truly informed decisions require that patients receive and understand accurate information about their condition and prognosis, the nature of the proposed intervention, alternatives, and risks and benefits. The patient must be able to deliberate and choose among alternatives and be able to relate the decision to a stable framework of values. When decision-making capacity is temporarily impaired by factors such as concurrent illness, medications, or depression, treatment of these conditions may restore capacity. When patient preferences are uncertain, emergency conditions should be treated until those preferences can be clarified.

#### Advance Directives, Living Wills, and Patient Self-Determination 

An advance directive is any expression of a person’s thoughts, wishes, or preferences for his or her end-of-life care. Advance directives can be based on conversations, written directives, living wills, or durable powers of attorney for health care. The legal validity of various forms of advance directives varies from jurisdiction to jurisdiction. …