tbuckley/cabot-search huggingface dataset:
Abstract 3790: Targeting the one-carbon metabolism protein MTHFD2 for cancer therapy: Exploiting the unique redox status of cancer cells
Authors: Andrea Glasauer, Michael Steckel, Andrea Haegebarth, Marcus Bauser, Luisella Toschi
Journal: Cancer Research (2016)

Abstract Two well-established hallmarks of cancer are the need for nucleotides to support continuous cell proliferation and the requirement for cancer cell redox balance. In that respect cancer cells are characterized by an increased rate of reactive oxygen species (ROS) production which can be toxic to cancer cells. In this sense, cancer cells often display an increased ROS scavenging capacity, through antioxidants and NADPH that prevents ROS levels from reaching cytotoxic levels. Mitochondrial methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is a critical component of one-carbon metabolism and promotes the reaction of 5, 10-methylene tetrahydrofolate to 10-formyl tetrahydrofolate which is coupled to purine synthesis and the production of NAD(P)H. In its role, MTHFD2 is required for maintaining nucleotide biosynthesis and cancer cell redox balance. Recent studies have shown that MTHFD2 expression is elevated in many cancers compared to normal tissue and expression is correlated with poor survival in breast cancer. In order to validate MTHFD2 as a potential cancer target we show that genetic knockdown of MTHFD2 led to impaired cancer cell survival and proliferation. In breast cancer cells MTHFD2 inhibition caused a decrease in NADPH, an increase in the levels of oxidized glutathione and also promoted the expression of DNA damage and death markers specifically in cancer cells with high MTHFD2 protein expression. Interestingly, ROS-scavenging antioxidants reversed these phenotypes in the presence of MTHFD2 knockdown. Normal cells and low MTHFD2 expressing breast cancer cells had a higher tolerance for the inhibition of the protein. Based on our data, MTHFD2 inhibition leads to the impairment of cancer cells’ antioxidant capacity and ROS-mediated cell death. Therefore, MTHFD2 inhibition may have clinical potential for the treatment of patients with breast cancer, and potentially various other cancers. Citation Format: Andrea Glasauer, Michael Steckel, Andrea Haegebarth, Marcus Bauser, Luisella Toschi. Targeting the one-carbon metabolism protein MTHFD2 for cancer therapy: Exploiting the unique redox status of cancer 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 3790.
Cell-free DNA genotyping using digital PCR for early detection of pancreatic neoplasm.
Authors: Hidenori Karasaki, Yusuke Ono, Kazuya Koizumi, Kiyohiro Andoh, Shingo Asahara, Tomoki Yokochi, Kuniyuki Takahashi, Hiroyuki Maguchi, Masataka Yamada, Munehiko Ogata, Ayumu Sugitani, Toru Kono, Kazuo Nagashima, Yusuke Mizukami
Journal: Journal of Clinical Oncology (2016)

TPS464 Background: Pancreatic ductal adenocarcinoma (PDA) is still a dismal disease, and there is an urgent need to establish novel tool for early diagnosis of the tumor. There are two main types of pathologically and genetically distinct precursors for PDA — pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasia (IPMN). Non-invasive markers for these precursor lesions have the potential to predict subsequent invasive tumor. Methods: Circulating cell-free DNA (cfDNA) released from tumor cells into the blood has been intensively studied as a novel way to monitor the genetic changes. To detect the cfDNA representing for the initiation and progression of PDA could be of the candidate for them. The role of cfDNA genotyping targeting the major driver mutations in these precursors, such as KRAS and GNAS, are currently under investigation in Japanese patients who have pancreatic tumors (UMIN000012810). The major technical challenge is to specifically detect the small fraction of tumor-derived DNA in patient plasma and urine. Since sequencing of target mutant alleles in cfDNA has a limitation to detect very low frequency variants, we sought to establish protocols for super-sensitive and absolute quantification of the “key drivers” for pancreatic tumor using a droplet digital PCR platform (Bio-Rad; QX200). The primary endpoint of this multi-center prospective analysis is to evaluate whether such an approach can appropriately monitor the risk of IPMN progression and detect localized early-stage PDA. Thirty cases of PDA and 90 cases of IPMN have been enrolled thus far. Detailed protocol for the study and improved technical points to quantify low-frequency variants will be discussed.
An ethical dilemma: malignant melanoma in a 51‐year‐old patient awaiting simultaneous kidney and pancreas transplantation for type 1 diabetes
Authors: L. C. Kirby, A. Banerjee, T. Augustine, J.F. Douglas
Journal: British Journal of Dermatology (2016)

Malignant melanoma is a high‐risk skin cancer that, in potential transplant recipients, is considered a substantial contraindication to solid organ transplantation due to significant risk of recurrence with immunosuppression.1 Current guidelines stipulate waiting between 3 and 10 years after melanoma diagnosis.1 However, in young patients with end‐stage organ failure and malignant melanoma, complex ethical and moral issues arise. Assessment of the true risk associated with transplantation in these patients is difficult due to lack of prospective data, but an autonomous patient can make a decision that clinicians may perceive to be high risk. The national and worldwide shortage of available organs also has to be incorporated into the decision to maximize the net benefit and minimize the risk of graft failure and mortality. The incidence of malignant melanoma worldwide is increasing faster than that of any other cancer and continues to pose ethically challenging decisions for transplant specialists evaluating recipients for solid organ transplantation.2
Faisabilité et sécurité de la dissection sous-muqueuse (DSM) pour les lésions de la valvule iléo-caecale
Authors: E. Coron
Journal: Endoscopy (2016)

La dissection sous-muqueuse (DSM) permet la résection en monobloc des adénomes et des cancers superficiels du tube digestif. Elle permet à la fois de réaliser une analyse anatomopathologique de grande qualité et de diminuer le taux de récidive par rapport aux résections en plusieurs fragments à l’anse. Depuis 10 ans, la DSM connait un fort développement dans la plupart des pays mais il s’agit d’une technique dont la courbe d’apprentissage est longue et pour laquelle certaines localisations constituent encore de véritables challenges thérapeutiques. Ainsi, la possibilité de réséquer par DSM les lésions adénomateuses à extension latérale (ou LST pour ‘laterally spreading tumors’) infiltrant la valvule de Bauhin reste débattue.
Abstract 4840: The role of the metal scaffold in the development of cytotoxic metal complexes
Authors: Edith C. Glazer
Journal: Cancer Research (2016)

Abstract Multiple cytotoxic metal compounds are known, but structure activity relationships can be difficult to determine in these complex molecules. It is tempting to generalize the activity or off-target effects of the compounds to being related to the identity of the metal, or alternatively, to some specific “active” ligand features, but this is a misleading oversimplification that can slow the development of new therapeutics. In this presentation a systematic study of the impact of the metal center, one specific “active” ligand, and the inactive “coligands” that create the metal scaffold will be presented. There is clear evidence that each component plays a role in both desired and potentially deleterious off-target activities, providing the opportunity to adjust each of these three components independently to generate optimized potential anti-cancer agents. Citation Format: Edith C. Glazer. The role of the metal scaffold in the development of cytotoxic metal complexes. [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 4840.
Abstract 4549: Proteomic analysis of ubiquitination identifies the interplay between HSP90 inhibition and CUL5 in the control of autophagy
Authors: Silvia A a Batista, Rahul Samant, Paul A. Clarke, Paul Workman
Journal: Cancer Research (2016)

Abstract HSP90 has emerged as an important target in cancer therapy as inhibition of HSP90 can result in the degradation of many oncogenic client proteins. The two major cellular protein degradation pathways are the ubiquitin-proteasome system and autophagy. The role of the ubiquitin-proteasome pathway in client protein degradation following HSP90 inhibition is well established. We recently described how this process is controlled by an E3-ubiquitin ligase, cullin 5 (CUL5). We sought to further understand how both major protein degradation pathways are regulated in response to HSP90 inhibition. To do this, we performed a proteomic screen on the ubiquitination status of proteins extracted from HT29 cells following HSP90 inhibition by 17-AAG and / or siRNA silencing of CUL5 expression. We found the level of ubiquitination of 125 proteins increased by more than 2 fold in response to 17-AAG treatment. For 66 of these proteins, CUL5 silencing eliminated the 17-AAG-induced increase in ubiquitination; for 30 proteins CUL5 silencing partially reduced the 17-AAG-induced increase in ubiquitination; and for 29 proteins CUL5 silencing had no effect. Importantly, we found some known regulators of autophagy to be among those proteins ubiquitinated in response to 17-AAG treatment and rescued by CUL5 silencing. There was a correlation between levels of ubiquitination and levels of protein degradation. We measured markers of autophagic flux, LC3B and p62, and found clear evidence for altered pathway flux in response to HSP90 inhibition and CUL5 silencing. This study indicates that the interplay between HSP90 inhibition and CUL5 can control both proteasomal degradation and autophagy. Citation Format: Silvia A a Batista, Rahul Samant, Paul A. Clarke, Paul Workman. Proteomic analysis of ubiquitination identifies the interplay between HSP90 inhibition and CUL5 in the control of autophagy. [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 4549.
Two-Year COMPASS Trial Results: Supraciliary Microstenting with Phacoemulsification in Patients with Open-Angle Glaucoma and Cataracts
Authors: Steven Vold, Iqbal Ike K. Ahmed, E. Randy Craven, Cynthia Mattox, Robert Stamper, Mark Packer, Reay H. Brown, Tsontcho Ianchulev
Journal: Ophthalmology (2016)
Abstract 2543: A family affair: Prostate cancer risk and family history of breast or prostate cancer
Authors: Lauren E. Barber, Travis A. Gerke, Sarah C. Markt, Giovanni Parmigiani, Lorelei A. Mucci
Journal: Cancer Research (2016)

Abstract Background - There is suggestive evidence of familial clustering of breast and prostate cancer in first-degree relatives; women with a family history of prostate cancer are at increased risk of breast cancer. Few studies have investigated joint family history of breast and prostate cancer and prostate cancer risk, and no study to date has examined lethal prostate cancer. Methods - We studied 42,672 from the Health Professionals Follow-up Study between 1996 to 2012. During follow-up, 4,258 prostate cancer cases were diagnosed, of whom 380 were lethal disease. Men self-reported family history of breast and prostate cancer, including in siblings or parents. Using cause-specific hazards regression, we estimated hazard ratios (HR) and 95% confidence intervals (CI) of the association between family history and prostate cancer risk and progression. Results - About 8% of men had a family history of prostate cancer, 8.7% had a family history of breast cancer, and 1.4% of men had a family history of both breast and prostate cancer. A family history of prostate cancer was significantly associated with an increased risk of prostate cancer (HR: 1.69; 95% CI: 1.54-1.85). Increased risk was higher for men with a father diagnosed with prostate cancer (HR: 1.64 95% CI: 1.49-1.80) than for men with a diagnosis in a brother(s) (HR: 1.51 95% CI: 1.27-1.80). A positive family history of breast cancer was associated with a small, but significant 22% increased risk (HR: 1.22; 95% CI: 1.11-1.35). Familial breast cancer in a sister (HR: 1.22 95% CI: 1.06-1.41) increased risk more than familial breast cancer in a mother (HR: 1.12; 95% CI: 0.99-1.25). Men with a family history of both prostate and breast cancer had a 52% (HR: 1.52; 95%CI: 1.23-1.88) increased risk of prostate cancer compared to men with no family history of either cancer. Risk of lethal prostate cancer was also significantly increased for men with a positive family history of prostate cancer (HR: 1.64; 95% CI: 1.20-2.24), as well as for men with a family history of breast cancer (HR: 1.47; 95% CI: 1.07-2.01). Conclusions - These results support the findings of familial aggregation of breast and prostate cancer, and for the first time suggest an association between familial breast cancer and lethal prostate cancer. Data from this prospective study have translational relevance for family counseling of cancer patients. Citation Format: Lauren E. Barber, Travis A. Gerke, Sarah C. Markt, Giovanni Parmigiani, Lorelei A. Mucci. A family affair: Prostate cancer risk and family history of breast or 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 2543.
Abstract 2059: Identification of novel paclitaxel sensitivity genes via lentiviral CRISPR/Cas9 screening in haploid human cells
Authors: Jessica R. Hunt, Steffen Lawo, David Walter, Isabelle Nett, Joanne Yarker, Benedict C S Cross, Jonathan D. Moore
Journal: Cancer Research (2016)

Abstract Some cancers lack clearly druggable driver mutations and might also have too few neo-antigen generating mutations to provoke a tumor-specific immune response, even in the presence of antibodies targeting immune checkpoint mechanisms. Synthetic lethal/non-oncogene addiction represents an alternative approach to the therapy of such cancers, as exemplified by the recent approval of olaparib. RNA interference has identified several putative synthetic lethal targets, but few, if any, of these have have withstood vigorous validation. The recent application of RNA-guided gene editing to mammalian cells offers new prospects for target identification. The complete ablation of gene expression, which this technology permits allows the identification of targets that have no phenotype when partially depleted by RNA interference. Horizon has recently established a capability for CRISPR-Cas9 KO screening. Screens are performed by transducing a pool of cells with a complex lentiviral library. Next generation sequencing is then used to identify which sgRNAs are accumulating or being depleted from the population. As there are multiple sgRNAs per gene, we can rank genes for their likelihood of having a phenotype under the conditions used in the screen. Our proof-of-principle small molecule resistance and sensitivity screens using both whole-genome libraries and custom subset libraries have successfully identified previously published hits and also yielded novel hits. Horizon has also developed a fully haploid cell line (eHAP), which has the potential to provide additional clarity in genetic screening. To evaluate the power of CRISPR-Cas9 KO screening in haploid cells, we have used our screening platform to identify genes required for survival in low doses of paclitaxel. Whole-genome screening using the GeCKOv2 library identified three kinesins amongst the most prominent of the hits whose depletion sensitised cells to this microtubule stabilising agent. Intriguingly, two of these kinesins, KIF2A and KIF2C are thought to destabilise mitotic microtubules, providing an attractive explanation for the synthetic lethality. We will also present results from a second genome-wide CRISPR KO screen in haploid cells to identify genes required for survival under glucose starvation. Prominent hits included components of the electron transport chain and the tuberous sclerosis complex. Citation Format: Jessica R. Hunt, Steffen Lawo, David Walter, Isabelle Nett, Joanne Yarker, Benedict C S Cross, Jonathan D. Moore. Identification of novel paclitaxel sensitivity genes via lentiviral CRISPR/Cas9 screening in haploid 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 2059.
Stromal cell–derived factor-1 is upregulated by dipeptidyl peptidase-4 inhibition and has protective roles in progressive diabetic nephropathy
Authors: Satoru Takashima, Hiroki Fujita, Hiromi Fujishima, Tatsunori Shimizu, Takehiro Sato, Tsukasa Morii, Katsushi Tsukiyama, Takuma Narita, Takamune Takahashi, Daniel J. Drucker, Yutaka Seino, Yuichiro Yamada
Journal: Kidney International (2016)
Spectrum of Movement Disorders in Mitochondrial Disorders–Reply
Authors: Mika H. Martikainen, David J. Burn, Doug M. Turnbull
Journal: JAMA Neurology (2016)

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Abstract 3286: Targeting mir101/ EZH2/NFkb axis by FGFR1 inhibitor in mantle cell lymphoma
Authors: Lalit Sehgal, Neeraj Jain, Tamer Khashab, xin wang, Sattva Neelapu, Felipe Samaniego
Journal: Cancer Research (2016)

Abstract Mantle cell lymphoma is classified as distinct non-Hodgkin's lymphoma subtype characterized by the t(11;14)(q13;q32) translocation, which results in overexpression of Cyclin D1. The clinical presentation often includes extra-nodal involvement, of the bone marrow and gut. The prognosis of patients with mantle cell lymphoma (median overall survival, 3-5 years) is poorest among B-cell lymphoma patients. However, MCL pathogenesis has been delayed until the recent development of a tissue culture system, using stromal cells and adipocytes, suitable for propagating primary MCL cells. We hypothesized that tumor microenvironment might activate survival-signaling pathways essential for survival and maintenance of MCL, and targeting the identified signaling pathways might be an ideal for designing of curative treatment strategies. We developed an in-vitro culture system, mimicking bone marrow microenvironment that can be exploited to understand the biology of MCL resistance to death pathways. Primary MCL cells grown in co-culture with bone marrow stromal cells grew faster than cells cultured alone. We identified the soluble factors responsible for survival of MCL cancer stem cells (MCL-IC) that can be targeted to prevent relapse. We found the IL6 secretion triggered FGF-2 autocrine loop in MCL cells contributing to cell survival and growth by regulating mir101/EZH2/NFkb axis. The death signaling pathways inactive in MCL are restored upon therapeutic intervention by specific pathways inhibitors. In conclusion, we delineated three different signaling arm regulated in MCL cells to promote cell survival and resistance. We defined the factors supporting MCL and MCL-ICs survival essential for forming new targeting treatment strategies. To overcome MCL resistance to death pathways we have outlined the hMSCs-mediated support of MCL and identified drug targets to sensitize MCL to apoptosis. Citation Format: Lalit Sehgal, Neeraj Jain, Tamer Khashab, xin wang, Sattva Neelapu, Felipe Samaniego. Targeting mir101/ EZH2/NFkb axis by FGFR1 inhibitor in mantle cell lymphoma. [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 3286.
Minority ethnic people find home BP monitoring less acceptable than white British, study shows
Authors: Susan Mayor
Journal: BMJ (2016)

People of South Asian or African-Caribbean ethnicity find home blood pressure (BP) monitoring and ambulatory monitoring less acceptable than white British patients, a general practice study has shown.1 The researchers suggest that BP monitoring methods should take patient preferences into account.

BP has traditionally been measured in clinics, but evidence has shown that monitoring at home, particularly using ambulatory monitoring, is more accurate in diagnosing hypertension, and it is now recommended in guidelines.

“Use of out-of-office blood pressure monitoring is likely to be strongly influenced by acceptability to patients,” said …