tbuckley/cabot-search huggingface dataset:
Abstract 49: Mir-21 Contributes to Cardiac Aging by Targeting Pten
Authors: Xiaoting Wu, Xiuzhi Wang, Lichan Tao, Yihua Bei, Junjie Xiao, Xinli Li
Journal: Circulation Research (2015)

Background— Aging is among predominant risk factors for cardiovascular diseases and it also contributes to a significantly worse outcome in patients with acute myocardial infarction. MicroRNAs (miRNAs, miRs) have been indicated in aging. However, the regulatory mechanisms of miRNAs which govern the aging progress are poorly understood. Objective— To identify miRNAs responsible for cardiac aging besides miR-34 family members. Methods and Results— miRNA arrays were used to determine the dysregulated miRNAs in cardiac aging using cardiac ventricles from mice at 8 weeks and 15months of age. Besides miR-34 family members, miR-21 was also found to be elevated 3-fold in ventricles from mice aged 15 months compared to mice aged 8 weeks. Over-expression of miR-21 in the neonatal rat cardiomyocytes (NRCM) shortened the telomere length, attenuated and strengthened the activity of telomerase and senescence-related beta[[Unable to Display Character: &amp;#8211;]]galactosidase, respectively, which was similar to the aging caused by doxorubicin (DOX). Using the quantitative PCRs and Western blotting, phosphatase and tensin homologue (PTEN) gene was found to be negatively regulated by miR-21 in NRCM. Moreover, knockdown of PTEN using siRNA mimics the effects of miR-21 in pro-aging in NRCM. Interestingly, knockdown of miR-21, as well as up-regulation of PTEN, repressed NRCM aging induced by DOX. Conclusions— These findings suggest that ectopic up- or down-modulation of miR-21 may be an important regulatory mechanism governing cardiac aging by targeting PTEN. Inhibition of miR-21 represent a novel therapy for cardiac aging.
Abstract 1646: Highly cytotoxic, completely human constructs targeting HER2 and containing the immuno-oncology payload granzyme B
Authors: Lawrence H. Cheung, Yunli Zhao, Khalid A. Mohamedali, Ana Alvarez-Cienfuegos, Walter N. Hittelman, Michael G. Rosenblum
Journal: Cancer Research (2017)

Abstract Recent immunotherapeutic approaches designed to augment T- and B-cell mediated killing of tumor cells has met with clinical success suggesting that immuno-oncology (IO) approaches have tremendous potential for treatment in a broad spectrum of tumor types. After complex recognition of target cells by T and B cells, delivery of the serine protease granzyme B (GrB) to tumor cells comprises the cytotoxic insult resulting in a well-characterized, multimodal apoptotic cascade. We designed a recombinant fusion construct composed of a human anti-Her2 scFv fused to active GrB for recognition and delivery of GrB to tumor cells simulating T and B-cell therapy. The GrB-Fc-4D5 dimeric construct (mw 160 kDa) was generated and expressed in stably-transfected CHO-S cells at ~60 mg/L and purified to homogeneity. The enzymatic activity of the fusion construct was similar to commercially-available GrB and the affinity of the construct for purified Her2 extracellular domain (ECD) was 0.328 nM, comparable to that of Herceptin (0.150 nM). The GrB-Fc-4D5 construct was highly cytotoxic to Her2-positive cells such as SKBR3, MCF7 and MDA-MB-231 with IC50 values of 56, 99 and 27 nM respectively. Using immunofluorescence, the fusion construct internalized rapidly into target (SKBR3 or SKOV3) cells within 1 h of exposure, rapidly delivering GrB to the cytoplasmic compartment in a similar manner to that of immune T and B-cell targeting but without the action of the transmembrane pore-forming agent perforin. Against a large panel of various tumor types, GrB-Fc-4D5 was highly cytotoxic to virtually all cells regardless of natural expression levels of the nominal endogenous GrB inhibitor PI-9. Contemporaneous studies with Kadcyla demonstrate similar levels of in vitro activity against virtually all HER2-positive cells tested. GrB-Fc-4D5 demonstrated activity against both log-phase and confluent tumor cells. In keeping with its relatively high molecular weight (~160 kDa), the construct demonstrated a terminal-phase half-life of 13.6 hrs. In vivo efficacy studies are currently ongoing in several orthotopic xenograft models. Also ongoing are pre-IND toxicology, histopathology and clinical chemistry studies. Research conducted, in part, by the Clayton Foundation for Research. Citation Format: Lawrence H. Cheung, Yunli Zhao, Khalid A. Mohamedali, Ana Alvarez-Cienfuegos, Walter N. Hittelman, Michael G. Rosenblum. Highly cytotoxic, completely human constructs targeting HER2 and containing the immuno-oncology payload granzyme B [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1646. doi:10.1158/1538-7445.AM2017-1646
Abstract 3019: The role of TACC3 in the progression from ductal carcinoma in situ to invasive breast cancer
Authors: Loredana Campo, Maya Mathew, Eun-Kyoung breuer, William Small
Journal: Cancer Research (2017)

Abstract Ductal carcinoma in situ (DCIS) is a non-invasive breast cancer with the potential to become invasive/metastatic. The development of DCIS to invasive breast cancer is an important aspect of breast tumor aggressiveness, however, little is known about the genetic and molecular alterations involved in this progression. Also, analysis of molecular markers and genetic signatures of DCIS and invasive breast cancer have failed to identify transition-specific biomarkers or pathways. Hence, identifying the molecular mechanisms by which DCIS progresses to invasive breast cancer is critical for the success of diagnosis, prognosis and therapy of breast cancer. Members of the transforming acidic coiled-coil (TACC) protein family are key players in the maintenance of centrosome integrity, the regulation of microtubule assembly, and spindle stability during mitosis. TACC3 has been shown to be involved in the regulation of centrosome-microtubule dynamic networks, cell growth and differentiation, and transcription/gene expression through interactions with other molecules. Mounting evidence indicates that high levels of TACC3 may contribute to breast cancer development. Here, we investigated the significance of TACC3 in the transition of DCIS to invasive breast cancer. First, we examined the expression of TACC3 in non-tumorigenic human mammary epithelial MCF10A cells and MCF10DCIS.COM cells, which are known to form DCIS-like lesions in mice and to progress to invasive cancer, and found that the expression of TACC3 is elevated in MCF10DCIS.COM cells compared to MCF10A cells. By analyzing tissue microarray data, we found that expression of TACC3 gradually increased from normal breast to DCIS, and further increased in invasive breast cancer. In addition, ectopic expression of TACC3 in MCF10DCIS.COM cells promoted cell proliferation, migratory and invasive capabilities as well as the epithelial-mesenchymal transition (EMT)-like phenotype. Moreover, MCF10DCIS.COM cells stably expressing TACC3 exhibited increased expression of stemness markers. Interestingly, a small molecule inhibitor of TACC3, KHS101 treatment in MCF10DCIS.COM cells significantly suppressed cell proliferation and the PI3K/AKT signaling pathway while having little effect on MCF10A cells. Our findings, therefore, suggest that TACC3 may play an important role in the progression from DCIS to invasive breast cancer and that targeting TACC3 could be a promising new therapeutic strategy for DCIS patients. Citation Format: Loredana Campo, Maya Mathew, Eun-Kyoung breuer, William Small. The role of TACC3 in the progression from ductal carcinoma in situ to invasive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3019. doi:10.1158/1538-7445.AM2017-3019
Abstract 1665: MuScreenTM : A well-characterized syngeneic model platform for rapid <i>in vivo</i> screening
Authors: Lan Zhang, Binchen Mao, Qian Shi
Journal: Cancer Research (2017)

Abstract Background: Syngeneic tumor models, many shelved for decades, have been revived as effective models for immunotherapy, accompanying the clinical success of the immuno-checkpoint inhibitors (e.g. anti-CTLA4, anti-PD1, anti-PD-L1 antibodies). In vitro cell-based screens that are frequently used in oncology to quickly identify responsive cells and assess PD effects, often fail in immuno-oncology, due to immunotherapeutics targeting the complex host immune system. Alternatively, an in vivo screen with a panel of models addresses many of these questions, e.g. PD and efficacy, but may be cost prohibitive. Material and methods: Leveraging in-house detailed profiling data on our syngeneic models, including efficacy benchmarking with anti PD-1, PD-L1, CTLA-4, OX-40, GITR , LAG3 and TIM3 antibodies, RNAseq data on tumor samples, and FACS analysis on both baseline and post-treatment tumor samples, we created a new in vivo screening tool for immune-oncology: MuScreen. MuScreen includes up to 20 well-characterized syngeneic models in a 3 month screening run. Both PD and efficacy may be determined in the run, allowing researchers to make decisions based on results observed from a large dataset. To address the cost issue, test agents from multiple clients are pooled together for each run (sharing vehicle and other common groups) providing a significant reduction in the number of animals used and the associated costs. Results: CrownBio has established the largest collection of syngeneic models with well-characterized immunotherapy data. With the three MuScreen runs, we have generated new data on common IO agents (e.g. aPD-1 antibody) and combinations treatments, with FACS analysis, IHC, and efficacy data. Based on these data, a bioinformatics analyses were further explored to identify the makers/pathways that could be correlated with the efficacy or PD effect of the tested IO treatment. Conclusions: MuScreen, the first in vivo screening tool for cancer immunotherapeutics, provides detailed response data on a panel of syngeneic models, and may help on biomarker discovery in a cost and time efficient manner. Citation Format: Lan Zhang, Binchen Mao, Qian Shi. MuScreenTM : A well-characterized syngeneic model platform for rapid in vivo screening [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1665. doi:10.1158/1538-7445.AM2017-1665
Defining Potential Use of Nonstatin Therapies to Lower Blood Cholesterol Levels
Authors: Sidney C. Smith
Journal: JAMA Cardiology (2017)

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Abstract 3200: Targeting PHF5A for the treatment of glioblastoma and other Myc-driven cancers
Authors: Andrew J. Mhyre, Shanon Turnbaugh, Shelli M. Morris, Hu Xin, Patrick J. Paddison, Marc Ferrer, James M. Olson
Journal: Cancer Research (2017)

Abstract Glioblastoma multiforme (GBM) is one of the most aggressive and invasive types of brain cancer, but targeted treatment options remain elusive. The standard of care (surgery chemotherapy and radiation) falls far short of where it should be with two-year survival rates less than 10%. Using stem cell isolates from GBM patients, we found that perturbing PHF5A, a component of the spliceosome machinery, was lethal and caused hundreds of genes to be mis-spliced. These mis-splicing events included both exon skipping and intron inclusions. In contrast, similar levels of PHF5A suppression in normal control stem cells and astrocytes failed to induce cell death and mis-splicing, indicating that PHF5A plays a specific role in the cancer biology. Moreover, when normal astrocytes were transformed with the Myc oncogene, they became sensitive to PHF5A perturbation. Taken together, these results suggested that specifically inhibiting PHF5A would be an effective therapy for glioblastoma and other Myc-driven cancers. Specifically targeting PHF5A would also likely result in reduced side-effects seen with general spliceosome inhibitors. Unfortunately, there are currently no known inhibitors that target PHF5A. In order to discovery novel PHF5A inhibitors, we created a mini-gene mis-splicing reporter assay that was sensitive to both general spliceosome inhibitors and PHF5A perturbation. In a 96-well assay format, the assay was robust with a 200-fold assay window and Z’ values over 0.8. Following miniaturization to a 1536-well format, we conducted a high throughput screening (HTS) campaign testing 450,000 small molecule compounds. The initial hits were retested and counter-screened yielding 381 confirmed actives and we are further interrogating these actives in secondary and tertiary assays. Future efforts will focus on developing an SAR of the lead and backup series and identifying potential liabilities that will be addressed, if necessary, in further lead optimization efforts. We are enthusiastic about the potential of developing a targeted PHF5A inhibitor as a novel and effective therapy for patients and their families fighting GBM and other Myc-driven cancers. Citation Format: Andrew J. Mhyre, Shanon Turnbaugh, Shelli M. Morris, Hu Xin, Patrick J. Paddison, Marc Ferrer, James M. Olson. Targeting PHF5A for the treatment of glioblastoma and other Myc-driven cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3200. doi:10.1158/1538-7445.AM2017-3200
Magnetically responsive microbubbles as delivery vehicles for targeted sonodynamic and antimetabolite therapy of pancreatic cancer
Authors: Yingjie Sheng, Estelle Beguin, Heather Nesbitt, Sukanta Kamila, Joshua Owen, Lester C. Barnsley, Bridgeen Callan, Christopher O'Kane, Nikolitsa Nomikou, Rifat Hamoudi, Mark A. Taylor, Mark Love, Paul Kelly, Declan O'Rourke, Eleanor Stride, Anthony P. McHale, John F. Callan
Journal: Journal of Controlled Release (2017)

Magnetically responsive microbubbles (MagMBs), consisting of an oxygen gas core and a phospholipid coating functionalised with Rose Bengal (RB) and/or 5-fluorouracil (5-FU), were assessed as a delivery vehicle for the targeted treatment of pancreatic cancer using combined antimetabolite and sonodynamic therapy (SDT). MagMBs delivering the combined 5-FU/SDT treatment produced a reduction in cell viability of over 50% when tested against a panel of four pancreatic cancer cell lines in vitro. Intravenous administration of the MagMBs to mice bearing orthotopic human xenograft BxPC-3 tumours yielded a 48.3% reduction in tumour volume relative to an untreated control group (p<0.05) when the tumour was exposed to both external magnetic and ultrasound fields during administration of the MagMBs. In contrast, application of an external ultrasound field alone resulted in a 27% reduction in tumour volume. In addition, activated caspase and BAX protein levels were both observed to be significantly elevated in tumours harvested from animals treated with the MagMBs in the presence of magnetic and ultrasonic fields when compared to expression of those proteins in tumours from either the control or ultrasound field only groups (p<0.05). These results suggest MagMBs have considerable potential as a platform to enable the targeted delivery of combined sonodynamic/antimetabolite therapy in pancreatic cancer.
Abstract SY19-01: Tumor-elicited inflammation in colorectal cancer
Authors: Michael Karin
Journal: Cancer Research (2017)

Abstract The majority of sporadic human colorectal cancer is initiated by genetic loss or inactivation of tumor suppressor APC (Absent in Polyposis Coli). In addition to activation of beta-catenin signaling, we found that loss of APC results in upregulation of IL-6 signal transducer (IL6/gp130), thereby leading to activation of STAT3 and YAP, two transcription factors that make important contributions to colorectal tumorigenesis. In addition, APC loss results in deterioration of the intestinal epithelial barrier and immune homeostasis, barrier loss due to downregulation of genes encoding tight junction proteins, and suppression of mucin production. Together, such changes promote the invasion of inflammation-inducing colitogenic bacteria and their products. Loss of immune homeostasis is due to defective luminal transport of IgA dimers caused by loss of polyimmunoglobin receptor (PIgR) and CCL28, a chemokine responsible for recruitment of IgA-producing plasma cells. Defective luminal transport of IgA results in dysbiosis and over-representation of inflammation-causing bacteria that can accelerate colorectal tumor genesis through upregulation of IL-17 production. Citation Format: Michael Karin. Tumor-elicited inflammation in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr SY19-01. doi:10.1158/1538-7445.AM2017-SY19-01
Controversies in cardiology
Authors: Lippincott Williams Wilkins
Journal: Circulation (2005)

There are several areas of therapeutics where current practice differs between the United States and Europe. In the case of nesiritide, the use of this drug is undoubtedly controversial. This recombinant human brain natriuretic peptide is given to tens of thousands of patients in the United States every week at a cost of about $500 for each dose, and many physicians there are extremely enthusiastic about this new treatment for acute decompensated heart failure (ADHF).

Aggressive marketing by the manufacturer, Scios Inc, has been suggested as one reason for its increasing use1 while many cardiologists in Europe are far less enthusiastic and have …
Routine HIV testing when registering with GP is cost effective, shows UK study
Authors: Susan Mayor
Journal: BMJ (2017)

Offering HIV testing as part of routine health checks when people register at a new GP surgery is cost effective in areas with high prevalence, a UK study has shown. The researchers said that the findings support introducing routine HIV screening in primary care in all areas with similarly high rates.

The study, reported in Lancet HIV ,1 analysed the cost effectiveness of HIV testing as part of registering with a new GP, on the basis of a fourfold increase in diagnosis seen in a randomised trial of routine rapid finger prick HIV testing at 40 general …
Abstract 3178: The p53 tumor suppressor protein paradoxically drives chemo-resistance in human medulloblastoma cells through suppressing the mTOR AKT pathway
Authors: Aisha Naeem, Muhammad U. Choudhry, Maria L. Avantaggiati, Olga C. Rodriguez, Chris Albanese
Journal: Cancer Research (2017)

Abstract Medulloblastoma (MB) accounts for approximately 25% of childhood brain tumors with 70% of the cases occurring in children under 10. Prognosis for children less than three years old is considerably worse and, due to its destructive effects on the developing nervous system, irradiation is largely avoided in this age group. The p53 pathway is considered a key determinant of anti-tumor responses in many tumors; however, its role in the regulation of cell survival, chemo-sensitivity and chemo-resistance in MB is much less well defined. It has been shown that p53 pathway defects, mutations and nuclear levels increase significantly from MB diagnosis to relapse and correlate with an adverse prognosis. We recently reported on the highly novel and unexpected finding that both the genetic (sh-RNA) and chemical silencing of p53 led to a significant increase in cell death by the drug VMY in MB cell lines with elevated basal p53 (e.g. in D556 cells which express wild type p53 and in DAOY cells that contain mutant p53) as measured by colony forming assays, DNA degradation assays and annexin-V staining, suggesting a surprising commonality in the p53 signaling in both cell lines despite the differences in their p53 status. Equally surprising was the observation that the silencing of p53 in D556 cells enhanced cell death by the clinically used drugs doxorubicin and vincristine. Conversely, we now find that suppressing p53 with sh-RNA in D283 cells, which express much lower levels of wild type p53 compared to D556, resulted in the more classical chemoresistance profile, suggesting a form of p53 ‘addiction’ in D556 and DAOY cells. Mechanistically, we observed that suppressing p53 with sh-RNA in D556 cells treated with VMY or doxorubicin significantly increased the levels of phosphorylated Chk1, S6K, gH2AX, and MDM2. Importantly, phospho-mTOR levels were also significantly increased in the D556/p53 sh-RNA cells and the suppression of mTOR enhanced chemoresistance. These somewhat paradoxical findings suggest that activated Akt/mTOR may induce MB cell death and that suppression of mTOR by p53 enhances chemoresistance. Our data provide new mechanistic insights into the role of p53 in primitive neuroectodermal tumors and may provide new approaches for enhancing the clinical outcome of patients with MB. Citation Format: Aisha Naeem, Muhammad U. Choudhry, Maria L. Avantaggiati, Olga C. Rodriguez, Chris Albanese. The p53 tumor suppressor protein paradoxically drives chemo-resistance in human medulloblastoma cells through suppressing the mTOR AKT pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3178. doi:10.1158/1538-7445.AM2017-3178