tbuckley/cabot-search huggingface dataset:
Abstract 2109: Prognostic and functional significance of interleukin 22 in colorectal cancer
Authors: Eleonora Cremonesi, Nadia Tosti, Francesca Amicarella, Benjamin Weixler, Silvio Däster, Valeria Governa, Giulio C. Spagnoli, Luigi Terracciano, Luigi Tornillo, Serenella Eppenberger-Castori, Giandomenica Iezzi, Raoul Droeser
Journal: Cancer Research (2018)

Abstract T cell infiltration has been recognized to significantly impact clinical outcome in human colorectal cancer (CRC). Interleukin 22 (IL-22), a cytokine secreted by IL-17-producing CD4+ T cells (Th17) is known to play a crucial role in inflammatory bowel disease and has been shown to have protumorigenic activity in mouse tumor models. However, its role in human CRC is still unclear. In a previous study we could demonstrate the dual role of Th17 in CRC. As consequence we evaluated the prognostic and functional impact of IL-22 producing cells in human CRC in this follow-up study. Upon staining of a tissue microarray (TMA), including 423 CRC cases, IL-22 positive cells were detected both within tumor cells and tumor infiltrating immune cells. Whereas, IL-22 expression by tumor cells did not impact on prognosis, densities of IL-22 positive immune cells were found to be significantly associated with early T stage and MMR-deficient microsatellite stability. Importantly, IL-22 expression by CRC infiltrating immune cells was predictive of improved overall survival independent of known prognostic factors such as T stage, N stage, tumor grade, vascular invasion, tumor border configuration and MMR status. Phenotypic characterization of IL-22 positive cells performed by flow cytometry revealed that they consist mainly of Th17 cells, also producing IL-17. In vitro experiments showed no direct effect of IL-22 on CRC cell proliferation. On-going studies are validating the prognostic effect on a TMA cohort with corresponding transcriptomic data and evaluating potential effects mediated by IL-22 on other cell types of CRC microenvironment. Citation Format: Eleonora Cremonesi, Nadia Tosti, Francesca Amicarella, Benjamin Weixler, Silvio Däster, Valeria Governa, Giulio C. Spagnoli, Luigi Terracciano, Luigi Tornillo, Serenella Eppenberger-Castori, Giandomenica Iezzi, Raoul Droeser. Prognostic and functional significance of interleukin 22 in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2109.
Abstract 2666: Subtype-selective lethal molecules disrupt the regulatory module that drives high-risk neuroblastoma
Authors: Michael E. Stokes, Alessandro Vasciaveo, Jonnell Candice Small, Presha Rajbhandari, Gonzalo Lopez, Andrea Califano, Brent R. Stockwell
Journal: Cancer Research (2018)

Abstract Neuroblastoma (NBL) is a tumor that is derived from the developing neural crest, resulting in approximately 15% of pediatric cancer deaths. This cancer is characterized by multiple tumor subtypes that vary in their aggressiveness and clinical prognosis. Though MYCN amplification is associated with an aggressive subtype and poor prognosis, recent molecular classification identified a novel aggressive subtype driven by a mesenchymal gene signature. To understand the molecular mechanisms underpinning each subtype, network-based analysis identified key transcriptional regulators for each subtype that act in concert to drive tumor pathology. We hypothesize that chemical inhibitors disrupting this regulatory module will have greater chance of success in vivo, by targeting the specific drivers of the tumor subtype. In an effort to identify subtype-selective lethal molecules that could be developed into targeted therapies, we screened ~5500 bioactive molecules across a panel of four NBL cell lines representing either MycNAMP or the newly identified mesenchymal subtype (MESN). A number of subtype selective compounds were identified, and their effect on the regulatory module was evaluated using high-throughput transcriptome analysis (PLATE-Seq) (Bush EC et al., 2017) followed by Virtual Inference of Protein activity by Enriched Regulon (VIPER) analysis (Alvarez MJ et al., 2016). This analysis revealed 15 compounds that exhibited greater potency in MycNAMP cells, and inverted the MR signature that characterizes this subtype. Compounds that reverted the signature caused destabilization of MycN through diverse mechanisms, highlighting new therapeutic approaches to targeting the MycNAMP subtype. This screening strategy also identified MESN-selective compounds, including multiple statin drugs that inhibit mevalonate biosynthesis in cells. The subtype-selectivity of these well-studied drugs is being used to define their lethal mechanisms in the MESN subtype, and to understand how MycNAMP cells evade their inhibitory effects. Our multifaceted approach, including cell line-selective chemical screening coupled with high-throughput transcriptome and network analysis, can serve as a framework for future drug discovery in a variety of cancers. Citation Format: Michael E. Stokes, Alessandro Vasciaveo, Jonnell Candice Small, Presha Rajbhandari, Gonzalo Lopez, Andrea Califano, Brent R. Stockwell. Subtype-selective lethal molecules disrupt the regulatory module that drives high-risk neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2666.
Maurice William Beaver
Authors: Rosemary Beaver, Rachel Beaver, Ruth Beaver
Journal: BMJ (2018)

Maurice William Beaver was brought up in London and Cornwall during the second world war and was educated at Ilford County High School for Boys. In 1949 he went to study medicine at University College Hospital Medical School in London. He served as a junior house officer with a consultant surgeon in Portsmouth and at the Scott Isolation Hospital for Infectious diseases in Plymouth, where he acquired experience in general and genitourinary medicine.

Maurice qualified in 1955, and national service took him overseas to serve as a captain, in the Royal Army Medical Corps in Malaya. He enjoyed his time there, as doctor to a British Army regiment, an Australian army regiment, and a Gurkha regiment—particularly his work supporting the Gurkha soldiers and their families.

On returning to the UK in 1957, Maurice secured a post as a house officer in the department of obstetrics, gynaecology, and genitourinary medicine at King’s Lynn General Hospital in Norfolk, where he met his future wife, Marian Pollyn, a midwifery sister. Originally he had planned to take up a further commission in the RAMC and thereafter to become a general practitioner in Cornwall. Unfortunately, however, in 1958 he …
Vacuolar H <sup>+</sup> -ATPase Plays a Crucial Role in Growth and Phenotypic Modulation of Myofibroblasts in Cultured Human Saphenous Vein
Authors: Hajime Otani, Tadashi Yamamura, Yoshihisa Nakao, Reiji Hattori, Hirohumi Fujii, Hideki Ninomiya, Masakuni Kido, Hideki Kawaguchi, Motohiko Osako, Hiroji Imamura, Tetsuo Ohta, Shoji Ohkuma
Journal: Circulation (2000)

Background —The molecular mechanism of neointimal hyperplasia after vein graft surgery remains elusive. Vacuolar H + -ATPase (V-ATPase) is involved in intracellular trafficking and may play a crucial role in neointimal cell growth. Methods and Results —Cultured human saphenous vein segments developed neointimal formation within 10 days. Neointimal cells were positive for vimentin and α-smooth muscle actin but negative for desmin, which is indicative of myofibroblasts. Those myofibroblasts were found to have originated from periadventitial fibroblasts, which upregulated the expression of 16-kDa proteolipid of V-ATPase before proliferation and phenotypic modulation. Neointimal myofibroblast growth and survival were highly sensitive to inhibition of V-ATPase by bafilomycin A 1 (BA 1 ), because the incorporation of [ 3 H]thymidine into the myofibroblasts was significantly inhibited by nanomolar concentrations of BA 1 and apoptotic cell death was induced by a similar concentration range of BA 1 . In contrast, endothelial cells and differentiated smooth muscle cells were resistant to apoptosis by BA 1 . Conclusions —These results suggest that V-ATPase plays a crucial role in growth and phenotypic modulation of myofibroblasts that contributes to neointimal formation in cultured human saphenous vein.
Chymase-Dependent Angiotensin II Formation in Human Vascular Tissue
Authors: ShinjiTakai, DenanJin, MasatoSakaguchi, MizuoMiyazaki
Journal: Circulation (1999)

Background—Some reports have suggested that, in vitro, human heart chymase in homogenates contributes little to angiotensin (Ang) II formation in the presence of natural protease inhibitors such as α-antitrypsin. We studied whether chymase bound to heparin, resembling an in vivo form, could contribute to Ang II formation in the presence of natural protease inhibitors. Methods and Results—The Ang II formation was increased time-dependently after incubation in an extract (1 mg of protein/mL) of human vascular tissues containing Ang I. The concentration of Ang II in the extract after incubation for 30 minutes was 1.67±0.06 nmol/mL, and we regarded this quantity of Ang II as 100%. The Ang II formation was inhibited 10%, 95%, and 96% by 1 μmol/L lisinopril, 100 μmol/L chymostatin, and 0.1 g/L α-antitrypsin, respectively. The extract was applied to a heparin affinity column. After the column was washed with PBS, the eluted PBS contained a weak Ang II-forming activity, which was completely inhibited by lisinopri...
Rosuvastatin Decreases Caveolin-1 and Improves Nitric Oxide–Dependent Heart Rate and Blood Pressure Variability in Apolipoprotein E−/− Mice In Vivo
Authors: MichelPelat, ChantalDessy, PaulMassion, Jean-PierreDesager, OlivierFeron, Jean-LucBalligand
Journal: Circulation (2003)

Background— Decreased heart rate variability (HRV) and increased blood pressure variability (BPV), determined in part by nitric oxide (NO)–dependent endothelial dysfunction, are correlated with adverse prognosis in cardiovascular diseases. We examined potential alterations in BPV and HRV in genetically dyslipidemic, apolipoprotein (apo) E−/−, and control mice and the effect of chronic statin treatment on these parameters in relation to their NO synthase (NOS)–modifying properties. Methods and Results— BP and HR were recorded in unrestrained, nonanesthetized mice with implanted telemetry devices with or without rosuvastatin. Cardiac and aortic expression of endothelial NOS and caveolin-1 were measured by immunoblotting. Both systolic BP and HR were elevated in apoE−/− mice, with abolition of their circadian cycles. Spectral analysis showed an increase in their systolic BPV in the very-low-frequency (+17%) band and a decrease in HRV in the high-frequency (−57%) band, reflecting neurohumoral and autonomic dy...
A Clinical and Molecular Phase II Trial of Oral ENMD-2076 in Ovarian Clear Cell Carcinoma (OCCC): A Study of the Princess Margaret Phase II Consortium
Authors: Stephanie Lheureux, Anna Tinker, Blaise Clarke, Prafull Ghatage, Stephen Welch, Johanne I. Weberpals, Neesha C. Dhani, Marcus O. Butler, Katia Tonkin, Qian Tan, David S.P. Tan, Kelly Brooks, Janelle Ramsahai, Lisa Wang, Nhu-An Pham, Patricia A. Shaw, Ming S. Tsao, Swati Garg, Tracey Stockley, Amit M. Oza
Journal: Clinical Cancer Research (2018)

Abstract Purpose: Patients with recurrent ovarian clear cell carcinoma (OCCC) have limited effective options due to chemoresistance. A phase II study was designed to assess the activity of ENMD-2076, an oral multitarget kinase selective against Aurora A and VEGFR. Patients and Methods: This multicenter phase II study included patients with recurrent OCCC who received prior platinum-based chemotherapy. Primary endpoints were objective response and 6-month progression-free survival (PFS) rates. Correlative analyses include ARID1A and PTEN expression by IHC and gene sequencing with a targeted custom capture next-generation sequencing panel. Results: Forty patients were enrolled with a median age of 54, of which 38 patients were evaluable. ENMD-2076 was well tolerated with main related grade 3 toxicities being hypertension (28%), proteinuria (10%), and diarrhea (10%). Best response was partial response for 3 patients (1 unconfirmed) and stable disease for 26 patients. The overall 6-month PFS rate was 22% and differed according to ARID1A expression (ARIDIA− vs. ARID1A+; 33% vs. 12%, P = 0.023). PTEN-positive expression was observed in 20 of 36 patients, and there was no correlation with outcome. Median PFS in patients with PI3KCA wild-type versus PI3KCA-mutated group was 5 versus 3.7 months (P = 0.049). Molecular profiling showed variants in PI3KCA (27%), ARID1A (26%), and TP53 (7%). The patient with the longest treatment duration (22 months) was PTEN wild-type, diploid PTEN with putative biallelic inactivation of ARID1A. Conclusions: Single-agent ENMD-2076 did not meet the preset bar for efficacy. Loss of ARID1A correlated with better PFS on ENMD-2076 and warrants further investigation as a potential predictive biomarker.
Label-free imaging of hemoglobin degradation and hemosiderin formation in brain tissues with femtosecond pump-probe microscopy
Authors: Lili Zhang, Xiang Zou, Bohan Zhang, Liyuan Cui, Jiayi Zhang, Ying Mao, Liang Chen, Minbiao Ji
Journal: Theranostics (2018)

The degradation of hemoglobin in brain tissues results in the deposition of hemosiderin, which is a major form of iron-storage protein and closely related to neurological disorders such as epilepsy. Optical detection of hemosiderin is vitally important yet challenging for the understanding of disease mechanisms, as well as improving surgical resection of brain lesions. Here, we provide the first label-free microscopy study of sensitive hemosiderin detection in both an animal model and human brain tissues. Methods: We applied spectrally and temporally resolved femtosecond pump-probe microscopy, including transient absorption (TA) and stimulated Raman scattering (SRS) techniques, to differentiate hemoglobin and hemosiderin in brain tissues. The label-free imaging results were compared with Perls' staining to evaluate our method for hemosiderin detection. Results: Significant differences between hemoglobin and hemosiderin transient spectra were discovered. While a strong ground-state bleaching feature of hemoglobin appears in the near-infrared region, hemosiderin demonstrates pure excited-state absorption dynamics, which could be explained by our proposed kinetic model. Furthermore, simultaneous imaging of hemoglobin and hemosiderin can be rapidly achieved in both an intracerebral hemorrhage (ICH) rat model and human brain surgical specimens, with perfect correlation with Perls' staining. Conclusion: Our results suggest that rapid, label-free detection of hemosiderin in brain tissues could be realized by femtosecond pump-probe microscopy. Our method holds great potential in providing a new tool for intraoperative detection of hemosiderin during brain surgeries.
Abstract 4597: The Blood Profiling Atlas in Cancer: Accelerating progress through collaboration in liquid biopsy
Authors: Jim Godsey
Journal: Cancer Research (2018)

Abstract Liquid biopsies have the potential to improve early cancer detection, reduce the need for invasive tumor biopsies, and improve personalized oncology treatment. To help drive development within this space, the Blood Profiling Atlas in Cancer (BloodPAC) was created as an initiative born out of the 2016 White House Cancer Moonshot. The BloodPAC seeks to create an open database commons for liquid biopsies with the goal of accelerating the development and approval of safe and effective blood profiling diagnostic technologies for patient benefit. BloodPAC was established as an independent not-for-profit in February 2017 and has made exciting progress in advancing the liquid biopsy landscape. Today, BloodPAC is comprised of over 30 member groups with a diverse range of stakeholders, representing government agencies, academia, pharmaceutical, and diagnostic companies as well as disease specific foundations, payers groups and patient advocates. BloodPAC members actively contribute datasets that include sequencing data from circulating tumor cells, circulating tumor DNA (ctDNA), and exosome assays, alongside relevant clinical data into the BloodPAC Data Commons. The BloodPAC Data Commons helps facilitate the aggregation and harmonization of submitted datasets, allowing researchers to generate study cohorts size to make statistically significant inference in a scalable, reproducible, and secure way. Establishing a comprehensive knowledge base through the BloodPAC Data Commons provides an invaluable reference for anyone entering into the liquid biopsy field, helps develop the evidence required to support clinical utility, assay reproducibility, and provides support for FDA approval and payer reimbursement. This presentation will discuss current progress made within the BloodPAC as an innovative consortium along with the development of the BloodPAC Data Commons, lessons learned, and upcoming next steps. The discussion will focus on examining the BloodPAC consortium's strategy over the past year, the group's work in developing pre- analytical standards, an overview of the contributed data, as well as the collaborative process that has been established with the FDA and CAP to maximize the organization's impact and effectiveness. Citation Format: Jim Godsey. The Blood Profiling Atlas in Cancer: Accelerating progress through collaboration in liquid biopsy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4597.
Termination of Atrioventricular Nodal Reentrant Tachycardia by Premature Stimulation From Ablating Catheter
Authors: JasbirSra, MohammadJazayeri, AndreaNatale, AnwerDhala, ZalmenBlanck, SanjayDeshpande, CherylMaglio, SiobhanBremner, MasoodAkhtar
Journal: Circulation (1995)

Background Slow-pathway ablation is currently used more frequently to control atrioventricular nodal reentrant tachycardia (AVNRT). However, in patients with the common type of AVNRT, successful ablation of the slow pathway can be difficult and time-consuming. We tested a simple method to predict a site for slow-pathway ablation in patients with AVNRT of the common variety. Methods and Results Twenty patients with symptomatic common AVNRT (13 women and 7 men; mean age, 41±21 years) were included in the study. Once the AVNRT had a stable cycle length (±10 ms) for at least 20 cycles, single extrastimuli were delivered from the ablating catheter tip beginning with 20 ms less than the tachycardia cycle length and decrementing by 10 ms until tachycardia terminated or loss of capture occurred at the pacing site. The pacing protocol was performed systematically in a stepwise fashion at four adjacent sites starting from the posterior/inferior interatrial septum near the tricuspid annulus and moving progressively ...
Abstract 1274: Effects of diet on lung adenoma carcinogenesis in metformin treated A/J mice
Authors: Vannesa Souksavong, Beverly R. Wuertz, Donna Seabloom, Frank G. Ondrey
Journal: Cancer Research (2018)

Abstract There has been considerable interest in the effects of biguanides, utilized to treat type 2 diabetes, on human carcinogenesis. Several population studies established diabetes patients treated with metformin and other type 2 diabetes agents experience decreased cancers in several organ systems. However, the effects are not universal in all organ systems and metabolically complex. In the present study, we utilized a dosing regimen of dietary metformin in benzo[a]pyrene treated mice known to reduce lung adenoma formation in A/J mice by approximately 50% over controls. For the duration of this study we used several animal diets commonly employed for mouse chemoprevention experiments with and without 850 mg/kg/day metformin added to the diet. These included AIN93M, AIN76A, D62 (Dr. Lee Wattenberg's chemoprevention diet), a modification of D62 with added maltodextrin and sucrose, and Teklad 4% fat pellets from Envigo. At the conclusion of the study, animals were sacrificed and surface adenoma counts were performed on fresh lungs from each group of animals. We found 850 mg/kg/day metformin for 16 weeks reduced adenoma formation by 35-60% in the diets we employed for the study. Interestingly, the Teklad diet which contains dehulled soybean meal had significantly reduced tumor formation in the control animals, demonstrating some animal diets provide chemoprevention efficacy independent of any pharmaceutical effects. There was no observed toxicity of metformin in the animals; however we have observed significant differences in the average end weights of animals treated with metformin. We conclude metformin is an efficacious agent in lung adenoma chemoprevention and similar reductions in adenoma formation occurred in several of the diets commonly employed for chemoprevention studies in B[a]P treated mice. However, attention to diet formulation is vital due to potential chemoprevention and metabolic effects independent of metformin treatment. Citation Format: Vannesa Souksavong, Beverly R. Wuertz, Donna Seabloom, Frank G. Ondrey. Effects of diet on lung adenoma carcinogenesis in metformin treated A/J mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1274.