tbuckley/cabot-search huggingface dataset:
Cerebrovascular amyloid Angiopathy in bioengineered vessels is reduced by high-density lipoprotein particles enriched in Apolipoprotein E
Authors: Jerome Robert, Emily B. Button, Emma M. Martin, Luke McAlary, Zoe Gidden, Megan Gilmour, Guilaine Boyce, Tara M. Caffrey, Andrew Agbay, Amanda Clark, Judith M. Silverman, Neil R. Cashman, Cheryl L. Wellington
Journal: Molecular Neurodegeneration (2020)

Several lines of evidence suggest that high-density lipoprotein (HDL) reduces Alzheimer's disease (AD) risk by decreasing vascular beta-amyloid (Aβ) deposition and inflammation, however, the mechanisms by which HDL improve cerebrovascular functions relevant to AD remain poorly understood.Here we use a human bioengineered model of cerebral amyloid angiopathy (CAA) to define several mechanisms by which HDL reduces Aβ deposition within the vasculature and attenuates endothelial inflammation as measured by monocyte binding.We demonstrate that HDL reduces vascular Aβ accumulation independently of its principal binding protein, scavenger receptor (SR)-BI, in contrast to the SR-BI-dependent mechanism by which HDL prevents Aβ-induced vascular inflammation. We describe multiple novel mechanisms by which HDL acts to reduce CAA, namely: i) altering Aβ binding to collagen-I, ii) forming a complex with Aβ that maintains its solubility, iii) lowering collagen-I protein levels produced by smooth-muscle cells (SMC), and iv) attenuating Aβ uptake into SMC that associates with reduced low density lipoprotein related protein 1 (LRP1) levels. Furthermore, we show that HDL particles enriched in apolipoprotein (apo)E appear to be the major drivers of these effects, providing new insights into the peripheral role of apoE in AD, in particular, the fraction of HDL that contains apoE.The findings in this study identify new mechanisms by which circulating HDL, particularly HDL particles enriched in apoE, may provide vascular resilience to Aβ and shed new light on a potential role of peripherally-acting apoE in AD.
Mineralization of calcium phosphate controlled by biomimetic self-assembled peptide monolayers via surface electrostatic potentials
Authors: Shuo Wang, Yongdong Yang, Ronghan Wang, Xiangdong Kong, Xiumei Wang
Journal: Bioactive Materials (2020)

The functions of acidic-rich domains in non-collagenous protein during biomineralization are thought to induce nucleation and control the growth of hydroxyapatite. The tripeptide Asp-Ser-Ser (DSS) repeats are the most common acidic-rich repeated unit in non-collagenous protein of dentin phosphoprotein, the functions of which have aroused extensive interests. In this study, biomimetic peptides (DSS)n (n = 2 or 3) were designed and fabricated into self-assembled monolayers (SAMs) on Au (111) surface as biomimetic organic templates to regulate hydroxyapatite (HAp) mineralization in 1.5 simulated body fluid (1.5 SBF) at 37 °C. The early mineralization processes and minerals deposited on the SAMs were characterized by X-ray diffraction, scanning electron microscope, and Fourier transform infrared spectroscopy analyses. The SAM-DSS9/DSS9G showed the highest capacity to induce HAp nucleation and growth, followed by SAM-DSS6/DSS6G, SAM-COOH, and SAM-OH. The SAM-(DSS)n had more negative zeta potentials than SAM-COOH surface, indicating that DSS repeats contributed to the biomineralization, which not only provided strong affinity with Ca2+ ions through direct electrostatic bonds, but more importantly influence surface electrostatic potentials of the assembled organic template for nucleation.
2017 ACC/AHA/HRS Guideline for the Evaluation and Management of Patients With Syncope
Authors: Win-Kuang Shen, Robert S. Sheldon, David G. Benditt, Mitchell I. Cohen, Daniel E. Forman, Zachary D. Goldberger, Blair P. Grubb, Mohamed H. Hamdan, Andrew D. Krahn, Mark S. Link, Brian Olshansky, Satish R. Raj, Roopinder Kaur Sandhu, Dan Sorajja, Benjamin C. Sun, Clyde W. Yancy
Journal: Journal of the American College of Cardiology (2017)
Abstract P3-03-10: Targeting Wnt/β-catenin pathway by antidepressant imipramine for triple negative breast cancer treatment
Authors: Subapriya Rajamanickam, Santosh Timilsina, Ismoil Jatoi, Virginia Kaklamani, Ratna K Vadlamudi, Manjeet K Rao
Journal: Cancer Research (2020)

Abstract Aberrant activation of Wnt signaling has been implicated in various human cancers including breast cancer. Several intra-cellular signal transduction pathways are induced by Wnt, notably by Wnt/β-catenin dependent pathway. In breast cancer, triple negative breast cancer (TNBC) subtypes have increased Wnt/β-catenin signaling associated with high grade tumors, metastasis, poor prognosis and tumor regression. Importantly, significant upregulation of Wnt/β-catenin pathway and overexpression of Wnt transcriptional targets have emerged in breast cancer stem cells (BCSCs) than normal mammary epithelial stem cells. Blockade of Wnt/β-catenin signaling has been reported to suppress breast cancer growth, invasion, migration and induced apoptosis and “stemness”. WNT pathway inhibition preferentially reduces stem cell like activity in patient-derived metastatic breast cancer compared to normal cells. Collectively, these studies suggest that Wnt/β-catenin pathway could be the potential target in inhibiting TNBC growth, metastatic progression and “stemness”. We recently identified that imipramine, an FDA approved antidepressant used to treat chronic depression, inhibits TNBC growth and progression. Imipramine treatment significantly reduced cell viability, migration and invasion of breast cancer cells in general and TNBC cells in particular. Our preliminary findings demonstrated that systemic delivery of imipramine suppressed TNBC growth in orthotopic mouse xenograft model. Our studies further show that imipramine inhibits several Wnt/β-catenin catenin pathway proteins including WNT1, FZD1, β-catenin, cyclin D1 and c-myc, which are reported to support breast cancer “stemness” and metastasis. Importantly, our preliminary studies revealed that imipramine inhibits TNBC stem cells as evidenced by reduced CD44+ population. Our results suggest the therapeutic efficacy of imipramine as a single/or neo-adjuvant agent for treating TNBC patients. Citation Format: Subapriya Rajamanickam, Santosh Timilsina, Ismoil Jatoi, Virginia Kaklamani, Ratna K Vadlamudi, Manjeet K Rao. Targeting Wnt/β-catenin pathway by antidepressant imipramine for triple negative breast cancer treatment [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-03-10.
Liver transplantation for combined hepatocellular-cholangiocarcinoma
Authors: Volkan Ince, Bora Barut, Adil Baskiran, Veysel Ersan, Fatih Gonultas, Fatih Ozdemir, Emrah Otan, Cemalettin Koc, Tolga Tevfik Sahin, Ramazan Kutlu, Cuneyt Kayaalp, Sezai Yilmaz
Journal: International Journal of Surgery (2020)
Maternal sucralose intake alters gut microbiota of offspring and exacerbates hepatic steatosis in adulthood
Authors: Xin Dai, Zixuan Guo, Danfeng Chen, Lu Li, Xueli Song, Tianyu Liu, Ge Jin, Yun Li, Yi Liu, Aihemaiti Ajiguli, Cheng Yang, Bangmao Wang, Hailong Cao
Journal: Gut Microbes (2020)

Background Nonalcoholic fatty liver disease (NAFLD) is considered to be associated with diet and gut dysbiosis. Excessive sucralose can induce gut dysbiosis and negatively affect host health. Maternal diet shapes the microbial communities of neonate and this effect continues in later life. We aimed to investigate the effects of maternal sucralose (MS) intake on the susceptibility of offspring to hepatic steatosis in adulthood.Methods C57BL/6 pregnant mice were randomized into MS group (MS during gestation and lactation) and maternal control (MC) group (MC diet). After weaning, all offspring were fed a control diet until 8 weeks of age, and then treated with a high-fat diet (HFD) for 4 weeks. The intestinal development, mucosal barrier function, and gut microbiota were assessed in the 3-week-old offspring. Moreover, the severity of hepatic steatosis, serum biochemistry, lipid metabolism, and gut microbiota was then assessed in the 12th week.Results MS significantly inhibited intestinal development and disrupted barrier function in 3-week-old offspring. MS also induced intestinal low-grade inflammation, significantly changed the compositions and diversity of gut microbiota including reducing butyrate-producing bacteria and cecal butyrate production with down-regulation of GPR43. Mechanically, blocking GPR43 blunted the anti-inflammatory effect of one of the butyrate-producing bacteria, Clostridium butyricum in vitro. After HFD treatment, MS exacerbated hepatic steatosis, and disturbed fatty acid biosynthesis and metabolism, accompanied by inducing gut dysbiosis compared with MC group.Conclusions MS intake inhibits intestinal development, induces gut dysbiosis in offspring through down-regulation of GPR43, and exacerbates HFD-induced hepatic steatosis in adulthood.
Middle hepatic vein (MHV) anatomy and late thrombosis, its effect on the outcomes in modified right lobe (MRL) grafts in living donor liver transplant (LDLT)
Authors: Bhargava Chikkala, Shaleen Agarwal, Selva Naganathan, Rajesh Dey, Rajashekar Kandagaddala, Subhash Gupta
Journal: International Journal of Surgery (2020)
Meaningful survival benefit for single lung transplantation in idiopathic pulmonary fibrosis patients over 65 years of age
Authors: Peter Riddell, Jana Kleinerova, Donna Eaton, David G. Healy, Hossein Javadpour, Jim F. McCarthy, Lars Nolke, Karen C. Redmond, Jim J. Egan
Journal: European Respiratory Journal (2020)

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease that results in progressive respiratory failure and death. Antifibrotic therapy has been shown to slow disease progression [1, 2]. For many patients [3], lung transplantation is the only intervention recognised to provide significant survival benefit [4]. IPF commonly affects older patients, with a median age at diagnosis of 66 years old [5]. Without transplantation, the median survival from diagnosis is 2–4 years [5]. However, registry data indicates impaired outcomes following lung transplantation for older patients 6]. These data have prompted many centres in Europe to avoid offering transplantation to older IPF patients. This study demonstrates a clinically meaningful survival benefit of lung transplantation for IPF patients aged ≥65 years <http://bit.ly/39pwH2h>
Mortality in biopsy-proven alcohol-related liver disease: a population-based nationwide cohort study of 3453 patients
Authors: Hannes Hagström, Maja Thiele, Bjorn Roelstraete, Jonas Söderling, Jonas F Ludvigsson
Journal: Gut (2020)

Objective Patients with alcohol-related liver disease (ALD) are at increased risk of death, but studies have rarely investigated the significance of histological severity or estimated relative risks compared with a general population. We examined mortality in a nationwide cohort of biopsy-proven ALD. Design Population-based cohort study in Sweden comparing 3453 individuals with an International Classification of Disease (ICD) code for ALD and a liver biopsy from 1969 to 2017 with 16 535 matched general population individuals. Swedish national registers were used to ascertain overall and disease-specific mortality, starting follow-up at the latest of first ICD diagnosis or liver biopsy plus 3 months. Cox regression adjusted for relevant confounders was used to estimate HRs in ALD and histopathological subgroups. Results Median age at diagnosis was 58 years, 65% were men and 52% had cirrhosis at baseline. Five-year cumulative mortality was 40.9% in patients with ALD compared with 5.8% in reference individuals. The risk for overall mortality was significantly increased (adjusted HR (aHR)=4.70, 95% CI 4.35 to 5.08). The risk of liver-related death was particularly high (43% of all deaths, aHR=167.6, 95% CI 101.7 to 276.3). Mortality was significantly increased also in patients with ALD without cirrhosis and was highest in the first year after baseline but persisted after ≥10 years of follow-up (aHR=2.74, 95% CI 2.37 to 3.16). Conclusion Individuals with biopsy-proven ALD have a near fivefold increased risk of death compared with the general population. Individuals with ALD without cirrhosis were also at increased risk of death, reaffirming the need to increase vigilance in the management of these individuals.
Abstract P3-03-01: Double <i>PIK3CA</i> mutations in <i>cis</i> drive oncogene addiction and enhance sensitivity to PI3K alpha inhibitors in breast cancer
Authors: Neil Vasan, Pedram Razavi, Jared L Johnson, Hong Shao, Timothy Wilson, Frauke Schimmoller, Hardik Shah, Alesia Antoine, Erik Ladewig, Alexander Gorelick, Ting-Yu Lin, Eneda Toska, Guotai Xu, Abiha Kazmi, Matthew T Chang, Barry S. Taylor, Maura N. Dickler, Komal Jhaveri, Sarat Chandarlapaty, Raul Rabadan, Ed Reznik, Melissa L Smith, Robert Sebra, Lori Friedman, Lewis C Cantley, Maurizio Scaltriti, José Baselga
Journal: Cancer Research (2020)

Abstract Activating mutations in PIK3CA, the gene coding for the catalytic subunit (p110α) of phosphoinositide-3-kinase (PI3K), are the most frequent oncogenic alterations in estrogen receptor-positive (ER+) breast cancer and are also prevalent in other tumor types. PI3Kα inhibitors including alpelisib have recently been shown to be clinically active in ER+ PIK3CA mutant breast cancer. To characterize determinants of sensitivity to these agents, we undertook a comprehensive analysis of PIK3CA mutant cancer genomes and observed the presence of double PIK3CA mutations in 12-15% of breast cancer and other tumor types. These double PIK3CA mutations are clonal, located in cis on the same allele, and are composed of a single hotspot mutation combined with a recurrent second-site mutation. Double PIK3CA mutations in cis result in increased PI3K activity and downstream signaling together with enhanced cell proliferation and tumor growth compared to single hotspot mutations. The biochemical mechanisms underlying this increased oncogenicity include increased disruption of p110α binding to the inhibitory subunit p85α, which relieves its catalytic inhibition, and increased membrane lipid binding. Finally, these double PIK3CA mutations predict for increased sensitivity to PI3Kα inhibitors compared to single hotspot mutations (e.g. E545K or H1047R) in experimental models and in patients with ER+ PIK3CA mutant metastatic breast cancer from the SANDPIPER randomized phase III clinical trial. These findings implicate double PIK3CA mutations in cis as a novel mechanism of oncogene addiction relative to single hotspot mutations, providing a rationale to develop PI3Kα inhibitors for the therapy of double PIK3CA mutant cancers. Citation Format: Neil Vasan, Pedram Razavi, Jared L Johnson, Hong Shao, Timothy Wilson, Frauke Schimmoller, Hardik Shah, Alesia Antoine, Erik Ladewig, Alexander Gorelick, Ting-Yu Lin, Eneda Toska, Guotai Xu, Abiha Kazmi, Matthew T Chang, Barry S. Taylor, Maura N. Dickler, Komal Jhaveri, Sarat Chandarlapaty, Raul Rabadan, Ed Reznik, Melissa L Smith, Robert Sebra, Lori Friedman, Lewis C Cantley, Maurizio Scaltriti, José Baselga. Double PIK3CA mutations in cis drive oncogene addiction and enhance sensitivity to PI3K alpha inhibitors in breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-03-01.
Abstract C10: Glutamine deprivation triggers hexosamine salvage in pancreatic cancer cells
Authors: Sydney L. Campbell, Clementina A. Mesaros, Tiffany Tsang, Michael Noji, Salisa Kruijning, Sophie Trefely, Luke Izzo, Ian A. Blair, Kathryn E. Wellen
Journal: Cancer Research (2019)

Abstract Pancreatic ductal adenocarcinoma (PDA) remains one of the most difficult cancers to effectively treat. Over 90% of PDA are driven by oncogenic KRAS, which leads to metabolic rewiring in the cell, including increased glucose uptake and increased flux through the hexosamine biosynthesis pathway (HBP). The HBP, which branches off from glycolysis at fructose-6-phosphate and also requires glutamine, acetyl-CoA, and uridine triphosphate, is responsible for synthesizing uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), a major substrate for glycosylation in the cell. UDP-GlcNAc can also be generated through recycling of GlcNAc via N-acetylglucosamine kinase (NAGK). Glycans are important for maintaining protein homeostasis and cell signaling. However, while there is increased HBP flux in PDA and glycosylation is elevated in a range of cancers, how this is regulated and the functional significance of increased glycosylation in cancer are not well understood. Because of the multiple metabolic inputs required for UDP-GlcNAc synthesis, the HBP has been proposed as a nutrient sensing pathway. Surprisingly, however, we found that PDA cells robustly maintain both O-GlcNAc and N-glycosylation when exposed to nutrient deprivation. The enzyme N-acetylglucosamine kinase (NAGK) is upregulated under low glutamine conditions, and through stable isotope tracing studies, we demonstrate that PDA cells are able to switch to use of the salvage pathway over the HBP for generation and maintenance of the UDP-GlcNAc pool via NAGK. Together, this work points to a mechanism of metabolic flexibility in generating UDP-GlcNAC that allows PDA cells to grow in a nutrient-poor environment. Citation Format: Sydney L. Campbell, Clementina A. Mesaros, Tiffany Tsang, Michael Noji, Salisa Kruijning, Sophie Trefely, Luke Izzo, Ian A. Blair, Kathryn E. Wellen. Glutamine deprivation triggers hexosamine salvage in pancreatic cancer cells [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr C10.
Abstract P5-01-02: Identification and validation of a serum microRNA panel for detection of early-stage breast cancer
Authors: Lihan Zhou, Ruiyang Zou, Sau Yeen Loke, Mikael Hartman, Patrick C.K Goo, Ann S.G. Lee-Lim, Heng-Phon Too
Journal: Cancer Research (2020)

Abstract Background: Survival outcomes of breast cancer patients can be significantly improved by early detection and treatment. Implementation of mammogram-based screening has significantly improved early detection of breast cancer in the west. However, the use of screening mammography is less prevalent in Asia partly due to social and cultural reasons. The aim of this study was to determine if a serum microRNA (miRNA) panel could be used as blood-based biomarkers to assist in the early detection of breast cancer. Methods: We carried out a multi-center, multi-ethnic study to identify and validate miRNA biomarkers for the early detection of breast cancer. A total of 1042 subjects including 540 breast cancer cases (predominantly stage 1 and 2 cases) and 502 matched controls from 6 independent sources were included in this study. Among these, there were 750 American and European subjects recruited by biobanks and 292 Singaporean Asian Subjects recruited at the National Cancer Centre Singapore and the National University Hospital. The study was conducted in 3 phases in which sera of 289 European Caucasian serum samples (Discovery Cohort) were first interrogated to identify differentially expressed miRNAs between early-stage breast cancer cases and matched controls among 520 circulating miRNA candidates by quantitative RT-PCR using MiRXES assays. The remaining 753 subjects from 5 independent sources were assigned into two groups for biomarker optimization/algorithm development (Optimization Cohort, n=374) and validation (Validation Cohort, n=379). Results: Among the 520 circulating miRNAs measured, 241 were quantified in absolute copy numbers for 289 subjects in the Discovery Cohort. Thirty-three candidate miRNAs were identified. These miRNAs consistently showed differential expression between cancer and control subjects in the Optimization Cohort. A multi-variant panel of 8 miRNAs and an algorithm was developed using the Discovery and Optimization Cohort, with an AUC of 0.981 and 0.918 respectively. When validated in the independent Validation Cohort, the panel demonstrated an AUC of 0.915. Conclusion: We developed and validated a serum miRNA panel that is both sensitive (72.2 - 77.4%) and specific (90.2 - 91.5%) in detecting early stage of breast cancer in both Caucasian and Asian populations. Citation Format: Lihan Zhou, Ruiyang Zou, Sau Yeen Loke, Mikael Hartman, Patrick C.K Goo, Ann S.G. Lee-Lim, Heng-Phon Too. Identification and validation of a serum microRNA panel for detection of early-stage breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-01-02.
Sub-megabase resolution array CGH profiling of small cell lung cancer cell lines.
Authors: Bradley P. Coe, Eric Lee, Adi F. Gazdar, John D. Minna, Stephen Lam, Calum Macaulay, Wan L. Lam
Journal: Cancer Research (2004)

3430  Background: Small cell lung cancer (SCLC) accounts for 20% of the yearly cases of lung cancer in the United States. Survival rates for this disease have improved little over the last 20 years with median survival times of only 7-13 months. This may in part be due to the high frequency of relapse with resistant micrometastatic disease after initial chemotherapy. The identification of molecular targets for prognosis and therapy of the disease may be crucial in improving survival rates of SCLC. Array comparative genomic hybridization (aCGH) is a new method for detecting genomic alterations in human cancers, which may allow the rapid discovery of novel genes involved in tumorigenesis. We have designed a CGH array which represents a >100-fold increase in resolution over conventional metaphase CGH allowing for genome-wide identification of genetic alterations at a resolution of 100kbp. Objectives: To identify novel genetic alterations in SCLC cell lines by high resolution copy number profiling of the entire human genome. Design: Utilizing a human whole-genome 32,433 overlapping BAC clone set we have created a CGH array spanning the entire genome at an average density of 10 clones per megabase. This array was then used to profile 15 SCLC cell lines for copy number changes. Sample DNA was labeled with cyanine 5 through a random priming reaction and co-hybridized with a cyanine 3 labeled reference DNA to the arrays. Post-hybridization the arrays were scanned using a CCD based imaging system from Applied Precision. Signal ratios were then determined using the Softworx array analysis program. Results: We have delineated breakpoints in SCLC lines to within one BAC clone in single experiments. This high resolution profiling has allowed us to identify both the expected alterations at loci such as hTERT, ATM and MYC as well as novel micro-amplifications and deletions as small as 200kb that have not been detected by conventional methodologies. This has allowed us to rapidly identify novel candidate genes associated with SCLC tumorigenesis. Conclusions High resolution genome wide array CGH has allowed the rapid identification of novel candidate genes associated with lung cancer tumorigenesis. This work was supported by grants from Genome Canada/B.C., NCIC Terry Fox New Frontiers, and Lung SPORE P50 CA70907.
The legacy of Professor Aron Goldhirsch
Authors: R.D. Gelber, A.S. Coates, S. Gelber, R. Orecchia, P. Veronesi, A. Di Leo, M. Colleoni, E.P. Winer, H.J. Burstein, G. Viale, H.-J. Senn, M. Piccart, G. Curigliano
Journal: Annals of Oncology (2020)