tbuckley/cabot-search huggingface dataset:
Lipopolysaccharide Reverses Hepatic Stellate Cell Activation Through Modulation of cMyb, Small Mothers Against Decapentaplegic, and CCAAT/Enhancer‐Binding Protein C/EBP Transcription Factors
Authors: Akanksha Sharma, Alok K. Verma, Matthew Kofron, Ramesh Kudira, Alexander Miethke, Tong Wu, Jiang Wang, Chandrashekhar R. Gandhi
Journal: Hepatology (2020)

Background and Aims During liver injury, quiescent hepatic stellate cells (qHSCs) transdifferentiate into proliferative and fibrogenic activated myofibroblastic phenotype (activated hepatic stellate cell; aHSCs) expressing smooth muscle α‐actin (αSMA) and platelet‐derived growth factor beta receptor (PDGFβR). Their interactions with gut‐derived bacterial lipopolysaccharide (LPS) are implicated in hepatic fibrogenesis. However, LPS can also attenuate fibrogenic characteristics of aHSCs. Approach and Results We examined molecular mechanisms of antifibrogenic effects of LPS on aHSCs in vitro and in vivo . Culture‐activated rat HSCs were exposed to 0‐100 ng/mL of LPS or its active component, diphosphoryl‐lipid A (DPLA), and parameters of fibrosis and inflammatory cytokines/chemokines were determined by qRT‐PCR, western, and immunohistochemical analyses. In vivo , HSCs were activated by repeated CCl 4 administration to rats every 3 days for 3 or 8 weeks, then challenged with LPS (5 mg/kg; IP). HSCs were isolated 24 hours later, and fibrogenic/inflammatory parameters were analyzed. LPS induced phenotypic changes in aHSCs (rounding, size reduction) and loss of proliferation. LPS down‐regulated expression of αSMA, PDGFβR, transforming growth factor beta receptor 1 (TGFβR1), collagen 1α1 (Col1α1), and fibronectin while up‐regulating tumor necrosis factor alpha, interleukin‐6, and C‐X‐C motif chemokine ligand 1 expression. LPS did not increase peroxisome proliferation‐activated receptor gamma expression or lipid accumulation typical of qHSCs. DPLA elicited the same effects as LPS on aHSCs, indicating specificity, and monophosphoryl lipid A down‐regulated fibrogenic markers, but elicited very weak inflammatory response. LPS down‐regulated the expression of cMyb, a transcription factor for αSMA, and up‐regulated small mother against decapentaplegic (SMAD)7 and CCAAT/enhancer‐binding protein (C/EBP)δ, the transcriptional inhibitors of Col1α1 expression. In vivo LPS treatment of aHSCs inhibited their proliferation, down‐regulated PDGFβR, αSMA, TGFβR1, Col1α1, and cMyb expression, and increased expression of SMAD7, C/EBPα, and C/EBPδ. Conclusions In conclusion, LPS induces a unique phenotype in aHSCs associated with down‐regulation of key fibrogenic mechanisms and thus may have an important role in limiting fibrosis.
Meta-Analysis of Relationship between Skin Rash and Outcome in Non-Small-Cell Lung Cancer (NSCLC) Patients Treated with Erlotinib (E) and Gefitinib (G)
Authors: K.F. Borgonovo, F. Petrelli, M. Cabiddu, M. Ghilardi, M. Cremonesi, F. Maspero, S. Barni
Journal: Annals of Oncology (2012)
EDTA-Modified 17β-Estradiol-Laden Upconversion Nanocomposite for Bone-Targeted Hormone Replacement Therapy for Osteoporosis
Authors: Xiaoting Chen, Xingjun Zhu, Yan Hu, Wei Yuan, Xiaochen Qiu, Tianyuan Jiang, Chao Xia, Liqin Xiong, Fuyou Li, Yanhong Gao
Journal: Theranostics (2020)

Hormone therapy (HT) is one of the most effective treatments for osteoporosis.However, the nonselective accumulation of hormone in organs such as breast, heart and uterus other than bones causes serious side effects, which impedes the application of HT.Hence, it is critically important to develop a HT strategy with reduced non-specific enrichment of hormone drugs in non-target tissues and enhanced bone-targeting ability.Methods: Herein, a 17β-estradiol (E2)-laden mesoporous silica-coated upconversion nanoparticle with a surface modification of ethylenediaminetetraacetic acid (EDTA) (NaLuF4:Yb,Tm@NaLuF4@ mSiO2-EDTA-E2, E2-csUCNP@MSN-EDTA) is developed for bone-targeted osteoporosis hormone therapy.EDTA was attached onto the surface of E2 upconversion nanocomposite to enhance its affinity and efficiency targeting bone tissue and cells to optimize hormone replacement therapy for osteoporosis.We characterized the size, cytotoxicity, loading and release efficiency, in situ and ex vivo imaging.Further, in vitro and in vivo osteogenic ability was tested using preosteoblast and ovariectomy mouse model of osteoporosis. Results:The upconversion core of E2-csUCNP@MSN-EDTA nanoparticle serves as an excellent imaging agent for tracking the loaded hormone drug in vivo.The mesoporous silica layer has a high loading efficiency for E2 and provides a relatively long-lasting drug release within 50 h.EDTA anchored on the silica layer endows the nanocomposite with a bone targeting property.The nanocomposite effectively reverses estrogen deficiency-induced osteoporosis and reduces the damage of hormone to the uterus.The bone mineral density in the nanocomposite treatment group is nearly twice that of the ovariectomized (OVX) group.Compared with the E2 group, the uterine weight and luminal epithelial height were significantly lower in the nanocomposite treatment group.Conclusion: This work demonstrated that E2-csUCNP@MSN-EDTA alleviates the side effect of hormone therapy while maintaining its therapeutic efficacy, which has great potential for developing the next generation of methods for osteoporosis treatment.
Cyber security threats in the microbial genomics era: implications for public health
Authors: Iliya Fayans, Yair Motro, Lior Rokach, Yossi Oren, Jacob Moran-Gilad
Journal: Eurosurveillance (2020)

Next generation sequencing (NGS) is becoming the new gold standard in public health microbiology. Like any disruptive technology, its growing popularity inevitably attracts cyber security actors, for whom the health sector is attractive because it combines mission-critical infrastructure and high-value data with cybersecurity vulnerabilities. In this Perspective, we explore cyber security aspects of microbial NGS. We discuss the motivations and objectives for such attack, its feasibility and implications, and highlight policy considerations aimed at threat mitigation. Particular focus is placed on the attack vectors, where the entire process of NGS, from sample to result, could be vulnerable, and a risk assessment based on probability and impact for representative attack vectors is presented. Cyber attacks on microbial NGS could result in loss of confidentiality (leakage of personal or institutional data), integrity (misdetection of pathogens) and availability (denial of sequencing services). NGS platforms are also at risk of being used as propagation vectors, compromising an entire system or network. Owing to the rapid evolution of microbial NGS and its applications, and in light of the dynamics of the cyber security domain, frequent risk assessments should be carried out in order to identify new threats and underpin constantly updated public health policies.
Abstract 17567: Low Expression of a Mesenchymal Stem Cell Marker CD271 in Peripheral Blood in Acute Coronary Syndrome Predicts Repetitive Coronary Interventions at de novo Lesions
Authors: Shinichiro Takashima, Soichiro Usui, Oto Inoue, Takeshi Kato, Hisayoshi Murai, Hiroshi Furusho, Kazuo Usuda, Koji Kubota, Shuichi Kaneko, Masayuki Takamura
Journal: Circulation (2017)

Introduction: Despite statin therapy, the residual risk of repetitive coronary events at new lesions is a problem to be solved. Circulating progenitor cells or stem cells such as endothelial progen...
Dual Oxidase-Induced Sustained Generation of Hydrogen Peroxide Contributes to Pharmacologic Ascorbate-Induced Cytotoxicity
Authors: Adrienne R. Gibson, Brianne R. O'Leary, Juan Du, Ehab H. Sarsour, Amanda L. Kalen, Brett A. Wagner, Jeffrey M. Stolwijk, Kelly C. Falls-Hubert, Matthew S. Alexander, Rory S. Carroll, Douglas R. Spitz, Garry R. Buettner, Prabhat C. Goswami, Joseph J. Cullen
Journal: Cancer Research (2020)

Abstract Pharmacologic ascorbate treatment (P-AscH−, high-dose, intravenous vitamin C) results in a transient short-term increase in the flux of hydrogen peroxide that is preferentially cytotoxic to cancer cells versus normal cells. This study examines whether an increase in hydrogen peroxide is sustained posttreatment and potential mechanisms involved in this process. Cellular bioenergetic profiling following treatment with P-AscH− was examined in tumorigenic and nontumorigenic cells. P-AscH− resulted in sustained increases in the rate of cellular oxygen consumption (OCR) and reactive oxygen species (ROS) in tumor cells, with no changes in nontumorigenic cells. Sources for this increase in ROS and OCR were DUOX 1 and 2, which are silenced in pancreatic ductal adenocarcinoma, but upregulated with P-AscH− treatment. An inducible catalase system, to test causality for the role of hydrogen peroxide, reversed the P-AscH−–induced increases in DUOX, whereas DUOX inhibition partially rescued P-AscH−–induced toxicity. In addition, DUOX was significantly downregulated in pancreatic cancer specimens compared with normal pancreas tissues. Together, these results suggest that P-AscH−–induced toxicity may be enhanced by late metabolic shifts in tumor cells, resulting in a feed-forward mechanism for generation of hydrogen peroxide and induction of metabolic stress through enhanced DUOX expression and rate of oxygen consumption. Significance: A high dose of vitamin C, in addition to delivering an acute exposure of H2O2 to tumor cells, activates DUOX in pancreatic cancer cells, which provide sustained production of H2O2.
In vitro corrosion resistance of layer-by-layer assembled polyacrylic acid multilayers induced Ca–P coating on magnesium alloy AZ31
Authors: Lan-Yue Cui, Shen-Cong Cheng, Lu-Xian Liang, Jing-Chao Zhang, Shuo-Qi Li, Zhen-Lin Wang, Rong-Chang Zeng
Journal: Bioactive Materials (2020)

Biodegradable magnesium (Mg)-based alloys have aroused great concern owing to their promising characteristics as temporary implants for orthopedic application. But their undesirably rapid corrosion rate under physiological conditions has limited the actual clinical application. This study reports the use of a novel biomimetic polyelectrolyte multilayer template, based on polyvinylpyrrolidone (PVP) and polyacrylic acid (PAA) via layer-by-layer (LbL) assembly, to improve the corrosion resistance of the alloy. Surface characterization techniques (field-emission scanning electron microscopy, Fourier transform infrared (FTIR) spectrophotometer and X-ray diffractometer) confirmed the formation of biomineralized Ca–P coating on AZ31 alloy. Both hydrogen evolution and electrochemical corrosion tests demonstrated that the corrosion protection of the polyelectrolyte-induced Ca–P coating on AZ31 alloy. The formation mechanism of biomineralized Ca–P coating was proposed.
Targeted Brain Tumor Radiotherapy Using an Auger Emitter
Authors: Giacomo Pirovano, Stephen A. Jannetti, Lukas M. Carter, Ahmad Sadique, Susanne Kossatz, Navjot Guru, Paula Demétrio De Souza França, Masatomo Maeda, Brian M. Zeglis, Jason S. Lewis, John L. Humm, Thomas Reiner
Journal: Clinical Cancer Research (2020)

Abstract Purpose: Glioblastoma multiforme is a highly aggressive form of brain cancer whose location, tendency to infiltrate healthy surrounding tissue, and heterogeneity significantly limit survival, with scant progress having been made in recent decades. Experimental Design: 123I-MAPi (Iodine-123 Meitner-Auger PARP1 inhibitor) is a precise therapeutic tool composed of a PARP1 inhibitor radiolabeled with an Auger- and gamma-emitting iodine isotope. Here, the PARP inhibitor, which binds to the DNA repair enzyme PARP1, specifically targets cancer cells, sparing healthy tissue, and carries a radioactive payload within reach of the cancer cells' DNA. Results: The high relative biological efficacy of Auger electrons within their short range of action is leveraged to inflict DNA damage and cell death with high precision. The gamma ray emission of 123I-MAPi allows for the imaging of tumor progression and therapy response, and for patient dosimetry calculation. Here we demonstrated the efficacy and specificity of this small-molecule radiotheranostic in a complex preclinical model. In vitro and in vivo studies demonstrate high tumor uptake and a prolonged survival in mice treated with 123I-MAPi when compared with vehicle controls. Different methods of drug delivery were investigated to develop this technology for clinical applications, including convection enhanced delivery and intrathecal injection. Conclusions: Taken together, these results represent the first full characterization of an Auger-emitting PARP inhibitor which demonstrate a survival benefit in mouse models of GBM and confirm the high potential of 123I-MAPi for clinical translation.
Drug Coated Balloon Angioplasty in Peripheral Vasculature: Review of Literature
Authors: Valerie F. Civelli, Vincent Ngo, Mukul Anand, Ojas Sharma, Sarabjeet Singh, Sanjiv Sharma
Journal: Clinical Cardiology and Cardiovascular Interventions (2019)

Drug-coated balloons (DCB) are commonly used to treat peripheral artery disease (PAD) and are often used in combination with or in place of a stent or rotational atherectomy. DCB’s are manufactured with the drug, Paclitaxel with the first-line indication of preventing restenosis of arteries following an intervention. Recent literature has suggested an increased mortality risk at years 2 and 5 post DCB angioplasty. Inspired by Katsanos et al. and their important work in researching outcomes for DCBs in PAD, we conducted a thorough review of all literature to compile an informed conclusion.
Long-Term LV Characterization Using CMR in Patients With Spontaneous Coronary Artery Dissection
Authors: Felipe Diez-Delhoyo, Ricardo Sanz-Ruiz, Esther Perez-David, Enrique Gutierrez-Ibañes, Hugo González-Saldivar, Maria Jesus Ledesma-Carbayo, Maria Eugenia Vazquez-Alvarez, Ana Gonzalez-Mansilla, Javier Soriano, Jose Angel Quiroz-Burgos, Jaime Elizaga, Raquel Prieto-Arevalo, Maria Angeles Espinosa, Pablo Martínez-Legazpi, Javier Bermejo, Francisco Fernandez-Aviles
Journal: JACC. Cardiovascular imaging (2020)
Abstract ES11-3: Local treatments in patients who achieve pathologic complete response
Authors: J White
Journal: Cancer Research (2020)

Abstract Local regional treatment of breast cancer has been historically based on anatomic extent of disease in the breast and ipsilateral axilla at presentation. An adjustment in this paradigm is evolving as more breast cancer patients receive neoadjuvant systemic therapy with increasingly more effective agents leading to higher rates of pathologic complete response. In the neoadjuvant setting, breast cancer subtype and pathologic complete response (pCR) may prove to have similar influence on local regional treatment as anatomic stage at presentation. In the ALLIANCE-ACOSOG 1071 clinical trial, rates of pCR (breast and axilla) were highest in the triple-negative (38.2%) and HER2-positive (45.4%) cases and similarly had the highest breast conservation rates of 46.3% and 43.8%, respectively. In addition, breast cancer patients that present with clinical N1 axillary involvement and have complete pathologic response can potentially avoid axillary node dissection with careful use of sentinel node biopsy based on the Sentina and SN FNAC trials. It may be that surgical resection will prove unnecessary for breast conservation in select cases with complete clinical and imaging response when breast radiation is intended and clinical trials are underway. Radiation therapy indications have likewise been established from extent of disease when surgery is the first line of therapy. Retrospective analyses of local regional recurrence incidence in neoadjuvant chemotherapy clinical trials demonstrates it is lowest in those with pathologic compete response in the breast and axillary nodes; as shown in a combined analysis of the NSABP B18 and 27 trials and again seen from analysis of the EORTC 10994/ BIG 1-00 trial. The ongoing NRG NSABP B51 RTOG 1304 clinical trial will determine if regional nodal irradiation is beneficial if positive axillary nodes at presentation convert to negative by neoadjuvant chemotherapy. Complete pathologic response may allow complete omission of post mastectomy radiation in some settings as well reduced extent of breast radiation following breast-conserving surgery. Citation Format: J White. Local treatments in patients who achieve pathologic complete response [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 ES11-3.
Abstract 18446: Reciprocating Bigeminy: A Possible Mechanism of Bidirectional Ventricular Tachycardia
Authors: Alex A Baher, Matthew J Uy, Zhilin Qu, Alan Garfinkel, James N Weiss
Journal: Circulation (2010)

Bidirectional ventricular tachycardia (BVT), characterized by alternating electrocardiographic QRS axis on alternate beats, is a rare but intriguing arrhythmia associated with digitalis toxicity, f...
Genotype‐phenotype correlation and molecular heterogeneity in pyruvate kinase deficiency
Authors: Paola Bianchi, Elisa Fermo, Kimberly Lezon‐Geyda, Eduard J. van Beers, Holmes D. Morton, Wilma Barcellini, Bertil Glader, Satheesh Chonat, Yaddanapudi Ravindranath, Peter E. Newburger, Nina Kollmar, Jenny M. Despotovic, Madeleine Verhovsek, Mukta Sharma, Janet L. Kwiatkowski, Kevin H. M. Kuo, Marcin W. Wlodarski, Hassan M. Yaish, Susanne Holzhauer, Heng Wang, Joachim Kunz, Kathryn Addonizio, Hasan Al‐Sayegh, Wendy B. London, Oliver Andres, Richard van Wijk, Patrick G. Gallagher, Rachael F. F. Grace
Journal: American Journal of Hematology (2020)

Pyruvate kinase (PK) deficiency is a rare recessive congenital hemolytic anemia caused by mutations in the PKLR gene. This study reports the molecular features of 257 patients enrolled in the PKD Natural History Study. Of the 127 different pathogenic variants detected, 84 were missense and 43 non-missense, including 20 stop-gain, 11 affecting splicing, five large deletions, four in-frame indels, and three promoter variants. Within the 177 unrelated patients, 35 were homozygous and 142 compound heterozygous (77 for two missense, 48 for one missense and one non-missense, and 17 for two non-missense variants); the two most frequent mutations were p.R510Q in 23% and p.R486W in 9% of mutated alleles. Fifty-five (21%) patients were found to have at least one previously unreported variant with 45 newly described mutations. Patients with two non-missense mutations had lower hemoglobin levels, higher numbers of lifetime transfusions, and higher rates of complications including iron overload, extramedullary hematopoiesis, and pulmonary hypertension. Rare severe complications, including lower extremity ulcerations and hepatic failure, were seen more frequently in patients with non-missense mutations or with missense mutations characterized by severe protein instability. The PKLR genotype did not correlate with the frequency of complications in utero or in the newborn period. With ICCs ranging from 0.4 to 0.61, about the same degree of clinical similarity exists within siblings as it does between siblings, in terms of hemoglobin, total bilirubin, splenectomy status, and cholecystectomy status. Pregnancy outcomes were similar across genotypes in PK deficient women. This report confirms the wide genetic heterogeneity of PK deficiency.
Polyploidy in Cardiomyocytes
Authors: Wouter Derks, Olaf Bergmann
Journal: Circulation Research (2020)

The hallmark of most cardiac diseases is the progressive loss of cardiomyocytes. In the perinatal period, cardiomyocytes still proliferate, and the heart shows the capacity to regenerate upon injury. In the adult heart, however, the actual rate of cardiomyocyte renewal is too low to efficiently counteract substantial cell loss caused by cardiac injury. In mammals, cardiac growth by cell number expansion changes to growth by cardiomyocyte enlargement soon after birth, coinciding with a period in which most cardiomyocytes increase their DNA content by multinucleation and nuclear polyploidization. Although cardiomyocyte hypertrophy is often associated with these processes, whether polyploidy is a prerequisite or a consequence of hypertrophic growth is unclear. Both the benefits of cardiomyocyte enlargement over proliferative growth of the heart and the physiological role of polyploidy in cardiomyocytes are enigmatic. Interestingly, hearts in animal species with substantial cardiac regenerative capacity dominantly comprise diploid cardiomyocytes, raising the hypothesis that cardiomyocyte polyploidy poses a barrier for cardiomyocyte proliferation and subsequent heart regeneration. On the contrary, there is also evidence for self-duplication of multinucleated myocytes, suggesting a more complex picture of polyploidy in heart regeneration. Polyploidy is not restricted to the heart but also occurs in other cell types in the body. In this review, we explore the biological relevance of polyploidy in different species and tissues to acquire insight into its specific role in cardiomyocytes. Furthermore, we speculate about the physiological role of polyploidy in cardiomyocytes and how this might relate to renewal and regeneration.
Abstract PD8-08: Characterization of spatial and temporal heterogeneity of ER positive metastatic breast cancer using serial biopsies
Authors: Read K. Allen, Christopher J. Pinto, Donna M. Fitzgerald, Tiffany G. Huynh, Christopher T. Chen, Dejan Juric
Journal: Cancer Research (2020)

Abstract Background: Metastatic breast cancer is characterized by a remarkable level of temporal and spatial heterogeneity. Management decisions based on a single tissue biopsy are therefore inherently limited by sampling bias and by dynamic changes in the receptor status and the mutational profile of the tumor. Methods: We characterized 41 serially enrolled patients on the tissue collection protocol DFHCC 13-416, who had ER+/HER2- breast cancer at the time of diagnosis of early stage disease. Results: 36 out of 41 patients (87.8%) had at least one biopsy in the metastatic setting. The number of biopsies in the metastatic setting ranged from one to seven. Two most frequently biopsied sites were liver (24.4%) and recurrent breast lesions (22.0%). Six out of 41 patients (14.6%) developed ER loss over the course of treatment. Estrogen receptor status conversions were noted in both the liver and in the recurrent breast lesions. PR loss was far more common, noted in 24 out of 41 patients (58.5%). Nine of these patients (21.9%) were PR negative at the time of diagnosis and an additional 15 patients (36.6%) lost PR expression during the course of their therapy. Median time to the loss of ER expression was 6.83 years from the initial diagnosis, while the median time to the loss of PR expression was 4.97 years, consistent with sequential decrease in ER dependence, resulting in loss of PR expression and increased dependence on other survival pathways. Genomic and transcriptomic profiling of all serially collected tissues with reconstruction of phylogenetic trees is ongoing and will be presented at the meeting. Conclusions: Compared to previously published reports, high proportion of patients in this cohort had their metastatic disease confirmed and subsequently followed by serial biopsies. In majority of patients, receptor status changes follow a predictable pattern starting with loss of PR expression, followed by complete loss of ER expression. Concomitant changes in the mutation status of both ER and other co-mutated genes, as well as any associated transcriptomic changes may shed light into new interdependencies and vulnerabilities associated with these dynamic receptor status changes. Citation Format: Read K. Allen, Christopher J. Pinto, Donna M. Fitzgerald, Tiffany G. Huynh, Christopher T. Chen, Dejan Juric. Characterization of spatial and temporal heterogeneity of ER positive metastatic breast cancer using serial biopsies [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 PD8-08.