tbuckley/cabot-search huggingface dataset:
Towards a new era in medicine: therapeutic genome editing
Authors: Matthew H. Porteus
Journal: Genome biology (2015)

Genome editing is the process of precisely modifying the nucleotide sequence of the genome. It has provided a powerful approach to research questions but, with the development of a new set of tools, it is now possible to achieve frequencies of genome editing that are high enough to be useful therapeutically. Genome editing is being developed to treat not only monogenic diseases but also infectious diseases and diseases that have both a genetic and an environmental component.
Regulation of Cholesterol Homeostasis by Hedgehog Signaling in Osteoarthritic Cartilage
Authors: Shabana Amanda Ali, Mushriq Al‐Jazrawe, Henry Ma, Heather Whetstone, Raymond Poon, Sarah Farr, Mark Naples, Khosrow Adeli, Benjamin A. Alman
Journal: Arthritis & Rheumatology (2015)

Objective With no effective therapies to attenuate cartilage degeneration in osteoarthritis (OA), the result is pain and disability. Activation of hedgehog (HH) signaling causes changes related to the progression of OA, with higher levels of Gli‐mediated transcriptional activation associated with increased disease severity. To elucidate the mechanism through which this occurs, this study sought to identify genes regulated by HH signaling in human OA chondrocytes. Methods Using human OA cartilage samples, microarray analyses were performed to detect changes in gene expression when the HH pathway was modulated. Results were analyzed for differentially expressed genes, grouped into functional networks, and validated in independent samples. To investigate the effects of chondrocyte‐specific sterol accumulation, we generated mice lacking Insig1 and Insig2 , which are major negative regulators of cholesterol homeostasis, under Col2a1 regulatory elements. Results HH signaling was found to regulate genes that govern cholesterol homeostasis, and this led to alterations in cholesterol accumulation in chondrocytes. A higher level of Gli‐mediated transcription resulted in accumulation of intracellular cholesterol. In genetically modified mice, chondrocyte‐specific cholesterol accumulation was associated with an OA phenotype. Reducing cholesterol accumulation attenuated the severity of OA in mice in vivo and decreased the expression of proteases in human OA cartilage in vitro. Conclusion HH signaling regulates cholesterol homeostasis in chondrocytes, and intracellular cholesterol accumulation contributes to the severity of OA. Our findings have therapeutic implications, since reduction of HH signaling reversed cholesterol accumulation and statin treatment attenuated cartilage degeneration.
CLIN-RADIATION THERAPY
Authors: W.-S. Yoon, J.-T. Kim, Y.-M. Han, D.-S. Chung, Y.-S. Park, K. J. Lizarraga, M. Allen-Auerbach, A. A. De Salles, W. H. Yong, W. Chen, M. I. Ruge, P. Kickingereder, T. Simon, H. Treuer, V. Sturm, P. R. D'Alessandro, J. Jarrett, S. A. Walling, I. G. Fleetwood, T. G. Kim, D. H. Lim, S. L. McGovern, D. Grosshans, M. F. McAleer, M. Chintagumpala, S. Khatua, T. Vats, A. Mahajan, P. D. Beauchesne, G. Faure, G. Noel, T. Schmitt, L. Martin, E. Jadaud, C. Carnin, A. Astradsson, P. M. a. Rosenschold, A. K. W. Lund, U. Feldt-Rasmussen, H. Roed, M. Juhler, N. Kumar, R. Kumar, S. C. Sharma, K. K. Mukherjee, N. Khandelwal, R. Kumar, P. K. Gupta, A. Bansal, R. Kapoor, S. Ghosal, C. L. Barney, A. P. Brown, M. C. Lowe, M. F. McAleer, D. R. Grosshans, J. F. de Groot, V. Puduvalli, M. R. Gilbert, T. S. Vats, P. D. Brown, A. Mahajan, B. E. Pollock, S. L. Stafford, M. J. Link, P. D. Brown, Y. I. Garces, R. L. Foote, S. Ryu, E. Y. Kim, R. Yechieli, J. K. Kim, T. Mikkelsen, S. Kalkanis, J. Rock, G. K. Prithviraj, P. Oppelt, L. Arfons, K. C. Cuneo, J. Vredenburgh, A. Desjardins, K. Peters, J. Sampson, Z. Chang, J. Kirkpatrick, S. K. Nath, A. D. Sheridan, P. J. Rauch, J. N. Contessa, J. B. Yu, J. P. Knisely, F. J. Minja, A. O. Vortmeyer, V. L. Chiang, M. Koto, A. Hasegawa, R. Takagi, G. Sasahara, H. Ikawa, T. Kamada, Y. Iwadate, M. Matsutani, A. A. Kanner, G. Sela, E. Gez, D. Matceyevsky, N. Strauss, B. W. Corn, D. G. Brachman, K. A. Smith, P. Nakaji, S. Sorensen, K. J. Redmond, E. M. Mahone, L. Kleinberg, S. Terezakis, T. McNutt, H. Agbahiwe, K. Cohen, M. Lim, M. Wharam, A. Horska, B. Amendola, A. Wolf, S. Coy, L. Blach, F. Mesfin, D. Suki, A. Mahajan, G. Rao, V. A. R. Palkonda, N. More, P. Ganesan, R. Kesavan, M. Shunmugavel, T. Kasirajan, V. R. Maram, S. Kakkar, P. Upadhyay, S. Das, S. Nigudgi, J. S. Katz, J. P. Knisely, M. Ghaly, M. Schulder, V. A. R. Palkonda, N. More, M. Shunmugavel, T. Kasirajan, P. Ganesan, S. Kakkar, V. R. Maram, S. Nigudgi, P. Upadhyay, S. Das, R. Kesavan, R. B. Taylor, P. E. Schaner, A. F. Dragovic, J. M. Markert, B. L. Guthrie, M. C. Dobelbower, S. A. Spencer, J. B. Fiveash, J. S. Katz, J. P. Knisely, M. Ghaly, M. Schulder, L. Chen, H. Guerrero-Cazares, E. Ford, T. McNutt, L. Kleinberg, M. Lim, A. Quinones-Hinojosa, K. Redmond, A. G. Wernicke, K. C. Chao, D. Nori, B. Parashar, M. Yondorf, J. A. Boockvar, S. Pannullo, P. Stieg, T. H. Schwartz, J. E. Leeman, D. A. Clump, J. C. Flickinger, S. A. Burton, A. H. Mintz, D. E. Heron, S. H. O'Neil, K. Wong, C. Buranahirun, B. Gonzalez-Morkos, R. J. Brown, A. Hamilton, J. Malvar, R. Sposto, G. Dhall, J. Finlay, A. Olch, K. Reddy, D. Damek, L. Gaspar, D. Ney, B. Kavanagh, A. Waziri, K. Lillehei, K. Stuhr, C. Chen, K. Kalakota, O. Offor, R. Patel, R. Dess, A. Schumacher, I. Helenowski, M. Marymont, P. Sperduto, S. J. Chmura, M. Mehta, G. Zadeh, W. Shi, H. Liu, M. Studenski, L. Fu, C. Peng, V. Gunn, S. Rudoler, C. Farrell, D. Andrews, J. Chu, J. Turian, J. W. Rooney, J. A. B. Ramiscal, N. N. Laack, K. Shah, M. Surucu, E. Melian, D. Anderson, V. Prabhu, T. Origitano, A. Sethi, B. Emami
Journal: Neuro-Oncology (2012)
Management of dose variability and side effects for individualized cancer pharmacotherapy with tyrosine kinase inhibitors
Authors: Tomohiro Terada, Satoshi Noda, Ken-ichi Inui
Journal: Pharmacology & Therapeutics (2015)

Molecular-targeted therapies with tyrosine kinase inhibitors (TKIs) have provided a major breakthrough in cancer treatment. These agents are given orally and demonstrated to be substrates for drug transporters. In clinical settings, TKIs are mainly used at a fixed dose, but wide interpatient variability has been observed in their pharmacokinetics and/or pharmacodynamics. Genetic polymorphisms of ABC transporters, drug-drug interaction and adherence are among the factors causing such variation. To overcome these problems, therapeutic drug monitoring has been applied in clinical practice for patient care. Skin disorders are frequently observed as adverse drug reactions when using TKIs, and are commonly managed by symptomatic therapy based on clinical experience. Recent studies have provided some insights into the molecular mechanisms underlying skin disorders induced by TKIs. This review article summarizes the accumulated clinical and basic pharmacological evidence of TKIs, focusing on erlotinib, sorafenib and sunitinib.
Prenatal Exposure to NO <sub>2</sub> and Ultrasound Measures of Fetal Growth in the Spanish INMA Cohort
Authors: Carmen Iñiguez, Ana Esplugues, Jordi Sunyer, Mikel Basterrechea, Ana Fernández-Somoano, Olga Costa, Marisa Estarlich, Inmaculada Aguilera, Aitana Lertxundi, Adonina Tardón, Mònica Guxens, Mario Murcia, Maria-Jose Lopez-Espinosa, Ferran Ballester
Journal: Environmental Health Perspectives (2015)

Air pollution exposure during pregnancy has been associated with impaired fetal growth. However, few studies have measured fetal biometry longitudinally, remaining unclear as to whether there are windows of special vulnerability.The aim was to investigate the impact of nitrogen dioxide (NO2) exposure on fetal and neonatal biometry in the Spanish INMA study.Biparietal diameter (BPD), femur length (FL), abdominal circumference (AC), and estimated fetal weight (EFW) were evaluated for up to 2,478 fetuses in each trimester of pregnancy. Size at 12, 20, and 34 weeks of gestation and growth between these points, as well as anthropometry at birth, were assessed by SD scores derived using cohort-specific growth curves. Temporally adjusted land-use regression was used to estimate exposure to NO2 at home addresses for up to 2,415 fetuses. Associations were investigated by linear regression in each cohort and subsequent meta-analysis.A 10-μg/m(3) increase in average exposure to NO2 during weeks 0-12 was associated with reduced growth at weeks 0-12 in AC (-2.1%; 95% CI: -3.7, -0.6) and EFW (-1.6%; 95% CI: -3.0, -0.3). The same exposure was inversely associated with reduced growth at weeks 20-34 in BPD (-2.6%; 95% CI: -3.9, -1.2), AC (-1.8%; 95% CI: -3.3, -0.2), and EFW (-2.1%; 95% CI: -3.7, -0.2). A less consistent pattern of association was observed for FL. The negative association of this exposure with BPD and EFW was significantly stronger in smoking versus nonsmoking mothers.Maternal exposure to NO2 in early pregnancy was associated with reduced fetal growth based on ultrasound measures of growth during pregnancy and measures of size at birth.
The modulation of co-stimulatory molecules by circulating exosomes in primary biliary cirrhosis
Authors: Takashi Tomiyama, Guo-Xiang Yang, Ming Zhao, Weici Zhang, Hajime Tanaka, Jing Wang, Patrick SC Leung, Kazuichi Okazaki, Xiao-Song He, Qianjin Lu, Ross L Coppel, Christopher L Bowlus, M Eric Gershwin
Journal: Cellular and Molecular Immunology (2015)
The role of PSMB9 upregulated by interferon signature in the pathophysiology of cutaneous lesions of dermatomyositis and systemic lupus erythematosus
Authors: K. Nakamura, M. Jinnin, H. Kudo, K. Inoue, W. Nakayama, N. Honda, I. Kajihara, S. Masuguchi, S. Fukushima, H. Ihn
Journal: British Journal of Dermatology (2015)

Dermatomyositis (DM) and systemic lupus erythematosus (SLE) have common skin features, including dermal mucin deposition and interferon signature, although their roles are unknown.To identify common or specific molecular changes in DM and SLE skin.Proteomic analysis was performed using DM and healthy skin. Glycosaminoglycans were analysed by high-performance liquid chromatography.The expression of 60 proteins was upregulated or downregulated in DM skin compared with healthy skin in the proteomic analysis. Among those proteins, PSMB9, an immunoproteasome subunit, was upregulated in the epidermis of DM and SLE, but not in other skin diseases. Furthermore, versican V1, a core protein for glycosaminoglycans, was upregulated, while type I collagen was downregulated in the dermis of DM and SLE skin. Interferon stimulated PSMB9 expression in cultured keratinocytes and reduced collagen expression in dermal fibroblasts, but did not affect versican expression. The PSMB9 knock-down in keratinocytes led to significant suppression of transforming growth factor (TGF)-β2 and TGF-β3, inducers of versican synthesis. TGF-β3 expression was upregulated in both DM and SLE, while TGF-β2 expression was increased only in the DM epidermis. ΔDiHS-diS1, a component of heparan sulfate, was significantly increased only in DM. TGF-β2 expression significantly increased the ΔDiHS-diS1 expression in dermal fibroblasts in vitro.The interferon signature in DM and SLE skin reduces collagen in dermal fibroblasts, whereas overexpression of PSMB9 induced by interferon stimulates versican inducers in epidermal keratinocytes. In addition, the TGF-β2-ΔDiHS-diS1 pathway may be responsible for the specific molecular change in DM skin.
Potential therapeutic role of microRNA in lung cancer treatment
Authors: Phong Trang
Journal: Cancer Research (2008)

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

SY31-01 

MicroRNAs (miRNAs) are regulatory RNAs found in multicellular eukaryotes, including humans where they are implicated in cancer . miRNAs control gene expression through complementary elements in the 3’UTRs of target mRNAs. The let-7 microRNA is phylogenetically conserved and temporally expressed in many animals. C. elegans let-7 controls terminal differentiation in a stem cell-like lineage in the skin, while human let-7 has been implicated in lung cancer. Four closely related miRNAs constitute the C. elegans let-7 family.    To elucidate let-7 ’s role in temporal control of nematode development, we used sequence analysis and reverse genetics to identify candidate let-7 target genes . Additionally we found that one let-7 family member, mir-84 , is expressed dynamically in vulval precursor cells at the time that they are specified for distinct roles in vulval morphogenesis. Specifically, mir-84 is absent when let-60/ras is actively specifying the 1 vulval fate in P6.p. The 3’UTR of let-60/ras contains multiple mir-84 miRNA complementary sites, and restricts reporter gene expression to P6.p. mir-84 over-expression suppresses the multivulva phenotype of activating let-60/ras mutations. This suggests that let-60/ras is a target of mir-84 , which modulates ras signaling leading to vulval cell fate specification. In addition, mammalian HRAS , KRAS and NRAS 3’UTRs contain multiple let-7 complementary sites, suggesting conservation of gene interactions .    The 3’ UTRs of the human RAS genes contain multiple LCSs, allowing let-7 to regulate RAS expression. let-7 expression is lower in lung tumors than in normal lung tissue while RAS protein is significantly higher in lung tumors , providing a possible mechanism for let-7 in cancer. The RAS family makes up major oncogenes in various cancers, including lung cancer. We showed that let-7 is highly expressed in lung tissue and that inhibiting let-7 function leads to increased cell division in A549 lung cancer cells, providing evidence that let-7 functions as a tumor suppressor in lung cells . Over-expression of let-7 in cancer cell lines alters cell cycle progression and reduces cell division. let-7 was previously shown to regulate the expression of the RAS lung cancer oncogenes. We also showed that multiple genes involved in cell cycle and cell division functions are also directly or indirectly repressed by let-7.     This work reveals the let-7 microRNA to be a master regulator of cell proliferation pathways. This work also suggests that the level of expression of the let-7 miRNA might be an important factor in limiting or contributing to oncogenesis. This may also be the first step in a possible cancer therapy, targeting RAS with a microRNA.    This work was supported by a grant from the Connecticut Department of Public Health and from Asuragen, Inc.
Impact of Fluorine-18 Fluorodeoxyglucose Positron Emission Tomography on Patient Management: First Year’s Experience in a Clinical Center
Authors: Robert Tucker, Marc Coel, Jehoon Ko, Paul Morris, George Druger, Pat McGuigan
Journal: Journal of Clinical Oncology (2001)

PURPOSE: To measure the impact of whole-body fluorodeoxyglucose (FDG) positron emission tomography (PET) on patient management during its first year of use in a community hospital. MATERIALS AND METHODS: First-year FDG-PET impact was determined from 463 referring physicians’ evaluations of their patients’ PET imaging results using two surveys. Survey 1 was given to all physicians referring patients to PET to discover whether PET changed patient management or had decision-making value in the patient’s clinical algorithm. Survey 2 was given to one surgeon and one pulmonologist after therapy to determine how PET affected the surgical, chemotherapeutic, and/or radiotherapeutic treatment for the 53 cancer patients they referred. RESULTS: The 463 responses to survey 1 described 23 different PET indications. Lung (40%), head and neck (18%), and colorectal cancers (11%) were the three leading causes of referral. PET changed patient management/therapy in 45% of all patients referred and had inferential/decision-making value in another 44%. Overall, PET had some type of positive influence in 412 (89%) of the patients. Survey 2 provided a more detailed assessment of 53 referrals from two specialists. PET positively affected surgery in 31 patients (58%), prompted the addition of chemotherapy or radiation therapy in nine patients (17%), and eliminated chemotherapy or radiation therapy in four cases (8%). Overall, PET affected patient management/therapy in 70% of the cases and had some decision-making value in another 26%, for a combined PET impact on patient management of 96%. CONCLUSION: FDG-PET can be valuable for physicians in clinical practice. Its sensitivity and specificity in metabolic imaging, when combined with complementary anatomic imaging techniques, contribute significantly to the clinical treatment of cancer patients. In addition, the high accuracy of FDG-PET makes it a cost-effective radiologic procedure in the work-up of all suspected and/or recurrent cancer patients. Further research is needed to link this demonstrated impact on patient management to cost-effectiveness.
A phase II trial of BAY 43–9006 in patients with recurrent and/or metastatic head and neck squamous cell carcinoma (HNSCC): A Southwest Oncology Group (SWOG) trial
Authors: S. K. Williamson, J. Moon, C. H. Huang, P. Guaglianone, G. T. Wolf, S. G. Urba
Journal: Journal of Clinical Oncology (2006)

5550 Background: Bay 43–9006 (Sorafenib) is a potent Raf-1 and B-Raf kinase inhibitor of the RAS/RAF/MEK/ERK pathway. The compound also inhibits protein tyrosine kinases associated with VEGFR-2 and 3 as well as PDGFR-B. We conducted a phase II trial to evaluate the efficacy of BAY 43–9006 in chemotherapy naive patients with metastatic or recurrent HNSCC. Methods: Chemotherapy naïve patients with histologically proven squamous cell carcinoma of the head and neck either metastatic, persisted or recurred following definitive surgery and/or radiation therapy, and not amenable to salvage surgical resection were eligible. Patients may have received only one induction or adjuvant chemotherapy regimen provided that at least 6 months have elapsed since the last course was administered. Patients must have adequate cardiac, hematologic, renal and hepatic function and a Zubrod Performance Status of ≤ 1. Specimens were obtained from either archival or fresh pre-treatment biopsies and at the time of progression of disease for molecular correlative studies. BAY 43–9006 was administered orally at 400 mg BID on a continuous basis, in 28-day cycles. Responses were evaluated every 8 weeks according to RECIST criteria. Initially 20 patients will be registered. If one or more confirmed responses are observed in the first 20 patients, an additional 20 patients will be registered. Results: Thirty-eight patients (31 males, 7 females, median age 64 years) have been enrolled to date. Twenty-seven patients are evaluable for toxicity. The drug was generally well tolerated. There have been 2 Grade 4 toxic events - one cerebral ischemia and an asymptomatic pulmonary embolus. Grade 3 toxicities include 2 patients with hand/foot syndrome, 4 with stomatitis or oral pain, and one episode each of anorexia, dysphagia, hypertension, and ulceration. The most common grade 2 toxic events were fatigue (8 pts.), anorexia (8 pts.), stomatitis (5 pts.), and hypertension (4 pts.). Complete accrual to 40 patients is anticipated by January 31, 2006. Conclusions: BAY 43–9006 is well tolerated. Updated toxicity data will be reported. Preliminary response, time to progression and survival data will be presented. [Table: see text]
Adjuvant dendritic cell vaccination in high-risk uveal melanoma patients
Authors: Kalijn Bol, Thomas van den Bosch, Gerty Schreibelt, Cornelis Punt, Carl Figdor, Dion Paridaens, Jolanda de Vries
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts The presence of monosomy 3 in the primary tumor is widely accepted as the most reliable prognostic parameter, identified in approximately 50% of patients with primary uveal melanoma [[1][1]]. Long term studies have shown a 3-year survival rate of 40% if monosomy 3 is present,
CALGB 40502/NCCTG N063H: Randomized phase III trial of weekly paclitaxel (P) compared to weekly nanoparticle albumin bound nab-paclitaxel (NP) or ixabepilone (Ix) with or without bevacizumab (B) as first-line therapy for locally recurrent or metastatic breast cancer (MBC).
Authors: Hope S. Rugo, William Thomas Barry, Alvaro Moreno-Aspitia, Alan P. Lyss, Constance Cirrincione, Erica L. Mayer, Michael Naughton, Rachel M. Layman, Lisa A. Carey, Robert A. Somer, Edith A. Perez, Clifford Hudis, Eric P. Winer
Journal: Journal of Clinical Oncology (2012)

CRA1002 The full, final text of this abstract will be available at abstract.asco.org at 12:01 AM (EDT) on Monday, June 4, 2012, and in the Annual Meeting Proceedings online supplement to the June 20, 2012, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Monday edition of ASCO Daily News.
Cytoplasmic levels of cFLIP determine a broad susceptibility of breast cancer stem/progenitor-like cells to TRAIL
Authors: Rhiannon French, Olivia Hayward, Samuel Jones, William Yang, Richard Clarkson
Journal: Molecular Cancer (2015)

The clinical application of TRAIL receptor agonists as a novel cancer therapy has been tempered by heterogeneity in tumour responses. This is illustrated in breast cancer, where TRAIL is cytotoxic in cell lines of mesenchymal origin but refractory in lines with an epithelial-like phenotype. However, it is now evident that intra-tumour heterogeneity includes a minority subpopulation of tumour-initiating stem/progenitor-like cells (CSCs) that possess mesenchymal characteristics. We hypothesised therefore that TRAIL may target these phenotypically distinct CSC-like cells that are common to most - if not all - breast cancers, thus impacting on the source of malignancy in a much broader range of breast tumour subtypes than previously envisaged. We used colony formation, tumoursphere, flow cytometry and xenograft tumour initiation assays to observe the TRAIL sensitivity of CSC-like cells in a panel of two mesenchymal-like (TRAIL-sensitive) and four epithelial-like (TRAIL-resistant) breast cancer cell lines. Subcellular levels of the endogenous TRAIL inhibitor, cFLIP, were determined by western blot and immunofluorescence microscopy. The effect of the subcellular redistribution of cFLIP on TRAIL sensitivity and Wnt signalling was determined using cFLIP localisation mutants and the TOPFlash reporter assay respectively. TRAIL universally suppressed the clonal expansion of stem/progenitors in all six of the breast cancer cell lines tested, irrespective of their phenotype or overall sensitivity to TRAIL. A concomitant reduction in tumour initiation was confirmed in the TRAIL-resistant epithelial cell line, MCF-7, following serial dilution xenotransplantation. Furthermore TRAIL sensitivity of breast CSCs was inversely proportional to the relative cytoplasmic levels of cFLIP while overexpression of cFLIP in the cytosol using subcellular localization mutants of cFLIP protected these cells from cytotoxicity. The accumulation of nuclear cFLIP on the other hand did not influence TRAIL cytotoxicity but instead promoted Wnt-dependent signalling. These data propose a novel role for TRAIL as a selective CSC agent with a broad specificity for both epithelial and mesenchymal breast tumour subtypes. Furthermore we identify a dual role for cFLIP in the maintenance of breast CSC viability, dependent upon its subcellular distribution.