tbuckley/cabot-search huggingface dataset:
970. A Fiber Modified SLPI Promoter Based Conditionally Replicating Adenovirus for Treatment of Ovarian Cancer
Authors: Daniel T. Rein, Martina Breidenbach, Minghui Wang, Tyler O. Kirby, Gene P. Siegal, Gerd J. Bauerschmitz, Peter Dall, Dirk M. Nettelbeck, Akseli Hemminki, Ronald D. Alvarez, David T. Curiel
Journal: Molecular Therapy (2004)

Top of pageAbstract
Conditionally replicating adenoviruses (CRADs) are a novel approach for treatment of cancer. The oncolytic potency of CRADs is determined by their capability to infect tumor cells. Most adenoviruses used for gene therapy have been based on serotype 5 (Ad5). Unfortunately, expression of the primary receptor for Ad5 is highly variable on ovarian cancer cells. Genetic fiber pseudotyping is an approach to circumvent this problem by using the alternative Ad serotype 3 receptor for entry into, and killing of ovarian cancer cells. Furthermore, restriction of the CRAD replication to tumor cells minimizes nontumor tissue injury. One way to gain this selectivity is to control replication regulation genes with promoters active only in specific tumor cells. In this study, we constructed a fiber-modified CRAD containing the secretory leukoprotease inhibitor (SLPI) promoter to control viral replication via the E1A gene (Ad5/3SLPI). SLPI has been shown to be over-expressed in various tumors including ovarian cancer but minimally active in normal tissues. Viral replication and oncolysis were assessed in various ovarian cancer cell lines. Replication was also analyzed with quantitative PCR on three-dimensional primary tumor cell sheroids purified from fresh patient samples. Moreover, in a therapeutic orthotopic mouse model of peritoneal carcinomatosis, dramatically enhanced survival was noted with Ad5/3SLPI. To assess the selectivity of Ad5/3SLPI in comparison with Ad5wt, Ad5/3wt and a non replicative control virus Ad5/3luc, we evaluated the ability of the viruses to replicate in non-target liver cells in vivo. Ad5/3Δ24, a type 1 CRAD replicates in cancer cells inactive in the Rb/p16 pathway, was included as a control. Serum levels of liver enzymes, liver pathology, viral E1A DNA copy numbers and E1A RNA levels were evaluated 48 hours after i.v. injection of viruses into immunocompetent mice. Little to no hepatotoxicity was seen with the non replicative E1-deleted vector whereas pronounced effects were seen with the replication competent Ad5/3wt vector. Toxicities included submassive hepatic necrosis, high E1A DNA copy number and E1A RNA levels. Ad5/3SLPI demonstrated significantly lower liver pathology and E1A DNA and RNA copy numbers in comparison to Ad5/3wt and Ad5/3Δ24. In summary, Ad5/3SLPI is a promising candidate for treating metastatic ovarian cancer and showed robust virus replication, oncolysis, and in vivo therapeutic efficacy. Ad5/3SLPI showed comparatively low liver toxicity and therefore holds great potential for clinical testing.
Abstract 19506: Phenotype-Based High-Content Chemical Library Screening Identifies Small Molecules That Enhance Endothelial Cell Branching and Tubulogenesis
Authors: Ayman Al Haj Zen, Dorota Nawrot, Alison Howarth, Daniel Ebner, Shoumo Bhattacharya
Journal: Circulation (2014)

The goal of therapeutic angiogenesis is enhancing new vessel growth that can effectively provide blood supply to ischemic tissues. The endothelial cellular process such as establishment of new connections, branching and tubulogenesis are essential aspects in the growing of a functional vascular network. With the aim of identifying novel small molecule enhancers of these aspects during angiogenesis, we used endothelial tube formation assay to develop an automated assay that enables high-throughput/content screening of small molecule libraries.   Methods:  The assay is automated and miniaturized into a 384-well format enabling to profile a library of 1280 Pharmacologically Active Compounds (LOPAC1280) for their angiogenic activity. The screen was conducted in duplicate at a final compound concentration of 10 μM using primary Human Umbilical Vein Endothelial Cells. Following cell fixation and staining, the plates were imaged using a high content microscopy system (Operetta). The images were processed and analyzed using fully-automated Metamorph image analysis software.   Results:  The screen resulted in an initial active compound list of 74 inhibitors and 14 enhancers. Hit characterization revealed 8 enhancer small molecules that reproducibly increased significantly both branching points and total tubule length in a dose dependent manner with low micromolar range (EC50   Conclusions:  Our findings suggest that high-throughput/content approach provides a powerful tool to identify new potential targets or to prioritize therapeutic agent candidates for in vivo and clinical testing of pro-angiogenic therapies for ischemic diseases.
Modulation of red blood cell population dynamics is a fundamental homeostatic response to disease
Authors: Harsh H. Patel, Hasmukh R. Patel, John M. Higgins
Journal: American Journal of Hematology (2015)

Increased red blood cell (RBC) volume variation (RDW) has recently been shown to predict a wide range of mortality and morbidity: death due to cardiovascular disease, cancer, infection, renal disease, and more; complications in heart failure and coronary artery disease, advanced stage and worse prognosis in many cancers, poor outcomes in autoimmune disease, and many more. The mechanisms by which all of these diseases lead to increased RDW are unknown. Here we use a semi-mechanistic mathematical model of in vivo RBC population dynamics to dissect the factors controlling RDW and show that elevated RDW results largely from a slight reduction in the in vivo rate of RBC turnover. RBCs become smaller as they age, and a slight reduction in the rate of RBC turnover allows smaller cells to continue circulating, expanding the low-volume tail of the RBC population's volume distribution, and thereby increasing RDW. Our results show that mildly extended RBC lifespan is a previously unrecognized homeostatic adaptation common to a very wide range of pathologic states, likely compensating for subtle reductions in erythropoietic output. A mathematical model-based estimate of the clearance rate may provide a novel early-warning biomarker for a wide range of morbidity and mortality.
Scientific Foundations of Surgery.
Authors: Charles Wells, James Kyle, J. Englebert Dunphy
Journal: Annals of Internal Medicine (1967)

The cell immunology the endocrine system and reproduction bone and joint tissues central nervous system peripheral and autonomic nervous systems the heart the blood shock, burns and cardiac arrest vascular systems respiratory tract alimentary tract the liver, gallbladder and ducts water and electrolytes urinary tract general tissue changes and responses cancer and cancer therapy infections and inflammation imagery in surgery.
Abstract 17189: Superior Vena Cava as the Substrate of Various Forms of Atrial Tachycarrhythmias: Consideration into the Mechanism and Tachycardia Circuit
Authors: Hiroshige Yamabe, Hisanori Kanazawa, Tadashi Hoshiyama, Miwa Ito, Hisao Ogawa
Journal: Circulation (2014)

Background: The superior vena cava (SVC) is known to possess the myocardial sleeves extending from the right atrium which has been shown to be a substrate for various atrial tachyarrhythmias. However, the precise mechanisms and electrophysiologic feature of these atrial tachyarrhythmias, originating from the SVC has not been elucidated well. Objective: The purpose of this study was to define the mechanisms and electrophysiologic characteristics of atrial tachyarrhythmias originating from the SVC. Methods: In 21 patients with atrail tachycarrhythmias originating from the SVC, the mechanism and tachycardia circuit were examined by the contact or non-contact mapping system (EnSite NavX or 3000). Results: There were 5 reentrant atrial tachycardia (AT), 4 focal ATs and 12 atrial fibrillation (AF). Three reentrant ATs showed a macro-reentrant activation around the SVC sleeve with critical slow conduction zone (SCZ) in the SVC and the remaining 2 showed a localized reentry within the SVC. Four focal AT showed a focal discharge source in the SVC. In 8 of 9 ATs, SCZ or focal discharge source was observed at the area extending from the anterior to lateral portions of the SVC. All 12 AF were initiated by the repetitive discharge from SVC and was maintained by the meandering reentrant activation within the SVC involving the junction between the SVC and right atrium during AF. All 9 ATs were terminated by the radiofrequency energy delivery to the SCZ (n=4) and the focal discharge source (n=3) or isolation of SVC (n=2). All 12 AF were terminated by the circular application of radiofrequency energy delivery around the junction between SVC and right atrium, resulting in the SVC isolation in 9 patients. Conclusions: SVC provides the focal discharge source and the substrate of SCZ of AT. These critical area for maintaining AT mostly located at the antero-lateral portions of the SVC. Focal discharge source and substrate for meandering reentry within the SVC also maintained the SVC origin AF. These unique electrophysiologic characteristics of SVC provide the substrate of various forms of atrial tachycarrhythmias.
Topical betamethasone 17-valerate is an anticorticosteroid in the rat.
Authors: JOHN M. YOUNG, BRUCE E. YOXALL, BONNIE M. WAGNER
Journal: British Journal of Dermatology (1978)

In the albino rat, topical betamethasone 17-valerate acts as an anticorticosteroid. This steroid is inactive in a dermal atrophy assay over a dose range where betamethasone and hydrocortisone display atrophogenic activity. At appropriate concentrations betamethasone 17-valerate competitively inhibits the atrophogenic effects of both betamethasone and triamcinolone acetonide. Since betamethasone and betamethasone 17-valerate penetrate rat skin in vivo at essentially the same rate, it is concluded that the latter compound is relatively resistant to hydrolysis during penetration, and that it binds to rat corticosteroid receptor proteins in such a manner as to prevent expression of corticosteroid activity. Therefore, the rat cannot be used as a model species to predict activity in man for this compound.
Antibiotic resistance genotype trend and association with host clinical characteristics in respiratory isolates of streptococcus pneumoniae
Authors: Eri Hagiwara, Yoshihiro Suido, Atsuhito Nakazawa, Akimasa Sekine, Hideya Kitamura, Tomohisa Baba, Takeshi Shinohara, Ryuichi Nishihira, Shigeru Komatsu, Terufumi Kato, Takashi Ogura
Journal: European Respiratory Journal (2014)

Background & Objectives: Antibiotic resistance of  Streptococcus pneumoniae , especially against β-lactam antibiotics, is a global concern. We aimed to analyze ten-year trend in resistance genotype of respiratory isolates of  S. pneumoniae , and to clarify whether resistance genotypes were correlated with phenotypic susceptibility, pathogenicity and host clinical background.  Methods: Respiratory isolates of  S. pneumoniae  from 2003 to 2012 were analyzed with polymerase chain reaction for the presence of β-lactam resistance gene mutation on  pbp1a ,  pbp2x , and  pbp2b . Sixty-eight strains isolated from different patients in 2012 were particularly analyzed for the association between genotypes and clinical data.  Results: Ten-year trend analysis showed the recent increase of gPRSP which has all three β-lactam resistance genes (21.7% to 35.3% in three years) and the steady share of gPSSP without any β-lactam resistance genes (13.2% in 2012). This resistance trend in genotypes was more prominent than resistance phenotypes derived from drug susceptibility test. The probability of being causative pathogen did not differ in gPSSP (56%), gPISP (54%), and gPRSP (54%). There was no significant difference in the ratio of patients who presented with respiratory failure in respiratory infection caused by gPSSP, gPISP, or gPRSP. Host clinical characteristics including age and gender were not different among resistance genotypes.  Conclusions: Genotype resistance in respiratory isolates of  S. pneumoniae  insidiously prevailed more than phenotypic antibiotic resistance. There was no difference in pathogenicity or clinical background between gPSSP, gPISP, and gPRSP.
Evaluation of the clinical efficacy of the 1450 nm laser in acne vulgaris: a randomized split-face, investigator-blinded clinical trial
Authors: S. Darné, E.L. Hiscutt, D.C. Seukeran
Journal: British Journal of Dermatology (2011)

Background The 1450 nm laser shrinks sebaceous glands histologically, reduces seborrhoea and has been shown in numerous small uncontrolled studies to improve inflammatory acne. Objectives To assess objectively the clinical efficacy and long‐term outcome of the 1450 nm laser for inflammatory acne vulgaris. Methods Participants over 16 years of age with moderate to severe acne vulgaris were recruited from a secondary care dermatology department. A split‐face format was used: the side of the face to be treated was randomized with the other side serving as a within‐patient control. Treatment was delivered with the Candela 1450 nm Smoothbeam laser (Candela, Cwmbran, U.K.) using a double‐pass technique, 6 mm spot size, 210 ms pulse duration and fluence of 8 or 9 J cm−2. Three treatments were performed monthly. The primary outcome was the change in inflammatory lesion count and grading (using the Leeds Revised Acne Grading Scale) between baseline and 4 weeks after the third treatment on the treated side as compared with the change in the control side. Participants were followed up every 3 months for 12 months after the last treatment. The single assessor was blinded as to the side treated. Results Thirty‐eight participants entered the study and 32 completed the study at the primary outcome measure. Within participants, on average, the lesion count reduced by the same amount on both sides of the face [median 0, 95% confidence interval (CI) −4 to 2]. On average, acne grade reduced by the same amount on both sides (median 0, 95% CI −1 to 0). Twelve months after the last treatment (n =23) the change in lesion count and grade between the treated and control sides of the face remained similar. Treatment was well tolerated. Conclusions Treatment with the 1450 nm laser does not reduce inflammatory lesion count or acne grade when compared with a control side, using a split‐face format in participants recruited from secondary care. Both sides of the face improved and a systemic effect of the laser is possible.
1025. Efficiency, Specificity and Efficacy of Genetically-Modified Adenovirus Vector on Peritoneal Cancers
Authors: Elizabeth M. Hadac, Kah-Whye Peng, Takafumi Nakamura, Laurence J. Miller, Stephen J. Russell
Journal: Molecular Therapy (2004)

Pancreatic cancer is one of the most lethal of all major malignancies. Although pancreatic cancer only accounts for 2% of all newly diagnosed cancers in the US, annually it is responsible for 5% of cancer deaths. We are developing a treatment approach for pancreatic cancer based on the oncolytic properties of the attenuated Edmonston strain of measles virus. While MV-Edm does not cause disease in humans it can infect cells through CD46 and SLAM receptors causing cell fusion forming multi-nucleated syncytia that eventually die via apoptosis. We have demonstrated this cytopathic effect in vitro on a panel of human pancreatic cancer cell lines (BxPC-3, L3.6pl, Panc-1, SU.86.86, MiaPaCa). We have further demonstrated the efficacy of this virus in vivo with a subcutaneous tumor model of the BxPC-3 cells. Mice treated with intra-tumoral MV-therapy out-lived the control group with a median survival ratio of 1.62 (p=0.0046). To further enhance the ability of the measles virus to more specifically target pancreatic cancer cells we developed a strategy for display of scFvs by fusion to the C-terminus of the viral attachment protein H. We have recently reported the identification of mutations in MV-H that ablate CD46 and SLAM binding (481A, 533A). Using this ablated platform we subcloned the HAA displaying human anti-CD38 or anti-EGFR scFv into full length MV-eGFP and successfully rescued these viruses. The MV-GFP-HAA αEGFR virus is an exceptional therapeutic agent for pancreatic cancer because of the over expression of EGFR on these tumor cells. As a specificity control, we have used a virus displaying a scFv against CD38, a myeloma antigen. The tropisms of the new viruses were compared against the parental MV-eGFP virus on a panel of receptor positive and negative cell lines to test the accuracy and efficiency of virus-cell entry and cell-to-cell fusion. These viruses were also characterized by western blot to confirm the chimeric H-protein. When these EGFR retargeted viruses are used to infect the pancreatic cancer cell line BxPC-3 we are able to show slightly greater levels of transduction to that observed with the parent virus that enters through CD46 and SLAM. These retargeted viruses will have the significant therapeutic advantage of binding and killing only tumor cells displaying the appropriate receptor.
Advances in Merkel cell carcinoma pathogenesis and management: a recently discovered virus, a new international consensus staging system and new diagnostic codes
Authors: E. Nicolaidou, A. Mikrova, C. Antoniou, A.D. Katsambas
Journal: British Journal of Dermatology (2011)

Journal Article Advances in Merkel cell carcinoma pathogenesis and management: a recently discovered virus, a new international consensus staging system and new diagnostic codes Get access E. Nicolaidou, E. Nicolaidou 1st Department of Dermatology and Venereology, University of Athens School of Medicine, 'Andreas Sygros' Hospital, Athens, Greece E. Nicolaidou. E‐mail: electra.nicol@gmail.com Search for other works by this author on: Oxford Academic Google Scholar A. Mikrova, A. Mikrova 1st Department of Dermatology and Venereology, University of Athens School of Medicine, 'Andreas Sygros' Hospital, Athens, Greece Search for other works by this author on: Oxford Academic Google Scholar C. Antoniou, C. Antoniou 1st Department of Dermatology and Venereology, University of Athens School of Medicine, 'Andreas Sygros' Hospital, Athens, Greece Search for other works by this author on: Oxford Academic Google Scholar A.D. Katsambas A.D. Katsambas 1st Department of Dermatology and Venereology, University of Athens School of Medicine, 'Andreas Sygros' Hospital, Athens, Greece Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 166, Issue 1, 1 January 2012, Pages 16–21, https://doi.org/10.1111/j.1365-2133.2011.10562.x Published: 01 January 2012 Article history Accepted: 29 July 2011 Published: 01 January 2012
Development of a Novel Echocardiography Ramp Test for Speed Optimization and Diagnosis of Device Thrombosis in Continuous-Flow Left Ventricular Assist Devices
Authors: Nir Uriel, Kerry A. Morrison, Arthur R. Garan, Tomoko S. Kato, Melana Yuzefpolskaya, Farhana Latif, Susan W. Restaino, Donna M. Mancini, Margaret Flannery, Hiroo Takayama, Ranjit John, Paolo C. Colombo, Yoshifumi Naka, Ulrich P. Jorde
Journal: Journal of the American College of Cardiology (2012)
Sequelae of bereavement resulting from suicide
Authors: D E Ness, C R Pfeffer
Journal: American Journal of Psychiatry (1990)

Although clinical experience suggests that individuals who have been bereaved as a result of suicide may be especially vulnerable to adverse sequelae, such as unusually severe grief or increased risk of committing suicide themselves, the idea that this type of bereavement is special has received only limited systematic investigation. The authors review the literature on the subject, with special attention to the clinical and research evidence about whether bereavement resulting from suicide is different from bereavement due to other types of death, and make suggestions for further clinical and epidemiological research on this question.
Chlorambucil plus rituximab with or without maintenance rituximab as first‐line treatment for elderly chronic lymphocytic leukemia patients
Authors: Robin Foà, Ilaria Del Giudice, Antonio Cuneo, Giovanni Del Poeta, Stefania Ciolli, Francesco Di Raimondo, Francesco Lauria, Emanuele Cencini, Gian Matteo Rigolin, Agostino Cortelezzi, Francesco Nobile, Vincenzo Callea, Maura Brugiatelli, Massimo Massaia, Stefano Molica, Livio Trentin, Rita Rizzi, Giorgina Specchia, Francesca Di Serio, Lorella Orsucci, Achille Ambrosetti, Marco Montillo, Pier Luigi Zinzani, Felicetto Ferrara, Fortunato Morabito, Maria Angela Mura, Silvia Soriani, Nadia Peragine, Simona Tavolaro, Silvia Bonina, Marilisa Marinelli, Maria Stefania De Propris, Irene Della Starza, Alfonso Piciocchi, Alessandra Alietti, Eva Josephine Runggaldier, Enrica Gamba, Francesca Romana Mauro, Sabina Chiaretti, Anna Guarini
Journal: American Journal of Hematology (2014)

In a phase II trial, we evaluated chlorambucil and rituximab (CLB‐R) as first‐line induction treatment with or without R as maintenance for elderly chronic lymphocytic leukemia (CLL) patients. Treatment consisted of eight 28‐day cycles of CLB (8 mg/m 2 /day, days 1–7) and R (day 1 of cycle 3, 375 mg/m 2 ; cycles 4–8, 500 mg/m 2 ). Responders were randomized to 12 8‐week doses of R (375 mg/m 2 ) or observation. As per intention‐to‐treat analysis, 82.4% (95% CI, 74.25–90.46%) of 85 patients achieved an overall response (OR), 16.5% a complete response (CR), 2.4% a CR with incomplete bone marrow recovery. The OR was similar across Binet stages (A 86.4%, B 81.6%, and C 78.6%) and age categories (60–64 years, 92.3%; 65–69, 85.2%; 70–74, 75.0%; ≥75, 81.0%). CLB‐R was well tolerated. After a median follow‐up of 34.2 months, the median progression‐free survival (PFS) was 34.7 months (95% CI, 33.1–39.5). TP53 abnormalities, complex karyotype, and low CD20 gene expression predicted lack of response; SF3B1 mutation and BIRC3 disruption low CR rates. IGHV mutations significantly predicted PFS. R maintenance tended towards a better PFS than observation and was safe and most beneficial for patients in partial response and for unmutated IGHV cases. CLB‐R represents a promising option for elderly CLL patients. Am. J. Hematol. 89:480–486, 2014. © 2014 Wiley Periodicals, Inc.
Autologous stem cell transplantation for autoimmunity induces immunologic self-tolerance by reprogramming autoreactive T cells and restoring the CD4+CD25+ immune regulatory network
Authors: Ismé de Kleer, Bas Vastert, Mark Klein, Gijs Teklenburg, Ger Arkesteijn, Gisella Puga Yung, Salvo Albani, Wietse Kuis, Nico Wulffraat, Berent Prakken
Journal: Blood (2005)