tbuckley/cabot-search huggingface dataset:
Abstract 1683: Novel combination approach using platinum drugs and mitochondrial division inhibitor 1 (mdivi-1) overcomes platinum resistance by synergistically inducing mitochondrial outer membrane permeabilization (MOMP) and apoptosis independent of Drp1
Authors: Wei Qian, Jingnan Wang, Vera Roginskaya, Lee McDermott, Robert Edwards, Donna Stolz, Fabien Llambi, Douglas Green, Bennett Van Houten
Journal: Cancer Research (2014)

Abstract Platinum based anticancer agents, including cisplatin, are among the most effective and widely used anticancer drugs. However, inherent and acquired resistance to these drugs in tumors lead to treatment failure. We found a class of thioquinazolinone derivatives, including the mitochondrial division inhibitor-1 (mdivi-1), that overcome both the inherent and acquired resistance to cisplatin in tumor cell lines and also in primary ovarian tumors isolated from cisplatin refractory patients. The combination of cisplatin and mdivi-1 produces synergistic effect in inducing rapid apoptosis. Using Drp1 (a mitochondrial fission protein and the reported target of mdivi-1) knockout MEF cells we demonstrated that the combination of cisplatin and mdivi-1 overcomes cisplatin resistance in a Drp1-independent manner. Mdivi-1 causes replication defects and its combination with cisplatin triggers synergistic increases of replication stress and DNA damage. Comparing the treatment with cisplatin and mdivi-1 alone, the combination of the two agents enhances mitochondrial apoptotic signaling by specifically upregulating the expression of a pro-apoptotic Bcl-2 family protein Noxa, which promotes Bax/Bak-mediated mitochondrial outer membrane permeabilization (MOMP). Intriguingly, the combination of cisplatin and mdivi-1 also causes mitochondrial swelling that triggers a Bax/Bak-independent MOMP. Thus, the combination of cisplatin and mdivi-1 activates two distinct mechanisms that converge on mitochondria contributing to the enhancement of MOMP. This novel combination represents a potential effective strategy in overcoming platinum drug resistance by combining cisplatin with compounds that together are able to trigger the coinitiation of Bax/Bak-dependent and-independent mitochondrial apoptotic signaling. (Work was supported by P30CA047904, UPCI and PA Dept of Health CURE program) Citation Format: Wei Qian, Jingnan Wang, Vera Roginskaya, Lee McDermott, Robert Edwards, Donna Stolz, Fabien Llambi, Douglas Green, Bennett Van Houten. Novel combination approach using platinum drugs and mitochondrial division inhibitor 1 (mdivi-1) overcomes platinum resistance by synergistically inducing mitochondrial outer membrane permeabilization (MOMP) and apoptosis independent of Drp1. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1683. doi:10.1158/1538-7445.AM2014-1683
Incidence of insulin dependent diabetes in children aged under 15: Authors' reply
Authors: M A. Metcalfe, J D. Baum
Journal: BMJ (1991)

question of the partner not undergoing the procedure having the right of veto.The Department of Health took the decision not to include reference to the patient's partner on the consent form as a result of the representations received following a consultation exercise.There was a clear feeling that respondents did not consider it correct to include such a "reminder" on the form.Among those making that point were medical and nursing professional bodies plus consumer groups.As the consultation-for any medical treatment is a private one between health professional and patient we felt able to agree that the consent form was not the right place to require consideration of the partner's interest.The department has of course issued detailed guidance on family planning services, which includes advice on the need for full counselling for both partners before deciding on the operation.This guidance is still current.'Although it is not a legal requirement and the form therefore makes no specific provision for obtaining a partner's consent, the department's view is that doctors may still, as a matter ofgood practice, seek the partner's agreement if the patient accepts that this should be done and record this locally if desired.
A long-term study of a patient with anti-p200 pemphigoid: correlation of autoantibody levels with disease activity and an example of epitope spreading
Authors: B. Monshi, S. Groth, L. Richter, E. Schmidt, D. Zillikens, K. Rappersberger
Journal: British Journal of Dermatology (2012)

Anti-p200 pemphigoid is a rare subepidermal blistering disease associated with autoantibodies against a 200-kDa protein, reportedly corresponding to laminin γ1. However, direct evidence of the pathogenic potential of these antibodies has not been proven. For 5 years we have followed up a patient with anti-p200 pemphigoid. During this period she experienced a total of three generalized relapses. Quantifying our patient's autoantibody concentrations against laminin γ1 by enzyme-linked immunosorbent assay throughout the course of her disease we demonstrated a clear correlation with disease activity, thus providing the first evidence of the possible pathogenic role of antibodies against laminin γ1 in anti-p200 pemphigoid. Further analysis by Western blotting revealed the occurrence of additional autoantibodies against the α3 chain of laminin 332, 1·5 years after diagnosis, suggestive of intermolecular epitope spreading. Yet, the clinical appearance was unchanged and mucous membranes remained unaffected at any stage of the disease.
The Carcinogenicities of Derivatives of Fluorene and Biphenyl: Fluoro Derivatives as Probes for Active Sites in 2-Acetylaminofluorene
Authors: Elizabeth C. Miller, T. Lloyd Fletcher, Alfredo Margreth, James A. Miller
Journal: Cancer Research (1962)

Summary  The carcinogenic activities of the 1-, 3-, 4-, 5-, 6-, and 8-monofluoro derivatives of 2-acetylaminofluorene (AAF) were compared with the activity of AAF in male and female rats. Each of these monofluoro derivatives and the 7-fluoro derivative reported previously was found to possess approximately the same carcinogenic activity as AAF in two or more of the four tissues in which AAF commonly produces tumors in the Holtzman rat. This result suggests that none of the aromatic ring-positions of AAF is a site of covalent bond formation necessary for carcinogenesis by this amide. Thus, the carcinogenicities of the monofluoro derivatives of AAF are consistent with the recent finding that  N -hydroxylation of AAF is directly involved in carcinogenesis with this compound.  Comparative carcinogenicities were also determined in the rat for a series of other fluorene derivatives related to AAF and for several compounds related to 4-acetylaminobiphenyl. 2-Trifluoroacetylaminofluorene, 2-trifluoroacetylaminofluoren-9-one, 2-formylaminofluorene, 2,7-dinitrofluorene, 2,5-bis(acetylamino)fluorene, and 3′-fluoro-4-acetylaminobiphenyl induced moderate to high incidences of tumors at one or more sites. Introduction of a 3-methyl group into 4-acetylaminobiphenyl reduced its activity for the mammary gland, but enhanced its activity toward the ear duct gland. 3-Fluoro-4-acetylaminobiphenyl was strongly carcinogenic for the mammary glands of both female and male rats. 2,5-Dinitrofluorene, 2-dimethylamino-3-nitrofluorene, 2-acetylamino-9-( p -fluorophenylimino)fluorene,  p,p′ -methylenediacetanilide, 4′-methyl-4-acetylaminobiphenyl, 2-acetylthiofluorene, 2-maleimidofluorene, and 2-methylthiofluorene had little or no activity in any tissue under the conditions employed.  Syntheses of the following new compounds are described: 3- and 3′-fluoro-4-acetylbiphenyl and their oximes, 3- and 3′-fluoro-4-acetylaminobiphenyl (synthesized by F. Chubb and R. B. Sandin), and 2-formylaminofluorene.
Lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) regulate tumor cell invasion of three-dimensional collagen matrices via coordinated activation of EDG1/S1P1, EDG2/LPA1, and membrane type-1 matrix metalloproteinase (MT1-MMP)
Authors: Kevin E. Fisher, Wonshill Koh, W. Brian Saunders, George E. Davis
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

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Tumor cell invasion of three-dimensional (3D) matrices differs from cell migration on two-dimensional substrata. Here we utilize new microassay systems that assess the ability of lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) to regulate tumor cell invasion of three-dimensional collagen matrices. In migration assays, LPA stimulated migration while S1P inhibited migration of most tumor cell lines. HT1080 fibrosarcoma cells uniquely migrated in response to both lipids. Likewise, HT1080 cells invaded dramatically in 3D type I collagen invasion assays with either lipid. siRNA targeting of EDG1/S1P1 or EDG2/LPA1 specifically inhibited S1P-induced or LPA-induced HT1080 invasion, respectively. siRNA targeting of Rac1 or Cdc42 also decreased invasion of collagen matrices. Synthetic matrix metalloproteinase (MMP) inhibitors or tissue inhibitors of metalloproteinases (TIMPs)-2, -3, and -4 blocked HT1080 invasion but not migration suggesting a role for membrane-type MMPs (MT-MMPs) specifically in invasion. siRNA targeting of MT1-MMP markedly inhibited both S1P- and LPA-induced HT1080 invasion. These data suggest that coordinated signaling between LPA and S1P receptors and their effectors are required for cell motility, yet additional involvement of MT1-MMP is required during cellular invasive events. The assays described provide an effective means to identify the molecular requirements for either tumor cell migration or invasion of extracellular matrices.
The importance of school and social activities in the transmission of influenza A(H1N1)v: England, April – June 2009
Authors: I Kar-Purkayastha, C Ingram, H Maguire, A Roche
Journal: Eurosurveillance (2009)

During the containment phase in the United Kingdom (April to June 2009), a cluster of influenza A(H1N1)v cases was identified prompting further investigation and public health action by the Health Protection Agency. The first confirmed case, a pupil at a school in England, was imported. During the following two weeks, 16 further cases were confirmed with epidemiological links to the first imported case. In this cluster, we found that significant transmission occurred in two classes with attack rates of 17.4% and 7.4%. In each of the two classes a case had attended school whilst symptomatic. Other settings included a choir and a party. Minimum and maximum attack rates were 3.6% and 4.2% for the choir and 14.3% and 25% for the party. We did not find any evidence of transmission on two school bus trips despite exposure over 50 minutes to a symptomatic case and over two periods of 30 minutes to a case during the prodromal phase (i.e. within 12 hours of symptom onset). Nor was there onward transmission in another school despite exposure over several hours to two cases, both of whom attended school during the prodromal phase.
Morbidity and Mortality Due to Liver Disease in Children Undergoing Allogeneic Bone Marrow Transplantation: A 10-Year Prospective Study
Authors: Anna Locasciulli, Marina Testa, Maria Grazia Valsecchi, Laura Vecchi, Daniela Longoni, Paola Sparano, Attilio Rovelli, Cornelio Uderzo, Giuseppe Masera, Alfredo Alberti
Journal: Blood (1997)
137. pFex: A Novel Fiber Exchange System for the Creation of Modified-Fiber Gene Therapy Vectors
Authors: Shawn E. Lupold, Wasim H. Chowdhury, Ronald Rodriguez
Journal: Molecular Therapy (2004)

The application of conditionally replicating adenoviruses to cancer gene therapy has shown much promise. However, it has become apparent that these vectors must be more specifically re-targeted to increase therapeutic effect. Although the number of re-targeted vectors is growing, the total number is small, mostly due to cloning difficulties associated with the large viral genome. Here, we have developed a unidirectional shuttle exchange system, called pFex, where one can easily transfer modified fiber genes from a smaller shuttle vector directly into the fiber portion of the Adenovirus genome. The adenoviral acceptor vector, termed pFex, was derived from the AdEasy1 vector where the entire fiber gene has been replaced by the sucrose lethal gene, SacB, and two flanking non-compatible half-mutant lox sites. Several smaller shuttle vectors contain the modified fiber gene, which is also flanked by two non-compatible half mutant lox sites. In the presence of Cre recombinase, the modified fiber gene is shuttled into pFex, replacing SacB. The resulting lox sites are fully mutated and no longer recognized by Cre recombinase, producing a unidirectional exchange. The combination of several selection markers allows one to exchange fiber either before or after the traditional RecA mediated E1 region recombination. The pFex system is highly efficient and has been used to produce eight recombinant viral vectors in less than two weeks. This exchange system should dramatically increase the output of re-targeting adenoviral vectors.
Aberrant promoter methylation of SFRP1 (Secreted Frizzled-Related Protein1) gene in medulloblastoma and glioblastoma.
Authors: Mehdi Shahi, Mohammad Afzal, Subrata Sinha, Javier Castresana
Journal: Clinical Cancer Research (2008)

A23   SFRP1 (Secreted Frizzled-Related Protein1) is a putative tumor suppressor, WNT antagonist, and hedgehog signaling target gene, as its promoter has a Gli1 binding site. The SFRP1 locus at 8p11.21 has been reported to be inactivated in gastric and colorectal cancer and other tumors by epigenetic regulation at its promoter and deletion of the other allele.  In this study we found either absent expression in 1/6 (TE671) or low expression in 3/6 (PFSK-1, TE671c2 and D283) medulloblastoma cell lines, and absent expression in 2/8 (LN405 and SW1088) or low expression in 5/8 (U87MG, A172, T98G, CCF-STTG-1 and GOS-3) glioblastoma cell lines. Also 9/14 medulloblastoma samples and 25/27 glioma tumors showed low expression checked by real time RT-PCR. Further exploration of promoter methylation showed complete methylation in 3/8 glioblastoma cell lines and in 6/43 glioma samples. Partial methylation was demonstrated in 2/8 glioblastoma cell lines, 18/43 glioblastoma samples, 3/6 medulloblastoma cell lines and 5/14 medulloblastoma samples. Treatments of the medulloblastoma (TE671) and glioblastoma (U87MG and A172) cell lines with the demethylating drug 5-Aza-29-Deoxycytidine and the histone deacetylation agent Trichostatin A restored the expression of SFRP1.
Implantable defibrillators for life threatening ventricular arrhythmias
Authors: J. P Causer, D. T Connelly
Journal: BMJ (1998)

Increasing numbers of patients are surviving a first episode of life threatening ventricular arrhythmia. In the absence of an acute myocardial infarction, patients who survive either ventricular fibrillation or sustained ventricular tachycardia have a high risk of further episodes, which may be fatal.1 Until recently class I and class III antiarrhythmic drugs have been the standard treatment for these patients, with amiodarone2 and sotalol3 having been shown to be superior to class I drugs. Nevertheless, even with the best medical therapy, arrhythmia recurrence rates are still 40-50% at five years. There is now growing evidence to support the wider use of implantable cardioverter-defibrillator devices as primary treatment in some patients with serious ventricular arrhythmias.

These devices were developed in the 1970s, with the first human implant in 1980.4 Early devices had a single therapy option of defibrillation only; the generator was implanted abdominally; and thoracotomy was required for electrode placement. The units are now smaller (current devices are little bigger than a pacemaker) and can …
Electrophysiology of the Heart.
Authors: Brian F. Hoffman, Paul F. Cranefield
Journal: Annals of Internal Medicine (1960)

Relief of Symptoms. By Walter Modell. M.D., F.A.C.P. Second edition. Price, $11.50. Pp. 374. The C. V. Mosby Company, 3207 Washington Blvd., St. Louis 3, 1961. This has been a popular book. It covers the field of symptomatology in a remarkably complete way, in 32 short chapters. The style is informal, almost chatty, but engaging. Symptoms are looked at broadly in terms of their significance to the patient,
Abstract 995: Is Gender Still Relevant to the Outcome of Patients Undergoing Primary Percutaneous Coronary Intervention for ST-Elevation Myocardial Infarcation in the Contemporary Era? Insights From the Blue Cross Blue Shield of Michigan Cardiovascular Consortium (BMC2)
Authors: Elizabeth Jackson, Mauro Moscucci, Dean E Smith, David Share, Simon Dixon, Adam Greenbaum, Hitinder S Gurm
Journal: Circulation (2009)
Abstract 93: Phosphodiesterase III Inhibitor Is Useful in Takotsubo Cardiomyopathy with Shock
Authors: Masaki Okajima, Masayuki Takamura, Takumi Taniguchi
Journal: Circulation (2014)

Introduction: Takotsubo cardiomyopathy characterized by acute left ventricular dysfunction with transient apical ballooning often causes cardiogenic shock. However catecholamine agents should be avoided to use if possible because those agents have a causative role in development of this cardiomyopathy. Phosphodiesterase III inhibitor is one of the most useful drugs for cardiogenic shock. But the use of PDE III inhibitor has not been described previously in takotsubo cardiomyopathy with shock. Objective: To investigate if PDE III inhibitor can improve effectively and safely cardiaogenic shock with takotsubo cardiomyopathy. Patients and Methods: We reviewed all patients with takotsubo cardiomyopathy who admitted to our ICU between April 2009 and March 2012. Among them, patients who were treated with PDE III inhibitor were chosen. The data of arterial pressure, heart rate, SvO2, pulmonary arterial pressure and cardiac index were obtained every 4hour. We also checked if there was the event of ventricular tach...
Genetic Factors Influencing Irradiation Protection by Bone Marrow. II. The Histocompatibility-2 (&lt;italic&gt;H-2&lt;/italic&gt;) Locus
Authors: Delta E. Uphoff, L. W. Law
Journal: JNCI Journal of the National Cancer Institute (1958)

Genetic Factors Influencing Irradiation Protection by Bone Marrow. II. The Histocompatibility-2 (H-2) Locus Get access Delta E. Uphoff, Delta E. Uphoff National Cancer Institute,3Bethesda, Maryland Search for other works by this author on: Oxford Academic PubMed Google Scholar L. W. Law L. W. Law National Cancer Institute,3Bethesda, Maryland Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 20, Issue 3, March 1958, Pages 617–624, https://doi.org/10.1093/jnci/20.3.617 Published: 01 March 1958 Article history Received: 05 November 1957 Published: 01 March 1958
Heparin-induced antiheparin-platelet antibody associated with retinal venous thrombosis1 1The scientific work presented in this manuscript was completed while Drs. Nguyen and Do were a Retina Fellow and a Medical Intern, respectively, at Harvard Medical School. Drs. Nguyen and Do are currently at the Wilmer Ophthalmological Institute.
Authors: Quan Dong Nguyen, Diana Van Do, Gilbert T Feke, Zareh Nazareth Demirjian, Kameran Lashkari
Journal: Ophthalmology (2003)
CX-5461 selectively inhibits the SL1 Component of RNA Polymerase I in the ribosome biogenesis pathway and gives potent antitumor activity in models of cancer
Authors: Jeffery Whitten, Denis Drygin, Mustapha Haddach, Caroline Ho, Amy Lin, Johnny Nagasawa, Sean O'Brien, Fabrice Pierre, Katy Trent, William Rice
Journal: Cancer Research (2008)

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

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The ribosome controls the rate of cell proliferation and eventually its fate. A central component of the ribosome is rRNA, which is synthesized in the nucleolus by RNA Polymerase I (Pol I). The synthesis of rRNA is initiated by the assembly of Pol I and a defined set of transcription factors to form the pre-initiation complex (PIC). Part of the PIC is the TBP-TAF assembly of proteins called SL1, and Pol I cannot function without it. Several known tumor-suppressors (p53, Rb, PTEN) that are often lost during tumorigenesis were shown to negatively effect the functioning of SL1 making it a lucrative target for oncology. Here we report a small molecule CX-5461 that selectively inhibits rRNA synthesis by interfering with SL1. As expected, with a compound that modulates ribosome biogenesis, CX-5461 demonstrated strong anti-proliferative potency against a broad range of tumor cell lines in vitro , and it has also shown potent oral activity in mouse xenograft models of human cancers.    CX-5461 was tested for the inhibition of various human RNA Polymerases with a series of nuclear extract-based transcriptional assays and demonstrated good potency and selectivity for Pol I IC50 = 0.7 uM, versus Pol II (11 uM) and Pol III (4 uM). The potency and selectivity are also translated to cell culture. qRT-PCR analysis of total RNA from cells treated with CX-5461 showed that drug was more potent in depleting the pre-rRNA levels (IC50 = 0.25 uM) than RNA Polymerase II transcribed c-Myc mRNA levels (IC50 = 3.72 uM). The compounds mechanism of action studies based on ChiP assay showed that drug interfered with SL1 induced assembly of PIC. In Alamar Blue cell viability assays CX-5461 had an average IC50 against 20 varied cell lines from those of pancreas, prostate, colorectal, lung, breast, ovary etc of 78nM. In mouse xenograft model of human pancreatic cancer (Mia PaCa-2) CX-5461 demonstrated strong tumor reduction when given orally with T/C of 37% and insignificant weight loss.    Selective inhibition of SL1 is effective in models of cancer and gives good efficacy with low side effects. Compound CX-5461 is an orally active small molecule that is in preclinical development as a broad spectrum antitumor agent.
Abstract 18054: Metabolic Remodeling in Mice with Cardiomyocyte-Specific Fatty Acid Overload
Authors: Aly Elezaby, Aaron L Sverdlov, Vivian H Tu, Fuzhong Qin, Jamie Rimer, Jean E Schaffer, Wilson S Colucci, Edward J Miller
Journal: Circulation (2014)

Introduction: In obesity it is unclear how lipid accumulation in the cardiomyocyte contributes to the pathophysiology of metabolic heart disease (MHD). Potential mechanisms of lipid-induced dysfunction include toxic effects or signaling from lipid species and/or increased mitochondrial reactive oxygen species (ROS) production to decrease mitochondrial function. To determine how excess cardiomyocyte lipids mediate MHD, we measured lipid metabolites, lipid sensitive signaling and ROS production in mice with cardiomyocyte-specific overexpression of the fatty acid transport protein-1 (FATP1) in which increased uptake of fatty acids (FA) leads to MHD in the absence of systemic obesity or perturbation of systemic lipid metabolism. Hypothesis: Accumulation of FA in the cardiomyocyte leads to mitochondrial dysfunction and MHD via lipid metabolites and/or mitochondrial oxidant production. Methods and Results: FATP1 and wild type (WT) mice were studied at 5-8 weeks of age. In FATP1 hearts, LC-MS showed increased lo...