tbuckley/cabot-search huggingface dataset:
Discovery of α-folate receptor specific GARFTase inhibitors as selective antitumor agents
Authors: Aleem Gangjee, Yiqiang Wang, Yijun Deng, Christina Cherian, Zhanjun Hou, Larry Matherly
Journal: Cancer Research (2008)

1309  One of the major hurdles in cancer chemotherapy is the inability of the chemotherapeutic agent to selectively target tumor cells. The over expression of the α-folate receptor (FRα) on the surface of a number of tumors including ovarian, endometrial, kidney, lung, breast and brain provides an opportunity to specifically target these tumors. This is particularly important as most normal cells do not express FRα. Agents that only utilize the FRα to gain entry into these tumors would thus be highly specific. We have recently discovered a series of pyrrolo[2,3-d]pyrimidine classical antifolates that are specifically taken up the FRα and inhibit FRα expressing tumor cells (KB and IGROV1) at nanomolar IC50 values. In addition, these analogs are not transported in normal cells via the reduced folate carrier (RFC). In situ assays with recombinant murine glycinamide ribonucleotide formyl transferase (GARFTase) inhibition afforded nanomolar IC50 values for some of the compounds and confirmed GARFTase as the target. In an attempt to optimized the chain length between the pyrrolo[2,3-d]pyrimidine and the benzoyl-L-glutamate, analogs with 3-, 4-, 5- and 6-carbon atom chains were synthesized. The analogs were synthesized from the appropriate triphenylphosphonium alkyl (3-6 carbon atoms) carboxylic acid and methyl 4-formylbenzoate followed by reduction to give the methyl carbomethoxyphenyl alkyl acids. Conversion to the corresponding α-haloketones and cyclization with 2, 6-diamino-4-oxo-pyrimidine afforded the substituted methyl pyrrolo[2,3-d]pyrimidine alkyl benzoates. Saponification followed by coupling with diethyl-L-glutamate and ester hydrolysis afforded the desired analogs. The 3- and 4- atom chain lengths were the most inhibitory to both tumor cells as well as GARFTase. To our knowledge, these analogs are unique in that some of them are potently cytotoxic to tumor cells via GARFTase inhibition, specifically target the FRα, and are not appreciably transported by the RFC.
Abstract 17772: Dimer Conversion of PPARalpha/RXR To PPARalpha/Sirt1 Suppresses Fatty Acid Oxidation Genes
Authors: Shinichi Oka, Peiyong Zhai, Takanobu Yamamoto, Junichi Sadoshima
Journal: Circulation (2013)

A decline in fatty acid oxidation (FAO) is a hallmark of the failing heart. The PPARα/RXR dimer transcribes genes involved in FAO through a DNA binding element called direct repeat 1 (DR1). However...
Principles and Practice of Medical Therapy in Pregnancy
Authors: Norbert Gleicher, Louis Buttino
Journal: Annals of Internal Medicine (1992)

General aspects of medical care during pregnancy genetic considerations before and during pregnancy nutritional disturbances and requirements diseases caused by chemical and physical agents metabolic disease hormonal diseases immune system infectious diseases - general aspects of infectious diseases infections caused by gram-positive cocci infections caused by gram-negative cocci aerobic bacterial infections anaerobic bacterial infections in pregnancy infections caused by nycobacteria, ectoparasites and spirocheta infections caused by higher bacteria, fungi, rickettsia, mycoplasma and chlamydia TORCH infections viral infections central nervous system viruses miscellaneous and presumptive viral infections protozoan and helminthic infections obstetrics and gynaecologicinfections pulmonary diseases cardiovascular diseases hypertensive disease renal and urinary tract diseases gastrointestinal tract liver and pancreas haematologic diseases malignant diseases diseases of the breast skin, cartilage and bone diseases of the eye and ear psychiatric, neurologic and striated muscle critical care, trauma and surgey in pregnancy the foetus as a patient. (Part contents)
847. Hyaluronic Acid as a Self-Assembled Coating of Plasmid / Polycation Complexes for Cell-Specific Gene Delivery
Authors: Tomoko Ito, Naoko Iida Tanaka, Toshinori Sato, Zhihong Yang, Takuro Niidome, Takahito Kawano, Yoshiyuki Koyama
Journal: Molecular Therapy (2004)

Top of pageAbstract
As non-viral vectors for gene therapy, uncontrolled interaction of the cationic DNA/polycation complexes with the extracellular matrix or the serum proteins has been obstacle to the in vivo gene therapy. We have reported that the poly(ethylene glycol) derivatives having carboxylic acid-side chains (PEG-C) coated the DNA/polycation complexes, and protect them from these uncontrollable interactions1. Introducing the ligand into the side chains of the polymer allowed the receptor-mediated cell-specific and highly effective gene transfection2.

PEG-C could be deposited onto the surface of the plasmid/ polycation complexes, and the ternary complex was formed. But common polyanions like polyacrylic acid, or heparin would decompose the complex and substitute with the plasmid releasing the free DNA molecules.

Hyaluronic acid (HA) is a natural acidic mucopolysaccharide, and was found to coat the DNA/polycation complexes without decomposition. CD44, a receptor for HA, is known to be overexpressed on the various tumor cell surfaces, and HA is thus expected to form ternary complexes with plasmid and polycation, expressing the binding site to the receptors on the malignant cell surfaces.

In this study, we investigated the effect of the HA-coating of the plasmid/polycation complex on the suppression of the undesired interaction with serum protein, and the gene-transfection efficiency on the CD44-presenting CHO cells.

(1) Microscopic observation of the plasmid/polycation/HA ternary complex: The fluorescence microscopic images of the DAPI-DNA, fluorescein-PEI and rhodamine-HA mixture were all observed at the same position as brightening dots, indicating the formation of the ternary complexes. Albumin induced the aggregation of the plasmid/polycation binary complexes, but not the HA-coated ternary complexes, which remained to fluctuate for a long time after the albumin addition, showing the protecting effect of HA against the serum protein.

The efficient binding of the fluorescence-labeled plasmid/PEI/HA ternary complex to the CHO cells was observed under the fluorescence microscopic observation.

(2) Gene expression study: HA obviously enhanced the gene-expression on CHO cells mediated by HelΔ1 (a cationic amphiphilic peptide) up to 30-fold higher than those without HA. Transfection efficiency mediated by chitosan, or linear-PEI was also 3-4 times improved by HA. Such enhancing effect was, however, not observed on the CD44-negative COS-7 cells. Far excess addition of HA or the pretreatment by the polysaccharide diminished the gene-expression, indicating the receptor-mediated mechanism of the HA-coated ternary complex.
Abstract 12813: Assessment of Coronary Artery Disease Severity and Prognostic Factors for Cardiovascular Events in Patients With Lower Limb Artery Disease
Authors: Hiroyuki Hikita, Yosuke Yamakami, Keisuke Kojima, Yuichiro Sagawa, Hirofumi Ohtani, Keiichi Hishikari, Tomoyo Sugiyama, Shigeki Kimura, Atsushi Takahashi, Mitsuaki Isobe
Journal: Circulation (2014)

Introduction: Cardiovascular mortality in patients with lower limb artery disease is higher in critical limb ischemia (CLI) than in intermittent claudication (IC). We sought to evaluate differential characteristics of coronary artery disease severity and prognostic factors for cardiovascular events between CLI and IC patients. Methods: Coronary and lower limb angiography was performed on 242 patients (age 73±8 years, mean±sd, men 186) without cardiac symptoms and with symptoms of either CLI or IC. From the coronary angiogram of each study patient, Gensini Score as an index of coronary angiographic severity and an incidence of significant stenosis (AHA classification, ≥75% stenosis) in at least one of major coronary arteries were evaluated. High sensitivity troponin T (hs-TnT), eicosapentaenoic acid-arachidonic acid ratio (EPA/AA), and lipoprotein (a), as biomarkers for prognostic factors, were measured from blood samples at rest in the fasting state. Results: The study patients were divided into CLI-group (42 patients) and IC-group (200 patients). Coronary angiography showed that Gensini Score and an incidence of significant stenosis (AHA classification, ≥75% stenosis) in at least one of major coronary arteries were higher in the CLI-group than in the IC-group (39±32 vs 8±8, p&lt;0.001, 59.5% vs 22.0%, p&lt;0.001, respectively). Hs-TnT and lipoprotein (a) values were higher in the CLI-group than the IC-group (0.15±0.19 ng/ml vs 0.05±0.09, p&lt;0.001, 45.9±23.3 mg/dl vs 26.2±27.7, p&lt;0.001, respectively) and EPA/AA was lower in the CLI-group than in the IC-group (0.22±0.11 vs 0.38±0.29, p&lt;0.005, respectively). Conclusions: Greater coronary artery disease severity, higher hs-TnT and lipoprotein (a), and lower EPA/AA were observed in the CLI patients, which may explain higher cardiovascular events in CLI patients than IC.
Hypoxia-Inducible Factor-1a DNA Induced Angiogenesis in Cerebral Ischemia Model in the Rat
Authors: Tatsuya Abe, Tsuyoshi Matsuda, Jian Liang Wu, Ryo Inoue, Minoru Fujiki, Hidenori Kobayashi
Journal: Molecular Therapy (2004)

Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that regulates the adaptive response to hypoxia in mammalian cells. It consists of a regulatory subunit HIF-1a, which accumulates under hypoxic conditions, and a constitutively expressed subunit HIF-1b. In this study, we investigated HIF-1a naked DNA induced angiogenesis in cerebral ischemic model in vivo. We utilized encephalo-myo-synangiosis (EMS) model of rat and inoculated HIF-1a DNA on brain surface or into temporal muscle. Histological section of rat treated with HIF-1a DNA showed the increased expression of HIF-1a and VEGF and induced collateral circulation, in comparison with control DNA (P<0.05). The HIF-1a transcription factor is able to promote significant development of angiogenesis. These results suggest the feasibility of a novel approach for therapeutic collateral circulation of cerebral ischemia in which neovascularization may be achieved indirectly by use of a transcriptional regulatory strategy.
Angioedema induced by cardiovascular drugs: new players join old friends
Authors: M. Bas, J. Greve, U. Strassen, F. Khosravani, T. K. Hoffmann, G. Kojda
Journal: Allergy (2015)

During the last years, two new cardiovascular drug classes, namely inhibitors of DPP IV or neprilysin, have been developed. In both cases, there is clinical evidence for their potential to induce angioedema as known already from blockers of the renin-angiotensin-aldosterone system (RAAS). The majority of angioedema induced by DPP IV inhibitors occurs during concomitant treatment with ACEi and is therefore likely mediated by overactivation of bradykinin type 2 receptors (B2). In striking contrast, the molecular pathways causing angioedema induced by neprilysin inhibitors, that is, sacubitril, are unclear, although a contribution of bradykinin appears likely. Nevertheless, there is no clinical evidence suggesting that inhibition of B2 might relieve the symptoms and/or prevent invasive treatment including coniotomy or tracheotomy in angioedema caused by these drugs. Therefore, the risk of angioedema should always be considered, especially in ambulatory care situations where patients have no rapid access to intensive care.
Expression of VEGFR-2 and AC133 by circulating human CD34+ cells identifies a population of functional endothelial precursors
Authors: Mario Peichev, Afzal J. Naiyer, Daniel Pereira, Zhenping Zhu, William J. Lane, Mathew Williams, Mehmet C. Oz, Daniel J. Hicklin, Larry Witte, Malcolm A. S. Moore, Shahin Rafii
Journal: Blood (2000)
Ischemic preconditioning increases adenosine release and 5'-nucleotidase activity during myocardial ischemia and reperfusion in dogs. Implications for myocardial salvage.
Authors: M Kitakaze, M Hori, S Takashima, H Sato, M Inoue, T Kamada
Journal: Circulation (1993)

BACKGROUND Adenosine has been reported to mediate the necrosis-limiting effects of ischemic preconditioning; however, it is unclear how this mediation occurs. The present study was undertaken to test the hypothesis that ischemic preconditioning increases 5'-nucleotidase activity and adenosine release during sustained ischemia and subsequent reperfusion. METHODS AND RESULTS After thoracotomy, the left anterior descending coronary artery was cannulated and perfused with blood redirected from the left carotid artery in 32 dogs. Ischemic preconditioning was produced by four cycles in which the coronary artery was occluded and then reperfused for 5 minutes each. After the last cycle of ischemia and reperfusion, the coronary artery was occluded for 40 minutes. This was followed by 120 minutes of reperfusion. In the control group, the coronary artery was occluded for 40 minutes and reperfused for 120 minutes without ischemic preconditioning. The plasma adenosine concentration was measured and blood gases were analyzed in coronary arterial and venous blood samples taken during 120 minutes of reperfusion. Myocardial 5'-nucleotidase activity was measured before and at 40 minutes of sustained ischemia with and without ischemic preconditioning. The adenosine concentration in coronary venous blood during reperfusion was significantly higher in preconditioned hearts than in the control hearts: 1 minute after the onset of reperfusion, 546 +/- 57 versus 244 +/- 41 pmol/ml; 10 minutes after, 308 +/- 30 versus 114 +/- 14 pmol/ml; 30 minutes after, 175 +/- 24 versus 82 +/- 16 pmol/ml, respectively (p &lt; 0.01). Ectosolic and cytosolic 5'-nucleotidase activities increased in both endocardial and epicardial myocardium in the ischemia-preconditioned hearts. Furthermore, 40 minutes of ischemia increased 5'-nucleotidase activity in ischemia-preconditioned hearts more than in control hearts. CONCLUSIONS Ischemic preconditioning increases adenosine release and 5'-nucleotidase activity during sustained ischemia and subsequent reperfusion.
Abstract 258: Characterizing cancer gene mutations in non-small cell lung cancer from African American patients
Authors: Aliccia Bollig-Fischer, Shirish Gadgeel, Wei Chen, Michele Cote, Ann G. Schwartz, Gerold Bepler
Journal: Cancer Research (2014)

Abstract Background and Hypothesis: Lung cancer is the leading cause of cancer-related deaths in the United States. The reasons for higher incidence and inferior survival rates among African American lung cancer patients have not been adequately defined. We hypothesized that molecular differences, specifically differential incidence of somatic cancer gene mutations, may be a contributing factor to these population-based disparities. Large-scale, high-throughput genomic studies of the major subtype of lung cancer, non-small cell lung cancer (NSCLC), have so far neglected to adequately represent African American patients. Such information holds potential to transform treatment decisions to improve care for subsets of patients and address disparities. Methods: We tested our hypothesis using a MALDI-TOF mass spectrometry approach to analyze tumor DNA for 214 coding mutations in 26 cancer genes previously linked to NSCLC, including oncogenes and tumor suppressor genes. The sample sets investigated included NSCLC specimens from 335 patients of European ancestry and 137 African Americans. For 299 of these 472, DNA from normal matched specimens was available and included in the study, thus totaling 771 samples. Results: There was no significant difference in frequencies for somatic cancer gene coding mutations across populations and gene mutation frequencies were within reported ranges, e.g., KRAS (11%), EGFR (10%) and PIK3CA (2%). However, this study also uncovered a previously unrecognized germ line variant in the DDR2 oncogene. In addition, we found that the frequencies of single nucleotide polymorphisms (SNPs) in STK11, cMet, and NOTCH differ between African American and European ancestry patients. Conclusion: This body of work is among the largest reported on to date comparing somatic cancer gene mutations in African American and European-ancestry patients. The outcomes show that across a broad spectrum of coding mutations, genomic tumor testing could equally benefit both populations. Citation Format: Aliccia Bollig-Fischer, Shirish Gadgeel, Wei Chen, Michele Cote, Ann G. Schwartz, Gerold Bepler. Characterizing cancer gene mutations in non-small cell lung cancer from African American patients. [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 258. doi:10.1158/1538-7445.AM2014-258
Activated protein C β-glycoform promotes enhanced noncanonical PAR1 proteolysis and superior resistance to ischemic injury
Authors: Eimear M. Gleeson, María G. Dichiara, Agustina Salicio, Louise M. Quinn, Clive Drakeford, Shane E. Russell, Patrick T. Walsh, Josune Orbe, José Hermida, Owen P. Smith, James S. O’Donnell, Ramón Montes, Roger J. S. Preston
Journal: Blood (2015)
Feasibility and safety of propofol sedation in flexible bronchoscopy
Authors: Peter Grendelmeier, Gabriel Kurer, Eric Pflimlin, Michael Tamm, Daiana Stolz
Journal: European Respiratory Journal (2011)

Background:  Propofol is a sedative-hypnotic with a rapid onset of action. There are only limited data evaluating propofol for flexible bronchoscopy. We analyzed the feasibility and safety of propofol for bronchoscopy in a high output tertiary care center.   Methods:  Prospective data on patients undergoing flexible bronchoscopy at the University Hospital Basel, Switzerland were analyzed. Patient demographics, ASA class, Mallampati class, indication for bronchoscopy, bronchoscopic procedures, duration of examination, medication requirements, minor and major adverse events, hemodynamic parameters, as well as cough scores during the procedure were documented. Patients were followed up to discharge from the bronchoscopy suite.   Results:  Data on 440 patients with mean age 60 years (± 15.5, 260 male) were analyzed. Main indication for bronchoscopy was suspicion of malignancy. The most common diagnostic procedures were bronchoalveolar lavage in 253 cases (31.5%) and bronchial washing in 174 cases (21.7%). The mean duration of the procedure was 19.6 min (± 12.08). The mean propofol dose was 200 mg (± 107.5) corresponding to 2.89 mg/kg (± 1.70). Minor adverse events included oxygen desaturation in 72 (16.4%), hypotension in 68 (15.4%) and minor bleeding in 11 (2.5%) patients. No major adverse events were recorded. The median decline in systolic blood pressure after initiation of sedation was 14 mmHg (3 - 28). A drop in systolic blood pressure greater than 20 mmHg was observed in 166 of the 440 patients (37%).   Conclusion:  Propofol sedation for flexible bronchoscopy is feasible and safe.
Abstract 1905: Defining a therapeutic classification of breast cancer by actionable targets
Authors: Manuel Salto-Tellez, David P. Boyle, Darragh McArt, Gareth Irwin, Charlotte Charlotte Wilhelm-Benartzi, Tong G. LIoe, Martha Minter, Stephen McQuaid, Paul Mullan, Richard D. Kennedy, Peter Hamilton, D P. Harkin
Journal: Cancer Research (2014)

Abstract Breast cancer remains a frequent cause of female cancer death despite the great strides in elucidation of biological subtypes and their reported clinical and prognostic significance. We have defined a general cohort of breast cancers in terms of putative actionable targets, involving growth and proliferative factors, the cell cycle, and apoptotic pathways, both as single biomarkers across a general cohort and within intrinsic molecular subtypes. We identified 293 patients treated with adjuvant chemotherapy. Additional hormonal therapy and trastuzumab was administered depending on hormonal and HER2 status respectively. We performed immunohistochemistry for ER, PR, HER2, MM1, CK5/6, p53, TOP2A, EGFR, IGF1R, PTEN, p-mTOR and e-cadherin. The cohort was classified into luminal (62%) and non-luminal (38%) tumors as well as luminal A (27%), luminal B HER2 negative (22%) and positive (12%), HER2 enriched (14%) and triple negative (25%). Patients with luminal tumors and co-overexpression of TOP2A or IGF1R loss displayed worse overall survival (p=0.0251 and p=0.0008 respectively). Non-luminal tumors had much greater heterogeneous expression profiles with no individual markers of prognostic significance. Non-luminal tumors were characterised by EGFR and TOP2A overexpression, IGF1R, PTEN and p-mTOR negativity and extreme p53 expression. Our results indicate that only a minority of intrinsic subtype tumors purely express single novel actionable targets. This lack of pure biomarker expression is particular prevalent in the triple negative subgroup and may allude to the mechanism of targeted therapy inaction and myriad disappointing trial results. Utilising a combinatorial biomarker approach may enhance studies of targeted therapies providing additional information during design and patient selection while also helping decipher negative trial results. Citation Format: Manuel Salto-Tellez, David P. Boyle, Darragh McArt, Gareth Irwin, Charlotte Charlotte Wilhelm-Benartzi, Tong G. LIoe, Martha Minter, Stephen McQuaid, Paul Mullan, Richard D. Kennedy, Peter Hamilton, D P. Harkin. Defining a therapeutic classification of breast cancer by actionable targets. [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 1905. doi:10.1158/1538-7445.AM2014-1905
Differential expression of Rel/NF-κB and octamer factors is a hallmark of the generation and maturation of dendritic cells
Authors: M. Neumann, H.-W. Fries, C. Scheicher, P. Keikavoussi, A. Kolb-Mäurer, E.-B. Bröcker, E. Serfling, E. Kämpgen
Journal: Blood (2000)
Mutant <i>COQ2</i> in Multiple-System Atrophy
Authors: Catarina M Quinzii, Michio Hirano, Salvatore DiMauro
Journal: New England Journal of Medicine (2014)

To the Editor: Tsuji and colleagues (July 18 issue) 1 report that variants in the gene encoding coenzyme Q 2 (COQ2) increase the risk of multiple-system atrophy.They observed homozygous COQ2 variants encoding the substitutions M78V and V343A in a consanguineous Japanese family with multiple-system atrophy subtype P and noted an association between V343A and sporadic multiple-system atrophy (minor-allele frequency [MAF], 4.8% of cases vs. 1.6% of controls; odds ratio, 3.05; 95% confidence interval, 1.65 to 5.85).However, the authors erroneously labeled human COQ2 variability from the fourth ATG start codon in exon 1, which encodes the smallest protein isoform and does not functionally complement the yeast coq2-null mutant. 2On the basis of the National Center for Biotechnology Information (NCBI) Reference Sequence (NM_015697.7),M78V should be labeled COQ2 c.382A→G (p.M128V) and V343A should be labeled c.1178T→C (p.V393A).We sequenced COQ2 in 299 Korean persons with multiple-system atrophy and 365 unaffected Korean persons and observed heterozygous COQ2 c.320G→C (encoding p.S107T) and c.382A→T (encoding p.M128R) in 2 patients with sporadic multiple-system atrophy; COQ2 c.1178T→C (p.V393A) was not associated with multiple-system atrophy (MAF, 2.7% of cases vs. 2.6% of controls).It is a challenge to reconcile recessive linkage of homozygous COQ2 mutations in familial multiple-system atrophy with a heterozygous, presumably dominant-negative association in sporadic multiple-system atrophy.Respectfully, we suggest that Tsuji and colleagues reconsider whether variations in COQ2 represent a risk factor for multiple-system atrophy.Genomic multiplications of the SNCA 6.4-Mb locus telomeric to COQ2 have previously been implicated in parkinsonism and multiple-system atrophy 3 ; copy number analysis of linked loci, or genomewide analysis, should be considered.