tbuckley/cabot-search huggingface dataset:
At the Transition from Invertebrates to Vertebrates, a Novel GnRH-Like Peptide Emerges in Amphioxus
Authors: Graeme J. Roch, Javier A. Tello, Nancy M. Sherwood
Journal: Molecular Biology and Evolution (2013)

Gonadotropin-releasing hormone (GnRH) is a critical reproductive regulator in vertebrates. Homologous peptides are also found in invertebrates, with a variety of characterized functions. In the amphioxus, an invertebrate that provides the best model for the transition to vertebrates, four GnRH receptors (GnRHRs) were previously described, but their native ligands were not identified. Using a more sensitive search methodology with hidden Markov models, we identified the first GnRH-like peptide confirmed in the amphioxus Branchiostoma floridae. This peptide specifically activated one of the four GnRHRs. Although the primary structure of this peptide was divergent from any previously isolated GnRH peptide, the minimal conserved residues found in all other GnRH superfamily members were retained. The peptide was immunolocalized in proximity of the central canal of the anterior nerve cord, a region where other neuropeptides and receptors have been found. Additionally, the amphioxus GnRH-like gene was positioned in a locus surrounded by syntenic homologs of the human GnRH paralogon. The amphioxus GnRH-like peptide, with its distinct primary structure, activated a receptor with equal potency to multiple ligands that span the GnRH superfamily.
Antibody-Mediated Inhibition of Cathepsin S Blocks Colorectal Tumor Invasion and Angiogenesis
Authors: Roberta E. Burden, Julie A. Gormley, Thomas J. Jaquin, Donna M. Small, Derek J. Quinn, Shauna M. Hegarty, Claire Ward, Brian Walker, James A. Johnston, Shane A. Olwill, Christopher J. Scott
Journal: Clinical Cancer Research (2009)

Abstract Purpose: Cathepsin S is a cysteine protease that promotes the invasion of tumor and endothelial cells during cancer progression. Here we investigated the potential to target cathepsin S using an antagonistic antibody, Fsn0503, to block these tumorigenic effects. Experimental Design: A panel of monoclonal antibodies was raised to human cathepsin S. The effects of a selected antibody were subsequently determined using invasion and proteolysis assays. Endothelial cell tube formation and aorta sprouting assays were done to examine antiangiogenic effects. In vivo effects were also evaluated using HCT116 xenograft studies. Results: A selected cathepsin S antibody, Fsn0503, significantly blocked invasion of a range of tumor cell lines, most significantly HCT116 colorectal carcinoma cells, through inhibition of extracellular cathepsin S–mediated proteolysis. We subsequently found enhanced expression of cathepsin S in colorectal adenocarcinoma biopsies when compared with normal colon tissue. Moreover, Fsn0503 blocked endothelial cell capillary tube formation and aortic microvascular sprouting. We further showed that administration of Fsn0503 resulted in inhibition of tumor growth and neovascularization of HCT116 xenograft tumors. Conclusions: These results show that blocking the invasive and proangiogenic effects of cathepsin S with antibody inhibitors may have therapeutic utility upon further preclinical and clinical evaluation. (Clin Cancer Res 2009;15(19):6042–51)
Molecular Approach to Adenosine Receptors: Receptor-Mediated Mechanisms of Tissue Protection
Authors: J Linden
Journal: The Annual Review of Pharmacology and Toxicology (2001)

Adenosine accumulation during ischemia and inflammation protects tissues from injury. In ischemic tissues adenosine accumulates due to inhibition of adenosine kinase, and in inflamed tissues adenosine is formed from adenine nucleotides that are released from many cells including platelets, mast cells, nerves, and endothelium. Nucleotides are rapidly converted to adenosine by a family of ecto-nucleotidases including CD39 and CD73. Activation of A 1 and possibly A 3 adenosine receptors (ARs) protects heart and other tissues by preconditioning through a pathway including protein kinase C and mitochondrial K ATP channels. Activation of A 2A receptors limits reperfusion injury by inhibiting inflammatory processes in neutrophils, platelets, macrophages and T cells. Adenosine produces proinflammatory responses mediated by receptors that vary among species; A 3 and A 2B receptors mediate degranulation of rodent and human or canine mast cells, respectively. Novel adenosine receptor subtype–selective ligands have recently been developed. These include MRS1754 (A 2B blocker), MRS1220 (A 3 blocker), MRE 3008F20 (human A 3 blocker), MRS1523 (rat A 3 blocker), and ATL146e (A 2A agonist). These new pharmacologic tools will help investigators to sort out how adenosine protects tissues from injury and to identify new therapeutic agents that hold promise for the treatment of inflammatory and ischemic diseases.
Transthoracic Ventricular Defibrillation with Triangular and Trapezoidal Waveforms
Authors: JOHN C. SCHUDER, GLENN A. RAHMOELLER, HARRY STOECKLE
Journal: Circulation Research (1966)

From 7, 200 fibrillation-defibrillation episodes in anesthetized dogs, the effectiveness of 6 classes of unidirectional shocks in reversing ventricular fibrillation of 30-sec duration was determined. The shocks lasted for 1 to 256 msec. Three waveforms (ascending ramp triangular, descending ramp triangular, and trapezoidal) were studied at peak currents of 10 amp and 20 amp. Families of curves of per cent success vs. energy were derived from the data for the 6 classes of waveforms studied and from corresponding curves for 3 classes of unidirectional square-wave shocks previously studied by our group. The families of curves were used as a basis for an analysis of the influence of various parameters on the effectiveness of shocks. We conclude that an appropriate energy content is a necessary, but not sufficient condition for effective ventricular defibrillation, that long, low-amplitude tails on shocks are detrimental and that excessive energy content is detrimental.
Intratumor Molecular and Phenotypic Diversity in Hepatocellular Carcinoma
Authors: Jean-Charles Nault, Augusto Villanueva
Journal: Clinical Cancer Research (2015)

Hepatocellular carcinoma is a highly heterogeneous disease both at the molecular and clinical levels. Intratumor morphologic and genetic heterogeneity adds a new level of complexity in our understanding of liver carcinogenesis, and it is likely an important determinant of primary and secondary resistance to targeted therapies. Clin Cancer Res; 21(8); 1786-8. ©2015 AACR. See related article by Friemel et al., p. 1951.
c-Jun NH2-Terminal Kinase Activation Contributes to Hypoxia-Inducible Factor 1α–Dependent P-Glycoprotein Expression in Hypoxia
Authors: Katrina M. Comerford, Eoin P. Cummins, Cormac T. Taylor
Journal: Cancer Research (2004)

We previously have shown that hypoxia increases the expression of P-glycoprotein, which in turn increases tumor cell capacity to actively extrude chemotherapeutic agents and may contribute to tumor drug resistance. This event is mediated through the hypoxia-inducible factor (HIF-1). Here, we investigated the role of the stress-activated protein kinase c-Jun NH(2)-terminal kinase (JNK) in the signaling mechanisms underlying these events. Hypoxia activates JNK activity in vitro and in vivo. Overexpression of mitogen-activated protein kinase (MAPK) kinase kinase (MEKK-1), which preferentially activates JNK, mimics, in a nonadditive way, hypoxia-induced activity of the MDR1 promoter and expression of MDR1 mRNA and P-glycoprotein. Furthermore, the JNK inhibitor SP600125 selectively and specifically inhibits hypoxia- and MEKK-1-induced MDR1 promoter activity in a dose-dependent manner. JNK inhibition also reversed hypoxia- and MEKK-1-induced activity of an HIF-1-dependent reporter gene. MEKK-1-induced MDR1 expression depends on a functional HIF-1 binding site (hypoxia-responsive element). Hypoxia- but not cobalt chloride-dependent HIF-1-DNA binding and transcriptional activation was inhibited by SP600125, indicating that hypoxia-induced signaling to HIF-1 depends on JNK activation. Because it has been reported that reactive oxygen species are increased in hypoxia and related to JNK activation, we investigated their role in signaling this response. Whereas exogenous addition of H(2)O(2) was sufficient to activate JNK, reactive oxygen species scavengers were without effect on hypoxia-induced JNK or HIF-1 activation. Thus, hypoxia-elicited MDR1 expression, which depends on HIF-1 activation, depends at least in part on signaling via activation of JNK. Furthermore, these events are independent of the generation of reactive oxygen intermediates. Thus, JNK may represent a therapeutic target in the prevention of tumor resistance to chemotherapeutic treatment.
THE INTERACTION BETWEEN <i>TOXOPLASMA GONDII</i> AND MAMMALIAN CELLS
Authors: Thomas C. Jones, James G. Hirsch
Journal: The Journal of Experimental Medicine (1972)

Electron microscope methods have been used to study delivery of macrophage primary or secondary lysosomal contents to phagocytic vacuoles containing living or dead toxoplasmas. Secondary lysosomes were labeled by culturing the cells in colloidal thorium dioxide (thorotrast) or in ferritin. Acid phosphatase cytochemistry was employed for detection of primary as well as secondary lysosomal constituents. These various lysosomal labels were present in nearly all vacuoles containing toxoplasmas killed with glutaraldehyde, or in vacuoles containing those parasites undergoing degeneration 1 hr after the uptake of living toxoplasmas. In contrast, at times ranging from 1 to 20 hr after infection, no vacuoles containing morphologically normal, apparently viable toxoplasmas were thorotrast or ferritin positive, and only rarely did these vacuoles react for acid phosphatase. In many instances vacuoles containing viable toxoplasmas and no lysosomal markers were situated in the same cell nearby to vacuoles containing degenerating toxoplasmas and lysosomal constituents, thus indicating that the determinants of lysosomal fusion were operating locally in the immediate vicinity of the phagocytic vacuole, and not operating to influence general cell function. Thus, some toxoplasmas are able to prevent the delivery of lysosomal contents, and apparently the phagocytic vacuole provides for these parasites a sheltered microenvironment ideal for their growth. Morphologic evidence indicated that living toxoplasmas altered the phagocytic vacuolar membrane in macrophages, fibroblasts, and HeLa cells. Within minutes after phagocytosis, the vacuole became surrounded by closely apposed strips of endoplasmic reticulum and mitochondria; somewhat later, microvillous protrusions of the membrane into the vacuole were seen. These morphologic features of phagocytic vacuoles containing living toxoplasmas may be of importance in relation to the absence of lysosomal fusion, or they may serve some function in protecting the host cell or in nourishing the parasite.
Detection and Significance of Myocardial Ischemia in Stable Patients After Recovery From an Acute Coronary Event
Authors: Arthur J. Moss
Journal: JAMA (1993)

<h3>Objective.</h3> —To determine the clinical significance of silent and symptomatic myocardial ischemia detected by noninvasive testing in stable postcoronary patients. <h3>Design.</h3> —Cohort study with a mean 23-month follow-up. <h3>Setting.</h3> —Ambulatory outpatients after recent hospitalization for an acute coronary event. <h3>Patients.</h3> —Nine hundred thirty-six patients (76% male; mean age, 58 years) who were clinically stable 1 to 6 months after hospitalization for acute myocardial infarction or unstable angina. <h3>Interventions.</h3> —Noninvasive testing involved rest, ambulatory, and exercise electrocardiograms and stress thallium-201 scintigraphy. <h3>Main Outcome Measures.</h3> —Cox regression analysis was used to evaluate the risk (hazard ratio) of first recurrent primary events (cardiac death, nonfatal infarction, or unstable angina) or restricted events (cardiac death or nonfatal infarction) associated with ischemic noninvasive test results. <h3>Results.</h3> —ST segment depression on the rest electrocardiogram was the only noninvasive test variable that identified a significantly increased risk (<i>P</i>=.05) for first recurrent primary events (hazard ratio; 95% confidence limits): rest electrocardiogram ST depression (1.5; 1.00,2.25); ambulatory electrocardiogram ST depression (0.86; 0.49,1.51); exercise electrocardiogram ST depression (1.13; 0.82,1.56); and stress thallium-201 reversible defects (1.3; 0.96,1.74). Test results were similar for first recurrent restricted events, and in patients with and without angina. Significantly increased risk (<i>P</i>&lt;.05) was noted when exercise-induced ST depression occurred in patients who also had reduced exercise duration (hazard ratio, 3.4) or when reversible thallium-201 defects occurred in patients who also had increased lung uptake (hazard ratio, 2.8). Each high-risk subset made up less than 3% of the population and contained less than 6% of patients with first primary events. <h3>Conclusion.</h3> —Detection of silent or symptomatic myocardial ischemia by noninvasive testing in stable patients 1 to 6 months after an acute coronary event is not useful in identifying patients at increased risk for subsequent coronary events. (<i>JAMA</i>. 1993;269:2379-2385)
Impact of Metabolic Syndrome on Procedural Outcomes in Patients With Atrial Fibrillation Undergoing Catheter Ablation
Authors: Sanghamitra Mohanty, Prasant Mohanty, Luigi Di Biase, Rong Bai, Agnes Pump, Pasquale Santangeli, David Burkhardt, Joseph G. Gallinghouse, Rodney Horton, Javier E. Sanchez, Shane Bailey, Jason Zagrodzky, Andrea Natale
Journal: Journal of the American College of Cardiology (2012)
Role of Adenine Nucleotides, Adenosine, and Inorganic Phosphate in the Regulation of Skeletal Muscle Blood Flow
Authors: James G. Dobson, Rafael Rubio, Robert M. Berne
Journal: Circulation Research (1971)

Experiments were performed on isolated frog sartorius muscle and in situ dog skeletal muscle to determine whether adenine nucleotides and their degradation products are released during contraction in concentrations capable of producing arteriolar dilation ATP was not detectable (&gt;10 -8 M) in the bathing solution of the resting or contracting frog sartorius muscle. Inorganic phosphate (P 1 ) in the muscle bath increased from 9 x 10 -5 M to 28 x 10 -5 M with 30 minutes of contraction (2 Hz) or with rest. With the dog hindlirnb preparation, ATP, ADP, and AMP were not detectable (&gt;5 x 10 ⊟8 M in the venous blood collected after 5 minutes of ischemic contraction whereas P 1 was present at a concentration of 3.7 x 10 x8 M. Arterial blood levels required to elicit detectable vasodilation for ATP, ADP, AMP, and P 1 were 28.7 x 10 -8 M, 27.1 x 10 -8 M 31.4 x 10 -8 M and 7.2 ⊠ 10 -4 M respectively. The adenosine concentration in dog muscle increased from 0.7 to 1.5 nmole/g with ischemic contraction, and hypoxanthine and inosine increased from 4.5 to 8.5 nmole/g and 2.0 to 5.5 nmole/g, respectively. The adenosine concentration in venous plasma collected from the hiodlimb immediately after termination of the irchemic contraction period was 2.2 x 10 -7 MM as compared to 0.4 x 10 -7 M in control venous and arterial blood samples. Hypoxanthine and inosine concentrations in venous blood increased 22- and 270-fold, respectively, foflowing ischemic contraction. The calculated interstitial fluid adenosine concentration was twice the arterial concentration of adenosine required to elicit maximal arteriolar dilation. These findings suggest that adenosine may play a role in the metabolic regulation of skeletal muscle blood flow, whereas ATP, ADP, AMP, and P 1 may not.
Cancer Rates After Year 2000 Significantly Decrease in Children With Perinatal HIV Infection: A Study by the Italian Register for HIV Infection in Children
Authors: Elena Chiappini, Luisa Galli, Pier-Angelo Tovo, Clara Gabiano, Catiuscia Lisi, Carlo Giaquinto, Osvalda Rampon, Guido Castelli Gattinara, Giulio De Marco, Patrizia Osimani, Mariano Manzionna, Angela Miniaci, Carlo Pintor, Raffaella Rosso, Susanna Esposito, Alessandra Viganò, Icilio Dodi, Anna Maccabruni, Carlo Fundarò, Maurizio de Martino
Journal: Journal of Clinical Oncology (2006)

To evaluate the impact of highly active antiretroviral therapy (HAART) on cancer incidence in HIV-infected children throughout a 20-year period.An observational population study was conducted on 1,190 perinatally HIV-infected children enrolled onto the Italian Register for HIV Infection in Children from 1985 to 2004 and never lost to follow-up (total observation time, 10,037.66 years). Cancer rates were calculated in the pre-HAART (1985 to 1995), early HAART (1996 to 1999), and late HAART (2000 to 2004) periods and compared using Poisson regression adjusted for age. The proportion of HAART-treated children increased from 4.1% in 1996 to 60.4% in 1999 and to 81.5% in 2004. In the same time frame, the proportion of children receiving HAART for at least 2 years increased from 3.1% to 77.0%.Overall, 35 cancers occurred. Cancer rates were 4.49 (95% CI, 2.37 to 6.64), 4.09 (95% CI, 1.68 to 6.50), and 0.76 (95% CI, 0.00 to 1.80) per 1,000 children per year in 1985 to 1995, 1996 to 1999, and 2000 to 2004, respectively. Notably, there was no significant difference comparing the periods from 1985 to 1995 and 1996 to 1999 (P = .081). By contrast, cancer rates were significantly lower in the period from 2000 to 2004 than in 1996 to 1999 (P < .0001). Results were confirmed by separately analyzing data from children observed from birth (P = .418 for 1985 to 1995 v 1996 to 1999; P = .001 for 1996 to 1999 v 2000 to 2004).Dramatically reduced cancer rates were observed only in the late HAART period in parallel to the increasing proportion of children receiving HAART therapy.
Psychiatric Hospitalizations among Survivors of Cancer in Childhood or Adolescence
Authors: Lone Ross, Christoffer Johansen, Susanne Oksbjerg Dalton, Lene Mellemkjær, Lars H. Thomassen, Preben Bo Mortensen, Jørgen H. Olsen
Journal: New England Journal of Medicine (2003)

We investigated whether children and adolescents who survive cancer are at increased risk for psychiatric hospitalization.
Carbamazepine-Induced Toxic Effects and HLA-B*1502 Screening in Taiwan
Authors: Pei Chen, Juei-Jueng Lin, Chin-Song Lu, Cheung-Ter Ong, Peiyuan F. Hsieh, Chih-Chao Yang, Chih-Ta Tai, Shey-Lin Wu, Cheng-Hsien Lu, Yung-Chu Hsu, Hsiang-Yu Yu, Long-Sun Ro, Chung-Ta Lu, Chun-Che Chu, Jing-Jane Tsai, Yu-Hsiang Su, Sheng-Hsing Lan, Sheng-Feng Sung, Shu-Yi Lin, Hui-Ping Chuang, Li-Chen Huang, Ying-Ju Chen, Pei-Joung Tsai, Hung-Ting Liao, Yu-Hsuan Lin, Chien-Hsiun Chen, Wen-Hung Chung, Shuen-Iu Hung, Jer-Yuarn Wu, Chi-Feng Chang, Luke Chen, Yuan-Tsong Chen, Chen-Yang Shen
Journal: New England Journal of Medicine (2011)

Carbamazepine, an anticonvulsant and a mood-stabilizing drug, is the main cause of the Stevens-Johnson syndrome (SJS) and its related disease, toxic epidermal necrolysis (TEN), in Southeast Asian countries. Carbamazepine-induced SJS-TEN is strongly associated with the HLA-B*1502 allele. We sought to prevent carbamazepine-induced SJS-TEN by using HLA-B*1502 screening to prospectively identify subjects at genetic risk for the condition.From 23 hospitals in Taiwan, we recruited 4877 candidate subjects who had not taken carbamazepine. We genotyped DNA purified from the subjects' peripheral blood to determine whether they carried the HLA-B*1502 allele. Those testing positive for HLA-B*1502 (7.7% of the total) were advised not to take carbamazepine and were given an alternative medication or advised to continue taking their prestudy medication; those testing negative (92.3%) were advised to take carbamazepine. We interviewed the subjects by telephone once a week for 2 months to monitor them for symptoms. We used the estimated historical incidence of SJS-TEN as a control.Mild, transient rash developed in 4.3% of subjects; more widespread rash developed in 0.1% of subjects, who were hospitalized. SJS-TEN did not develop in any of the HLA-B*1502-negative subjects receiving carbamazepine. In contrast, the estimated historical incidence of carbamazepine-induced SJS-TEN (0.23%) would translate into approximately 10 cases among study subjects (P<0.001).The identification of subjects carrying the HLA-B*1502 allele and the avoidance of carbamazepine therapy in these subjects was strongly associated with a decrease in the incidence of carbamazepine-induced SJS-TEN. (Funded by the National Science Council of Taiwan and the Taiwan Drug Relief Foundation.).
Research-Design Issues in Cancer-Symptom–Management Trials Using Complementary and Alternative Medicine: Lessons From the National Cancer Institute Community Clinical Oncology Program Experience
Authors: David R. Buchanan, Jeffrey D. White, Ann M. O'Mara, Joseph W. Kelaghan, Wendy B. Smith, Lori M. Minasian
Journal: Journal of Clinical Oncology (2005)

To identify major research-design issues in proposals submitted by investigators in the Community Clinical Oncology Program (CCOP) for clinical trials of complementary and alternative medicine (CAM) for cancer-symptom management.We conducted content analysis of all scientific reviews of concepts and protocols submitted by the CCOP to the National Cancer Institute (NCI) to identify research challenges in conducting clinical trials designed to evaluate CAM interventions for cancer-symptom management.Since the inception of the NCI Office of Cancer Complementary and Alternative Medicine in 1998, a total of 46 symptom-management studies using CAM interventions have been proposed by CCOP investigators, with 20 studies now in progress comprising 22% of the current total CCOP symptom-management portfolio. Proposals fell into four categories: complex natural products; nutritional therapeutics; mind-body interventions; and alternative medical systems. The most significant research-design issues arose as a consequence of the lack of preclinical data for CAM interventions and the lack of quality-control standards comparable with those used in regulating new pharmaceutical agents.Across the different types of CAM interventions, the most common problems found in proposed research designs are related to unwarranted assumptions about the consistency and standardization of CAM interventions, the need for data-based justifications for the study hypotheses, and the need to implement appropriate quality control and monitoring procedures during the course of the trial. To advance the state of the science, future research must address these critical issues if CAM interventions are to be evaluated rigorously and have a consequent impact on clinical practice and general public awareness.