tbuckley/cabot-search huggingface dataset:
Effects of phorbol esters on pial arteriolar diameter and brain production of prostanoids in piglets.
Authors: D W Busija, C W Leffler
Journal: Circulation Research (1991)

We determined the effects of phorbol 12,13-dibutyrate (PDB), which activates protein kinase C, on pial arteriolar diameter and cerebrospinal fluid (CSF) prostanoid levels in newborn pigs. A closed cranial window was implanted, and the diameter of one pial arteriole was determined by intravital microscopy. In addition, CSF was sampled from under the window, and prostanoid levels (prostaglandin [PG] E2, 6-keto-PGF1 alpha, PGF2 alpha, and thromboxane B2) were determined by radioimmunoassay. Diameter and CSF prostanoid levels were determined during application of artificial CSF containing no drugs and during application of 10(-8), 10(-7), and 10(-6) M PDB. We also determined effects of 4 alpha-phorbol 12,13-didecanoate (4 alpha-PDD), a phorbol ester that does not activate protein kinase C, and dimethyl sulfoxide, the vehicle for the phorbol esters, on pial arteriolar diameter and CSF prostanoid levels. Initial diameters were 100-200 microns. At 10(-8)-10(-6) M, PDB progressively constricted pial arterioles and increased CSF levels of prostanoids; the other phorbol ester and dimethyl sulfoxide had no such effects. Baseline arteriolar diameter was 147 +/- 17 microns (mean +/- SEM), and diameter was 140 +/- 17 microns at 10(-8) M PDB, 120 +/- 18 microns at 10(-7) M PDB (p less than 0.05), and 108 +/- 14 microns at 10(-6) M PDB (p less than 0.05) (n = 5).(ABSTRACT TRUNCATED AT 250 WORDS)
Hidden localization motifs: naturally occurring peroxisomal targeting signals in non-peroxisomal proteins.
Authors: Georg Neuberger, Markus Kunze, Frank Eisenhaber, Johannes Berger, Andreas Hartig, Cecile Brocard
Journal: Genome biology (2004)

Abstract Background Can sequence segments coding for subcellular targeting or for posttranslational modifications occur in proteins that are not substrates in either of these processes? Although considerable effort has been invested in achieving low false-positive prediction rates, even accurate sequence-analysis tools for the recognition of these motifs generate a small but noticeable number of protein hits that lack the appropriate biological context but cannot be rationalized as false positives. Results We show that the carboxyl termini of a set of definitely non-peroxisomal proteins with predicted peroxisomal targeting signals interact with the peroxisomal matrix protein receptor peroxin 5 (PEX5) in a yeast two-hybrid test. Moreover, we show that examples of these proteins - chicken lysozyme, human tyrosinase and the yeast mitochondrial ribosomal protein L2 (encoded by MRP7 ) - are imported into peroxisomes in vivo if their original sorting signals are disguised. We also show that even prokaryotic proteins can contain peroxisomal targeting sequences. Conclusions Thus, functional localization signals can evolve in unrelated protein sequences as a result of neutral mutations, and subcellular targeting is hierarchically organized, with signal accessibility playing a decisive role. The occurrence of silent functional motifs in unrelated proteins is important for the development of sequence-based function prediction tools and the interpretation of their results. Silent functional signals have the potential to acquire importance in future evolutionary scenarios and in pathological conditions.
Mortality From Site-Specific Malignancies in Type 2 Diabetic Patients From Verona
Authors: Giuseppe Verlato, Giacomo Zoppini, Enzo Bonora, Michele Muggeo
Journal: Diabetes Care (2003)

The aim of the present work was to compare mortality from site-specific malignancies in type 2 diabetic patients with those in the general population.Mortality from site-specific cancers was assessed in a population-based cohort of 7,148 type 2 diabetic patients from Verona (Northern Italy) during a 10-year follow-up (1987-1996) by reviewing death certificates. Standardized mortality ratio (SMR) data were computed using as reference mortality rates in the general population of Verona.During follow-up, 641 patients (378 men and 263 women) died of malignancies. The most common causes of death among site-specific malignancies were digestive tumors both in men (140 of 378, 37.0%) and women (105 of 263, 39.9%), respiratory tumors in men (103 of 378, 27.2%), and tumors of the reproductive system in women (79 of 263, 30.0%). A slight increase in the overall mortality from malignancies was observed in diabetic patients and achieved statistical significance in women (observed/expected = 1.16, 95% CI 1.02-1.30; P = 0.019) but not in men (observed/expected = 1.07, 0.97-1.19; P = 0.163). Excess mortality from hepatic cancer (SMR = 1.86, 1.44-2.38) was observed in both men and women. In addition, women with diabetes experienced a higher mortality from pancreatic tumors (observed/expected = 1.78, 1.13-2.67) and breast tumors (observed/expected = 1.40, 1.06-1.81). Excess mortality from breast cancer was confined to obese women with diabetes.Mortality from site-specific malignancies is different in type 2 diabetic patients than in the general population. Better control of body weight seems necessary to prevent the excess mortality from breast cancer in women.
Acquisition of high metastatic capacity after in vitro fusion of a nonmetastatic tumor line with a bone marrow-derived macrophage.
Authors: L Larizza, V Schirrmacher, E Pflüger
Journal: The Journal of Experimental Medicine (1984)

A low metastatic, thioguanine-resistant murine T lymphoma line (EbTGR) was hybridized in vitro, with the help of polyethylene glycol, with syngeneic bone marrow-derived macrophages. Two HAT-resistant hybrid lines (Eb-F1 and Eb-F2) were obtained from independent fusion cultures. A cytogenetic analysis revealed that most of the macrophage chromosomes except No. 12 had segregated or become rearranged 60 d after fusion, a time at which the cell lines had become stabilized in culture. Syngeneic mice inoculated subcutaneously with the tumor macrophage hybrid lines developed, very quickly, visceral metastases and died after less than 2 wk, while those inoculated with the parental line lived for greater than 6 wk and developed only localized, large primary tumors. The metastatic hybridomas expressed a similar tumor antigen as a spontaneous, in vivo derived, high metastatic variant (ESb) of the same tumor. This suggests that ESb cells might have arisen from a spontaneous fusion with a host macrophage.
Pancoast tumours: clinical assessment and long-term results of combined radiosurgical treatment
Authors: G. Muscolino, M. Valente, S. Andreani
Journal: Thorax (1997)

Many oncologists have now accepted a combined radiosurgical approach as the treatment of choice in patients with Pancoast tumour but most reports show an incorrect assessment of the disease.Stage III lung cancer was classified as Pancoast tumour if the pulmonary extent was limited to the upper apical segment and if at least one of the features of Pancoast syndrome, indicating tumour spread to the para-apical structures, was present. Between 1984 and 1988 15 consecutive patients were treated with primary radiotherapy followed by surgery or with primary excision and subsequent radiotherapy in the absence of an initial histological diagnosis.The mortality of patients given the combined treatment was 6.6% (one death due to pulmonary embolism), and the five year survival rate was 26.6% for all patients and 57% for those who underwent complete resection without N2 disease. Long-term survival was 0% for those cases with incomplete resection, N2 disease, or malignant invasion of the first rib.Stage III lung cancer, classified as Pancoast tumour according to strict, consistent criteria, is best treated by primary radiotherapy; combined treatment should be used only for patients with potentially resectable cancer without N2 disease and/or malignant invasion of the first rib.
BIRTH AFTER REPLACEMENT OF HATCHING BLASTOCYST CRYOPRESERVED AT EXPANDED BLASTOCYST STAGE
Authors: Jacques Cohen, RogerF Simons, CaroleB Fehilly, SimonB Fishel, RobertG Edwards, Jonathan Hewitt, GeorgeF Rowland, PatrickC Steptoe, JohnM Webster
Journal: The Lancet (1985)
Impact of Randomized Clinical Trial Results in the National Comprehensive Cancer Network on the Use of Tamoxifen After Breast Surgery for Ductal Carcinoma in Situ
Authors: Tina W.F. Yen, Henry M. Kuerer, Rebecca A. Ottesen, Layla Rouse, Joyce C. Niland, Stephen B. Edge, Richard L. Theriault, Jane C. Weeks
Journal: Journal of Clinical Oncology (2007)

The National Surgical Adjuvant Breast and Bowel Project B-24 trial, published in June 1999, demonstrated that tamoxifen after breast-conserving surgery (BCS) and radiotherapy for ductal carcinoma in situ (DCIS) reduced the absolute occurrence of ipsilateral and contralateral breast cancer. We assessed the impact of B-24 on practice patterns at selected National Comprehensive Cancer Network (NCCN) centers.Tamoxifen use after surgery was examined among 1,622 patients presenting for treatment of unilateral DCIS between July 1997 and December 2003 at eight NCCN centers. Associations of clinicopathologic and treatment factors with tamoxifen use were assessed in univariate and multivariable logistic regression analyses.Overall, 41% of patients (665 of 1,622) received tamoxifen. The proportion increased from 24% before July 1, 1999, to 46% on or after July 1, 1999. Factors significantly associated with receipt of tamoxifen included diagnosis on or after July 1, 1999 (odds ratio [OR], 3.85; P < .0001), BCS in patients younger than 70 years (OR, 3.21; P = .0073), no history of cerebrovascular or peripheral vascular disease (OR, 3.13; P = .0071), receipt of radiotherapy (OR, 1.82; P = .0009), and previous hysterectomy (OR, 1.34; P = .0459). Tamoxifen use varied significantly by center, from 34% to 74% after BCS and 17% to 53% after mastectomy (P < .0001).Tamoxifen use after surgery for DCIS at NCCN centers increased after presentation of the B-24 results. Rates varied substantially by institution, suggesting that physicians differ in how they weigh the modest reduction in breast cancer risk with tamoxifen against its potential adverse effects in this population.
miR-187 Is an Independent Prognostic Factor in Breast Cancer and Confers Increased Invasive Potential<i>In Vitro</i>
Authors: Laoighse Mulrane, Stephen F. Madden, Donal J. Brennan, Gabriela Gremel, Sharon F. McGee, Sara McNally, Finian Martin, John P. Crown, Karin Jirström, Desmond G. Higgins, William M. Gallagher, Darran P. O'Connor
Journal: Clinical Cancer Research (2012)

Abstract Purpose: Here, we describe an integrated bioinformatics, functional analysis, and translational pathology approach to identify novel miRNAs involved in breast cancer progression. Experimental Design: Coinertia analysis (CIA) was used to combine a database of predicted miRNA target sites and gene expression data. Using two independent breast cancer cohorts, CIA was combined with correspondence analysis and between group analysis to produce a ranked list of miRNAs associated with disease progression. Ectopic expression studies were carried out in MCF7 cells and miRNA expression evaluated in two additional cohorts of patients with breast cancer by in situ hybridization on tissue microarrays. Results: CIA identified miR-187 as a key miRNA associated with poor outcome in breast cancer. Ectopic expression of miR-187 in breast cancer cells resulted in a more aggressive phenotype. In a test cohort (n = 117), high expression of miR-187 was associated with a trend toward reduced breast cancer–specific survival (BCSS; P = 0.058), and a significant association with reduced BCSS in lymph node–positive patients (P = 0.036). In a validation cohort (n = 470), high miR-187 was significantly associated with reduced BCSS in the entire cohort (P = 0.021) and in lymph node–positive patients (P = 0.012). Multivariate Cox regression analysis revealed that miR-187 is an independent prognostic factor in both cohorts [cohort 1: HR, 7.37; 95% confidence interval (CI), 2.05–26.51; P = 0.002; cohort 2: HR, 2.80; 95% CI, 1.52–5.16; P = 0.001] and in lymph node–positive patients in both cohorts (cohort 1: HR, 13.74; 95% CI, 2.62–72.03; P = 0.002; cohort 2: HR, 2.77; 95% CI, 1.32–5.81; P = 0.007). Conclusions: miR-187 expression in breast cancer leads to a more aggressive, invasive phenotype and acts as an independent predictor of outcome. Clin Cancer Res; 18(24); 6702–13. ©2012 AACR.
Tumor Regression and Curability of Preclinical Neuroblastoma Models by PEGylated SN38 (EZN-2208), a Novel Topoisomerase I Inhibitor
Authors: Fabio Pastorino, Monica Loi, Puja Sapra, Pamela Becherini, Michele Cilli, Laura Emionite, Domenico Ribatti, Lee M. Greenberger, Ivan D. Horak, Mirco Ponzoni
Journal: Clinical Cancer Research (2010)

Treatment of neuroblastoma is successful in less than half of patients with high-risk disease. The antitumor activity of a water soluble pegylated SN38 drug conjugate, EZN-2208, was compared with CPT-11 (a prodrug for SN38) in preclinical models of human neuroblastoma.The in vitro cytotoxicity of EZN-2208 was tested by counting trypan blue dye- and Annexin V-positive cells, whereas its therapeutic efficacy was evaluated, in terms of survival, and antitumor and antiangiogenic activities, in s.c. luciferase-transfected, pseudometastatic, and orthotopic neuroblastoma animal models.EZN-2208 was about 100-fold more potent than CPT-11 in vitro, by inducing apoptosis/necrosis and p53 expression and by reducing hypoxia-inducible factor (HIF)-1α/HIF-2α expression. EZN-2208 gave superior antitumor effects compared with CPT-11 in neuroblastoma xenografts. EZN-2208 treatment always resulted in lack of tumor detection at the end of trials whereas only small therapeutic effects were observed with CPT-11, as assessed by luciferase assay or tumor size, or even by staining histologic sections of tumors with antibodies recognizing neuroblastoma cells and cell proliferation. In a neuroblastoma model resistant to doxorubicin, cisplatin, vincristine, fenretinide, and topotecan, EZN-2208 induced 100% curability. It also blocked tumor relapse after topotecan-vincristine-doxorubicin combined treatment. Mechanistic experiments showed statistically significantly enhanced terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling and Histone H2ax staining as well as decreased vascular endothelial growth factor, CD31, matrix metalloproteinase (MMP)-2, and MMP-9 expression in tumors removed from EZN-2208-treated mice and radiating vessels invading the tumor implanted onto the chorioallantoic membranes.EZN-2208 should be considered a most promising novel antineuroblastoma agent. An ongoing phase I study in pediatric patients should identify the optimal dose for a phase II study.
Effect on Left Ventricular Performance of Stimulation of an Afferent Nerve from Muscle
Authors: JERE H. MITCHELL, DONALD S. MIERZWIAK, KERN WILDENTHAL, WILLIAM D. WILLIS, ALVIN M. SMITH
Journal: Circulation Research (1968)

The effect on left ventricular performance of electrical stimulation of the cut central end of the quadriceps nerve was studied in open-chest dogs. Stimulation of the nerve at 2 to 4 times threshold for the flexion reflex, which presumably activated intermediate-sized afferent fibers, caused a decrease in heart rate and arterial pressure. Stimulation at 5 to 25 times threshold, which presumably activated small-sized, high-threshold afferent fibers, increased heart rate, arterial pressure, and cardiac output. When heart rate, arterial pressure, and cardiac output were controlled, activation of high-threshold afferent fibers caused a significant increase in the maximal rate of pressure rise, stroke power, and mean rate of ejection of the left ventricle without an increase in the end-diastolic pressure. These same fibers may in some way be activated during muscular exercise and be partially responsible for the increase in left ventricular contractility that occurs during that time.
Duodenal ulcer: does pathophysiology equal aetiology?
Authors: K G Wormsley
Journal: Gut (1983)

<h3>Background</h3> The Korea Centers for Disease Control and Prevention established the new nationwide surveillance system and conducted the first nationwide surveillance of antimicrobial resistance for three major sexually transmitted pathogens; <i>Neisseria gonorrhoeae</i>, <i>Chlamydia trachomatis</i>, and <i>Mycoplasma genitalium</i>. <h3>Methods</h3> The urethral discharge was collected from male patients with urethritis at 20 primary urologic clinics from January 2017 to December 2018. The cervical swab was collected from female patients with cervicitis at 8 primary gynecological clinics from January to December 2018. All specimens were sent to the 4 regional or the central laboratories. <h3>Results</h3> A total of 224 <i>N</i><i>. gonorrhoeae</i> isolates were collected. Of these, 90.6% were resistant to tetracycline, 95.3% to ciprofloxacin, and 58.0% to penicillin. None of the strains was resistant to ceftriaxone and spectinomycin. The minimum inhibitory concentration (MIC) range of ceftriaxone was ≤0.008–0.25 μg/mL and the MIC50 and MIC90 were 0.06 μg/mL and 0.12 μg/mL. Twenty-two strains were resistant to cefixime (MIC 0.5 μg/mL). Most of the penA genotypes were type X. In particular, the proportion of mosaicism in DNA specimens has been steadily increasing, and the spread of penA-34.001 was confirmed in 2018. Reduced azithromycin susceptibility (defined MIC ≥1.0 μg/mL) increased from 0% in 2017 to 13% in 2018. The MIC range, MIC50 and MIC90 of gentamicin were 2–16 μg/mL, 4 μg/mL and 8 μg/mL, respectively. <h3>Conclusion</h3> In South Korea, the antimicrobial resistance of <i>N. gonorrhoeae</i> is very severe and most isolates are multi-drug resistant to penicillin G, tetracycline, and fluoroquinolones. PenA-10.001 and penA-34.001, which are mainly isolated in South Korea, are thought to be the pre-stage of ceftriaxone-resistant germs in Japan and Europe, and the possibility of highly resistant germs is highly increased in South Korea. Enhanced antimicrobial resistance surveillance is necessary to prevent transmission of these strains. <h3>Disclosure</h3> No significant relationships.
Career-ending injuries to professional jockeys in British horse racing (1991–2005)
Authors: G Balendra, M Turner, P McCrory
Journal: British Journal of Sports Medicine (2007)

Background: It has been previously shown that professional jump and flat racing jockeys suffer a high incidence of injury as a consequence of their profession. This paper specifically examines career-ending injuries to professional jockeys in Great Britain. Aims: To investigate career-ending injuries in professional jockeys. Method: Analysis of prospectively collected injury database on professional jockeys. Results: The majority of injuries in this study occurred to the head, shoulder or torso. Fractures were the most common type of injury that led to a decision to end a career, followed by neurological injury to the head and/or spine. Conclusion: Injuries to the head are the most common career-ending injuries, and consideration of injury counter measures could be an important strategy in equestrian sports.
Large-scale search for genes on which positive selection may operate
Authors: T. Endo, K. Ikeo, T. Gojobori
Journal: Molecular Biology and Evolution (1996)

We conducted a systematic search for the candidate genes on which positive selection may operate, on the premise that for such genes the number of nonsynonymous substitution is expected to be larger than that of synonymous substitutions when the nucleotide sequences of genes under investigation are compared with each other. By obtaining 3,595 groups of homologous sequences from the DDBJ, EMBL, and GenBank DNA sequence databases, we found that 17 gene groups can be the candidates for the genes on which positive selection may operate. Thus, such genes are found to occupy only about 0.5% of the vast number of gene groups so far available. Interestingly enough 9 out of the 17 gene groups were the surface antigens of parasites or viruses.
Observations on the Heart-Lung Preparation in the Rat
Authors: J. M. LEDINGHAM, B. F. Burns
Journal: Circulation Research (1961)

A technique for producing and studying a heart-lung preparation in the rat is described. The relationship between filling pressure and cardiac output was found to remain constant for 60 to 90 minutes after the start of the extracorporeal circulation. The influence on this relationship of alterations in pulmonary ventilation, arterial pulse pressure, and heart rate has not been found to be critical. The mechanisms underlying deterioration of the preparation have been investigated, but no firm conclusions have been reached. Deterioration was not prevented by the introduction of fresh blood into the circulation. During prolonged experiments, the extracellular-fluid content of the heart was found to increase, the intracellular potassium was unaltered, and the intracellular sodium was reduced. Acute elevation of the sodium concentration in the circulating blood lowered, whereas potassium raised, the cardiac output for a given filling pressure. These opposing actions were found to summate. Slowing of the heart brought about by high concentrations of potassium was antagonized by sodium.
A Novel Signaling Axis of Matriptase/PDGF-D/β-PDGFR in Human Prostate Cancer
Authors: Carolyn V. Ustach, Wei Huang, M. Katie Conley-LaComb, Chen-Yong Lin, Mingxin Che, Judith Abrams, Hyeong-Reh Choi Kim
Journal: Cancer Research (2010)

Increasing evidence indicates the significance of platelet-derived growth factor receptor-β (β-PDGFR) signaling in prostate cancer (PCa). Accordingly, preclinical studies suggest the potential of β-PDGFR as a therapeutic target in metastatic PCa. However, a ligand responsible for β-PDGFR activation in PCa was unknown, and recent clinical trials with imatinib mesylate showed limited success due to normal tissue toxicity. Similarly, in spite of mounting evidence indicating the significance of matriptase in PCa, little is known about its substrates or molecular actions during PCa progression. Here, we identified PDGF-D as a ligand for β-PDGFR in PCa and discovered matriptase as its regulator. Matriptase activates PDGF-D by proteolytic removal of the CUB domain in a 2-step process, creating a hemidimer, followed by growth factor domain dimer (GFD-D) generation. Matriptase can deactivate PDGF-D by further proteolytic cleavage within the GFD, revealing its biphasic regulation. Importantly, PDGF-D/matriptase colocalization is accompanied with β-PDGFR phosphorylation in human PCa tissues. This study unveiled a novel signaling axis of matriptase/PDGF-D/β-PDGFR in PCa, providing new insights into functional interplay between serine protease and growth factor signaling networks.
What has made the population of Japan healthy?
Authors: Nayu Ikeda, Eiko Saito, Naoki Kondo, Manami Inoue, Shunya Ikeda, Toshihiko Satoh, Koji Wada, Andrew Stickley, Kota Katanoda, Tetsuya Mizoue, Mitsuhiko Noda, Hiroyasu Iso, Yoshihisa Fujino, Tomotaka Sobue, Shoichiro Tsugane, Mohsen Naghavi, Majid Ezzati, Kenji Shibuya
Journal: The Lancet (2011)
Review: Evidence for the effect of vitamin D supplementation on many patient outcomes was assessed
Authors: Robert H. Fletcher
Journal: Annals of Internal Medicine (2014)

Source Citation Theodoratou E, Tzoulaki I, Zgaga L, Ioannidis JP. Vitamin D and multiple health outcomes: umbrella review of systematic reviews and meta-analyses of observational studies and randomised trials. BMJ. 2014;348:g2035. 24690624