tbuckley/cabot-search huggingface dataset:
Angiotensin II–Induced Cardiac Hypertrophy and Hypertension Are Attenuated by Epidermal Growth Factor Receptor Antisense
Authors: Shuntaro Kagiyama, Satoru Eguchi, Gerald D. Frank, Tadashi Inagami, Yuan Clare Zhang, M. Ian Phillips
Journal: Circulation (2002)

Background— Angiotensin II (Ang II) is a vasoconstrictor but also a growth factor. However, the Ang II type 1 receptor does not have a tyrosine kinase domain that mediates the cellular signals for mitosis. We have shown that Ang II acts via “ trans” -activation of the epidermal growth factor receptor (EGFR) to induce activation of tyrosine kinase and mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) in vascular smooth muscle cells (VSMCs). To examine whether EGFR is involved in the development of left ventricular hypertrophy (LVH), we inhibited EGFR with a specific antisense oligodeoxynucleotide to attenuate the Ang II–induced cardiovascular hypertrophic effects. Methods and Results— The antisense oligodeoxynucleotide to EGFR (EGFR-AS) was designed and tested on Ang II–induced ERK activation in cultured VSMCs. We also investigated the effects of EGFR-AS on LVH and blood pressure (BP) in Ang II–infused hypertensive rats. In VSMCs, EGFR-AS (2.5 μmol/L) reduced EGFR expression and inhibited the Ang II–induced phosphorylation of ERK. In rats, Ang II (150 ng/h for 14 days) increased BP compared with controls (184±6 mm Hg versus 122±3 mm Hg; n=7; P &lt;0.01). Continuous intravenous infusion of EGFR-AS (2 mg/kg) decreased BP (169±8 mm Hg; n=8; P &lt;0.05). Ang II infusion increased the left ventricular/body weight (LV/BW) ratio compared with control rats (2.75±0.08 versus 2.33±0.07; P &lt;0.01). EGFR-AS, but not EGFR-sense, normalized the LV/BW in Ang II–infused rats (2.32±0.06; P &lt;0.01) and attenuated Ang II–enhanced EGFR expression and ERK phosphorylation. Conclusion— Ang II requires EGFR to mediate ERK activation in VSMCs and the heart. EGFR plays a critical role in the LVH induced by Ang II.
E3 ubiquitin ligase CHIP facilitates Toll-like receptor signaling by recruiting and polyubiquitinating Src and atypical PKCζ
Authors: Mingjin Yang, Chen Wang, Xuhui Zhu, Songqing Tang, Liyun Shi, Xuetao Cao, Taoyong Chen
Journal: The Journal of Experimental Medicine (2011)

The carboxyl terminus of constitutive heat shock cognate 70 (HSC70)-interacting protein (CHIP, also known as Stub1) is a U box-containing E3 ubiquitin ligase that is important for protein quality control. The role of CHIP in innate immunity is not known. Here, we report that CHIP knockdown inhibits Toll-like receptor (TLR) 4- and TLR9-driven signaling, but not TLR3-driven signaling; proinflammatory cytokine and type 1 interferon (IFN) production; and maturation of antigen-presenting cells, including macrophages and dendritic cells. We demonstrate that CHIP can recruit the tyrosine kinase Src and atypical protein kinase C ζ (PKCζ) to the TLR complex, thereby leading to activation of IL-1 receptor-associated kinase 1, TANK-binding kinase 1, and IFN regulatory factors 3 and 7. CHIP acts as an E3 ligase for Src and PKCζ during TLR signaling. CHIP-mediated enhancement of TLR signaling is inhibited by IFNAR deficiency or expression of ubiquitination resistant mutant forms of Src or PKCζ. These findings suggest that CHIP facilitates the formation of a TLR signaling complex by recruiting, ubiquitinating, and activating Src and PKCζ.
Primary diffuse alveolar septal amyloidosis.
Authors: S C Poh, T S Tjia, H C Seah
Journal: Thorax (1975)

The case is reported of a 61-year-old man with primary diffuse alveolar septal pulmonary amyloidosis. Amyloid infiltration of the heart and other organs was also observed. The clinical findings and laboratory investigations reveal features characteristic of defective gas transfer with pulmonary oedema due to left ventricular failure from myocardial involvement.
Feline Polycystic Kidney Disease Mutation Identified in PKD1
Authors: Leslie A. Lyons, David S. Biller, Carolyn A. Erdman, Monika J. Lipinski, Amy E. Young, Bruce A. Roe, Baifang Qin, Robert A. Grahn
Journal: Journal of the American Society of Nephrology (2004)

Autosomal dominant polycystic kidney disease (ADPKD) is a commonly inherited disorder in humans that causes the formation of fluid-filled renal cysts, often leading to renal failure. PKD1 mutations cause 85% of ADPKD. Feline PKD is autosomal dominant and has clinical presentations similar to humans. PKD affects approximately 38% of Persian cats worldwide, which is approximately 6% of cats, making it the most prominent inherited feline disease. Previous analyses have shown significant linkage between the PKD phenotype and microsatellite markers linked to the feline homolog for PKD1. In this report, the feline PKD1 gene was scanned for causative mutations and a C>A transversion was identified at c.10063 (human ref NM_000296) in exon 29, resulting in a stop mutation at position 3284, which suggests a loss of approximately 25% of the C-terminus of the protein. The same mutation has not been identified in humans, although similar regions of the protein are truncated. The C>A transversion has been identified in the heterozygous state in 48 affected cats examined, including 41 Persians, a Siamese, and several other breeds that have been known to outcross with Persians. In addition, the mutation is segregating concordantly in all available PKD families. No unaffected cats have been identified with the mutation. No homozygous cats have been identified, supporting the suggestion that the mutation is embryonic lethal. These data suggest that the stop mutation causes feline PKD, providing a test to identify cats that will develop PKD and demonstrating that the domestic cat is an ideal model for human PKD.
The Operonic Location of Auto-transcriptional Repressors Is Highly Conserved in Bacteria
Authors: N. D. Rubinstein, D. Zeevi, Y. Oren, G. Segal, T. Pupko
Journal: Molecular Biology and Evolution (2011)

Bacterial genes are commonly encoded in clusters, known as operons, which share transcriptional regulatory control and often encode functionally related proteins that take part in certain biological pathways. Operons that are coregulated are known to colocalize in the genome, suggesting that their spatial organization is under selection for efficient expression regulation. However, the internal order of genes within operons is believed to be poorly conserved, and hence expression requirements are claimed to be too weak to oppose gene rearrangements. In light of these opposing views, we set out to investigate whether the internal location of the regulatory genes within operons is under selection. Our analysis shows that transcription factors (TFs) are preferentially encoded as either first or last in their operons, in the two diverged model bacteria Escherichia coli and Bacillus subtilis. In a higher resolution, we find that TFs that repress transcription of the operon in which they are encoded (autorepressors), contribute most of this signal by specific preference of the first operon position. We show that this trend is strikingly conserved throughout highly diverged bacterial phyla. Moreover, these autorepressors regulate operons that carry out highly diverse biological functions. We propose a model according to which autorepressors are selected to be located first in their operons in order to optimize transcription regulation. Specifically, the first operon position helps autorepressors to minimize leaky transcription of the operon structural genes, thus minimizing energy waste. Our analysis provides statistically robust evidence for a paradigm of bacterial autorepressor preferential operonic location. Corroborated with our suggested model, an additional layer of operon expression control that is common throughout the bacterial domain is revealed.
Carcinogenesis Induced by 7,12-Dimethylbenz[a]anthracene in C3H-A vyfB Mice: Influence of Different Dietary Fats
Authors: G. J. Hopkins, G. C. Hard, C. E. West
Journal: JNCI Journal of the National Cancer Institute (1978)

The effect of a diet containing either sunflowerseed oil (polyunsaturated fat diet) or tallow (saturated fat diet) on 7, 12-dimethylbenz[a]anthracene (DMBA)-induced carcinogenesis in C3H-A vyfB mice was examined. After receiving either diet for 28 days, some of the mice were given an intragastric dose of 5 mg DMBA. To identify the stage of carcinogenesis that might be influenced by dietary fat, the diets of half of the mice were then interchanged so that those previously fed the saturated fat diet were fed the polyunsaturated fat diet and vice versa. The cumulative incidence of tumor-bearing mice was significantly greater among the females fed the polyunsaturated fat diet compared to those fed the saturated fat diet. This enhancement of carcinogenesis was observed only when the mice were fed the polyunsaturated fat diet after DMBA administration. Similar trends were observed in the male mice, but these mice developed fewer tumors and none of the differences between the tumor incidences were statistically significant. The most common sites for tumors in the male mice were the liver, lungs, and skin, whereas those for tumors in the females were the mammary glands and ovaries. The differences in tumor incidence suggest that carcinogenesis was enhanced by the polyunsaturated fat diet during the promotion stage of carcinogenesis.
Rhabdomyolysis and Acute Kidney Injury
Authors: Xavier Bosch, Esteban Poch, Josep M. Grau
Journal: New England Journal of Medicine (2009)

The causes of acute rhabdomyolysis include trauma, drugs, toxins, and certain infections. Acute kidney injury is a dangerous complication of severe rhabdomyolysis. This review summarizes current views on the pathogenesis of myoglobin-induced kidney injury as well as on its prevention and treatment.
A Detailed Comparison of Physician Services for the Elderly in the United States and Canada
Authors: W. Pete Welch, Diana Verrilli, Steven J. Katz, Eric Latimer
Journal: JAMA (1996)

To assess the relative volume and price of physician services in Canada and the United States.A comparative analysis of 1992 claims data from Canadian provincial ministries of health and from the US Health Care Financing Administration.All elderly individuals in the 3 largest Canadian provinces, Ontario, Quebec, and British Columbia, and a 1% random sample of US elderly Medicare beneficiaries not enrolled in health maintenance organizations.The volume of physician services measured in terms of the relative value units used in the Medicare fee schedule to calculate payments, with services disaggregated into clinically meaningful categories.Canadian elderly receive a higher volume of physician services than US elderly. Because the provinces examined paid a much lower price per service, Canada had overall lower expenditures per elderly person than the United States. Canadian elderly received 44% more evaluation and management services, but 25% fewer procedures. Canada has a disproportionately lower volume of procedures for which there is low clinical consensus as to when they are indicated. Such procedures include cataract extractions and knee replacements.The lower prices for physician services in Canada permit Canadian elderly to receive a higher volume of evaluation and management services, on the other hand, are constrained by both price and volume. These differences in the volume of physician services may be the result of differences in facility and physician supply.
Calcium-mediated cell death during myocardial reperfusion
Authors: D. Garcia-Dorado, M. Ruiz-Meana, J. Inserte, A. Rodriguez-Sinovas, H. M. Piper
Journal: Cardiovascular Research (2012)

Reperfusion may induce additional cell death in patients with acute myocardial infarction receiving primary angioplasty or thrombolysis. Altered intracellular Ca(2+) handling was initially considered an essential mechanism of reperfusion-induced cardiomyocyte death. However, more recent studies have demonstrated the importance of Ca(2+)-independent mechanisms that converge on mitochondrial permeability transition (MPT) and are shared by cardiomyocytes and other cell types. This article analyses the importance of Ca(2+)-dependent cell death in light of these new observations. Altered Ca(2+) handling includes increased cytosolic Ca(2+) levels, leading to activation of calpain-mediated proteolysis and sarcoplasmic reticulum-driven oscillations; this can induce hypercontracture, but also MPT due to the privileged Ca(2+) transfer between sarcoplasmic reticulum and mitochondria through cytosolic Ca(2+) microdomains. In the opposite direction, permeability transition can worsen altered Ca(2+) handling and favour hypercontracture. Ca(2+) appears to play an important role in cell death during the initial minutes of reperfusion, particularly after brief periods of ischaemia. Developing effective and safe treatments to prevent Ca(2+)-mediated cardiomyocyte death in patients with transient ischaemia, by targeting Ca(2+) influx, intracellular Ca(2+) handling, or Ca(2+)-induced cell death effectors, is an unmet challenge with important therapeutic implications and large potential clinical impact.
Host immunity contributes to the anti-melanoma activity of BRAF inhibitors
Authors: Deborah A. Knight, Shin Foong Ngiow, Ming Li, Tiffany Parmenter, Stephen Mok, Ashley Cass, Nicole M. Haynes, Kathryn Kinross, Hideo Yagita, Richard C. Koya, Thomas G. Graeber, Antoni Ribas, Grant A. McArthur, Mark J. Smyth
Journal: Journal of Clinical Investigation (2013)

The BRAF mutant, BRAFV600E, is expressed in nearly half of melanomas, and oral BRAF inhibitors induce substantial tumor regression in patients with BRAFV600E metastatic melanoma. The inhibitors are believed to work primarily by inhibiting BRAFV600E-induced oncogenic MAPK signaling; however, some patients treated with BRAF inhibitors exhibit increased tumor immune infiltration, suggesting that a combination of BRAF inhibitors and immunotherapy may be beneficial. We used two relatively resistant variants of BrafV600E-driven mouse melanoma (SM1 and SM1WT1) and melanoma-prone mice to determine the role of host immunity in type I BRAF inhibitor PLX4720 antitumor activity. We found that PLX4720 treatment downregulated tumor Ccl2 gene expression and decreased tumor CCL2 expression in both BrafV600E mouse melanoma transplants and in de novo melanomas in a manner that was coincident with reduced tumor growth. While PLX4720 did not directly increase tumor immunogenicity, analysis of SM1 tumor-infiltrating leukocytes in PLX4720-treated mice demonstrated a robust increase in CD8+ T/FoxP3+CD4+ T cell ratio and NK cells. Combination therapy with PLX4720 and anti-CCL2 or agonistic anti-CD137 antibodies demonstrated significant antitumor activity in mouse transplant and de novo tumorigenesis models. These data elucidate a role for host CCR2 in the mechanism of action of type I BRAF inhibitors and support the therapeutic potential of combining BRAF inhibitors with immunotherapy.
Benign intercostal schwannoma mimicking a solitary metastasis from lung cancer
Authors: H. Moon, S. J. Park, S. R. Kim, H. S. Park, Y. C. Lee
Journal: Thorax (2010)

A 61-year-old woman who had suffered from cough and sputum was referred for the evaluation of chronic consolidation on the left lower lung (LLL). Before she visited our hospital, she had been taking antibiotics, having received a diagnoss of pneumonia. However, her symptoms and radiological consolidation on the LLL had not improved.

Chest radiography showed a dense consolidation on the LLL. Chest CT scan revealed a diffused consolidation combined with ground glass opacity on the LLL and a 2×1.5 cm heterogeneously enhanced mass with a smooth margin on the left seventh intercostal space (figure 1A,B). A percutaneous needle biopsy of the consolidative lesion on the LLL was performed. Histological examination revealed malignant cells along the alveolar septa (figure 2A,B), and this finding was interpreted as bronchioloalveolar carcinoma.



Figure 1 
(A, B) CT scan of the chest showed …
Active Surveillance Program for Prostate Cancer: An Update of the Johns Hopkins Experience
Authors: Jeffrey J. Tosoian, Bruce J. Trock, Patricia Landis, Zhaoyong Feng, Jonathan I. Epstein, Alan W. Partin, Patrick C. Walsh, H. Ballentine Carter
Journal: Journal of Clinical Oncology (2011)

Purpose We assessed outcomes of men with prostate cancer enrolled in active surveillance. Patients and Methods Since 1995, a total of 769 men diagnosed with prostate cancer have been followed prospectively (median follow-up, 2.7 years; range, 0.01 to 15.0 years) on active surveillance. Enrollment criteria were for very-low-risk cancers, defined by clinical stage (T1c), prostate-specific antigen density &lt; 0.15 ng/mL, and prostate biopsy findings (Gleason score ≤ 6, two or fewer cores with cancer, and ≤ 50% cancer involvement of any core). Curative intervention was recommended on disease reclassification on the basis of biopsy criteria. The primary outcome was survival free of intervention, and secondary outcomes were rates of disease reclassification and exit from the program. Outcomes were compared between men who did and did not meet very-low-risk criteria. Results The median survival free of intervention was 6.5 years (range, 0.0 to 15.0 years) after diagnosis, and the proportions of men remaining free of intervention after 2, 5, and 10 years of follow-up were 81%, 59%, and 41%, respectively. Overall, 255 men (33.2%) underwent intervention at a median of 2.2 years (range, 0.6 to 10.2 years) after diagnosis; 188 men (73.7%) underwent intervention on the basis of disease reclassification on biopsy. The proportions of men who underwent curative intervention (P = .026) or had biopsy reclassification (P &lt; .001) were significantly lower in men who met enrollment criteria than in those who did not. There were no prostate cancer deaths. Conclusion For carefully selected men, active surveillance with curative intent appears to be a safe alternative to immediate intervention. Limiting surveillance to very-low-risk patients may reduce the frequency of adverse outcomes.
Novel stabilin-1 interacting chitinase-like protein (SI-CLP) is up-regulated in alternatively activated macrophages and secreted via lysosomal pathway
Authors: Julia Kzhyshkowska, Srinivas Mamidi, Alexei Gratchev, Elisabeth Kremmer, Christina Schmuttermaier, Liis Krusell, Georg Haus, Jochen Utikal, Kai Schledzewski, Joachim Scholtze, Sergij Goerdt
Journal: Blood (2005)
Reduction by prostacyclin of acetaminophen-induced liver toxicity in the mouse
Authors: Francisco Guarner, Nigel K. Boughton-Smith, Geoffrey J. Blackwell, Salvador Moncada
Journal: Hepatology (1988)

The effect of prostacyclin on acetaminophen-induced liver injury has been investigated in the mouse. Two structurally unrelated thromboxane synthetase inhibitors, OKY 1581 and benzyl imidazole, were also examined in order to investigate the role of the prostacyclin-thromboxane balance in the development of hepatic lesions. Whereas prostacyclin or OKY 1581 given shortly after acetaminophen prevented mortality and reduced liver necrosis, as assessed by serum ALT activity and histology, benzyl imidazole was only effective if given prior to acetaminophen. Acetaminophen overdose resulted in an enhanced prostaglandin and thromboxane generation by liver homogenates. While OKY 1581 inhibited thromboxane production by the liver homogenates, prostacyclin synthesis was increased. Pretreatment with the cyclooxygenase inhibitor indomethacin blocked both the increase in prostacyclin generation and the protective effect of OKY 1581. Benzyl imidazole inhibited the synthesis of thromboxane but did not enhance prostacyclin production. In addition, the protective effect of benzyl imidazole was unaltered by indomethacin pretreatment. Furthermore, whereas benzyl imidazole interfered with hepatic drug metabolism, as assessed by prolongation of the pentobarbitone sleeping time, prostacyclin and OKY 1581 were without activity. Prostacyclin treatment can prevent acetaminophen-induced liver necrosis in mice. Enhanced prostacyclin synthesis by the selective thromboxane synthetase inhibitor OKY 1581 also exerts a protective role in this model.
Myelin basic protein serum factor. An endogenous neuroantigen influencing development of experimental allergic encephalomyelitis in Lewis rats.
Authors: R S Fujinami, P Y Paterson, E D Day, V A Varitek
Journal: The Journal of Experimental Medicine (1978)

Age-related concentrations of myelin basic protein serum factor (MBP-SF), an endogenous neuroantigen detected and quantitated by inhibition of binding of rat myelin basic protein (RMBP) antibody with 125I-RMBP reagent antigen and immunochemically indistinguishable from native RMBP in this respect, reach peak levels as high as 21 ng/microliter among 2-3-wk-old normal suckling Lewis rats. Levels then progressively decline to low, usually undetectable levels of less than or equal to 0.6 ng/microliter MBP-equivalents in adult animals by 7 wk of age. MBP-SF levels are inversely related to the age-related increasing capacity of maturing Lewis rats to develop experimental allergic encephalomyelitis (EAE) after sensitization to MBP of syngeneic, but not xenogeneic, origin. MBP-SF appears to be an endogenous neuroimmunoregulatory product of potential importance for immunologic tolerance to autologous RMBP in Lewis rats.
Systolic and Diastolic Abnormalities Reduce the Cardiac Response to Exercise in Adolescents With Type 2 Diabetes
Authors: Teresa E. Pinto, Silmara Gusso, Paul L. Hofman, José G.B. Derraik, Tim S. Hornung, Wayne S. Cutfield, J. Chris Baldi
Journal: Diabetes Care (2014)

To better understand the cardiac limitations during exercise in adolescents with type 2 diabetes mellitus (T2DM), we measured left ventricular performance with magnetic resonance imaging (MRI) during exercise in diabetic and nondiabetic adolescents.Thirteen subjects with T2DM, 27 overweight/obese nondiabetic (ObeseND) subjects, and 19 nondiabetic nonobese control subjects were recruited. Cardiac (left ventricular) MRI scans were performed at rest and during submaximal exercise.Vo2 peak indexed to fat-free mass was reduced in T2DM and ObeseND subjects compared with control subjects (P < 0.0001). Indexed cardiac output increased less during exercise and was 20% lower in T2DM subjects due to reduced stroke volume. This was a consequence of reduced ventricular filling with smaller end-diastolic volume, which decreased further during exercise in T2DM subjects, but not in ObeseND or control subjects. End-systolic volume was also smaller in T2DM subjects. These changes were associated with increased resting and exercise diastolic blood pressure, and total peripheral resistance in T2DM subjects.Independently of obesity, T2DM impairs cardiac function during exercise in adolescents.
GRK3 Deficiency Enhances Parathyroid Hormone (PTH) Receptor Function On Bone Marrow Mesenchymal Stem Cells And May Enhance Hematopoiesis
Authors: M.W. McGinnis, R.G. Timoshchenko, D.S. Serafin, N. Case, J. Rubin, T.K. Tarrant
Journal: Journal of Allergy and Clinical Immunology (2012)
Characteristics of Cocaine-Dependent Patients Who Attempt Suicide
Authors: Alec Roy
Journal: American Journal of Psychiatry (2001)

OBJECTIVE: Although suicidal behavior is frequent among cocaine-dependent patients, it has been little studied. Therefore, the author examined the characteristics of cocaine-dependent patients who had attempted suicide. METHOD: Cocaine-dependent patients who had attempted suicide (N=84) were compared with cocaine-dependent patients who had never attempted suicide (N=130) on clinical, personality, psychiatric, and physical variables. RESULTS: Significantly more of the patients who had attempted suicide were female and had a family history of suicidal behavior; they reported significantly more childhood trauma and were significantly more introverted, neurotic, and hostile. They had also had significantly more comorbidity with alcohol and/or opiate dependence, major depression, and physical disorders. CONCLUSIONS: The clinical implications are that family, childhood, personality, psychiatric, and physical risk factors contribute to suicidal behavior in cocaine-dependent patients. Comorbidity appears to be an important determinant of suicidal behavior.