tbuckley/cabot-search huggingface dataset:
Lost in Translation: The Unintended Consequences of Advance Directive Law on Clinical Care
Authors: Lesley S. Castillo, Brie A. Williams, Sarah M. Hooper, Charles P. Sabatino, Lois A. Weithorn, Rebecca L. Sudore
Journal: Annals of Internal Medicine (2011)

Background: Advance directive law may compromise the clinical effectiveness of advance directives. Purpose: To identify unintended legal consequences of advance directive law that may prevent patients from communicating end-of-life preferences. Data Sources: Advance directive legal statutes for all 50 U.S. states and the District of Columbia and English-language searches of LexisNexis, Westlaw, and MEDLINE from 1966 to August 2010. Study Selection: Two independent reviewers selected 51 advance directive statutes and 20 articles. Three independent legal reviewers selected 105 legal proceedings. Data Extraction: Two reviewers independently assessed data sources and used critical content analysis to determine legal barriers to the clinical effectiveness of advance directives. Disagreements were resolved by consensus. Data Synthesis: Legal and content-related barriers included poor readability (that is, laws in all states were written above a 12th-grade reading level), health care agent or surrogate restrictions (for example, 40 states did not include same-sex or domestic partners as default surrogates), and execution requirements needed to make forms legally valid (for example, 35 states did not allow oral advance directives, and 48 states required witness signatures, a notary public, or both). Vulnerable populations most likely to be affected by these barriers included patients with limited literacy, limited English proficiency, or both who cannot read or execute advance directives; same-sex or domestic partners who may be without legally valid and trusted surrogates; and unbefriended, institutionalized, or homeless patients who may be without witnesses and suitable surrogates. Limitation: Only appellate-level legal cases were available, which may have excluded relevant cases. Conclusion: Unintended negative consequences of advance directive legal restrictions may prevent all patients, and particularly vulnerable patients, from making and communicating their end-of-life wishes and having them honored. These restrictions have rendered advance directives less clinically useful. Recommendations include improving readability, allowing oral advance directives, and eliminating witness or notary requirements. Primary Funding Source: U.S. Department of Veterans Affairs and the Pfizer Foundation.
VEGF-A and FGF gene therapy accelerate healing of ischemic colonic anastomoses (experimental study)
Authors: Gokhan Adas, Askın Percem, Mine Adas, Ozgur Kemik, Soykan Arikan, Duran Ustek, Aris Cakiris, Neslihan Abaci, Ahu Sarbay Kemik, Gulcin Kamali, Servet Karahan, Adem Akcakaya, Oguzhan Karatepe
Journal: International Journal of Surgery (2011)
Drug-Induced Long QT Syndrome
Authors: Prince Kannankeril, Dan M. Roden, Dawood Darbar
Journal: Pharmacological Reviews (2010)

The drug-induced long QT syndrome is a distinct clinical entity that has evolved from an electrophysiologic curiosity to a centerpiece in drug regulation and development. This evolution reflects an increasing recognition that a rare adverse drug effect can profoundly upset the balance between benefit and risk that goes into the prescription of a drug by an individual practitioner as well as the approval of a new drug entity by a regulatory agency. This review will outline how defining the central mechanism, block of the cardiac delayed-rectifier potassium current I<sub>Kr</sub>, has contributed to defining risk in patients and in populations. Models for studying risk, and understanding the way in which clinical risk factors modulate cardiac repolarization at the molecular level are discussed. Finally, the role of genetic variants in modulating risk is described.
The Epidermal Growth Factor Receptor Antibody Cetuximab Induces Autophagy in Cancer Cells by Downregulating HIF-1α and Bcl-2 and Activating the Beclin 1/hVps34 Complex
Authors: Xinqun Li, Zhen Fan
Journal: Cancer Research (2010)

Abstract Autophagy is a regulated catabolic process triggered in cells deprived of nutrients or growth factors that govern nutrient uptake. Here, we report that autophagy is induced by cetuximab, a therapeutic antibody that blocks epidermal growth factor receptor function. Cancer cell treatment with cetuximab triggered autophagosome formation, conversion of microtubule-associated protein 1 light chain 3 from its cytoplasmic to membrane-associated form, and increased acidic vesicular organelle formation. Autophagy occurred when cetuximab inhibited the class I phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin pathway, but not when it inhibited only the mitogen-activated protein/extracellular signal-regulated kinase kinase/Erk pathway, and it was accompanied by decreased levels of hypoxia inducible factor-1 α (HIF-1α) and Bcl-2. Stable overexpression of a HIF-1α mutant prevented cetuximab-induced autophagy and decrease in Bcl-2 levels. Knockdown of autophagy regulator beclin 1 or cell treatment with autophagy inhibitor 3-methyladenine, a class III PI3K (hVps34) inhibitor, also inhibited cetuximab-induced autophagy. Furthermore, knockdown of beclin 1 or Atg7 or treatment with the lysosome inhibitor chloroquine sensitized cancer cells to cetuximab-induced apoptosis. Mechanistic analysis argued that cetuximab acted by promoting an association between beclin 1 and hVps34, which was inhibited by overexpression of Bcl-2. Our findings suggest that the autophagy protects cancer cells from the proapoptotic effects of cetuximab. Cancer Res; 70(14); 5942–52. ©2010 AACR.
Propranolol in Angina Pectoris
Authors: Emanuel J. Cohen
Journal: JAMA (1969)

<h3>To the Editor:—</h3> The anginal pains in pheochromocytoma raises the question of the mechanism of this pain during the release of sympathetic neurohormones (epinephrine and norepinephrine) which are coronary dilators. These adrenergic neurohormones produce at the same time an increase in myocardial demands (the catabolic action of the sympathetic) to a greater degree than is met by the increased blood supply. The insufficient increase of blood supply related to the myocardial needs is also the cause of angina pectoris in patients with coronary artery disease. This catabolic action of the sympathetic nervous system and the insufficient increase in blood supply are signs of sympathetic overactivity, but other cardiovascular signs of angina pectoris are related to this overactivity such as tachycardia, increase of blood pressure, and arterial hypertonia. Overactivity of the sympathetic in anginal attacks explains why drugs useful here are sympatholytics, including the beta-adrenergic blocking agent, propranolol hydrochloride. This explains
Predicting and Communicating the Risk of Recurrence and Death in Women With Early-Stage Breast Cancer: A Systematic Review of Risk Prediction Models
Authors: Ellen G. Engelhardt, Mirjam M. Garvelink, J. (Hanneke) C.J.M. de Haes, Jacobus J.M. van der Hoeven, Ellen M.A. Smets, Arwen H. Pieterse, Anne M. Stiggelbout
Journal: Journal of Clinical Oncology (2013)

It is a challenge for oncologists to distinguish patients with breast cancer who can forego adjuvant systemic treatment without negatively affecting survival from those who cannot. Risk prediction models (RPMs) have been developed for this purpose. Oncologists seem to have embraced RPMs (particularly Adjuvant!) in clinical practice and often use them to communicate prognosis to patients. We performed a systematic review of published RPMs and provide an overview of the prognosticators incorporated and reported clinical validity. Subsequently, we selected the RPMs that are currently used in the clinic for a more in-depth assessment of clinical validity. Finally, we assessed lay comprehensibility of the reports generated by RPMs.Pubmed, EMBASE, and Web of Science were searched. Two reviewers independently selected relevant articles and extracted data. Agreement on article selection and data extraction was achieved in consensus meetings.We identified RPMs based on clinical prognosticators (N = 6) and biomolecular features (N = 14). Generally predictions from RPMs seem to be accurate, except for patients ≤ 50 years or ≥ 75 years at diagnosis, in addition to Asian populations. RPM reports contain much medical jargon or technical details, which are seldom explained in lay terms.The accuracy of RPMs' prognostic estimates is suboptimal in some patient subgroups. This urgently needs to be addressed. In their current format, RPM reports are not conducive to patient comprehension. Communicating survival probabilities using RPM might seem straightforward, but it is fraught with difficulties. If not done properly, it can backfire and confuse patients. Evidence to guide best communication practice is needed.
A9.11 NF-kB Inducing Kinase (NIK) is a Key Regulator of Inflammation-Induced Angiogenesis
Authors: AR Noort, KPM van Zoest, P Koolwijk, PP Tak, SW Tas
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> In rheumatoid arthritis (RA) synovial tissue (ST) angiogenesis can be observed already in the earliest phase of disease. The chemokine CXCL12, which is induced via the non-canonical nuclear factor-kappaB (NF-kB) pathway, plays an important role in angiogenesis, lymphocyte transendothelial migration, and the homing of endothelial progenitor cells. Therefore, the non-canonical pathway, with its key mediator NF-kB inducing kinase (NIK), may play an important role in pathological angiogenesis and the perpetuation of synovial inflammation in RA. <h3>Objective</h3> To study the role of non-canonical NF-kB signalling in pathological angiogenesis in RA. <h3>Methods</h3> Expression of NIK and CXCL12 in RA ST was evaluated using immunofluorescence microscopy (IF). Angiogenesis was studied in endothelial cells (EC) in vitro using the tube formation assay and ex vivo by comparing WT and NIK<sup>-/-</sup> mice in the aortic ring assay. Physiological (developmental) angiogenesis was evaluated by isolectin B4 staining of the retina followed by confocal microscopy. The contribution of NIK to synovial angiogenesis was studied in vivo in antigen-induced arthritis (AIA). <h3>Results</h3> NIK, p52 and CXCL12 were highly expressed in EC in RA ST, mainly in small (newly formed) blood vessels. Stimuli that induce non-canonical NF-kB signalling (lymphotoxin (LT), LIGHT, and CD40L) significantly enhanced in vitro tube formation 2.5-fold (p &lt; 0.05), which could be completely blocked by siRNA targeting NIK or IKKα. Aortic rings from WT and NIK<sup>-/-</sup> mice showed normal TNF- and VEGF-induced microvessel outgrowth. In contrast, whereas non-canonical NF-kB stimuli induced microvessel outgrowth in WT mice (unstim 29.94 ± 6.08 versus LT 159.1 ± 50.24 versus LIGHT 110.3 ± 17.68 (mm <sup>2</sup>) p &lt; 0.05), no microvessel outgrowth was observed in aortic rings from NIK<sup>-/-</sup> mice (unstim 28.74 ± 15.89 versus LT 45.9 ± 16.71 versus LIGHT 43.41 ± 15.73 (mm <sup>2</sup>)). In line with this, NIK<sup>-/-</sup> mice exhibited normal developmental angiogenesis in the retina, but a 50% reduction in pathological angiogenesis in synovial inflammation (blood vessels in synovial tissue WT 20 ± 5.07 versus NIK<sup>-/-</sup> 10.2 ± 3.02). <h3>Conclusions</h3> NIK is preferentially expressed in EC in RA ST and non-canonical NF-kB signalling in EC results in enhanced angiogenesis in vitro. NIK<sup>-/-</sup> mice exhibited normal developmental and VEGF-induced angiogenesis, but reduced pathological angiogenesis in AIA. These findings point towards an important role of the non-canonical NF-kB pathway in pathological angiogenesis associated with chronic (synovial) inflammation. This could be exploited for the development of future new therapies for<i> RA.</i>
Experiments with Control Substances
Authors: C. R. B. Joyce
Journal: Annals of the Rheumatic Diseases (1961)

<i>BACKGROUND AND PURPOSE:</i> Intra-arterial therapies for ischemic stroke offer promise as a means to extend the time window for acute treatment. The purpose of this study was to identify the percentage of the US population with potential access to interventional neuroradiologic expertise within 6 hours of the onset of stroke symptoms. <i>METHODS:</i> Hospital locations of interventional neuroradiologists were identified from the 2002 roster of the American Society of Interventional and Therapeutic Neuroradiology. Data for populations in surrounding regions were extracted from US Census 2001 data by zip code. Standard transport speeds for emergency medical services were used in our estimates of the population living within a 5-hour transport time, which was a 6-hour treatment window less a 1-hour door-to-needle time, resulting in a 200-mile radius. A 2-hour transport time, or 3-hour treatment window, reflected a 65-mile radius. <i>RESULTS:</i> A total of 385 interventional neuroradiologists were identified, practicing in 45 states. With a 200-mile radius, 99% of the total US population had access to neurointerventional treatment within 6 hours of symptom onset. With a 65-mile radius, 82% of the population had access within 3 hours of symptom onset. Alaska and the Mid-Northwest region covering Idaho, Wyoming, North Dakota, and South Dakota had limited coverage. <i>CONCLUSION:</i> Most of the US population has access to interventional neuroradiologic expertise for acute stroke therapy. These data suggest that interventional therapies that extend the time window for treating acute ischemic stroke could have a major effect on public health and merit further research development and investment.
On the occurrence of cytochrome P-450 and aryl hydrocarbon hydroxylase activity in rat brain.
Authors: J A Cohn, A P Alvares, A Kappas
Journal: The Journal of Experimental Medicine (1977)

The difference spectra of the carbon monoxide-complex of dithionite-reduced rat brain microsomes, compared with both reduced microsomes, alone, and the carbon monoxide-complex of oxidized microsomes, indicate the presence of small amounts of cytochrome P-450 in brain. As in liver, cytochrome P-450 in brain is degraded in vitro to its inactive form, cytochrome P-420 by methylmercury chloride. Aryl hydrocarbon hydroxylase activity is also present in rat brain microsomes and, at lower specific activity, in brain homogenates. This carcinogen metabolizing activity is increased four-fold in rats pretreated with 3-methylcholanthrene.
Anti-idiotype induced regulation of helper cell function for the response to phosphorylcholine in adult BALB/c mice.
Authors: K Bottomly, B J Mathieson, D E Mosier
Journal: The Journal of Experimental Medicine (1978)

An adoptive secondary antibody response to phosphorylcholine (PC) can be generated by the transfer of keyhole limpet hemocyanin (KLH)-primed T cells, PC-bovine gamma globulin-primed B cells, and PC-KLH into irradiated syngeneic BALB/c mice. If the KLH-primed T-cell donors were pretreated with anti-idiotype antibodies directed against the BALB/c PC-binding myeloma TEPC 15, their T cells were unable to collaborate effectively with PC-primed B cells; moreover, they could suppress the helper activity of T cells from normal mice for the PC-KLH response. The Ly phenotype of these T cells was found to be Ly 1-, 2+. The specificity of the suppressor T-cell population induced by anti-T15 treatment appears to be both for idiotype (hapten) and carrier, since the suppressor T cells fail to interfere with the antibody response to PC on a heterologous carrier, nor do they suppress the response to trinitrophenol-KLH.
Mechanism of Increased Angiotensin II Levels in Glomerular Mesangial Cells Cultured in High Glucose
Authors: Rekha Singh, Ashok K Singh, Nahid Alavi, David J Leehey
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. Previous studies have shown that glucose increases angiotensin II (AngII) levels in rat glomerular mesangial cells and that AngII mediates the inhibitory effects of high glucose on matrix degradation in these cells. The present study addresses the following questions: (<i>1</i>) What are the mechanisms for the generation of AngII in mesangial cells? (<i>2</i>) What are the effects of glucose on AngII generation by these mechanisms? Experiments employed primary mesangial cells from normal Sprague-Dawley rats. The levels of immunoreactive angiotensinogen (AGT), angiotensin I (AngI), and angiotensin II (AngII) were measured by ELISA. AGT mRNA expression was determined by Northern blot analysis. Incubation of cells for 24 h in high glucose (30 mM) increased AGT levels by 1.5-fold and increased AGT mRNA expression; this was accompanied by a 1.5-fold increment in AngI and 1.7-fold increment in AngII levels. Renin activity (measured as AngI generation in the presence of excess AGT) and ACE levels and activity were not altered by high glucose. In further experiments, the effect of high glucose on formation of Ang peptides from exogenous AngI in mesangial cell extracts was examined using HPLC. Exogenous AngI was converted into various Ang peptides, including AngII, Ang(1-9), Ang(1-7), and Ang(3-8). A significant increase in formation of AngII from AngI was observed in cells incubated in high glucose. In addition, AngII production from exogenous Ang(1-9) in cell extracts was also stimulated by high glucose. These findings demonstrate that glucose increases mesangial AngII levels via an increase in AGT and AngI. In addition, this study provides new information that Ang(1-9) is produced by mesangial cells, can be converted to AngII, and that this conversion is also stimulated under high-glucose conditions. E-mail: dleehey@lumc.edu
Altered protein prenylation in Sertoli cells is associated with adult infertility resulting from childhood mumps infection
Authors: Xiu-Xing Wang, Pu Ying, Fan Diao, Qiang Wang, Dan Ye, Chen Jiang, Ning Shen, Na Xu, Wei-Bo Chen, Shan-Shan Lai, Shan Jiang, Xiao-Li Miao, Jin Feng, Wei-Wei Tao, Ning-Wei Zhao, Bing Yao, Zhi-Peng Xu, Hai-Xiang Sun, Jian-Min Li, Jia-Hao Sha, Xing-Xu Huang, Qing-Hua Shi, Hong Tang, Xiang Gao, Chao-Jun Li
Journal: The Journal of Experimental Medicine (2013)

Mumps commonly affects children 5–9 yr of age, and can lead to permanent adult sterility in certain cases. However, the etiology of this long-term effect remains unclear. Mumps infection results in progressive degeneration of the seminiferous epithelium and, occasionally, Sertoli cell–only syndrome. Thus, the remaining Sertoli cells may be critical to spermatogenesis recovery after orchitis healing. Here, we report that the protein farnesylation/geranylgeranylation balance is critical for patients’ fertility. The expression of geranylgeranyl diphosphate synthase 1 (GGPPS) was decreased due to elevated promoter methylation in the testes of infertile patients with mumps infection history. When we deleted GGPPS in mouse Sertoli cells, these cells remained intact, whereas the adjacent spermatogonia significantly decreased after the fifth postnatal day. The proinflammatory MAPK and NF-κB signaling pathways were constitutively activated in GGPPS−/− Sertoli cells due to the enhanced farnesylation of H-Ras. GGPPS−/− Sertoli cells secreted an array of cytokines to stimulate spermatogonia apoptosis, and chemokines to induce macrophage invasion into the seminiferous tubules. Invaded macrophages further blocked spermatogonia development, resulting in a long-term effect through to adulthood. Notably, this defect could be rescued by GGPP administration in EMCV-challenged mice. Our results suggest a novel mechanism by which mumps infection during childhood results in adult sterility.
Prospective Trial of the Herbal Supplement PC-SPES in Patients With Progressive Prostate Cancer
Authors: Eric J. Small, Mark W. Frohlich, Robert Bok, Katsuto Shinohara, Gary Grossfeld, Zinovi Rozenblat, Wm. Kevin Kelly, Michele Corry, David M. Reese
Journal: Journal of Clinical Oncology (2000)

PURPOSE: PC-SPES is an herbal supplement for which there are anecdotal reports of anti–prostate cancer activity. This phase II study was undertaken to assess the efficacy and toxicity of PC-SPES in prostate cancer patients. PATIENTS AND METHODS: Thirty-three patients with androgen-dependent prostate cancer (ADPCa) and 37 patients with androgen-independent prostate cancer (AIPCa) were treated with PC-SPES at a dose of nine capsules daily. Clinical outcome was assessed with serial serum prostate-specific androgen (PSA) level measurement and imaging studies. RESULTS: One hundred percent of ADPCa patients experienced a PSA decline of ≥ 80%, with a median duration of 57+ weeks. No patient has developed PSA progression. Thirty-one patients (97%) had declines of testosterone to the anorchid range. Two ADPCa patients had positive bone scans; both improved. One patient with a bladder mass measurable on computed tomography scan experienced disappearance of this mass. Nineteen (54%) of 35 AIPCa patients had a PSA decline of ≥ 50%, including eight (50%) of 16 patients who had received prior ketoconazole therapy. Median time to PSA progression was 16 weeks (range, 2 to 69+ weeks). Of 25 patients with positive bone scans, two had improvement, seven had stable disease, 11 had progressive disease, and five did not have a repeat bone scan because of PSA progression. Severe toxicities included thromboembolic events (n = 3) and allergic reactions (n = 3). Other frequent toxicities included gynecomastia/gynecodynia, leg cramps, and grade 1 or 2 diarrhea. CONCLUSION: PC-SPES seems to have activity in the treatment of both ADPCa and AIPCa and has acceptable toxicity. Further study is required to determine whether its effects exceed those expected with estrogen therapy.
Small Molecule Inhibitors of CXCR4
Authors: Bikash Debnath, Shili Xu, Fedora Grande, Antonio Garofalo, Nouri Neamati
Journal: Theranostics (2013)

CXCR4 is a G-protein-coupled receptor involved in a number of physiological processes in the hematopoietic and immune systems.The SDF-1/CXCR4 axis is significantly associated with several diseases, such as HIV, cancer, WHIM syndrome, rheumatoid arthritis, pulmonary fibrosis and lupus.For example, CXCR4 is one of the major co-receptors for HIV entry into target cells, while in cancer it plays an important role in tumor cell metastasis.Several promising CXCR4 antagonists have been developed to block SDF-1/CXCR4 interactions that are currently under different stages of development.The first in class CXCR4 antagonist, plerixafor, was approved by the FDA in 2008 for the mobilization of hematopoietic stem cells and several other drugs are currently in clinical trials for cancer, HIV, and WHIM syndrome.While the long-term safety data for the first generation CXCR4 antagonists are not yet available, several new compounds are under preclinical development in an attempt to provide safer and more efficient treatment options for HIV and cancer patients.