tbuckley/cabot-search huggingface dataset:
Abstract 2579: YK5, a small molecule inhibitor of Hsp70 and Hsc70, reveals a multifaceted role for the Hsp70 chaperones in regulating oncogenic and non-oncogenic addiction of tumors
Authors: Anna Rodina, Yanlong Kang, Tony Taldone, Hardik Patel, Pallav Patel, Eloisi Caldas-Lopes, Hediye Erdjument-Bromage, Monica Guzman, Jason C. Young, Ari Melnick, Gabriela Chiosis
Journal: Cancer Research (2011)

Abstract Background. The cancerous phenotype evolves through accumulation of a large repertoire of elements that allow for increased proliferative potential, self-sufficiency in growth signals and resistance to apoptotic and antiproliferative signals. While much is now gained in understanding the many factors that lead to a malignant phenotype, little remains known on how cancer cells are able to accumulate and to survive with such complexity and high load of aberrant processes. Study design. Here we use the novel dual Hsp70 and Hsc70 inhibitor, YK5, and its biotinylated derivative, YK55, to investigate the interactome of cytosolic Hsp70s. Results. We show that heat shock protein 70 family members (Hsp70s) keep active conformations of key oncoproteins and inhibit the function of tumor suppressors. Hsp70s also buffer levels of activated molecules by maintaining them in a conformation that alters their dephosphorylation by phosphatases. Pharmacologic inhibition of Hsp70s by YK5 impairs oncoprotein stability and function, restores tumor suppressor activity, affects major cancer hallmarks and is selectively lethal to cancer cells. We show that enhanced affinity of YK5 for cancer cell-Hsp70s species is an essential mechanism for providing selective tumor lethality. Conclusion. By demonstrating that pharmacologic dual inhibitors of Hsp70 and Hsc70, such as YK5, confer specific and broad tumor lethality, and interact selectively with tumor Hsp70s species, this work proposes Hsp70s inhibitors as potential anti-cancer therapeutics with a large spectrum of activity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2579. doi:10.1158/1538-7445.AM2011-2579
Atrial natriuretic peptide antagonizes endothelin-induced calcium increase and cell contraction in cultured human hepatic stellate cells
Authors: Nieves M. Görbig, Pere Ginès, Ramón Bataller, Josep M. Nicolás, Eva Garcia-Ramallo, Ester Tobías, Esther Titos, María Jes Rey, Joan Clària, Vicente Arroyo, Juan Rodés
Journal: Hepatology (1999)

Hepatic stellate cells (HSCs) participate in the regulation of hepatic microcirculation and have receptors for many vasoconstrictor factors. It is unknown whether HSCs have receptors for circulating vasodilators such as atrial natriuretic peptide (ANP). This study investigated the presence of ANP receptors in human HSCs and whether ANP antagonizes the effects of endothelin-1 in these cells. ANP receptors were assessed by binding and cross-linking studies, reverse-transcriptase polymerase chain reaction (PCR), and measuring intracellular cyclic guanosine monophosphate concentration. Intracellular calcium concentration ([Ca 2+ ] i ) and cell contraction were measured in individual cells loaded with fura-2 using a morphometric method. Binding and cross-linking affinity experiments showed the existence of ANP receptors in human HSCs. PCR products with the expected length were obtained for guanylate cyclase A receptor, the physiological receptor of ANP, both in quiescent and activated human cells. ANP induced a dose-dependent increase in intracellular cyclic guanosine monophosphate concentration and blunted the increase in [Ca 2+ ] i elicited by endothelin-1. Most importantly, ANP markedly reduced cell contraction induced by endothelin-1. HSCs isolated from rats with carbon tetrachloride-induced cirrhosis showed a higher number of ANP receptors compared with HSCs isolated from normal rats, indicating that in vivo activation of HSCs is associated with an up-regulation of ANP receptors. These results indicate that human HSCs have receptors for ANP, the activation of which reduces the effects of endothelin-1 on [Ca 2+ ] i and cell contraction. ANP could participate in regulating the contractility of HSCs by antagonizing the effect of vasoconstrictors.
Randomized Placebo-controlled Trial of Continuous Positive Airway Pressure on Blood Pressure in the Sleep Apnea–Hypopnea Syndrome
Authors: JACQUELINE F. FACCENDA, THOMAS W. MACKAY, NICHOLAS A. BOON, NEIL J. DOUGLAS
Journal: American Journal of Respiratory and Critical Care Medicine (2001)

Arterial blood pressure rises at apnea termination, and there is increasing evidence that the sleep apnea–hypopnea syndrome (SAHS) is associated with daytime hypertension but no randomized controlled trial evidence of whether SAHS treatment reduces blood pressure exists. We, therefore, conducted a randomized placebo-controlled cross-over study of the effects of 4 wk of continuous positive airway pressure (CPAP) or oral placebo on 24-h blood pressure in 68 patients (55 males, 13 females; median apnea–hypopnea index [AHI], 35) not receiving hypotensive medication. Ambulatory blood pressure was recorded for the last 48 h of each treatment. Epworth Sleepiness Score (ESS) and Functional Outcomes of Sleep Questionnaire (FOSQ) were also recorded. All patients were normotensive. There was a small decrease in 24-h diastolic blood pressure (placebo, 79.2 [SE 0.9] mm Hg; CPAP, 77.8 [SE 1.0] mm Hg; p = 0.04) with the greatest fall occurring between 2:00 a.m. and 9:59 a.m. The observed decrease in 24-h diastolic blood pressure was greater in two a priori groups, CPAP use ⩾ 3.5 h per night (81.5 [SE 1.2] mm Hg; 79.6 [SE 1.2] mm Hg; p = 0.03) and those with more than twenty 4% desaturations per hour (82.4 [SE 2.1] mm Hg; 77.4 [SE 2.1] mm Hg; p = 0.002). Systolic pressure also fell in the latter group (133.1 [SE 2.8] mm Hg; 129.1 [SE 2.1] mm Hg; p = 0.009). Desaturation frequency was the best predictor of diastolic blood pressure fall with CPAP (r = 0.38; p = 0.002). Both ESS and FOSQ domains improved. Thus, CPAP can reduce blood pressure in patients with SAHS, particularly in those with nocturnal oxygen desaturation, but the decrease is small.
Cancer Theranostics: Facile Preparation of Doxorubicin‐Loaded Upconversion@Polydopamine Nanoplatforms for Simultaneous In Vivo Multimodality Imaging and Chemophotothermal Synergistic Therapy (Adv. Healthcare Mater. 4/2015)
Authors: Fuyao Liu, Xiuxia He, Zhen Lei, Liang Liu, Junping Zhang, Hongpeng You, Huimao Zhang, Zhenxin Wang
Journal: Advanced Healthcare Materials (2015)

On page 559, H. M. Zhang, Z. X. Wang, and colleagues directly coat polydopamine (PDA) on hydrophobic upconversion nanoparticle (UCNP) to form UCNP@PDA core–shell nanosphere via a microemulsion approach, further modified with polyethylene glycol (PEG). After loading with DOX, the UCNP@PDA-PEG-DOX can completely eradicate mouse-bearing colorectal cancer without regrowth guided by multimodal imaging, demonstrating highly effective combined photothermal and chemotherapy of the nanocomposites.
Adequacy of Well-Child Care and Immunization
Authors: Michael A. Fragoso
Journal: JAMA (1995)

<h3>To the Editor.</h3> —Much has been made of "missed opportunities" by primary care physicians by Dr Mustin and colleagues<sup>1</sup>as well as Drs Orenstein and Bernier.<sup>2</sup>As a primary care pediatrician, I am committed to immunizing every child in my practice in a timely manner. This has, however, become increasingly difficult and frustrating. It is even shameful when our abysmal immunization rates are pointed out by colleagues from developing countries. In some of these countries, mortality and morbidity from malnutrition and poor hygienic and sanitary measures are high, but they can proudly point to a 90% to 95% immunization rate. It is difficult and frustrating to try to convince patients that immunizations are good and safe for their children when the print and electronic media have created an atmosphere of distrust, hostility, and litigiousness. What is needed is a national movement that promotes immunizations and good health. When MTV runs
Reconnecting ”missing” part of duct by needle knife using rendezvous technique
Authors: R. Rerknimitr, N. Geratikornsupuk, A. Janchai, P. Kullavanijaya
Journal: Endoscopy (2008)

A 73-year-old Thai woman presented with a recurrent episode of cholangitis. Two months previously, she had presented with acute cholangitis and underwent endoscopic retrograde cholangiopancreatography (ERCP) with sphincterotomy and balloon extraction for common bile duct stones. This time, a repeat ERCP was performed. Surprisingly, the cholangiogram showed a cut-off sign at the mid extrahepatic duct ([Fig. 1]). A CT scan of the abdomen showed air in the gallbladder, but no mass or cause of biliary obstruction was found ([Fig. 2]). The patient subsequently underwent percutaneous biliary drainage, and a cholangiogram confirmed the mid extrahepatic duct obstruction ([Fig. 3]). In addition, contrast extravasation from the gallbladder into the jejunum was observed. A third ERCP performed under the rendezvous technique demonstrated a thin area of disconnected common bile duct. An attempt to traverse the obstruction with a guide wire from both sides was unsuccessful. A triple-lumen needle knife (Microvasive, Natick, Massachusetts, USA) was introduced intraductally ([Fig. 4]). Under fluoroscopic guidance, a puncture was successfully made into the upstream disconnected duct ([Fig. 5]). Finally, a 10-Fr plastic stent was inserted to bridge the duct ([Fig. 6]). The patient was discharged home within 2 days and reported no symptom that related to perforation or bleeding. Currently, she is rescheduled for repeat ERCP for stent upsizing.
Abstract 3755: Phosphorylated STAT3 in polymorphonucleur cells (PMNs) as a potential surrogate marker to evaluate the efficiency of sorafenib therapy
Authors: Jun Wu, Yan Wang, Yun Yen, Karen L. Reckamp
Journal: Cancer Research (2010)

Abstract Sorafenib tosylate (BAY43-9006) is an oral multi-kinase inhibitor which targets c-Raf and b-Raf, and thus interrupts this critical oncogenic pathway. Sorafenib has been successfully applied in the clinic to treat patients with certain types of renal cell carcinoma and hepatocellular carcinoma. Signal transducer and activator of transcription 3 (STAT3) plays an important role in the pathogenesis and progression of cancer. Furthermore, the inhibition of STAT3 by sorafenib has been previously described. In order to evaluate STAT3 within polymorphonucleur cells (PMNs) as a potential surrogate marker of phosphorylated STAT3 (p-STAT3) in tumor tissue, we proposed a preclinical animal model to examine the relationship of p-STAT3 as in tumors and PMNs during treatment with sorafenib. Both normal balb/c mice (female and male, 10 weeks old) and immunodeficient NOD/SCID/IL2Rgamma null (NSG) mice (female at 10 weeks old) were used in the animal studies. Human ovarian cancer cells OV-90 were inoculated subcutaneously into the dorsal area of NSG mice to create a xenograft model. Sorafenib was given at 50 or 100 mg/kg in balb/c mice and 60 mg/kg in NSG mice via oral gavage for three doses before tissue sampling. Two hours after the last drug treatment, the mice were euthanized and the blood and tumor tissues were harvested for pSTAT3 level assays. Phosphorylated STAT3 expression levels were analyzed by flow cytometry and western blot. Suppression of pSTAT3 levels in PMNs from balb/c mice was observed in 1/3 of mice at 50 mg/kg and 2/3 of mice at 100 mg/kg by both western blot and flow cytometry, however the difference between the vehicle control and sorafenib group was not significant. Suppression of pSTAT3 levels in OV-90 tumor tissue from sorafenib-treated NSG mice was significant by western blot analysis. However the suppression of pSTAT3 on the PMNs from the corresponding NSG mice was minor by flow cytometry analysis. In conclusion, in this murine model, pSTAT3 in PMNs was not a consistent surrogate marker for the evaluation of sorafenib activity. Based on the emerging data linking escalating doses of sorafenib to STAT3 inhibition in cancer cells, and the tumor responses seen with increasing doses, evaluation of surrogate biomarkers to predict clinical efficacy will be useful. Supported by NCI K12 CA 01727 and the Phase One Foundation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3755.
Antiretroviral Strategies to Prevent Mother-to-Child Transmission of HIV: Striking a Balance between Efficacy, Feasibility, and Resistance
Authors: Dara A. Lehman, Grace C. John-Stewart, Julie Overbaugh
Journal: PLoS Medicine (2009)

Dara Lehman and colleagues discuss a randomized trial that found that adding up to a week of twice-daily zidovudine+lamivudine to single-dose nevirapine reduces the risk of resistance in mothers and infants.
From an Observer
Authors: Bonnie B. Smith
Journal: Annals of Internal Medicine (1995)

On Being a Doctor15 April 1995From an ObserverBonnie B. Smith, PhDBonnie B. Smith, PhDUniversity of Health Sciences, College of Osteopathic Medicine, Kansas City, MO 64124-2395Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-122-8-199504150-00014 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail I teach Virology to second-year medical students. In my job as an educator, I try to present information my students will need to function as competent doctors. But at times I wonder if I can determine what they need to know. I often ask myself if I include information truly important or only of interest to basic scientists like myself. When I teach Virology, for instance, I know that for my students to understand viral replication they must understand macromolecular synthesis. I am comfortable teaching that material. But how much of that do they need to know? What will they ... Author, Article, and Disclosure InformationAffiliations: University of Health Sciences, College of Osteopathic Medicine, Kansas City, MO 64124-2395Corresponding Author: Bonnie B. Smith, PhD, Department of Microbiology, University of Health Sciences, 2105 Independence Avenue, Kansas City, MO 64124-2395. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited byDehumanisation in language and thought 15 April 1995Volume 122, Issue 8Page: 628-629KeywordsAIDSChartsEmotionsFearIntensive care unitsLymphomaPharynxPneumoniaScientistsVirology Issue Published: 15 April 1995 Copyright & PermissionsCopyright © 1995 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
CLINICAL AND ECHOCARDIOGRAPHIC PREDICTORS OF LONG-TERM OUTCOME IN ASYMPTOMATIC PATIENTS WITH SIGNIFICANT AORTIC STENOSIS
Authors: Duk-Hyun Kang, Jeong-Sook Seo, Byung Joo Sun, Jung Min Ahn, Dae-Hee Kim, Jong-Min Song, Jae-Kwan Song, Hyun Song, Joo Hee Zo
Journal: Journal of the American College of Cardiology (2010)
Sigmoidoscopy screening every five years may be too frequent
Authors: S. Gottlieb
Journal: BMJ (2003)

Although current US guidelines recommend that adults aged more than 50 years undergo sigmoidoscopy screening for colon cancer every five years, that may be unnecessarily frequent, a new study says.

Screening methods for colorectal cancer include fecal occult blood testing—to identify blood in the stool—and colonoscopy and sigmoidoscopy, in which a flexible, lighted tube is inserted into the rectum and passed through the colon to identify any polyps, or small growths, that can develop into cancer. Colonoscopy examines the …
Pulmonary Vascular Dysfunction Is Associated with Poor Outcomes in Patients with Acute Lung Injury
Authors: Todd M. Bull, Brendan Clark, Kim McFann, Marc Moss
Journal: American Journal of Respiratory and Critical Care Medicine (2010)

Rationale: Despite the recognition that acute lung injury (ALI) can elevate pulmonary artery (PA) pressure and right ventricular afterload, the impact of pulmonary vascular dysfunction on outcomes of these patients is not well defined.Objectives: To investigate the impact of pulmonary vascular dysfunction in patients with acute lung injury.Methods: Secondary analysis of the Fluid and Catheter Treatment Trial. A total of 501 patients who received a PA catheter were evaluated for associations between increases in transpulmonary gradient (TPG) (PA mean pressure − PA occlusion pressure) or pulmonary vascular resistance index (PVRi) and 60-day mortality, ventilator-, intensive care unit (ICU)–, and cardiovascular-free days (days with mean arterial pressure ≥ 60 mm Hg off vasopressor support).Measurements and Main Results: We were able to measure the TPG in 475 (95%) and the PVRi in 470 (92%) patients. Patients with an elevated baseline TPG had an increased 60-day mortality (30 versus 19%; P = 0.02), and lower numbers of median ventilator- [25–75% quartiles] (15 [0–22] versus 19 [7–24]; P = 0.005), ICU- (14 [0–21] versus 18 [5–22]; P = 0.005), and cardiovascular-free days (23 [12–27] versus 25 [18–27]; P = 0.03). The median PVRi (305 [204–431] dyne s/cm5/m2) was elevated early in the course of ALI. PVRi was statistically higher in patients who died (326 [209–518] versus 299 [199–416]; P = 0.01). In individual multivariate models, TPG and PVRi remained independent risk factors for 60-day mortality and decrease in the number of ventilator-, ICU-, and cardiovascular-free days.Conclusions: Pulmonary vascular dysfunction is common in ALI, and is independently associated with poor outcomes. Future trials targeting pulmonary vascular dysfunction may be indicated.
Letter: Idiosyncrasy to phenothiazines in phenylbutazone-associated aplastic anaemia.
Authors: J Rapoport, J Barratt
Journal: BMJ (1974)

thidine, and mecamylamine, the patient was given 10 mg of propranolol twice, six hours apart.She had no apparent response to the first dose; however, within two hours of the second dose her pulse rate fell from 120 to 60/min and her blood pressure from 240/120 to 90/50 mm Hg, and she became unresponsive.An intravenous infusion of isoprenaline was required for several hours to restore and maintain pulse rate and blood pressure at noraml levels.Within a day thereafter, without additional medication, the patient's tachycardia and hyper- tension returned.She had no symptomatic or objective response of visceral or peripheral neuropathy to propranolol.Several days later the patient developed bleeding due to "stress" ulceration of the gastric mucosa.While receiving fluid and blood replacement she developed acute congestive heart failure and pulmonary oedema at a time when her blood pressure was low and clinically it was felt her intravascular volume depletion had not been corrected entirely.We interpret these events as indicating that our patient was compensat-ing haemodynamnically for elevated blood pressure (before and during her acute attack) by fl-adrenergic stimulation of cardiac function.This increase in /3-adrenergic activities may have resulted from physiological reflex mechanisms and/or from an influence of acute intermittent porphyria on the sympathetic nervous system.Irn any event the positive chronotropic and inotropic effects of endogenous catecholamines appeared essential to cardiovascular homoeostasis, which was adversely and severely affected even by a ma'lll amou-nt of ipropranolol.While propranolol is of benefit in some patients in poriphyric relapsse, it is not with- out risk in oatients with incipient cardiac failure.It may also be of risk in the pro- nounced hypovolaemic states which have been observed in patients with acute inter- mittent porphyria8 in the absence of apparent excessive volume loss.Beta-adrenergic stimulation in some episodes of porphyria may provide haemodynaniic compensation ra:her than being simply a manifestation of acute relapse.-Weare, etc.,
World Health Organization Strategy for Emerging Infectious Diseases
Authors: James W. LeDuc
Journal: JAMA (1996)

Recent outbreaks of infectious diseases have clearly demonstrated that the concerns risen in the Institute of Medicine report,<i>Emerging Infections</i>, are more than theoretical.<sup>1</sup>Whether due to diseases previously unknown to medical science, such as<i>Hantavirus</i>pulmonary syndrome or the<i>Morbillivirus</i>pneumonia of horses, or the return of known scourges like plague, cholera, and tuberculosis, infectious diseases are in a state of flux globally.<sup>2-6</sup>The causes for this resurgence are many and complex and include overcrowded cities where population growth has outpaced supplies of clean water and adequate housing; increases in national and international travel; changes in food handling, shipping, and processing; and the concurrent deterioration of traditional public health activities such as surveillance and diagnostic laboratories needed to quickly recognize emerging problems.<sup>7</sup>The net result is that national health has become an international challenge. Infectious diseases do not respect international boundaries; consequently, an outbreak of disease
β-Catenin in the Alveolar Epithelium Protects from Lung Fibrosis after Intratracheal Bleomycin
Authors: Harikrishna Tanjore, Amber L. Degryse, Peter F. Crossno, Xiaochuan C. Xu, Melinda E. McConaha, Brittany R. Jones, Vasiliy V. Polosukhin, Andrew J. Bryant, Dong-Sheng Cheng, Dawn C. Newcomb, Frank B. McMahon, Linda A. Gleaves, Timothy S. Blackwell, William E. Lawson
Journal: American Journal of Respiratory and Critical Care Medicine (2013)

Alveolar epithelial cells (AECs) play central roles in the response to lung injury and the pathogenesis of pulmonary fibrosis.We aimed to determine the role of β-catenin in alveolar epithelium during bleomycin-induced lung fibrosis.Genetically modified mice were developed to selectively delete β-catenin in AECs and were crossed to cell fate reporter mice that express β-galactosidase (βgal) in cells of AEC lineage. Mice were given intratracheal bleomycin (0.04 units) and assessed for AEC death, inflammation, lung injury, and fibrotic remodeling. Mouse lung epithelial cells (MLE12) with small interfering RNA knockdown of β-catenin underwent evaluation for wound closure, proliferation, and bleomycin-induced cytotoxicity.Increased β-catenin expression was noted in lung parenchyma after bleomycin. Mice with selective deletion of β-catenin in AECs had greater AEC death at 1 week after bleomycin, followed by increased numbers of fibroblasts and enhanced lung fibrosis as determined by semiquantitative histological scoring and total collagen content. However, no differences in lung inflammation or protein levels in bronchoalveolar lavage were noted. In vitro, β-catenin-deficient AECs showed increased bleomycin-induced cytotoxicity as well as reduced proliferation and impaired wound closure. Consistent with these findings, mice with AEC β-catenin deficiency showed delayed recovery after bleomycin.β-Catenin in the alveolar epithelium protects against bleomycin-induced fibrosis. Our studies suggest that AEC survival and wound healing are enhanced through β-catenin-dependent mechanisms. Activation of the developmentally important β-catenin pathway in AECs appears to contribute to epithelial repair after epithelial injury.