tbuckley/cabot-search huggingface dataset:
Transfection of poly(I:C) can induce reactive oxygen species-triggered apoptosis and interferon-β-mediated growth arrest in human renal cell carcinoma cells via innate adjuvant receptors and the 2-5A system
Authors: Nanae Harashima, Takafumi Minami, Hirotsugu Uemura, Mamoru Harada
Journal: Molecular Cancer (2014)

Synthetic double-stranded RNA poly(I:C) is a useful immune adjuvant and exhibits direct antitumor effects against several types of cancers. In this study, we elucidated the mechanisms underlying the effects induced in poly(I:C)-transfected human renal cell carcinoma (RCC) cells. In contrast to the lack of an effect of adding poly(I:C), poly(I:C) transfection drastically decreased RCC cell viability. Poly(I:C) transfection induced reactive oxygen species (ROS)-dependent apoptosis in RCC cells and decreased the mitochondrial membrane potential (ΔΨm). Treatment with N-acetyl-l-cysteine (NAC), a ROS scavenger, suppressed apoptosis and restored the ΔΨm. Although the levels of phosphorylated γH2A.X, an indicator of DNA damage, increased in poly(I:C)-transfected RCC cells, NAC treatment decreased their levels, suggesting ROS-mediated DNA damage. Furthermore, poly(I:C) transfection increased the levels of phosphorylated p53, NOXA, and tBid. Immunoblots and assays with a panel of caspase inhibitors revealed that poly(I:C) transfection-induced apoptosis was dependent on caspase-8 and -9, as well as caspase-2. Alternatively, poly(I:C) transfection increased mRNA expression of interferon (IFN)-β, and treatment with IFN-β suppressed growth of RCC cells without apoptosis. In addition, cyclinD1 and c-Myc expression decreased in poly(I:C)-transfected RCC cells. Moreover, RNA interference experiments revealed that poly(I:C) transfection exerted apoptotic effects on RCC cells through innate adjuvant receptors and the 2-5A system, the latter of which induces apoptosis in virus-infected cells. These results suggest that poly(I:C) transfection induced two types of effects against RCC cells such as apoptosis, as a result of ROS-mediated DNA damage, and IFN-β-mediated growth arrest, both of which were exerted via innate adjuvant receptors and the 2-5A system.
Recommendations for the Management of Patients With Unruptured Intracranial Aneurysms
Authors: Joshua B. Bederson, Issam A. Awad, David O. Wiebers, David Piepgras, E. Clarke Haley, Thomas Brott, George Hademenos, Douglas Chyatte, Robert Rosenwasser, Cynthia Caroselli
Journal: Circulation (2000)
CD27 Signaling Increases the Frequency of Regulatory T Cells and Promotes Tumor Growth
Authors: Christina Claus, Carsten Riether, Christian Schürch, Matthias S. Matter, Tamara Hilmenyuk, Adrian F. Ochsenbein
Journal: Cancer Research (2012)

Abstract Signaling of the TNF receptor superfamily member CD27 activates costimulatory pathways to elicit T- and B-cell responses. CD27 signaling is regulated by the expression of its ligand CD70 on subsets of dendritic cells and lymphocytes. Here, we analyzed the role of the CD27–CD70 interaction in the immunologic control of solid tumors in Cd27-deficient mice. In tumor-bearing wild-type mice, the CD27–CD70 interaction increased the frequency of regulatory T cells (Tregs), reduced tumor-specific T-cell responses, increased angiogenesis, and promoted tumor growth. CD27 signaling reduced apoptosis of Tregs in vivo and induced CD4+ effector T cells (Teffs) to produce interleukin-2, a key survival factor for Tregs. Consequently, the frequency of Tregs and growth of solid tumors were reduced in Cd27-deficient mice or in wild-type mice treated with monoclonal antibody to block CD27 signaling. Our findings, therefore, provide a novel mechanism by which the adaptive immune system enhances tumor growth and may offer an attractive strategy to treat solid tumors. Cancer Res; 72(14); 3664–76. ©2012 AACR.
Therapeutic Drug Monitoring for the Individualization of Docetaxel Dosing: A Randomized Pharmacokinetic Study
Authors: Frederike K. Engels, Walter J. Loos, Jessica M. van der Bol, Peter de Bruijn, Ron H.J. Mathijssen, Jaap Verweij, Ron A.A. Mathot
Journal: Clinical Cancer Research (2011)

Docetaxel pharmacokinetic (PK) parameters, notably clearance and exposure (AUC), are characterized by large interindividual variability. The purpose of this study was to evaluate the effect of PK-guided [area under the plasma concentration versus time curve (AUC) targeted], individualized docetaxel dosing on interindividual variability in exposure.A limited sampling strategy in combination with a validated population PK model, Bayesian analysis, and a predefined target AUC was used. Fifteen patients were treated for at least 2 courses with body surface area-based docetaxel and 15 with at least 1 course of PK-guided docetaxel dosing.Interindividual variability (SD of ln AUC) was decreased by 35% (N = 15) after 1 PK-guided course; when all courses were evaluated, variability was decreased by 39% (P = 0.055). PK-guided dosing also decreased the interindividual variability of percentage decrease in white blood cell and absolute neutrophil counts by approximately 50%.Further research is required to determine whether the decrease in PK variability can contribute to a reduction in interindividual variability in efficacy and toxicity.
Clonally expanded novel multipotent stem cells from human bone marrow regenerate myocardium after myocardial infarction
Authors: Young-sup Yoon, Andrea Wecker, Lindsay Heyd, Jong-Seon Park, Tengiz Tkebuchava, Kengo Kusano, Allison Hanley, Heather Scadova, Gangjian Qin, Dong-Hyun Cha, Kirby L. Johnson, Ryuichi Aikawa, Takayuki Asahara, Douglas W. Losordo
Journal: Journal of Clinical Investigation (2005)

We have identified a subpopulation of stem cells within adult human BM, isolated at the single-cell level, that self-renew without loss of multipotency for more than 140 population doublings and exhibit the capacity for differentiation into cells of all 3 germ layers. Based on surface marker expression, these clonally expanded human BM-derived multipotent stem cells (hBMSCs) do not appear to belong to any previously described BM-derived stem cell population. Intramyocardial transplantation of hBMSCs after myocardial infarction resulted in robust engraftment of transplanted cells, which exhibited colocalization with markers of cardiomyocyte (CMC), EC, and smooth muscle cell (SMC) identity, consistent with differentiation of hBMSCs into multiple lineages in vivo. Furthermore, upregulation of paracrine factors including angiogenic cytokines and antiapoptotic factors, and proliferation of host ECs and CMCs, were observed in the hBMSC-transplanted hearts. Coculture of hBMSCs with CMCs, ECs, or SMCs revealed that phenotypic changes of hBMSCs result from both differentiation and fusion. Collectively, the favorable effect of hBMSC transplantation after myocardial infarction appears to be due to augmentation of proliferation and preservation of host myocardial tissues as well as differentiation of hBMSCs for tissue regeneration and repair. To our knowledge, this is the first demonstration that a specific population of multipotent human BM-derived stem cells can induce both therapeutic neovascularization and endogenous and exogenous cardiomyogenesis.
Use of Permanent Hair Dyes and Risk of Breast Cancer&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Adele Green, Walter C. Willett, Graham A. Colditz, Meir J. Stampfer, Christopher Bain, Bernard Rosner, Charles H. Hennekens, Frank E. Speizer
Journal: JNCI Journal of the National Cancer Institute (1987)

Aromatic amines contained in permanent hair dyes can be absorbed percutaneously and are mutagenic and carcinogenic in some laboratory studies. Concern has been raised that use of these dyes may increase the risk of human cancers. Therefore, the present study examined the relationship between permanent hair dye use and incidence of breast cancer among 118,404 U.S. women aged 30–55 years who were followed prospectively for 6 years. Among women who had ever used permanent hair dyes, 353 developed breast cancer during 246,848 person-years of follow-up, while 505 cases occurred during 397,460 person-years among never users (age-adjusted rate ratio = 1.1; 95% confidence interval = 0.9–1.2). Identical rate ratios were observed when women who had ever used hair dyes were subdivided into current and past users. Adjustment for known determinants of breast cancer in multivariate models did not alter these relationships. The risk of breast cancer did not increase with more frequent use, longer duration of use, or interval since first use. On the basis of these data and previous findings, it appears unlikely that the use of permanent hair dyes causes any important increase in risk of breast cancer.
Acute Release of Plasminogen Activator Inhibitor-1 in ST-Segment Elevation Myocardial Infarction Predicts Mortality
Authors: J.P. Collet, G. Montalescot, E. Vicaut, A. Ankri, F. Walylo, C. Lesty, R. Choussat, F. Beygui, M. Borentain, N. Vignolles, D. Thomas
Journal: Circulation (2003)

A few studies have suggested that von Willebrand factor (vWF) or plasminogen activator inhibitor-1 (PAI-1) can be associated with outcomes of acute coronary syndromes. The present study was designed to assess the acute release of these markers in ST-segment elevation myocardial infarction (STEMI) and their relations to death.In 153 consecutive patients with STEMI, vWF and PAI-1 antigens were measured on admission (H0) and 24 hours later (H24). At 30 days, the death rate was 7.2%. Heart failure (Killip stage > or =3) on admission was present in 13.7% of patients. The acute release of PAI-1 (H24-H0, in ng/mL) and of vWF (H24-H0, in %) was dramatically higher in patients who died than in those who survived (46.9+/-26.3 versus -0.6+/-2.8 ng/mL, P=0.0001 and 65.8+/-20.0% versus 10.0+/-5.1%, P=0.004 for PAI-1 and vWF, respectively) and in patients developing heart failure compared with those without (24.8+/-10.1 versus -1.1+/-3.3 ng/mL, P=0.004 and 47.3+/-11.0% versus 8.1+/-5.6%, P=0.005 for PAI-1 and vWF, respectively). The release of PAI-1 correlated weakly with the left ventricular ejection fraction (R=-0.195, P=0.01) and the peak of troponin (R=0.149, P=0.045). Postangioplasty TIMI-3 flow and the acute release of PAI-1 were the only 2 independent predictors of death at 30 days.The acute release of vWF and PAI-1 over the first 24 hours of STEMI is associated with death and heart failure. The acute rise of PAI-1 is also a strong independent predictor of death at 30 days.
New Insights Into the Role of Sequestosome 1/p62 Mutant Proteins in the Pathogenesis of Paget's Disease of Bone
Authors: Sarah L. Rea, John P. Walsh, Robert Layfield, Thomas Ratajczak, Jiake Xu
Journal: Endocrine Reviews (2013)

Paget's disease of bone (PDB) is characterized by focal areas of aberrant and excessive bone turnover, specifically increased bone resorption and disorganized bone formation. Germline mutations in the sequestosome 1/p62 (SQSTM1/p62) gene are common in PDB patients, with most mutations affecting the ubiquitin-associated domain of the protein. In vitro, osteoclast precursor cells expressing PDB-mutant SQSTM1/p62 protein are associated with increases in nuclear factor κB activation, osteoclast differentiation, and bone resorption. Although the precise mechanisms by which SQSTM1/p62 mutations contribute to disease pathogenesis and progression are not well defined, it is apparent that as well as affecting nuclear factor κB signaling, SQSTM1/p62 is a master regulator of ubiquitinated protein turnover via autophagy and the ubiquitin-proteasome system. Additional roles for SQSTM1/p62 in the oxidative stress-induced Keap1/Nrf2 pathway and in caspase-mediated apoptosis that were recently reported are potentially relevant to the pathogenesis of PDB. Thus, SQSTM1/p62 may serve as a molecular link or switch between autophagy, apoptosis, and cell survival signaling. The purpose of this review is to outline recent advances in understanding of the multiple pathophysiological roles of SQSTM1/p62 protein, with particular emphasis on their relationship to PDB, including challenges associated with translating SQSTM1/p62 research into clinical diagnosis and treatment.
Relationship of splanchnic blood flow and portal venous resistance to elevated portal pressure in the dog.
Authors: C L Witte, G R Tobin, D S Clark, M H Witte
Journal: Gut (1976)

To determine the relationship of splanchnic blood flow and portal venous resistance to elevated portal pressure, in situ perfusion of the splanchnic circuit was carried out in 12 freshly killed dogs at varying perfusion rates and degrees of acute and chronic portal vein constriction. In six normal dogs before being killed, portal pressure averaged 8-8 +/- 1-2 mmHg and portal flow 658 +/- 81 ml/min. In the absence of portal vein constriction, increasing splanchnic perfusion to 1800 ml/min, minimally raised portal pressure (12-8 +/- 1-5 mmHg). With progressive acute constriction of the portal vein, however, comparable perfusion rates lead to progressively higher portal pressure levels and with greater than 90% constriction, portal pressure was greater than 30 mmHg with minimal elevation in splanchnic flow rate. In six other dogs before being killed but live to nine weeks after placement of an ameroid constrictor on the portal vein, portal pressure averaged 13-6 +/- 1-4 mmHg or slightly higher than in normal dogs (P greater than 0-02). Mesenteric venography and necropsy findings uniformly demonstrated 90% occlusion of the portal vein with extensive portasystemic collateralization. With increased perfusion of the splanchnic bed, portal pressure rose rapidly to approximately 35 mmHg with a flow rate of 1 800 ml/min.. These data suggest that, in disorders where resistance to transhepatic portal flow is marked, a small increment in splanchnic blood flow, which normally exerts little or no influence on portal pressure, promotes profound portal hypertension and may account for spontaneous 9rupture9 of oesophageal varices. On the other hand, where resistance to transhepatic portal flow is mild but splanchnic blood flow is markedly hyperdynamic, reducing inflow may be sufficient to ameliorate extreme portal hypertension and its sequelae.
Back pain in a young adult
Authors: S. Agius, D. Gatt, M. Rogers, A. Borg
Journal: BMJ (2015)

A 32 year old man was referred to the emergency department with a one week history of worsening mid-thoracic back pain. The pain radiated bilaterally and he occasionally felt it anteriorly in the chest. It was constant in nature and there were no associated symptoms.

He did not look unkempt and was accompanied by his girlfriend and brother. He had no medical history of note but was a known intravenous drug user. He admitted to injecting drugs through “a vein in his armpit” and claimed that the last time he had heroin it looked “thicker” than usual.

His physical examination was unremarkable and the following blood test results were obtained: white blood cell count 11.0×109/L (reference range 4.3-11.4), haemoglobin (11.9 g/L (14.1-17.2), and troponin <0.01 µg/L (0.006-0.04).

A chest radiograph was normal.

He was sent home with advice about back pain and analgesia.

The pain persisted and he re-presented to the emergency department but was discharged again after a normal physical examination and thoracic spine radiography, which was reported as normal.

Two days later he returned with worsening back pain, which was now waking him up at night. On percussion of the spine he was tender over the mid-thoracic area. At this stage he was febrile and had a wide based gait, with his left lower limb being spastic when compared with the right. Tone was increased on the left, whereas his lower limb power was decreased on the left (4/5) compared with the right. Sensation to light touch and pin prick was decreased (but present) from the nipple downwards on both sides. Joint position sense was present at both ankles and vibratory sensation was decreased but present at both big toes and normal at the ankles. Knee and ankle jerks were increased on the left more than …
Is small-bore catheter efficient in different type of pleural pathologies?
Authors: Serife Liman, Aykut Eliçora, Asli Akgul, Salih Topcu, Seymur Mehmetoglu, Serkan Ozbay, Fatih Sezer, Can Koska, Ahmet Ilgazli
Journal: European Respiratory Journal (2012)

In recent years, there is a tendency to use small-bore catheters for pleural pathologies. We aimed to share our experiences about small-bore catheter usage in different pleural diseases.  Between 2006 and 2011, 287 patients with pleural pathologies were treated via 309 small-bore (10F) thoracic catheters. There were 204 male and 83 female patients (mean age: 52). There were 265 unilateral single catheter insertions, 15 bilateral insertions and 7 two-catheters insertions in same hemithorax consecutively. The most frequent indication was pleural effusion (147 catheters), 103 of them were due to malignant pleural diseases. Small-bore catheters were performed in 133 cases with pneumothorax, 21 cases with hemothorax and 8 cases with hemopneumothorax. Pleurodesis were performed effectively with povidion iodine in one, talc in 35 cases.  In 7 patients (3 malignant pleural effusion, 1 empyema, 2 spontaneous pneumothorax and 1 traumatic pneumothorax) second catheter insertion in different localization was needed. In 15 patients (7 spontaneous pneumothorax and 5 malignant pleural effusion, 1 barotrauma pneumothorax, 1 pneumothorax as complication, 1 empyema) pleurocan catheters were ineffective and they changed with small-bore trocar catheters. Our results showed 7.2% failure ratio.  Six patients underwent operation because of persisted air leakage.  Mean duration time of the catheters were 5.6 days (1-20 days). They showed difference depending upon the pleural pathologies. For pleurodesis, mean duration time of plerocan catheters was 4.7 days.  We found small bore catheters very effective in not only malignant pleural effusion and pneumothorax but also in hemothorax and parapneumonic effusions.
Carcinoma of the bronchus in the Yorkshire region of England 1976-1990: trends since 1984
Authors: CK Connolly, SM Crawford, PL Rider, AD Smith, CF Johnston, MF Muers
Journal: European Respiratory Journal (1997)

We wished to confirm that, in patients with lung cancer, trends in demography and histology, together with modest improvements in survival, first seen in the 1976-1983 cohorts, continued to 1990. All lung cancer patients resident in Yorkshire are notified to the Cancer Registry, whose database was analysed for this report. A total of 38,275 patients were notified. There was no change in annual notification for males but an increase from 513 to 815 annual notifications in females between 1976 and 1990. Mean age increased by 3 yrs, in males to 67.4 yrs and in females to 67.2 yrs. Histological confirmation rate increased from 43% to 60% (mean age from 60.8 to 64.5 yrs). Annual notifications of adenocarcinoma increased consistently from 108 to 253. Two year surgical survival improved from 37.4 to 44.3%, doubling in subjects aged > or = 70 yrs to 43.8%. Over the 15 year period, there was no improvement in survival aged < 60 yrs, but a significant improvement in the 60-69 and > or = 70 yrs age groups. Analysis of survival by quartiles showed significant improvement at all levels (first interval 20 to 24 days, median 79 to 91 days, third interval 224 to 266 days). The modest improvement in outlook was confirmed, confined to older subjects after 1983, and partially masked by increasing age. Survival after surgery is now independent of age.
Randomized trial of adjuvant ovarian suppression in 926 premenopausal patients with early breast cancer treated with adjuvant chemotherapy
Authors: R. Arriagada, M.G. Lê, M. Spielmann, L. Mauriac, J. Bonneterre, M. Namer, T. Delozier, C. Hill, T. Tursz
Journal: Annals of Oncology (2005)
Impact of Number of Nodes Retrieved on Outcome in Patients With Rectal Cancer
Authors: Joel E. Tepper, Michael J. O’Connell, Donna Niedzwiecki, Donna Hollis, Carolyn Compton, Al B. Benson, Bernard Cummings, Leonard Gunderson, John S. Macdonald, Robert J. Mayer
Journal: Journal of Clinical Oncology (2001)

We postulated that the pathologic evaluation of the lymph nodes of surgical specimens from patients with rectal cancer can have a substantial impact on time to relapse and survival.We analyzed data from 1,664 patients with T3, T4, or node-positive rectal cancer treated in a national intergroup trial of adjuvant therapy with chemotherapy and radiation therapy. Associations between the number of lymph nodes found by the pathologist in the surgical specimen and the time to relapse and survival outcomes were investigated.Patients were divided into groups by nodal status and the corresponding quartiles of numbers of nodes examined. The number of nodes examined was significantly associated with time to relapse and survival among patients who were node-negative. For the first through fourth quartiles, the 5-year relapse rates were 0.37, 0.34, 0.26, and 0.19 (P: = .003), and the 5-year survival rates were 0.68, 0.73, 0.72, and 0.82 (P: = .02). No significant differences were found by quartiles among patients determined to be node-positive. We propose that observed differences are primarily related to the incorrect determination of nodal status in node-negative patients. Approximately 14 nodes need to be studied to define nodal status accurately.These results suggest that the pathologic assessment of lymph nodes in surgical specimens is often inaccurate and that examining greater number of nodes increases the likelihood of proper staging. Some patients who might benefit from adjuvant therapy are misclassified as node-negative due to incomplete sampling of lymph nodes.
Induction chemoradiation in stage IIIA/N2 non-small-cell lung cancer: a phase 3 randomised trial
Authors: Miklos Pless, Roger Stupp, Hans-Beat Ris, Rolf A Stahel, Walter Weder, Sandra Thierstein, Marie-Aline Gerard, Alexandros Xyrafas, Martin Früh, Richard Cathomas, Alfred Zippelius, Arnaud Roth, Milorad Bijelovic, Adrian Ochsenbein, Urs R Meier, Christoph Mamot, Daniel Rauch, Oliver Gautschi, Daniel C Betticher, René-Olivier Mirimanoff, Solange Peters
Journal: The Lancet (2015)
Failing hospitals should be taken over and not merged, says think tank
Authors: A. O'Dowd
Journal: BMJ (2012)

Poorly performing NHS hospitals in England should be taken over by either the private sector or the best foundation trusts rather than be allowed to merge, says a new report.

Clinicians will also have to be encouraged to take on more of a leadership role and be persuaded that a takeover can mean safer and higher quality care for patients and better working conditions for staff, it says.

The report is published by the independent think tank Reform and was coauthored by Paul Corrigan, who was a health adviser to the former prime minister Tony Blair.

Takeover: Tackling Failing NHS Hospitals says that the current favoured policy of merging failing NHS hospitals does not work, and it …