tbuckley/cabot-search huggingface dataset:
Butterfly and Renal Cell Cancer: Out of Chaos Comes Order
Authors: Giuseppe Procopio, Elena Verzoni, Filippo De Braud
Journal: Journal of Clinical Oncology (2014)

TO THE EDITOR: You are no doubt familiar with the butterfly effect paradigm to describe the chaos theory. The proverbial butterfly flaps its wings on a remote Caribbean island and causes a hurricane in Europe a few weeks later. A small change in one place can cause widely diverging outcomes in another. In patients with cancer the butterfly effect can have devastating effects. Over our many years of treating cancer, it has become evident that not everything can be anticipated/predicted but our ultimate goal remains unchanged. It has been said that ‘out of chaos comes order’. We believe at this important juncture, treatment of renal cell carcinoma (RCC) requires “order” to be restored. We have a veritable smorgasbord of potential therapeutic agents but we are at a loss how best to use them. Three recent papers in the journal—two clinical trial reports and one opinion piece—highlight the ongoing dilemmas in RCC management. 1-3 Hwang and Heath 1 reviewedresultsofrecenttrialsanddiscussedtheirimplicationswithin the framework of a clinical case with the aim of defining a treatment algorithm. They suggest a second tyrosine kinase inhibitor (TKI) followinganinitialresponseofgreaterthan6monthsandamammalian target of rapamycin when response is less than 6 months. While this approach is not without its merits, the heterogeneity of RCC and the lack of comparative data make one hesitate to advocate its widespread adoption. To comment on the detail—we acknowledge that pazopanib mightbeconsideredoversunitinibduetoitsbettertolerabilitybutthe lack of data on the former in a patient population with sarcomatoid features, brain metastases or with no previous nephrectomy, suggests thatinthesesubgroupsofpatientssunitinibisthepreferredtreatment approach. We agree that temsirolimus should be considered as standard in poor-risk patients, but that sunitinib is a good alternative particularly in patients with normal lactate dehydrogenase and those with symptoms due to tumor burden, as sunitinib can shrink the tumor and provide symptomatic relief. Wealsoconsiderthatthedurationofresponseshouldbeviewed as a prognostic not a predictive factor to be used in determining second-line therapy. A prolonged response to a TKI is potentially associated with a better outcome, independently of subsequent therapies.Patients,whohavenoresponseorashortresponsetoafirstTKI,
Derivative chromosome 9 deletions in chronic myeloid leukemia: poor prognosis is not associated with loss of ABL-BCRexpression, elevated BCR-ABL levels, or karyotypic instability
Authors: Brian J. P. Huntly, Anthony J. Bench, Eric Delabesse, Alistair G. Reid, Juan Li, Mike A. Scott, Lynda Campbell, Jennie Byrne, Eleanor Pinto, Andre Brizard, Deitger Niedermeiser, Elizabeth P. Nacheva, Francois Guilhot, Michael Deininger, Anthony R. Green
Journal: Blood (2002)
Phase I Dendritic Cell p53 Peptide Vaccine for Head and Neck Cancer
Authors: Patrick J. Schuler, Malgorzata Harasymczuk, Carmen Visus, Albert DeLeo, Sumita Trivedi, Yu Lei, Athanassios Argiris, William Gooding, Lisa H. Butterfield, Theresa L. Whiteside, Robert L. Ferris
Journal: Clinical Cancer Research (2014)

p53 accumulation in head and neck squamous cell carcinoma (HNSCC) cells creates a targetable tumor antigen. Adjuvant dendritic cell (DC)-based vaccination against p53 was tested in a phase I clinical trial.
Multi-breath and single breath helium dilution lung volumes as a test of airway obstruction
Authors: CM Roberts, KD MacRae, WA Seed
Journal: European Respiratory Journal (1990)

Total lung capacity (TLC) and residual volume (RV) measurements derived from multi-breath and single breath helium dilution methods were combined to produce four indices of gas mixing: single breath volume/multi-breath volume ratio (TLCr, RVr) or multi-breath volume minus single breath volume difference (TLCd, RVd). The reproducibility of these indices and their sensitivity and specificity in discriminating between normal subjects and those with mild asthma and severe chronic obstructive pulmonary disease (COPD) was assessed. The total lung capacity ratio (TLCr) was the superior variable overall, providing a single range for both sexes with a specificity and sensitivity similar to that of the forced expiratory volume in one second (FEV1) in the diagnosis of airflow obstruction. Despite the similar sensitivity, correlation between TLCr and FEV1 was only moderate (r = 0.56). This may reflect greater influence of peripheral rather than central airflow obstruction on TLCr. Combining both tests improved sensitivity in the detection of airways obstruction in the asthmatic and COPD groups studied.
Red Wine Polyphenols Enhance Endothelial Nitric Oxide Synthase Expression and Subsequent Nitric Oxide Release From Endothelial Cells
Authors: Jürgen F. Leikert, Thomas R. Räthel, Paulus Wohlfart, Véronique Cheynier, Angelika M. Vollmar, Verena M. Dirsch
Journal: Circulation (2002)

Population-based studies suggest a reduced incidence of morbidity and mortality from coronary heart disease caused by moderate and regular consumption of red wine. Endothelial nitric oxide (NO) is a pivotal vasoprotective molecule. This study examines the influence of red wine polyphenols on the regulation of endothelial nitric oxide synthase (eNOS) expression and subsequent NO synthesis, focusing on the putative long-lasting antiatherosclerotic effects of red wine.Treatment (20 hours) of human umbilical vein endothelial cells (HUVECs) and of the HUVEC-derived cell line EA.hy926 with a alcohol-free red wine polyphenol extract (RWPE) led to a concentration-dependent (100 to 600 microg/mL), significant increase in NO release (up to 3.0-fold/HUVEC and 2.0-fold/EA.hy926) as shown by use of the fluorescent probe DAF-2. This effect was corroborated by the [14C]L-arginine/L-citrulline conversion assay in intact EA.hy926 cells. RWPE (20 hours, 100 to 600 microg/mL) also significantly increased eNOS protein levels up to 2.1-fold. Furthermore, we found an increased human eNOS promotor activity (up to 2-fold) in response to red wine polyphenols (18 hours, 100 to 600 microg/mL), as demonstrated by a luciferase reporter gene assay.We provide conclusive data showing for the first time that a RWPE increases eNOS expression and subsequent endothelial NO release. Increased active eNOS levels may antagonize the development of endothelial dysfunction and atherosclerosis, a hypothesis that supports the view that red wine indeed may have long-term protective cardiovascular properties mediated by its polyphenols.
A role for whey acidic protein four-disulfide-core 12 (WFDC12) in the regulation of the inflammatory response in the lung
Authors: Arlene M A Glasgow, Donna M Small, Aaron Scott, Denise T McLean, Nicolas Camper, Umar Hamid, Shauna Hegarty, Dhruv Parekh, Cecilia O'Kane, Fionnuala T Lundy, Paul McNally, J Stuart Elborn, Danny F McAuley, Sinéad Weldon, Clifford C Taggart
Journal: Thorax (2015)

Secretory leucocyte protease inhibitor and elafin are members of the whey acidic protein (WAP), or WAP four disulfide-core (WFDC), family of proteins and have multiple contributions to innate defence including inhibition of neutrophil serine proteases and inhibition of the inflammatory response to lipopolysaccharide (LPS). This study aimed to explore potential activities of WFDC12, a previously uncharacterised WFDC protein expressed in the lung.Recombinant expression and purification of WFDC12 were optimised in Escherichia coli. Antiprotease, antibacterial and immunomodulatory activities of recombinant WFDC12 were evaluated and levels of endogenous WFDC12 protein were characterised by immunostaining and ELISA.Recombinant WFDC12 inhibited cathepsin G, but not elastase or proteinase-3 activity. Monocytic cells pretreated with recombinant WFDC12 before LPS stimulation produced significantly lower levels of the pro-inflammatory cytokines interleukin-8 and monocyte chemotactic protein-1 compared with cells stimulated with LPS alone. Recombinant WFDC12 became conjugated to fibronectin in a transglutaminase-mediated reaction and retained antiprotease activity. In vivo WFDC12 expression was confirmed by immunostaining of human lung tissue sections. WFDC12 levels in human bronchoalveolar lavage fluid from healthy and lung-injured patients were quantitatively compared, showing WFDC12 to be elevated in both patients with acute respiratory distress syndrome and healthy subjects treated with LPS, relative to healthy controls.Together, these results suggest a role for this lesser known WFDC protein in the regulation of lung inflammation.
Parents do not see GPs as source of help for emotionally disturbed schoolchildren
Authors: S. Turner
Journal: BMJ (1998)

EDITOR—The general practice in which I work currently has a project (“Innocence and experience”) to increase our awareness and understanding of emotional disorders in children, which Robinson's editorial recognises to be common.1To establish their incidence in our practice we sent the Rutter revised questionnaire2 to the parents of all the 880 children at primary school; 737 (84%) were returned completed. Altogether 125 had coding levels suggestive of emotional disorder (13).3

To find out what …
Sympathetic Denervation in the Treatment of Acute Arterial Occlusion
Authors: JACK FLASHER, ALBERT E. WHITE, DOUGLAS R. DRURY
Journal: Circulation (1954)

The effect of sympathectomy on the size of the collateral vessels in acute arterial ligation in a hind limb was measured by an angiographic angiometric technic and by noting the pressure in the ligated artery distal to the ligature. The size of the largest collateral vessel present on the sympathectomized side was the same as that on the innervated side. The blood pressure in the ligated artery distal to the ligature was quite similar on the sympathectomized and innervated sides. The usual increase in temperature on the sympathectomized side was noted. This must be due to a shift of blood from the deeper tissues of the hind limb to the arteriovenous shunts of the skin of the toes, rather than to an increase in collateral blood flow.
Prognostic Value of a Treadmill Exercise Score in Symptomatic Patients With Nonspecific ST-T Abnormalities on Resting ECG
Authors: Jennifer M. F. Kwok
Journal: JAMA (1999)

Exercise testing of patients with ST-T abnormalities on the resting electrocardiogram (ECG) is problematic because in the presence of pre-existing ST-T abnormalities, the exercise test is less specific for the diagnosis of coronary artery disease. The prognostic capability of the Duke treadmill score in patients with ST-T abnormalities vs those with normal findings on resting ECG has, to our knowledge, not been evaluated.To compare the prognostic accuracy of the Duke treadmill score in patients with nonspecific ST-T abnormalities vs those with normal results on resting ECG.Inception cohort study with 7 years of follow-up.Nuclear cardiology laboratory of a US referral center.All symptomatic patients who underwent exercise thallium testing between 1989 and 1991,939 of whom had nonspecific ST-T abnormalities and 1466 of whom had normal findings on resting ECG. Exclusion criteria included congenital, valvular, or cardiomyopathic heart disease; prior coronary artery revascularization; resting ECG with secondary ST-T abnormalities; or missing data.Rates of overall mortality and cardiac death for subjects classified by Duke treadmill score risk group.For the end point cardiac death, 7-year survival in the study population in the low-, intermediate-, and high-risk groups was 97%, 92%, and 76%, respectively (P<.001). Compared with the control group, the study group had lower 7-year survival (94% vs 98%; P<.001), fewer low-risk patients (426 [45%] vs 811 [55%]; P<.001) with worse 7-year survival (97% vs 99%; P= .008), and more high-risk patients (49 [5%] vs 34 [2%];P<.001) with a nonsignificant trend toward worse 7-year survival (76% vs 93%; P= .36).The Duke treadmill score can effectively risk-stratify patients with ST-T abnormalities on the resting ECG. In classified risk categories, patients with ST-T abnormalities have a worse prognosis than those with normal results on resting ECG.
Repeated Δ<sup>9</sup>-Tetrahydrocannabinol Exposure in Adolescent Monkeys: Persistent Effects Selective for Spatial Working Memory
Authors: Christopher D. Verrico, Hong Gu, Melanie L. Peterson, Allan R. Sampson, David A. Lewis
Journal: American Journal of Psychiatry (2014)

Epidemiological findings suggest that, relative to adults, adolescents are more vulnerable to the adverse persistent effects of cannabis on working memory. However, the potential confounds inherent in human studies preclude direct determination of a cause-and-effect relationship between adolescent cannabis use and heightened susceptibility to persistent working memory impairments. Consequently, the authors examined the effects of repeated exposure to Δ9-tetrahydrocannabinol (THC) on performance of spatial and object working memory tasks in adolescent monkeys.Seven pairs of male adolescent rhesus monkeys, matched for baseline cognitive performance, received vehicle or THC intravenously 5 days/week for 6 months. Performance on spatial and object memory tasks was assessed 23 or 71 hours after drug administration throughout the study. In addition, acute effects on working memory were also assessed at the beginning and end of the 6-month period.Relative to the vehicle-exposed control animals, those with repeated THC exposure had a blunted trajectory of accuracy improvements on the spatial working memory task in a delay-dependent manner. Accuracy improvements on the object working memory task did not differ between groups. Relative to the acute effects of THC on working memory at the beginning of the study, neither sensitivity nor tolerance was evident after 6 months of THC exposure.Because maturation of performance is later for spatial than for object working memory, these findings suggest that persistent effects of THC on cognitive abilities are more evident when exposure coincides with the developmental stage during which the underlying neural circuits are actively maturing.
Transient Receptor Potential Melastatin 7 Ion Channels Regulate Magnesium Homeostasis in Vascular Smooth Muscle Cells
Authors: Ying He, Guoying Yao, Carmine Savoia, Rhian M. Touyz
Journal: Circulation Research (2005)

Magnesium modulates vascular smooth muscle cell (VSMC) function. However, molecular mechanisms regulating VSMC Mg2+ remain unknown. Using biochemical, pharmacological, and genetic tools, the role of transient receptor potential membrane melastatin 7 (TRPM7) cation channel in VSMC Mg2+ homeostasis was evaluated. Rat, mouse, and human VSMCs were studied. Reverse transcriptase polymerase chain reaction and immunoblotting demonstrated TRPM7 presence in VSMCs (membrane and cytosol). Angiotensin II (Ang II) and aldosterone increased TRPM7 expression. Gene silencing using small interfering RNA (siRNA) against TRPM7, downregulated TRPM7 (mRNA and protein). Basal [Mg2+]i, measured by mag fura-2AM, was reduced in siRNA-transfected cells (0.39+/-0.01 mmol/L) versus controls (0.54+/-0.01 mmol/L; P<0.01). Extracellular Mg2+ dose-dependently increased [Mg2+]i in control cells (Emax 0.70+/-0.02 mmol/L) and nonsilencing siRNA-transfected cells (Emax 0.71+/-0.04 mmol/L), but not in siRNA-transfected cells (Emax 0.5+/-0.01 mmol/L). The functional significance of TRPM7 was evaluated by assessing [Mg2+]i and growth responses to Ang II in TRPM7 knockdown cells. Acute Ang II stimulation decreased [Mg2+]i in control and TRPM7-deficient cells in a Na+-dependent manner. Chronic stimulation increased [Mg2+]i in control, but not in siRNA-transfected VSMCs. Ang II-induced DNA and protein synthesis, measured by 3[H]-thymidine and 3[H]-leucine incorporation, respectively, were increased in control and nonsilencing cells, but not in TRPM7 knockdown VSMCs. Our data indicate that VSMCs possess membrane-associated, Ang II-, and aldosterone-regulated TRPM7 channels, which play a role in regulating basal [Mg2+]i, transmembrane Mg2+ transport and DNA and protein synthesis. These novel findings identify TRPM7 as a functionally important regulator of Mg2+ homeostasis and growth in VSMCs.
Mechanical stress-induced cardiac hypertrophy: mechanisms and signal transduction pathways
Authors: C Ruwhof
Journal: Cardiovascular Research (2000)

Cardiac hypertrophy is a well known response to increased hemodynamic load. Mechanical stress is considered to be the trigger inducing a growth response in the overloaded myocardium. Furthermore, mechanical stress induces the release of growth-promoting factors, such as angiotensin II, endothelin-1, and transforming growth factor-β, which provide a second line of growth induction. In this review, we will focus on the primary effects of mechanical stress: how mechanical stress may be sensed, and which signal transduction pathways may couple mechanical stress to modulation of gene expression, and to increased protein synthesis. Mechanical stress may be coupled to intracellular signals that are responsible for the hypertrophic response via integrins and the cytoskeleton or via sarcolemmal proteins, such as phospholipases, ion channels and ion exchangers. The signal transduction pathways that may be involved belong to two groups: (1) the mitogen-activated protein kinases (MAPK) pathway; and (2) the janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway. The MAPK pathway can be subdivided into the extracellular-regulated kinase (ERK), the c-Jun N-terminal kinase (JNK), and the 38-kDa MAPK (p38 MAPK) pathway. Alternatively, the stress signal may be directly submitted to the nucleus via the cytoskeleton without the involvement of signal transduction pathways. Finally, by promoting an increase in intracellular Ca2+ concentration stretch may stimulate the calcium/calmodulin-dependent phosphatase calcineurin, a novel hypertrophic signalling pathway.
A Multisite Analysis of the Fluctuating Course of Posttraumatic Stress Disorder
Authors: Richard A. Bryant, Meaghan L. O’Donnell, Mark Creamer, Alexander C. McFarlane, Derrick Silove
Journal: JAMA Psychiatry (2013)

Delayed-onset posttraumatic stress disorder (PTSD) accounts for approximately 25% of PTSD cases. Current models do not adequately explain the delayed increases in PTSD symptoms after trauma exposure.To test the roles of initial psychiatric reactions, mild traumatic brain injury (MTBI), and ongoing stressors on delayed-onset PTSD.In this prospective cohort study, patients were selected from recent admissions to 4 major trauma hospitals across Australia. A total of 1084 traumatically injured patients were assessed during hospital admission from April 1, 2004, through February 28, 2006, and 785 (72.4%) were followed up at 3, 12, and 24 months after injury.Severity of PTSD was determined at each assessment with the Clinician-Administered PTSD Scale.Of those who met PTSD criteria at 24 months, 44.1% reported no PTSD at 3 months and 55.9% had subsyndromal or full PTSD. In those who displayed subsyndromal or full PTSD at 3 months, PTSD severity at 24 months was predicted by prior psychiatric disorder, initial PTSD symptom severity, and type of injury. In those who displayed no PTSD at 3 months, PTSD severity at 24 months was predicted by initial PTSD symptom severity, MTBI, length of hospitalization, and the number of stressful events experienced between 3 and 24 months.These data highlight the complex trajectories of PTSD symptoms over time. This study also points to the roles of ongoing stress and MTBI in delayed cases of PTSD and suggests the potential of ongoing stress to compound initial stress reactions and lead to a delayed increase in PTSD symptom severity. This study also provides initial evidence that MTBI increases the risk of delayed PTSD symptoms, particularly in those with no acute symptoms.
A Clinical Lecture ON THE VIBRATING SENSATION IN DISEASES OF THE NERVOUS SYSTEM: Delivered at the Manchester Royal Infirmary
Authors: R. T. Williamson
Journal: BMJ (1907)

WHEN the foot of a vibrating tuning-fork over eubcutaneous bony prominences or surfaces, parts of the body, a pecaliar vibrating To this sensation the names of "' vibrating sensation feeling," " bone sensibility," and " " been given.Though the sensations produced tuning-forks had beenstudied by Rumpf in Germany many years ago, it was Egger, especially directed attention to the subject Subsequently the vibrating sensation has carefully studied by Seiffer and Rydel, by Goldscheider, -others in Germany, by Mdinor, and by Sterling in Russia, and by Marinesco in Roumania.Some tuning-Iorks produce a much better vibrating sensation than others.Many of the smaller English tuning forks pro- duce very little of the sensiation, and are almost useleSs in clinical work.Moreover, there is often consider-
On a mission: how Cuba uses its doctors abroad
Authors: Sara Carrillo de Albornoz
Journal: BMJ (2006)

CD27 is a 120-kDa transmembrane homodimeric molecule expressed on the majority of T cells, B cells, and NK cells that belongs to the TNFR/nerve growth factor receptor family. The interaction between CD27 and its ligand, CD70, is thought to play an important role in T cell activation. In this paper we have examined the signal-transducing potential of CD27 in T cell costimulation. Anti-CD27 mAb, anti-1A4, induced substantial proliferation of peripheral blood T cells in the presence of a suboptimal dose of PMA, phytohemagglutinin, anti-CD2, or anti-CD3 together with a second Ab to cross-link the CD27 molecule. This T cell proliferation was also observed by using CD70 transfectant cells. CD27 cross-linking maximally induced proliferation of CD45RA+CD4 T cells but only slightly induced proliferation of CD45RO+CD4 T cells. CD27-mediated T cell proliferation did not seem to be dependent on the IL-2/IL-2R system because no detectable level of IL-2 was secreted, and only a partial inhibition was observed with anti-IL-2 and anti-IL-2R Abs. Furthermore, an increase in intracellular Ca2+ was observed in PMA-treated T cells when the CD27 molecule was cross-linked. More importantly, CD27 ligation induced protein tyrosine phosphorylation, especially 70 kDa of cellular substrate, including ZAP-70, in T cells. Herbimycin A, a protein tyrosine kinase inhibitor, and staurosporine, a protein kinase C inhibitor, blocked T cell proliferation induced by CD27 ligation, suggesting the possibility that the activation of protein tyrosine kinase and protein kinase C is required for CD27-mediated T cell costimulation. These results clearly demonstrate that the CD27/CD70 interaction induces costimulatory signals in T cells, especially CD45RA+ naive T cells, indicating that CD27 serves as a T cell signal-transducing molecule.
Generation of reentrant arrhythmias by dominant-negative inhibition of connexin43 in rat cultured myocyte monolayers
Authors: Takuo Nakagami, Hideo Tanaka, Ping Dai, Shien-Fong Lin, Takuji Tanabe, Hiroki Mani, Katsuji Fujiwara, Hiroaki Matsubara, Tetsuro Takamatsu
Journal: Cardiovascular Research (2008)

AimsAlteration of connexin43 (Cx43)-mediated intercellular communication is known to promote susceptibility to ventricular tachyarrhythmias. However, the precise mechanism of the altered Cx43 responsible for arrhythmogenesis remains unclear. We sought to understand changes in impulse propagation of ventricular myocytes under dominant-negative (DN) inhibition of Cx43 in the development of arrhythmias.