tbuckley/cabot-search huggingface dataset:
Scrib:Rac1 interactions are required for the morphogenesis of the ventricular myocardium
Authors: Veronika Boczonadi, Rachel Gillespie, Iain Keenan, Simon A. Ramsbottom, Charlotte Donald-Wilson, Mariana Al Nazer, Patrick Humbert, Robert J. Schwarz, Bill Chaudhry, Deborah J. Henderson
Journal: Cardiovascular Research (2014)

The organization and maturation of ventricular cardiomyocytes from the embryonic to the adult form is crucial for normal cardiac function. We have shown that a polarity protein, Scrib, may be involved in regulating the early stages of this process. Our goal was to establish whether Scrib plays a cell autonomous role in the ventricular myocardium, and whether this involves well-known polarity pathways.Deletion of Scrib in cardiac precursors utilizing Scrib(flox) mice together with the Nkx2.5-Cre driver resulted in disruption of the cytoarchitecture of the forming trabeculae and ventricular septal defects. Although the majority of mice lacking Scrib in the myocardium survived to adulthood, they developed marked cardiac fibrosis. Scrib did not physically interact with the planar cell polarity (PCP) protein, Vangl2, in early cardiomyocytes as it does in other tissues, suggesting that the anomalies did not result from disruption of PCP signalling. However, Scrib interacted with Rac1 physically in embryonic cardiomyocytes and genetically to result in ventricular abnormalities, suggesting that this interaction is crucial for the development of the early myocardium.The Scrib-Rac1 interaction plays a crucial role in the organization of developing cardiomyocytes and formation of the ventricular myocardium. Thus, we have identified a novel signalling pathway in the early, functioning, heart muscle. These data also show that the foetus can recover from relatively severe abnormalities in prenatal ventricular development, although cardiac fibrosis can be a long-term consequence.
Therapeutic Destruction of Insulin Receptor Substrates for Cancer Treatment
Authors: Hadas Reuveni, Efrat Flashner-Abramson, Lilach Steiner, Kirill Makedonski, Renduo Song, Alexei Shir, Meenhard Herlyn, Menashe Bar-Eli, Alexander Levitzki
Journal: Cancer Research (2013)

Abstract Insulin receptor substrates 1 and 2 (IRS1/2) mediate mitogenic and antiapoptotic signaling from insulin-like growth factor 1 receptor (IGF-IR), insulin receptor (IR), and other oncoproteins. IRS1 plays a central role in cancer cell proliferation, its expression is increased in many human malignancies, and its upregulation mediates resistance to anticancer drugs. IRS2 is associated with cancer cell motility and metastasis. Currently, there are no anticancer agents that target IRS1/2. We present new IGF-IR/IRS-targeted agents (NT compounds) that promote inhibitory Ser-phosphorylation and degradation of IRS1 and IRS2. Elimination of IRS1/2 results in long-term inhibition of IRS1/2-mediated signaling. The therapeutic significance of this inhibition in cancer cells was shown while unraveling a novel mechanism of resistance to B-RAFV600E/K inhibitors. We found that IRS1 is upregulated in PLX4032-resistant melanoma cells and in cell lines derived from patients whose tumors developed PLX4032 resistance. In both settings, NT compounds led to the elimination of IRS proteins and evoked cell death. Treatment with NT compounds in vivo significantly inhibited the growth of PLX4032-resistant tumors and displayed potent antitumor effects in ovarian and prostate cancers. Our findings offer preclinical proof-of-concept for IRS1/2 inhibitors as cancer therapeutics including PLX4032-resistant melanoma. By the elimination of IRS proteins, such agents should prevent acquisition of resistance to mutated-B-RAF inhibitors and possibly restore drug sensitivity in resistant tumors. Cancer Res; 73(14); 4383–94. ©2013 AACR.
A Multi-Institutional Phase II Study of the Efficacy and Tolerability of Lapatinib in Patients with Advanced Hepatocellular Carcinomas
Authors: Tanios Bekaii-Saab, Joseph Markowitz, Nichole Prescott, Wolfgang Sadee, Nyla Heerema, Lai Wei, Zunyan Dai, Audrey Papp, Angela Campbell, Kristy Culler, Catherine Balint, Bert O'Neil, Ruey-min Lee, Mark Zalupski, Janet Dancey, Helen Chen, Michael Grever, Charis Eng, Miguel Villalona-Calero
Journal: Clinical Cancer Research (2009)

Abstract Background: Hepatocellular carcinoma (HCC) is on the rise worldwide. HCC responds poorly to chemotherapy. Lapatinib is an inhibitor of epidermal growth factor receptor and HER2/NEU both implicated in hepatocarcinogenesis. This trial was designed to determine the safety and efficacy of lapatinib in HCC. Methods: A Fleming phase II design with a single stage of 25 patients with a 90% power to exclude a true response rate of &amp;lt;10% and detect a true response rate of ≥30% was used. The dose of lapatinib was 1,500 mg/day administered orally in 28-day cycles. Tumor and blood specimens were analyzed for expression of HER2/NEU/CEP17 and status of downstream signal pathway proteins. Results: Twenty-six patients with HCC enrolled on this study. Nineteen percent had one prior therapy. Most common toxicities were diarrhea (73%), nausea (54%), and rash (42%). No objective responses were observed. Ten (40%) patients had stable disease as their best response including six (23%) with stable disease lasting &amp;gt;120 days. Median progression-free survival was 1.9 months and median overall survival was 12.6 months. Patients who developed a rash had a borderline statistically significant longer survival. Tissue and blood specimens were available on &amp;gt;90% of patients. No somatic mutations in EGFR (exons 18-21) were found. In contrast to our previous findings, we did not find evidence of HER2/NEU somatic mutations. PTEN, P-AKT, and P70S6K expression did not correlate with survival. Conclusions: Lapatinib is well-tolerated but seems to benefit only a subgroup of patients for whom predictive molecular or clinical characteristics are not yet fully defined. (Clin Cancer Res 2009;15(18):5895–901)
The Two-Edged Sword of Curing Childhood Cancer
Authors: Philip M. Rosoff
Journal: New England Journal of Medicine (2006)

In the June 3, 1948, issue of the Journal, Sydney Farber and his colleagues reported that they had successfully used aminopterin to induce temporary remission in children with lymphoid leukemia. This exciting article suggested that what had been a uniformly fatal disease might be amenable to treatment and, some dared to hope, cure. Then, in 1970, DeVita and his colleagues at the National Cancer Institute showed that a combination of non–cross-reactive chemotherapeutic agents, the MOPP regimen (mechlorethamine, vincristine, procarbazine, and prednisone), could induce sustained remission in advanced Hodgkin's disease. From such beginnings, an extraordinary success story unfolded, and today, more . . .
Exhaled nitric oxide in 4-year-old children: relationship with asthma and atopy
Authors: S. W. Turner
Journal: European Respiratory Journal (2005)

Exhaled nitric oxide in 4-year-old children: relationship with asthma and atopyTo the Editors:The paper by BRUSSEE et al. [1] describes the first large survey of the fraction of exhaled nitric oxide (FeNO) in a young population.The authors should be congratulated for undertaking such a study in an age range where great patience and persistence are required to obtain data.
Decreased indoleamine 2,3-dioxygenase activity and IL-10/IL-17A ratio in patients with COPD
Authors: Kittipong Maneechotesuwan, Kanda Kasetsinsombat, Adisak Wongkajornsilp, Peter J Barnes
Journal: Thorax (2012)

<h3>Rationale</h3> Indoleamine 2,3-dioxygenase (IDO) induces generation of regulatory T cells but suppresses Th17 cells and therefore might attenuate neutrophilic inflammation. The role of IDO in neutrophilic airway diseases such as chronic obstructive pulmonary disease (COPD) remains unknown. We evaluated IDO activity and expression and interleukin (IL)-10 and IL-17A levels in sputum from patients with COPD. <h3>Methods</h3> IDO activity and cytokine concentrations in sputum supernatants from patients with COPD of varying severity and in smoking and non-smoking control subjects were determined by high-performance liquid chromatography and ELISA, respectively. <h3>Results</h3> Patients with COPD had reduced sputum IDO activity and expression and IL-10 levels, with increased IL-17A, IL-6 and CXCL8 concentrations and sputum neutrophils. These changes were significantly correlated with disease severity. IDO activity was decreased, but to a lesser extent, in normal smokers compared with non-smoking controls. <h3>Conclusions</h3> Patients with COPD have a progressive reduction in IDO activity with reversal of the balance between IL-10 and IL-17A, resulting in chronic airway neutrophilic inflammation.
The surface of rat hepatocytes can transfer iron from stable chelates to external acceptors
Authors: Barbara Scheiber, Hans Goldenberg
Journal: Hepatology (1998)

The chelator diethylenetriaminepentaacetate (DTPA) forms a stable complex with iron that does not donate iron to transferrin under physiological conditions, i.e., pH above 7 and isotonic milieu. It does, however, deliver iron to hepatocytes. This uptake is initiated by a mobilization of the metal from the complex by the cell surface. When an external chelator is added simultaneously, it can bind the iron and inhibit its accumulation by the cells. This is shown here with the impermeant siderophore conjugate hydroxyethyl-starch coupled desferrioxamine, as well as with apo-transferrin. We also demonstrate exchange of iron between DTPA and holo-transferrin, or at least movement from the chelator to the protein, which may have lost its iron to the cell in advance, providing new binding sites for mobilized iron. The efficient hepatocyte iron donor lactoferrin greatly stimulates iron uptake from DTPA, apparently by binding iron and transferring it into the cells by endocytosis. Ferritin is unable to do this; therefore, the mobilization of iron is not caused by a reducing activity at the cell surface, because iron is readily transferred from DTPA to ferritin by the reductant ascorbic acid. The transfer process is dependent on the temperature, the time, and the amount of cells present, and is partly inhibited by sulfhydryl reagents. We conclude that this activity represents a hitherto unidentified first step in the movement of iron through the cell membrane and may be relevant for transferrin-bound, as well as for non–transferrin-bound, iron uptake by hepatocytes.
The relationship between social deprivation and hospital admissions with asthma
Authors: Sheila Grecian, Robert Grecian, Sandra Dermott, Haval Balata, Abdul Ashish, Imran Aziz
Journal: European Respiratory Journal (2013)

Background 

Many factors are known to predispose to hospital admissions with acute asthma. However there are no recent studies addressing the relationship between social deprivation and asthma admissions.

Aims and Objectives 

To analyse the effect of social deprivation on hospital admissions and length of stay in patients with acute asthma.

Methods 

Retrospective review of hospitalisation of patients with a primary diagnosis of asthma between 01/09/11 and 31/08/12 in Wigan UK. Patients were assigned an index of multiple deprivation score based on postcode and subdivided into quintiles. For each quintile, total admissions and length of stay per admission were calculated and corrected for population size (per 100,000 residents). Fishers exact test (two tailed) was used to compare quintiles. The least derived group constituted only <5% of the population and was excluded.

Results 

There were significantly higher numbers of admissions in patients from more deprived postcodes compared to affluent areas (p<0.0001). There was no significant difference in mean length of stay between quintiles.

View this table:

Asthma admissions and length of stay





Conclusions 

Patients from socio-economically deprived backgrounds have higher rates of hospital admissions with acute asthma in Wigan. Deprivation does not appear to influence length of stay. Increasing healthcare investement in deprived areas should be considered.
Involvement of Heat Shock Factor 1 in Statin-Induced Transcriptional Upregulation of Endothelial Thrombomodulin
Authors: Qiang Fu, Junru Wang, Marjan Boerma, Maaike Berbée, Xiaohua Qiu, Louis M. Fink, Martin Hauer-Jensen
Journal: Circulation Research (2008)

Statins upregulate endothelial thrombomodulin (TM) by mechanisms that involve members of the Kruppel-like factor family. Although Kruppel-like factors are unequivocally implicated in this process, experimental evidence points to additional mechanisms. Deletion/mutation analysis of reporter constructs was used to demonstrate that mutation of the SP1/Kruppel-like factor element in the TM promoter only partially abolishes statin-induced TM upregulation, whereas simultaneous mutation of relevant heat shock elements and SP1/Kruppel-like factor element completely prevents statin-induced TM upregulation, thus demonstrating a role for heat shock factors (HSFs). We further identified the pathway by which statins increase binding of HSF1 to heat shock elements in the TM promoter. Specifically, statins caused NO-dependent dissociation of HSF1 from heat shock protein 90, nuclear translocation of HSF1, and binding to heat shock elements in the TM promoter. Statins also decreased nuclear content of the HSF1 chaperone 14-3-3beta. In addition to reducing TM upregulation, inhibition of HSF1 reduced statin-induced upregulation of tissue plasminogen activator, whereas downregulation of thrombomospondin, plasminogen activator inhibitor 1, or connective tissue growth factor was unaffected. Knockdown of 14-3-3beta or inhibition of HSF1 phosphorylation enhanced the effect of statins on TM and tissue plasminogen activator, but did not influence thrombomospondin, plasminogen activator inhibitor 1, or connective tissue growth factor. These data demonstrate that HSF1 is involved in statin-induced regulation of TM. They also suggest that analogous mechanisms may apply to genes that are upregulated by statins, but not to downregulated genes. These results may have broad implications and suggest the use of heat shock protein modulators to selectively regulate pleiotropic statin effects.
Commentary: Use of registries to investigate the past and develop the future
Authors: S. James, J.-C. Daubert, F. V. d. Werf
Journal: BMJ (2011)

Ideally, collection of clinical data should be an integral part of healthcare systems. Without systematic collection of individual patient data and outcome it is impossible for individual doctors, healthcare providers, or regulatory agencies to understand how, when, and to whom healthcare is provided and the actual outcome of specific procedures or devices...
First trimester prenatal diagnosis using transcervical cells: an evaluation
Authors: M Adinolfi
Journal: Human Reproduction Update (1997)

Human trophoblastic cells can be retrieved by minimally invasive procedures from the endocervical canal between 6 and 15 weeks gestation. The incidence with which fetal cells can be detected in transcervical cell (TCC) samples varies according to the method of collection and the molecular techniques employed for their identification. Fluorescence in-situ hybridization (FISH) and polymerase chain reaction (PCR) assays have been successfully used to detect aneuploidies and Y-derived DNA sequences in TCC samples obtained from male fetuses. Chromosome specific polymorphic DNA sequences (small tandem repeats) have also been employed to identify, by quantitative fluorescent PCR, fetal cells in TCC samples. Furthermore, Rh(D) sequences have been amplified in samples retrieved from Rh(D) negative mothers. Preliminary results also suggest that prenatal diagnoses of thalassaemia and sickle cell anaemia can be performed on clumps of cells isolated from TCC samples. Overall systematic studies allow optimism about the possibility of using TCC samples for the prenatal diagnosis of selected inherited disorders.
Methicillin resistant Staphylococcus aureus: toward a coordinated response to a continuing challenge
Authors: M J Struelens, O Denis
Journal: Eurosurveillance (2000)

Methicillin resistant Staphylococcus aureus (MRSA) represents a major public health challenge in many health care institutions worldwide. It is a common cause of outbreaks of cross infection and has become endemic in many regions where it adds to the morb
RE: Net Risk Reclassification P Values: Valid or Misleading?
Authors: M. J. Pencina, B. Neely, E. W. Steyerberg
Journal: JNCI Journal of the National Cancer Institute (2014)

Biomedical research of the last few decades has been characterized by an overreliance on statistical testing. Researchers like many zeros in their P values to convince their audience on the validity of their claims from empirical observations. The area of predictive modeling has been no exception. When the focus shifted from association, eg, expressed by hazard ratios, to the added predictive ability of new biomarkers, P values remained at the forefront in reporting. A contributing factor is the difficult
Long-term Reproducibility of Ventricular Tachycardia Induction in Patients With Implantable Cardioverter/Defibrillators
Authors: Anne M. Gillis, Robert S. Sheldon, D. George Wyse, James W. Leitch, Raymond Yee, George J. Klein, Henry J. Duff, L. Brent Mitchell
Journal: Circulation (1995)

Background Noninvasive electrophysiological studies (EPSs) can be performed in current implantable antitachycardia pacemaker/cardioverter/defibrillators (ICDs). Thus, these devices may be used as tools to study changes in the electrophysiological substrate and ventricular tachycardia characteristics over time. Methods and Results Fifty-five patients receiving an ICD for treatment of sustained ventricular tachyarrhythmias underwent serial EPSs after implantation of the ICD. Studies were performed before hospital discharge and 1, 3, 5, 9, 12, 18, 24, and 36 months after ICD implantation. Sustained monomorphic ventricular tachycardia (VT) was induced in 37 patients (group 1) at the predischarge EPS, whereas no sustained arrhythmia could be induced in 18 patients (group 2) at baseline. Group 1 patients underwent 165 noninvasive EPSs after discharge. Sustained monomorphic VT was induced during 72% of the follow-up EPSs, ventricular fibrillation (VF) was induced during 11% of follow-up EPSs, and no sustained VT or VF was induced during 17% of follow-up visits. Sustained VT was induced at every follow-up EPS in 23 patients (62%), whereas no sustained VT/VF could be induced at least once during follow-up in 14 patients (38%). Clinical or electrophysiological variables did not predict noninducibility during follow-up. However, the probability that a patient would experience spontaneous VT decreased significantly over time in patients in whom VT was not inducible during at least 1 follow-up EPS ( P =.05). Group 2 patients underwent 86 noninvasive EPSs after discharge. Sustained monomorphic VT was induced during 22% of follow-up EPSs, VF was induced during 19% of follow-up EPSs, and no sustained VT/VF could be induced during 68% of follow-up EPSs. No sustained VT/VF could be induced during every follow-up EPS in 9 patients (50%), whereas sustained monomorphic VT was induced at least once during follow-up in 7 patients (34%). Persistent noninducibility of VT during follow-up was associated with low probability of occurrence of spontaneous VT (11%), whereas inducibility of VT at least once during follow-up was associated with the occurrence of spontaneous VT (89%, P =.003). Conclusions Considerable variability of VT induction is observed over a lengthy period in patients presenting with sustained VT/VF. Persistent noninducibility of VT is associated with a reduced probability of spontaneous VT. These observations suggest that the substrates for inducible and spontaneous VT change in parallel over time.
The Hypoxia-Activated ProDrug AQ4N Penetrates Deeply in Tumor Tissues and Complements the Limited Distribution of Mitoxantrone
Authors: Olivier Trédan, Alaina B. Garbens, Alshad S. Lalani, Ian F. Tannock
Journal: Cancer Research (2009)

Hypoxic tumor cells are likely to be resistant to conventional chemotherapy, in large part because many anticancer drugs are unable to penetrate into poorly oxygenated tumor tissue. Here, we used quantitative immunofluorescence to study the distribution of mitoxantrone and AQ4N in tumor tissue. AQ4N is a prodrug activated under hypoxic conditions to AQ4, which is structurally similar to mitoxantrone and inhibits topoisomerase II. We characterized the penetration of mitoxantrone and AQ4N/AQ4 through multilayered cell cultures (MCC) and in relation to blood vessels and hypoxic regions in human tumor xenografts. We also studied tumor growth delay after treatment with each agent alone and with the combination. In both MCC and xenografts, mitoxantrone is taken up by proximal cells and penetrates slowly to distant regions. In contrast, AQ4N rapidly penetrates MCC and tumor tissue in vivo, and AQ4N (or its reduced form AQ4) is detected at high concentration within hypoxic regions. The targeting of mitoxantrone to oxygenated regions and AQ4N/AQ4 to hypoxic tumor regions results in effective drug exposure over the entire tumor after combined treatment and increases tumor growth delay compared with either drug alone. The combination of a clinically used anticancer drug with limited tissue penetration and a structurally related drug activated in regions of tumor hypoxia is an effective strategy to overcome chemoresistance due to the tumor microenvironment. This study supports clinical evaluation of AQ4N in combination with conventional anticancer agents, such as mitoxantrone.
The Auditory Hair Cell Ribbon Synapse: From Assembly to Function
Authors: Saaid Safieddine, Aziz El-Amraoui, Christine Petit
Journal: Annual Review of Neuroscience (2012)

Cochlear inner hair cells (IHCs), the mammalian auditory sensory cells, encode acoustic signals with high fidelity by Graded variations of their membrane potential trigger rapid and sustained vesicle exocytosis at their ribbon synapses. The kinetics of glutamate release allows proper transfer of sound information to the primary afferent auditory neurons. Understanding the physiological properties and underlying molecular mechanisms of the IHC synaptic machinery, and especially its high temporal acuity, which is pivotal to speech perception, is a central issue of auditory science. During the past decade, substantial progress in high-resolution imaging and electrophysiological recordings, as well as the development of genetic approaches both in humans and in mice, has produced major insights regarding the morphological, physiological, and molecular characteristics of this synapse. Here we review this recent knowledge and discuss how it enlightens the way the IHC ribbon synapse develops and functions.
ENCEPHALOMYELITIS OF MICE
Authors: Max Theiler, Sven Gard
Journal: The Journal of Experimental Medicine (1940)

1. In the feces of approximately two-thirds of normal mice 6 weeks of age an agent in all respects similar to the virus of mouse encephalomyelitis can be recovered. 2. In isolated mice, fed on sterile food and water, excretion of virus has been shown to persist up to 53 days after isolation. 3. In normal mice known to be virus carriers virus has been demonstrated in the gastro-intestinal tract but not in the central nervous system, thoracic or abdominal viscera, or any organs of the head. 4. The source of the virus excreted in the feces has been shown to be located in all probability in the intestinal wall. 5. Evidence is presented that the virus can invade the animal organism, as virus has been demonstrated in the mesenteric lymph glands.
Definition and classification of cancer cachexia: an international consensus
Authors: Kenneth Fearon, Florian Strasser, Stefan D Anker, Ingvar Bosaeus, Eduardo Bruera, Robin L Fainsinger, Aminah Jatoi, Charles Loprinzi, Neil MacDonald, Giovanni Mantovani, Mellar Davis, Maurizio Muscaritoli, Faith Ottery, Lukas Radbruch, Paula Ravasco, Declan Walsh, Andrew Wilcock, Stein Kaasa, Vickie E Baracos
Journal: The Lancet Oncology (2011)