tbuckley/cabot-search huggingface dataset:
MAP-ing glioma invasion: MKK3 and p38 are drivers of glioma invasion and predict patient survival
Authors: Tim Demuth, Linsey B. Reavie, Jessica L. Rennert, Mitsutoshi Nakada, Christian Beaudry, Domninique B. Hoelzinger, Satoko Nakada, Jean C. Zenklusen, Howard A. Fine, Thomas Mikkelsen, Michael E. Berens
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

3527 

The early and pervasive tendency of glioma cells to invade into peritumoral normal brain underlies the poor prognosis for patients with glial tumors. This malignant diffusion of glioma prevents complete surgical resection, positions tumor cells behind an intact blood-brain barrier, and sequesters tumor cells outside the fields of focal radiation; each of these leads to heightened (almost certain) tumor recurrence. A three dimensional spheroid invasion assay was employed to determine the transcriptome of invasive glioma cells compared to their non-invading counterparts from the spheroid center. Cells from invasive rim and spheroid core were collected from three biological replicates by laser capture microdissection and prepared for whole human genome microarray analysis. Here we report Mitogen activated protein Kinase Kinase 3 (MKK3), a member of the MAP-kinase family, to be significantly up-regulated in invasive cells. MKK3 is involved in stress signaling, tumor cell invasion, apoptosis resistance and activates p38. Phosphorylated forms of MKK3 and p38 were found to be increased during in-vitro invasion as assessed by immunoblotting. Phosphorylated MKK3 and p38 were exclusively detected in high-grade glioma specimens (n= 40) by immunoblotting; tissue-microarray of glioma invasion exhibited stronger staining intensity for MKK3 in invasive glioma cells compared to their stationary cognates. In an expression data set of 170 glial tumors MKK3 and p38 were found to be predictors for poor survival as assessed by cox proportional hazard analysis. Inhibition of MKK3 by siRNA and p38 by small molecule revealed decreased invasiveness of spheroids in-vitro and ex-vivo in rat brain slices while sensitizing to apoptosis induction through temozolomide, confirming significance of this pathway for glioma invasion and survival. MKK3 and p38 were identified to be important drivers of glioma invasion that strongly predict patient survival. Small molecule inhibition of p38 resulted in decreased invasiveness and heightened glioma cells susceptibility to undergo apoptosis rendering MKK3 and p38 novel targets for anti-invasive therapies in combination with cytotoxic agents.
Abstract 1804: New insights in the induction of cell death by the imidazolium based compound YM155
Authors: David Danielpour, Eswar Shankar, Sarah L. Corum
Journal: Cancer Research (2014)

Abstract The inhibitor of apoptosis protein (IAP) Survivin is robustly over-expressed in a variety of cancers including prostate carcinomas, and has been shown to play pivotal roles in cancer progression and resistance to chemotherapy. The imidazolium based small molecule YM155, which was first identified as a robust suppressor of the Survivin promoter of PC-3 prostate carcinoma and under clinical investigation for the treatment of multiple cancers, is a potent apoptosis inducer of castration-resistant prostate cancer (CRPC) cells. However, the mechanisms by which it inhibits the expression of Survivin and kills cancer cells remain unclear. Here we studied early signaling responses to YM155 in a panel of prostate and kidney cancer cell lines in standard cell culture conditions and showed that YM155 rapidly decreases the expression of cyclin Ds 1, 2 and 3, and activates the retinoblastoma protein (Rb), leading to the downregulation of the Survivin promoter. However, despite the robust lost of cyclin Ds, YM155 promotes an S-phase arrest rather than arrests cells at either G1 or G2/M. This suggests cell killing by YM155 involves S-phase arrest, consistent with a DNA damage response. In addition, we show that YM155 also downregulates the expression of the anti-apoptotic protein Mcl-1 and induces the expression of proapoptotic proteins Bad and Bim followed by the activation of caspases -3 and -8. Moreover, early time course experiments show that YM155 induces rapid (10 - 60 min) but transient activation of Akt and Erk1/2 followed by a marked suppression by 4 to 8 h likely via the induced expression of phosphatases 1 and 5 (DUSP1 and 5). Taken together we suggest YM155 induces apoptosis of prostate epithelial cells through a complex mechanism involving Akt, Erk1/2, DUSPs, cyclin Ds, Rb, S-phase arrest, Bim, Bad, Mcl-1,Survivin, and activation of caspases -3 and -8. Citation Format: David Danielpour, Eswar Shankar, Sarah L. Corum. New insights in the induction of cell death by the imidazolium based compound YM155. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1804. doi:10.1158/1538-7445.AM2014-1804
an imperfect compromise
Authors: M. Dennis
Journal: BMJ (2003)

Boter and colleagues have proposed a compromise to obtaining fully informed consent before enrolment for randomised trials that have primary outcomes based on a subjective measure, which makes blinding impossible and bias likely. This compromise aims to involve the patient and show them as much respect as possible. As with all compromises it is imperfect. From the trialists' point of view it still has several drawbacks compared with obtaining consent only for follow up.

Telling patients that there is a secret additional research question is likely to reduce the proportion of patients who agree to participate …
Row over Nottingham tobacco cash deepens
Authors: Mark Hunter
Journal: BMJ (2001)

The decision by Nottingham University to accept a £3.8m ($5.3m) donation from British American Tobacco (BAT) has led directly to the loss of cancer research funding and prestigious research staff from the university.

The money, which is to be used to fund an international centre for corporate responsibility, has sparked a furore among antismoking campaigners and cancer researchers.

Last week the BMJ 's editor, Richard Smith, resigned from his unpaid, part time post as professor of medical …
Personal paper: Waiting for a transplant A patient's perspective The referring consultant's perspective
Authors: J. Rickman
Journal: BMJ (2001)

# Waiting for a transplant {#article-title-2}

With modern evidence based medicine and audit, are we somehow getting away from the basic humanity of the doctor-patient relationship? Here a patient describes her experience of being on a waiting list and her consultant reacts to her being removed from that list

# A patient's perspective {#article-title-3}

I have lived with bronchiectasis since childhood when, aged 4, I had measles and whooping cough. My mother was told that my life expectancy was not brilliant, but here I was, more than 50 years later, being asked by my consultant how I felt about his making inquiries into a lung transplant. I agreed.

My consultant got in touch with a transplant hospital to see if they would consider me. The hospital wrote back in March 1997 to say that they would assess me for a double lung transplant.

I attended the transplant unit for assessment. Everyone was so nice and helpful and explained everything. At the end the surgeon offered me the operation, and I accepted. Suddenly life was different. I was given a bleeper so that they could always get in touch at any time. I packed my case … I was ready.

For the first few weeks we lived from day-to-day, waiting for the telephone to ring. I came to realise that the waiting can go on for a very long time, but I was confident that I could cope.

The phone rang at 9 55 pm. It was the transplant unit. I was off. Within 10 minutes the ambulance was at the door; two hours later I arrived at the hospital (my husband was coming in the car) to be told they had just heard that the organs were not suitable for transplantation. On the way, in the ambulance, I had been thinking “this time tomorrow it will all be over.” I even …
Death Foretold: Prophecy and Prognosis in Medical Care
Authors: Joanne Lynn
Journal: BMJ (2001)

Nicholas A Christakis 

University of Chicago Press, £19, pp 296

ISBN 0 226 10470 2

Rating: ![Graphic][1] ![Graphic][2] ![Graphic][3] 

When I visit a teaching hospital and review a seriously ill patient's case with trainees, I often ask something like, “What do you imagine this lady's life will be like in a few months?” Until recently, I was regularly met with an answer like, “I'm glad that's not my job.” As a …

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Osteoprotegerin blocks bone cancer-induced skeletal destruction, skeletal pain and pain-related neurochemical reorganization of the spinal cord
Authors: Prisca Honore, Nancy M. Luger, Mary Ann C. Sabino, Matthew J. Schwei, Scott D. Rogers, David B. Mach, Patrick F. O'keefe, Margaret L. Ramnaraine, Denis R. Clohisy, Patrick W. Mantyh
Journal: Nature Medicine (2000)
Is transmitted drug resistance in HIV on the rise?
Authors: S. J Little
Journal: BMJ (2001)

It seems so 

Papers p 1087 

The transmission of drug resistant variants of HIV-1 has the potential seriously to limit the therapeutic options of newly infected patients. The selection of HIV drug resistant variants among individuals who are already receiving treatment also clearly limits both the size and duration of the viral supression induced by drug treatment. 1 2 Reports from North America and Europe indicate that up to 14% of recently infected patients have been infected with a strain of virus bearing well characterised drug resistance mutations (in 1-10% of cases) or reduced susceptibility to a particular drug (2-14% of cases).3–5 Temporal trends in the transmission of drug resistance for these populations are not yet available, but a …
Abstract 809: BRAF wild-type melanoma survival hinges upon AKT activity and adaptive autophagic reprogramming in response to chemotherapy
Authors: Vito W. Rebecca, Renato Massaro, Inna Fedorenko, Geoffrey T. Gibney, Vernon K. Sondak, Ravi K. Amaravadi, Shengkan Jin, Silvya S. Maria-Engler, Ragini Kudchadkar, Keiran S. M. Smalley
Journal: Cancer Research (2014)

Abstract Strategies for patients whose melanomas are BRAF wild-type are completely lacking. We here report on the mechanisms underlying the long-term responses (&amp;gt;12 months) of 2 BRAF wild-type (WT) melanoma patients to the AKT inhibitor MK-2206 in combination with paclitaxel and carboplatin. A panel of 7 BRAF/NRAS-WT cell lines was leveraged to investigate strategies to overcome chemoresistance. Electron microscopy, western blotting and flow cytometry assays were integrated to simultaneously follow fluctuations in autophagic flux, reactive oxygen species levels and cytotoxicity caused from chronic treatment of cells with chemotherapy, MK-2206, lysomotropic agents and/or anti-oxidants. MK-2206 potently inhibited phospho-AKT signaling, but did not impact melanoma growth or survival. The combination of MK-2206 with paclitaxel and carboplatin induced little apoptosis following 3-day treatment, but led to cytotoxicity in long-term colony formation and 3D spheroid assays. Mechanistically the combination was noted to induce autophagy and disrupt reactive oxygen species homeostasis, as shown by increased LC3-II expression, the formation of LC3 punctae, acridine orange protonation, the accumulation of autophagosomes and increased ROS detection using DHR-123. At earlier time points, autophagy was protective with cytotoxicity enhanced following chloroquine and bafilomycin treatment as well as the increased cytotoxic effects seen in ATG5-/- MEFs. Although prolonged MK-2206/chemotherapy treatment (6-9 days) led to high levels of autophagy induction and a switch to caspase-dependent apoptosis, drug resistant clones still eventually emerged. The importance of autophagy for the escape process was suggested by the lack of ATG5-/- MEF colonies seen following combination therapy treatment. Autophagy inhibition enhanced the cell death response through increased generation of ROS and could be reversed by anti-oxidants. In summary, we demonstrate for the first time that AKT inhibition in combination with chemotherapy may have clinical activity in BRAF WT melanoma. We further show that the administration of an autophagy inhibitor may prevent resistance from emerging to this drug combination. Citation Format: Vito W. Rebecca, Renato Massaro, Inna Fedorenko, Geoffrey T. Gibney, Vernon K. Sondak, Ravi K. Amaravadi, Shengkan Jin, Silvya S. Maria-Engler, Ragini Kudchadkar, Keiran S. M. Smalley. BRAF wild-type melanoma survival hinges upon AKT activity and adaptive autophagic reprogramming in response to chemotherapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 809. doi:10.1158/1538-7445.AM2014-809
Abstract 11611: Muscle Superoxide Dismutase and Augmented Autonomic Responsiveness in Rats With Peripheral Artery Disease
Authors: Jihong Xing, Jian Lu, Jiahao Liu, Jianhua Li
Journal: Circulation (2014)

Background: During exercise, responses of sympathetic nerve and blood pressure are amplified in patients with peripheral artery disease (PAD). This worsens the restricted blood flow directed to the limbs in this disease. The purpose of this study was to determine the role played by muscle oxidative stress in regulating the augmented autonomic responses to static exercise in PAD. Superoxide dismutases (SOD) is a class of enzymes to catalyze the dismutation of superoxide into oxygen and hydrogen peroxide, and considered as an important antioxidant. Thus, our specific hypothesis was that limb ischemia impairs muscle SOD and thereby leads to abnormal autonomic responsiveness observed in PAD. Methods and Results: We used a rat model of femoral artery ligation to study PAD. Note that all data are presented as mean ± SE. First, western blot analysis shows that 72 hours of femoral occlusion significantly decreased the protein levels of SOD in the oxidative muscle (optical density: 1.02±0.03 in control vs. 0.21±0.02 after ligation, P&lt; 0.05; n = 6 in each group) and glycolytic muscle (optical density: 1.03±0.03 in control vs. 0.65±0.04 after ligation, P&lt; 0.05; n = 6 in each group). Additional immunofluorescence study demonstrates down-regulation of SOD in the ischemic hindlimb muscles. Second, the reflex blood pressure response to static muscle contraction was examined in control rats (n=5) and rats with 72 hours of femoral occlusion (n=6). The data show that the augmented reflex pressor response to muscle contraction was significantly attenuated after compensating SOD in ischemic muscles by chronic administration of tempol (a mimetic of SOD, 30 mg over a period of 72 hours) into the hindlimb. In the ligated rats, mean arterial pressure response was 26±3 mmHg with no tempol (n=6) and 12±2 mmHg with tempol application ( P&lt; 0.05 vs. group with no tempol; n =5). Conclusions: Muscle SOD is blunted in the ischemic limbs and supplement of SOD mimetic for anti-oxidation improves the augmented blood pressure response during static exercise, which is beneficial to the restricted blood flow to the limbs in PAD patients.
Early Anthrax Identification
Authors: Mike Mitka
Journal: JAMA (2002)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Mutations in the gene encoding 3β- hydroxysteroid-Δ8,Δ7- isomerase cause X-linked dominant Conradi-Hünermann syndrome
Authors: Nancy Braverman, Paul Lin, Fabian F. Moebius, Cassandra Obie, Ann Moser, Hartmut Glossmann, William R. Wilcox, David L. Rimoin, Moyra Smith, Lisa Kratz, Richard I. Kelley, David Valle
Journal: Nature Genetics (1999)
un poco mosso
Authors: Daniel Ma
Journal: JAMA (2005)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Multiple myeloma cell killing by 8-chloro-adenosine overcomes the survival mechanisms generated by the receptor tyrosine kinase, MET
Authors: Christine M. Stellrecht, Varsha Gandhi
Journal: Cancer Research (2005)

5878   Multiple myeloma (MM) is an invariably fatal plasma cell malignancy, primarily due to therapeutic resistance that ultimately arises. Much of the resistance is due to the expression of survival factors such as MET, BCL-X L , and IL-6. Despite this, we have established that the ribonucleoside analog, 8-chloro-adenosine (8-Cl-Ado), is cytotoxic to a number of MM cell lines that are resistant to traditional chemotherapeutic agents. Previously we demonstrated that 8-Cl-Ado treatment of a MM cell line, MM.1S, results in a dose-dependent accumulation of its triphosphate with a progressive decrease of the endogenous ATP pool [Cancer Res. 61: 5474, 2001]. In addition, we have shown that the analog is incorporated into RNA and prematurely terminates transcription. These events lead to an inhibition of RNA synthesis with a maximum effect on mRNA synthesis [Cancer Res. 63: 7968, 2003]. Because 8-Cl-Ado is able to overcome strong survival signals present in MM cells and inhibits mRNA synthesis it is likely that the drug induces cytotoxicity by diminishing the expression of critical MM survival genes. MET, a receptor tyrosine kinase, promotes survival signaling in numerous cell types and is an autocrine-loop with its ligand, hepatocyte growth factor (HGF), in both primary MM cells and cell lines. Furthermore, MM patients with high serum HGF levels have been associated with a poorer prognosis. We found that 8-Cl-Ado treatment reduces the expression level of  MET  mRNA by >60%. This was accompanied with a reduction in MET protein levels and induction of cell death. To establish the role of MET on survival of MM cells, we have generated MM.1S clones stably expressing the pU1-MET 560  hammerhead ribozyme. Of the clones isolated, 18 out of 24 had reduced level levels of  MET.  No clones with  MET  mRNA were found to endure the selection process, suggesting MET may be necessary for MM cell survival under normal conditions. We hypothesized that clones with lower levels of MET mRNA would be more sensitive to 8-Cl-Ado-induced toxicity. To test this, clones with 30-50% of the basal  MET  mRNA levels were assessed for 8-Cl-Ado mediated effects. Preliminary data using real-time RT-PCR assays indicate that treatment with 8-Cl-Ado further reduced  MET  transcript levels in these clones. Kinetic analysis of 8-Cl-Ado-induced caspase 3 activity showed a >2 fold caspase 3 induction in the MET ribozyme clones 6-12 hours earlier than the parental line. Likewise, PARP immunoblot analysis also showed an induction of PARP cleavage in  MET  expression levels; thus, 8-Cl-Ado-induced cytotoxicity is enhanced in cells with lower basal levels of  MET .
Development and specificities of anti-interferon neutralizing antibodies in patients with chronic hepatitis C treated with pegylated interferon-α
Authors: C. Scagnolari, S. Trombetti, A. Soldà, M. Milella, G.B. Gaeta, G. Angarano, G. Scotto, N. Caporaso, F. Morisco, R. Cozzolongo, G. Giannelli, M. Fasano, T. Santantonio, G. Antonelli
Journal: Clinical Microbiology and Infection (2011)

Only limited data are available on the development of neutralizing antibodies (NAB) in patients with chronic hepatitis C (CHC) treated with pegylated interferon-α (PEG-IFN-α). The aim of this study was to evaluate the immunogenicity of PEG-IFN-α when administered to CHC patients who had or had not previously received standard IFN-α therapy. In addition, the specificities of NAB, together with the ability of leucocyte (LE) -IFN-α to re-establish therapeutic responsiveness in NAB-positive patients, were evaluated. NAB were assessed using a quantitative, standardized, virus-induced cytopathic effect assay. The seroconversion rate to PEG-IFN-α was higher in patients who had received previous standard IFN-α treatment than in those treated exclusively with PEG-IFN-α. Also, NAB produced during PEG-IFN-α therapy were unable to neutralize LE-IFN-α entirely, even though they can neutralize several IFN-α subtypes. In addition, the results indicate that a change to LE-IFN-α therapy can be associated with restoration of clinical responses in NAB-positive patients who had become resistant after showing an initial response to PEG-IFN-α treatment. This study emphasizes the importance of evaluating NAB development in CHC patients who become resistant to PEG-IFN-α treatment, and suggests management alternatives for patients who develop NAB.
605. Cytokine Profile Assessment of Mesothelioma Patients Treated with Escalating Doses of Intrapleurally Administered, Genetically Modified PA1STK Cells and a Twice Daily Regiment of Ganciclovir. A Phase I Clinical Trial
Authors: Patrick S. Byrne, Paul O. Schwarzenberger, Lynn Harrison, Judy Norton, Jay K. Kolls
Journal: Molecular Therapy (2004)

Malignant Mesothelioma (MM) is a rapidly progressing, incurable neoplasm of the pleura or peritoneum. The etiology and development of MM is strongly associated with previous asbestos exposure. Despite the advances made in cancer biology no current therapeutic modality is successful in treating the disease. Given the localized nature of mesothelioma and its confinement to the pleural cavity, makes it an ideal disease in which to evaluate new treatment modalities such as gene therapy. Here, we investigated the use of an HSV-tk gene modified ovarian cancer cell line, PA1STK as a delivery system for this disease by direct administration into the tumor site.