tbuckley/cabot-search huggingface dataset:
Transepithelial water permeability in an in vitro model of renal cysts.
Authors: R Mangoo-Karim, J J Grantham
Journal: Journal of the American Society of Nephrology (1990)

Renal cysts develop from microscopic tubules and may enlarge progressively several thousandfold. Sustained epithelial proliferation, intracavitary fluid accumulation, and extracellular matrix remodeling are central elements in a multistep process that leads to the formation and enlargement of cysts. MDCK cells suspended within medium-hydrated collagen gels grow to form spherical, monolayered, fluid-filled cysts that enlarge steadily. Vasopressin and other agents that increase intracellular levels of cAMP stimulate the rate of MDCK cyst growth and net fluid/solute secretion when added to defined medium in vitro. In this model, net fluid secretion is the only means by which fluid can accumulate within the cyst cavity. We used this cyst-forming line of epithelial cells to evaluate several membrane transport properties that are important in the coupled movements of solute and water in the process of secretory fluid transport. Individual cysts were microdissected from collagen gels, held by a micropipet in a thermostated chamber, and examined at a high magnification by video microscopy. Transepithelial water flow was initiated by rapidly exchanging the bath medium with hyperosmotic solutions. Net water flux, Jv, determined from the initial rate of decrease in cyst diameter, was proportionate to the transmembrane osmotic gradient of NaCl or raffinose; the reflection coefficient for NaCl was indistinguishable from 1.0. Osmotic water permeability (cm3/cm2/osm/min x 10(-6)) was 739 +/- 99 (N = 11) in medium augmented by an NaCl concentration of 100 mosmol/kg. Hydraulic conductivity (Pt), estimated in control cysts, was 6.8 +/- 0.9 microns/s, a value similar to that of medullary and cortical thick ascending limbs of Henle.(ABSTRACT TRUNCATED AT 250 WORDS)
Sumo E2 Enzyme UBC9 Is Required for Efficient Protein Quality Control in Cardiomyocytes
Authors: Manish K. Gupta, James Gulick, Ruijie Liu, Xuejun Wang, Jeffery D. Molkentin, Jeffrey Robbins
Journal: Circulation Research (2014)

Impairment of proteasomal function is pathogenic in several cardiac proteinopathies and can eventually lead to heart failure. Loss of proteasomal activity often results in the accumulation of large protein aggregates. The ubiquitin proteasome system (UPS) is primarily responsible for cellular protein degradation, and although the role of ubiquitination in this process is well studied, the function of an ancillary post-translational modification, SUMOylation, in protein quality control is not fully understood.To determine the role of ubiquitin-conjugating enzyme 9 (UBC9), a small ubiquitin-like modifier-conjugating enzyme, in cardiomyocyte protein quality control.Gain- and loss-of-function approaches were used to determine the importance of UBC9. Overexpression of UBC9 enhanced UPS function in cardiomyocytes, whereas knockdown of UBC9 by small interfering RNA caused significant accumulations of aggregated protein. UPS function and relative activity was analyzed using a UPS reporter protein consisting of a short degron, CL1, fused to the COOH-terminus of green fluorescent protein (GFPu). Subsequently, the effects of UBC9 on UPS function were tested in a proteotoxic model of desmin-related cardiomyopathy, caused by cardiomyocyte-specific expression of a mutated αB crystallin, CryAB(R120G). CryAB(R120G) expression leads to aggregate formation and decreased proteasomal function. Coinfection of UBC9-adenovirus with CryAB(R120G) virus reduced the proteotoxic sequelae, decreasing overall aggregate concentrations. Conversely, knockdown of UBC9 significantly decreased UPS function in the model and resulted in increased aggregate levels.UBC9 plays a significant role in cardiomyocyte protein quality control, and its activity can be exploited to reduce toxic levels of misfolded or aggregated proteins in cardiomyopathy.
PFS: The Endpoint We Love and Love to Hate
Authors: Susan E. Bates
Journal: Clinical Cancer Research (2013)

One of the major challenges in oncology drug development is the identification of appropriate endpoints that indicate direct benefit to the patient. The U.S. Food and Drug Administration (FDA) has clearly defined meaningful clinical benefit as improvement in patient-reported symptomatology or improvement in survival and has considered these patient-directed endpoints in clinical trials as the basis for registration of new agents (1). However, the FDA has also recognized that such endpoints may be difficult to obtain and so has allowed the establishment of surrogates that may substitute for the above endpoints, often then requiring later confirmation through further clinical study. The most widely used and perhaps the most controversial surrogate is progression-free survival (PFS), which measures the amount of time from study enrollment to a prespecified point at which a tumor is no longer considered to be affected by the administered therapy, generally a 20% increase in tumor size above the starting value or an achieved nadir. Interpretation of PFS remains a challenge despite its use as an endpoint in oncology for over 40 years, illustrated in the 1969 Moertel and colleagues PFS plot (Fig. 1; ref. 2). Parenthetically, it should be noted that this 20% cutoff has never been proven to actually indicate treatment failure, as the boundary may be crossed despite ongoing tumor growth delay—efficiently termed a “cytolentic,” or cell-slowing effect. More widely discussed is the point that the determination of progression is susceptible to multiple sources of error. Those errors can introduce missing or incomplete data in randomized trials. Missing data, in turn, can cause informative censoring. This CCR Focus section delves deeply into PFS measurement with John J. Crowley, former Director of the Statistical Center of SWOG (previously known as the Southwest Oncology Group), as Guest Editor. Experts in the field identify sources of error in PFS determination, propose strategies to limit the error, and introduce two new approaches in clinical trial methodologies. These approaches, embracing an audit strategy to reduce missing data events in randomized trials, and using a new phase II/III trial design, should expedite drugs through the development pipeline and deserve a close look. As with every edition of CCR Focus, it is hoped that these articles will stimulate discussion among colleagues, inspire those already working in drug development, and inform those desiring a more in-depth understanding of this important challenge in oncology.Susan E. BatesDeputy Editor, CCR FocusNational Cancer Institute
Characterization of immunotoxins active against ovarian cancer cell lines.
Authors: R Pirker, D J FitzGerald, T C Hamilton, R F Ozols, W Laird, A E Frankel, M C Willingham, I Pastan
Journal: Journal of Clinical Investigation (1985)

The purpose of the present study was to develop immunotoxins directed against human ovarian carcinoma cells. Four monoclonal antibodies (260F9, 454C11, 280D11, and 245E7) were chosen because they were found to bind to various ovarian carcinoma cell lines. These antibodies were covalently linked to either Pseudomonas exotoxin (PE) or ricin A chain (RTA), and the conjugates were tested against five ovarian cancer cell lines (OVCAR-2, -3, -4, -5; A1847). The ability of the immunotoxins to inhibit both protein synthesis and colony formation was evaluated. Qualitatively similar results were obtained for both types of assays. Usually, PE conjugates were more toxic than their corresponding RTA conjugates. 454C11-PE was very toxic for all ovarian carcinoma lines, whereas 454C11-RTA had low activity. Both 260F9-PE and 260F9-RTA were active in all OVCAR cell lines but not in A1847 cells. 280D11-PE was toxic for OVCAR-4; otherwise, 280D11-PE and RTA conjugates of both 280D11 and 245E7 had little activity. Specificity of immunotoxin action was shown by competition by excess antibody, nontoxicity in nontarget cells, and inactivity of an irrelevant immunotoxin. To investigate the basis of antibody-dependent differences in activity of the various immunotoxins, antibody uptake was studied in OVCAR-2 cells, and the results indicate that antibody internalization is one important factor in the activity of immunotoxins.
British patients willing to travel abroad for treatment
Authors: L. Beecham
Journal: BMJ (2002)

More than four out of 10 patients questioned in a nationwide poll said that they would be willing to travel outside the United Kingdom for treatment, and over a half thought that involving other organisations, including the private sector, would improve the provision of NHS health care.

The poll, conducted by the MORI Social Research Institute for the BMA, asked nearly 2000 adults last month how far they …
Abnormally expressed ER stress response chaperone Gp96 in CD favours adherent-invasive Escherichia coli invasion
Authors: N. Rolhion, N. Barnich, M.-A. Bringer, A.-L. Glasser, J. Ranc, X. Hebuterne, P. Hofman, A. Darfeuille-Michaud
Journal: Gut (2010)

<h3>Background and aims</h3> Crohn9s disease (CD) ileal lesions are colonised by pathogenic adherent-invasive <i>Escherichia coli</i> (AIEC) producing outer membrane vesicles (OMVs) that contribute to the bacterial invasion process. In addition, increased expression of endoplasmic reticulum (ER)-localised stress response proteins, due to ER stress, is observed in patients with CD. The expression of the ER-localised stress response protein Gp96 in patients with CD and its biological role with regards to the ability of AIEC to invade intestinal epithelial cells were analysed. <h3>Methods and results</h3> Immunohistochemistry on tissue arrays showed that, together with CEACAM6 (carcinoembryonic antigen-related cell adhesion molecule 6) or the ER stress protein Grp78, Gp96 is also strongly expressed at the apical plasma membrane of the ileal epithelial cells of 50% of patients with CD. Invasion experiments in the presence of antibodies raised against Gp96, or after transfection of Intestine-407 cells with <i>gp96</i> small interfering RNA (siRNA), indicated that Gp96 is essential to promote AIEC LF82 invasion, allowing, via the recognition of the outer membrane protein OmpA, OMVs to fuse with intestinal epithelial cells. <h3>Conclusions</h3> Gp96 is overexpressed on the apical surface of ileal epithelial cells in patients with CD and acts as a host cell receptor for OMVs, promoting AIEC invasion. From the results shown here, it is speculated that AIEC could take advantage of the abnormal expression of Gp96 in patients with CD to invade the ileal mucosa.
Cisplatin, Fluorouracil, and Leucovorin Induction Chemotherapy Followed by Concurrent Cisplatin Chemoradiotherapy for Organ Preservation and Cure in Patients With Advanced Head and Neck Cancer: Long-Term Follow-Up
Authors: A. Psyrri, M. Kwong, S. DiStasio, L. Lekakis, M. Kassar, C. Sasaki, L.D. Wilson, B.G. Haffty, Y.H. Son, D.A. Ross, P.M. Weinberger, G.G. Chung, D. Zelterman, B.A. Burtness, D.L. Cooper
Journal: Journal of Clinical Oncology (2004)

The poor functional outcome in patients with advanced head and neck squamous cell carcinoma (HNSCC) with surgery and radiation has led to alternative approaches to advanced disease. We conducted a phase II study of induction chemotherapy followed by concurrent chemoradiotherapy for organ preservation in patients with advanced resectable and unresectable (nasopharyngeal) tumors.Forty-two patients with stage III to IV resectable HNSCC and nasopharyngeal tumors received induction chemotherapy with two courses of cisplatin (20 mg/m2/d continuous infusion [CI]), fluorouracil (800 mg/m2/d CI), and leucovorin (500 mg/m2/d CI; PFL) for 4 days followed by concurrent therapy with cisplatin (100 mg/m2/d on days 1 and 22) and approximately 70 Gy of external-beam radiotherapy.Response to induction chemotherapy included partial response rate of 52% and complete response rate of 24%. The most common grade 3 or 4 toxicity was neutropenia (59%). After cisplatin chemoradiotherapy the complete response rate was 67%. Toxicities of cisplatin chemoradiotherapy consisted of grade 3 or 4 mucositis (79%) and neutropenia (51%). At a median follow-up of 71.5 months, 43% of the patients are still alive and disease-free. The 5-year progression-free survival (PFS) rate was 60%, and the 2- and 5-year overall survival (OS) rates were 67% and 52%, respectively. Three patients died of second primaries. Late complications of treatment included xerostomia and hoarseness. One patient had persistent dysphagia and required laser epiglotectomy 108 months after treatment.Induction chemotherapy with PFL followed by concurrent cisplatin chemoradiotherapy is well tolerated and results in a good likelihood of organ preservation and excellent PFS and OS.
Phase III Randomized Placebo-Controlled Trial of Two Doses of Megestrol Acetate as Treatment for Menopausal Symptoms in Women With Breast Cancer: Southwest Oncology Group Study 9626
Authors: J. Wendall Goodwin, Stephanie J. Green, Carol M. Moinpour, James D. Bearden, Jeffrey K. Giguere, Caroline S. Jiang, Scott M. Lippman, Silvana Martino, Kathy S. Albain
Journal: Journal of Clinical Oncology (2008)

Purpose Prior progestin studies treating hot flashes in women have been short duration and single dose. This study tests the progestin megesterol acetate (MA) at two doses versus placebo over 6 months. Patients and Methods Patients with T1-3, N0-1, M0 breast cancer were eligible after completion of surgery and chemotherapy and at least 4 months of tamoxifen (if prescribed). Women were required to have at least 10 hot flashes of any severity or at least five severe episodes per week. Patients were randomly assigned to placebo, MA 20 mg, or MA 40 mg for 3 months. Success at 3 months was defined as completion of treatment with a ≥ 75% reduction in hot flashes from baseline. If success was achieved, drug treatment for another 3 months was given on the same blinded arm; if not, open-label MA 20 mg was added to blinded study drug and continued for 3 months. Other menopausal symptoms were also assessed. Results Two hundred eighty eight eligible women were randomly assigned (286 eligible), of whom 85% were on tamoxifen, 40% had over 63 hot flashes/week, and 75% had vasomotor symptoms for ≥ 6 months. Success at 3 months was 14% on placebo, 65% on 20 mg, and 48% on 40 mg (both MA doses superior to placebo; P &lt; .0001). Most successes at 3 months were maintained at 6 months (77% on 20 mg and 81% on 40 mg). Conclusion MA significantly reduced vasomotor symptoms with durable benefit over 6 months. MA 20 mg/d is the preferred dose. There was no significant impact on other menopausal symptoms.
Tuberculosis, HIV seroprevalence and intravenous drug abuse in prisoners
Authors: F. A. Drobniewski, Y. M. Balabanova, M. C. Ruddy, C. Graham, S. I. Kuznetzov, G. I. Gusarova, S. M. Zakharova, A. S. Melentyev, I. M. Fedorin
Journal: European Respiratory Journal (2005)

High rates of tuberculosis (TB) and HIV are believed to exist in Russian prisons. Prisoners with TB were studied in order to identify the following: 1) prevalence of HIV, and risk factors for HIV and other blood-borne virus infections; and 2) clinical and social factors that might compromise TB treatment effectiveness and/or patient adherence and, hence, encourage treatment failure. A 1-yr cross-sectional prevalence study of 1,345 prisoners with TB was conducted at an in-patient TB facility in Samara, Russian Federation. HIV and hepatitis B and/or C co-infection occurred in 12.2% and 24.1% of prisoners, respectively, and rates were significantly higher than in civilians. Overall, 48.6% of prisoners used drugs, of which 88.3% were intravenous users. Prisoners were more likely to be intravenous drug users and HIV positive compared with civilians with TB, and 40.2% of prisoners shared needles. Two-thirds of prisoners (68.6%) had received previous TB drug therapy (frequently multiple, interrupted courses) and were significantly more likely than civilians to have had previous therapy consistent with the high drug-resistance rates seen. Prisons are major drivers of the tuberculosis and HIV epidemics. Novel strategies are needed to reduce the spread of blood borne diseases, particularly in intravenous drug users.
TCT-100 Long Term Clinical And Angiographic Outcomes With Everolimus-Eluting Stents For Cardiac Allograft Vasculopathy
Authors: Boris Arbit, Christopher T. Vanichsarn, David Chang, Jignesh Patel, Raj Makkar, Jon Kobashigawa, Babak Azarbal
Journal: Journal of the American College of Cardiology (2014)
GM-CSF–dependent, CD103+ dermal dendritic cells play a critical role in Th effector cell differentiation after subcutaneous immunization
Authors: Irah L. King, Mark A. Kroenke, Benjamin M. Segal
Journal: The Journal of Experimental Medicine (2010)

Dendritic cells (DCs) play an important role in CD4+ T helper (Th) cell differentiation and in the initiation of both protective and pathogenic immunity. Granulocyte/macrophage colony-stimulating factor (GM-CSF) is a DC growth factor critical for the induction of experimental autoimmune encephalomyelitis (EAE) and other autoimmune diseases, yet its mechanism of action in vivo is not fully defined. We show that GM-CSF is directly required for the accumulation of radiosensitive dermal-derived langerin+CD103+ DCs in the skin and peripheral lymph nodes under steady-state and inflammatory conditions. Langerin+CD103+ DCs stimulated naive myelin-reactive T cells to proliferate and produce IFN-γ and IL-17. They were superior to other DC subsets in inducing expression of T-bet and promoting Th1 cell differentiation. Ablation of this subset in vivo conferred resistance to EAE. The current report reveals a previously unidentified role for GM-CSF in DC ontogeny and identifies langerin+CD103+ DCs as an important subset in CD4+ T cell–mediated autoimmune disease.
Myosin IIb Regulates Actin Dynamics during Synaptic Plasticity and Memory Formation
Authors: Christopher S. Rex, Cristin F. Gavin, Maria D. Rubio, Eniko A. Kramar, Lulu Y. Chen, Yousheng Jia, Richard L. Huganir, Nicholas Muzyczka, Christine M. Gall, Courtney A. Miller, Gary Lynch, Gavin Rumbaugh
Journal: Neuron (2010)
Evaluation of Circulating Tumor Cells and Circulating Tumor DNA in Non–Small Cell Lung Cancer: Association with Clinical Endpoints in a Phase II Clinical Trial of Pertuzumab and Erlotinib
Authors: Elizabeth A. Punnoose, Siminder Atwal, Weiqun Liu, Rajiv Raja, Bernard M. Fine, Brett G.M. Hughes, Rodney J. Hicks, Garret M. Hampton, Lukas C. Amler, Andrea Pirzkall, Mark R. Lackner
Journal: Clinical Cancer Research (2012)

Elevated levels or increases in circulating tumor cells (CTC) portend poor prognosis in patients with epithelial cancers. Less is known about CTCs as surrogate endpoints or their use for predictive biomarker evaluation. This study investigated the utility of CTC enumeration and characterization using the CellSearch platform, as well as mutation detection in circulating tumor DNA (ctDNA), in patients with advanced non-small cell lung cancer (NSCLC).Forty-one patients were enrolled in a single-arm phase II clinical trial of erlotinib and pertuzumab. Peripheral blood was analyzed for CTC enumeration, EGFR expression in CTCs, and detection of oncogenic mutations in CTCs and ctDNA. Changes in CTC levels were correlated with 2[18F]fluoro-2-deoxy-D-glucose-positron emission tomographic (FDG-PET) and computed tomographic (CT) imaging and survival endpoints.CTCs were detected (≥ 1 CTC) at baseline in 78% of patients. Greater sensitivity for mutation detection was observed in ctDNA than in CTCs and detected mutations were strongly concordant with mutation status in matched tumor. Higher baseline CTC counts were associated with response to treatment by Response Evaluation Criteria in Solid Tumors (RECIST, P = 0.009) and decreased CTC counts upon treatment were associated with FDG-PET and RECIST response (P = 0.014 and P = 0.019) and longer progression-free survival (P = 0.050).These data provide evidence of a correlation between decreases in CTC counts and radiographic response by either FDG-PET or RECIST in patients with advanced NSCLC. These findings require prospective validation but suggest a potential role for using CTC decreases as an early indication of response to therapy and ctDNA for real-time assessment of mutation status from blood.
<i>PAX3/FOXO1</i> Fusion Gene Status Is the Key Prognostic Molecular Marker in Rhabdomyosarcoma and Significantly Improves Current Risk Stratification
Authors: Edoardo Missiaglia, Dan Williamson, Julia Chisholm, Pratyaksha Wirapati, Gaëlle Pierron, Fabien Petel, Jean-Paul Concordet, Khin Thway, Odile Oberlin, Kathy Pritchard-Jones, Olivier Delattre, Mauro Delorenzi, Janet Shipley
Journal: Journal of Clinical Oncology (2012)

To improve the risk stratification of patients with rhabdomyosarcoma (RMS) through the use of clinical and molecular biologic data.Two independent data sets of gene-expression profiling for 124 and 101 patients with RMS were used to derive prognostic gene signatures by using a meta-analysis. These and a previously published metagene signature were evaluated by using cross validation analyses. A combined clinical and molecular risk-stratification scheme that incorporated the PAX3/FOXO1 fusion gene status was derived from 287 patients with RMS and evaluated.We showed that our prognostic gene-expression signature and the one previously published performed well with reproducible and significant effects. However, their effect was reduced when cross validated or tested in independent data and did not add new prognostic information over the fusion gene status, which is simpler to assay. Among nonmetastatic patients, patients who were PAX3/FOXO1 positive had a significantly poorer outcome compared with both alveolar-negative and PAX7/FOXO1-positive patients. Furthermore, a new clinicomolecular risk score that incorporated fusion gene status (negative and PAX3/FOXO1 and PAX7/FOXO1 positive), Intergroup Rhabdomyosarcoma Study TNM stage, and age showed a significant increase in performance over the current risk-stratification scheme.Gene signatures can improve current stratification of patients with RMS but will require complex assays to be developed and extensive validation before clinical application. A significant majority of their prognostic value was encapsulated by the fusion gene status. A continuous risk score derived from the combination of clinical parameters with the presence or absence of PAX3/FOXO1 represents a robust approach to improving current risk-adapted therapy for RMS.
CSF1R inhibition with emactuzumab in locally advanced diffuse-type tenosynovial giant cell tumours of the soft tissue: a dose-escalation and dose-expansion phase 1 study
Authors: Philippe A Cassier, Antoine Italiano, Carlos A Gomez-Roca, Christophe Le Tourneau, Maud Toulmonde, Michael A Cannarile, Carola Ries, Anne Brillouet, Claudia Müller, Anna-Maria Jegg, Ann-Marie Bröske, Markus Dembowski, Katharine Bray-French, Christine Freilinger, Georgina Meneses-Lorente, Monika Baehner, Ross Harding, Jayantha Ratnayake, Keelara Abiraj, Nathalie Gass, Karen Noh, Randolph D Christen, Lidia Ukarma, Emmanuelle Bompas, Jean-Pierre Delord, Jean-Yves Blay, Dominik Rüttinger
Journal: The Lancet Oncology (2015)