tbuckley/cabot-search huggingface dataset:
New Challenges in Endpoints for Drug Development in Advanced Melanoma
Authors: Antoni Ribas, Peter Hersey, Mark R. Middleton, Helen Gogas, Keith T. Flaherty, Vernon K. Sondak, John M. Kirkwood
Journal: Clinical Cancer Research (2011)

During the past 3 decades, the field of clinical research for the treatment of advanced melanoma lacked significant advances. Available drugs had low antitumor activity and no proven benefit in overall survival. Recently, new drugs developed based on an in-depth understanding of the biology of this disease have shown significant benefit, with ipilimumab and vemurafenib having recently shown a positive impact in overall survival in patients with metastatic melanoma leading to approval in this indication by the U.S. Food and Drug Administration. This rapid introduction of new active agents is likely to challenge current notions on how to develop future agents for the treatment of melanoma. The strong evidence of benefit for initial agents that modulate immune regulatory checkpoints or target driver oncogenes has spurred great interest in developing other similarly acting agents. However, this will pose problems in the choice of endpoints for the future definitive clinical trials, and the hurdles for achieving these endpoints will be higher given the similar activity for comparator agents or the availability of competing agents for salvage therapy. This new reality will likely require tailoring registrational clinical trial endpoints to the patient benefits shown in early clinical testing. In this perspective article, we illustrate the challenges in the choice of endpoints for registrational trials in metastatic melanoma and that, with an improved understanding of the agent being developed, the design of the registrational programs can be informed by earlier mechanistic studies to define the assumptions for definitive clinical testing.
Clinical significance of intrahepatic hepatitis C virus levels in patients with chronic HCV infection
Authors: G H Haydon, L M Jarvis, C S Blair, P Simmonds, D J Harrison, K J Simpson, P C Hayes
Journal: Gut (1998)

The clinical significance of a single assessment of circulating hepatitis C virus (HCV) RNA and its relation to the level of intrahepatic HCV RNA remains unclear.To investigate the relation between intrahepatic HCV levels and clinicopathological characteristics of chronic HCV infection.Ninety eight consecutive patients with chronic HCV infection were studied; none had received alpha interferon therapy. Of these, 12 patients were repeatedly negative for HCV RNA in serum by reverse transcriptase polymerase chain reaction (RT-PCR).After diagnostic laparoscopy and liver biopsy, semiquantitative analysis of intrahepatic HCV RNA levels was carried out by limiting dilution of HCV cDNA. HCV genotypes were assessed in 96 patients by restriction fragment length polymorphism analysis of HCV cDNA.Ten out of 12 patients who were RT-PCR negative for HCV RNA in serum were RT-PCR positive in liver; however, this group had a significantly lower intrahepatic HCV level and serum aminotransferase level than the remaining 86 patients. Histological severity (cirrhosis: n = 10); histological activity index; HCV genotype (genotype 1: n = 41; genotype 2: n = 12; genotype 3: n = 36; genotype 4: n = 7); mode of infection (intravenous drug abuse: n = 58; post-transfusion: n = 10; haemophiliac: n = 4; sporadic: n = 26) and alcohol abuse did not affect the intrahepatic virus level. There was no correlation between patient age, duration of infection, and intrahepatic HCV level.Intrahepatic virus levels were not determined by host factors (age of patient, mode or duration of infection) or by virus factors (HCV genotype). Repeatedly negative RT-PCR for HCV RNA in serum does not indicate absence of HCV from the liver.
Increased Cytosolic pH in Multidrug-Resistant Human Lung Tumor Cells: Effect of Verapamil
Authors: H. G. Keizer, H. Joenje
Journal: JNCI Journal of the National Cancer Institute (1989)

Journal Article Increased Cytosolic pH in Multidrug-Resistant Human Lung Tumor Cells: Effect of Verapamil Get access Hiskias G. Keizer, Hiskias G. Keizer Department of ToxicologyDuphar, B. V., Weesp, The Netherlands Search for other works by this author on: Oxford Academic PubMed Google Scholar Hans Joenje Hans Joenje * Institute of Human Genetics, Free University, Van der Boechorststraat7, 1081 BT Amsterdam, The Netherlands *Correspondence to: Dr. H. Joenje, Institute of Human Genetics, Free University, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands. Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 81, Issue 9, 3 May 1989, Pages 706–709, https://doi.org/10.1093/jnci/81.9.706 Published: 03 May 1989 Article history Received: 23 August 1988 Revision received: 03 February 1989 Accepted: 10 February 1989 Published: 03 May 1989
ISOLATION AND PARTIAL CHARACTERIZATION OF LYMPHOCYTE SURFACE IMMUNOGLOBULINS
Authors: John J. Marchalonis, Robert E. Cone, John L. Atwell
Journal: The Journal of Experimental Medicine (1972)

Immunoglobulins were isolated from the surfaces of lymphocytes from a variety of lymphocyte populations including murine and human thymus lymphocytes and murine spleen and thoracic duct lymphocytes. Cell surface proteins were labeled with iodide-(125)I by lactoperoxidase-catalyzed iodination, and recovered in solution either by solubilization in dissociating solvents or active metabolic release. Immunoglobulins were identified and isolated by immunological coprecipitation. The polypeptide chain structure of immunoglobulins isolated from lymphocyte surfaces was analyzed by polyacrylamide gel electrophoresis of reduced, alkylated samples in acid urea. Human and murine thymus lymphocytes possessed only IgM immunoglobulin on their surfaces. This protein contained light chains and micro-type heavy chains and was characterized by a molecular weight of approximately 200,000. Murine splenic lymphocytes from CBA x C57 animals and congenitally athymic (nu/nu) mice possessed both IgM and IgG on their surfaces. The ratio of micro-chain to gamma-chain was about 3/1. The presence of IgM on thymus lymphocytes probably does not reflect trace contamination by B lymphocytes because comparable quantities of IgM were isolated from both cell populations. Metabolic turnover data suggest that this immunoglobulin is synthesized by the cell population studied. These results provide direct evidence for the presence of immunoglobulins composed of light and heavy polypeptide chains on the surfaces of lymphocytes of all classes.
Design of NDA Intercalators To Overcome Topoisomerase II-Mediated Multidurg Resistance
Authors: B. C. Baguley, K. M. Holdaway, L. M. Frey
Journal: JNCI Journal of the National Cancer Institute (1990)

Murine P388 (P) leukemia cell lines resistant to amsacrine (P/AMSA), dactinomycin (P/DACT), and doxorubicin (P/ DOX) were compared with the parental strain in their sensitivity to a number of derivatives of amsacrine. The P/DACT cell line, which shows the characteristics of a transport-mediated multidrug-resistant cell line, was cross-resistant to vincristine, doxorubicin, etoposide, and a number of acri-dine-substituted amsacrine derivatives, but was sensitive in vitro and in vivo to amsacrine and its analog CI-921. The P/DOX cell line was cross-resistant to amsacrine but showed a similar pattern of cross-resistance to that of P/DACT in its in vitro response to amsacrine derivatives. In contrast, the P/AMSA line was substantially cross-resistant (from 27- to 146-fold) to all acridine-substituted amsacrine derivatives. However, when the substituents on the anilino side chain of amsacrine were changed, the in vitro cross-resistance of the P/AMSA line could be substantially reduced and even overcome. Derivatives with low cross-resistance ratios were tested in vivo against the P/AMSA leukemia and, in contrast to amsacrine and CI-921, were found to be active. Since the target enzyme for amsacrine action, topoisomerase II, is thought to be structurally modified in the P/AMSA line as well as in some other multidrug-resistant lines, these results suggest the feasibility of tailoring topoisomerase II-directed drugs specifically for the altered enzymes in resistant cells. New drug design approaches are therefore available for overcoming two major types of multidrug resistance. [J Natl Cancer Inst 82: 398–402, 1990]
Transforming growth factor beta 2 (TGFbeta 2) produces effective pleurodesis in sheep with no systemic complications
Authors: Y C G Lee
Journal: Thorax (2000)

<h3>BACKGROUND</h3> We have recently shown that transforming growth factor (TGF)β<sub>2</sub>induces effective pleurodesis in rabbits. However, rabbits have a thin pleura while humans have a thick visceral pleura. The effect of intrapleural administration of TGFβ<sub>2</sub> in animals with a thick pleura and its associated systemic effects have not been investigated. This study was undertaken (1) to develop a new animal model for the study of pleurodesis using sheep which have a thick pleura resembling that of humans; (2) to study the efficacy of TGFβ<sub>2</sub> as a pleurodesis agent in the sheep model; and (3) to assess whether histological changes occur in extrapulmonary organs after intrapleural administration of TGFβ<sub>2</sub>. <h3>METHODS</h3> Twelve sheep were divided into four groups and were given a single intrapleural injection of TGFβ<sub>2</sub> in a concentration of 1.0 μg/kg, 0.5 μg/kg, 0.25 μg/kg or 0.125 μg/kg to the right pleural cavity via a chest tube. The left pleural cavity served as the control. Any pleural fluid that accumulated after the intrapleural TGFβ<sub>2</sub> injection was collected and analysed. The degree of pleurodesis was graded from 1 (no adhesions) to 8 (complete symphysis &gt;50% of chest wall) at day 14 when the sheep were killed. Biopsy specimens were taken from the lungs and extrapulmonary organs. <h3>RESULTS</h3> All sheep that received ⩾0.25 μg/kg TGFβ<sub>2</sub> developed excellent pleurodesis (score = 8) while those that received 0.125 μg/kg had a median score of 6. The pleurodesis score did not exceed 2 in the control (left) side of any sheep. Sheep receiving ⩾0.50 μg/kg TGFβ<sub>2</sub> developed large exudative pleural effusions while those receiving a lower dose did not. The production of effusions neither hindered nor was necessary for inducing pleurodesis. There were no significant fibrotic changes in any of the extrapulmonary organs. <h3>CONCLUSION</h3> Intrapleural injection of 0.25–1.0 μg/kg TGFβ<sub>2</sub> produces excellent pleurodesis in a new sheep model with no evidence of extrapulmonary fibrosis.
Possible dietary protective factors in relation to the distribution of duodenal ulcer in India and Bangladesh.
Authors: A P Jayaraj, F I Tovey, C G Clark
Journal: Gut (1980)

In India there are regions of high incidence and regions of low incidence of duodenal ulcer. Rats prefed for two weeks on diets from low incidence areas developed significantly fewer rumenal ulcers after pyloric ligation than rats fed on diets from high incidence areas. The protective action was found in various individual items of food taken from the diets of low incidence areas. Unrefined wheat and rice, certain pulses (black gram, green gram, horse gram), some millets (sava, kutki, ragi), soya bean, ladies' fingers, cabbage, spinach, and whole cream milk were protective. Refined wheat, polished rice, maize, cornflour, sorghum vulgare, sugar, bananas, amaranthus, brinjal, peanut oil, some pulses (Bengal gram, turdhal), and skimmed milk were non-protective. The protective factor seems to be either a lipid or a liposoluble substance which is active whether given orally or parenterally. Horse gram (Dolichos biflorus) is a particularly potent source.
ATM regulates target switching to escalating doses of radiation in the intestines
Authors: Hui-Ju Ch'ang, Jerzy G Maj, François Paris, H Rosie Xing, Jianjun Zhang, Jean-Philip Truman, Carlos Cardon-Cardo, Adriana Haimovitz-Friedman, Richard Kolesnick, Zvi Fuks
Journal: Nature Medicine (2005)
Circulating fibrocytes traffic to the lungs in response to CXCL12 and mediate fibrosis
Authors: Roderick J. Phillips, Marie D. Burdick, Kurt Hong, Marin A. Lutz, Lynne A. Murray, Ying Ying Xue, John A. Belperio, Michael P. Keane, Robert M. Strieter
Journal: Journal of Clinical Investigation (2004)

Previous reports have identified a circulating pool of CD45+ collagen I+ CXCR4+ (CD45+Col I+CXCR4+) cells, termed fibrocytes, that traffic to areas of fibrosis. No studies have demonstrated that these cells actually contribute to fibrosis, however. Pulmonary fibrosis was originally thought to be mediated solely by resident lung fibroblasts. Here we show that a population of human CD45+Col I+CXCR4+ circulating fibrocytes migrates in response to CXCL12 and traffics to the lungs in a murine model of bleomycin-induced pulmonary fibrosis. Next, we demonstrated that murine CD45+Col I+CXCR4+ fibrocytes also traffic to the lungs in response to a bleomycin challenge. Maximal intrapulmonary recruitment of CD45+Col I+CXCR4+ fibrocytes directly correlated with increased collagen deposition in the lungs. Treatment of bleomycin-exposed animals with specific neutralizing anti-CXCL12 Ab’s inhibited intrapulmonary recruitment of CD45+Col I+CXCR4+ circulating fibrocytes and attenuated lung fibrosis. Thus, our results demonstrate, we believe for the first time, that circulating fibrocytes contribute to the pathogenesis of pulmonary fibrosis.
Unusual presentation of appendicitis.
Authors: B G Baliga
Journal: BMJ (1980)

effective methods and monitoring and validating existing and new techniques" for health education.15While more evaluation of how best to transmit "healthy" messages is welcome, it can distract from the careful scrutiny of what is being transmitted.Increased "effectiveness" can come from improving means of communication, but it currently seems more likely to result from changing the content and focus of education.A discussion of such issues should address the equally imnportant questions of whose job it is to undertake type 3 health education, who should provide the resources, and what forms of training are most appropriate.At a time when health pro- fessionals are under great pressure and not infrequently deni- grated as "unproductive workers," careful thought needs to be given by all those concerned to the most effective means of organising health education.
Brief Communication: Rituximab in HIV-Associated Multicentric Castleman Disease
Authors: Mark Bower, Tom Powles, Sarah Williams, Tom Newsom Davis, Mark Atkins, Silvia Montoto, Chloe Orkin, Andy Webb, Martin Fisher, Mark Nelson, Brian Gazzard, Justin Stebbing, Peter Kelleher
Journal: Annals of Internal Medicine (2007)

Background: HIV-associated multicentric Castleman disease is a rare lymphoproliferative disorder with marked systemic symptoms attributed to cytokine disarray. Many therapeutic approaches in small series of patients have proved largely unsuccessful to date. Objective: To investigate the efficacy and clinicopathologic variables associated with first-line treatment for HIV-associated multicentric Castleman disease with the anti-CD20 monoclonal antibody rituximab. Design: Single-group, open-label, phase II trial. Setting: 3 teaching hospitals in England. Patients: Previously untreated patients with histologically proven HIV-associated multicentric Castleman disease. Intervention: 4 infusions of rituximab, 375 mg per m2 of body surface area, at weekly intervals. Measurements: Response was evaluated clinically and radiologically and by measuring plasma Kaposi sarcoma–associated herpesvirus viral load. Results: 21 consecutive patients (18 men) with plasmablastic multicentric Castleman disease were recruited. The median follow-up was 12 months (range, 1 to 49 months). One patient died before completing therapy, 20 achieved remission of symptoms, and 14 (67%) achieved a radiologic response. The overall and disease-free survival rates at 2 years were 95% (95% CI, 86% to 100%) and 79% (CI, 49% to 100%), respectively. Plasma acute-phase proteins, immunoglobulins, and Kaposi sarcoma–associated herpesvirus viral load decreased after rituximab therapy. The main adverse effect was reactivation of Kaposi sarcoma. Limitation: The study had no comparison group. Conclusion: Rituximab may be clinically valuable as initial therapy for HIV-associated multicentric Castleman disease.
Worldwide trends in the prevalence of asthma symptoms: phase III of the International Study of Asthma and Allergies in Childhood (ISAAC)
Authors: N. Pearce, N. Ait-Khaled, R. Beasley, J. Mallol, U. Keil, E. Mitchell, C. Robertson
Journal: Thorax (2007)

<b>Background:</b> Phase I of the International Study of Asthma and Allergies in Childhood (ISAAC) was designed to allow worldwide comparisons of the prevalence of asthma symptoms. In phase III the phase I survey was repeated in order to assess changes over time. <b>Methods:</b> The phase I survey was repeated after an interval of 5–10 years in 106 centres in 56 countries in children aged 13–14 years (n = 304 679) and in 66 centres in 37 countries in children aged 6–7 years (n = 193 404). <b>Results:</b> The mean symptom prevalence of current wheeze in the last 12 months changed slightly from 13.2% to 13.7% in the 13–14 year age group (mean increase of 0.06% per year) and from 11.1% to 11.6% in the 6–7 year age group (mean increase of 0.13% per year). There was also little change in the mean symptom prevalence of severe asthma or the symptom prevalence measured with the asthma video questionnaire. However, the time trends in asthma symptom prevalence showed different regional patterns. In Western Europe, current wheeze decreased by 0.07% per year in children aged 13–14 years but increased by 0.20% per year in children aged 6–7 years. The corresponding findings per year for the other regions in children aged 13–14 years and 6–7 years, respectively, were: Oceania (−0.39% and −0.21%); Latin America (+0.32% and +0.07%); Northern and Eastern Europe (+0.26% and +0.05%); Africa (+0.16% and +0.10%); North America (+0.12% and +0.32%); Eastern Mediterranean (−0.10% and +0.79%); Asia-Pacific (+0.07% and −0.06%); and the Indian subcontinent (+0.02% and +0.06%). There was a particularly marked reduction in current asthma symptom prevalence in English language countries (−0.51% and −0.09%). Similar patterns were observed for symptoms of severe asthma. However, the percentage of children reported to have had asthma at some time in their lives increased by 0.28% per year in the 13–14 year age group and by 0.18% per year in the 6–7 year age group. <b>Conclusions:</b> These findings indicate that international differences in asthma symptom prevalence have reduced, particularly in the 13–14 year age group, with decreases in prevalence in English speaking countries and Western Europe and increases in prevalence in regions where prevalence was previously low. Although there was little change in the overall prevalence of current wheeze, the percentage of children reported to have had asthma increased significantly, possibly reflecting greater awareness of this condition and/or changes in diagnostic practice. The increases in asthma symptom prevalence in Africa, Latin America and parts of Asia indicate that the global burden of asthma is continuing to rise, but the global prevalence differences are lessening.
TERMINATION OF ACQUIRED IMMUNOLOGICAL TOLERANCE TO PROTEIN ANTIGENS FOLLOWING IMMUNIZATION WITH ALTERED PROTEIN ANTIGENS
Authors: William O. Weigle
Journal: The Journal of Experimental Medicine (1962)

Acquired tolerance to BSA in rabbits was terminated following the injection of certain preparations of altered BSA. Injections of Freund's adjuvant containing BSA complexed to anti-BSA, heat-denatured BSA, acetyl-BSA, picryl-BSA, or arsanil-BSA failed to terminate the tolerant state. Except in an occasional tolerant rabbit, injections of these preparations failed to cause the production of precipitating antibody to the altered preparation. Similar results were obtained following injections of alum-precipitated preparations of pepsin-degraded BSA, acetyl-BSA, and picryl-BSA. Injections of Freund's adjuvant containing sulfanil-BSA terminated the tolerant state, but only small amounts of non-precipitating anti-BSA were produced. Injections of Freund's adjuvant containing picryl-acetyl-BSA terminated the tolerant state in two of six rabbits, but again, only small amounts of non-precipitating anti-BSA were produced. Injections of an alum-precipitated preparation of picryl-acetyl-BSA failed to terminate the tolerant state. On the other hand, injections of Freund's adjuvant containing arsanil-sulfanil-BSA terminated the tolerant state in eleven of eleven rabbits and caused the production of precipitating anti-BSA in all nine of the rabbits tested. The tolerant state was terminated also in six of six rabbits injected with an alum-precipitated preparation of arsanil-sulfanil-BSA. Only one of these rabbits produced precipitating anti-BSA. In addition, the injection of BGG-tolerant rabbits with arsanil-BGG, sulfanil-BGG, or arsanil-sulfanil-BGG terminated the tolerant state. These results were discussed in relation to both the clonal selection theory of antibody production and autoimmunity.
Unusual skin ulceration in an HIV-positive patient who had cutaneous syphilis and neurosyphilis
Authors: S.C TUCKER, V.M YATES, I.V. THAMBAR
Journal: British Journal of Dermatology (1997)

We present a case of a patient coinfected with syphilis and the human immunodeficiency virus (HIV) who had unusual and severe cutaneous ulceration. The profound immune defects associated with HIV may lead to an altered clinical presentation and a more aggressive course in patients infected with Treponema pallidum. Despite non-confirmatory histological findings, we feel our patient's cutaneous ulcers probably represent superficial gummata, which have failed to resolve completely following currently accepted high-dose antisyphilis chemotherapy.
mTORC1 Inhibitors Suppress Meningioma Growth in Mouse Models
Authors: Doreen Pachow, Nadine Andrae, Nadine Kliese, Frank Angenstein, Oliver Stork, Annette Wilisch-Neumann, Elmar Kirches, Christian Mawrin
Journal: Clinical Cancer Research (2013)

Abstract Purpose: To evaluate the mTORC1 (mammalian target of rapamycin complex 1) pathway in meningiomas and to explore mTORC1 as a therapeutic target in meningioma cell lines and mouse models. Experimental Design: Tissue microarrays (53 meningiomas of all WHO grades) were stained for phosphorylated polypeptides of mTOR, Akt, and the mTORC1 targets 4EBP1 and p70S6K, the latter being the consensus marker for mTORC1 activity. Expression of proteins and mRNAs was assessed by Western blotting and real-time PCR in 25 tumors. Cell lines Ben-Men-1 (benign), IOMM-Lee and KT21 (malignant), and pairs of merlin-positive or -negative meningioma cells were used to assess sensitivity toward mTORC1 inhibitors in methyl-tetrazolium and bromodeoxyuridine (BrdUrd) assays. The effect of temsirolimus (20 mg/kg daily) on tumor weight or MRI-estimated tumor volume was tested by treatment of eight nude mice (vs. 7 controls) carrying subcutaneous IOMM-Lee xenografts, or of eight (5) mice xenotransplanted intracranially with IOMM-Lee (KT21) cells in comparison to eight (5) untreated controls. Results: All components of the mTORC1 pathway were expressed and activated in meningiomas, independent of their WHO grade. A significant dosage-dependent growth inhibition by temsirolimus and everolimus was observed in all cell lines. It was slightly diminished by merlin loss. In the orthotopic and subcutaneous xenograft models, temsirolimus treatment resulted in about 70% growth reduction of tumors (P &amp;lt; 0.01), which was paralleled by reduction of Ki67 mitotic index (P &amp;lt; 0.05) and reduction of mTORC1 activity (p70S6K phosphorylation) within the tumors. Conclusion: mTORC1 inhibitors suppress meningioma growth in mouse models, although the present study did not measure survival. Clin Cancer Res; 19(5); 1180–9. ©2012 AACR.