tbuckley/cabot-search huggingface dataset:
Synergistic Antitumor Activity of ZD6474, An Inhibitor of Vascular Endothelial Growth Factor Receptor and Epidermal Growth Factor Receptor Signaling, with Gemcitabine and Ionizing Radiation against Pancreatic Cancer
Authors: Cataldo Bianco, Elisa Giovannetti, Fortunato Ciardiello, Valentina Mey, Sara Nannizzi, Giampaolo Tortora, Teresa Troiani, Francesco Pasqualetti, Gail Eckhardt, Mario de Liguoro, Simona Ricciardi, Mario Del Tacca, David Raben, Luca Cionini, Romano Danesi
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Standard treatments have modest effect against pancreatic cancer, and current research focuses on agents targeting molecular pathways involved in tumor growth and angiogenesis. This study investigated the interactions between ZD6474, an inhibitor of tyrosine kinase activities of vascular endothelial growth factor receptor-2 and epidermal growth factor receptor (EGFR), gemcitabine, and ionizing radiation in human pancreatic cancer cells and analyzed the molecular mechanisms underlying this combination. Experimental Design: ZD6474, ionizing radiation, and gemcitabine, alone or in combination, were given in vitro to MIA PaCa-2, PANC-1, and Capan-1 cells and in vivo to MIA PaCa-2 tumor xenografts. The effects of treatments were studied by the evaluation of cytotoxicity, apoptosis, cell cycle, EGFR and Akt phosphorylation, modulation of gene expression of enzymes related to gemcitabine activity (deoxycytidine kinase and ribonucleotide reductase), as well as vascular endothelial growth factor immunohistochemistry and microvessel count. Results: In vitro, ZD6474 dose dependently inhibited cell growth, induced apoptosis, and synergistically enhanced the cytotoxic activity of gemcitabine and ionizing radiation. Moreover, ZD6474 inhibited phosphorylation of EGFR and Akt and triggered cell apoptosis. PCR analysis showed that ZD6474 increased the ratio between gene expression of deoxycytidine kinase and ribonucleotide reductase. In vivo, ZD6474 showed significant antitumor activity alone and in combination with radiotherapy and gemcitabine, and the combination of all three modalities enhanced MIA PaCA-2 tumor growth inhibition compared with gemcitabine alone. Conclusions: ZD6474 decreases EGFR and Akt phosphorylation, enhances apoptosis, favorably modulates gene expression in cancer cells, and acts synergistically with gemcitabine and radiotherapy to inhibit tumor growth. These findings support the investigation of this combination in the clinical setting.
Home treatment of convulsions
Authors: A Stephen
Journal: BMJ (1976)

only in this position and even slept in this manner.This was not an individual habit and had not been present before the onset of this illness.The only other physical signs were in the abdomen, where there was slight general distension and a characteristic tumour palpable in the left iliac fossa.Rectal examination was normal.Laparotomy was performed that evening, and an easily reducible caecocolic intussusception was found, which, owing to partial spontaneous reduction, was in the left hypochondrium.Numerous enlarged lymph nodes were found in the mesentery, and histological examination of one of these showed reactive hyperplasia.The child made an uneventful recovery.The position adopted by this child clearly relieved his pain, and in view of the anatomy in this particular case it would seem likely that the child was unconsciously using gravity in an attempt to reduce the intussusception.This sign does not feature in textbooks and is obviously unusual.It was not encountered in any of 67 cases described in clinical detail by Kark and Rundle.'However, although unusual, the sign is a dramatic one and should alert one -to the diagnosis at a glance if its significance is appreciated.
T-Cell–Depleted Reduced-Intensity Transplantation Followed by Donor Leukocyte Infusions to Promote Graft-Versus-Lymphoma Activity Results in Excellent Long-Term Survival in Patients With Multiply Relapsed Follicular Lymphoma
Authors: Kirsty J. Thomson, Emma C. Morris, Don Milligan, Anne N. Parker, Ann E. Hunter, Gordon Cook, Adrian J.C. Bloor, Fiona Clark, Majid Kazmi, David C. Linch, Ronjon Chakraverty, Karl S. Peggs, Stephen Mackinnon
Journal: Journal of Clinical Oncology (2010)

Follicular lymphoma (FL) is an indolent disorder that is treatable but considered incurable with chemotherapy alone. The curative potential of allogeneic transplantation using conventional myeloablative conditioning has been demonstrated, but this approach is precluded in the majority of patients with FL because of excessive toxicity. Thus, reduced-intensity conditioning regimens are being explored.This study reports the outcome of 82 consecutive patients with FL who underwent transplantation using fludarabine, melphalan, and alemtuzumab for in vivo T-cell depletion. Patients were heavily pretreated, having received a median of four lines of prior therapy, and 26% had experienced treatment failure with previous autologous transplantation. Median patient age was 45 years, and 52% of patients received stem cells from unrelated donors.With a median follow-up time of 43 months, the nonrelapse mortality was 15% at 4 years (8% for sibling and 22% for unrelated donor transplantations), acute grade 2 or 3 graft-versus-host disease (GVHD) occurred in 13%, and the incidence of extensive chronic GVHD was only 18%. Although relapse risk was 26%, this was significantly reduced where mixed chimerism had been converted to full donor chimerism by the use of donor lymphocyte infusion (DLI; P = .03). In addition, 10 (77%) of 13 patients given DLI for relapse after transplantation experienced remission, with nine of these responses being sustained. Current progression-free survival at 4 years was 76% for the whole cohort (90% for those with sibling donors and 64% for those with unrelated donors).The excellent long-term survival with associated low rates of GVHD and the frequency and durability of DLI responses make this an extremely encouraging strategy for the treatment and potential cure of FL.
Epitopes in Medicine
Authors: J. David Bessman
Journal: JAMA (1988)

In this issue ofThe Journal, Triplett et al<sup>1</sup>discuss the relationship among an established laboratory test (lupus anticoagulant), an experimental laboratory test (anticardiolipin antibody), and a clinical phenomenon (thrombosis). To understand the conclusion of their work, a little background is needed. They observe that the target of the anticardiolipin assay may be an "epitope" of the lupus anticoagulant. An epitope (from the Greek word for "nearby place") is an antigenic determinant, a structure that can be identified by an antibody. However, the antigenic determinant may be unrelated except by proximity, not by cause, to some other structure of interest. See also p 550. Why the interest in epitopes? There is rapidly increasing interest in using specific antibodies for both therapy<sup>2,3</sup>and diagnosis. With the development of monoclonal antibodies, much smaller targets can be used. An antibody to a given molecule may be directed only to part of
New Hematologic Response Criteria Predict Survival in Patients With Immunoglobulin Light Chain Amyloidosis Treated With High-Dose Melphalan and Autologous Stem-Cell Transplantation
Authors: Saulius Girnius, David C. Seldin, Maria Teresa Cibeira, Vaishali Sanchorawala
Journal: Journal of Clinical Oncology (2013)
The Subendothelial Extracellular Matrix Modulates JNK Activation by Flow
Authors: Cornelia Hahn, A. Wayne Orr, John M. Sanders, Krishna A. Jhaveri, Martin Alexander Schwartz
Journal: Circulation Research (2009)

Atherosclerosis begins as local inflammation of artery walls at sites of disturbed flow. JNK (c-Jun NH(2)-terminal kinase) is thought to be among the major regulators of flow-dependent inflammatory gene expression in endothelial cells in atherosclerosis. We now show that JNK activation by both onset of laminar flow and long-term oscillatory flow is matrix-specific, with enhanced activation on fibronectin compared to basement membrane protein or collagen. Flow-induced JNK activation on fibronectin requires new integrin ligation and requires both the mitogen-activated protein kinase kinase MKK4 and p21-activated kinase. In vivo, JNK activation at sites of early atherogenesis correlates with the deposition of fibronectin. Inhibiting p21-activated kinase reduces JNK activation in atheroprone regions of the vasculature in vivo. These results identify JNK as a matrix-specific, flow-activated inflammatory event. Together with other studies, these data elucidate a network of matrix-specific pathways that determine inflammatory events in response to fluid shear stress.
Radiation Therapy and Tamoxifen: Concurrent or Sequential? That Is the Question
Authors: Timothy Whelan, Mark Levine
Journal: Journal of Clinical Oncology (2004)

Randomized controlled trials have had an important impact on the treatment of women with early breast cancer. Many women routinely receive breast-conserving surgery plus radiation therapy, adjuvant chemotherapy, or hormonal therapy based on the results of randomized trials. However, despite the extensive use of combinations of chemotherapy, hormonal therapy, and radiation therapy, the optimal sequencing of these different adjuvant treatments for patients with early breast cancer remains unclear. Unfortunately, there have been few randomized trials addressing this important issue. In a randomized trial by Recht et al, 1 the optimal sequencing of radiation and chemotherapy in patients treated with breast-conserving surgery was evaluated. Of 244 patients, 122 were allocated to receive radiation therapy before anthracycline-based chemotherapy and 122 were allocated to receive radiation therapy after the same chemotherapy. The median length of follow-up was 58 months. Although the study was relatively small by today’s standards, there was a trend for an increased risk of distant recurrence for patients treated with radiation therapy first (36% v 25%; hazard ratio [HR], 1.62; 95% CI, 1.01 to 2.62;P .05). As a result, breast irradiation is now usually given after anthracycline-based chemotherapy. In early 1990s, investigators from the North American Breast Intergroup conducted a randomized trial in postmenopausal women with node-positive, hormone receptor–positive breast cancer, which compared tamoxifen, administered concurrently with cyclophosphamide, doxorubicin, and fluorouracil (n 550) with tamoxifen given after the completion of the same chemotherapy (n 566). 2 This was an important clinical question because there was some concern that the cytostatic effect of concurrent tamoxifen might interfere with the cytotoxic effects of chemotherapy on cancer cells. Preclinical data had demonstrated that human breast tumor cells in culture pretreated with tamoxifen were protected from the cytotoxicity of chemotherapy. 3 This concern was not shared by all investigators; several cooperative groups recommended the concurrent use of chemotherapy and tamoxifen in trials evaluating these agents. Furthermore, it had already been observed that combined chemotherapy and tamoxifen increased the risk of thromboembolic complications in patients. 4 With a median follow-up of 8.5 years, the results of the Intergroup study were presented at the 2000 American Society of Clinical Oncology Annual Meeting. The 8-year disease-free survival estimates were 67% for patients treated with sequential chemotherapy and tamoxifen compared with 62% for patients treated with concurrent chemotherapy and tamoxifen (P .05). 2 This study led to important
Neighbor Joining and Maximum Likelihood with RNA Sequences: Addressing the Interdependence of Sites
Authors: E. Tillier, R. Collins
Journal: Molecular Biology and Evolution (1995)

Intrastrand base pairings give ribosomal and other RNA molecules characteristic structures that are important for their function. In order to maintain these structures, a substitution at one paired site may have to be compensated for by an appropriate substitution at the complementary site. Thus paired sites do not evolve independently of one another. Most current methods for inferring phylogeny from molecular sequences assume that the sites are independent and will therefore give statistically unreliable and possibly erroneous results when used on structured RNA sequences. We analyze a new probabilistic model for the evolution of double-stranded RNA molecules that considers substitutions of the base pairs rather than of each of the bases independently. The new model, called the double-stranded model, was incorporated into the neighbor-joining distance and maximum likelihood methods. Computer simulations show that maximum likelihood is very robust to the violation of the assumption of the independence of sites. In contrast, the neighbor-joining method is sensitive to such violations: the double-stranded model can provide a significant increase in the chance of obtaining the correct tree topologies with neighbor joining when distances are large and the tree is difficult to obtain. The new model also leads to lower but more realistic estimates for the statistical confidence in the branch lengths and tree topologies.
MR1 uses an endocytic pathway to activate mucosal-associated invariant T cells
Authors: Shouxiong Huang, Susan Gilfillan, Sojung Kim, Bruce Thompson, Xiaoli Wang, Andrea J. Sant, Daved H. Fremont, Olivier Lantz, Ted H. Hansen
Journal: The Journal of Experimental Medicine (2008)

Like CD1d-restricted iNKT cells, mucosal-associated invariant T cells (MAITs) are “innate” T cells that express a canonical TCRα chain, have a memory phenotype, and rapidly secrete cytokines upon TCR ligation. Unlike iNKT cells, MAIT cells require the class Ib molecule MHC-related protein I (MR1), B cells, and gut flora for development and/or expansion, and they preferentially reside in the gut lamina propria. Evidence strongly suggests that MAIT cell activation is ligand-dependent, but the nature of MR1 ligand is unknown. In this study, we define a mechanism of endogenous antigen presentation by MR1 to MAIT cells. MAIT cell activation was dependent neither on a proteasome-processed ligand nor on the chaperoning by the MHC class I peptide loading complex. However, MAIT cell activation was enhanced by overexpression of MHC class II chaperones Ii and DM and was strikingly diminished by silencing endogenous Ii. Furthermore, inhibiting the acidification of the endocytic compartments reduced MR1 surface expression and ablated MAIT cell activation. The importance of the late endosome for MR1 antigen presentation was further corroborated by the localization of MR1 molecules in the multivesicular endosomes. These findings demonstrate that MR1 traffics through endocytic compartments, thereby allowing MAIT cells to sample both endocytosed and endogenous antigens.
Case of Thrombophlebitis Migrans
Authors: C. A. H. Howell
Journal: BMJ (1949)

BDICA JOUR 989 remission following dietetic and /or parenteral liver therapy occurred in 69.4% of these cases and definite relapse in 16.1 %, nearly all of whom first relapsed during transit to England.A brief review of the effective factors of treatment is given and the action of parenteral liver therapy analysed.
Treatment of bronchiectasis in adults
Authors: Nick H T ten Hacken, Peter J Wijkstra, Huib A M Kerstjens
Journal: BMJ (2007)

#### Summary points

Patients with bronchiectasis usually need lifelong medical support from their doctor, especially given the frequent episodes of infection. This article focuses on the treatment of bronchiectasis in adults and does not include a discussion of bronchiectasis caused by cystic fibrosis. The prevalence of bronchiectasis not linked to cystic fibrosis is unclear, but every general practitioner in the United Kingdom probably has a few patients.

Bronchiectasis refers to the permanent abnormal dilatation of the central and medium sized bronchi as a result of a vicious cycle of transmural infection and inflammation with mediator release.1 Symptoms include chronic productive cough, wheeze, and dyspnoea. Infective exacerbations are associated with worsening of symptoms and signs of pneumonia. Haemoptysis can occur, but amounts of blood are usually small, and serious haemoptysis requiring selective arteriography and embolisation or surgery is rare. 

The most frequently used classification system distinguishes between cylindrical, varicose, and saccular or cystic bronchiectasis.w1 Although insightful, this classification has no clinical or therapeutic uses. A modern clinical definition includes the daily production of mucopurulent phlegm and chest imaging that demonstrates dilated and thickened airways.w2 The clinical suspicion of bronchiectasis …
Comparative analysis of minimal residual disease by 4 color flow cytometry (4CFC) and quantitative IgH PCR (RQ-PCR) in chronic lymphocytic leukemia (CLL) after stem cell transplantation (SCT)
Authors: S. Boettcher, M. Ritgen, P. Dreger, M. Kneba
Journal: Journal of Clinical Oncology (2004)

6523 Background: Modern treatment modalities for CLL frequently result in complete clinical remission making assessment of minimal residual disease (MRD) desirable in order to guide the therapeutic strategy. RQ-PCR and 4CFC are competitive methods for quantitative MRD detection regarding sensitivity, speed, quality and cost effectiveness. Methods: We prospectively evaluated MRD in 184 blood samples of 73 CLL patients after autologous (105/63) and allogeneic (79/12) SCT between 07/02 and 11/03 using 4CFC with consensus PCR and/or RQ-PCR. For 4CFC 1E+6 leucocytes were stained with CD19/CD43/CD20/CD5. For consensus (C-)PCR FR1 primers and JH consensus primers were used and analyzed by gene scanning. For 36 patients, an allele specific RQ-PCR could be designed. Results: 77 of 168 (45.8%) samples analyzed by both FC-MRD and C-PCR were 4CFC-MRD positive. 68.8% of 4CFC-MRD positive samples were C-PCR positive, whereas 29.9% were PCR negative. 4CFC-MRD levels showed a very good correlation with MRD levels determined by RQ-PCR (84 samples, r = 0.944; p<0.0001). In one sample MRD levels differed by one order of magnitude. 16.6% of these samples (14/84) were 4CFC negative but RQ-PCR positive (MRD 1E-5 7E-4). None of the RQ-PCR negative samples were 4CFC-MRD positive. A three color combination (CD19/CD5/CD20) predicted MRD levels as good as the 4 color combination (r = 0.944; p<0.0001). Clinical relapses were not observed in patients with durable MRD negativity below 1E-4 (which occurred only after allogeneic SCT). Conclusions: Both 4CFC and RQ-PCR can be similarly used for quantitative measurement of MRD in the range between 5E-4 and 1E-1. Due its higher sensitivity, however, only RQ-PCR appears to be suitable for MRD levels of 1E-4 or lower. To increase the sensitivity of 4CFC, more cells have to be analyzed rather than using additional markers. No significant financial relationships to disclose.
Cancer Risks For Mismatch Repair Gene Mutation Carriers: A Population-Based Early Onset Case-Family Study
Authors: Mark A. Jenkins, Laura Baglietto, James G. Dowty, Christine M. Van Vliet, Letitia Smith, Leeanne J. Mead, Finlay A. Macrae, D. James B. St. John, Jeremy R. Jass, Graham G. Giles, John L. Hopper, Melissa C. Southey
Journal: Clinical Gastroenterology and Hepatology (2006)
Hepatitis B virus precore mutant infection is associated with severe recurrent disease after liver transplantation
Authors: Peter W. Angus, Stephen A. Locarnini, Geoffrey W. McCaughan, Robert M. Jones, Janine S. McMillan, Scott D. Bowden
Journal: Hepatology (1995)

The factors that predispose patients undergoing liver transplantation for hepatitis B virus (HBV) disease to severe recurrence of infection are unclear. In this study we examined the effect of pretransplantation infection with HBV and precore variant strains of HBV on posttransplantation outcome and allograft histology in 24 patients who survived more than 3 months after liver transplantation. Based on pretransplantation serum HBV DNA status as detected by the polymerase chain reaction (PCR) and direct sequencing, the 24 patients could be assigned to three groups. In group 1 there were 4 patients HBV DNA-negative before transplantation and none of these patients suffered recurrence of infection posttransplantation. In group 2, of 10 patients with pretransplantation infection with wild-type virus, 7 became reinfected, and 1 of these developed HBV-related graft failure. In group 3, 9 of 10 patients infected with precore mutant HBV strains became reinfected. However, in contrast to the patients in group 2, 7 patients in group 3 developed HBV-related graft loss, and 5 of these patients had fibrosing cholestatic hepatitis (FCH). These results indicate that infection with precore mutant strains of HBV predisposes a patient to early graft loss following transplantation.
Ligand-inducible interaction of the DRIP/TRAP coactivator complex with retinoid receptors in retinoic acid–sensitive and –resistant acute promyelocytic leukemia cells
Authors: Wenlin Shao, Angelika Rosenauer, Koren Mann, Chao-Pei Betty Chang, Christophe Rachez, Leonard P. Freedman, Wilson H. Miller
Journal: Blood (2000)
Detection of Hypoxic cells in a Murine Tumour With the Use of the Comet Assay
Authors: P. L. Olive, R. E. Durand
Journal: JNCI Journal of the National Cancer Institute (1992)

Background: Hypoxic cells within solid tumors are likely to limit tumor curability by radiation therapy and some chemotherapeutic agents. Purpose: To quantify a hypoxic fraction insolid tumors, we developed a method which measures radiationinduced DNA singlestrand breaks in individual tumor cells and makes use of the fact that three times more strand breaks are produced in aerobic than in hypoxic cells. Methods: Immediately after irradiation with doses of 4–20 Gy, SCCVII squamous cell carcinomas growing in C3H mice were removed and cooled, and a singlecell suspension was prepared. These cells were then embedded in agarose, lysed in an alkaline solution, subjected to electrophoresis, and stained with a fluorescent DNAbindirg dye. The amount and migration distance of damaged DNA from individual cells were scored by using a fluorescence image processing system, where differentially radiosensitive aerobic and hypoxic cell populations resulted in bimodal damage distributions. Curvefitting routines provided quantitative estimates of the fraction of hypoxic cells. Results: After the mice were exposed to 10–20 Gy, the SCCVII tumors (450–600 mg) were shown to have a hypoxic fraction of 18.5% ± 10.6% (mean ± SD for 11 tumors), which compares well with the value of 11.6% observed using the paired survival curve method. Conclusions: Our results indicate that this method, which requires only a few thousand cells, is a rapid and sensitive way to detect hypoxic cells in solid animal tumors. Implications: Estimating hypoxia in accessible human tumors undergoing radiotherapy may be possible if the sensitivity of the method can be improved to allow detection of hypoxic cells after a dose of 2 Gy. [J NatI Cancer Inst 84:707–711, 1992]