tbuckley/cabot-search huggingface dataset:
Thalidomide in the treatment of sixty cases of chronic discoid lupus erythematosus
Authors: J. KNOP, G. BONSMANN, R. HAPPLE, A. LUDOLPH, D.R. MATZ, E.J. MIFSUD, E. MACHER
Journal: British Journal of Dermatology (1983)

The therapeutic effect of thalidomide in chronic discoid lupus erythematosus (CDLE) was studied in sixty patients who were followed up for 2 years. In fifty‐four patients (90%) a complete or marked regression of the disease was observed, but when the thalidomide was stopped, thirty out of forty‐one (71%) patients relapsed. Patients undergoing a second course of thalidomide treatment again responded well. Nine of the patients in whom the disease recurred after successful treatment with thalidomide and who had been unresponsive to intermittent treatment with antimalarials, showed a good response to a second or third course with thalidomide. Mild side‐effects were common and 25% of patients complained of slight to moderate polyneuritic symptoms. Since electroneurological examinations had not been performed before the thalidomide therapy, the frequency of neurological side‐effects cannot be accurately calculated but we recommend neurological examinations before and periodically during thalidomide treatment. Thalidomide is a very effective drug in CDLE, but in most cases it exerts its effect only whilst treatment is continued. Its use should be restricted to patients resistant to topical steroids and systemic antimalarials.
Deficiency in Mammalian Histone H2B Ubiquitin Ligase Bre1 (Rnf20/Rnf40) Leads to Replication Stress and Chromosomal Instability
Authors: Sophia B. Chernikova, Olga V. Razorenova, John P. Higgins, Brock J. Sishc, Monica Nicolau, Jennifer A. Dorth, Diana A. Chernikova, Shirley Kwok, James D. Brooks, Susan M. Bailey, John C. Game, J. Martin Brown
Journal: Cancer Research (2012)

Mammalian Bre1 complexes (BRE1A/B (RNF20/40) in humans and Bre1a/b (Rnf20/40) in mice) function similarly to their yeast homolog Bre1 as ubiquitin ligases in monoubiquitination of histone H2B. This ubiquitination facilitates methylation of histone H3 at K4 and K79, and accounts for the roles of Bre1 and its homologs in transcriptional regulation. Recent studies by others suggested that Bre1 acts as a tumor suppressor, augmenting expression of select tumor suppressor genes and suppressing select oncogenes. In this study, we present an additional mechanism of tumor suppression by Bre1 through maintenance of genomic stability. We track the evolution of genomic instability in Bre1-deficient cells from replication-associated double-strand breaks (DSB) to specific genomic rearrangements that explain a rapid increase in DNA content and trigger breakage-fusion-bridge cycles. We show that aberrant RNA-DNA structures (R-loops) constitute a significant source of DSBs in Bre1-deficient cells. Combined with a previously reported defect in homologous recombination, generation of R-loops is a likely initiator of replication stress and genomic instability in Bre1-deficient cells. We propose that genomic instability triggered by Bre1 deficiency may be an important early step that precedes acquisition of an invasive phenotype, as we find decreased levels of BRE1A/B and dimethylated H3K79 in testicular seminoma and in the premalignant lesion in situ carcinoma.
Progression-Free Survival Rate As Primary End Point for Phase II Cancer Clinical Trials: Application to Mesothelioma—The EORTC Lung Cancer Group
Authors: Julie Francart, Catherine Legrand, Richard Sylvester, Martine Van Glabbeke, Jan P. van Meerbeeck, Annie Robert
Journal: Journal of Clinical Oncology (2006)

Phase II cancer clinical trials play a key role in the development of new drugs. These trials should be designed to accurately determine if the drug should be abandoned or if it is sufficiently promising for further investigation in phase III trials. With new cytostatic agents or when the response assessment is difficult, using the progression-free survival rate (PFSR) at a fixed time point, such as 3, 4, 5, or 6 months, instead of the response rate (RR) as the primary end point is an alternative approach. To design future phase II trials, reference values for PFSRs that correspond to drugs with insufficient (P0) and sufficient (P1) clinical activity (CA) are necessary. This article provides these values in mesothelioma.The European Organisation for Research and Treatment of Cancer database registered ten closed mesothelioma trials (nine phase II trials and one phase III trial) with 523 total patients. Trials were grouped into three categories according to the published RR: significant (n = 259), moderate (n = 142), and insufficient (n = 122) CA.The PFSRs at 3, 4, 5, and 6 months, respectively, were as follows: 72%, 67%, 51%, and 43% in the group with significant CA; 59%, 51%, 42%, and 35% with moderate CA; and 52%, 40%, 34%, and 28% with insufficient CA.These values may be used to define relevant P0 and P1 values in future phase II mesothelioma trials that use PFSR as the primary end point.
ART failure: oocyte contributions to unsuccessful fertilization
Authors: J. E. Swain, T. B. Pool
Journal: Human Reproduction Update (2008)

The complexity of fertilization failure during assisted reproductive technologies (ART) is often under-appreciated, as this failure can occur at any number of essential mechanistic and cellular events. Importantly, successful fertilization is heavily dependent upon inherent qualities of the oocytes, and thus reliant upon fidelity of oocyte maturation.Pubmed and medline were searched up to April 2008 for papers on oocyte fertilization and its mechanistic components. References to clinical/human studies were selected wherever possible.Successful oocyte maturation cannot simply be determined via visual assessment of polar body extrusion, but rather entails coordination of numerous cytoplasmic processes not readily observed. Proper regulation of intra-oocyte signaling cascades is crucial for sufficient production and storage of carbohydrates and proteins, successful relocation of organelles and regulation of metabolic pathways required for an apparently mature metaphase II oocyte to complete subsequent fertilization events; such as cumulus penetration, sperm/oocyte binding, fusion, oocyte activation, sperm processing and pronuclear (PN) formation. Regulation of oocyte maturation begins during oocyte growth and is intimately connected with events influencing folliculogenesis. Therefore, the oocyte is subject to a multitude of potential effector impacting fertilization potential and developmental competence long before encountering the artificial environment of the IVF laboratory.Although meticulous care and continued research is essential for future improvement, failure to fertilize and properly form PN following clinical ART is likely to be dependent on historical events in oocyte maturation, not easily explained or prevented through simple modification of contemporary laboratory protocols.
Host factors that impact the biodistribution and persistence of multipotent adult progenitor cells
Authors: Jakub Tolar, Matthew J. O'Shaughnessy, Angela Panoskaltsis-Mortari, Ron T. McElmurry, Scott Bell, Megan Riddle, R. Scott McIvor, Stephen R. Yant, Mark A. Kay, Diane Krause, Catherine M. Verfaillie, Bruce R. Blazar
Journal: Blood (2006)
Blockade of atrial-specific K+-currents increases atrial but not ventricular contractility by enhancing reverse mode Na+/Ca2+-exchange
Authors: U SCHOTTEN, S DEHAAN, S VERHEULE, E HARKS, D FRECHEN, E BODEWIG, M GREISER, R RAM, J MAESSEN, M KELM
Journal: Cardiovascular Research (2006)

AVE0118 (2'-{[2-(4-Methoxy-phenyl)-acetylamino]-methyl}-biphenyl-2-carboxylic acid (2-pyridin-3-yl-ethyl)-amide) blocks atrial ultrarapid delayed rectifier currents (I(Kur)) and prolongs the atrial action potential (AP) plateau without affecting ventricular repolarisation. In patients with atrial contractile dysfunction due to atrial tachyarrhythmias, this response might increase atrial contractility without risk of ventricular proarrhythmia. This study was designed to evaluate the inotropic mechanisms of AVE0118.In isometrically contracting atrial trabeculae, AVE0118 increased contractile force by 55.4% in sinus rhythm patients (n = 9) and by 107.4% in patients with atrial fibrillation (n = 8). In freshly isolated canine atrial myocytes studied under perforated patch current clamp (37 degrees C), AVE0118 increased myocyte fractional shortening from 3.8+/-0.6 to 9.6+/-0.8% and prolonged action potential duration at 30% repolarisation from 9+/-2 to 102+/-11 ms. Clamping cells to an AP waveform recorded during exposure to AVE0118 produced the same inotropic response as the drug itself. In action potential clamp, peak Ca2+ inward current (I(CaL)) current declined from 5.5+/-1.3 pA/pF during control to 4.1+/-0.7 pA/pF when an AP recorded in the presence of AVE0118 was used as command waveform. However, I(CaL) was more sustained with AVE0118 and the time integral did not change (135+/-37 vs. 173+/-30 pA/pFms, p = ns). Importantly, blockade of reverse mode Na+/Ca2+-exchanger activity with 5 microM KBR7943 or using a Na+-free pipette solution abolished the positive inotropic effect of the AP recorded in the presence of AVE0118. In ventricular myocytes AVE0118 did not elicit a positive inotropic response.Block of I(Kur) by AVE0118 enhances atrial contractility both in patients with sinus rhythm and atrial fibrillation. The positive inotropic effect is atrial-specific and due to the changes of the action potential configuration which enhances Ca2+ entry via reverse mode Na+/Ca2+ exchange.
The Osteoclast: Friend or Foe?
Authors: Deborah V. Novack, Steven L. Teitelbaum
Journal: Annual Review of Pathology Mechanisms of Disease (2008)

Bone is a dynamic organ constantly remodeled to support calcium homeostasis and structural needs. The osteoclast is the cell responsible for removing both the organic and inorganic components of bone. It is derived from hematopoietic progenitors in the macrophage lineage and differentiates in response to the tumor necrosis factor family cytokine receptor activator of NF kappa B ligand. alpha v beta 3 integrin mediates cell adhesion necessary for polarization and formation of an isolated, acidified resorptive microenvironment. Defects in osteoclast function, whether genetic or iatrogenic, may increase bone mass but lead to poor bone quality and a high fracture risk. Pathological stimulation of osteoclast formation and resorption occurs in postmenopausal osteoporosis, inflammatory arthritis, and metastasis of tumors to bone. In these diseases, osteoclast activity causes bone loss that leads to pain, deformity, and fracture. Thus, osteoclasts are critical for normal bone function, but their activity must be controlled.
Keeping Out the Bad Guys: Gateway to Cellular Target Therapy
Authors: Takanori Kitamura, Makoto M. Taketo
Journal: Cancer Research (2007)

Tumor-stromal interaction is implicated in many stages of tumor development, although it remains unclear how genetic lesions in tumor cells affect stromal cells. We have recently shown that inactivation of transforming growth factor-beta family signaling within colon cancer epithelium increases chemokine CC chemokine ligand 9 (CCL9) and promotes recruitment of the matrix metalloproteinase (MMP)-expressing stromal cells that carry CC chemokine receptor 1 (CCR1), the cognate receptor for CCL9. We have further shown that lack of CCR1 prevents the accumulation of MMP-expressing cells at the invasion front and suppresses tumor invasion. These results provide the possibility of a novel therapeutic strategy for advanced cancer--prevention of the recruitment of MMP-expressing cells by chemokine receptor antagonist.
Liver stiffness measurement by transient elastography predicts early recovery from acute hepatitis
Authors: V. Di Marco, V. Calvaruso, A. Iaco, F. Bronte, L. Biasi, K. Prestini, P. Sacchi, G. Amaddeo, G. Squadrito, R. Bruno, M. Puoti, A. Craxi
Journal: Gut (2010)

We read with interest the lead article by Castera and Pinzani,1 particularly the comment regarding the role of transient elastography (TE) in the context of acute hepatitis (AH).

The assumption that liver stiffness is determined exclusively by hepatic fibrosis has been challenged by evidence that patients with AH can have high values of liver stiffness measurement (LSM) by TE.2 AH is a suitable model for studying the kinetics of LSM, since inflammation and necrosis increase rapidly and sometimes massively, but may revert with equal speed.

We evaluated 92 consecutive patients (mean age 41.8±16.3 years, 71.7% males) with symptomatic AH to assess how LSM was influenced by aetiology, and whether LSM kinetics correlated with the clinical course of AH. Twelve patients (13%) had …
Extralymphatic Tumors Prepare Draining Lymph Nodes to Invasion via a T-Cell Cross-Tolerance Process
Authors: Olivier Preynat-Seauve, Emmanuel Contassot, Prisca Schuler, Vincent Piguet, Lars E. French, Bertrand Huard
Journal: Cancer Research (2007)

Abstract Metastases often develop in lymphoid organs. However, the immunologic mechanism allowing such invasion is not known because these organs are considered to be hostile to tumor cells. Here, we analyzed the interactions between tumor cells and CD8+ T cells in such lymphoid organs. Tumor cells implanted into lymph nodes were able to induce tumor-specific cytotoxic CD8+ T-cell responses, conducting to tumor rejection, in contrast to primary extralymphatic tumors rapidly anergizing T cells in draining lymph nodes (DLN) via a cross-presentation process. This abortive CD8+ T-cell response to extralymphatic tumor is independent of the subcellular localization of antigen in tumor cells and is consistent with a lack of CD4+ T-cell help. Notably, this anergy was potent enough to allow successful DLN implantation of tumor cells. Such distant cross-tolerization of tumor-specific CD8+ T cells may be a determinant permissive event leading to invasion of DLN. In this situation, metastatic tumor cells do not need to down-regulate their immunogenicity to spread. [Cancer Res 2007;67(10):5009–16]
Natural Killer Cells Produce T Cell–Recruiting Chemokines in Response to Antibody-Coated Tumor Cells
Authors: Julie M. Roda, Robin Parihar, Cynthia Magro, Gerard J. Nuovo, Susheela Tridandapani, William E. Carson
Journal: Cancer Research (2006)

Abstract In the current report, we have examined the ability of natural killer (NK) cells to produce T cell–recruiting chemokines following dual stimulation with interleukin (IL)-2 or IL-12 and human breast cancer cells coated with an antitumor antibody (trastuzumab). NK cells stimulated in this manner secreted an array of T cell–recruiting chemotactic factors, including IL-8, macrophage-derived chemokine, macrophage inflammatory protein 1α (MIP-1α), monocyte chemoattractant protein 1, and regulated on activation, normal T-cell expressed and secreted (RANTES), whereas stimulation of NK cells with either agent alone had minimal effect. Furthermore, these factors were functional for T-cell chemotaxis as culture supernatants derived from costimulated NK cells induced migration of both naïve and activated T cells in an in vitro chemotaxis assay. T-cell migration was significantly reduced when neutralizing antibodies to IL-8, MIP-1α, or RANTES were added to culture supernatants before their use in the chemotaxis assay. In addition, coadministration of trastuzumab-coated tumor cells and IL-12 to mice led to enhanced serum MIP-1α. As a clinical correlate, we examined the chemokine content of serum samples from breast cancer patients enrolled on a phase I trial of trastuzumab and IL-12, and found elevated levels of IL-8, RANTES, IFN-γ inducible protein 10, monokine induced by IFN-γ, and MIP-1α, specifically in those patients that experienced a clinical benefit. Sera from these patients exhibited the ability to direct T-cell migration in a chemotaxis assay, and neutralization of chemokines abrogated this effect. These data are the first to show chemokine production by NK cells, specifically in response to stimulation with antibody-coated tumor cells, and suggest a potential role for NK cell–derived chemokines in patients receiving therapeutic monoclonal antibodies. (Cancer Res 2006; 66(1): 517-26)
Wound Chronicity, Inpatient Care, and Chronic Kidney Disease Predispose to MRSA Infection in Diabetic Foot Ulcers
Authors: Christopher Yates, Kerry May, Thomas Hale, Bernard Allard, Naomi Rowlings, Amy Freeman, Jessica Harrison, Jane McCann, Paul Wraight
Journal: Diabetes Care (2009)

OBJECTIVE To determine the microbiological profile of diabetes-related foot infections (DRFIs) and the impact of wound duration, inpatient treatment, and chronic kidney disease (CKD). RESEARCH DESIGN AND METHODS Postdebridement microbiological samples were collected from individuals presenting with DRFIs from 1 January 2005 to 31 December 2007. RESULTS A total of 653 specimens were collected from 379 individuals with 36% identifying only one isolate. Of the total isolates, 77% were gram-positive bacteria (staphylococci 43%, streptococci 13%). Methicillin-resistant Staphylococcus aureus (MRSA) was isolated from 23%; risk factors for MRSA included prolonged wound duration (odds ratio 2.31), inpatient management (2.19), and CKD (OR 1.49). Gram-negative infections were more prevalent with inpatient management (P = 0.002) and prolonged wound duration (P &amp;lt; 0.001). Pseudomonal isolates were more common in chronic wounds (P &amp;lt; 0.001). CONCLUSIONS DRFIs are predominantly due to gram-positive aerobes but are usually polymicrobial and increase in complexity with inpatient care and ulcer duration. In the presence of prolonged duration, inpatient management, or CKD, empiric MRSA antibiotic cover should be considered.
Protein kinase C. Its role in ischemic preconditioning in the rat.
Authors: M E Speechly-Dick, M M Mocanu, D M Yellon
Journal: Circulation Research (1994)

The present study investigated whether protein kinase C (PKC) plays a role in ischemic preconditioning in the rat heart. Chelerythrine, a specific antagonist of PKC, and 1,2-dioctanoyl-sn-glycerol (DOG), a diacylglycerol analogue and specific antagonist of PKC, were used to determine whether preconditioning could be blocked or triggered, respectively. Sprague-Dawley rats were anesthetized and instrumented for coronary occlusion and reperfusion. All animals were subjected to 45 minutes of regional ischemia (ISC) followed by 2.5 hours of reperfusion. The preconditioning protocol consisted of 5 minutes of ischemia and then 10 minutes of reperfusion. There were six groups: (1) control (group C, n = 5), (2) preconditioned and ISC (group PC, n = 6), (3) chelerythrine given 2 minutes before ISC (group CC, n = 5), (4) preconditioned and chelerythrine given 2 minutes before ISC (group PCC, n = 6), (5) DOG (dissolved in dimethylsulfoxide [DMSO]) given 10 minutes before ISC (group CD, n = 5), and (6) DMSO given 10 minutes before ISC (group DMSO, n = 3). The end point was infarct size measured using triphenyl tetrazolium chloride and expressed as a percentage of the volume at risk (I/R), measured with fluorescent particles. I/R was significantly reduced by preconditioning (group C, 58.6 +/- 5.0%; group PC, 32.7 +/- 6.3%; P &lt; .01) and by the PKC agonist DOG, which reduced I/R to a similar extent as preconditioning (group C, 58.6 +/- 5.0%; group CD, 28.0 +/- 7.0%; P &lt; .01).(ABSTRACT TRUNCATED AT 250 WORDS)
Radioiodine Therapy in Benign Thyroid Diseases: Effects, Side Effects, and Factors Affecting Therapeutic Outcome
Authors: Steen Joop Bonnema, Laszlo Hegedüs
Journal: Endocrine Reviews (2012)

Radioiodine ((131)I) therapy of benign thyroid diseases was introduced 70 yr ago, and the patients treated since then are probably numbered in the millions. Fifty to 90% of hyperthyroid patients are cured within 1 yr after (131)I therapy. With longer follow-up, permanent hypothyroidism seems inevitable in Graves' disease, whereas this risk is much lower when treating toxic nodular goiter. The side effect causing most concern is the potential induction of ophthalmopathy in predisposed individuals. The response to (131)I therapy is to some extent related to the radiation dose. However, calculation of an exact thyroid dose is error-prone due to imprecise measurement of the (131)I biokinetics, and the importance of internal dosimetric factors, such as the thyroid follicle size, is probably underestimated. Besides these obstacles, several potential confounders interfere with the efficacy of (131)I therapy, and they may even interact mutually and counteract each other. Numerous studies have evaluated the effect of (131)I therapy, but results have been conflicting due to differences in design, sample size, patient selection, and dose calculation. It seems clear that no single factor reliably predicts the outcome from (131)I therapy. The individual radiosensitivity, still poorly defined and impossible to quantify, may be a major determinant of the outcome from (131)I therapy. Above all, the impact of (131)I therapy relies on the iodine-concentrating ability of the thyroid gland. The thyroid (131)I uptake (or retention) can be stimulated in several ways, including dietary iodine restriction and use of lithium. In particular, recombinant human thyrotropin has gained interest because this compound significantly amplifies the effect of (131)I therapy in patients with nontoxic nodular goiter.
Scottish Green Paper
Authors: P. G. Gaskell
Journal: BMJ (1969)

ABCG2 is an ATP-binding-cassette (ABC) transporter that confers multidrug resistance (MDR) to tumor cells by extruding a broad variety of chemotherapeutic agents, ultimately leading to failure of cancer therapy. Thus, the down-regulation of ABCG2 expression and/or function has been proposed as part of a regimen to improve cancer therapeutic efficacy. In this study, we found that a group of xanthines including caffeine, theophylline, and dyphylline can dramatically decrease ABCG2 protein in cells that have either moderate (BeWo, a placental choriocarcinoma cell line) or high (MCF-7/MX100, a breast cancer drug-resistant cell subline) levels of ABCG2 expression. This down-regulation is time-dependent, dose-dependent, and reversible. Using lysosomal inhibitors, we found that xanthines decreased ABCG2 by inducing its rapid internalization and lysosome-mediated degradation. As a consequence, caffeine treatment significantly increased the retention of an established ABCG2 substrate in MCF-7/MX100 cells but not in parental MCF-7 cells and sensitized the MDR cells to the chemotherapeutic agent mitoxantrone (MX); combination treatment with MX and caffeine decreased the IC<sub>50</sub> of MX ∼10-fold and induced a greater degree of apoptotic cell death than MX treatment alone. Taken together, our results describe a novel function for this large class of therapeutically relevant compounds and suggest that a subset of xanthines could be developed as combination therapy to improve the efficacy of anticancer drugs that are ABCG2 substrates.