tbuckley/cabot-search huggingface dataset:
Immune Complexes and the Evolution of Lyme Arthritis
Authors: John A. Hardin, Allen C. Steere, Stephen E. Malawista
Journal: New England Journal of Medicine (1979)

In a prospective study of 78 patients with Lyme arthritis, abnormal serum C1q binding activity was present at the initial onset of erythema chronicum migrans in nearly all cases. The abnormal binding persisted in patients with subsequent nerve or heart involvement. In contrast, among those with only subsequent arthritis, it usually disappeared within three months (P = 0.018). However, in the synovial fluid of affected joints, abnormal binding was uniformly present, and always to a greater extent than in the circulation. The abnormally reactive material behaved like antigen-antibody complexes. It had a density of 19S or greater, dissociated below pH 4.2, and lacked antiglobulin activity. Cryoprecipitates containing immunoglobulin were good but insensitive predictors of its presence, but immune complexes themselves did not seem primarily responsible for cryoprecipitability. Thus, as judged by C1q binding, immune complexes remain disseminated in certain patients with Lyme arthritis but localize to joints in others. (N Engl J Med 301:1358–1363, 1979)
Abstract PD05-04: Targeted resequencing in oncogenetics: developing a new approach for molecular diagnostics
Authors: N Sevenet, D Lafon, J Dupiot-Chiron, C Hubert, N Jones, M Debled, C de Lara Tunon, M Longy, F Bonnet
Journal: Cancer Research (2012)

Abstract Introduction: Next-generation sequencing (NGS) appears to be an accurate tool adapted for molecular oncogenetics. In contrast to certain somatic mutations, a lack of germline mutation hotspots in genes involved in cancer predisposition syndromes, especially hereditary breast and ovarian cancer (HBOC), force the molecular biologist to screen the entire coding sequence. Material &amp; methods: In order to screen a panel of genes predominantly involved in HBOC &amp; Cowden disease in a molecular diagnostic setting, we captured 408 exons (and their surrounding intronic sequences) of 25 genes using the SureSelect oligonucleotide library capture (Agilent technologies). The bioinformatics resources Earray (Agilent technologies), Ensembl human genome v62 and UCSC repeat masker were used to create the capture design. This gave us 2899 unique 120-mers oligonucleotide probes which were duplicated 19 to 38 times depending on the GC content or the size of the targeted regions. Germline DNA of 190 patients (40 with previously identified mutations and 150 without previous molecular genetic analysis) was sequenced using a MiSeq bench top next-generation sequencer (Illumina) and in parallel was analyzed using our current screening method (EMMA, Enhanced Mismatch Mutation Analysis, similar to high resolution melting). Samples were prepared according the manufacturer's recommendations (Agilent technologies). Results: All previously identified mutations along with 33 mutations in previously unscreened patients were detected. In addition, more than five hundred variants described as polymorphisms were identified. NGS seems to be more sensitive than our current screening method due to its detection and identification of homozygous variants. In order to limit the interpretation time, we restricted sequence analysis to the exon, −50 bp (including the acceptor splice site of the upstream intron) and +50 bp (including the donor splice site of the downstream intron). We have validated NGS as a technique adapted for germline mutation screening in oncogenetics. From the beginning of 2013, all germline DNA samples will be screened by NGS for oncogenetic molecular diagnostics. Sample preparation, technical organization, bioinformatics workflow and comprehensive results will be presented. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD05-04.
Case 4-2000
Authors: Lawrence J. Brandt, Eugene J. Mark
Journal: New England Journal of Medicine (2000)

Presentation of CaseA 64-year-old man was admitted to the hospital because of hyperadrenocorticism.The patient had a history of angina pectoris and had undergone five-vessel coronary-artery bypass surgery nine years before admission. He had long-standing heartburn, and for two years had had intermittent upper abdominal pain that responded to ranitidine. The results of upper gastrointestinal endoscopy were normal. Six months before admission, he began to bruise easily; weakness, emotional lability, moon facies, and peripheral edema developed; and his weight increased by 5 kg. Three months before admission, a tremor developed in his hands. One month later, bouts of tachycardia . . .
Abstract LB-11: Reduced cardiotoxicity and improved antitumor effect of the epirubicin-incorporating micelle NC-6300 in a hepatocellular carcinoma model
Authors: Yoshiyuki Yamamoto, Ichinosuke Hyodo, Amane Takahashi, Masahiro Yasunaga, Yoshikatsu Koga, Mitsunori Harada, Hiroyuki Saito, Ryosuke Tanaka, Tatsuyuki Hayashi, Yasuki Kato, Yasuhiro Matsumura
Journal: Cancer Research (2012)

Abstract Background: Epirubicin, an anthracycline antitumor drug, has been approved for the treatment of various human tumors. However, epirubicin has significant dose-limiting cardiotoxicity, and there are no effective therapies to prevent or reduce this cardiotoxicity. Therefore, we investigated whether the epirubicin-incorporating micelle NC-6300 was more effective than epirubicin alone in reducing cardiotoxicity and improving the antitumor effect. Method: NC-6300 comprises epirubicin covalently bound to the polyaspartate chain of the polyethylene glycol-polyaspartate block copolymer via an acid-labile hydrazone bond. The conjugate spontaneously forms a micellar structure in an aqueous milieu. The diameter of NC-6300 is 60-70 nm, and the micellar formulation is stable under physiological condition. For evaluating the antitumor effects, NC-6300 (10 or 15 mg/kg) and epirubicin (10 mg/kg) were intravenously administered once a week for 3 weeks to C57BL/6 mice bearing human hepatocellular carcinoma (HCC) Hep3B xenografts implanted subcutaneously or orthotopically (n = 6-10). Cardiotoxicity was evaluated by using echocardiography to the mice that were given NC-6300 (10 or 15 mg/kg) or epirubicin (10 mg/kg) on days 1, 8, and 15 every 4 weeks, to a total of 9 administrations for 12 weeks (n = 6 for each evaluation point). Results: Compared to epirubicin, NC-6300 showed significant antitumor activity against Hep3B. Moreover, the survival rate in the orthotopic tumor model of Hep3B was significantly higher with NC-6300 treatment than with epirubicin treatment. With respect to cardiotoxicity, epirubicin-treated mice showed significantly deteriorated fractional shortening (FS) and ejection fraction (EF) 21 days after the beginning of administration. In contrast, no mice treated with NC-6300 experienced cardiotoxicity in terms of EF or FS during the observation period. Conclusion: The findings of this study imply that NC-6300 has a strong antitumor effect against HCC. Furthermore, NC-6300 significantly reduces the cardiotoxicity of epirubicin and warrants a clinical evaluation in patients with advanced solid tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-11. doi:1538-7445.AM2012-LB-11
Uncertainty about the value of quantum probability for cognitive modeling
Authors: Christina Behme
Journal: Behavioral and Brain Sciences (2013)

Abstract I argue that the overly simplistic scenarios discussed by Pothos &amp; Busemeyer (P&amp;B) establish at best that quantum probability theory (QPT) is a logical possibility allowing distinct predictions from classical probability theory (CPT). The article fails, however, to provide convincing evidence for the proposal that QPT offers unique insights regarding cognition and the nature of human rationality.
Abstract 5246: Use of γH2aX and other biomarkers to quantify distribution of drug activity in solid tumors
Authors: Jasdeep K. Saggar, ian F. tannock
Journal: Cancer Research (2012)

Abstract Background: The disorganized vasculature within solid tumors leads to decreased drug delivery and poor penetration of drugs from blood vessels to the tumor cells. Our laboratory has used quantitative immunohistochemistry (IHC) to show limited intratumoral distribution of the auto-fluorescent drugs doxorubicin and mitoxantrone. Most anti-cancer drugs are not fluorescent and do not have antibodies that recognize them; there is a need for biomarkers that can be used to quantify their distribution and efficacy in different regions of solid tumors. The aim of the present study was to characterize the spatial distribution within solid tumors of biomarkers of drug effect that can be used to test drug efficacy. Methods: Cleaved caspase 3 (a marker of apoptosis), γH2aX (a marker of DNA damage) and Ki67 (a marker of cell proliferation) were quantified in tumor sections in relation to blood vessels (recognized by CD31) using monoclonal antibodies and IHC. To validate the use of these biomarkers we compared their time-dependent distribution with (i) the distribution of auto-fluorescent doxorubicin and (ii) the distribution of a fluorescent monoclonal antibody that detects melphalan-induced DNA adducts. The biomarkers were then used to study the distribution of docetaxel in relation to tumor blood vessels. Results: The distributions of doxorubicin in MCF7 &amp; MDA-MB-231 xenografts and of melphalan-induced DNA adducts in MCF-7 &amp; EMT-6 tumors decreased exponentially with increasing distance from tumor blood vessels; they were similar to the distribution of γH2aX at 10 minutes after injection of these drugs. The distributions of cleaved caspase 3 and of change in Ki-67 at 24 hours following treatment also mirrored the distribution of the drugs. The distribution of these biomarkers following injection of docetaxel also showed a sharp decrease in drug activity with increasing distance from tumor blood vessels in solid tumors (MCF-7, PC-3 &amp; A431). Conclusions: Activation of γH2aX occurs within 10 minutes after injection of several drugs and is the preferred biomarker for studying distribution of drug activity in tumors. There is heterogeneity of activity of many anticancer drugs in solid tumors, with rapid decrease in activity with increasing distance from tumor blood vessels. Poor distribution of drugs to cells within tumors is an important cause of drug resistance. Supported by a research grant from the Canadian Institutes of Health Research Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5246. doi:1538-7445.AM2012-5246
Abstract 2665: Impact of structural modifications on bioactivity and metabolic stability of indirubins
Authors: Gerhard Eisenbrand, Xinlai Cheng, Jochen Zeller, Karl-Heinz Merz
Journal: Cancer Research (2010)

Abstract Indirubins are potent inhibitors of a series of protein kinases. They induce cell cycle arrest in G1/S and/or G2/M followed by apoptosis and potently inhibit proliferation of human tumor cells. However, most indirubins are extremely poorly soluble in solvents, resulting in a low bioavailability. Furthermore, they are prone to deactivating metabolic transformations. As reported previously1, incubation of 5-methylindirubin (E224) with bovine and rat liver microsomes in the presence of a NADPH-generating system resulted in the formation of two main hydroxylated metabolites, 6-hydroxy- and 6,7′-dihydroxy-5- methyl-indirubin. The antiproliferative activity of the former metabolite was decreased, the activity of the latter was abrogated nearly completely. To improve metabolic stability and solubility, novel indirubins were synthesized: 7′-Aza-5-methylindirubin (E844), N,N-dimethylaminophenyl indirubin-5-carboxamide (E744), and indirubins carrying a hydrophilic N-methylpiperazinoethyl group attached to the indirubin core by a 5-carboxamide anchor (E748) or by a 3′-oxime ether link (E857). Compounds were in vitro incubated with liver microsomes (rat and bovine) and metabolites formed were isolated and analyzed. The main metabolites of E844 were identified to be 7′-aza-5-methyl-6-hydroxy-indirubin and 7′-aza-5-hydroxymethyl-indirubin. From incubations of E748, the 7′-hydroxy derivative was isolated as main metabolite and structurally elucidated by 1H-NMR. In contrast to E748 with an N-methylpiperazinoethyl side chain, E744 did not appear to undergo appreciable metabolic transformation. Moreover, E857 and its water soluble hydrochloride (E857a) were found not to be hydroxylated at the respective bisindole positions. Instead, the main biotransformation of E857 occured in the side chain leading to the corresponding N-methylpiperazinoethyl-N-oxide metabolite. The structure was confirmed by synthesis. E857a was found to carry a hydroxylated methylpiperazino group after incubation. In summary, deactivating metabolic transformation of indirubins is decreased by variation of the electron density of the heterocyclic aromatic system. Furthermore, attachment of appropriate substituents at position 3′ directs metabolic transformation into the side chain of such substituents that ensure improved water solubility, bringing about increased metabolic stability of the pharmacophore. 1 AACR Annual Meeting 2007 abstr. #3957 Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2665.
Novartis wined and dined doctors at 80 000 “sham events” to increase prescribing, US alleges
Authors: Owen Dyer
Journal: BMJ (2016)

The drug company Novartis is fighting a demand from US attorneys for thousands of documents detailing 80 000 events in which doctors allegedly received money and expensive meals as kickbacks for prescribing the company’s drugs and billing various public payers.

The government has claimed that, from 2002 until at least January 2011, thousands of meetings that Novartis described as speaker programs were really just paid entertainment for small groups of physicians, at which clinical issues were discussed only cursorily or not at all. Slide shows, which are mandated by company policy on speaker programs, often were not shown or were sharply curtailed.

“Novartis simply wined and dined the doctors at high end restaurants with astronomical costs, as well as in sports bars, on fishing trips, and at other venues not conducive to an educational program,” US attorneys alleged. Company and industry ethics rules limiting spending on meals were routinely violated, they said, and sales workers who broke the rules were never meaningfully punished and were often promoted.

The …
P720Notch3 is an important mediator of cardiac adaptation to pressure overload
Authors: H Ragot, R Merval, M Baudet, L Fazal, E Polidano, C Delcayre, C Chatziantoniou, J-L Samuel
Journal: Cardiovascular Research (2014)

Notch3, a receptor expressed in vascular smooth muscle cells (VSMC) and pericytes, has a key role in the integrity of resistance arteries by controlling the maturation of VSMC and the arterial differentiation. The goal of the study was to decipher the role of Notch3 in the normal heart and in the response to pressure overload.
The Patient Experience and Health Outcomes
Authors: Matthew P. Manary, William Boulding, Richard Staelin, Seth W. Glickman
Journal: New England Journal of Medicine (2012)

Interview with Susan Edgman-Levitan on patient-experience measures and their relationship to health outcomes. (00:00)Download Despite criticism of patient-satisfaction measures, patient-experience surveys that are designed and administered appropriately provide robust measures of the quality of health care and offer insight into a dimension that's otherwise difficult to measure objectively.
AB0330 Characteristics of a moderate rheumatoid arthritis patient population who lost remission or low disease activity: Data from the consortium of rheumatology researchers of north america, INC. (CORRONA)
Authors: S. Kotak, A. Koenig, D. Collier, K. Saunders, P. He, J. Kremer, G. Reed
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Studies on patients with severe rheumatoid arthritis (RA) are widely reported. However, limited data are available on patients with moderate disease activity (MOD). Recent evidence, including data from the PRESERVE trial (1), have highlighted the disease burden in MOD patients, and further warrant an understanding of this patient population from longitudinal clinical registries. <h3>Objectives</h3> To describe the demographics and disease burden of patients enrolled in the CORRONA database that lose remission or low disease activity (LDA) and move to MOD. <h3>Methods</h3> Patients enrolled in CORRONA (a large US multicenter, longitudinal database of RA patients) from March 2002 through January 2012, aged ≥18 years, who moved from LDA (CDAI≤10) to MOD (10&lt;10CDAI&lt;22) were analyzed. Demographic, clinical, disease burden and descriptive changes between the last LDA visit and first Mod visit from LDA were reported. <h3>Results</h3> 7,166 out of 22,496 (32%) RA patients moved from LDA to MOD; of these 41% (2,960/7,166) were on a biologic. The median time between LDA and MOD visit is 4 months (IQR: 3-6 months). MOD patients had clinically relevant increase in CDAI (∼9 points) and ∼1.2 increase in DAS28 scores. Clinically important worsening (&gt;10 points) were reported in patient global, physician global and pain assessments in MOD patients. <h3>Conclusions</h3> RA patients from a longitudinal clinical registry who progressed from LDA to MOD had predictably higher disease burden, in addition to worsening function; however had lower smoking and little difference in employment rates. In spite of prior DMARD (non-biologic and biologic) use, 32% patients progressed to MOD within 6 to 15 months of LDA. Future work should assess change over time in clinical and patient reported outcomes between cohorts of stable and progressive LDA patient populations, in longitudinal registries to assess the impact of biologic therapy on moderate RA patients. <h3>References</h3> Smolen JS, Pavelka K, Nash P, Miranda P, Freundlich B, Hammond C, Vlahos B, Pedersen R, Koenig AS. Impact of etanercept-methotrexate therapy on disease activity and radiographic progression in moderately active rheumatoid arthritis: Interim results from the PRESERVE trial. Ann Rheum Dis. 2011;70(Suppl 3):710. <h3>Disclosure of Interest</h3> S. Kotak Shareholder of: Pfizer, Employee of: Pfizer, A. Koenig Shareholder of: Pfizer, Employee of: Pfizer, D. Collier Shareholder of: Amgen, Employee of: Amgen, K. Saunders Employee of: CORRONA, P. He: None Declared, J. Kremer: None Declared, G. Reed Grant/Research support from: CORRONA, Consultant for: CORRONA, Employee of: University of Massachusetts Medical School, Paid Instructor for: Harvard Medical School
IMPACT OF ULTRASOUND FOLLOW-UP TO MANAGE IN-STENT RESTENOSIS IN FEMOROPOPLITEAL ARTERY
Authors: Atsushi Tosaka, Yoshimitsu Soga, Seiichi Hiramori, Kimihiro Osada, Akira Miyabe, Ryuma Ishihara, Yuriko Sato, Taisuke Mizumura, Yoichi Sugimura
Journal: Journal of the American College of Cardiology (2016)
PTU-108 Crohn’s Disease And Anogenital Granulomatosis Presenting With Genital Oedema
Authors: R Mellor, K Gordon, P Mortimer, R Pollok
Journal: Gut (2014)

<h3>Introduction</h3> Anogenital granulomatosis (AGG) is a recently recognised cause of genital lymphoedema<sup>1–3 </sup>an association of CD with AGG has been noted in previous case reports.<sup>1,3</sup> It presents with genital erythema and swelling, and flares are frequently misdiagnosed as cellulitis. We present a large case series. <h3>Methods</h3> Patients were identified from referrals to the regional to the Lymphoedema Service at St George’s Hospital after failure of antibiotics and topical steroids to improve symptoms. Demographic, clinical and endoscopic finding were correlated in patients with histological features of AGG in patients. <h3>Results</h3> Sixteen patients (15 male, 1 female; aged 34.8 ± 15.0 yr (mean ± s.d.)), were referred with AGG. 14 of 16 patients initially presented with genital swelling whilst 2 others presented with buttock swelling. Swelling of additional sites was noted in several patients (mons pubis – 25% of patients; natal cleft – 25%; peri-anally – 19%; buttocks – 12.5%). Although initially intermittent (15/16 patients), genital swelling was typically well established and irreversible by the time of presentation to the Lymphoedema Clinic. Flares involved erythema and deterioration of swelling which failed to return to baseline. Established swelling was associated with an increased risk of cellulitis in addition to the non-cellulitic flares. Histological examination of the affected areas demonstrated dermal (and one case of intra-lymphatic) non-caseating granulomas in 12 patients with the remainder diagnosed clinically. Gastroenterology review, including colonoscopy, confirmed a diagnosis of Crohn’s disease in 37.5% of patients. Treatment of AGG has proven difficult. Initial treatment with compression garments and prednisolone showed a reduction (but not elimination) of scrotal and penile shaft swelling in 9/11 patients. Antibiotics reduced the frequency of flares in only 3/11 patients. Steroid-sparing immunosuppression was successful in 4/11 patients. In 6 patients, lymphoedema of the foreskin caused difficulties in micturition and therefore circumcision was successfully utilised to improve urinary flow. Debulking surgery has been used in only a small number of our cases to date. <h3>Conclusion</h3> AGG should be considered in all patients (especially male) presenting with isolated genital lymphoedema and may unusually be the presenting feature of Crohn’s disease. Early diagnosis allows for prompt initiation of systemic immunosuppression therapy which is currently the treatment of choice. We hypothesise that swelling is precipitated by non-infective granulomas blocking lymphatic vessels, research in this regard is in progress. <h3>References</h3> Van de Scheur <i>et al</i>.<i> Eur Acad Dermatol Venereol</i>. 2002;17:184–9 Saracino <i>et al</i>. <i>Aus J Dermatol</i>. 2012;Epub Gordon <i>et al</i>. <i>Int J STD AIDS</i>. 2013;Epub <h3>Disclosure of Interest</h3> None Declared.