tbuckley/cabot-search huggingface dataset:
Abstract 4104: Protease-activated receptor 2, a KLK14 target in colon cancer cells
Authors: Valérie Gratio, Céline Loriot, Katerina Oikonomopoulou, Hyunjae Chung, Eleftherios P. Diamandi, Morley D. Hollenberg, Dalila Darmoul
Journal: Cancer Research (2010)

Abstract Serine proteinases signal through proteinase-activated receptors (PARs). Our studies have implicated PAR1 and PAR4 (thrombin receptors) and PAR2 (trypsin receptor) in human colon cancer growth. However, endogenous activators of PARs in colon tumors are still unknown. Recently, members of the kallikrein-related peptidase (KLK) family have been shown to activate PARs in many cell systems. Thus, our aim was to determine if KLK14, a KLK family member, is expressed in colonic tumors and to see if this KLK can activate PARs in human colon cancer cells. The presence of KLK14 in colon cancer cell lines was assessed by RT-PCR, ELISA and immunofluorescence, and its expression in human colonic tissue was assessed by immunohistochemistry. The effects of recombinant KLK14 in parallel with PAR1/2 agonists (SFLLRN-NH2, an activating peptide for both PAR1 and PAR2; TFLLR-NH2, a selective activating peptide for PAR1 and the selective PAR2 agonists, 2-furoyl-LIGRLO-NH2; SLIGRL-NH2) were assessed for calcium flux, receptor internalization and ERK1/2 phosphorylation in a human colon cancer-derived HT29 cell line that expresses PAR1 and PAR2. We found that: a) KLK14 mRNA (RT-PCR) was present in 16 out of 16 human colon cancer cell lines, b) KLK14 protein is present (ELISA) in HT29 conditioned media and other colon cancer cell lines; c) there was strong staining of KLK14 in the cytoplasmic compartment of HT29 cells and of human colonic tumors (immunofluorescence and immunohistochemistry; paraffin sections) d) KLK14 (0.1 µM) caused prompt increases in intracellular calcium ([Ca2+]i) in HT29 cells (Microspectrofluorimetry with Fura 2/fluo-3). The KLK14-induced Ca2+-flux was abrogated after an initial challenge of the cells with SFLLRN-NH2 (100 µM), which desensitizes PAR1 and PAR2 simultaneously. Desensitization with 2-furoyl-LIGRLO-NH2 (10 µM) a potent PAR2 agonist, attenuated most of the Ca2+ flux induced by KLK14, whereas responses to TFLLR-NH2, the PAR1 agonist, were minimally affected. Consistently, a first challenge with thrombin did not affect KLK14-induced Ca2+ flux. These results strongly suggest that KLK14 activates preferentially PAR2 in HT29 cells. e) KLK14 initiates a dramatic loss of cell surface PAR2 (microscopic analysis) due to its internalization and f) KLK14 induces a rapid (within 5-10 min) and significant ERK1/2 phosphorylation in HT29 cells. This KLK14-PAR signaling pathway may represent a novel therapeutic target for colon tumorigenesis. 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 4104.
P327 PROFILING NEW BIOMARKERS FOR THE DIAGNOSIS OF DRUG INDUCED LIVER NECROSIS. A PILOT STUDY ASSESSING PERFORMANCE OF CLEAVED OR FULL-LENGTH CYTOKERATIN 18, AND MICRO-RNA-122
Authors: H. Perazzo, C. Tse, M. Munteanu, A.D.K. Fankem, F. Imbert-Bismut, L.B. Casals, C. Corpechot, F. Charlotte, V. Ratziu, O. Chazouilleres, C. Housset, B. Hainque, T. Poynard
Journal: Journal of Hepatology (2014)
Abstract P4-11-14: Pulsed Reduced Dose-Rate Radiotherapy: A Re-Irradiation Strategy for Breast Cancer Patients with Brain and Spinal Cord Metastasis
Authors: SP Howard, GM Richards, HI Robins, PM Mahler, TA. Wolfgang
Journal: Cancer Research (2010)

Abstract Background: Radiotherapy delivered at reduced dose-rates has the potential to preferentially reduce normal tissue toxicity, while still yielding almost identical tumor cell kill due to the superior repair capacity of late responding normal tissue. In conventional radiotherapy a 2 Gy dose is delivered at a dose-rate of 4-6Gy/min. A reduced dose-rate can be obtained by dividing a standard treatment fraction into a number of sub-fractions delivered in a pulsed manner separated by a fixed time interval. This increases the overall treatment time, allowing normal tissue repair during these sessions. Radiobiological modeling shows that a 2 Gy fraction can be delivered in a series of 0.2 Gy pulses separated by 3-minute intervals, creating an effective dose-rate of 0.0667 Gy/min. We have termed this re-irradiation technique pulsed reduced dose-rate radiotherapy (PRDR).* Methods: Between November 2000 and April 2010, 21 previously irradiated and heavily pretreated patients (pts) with progressive metastatic breast cancer were re-irradiated with PRDR to the whole brain (WB) (15) or spinal cord (SC) (6). The mean prior RT dose to the whole brain was 34.5 Gy (range 30-40 Gy) and the spinal cord was 39.9 Gy (range 30-50 Gy). A mean PRDR dose to the WB of 27.8 Gy (range 18-36 Gy) and SC of 31.3 Gy (range 28-40 Gy) was delivered in 1.8 or 2.0 Gy per fraction. Results: Mean overall survival (OS) of pts treated to the WB was 5.9 months (M) (range 0.5-21.3 M) and for pts treated to the SC was 18.9 M (range 5.6-43 M); 2 pts remain alive as of this report. Treatment was well tolerated: no grade 4 or 5 acute toxicities or grade 3 or 4 late toxicities were observed. Despite a mean cumulative dose of 64.9 Gy (range 54-80 Gy), there was no clinical or radiographic evidence of radionecrosis and/or neurological sequela. There appeared to be a correlation between KPS and OS. Conclusions: PRDR is a well-tolerated and effective radio-therapeutic method for the treatment of breast cancer patients with progressive metastatic CNS disease that have received prior radiotherapy. * Reirradiation of Large-Volume Recurrent Glioma with Pulsed Reduced- Dose-Rate Radiotherapy. Adkison JB, Tome W, Seo S, Richards GM, Robins HI, Rassmussen K, Welsh JS, Mahler PA, Howard SP. Int J Radiat Oncol Biol Phys. 2010 May 14. [Epub ahead of print] PMID: 20472350 Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-11-14.
THU0481-HPR Lessons from patient reported outcomes of biologic treatment: Improvements in quality of life and health status are stable over time despite declining physical function
Authors: T. Harrison, C. Barnabe, L. Martin, S.G. Barr
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Patient reported outcomes are an important aspect of outcome evaluation, and supplement the argument for the necessity of these therapies. <h3>Objectives</h3> To evaluate improvements in RA treated biologic patients’ reported function, quality of life and health status over the course of treatment. <h3>Methods</h3> The Alberta Biologics Pharmacosurveillance Program captures the clinical efficacy and safety of biologic therapies in RA since 2000. HAQ scores, SF-36 and the EQ-5D are completed every six months. <h3>Results</h3> Our cohort includes 605 patients (74% female, mean age 43 years). Mean disease activity at baseline was: DAS28 5.73, patient global score 6.8, TJC 4.4 and SJC 3.2. Improvement in the 8 domains of the SF-36 occurred over the first year of treatment and stabilized thereafter (Figure 1). A similar trend occurred in the 5 domains of the EQ-5D. HAQ scores showed improvement in the first year of therapy (mean baseline HAQ 1.59, HAQ at 1 year 0.76), followed by stabilization but began to rise again after 4 years (mean HAQ at 7 years 0.96). <h3>Conclusions</h3> Health status and quality of life significantly improve with biologic therapy, with the most impressive benefit in the first year of therapy followed by a period of stabilization lasting over 11 years. The worsening of physical function after 4 years is not associated with deterioration in other domains, which is unexpected. <h3>Disclosure of Interest</h3> None Declared
THE RATIO OF ENDOCARDIAL LONGITUDINAL STRAIN JUST AFTER EXERCISE STRESS TO THAT AT REST IS USEFUL IN DETECTING FUNCTIONAL MYOCARDIAL ISCHEMIC SEGMENTS IN STABLE PATIENTS WITH CORONARY ARTERY DISEASE
Authors: Takeshi Nishi, Nobusada Funabashi, Koya Ozawa, Masayuki Takahara, Hiroyuki Takaoka, Yoshihide Fujimoto, Yoshio Kobayashi
Journal: Journal of the American College of Cardiology (2016)
P1-11-10: Quality of Breast Cancer Care in a Boston Area Patient Navigator Program.
Authors: A Raj, N Ko, T Battaglia, B Moy
Journal: Cancer Research (2011)

Abstract Background: Elimination of disparities is critically important for lessening the burden of cancer. Patient navigator programs (PNPs) assist with all aspects of care, including access, cancer prevention, screening, post-diagnosis care, and survivorship care. Little is known about the effect of PNPs on patient care and outcomes following the diagnosis of breast cancer (BC). We examined quality measures (QMs) of breast cancer care among women participating in the Massachusetts General Hospital Avon Breast Care Patient Navigator Program (MABCP), which provides patient navigation services to disadvantaged minority communities in the greater Boston area. Methods: Women diagnosed with BC who participated in the MABCP from 2001 to 2011 were followed to determine the proportion whose care was concordant with American Society of Clinical Oncology/National Comprehensive Cancer Network (ASCO/NCCN) QMs. QMs included 1) hormonal therapy (HT) within 1 year of diagnosis for HR+ tumors &amp;gt; 1 cm; 2)chemotherapy within 120 days of diagnosis of HR- &amp;gt;1cm tumors for women &amp;lt;70 years; and 3) post-lumpectomy radiation therapy (XRT). Descriptive statistics were used to report characteristics of MABCP patients. Results: Of the 186 MABCP patients diagnosed with BC, some treatment data was available on 158 (85%) and race/stage information was available on 149 (80%) [Table 1]. Among the MABCP patients, concordant care was received by 70/74 (95%) for the HT QM, 15/17 (88%) for the chemotherapy QM, and 65/71 (92%) for the XRT QM. In comparison, available benchmark concordance rates of BC patients treated at 8 NCCN centers from 2003–6 are: 340/382 (89%) for the HT QM, 156/179 (87%) for the chemotherapy QM, and 141/148 (95%) for the XRT QM. Conclusions: Overall, breast cancer care in the MABCP PNP is concordant with published ASCO/NCCN quality measures. At present, the sample is insufficient to compare concordance rates with NCCN patients but preliminarily, it appears that the quality of care is comparable. Future research should include prospective analyses of quality metrics to assess the process and outcomes of patient navigation in diverse settings, compared with control populations. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-11-10.
Martyrdom's would-be myth buster
Authors: Scott Atran
Journal: Behavioral and Brain Sciences (2014)

Abstract Lankford overgeneralizes individual psychology from limited, fragmentary and doubtful materials, and underplays strategic, ideological, and group dynamical factors. His speculative claims manifest a form of fundamental attribution error: the tendency – especially evident in popular attachment to moral presumptions of individual responsibility and volition – to overestimate effects of personality and underestimate situational effects in explaining social behavior. The book's appeal may owe more to ideological preference than to interests of science or national security.
Tendances temporelles du taux de détection des adénomes colorectaux en population générale
Authors: V Cottet, AM Bouvier, V Jooste, C Michiels, C Bonithon-Kopp, J Faivre
Journal: Endoscopy (2008)

Introduction: La détection des adénomes permet d'envisager la prévention secondaire du cancer colorectal. Au cours des dernières décennies, l'offre de soins et les techniques endoscopiques ont progressé mais leur influence sur le taux de détection des adénomes colorectaux n'est pas connue.
OP05 Medium term outcome of de novo autoimmune hepatitis after liver transplantation in children; a single centre experience
Authors: M Hii, A Grammatikopoulus, N Hadzic, M Rela, G Mieli-Vergani, D Vergani
Journal: Gut (2010)

Introduction  Post-transplant de novo autoimmune hepatitis (dn-AIH) is a cause of late graft dysfunction characterized by hypergammaglobulinemia, elevated titres of serum auto-antibodies, histological features of chronic hepatitis with portal and periportal inflammation with lymphocytes and plasma cells, and clinical response to the treatment for classical autoimmune liver disease with steroids and azathioprine (aza) or mycophenolate mofetil (MMF).  Aim  To establish the prevalence and the medium term outcome of dn-AIH.  Method  Retrospective review of case notes of patients who were diagnosed with dn-AIH since the initial case description in 1995 to date.  Results  Thirty children (17, 57% female) were diagnosed using the above criteria. Overall incidence was around 5 %. The aetiologies leading to liver transplant (LT) were: biliary atresia (16), Alagille syndrome (3), alpha 1-antitrypsin deficiency (3), progressive familial intrahepatic cholestasis (2), glycogen storage disease type 1b (2), familial hypercholesterolemia (1), non-A-E hepatitis (1), Crigler-Najjar syndrome type 1 (1) and cryptogenic end-stage liver disease (1). Four (13.3%) patients received whole grafts, while the remainder received segmental grafts, including 2 (6.7%) auxiliary and 4 (13.3%) living-related grafts. The median age at diagnosis of dn-AIH was 11.2 years (range, 2.6–19.3). The median post-LT interval to develop dn-AIH was 4.1 years (range, 0.2–11.0). The median follow up after diagnosis of dn-AIH was 8.2 years (range, 0.3–14.8). Auto-antibodies detected included ANA (n=21), SMA (n=20), anti-mitochondrial antibody (n=4), anti-LKM (n=2) and anti-liver cytosol-1 (n=1). Immunosuppressive regimens at the time of dn-AIH diagnosis included: CyA/aza/pred (9), Tac/aza/pred (6), Tac/MMF/pred (6), CyA/MMF/pred (4), and Tac/pred (5). Dn-AIH was treated with increased dose of steroids and increased dose or addition of aza or MMF. Eleven (36.7%) patients did not adhere to medications during follow up. Of these, 10 (33.3%) developed chronic liver failure (CLF) and 6 (20%) required re-LT, after a median period of 5.8 years. Two (6.7%), including a non-adherent child, died with multiorgan failure after re-LT for CLF. Of 4 further children with CLF, 3 (10%), all with history of non-adherence, are currently listed for re-LT, while one (3.3%) is stable. Twenty patients (66.6%) have no evidence of graft dysfunction.  Conclusion  The medium-term prognosis of dn-AIH is severe in a considerable proportion of patients and is determined by adherence to medications.
Penicillin and the Marked Decrease in Morbidity and Mortality from Rheumatic Fever in the United States
Authors: B F Massell, C G Chute, A M Walker, G S Kurland
Journal: New England Journal of Medicine (1988)

There has been a marked decline in mortality due to rheumatic fever in the United States. We present evidence for the important role of penicillin in changing the severity of rheumatic carditis, beginning about 1946. Since that year, mortality due to rheumatic carditis has rapidly decreased to zero at the hospital we studied (House of the Good Samaritan, Boston), the rate of loss of all murmurs in patients at the study hospital accelerated simultaneously and exceeded 40 percent by 1970, and the rates of decline in national mortality due to rheumatic carditis accelerated fourfold with the advent of antibiotics. These data, together with reports of recent outbreaks of rheumatic fever, emphasize the importance of continued efforts to diagnose and treat Group A streptococcal pharyngitis. (N Engl J Med 1988; 318:280–6.)
Abstract 2864: Targeting cathepsin S induces tumor cell autophagy via the EGFR-ERK signaling pathway
Authors: Kuo-Li Chen, Wun-Shaing Wayne Chang, Chun-Cheng Lin, Chun-Hei Antonio Cheung, Chang-Po Kuo, Ching-Chuan Kuo, Yi-Hsun Chang, Ko-Jiunn Liu, Jang-Yang Chang
Journal: Cancer Research (2011)

Abstract Cathepsin S is a vital cellular cysteine protease that is frequently amplified and over-expressed in various human cancers. In this study, we report that targeting cathpesin S could induce tumor cell autophagy via the EGFR-ERK signaling pathway. Cancer cells treated with cathepsin S inhibitors [α-ketoamide inhibitor (6r), Z-FL-COCHO (ZFL)] and cathepsin S-specific siRNA induced autophagy as indicated by an increase in the cleavage of the microtubule-associated protein light chain 3B (LC3B) and the formation of membrane-bound autophagic vacuoles (AVOs). In addition, co-treatment of a specific inhibitor of autophagy, 3-methyladenine (3MA), inhibited the 6r-induced autophagy in cancer cells. Further Western blot analysis revealed that targeting cathepsin S induced cancer cell autophagy through the activation of EGF receptor and its downstream MAPK-related signaling pathways. The induction of autophagy by targeting cathepsin S subsequently leads to the activation of apoptosis as indicated by both the up-regulation of caspase-9/3 activity, the down-regulation of Bcl-2, Bcl-XL and the altered mitochondrial membrane retention potential in cells. The application of the autophagy inhibitor, 3MA, was able to inhibit the process of apoptosis induced by the cathepsin S inhibitor 6r in cancer cells. In conclusion, the current study reveals that cathepsin S inhibitor is able to induce cancer cell autophagy through the EGF receptor signaling pathways, which may provide therapeutic benefit in cancer patients who are less sensitive to apoptosis-inducing agents. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2864. doi:10.1158/1538-7445.AM2011-2864
THU0246 Psychiatric disorders in rheumatology: Evaluation of a screening protocol in 100 hospitalized patients
Authors: F. Lumetti, D. Giuggioli, A. Manfredi, D. Ferrari, E. Tedeschini, E. Simoni, M. Rigatelli, C. Ferri
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Psychiatric disorders, namely depression (D) and anxiety (A) can frequently occur in course of chronic rheumatic diseases. These comorbidities remain often misdiagnosed and consequently not correctly treated. <h3>Objectives</h3> Aims of our study are to evaluate the frequency of D and A in a hospitalized sample of rheumatic patients, and to test the efficacy of a screening by mean of questionnaires to detect D and A. <h3>Methods</h3> 100 consecutive patients affected by rheumatic diseases were evaluate using the Italian version of Beck Depression Inventory (BDI) and the Sheehan Patient Rated Anxiety <i>Scale</i> (SPRAS). Furthermore, a clinical psychiatric evaluation was performed by rheumatologist’s decision or when questionnaires were positive. <h3>Results</h3> Of 100 patients studied 28% were affected by arthritis, 38% by connective tissue disease, 22% by vasculitis, 12% by miscellanea. Mean age was 57.2±11.4 years, 82% were females, 68% were married, 10.4% lived alone, 11.2% were unable to work because of their disease, 29.4% underwent a psychopharmacological therapy at the moment of the hospitalization. BDI score was suggestive for D (&gt;17) in 17/100 (17%), but only in 12/100 (12%) D was confirmed by psychiatris evaluation; in the same way, SPRAS score was suggestive for A (&gt;30) in 21/100 (21%) and the diagnosis was confirmed by the psychiatrist in 16/100 (16%). On the whole, 31 psychiatric visits were performed (18 because of questionnaires, 9 after rheumatologist’s prescription + questionnaires, 4 after rheumatologist’s prescription only); D and/or A was diagnosed in 22/100 (22%) and an appropriate psychopharmacological therapy was consequently prescribed (78% SSRI + BDZ). <h3>Conclusions</h3> Depression and anxiety were frequently detected in our population, with a percentage respectively of 12% and 16%. A screening performed using questionnaires is useful to identify a psychiatric comorbidity in these patients; in fact, in our study it proved to have an higher sensitivity than the only rheumatologic evaluation. Nevertheless, because of the presence of false positive results, a psychiatric visit is always necessary to confirm the diagnosis. <h3>Disclosure of Interest</h3> None Declared
A9.12 Non-Canonical NF-Kappab Signaling Induces a Proangiogenic Response in Rheumatoid Arthritis Synovial Fibroblasts and Endothelial Cells
Authors: CX Maracle, AR Noort, Kpm van Zoest, SW Tas
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Synovial fibroblasts (SF) play a pivotal role in the pathophysiology of rheumatoid arthritis (RA). RASF not only promote inflammation and cartilage destruction of the joint, but also stimulate angiogenesis. Angiogenesis allows for increased leukocyte entry into the inflamed synovium and is regarded as a switch from acute to chronic inflammation. The non-canonical nuclear factor kappaB (NF-kB) pathway, with its main regulator NF-kB inducing kinase (NIK), may play a central role in this process. <h3>Objectives</h3> To determine the effect of non-canonical NF-kB signalling on pro-angiogenic gene expression in RASF and on the angiogenic potential of human umbilical vein endothelial cells (HUVEC). <h3>Methods</h3> RASF were stimulated with lymphotoxin α<sub>1</sub>β<sub>2</sub> (LT) or LIGHT to activate non-canonical NF-kB signalling, and/or TNF to selectively activate the canonical NF-kB pathway. To effectively block the non-canonical pathway, a dominant negative NIK expressing adenovirus (Ad.NIKdn) was used. Changes in pro-angiogenic gene expression were measured by RT-PCR. Furthermore, to determine the effect on EC proliferation, RASF and HUVEC were co-cultured in the absence or presence of LT, LIGHT, TNF or VEGF EC were visualised through immunohistochemical staining of CD31, which was then semi-quantitatively scored. <h3>Results</h3> Gene expression analysis of RASF revealed an increase in mRNA levels of VCAM-1 and IL-6 after stimulation with LT, LIGHT and TNF. Increased expression of IL-8 and MMP-3 was also observed in cells treated with both TNF and LT or LIGHT. These levels were attenuated in cells transduced with Ad.NIKdn prior to stimulation, indicating that the increased expression levels were at least in part non-canonical NF-kB dependent. CCL2 and bFGF were expressed continuously by RASF regardless of stimulation. In the co-culture, proliferation levels of EC increased under all stimulation conditions, with LIGHT inducing almost a 2-fold increase (p &lt; 0.05), which was comparable to VEGF (p &lt; 0.05). <h3>Conclusions</h3> RASF contribute to synovial angiogenesis through the expression of adhesion molecules, cytokines, chemokines, matrix remodelling enzymes and growth factors. We demonstrate that the non-canonical NF-kB pathway plays an important role in this process by regulating pro-angiogenic genes and promoting EC proliferation. Further investigation of this pathway could lead to novel non-canonical NF-kB blocking therapeutics that inhibit angiogenesis in RA, thereby halting disease progression.
NHS is unprepared for risks posed by climate change, warn leading UK health bodies
Authors: Gareth Iacobucci
Journal: BMJ (2016)

A newly formed coalition of leading UK health bodies has written to England’s health secretary, Jeremy Hunt, to urge that the NHS should be better prepared to deal with climate change risks.

The UK Health Alliance on Climate Change, which includes numerous royal colleges and The BMJ among its members, said that NHS services were ill equipped for dealing with the risks posed by extreme weather events, such as flooding and heatwaves, that were becoming more intense and frequent as the climate changes.

It said that the threats posed “direct risks to people’s health and systemic threats to hospitals and health services,” alongside other factors such as increased air pollution.

The alliance, as well as calling on the …