tbuckley/cabot-search huggingface dataset:
Association between c-Met expression, miR-31-3p expression and progression free survival in the New EPOC study.
Authors: Sian Alexandra Pugh, John A. Bridgewater, Karwan Moutasim, Gareth Thomas, Pierre Laurent-Puig, Raphaële Thiébaut, Francois Liebaert, Alexander H Mirnezami, Maria Lopez, Toby Mellows, Stephen Falk, Meg Finch-Jones, Juan W. Valle, Myrddin Rees, Joanne Hornbuckle, Louise Stanton, O James Garden, David Cunningham, Tim Maughan, John Neil Primrose
Journal: Journal of Clinical Oncology (2015)

3545 Background: Cetuximab in combination with chemotherapy resulted in a shorter progression free survival (PFS) when given before and after resection for colorectal liver metastases (CRLM) in the New EPOC study. MiR-31-3p expression in the primary tumor of these patients was shown to be predictive of the effect of cetuximab and other studies implicate c-Met in resistance to anti-EGFR therapy. We evaluated if c-Met expression in CRLM, in parallel with miR-31-3p, was associated with the earlier progression seen with cetuximab. Methods: MiR-31-3p expression was determined by qPCR and c-Met protein expression by immunohistochemistry in paired primary tumor and CRLM tissue for 94 New EPOC patients (Chemo (CT) n = 48, ChemoCetux (CTC) n = 46). c-Met expression was scored dependent on staining intensity; 0, negative; 1, weak; 2, moderate; 3, strong. Consequences of elevation or lowering of c-MET and miR-31-3p expression in paired primary tumor and CRLM on PFS were studied. Results: Expression of miR-31-3p and c-Met in primary tumor and matching CRLM were correlated in CT (miR-31-3p: r = 0.6 p = 0.00001, c-Met: r = 0.3 p = 0.03) but not CTC patients (miR-31-3p: r = 0.1 p = 0.47, c-Met r = 0.1 p = 0.36). In CTC, median PFS was 27.9 months for patients in whom c-Met expression was lower in the CRLM vs 14.5 months for those in whom c-Met was unchanged/elevated (HR 3.54 95%CI 1.36, 7.37 p = 0.007). This difference was not observed in CT (HR 1.01 95%CI 0.41, 2.49 p = 0.991). Patients treated with CTC (but not CT) in whom c-Met was lower and miR-31-3p was elevated in CLRM (compared to primary) had a particularly favourable PFS (median not reached) compared to the other 3 groups (log rank p = 0.002). Conclusions: In a trial that showed substantial detriment with EGFR inhibition a subgroup has been identified who derived significant benefit from cetuximab. The loss of correlation between primary tumors and CRLM suggests that cetuximab may modulate miR-31-3p and c-Met expression and that these may be implicated in the mechanism by which earlier progression occurred in these patients. Clinical trial information: 22944367.
Activity of AUY922 in NSCLC patients with EGFR exon 20 insertions.
Authors: Zofia Piotrowska, Daniel Botelho Costa, Mark Huberman, Geoffrey R. Oxnard, Justin F. Gainor, Rebecca Suk Heist, Alona Muzikansky, Alice Tsang Shaw, Matthew J. Niederst, Linnea Fulton, Jeffrey A. Engelman, Lecia V. Sequist
Journal: Journal of Clinical Oncology (2015)

8015 Background: EGFR exon 20 insertions (ins20) represent a rare subtype (4%) of EGFR mutations and are refractory to EGFR-specific tyrosine kinase inhibitors (TKIs). No effective targeted therapies exist for patients (pts) with ins20; median PFS on the irreversible EGFR TKI Afatinib is 2.8 months (mos). A pt with EGFR ins20 achieved a durable RECIST partial response (PR) to AUY922, a Heat Shock Protein 90 (Hsp90) inhibitor, in a previous study (NCT01124864), so we designed this phase II investigator-initiated trial to assess the activity of AUY922 in NSCLC pts with EGFR ins20. Methods: This was a single-arm, multi-center, open-label study of AUY922 in advanced NSCLC pts with EGFR ins20 mutations. A Simon two-stage design was used, with a plan to enroll 10 pts in the 1st stage and an additional 19 pts in the 2nd stage if >1 PR or stable disease (SD) lasting > 3 mos was observed in the 1st stage. All pts were treated with AUY922 at 70mg/m2 IV weekly. The primary aim was to evaluate objective response rate (ORR) to AUY922. Here we report the complete results of the 1st stage. Results: Ten pts, including 7 females and 3 males, average age 55 (range 44-69), were enrolled. Median number of prior therapies = 1 (range 1-6.) 3 had received a prior EGFR TKI; none responded to TKI monotherapy. The most common toxicities were grade 1-2 visual changes (9 pts), diarrhea (9) and fatigue (8.) The only treatment-related grade 3 toxicity was hypertension (2).Among the 10 pts, we observed one PR and three SD lasting > 3 mos, thus triggering full enrollment to the 2nd stage of the study (Table). Median PFS estimate is 6.1 mos (95% CI, 1.2 to NR). Updated results and correlation with specific ins20 mutations will be presented. Conclusions: AUY922 may be an effective therapy for pts with EGFR ins20 mutations with med PFS 6.1 mo and is generally well-tolerated, though reversible low-grade ocular toxicity is common. To our knowledge, this is the first trial designed specifically for pts with this rare genotype. Further study of AUY922 in this population is warranted. Clinical trial information: NCT01854034 Clinical trial information: NCT01854034. Patient Duration of Treatment (Months) Best RECIST Response 1 8.4 -35% 2 2.6 -25% 3 6.1 -11% 4 2.9 -4% 5 10.7+ -3% 6 1.4 0% 7 2.9 12% 8 4.6+ -29% 9 1.2 15% 10 2.5+ 0% + Treatment is ongoing
Abstract 1016: Caveolin-1-dependent and -independent uPAR signaling pathways contribute to ganglioside GT1b-induced early apoptosis in A549 lung cancer cells
Authors: Hyun-Jin Jang, Young-Ho Chung, Junsoo Park, Ik-Soon Jang
Journal: Cancer Research (2015)

Abstract Urokinase receptor interacts with α5β1-integrin and enhances cancer cell proliferation and metastasis. Activation of α5β1-integrin requires caveolin-1 and is regulated by uPAR, which upregulates persistently the activated ERK necessary for tumor growth. In this study, we show that the ganglioside GT1b induces proapoptotic signaling through two uPAR-ERK signaling pathways in A549 lung cancer cells. GT1b downregulated the expression of α5β1 integrin, caveolin-1, fibronectin, FAK, and ERK, whereas GT1b upregulated the expression of p53 and uPAR, suggesting GT1b mediated depletion of caveolin-1 in uPAR-expressing A549 cells also disrupts uPAR/integrin complexes, resulting in downregulation of fibronectin-α5β1-integrin-ERK signaling. Following p53 siRNA treatment, FAK and ERK expression was recovered, meaning the presence of reentry uPAR-FAK-ERK signaling pathway. These findings reveal that GT1b is involved in both caveolin-1-dependent uPAR-α5β1-integrin-ERK signaling and caveolin-1-independent uPAR-FAK-ERK signaling. These results suggest a novel function of GT1b as a dual regulator of ERK by modulating caveolin-1 and p53 Citation Format: Hyun-Jin Jang, Young-Ho Chung, Junsoo Park, Ik-Soon Jang. Caveolin-1-dependent and -independent uPAR signaling pathways contribute to ganglioside GT1b-induced early apoptosis in A549 lung cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1016. doi:10.1158/1538-7445.AM2015-1016
PWE-059 Endoscopic Resection Of Giant Colonic polyps – Size Matters!: Abstract PWE-059 Table 1
Authors: R Bhattacharyya, G Longcroft-Wheaton, P Bhandari
Journal: Gut (2014)

<h3>Introduction</h3> Colonic polyps sized 50 mm and above are traditionally treated by surgical resection. Endoscopic resection has now become increasingly common as the expertise of western endoscopists improves. There is very little published literature on endoscopic resection of these giant polyps. We aim to evaluate the feasibility, safety and efficacy of endoscopic resection of giant polyps ≥50 mm in size. <h3>Methods</h3> Prospective cohort study. All patients who underwent endoscopic resection of colonic polyps ≥50 mm from 2007–2013 were prospectively entered into a database. We excluded all polyps with fibrosis related to previous intervention. All patients were tertiary referrals from experienced gastroenterologists. All procedures were performed by a single experienced endoscopist. <h3>Results</h3> N = 124 polyps in 122 patients. Mean polyp size = 71 mm. Range 50–170 mm. 27(22%) in right colon and 97 (78%) in left colon. M:F ratio 1.1:1. All polyps were resected in a piecemeal fashion. The mean procedure time was 120 min (range 90 to 240). The complication rate was 11/124(8.9%). All these patients required inpatient stay. There were 9 bleeds (3 immediate and 6 delayed), 1 post polypectomy syndrome and 1 case of split muscle fibres (clipped endoscopically). 1 case of immediate bleeding required surgery to control the bleeding. All the others were managed conservatively. 4 of the 9 bleeds required blood transfusion. The complication rate was independent of polyp size, resection technique or site of the lesion. Follow up data was available for 90 polyps. The recurrence rate was 21/90 (23.3%). Of the 21 recurrences, 16/21(76%) patients achieved complete clearance with a further 1 to 2 endoscopic procedures. The recurrence rate was significantly dependent on polyp size and was not dependent on the resection technique or the site of the lesion. Recurrence gradually increased with an increase in polyp size up to 70 mm. Recurrence was seen in 3/34(8.8%) polyps ≤55 mm, in 7/54 (12.9%) polyps ≤60 , Shemm and in 9/63 (14.2%) polyps ≤70 mm. However, in polyps &gt;70 mm, the recurrence rate greatly increased to 12/27 (44%) <b>(p = 0.002)</b>. <h3>Conclusion</h3> It is safe and feasible to endoscopically resect polyps 50–170 mm in size. Recurrence is significantly dependent on polyp size. Giant polyps resected endoscopically have a significant recurrence rate. The majority of these can be cleared by further endoscopic procedures. However, we believe that the recurrence rate in polyps above 70 mm is very high and surgery should be considered in these cases. Complication rates are independent of size. <h3>Disclosure of Interest</h3> None Declared.
Screening for psoriatic arthritis using the Psoriasis Epidemiology Screening Tool questionnaire: examining the optimal cut-off
Authors: E.F.A. Leijten, V. Sigurdsson, M.H. Wenink, T.R.D.J. Radstake
Journal: British Journal of Dermatology (2016)

With great interest we read the recently published article in this journal by Laura Coates et al(1). Indeed, early detection of psoriatic arthritis (PsA) in patients with psoriasis is necessary to adequately treat concomitant joint disease, which can significantly impact quality of life(2,3).

This article is protected by copyright. All rights reserved.
Next-Generation Sequencing Reveal Proviral Genome and Transcriptome in Adult T-Cell Leukemia/Lymphoma
Authors: Keisuke Kataoka, Yasunobu Nagata, Akira Kitanaka, Yuichi Shiraishi, Yasushi Totoki, Jun-ichirou Yasunaga, Kenichi Chiba, Aiko Sato-Otsubo, Masashi Sanada, Hiroko Tanaka, Yusuke Shiozawa, Tetsuichi Yoshizato, Kenichi Yoshida, Hideki Makishima, Masakatsu Hishizawa, Hidehiro Itonaga, Yoshitaka Imaizumi, Wataru Munakata, Nakamura Hiromi, Natsuko Hama, Kotaro Shide, Yoko Kubuki, Tomonori Hidaka, Takuro Kameda, Tsuyoshi Nakamaki, Kensei Tobinai, Yasushi Miyazaki, Akifumi Takaori-Kondo, Masao Matsuoka, Tatsuhiro Shibata, Satoru Miyano, Kazuya Shimoda, Seishi Ogawa
Journal: Blood (2015)
Increased Gonorrhea Cases — Utah, 2009–2014
Authors: Joanna Watson, Jerry Carlile, Angela Dunn, Megan Evans, Erin Fratto, Joel Hartsell, Lynn Meinor, Matthew Mietchen, Allyn Nakashima
Journal: MMWR Morbidity and Mortality Weekly Report (2016)

Gonorrhea (caused by infection with Neisseria gonorrhoeae) is the second most commonly reported notifiable disease in the United States (1). Left untreated, gonorrhea is associated with serious long-term adverse health effects, including pelvic inflammatory disease, ectopic pregnancy, and infertility. Infection also facilitates transmission of human immunodeficiency virus (2,3). Effective gonorrhea control relies upon early detection and effective antimicrobial treatment. To assess gonorrhea rate trends in Utah, the Utah Department of Health (UDOH) analyzed Utah National Electronic Disease Surveillance System (UT-NEDSS) data for the state during 2009-2014. After declining during 2009-2011, the statewide gonorrhea rate increased fivefold to 49 cases per 100,000 population in 2014. During 2009-2014, the proportion of cases among women increased from 21% to 39% (decreasing among males from 79% to 61%). Among male patients, the proportion who identified as men who have sex with men (MSM) decreased from 67% to 42%. These demographic changes suggest that increased heterosexual transmission of gonorrhea in Utah might be occurring. Health departments need to work with providers to ensure populations at high risk are being screened and properly treated for gonorrhea. Clinicians need to be aware of increases in the risk for infection among women and non-MSM males when making screening and testing decisions and educate their patients regarding gonorrhea transmission and prevention practices.
Dengue Virus Perturbs Mitochondrial Morphodynamics to Dampen Innate Immune Responses
Authors: Laurent Chatel-Chaix, Mirko Cortese, Inés Romero-Brey, Silke Bender, Christopher John Neufeldt, Wolfgang Fischl, Pietro Scaturro, Nicole Schieber, Yannick Schwab, Bernd Fischer, Alessia Ruggieri, Ralf Bartenschlager
Journal: Cell Host & Microbe (2016)
Tribunal orders university to release data from PACE chronic fatigue study
Authors: Ingrid Torjesen
Journal: BMJ (2016)

A tribunal has ruled that Queen Mary University of London must release data from a trial looking at treatment of chronic fatigue syndrome, which found that cognitive behavioural therapy and graded exercise therapy helped to alleviate the symptoms of the condition.1

The findings of the PACE (Pacing, graded Activity, and Cognitive behaviour therapy: a randomised Evaluation) trial, published in the Lancet in 2011,2 were questioned by some academics and patients, who argued that the PACE programme could harm patients.

In March 2014 Alem Matthees, a patient in Australia, submitted a freedom of information request to Queen Mary University of London, where some of the PACE researchers were based, asking …
Primary care as part of US Health Services Reform
Authors: H. S. Goodman
Journal: JAMA (1993)

To the Editor.  —The recent article by Starfield and Simpson 1 appropriately and eloquently calls for the embodiment of primary health care services as a cornerstone for a reformed US health care delivery system. The authors quite correctly lament the inattentiveness currently paid to primary care. However, in their recommendations to construct a primary care infrastructure, they are inherently self-defeating and exclusionary by implying that only physicians can provide primary care. The reliance on physicians is based on the restrictive interpretation of four characteristics of primary care developed by Starfield and Simpson: first-contact care, coordination, longitudinality, and comprehensiveness. 2   The recognition of other professions as primary care services would extend primary care's scope of patient service and management as well as broaden its base of support for inclusion into the health care delivery system. Dentistry, for one, plays a vital role in the provision of primary health care services and can
Abstract 28: Non-alcoholic Fatty Liver Disease is Associated with Arterial Distensibility, Carotid Intima Media Thickness and Coronary Artery Calcification: The Multi-Ethnic Study of Atherosclerosis
Authors: Ebenezer T Oni, Matthew J Budoff, Irfan Zeb, Dong Li, Emir Veledar, Joseph F Polak, Ron Blankstein, Nathan D Wong, Arthur S Agatston, Michael J Blaha, Roger S Blumenthal, Khurram Nasir
Journal: Circulation (2016)

Non-alcoholic fatty liver disease (NAFLD) is considered an independent risk factor for increased cardiovascular disease (CVD). Methods: The Multi-Ethnic Study of Atherosclerosis (MESA) cohort enrolled 6814 adults without prior CVD. We excluded 2,692 participants who had missing variables, heavy drinkers, history of steroid use and chronic liver disease. NAFLD was defined using non-contrast cardiac CT and a liver/spleen attenuation ratio (L/S) &lt; 1. Arterial compliance and stiffness, was expressed as Distensibility coefficient and Young’s modulus. Common and internal carotid intima media thickness (IMT) and coronary artery calcium (CAC) &gt; 0 were used as markers of subclinical CVD. A multivariate robust linear regression and logistic regression analysis was done to evaluate the association of NAFLD and this subclinical CVD markers. RESULTS: Our analysis of 4,123 participants showed a NAFLD prevalence 17% (n=665), 55% were female with a mean age of 63 (±10) years, 39% white, 10% Chinese, 28% African American, and 23% were Hispanic. Individuals with NAFLD had Distensibility coefficient (10 -3 mmHg -1 ) of 2.4 vs. 2.5 without NAFLD, p=0.05. CIMT (mm) was 0.88 in NAFLD vs. 0.87 without NAFLD, p=0.003. Multivariate linear regression analysis showed the presence of NAFLD was associated with both the common carotid and internal carotid IMT and logCAC. Logistic analysis only showed an independent association with CAC&gt;0 (OR 1.44 95% CI 1.18, 1.75) and CIMT &gt;1mm (OR 1.30 95% 1.08, 1.56). When stratified by race the association with CIMT &gt;1mm was only significant among Caucasian whites (OR 1.37 95% 1.00, 1.90) and Hispanic (OR 1.53 95% 1.08, 2. 17) and CAC&gt;0 was only significant among Hispanics (OR 1.52 95% 1.06, 2.19). Conclusion: NAFLD is independently associated with Carotid IMT and coronary artery calcification in a multi-ethnic population. This study reaffirms the role of NAFLD in early atherosclerosis and provides opportunity to explore strategies for early screening for subclinical CVD and aggressive preventive therapies.
Interruption of progerin–lamin A/C binding ameliorates Hutchinson-Gilford progeria syndrome phenotype
Authors: Su-Jin Lee, Youn-Sang Jung, Min-Ho Yoon, So-mi Kang, Ah-Young Oh, Jee-Hyun Lee, So-Young Jun, Tae-Gyun Woo, Ho-Young Chun, Sang Kyum Kim, Kyu Jin Chung, Ho-Young Lee, Kyeong Lee, Guanghai Jin, Min-Kyun Na, Nam Chul Ha, Clea Bárcena, José M.P. Freije, Carlos López-Otín, Gyu Yong Song, Bum-Joon Park
Journal: Journal of Clinical Investigation (2016)

Hutchinson-Gilford progeria syndrome (HGPS) is a rare autosomal dominant genetic disease that is caused by a silent mutation of the LMNA gene encoding lamins A and C (lamin A/C). The G608G mutation generates a more accessible splicing donor site than does WT and produces an alternatively spliced product of LMNA called progerin, which is also expressed in normal aged cells. In this study, we determined that progerin binds directly to lamin A/C and induces profound nuclear aberrations. Given this observation, we performed a random screening of a chemical library and identified 3 compounds (JH1, JH4, and JH13) that efficiently block progerin–lamin A/C binding. These 3 chemicals, particularly JH4, alleviated nuclear deformation and reversed senescence markers characteristic of HGPS cells, including growth arrest and senescence-associated β-gal (SA–β-gal) activity. We then used microarray-based analysis to demonstrate that JH4 is able to rescue defects of cell-cycle progression in both HGPS and aged cells. Furthermore, administration of JH4 to LmnaG609G/G609G-mutant mice, which phenocopy human HGPS, resulted in a marked improvement of several progeria phenotypes and an extended lifespan. Together, these findings indicate that specific inhibitors with the ability to block pathological progerin–lamin A/C binding may represent a promising strategy for improving lifespan and health in both HGPS and normal aging.
The Epidemiology of Missing Records
Authors: T. Shelly Ashbell
Journal: JAMA (1988)

<h3>To the Editor.</h3> —The letter entitled "The Epidemiology of Missing Records" by Sacks et al<sup>1</sup>and a related article entitled "A Nurse-Associated Epidemic of Cardiac Arrests in an Intensive Care Unit" by Sacks et al<sup>2</sup>suggest another possible cause for missing records, though this cause was apparently not considered or studied. I am referring to the intentional and surreptitious destruction of records in an attempt to eliminate incriminating information, or entries, to avoid legal liability when there is a potential for medical malpractice litigation. Such records destruction is not unheard of. It is the result of the misguided belief that if the evidence of negligence contained in these records disappears, one's liability cannot be proved in court. The statement on page 694 that "the charts of Nurse 14's patients were more often missing cardiac arrest forms," when this nurse's patients were 47.5 times more likely to suffer cardiac
Neurometabolic Disorders: Potentially Treatable Abnormalities in Patients With Treatment-Refractory Depression and Suicidal Behavior
Authors: Lisa A. Pan, Petra Martin, Thomas Zimmer, Anna Maria Segreti, Sivan Kassiff, Brian W. McKain, Cynthia A. Baca, Manivel Rengasamy, Keith Hyland, Nicolette Walano, Robert Steinfeld, Marion Hughes, Steven K. Dobrowolski, Michele Pasquino, Rasim Diler, James Perel, David N. Finegold, David G. Peters, Robert K. Naviaux, David A. Brent, Jerry Vockley
Journal: American Journal of Psychiatry (2016)

Treatment-refractory depression is a devastating condition with significant morbidity, mortality, and societal cost. At least 15% of cases of major depressive disorder remain refractory to treatment. The authors previously identified a young adult with treatment-refractory depression and multiple suicide attempts with an associated severe deficiency of CSF tetrahydrobiopterin, a critical cofactor for monoamine neurotransmitter synthesis. Treatment with sapropterin, a tetrahydrobiopterin analogue, led to dramatic and long-lasting remission of depression. This sentinel case led the authors to hypothesize that the incidence of metabolic abnormalities contributing to treatment-refractory depression is underrecognized.The authors conducted a case-control, targeted, metabolomic evaluation of 33 adolescent and young adult patients with well-characterized histories of treatment-refractory depression (at least three maximum-dose, adequate-duration medication treatments), and 16 healthy comparison subjects. Plasma, urine, and CSF metabolic profiling were performed by coupled gas chromatography/mass spectrometry and high-performance liquid chromatography electrospray ionization tandem mass spectrometry.CSF metabolite abnormalities were identified in 21 of the 33 participants with treatment-refractory depression. Cerebral folate deficiency (N=12) was most common, with normal serum folate levels and low CSF 5-methyltetrahydrofolate (5-MTHF) levels. All patients with cerebral folate deficiency, including one with low CSF levels of 5-MTHF and tetrahydrobiopterin intermediates, showed improvement in depression symptom inventories after treatment with folinic acid; the patient with low tetrahydrobiopterin also received sapropterin. None of the healthy comparison subjects had a metabolite abnormality.Examination of metabolic disorders in treatment-refractory depression identified an unexpectedly large proportion of patients with potentially treatable abnormalities. The etiology of these abnormalities remains to be determined.
Overall Survival and Prognosis In Patients With First-Line Imatinib Treatment Under Consideration Of Death Due To Any Cause and Death Due To Chronic Myeloid Leukemia Only
Authors: Markus Pfirrmann, Susanne Saussele, Michele Baccarani, Joelle Guilhot, Francisco Cervantes, Gert J. Ossenkoppele, Doris Lindörfer, Verena S Hoffmann, Fausto Castagnetti, Rüdiger Hehlmann, Bengt Simonsson
Journal: Blood (2013)
Impact of Macrophage Activation on Delayed Engraftment Following Allogeneic Hematopoietic Stem Cell Transplantation: Mac Ratio, a New Predictive Index
Authors: Naomi Kawashima, Satoshi Nishiwaki, Seitaro Terakura, Sonoko Kamoshita, Kyoko Watakabe, Emi Yokohata, Daisuke Koyama, Naoko Shimizu, Shingo Kurahashi, Yukiyasu Ozawa, Masafumi Ito, Koichi Miyamura
Journal: Blood (2013)