tbuckley/cabot-search huggingface dataset:
FGFR1 Cooperates with EGFR in Lung Cancer Oncogenesis, and Their Combined Inhibition Shows Improved Efficacy
Authors: Alvaro Quintanal-Villalonga, Sonia Molina-Pinelo, Cristina Cirauqui, Laura Ojeda-Márquez, Ángela Marrugal, Rocío Suarez, Esther Conde, Santiago Ponce-Aix, Ana Belén Enguita, Amancio Carnero, Irene Ferrer, Luis Paz-Ares
Journal: Journal of Thoracic Oncology (2019)

IntroductionThere is substantial evidence for the oncogenic effects of fibroblast growth factor receptor 1 (FGFR1) in many types of cancer, including lung cancer, but the role of this receptor has not been addressed specifically in lung adenocarcinoma.MethodsWe performed FGFR1 and EGFR overexpression and co-overexpression assays in adenocarcinoma and in inmortalized lung cell lines, and we also carried out surrogate and interaction assays. We performed monotherapy and combination EGFR/FGFR inhibitor sensitivity assays in vitro and in vivo in cell line– and patient-derived xenografts. We determined FGFR1 mRNA expression in a cohort of patients with anti–EGFR therapy–treated adenocarcinoma.ResultsWe have reported a cooperative interaction between FGFR1 and EGFR in this context, resulting in increased EGFR activation and oncogenic signaling. We have provided in vitro and in vivo evidence indicating that FGFR1 expression increases tumorigenicity in cells with high EGFR activation in EGFR-mutated and EGFR wild-type models. At the clinical level, we have shown that high FGFR1 expression levels predict higher resistance to erlotinib or gefitinib in a cohort of patients with tyrosine kinase inhibitor–treated EGFR-mutated and EGFR wild-type lung adenocarcinoma. Dual EGFR and FGFR inhibition in FGFR1-overexpressing, EGFR-activated models shows synergistic effects on tumor growth in vitro and in cell line– and patient-derived xenografts, suggesting that patients with tumors bearing these characteristics may benefit from combined EGFR/FGFR inhibition.ConclusionThese results support the extended the use of EGFR inhibitors beyond monotherapy in the EGFR-mutated adenocarcinoma setting in combination with FGFR inhibitors for selected patients with increased FGFR1 overexpression and EGFR activation.
Unfolding the Role of Calreticulin in Myeloproliferative Neoplasm Pathogenesis
Authors: Tiffany R. Merlinsky, Ross L. Levine, Elodie Pronier
Journal: Clinical Cancer Research (2019)

Abstract In 2013, two seminal studies identified gain-of-function mutations in the Calreticulin (CALR) gene in a subset of JAK2/MPL-negative myeloproliferative neoplasm (MPN) patients. CALR is an endoplasmic reticulum (ER) chaperone protein that normally binds misfolded proteins in the ER and prevents their export to the Golgi and had never previously been reported mutated in cancer or to be associated with hematologic disorders. Further investigation determined that mutated CALR is able to achieve oncogenic transformation primarily through constitutive activation of the MPL–JAK–STAT signaling axis. Here we review our current understanding of the role of CALR mutations in MPN pathogenesis and how these insights can lead to innovative therapeutics approaches.
Epidemiologic and Clinical Analysis of Cervical Cancer Using Data from the Population-Based Osaka Cancer Registry
Authors: Asami Yagi, Yutaka Ueda, Mamoru Kakuda, Yusuke Tanaka, Sayaka Ikeda, Shinya Matsuzaki, Eiji Kobayashi, Toshitaka Morishima, Isao Miyashiro, Keisuke Fukui, Yuri Ito, Tomio Nakayama, Tadashi Kimura
Journal: Cancer Research (2019)

Cervical cancer screening rate is extremely low and the governmental recommendation of HPV vaccine has been suspended for 5 years in Japan. Here, we utilized data from the Osaka Cancer Registry, collected between 1976 and 2012, to evaluate cervical cancer trends in Japan. Age-adjusted incidence, relative survival, and conditional survival rates were calculated using multiple imputation methods and period analyses in 25,826 cervical cancer cases. Association of survival rates and clinical factors, including patients' age, clinical stage, and treatment procedures, were also analyzed. A trend for significantly decreasing age-adjusted incidence of cervical cancer (per 100,000) began in 1976 but reversed after 2000, increasing significantly to date (annual percent change = 3.8, 95% confidence interval, 2.7-4.8; age-adjusted rate: 28.0 in 1976, 9.1 in 2000, 14.1 in 2012). The 10-year relative survival rate improved significantly after 2002, especially in cases of "localized" and "adjacent organs" disease; this was likely due to the introduction of concurrent chemotherapy and radiation. The conditional 5-year relative survival rate improved significantly yearly until the fourth survival year. In the surgery-based group, we observed no age-dependent differences in outcomes. Unexpectedly, however, prognosis for younger age groups was poorer in the radiation-based treatment group. These results indicate that although relative survival rates have recently increased, treatment for more advanced cases with distant metastasis requires further improvement. In addition, this study is the first to suggest that age might be an important predictor of radiotherapy resistance in cervical cancer.Significance: A large-cohort analysis of cervical cancer cases reveals that age-adjusted incidence in Japan has increased since 2000 and that age may negatively correlate with resistance to radiotherapy.
Combination Lenalidomide and Azacitidine: A Novel Salvage Therapy in Patients Who Relapse After Allogeneic Stem-Cell Transplantation for Acute Myeloid Leukemia
Authors: Charles Craddock, Daniel Slade, Carmela De Santo, Rachel Wheat, Paul Ferguson, Andrea Hodgkinson, Kristian Brock, Jamie Cavenagh, Wendy Ingram, Mike Dennis, Ram Malladi, Shamyla Siddique, Francis Mussai, Christina Yap
Journal: Journal of Clinical Oncology (2019)

Salvage options for patients who relapse after allogeneic stem-cell transplantation (allo-SCT) for acute myeloid leukemia (AML) and myelodysplasia (MDS) remain limited, and novel treatment strategies are required. Both lenalidomide (LEN) and azacitidine (AZA) possess significant antitumor activity effect in AML. Administration of LEN post-transplantation is associated with excessive rates of graft-versus-host disease (GVHD), but AZA has been shown to ameliorate GVHD in murine transplantation models. We therefore examined the tolerability and activity of combined LEN/AZA administration in post-transplantation relapse.
C-Kit Cells Do Not Significantly Contribute to Cardiomyogenesis During Neonatal Heart Regeneration
Authors: Waleed M. Elhelaly, Alisson C. Cardoso, Ana Helena M. Pereira, Abdallah Elnawasany, Shayda Ebrahimi, Yuji Nakada, Hesham A. Sadek
Journal: Circulation (2019)
AB0639 Risk of mortality in sjogren’s syndrome after 1st admission
Authors: Y.-C. Chen
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> The long-term prognosis of patients with SS is unclear. Population-based studies have shown conflicting evidence regarding relative mortality in SS. <h3>Objectives</h3> There is conflicting evidence regarding prognosis in patients with SS (pSS). The aim of this study was to estimate the risk factors of mortality in patients with SS through a in hospital review. <h3>Methods</h3> Through a review of databases through October 2002 till 2016, we identified cohort studies reporting relative risk (compared with standardised population), risk factors and causes of mortality in patients with SS. <h3>Results</h3> We identified 695 (83.2% females) with SS, of whom 88 patients died over a median average follow-up of 13 years. Leading causes of mortality were infections; Risk factors associated with increased mortality were advanced age at diagnosis [HR 1.045 (95% CI 1.024, 1.067], male sex [RR 2.18 (95% CI 1.45, 3.27)], associated with SLE [HR 2.448 (95% CI 1.108, 5.406)], diabetes [HR 1.986 (95% CI 1.125, 3.505)] <h3>Conclusions</h3> After first admission, the risk factor for mortality include old age, associated with SLE and diabetes. These require close follow-up. <h3>Reference</h3> [1] Baldini C, Pepe P, Quartuccio L, et al. Primary Sjogren's syndrome as a multi-organ disease: impact of the serological profile on the clinical presentation of the disease in a large cohort of Italian patients. Rheumatology2014;53 <h3>Acknowledgements</h3> We thanks to Kaohsiung CGMH for data support <h3>Disclosure of Interest</h3> None declared
Response to Comment on Mathew et al. Therapeutic Lifestyle Changes Improve HDL Function by Inhibiting Myeloperoxidase-Mediated Oxidation in Patients With Metabolic Syndrome. Diabetes Care 2018;41:2431–2437
Authors: Anna V. Mathew, Subramaniam Pennathur
Journal: Diabetes Care (2019)

We thank Holzer and Marsche (1) for their interest in our work on the impact of therapeutic lifestyle changes (TLC) on HDL function in patients with metabolic syndrome (2). They suggest that a modified isolation technique for HDL2 and HDL3 proposed by their group removes proteins such as albumin (most abundant plasma protein) and apolipoprotein (apo)B (the major constituent of LDL), thereby enhancing HDL purity. It is well known that HDL protein composition is highly heterogeneous, and different HDL isolation techniques—such as sequential ultracentrifugation (KBr or D2O/sucrose), size exclusion chromatography, immune affinity capture, ion exchange chromatography, or isoelectric focusing—yield variable combinations of ∼95 proteins, as reviewed (3) and as updated periodically on the website http://homepages.uc.edu/∼davidswm/HDLproteome.html. These proteins …
SAT0653 Relationship between cardiac valvular calcification, carotid atherosclerosis, and coronary calcification in patients with rheumatoid arthritis
Authors: H. Udachkina, D. Novikova, T. Popkova, E. Markelova, I. Kirillova, E. Gerasimova
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> The prevalence and relationship of VC with arterial atherosclerosis in patients with rheumatoid arthritis (RA) is under-investigated. <h3>Objectives</h3> investigate the prevalence of VC in patients with RA and its relationship with carotid atherosclerosis (CA) and coronary artery calcification (CAC). <h3>Methods</h3> Study population was consisted of 128 adult patients (65.6% women, age 55<sup>43;61</sup> years) with RA according to ACR/EULAR criteria (disease duration 6<sup>5;18</sup> month) with moderate/high RA activity (DAS28 5.3 [5.0; 6.1]). Arterial hypertension (AH) was found in 64%, ischaemic heart disease (IHD) – in 14%, dyslipidemia – in 54.7%, smoking – in 20.3%, diabetes mellitus type 2 – in 7%, myocardial infarction – in 1.6%, stroke – in 1.6%. Cardiac VC was evaluated by transthoracic echocardiography; CAC scoring was done with 32-row scanner by standard Agatston method; CA was evaluated with duplex ultrasound. <h3>Results</h3> Patients were divided on 3 groups depending on valve condition: normal (34.3%); leaves thickening (30.5%); VC (35.25%). The VC group consisted of isolated mitral VC – in 11%, isolated aortic VC – in 51%, calcification of both valve – in 38%. Mitral regurgitation (3 degree) was detected in 0.8% patient, mitral stenosis (mild) – 0.8%, aortic regurgitation (1 degree) – in 25%, aortic stenosis (mild) – in 0.8%. Age, BMI, SBP and frequency of AH, IHD, CA, CAC significant increased from 1 to 3 group (p&lt;0.05). There was no significant difference in the sex, lipid levels, Rg-stage, RA duration and level of parameters of RA activity (DAS28, CRP, ESR) between investigated groups. <h3>Conclusions</h3> Among RA patients, more than half have a modified valve structure and in 1/3 of them VC. The presence of VC is correlated with traditional cardiovascular risk factors, but not with lipid levels, activity and severity of RA. The probability of CA and CAC presence is significantly increased when there is VC. <h3>Disclosure of Interest</h3> None declared
Assessment of the Prevalence of Mucosal Involvement in Bullous Pemphigoid
Authors: Khalaf Kridin, Reuven Bergman
Journal: JAMA Dermatology (2019)

<h3>Importance</h3> The prevalence of mucosal involvement in bullous pemphigoid (BP) is inconsistent. Nonoral mucosal involvement was reported anecdotally in few patients with BP. <h3>Objective</h3> To evaluate the prevalence of mucosal involvement in patients with BP, and to characterize the subgroup of patients with mucosal lesions. <h3>Design, Setting, and Participants</h3> A retrospective cohort study was performed including 328 consecutive patients diagnosed with immunopathologically validated BP at a tertiary care referral center for autoimmune bullous diseases in northern Israel between January 1, 2000, and December 31, 2017. <h3>Main Outcome and Measures</h3> The study was conducted to estimate the prevalence and distribution of mucosal involvement among patients with BP. Patients with mucosal involvement were compared with the remaining BP patients regarding clinical and immunological features, laboratory analyses, and treatments. <h3>Results</h3> The study cohort included 139 (42.4%) male and 189 (57.6%) female patients, with a mean (SD) age of 78.0 (11.8) years at presentation. Fifty-six patients (17.1%) presented with mucosal lesions. The oral mucosa was the most frequently affected mucosal surface (n = 44; 13.7%), followed by the laryngeal (n = 16; 4.9%) and the genital (n = 10; 3.0%) mucosae. Among patients with oral lesions, the most involved oral structures were the buccal mucosa (n = 25; 55.6%) and the soft palate (n = 24; 53.3%). Compared with other patients with BP, patients with mucosal involvement were younger (71.8 [14.4] years vs 79.3 [10.8] years;<i>P</i> &lt; .001), presented more frequently with extensive disease (55.4% vs 39.7%;<i>P</i> = .002), had less peripheral eosinophilia (17.8% vs 41.9%;<i>P</i> &lt; .001), and were treated with higher doses of corticosteroids (prednisone &gt;1 mg/kg: 67.9% vs 51.8%;<i>P</i> = .03). <h3>Conclusions and Relevance</h3> Mucosal lesions are present in a notable subgroup of patients with BP and are associated with disease severity. Laryngeal involvement is more common than previously appreciated.
THU0638 Clinical characteristic of a group of patients with pstpip1-associated myeloid-related proteinemia inflammatory syndrome (PAMI)
Authors: V.I. Burlakov, A. Kozlova, I. Mersiyanova, A. Laberko, E. Viktorova, O. Shvets, D. Yukhacheva, G. Gordeeva, E. Raykina, V. Zakharova, J. Rodina, A. Shcherbina
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> PSTPIP1-gene associated autoinflammatory diseases is a group of clinically diverse syndromes predominantly manifested by various skin conditions (pyoderma gangrenosum, acne, hidradenitis suppurativa, necrotizing fasciitis). Yet one of them – PAMI – manifests mainly with haematologic abnormalities and autoinflammation with or without purulent features, presenting diagnostic difficulties for treating physicians – mainly haematologists. PAMI treatment is also challenging as IL-1 inhibitors alleviate inflammatory symptoms but cytopenias usually require additional therapeutic agents. <h3>Methods</h3> We describe five PAMI patients from 3 families: (2 girls, 2 boys, and affected mother of two patients). c.748G&gt;A(p.E250K) heterozygous mutation in PSTPIP1 was detected in all patients via targeted panel next generation sequencing and confirmed by Sanger sequencing. <h3>Results</h3> The median age of disease onset was 2 years (varied from at-birth onset to 7 years), the adult patient manifested at the age of 3. As described all patients manifested with cytopenias: thrombocytopenia in three, severe anaemia in five, neutropenia in three. All patients had elevated CRP and zinc levels, as previously described. Splenomegaly was noted in five, lymphadenopathy in one, colitis in one, severe arthritis in one (adult patient) and arthropathy in two patients. Mild pyodermia was noted only in one patient, two patients had skin vasculitis. One patient developed myelodisplastic syndrome and underwent successful hematopoietic stem cell transplantation (HSCT). All patients received various immunosuppression prior to diagnosis with partial effect. After PAMI diagnosis rituximab was effective in two out of three, tocilizumab in one out of two, high dose anakinra in one patient. The girl who underwent HSCT is currently well, with full donor chimerism. <h3>Conclusions</h3> Haematologists need to be aware of the PAMI phenotype and include it in the diagnostic algorithm. Treatment still remains challenging and requires further investigation in larger groups of patients. <h3>Disclosure of Interest</h3> None declared
Abstract P047: The Effect of Serum C-reactive Protein (CRP) or Handgrip Strength Inclusion on the Framingham Risk Score Model of CVD Risk in a Cohort of Middle-aged to Elderly Australian Men
Authors: Sean A Martin, Andrew Vincent, Anne W Taylor, Robert J Adams, Peter O’Loughlin, Gary A Wittert
Journal: Circulation (2017)

Introduction: Cardiovascular disease (CVD) risk prediction models are used extensively in clinical practice. Recent reviews have suggested that such models would benefit from the identification of novel predictors to improve specificity and sensitivity. Both serum CRP and lower handgrip strength have been demonstrated to predict incident CVD suggesting its utility as a prognostic CVD marker. Objectives: To determine whether handgrip strength improves global CVD risk prediction models based on the Framingham Risk Score (FRS) (using NCEP-ATP-III criteria), and to validate CRP as a marker adding predictive value. Method: Participants were drawn from a randomly-selected, community-dwelling cohort of men residing in Adelaide, Australia. Of these, n=2162 men without CVD at baseline (2002-5) and covariate data (age, fasting total &amp; HDL cholesterol, smoking status, mean systolic blood pressure, and anti-hypertensive usage) were followed for a median period of 8.3 years. Incident CVD events (n=248) were identified through a state-wide registry of in-hospital events (emergency department visit or hospital separation) and cardiac-specific mortality. Mean handgrip strength (by dynamometry) and serum high-sensitivity CRP were obtained at baseline visit. The added prognostic value of handgrip strength and CRP was assessed using splines and log-likelihood ratio tests of nested Cox proportional models, BIC and AIC. Model discrimination was assessed using Harrell’s c-index. Results: Within the FRS 10-year risk groups 0-&lt;5%, 5-&lt;10%, 10-&lt;20%, and 20+% the estimated 10-year CVD event rates were 3% (95%CI: 2-5%), 7% (5-10%), 15% (13-18%) and 22% (17-27%), respectively. Hand grip strength did not add predictive value above standard Framingham risk factors ( p =0.25). CRP made a contribution to estimating global CVD risk ( p =0.002). Both the BIC and AIC were reduced (4.9 and 7.9 units, respectively) and the c-index increased from 0.727 to 0.732 (SE=0.024). Conclusions: A global risk prediction model that includes serum CRP improves CV risk classification in men.
Abstract 2223: Angioscopic Evaluation of Neointima Coverage: Sirolimus Drug-Eluting Stent vs. Bare Metal Stent
Authors: Yasunori Ueda, Jota Oyabu, Katsuki Okada, Nobuyuki Ogasawara, Atsushi Hirayama, Kazuhisa Kodama
Journal: Circulation (2006)
Functional cooperativity of p97 and histone deacetylase 6 in mediating DNA repair in mantle cell lymphoma cells
Authors: Pratikkumar H. Vekaria, Amar Kumar, Dharmalingam Subramaniam, Neil Dunavin, Anusha Vallurupalli, Frank Schoenen, Siddhartha Ganguly, Shrikant Anant, Joseph P. McGuirk, Roy A. Jensen, Rekha Rao
Journal: Leukemia (2019)
Association of Pharmaceutical Industry Marketing of Opioid Products With Mortality From Opioid-Related Overdoses
Authors: Scott E. Hadland, Ariadne Rivera-Aguirre, Brandon D. L. Marshall, Magdalena Cerdá
Journal: JAMA Network Open (2019)

<h3>Importance</h3> Prescription opioids are involved in 40% of all deaths from opioid overdose in the United States and are commonly the first opioids encountered by individuals with opioid use disorder. It is unclear whether the pharmaceutical industry marketing of opioids to physicians is associated with mortality from overdoses. <h3>Objective</h3> To identify the association between direct-to-physician marketing of opioid products by pharmaceutical companies and mortality from prescription opioid overdoses across US counties. <h3>Design, Setting, and Participants</h3> This population-based, county-level analysis of industry marketing information used data from the Centers for Medicare &amp; Medicaid Services Open Payments database linked with data from the Centers for Disease Control and Prevention on opioid prescribing and mortality from overdoses. All US counties were included, with data on overdoses from August 1, 2014, to December 31, 2016, linked to marketing data from August 1, 2013, to December 31, 2015, using a 1-year lag. Statistical analyses were conducted between February 1 and June 1, 2018. <h3>Main Outcomes and Measures</h3> County-level mortality from prescription opioid overdoses, total cost of marketing of opioid products to physicians, number of marketing interactions, opioid prescribing rates, and sociodemographic factors. <h3>Results</h3> Between August 1, 2013, and December 31, 2015, there were 434 754 payments totaling $39.7 million in nonresearch-based opioid marketing distributed to 67 507 physicians across 2208 US counties. After adjustment for county-level sociodemographic factors, mortality from opioid overdoses increased with each 1-SD increase in marketing value in dollars per capita (adjusted relative risk, 1.09; 95% CI, 1.05-1.12), number of payments to physicians per capita (adjusted relative risk, 1.18; 95% CI, 1.14-1.21, and number of physicians receiving marketing per capita (adjusted relative risk, 1.12; 95% CI, 1.08-1.16). Opioid prescribing rates also increased with marketing and partially mediated the association between marketing and mortality. <h3>Conclusions and Relevance</h3> In this study, across US counties, marketing of opioid products to physicians was associated with increased opioid prescribing and, subsequently, with elevated mortality from overdoses. Amid a national opioid overdose crisis, reexamining the influence of the pharmaceutical industry may be warranted.
New business models would boost GP partnerships, says review
Authors: Gareth Iacobucci
Journal: BMJ (2019)

GP partnerships in England should be free to operate under different legal models to reduce the personal risk that is putting off many GPs from becoming partners, a government commissioned review has advised.1 The independent review, commissioned a year ago to tackle concerns about the sharp decline in the number of GP partners,2 makes a range of recommendations for strengthening the partnership model, spanning issues such as financial risk, workload, and workforce (box 1). Box 1 ### The report’s key recommendationsRETURN TO TEXT