tbuckley/cabot-search huggingface dataset:
Effect of Standard vs Intensive Blood Pressure Control on the Risk of Recurrent Stroke
Authors: Kazuo Kitagawa, Yasumasa Yamamoto, Hisatomi Arima, Toshiki Maeda, Norio Sunami, Takao Kanzawa, Kazuo Eguchi, Kenji Kamiyama, Kazuo Minematsu, Shinichiro Ueda, Hiromi Rakugi, Yusuke Ohya, Takahide Kohro, Koji Yonemoto, Yasushi Okada, Jitsuo Higaki, Norio Tanahashi, Genjiro Kimura, Satoshi Umemura, Masayasu Matsumoto, Kazuaki Shimamoto, Sadayoshi Ito, Takao Saruta, Kazuyuki Shimada
Journal: JAMA Neurology (2019)

The Systolic Blood Pressure Intervention Trial (SPRINT) demonstrated that a systolic blood pressure (BP) target less than 120 mm Hg was superior to less than 140 mm Hg for preventing vascular events. This trial excluded patients with prior stroke; therefore, the ideal BP target for secondary stroke prevention remains unknown.To assess whether intensive BP control would achieve fewer recurrent strokes vs standard BP control.Randomized clinical trial (RCT) of standard vs intensive BP control in an intent-to-treat population of patients who had a history of stroke. Patients were enrolled between October 20, 2010, and December 7, 2016. For an updated meta-analysis, PubMed and the Cochrane Central Library database were searched through September 30, 2018, using the Medical Subject Headings and relevant search terms for cerebrovascular disease and for intensive BP lowering. This was a multicenter trial that included 140 hospitals in Japan; 1514 patients who had a history of stroke within the previous 3 years were approached, but 234 refused to give informed consent.In total, 1280 patients were randomized 1:1 to BP control to less than 140/90 mm Hg (standard treatment) (n = 640) or to less than 120/80 mm Hg (intensive treatment) (n = 640). However, 17 patients never received intervention; therefore, 1263 patients assigned to standard treatment (n = 630) or intensive treatment (n = 633) were analyzed.The primary outcome was stroke recurrence.The trial was stopped early. Among 1263 analyzed patients (mean [SD] age, 67.2 [8.8] years; 69.4% male), 1257 of 1263 (99.5%) completed a mean (SD) of 3.9 (1.5) years of follow-up. The mean BP at baseline was 145.4/83.6 mm Hg. Throughout the overall follow-up period, the mean BP was 133.2/77.7 (95% CI, 132.5-133.8/77.1-78.4) mm Hg in the standard group and 126.7/77.4 (95% CI, 125.9-127.2/73.8-75.0) mm Hg in the intensive group. Ninety-one first recurrent strokes occurred. Nonsignificant rate reductions were seen for recurrent stroke in the intensive group compared with the standard group (hazard ratio [HR], 0.73; 95% CI, 0.49-1.11; P = .15). When this finding was pooled in 3 previous relevant RCTs in a meta-analysis, the risk ratio favored intensive BP control (relative risk, 0.78; 95% CI, 0.64-0.96; P = .02; absolute risk difference, -1.5%; 95% CI, -2.6% to -0.4%; number needed to treat, 67; 95% CI, 39-250).Intensive BP lowering tended to reduce stroke recurrence. The updated meta-analysis supports a target BP less than 130/80 mm Hg in secondary stroke prevention.ClinicalTrials.gov identifier: NCT01198496.
How to select patients for antireflux surgery? The ICARUS guidelines (international consensus regarding preoperative examinations and clinical characteristics assessment to select adult patients for antireflux surgery)
Authors: Ans Pauwels, Veerle Boecxstaens, Christopher N Andrews, Stephen E Attwood, Richard Berrisford, Raf Bisschops, Guy E Boeckxstaens, Serhat Bor, Albert J Bredenoord, Michele Cicala, Maura Corsetti, Fernando Fornari, Chandra Prakash Gyawali, Jan Hatlebakk, Scott B Johnson, Toni Lerut, Lars Lundell, Sandro Mattioli, Hiroto Miwa, Philippe Nafteux, Taher Omari, John Pandolfino, Roberto Penagini, Thomas W Rice, Philip Roelandt, Nathalie Rommel, Vincenzo Savarino, Daniel Sifrim, Hidekazu Suzuki, Radu Tutuian, Tim Vanuytsel, Marcelo F Vela, David I Watson, Frank Zerbib, Jan Tack
Journal: Gut (2019)

Objective Antireflux surgery can be proposed in patients with GORD, especially when proton pump inhibitor (PPI) use leads to incomplete symptom improvement. However, to date, international consensus guidelines on the clinical criteria and additional technical examinations used in patient selection for antireflux surgery are lacking. We aimed at generating key recommendations in the selection of patients for antireflux surgery. Design We included 35 international experts (gastroenterologists, surgeons and physiologists) in a Delphi process and developed 37 statements that were revised by the Consensus Group, to start the Delphi process. Three voting rounds followed where each statement was presented with the evidence summary. The panel indicated the degree of agreement for the statement. When 80% of the Consensus Group agreed (A+/A) with a statement, this was defined as consensus. All votes were mutually anonymous. Results Patients with heartburn with a satisfactory response to PPIs, patients with a hiatal hernia (HH), patients with oesophagitis Los Angeles (LA) grade B or higher and patients with Barrett’s oesophagus are good candidates for antireflux surgery. An endoscopy prior to antireflux surgery is mandatory and a barium swallow should be performed in patients with suspicion of a HH or short oesophagus. Oesophageal manometry is mandatory to rule out major motility disorders. Finally, oesophageal pH (±impedance) monitoring of PPI is mandatory to select patients for antireflux surgery, if endoscopy is negative for unequivocal reflux oesophagitis. Conclusion With the ICARUS guidelines, we generated key recommendations for selection of patients for antireflux surgery.
Prognostic role of c-met tyrosine kinase receptor expression in breast carcinoma
Authors: I. Gisterek, R. Matkowski, E. Suder, A. Lacko, D. Ramsey, J. Szelachowska, J. Kornafel
Journal: Journal of Clinical Oncology (2006)

10552 Background: Hepatocyte growth factor is a pleotropic growth factor that regulates cell proliferation, survival, tumor angiogenesis and metastasis. Its biological effects are mediated through interaction with its receptor: c-met protein.In this study, we evaluated c-met expression in the homogenous group of 99 patients diagnosed with stage II ductal breast carcinomas (G2, G3). We analyzed 5 and 10-years overall (OS) and disease free survival (DFS). Methods: Microscopic studies were performed on formalin-fixed, paraffin-embedded tumor tissue, obtained during surgery and stained routinely with haematoxylin and eosin. Expression of c-met was evaluated using a standard immunoperoxidase technique and percentage of cells with protein expression was counted. Survival was estimated using Kaplan-Meier method. Results: The expression of c-met was found in 37 (37.37%) tumors, with the strong expression of c-met observed only in 7 (7.07%) specimens. The 5-year DFS in patients with overexpression of c-met was statistically significantly worse (p =0.00493) compared with the group with low or no expression (recurrent rates: 57.14% vs 20.65%). Also with a time horizon of 10 years, high values of c-met expression were associated with the higher rate of recurrences (71.43% vs 30.77%, p = 0.01351). The 5-years OS rate in patients with c-met overexpression was 71.43% compared with 84.78% in the group with low or no expression, but this result did not reach statistical significance (p = 0.30345). Comparable tendency was seen in 10-years OS, which was 42.86% in patients with overexpression and 73.63% with low or no expression (p = 0.06154). Conclusions: The results of the study suggest that c-met overexpression is associated with shorter disease-free survival and it may be a useful prognostic indicator of more aggressive disease in patients with breast carcinoma. No significant financial relationships to disclose.
Elastase 3B mutation links to familial pancreatitis with diabetes and pancreatic adenocarcinoma
Authors: Paul C. Moore, Jessica T. Cortez, Chester E. Chamberlain, Diana Alba, Amy C. Berger, Zoe Quandt, Alice Chan, Mickie H. Cheng, Jhoanne L. Bautista, Justin Peng, Michael S. German, Mark S. Anderson, Scott A. Oakes
Journal: Journal of Clinical Investigation (2019)

While improvements in genetic analysis have greatly enhanced our understanding of the mechanisms behind pancreatitis, it continues to afflict many families for whom the hereditary factors remain unknown. Recent evaluation of a patient with a strong family history of pancreatitis sparked us to reexamine a large kindred originally reported over 50 years ago with an autosomal dominant inheritance pattern of chronic pancreatitis, diabetes and pancreatic adenocarcinoma. Whole exome sequencing analysis identified a rare missense mutation in the gene encoding pancreas-specific protease Elastase 3B (CELA3B) that cosegregates with disease. Studies of the mutant protein in vitro, in cell lines and in CRISPR-Cas9 engineered mice indicate that this mutation causes translational upregulation of CELA3B, which upon secretion and activation by trypsin leads to uncontrolled proteolysis and recurrent pancreatitis. Although lesions in several other pancreatitic proteases have been previously linked to hereditary pancreatitis, this is the first known instance of a mutation in CELA3B and a defect in translational control contributing to this disease.
Abstract 827: Total Body ABCG1-Deficiency Increases Atherosclerotic Lesion Development In LDL-Receptor Knockout Mice
Authors: Illiana Meurs, Ruud Out, Menno Hoekstra, Reeni B Hildebrand, Theo J Van Berkel, Miranda Van Eck
Journal: Circulation (2007)

ATP-binding cassette transporter G1 (ABCG1) facilitates the efflux of cholesterol from macrophages to HDL. As ABCG1 plays a role in preventing cellular lipid accumulation, macrophage ABCG1 expression has been suggested to protect against atherosclerosis. In bone marrow transplantation studies, however, we and others obtained different effects of specific macrophage ABCG1-deficiency on atherosclerotic lesion development under different experimental settings. The objective of this study was to further define the effect of ABCG1-deficiency on lipid metabolism and atherosclerotic lesion development. ABCG1 knockout (KO) mice upon atherogenic diet feeding develop only modest atherosclerotic lesions, therefore, we recently cross-bred ABCG1 KO mice with LDL-receptor KO (LDLr KO) mice. LDLr KO and LDLr/ABCG1 double KO (dKO) littermates were fed a high-fat, high-cholesterol Western-type diet (WTD) containing 0.25% cholesterol and 15% fat for 10 weeks to induce atherosclerotic lesion formation. Both on chow diet and on WTD, serum lipid levels and lipoprotein profiles showed no significant differences between the LDLr KO and LDLr/ABCG1 dKO mice. However, after 10 weeks of diet feeding, a significant 1.5-fold increase in atherosclerotic lesion size was observed in the aortic root of LDLr/ABCG1 dKO mice (130 ± 12x10 3 μm 2 [n = 8] compared to 88 ± 11x10 3 μm 2 [n=7] for LDLr KO mice; p =0.026). In addition, macrophage-rich areas of the lungs and spleens of LDLr/ABCG1 dKO mice exhibited excessive lipid accumulation compared with LDLr KO mice. Furthermore, in vitro studies using bone marrow derived macrophages of LDLr KO and LDLr/ABCG1 dKO mice showed that disruption of ABCG1 results in a 15% decrease in cholesterol efflux to HDL ( p&lt; 0.001), whereas the cholesterol efflux to ApoAI was unaffected. These studies reveal that total-body ABCG1 deficiency leads to increased atherosclerotic lesion development and massive lipid accumulation in macrophages of the lung and spleen, possibly due to impaired efflux of cholesterol from macrophages deficient in ABCG1. In conclusion, the expression of ABCG1 protects against atherosclerotic lesion development.
Abstract 20140: Interaction of Shroom3 With Fyn Impacts Phosphorylation of Nephrin Causing Proteinuria With Foot Process Effacement
Authors: Madhav C Menon, Nimrod Philippe, Chengguo Wei, Ruijie Liu, Cijiang He, Barbara Murphy
Journal: Circulation (2017)

In the translational GoCAR study, we identified that a CKD-associated SHROOM3-SNP, and tubular Shroom3 expression correlated with the development of fibrosis in renal allografts. We showed that SHR...
Multitargeted Nanoparticles Deliver Synergistic Drugs across the Blood–Brain Barrier to Brain Metastases of Triple Negative Breast Cancer Cells and Tumor‐Associated Macrophages
Authors: Tian Zhang, Hoyin Lip, Chunsheng He, Ping Cai, Zhigao Wang, Jeffrey T. Henderson, Andrew M. Rauth, Xiao Yu Wu
Journal: Advanced Healthcare Materials (2019)

Patients with brain metastases of triple negative breast cancer (TNBC) have a poor prognosis owing to the lack of targeted therapies, the aggressive nature of TNBC, and the presence of the blood-brain barrier (BBB) that blocks penetration of most drugs. Additionally, infiltration of tumor-associated macrophages (TAMs) promotes tumor progression. Here, a terpolymer-lipid hybrid nanoparticle (TPLN) system is designed with multiple targeting moieties to first undergo synchronized BBB crossing and then actively target TNBC cells and TAMs in microlesions of brain metastases. In vitro and in vivo studies demonstrate that covalently bound polysorbate 80 in the terpolymer enables the low-density lipoprotein receptor-mediated BBB crossing and TAM-targetability of the TPLN. Conjugation of cyclic internalizing peptide (iRGD) enhances cellular uptake, cytotoxicity, and drug delivery to brain metastases of integrin-overexpressing TNBC cells. iRGD-TPLN with coloaded doxorubicin (DOX) and mitomycin C (MMC) (iRGD-DMTPLN) exhibits higher efficacy in reducing metastatic burden and TAMs than nontargeted DMTPLN or a free DOX/MMC combination. iRGD-DMTPLN treatment reduces metastatic burden by 6-fold and 19-fold and increases host median survival by 1.3-fold and 1.6-fold compared to DMTPLN or free DOX/MMC treatments, respectively. These findings suggest that iRGD-DMTPLN is a promising multitargeted drug delivery system for the treatment of integrin-overexpressing brain metastases of TNBC.
Weekly docetaxel and cisplatin with capecitabine and bevacizumab (AVDCX) in patients with advanced esophagogastric cancer: Results of a phase Ib/II study.
Authors: Ofer Purim, Yulia Kundel, Udi Sadeh Gonik, Efraim Idelevich, Gal Medalia, Noa Gordon, Aaron Sulkes, Baruch Brenner
Journal: Journal of Clinical Oncology (2013)

e15078 Background: Many efforts are being made to improve treatment options for advanced esophagogastric cancer (AEGC). The aim of this phase Ib/II study was to evaluate the safety and efficacy of a novel regimen, AVDCX, consisting of weekly docetaxel and cisplatin together with capecitabine and bevacizumab, in AEGC. Methods: Patients with AEGC received treatment with different dose levels of AVDCX (cisplatin and docetaxel 25-35 mg/m 2 , days 1,8, capecitabine 1,600 mg/m 2 days 1-14, bevacizumab 7.5 mg/kg, day 1, Q:21 days). To assure regimen's safety a short phase Ib part, with three dose levels, was planned. The study's primary objectives were to establish the recommended phase II doses of docetaxel and cisplatin in AVDCX and to determine the tumor response rate. Results: The study was closed early, after the accrual of 22 patients, due to accumulating toxicity-related deaths. The median age was 59 years and 77% of patients had gastric or gastroesophageal adenocarcinomas. Grade ≥3 adverse events were documented in 18 patients (82%) and these were usually neutropenia (36%), fatigue (54%) or diarrhea (23%). There were three fatal toxicities (14%): mesenteric thromboembolism, gastric perforation and pancytopenic sepsis. Eventually, the recommended phase II doses of cisplatin and docetaxel were determined to be 25 mg/m 2 and 30 mg/m 2 , respectively. Twenty-one patients were evaluable for response: 12 (54%) had partial response (PR), 4 (18%) had stable disease (SD) and none had complete response (CR). The objective response rate (CR+PR) was 54% and the disease control rate (CR+PR+SD) was 72%. Eighteen patients (82%) derived a clinical benefit: improvement of pain, weight or performance status without a deterioration of any of these factors, from treatment. The median overall survival was 11.3 months (range, 1.5-39.2+ months) and median progression-free survival was 8.7 months (range, 1.3–26.6 months). The 2-year OS rate reached 22.7%. Conclusions: AVDCX was associated with bevacizumab-related fatal toxicities. It seems to reproduce the efficacy of bevacizumab regimen AVAGAST trial, without a clue for significant improvement over common docetaxel regimens in AEGC.
Identification of baseline predictive markers of sunitinib activity using a human cytokine antibody array in patients with metastatic renal cell carcinoma (MRCC)
Authors: J. Perez-Gracia, C. Prior, F. Guillen-Grima, A. Gonzalez, A. Panizo, V. Segura, E. Grande-Pulido, A. Gurpide, I. Melero, A. Calvo
Journal: Journal of Clinical Oncology (2009)

5113 Background: Several drugs are available for treatment of MRCC and predictive markers to select the most appropriate therapy for each patient are needed to improve efficacy and to avoid unnecessary toxicities and costs. Methods: Serum samples were collected prospectively in 31 patients treated with sunitinib at baseline and at the time of response evaluation by RECIST criteria. Serums of 6 patients with extreme phenotypes of marked responses (3) or clear progressions (3) were analyzed with a Human Cytokine Antibody Array (Series 2000, RayBiotech, Norcross, GA. USA) which evaluates 174 cytokines related to angiogenesis and tumor proliferation pathways and has been validated in clinical studies. Cytokine intensity levels were compared between both groups at baseline and after response evaluation and fold-change differences were calculated. Following array data normalization, the most relevant cytokines based on statistical significance and on biological plausibility, were assessed with ELISA in the whole group of patients and the results were correlated with clinical benefit (response or disease stabilization) or progression. Results: 27 of the 174 cytokines varied significantly between patients presenting response or progression. Six of them (TNF-α, MMP-9, ICAM-1, BDNF, SDF-1α and VEGF) were assessed with ELISA in 22 evaluable patients. TNF-α and MMP-9 baseline levels were significantly increased in non-responders and they were significantly associated with progression-free and overall survival respectively. The area under the ROC curves of TNF-α and MMP-9 as predictive factors of sunitinib clinical benefit were respectively 0.8287 and 0.7685, indicating good accuracy. Conclusions: Baseline serum levels of TNF-α and MMP-9 warrant further study as predictive markers of sunitinib activity in patients with MRCC. Selection of patients with extreme phenotypes seems a valid method to identify potential predictive factors of response. [Table: see text] [Table: see text]
Ethnicity, CVD Risk Factor Clustering and the Progression of Microvascular Disease: The Insulin Resistance and Atherosclerosis Study
Authors: Ronny A. Bell, Daniel J. Zaccaro, Lynne E. Wagenknecht, Elizabeth J. Mayer-Davis
Journal: Circulation (2001)

P31 Ethnic disparities in cardiovascular disease (CVD) and end-stage renal disease exist in the US, with African Americans (AAs) and Hispanic Americans (HAs) being at greater risk compared to non-Hispanic whites (NHWs). This maybe related to variations in individual and/or clusters of CVD risk factors across ethnic groups. We have previously shown ethnic differences in cross-sectional analyses from the Insulin Resistance and Atherosclerosis Study (IRAS) data in the effect of CVD risk factor clustering, with AAs being more greatly affected for nephropathy risk, and NHWs being more affected for CVD. We examined the effect of CVD risk factor clustering on the 5-year progression of albuminuria, which itself is a known CVD risk factor. Data were analyzed from the IRAS study, a multi-center epidemiologic cohort study that included roughly similar numbers of persons with normal and impaired glucose tolerance and type 2 diabetes, at baseline and 5-year follow-up. Comparisons were made forAAs and NHWs (Oakland/LAclinics), and for HAs and NHWs (San Antonio/San Luis Valley clinics). Data were available on 1256 IRAS subjects on nephropathy progression status, of which about 10% progressed from normal, defined as albumin/creatinine ratio less than 30 mg/g, to microalbuminuria (ACR of ≥30 and &lt; 300) or macroalbuminuria (ACR ≥300) or from microalbuminuria to macroalbuminuria. CVD risk factors (dyslipidemia, BMI, waist-hip ratio, PAI-1, hypertension, diabetes status) at baseline were dichotomized, and subjects were classified as having high (≥ risk factors) or low (&lt; 3 risk factors) risk. Overall 30.9% of the sample were classified as high risk. After adjusting for age, gender, and baseline nephropathy status, risk factor clustering predicted nephropathy progression in both ethnic comparisons (OR 2.24, p&lt; 0.001 in AAs/NHWs group; OR 2.81, p&lt; 0.001 in the HAs/NHWs group). With risk status in the model, HAs were at no greater risk for progression compared to NHWs, but risk was about 80% greater for AAs compared to NHWs (p &lt; 0.05). These data indicate a risk of nephropathy among AAs that extends beyond the traditional CVD risk factor clusters.
Assessment of Relative Utility of Underlying vs Contributory Causes of Death
Authors: G. David Batty, Catharine R. Gale, Mika Kivimäki, Steven Bell
Journal: JAMA Network Open (2019)

In etiological research, investigators using death certificate data have traditionally extracted underlying cause of mortality alone. With multimorbidity being increasingly common, more than one condition is often compatible with the manner of death. Using contributory cause plus underlying cause would also have some analytical advantages, but their combined utility is largely untested.
Screening for Pancreatic Cancer
Authors: Aimee L. Lucas, Fay Kastrinos
Journal: JAMA (2019)

Nora B. Henrikson, PhD, MPH; Erin J. Aiello Bowles, MPH; Paula R. Blasi, MPH; Caitlin C. Morrison, MPH; Matt Nguyen, MPH; Venu G. Pillarisetty, MD; Jennifer S. Lin, MD, MCR
Ebola: one year anniversary of epidemic in DRC is “unwanted milestone”
Authors: Pat Lok, Stijntje Dijk
Journal: BMJ (2019)

The Democratic Republic of the Congo is grappling with the world’s second largest Ebola epidemic on record, with more than 1800 confirmed deaths and 2600 confirmed infections since the outbreak in the North Kivu province was declared exactly one year ago on 1 August 2018.

WHO declared the outbreak in DRC a “public health emergency of international concern” under the International Health Regulations on17 July, making it the fifth declaration of its kind.

At a press briefing to mark the anniversary WHO confirmed a second death from Ebola virus disease in Goma, a densely populated city of a million people on the border of Rwanda and a gateway for potential further transmission of the disease to other countries. The agency had previously cited …