tbuckley/cabot-search huggingface dataset:
Arthroscopic hip surgery compared with physiotherapy and activity modification for the treatment of symptomatic femoroacetabular impingement: multicentre randomised controlled trial
Authors: Antony J R Palmer, Vandana Ayyar Gupta, Scott Fernquest, Ines Rombach, Susan J Dutton, Ramy Mansour, Simon Wood, Vikas Khanduja, Tom C B Pollard, Andrew W McCaskie, Karen L Barker, Tony J M D Andrade, Andrew J Carr, David J Beard, Sion Glyn-Jones
Journal: BMJ (2019)

Abstract Objective To compare arthroscopic hip surgery with physiotherapy and activity modification for improving patient reported outcome measures in patients with symptomatic femoroacetabular impingement (FAI). Design Two group parallel, assessor blinded, pragmatic randomised controlled trial. Setting Secondary and tertiary care centres across seven NHS England sites. Participants 222 participants aged 18 to 60 years with symptomatic FAI confirmed clinically and with imaging (radiography or magnetic resonance imaging) were randomised (1:1) to receive arthroscopic hip surgery (n=112) or a programme of physiotherapy and activity modification (n=110). Exclusion criteria included previous surgery, completion of a physiotherapy programme targeting FAI within the preceding 12 months, established osteoarthritis (Kellgren-Lawrence grade ≥2), and hip dysplasia (centre-edge angle &lt;20 degrees). Interventions Participants in the physiotherapy group received a goal based programme tailored to individual patient needs, with emphasis on improving core stability and movement control. A maximum of eight physiotherapy sessions were delivered over five months. Participants in the arthroscopic surgery group received surgery to excise the bone that impinged during hip movements, followed by routine postoperative care. Main outcome measures The primary outcome measure was the hip outcome score activities of daily living subscale (HOS ADL) at eight months post-randomisation, with a minimum clinically important difference between groups of 9 points. Secondary outcome measures included additional patient reported outcome measures and clinical assessment. Results At eight months post-randomisation, data were available for 100 patients in the arthroscopic hip surgery group (89%) and 88 patients in the physiotherapy programme group (80%). Mean HOS ADL was 78.4 (95% confidence interval 74.4 to 82.3) for patients randomised to arthroscopic hip surgery and 69.2 (65.2 to 73.3) for patients randomised to the physiotherapy programme. After adjusting for baseline HOS ADL, age, sex, and study site, the mean HOS ADL was 10.0 points higher (6.4 to 13.6) in the arthroscopic hip surgery group compared with the physiotherapy programme group (P&lt;0.001)). No serious adverse events were reported in either group. Conclusions Patients with symptomatic FAI referred to secondary or tertiary care achieve superior outcomes with arthroscopic hip surgery than with physiotherapy and activity modification. Trial registration ClinicalTrials.gov NCT01893034 .
Excision repair cross-complementing group-1 (ERCC1) gene induction in peripheral blood mononuclear cells as a marker of outcome in patients with colorectal cancer treated with oxaliplatin.
Authors: Devika Rao, Atrayee Basu Mallick, Amartej Merla, Jeeshan Jiffry, Imran Chaudhary, Titto A Augustine, Lakshmi Rajdev, Andreas Kaubisch, Radhashree Maitra, Sanjay Goel
Journal: Journal of Clinical Oncology (2019)

542 Background: Oxaliplatin is a third generation platinum agent that confers tumoricidal effect by forming platinum-DNA adducts and is an integral part of the standard of care regimens for patients with colorectal cancer (CRC). Tissue resistance to oxaliplatin appears to be multifactorial, with the nucleotide excision repair (NER) pathway playing a major role. We have previously demonstrated that Excision Repair Cross-Complementing group-1 (ERCC1), can be induced in colorectal cell lines on exposure to Oxaliplatin and high levels confer resistance to apoptosis. We aim to further this knowledge by analyzing gene expression in vivo, using PBMC as a surrogate, to assess ERCC1 as a biomarker of sensitivity to Oxaliplatin therapy. Methods: Patients with CRC who received oxaliplatin were consented to blood (PBMC) sampling at 0, 2, 48 hours, and 14 days during any cycle of chemotherapy. ERCC1 gene expression was quantified by qPCR (quantitative real time polymerase chain reaction) and WB (western blotting). Clinical benefit from oxaliplatin was determined using the parameters of relapse free survival (RFS) for limited stage and progression free survival (PFS) for mCRC. Results: Fifty-four patients were enrolled on study, 25 (46.3%) had mCRC. Twenty-four patients were included in final analysis based on clinical data. Thirteen (52%) had an increase in ERCC expression from baseline, while 11 (48%) showed no change or decrease. Median PFS was 190 and 237 days respectively (log-rank test HR 2.35, CI 1.005-5.479; p = 0.0182). In the 29 patients with limited stage disease, 19 (65.5%) had an induction of ERCC. However, in these patients change in expression did not correlate with RFS. We did not find any significant correlation of PFS with baseline expression of ERCC1 in either group. Conclusions: We confirm our hypothesis that the ERCC1 gene is induced in vivo in a sub-population of patients on treatment with Oxaliplatin. This induction can serve as a potential marker of resistance to oxaliplatin based chemotherapy in mCRC as evidenced by the significant difference in PFS. Further analyses of the influence of ERCC1 polymorphisms on outcomes is underway.
GLUT1-mediated effective anti-miRNA21 pompon for cancer therapy
Authors: Qin Guo, Chao Li, Wenxi Zhou, Xinli Chen, Yu Zhang, Yifei Lu, Yujie Zhang, Qinjun Chen, Donghui Liang, Tao Sun, Chen Jiang
Journal: Acta Pharmaceutica Sinica B (2019)

Oncogenic microRNAs are essential components in regulating the gene expression of cancer cells. Especially miR21, which is a major player involved of tumor initiation, progression, invasion and metastasis in several cancers. The delivery of anti-miR21 sequences has significant potential for cancer treatment. Nevertheless, since anti-miR21 sequences are extremely unstable and they need to obtain certain concentration to function, it is intensely difficult to build an effective delivery system for them. The purpose of this work is to construct a self-assembled glutathione (GSH)-responsive system with tumor accumulation capacity for effective anti-miR21 delivery and cancer therapy. A novel drug delivery nanosphere carrying millions of anti-miR21 sequences was developed through the rolling circle transcription (RCT) method. GSH-responsive cationic polymer polyethyleneimine (pOEI) was synthesized to protect the nanosphere from degradation by Dicer or other RNase in normal cells and optimize the pompon-like nanoparticle to suitable size. Dehydroascorbic acid (DHA), a targeting molecule, which is a substrate of glucose transporter 1 (GLUT 1) and highly expressed on malignant tumor cells, was connected to pOEI through PEG, and then the polymer was used for contracting a RNA nanospheres into nanopompons. The anti-miR21 nanopompons showed its potential for effective cancer therapy.
Functional Characterization of Epigenetic Modifiers of Demethylating Therapy in AML
Authors: Desiree Melanie Redhaber, Laurent Phely, Sophia Ehrenfeld, Pia Veratti, Silvia Schäfer, Jan Mitschke, Jessica Beckert, Khalid Shoumariyeh, Justus Duyster, Cornelius Miething
Journal: Blood (2018)
Axis inhibition protein 1 (Axin1) Deletion–Induced Hepatocarcinogenesis Requires Intact β‐Catenin but Not Notch Cascade in Mice
Authors: Yu Qiao, Jingxiao Wang, Eylul Karagoz, Binyong Liang, Xinhua Song, Runze Shang, Katja Evert, Meng Xu, Li Che, Matthias Evert, Diego F. Calvisi, Junyan Tao, Bruce Wang, Satdarshan P. Monga, Xin Chen
Journal: Hepatology (2019)

Inactivating mutations of axis inhibition protein 1 (AXIN1), a negative regulator of the Wnt/β-Catenin cascade, are among the common genetic events in human hepatocellular carcinoma (HCC), affecting approximately 10% of cases. In the present manuscript, we sought to define the genetic crosstalk between Axin1 mutants and Wnt/β-catenin as well as Notch signaling cascades along hepatocarcinogenesis. We discovered that c-MET activation and AXIN1 mutations occur concomitantly in ~3%-5% of human HCC samples. Subsequently, we generated a murine HCC model by means of CRISPR/Cas9-based gene deletion of Axin1 (sgAxin1) in combination with transposon-based expression of c-Met in the mouse liver (c-Met/sgAxin1). Global gene expression analysis of mouse normal liver, HCCs induced by c-Met/sgAxin1, and HCCs induced by c-Met/∆N90-β-Catenin revealed activation of the Wnt/β-Catenin and Notch signaling in c-Met/sgAxin1 HCCs. However, only a few of the canonical Wnt/β-Catenin target genes were induced in c-Met/sgAxin1 HCC when compared with corresponding lesions from c-Met/∆N90-β-Catenin mice. To study whether endogenous β-Catenin is required for c-Met/sgAxin1-driven HCC development, we expressed c-Met/sgAxin1 in liver-specific Ctnnb1 null mice, which completely prevented HCC development. Consistently, in AXIN1 mutant or null human HCC cell lines, silencing of β-Catenin strongly inhibited cell proliferation. In striking contrast, blocking the Notch cascade through expression of either the dominant negative form of the recombinant signal-binding protein for immunoglobulin kappa J region (RBP-J) or the ablation of Notch2 did not significantly affect c-Met/sgAxin1-driven hepatocarcinogenesis. Conclusion: We demonstrated here that loss of Axin1 cooperates with c-Met to induce HCC in mice, in a β-Catenin signaling-dependent but Notch cascade-independent way.
Flagellin Induces Pro-inflammatory Cytokines, Chemokines and Metalloproteinases In Bronchial Epithelial Cells.
Authors: Sae-Hoon Kim, Mi-Hong Ji, Jung-Hyun Kim, Byung Keun Kim, Jin-Hee Kim, Yoon-Seok Chang
Journal: Journal of Allergy and Clinical Immunology (2019)
Effect of a Resuscitation Strategy Targeting Peripheral Perfusion Status vs Serum Lactate Levels on 28-Day Mortality Among Patients With Septic Shock
Authors: Glenn Hernández, Gustavo A. Ospina-Tascón, Lucas Petri Damiani, Elisa Estenssoro, Arnaldo Dubin, Javier Hurtado, Gilberto Friedman, Ricardo Castro, Leyla Alegría, Jean-Louis Teboul, Maurizio Cecconi, Giorgio Ferri, Manuel Jibaja, Ronald Pairumani, Paula Fernández, Diego Barahona, Vladimir Granda-Luna, Alexandre Biasi Cavalcanti, Jan Bakker
Journal: JAMA (2019)

Abnormal peripheral perfusion after septic shock resuscitation has been associated with organ dysfunction and mortality. The potential role of the clinical assessment of peripheral perfusion as a target during resuscitation in early septic shock has not been established.To determine if a peripheral perfusion-targeted resuscitation during early septic shock in adults is more effective than a lactate level-targeted resuscitation for reducing mortality.Multicenter, randomized trial conducted at 28 intensive care units in 5 countries. Four-hundred twenty-four patients with septic shock were included between March 2017 and March 2018. The last date of follow-up was June 12, 2018.Patients were randomized to a step-by-step resuscitation protocol aimed at either normalizing capillary refill time (n = 212) or normalizing or decreasing lactate levels at rates greater than 20% per 2 hours (n = 212), during an 8-hour intervention period.The primary outcome was all-cause mortality at 28 days. Secondary outcomes were organ dysfunction at 72 hours after randomization, as assessed by Sequential Organ Failure Assessment (SOFA) score (range, 0 [best] to 24 [worst]); death within 90 days; mechanical ventilation-, renal replacement therapy-, and vasopressor-free days within 28 days; intensive care unit and hospital length of stay.Among 424 patients randomized (mean age, 63 years; 226 [53%] women), 416 (98%) completed the trial. By day 28, 74 patients (34.9%) in the peripheral perfusion group and 92 patients (43.4%) in the lactate group had died (hazard ratio, 0.75 [95% CI, 0.55 to 1.02]; P = .06; risk difference, -8.5% [95% CI, -18.2% to 1.2%]). Peripheral perfusion-targeted resuscitation was associated with less organ dysfunction at 72 hours (mean SOFA score, 5.6 [SD, 4.3] vs 6.6 [SD, 4.7]; mean difference, -1.00 [95% CI, -1.97 to -0.02]; P = .045). There were no significant differences in the other 6 secondary outcomes. No protocol-related serious adverse reactions were confirmed.Among patients with septic shock, a resuscitation strategy targeting normalization of capillary refill time, compared with a strategy targeting serum lactate levels, did not reduce all-cause 28-day mortality.ClinicalTrials.gov Identifier: NCT03078712.
Epstein-Barr Virus Status in Diffuse Large B Cell Lymphoma Post-Transplant Lymphoproliferative Disorder
Authors: Angelo Fama, Rebecca L King, Matthew J. Maurer, Kay M. Ristow, William R Macon, Stephen M Ansell, Nora N Bennani, Randall C. Walker, Yogish C Kudva, Kymberly D Watt, Thomas R. Schwab, James R. Cerhan, Grzegorz S. Nowakowski, Thomas M. Habermann
Journal: Blood (2018)
The Risk of Heart Failure and Other Cardiovascular Hospitalizations After Early Stage Breast Cancer: A Matched Cohort Study
Authors: Husam Abdel-Qadir, Paaladinesh Thavendiranathan, Peter C Austin, Douglas S Lee, Eitan Amir, Jack V Tu, Kinwah Fung, Geoffrey M Anderson
Journal: JNCI Journal of the National Cancer Institute (2018)

Abstract Background Data are limited regarding the risk of heart failure (HF) requiring hospital-based care after early stage breast cancer (EBC) and its relationship to other types of cardiovascular disease (CVD). Methods We conducted a population-based, retrospective cohort study of EBC patients (diagnosed April 1, 2005–March 31, 2015) matched 1:3 on birth-year to cancer-free control subjects. We identified hospitalizations and emergency department visits for CVD through March 31, 2017. We used cumulative incidence function curves to estimate CVD incidence and cause-specific regression models to compare CVD rates between cohorts. All statistical tests were two-sided. Results We identified 78 318 EBC patients and 234 954 control subjects. The 10-year incidence of CVD hospitalization was 10.8% (95% confidence interval [CI] = 10.5% to 11.1%) after EBC and 9.1% (95% CI = 8.9% to 9.2%) in control subjects. Ischemic heart disease was the most common reason for CVD hospitalization after EBC. After regression adjustment, the relative rates compared with control subjects remained statistically significantly elevated for HF (hazard ratio [HR] = 1.21, 95% CI = 1.14 to 1.29, P &lt; .001), arrhythmias (HR = 1.31, 95% CI = 1.23 to 1.39, P &lt; .001), and cerebrovascular disease (HR 1.10, 95% CI = 1.04 to 1.17, P = .002) hospitalizations. It was rare for HF hospital presentations (2.9% of cases) to occur in EBC patients without recognized risk factors (age &gt;60 years, hypertension, diabetes, prior CVD). Anthracycline and/or trastuzumab were used in 28 950 EBC patients; they were younger than the overall cohort with lower absolute rates of CVD, hypertension, and diabetes. However, they had higher relative rates of CVD in comparison with age-matched control subjects. Conclusions Atherosclerotic diagnoses, rather than HF, were the most common reasons for CVD hospitalization after EBC. HF hospital presentations were often preceded by risk factors other than chemotherapy, suggesting potential opportunities for prevention.
Defining the Cell Types That Drive Idiopathic Pulmonary Fibrosis Using Single-Cell RNA Sequencing
Authors: Joanna M. Poczobutt, Oliver Eickelberg
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

mechanical ventilation again if deemed necessary, and they speculated that the "remembering-self" was probably the leading reason for this affirmation.This is in keeping with another study that showed that patients would choose to receive aggressive treatment, but only if survival was not associated with severe functional or cognitive impairment (15).The major factor in a patient-clinician interview is how it is conducted, and this detail is not specified in the article.It has been suggested that "little white lies" in this bidirectional communication are quite common; sometimes in an attempt to "please my doctor who saves my life," a patient may minimize his or her symptoms or bad experiences ( 16).In conclusion, this study, besides being well conducted and providing important clinical information, clarifies the issue that perception in medicine may be very misleading.Therefore, the patient and clinician, allied together, should never give up on the dream to liberate the patient from prolonged ventilation and recover a satisfactory quality of life.
Azacitidine is effective for targeting leukemia-initiating cells in juvenile myelomonocytic leukemia
Authors: Christopher F. Krombholz, Lorena Gallego-Villar, Sushree S. Sahoo, Pritam K. Panda, Marcin W. Wlodarski, Konrad Aumann, Mark Hartmann, Daniel B. Lipka, Michael Daskalakis, Christoph Plass, Charlotte M. Niemeyer, Miriam Erlacher, Christian Flotho
Journal: Leukemia (2019)
Greenness and Depression Incidence among Older Women
Authors: Rachel F. Banay, Peter James, Jaime E. Hart, Laura D. Kubzansky, Donna Spiegelman, Olivia I. Okereke, John D. Spengler, Francine Laden
Journal: Environmental Health Perspectives (2019)

Background: Recent evidence suggests that higher levels of residential greenness may contribute to better mental health. Despite this, few studies have considered its impact on depression, and most are cross-sectional. Objective: The objective of this study was to examine surrounding residential greenness and depression risk prospectively in the Nurses' Health Study. Methods: A total of 38,947 women (mean age throughout follow-up 70 y [range 54–91 y]) without depression in 2000 were followed to 2010. Residential greenness was measured using the satellite-based Normalized Difference Vegetation Index (NDVI) and defined as the mean greenness value within 250-m and 1,250-m radii of the women's residences in July of each year. Incidence of depression was defined according to the first self-report of either physician-diagnosed depression or regular antidepressant use. We used Cox proportional hazards models to examine the relationship between greenness and depression incidence and assessed physical activity as a potential effect modifier and mediator. Results: Over 315,548 person-years, 3,612 incident depression cases occurred. In multivariable-adjusted models, living in the highest quintile of residential greenness within 250m was associated with a 13% reduction in depression risk (HR=0.87 [95% confidence interval (CI): 0.78, 0.98]) compared with the lowest quintile. The association between greenness and depression did not appear to be mediated by physical activity, nor was there evidence of effect modification by physical activity. Conclusions: In this population of mostly white women, we estimated an inverse association between the highest level of surrounding summer greenness and the risk of self-reported depression. https://doi.org/10.1289/EHP1229
Phase I/II study of ramucirumab plus nivolumab in patients in second-line treatment for advanced gastric adenocarcinoma (NivoRam study).
Authors: Hiroki Hara, Hirokazu Shoji, Daisuke Takahari, Taito Esaki, Nozomu Machida, Kengo Nagashima, Kazunori Aoki, Kazufumi Honda, Takahiro Miyamoto, Narikazu Boku, Ken Kato
Journal: Journal of Clinical Oncology (2019)

129 Background: Nivolumab (Nivo) showed a survival benefit in salvage line of advanced gastric cancer (AGC) patients in ATTRACTION-2 trial. Based on synergistic anti-tumor effects by simultaneous blockade of PD-1 and VEGFR-2, this phase 1/2 study was conducted to investigate the safety and efficacy of Nivo plus ramucirumab (Ram) in the second line chemotherapy for AGC. Methods: AGC patients with measurable lesions, PS 0-1, disease progression on first line chemotherapy containing platinum were eligible. Patients received Nivo (3mg/kg, Q2W) and Ram (8mg/kg, Q2W) until unacceptable toxicity or disease progression. After feasibility was evaluated in six patients (phase 1 part), additional 40 patients were required in a phase 2 part with the primary analysis (expected 6-months progression-free survival (PFS) rate of 36%, threshold of 18%, one-sided alpha level of 10%, power of 90%). Secondary endpoints included overall response rate (ORR), disease control rate (DCR), PFS, overall survival (OS), and safety. Results: 46 AGC patients (median age 66 years, PS 1 40%) were enrolled. No dose limiting toxicities were observed in the phase 1 part. With median follow up time of 10.2 month, 6-month PFS rate was 37.4% (90% confidential intervals: 25.7-49.2%), which met the primary endpoint of the phase 2 part. ORR/DCR were 26.7%/62.2%. Median PFS/OS were 2.9/9.0 months. Among all enrolled patients, grade 3 or 4 treatment related adverse events were hypertension (n = 2), diarrhea (n = 2), perforation at jejunum (n = 1), hemorrhage (n = 1), colitis (n = 1), pancreatitis (n = 1), liver dysfunction (n = 1), cholangitis (n = 1), hematoma (n = 1), neutropenia (n = 1) and proteinuria (n = 1). There were no treatment-related deaths. Conclusions: Combination of Nivo and Ram showed promising antitumor activity and mild toxicity profile for second line AGC, which is worth evaluating in a further confirmatory study. Clinical trial information: NCT02999295.
MicroRNA-34a Promotes Renal Fibrosis by Downregulation of Klotho in Tubular Epithelial Cells
Authors: Yong Liu, Xianjin Bi, Jiachuan Xiong, Wenhao Han, Tangli Xiao, Xinli Xu, Ke Yang, Chi Liu, Wei Jiang, Ting He, Yanlin Yu, Yan Li, Jingbo Zhang, Bo Zhang, Jinghong Zhao
Journal: Molecular Therapy (2019)

Renal fibrosis is the main pathological characteristic of chronic kidney disease (CKD), whereas the underlying mechanisms of renal fibrosis are not clear yet. Herein, we found an increased expression of microRNA-34a (miR-34a) in renal tubular epithelial cells of patients with renal fibrosis and mice undergoing unilateral ureteral obstruction (UUO). In miR-34a-/- mice, miR-34a deficiency attenuated the progression of renal fibrosis following UUO surgery. The miR-34a overexpression promoted epithelial-to-mesenchymal transition (EMT) in cultured human renal tubular epithelial HK-2 cells, which was accompanied by sharp downregulation of Klotho, an endogenous inhibitor of renal fibrosis. Luciferase reporter assay revealed that miR-34a downregulated Klotho expression though direct binding with the 3' UTR of Klotho. Conversely, overexpression of Klotho prevented miR-34a-induced EMT in HK-2 cells. Furthermore, results showed that miR-34a was induced by transforming growth factor β1 (TGF-β1) through p53 activation, whereas dihydromyricetin could inhibit TGF-β1-induced miR-34a overexpression. Accordingly, dihydromyricetin administration dramatically restored the aberrant upregulation of miR-34a and Klotho reduction in obstructed kidney, and markedly ameliorated renal fibrosis in the Adriamycin nephropathy and UUO model mice. These findings suggested that miR-34a plays an important role in the progression of renal fibrosis, which provides new insights into the pathogenesis and treatment of CKD.