tbuckley/cabot-search huggingface dataset:
Regulation of Akt/PKB expression in colorectal cancer cells
Authors: Susanne Dihlmann, Matthias Kloor, Carmen Gurrola, Magnus Von Knebel Doeberitz
Journal: Cancer Research (2004)

3927  The serin/threonine kinase Akt/Protein kinase B (PKB) is a key regulator of the phosphatidylinositol 3-kinase pathway and plays a critical role in controlling the balance between cell survival and apoptosis. Upon activation, Akt delivers survival signals by inhibiting pro-apoptotic molecules such as Bad, Caspase-9, IkB kinase (IKK) and forkhead transcription factors. Several reports implicated Akt/PKB in the molecular pathogenesis of different human malignancies. Overexpression of Akt/PKB was recently demonstrated to be an early event in colorectal carcinogenesis. In the course of analysing the molecular effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on different cancer cell lines we observed that the Akt/PKB protein level is reduced in response to aspirin. Expression profiling of aspirin treated colon cancer cells using oligonucleotide microarrays and quantitative real time RT-PCR revealed that expression of Akt1 but not that of its isoforms Akt2 and 3 was downregulated within 24 hours upon treatment. Interestingly, Akt-downregulation thereby ran parallel to aspirin-induced inhibition of Wnt/beta-Catenin signalling. To further elucidate the regulation of Akt expression in colon cancer cells we generated reporter constructs containing the luciferase gene under control of the Akt1 promoter region. By database analysis of the genomic sequence we identified 9 putative beta-Catenin/TCF binding elements within 2200 bp upstream of the transcription start site of the Akt1 gene. Accordingly, we hypothesized that the Akt1 gene might be regulated by the Wnt/beta-Catenin pathway. Transient expression of different reporter constructs containing Akt1 promoter regions revealed that the Akt1 promoter is stimulated in colorectal cancer cell lines harbouring constitutively activated Wnt-signalling. Luciferase expression was stimulated 5-fold in SW948 cells and 20-fold in HCT116 cells. In contrast, the promoter construct showed only a weak response in 293 embryonic kidney cells. By co-expression of a constitutive active beta-Catenin mutant the activation was further enhanced, indicating beta-Catenin/TCF dependent transcription of the Akt1 gene in colon cancer cells. In addition, immunohistochemical staining of tumor sections derived from colorectal cancer patients revealed elevated expression levels of Akt1, correlating with enhanced nuclear expression of beta-Catenin. In summary we propose that Akt1 is directly regulated by beta-Catenin. Since activation of the Akt kinase in turn leads to stabilization and accumulation of beta-Catenin, this might result in an autocrine loop reducing the response to apoptotic stimuli.
Re: Malte W. Vetterlein, Jakob Klemm, Philipp Gild, et al. Improving Estimates of Perioperative Morbidity After Radical Cystectomy Using the European Association of Urology Quality Criteria for Standardized Reporting and Introducing the Comprehensive Complication Index. Eur Urol 2020;77:55–65
Authors: Francesco Montorsi, Marco Bandini, Andrea Necchi
Journal: European Urology (2020)
IL26, a Noncanonical Mediator of DNA Inflammatory Stimulation, Promotes TNBC Engraftment and Progression in Association with Neutrophils
Authors: Timothy N. Trotter, Casey W. Shuptrine, Li-Chung Tsao, Robert D. Marek, Chaitanya Acharya, Jun-Ping Wei, Xiao-Yi Yang, Gangjun Lei, Tao Wang, Herbert Kim Lyerly, Zachary C. Hartman
Journal: Cancer Research (2020)

Abstract IL26 is a unique amphipathic member of the IL10 family of cytokines that participates in inflammatory signaling through a canonical receptor pathway. It also directly binds DNA to facilitate cellular transduction and intracellular inflammatory signaling. Although IL26 has almost no described role in cancer, our in vivo screen of inflammatory and cytokine pathway genes revealed IL26 to be one of the most significant inflammatory mediators of mammary engraftment and lung metastatic growth in triple-negative breast cancer (TNBC). Examination of human breast cancers demonstrated elevated IL26 transcripts in TNBC specimens, specifically in tumor cells as well as in Th17 CD4+ T cells within clinical TNBC specimens. IL26 did not have an autocrine effect on human TNBC cells, but rather its effect on engraftment and growth in vivo required neutrophils. IL26 enhanced mouse-derived DNA induction of inflammatory cytokines, which were collectively important for mammary and metastatic lung engraftment. To neutralize this effect, we developed a novel IL26 vaccine to stimulate antibody production and suppress IL26-enhanced engraftment in vivo, suggesting that targeting this inflammatory amplifier could be a unique means to control cancer-promoting inflammation in TNBC and other autoimmune diseases. Thus, we identified IL26 as a novel key modulator of TNBC metastasis and a potential therapeutic target in TNBC as well as other diseases reliant upon IL26-mediated inflammatory stimulation. Significance: These findings identify IL26 as a unique, clinically relevant, inflammatory amplifier that enhances TNBC engraftment and dissemination in association with neutrophils, which has potential as a therapeutic target.
Abstract 17176: Excess Neurohormonal Activation-Induced Heart Failure Results in Significant but Non-Critical Cardiomyocyte Telomere Shortening, Which is Associated With Impaired Myocardial Fatty Acid Utilization and Downregulation of MiR-133a and Fatty Acid Translocase (CD36)
Authors: Moritz Brandt, Hendrik Dörschmann, Venkata Garlapati, Philip Wenzel
Journal: Circulation (2019)

Telomere shortening induces heart failure (HF). Yet, this has only been shown for a shortening of more than 50%, an extreme only achieved in late generation 4/5 (G4/5) mice inherently lacking telom...
Abstract MP002: Active Exercise Buddies Help Women With Young Children Improve Physical Activity
Authors: JiWon Choi
Journal: Circulation (2017)

Introduction: Women with young children are vulnerable to physical inactivity due to physical, emotional, or social changes resulting from pregnancy and child rearing. Family/friend social support is considered as an enabler to physical activity (PA) among physically inactive women with young children. However, little is known about how to utilize family/friend social support in this population. Purpose: The purpose of this pilot randomized controlled trial was to examine the potential efficacy of a 12-week buddy PA intervention in increasing PA among women with young children. Methods: Flyers posted in public places, advertisements via a local newspaper and campus shuttle buses as well as online postings through local parents’ groups were used for recruitment between January 2015 and March 2016. Out of 108 women who contacted the research team via telephone or email, 79 met the eligibility criteria. The inclusion criteria were 1) 18-44 years of age; 2) having at least one child aged less than 5 years; 3) having at least one family member or friend who can support PA and reside in the community with the participant; 4) 25 kg/m 2 ≤ body mass index &lt; 45 kg/m 2 ; and 5) intent to increase PA. After run-in, 49 women were randomized into one of the two groups (the buddy group and the control group). Women assigned to the buddy group designated an exercise buddy and received a face-to-face session along with their buddies. Both participant as well as buddy received an accelerometer and installed its mobile app on their mobile phones. The primary outcome was the mean number of steps per day for the prior week measured by accelerometer. The effect of the intervention versus control condition on the primary outcome was examined in an intent-to-treat approach. We also did per-protocol-analyses to compare three groups, dividing the buddy groups into 2 groups depending changes in PA among buddies (active buddy and inactive buddy) along with the control group. Results: 47 women completed the study. There were no significant differences between the intervention and control groups in steps at baseline ( p = 0.46) as well as in changes in mean steps per day ( p = 0.56). When the three groups (active buddy, inactive buddy, and control groups) were compared, there was no significant difference among groups in steps at baseline ( p = 0.61), but overall changes in mean steps per day during 12 weeks were significantly different among groups ( p = 0.018). The active buddy group ( p =0.005) and the control group ( p =0.023) showed significantly higher step changes than the inactive buddy group (1779 and 1272 vs. 76). Conclusions: The study findings indicate that having an inactive buddy for exercise would not help women to increase their PA and could be worse than having no buddy. Women may need to join a social network of physically active individuals and emulate other physically active people.
R3-Survey of traumatic brain injury management in European Brain IT centres year 2001
Authors: P. Enblad, P. Nilsson, I. Chambers, G. Citerio, H. Fiddes, T. Howells, K. Kiening, A. Ragauskas, J. Sahuquillo, Y. H. Yau, C. Contant, I. Piper
Journal: Intensive Care Medicine (2004)
Conflicting obligations in human social life
Authors: Jacob B Hirsh, Garriy Shteynberg, Michele J Gelfand
Journal: Behavioral and Brain Sciences (2020)

Abstract Tomasello describes how the sense of moral obligation emerges from a shared perspective with collaborative partners and in-group members. Our commentary expands this framework to accommodate multiple social identities, where the normative standards associated with diverse group memberships can often conflict with one another. Reconciling these conflicting obligations is argued to be a central part of human morality.
Age at menopause and lung function: a Mendelian randomisation study
Authors: Diana A. van der Plaat, Miguel Pereira, Giancarlo Pesce, James F. Potts, André F.S. Amaral, Shyamali C. Dharmage, Judith M. Garcia-Aymerich, John R. Thompson, Francisco Gómez Real, Deborah L. Jarvis, Cosetta Minelli, Bénédicte Leynaert
Journal: European Respiratory Journal (2019)

In observational studies, early menopause is associated with lower forced vital capacity (FVC) and a higher risk of spirometric restriction, but not airflow obstruction. It is, however, unclear if this association is causal. We therefore used a Mendelian randomisation (MR) approach, which is not affected by classical confounding, to assess the effect of age at natural menopause on lung function.We included 94 742 naturally post-menopausal women from the UK Biobank and performed MR analyses on the effect of age at menopause on forced expiratory volume in 1 s (FEV1), FVC, FEV1/FVC, spirometric restriction (FVC<lower limit of normal (LLN)) and airflow obstruction (FEV1/FVC<LLN). We used the inverse variance-weighted method, as well as methods that adjust for pleiotropy, and compared MR with observational analyses.The MR analyses showed higher FEV1/FVC and a 15% lower risk of airflow obstruction for women with early (<45 years) compared to normal (45-55 years) menopause. Despite some evidence of pleiotropy, the results were consistent when using MR methods robust to pleiotropy. Similar results were found among never- and ever-smokers, while the protective effect seemed less strong in women who had ever used menopause hormone treatment and in overweight women. There was no strong evidence of an association with FVC or spirometric restriction. In observational analyses of the same dataset, early menopause was associated with a pronounced reduction in FVC and a 13% higher risk of spirometric restriction.Our MR results suggest that early menopause has a protective effect on airflow obstruction. Further studies are warranted to better understand the inconsistency with observational findings, and to investigate the underlying mechanisms and role of female sex hormones.
Antibodies against immunogenic epitopes with high sequence identity to SARS-CoV-2 in patients with autoimmune dermatomyositis
Authors: Spyridon Megremis, Thomas D J Walker, Xiaotong He, William E R Ollier, Hector Chinoy, Lynne Hampson, Ian Hampson, Janine A Lamb
Journal: Annals of the Rheumatic Diseases (2020)

Idiopathic inflammatory myopathies (IIMs) are rare, heterogeneous, autoimmune musculoskeletal diseases, characterised clinically by muscle weakness. Extramuscular involvement includes the skin, respiratory and cardiovascular systems. Genetic and environmental factors contribute to IIM susceptibility, and viral or bacterial infection may contribute to disease pathogenesis.

Both the innate and adaptive immune systems are important in IIM pathology. Two-thirds of affected individuals have known myositis-specific or associated autoantibodies, often linked to particular clinical features,1 and directed against proteins involved in key intracellular processes. Interferon pathways are differentially activated in clinical subtypes of myositis2; this interferon response is critical to protect the host against viral infection and modulate the antiviral immune response.

We recently used a high-throughput approach combining disease-specific immunoglobulin epitope signature enrichment and antigen identification from the total microbial ‘exposome’ (including viruses, bacteria, archaea and fungi) and human proteins.3 We applied this serum antibody repertoire analysis pipeline to investigate the microbial and autoantigen antibody repertoire accumulated throughout life in 20 adult-onset dermatomyositis patients seropositive for TIF1γ (TRIM33) autoantibodies, compared with 20 age-matched and gender-matched healthy controls.3

Human coronaviruses are associated with the common cold, but can lead to fatal inflammatory responses and acute lung injury. Emergence of a novel coronavirus …
Survivre et vivre: When iNKT cells met a Hippo
Authors: Luc Van Kaer, Sebastian Joyce
Journal: The Journal of Experimental Medicine (2020)

Invariant natural killer T (iNKT) cells are innate-like lymphocytes with unique signaling requirements for their development and differentiation. In this issue of JEM, Raynor et al. (https://doi.org/10.1084/jem.20191157) report that the Hippo signaling pathway controls the maturation and effector differentiation of iNKT cells by modulating cellular metabolism.
PSMA-Ligand Imaging in the Diagnosis of Prostate Cancer
Authors: Ali Afshar-Oromieh
Journal: Clinical Nuclear Medicine (2020)

During the past years, the prostate-specific membrane antigen (PSMA) has received increased attention as an excellent target for prostate carcinoma (PC) imaging and therapy. PSMA, also known as glutamate carboxypeptidase II, N-acetyl-α-linked acidic dipeptidase I, or folate hydrolase, is an enzyme which is significantly overexpressed in prostate cancer cells. Another advantages of PSMA are its transmembraneous location with a large extracellular domain and its enzyme activity which allows the development of specific inhibitors and their internalization after ligand binding.
Abstract 257: Ventricular Fibrillation Amplitude Spectral Area to Assess the Myocardial Effect of Hemodynamic and Metabolic Interventions During Cardiac Resuscitation in a Rat Model
Authors: Salvatore Aiello, Lorissa Lamoureux, Alvin Baetiong, Jeejabai Radhakrishnan, Raul J Gazmuri
Journal: Circulation (2019)

Introduction: The amplitude spectral area (AMSA) of ventricular fibrillation (VF) has been shown to track the myocardial energy state and to predict the effect of defibrillation. We measured AMSA in a rat model of VF and assessed the effects of α-methylnorepinephrine (α-MNE) - a selective peripheral α 2 -adrenoreceptor agonist - given to increase the coronary perfusion pressure without myocardial β 1 -adrenoceptor stimulation and the effects of zoniporide (ZNP) - an inhibitor of the sodium-hydrogen exchanger isoform-1 - given to protect mitochondrial bioenergetic function from reperfusion injury. Methods: VF was electrically induced in 48 rats and left untreated for 8 minutes. Chest compression was then started and defibrillation attempted 8 minutes later. Rats were randomized to receive a 3-mg/kg bolus of ZNP or 0.9% NaCl control (Ctr) before starting chest compression and a 100-μg/kg bolus of α-MNE or 0.9% NaCl control (Ctr) at 2 minutes of chest compression yielding four groups of 12 rats each; ZNP/α-MNE, ZNP/Ctr, Ctr/α-MNE, and Ctr/Ctr. Results: AMSA (mV·Hz; mean±SEM) was 34.9±1.5 at minute one after induction of VF and decreased to 2.6±0.2 at minute eight. With chest compression, AMSA gradually increased attaining different levels among groups (p&lt;0.001). At minute seven of chest compression, AMSA was the highest with ZNP/α-MNE (29.9±2.5; p=0.012 vs Ctr/α-MNE and p&lt;0.001 vs Ctr/Ctr) followed by ZNP/Ctr (24.1±2.5; p=0.016 vs Ctr/Ctr), Ctr/α-MNE (18.9±2.3), and Ctr/Ctr (12.9±2.6). Survival at 240 minutes differed among groups (p=0.007) with the highest survival with ZNP/α-MNE. Analysis of the independent effects of the interventions revealed that AMSA at minute seven was significantly higher with ZNP (27.2±2.6 vs 16.2±1.6; p&lt;0.001) but not with α-MNE (22.9±2.1 vs 18.6±2.8; p=1.000). Survival was significantly higher with ZNP (18/24 vs 7/24; p=0.004) but not with α-MNE (12/24 vs 13/24; p=1.000). Conclusions: AMSA was the highest when ZNP was combined with α-MNE; a combination that also resulted in the highest 240-minute survival. This effect was primarily linked to ZNP without excluding a positive interaction with α-MNE. Accordingly, AMSA may also serve to assess the myocardial effects of metabolic interventions during cardiac resuscitation.
ADTH-01 Endoscopic full thickness resection in the colon: 3-year multicentre UK experience
Authors: Max Hu, Imdadur Rahman, Sauid Ishaq, Pradeep Bhandari, Stirling Pugh, Susi Green, Noriko Suzuki, Andrew Hopper, John Martin, Siwan Thomas-Gibson, Praful Patel, Phil Boger
Journal: Endoscopy (2018)

<h3>Introduction</h3> Endoscopic full thickness resection (eFTR) of the colon using the full thickness resection device (FTRD) is a novel method for removing lesions involving, or tethered to, deeper layers of the colonic wall. The UK FTRD registry collects data from multiple centres performing this procedure. We describe the feasibility and early outcomes of this technique. <h3>Methods</h3> Registry data from April 2015 – January 2018 was analysed. Main outcome measures were technical success, procedural time, specimen size, R0 resection, endoscopic clearance, and adverse events. Reported technical difficulties were collated. <h3>Results</h3> 38 cases were performed across 8 centres (median 2 cases per centre, range 1–23). Mean patient age was 70 years (39–93). Indications for eFTR include non-lifting adenoma (18 cases), T1 tumour resection (10), submucosal tumour (7), and appendix base adenoma (3). In 97.4% (37/38) of patients the lesion was reached with the FTRD. One caecal lesion could not be reached due to sigmoid diverticulosis. The procedure was technically successful in 91.9% of patients (34/37). Median procedure time was 41 minutes (11–86), median resection time 6 minutes (2–36), and median specimen size 22mm (10–30). R0 resection was achieved in 76.5% of patients (26/34). R0 resection was not achieved in 8 patients, of which 5 had no residual lesion on follow up, giving a total endoscopic clearance rate of 91.2% (31/34). Technical difficulty occurred in 9 patients; 6 due to snare failure and 3 due to lesion slippage on clip deployment. Of these 9 cases, 7 achieved R0 resection by use of further snare. Of the 2 patients with R1 resection, one has had follow up at 4 months with no evidence of residual lesion. Resection was unsuccessful in 3 patients; 2 due to significant tethering restricting lesion capture, and one due to haemodynamic instability from atrial fibrillation whilst pulling lesion into cap. Complications occurred in 2 patients; one acute appendicitis at day 6 after resection of appendix base adenoma, and one with mild asymptomatic stricture at eFTR site at follow up. There were no cases of bleeding, perforation, or fistula. <h3>Conclusions</h3> eFTR has a high success rate in treating lesions not previously amenable to endoscopic therapy. Whilst technical difficulties may arise; complication rates are low and outcomes acceptable, making eFTR a viable alternative to surgery.
Changing epidemiology and outcomes of acute kidney injury in hospitalized patients with cirrhosis – a US population-based study
Authors: Archita P. Desai, Shannon M. Knapp, Eric S. Orman, Marwan S. Ghabril, Lauren D. Nephew, Melissa Anderson, Pere Ginès, Naga P. Chalasani, Kavish R. Patidar
Journal: Journal of Hepatology (2020)
Erratum: SAMHD1 restricts the replication of human immunodeficiency virus type 1 by depleting the intracellular pool of deoxynucleoside triphosphates
Authors: Hichem Lahouassa, Waaqo Daddacha, Henning Hofmann, Diana Ayinde, Eric C Logue, Loïc Dragin, Nicolin Bloch, Claire Maudet, Matthieu Bertrand, Thomas Gramberg, Gianfranco Pancino, Stéphane Priet, Bruno Canard, Nadine Laguette, Monsef Benkirane, Catherine Transy, Nathaniel R Landau, Baek Kim, Florence Margottin-Goguet
Journal: Nature Immunology (2012)
PTH-004 Deep learning for real-time automated polyp localisation in colonoscopy videos
Authors: Omer F Ahmad, Imanol Luengo, Luis Garcia Peraza Herrera, Patrick Brandao, Wenqi Li, Martin Everson, Rehan Haidry, Roser Vega, Ed Seward, Tom Vercauteren, Laurence B Lovat
Journal: Endoscopy (2018)

<h3>Introduction</h3> Colonoscopic polypectomy can prevent colorectal cancer. Polyp detection rates vary considerably due to human error and missed adenomas may contribute to interval colorectal cancers. Automated polyp detection using deep learning may avoid these problems. Previous work focused on detecting the presence of polyps in individual frames captured from videos. Our aims in this pilot study were to extend this to video sequences and to explore future-proofing by using algorithms trained on old image processors to locate polyps found using newer endoscopic technologies. <h3>Methods</h3> We trained and validated a Convolutional Neuronal Network (CNN) on 18 517 frames created by merging research colonoscopy datasets (CVCClinic, ASUMayo, ETIS, CVCVideoDB and CVCColon) from the Medical Image Computing and Computer Assisted Intervention Society challenges. 75% of frames contained polyps in both standard and high definition (HD) from older processors including Olympus Exera II (160/165 series) and Pentax EPKi 7000 (90i series). Our test set consisted of 11 HD videos featuring polyps in white light collected using the latest Olympus 290 endoscopes at a UK tertiary centre. Estimated median polyp size was 4 mm (range 2–15) and morphology included (Paris Classification IIa=4, Is=6 and IIa +IIs LST-G=1). Images were manually annotated by drawing bounding boxes around polyps and quality controlled by removing uninformative frames (e.g. blurred). A total of 2611 polyp-containing frames were analysed in the test set. A true positive was scored if the computer-generated segmentation mask prediction overlapped with the bounding box. A false positive indicated a non-overlapping location (more than one can occur per frame). <h3>Results</h3> Our network operated at real-time video rate. F1-score accuracy was 92.5%. Sensitivity for polyp localisation was 98.5% and per-frame specificity 75.4%. Positive predictive value was 90.1%. Incorrect segmentation mask locations were predominantly limited to 3 videos and were generated by artefacts not represented during training. <h3>Conclusion</h3> We demonstrate through analysis of video frames that a CNN can locate polyps with high accuracy in real-time. The algorithm was trained using multiple endoscopy processors and worked with HD images from a new processor. This suggests that the CNN could remain useful as new endoscopic technologies are introduced. Further work will train our model on larger datasets including complete colonoscopy procedures. This should improve accuracy further. Such a system could be used as a red-flag technique to reduce missed adenomas during colonoscopy.