tbuckley/cabot-search huggingface dataset:
Transforming Growth Factor‐β and Axl Induce CXCL5 and Neutrophil Recruitment in Hepatocellular Carcinoma
Authors: Christine Haider, Julia Hnat, Roland Wagner, Heidemarie Huber, Gerald Timelthaler, Markus Grubinger, Cédric Coulouarn, Wolfgang Schreiner, Karin Schlangen, Wolfgang Sieghart, Markus Peck‐Radosavljevic, Wolfgang Mikulits
Journal: Hepatology (2018)

Transforming growth factor (TGF)-β suppresses early hepatocellular carcinoma (HCC) development but triggers pro-oncogenic abilities at later stages. Recent data suggest that the receptor tyrosine kinase Axl causes a TGF-β switch toward dedifferentiation and invasion of HCC cells. Here, we analyzed two human cellular HCC models with opposing phenotypes in response to TGF-β. Both HCC models showed reduced proliferation and clonogenic growth behavior following TGF-β stimulation, although they exhibited differences in chemosensitivity and migratory abilities, suggesting that HCC cells evade traits of anti-oncogenic TGF-β. Transcriptome profiling revealed differential regulation of the chemokine CXCL5, which positively correlated with TGF-β expression in HCC patients. The expression and secretion of CXCL5 was dependent on Axl expression, suggesting that CXCL5 is a TGF-β target gene collaborating with Axl signaling. Loss of either TGF-β or Axl signaling abrogated CXCL5-dependent attraction of neutrophils. In mice, tumor formation of transplanted HCC cells relied on CXCL5 expression. In HCC patients, high levels of Axl and CXCL5 correlated with advanced tumor stages, recruitment of neutrophils into HCC tissue, and reduced survival. Conclusion: The synergy of TGF-β and Axl induces CXCL5 secretion, causing the infiltration of neutrophils into HCC tissue. Intervention with TGF-β/Axl/CXCL5 signaling may be an effective therapeutic strategy to combat HCC progression in TGF-β-positive patients.
A Bayesian decision-making framework for replication
Authors: Tom E. Hardwicke, Michael Henry Tessler, Benjamin N. Peloquin, Michael C. Frank
Journal: Behavioral and Brain Sciences (2018)

Abstract Replication is the cornerstone of science – but when and why? Not all studies need replication, especially when resources are limited. We propose that a decision-making framework based on Bayesian philosophy of science provides a basis for choosing which studies to replicate.
D-2-Hydroxyglutarate Is an Intercellular Mediator in IDH-Mutant Gliomas Inhibiting Complement and T Cells
Authors: Lingjun Zhang, Mia D. Sorensen, Bjarne W. Kristensen, Guido Reifenberger, Thomas M. McIntyre, Feng Lin
Journal: Clinical Cancer Research (2018)

Abstract Purpose: Somatic mutations in the isocitrate dehydrogenase (IDH)-1 and -2 genes are remarkably penetrant in diffuse gliomas. These highly effective gain-of-function mutations enable mutant IDH to efficiently metabolize isocitrate to D-2-hydroxyglutarate (D 2-HG) that accumulates to high concentrations within the tumor microenvironment. D 2-HG is an intracellular effector that promotes tumor growth through widespread epigenetic changes in IDH-mutant tumor cells, but its potential role as an intercellular immune regulator remains understudied. Experimental Design: Complement activation and CD4+, CD8+, or FOXP3+ T-cell infiltration into primary tumor tissue were determined by immunohistochemistry using sections from 72 gliomas of World Health Organization (WHO) grade III and IV with or without IDH mutations. Ex vivo experiments with D 2-HG identified immune inhibitory mechanisms. Results: IDH mutation associated with significantly reduced complement activation and decreased numbers of tumor-infiltrating CD4+ and CD8+ T cells with comparable FOXP3+/CD4+ ratios. D 2-HG potently inhibited activation of complement by the classical and alternative pathways, attenuated complement-mediated glioma cell damage, decreased cellular C3b(iC3b) opsonization, and impaired complement-mediated phagocytosis. Although D 2-HG did not affect dendritic cell differentiation or function, it significantly inhibited activated T-cell migration, proliferation, and cytokine secretion. Conclusions: D 2-HG suppresses the host immune system, potentially promoting immune escape of IDH-mutant tumors. Clin Cancer Res; 24(21); 5381–91. ©2018 AACR.
Are doctors wrong for stating the elephant in the room?
Authors: Eugene Y H Yeung
Journal: BMJ (2018)

Sokol’s article “Doctors shouldn’t reveal so much” reminded me of the tale of the emperor’s new clothes.1 But Sokol seems to glorify people who stay quiet and criticise those who state the elephant in the room.

Doctors’ candour raises concerns about healthcare that readers debate to find solutions. According to the General Medical Council’s Good Medical Practice , doctors must promote and encourage a …
Impact of lenalidomide use among non-transfusion dependent patients with myelodysplastic syndromes
Authors: Andrew M. Brunner, Shicheng Weng, Angel Cronin, Amir T. Fathi, Anand R. Habib, Richard Stone, Tim Graubert, David P. Steensma, Gregory A. Abel
Journal: American Journal of Hematology (2018)

Chemotherapies approved for defined subgroups promise personalized oncologic care, but their off-label impact is unclear. Lenalidomide is approved for lower-risk, transfusion-dependent (TD) myelodysplastic syndromes (MDS) with del(5q), but frequently used in MDS outside this indication. We characterized lenalidomide use and outcomes among non-TD patients with MDS. Patients 65 or older diagnosed with MDS between 2007 and 2013 were identified using SEER; linked Medicare claims were evaluated for transfusions, lenalidomide use, and incident toxicities. TD was ≥2 transfusion episodes within an 8-week period; responses were transfusion independence (TI) and ≥50% transfusion reduction (minor response). We compared overall survival for non-TD patients receiving lenalidomide versus those not receiving lenalidomide, matched on disease and patient characteristics. We identified 676 patients who had received lenalidomide, including 275 (40.7%) TD and 401 (59.3%) non-TD; 18.5% (125/676) had zero claims for RBC transfusion prior to receiving lenalidomide. Incident toxicities among patients prescribed lenalidomide were similar in TD and non-TD groups, except incident thromboembolic events were higher among non-TD patients (10.8% vs. 6.0%, P = .04). Comparing 191 non-TD patients receiving lenalidomide within 6 months of MDS diagnosis to risk-matched MDS controls, lenalidomide was not associated with improved OS (P = .78). Among TD patients (n = 275), 31% achieved TI, and 30% achieved minor hematologic response, with a median time to TI of 4.1 weeks. In conclusion, we confirmed the benefit of lenalidomide among TD patients with MDS; however, many non-TD patients also received lenalidomide. These patients experienced accompanying toxicity without evidence of benefit in terms of transfusion needs or overall survival.
Junior doctors left without rotas weeks before starting new jobs, BMA warns
Authors: Abi Rimmer
Journal: BMJ (2018)

The BMA is calling for trusts’ compliance with rota deadlines to be treated with the same scrutiny as emergency department waiting time performance.

The association said it had been contacted by dozens of junior doctors from across England who had experienced delays in receiving their rotas before starting their new placements next week. It said that many doctors were still uncertain where and when they would be working.

BMA junior doctor representatives urged NHS Improvement and the Care Quality Commission (CQC) to impose the same scrutiny to trusts who don’t give junior doctors their rotas on time as those who fail to meet emergency department waiting time targets.

According to …
Airway Epithelial Cell-Derived Colony Stimulating Factor-1 Promotes Allergen Sensitization
Authors: Hyung-Geun Moon, Seung-jae Kim, Jong Jin Jeong, Seon-Sook Han, Nizar N. Jarjour, Hyun Lee, Sherry L. Abboud-Werner, Sangwoon Chung, Hak Soo Choi, Viswanathan Natarajan, Steven J. Ackerman, John W. Christman, Gye Young Park
Journal: Immunity (2018)
Abstract 15891: Relationship Between Peripheral Vascular Responses With Mental Stress and Mental Stress-induced Myocardial Ischemia
Authors: Muhammad Hammadah, Malik Obideen, Uphoff Irina, Naser Abdelhadi, Ayman Alkhoder, Oleksiy Levantsevych, Shuyang Fang, Ijeoma Ibeanu, Heval Mohamed Kelli, Pratik Pimple, Zakaria Almuwaqqat, Nino Isakadze, Mouwafak Moureiden, Ibhar Al Mheid, Ronnie Ramadan, Kobina Wilmot, Amit J Shah, Brad Pearce, Yan Sun, Ernest Garcia, Fabio Esteves, Paolo Raggi, J. Douglas Bremner, Viola Vaccarino, Arshed Quyyumi
Journal: Circulation (2016)

Background:  Mental stress-induced myocardial ischemia (MSIMI) in patients with CAD is unrelated to its severity and is associated with adverse cardiovascular outcomes. The impact of vascular function and its response to mental stress (MS) on the development of MSIMI remains unclear. We measured endothelial function and arterial stiffness, and their change with MS, with the hypothesis that abnormalities in the vascular functional responses will contribute to MSIMI.   Methods:  Patients with stable CAD underwent 99mTc sestamibi myocardial perfusion imaging during MS testing using a public speaking stressor. MSIMI was defined as impaired myocardial perfusion using a 17-segment model. Endothelial function [endothelium-dependent flow-mediated dilation (FMD)], microvascular reactivity [reactive hyperemia index (RHI, Endo-PAT2000)] and arterial stiffness [pulse wave velocity (PWV), Sphygmocor Inc.] were measured at rest and 30-min after MS.   Results:  Of 457 patients with CAD aged 63±9 years (75% male), 87 (15.5%) developed MSIMI. FMD decreased [Median (IQR) change: -0.8 (-2.5 - 0.6)%, p=0.002], PWV increased [median (IQR) change: 0.3 (-0.7 - 1.2) m/s, p=0.025], but there was no change in RHI after MS (Figure). There were no significant differences in either the baseline or post-MS vascular measures between patients with and without MSIMI (Figure).   Conclusion:  MS is associated with impairment of conductance vessel but not microvascular endothelial dysfunction and with increased arterial stiffness. The magnitude of these alterations is not a predictor of MSIMI in CAD.
Radiation Exposure From Pediatric CT Scans and Subsequent Cancer Risk in the Netherlands
Authors: Johanna M Meulepas, Cécile M Ronckers, Anne M J B Smets, Rutger A J Nievelstein, Patrycja Gradowska, Choonsik Lee, Andreas Jahnen, Marcel van Straten, Marie-Claire Y de Wit, Bernard Zonnenberg, Willemijn M Klein, Johannes H Merks, Otto Visser, Flora E van Leeuwen, Michael Hauptmann
Journal: JNCI Journal of the National Cancer Institute (2018)

Computed tomography (CT), a strong diagnostic tool, delivers higher radiation doses than most imaging modalities. As CT use has increased rapidly, radiation protection is important, particularly among children. We evaluate leukemia and brain tumor risk following exposure to low-dose ionizing radiation from CT scans in childhood.For a nationwide retrospective cohort of 168 394 children who received one or more CT scans in a Dutch hospital between 1979 and 2012 who were younger than age 18 years, we obtained cancer incidence, vital status, and confounder information by record linkage with external registries. Standardized incidence ratios were calculated using cancer incidence rates from the general Dutch population. Excess relative risks (ERRs) per 100 mGy organ dose were calculated with Poisson regression. All statistical tests were two-sided.Standardized incidence ratios were elevated for all cancer sites. Mean cumulative bone marrow doses were 9.5 mGy at the end of follow-up, and leukemia risk (excluding myelodysplastic syndrome) was not associated with cumulative bone marrow dose (44 cases). Cumulative brain dose was on average 38.5 mGy and was statistically significantly associated with risk for malignant and nonmalignant brain tumors combined (ERR/100 mGy: 0.86, 95% confidence interval = 0.20 to 2.22, P = .002, 84 cases). Excluding tuberous sclerosis complex patients did not substantially change the risk.We found evidence that CT-related radiation exposure increases brain tumor risk. No association was observed for leukemia. Compared with the general population, incidence of brain tumors was higher in the cohort of children with CT scans, requiring cautious interpretation of the findings.
Constraints on generality statements are needed to define direct replication
Authors: Daniel J. Simons, Yuichi Shoda, D. Stephen Lindsay
Journal: Behavioral and Brain Sciences (2018)

Abstract Whether or not a replication attempt counts as “direct” often cannot be determined definitively after the fact as a result of flexibility in how procedural differences are interpreted. Specifying constraints on generality in original articles can eliminate ambiguity in advance, thereby leading to a more cumulative science.
Additional Factors Regarding Clinical Outcomes of General Anesthesia and Conscious Sedation for Acute Ischemic Stroke
Authors: Kars C. J. Compagne, Rob A. van de Graaf, Aad van der Lugt
Journal: JAMA Neurology (2018)

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Synaptic Proteome Compensation and Resilience to Psychosis in Alzheimer’s Disease
Authors: Josh M. Krivinko, Susan L. Erickson, Ying Ding, Zhe Sun, Peter Penzes, Matthew L. MacDonald, Nathan A. Yates, Milos D. Ikonomovic, Oscar L. Lopez, Robert A. Sweet, Julia Kofler
Journal: American Journal of Psychiatry (2018)

Objective: The presence of psychosis in Alzheimer's disease denotes a phenotype with more rapid cognitive deterioration than in Alzheimer's disease without psychosis. Discovery of novel pharmacotherapies that engage therapeutic targets for prevention or treatment of Alzheimer's disease with psychosis would benefit from identifying the neurobiology of resilience to psychosis in Alzheimer's disease. The primary objective of this study was to determine whether alterations in the synaptic proteome were associated with resilience to psychotic symptoms in Alzheimer's disease and, if present, were independent of neuropathologic burden. Method: Quantitative immunohistochemistry was used to measure multiple neuropathologies in dorsolateral prefrontal cortex from subjects with early and middle-stage Alzheimer's disease who differed in psychosis status. Synaptic proteins were quantified by liquid chromatography–mass spectrometry in gray matter homogenates from these subjects and from neuropathologically unaffected subjects. The synaptic proteome was similarly evaluated in cortical gray matter homogenate and in postsynaptic density fractions from an APPswe/PSEN1dE9 mouse model of amyloidosis with germline reduction in Kalrn, which has been shown to confer resilience to progression of psychosis-associated behaviors relative to APPswe/PSEN1dE9 alone. Results: Subjects resilient to psychotic symptoms in Alzheimer's disease had higher levels of synaptic proteins compared with those with psychosis and unaffected control subjects. Neuropathologic burden predicted less than 20% of the variance in psychosis status and did not account for the synaptic protein level differences between groups. Reduction of Kalrn in APPswe/PSEN1dE9 mice resulted in higher levels of synaptic proteins in cortical homogenate and normalized protein levels in the postsynaptic density. Conclusions: Accumulation of synaptic proteins, particularly those that are enriched in the postsynaptic density, is associated with resilience to psychosis in Alzheimer's disease. One candidate mechanism for this synaptic proteome compensation is alteration in levels of proteins that facilitate the transport of synaptic proteins to and from the postsynaptic density.
A Coclinical Radiogenomic Validation Study: Conserved Magnetic Resonance Radiomic Appearance of Periostin-Expressing Glioblastoma in Patients and Xenograft Models
Authors: Pascal O. Zinn, Sanjay K. Singh, Aikaterini Kotrotsou, Islam Hassan, Ginu Thomas, Markus M. Luedi, Ahmed Elakkad, Nabil Elshafeey, Tagwa Idris, Jennifer Mosley, Joy Gumin, Gregory N. Fuller, John F. de Groot, Veera Baladandayuthapani, Erik P. Sulman, Ashok J. Kumar, Raymond Sawaya, Frederick F. Lang, David Piwnica-Worms, Rivka R. Colen
Journal: Clinical Cancer Research (2018)

Abstract Purpose: Radiomics is the extraction of multidimensional imaging features, which when correlated with genomics, is termed radiogenomics. However, radiogenomic biological validation is not sufficiently described in the literature. We seek to establish causality between differential gene expression status and MRI-extracted radiomic-features in glioblastoma. Experimental Design: Radiogenomic predictions and validation were done using the Cancer Genome Atlas and Repository of Molecular Brain Neoplasia Data glioblastoma patients (n = 93) and orthotopic xenografts (OX; n = 40). Tumor phenotypes were segmented, and radiomic-features extracted using the developed radiome-sequencing pipeline. Patients and animals were dichotomized on the basis of Periostin (POSTN) expression levels. RNA and protein levels confirmed RNAi-mediated POSTN knockdown in OX. Total RNA of tumor cells isolated from mouse brains (knockdown and control) was used for microarray-based expression profiling. Radiomic-features were utilized to predict POSTN expression status in patient, mouse, and interspecies. Results: Our robust pipeline consists of segmentation, radiomic-feature extraction, feature normalization/selection, and predictive modeling. The combination of skull stripping, brain-tissue focused normalization, and patient-specific normalization are unique to this study, providing comparable cross-platform, cross-institution radiomic features. POSTN expression status was not associated with qualitative or volumetric MRI parameters. Radiomic features significantly predicted POSTN expression status in patients (AUC: 76.56%; sensitivity/specificity: 73.91/78.26%) and OX (AUC: 92.26%; sensitivity/specificity: 92.86%/91.67%). Furthermore, radiomic features in OX were significantly associated with patients with similar POSTN expression levels (AUC: 93.36%; sensitivity/specificity: 82.61%/95.74%; P = 02.021E−15). Conclusions: We determined causality between radiomic texture features and POSTN expression levels in a preclinical model with clinical validation. Our biologically validated radiomic pipeline also showed the potential application for human–mouse matched coclinical trials.
Clinical Manifestations and Outcomes of Patients with Sarcomatoid Hepatocellular Carcinoma
Authors: Sih‐Han Liao, Tung‐Hung Su, Yung‐Ming Jeng, Po‐Chin Liang, Ding‐Shinn Chen, Chien‐Hung Chen, Jia‐Horng Kao
Journal: Hepatology (2018)

Hepatocellular carcinoma (HCC) is the fifth most common cancer and the second leading cause of cancer-related deaths worldwide. Sarcomatoid HCC is a rare histological subtype of HCC with largely unclear clinical manifestations and outcomes. We evaluated the clinical manifestations and outcomes of patients with sarcomatoid HCC. We identified 5,047 patients with histologically proven HCC from the Cancer Registry Database (1996-2016) of National Taiwan University Hospital. Among them, 40 patients with sarcomatoid HCC were identified from the pathology database of National Taiwan University Hospital. We included 160 patients with nonsarcomatoid HCC through propensity score matching according to sex, age, and Barcelona Clinic Liver Cancer stage. The majority of these patients with sarcomatoid HCC were men (75%); their median age was 58 years. Only 47.5% of the patients with sarcomatoid HCC presented with typical image patterns of HCC. The pathological grading of sarcomatoid HCC was more advanced compared with that of nonsarcomatoid HCC (42.5% vs. 23.8% in grade III and IV, P < 0.0001). The sarcomatoid group had significantly shorter median recurrence-free (13.3 vs. 84.2 months, log-rank P < 0.0001) and overall (8.3 vs. 69.3 months, log-rank P < 0.0001) survival than did the nonsarcomatoid group. The results of the multivariable Cox proportional hazard model revealed histological sarcomatoid subtype as an independent factor for all-cause mortality (hazard ratio [HR], 6.47; 95% confidence interval [CI], 3.12-13.43; P < 0.0001) and tumor recurrence (HR, 4.08; 95% CI, 1.72-9.66; P = 0.001). Conclusion: Compared with nonsarcomatoid HCC, sarcomatoid HCC was associated with more advanced histological grades and atypical image patterns. Histological sarcomatoid subtype is an independent predictor of tumor recurrence after curative treatment and all-cause mortality in patients with HCC.
Human iPS derived progenitors bioengineered into liver organoids using an inverted colloidal crystal poly (ethylene glycol) scaffold
Authors: Soon Seng Ng, Kourosh Saeb-Parsy, Samuel J.I. Blackford, Joe M. Segal, Maria Paola Serra, Marta Horcas-Lopez, Da Yoon No, Sotiris Mastoridis, Wayel Jassem, Curtis W. Frank, Nam Joon Cho, Hiromitsu Nakauchi, Jeffrey S. Glenn, S. Tamir Rashid
Journal: Biomaterials (2018)

Generation of human organoids from induced pluripotent stem cells (iPSCs) offers exciting possibilities for developmental biology, disease modelling and cell therapy. Significant advances towards those goals have been hampered by dependence on animal derived matrices (e.g. Matrigel), immortalized cell lines and resultant structures that are difficult to control or scale. To address these challenges, we aimed to develop a fully defined liver organoid platform using inverted colloid crystal (ICC) whose 3-dimensional mechanical properties could be engineered to recapitulate the extracellular niche sensed by hepatic progenitors during human development. iPSC derived hepatic progenitors (IH) formed organoids most optimally in ICC scaffolds constructed with 140 μm diameter pores coated with type I collagen in a two-step process mimicking liver bud formation. The resultant organoids were closer to adult tissue, compared to 2D and 3D controls, with respect to morphology, gene expression, protein secretion, drug metabolism and viral infection and could integrate, vascularise and function following implantation into livers of immune-deficient mice. Preliminary interrogation of the underpinning mechanisms highlighted the importance of TGFβ and hedgehog signalling pathways. The combination of functional relevance with tuneable mechanical properties leads us to propose this bioengineered platform to be ideally suited for a range of future mechanistic and clinical organoid related applications.
Mosaicism due to postzygotic mutations in women with focal dermal hypoplasia
Authors: L. Heinz, E. Bourrat, P. Vabres, J. Thevenon, A. Hotz, S. Hörer, J. Küsel, A.D. Zimmer, S. Alter, R. Happle, J. Fischer
Journal: British Journal of Dermatology (2018)

Focal dermal hypoplasia (FDH, Goltz syndrome, MIM #305600) constitutes a rare multisystem genetic disorder of the skin, skeleton, teeth and eyes with considerable variation in the clinical features. FDH is transmitted as an X-linked dominant trait and is caused by mutations in PORCN. In male children, hemizygous PORCN mutations are lethal in utero. Around 300 cases have been reported in the literature to date. About 10% of them are male patients presenting with either Klinefelter syndrome (karyotype 47, XXY) or mosaicism of a postzygotic mutation. Here we describe four cases of women with typical features of FDH, in whom a PORCN mutation was found in DNA from affected cutaneous tissue but not in DNA from peripheral blood. This study suggests that mosaicism caused by a postzygotic mutation occurs more often than assumed to date in female patients with FDH. A negative analysis performed on peripheral blood DNA does not exclude the diagnosis of FDH and it is therefore of practical importance to analyse DNA from the affected skin in order to identify low-level mosaicism and thus to improve diagnostic precision. In total, we found two missense variants, one novel indel and one novel splice-site variant. Individuals harbouring postzygotic mosaicism run a risk of transmitting the disorder to their daughters, because the maternal mosaic could also affect the gonads.