tbuckley/cabot-search huggingface dataset:
Patient-derived tumor organoids for prediction of cancer treatment response
Authors: Peter W. Nagle, John Th. M. Plukker, Christina T. Muijs, Peter van Luijk, Robert P. Coppes
Journal: Seminars in Cancer Biology (2018)

Cancer treatment, in particular radiotherapy and chemotherapy, is often hindered by an inherent resistance of cancer cells. Cancer stem cells in particular have previously been shown to be more resistant than other cells within a tumor and are thought repopulate the tumour after therapies. Therefore, it is of utmost importance to develop tools and techniques that can be used to study mechanisms of resistance of cancer stem cells as potential treatment targets. Organoids (and cancer-derived organoids), are three-dimensional tissue-resembling cellular clusters derived from tissue or tumor specific stem cells that mimic the in vivo (tumor) characteristics, as well as (tumor) cell heterogeneity. Cancer organoids may further enhance the in vitro and in vivo models that are currently available, improve our understanding of cancer stem cell resistance and can be used to develop novel cancer treatments by improved targeting of cancer stem cells. In this review, we compare organoids with the more traditional laboratory models, such as cell lines and xenografts, and review the literature of the current role of cancer organoids in determining treatment responses.
Phone App No Help in Controlling Hypertension
Authors: Anita Slomski
Journal: JAMA (2018)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Inotersen Treatment for Patients with Hereditary Transthyretin Amyloidosis
Authors: Merrill D Benson, Márcia Waddington-Cruz, John L Berk, Michael Polydefkis, Peter J Dyck, Annabel K Wang, Violaine Planté-Bordeneuve, Fabio A Barroso, Giampaolo Merlini, Laura Obici, Morton Scheinberg, Thomas H Brannagan, William J Litchy, Carol Whelan, Brian M Drachman, David Adams, Stephen B Heitner, Isabel Conceição, Hartmut H Schmidt, Giuseppe Vita, Josep M Campistol, Josep Gamez, Peter D Gorevic, Edward Gane, Amil M Shah, Scott D Solomon, Brett P Monia, Steven G Hughes, T Jesse Kwoh, Bradley W McEvoy, Shiangtung W Jung, Brenda F Baker, Elizabeth J Ackermann, Morie A Gertz, Teresa Coelho
Journal: New England Journal of Medicine (2018)

Hereditary transthyretin amyloidosis is caused by pathogenic single-nucleotide variants in the gene encoding transthyretin (TTR) that induce transthyretin misfolding and systemic deposition of amyloid. Progressive amyloid accumulation leads to multiorgan dysfunction and death. Inotersen, a 2′-O-methoxyethyl–modified antisense oligonucleotide, inhibits hepatic production of transthyretin.
Genetic Regulation of Fibroblast Activation and Proliferation in Cardiac Fibrosis
Authors: Shuin Park, Sara Ranjbarvaziri, Fides D. Lay, Peng Zhao, Mark J. Miller, Jasmeet S. Dhaliwal, Adriana Huertas-Vazquez, Xiuju Wu, Rong Qiao, Justin M. Soffer, Christoph Rau, Yibin Wang, Hanna K.A. Mikkola, Aldons J. Lusis, Reza Ardehali
Journal: Circulation (2018)

Background: Genetic diversity and the heterogeneous nature of cardiac fibroblasts (CFbs) have hindered characterization of the molecular mechanisms that regulate cardiac fibrosis. The Hybrid Mouse Diversity Panel offers a valuable tool to examine genetically diverse cardiac fibroblasts and their role in fibrosis. Methods: Three strains of mice (C57BL/6J, C3H/HeJ, and KK/HlJ) were selected from the Hybrid Mouse Diversity Panel and treated with either isoproterenol (ISO) or saline by an intraperitoneally implanted osmotic pump. After 21 days, cardiac function and levels of fibrosis were measured by echocardiography and trichrome staining, respectively. Activation and proliferation of CFbs were measured by in vitro and in vivo assays under normal and injury conditions. RNA sequencing was done on isolated CFbs from each strain. Results were analyzed by Ingenuity Pathway Analysis and validated by reverse transcription-qPCR, immunohistochemistry, and ELISA. Results: ISO treatment in C57BL/6J, C3H/HeJ, and KK/HlJ mice resulted in minimal, moderate, and extensive levels of fibrosis, respectively (n=7–8 hearts per condition). Isolated CFbs treated with ISO exhibited strain-specific increases in the levels of activation but showed comparable levels of proliferation. Similar results were found in vivo, with fibroblast activation, and not proliferation, correlating with the differential levels of cardiac fibrosis after ISO treatment. RNA sequencing revealed that CFbs from each strain exhibit unique gene expression changes in response to ISO. We identified Ltbp2 as a commonly upregulated gene after ISO treatment. Expression of LTBP2 was elevated and specifically localized in the fibrotic regions of the myocardium after injury in mice and in human heart failure patients. Conclusions: This study highlights the importance of genetic variation in cardiac fibrosis by using multiple inbred mouse strains to characterize CFbs and their response to ISO treatment. Our data suggest that, although fibroblast activation is a response that parallels the extent of scar formation, proliferation may not necessarily correlate with levels of fibrosis. In addition, by comparing CFbs from multiple strains, we identified pathways as potential therapeutic targets and LTBP2 as a marker for fibrosis, with relevance to patients with underlying myocardial fibrosis.
Inhaled TLR9 Agonist Renders Lung Tumors Permissive to PD-1 Blockade by Promoting Optimal CD4+ and CD8+ T-cell Interplay
Authors: Marilena Gallotta, Hikmat Assi, Émilie Degagné, Shravan Kumar Kannan, Robert L. Coffman, Cristiana Guiducci
Journal: Cancer Research (2018)

Currently approved inhibitors of the PD-1/PD-L1 pathway represent a major advance for the treatment of lung cancers, yet they are ineffective in a majority of patients due to lack of preexisting T-cell reactivity. Here, we show that a TLR9 agonist delivered by inhalation is able to prime T-cell responses against poorly immunogenic lung tumors and to complement the effects of PD-1 blockade. Inhaled TLR9 agonist causes profound remodeling in tumor-bearing lungs, leading to the formation of tertiary lymphoid structures adjacent to the tumors, CD8+ T-cell infiltration into the tumors, dendritic cell expansion, and antibody production. Inhalation of TLR9 agonist also increased the pool of functional PD-1lowT-bethigh effector CD8+ T cells in tumor-bearing lungs. Effector CD8+ T cells generated by inhaled TLR9 agonist treatment were licensed by PD-1 blockade to become highly functional CTLs, leading to a durable rejection of both lung tumors and tumor lesions outside the lungs. CD4+ T cells activated in response to inhaled TLR9 play a critical role in this process by controlling the proliferation, preventing exhaustion, and guiding the differentiation of optimally functional CTLs. This study characterizes a strategy to apply localized TLR9 stimulation to a tumor type not accessible for direct injection, a strategy that may expand the therapeutic potential of PD-1 blockade in non-small cell lung cancer.Significance: These findings demonstrate that local delivery of a toll-like receptor 9 agonist can change the immune content of an entire organ and enhance the efficacy of immune checkpoint inhibition.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/17/4943/F1.large.jpg Cancer Res; 78(17); 4943-56. ©2018 AACR.
The Impact of Glycated Hemoglobin (HbA1c) on Cardiovascular Disease Risk: A Mendelian Randomization Study Using UK Biobank
Authors: Shiu Lun Au Yeung, Shan Luo, C. Mary Schooling
Journal: Diabetes Care (2018)

OBJECTIVE Glycated hemoglobin (HbA1c) is positively associated with cardiovascular disease (CVD), although evidence is primarily observational. Mendelian randomization studies have only examined its relation with subtypes of CVD. We examined the relation of HbA1c with CVD and its subtypes in the UK Biobank using Mendelian randomization. RESEARCH DESIGN AND METHODS We used 38 genetic variants strongly and independently related to HbA1c (n = 123,665) applied to the UK Biobank (n = 392,038). We used inverse variance weighting (IVW) to obtain the associations of HbA1c with CVD, coronary artery disease (CAD), and stroke (overall and stroke subtypes). Sensitivity analyses included Mendelian randomization (MR)-Egger, a weighted median, and exclusion of potentially invalid single nucleotide polymorphisms (SNPs). We also applied the same genetic instruments to CARDIoGRAMplusC4D (Coronary ARtery DIsease Genome wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics) 1000 Genomes–based genome-wide association study (n = 184,305) as a validation for CAD. RESULTS In the UK Biobank, HbA1c was not associated with CVD using IVW (odds ratio [OR] 1.11 per %, 95% CI 0.83–1.48). However, HbA1c was associated with increased CAD risk (OR 1.50 per %, 95% CI 1.08–2.11) with directionally consistent results from MR-Egger and weighted median. The positive association with CAD was more pronounced when we excluded potentially invalid SNPs (OR 2.24 per %, 95% CI 1.55–3.25). The positive association was replicated in CARDIoGRAM (OR 1.52 per %, 95% CI 1.03–2.26). The association of HbA1c with stroke and its subtypes was less clear given the low number of cases. CONCLUSIONS HbA1c likely causes CAD. The underlying mechanisms remain to be elucidated.
Epistasis analysis uncovers hidden antibiotic resistance-associated fitness costs hampering the evolution of MRSA
Authors: Maho Yokoyama, Emily Stevens, Maisem Laabei, Leann Bacon, Kate Heesom, Sion Bayliss, Nicola Ooi, Alex J. O’Neill, Ewan Murray, Paul Williams, Anneke Lubben, Shaun Reeksting, Guillaume Meric, Ben Pascoe, Samuel K. Sheppard, Mario Recker, Laurence D. Hurst, Ruth C. Massey
Journal: Genome biology (2018)

Fitness costs imposed on bacteria by antibiotic resistance mechanisms are believed to hamper their dissemination. The scale of these costs is highly variable. Some, including resistance of Staphylococcus aureus to the clinically important antibiotic mupirocin, have been reported as being cost-free, which suggests that there are few barriers preventing their global spread. However, this is not supported by surveillance data in healthy communities, which indicate that this resistance mechanism is relatively unsuccessful. Epistasis analysis on two collections of MRSA provides an explanation for this discord, where the mupirocin resistance-conferring mutation of the ileS gene appears to affect the levels of toxins produced by S. aureus when combined with specific polymorphisms at other loci. Proteomic analysis demonstrates that the activity of the secretory apparatus of the PSM family of toxins is affected by mupirocin resistance. As an energetically costly activity, this reduction in toxicity masks the fitness costs associated with this resistance mutation, a cost that becomes apparent when toxin production becomes necessary. This hidden fitness cost provides a likely explanation for why this mupirocin-resistance mechanism is not more prevalent, given the widespread use of this antibiotic. With dwindling pools of antibiotics available for use, information on the fitness consequences of the acquisition of resistance may need to be considered when designing antibiotic prescribing policies. However, this study suggests there are levels of depth that we do not understand, and that holistic, surveillance and functional genomics approaches are required to gain this crucial information.
Abstract 4062: Progression of Coronary Artery Calcification at Middle Age in Women with Polycystic Ovary Syndrome
Authors: Evelyn E Talbott, Jeanne V Zborowski, Judith R Rager
Journal: Circulation (2006)

Introduction: Polycystic ovary syndrome (PCOS) is a reproductive endocrine disorder characterized by menstrual irregularity, anovulation, and hyperandrogenism, affecting 6 to 10% of all women. PCOS is associated with obesity, insulin resistance and type 2 diabetes. Increased prevalent coronary calcification (CAC), independent of age and BMI in women with PCOS compared to normal women has been documented. CAC has been shown to be a surrogate for increased atherosclerotic disease and is a predictor of future coronary heart disease risk. The present study considered the rate of progression of CAC in middle-aged women with PCOS and in non-PCOS (control) women of similar age.  Methods: A total of 117 PCOS cases and 151 controls aged 35 to 64 years (mean age 47.3 and 49.6) were evaluated at baseline (2001–2003) and again in 2003–2006 for CAC using electron beam computed tomography (EBT) (average follow-up = 2.8 years). The relationship between PCOS and CAC progression was explored with binary logistic regression analyses. CAC progression was defined as a change in CAC volume score of ≥+5 versus >>22>5 mm 3 /year. Separate models were run including and excluding women with type 2 diabetes and/or taking cholesterol-lowering statins.  Results: At baseline, women with PCOS had a higher prevalence (and increased severity) of CAC (63.2%) compared with controls (41.7%). Annual progression of at least 5 mm 3  was found in 24.8% of PCOS cases and 13.9% of controls. PCOS was a significant predictor of CAC progression in the total sample after adjustment for age and BMI (p= 0.034). PCOS was no longer significant when baseline CAC was included in the model. Results were similar when women with type 2 diabetes and/or on statins at baseline (n=26) were removed from the analysis.  Discussion: Women with PCOS are at higher risk for premature CAC than reproductively normal women. However, by middle age, the rate of progression of CAC in women is mediated more significantly by prevalent CAC than by the presence of PCOS alone. These findings suggest that among women with PCOS, clinical and lifestyle interventions to reduce cardiovascular disease risk should be be initiated in early adulthood before the appearance of prevalent CAC to impact later life development of CHD.
FAST education campaign did not improve response to minor strokes
Authors: Jacqui Wise
Journal: BMJ (2018)

The FAST (face, arm, speech, time) public education campaign did not lead to people seeking medical attention more quickly for transient ischaemic attack or minor stroke, although it did improve the response to major stroke, a UK study has found.1

The authors of the study, which was published in JAMA Neurology, said that public education campaigns should be tailored to transient and less severe symptoms of stroke to encourage the public to seek medical attention quickly. If left untreated, around 5% …
Questionable Assumptions Provided in Nonoperative Treatment of Appendicitis Survey—Reply
Authors: Marc D. Basson, Alexis L. Hanson, Ross D. Crosby
Journal: JAMA Surgery (2018)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Surgery HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Surgery journal
Abstract 2624: Dual PLK1 and BRD4 inhibition has synergistic therapeutic effects against high-risk rhabdomyosarcoma
Authors: Natalie Timme, Shuai Liu, Hailemichael Yosief, Heathcliff Dorado García, Ian MacArthur, Annabell Szymansky, Constantin Dohna, Georg Seifert, Patrick Hundsdörfer, Andrej Lissat, Angelika Eggert, Johannes Schulte, Wei Zhang, Anton Henssen
Journal: Cancer Research (2018)

Abstract Concomitant inhibition of multiple therapeutic targets is an established strategy to improve the durability of clinical responses to targeted therapies. Rhabdomyosarcoma is the most common childhood soft tissue solid tumor and cure rates for patients with high-risk rhabdomyosarcoma remain dismal. Resistance to intensive chemotherapy is common, and few molecular therapies have been introduced clinically. High-risk rhabdomyosarcoma is driven by expression of the oncogenic fusion protein PAX3-FOXO1, which acts as a transcription factor. Recently, many efforts have been made to identify pharmacological means of inhibiting PAX3-FOXO1, given its central role in rhabdomyosarcoma cell line survival. The BET protein BRD4 has been shown to be required for transcription of PAX3-FOXO1 and its target genes and pharmacological inhibition via BET protein inhibitors exhibits anti-rhabdomyosarcoma effects. Phosphorylation of PAX3-FOXO1 by the polo like kinase 1 (PLK1) increases the stability of the oncoprotein. Based on these previous observations, we hypothesized that simultaneous inhibition of BRD4 and PLK1 could synergistically target PAX3-FOXO1 stability and activity, leading to increased anti-rhabdomyosarcoma effects. Indeed, combination treatment with PLK1 and BRD4 inhibitors exhibited synergistic effects specifically against PAX3-FOXO1-driven rhabdomyosarcoma cell lines. Dual PLK1-BRD4 inhibition suppressed proliferation and induced apoptosis in rhabdomyosarcoma cell lines at low nanomolar concentrations. Our results demonstrate a new strategy towards achieving dual synergistic targeting of BRD4 and PLK1 with a single agent which may lead to clinical translation for therapy of refractory rhabdomyosarcoma. Citation Format: Natalie Timme, Shuai Liu, Hailemichael Yosief, Heathcliff Dorado García, Ian MacArthur, Annabell Szymansky, Constantin Dohna, Georg Seifert, Patrick Hundsdörfer, Andrej Lissat, Angelika Eggert, Johannes Schulte, Wei Zhang, Anton Henssen. Dual PLK1 and BRD4 inhibition has synergistic therapeutic effects against high-risk rhabdomyosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2624.
Face-to-Face and Internet-Based Mindfulness-Based Cognitive Therapy Compared With Treatment as Usual in Reducing Psychological Distress in Patients With Cancer: A Multicenter Randomized Controlled Trial
Authors: Félix Compen, Else Bisseling, Melanie Schellekens, Rogier Donders, Linda Carlson, Marije van der Lee, Anne Speckens
Journal: Journal of Clinical Oncology (2018)

Purpose Mindfulness-based cognitive therapy (MBCT) has been shown to alleviate psychological distress in patients with cancer. However, patients experience barriers to participating in face-to-face MBCT. Individual Internet-based MBCT (eMBCT) could be an alternative. The study aim was to compare MBCT and eMBCT with treatment as usual (TAU) for psychological distress in patients with cancer. Patients and Methods We obtained ethical and safety approval to include 245 patients with cancer with psychological distress (≥ 11 on the Hospital Anxiety and Depression Scale) in the study. They were randomly allocated to MBCT (n = 77), eMBCT (n = 90), or TAU (n = 78). Patients completed baseline (T0) and postintervention (T1) assessments. The primary outcome was psychological distress on the Hospital Anxiety and Depression Scale. Secondary outcomes were psychiatric diagnosis, fear of cancer recurrence, rumination, health-related quality of life, mindfulness skills, and positive mental health. Continuous outcomes were analyzed using linear mixed modeling on the intention-to-treat sample. Because both interventions were compared with TAU, the type I error rate was set at P &lt; .025. Results Compared with TAU, patients reported significantly less psychological distress after both MBCT (Cohen’s d, .45; P &lt; .001) and eMBCT (Cohen’s d, .71; P &lt; .001) . In addition, post-treatment prevalence of psychiatric diagnosis was lower with both MBCT (33% improvement; P = .030) and eMBCT (29% improvement; P = .076) in comparison with TAU (16%), but these changes were not statistically significant. Both interventions reduced fear of cancer recurrence and rumination, and increased mental health–related quality of life, mindfulness skills, and positive mental health compared with TAU (all Ps &lt; .025). Physical health–related quality of life did not improve ( P = .343). Conclusion Compared with TAU, MBCT and eMBCT were similarly effective in reducing psychological distress in a sample of distressed heterogeneous patients with cancer.