tbuckley/cabot-search huggingface dataset:
Adipose Tissue Insulin Resistance in Youth on the Spectrum From Normal Weight to Obese and From Normal Glucose Tolerance to Impaired Glucose Tolerance to Type 2 Diabetes
Authors: Joon Young Kim, Fida Bacha, Hala Tfayli, Sara F. Michaliszyn, Shahwar Yousuf, Silva Arslanian
Journal: Diabetes Care (2018)

OBJECTIVE Adipose tissue insulin resistance is one of the pathophysiological components of type 2 diabetes. Herein we investigated: 1) adipose insulin resistance index (Adipose-IR) (calculated as fasting insulin × free fatty acids [FFAs]) in youth across the spectrum of adiposity from normal weight to obese and the spectrum from normal glucose tolerance (NGT) to impaired glucose tolerance (IGT) to type 2 diabetes, 2) the relationship of Adipose-IR with physical and metabolic characteristics, and 3) the predictive power of Adipose-IR for determining dysglycemia in youth. RESEARCH DESIGN AND METHODS A total of 205 youth had fasting glucose, insulin, FFA, Adipose-IR, body composition, visceral adipose tissue (VAT), leptin, and adiponectin evaluated. RESULTS Adipose-IR was 2.2-fold higher in obese NGT, 4.3-fold higher in IGT, and 4.6-fold higher in type 2 diabetes compared with that in normal-weight peers (all P &amp;lt; 0.05). Females with dysglycemia (IGT and type 2 diabetes) had higher Adipose-IR than their male counterparts (P &amp;lt; 0.001). Adipose-IR correlated positively with total body and visceral adiposity, fasting glucose, HOMA-IR, and leptin and negatively with adiponectin. Receiver operating characteristic curve analysis yielded an optimal cutoff for Adipose-IR of 9.3 μU/mL × mmol/L for determining dysglycemia with 80% predictive power. CONCLUSIONS Adipose-IR is a simple surrogate estimate that reflects pathophysiological alterations in adipose tissue insulin sensitivity in youth, with progressive deterioration from normal weight to obese and from NGT to IGT to type 2 diabetes. Adipose-IR can be applied in large-scale epidemiological/observational studies of the natural history of youth-onset type 2 diabetes and its progression or reversal with intervention strategies.
A phase I/II trial of CRISPR-Cas9-mediated PD-1 knockout Epstein-Barr Virus cytotoxic lymphocytes (EBV-CTLs) for advanced stage EBV associated malignancies
Authors: B. Liu, J. Yan, S. Su, J. Shao, Y. Zhao, Q. Xu, Y. Yang, Z. Zou, X. Huang, J. Wei
Journal: Annals of Oncology (2018)
Abstract P373: Higher Plaque Volume but Not Density of Coronary Artery Calcium is Associated With Left Ventricular Mass
Authors: Nketi I Forbang, Erin Michos, Matthew Allison, Isac Thomas, Robyn McClelland, Veit Sandfort, Michael Criqui
Journal: Circulation (2017)

Coronary artery calcium (CAC) predicts future cardiovascular disease (CVD) events, including heart failure (HF), improves risk stratification beyond traditional CVD risk factors, and is associated with a higher left ventricular mass (LVM), a HF risk factor. Recent findings from the MESA have shown that for a given CAC volume, higher CAC density was inversely associated with incident CVD. It remains uncertain whether CAC volume and density associate differently with LVM. In a multi-ethnic cohort of community dwelling individuals free from clinical CVD at recruitment, we determined the independent cross-sectional associations of baseline CAC volume and density, measured by non-contrast cardiac CT, with LVM, measured by MRI. In 2432 participants with prevalent CAC (density can only be assessed in those with CAC &gt; 0), the mean age was 66 ± 10 years, 59% were men, 50% were European-, 22% were African-, 20% were Hispanic-, and 13% were Chinese-Americans. Median (25-75 th ) CAC volume was 78 (23-259) mm 3 , mean CAC density was 2.7 ± 0.7, and mean LVM was 151 ± 41 grams. CAC density and natural log ( ln ) CAC volume were correlated (correlation coefficient=0.60, P-value &lt; 0.01). Multivariable linear regression models investigated associations of ln (CAC volume) and CAC density with LVM. Model 1 adjusted for demographics (age, sex, and ethnicity) and body surface area. Model 2 included Model 1 plus CVD risk factors (smoking status, fasting glucose, total and HDL cholesterol, systolic blood pressure, and use of medications for hypertension, diabetes, and abnormal lipids). In fully adjusted models one log unit increase in CAC volume as associated with 1.7 gram increase in LVM (Beta = 1.7, 95% CI: 0.7 to 2.6, P &lt; 0.01). In contrast, a unit increase in CAC density was associated with 1.9 gram decrease in LVM (Beta = -1.9, 95% CI: -3.9 to 0.1, P = 0.07). Higher CAC volume, but not CAC density, was cross-sectionally associated with higher LVM; a risk factor for HF. Higher calcium density of coronary artery plaques may not be a hazard for ischemic heart disease mediated increase in LVM. Future studies should determine independent associations of CAC volume and density with incident HF.
Osteoblast-derived inflammatory cytokines are produced in response to human metastatic breast cancer cells
Authors: Karen Bussard, Andrea Mastro
Journal: Cancer Research (2007)

579  Breast cancer frequently metastasizes to bone. Although the precise mechanism underlying this preferential metastasis is unknown, bone likely provides a hospitable environment that attracts breast cancer cells and allows them to colonize and grow. Metastatic breast cancer cells induce osteoclast bone resorption, halt osteoblast bone deposition, and profoundly alter osteoblast properties. Current models suggest that chemokines and cytokines produced by breast cancer cells are key to understanding breast cancer metastasis. While cancer-derived cytokines may play an important role, we have evidence that osteoblasts can be directed by metastatic breast cancer cells to produce inflammatory cytokines that may be chemoattractants for both osteoclasts and cancer cells, as well as growth or maintenance factors for the cancer cells.  MC3T3-E1 murine osteoblasts (OB) were grown to different stages of differentiation (growth: 4 days, early differentiation: 10 days, and late differentiation: 20 days) and were treated for 24 hours with conditioned media (CM) from human metastatic breast cancer (BC) MDA-MB-231 cell variants (parental MDA-MB-231W, parental MDA-MB-231PY, bone-seeking MDA-MB-231BO, or brain-seeking MDA-MB-231BR). OB media was replaced with BC CM at 0, 10, 25, or 50%. Twenty-four hrs later, the culture media was collected and subjected to RayBio® mouse cytokine arrays and species-specific ELISAs to quantify OB-derived cytokines produced in response to human BC cells.  A RayBio® cytokine antibody array showed that BC CM treatment increased OB-derived inflammatory cytokine secretion. The increase in IL-6 levels was particularly notable. As quantitated by ELISAs, OB-derived IL-6 at day 4 doubled from control values when OBs were treated with MDA-MB-231BR CM. For days 10 and 20, OB-derived IL-6 was increased at least 10 fold over control values. Noteworthy increases in OB-derived IL-6 included greater than 80 fold increases from control values with the addition of 50% MDA-MB-231BR CM on day 10 and 50% MDA-MB-231PY CM on day 20. In summary, OB-derived IL-6 production increased in a dose-dependent manner with the addition of all types of BC CM at all points. Maximum induction of OB-derived IL-6 secretion occurred in more differentiated cells.  Literature suggests that IL-6 has numerous functions that could contribute to BC cell metastases to bone. These functions include effects on OBs, osteoclasts (OC), and BC cells. This study implicates OBs as an important source of IL-6 in the vicious cycle of BC bone metastasis. Comprehensive treatment of bone metastases must consider OBs, OCs, and BC cells in order to restore bone matrix deposition and limit osteolysis. Supported by the U.S. Army Medical Research and Materiel Command (W81XWH-06-1-0363, W81XWH-06-1-0432), Susan G. Koman Breast Cancer Foundation (BCTR0601044), and National Foundation for Cancer Research, Center for Metastasis Research.
P04.15 * LIGAND-ACTIVATED TRANSCRIPTION FACTORS PPAR AND PPAR EXPRESSION IN HUMAN GLIOMA
Authors: H. R. Haynes
Journal: Neuro-Oncology (2014)

INTRODUCTION: Agonists of the ligand-activated transcription factors PPARγ and PPARα are in routine clinical use for Type 2 diabetes and lipid control. In vitro studies suggest that PPARγ and PPARα exert antiproliferative and anti-invasive effects on gliomas. PPAR may therefore have a role as a diagnostic and prognostic biomarker or drug target in human gliomas. METHODS: 52 brain tumour samples diagnosed 2011-2013 (34 WHO Grade IV, 14 WHO Grade III, 4 WHO Grade II gliomas), banked at the Brain Tumour Bank Southwest UK were analysed for PPARγ and PPARα expression using dot and western blot techniques. mRNA expression was quantified using rt-PCR. The expression of PPARγ and PPARα was compared with survival data and stratified by WHO tumour grade. RESULTS: In our study PPARγ and PPARα protein expression differs with WHO glioma grade. WHO grade III gliomas show a higher expression of both PPARγ and PPARα when compared with WHO grade IV gliomas. CONCLUSIONS: Our results show for the first time that both PPARγ and PPARα protein expression is significantly increased in WHO grade III gliomas compared to WHO grade IV gliomas. PPARγ and PPARα agonists are in current clinical use and future trials stratified by PPARγ and PPARα expression may reveal a patient cohort with optimum clinical response to these agents.
Plasma Fucosylated Glycans and C-Reactive Protein as Biomarkers of HNF1A-MODY in Young Adult–Onset Nonautoimmune Diabetes
Authors: Agata Juszczak, Tamara Pavić, Frano Vučković, Amanda J. Bennett, Neha Shah, Edita Pape Medvidović, Christopher J. Groves, Mario Šekerija, Kyla Chandler, Carla Burrows, Nataša Rojnić Putarek, Marijana Vučić Lovrenčić, Jadranka Ćuća Knežević, Tim J. James, Anna L. Gloyn, Gordan Lauc, Mark I. McCarthy, Katharine R. Owen, Olga Gornik
Journal: Diabetes Care (2018)

OBJECTIVE Maturity-onset diabetes of the young (MODY) due to variants in HNF1A is the most common type of monogenic diabetes. Frequent misdiagnosis results in missed opportunity to use sulfonylureas as first-line treatment. A nongenetic biomarker could improve selection of subjects for genetic testing and increase diagnosis rates. We previously reported that plasma levels of antennary fucosylated N-glycans and high-sensitivity C-reactive protein (hs-CRP) are reduced in individuals with HNF1A-MODY. In this study, we examined the potential use of N-glycans and hs-CRP in discriminating individuals with damaging HNF1A alleles from those without HNF1A variants in an unselected population of young adults with nonautoimmune diabetes. RESEARCH DESIGN AND METHODS We analyzed the plasma N-glycan profile, measured hs-CRP, and sequenced HNF1A in 989 individuals with diabetes diagnosed when younger than age 45, persistent endogenous insulin production, and absence of pancreatic autoimmunity. Systematic assessment of rare HNF1A variants was performed. RESULTS We identified 29 individuals harboring 25 rare HNF1A alleles, of which 3 were novel, and 12 (in 16 probands) were considered pathogenic. Antennary fucosylated N-glycans and hs-CRP were able to differentiate subjects with damaging HNF1A alleles from those without rare HNF1A alleles. Glycan GP30 had a receiver operating characteristic curve area under the curve (AUC) of 0.90 (88% sensitivity, 80% specificity, cutoff 0.70%), whereas hs-CRP had an AUC of 0.83 (88% sensitivity, 69% specificity, cutoff 0.81 mg/L). CONCLUSIONS Half of rare HNF1A sequence variants do not cause MODY. N-glycan profile and hs-CRP could both be used as tools, alone or as adjuncts to existing pathways, for identifying individuals at high risk of carrying a damaging HNF1A allele.
Computational methods to model complex systems in sports injury research: agent-based modelling (ABM) and systems dynamics (SD) modelling
Authors: Adam Hulme, Scott Mclean, Paul M Salmon, Jason Thompson, Ben R Lane, Rasmus Oestergaard Nielsen
Journal: British Journal of Sports Medicine (2018)

‘Systems thinking’,1 2 complexity theory3 and the ‘complex systems approach’4–7 are gaining momentum among leading sports injury researchers. One reason for this is a growing recognition that traditional risk factor identification methods (eg, stepwise regression modelling) fail to reflect the complex mechanisms of sports injury causation.1 4 8 9 Effective sports injury prevention requires us to understand the complex relationships that occur among a ‘web of interacting determinants’,4 rather than try to isolate the causal effect of individual factors .1 To better understand sports injury mechanisms, researchers are exploring several different approaches. One of them—and the focus of this editorial—is using computational methods that have the potential to describe and simulate the complex and dynamic nature of sports injury causation and prevention in ‘complex systems’.1 4 5 7 

The main characteristics of complex systems are described in table 1. These characteristics justify the use of two computational modelling approaches: agent-based modelling (ABM) and systems dynamics (SD) modelling. It is important to note that static modelling (eg, computer-based spreadsheets), differential equations, automata and process algebraic models, Bayesian networks, machine learning, neural networks, social network analysis and Monte Carlo methods are, unlike ABM and SD modelling, not able to model or simulate dynamic causal feedback among fundamentally different factors. Rather, predictive and simple statistical modelling, as well as mathematical algorithms that forecast the probability of future events, are useful for understanding certain aspects of complex systems at fixed time points and/or across one or more levels. These latter approaches are still computational in nature; however, they serve a purpose for a specific type of problem. We also alert the reader that the use of advanced statistical modelling to better understand the complex relationships between time-varying exposures (eg, training/match workloads) and sports injury development (eg, …
Itacitinib, a JAK1 Selective Inhibitor Preserves Graft-Versus-Leukemia (GVL), Enhances Survival and Is Highly Efficacious in a MHC-Mismatched Mouse Model of Acute GvHD
Authors: Ashish Juvekar, Bruce Ruggeri, Sindy Condon, Andrew Borkowski, Reid Huber, Paul Smith
Journal: Blood (2018)
Association of PALB2 Messenger RNA Expression with Platinum-Docetaxel Efficacy in Advanced Non–Small Cell Lung Cancer
Authors: Niki Karachaliou, Jillian Wilhelmina Paulina Bracht, Manuel Fernandez Bruno, Ana Drozdowskyj, Ana Gimenez Capitan, Teresa Moran, Enric Carcereny, Manuel Cobo, Manuel Domine, Imane Chaib, Jose Luis Ramirez, Carlos Camps, Mariano Provencio, Alain Vergnenegre, Guillermo Lopez-Vivanco, Margarita Majem, Bartomeu Massuti, Rafael Rosell
Journal: Journal of Thoracic Oncology (2018)
The genomic landscape of plasma cells in systemic light chain amyloidosis
Authors: Eileen M. Boyle, Cody Ashby, Christopher P. Wardell, Dorota Rowczenio, Sajitha Sachchithanantham, Yan Wang, Sarah K. Johnson, Michael A. Bauer, Niels Weinhold, Martin F. Kaiser, David C. Johnson, John R. Jones, Charlotte Pawlyn, Paula Proszek, Carolina Schinke, Thierry Facon, Charles Dumontet, Faith E. Davies, Gareth J. Morgan, Brian A. Walker, Ashutosh D. Wechalekar
Journal: Blood (2018)
Type 2 diabetes affects 7000 young people in England and Wales, analysis shows
Authors: Gareth Iacobucci
Journal: BMJ (2018)

Paediatricians have called for urgent action to tackle childhood obesity after new figures showed that almost 7000 children and young adults in England and Wales are being treated for type 2 diabetes.

Recent figures from the national paediatrics diabetes audit1 showed that 715 people under 25 were receiving care for type 2 diabetes from paediatric diabetes units in England and Wales.

But an analysis by the charity Diabetes UK,2 incorporating data from general practice, shows that the prevalence of type 2 diabetes is far greater, …
Defining Risk Factors for Chemotherapeutic Intervention in Infants With Stage 4S Neuroblastoma: A Report From Children’s Oncology Group Study ANBL0531
Authors: Clare J. Twist, Arlene Naranjo, Mary Lou Schmidt, Sheena C. Tenney, Susan L. Cohn, Holly J. Meany, Peter Mattei, E. Stanton Adkins, Hiroyuki Shimada, Wendy B. London, Julie R. Park, Katherine K. Matthay, John M. Maris
Journal: Journal of Clinical Oncology (2018)

Infants with stage 4S neuroblastoma usually have favorable outcomes with observation or minimal chemotherapy. However, young infants with symptoms secondary to massive hepatomegaly or with unfavorable tumor biology are at high risk of death. Our aim was to improve outcomes for patients with symptomatic and/or unfavorable biology 4S neuroblastoma with a uniform treatment approach using a biology- and response-based algorithm.The subset of patients with 4S disease with MYCN-not amplified tumors with impaired or impending organ dysfunction, or with unfavorable histology and/or diploid DNA index, were eligible. Patients were assigned to receive two, four, or eight cycles of chemotherapy on the basis of histology, diploid DNA index, chromosome arm 1p or 11q loss of heterozygosity (LOH) status, and symptoms.Forty-nine eligible patients were enrolled: 41 were symptomatic and 28 had unfavorable biology. Seventeen patients (symptomatic, favorable biology) were assigned two cycles, 21 patients (any unfavorable biologic feature without 1p or 11q LOH) were assigned four cycles, and 11 patients (unfavorable biology including 1p and/or 11q LOH [n = 7] or symptomatic with unknown biology [n = 4]), were assigned eight cycles. The 3-year overall survival was 81.4% ± 5.8%. Eight of nine deaths were in patients younger than 2 months of age at diagnosis (median, 9 days [range, 1 to 68 days]): five acute deaths were a result of hepatomegaly and associated toxicities; two were a result of late relapse in patients with unfavorable biology; and two were a result of treatment complications. No deaths occurred after protocol-mandated pre-emptive treatment of infants younger than 2 months with hepatomegaly, regardless of symptoms. A new scoring algorithm for emergent chemotherapy in patients with 4S disease was developed on the basis of this experience.The outcome for 4S neuroblastoma can be improved with pre-emptive chemotherapy for evolving hepatomegaly or other baseline comorbidities in infants younger than 2 months of age.
Artificial intelligence in sports medicine radiology: what’s coming?
Authors: William Parker, Bruce B Forster
Journal: British Journal of Sports Medicine (2018)

Artificial intelligence (AI) is the new kid on the block. Every doctor and her/his medical student is talking about it. It seems like the answer to all of our problems. How will we overcome antibiotic resistance? AI will figure it out. What is on the X-ray? AI will know. Why is your partner mad at you? AI should be great for that. But what is AI exactly, and what will be its impact in sports medicine?

AI is the theory and development of computer systems which are able to perform tasks that normally require human intelligence, such as visual perception, speech recognition, decision-making and translation between languages.1 In order for a machine to become intelligent, it needs to learn. Enter machine learning.

Machine learning is a branch of AI based on the idea that systems can learn from data, identify patterns and make decisions with minimal human intervention.2 

Machine Learning is not a new concept in computer science circles but was popularised by Dr Geoffrey Hinton, a computer scientist from Toronto Ontario, who brought the technology into the limelight with his work on ImageNet, a computer program (called a neural network) that was able to identify the contents …
New leads on vitamin E succinate-induced apoptosis signaling in prostate cancer cells
Authors: Ke Zu, Lesleyann Hawthorn, Clement Ip
Journal: Cancer Research (2004)

Proc Amer Assoc Cancer Res, Volume 45, 2004

1390 

Previously α-tocopheryl succinate (vitamin E succinate, VES) has been reported to induce caspase-mediated apoptosis in PC-3 human prostate cancer cells (Zu K and Ip C. Cancer Res. 63: 6988-95, 2003). Caspase-9 was among several initiator caspases activated by VES, suggesting that the Bcl-2 family proteins, working via the mitochondrial pathway, were likely to be involved. To assess the effect of VES on mitochondrial regulation of apoptosis, several Bcl-2 member proteins were examined by Western blotting. The results showed that VES treatment increased the expression of some pro-apoptotic proteins, such as Bax and Bak. Although the expression level of Bcl-2 and Bad was unchanged by VES, the phosphorylation status of these two proteins was modulated in a manner consistent with an enhanced apoptotic response. The finding that VES caused changes in phosphorylated Bcl-2 and Bad implies that other kinase-type signaling molecules might also be recruited in the process. Microarray analysis was therefore carried out to identify additional VES targets that may contribute to apoptosis signaling. Akt1, an important cell survival molecule, emerged as a potential candidate, since it is known to phosphorylate Bad. Western blotting analysis comfirmed that phospho-Akt1, the active form of Akt1, was reduced by VES treatment in a time- and dose-dependent manner. Phospho-Forkhead transcription factor (FKHR), another downstream target of Akt1 associated with survival, was also decreased. Interestingly, the activity of PTEN and phosphoinositide-dependent kinase 1 (PDK 1), two upstream regulators of Akt1, was not affected. Nonetheless, the regulation of phospho-Akt1 by VES offers tantalizing clues with respect to the integration of the survival pathway and the mitochondrial control of apoptosis in VES signaling. Our microarray data also provided evidence that VES was able to activate the stress-induced MAPK cascade. Western blotting analysis showed increased protein level of Apoptosis signal-regulating kinase 1 (Ask1), JNK/Erk kinase (Sek1) and its cofactor GADD45, as well as increased phosphorylation of Sek1 and JNK. Further experimentation is currently underway to assess the functional significance of JNK pathway activation in VES-induced apoptosis. In summary, our study has generated a number of new leads regarding the molecular mechanism of action of VES in apoptosis induction.
A pilot case-control study of second or third-line treatment with cetuximab-containing chemotherapy (cetux-chemo) in patients (pts) with metastatic colorectal cancer (mCRC) who were previously treated with cetux-chemo
Authors: C.S. Ho, A.C. Cheng, L. Li, W.M. Ho, E.P. Hui, K.F. To, J.H.M. Tong, B.B.Y. Ma
Journal: Annals of Oncology (2018)