tbuckley/cabot-search huggingface dataset:
An osteopontin/CD44 immune checkpoint controls CD8+ T cell activation and tumor immune evasion
Authors: John D. Klement, Amy V. Paschall, Priscilla S. Redd, Mohammed L. Ibrahim, Chunwan Lu, Dafeng Yang, Esteban Celis, Scott I. Abrams, Keiko Ozato, Kebin Liu
Journal: Journal of Clinical Investigation (2018)

Despite breakthroughs in immune checkpoint inhibitor (ICI) immunotherapy, not all human cancers respond to ICI immunotherapy and a large fraction of patients with the responsive types of cancers do not respond to current ICI immunotherapy. This clinical conundrum suggests that additional immune checkpoints exist. We report here that interferon regulatory factor 8 (IRF8) deficiency led to impairment of cytotoxic T lymphocyte (CTL) activation and allograft tumor tolerance. However, analysis of chimera mice with competitive reconstitution of WT and IRF8-KO bone marrow cells as well as mice with IRF8 deficiency only in T cells indicated that IRF8 plays no intrinsic role in CTL activation. Instead, IRF8 functioned as a repressor of osteopontin (OPN), the physiological ligand for CD44 on T cells, in CD11b+Ly6CloLy6G+ myeloid cells and OPN acted as a potent T cell suppressor. IRF8 bound to the Spp1 promoter to repress OPN expression in colon epithelial cells, and colon carcinoma exhibited decreased IRF8 and increased OPN expression. The elevated expression of OPN in human colon carcinoma was correlated with decreased patient survival. Our data indicate that myeloid and tumor cell–expressed OPN acts as an immune checkpoint to suppress T cell activation and confer host tumor immune tolerance.
Prostaglandin E<sub>2</sub> hydrogel improves cutaneous wound healing via M2 macrophages polarization
Authors: Shuaiqiang Zhang, Yuanyuan Liu, Xin Zhang, Dashuai Zhu, Xin Qi, Xiaocang Cao, Yihu Fang, Yongzhe Che, Zhong-Chao Han, Zuo-Xiang He, Zhibo Han, Zongjin Li
Journal: Theranostics (2018)

Wound healing is regulated by a complex series of events and overlapping phases. A delicate balance of cytokines and mediators in tissue repair is required for optimal therapy in clinical applications. Molecular imaging technologies, with their versatility in monitoring cellular and molecular events in living organisms, offer tangible options to better guide tissue repair by regulating the balance of cytokines and mediators at injured sites. Methods: A murine cutaneous wound healing model was developed to investigate if incorporation of prostaglandin E2 (PGE2) into chitosan (CS) hydrogel (CS+PGE2 hydrogel) could enhance its therapeutic effects. Bioluminescence imaging (BLI) was used to noninvasively monitor the inflammation and angiogenesis processes at injured sites during wound healing. We also investigated the M1 and M2 paradigm of macrophage activation during wound healing. Results: CS hydrogel could prolong the release of PGE2, thereby improving its tissue repair and regeneration capabilities. Molecular imaging results showed that the prolonged release of PGE2 could ameliorate inflammation by promoting the M2 phenotypic transformation of macrophages. Also, CS+PGE2 hydrogel could augment angiogenesis at the injured sites during the early phase of tissue repair, as revealed by BLI. Furthermore, our results demonstrated that CS+PGE2 hydrogel could regulate the balance among the three overlapping phases-inflammation, regeneration (angiogenesis), and remodeling (fibrosis)-during cutaneous wound healing. Conclusion: Our findings highlight the potential of the CS+PGE2 hydrogel as a novel therapeutic strategy for promoting tissue regeneration via M2 macrophage polarization. Moreover, molecular imaging provides a platform for monitoring cellular and molecular events in real-time during tissue repair and facilitates the discovery of optimal therapeutics for injury repair by regulating the balance of cytokines and mediators at injured sites.
Recurrent vertigo associated with headaches
Authors: Georgios Kontorinis, Alok Tyagi, John A Crowther
Journal: BMJ (2018)

A 37 year old woman attended the otolaryngology department with episodes of dizziness (“a feeling of swaying”), occasional rotatory vertigo, and unilateral right sided headaches that usually occurred once a week and had been ongoing for six weeks. Her symptoms could last several hours and were sometimes preceded with the appearance of transient flashing lights. Some episodes were associated with short lasting blurred vision and occasional nausea. Her symptoms were unrelated to head or neck movements but could deteriorate with tiredness, bright light exposure, or high coffee consumption. They would improve after several hours if she could lie down in a dark room. The headaches would usually follow the dizziness/vertigo. There was catamenial exacerbation of her symptoms but no phonophobia, hearing problems, or tinnitus.

She had a history of similar episodes a few years ago that had gradually settled without medication.

Clinical examination was unremarkable. She underwent magnetic resonance imaging (MRI) of the brain and inner ear (fig 1).



Fig. 1 
Axial fast imaging using steady state acquisition (FIESTA) MRI of the internal auditory meatus and the brain (A) with a focus on the internal auditory meatus (B) 





Fig. 2 
No abnormalities seen on axial FIESTA-MRI. IAM: internal auditory meati. CPA: cerebellopontine angles bilaterally (no vestibular schwannoma). (1) White arrows point to the cochleovestibular nerves in the IAM. (2) Loop of the anterior-inferior cerebellar artery. (3) The labyrinth (in this section with the lateral semicircular canal). (4) Long dotted arrows show the cochlea. (5) White X marks the anterior end of …
Coaxial Cell Printing of Freestanding, Perfusable, and Functional In Vitro Vascular Models for Recapitulation of Native Vascular Endothelium Pathophysiology
Authors: Ge Gao, Ju Young Park, Byoung Soo Kim, Jinah Jang, Dong‐Woo Cho
Journal: Advanced Healthcare Materials (2018)

3D printing technology is used to produce channels within hydrogels followed by endothelial cells (ECs)-seeding to establish in vitro vascular models. However, as built-in bulk hydrogels, it is difficult to incorporate additional cells and molecules into the crosslinked matrix to study the pathophysiological responses of healthy endothelium. In this study, freestanding in vitro vascular models (VMs) are developed using the coaxial cell printing technique and a vascular tissue-specific bioink. It has various advantages in plotting tubular cell-laden vessels with designed patterns, providing pump-driven circulating perfusion, generating endothelium without ECs-seeding, and implementing further expansions to study vascular pathophysiology. Following the maturation of endothelium, the VMs exhibit representative vascular functions (i.e., selective permeability, antiplatelets/leukocytes adhesion, and vessel remodeling under shear stress). Moreover, with the expansions of the VMs, the directional angiogenesis and inflammatory responses are demonstrated by giving asymmetric distributions of proangiogenic factors and an airway inflammatory ambience, respectively. Therefore, the freestanding, perfusable, and functional VMs can be useful devices to engineer diverse in vitro platforms for a wide range of biomedical applications, from modeling blood vessel relevant diseases to building vascularized tissues/organs.
CXADR-Mediated Formation of an AKT Inhibitory Signalosome at Tight Junctions Controls Epithelial–Mesenchymal Plasticity in Breast Cancer
Authors: Azadeh Nilchian, Joel Johansson, Aram Ghalali, Sandra T. Asanin, Ana Santiago, Oskar Rosencrantz, Kerstin Sollerbrant, C. Theresa Vincent, Malin Sund, Ulla Stenius, Jonas Fuxe
Journal: Cancer Research (2018)

Tight junctions (TJ) act as hubs for intracellular signaling pathways controlling epithelial cell fate and function. Deregulation of TJ is a hallmark of epithelial-mesenchymal transition (EMT), which contributes to carcinoma progression and metastasis. However, the signaling mechanisms linking TJ to the induction of EMT are not understood. Here, we identify a TJ-based signalosome, which controls AKT signaling and EMT in breast cancer. The coxsackie and adenovirus receptor (CXADR), a TJ protein with an essential yet uncharacterized role in organogenesis and tissue homeostasis, was identified as a key component of the signalosome. CXADR regulated the stability and function of the phosphatases and AKT inhibitors PTEN and PHLPP2. Loss of CXADR led to hyperactivation of AKT and sensitized cells to TGFβ1-induced EMT. Conversely, restoration of CXADR stabilized PHLPP2 and PTEN, inhibited AKT, and promoted epithelial differentiation. Loss of CXADR in luminal A breast cancer correlated with loss of PHLPP2 and PTEN and poor prognosis. These results show that CXADR promotes the formation of an AKT-inhibitory signalosome at TJ and regulates epithelial-mesenchymal plasticity in breast cancer cells. Moreover, loss of CXADR might be used as a prognostic marker in luminal breast cancer. SIGNIFICANCE: The tight junction protein CXADR controls epithelial-mesenchymal plasticity in breast cancer by stabilizing the AKT regulators PTEN and PHLPP2.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/1/47/F1.large.jpg.
SAT0157 The prevalence of dyslipidemia and daily nutritional intake in rheumatoid arthritis patients: a study of the korean national health and nutrition examination survey (KNHANES)
Authors: S. H. Joo, Y. W. Song
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background:</h3> Lipid metabolism appear to be changed in rheumatoid arthritis (RA) patients because of disease activity and inflammation. <h3>Objectives:</h3> It was not clear in the previous studies that lipid profiles status is associated with nutritional intake in RA patients. <h3>Methods:</h3> We analyzed RA, dyslipidemia, serum lipid profiles (total cholesterol, TG, HDL, and LDL) and nutritional intake data related lipid from the data of KNHANES (N=22,948, estimated population size=48,402,221). We analyzed the prevalence of RA and abnormal status of lipid profiles using general linear model and logistic regression with complex sample design method adjusted by age and sex and evaluated the association between RA and dyslipidemia including nutritional intake data. <h3>Results:</h3> The prevalence of RA was 1.21% [95% CI: 1.07–1.38]. The prevalence of dyslipidemia with RA (3.31% [95% CI: 2.63–4.17]) was significantly increased compared with that of dyslipidemia without RA (1.37% [95% CI: 1.17–1.59], p&lt;0.001). LDL (RA vs. control: 117.77±3.87 mg/dL vs. 114.47±0.51 mg/dL, p&lt;0.001) was significantly increased, whereas TG (RA vs. control: 129.21±6.38 mg/dL vs. 136.72±1.20 mg/dL, p&lt;0.001) was significantly decreased in RA. Total cholesterol tended to be higher in RA (RA vs. control: 198.12±3.09 mg/dL vs. 188.11±0.39 mg/dL, p=0.051). but HDL (RA vs. control: 54.16±1.42 mg/dL vs. 52.46±0.15 mg/dL, p=0.98) was not different between two groups. There were no differences in nutritional intake volume including total diet volume, energy intake, water, carbohydrate, protein, fat, other fatty acids and dietary fiber (Table). <h3>Conclusions:</h3> We showed increased prevalence of dyslipidemia patients in the individuals with RA than those without RA. Serum LDL levels was increased and TG was decreased in RA patients of the Korean population survey. <h3>Disclosure of Interest:</h3> None declared
Cardiovascular Events after New-Onset Atrial Fibrillation in Adults with CKD: Results from the Chronic Renal Insufficiency Cohort (CRIC) Study
Authors: Nisha Bansal, Dawei Xie, Daohang Sha, Lawrence J. Appel, Rajat Deo, Harold I. Feldman, Jiang He, Kenneth Jamerson, John W. Kusek, Steven Messe, Sankar D. Navaneethan, Mahboob Rahman, Ana Catherine Ricardo, Elsayed Z. Soliman, Raymond Townsend, Alan S. Go
Journal: Journal of the American Society of Nephrology (2018)

Background Atrial fibrillation (AF), the most common sustained arrhythmia in CKD, is associated with poor clinical outcomes in both patients without CKD and patients with dialysis-treated ESRD. However, less is known about AF-associated outcomes in patients with CKD who do not require dialysis. Methods To prospectively examine the association of new-onset AF with subsequent risks of cardiovascular disease events and death among adults with CKD, we studied participants enrolled in the Chronic Renal Insufficiency Cohort Study who did not have AF at baseline. Outcomes included heart failure, myocardial infarction, stroke, and death occurring after diagnosis of AF. We used Cox regression models and marginal structural models to examine the association of incident AF with subsequent risk of cardiovascular disease events and death, adjusting for patient characteristics, laboratory values, and medication use. Results Among 3080 participants, 323 (10.5%) developed incident AF during a mean 6.1 years of follow-up. Compared with participants who did not develop AF, those who did had higher adjusted rates of heart failure (hazard ratio [HR], 5.17; 95% confidence interval [95% CI], 3.89 to 6.87), myocardial infarction (HR, 3.64; 95% CI, 2.50 to 5.31), stroke (HR, 2.66; 95% CI, 1.50 to 4.74), and death (HR, 3.30; 95% CI, 2.65 to 4.12). These associations remained robust with additional adjustment for biomarkers of inflammation, cardiac stress, and mineral metabolism; left ventricular mass; ejection fraction; and left atrial diameter. Conclusions Incident AF is independently associated with two- to five-fold increased rates of developing subsequent heart failure, myocardial infarction, stroke, or death in adults with CKD. These findings have important implications for cardiovascular risk reduction.
Abstract 13938: Relationships Between ‘Mediterranean’ and ‘Western’ Dietary Patterns and Biomarkers Associated With Increased Cardiovascular Risk in Patients With Stable Coronary Heart Disease in the Global STABILITY Trial
Authors: Ralph A Stewart, Harvey D White, Jocelyne Benatar, Nicolas Danchin, Emil Hagström, Claes Held, Steen Husted, Eva Lonn, Nermin Hadziosmanovic, Ola Vedin, David Watson, Agneta Siegbahn, Lars Wallentin
Journal: Circulation (2015)

Introduction: In the STabilization of Atherosclerotic plaque By Initiation of darapLadIb TherapY (STABILITY) trial greater adherence to a Mediterranean dietary pattern (MD) was associated with major cardiovascular (CV) events (MACE) but there was no association between a ‘Western Diet Score’ (WDS) and MACE. The lowest mortality and MACE was in patients with a MD score (MDS) ≥15. Hypothesis: Low adherence to a MD may be associated with higher plasma levels of biomarkers known to predict adverse CV events. Methods: At baseline, 15,482 (97.8%) trial participants completed a lifestyle questionnaire. MDS was calculated for increasing consumption of whole grains, fruits, vegetables, legumes, fish, and alcohol, and for less meat. WDS was calculated for increasing consumption of refined grains, sweets and desserts, sugared drinks, and deep-fried foods. In 15,287 of these participants hs C-reactive protein (hs-CRP), hs troponin T (hs-TnT), N-terminal B type natriuretic peptide (NT-proBNP), interleukin-6 (IL-6), cystatin-C, growth differentiation factor-15 (GDF-15) and lipoprotein-associated phospho-lipase A 2 (Lp-PLA 2 ) were measured from stored plasma samples taken at baseline. The ratios of the geometric mean level of each biomarker by diet group are reported adjusted for age, gender, darapladib treatment, geographic region, markers of disease severity, and CV risk factors including body mass index, diabetes, hypertension, and low and high-density lipoprotein cholesterol. Results: Lower MDS (13-14/ ≥15 and ≤12/ ≥15 respectively) was associated with higher hs-CRP 1.12 (95%CI 1.05; 1.19), 1.18 (1.11; 1.25), cystatin-C 1.01 (1.00; 1.02), 1.03 (1.01; 1.04), GDF-15 1.05 (1.02; 1.07), 1.06 (1.04; 1.09) and LpPLA2 1.02 (1.01; 1.04), 1.04 (1.02; 1.06) after adjusting for all co-variables (p&lt;0.01 for all). IL-6, hs-TnT and NT-proBNP were not independently associated with MDS. WDS was not independently associated with higher plasma levels of any biomarkers. Conclusions: MD may be associated with lower CV risk in part by effects on inflammatory activity and pathways of cellular function independent of plasma lipids. Greater consumption of food in the WDS was not associated with adverse CV events or with biomarkers known to be associated with risk.
Activating transcription factor 4 is a novel regulator of the cell cycle through direct interaction with p27kip1 and cdk4 in breast cancer
Authors: Rozita Bagheri-Yarmand, Kelly K Hunt, Khandan Keyomarsi
Journal: Cancer Research (2008)

5078  The cell cycle is frequently deregulated in human malignancy, including breast cancer. Loss of cell cycle control, and hence the ability to proliferate without appropriate checks and balances, is one of the hallmarks of cancer. Integral to the G1/S transition is the Rb pathway, which is controlled by cyclins D and E, together with their kinase partners, cdk4 and cdk2 respectively. These cyclin/cdk complexes are inhibited by p16, p21cip1 and p27kip1. A decrease in cdk levels or an increase in the levels of the inhibitors would effectively shutdown this cell cycle transition, leading to cell cycle arrest and inhibition of growth. Therefore, identifying a ‘master regulator’ that controls the G1/S transition would hold substantial clinical promise.  A protein that we are implicating to be involved in the G1/S transition is called Activating Transcription Factor 4 (ATF4). ATF4 has been identified as a protein that responds to different cellular stresses (e.g., lack of oxygen, lack of nutrients, etc). We have previously shown that overexpression of ATF4 under the control of βlactoglobulin promoter in mammary gland of transgenic mice severely impaired normal development of the mammary gland, which was associated with reduced proliferation and differentiation of mammary alveolar epithelium and upregulation of p27kip1 and p21cip1. Here we show thatectopic expression of ATF4 in the human MCF7 cell line inhibits cell proliferation and induces a G0/G1 arrest with increased expression p27Kip1. In addition, ATF4 binds directly to CDK4 and p27kip1 to inhibit the CDK4 and cyclin E associated kinase activities respectively. We next mapped the ATF4 binding site in p27kip1 using the PET fusion domains of p27kip1 and show that the CDK and cyclin binding domain of p27kip1 efficiently interact with ATF4. In addition, suppression of ATF4 in cells leads to decrease in p27kip1 expression, while overexpression of ATF4 results in rearrangement of cyclin-CDK complexes.Thus ATF4 is a novel regulator of mammary epithelial cell proliferation through regulation of p27kip1 expression, CDKs activities and reassortment of cyclin/CDK complexes. Our preliminary clinical studies using 52 human breast cancer samples reveals that ATF4 expression is decreased in more than 30% of the tumors examined. In addition, we found a positive correlation between ATF4 and p27kip1 expression levels by western blot as well as co-localizatin of ATF4 and p27kip1 in these tumor tissues by immunohistochemistry. Collectively, these results suggest that ATF4 is a novel tumor suppressor with specific actions in the phase of the cell cycle (i.e. the G1 to S transition) which is crucial for regulated cell division. These results underscore the importance of ATF4 as a cell cycle regulator and provide a rationale for use of ATF4 as a prognostic factor in association with p27kip1 in breast cancer that can also be exploited therapeutically.
Abstract P032: Cardiovascular Risk Factors and Brachial Distensibility in Children
Authors: Nicholas M Edwards, Philip R Khoury, Elaine M Urbina
Journal: Circulation (2016)

Introduction: Our previous cross-sectional studies demonstrated a relationship between elevated cardiovascular risk factors and arterial stiffness in adolescents. Other investigators showed longitudinal associations between cardiovascular risk factors at age 9 and adult arterial stiffness. Therefore we sought to determine if risk factor-related increase in arterial stiffness could be demonstrated even earlier in childhood. Hypothesis: In 10-year-old children, elevated blood pressure and BMI will be associated with less brachial distensibility (greater arterial stiffness). Methods: A community sample of 232 children (age 9.6 ± 0.5 years, 52% male, 83% white) in follow up from a longitudinal study were enrolled and had the following measures collected: height, weight, systolic blood pressure (SBP), diastolic blood pressure (DBP), brachial distensibility (BrachD, PulseMetric, San Diego, CA). Pearson correlation coefficients were calculated and general linear modeling was performed to evaluate the relationships between cardiovascular risk factors and arterial stiffness. Results: Participants had a mean BMI of 18.6 ± 3.4 kg/m^2, waist-to-hip ratio (WHR) of 0.9 ± 0.05, BMI z-score of 0.5 ± 1.1, SBP of 96 ± 9 mm Hg, DBP of 53 ± 11 mm Hg, SBP z-score of -0.5 ± 0.8, DBP z-score of -0.7 ± 1, and BrachD of 7.4 ± 2.2 percent change per mm Hg. The following cardiovascular risk factors were significantly associated with BrachD: WHR (r = -0.19, p = 0.005), BMI z-score (r = -0.16, p = 0.01), and SBP z-score (r = -0.14, p = 0.04). Modeling revealed both WHR and BMI z-score but not SBP z-score were associated with BrachD independent of age, sex, and race. After reducing a model simultaneously adjusting for all multiple risk factors and demographic variables, WHR, race, and age remained independently associated with BrachD. Conclusions: Associations between multiple cardiovascular risk factors (WHR, BMI, SBP) and arterial stiffness (brachial distensibility) are present in children as young as 10 years old, with WHR maintaining an independent association in a model adjusted for multiple covariates. These findings build on previous evidence that early exposure to cardiovascular risk factors can affect vascular health and support the contention that threats to cardiovascular health should be met aggressively in childhood.
Becoming a Caregiver — Lessons from My Dad
Authors: Audrey M. Provenzano
Journal: New England Journal of Medicine (2018)

My father's diagnosis came just before I graduated from medical school: cerebral amyloid angiopathy. Amyloid had weakened the blood vessels in his brain, causing hemorrhagic strokes. So I began a journey as a caregiver in two domains: as a doctor and as a daughter.