tbuckley/cabot-search huggingface dataset:
Abstract 12902: Association of Statin Use and Endogenous Serum Sex Hormone Levels in the Multi-ethnic Study of Atherosclerosis(MESA) Cohort
Authors: Oludamilola Oluleye, Richard Kronmal, Aaron Folsom, Pamela Ouyang, Dhananjay Vaidya, Daniel Duprez, Hirad Yarmohammadi, Adrian Dobs, Suma Konety
Journal: Circulation (2015)

Background: The new 2013 ACC/AHA cholesterol guidelines recommend statin therapy to reduce atherosclerotic cardiovascular disease. Statins inhibit cholesterol biosynthesis which may impair gonadal steroidogenesis. Higher levels of estradiol (E2) and lower levels of sex hormone binding globulin (SHBG) are associated with greater central obesity, metabolic syndrome and diabetes in both men and postmenopausal women. There is however limited information regarding the impact of statins on endogenous sex hormones in large population studies. Methods: We included 3163 men and 1977 women from the baseline examination of the MESA study who had measurement of serum sex hormones: total and bioavailable testosterone (T), E2, dehydroepiandrosterone (DHEA) and SHBG, and excluded those on hormone replacement therapy and non-statin lipid medications. Results: Of the 5140 individuals examined, statin users (n=812) were 67 + 9 years old, 57% males, 41% Whites, 29% Blacks, 11% Chinese and 19% Hispanics. After adjustment for age, gender and race, total cholesterol, HDL-c and BMI, compared to non-users of statins, statin users had significantly lower SHBG by 4.5 nmol/L (95% CI; -6.1, -2.9) and DHEAS by 0.9 nmol/L (95% CI; -1.4, -0.4). No significant gender interaction with statin was seen. No association was noted between statin use and E2, total and bioavailable T. Conclusion: Statin use is associated inversely with serum SHBG and DHEA levels. This is particularly interesting in light of the association of statin use and diabetes, raising the possibility of mediation by endogenous hormones.
Abstract 4420: MiR-182 suppresses invadopodia formation and metastasis in non-small cell lung cancer by targeting cortactin
Authors: Yongwen Li, Hongbing Zhang, Hongyu Liu, Jun Chen
Journal: Cancer Research (2018)

Abstract Metastasis is the leading cause of cancer mortality and is a major hurdle for lung cancer treatment. Invadopodia, which are cancer-specific protrusive structures, play a crucial role in the metastatic cascade through degradation of the basement membrane and surrounding stroma, but the exact mechanism of regulation is not yet fully understood. In this study, we show that cortactin (CTTN), an important component of invadopodia, is upregulated in lung cancer tissues and is a marker of poorer prognosis in human NSCLC. Phorbol 12,13-dibutyrate and hepatocyte growth factor can induce CTTN expression and motility, as well as invadopodia formation in non-small cell lung cancer (NSCLC). MicroRNA-182 (miR-182) suppresses metastasis and invadopodia formation by targeting CTTN in NSCLC. qRT-PCR results showed that CTTN expression was inversely correlated with expression of miR-182. miR-182/CTTN suppresses invadopodia formation of lung cancer cells via suppression of the Cdc42/N-WASP pathway. Furthermore, miR-182 negatively regulates invadopodia function and suppresses extracellular matrix degradation in lung cancer cells by inhibiting CTTN. In conclusion, our results demonstrated that miR-182 targets CTTN in NSCLC and suppresses lung cancer invadopodia formation and thus suppresses lung cancer metastasis, suggesting a therapeutic application of miR-182 in NSCLC. Citation Format: Yongwen Li, Hongbing Zhang, Hongyu Liu, Jun Chen. MiR-182 suppresses invadopodia formation and metastasis in non-small cell lung cancer by targeting cortactin [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 4420.
Abstract 4068: Galectin-1 intensifies immunosuppression in head and neck cancer by boosting myeloid-derived suppressive cell (MDSC) expansion
Authors: Dhanya K. Nambiar, Todd A. Aguilera, Joshua Daniel Bloomstein, Dadi Jiang, Hongbin Cao, Albert Koong, Quynh Thu Le
Journal: Cancer Research (2018)

Abstract Head and neck squamous cell carcinoma (HNSCC), with more than 450,000 newly diagnosed cases annually, is the 6th most common cancer worldwide. Recent literature shows that tumor induced suppression of the host immune system is critical to HNSCC progression and metastases. Tumor secreted factors directly influence the expansion of myeloid-derived suppressor cells (MDSCs), which are considered important contributors for tumor to escape from immune surveillance. The presence of expanded MDSCs peripherally and within the tumor microenvironment is associated with metastasis and recurrence after definitive treatment in HNSCC patients. In this study, we evaluated at the role of tumor secreted Galectin-1 in recruitment of MDSCs in HNSCC. We utilized HPV-negative as well as HPV-positive HNSCC models to test the effect of Galectin-1 knockout (KO) in the tumor microenvironment. CRISPR/Cas9 knock out Galectin-1 in MOC2 and MEERL models resulted in a ~50% reduction in the tumor growth. We further analyzed the tumor microenvironment of these tumors for MDSC recruitment. Both MOC2 and MEERL tumors showed highly inflammatory phenotype, with significant presence of MDSCs (&amp;gt;70% of CD45+ cells were of myeloid origin). Knocking out Galectin-1 led to a significant decrease in CD11b+Gr1+ MDSCs in both MOC2 and MEERL tumors. We also observed high level of MDSCs in both the spleen and the peripheral blood of mice bearing Galectin-1 wildtype (WT) tumors in both models. In contrast, knocking out Galectin-1 from the tumor reduced systemic MDSCs levels. To investigate how Galectin-1 modulates MDSC levels, we compared the secreted cytokine profiles between MOC2 WT and Galectin-1 KO tumors. Galectin-1 null cells secreted significantly lower levels of monocyte and macrophage recruiting chemokines: CCL5, CXCL1, and G-CSF. Analysis of the gene expression signatures of MOC-2 WT and KO tumor cells revealed critical signaling pathways differences, including down-regulation of PI3K-AKT pathway in KO-tumors. In conclusion, the present study reveals that tumor derived Galectin-1 can stimulate the recruitment of MDSCs, thereby potentiating an inflammatory tumor microenvironment which supports HNSCC progression. (Acknowledgements: BMS for Anti-Gal1 Abs. Dr R. Uppaluri, for MOC-2 oral cancer cells, Dr. W. Spanos for MEERL cells) Citation Format: Dhanya K. Nambiar, Todd A. Aguilera, Joshua Daniel Bloomstein, Dadi Jiang, Hongbin Cao, Albert Koong, Quynh Thu Le. Galectin-1 intensifies immunosuppression in head and neck cancer by boosting myeloid-derived suppressive cell (MDSC) expansion [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 4068.
Prognostic Values of Inflammatory and Redox Status Biomarkers on the Risk of Major Lower-Extremity Artery Disease in Individuals With Type 2 Diabetes
Authors: Mathilde Nativel, Fabrice Schneider, Pierre-Jean Saulnier, Elise Gand, Stéphanie Ragot, Olivier Meilhac, Philippe Rondeau, Elena Burillo, Maxime Cournot, Louis Potier, Gilberto Velho, Michel Marre, Ronan Roussel, Vincent Rigalleau, Kamel Mohammedi, Samy Hadjadj
Journal: Diabetes Care (2018)

OBJECTIVE Inflammation and oxidative stress play an important role in the pathogenesis of lower-extremity artery disease (LEAD). We assessed the prognostic values of inflammatory and redox status biomarkers on the risk of LEAD in individuals with type 2 diabetes. RESEARCH DESIGN AND METHODS Plasma concentrations of tumor necrosis factor-α receptor 1 (TNFR1), angiopoietin-like 2, ischemia-modified albumin (IMA), fluorescent advanced glycation end products, protein carbonyls, and total reductive capacity of plasma were measured at baseline in the SURDIAGENE (Survie, Diabete de type 2 et Genetique) cohort. Major LEAD was defined as the occurrence during follow-up of peripheral revascularization or lower-limb amputation. RESULTS Among 1,412 participants at baseline (men 58.2%, mean [SD] age 64.7 [10.6] years), 112 (7.9%) developed major LEAD during 5.6 years of follow-up. High plasma concentrations of TNFR1 (hazard ratio [95% CI] for second vs. first tertile 1.12 [0.62–2.03; P = 0.71] and third vs. first tertile 2.16 [1.19–3.92; P = 0.01]) and of IMA (2.42 [1.38–4.23; P = 0.002] and 2.04 [1.17–3.57; P = 0.01], respectively) were independently associated with an increased risk of major LEAD. Plasma concentrations of TNFR1 but not IMA yielded incremental information, over traditional risk factors, for the risk of major LEAD as follows: C-statistic change (0.036 [95% CI 0.013–0.059]; P = 0.002), integrated discrimination improvement (0.012 [0.005–0.022]; P &amp;lt; 0.001), continuous net reclassification improvement (NRI) (0.583 [0.294–0.847]; P &amp;lt; 0.001), and categorical NRI (0.171 [0.027–0.317]; P = 0.02). CONCLUSIONS Independent associations exist between high plasma TNFR1 or IMA concentrations and increased 5.6-year risk of major LEAD in people with type 2 diabetes. TNFR1 allows incremental prognostic information, suggesting its use as a biomarker for LEAD.
Acute Glucose Overload Abolishes Ca2+ Oscillation in Cultured Endothelial Cells From Bovine Aorta
Authors: ChiwakaKimura, MasahiroOike, YushiIto
Journal: Circulation Research (1998)

Abstract—Effects of acute glucose overload on [Ca2+]i were investigated in cultured endothelial cells from bovine aorta. Application of 0.1 μmol/L ATP elicited an oscillatory increase in [Ca2+]i (Ca2+ oscillation) in Krebs solution containing 11.5 mmol/L glucose. The frequency of Ca2+ oscillation induced by ATP increased in a concentration-dependent manner, ranging between 0.03 and 1 μmol/L. When cells were preincubated with 23 mmol/L glucose–containing Krebs solution (high glucose solution) for 3 hours, 0.1 μmol/L ATP failed to induce Ca2+ oscillation but evoked only a phasic followed by sustained increase in [Ca2+]i. Application of a higher concentration of ATP (10 μmol/L) evoked a transient increase in [Ca2+]i both in control and high glucose–treated cells. However, the falling phase of [Ca2+]i was prolonged in high glucose–treated cells. Thapsigargin (1 μmol/L), an inhibitor of endoplasmic Ca2+-ATPase, induced a transient followed by a sustained increase in [Ca2+]i in control cells. Preincubation with...
Association Between Severe Acute Contact Dermatitis Due to<i>Nigella sativa</i>Oil and Epidermal Apoptosis
Authors: Olivier Gaudin, Feyrouz Toukal, Camille Hua, Nicolas Ortonne, Haudrey Assier, Arnaud Jannic, Elena Giménez-Arnau, Pierre Wolkenstein, Olivier Chosidow, Saskia Ingen-Housz-Oro
Journal: JAMA Dermatology (2018)

Nigella sativa oil (NSO) is widely used for cosmetic and culinary purposes. Cases of severe acute contact dermatitis due to NSO are poorly described, with no histologic description.To describe the clinical and histologic features of severe acute contact dermatitis due to NSO and investigate the components responsible for such eruptions.A case series study of 3 patients with contact dermatitis admitted to the dermatology department between August 21, 2009, and February 19, 2017, was conducted. All patients had been referred to the dermatology department for acute contact dermatitis due to NSO and had patch tests performed.Clinical and histologic features of the cutaneous eruptions, length of hospital stay, chemical analysis of NSO, and results of patch tests.Three patients (3 women; median age, 27 years [range, 20-47 years]) were included in the case series. All patients had polymorphic skin lesions spreading beyond the area of NSO application: typical and atypical targets, patches with central blisters, erythematous or purpuric plaques with a positive Nikolsky sign mimicking Stevens-Johnson syndrome, or toxic epidermal necrolysis. Two patients had pustules. They had severe impairment, with more than 15% skin detachment and fever. The results of skin biopsies showed epidermal apoptosis characterized by vacuolar alteration of the basal layer, keratinocyte apoptosis, and a moderate perivascular infiltrate of lymphocytes in the dermis. The results of patch tests using the patients' NSO were all positive. The results of gas chromatography combined with mass spectrometry performed on the NSO of 1 patient identified several constituent substances, mainly terpenes, thymoquinone, linoleic acid, and fatty acids.These cases suggest that acute contact dermatitis due to NSO may induce topically triggered epidermal apoptosis, previously described as the concept of acute syndrome of apoptotic pan epidermolysis. Thymoquinone and p-cymene may be the main agents involved in the pathophysiologic characteristics of this acute contact dermatitis. Clinicians should be aware of such severe reactions to NSO and report these cases to pharmacovigilance authorities.
Abstract 1045: Development of patient derived orthotopic xenografts from metastatic colorectal cancer
Authors: Tiago Goss dos Santos, Bruno Roque, Caroline Roque, Maria Dirlei Begnani, Eduardo Lima, Felipe Coimbra, Rubens Chojniak
Journal: Cancer Research (2018)

Abstract The occurrence of liver metastasis is the major cause of death in colorectal cancer patients. The treatment consists of surgery and chemotherapy. However, the patient outcome is very unfavorable. Thus, the development of new therapeutic regimens to treat this condition is urgent and demand the establishment of good animal models. Among the models that have being used, the patient-derived xenografts (PDX) have emerged as one of the most promising. PDXs are preclinical models that faithfully represent the individuality of human cancer, by grafting fresh human tumor in severely immunodeficient mice which allows for higher tumor implantation rates and growth. Metastatic disease could be also modeled using orthotopic implantation into the affected organ. The patient-derived orthotopic xenografts (PDOX) can be interrogated for different treatment strategies based on the individualized gene signature of the human tumor, and the results can inform clinically relevant treatment strategies for the patient. With the objective to establish a PDOX from metastatic colorectal tumors in athymic nude mice, we implanted fresh tumor fragments into mouse liver parenchyma and propagated tumors from three patients which could be serially implanted in second and third mice generations. The morphological and immunohistochemical characterization indicate that xenografts recapitulate the tumor architecture and the expression of mismatch repair genes (MLH1, MSH2, MSH1, PMS2). After tumor implantation in first passage, the time of tumor growth decrease from 150-250 days to 30-100 days without loss of tumor identity. The growth of a post-transplantation lymphoproliferative disease (PTLD) was observed in one case. This pilot study was successful to establish the institutional PDX preclinical platform to study new therapeutic strategies, biomarkers of disease progression and treatment responsiveness. Citation Format: Tiago Goss dos Santos, Bruno Roque, Caroline Roque, Maria Dirlei Begnani, Eduardo Lima, Felipe Coimbra, Rubens Chojniak. Development of patient derived orthotopic xenografts from metastatic colorectal cancer [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 1045.
Deloading of the Left Ventricle by Ventricular Assist Device Normalizes Increased Expression of Endothelin ETA Receptors But Not Endothelin-Converting Enzyme-1 in Patients With End-Stage Heart Failure
Authors: HenningMorawietz, MartenSzibor, WinfriedGoettsch, BabettBartling, MatthiasBarton, SidneyShaw, ReinerKoerfer, Hans-ReinhardZerkowski, JuergenHoltz
Journal: Circulation (2000)

Background—Ventricular assist devices (VAD) are implanted in patients with end-stage heart failure for bridging the time until heart transplantation, resulting in hemodynamic unloading of the failing heart, improved cardiac contractile and mitochondrial function, and reversal of cardiac hypertrophy. It is unknown whether VAD unloading may affect the cardiac endothelin (ET) system, which has been proposed as one of the putative pathomechanisms of heart failure. Methods and Results—With the use of standard-calibrated, competitive reverse-transcription–polymerase chain reaction mRNA expression of components of the ET system was analyzed in left ventricular myocardium from nonfailing donor hearts, from failing hearts without and with ACE inhibitor therapy, and from patients with end-stage heart failure at the time of VAD implantation and 103±15 days after VAD implantation during removal with subsequent heart transplantation. ET receptor A (ETA) was markedly upregulated in failing human myocardium. This increa...
RAS–MAPK Pathway-Driven Tumor Progression Is Associated with Loss of CIC and Other Genomic Aberrations in Neuroblastoma
Authors: Thomas F. Eleveld, Linda Schild, Jan Koster, Danny A. Zwijnenburg, Lindy K. Alles, Marli E. Ebus, Richard Volckmann, Godelieve A. Tijtgat, Peter van Sluis, Rogier Versteeg, Jan J. Molenaar
Journal: Cancer Research (2018)

Mutations affecting the RAS-MAPK pathway frequently occur in relapsed neuroblastoma tumors, which suggests that activation of this pathway is associated with a more aggressive phenotype. To explore this hypothesis, we generated several model systems to define a neuroblastoma RAS-MAPK pathway signature. Activation of this pathway in primary tumors indeed correlated with poor survival and was associated with known activating mutations in ALK and other RAS-MAPK pathway genes. Integrative analysis showed that mutations in PHOX2B, CIC, and DMD were also associated with an activated RAS-MAPK pathway. Mutation of PHOX2B and deletion of CIC in neuroblastoma cell lines induced activation of the RAS-MAPK pathway. This activation was independent of phosphorylated ERK in CIC knockout systems. Furthermore, deletion of CIC caused a significant increase in tumor growth in vivo These results show that the RAS-MAPK pathway is involved in tumor progression and establish CIC as a powerful tumor suppressor that functions downstream of this pathway in neuroblastoma.Significance: This work identifies CIC as a powerful tumor suppressor affecting the RAS-MAPK pathway in neuroblastoma and reinforces the importance of mutation-driven activation of this pathway in cancer. Cancer Res; 78(21); 6297-307. ©2018 AACR.
Abstract 1327: Autophagy facilitates tumor promotion in PyMT tumors through up-regulation of Pparg
Authors: Takako Okamoto, Song Chen, Syn Yeo, Jun-Lin Guan
Journal: Cancer Research (2018)

Abstract Autophagy genes have been reported to have either tumor promoting or inhibition functions in various cancers, but it is convoluting because of autophagy-independent functions of the respective autophagy genes. We previously reported that suppression of Fip200, an essential autophagy gene, inhibited tumor growth of PyMT driven mammary tumors. To dissect the specific autophagy-dependent function of FIP200 in these tumors, we recently established Fip200 Knock-in PyMT tumor mice with MMTV-Cre (cKI), allowing for conditional inhibition of autophagy in PyMT driven tumors without perturbing the non-autophagy functions of FIP200 . Compared to wild type (WT) tumors, tumor initiation, growth and metastasis were significantly suppressed in both cKI tumors and conditional Fip200 deleted tumors (cKO). Microarray analysis (GSEA) showed that adipogenesis related genes were significantly enriched in WT tumors compared to cKO tumors. The mRNA expression and protein expression of Pparg, one of the master regulators of adipogenesis, were significantly increased with autophagy induction under starvation condition (especially Glucose starvation) in PyMT isogenic cells compared to Fip200 KO and KI cells. Many Pparg target genes were down-regulated in autophagy deficient tumors. Among these, CD36, a free fatty acid (FFA) transporter, was also decreased compared to WT tumors. This suggests that FFA may have important roles as an energy source for PyMT tumor cells to survive under starvation conditions. In conclusion, our results indicate that tumor promotion of PyMT driven tumors was dependent on canonical autophagy. Our future studies will address the detailed mechanism of autophagy dependent tumor growth through metabolic regulation by Pparg. Citation Format: Takako Okamoto, Song Chen, Syn Yeo, Jun-Lin Guan. Autophagy facilitates tumor promotion in PyMT tumors through up-regulation of Pparg [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 1327.
Development of a Conceptual Map of Negative Consequences for Patients of Overuse of Medical Tests and Treatments
Authors: Deborah Korenstein, Susan Chimonas, Brooke Barrow, Salomeh Keyhani, Aaron Troy, Allison Lipitz-Snyderman
Journal: JAMA Internal Medicine (2018)

Overuse of medical tests and treatments is an increasingly recognized problem across health systems; best practices for reducing overuse are not clear. Framing the problem in terms of the spectrum of potential patient harm is likely to be an effective strategy for clinician and patient engagement in efforts to reduce overuse, but the scope of negative consequences of overuse for patients has not been well described.We sought to generate a comprehensive conceptual map documenting the processes through which overused tests and treatments lead to multiple domains of negative consequences for patients. For map development, an iterative consensus process was informed by structured review of the literature on overuse using PubMed and input from a panel of 6 international experts. For map verification, a systematic review was performed of case reports involving overused services, identified through literature review and manual review of relevant article collections. The conceptual map documents that overused tests and treatments and resultant downstream services generate 6 domains of negative consequences for patients: physical, psychological, social, financial, treatment burden, and dissatisfaction with health care. Negative consequences can result from overused services and from downstream services; they can also trigger further downstream services that in turn can lead to more negative consequences, in an ongoing feedback loop. Case reports on overuse confirmed the processes and domains of the conceptual map. Cases also revealed strengths and weaknesses in published communication about overuse: they were dominated by physical harms, with other negative consequences receiving far less attention.This evidence-based conceptual map clarifies the processes by which overused tests and treatments result in negative consequences for patients; it also documents multiple domains of negative consequences experienced by patients. The map will be useful for facilitating comprehensive communication about overuse, estimating harms and costs associated with overused services, and informing health system efforts to reduce overuse.