tbuckley/cabot-search huggingface dataset:
Abstract 261: Endothelial Cells Contribute to RAS Activation in Microvascular Smooth Muscle Cells
Authors: Kayoko Miyata, Ryousuke Satou, L Gabriel Navar
Journal: Circulation Research (2012)

Introduction: We have demonstrated that Ang II augments angiotensinogen (AGT) expression in rat preglomerular vascular smooth muscle cells (VSMCs). However, it is unclear if endothelial cells (ECs) are involved in augmentation of AGT in renal afferent arterioles. Hypothesis: We assessed the hypothesis that the ECs respond to paracrine signals that Ang II contribute to AGT augmentation in VSMCs. Objective: We established primary cultures of preglomerular ECs and examined the effects of Ang II and/or culture medium from ECs on AGT expression in preglomerular VSMCs. Methods and Results: We established primary cultures of preglomerular ECs, isolated from afferent arterioles of Sprague-Dawley rats. The cells were identified as ECs by being positive for a marker, CD34 and endothelial NOS and negative for alpha-SMA (a marker for VSMCs) and P4H-b (a marker for Fibroblasts) by immnostaining. The expression levels of AGT mRNA and renin mRNA in preglomerular ECs were examined by real-time RT-PCR. Ang II (100 pmol/L) increased AGT mRNA levels (1.34 +/- 0.16, by 100 pmol/L, N=4) and Renin mRNA levels (6.16 +/- 0.96, by 100 nmol/L, N=4) in ECs. On the other hand, the same dose of Ang II suppressed Renin mRNA expression in isolated Juxtaglomerular cells (JGs). These results indicate that preglomerular ECs are respond to Ang II and exclude the possible contamination of JGs into ECs. 100 pmol/L of Ang II increased AGT mRNA expression levels (1.37 +/- 0.03, relative ratio, N=4) in preglomerular VSMCs and the culture medium of ECs without Ang II treatment also more increased AGT mRNA expression (1.62 +/- 0.13, relative ratio, N=4) in preglomerular VSMCs. The AGT mRNA expression augmentation was enhanced when preglomerular VSMCs were treated with culture medium of Ang II-treated preglomerular ECs (2.39 +/- 0.41, relative ratio, N=4). The synergistic effects of Ang II and preglomerular ECs were also observed in PAI-1 expression in preglomerular VSMCs. Conclusion: These data demonstrate that preglomerular ECs contribute to Ang II-upregulation of AGT in renal afferent arterioles leading to further Ang II augmentation, which leads to increases in inflammatory and sclerotic factors in preglomerular VSMCs.
An assay of angiogenic protein expression in human umbilical vein endothelial cells (HUVECs)
Authors: Philip C. Mack, Paul H. Gumerlock, Primo N. Lara, Quynh-Thu Le, Jeffrey A. Longmate, Kari Chansky, John J. Crowley, David R. Gandara
Journal: Cancer Research (2005)

1141   The growth and metastatic potential of solid tumors is dependent upon vasculature formation. Numerous quantitative assays are used to measure levels of angiogenesis in ovarian cancer, including molecular expression of cytokines and their receptors, functional or molecular expression of angiogenic proteins, microvessel counts and immunohistochemistry. We have initiated a pilot study to apply state-of-the-art quantitative microproteomic lysate array technology to cultured endothelial cells in order to optimize an assay of vascular protein expression. Twenty-four hours prior to the experiment, human umbilical vein endothelial cells (HUVECs) were starved in reduced serum-containing media. HUVECs were treated with low serum-containing medium alone (control), VEGF-165 for 15 min., or CoCl2 for 1 hr. to induce hypoxia. Cells were lysed and printed onto protein microarrays. Arrays were probed with pre-validated commercial antibodies against: CD31, cKit, p-cKit (Tyr719), Cox-2, eNOS, p-eNOS (ser 116), HIF-1 alpha, PDGFR beta, p-PDGFR beta (Tyr 716) and p-VEGFR-2 (Tyr 1175). Stained arrays were scanned and quantitated. Preliminary results show detectable changes in protein expression of cKit, p-cKit, eNOS and p-eNOS in response to angiogenic stimuli. CD31 protein was detected only in the endothelial cell component of the protein microarray, while Cox-2 was measurable in both endothelial cells and A431 carcinoma cell line controls. Relatively more Cox-2 was present in HUVECs than in A431 controls. This pilot study provides proof of concept that microproteomic technologies can be used to study in situ vascular signaling events. This assay will be further optimized in ovarian cancer tissue samples and cross-validated against standing techniques for the study of angiogenesis in clinical samples. This research was made possible through the Clinical Research Training Program, a public-private partnership supported jointly by the NIH and a grant to the Foundation for the NIH from Pfizer Pharmaceuticals Group.
Role of different germline BRCA mutations in response to platinum-based chemotherapy in patients (pts) with triple-negative breast cancer (TNBC).
Authors: Mona Frolova, Ekaterina Ignatova, Marina B. Stenina, Alexander Petrovsky, Sergei Tjulandin
Journal: Journal of Clinical Oncology (2016)

e13008 Background: TNBC is associated with aggressive behavior and poor prognosis. TNBC is the most common subtype seen in patients with hereditary BRCA associated breast cancer. Because of defects of homologous recombination these tumours may be extremely sensitive to DNA-damaging agents such as platinum. Little is known about influence of different germline BRCA mutations on response to chemotherapy. Previously we have shown that somatic BRCA1 mutations may determine different responses to platinum-based chemotherapy. Now we analyse efficacy of dose-dense schedule of doxorubicin, cisplatin and paclitaxel in pts with hereditary BRCA associated TNBC. Methods: Twenty eightpts with early (cT1-2N0-1M0) and locally advanced (cT2-4N2-3M0) hereditary BRCA associated TNBC were treated with dose-dense combination of doxorubicin, cisplatin and paclitaxel followed by surgery. Mutations distribution is summarized in table 1. Pathological response was evaluated according to the Chevallier classification. Results: Median agewas 37 (25-56) years, 45% of pts had tumor Grade 3, median Ki67 was 70%. All pts completed chemotherapy and underwent surgery. Pathological complete response (pCR) was achieved in 18 pts (64,3%). All pts with BRCA2 mutations, with BRCA1 LOH, BRCA1 185delAG and majority (12/17) of pts with BRCA1 5382insC mutations achieved pCR. Whereas all pts with BRCA1 C61G, BRCA1 4094T>G and 2/3 pts with BRCA1 4153delA mutations had residual disease. Conclusions: BRCA mutations may predispose different responses to platinum-based chemotherapy. Clinical trials with larger number of pts are required. Mutations distribution. BRCA mutation N=28 n (%) Pts with pCR n/N BRCA1 5382insC 17 (60,7) 12/17 BRCA1 185delAG 1 (3,6) 1/1 BRCA1 C61G 2 (7,1) 0/2 BRCA1 4153delA 3 (10,7) 1/3 BRCA1 4094T>G 1 (3,6) 0/1 BRCA1 loss of heterozygosity (LOH) 2 (7,1) 2/2 BRCA2 N372H 1 (3,6) 1/1 BRCA2 6174T/delT 1 (3,6) 1/1
Cancer in primary immunodeficiency diseases: An analysis of cancer incidence in the United States immune deficiency network (USIDNET) registry.
Authors: Paul Mayor, Kevin H. Eng, Kelly L. Singel, Scott I Abrams, Kirsten B. Moysich, Kunle Odunsi, Charlotte Cunningham-Rundles, Brahm H. Segal
Journal: Journal of Clinical Oncology (2016)

1520 Background: We reported the overall and site-specific incidence of cancer in the United States Immune Deficiency Network (USIDNET) Registry.We hypothesized that patients with Primary Immunodeficiency Diseases will have an increased incidence of cancer due to impaired immune function. Methods: Data were abstracted from the USIDNET Registry patients (n = 3,665) from 2003 to 2015. Site-specific cancer incidence rates were generated for patients within the registry. Age adjusted incidence rates for were generated using the SEER database for comparison to the patients within the USIDNET registry. Results: We observed a 1.34-fold excess relative risk of cancer (p < .001) in patients with PIDD compared to age-adjusted SEER population. In men we found this excess relative risk to increase to 1.8-fold excess relative risk of cancer (p < .001), however in women the increase risk of cancer was not significant. When analyzing the four most common malignancies diagnosed in men and women in the United States (lung, colon, breast, and prostate cancers) we found no statistically significant increase in these diagnoses in the USIDNET Registry patients. We observed statistically significant increases in lymphoma in both men (10-fold excess relative risk p < .001) and women (8-fold excess relative risk p < .001) in the registry. In men within the registry we observed a statistically significant increase in skin cancer (4.45 fold excess relative risk p < .001) and thyroid cancer (4-fold excess relative risk p = .002), and in women we observed a statistically significant increase in skin (3.19 fold excess relative risk p < .001) and stomach cancer (3-fold excess relative risk p = .015). Conclusions: Excess incidence of cancer occurred in patients within the USIDNET Registry. This increased incidence was principally driven by an excess of lymphoma in specific PIDD populations, while no increased risk of the most common solid tumor malignancies was observed. These data point to a restricted role of the immune system in protecting from specific cancers and question the role of immunosurveillance in incident risk of common solid tumor cancers.
A Phase II study to assess the safety and efficacy of the steroid sulfatase inhibitor Irosustat when added to an aromatase inhibitor in ER positive locally advanced or metastatic breast cancer patients (IRIS) – Trial Results.
Authors: Carlo Palmieri, Robert C. Stein, Xinxue Liu, Emma Hudson, Sadie Reed, Hanna Nicholas, Sophie Barrett, Christopher Holcombe, Adrian Lim, Richard L Hayward, Sacha Jon Howell, Charles Coombes
Journal: Journal of Clinical Oncology (2016)

549 Background: Lowering estradiol levels is a key treatment modality for estrogen-receptor positive (ER+) postmenopausal breast cancer (BC).Currently, only one of the two main enzymes for oestrogen biosynthesis is targeted therapeutically in BC, namely aromatase, with the second pathway steroid sulfatase (STS) yet to be exploited. Irosustat, is a first generation, orally active, irreversible steroid sulfatase (STS) inhibitor. We performed a multicentre, open label phase II trial of the addition of Irosustat to first-line aromatase inhibitor (AI) in patients (pts) with advanced BC to test the hypothesis that the addition of Irosustat to AI may result in clinical benefit. Methods: Postmenopausal women with ER+ locally advanced or metastatic breast cancer who had derived clinical benefit from a first line AI and who subsequently progressed were enrolled. The first line AI was continued and Irosustat (40mg orally daily) added. The primary endpoint was clinical benefit rate (CBR, as defined by SD, CR or PR for ≥ 6 months) and secondary endpoints included safety and tolerability, and pharmacodynamic end points. Results: From Feb 2013 to March 2014 27 patients were recruited. All received at least one dose of drug. Based on local reporting the CBR on an intent to treat (ITT) basis was 18.5% (95%CI: 6.3%-38.1%), increasing to 21.7% (95%CI 7.4-43.7%) in the per-protocol analysis. In those patients that achieved clinical benefit, the median (range) duration of clinical benefit was 9.4 (7.1-16.8) months in the ITT and per protocol analysis. The median progression free survival (PFS) time was 2.7 months (95%CI: 2.5-4.6) in both the ITT and per-protocol analysis. The most frequently reported grade 3/4 toxicities were dry skin (28%), nausea (13%), fatigue (13%), diarrhoea (8%), headache (7%), anorexia (7%) and lethargy (7%). Conclusions: This study supports the hypothesis that the blockade of STS following optimal aromatase inhibition can result in clinical benefit. These data support further investigation of STS inhibition in combination with AI’s to optimise endocrine therapy in ER+ BC. Clinical trial information: NCT01785992.
FDA analysis of patient enrollment by region in clinical trials for approved oncological indications.
Authors: Bindu Kanapuru, Harpreet Singh, Lola A. Fashoyin-Aje, Adrian Myers, Geoffrey Kim, Ann Farrell, Richard Pazdur
Journal: Journal of Clinical Oncology (2017)

2539 Background: Clinical trials are increasingly conducted on a global scale in an effort to accelerate accrual. This analysis attempts to quantify and characterize participants in trials submitted to support approval of drugs for oncology indications by the region of enrollment. Methods: Demographic information was extracted for patients enrolled in clinical trials submitted to the FDA from 2005-2015. Only trials submitted to support approval for malignant solid tumor or hematology indications were included. Countries were grouped into regions for further analysis. A total of 178,024 patients with information regarding age and country were included in this analysis. Results: Forty five percent (80,460) of clinical trial participants were enrolled from Europe, 36% (63,958) from North America (includes U.S.A and Canada) and 8.4% (14,975) from Asia. Countries in Latin America, Middle East/Africa and the Baltic States/Russia enrolled the remainder 10.5% of the patients. Among 99,556 participants &lt; 65 years of age; 38.7% (38,538) were enrolled from North America, 40.5% (40,362) from Europe, 9.7 % (9674) from Asia and 11% from the rest of the regions. Europe enrolled the highest number of cancer patients aged 65 years or older; 51.1% (40,098) compared to 32.4% (25,420) from North America and 6.8 % (5301) from Asia. Conclusions: Majority of patients enrolled into clinical trials submitted for oncology drug approvals were from regions other than North America, with highest number enrolled from Europe particularly in the older age group. While it is interesting to speculate, the reasons for differential enrollment of patients between Europe and North America and the impact of these findings on interpretation of clinical trial results need additional exploration. Analysis of trends over time may be useful to address this issue. [Table: see text]
A new method for taking into account cohort-effect in cancer studies: Application to breast cancer incidence in the E3N cohort.
Authors: Olivier Bouaziz, Gregory Nuel
Journal: Journal of Clinical Oncology (2016)

e12038 Background: In epidemiology, it is well known that survival data are subject to the so-called cohort effect. In a cohort study, the cancer incidence rates (ex: breast cancer) might be heterogeneous among individuals recruited or born at different times. Methods: We introduce a new method based on the Cox proportional hazard model that allows abrupt changes to occur either in terms of baseline hazard rates or in terms of proportional factors. It is implemented using a constrained Hidden Markov Model (HMM) method and the EM algorithm [1]. With this new model, we aim at two objectives: firstly, we want to estimate the incidence rates of breast cancer in the French population and the proportional factors in each homogenous region through the Cox model; secondly, we want to accurately provide the number and location of the breakpoints delimiting each homogenous region. Results: The new method is applied on the E3N cohort study on breast cancer data which contains more than 90,000 women [2]. In comparison with the classical age-period cohort model, the suggested method has the advantage to allow completely different baseline incidence for different periods (ex: breast cancer incidence before of after screening programs). Unlike the arbitrary stratifications on date of birth which are often used in the context of cancer incidence (ex: born before or after 1960), the new approach has the advantage to detect automatically the times where the change points in the cohort occur and to provide the full posterior distribution for a change point to occur at a given cohort year (including conf. interval estimates). Conclusions: Taking advantage of both a solid mathematical technique and of the extensive databases of the E3N cohort database, our new method allows us to detect when abrupt changes in the incidence rate happened and it provides very accurate estimate of the incidence rates in each period. [1] Luong et al. (2013), Comput. Stat. & Data Analysis, 68:129–140. [2] Clavel-Chapelon F. (2015) Cohort profile: the French E3N cohort study. International Journal of Epidemiology, 44(3):801-809. The dataset was obtained from équipe 9 du CESP, Inserm unité 1018, Université Paris Sud, Institut Gustave Roussy, Villejuif.
Bence Jones Proteinuria in Smoldering Multiple Myeloma As Predictor Marker of Progression to Symptomatic Multiple Myeloma
Authors: Veronica Gonzalez de la Calle, Ramon Garcia-Sanz, Eduardo Sobejano, Enrique M. Ocio, Noemi Puig, Norma Carmen Gutierrez, Alberto Melón, Joaquin Gonzalez, Alfonso Garcia de Coca, Jose M. Hernandez, Roberto Hernandez, Abelardo Barez, Jose M. Alonso, Carmen Aguilera, Fernando Escalante, Guillermo Martin, Rosa Lopez, Pilar de la Fuente, Maria-Victoria Mateos
Journal: Blood (2014)
Abstract 012: Directed Differentiation of c-kit+ Human Cardiac Stem Cells in vitro
Authors: Kyung U Hong, Tareq M Al-Maqtari, Afsoon Moktar, Bathri N Vajravelu, Aruni Bhatnagar, Roberto Bolli
Journal: Circulation Research (2013)

Although transplantation of c-kit+ cardiac stem cells (CSCs) significantly alleviates post-myocardial infarction (MI) left ventricular dysfunction, the exogenous CSCs in the recipient heart do not generate cardiomyocytes robustly. Controlling the fate of transplanted CSCs and inducing their robust differentiation would be important in further improving the efficacy of cardiac stem cell therapies. We assessed the hypothesis that differentiation of human c-kit+ CSCs can be enhanced by programming them with cardiac transcription factors, including GATA4, MEF2C, Nkx2.5 and Tbx5. Transcription factors were introduced into CSCs in culture via lentivirus either individually or in combination. The transduced cells were then cultured for 1 or 2 weeks and analyzed for expression of 36 different markers of differentiated cardiac cell types by quantitative RT-PCR. Introduction of GATA4 led to marked increases in both early and late markers of cardiomyocyte differentiation, such as BNP and troponin T. By 2 weeks, GATA4 also significantly induced some of the smooth muscle cell markers, including calponin-1 and smooth muscle myosin heavy chain, as well as fibroblast markers. Interestingly, these gene expression changes induced by GATA4 were accompanied by dramatic morphological changes in CSCs. Overexpression of Tbx5 in CSCs resulted in induction of some of the cardiomyocyte markers specifically, although the number of genes differentially expressed was significantly less than those by GATA4. Interestingly, introduction of multiple transcription factors in combinations did not further increase the expression of cardiac marker genes. In conclusion, these findings suggest that cardiac gene programs can be activated in CSCs via introduction of defined transcription factors and that the pattern of expression of differentiated cardiac markers is unique to each transcription factor. However, none of the transcription factors alone was sufficient to induce differentiation of CSCs into mature cardiomyocyte-like cells, indicating that multiple and additional factors as well as temporal changes in their expression may be required for full differentiation and maturation of CSCs.
Dynamic illumination of spatially restricted or large brain volumes via a single tapered optical fiber
Authors: Ferruccio Pisanello, Gil Mandelbaum, Marco Pisanello, Ian A Oldenburg, Leonardo Sileo, Jeffrey E Markowitz, Ralph E Peterson, Andrea Della Patria, Trevor M Haynes, Mohamed S Emara, Barbara Spagnolo, Sandeep Robert Datta, Massimo De Vittorio, Bernardo L Sabatini
Journal: Nature Neuroscience (2017)
Out-of-Hospital Cardiac Arrest
Authors: Jimmy Robert, Clément Derkenne, Daniel Jost, Jean-Pierre Tourtier
Journal: Circulation (2017)

ECG CHALLENGEAn 84-year-old man called the emergency service from his home because of recent chest pain associated with dyspnea.He had a long-standing history of coronary artery disease and chronic obstructive pulmonary disease.One minute after the basic life support team arrived, the patient went into cardiac arrest.The rescuers deployed their automated external defibrillator, and 1 electric shock was delivered.Thereafter, the patient received cardiopulmonary resuscitation.The prehospital emergency physician arrived at the scene 10 minutes later.At this time, the patient had pulseless electric activity (PEA).The ECG monitoring (lead 2) during cardiopulmonary resuscitation is shown in Figure 1.He received 1 mg adrenaline, continuous chest compressions, and orotracheal intubation.A few minutes later, the patient had recovered spontaneous circulation.Cardiac and pulmonary auscultations were normal.The patient was connected to a ventilator, which displayed normal pressure levels.He was then transported to the emergency department without any new clinical complications.What abnormalities are present in the ECG, and might they relate to a particular cause of the cardiac arrest?Please turn the page to read the diagnosis.
BMI change and abdominal girth as risk factors of breast cancer.
Authors: Yusuke Suzuki, Hiroko Tsunoda, Takeshi Kimura, Hideko Yamauchi
Journal: Journal of Clinical Oncology (2017)

e13082 Background: While obesity is considered the risk factors of breast cancer, Asian women are tends to be lower BMI compared with Western populations and there are not much reports that studied association between obesity and risk of breast cancer in Asian women. In this study, we analyzed the associations of breast cancer incidence and body mass index at age 18-20 (BMI 18-20y), BMI at research entry (BMI at entry), change of the BMI from BMI 18-20y to BMI at entry (BMI change), abdominal girth at research entry (AG), HbA1c [N] at research entry (HbA1c). Methods: We used data of the women who had undergone medical check-ups and opportunistic breast cancer screening at least twice at the Center for Preventive Medicine of St. Luke’s International Hospital between April 1, 2005 and March 31, 2014. Statistical analysis was done by using multivariate Cox proportional hazards model to investigate the hazard ratio (HR) at 95% confidence intervals (95% CI). Results: In this 10 year period, 30,109 women (20,043 women were premenopausal and 10,066 women were postmenopausal women) received opportunistic breast cancer screening at least twice. After analysis of 131656.6 person-years follow up during 10 years, 325 initial breast cancer cases were identified 202 cases in premenopausal women, and 123 cases in postmenopausal women. Among postmenopausal women, BMI change and AG were positively associated with breast cancer incidence. Women whose BMI change were major gain group (&gt; +5.0) were significantly likely to develop breast cancer compared with stable group (BMI change were between -2.5 to +2.5) [HR: 1.902 (95% CI = 1.202-3.009)]. Large AG ( &gt; 90cm) was significant risk to develop breast cancer versus less than 70cm [HR: 2.500 (95% CI = 1.091-5.730)]. In the analysis classified BMI18-20y more and less than 20 kg/m 2 , large BMI18-20y ( &gt; 20 kg/m 2 ) postmenopausal women with high HbA1c ( &gt; 6.5) was more likely to develop breast cancer compared with low HbA1c ( &lt; 5.5) [HR: 3.325(95% CI = 1.307-8.460)]. Conclusions: Increase of BMI after age of 18-20 years and large AG in postmenopausal women have positive association with breast cancer development. High HbA1c women whose BMI18-20y was over 20 kg/m2 are significantly to develop breast cancer.