bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impaired dynamic cerebral autoregulation in trained breath-hold divers
Authors: Moir M. Erin , Klassen Stephen A. , Al-Khazraji Baraa K. , Woehrle Emilie , Smith Sydney O. , Matushewski Brad J. , Kozić Duško , Dujić Željko , Barak Otto F. , Shoemaker J. Kevin 
Published: May 2019

Breath-hold divers (BHD) experience repeated bouts of severe hypoxia and hypercapnia with large increases in blood pressure. However, the impact of long-term breath-hold diving on cerebrovascular control remains poorly understood. The ability of cerebral blood vessels to respond rapidly to changes in blood pressure represents the property of dynamic autoregulation. The current investigation tested the hypothesis that breath-hold diving impairs dynamic autoregulation to a transient hypotensive stimulus. Seventeen BHD (3 women, 11 ± 9 yr of diving) and 15 healthy controls (2 women) completed two or three repeated sit-to-stand trials during spontaneous breathing and poikilocapnic conditions. Heart rate (HR), finger arterial blood pressure (BP), and cerebral blood flow velocity (BFV) from the right middle cerebral artery were measured continuously with three-lead electrocardiography, finger photoplethysmography, and transcranial Doppler ultrasonography, respectively. End-tidal carbon dioxide partial pressure was measured with a gas analyzer. Offline, an index of cerebrovascular resistance (CVRi) was calculated as the quotient of mean BP and BFV. The rate of the drop in CVRi relative to the change in BP provided the rate of regulation [RoR; (∆CVRi/∆T)/∆BP]. The BHD demonstrated slower RoR than controls ( P ≤ 0.001, d = 1.4). Underlying the reduced RoR in BHD was a longer time to reach nadir CVRi compared with controls ( P = 0.004, d = 1.1). In concert with the longer CVRi response, the time to reach peak BFV following standing was longer in BHD than controls ( P = 0.01, d = 0.9). The data suggest impaired dynamic autoregulatory mechanisms to hypotension in BHD. NEW & NOTEWORTHY Impairments in dynamic cerebral autoregulation to hypotension are associated with breath-hold diving. Although weakened autoregulation was observed acutely in this group during apneic stress, we are the first to report on chronic adaptations in cerebral autoregulation. Impaired vasomotor responses underlie the reduced rate of regulation, wherein breath-hold divers demonstrate a prolonged dilatory response to transient hypotension. The slower cerebral vasodilation produces a longer perturbation in cerebral blood flow velocity, increasing the risk of cerebral ischemia.
Effects of high PEEP and fluid administration on systemic circulation, pulmonary microcirculation, and alveoli in a canine model
Authors: He Huaiwu , Hu Qinhe , Long Yun , Wang Xu , Zhang Rui , Su Longxiang , Liu Dawei , Ince Can 
Published: May 2019

This study aimed to determine the response of systemic circulation, pulmonary microcirculation, and alveoli to high positive end-expiratory pressure (PEEP) in a canine model. This study was conducted in nine mixed-breed dogs on mechanical ventilation under anesthesia. The PEEP was initially set at 5 cmH2O (PEEP5), the PEEP was then increased to 25 cmH2O (PEEP25), and then saline was used for fluid loading. Data were obtained at the following time points: PEEP5; PEEP25 prefluid loading; and PEEP25 postfluid loading. The images of subpleural lung microcirculation were assessed by sidestream dark-field microscopy, and the hemodynamic data were collected from pulse contour waveform-derived measurements. Compared with PEEP5, the lung microvascular flow index (MFI, 2.3 ± 0.8 versus 0.9 ± 0.8, P = 0.001), lung perfused vessel density (PVD, 4.2 ± 2 versus 1.5 ± 1.8, P = 0.004), lung proportion of perfused vessel (PPV, 93 ± 14 versus 40 ± 4, P = 0.003), cardiac output (2.5 ± 0.6 versus 1.4 ± 0.5, P = 0.001), and mean blood pressure (116 ± 24 versus 91 ± 31, P = 0.012) were significantly lower at PEEP25 prefluid loading. After fluid loading, there were no significant differences in cardiac output or mean arterial pressure between the PEEP5 and PEEP25 postfluid loading levels. However, the lung microcirculatory MFI, PVD, and PPV at PEEP25 postfluid loading remain lower than at PEEP5. A significant increase in septal thickness was found at PEEP25 postfluid loading relative to septal thickness at PEEP25 prefluid loading (25.98 ± 5.31 versus 40.76 ± 7.9, P = 0.001). Under high PEEP, systemic circulation was restored after fluid loading, but lung microcirculation was not. Moreover, the septal thickness of alveoli significantly increased after fluid loading. NEW & NOTEWORTHY An excessively high positive end-expiratory pressure (PEEP) can impair the systemic circulation and alveolar microcirculation. In the high-PEEP condition, fluid loading restored the systemic circulation but did not affect the impaired lung microcirculation. The septal thickness of the alveoli significantly increased after fluid loading in the high-PEEP condition.
Abstract CN04-02: Phase I trials: Limits and limitations in proof of concept
Authors: Verweij Jaap 
Published: May 2019

Abstract
We could and maybe should ask the question what is meant by “proof of concept” in early drug development. Do we mean that the drug hits the molecular target it is supposed to hit, which in essence may still be clinically meaningless. Or do we mean that we can proof that the drug has the expected signal of biological anti-tumor activity in a human being? And if so, what level of evidence are we looking for? Obviously the ultimate proof that a drug is beneficial can only be obtained in appropriately designed phase III studies. But these are expensive trials, and it would be worthwhile to be able to estimate earlier on in the development if the drug might be doing what it is supposed to do according to the preclinical information obtained.
Is looking for proof of concept in a phase I study stage of development like asking the impossible? Enormous amounts of effort and money have recently been invested in early clinical trials trying to better predict the outcome of later phase studies. Most of the obtained information has not been very supportive for Go/No-Go decisions. Interestingly analyzing the data for some of the recently registered agents it turns out they in retrospect predicted their activity by showing anatomical size changes as classified by RECIST, in a small or larger subset of patients in the phase I studies. For some of these agents, molecular marker changes coincided with the anatomical size changes, but in no instance was a molecular marker change without an anatomical size change predictive of relevant activity.
We should bear in mind that when starting phase I studies we frequently still have limited knowledge on the pharmacodynamics of a new agent. Thus the selection of patients is often a limiting factor in trying to assess the desired activity. The more recent focused development of Hedgehoc and ALK-fusion protein inhibitors shows that with a focused patient selection, sometimes based on early observations in the phase I studies, proof of concept prediction seems to come into reach. However for the majority of agents, we still seem to be looking into a crystal ball. Tumor size changes can be considered as biomarkers and should only be replaced by something else once we have certainty that a molecular change coincides with size change. Based on these observations models can be build that might be helpful in clinical development.
The fact that more simple assays than measuring anatomical size have not yet been able to provide us with appropriate predictions of efficacy, should not stop us from trying to develop these simple tools. And early hints that we may be on track are available.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):CN04-02.
Abstract CN07-02: Disrupting insulin-like growth factor signaling with monoclonal antibodies
Authors: Yee Douglas , Fagan Dedra H. , Zhang Xihong , Oh Annabell S. , LaPara Kelly , Becker Marc , Sachdev Deepali , Zhang Hua 
Published: May 2019

Abstract
The insulin-like growth factor (IGF) system is composed of a network of ligands, receptors, and binding proteins. The type I IGF receptor (IGF1R) is a transmembrane tyrosine kinase receptor and shares a high degree of homology with the insulin receptor (InsR). Data from many sources implicate the IGF system in cancer biology. Because of the role for InsR in glucose homeostasis, specific targeting of IGF1R with monoclonal antibodies has been deemed desirable. Numerous monoclonal antibodies have been developed against this receptor and share similar properties in preclinical model systems. To date, all of the antibodies have been shown to bind IGF1R and cause its internalization and downregulation. Early clinical studies have shown that IGF1R antibodies have activity as single agents in some diseases (sarcoma) and have activity in combination with cytotoxic chemotherapy. These early promising results suggest that inhibition of this receptor will emerge as a new cancer therapy. In addition, these early clinical results raise additional questions regarding optimizing their use in cancer treatment. In a xenograft model, monoclonal antibodies to IGF1R do not suppress tumor growth of the MDA-435/LCC6 cell line yet inhibit tumor metastasis. These data suggest that a commonly measured clinical phenotype, tumor growth, may not be detected in early phase II clinical trials. Clinical trials have also shown that IGF1R monoclonal antibody therapy results in elevation of growth hormone, IGF-I, and insulin levels. Since InsR may also mediate signaling in the IGF system, it is possible that InsR is also a target for cancer therapy. To address this issue, we have used shRNA to downregulate InsR expression while leaving IGF1R levels intact. In the MDA-435/LCC6 cells, disruption of InsR decreases tumor growth and inhibits pulmonary metastases. We have also selected cells in increasing concentrations of IGF1R antibodies. Finally, long term incubation of cells with IGF1R monoclonal antibodies results in cells with low levels of receptor expression, yet the receptor remains biochemically functional and can be inhibited by IGF1R tyrosine kinase inhibitors. Thus, disruption of IGF1R signaling has promise as a new cancer therapy. Future consideration of the role of the ligands, the InsR, and combination therapies with other signaling disruptors will allow us to optimize this therapeutic strategy.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):CN07-02.
Abstract CN07-03: CD47 is an adverse prognostic factor and therapeutic antibody target on human AML stem cells
Authors: Majeti Ravindra , Chao Mark P. , Alizadeh Ash A. , Pang Wendy W. , Jaiswal Siddhartha , Gibbs Kenneth D. , Weissman Irving L. 
Published: May 2019

Abstract
Human acute myeloid leukemia (AML) is organized as a cellular hierarchy initiated and maintained by rare self-renewing leukemia stem cells (LSC), which must be eliminated in order to cure the patient. We identified increased expression of CD47 on human AML LSC compared to their normal counterparts. CD47 is a cell surface molecule that serves as the ligand for SIRP-alpha on the surface of phagocytes, which in turn transmits a dominant inhibitory signal for phagocytosis. In this way, CD47 essentially functions as a “don't eat me” signal. We hypothesized that increased CD47 expression contributes to pathogenesis by inhibiting phagocytosis of AML LSC. Consistent with this hypothesis, we found that increased CD47 expression predicted worse overall survival in 3 independent cohorts of adult AML patients. Furthermore, we predicted that disruption of the interaction of CD47 with SIRP-alpha would result in phagocytosis and elimination of AML LSC. We found that blocking monoclonal antibodies directed against CD47 enabled phagocytosis of AML LSC, but not normal CD34+ human bone marrow progenitor cells, by human macrophages in vitro. Additionally, coating of human AML LSC with anti-CD47 monoclonal antibodies inhibited their engraftment in vivo in a xenotransplantation assay. Finally, analogous to a clinical therapy, treatment of human AML-engrafted mice with anti-CD47 antibody eliminated AML cells in the peripheral blood and bone marrow and targeted LSC. In summary, increased CD47 expression is an independent poor prognostic factor that can be targeted on human AML stem cells with monoclonal antibodies capable of stimulating phagocytosis and elimination of LSC. Targeting of CD47 with blocking monoclonal antibodies to induce phagocytosis is a novel mechanism for antibody cancer therapy. While anti-CD47 antibodies can be effective monotherapy for human AML, such antibodies may be equally, if not more, effective as part of a combination strategy. The combination of an anti-CD47 antibody, able to block a strong inhibitory signal for phagocytosis, with a second antibody able to bind an LSC-specific molecule and engage Fc receptors on phagocytes, thereby delivering a strong positive signal for phagocytosis, may result in a synergistic stimulus for phagocytosis and specific elimination of AML LSC.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):CN07-03.
Abstract PL07-03: Targeting the hedgehog pathway in cancer
Authors: de Sauvage Frederic J. 
Published: May 2019

Abstract
The Hedgehog (Hh) pathway is an ancient signaling cascade that directs patterning in most animals and is crucial for proper development. While Hh signaling is very active during most stages in embryogenesis, it remains relatively quiet in adult life. However, aberrant reactivation of the pathway in adult tissue can lead to the development of cancer (1). Hh pathway activation in tumors such as basal cell carcinoma (BCC) and medulloblastoma is the result of inactivating mutations in PATCHED (PTCH) or activating SMOOTHENED (SMO) mutations. Targeting the Hh pathway with small molecule antagonists therefore provides a new therapeutic opportunity for the treatment of these tumor types. GDC-0449, a systemic Hedgehog (Hh) pathway inhibitor, was tested in a first-in-human, first-in-class, phase I study BCC patients. Strong anti-tumor activity was observed in patients with locally advanced, multifocal or metastatic thereby confirming the importance of inhibiting aberrant Hh signaling in BCC (2). In addition to its role in BCC and medulloblastoma, Hh pathway activation in other solid tumor types, such as pancreatic, ovarian or colon cancer is the result of upregulation of Hh ligand expression in epithelial tumor cells, which acts in a paracrine manner to activate the pathway in stromal fibroblasts (3, 4). These may in turn provide growth factor(s) and/or a microenvironement that promotes tumor growth directly or by affecting other compartments such as the vasculature. Inhibition of the Hh pathway may therefore also provide benefit in these tumors and is currently being explored in the clinic with GDC-0449.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):PL07-03.
Abstract A10: Analysis of gene expression and DNA methylation profiles of Notch signaling pathway genes in human glioblastoma
Authors: Aithal Madhuri G S , Narayanappa Rajeswari 
Published: May 2019

Abstract
In cancer, DNA methylation affects important signal transduction pathways leading to altered receptor function, disruption of normal cell-cell interaction, etc. Since methylation occurs at a very early stage, hypermethylated promoters hold great promise as biomarkers for early detection and an effective drug target for gene reactivation. The Notch signaling pathway is one such developmental pathway governing cell fate decisions. Dysregulated Notch signaling is found to have a prominent role in the development of various cancers. Glioblastoma is the most common primary brain tumor with a very poor prognosis. Therefore it is important to study genetic and epigenetic events leading to gliomagenesis and to guide new treatment strategies. The aim of this study was to detect Notch pathway genes potentially regulated by promoter methylation in human glioblastoma. We used real-time PCR and methylation-specific PCR to study gene expression and methylation status of seven Notch pathway genes (Notch1, Notch2, Notch3, Notch4, JAG1, JAG2 and DLL3) from human glioblastoma formalin fixed paraffin embedded sections. We identified Notch3 and JAG2 promoters as methylated and Notch4 with both methylated and unmethylated promoter. Despite methylation, Notch3 gene showed robust gene expression suggesting its partial dependency on promoter methylation and the presence of alternative regulatory mechanisms. However, low gene expression of JAG2 and the absence of Notch4 gene expression suggest a possibility of epigenetic silencing. This study for the first time provides gene expression and DNA methylation profiles of Notch pathway genes from glioblastoma patient samples. We have identified genes whose expression may be regulated by epigenetic mechanisms and thus can be used as markers that may guide treatment decisions.
Note: This abstract was not presented at the conference.
Citation Format: Madhuri G S Aithal, Rajeswari Narayanappa. Analysis of gene expression and DNA methylation profiles of Notch signaling pathway genes in human glioblastoma. [abstract]. In: Proceedings of the AACR Special Conference: Improving Cancer Risk Prediction for Prevention and Early Detection; Nov 16-19, 2016; Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(5 Suppl):Abstract nr A10.
Abstract A12: Urinary levels of PGE-M and estrogens are independently associated with postmenopausal breast cancer risk
Authors: Kim Sangmi , Campbell Jeff , Yoo Wonsuk , Taylor Jack A. , Sandler Dale P. 
Published: May 2019

Abstract
Prostaglandin E2 (PGE2) induces aromatase expression in adipose tissue leading to increased estrogen production that may promote the development and progression of breast cancer. However, few studies have simultaneously investigated systemic levels of PGE2 and estrogen in relation to postmenopausal breast cancer risk. In a case-cohort study of postmenopausal women (295 cases and 294 subcohort) we previously reported that high levels of PGE-M, a major metabolite of PGE2, were associated with an increased risk of breast cancer among postmenopausal women who did not regularly use nonsteroidal anti-inflammatory drugs (NSAIDs). Here we determined urinary estrogen metabolites (EMs) using mass spectrometry in the same case-cohort set and using linear regression estimated the effect of PGE-M on EMs. Hazard ratios (HRs) for the risk of developing breast cancer in relation to PGE-M and EMs were evaluated in Cox regression models with and without mutual adjustment. PGE-M was a significant predictor of estrone (E1), but not estradiol (E2) levels in multivariable analysis. Elevated E2 levels were associated with an increased risk of developing breast cancer (HRQ5vs.Q1 =1.54, 95% CI: 1.01-2.35), and this association remained unchanged after adjustment for PGE-M (HRQ5vs.Q1 =1.52, 95% CI: 0.99-2.33). Similarly, elevated levels of PGE-M were associated with increased risk of developing breast cancer (HRQ4vs.Q1 =2.01, 95% CI: 1.01-4.29), and this association was only nominally changed after consideration of E1 or E2 levels. Urinary levels of PGE-M and parent estrogens were independently associated with future risk of developing breast cancer among these postmenopausal women. Increased breast cancer risk associated with PGE-M might be attributable both to PGE2-mediated increases in estrogens, and to additional effects related to inflammation.
Note: This abstract was not presented at the conference.
Citation Format: Sangmi Kim, Jeff Campbell, Wonsuk Yoo, Jack A. Taylor, Dale P. Sandler. Urinary levels of PGE-M and estrogens are independently associated with postmenopausal breast cancer risk. [abstract]. In: Proceedings of the AACR Special Conference: Improving Cancer Risk Prediction for Prevention and Early Detection; Nov 16-19, 2016; Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(5 Suppl):Abstract nr A12.
Abstract B02: Recreational physical activity, sedentary time and the incidence of colorectal polyps in a screening population for colon cancer
Authors: Brenner Darren R. , Yannitsos Demetra H. , Warkentin Matthew , Shaw Eileen , Brockton Nigel T. , McGregor S. Elizabeth , Town Susanna , Hilsden Robert J. 
Published: May 2019

Abstract
Background: Despite the consistent association between regular recreational moderate to vigorous physical activity (rMVPA) and reduced risk of colorectal cancer (CRC), few studies have examined the effect of physical activity on carcinogenic development by examining colorectal adenomas (polyps). Furthermore, even fewer studies have examined the impact of sedentary behavior/time (ST) on the development of polyps. In this study we examined the associations between rMVPA and ST and the presence, number and type of colorectal polyps in a population undergoing screening for colorectal cancer in Calgary, Alberta, Canada.
Methods: A cross-sectional study of 2,499 individuals undergoing colonoscopy at the Forzani & MacPhail Colon Cancer Screening Centre in Calgary, Canada was conducted. Physical activity levels and ST were characterized using hours of rMVPA, meeting cancer prevention recommendations (≥150 mins/wk of rMVPA) and hours of ST using self-reported data from the Long Form International Physical Activity Questionnaire. Unconditional logistic regression models were used to estimate the crude and adjusted odds ratios (OR) for presence of polyps associated with rMVP and ST.
Results: Crude estimates for meeting cancer prevention guidelines (ORunadj=0.83, 95% CI: 0.70-0.98) and increasing rMVPA (ORunadj=0.75, 95% CI: 0.60-0.93 for 1-3 hrs/wk vs. 0) were associated with lower odds of having ≥1 polyp at screening. Effect estimates were attenuated in adjusted models. Threshold effects were observed for ST with significant associations observed for up to 20 hours/week of sitting time (ORadj per hour sitting=1.05, 95% CI: 1.01-1.09). Associations were strongest for rMVPA among females (ORadj=0.68, 95% CI: 0.48-0.97 for 1-3 hrs/wk vs. 0) and for ST among males (ORadj=1.74, 95% CI: 1.06-2.86 for 14-35hrs/wk of ST vs. 0-14 hrs/wk)
Conclusions: In this large population undergoing colonoscopy screening for colorectal cancer, rMVPA was associated with reduced prevalence of polyps at screening, particularly among females. Even low amounts of regular ST (2-5hrs/day) were associated with the presence of polyps, particularly among males. Strategies aimed at reducing the amount of pre-carcinogenic colon lesions should combine increasing rMVPA and reducing ST.
Citation Format: Darren R. Brenner, Demetra H. Yannitsos, Matthew Warkentin, Eileen Shaw, Nigel T. Brockton, S. Elizabeth McGregor, Susanna Town, Robert J. Hilsden. Recreational physical activity, sedentary time and the incidence of colorectal polyps in a screening population for colon cancer. [abstract]. In: Proceedings of the AACR Special Conference: Improving Cancer Risk Prediction for Prevention and Early Detection; Nov 16-19, 2016; Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(5 Suppl):Abstract nr B02.
Abstract B10: Development of a cancer risk prediction tool for use in the Risk Estimation For Lifestyle Enhancement Combined Trial (REFLECT)
Authors: Lophatananon Artitaya , Alajmi Kawthar , Thorpe Emma , Hughes John , Blodgett Joanna , Fisher Bernadette , Rogers Simon , Waters Erika K. , Muir Kenneth R. 
Published: May 2019

Abstract
This abstract is being presented as a short talk in the scientific program. A full abstract is printed in the Proffered Abstracts section (PR14) of the Conference Proceedings.
Citation Format: Artitaya Lophatananon, Kawthar Alajmi, Emma Thorpe, John Hughes, Joanna Blodgett, Bernadette Fisher, Simon Rogers, Erika K. Waters, Kenneth R. Muir. Development of a cancer risk prediction tool for use in the Risk Estimation For Lifestyle Enhancement Combined Trial (REFLECT). [abstract]. In: Proceedings of the AACR Special Conference: Improving Cancer Risk Prediction for Prevention and Early Detection; Nov 16-19, 2016; Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(5 Suppl):Abstract nr B10.