tbuckley/cabot-search huggingface dataset:
Respiratory Modulation of Muscle Sympathetic Nerve Activity in Patients With Chronic Heart Failure
Authors: YukikoGoso, HidetsuguAsanoi, HisanariIshise, TomokiKameyama, TadakazuHirai, TakashiNozawa, ShutaroTakashima, KatsumiUmeno, HiroshiInoue
Journal: Circulation (2001)

Background Sympathoexcitation and respiratory instability are closely related to worsening of chronic heart failure. To elucidate the dynamic nature of respiratory modulation of sympathetic activity in patients with heart failure, we studied within-breath variation of muscle sympathetic nerve activity (MSNA) under various ventilatory volumes. Methods and Results MSNA, blood pressure, and respiratory flow were recorded in 23 patients with left ventricular ejection fraction ≤45%. Within-breath suppression of MSNA (neural silence) was found in 11 patients (MSNA bursts: 71±10/100 heartbeats) but not in the remaining 12 patients (MSNA bursts: 88±8/100 heartbeats). Patients without neural silence had a smaller tidal volume (391±70 versus 267±75 mL/m2, P<0.01) and a higher respiratory rate (15±2 versus 19±4 breaths/min, P<0.01) during spontaneous respiration than those with neural silence. The relationship between tidal volume and minimal amplitude of MSNA bursts in each breath was obtained during random-interva...
Abstract 3772: Preclinical study of a novel TLR8 selective agonist for cancer immunotherapy
Authors: Yuxun Wang, Heping Yang, Xingzhong Zhang, Shuwen Ren, Huanping Li, Shuda Zhao, Longjun Gu, Yin Zhang, Yikun Zeng, Longsheng Wang, Guangliang Fu, Fang Bao, Fang Liu, Zhiheng Wu, Panhu Zhu, Hui Xu, Yaqiao Gao, Jian Zhang, Pei Wang, Shoujun Chen, Daxin Gao
Journal: Cancer Research (2018)

Abstract The innate immune system has emerged as one of the major pathways for drug discovery focusing on cancer immunotherapy. TLR8 plays a crucial role in activating innate immunity and facilitates adaptive immunity thereby exerting potent immune-mediated anticancer activity. We previously presented preliminary characterization of a novel TLR8 agonist DN-A1 (Abstract 2995, AACR Annual Meeting 2017). In the present study, we carried out further comprehensive comparative preclinical study of DN-A1 and motolimod, the only TLR8 selective drug candidate in clinical trials. The result indicated that DN-A1 clearly differentiated from motolimod. DN-A1 was highly selective for TLR8 while motolimod exhibited moderate activity over TLR7 in addition to its primary agonistic activity over TLR8. DN-A1 had superior in vitro ADMET and in vivo PK profiles. Moreover, DN-A1 displayed more potent in vitro and in vivo biological activity and produced stronger anticancer efficacy than motolimod. These findings were further supported by DN-A1's stronger effect than motolimod in activating innate immunity in both monkey in vivo and human PBMC ex vivo systems. Furthermore, DN-A1 significantly suppressed tumor growth as a single agent and combination with the chemotherapeutic agent enhanced efficacy of either agent alone in leukemia tumor model. GLP toxicity study in rats and preliminary toxicity study in monkeys revealed acceptable safety profile of DN-A1. Importantly, DN-A1 consistently caused skin injection site reaction (ISR) when administered subcutaneously in both rats and monkeys. In contrast, motolimod failed to induce ISR under the same condition where DN-A1 caused ISR. Recent reports of motolimod's clinical data indicated that ISR was strongly correlated with substantial survival benefit in cancer patients whereas there was no survival benefit when motolimod failed to induce ISR. Therefore, DN-A1 holds great potential as the best-in-class TLR8 selective immunotherapeutic drug candidate poised for human clinical trials. Citation Format: Yuxun Wang, Heping Yang, Xingzhong Zhang, Shuwen Ren, Huanping Li, Shuda Zhao, Longjun Gu, Yin Zhang, Yikun Zeng, Longsheng Wang, Guangliang Fu, Fang Bao, Fang Liu, Zhiheng Wu, Panhu Zhu, Hui Xu, Yaqiao Gao, Jian Zhang, Pei Wang, Shoujun Chen, Daxin Gao. Preclinical study of a novel TLR8 selective agonist for cancer immunotherapy [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 3772.
Abstract 4280: Improving the sensitivity of wide targeted cancer gene panels via novel genome analysis tools
Authors: Bahram G. Kermani, Evans L. Roberts, Theresa A. Boyle, Anthony M. Magliocco
Journal: Cancer Research (2018)

Abstract In the recent years, wide targeted gene panels have gained popularity, due to their ability to interrogate many genes at the same time. In cancer, particularly, there is a set of ~600 genes known as Cancer Gene Census for which mutations have been causally implicated. Many of the wide cancer panels, therefore, target a subset of these genes. As targeted panels widen, the average coverage of them reduces, if the total budget of the DNA reads remains constant. Therefore, wide panels usually have a more modest coverage, as compared to narrow panels. The reduction in coverage, along with the biases that exist in targeted enrichment approaches make a challenging environment for genome assembly pipelines. We argue that, in such systems, false negatives are prone to increase to non-trivial values, primarily due to: 1) inefficiencies in the enrichment methods, especially if they are hybridization-based; 2) sporadic insufficiency of coverage; 3) biases in the analysis pipelines; 4) filtering operations that take place, in attempt to reduce false positives. As much of the losses are due to the dependency of the assays and the pipelines to the reference genome, we have approached this issue by designing a tandem set of tools: 1) A hybrid-denovo genome assembly pipeline, which has significantly less bias to the reference genome, as compared to the conventional align-to-reference methods. This pipeline can be used in lieu of or in combination with the conventional pipelines; 2) An in-silico verification (ISV) tool that provides the experts with a multifaceted visual and textual information, to gauge the evidence (or lack thereof) for the variants of interest. While not meant to necessarily be a replacement to wet validation, ISV provides the ability to identify the errors that may otherwise seep through the system. In order to show feasibility of this approach, a small set of FFPE TruSight Tumor 170 samples including cases of lung and breast cancer was used. The comparisons were done for all RefSeq exonic bases on a hereditary cancer gene subset. Our preliminary analysis using this data shows that by using our proprietary genome analysis pipeline and ISV tool, the sensitivity of the reported variants could be improved from ~80% to ~98% or higher, without impairing the specificity. If we consider intronic bases which have reasonable coverage, including those involved in splicing, the sensitivity improvements could be even larger. Citation Format: Bahram G. Kermani, Evans L. Roberts, Theresa A. Boyle, Anthony M. Magliocco. Improving the sensitivity of wide targeted cancer gene panels via novel genome analysis tools [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 4280.
Abstract 2768: Potentiating the action of antibody-dependent cell-mediated cytotoxicity with immunocytokines
Authors: Patrizia Murer, Jonathan D. Kiefer, Louis Plüss, Dario Neri
Journal: Cancer Research (2018)

Abstract Intact antibodies in the IgG format typically display only moderate in vivo activity against solid tumor masses, when their mechanism of action relies on antibody-dependent cellular cytotoxicity (ADCC). The therapeutic activity is mainly limited by the lack of immune effector cells (and most notably NK cells) in the neoplastic mass. Our group had previously reported that the therapeutic activity of Rituximab and other intact immunoglobulins could be strongly potentiated by the antibody-based targeted delivery of interleukin-2 (IL2) to the tumor environment. The combination regimen induced complete remissions of established localized lymphomas and provided long-lasting protection from disseminated lymphoma, in mouse models that featured functional NK cells. In this study, we examined the ADCC activity of TA99, a monoclonal antibody which specifically recognizes gp75, a conserved tumor-associated antigen over-expressed in both murine and human melanoma cells. In a preventive setting TA99 in murine IgG2a format completely inhibited the formation of lung metastases in mice, which had been injected intravenously with B16F10 melanoma cells. However, when the B16F10 melanoma tumor was grown subcutaneously in immunocompetent mice, the ADCC activity was not potent enough to eradicate the pre-established tumors and only a modest tumor growth inhibition was observed. A microscopic tissue distribution analysis revealed that TA99-IgG2a had selectively accumulated in the tumor mass compared to normal organs and that NK cells within the neoplastic lesions were scarce. In order to increase NK cell density at the tumor site and potentiate ADCC activity, we developed fusion proteins of the TA99 antibody with murine TNFα, IL2 and IL12. The antibody-cytokine fusion proteins were used alone and in combination with TA99-IgG2a. Combination treatment led to a marked increase of anti-cancer activity against established subcutaneous tumors. Our findings indicate that the targeted delivery of certain pro-inflammatory cytokines to the tumor site potentiates the anti-cancer properties of intact antibodies, enhancing their ability to induce ADCC. Citation Format: Patrizia Murer, Jonathan D. Kiefer, Louis Plüss, Dario Neri. Potentiating the action of antibody-dependent cell-mediated cytotoxicity with immunocytokines [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 2768.
Abstract 4470: Loss of ARL6IP4 induces the epithelial mesenchymal transition in breast cancer metastasis by transcriptionally phosphorylating NF-<i>k</i>B
Authors: Mi Kyung Park, Ji Yun Jang, Hyun Jung Byun, Hyun Ji Kim, Ho Lee, Chang Hoon Lee
Journal: Cancer Research (2018)

Abstract The epithelial mesenchymal transition EMT is the major mechanism involved in cancer metastasis. During EMT, epithelial cells lose cell-cell adhesions to gain mesenchymal-like properties, such as increased invasive abilities. The function of ARL6IP4 in the EMT of breast cancers has not yet been studied. Here we show that the ARL6IP4 controls EMT in breast cancer metastasis. we demonstrate that the role of ARL6IP4 by analysis of ARL6IP4 conditional knockout animals, various in vitro and in vivo models of EMT and metastasis, a mouse mammary tumor virus-polyoma middle T antigen (MMTV-PyMT) model of breast cancer metastasis. We identified that loss of ARL6IP4 phosphorylated of nuclear factor-κB (NF-κB) by increasing the expression of the SNAIL and ZEB1 EMT transcription factors (EMT-TFs). Taken together, our findings establish that ARL6IP4 is a potential tumor suppressor by regulation the phosphorylation of NF-κB. Citation Format: Mi Kyung Park, Ji Yun Jang, Hyun Jung Byun, Hyun Ji Kim, Ho Lee, Chang Hoon Lee. Loss of ARL6IP4 induces the epithelial mesenchymal transition in breast cancer metastasis by transcriptionally phosphorylating NF-kB [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 4470.
Abstract IA17: Physical and in silico methods for improving sensitivity of detection of ctDNA for personalized medicine in high-grade serous ovarian cancer
Authors: James D. Brenton
Journal: Clinical Cancer Research (2018)

Abstract Early detection of high-grade serous ovarian cancer (HGSOC) remains a major challenge owing to early metastasis from the fallopian tube and lack of specific symptoms or clinical signs. Noninvasive analysis of circulating tumor DNA (ctDNA) for common mutations has the potential to provide highly specific tests for detecting ovarian cancer. We have previously shown that TP53 ctDNA is highly correlated with total volume of disease using 3D volumetric reconstruction of CT images. However, detection of ctDNA requires ctDNA concentration to be greater than 0.5% for adequate sensitivity. Improved methods for detection of ctDNA are also required for reliable response monitoring during treatment and detection of minimal residual disease after surgery and systemic therapy. I will discuss recent approaches in our lab that have investigated whether size selection of DNA fragments from plasma can increase the detection of ctDNA by enrichment away from cell free DNA of non-tumor origin. The majority of HGSOC ctDNA is in a size range of 90-150 bp based on whole-genome sequencing of cell free DNA from women with relapsed HGSOC and from HGSOC mouse xenografts. Using physical size selection in 35 patients with recurrent HGSOC and 16 additional patients with other cancer types yielded enrichment of mutated DNA fractions by a median of 4.3-fold allowing improved analysis by targeted, whole-exome, and whole-genome sequencing. This allowed identification of new mutations that otherwise were not observed. Size selection allows detection of tumor alterations masked by non-tumor DNA in plasma, and could improve the sensitivity of liquid biopsy for applications in early diagnosis, detection of minimal residual disease and for establishing mutational signatures from ctDNA. Citation Format: James D. Brenton. Physical and in silico methods for improving sensitivity of detection of ctDNA for personalized medicine in high-grade serous ovarian cancer. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr IA17.
Aortic Distensibility Independently Affects Exercise Tolerance in Patients With Dilated Cardiomyopathy
Authors: StefanoBonapace, AndreaRossi, MariantoniettaCicoira, LorenzoFranceschini, GiorgioGolia, LuisaZanolla, PaoloMarino, PieroZardini
Journal: Circulation (2003)

Background— Peak exercise oxygen consumption (Vo2) is crucial for the prognostic stratification of patients with congestive heart failure, but its hemodynamic determinants are still not completely understood. Aortic wall elasticity modulates left ventricular function and coronary blood flow. Whether an increased aortic pulse-wave velocity (PWV), a known marker of arterial stiffness, may predict peak Vo2 in patients with dilated cardiomyopathy (DCM) has to be clarified. Methods and Results— A total of 78 patients with clinical diagnosis of DCM (aged 62±11 years; female 29%; mean ejection fraction 34±9%) were selected. All patients underwent a complete echocardiographic-Doppler evaluation. Aortic PWV was measured by Doppler ultrasonography immediately before the exercise. A bicycle exercise test with expiratory gas exchange monitoring was performed to determine Vo2. Plasma concentration of the amino-terminal propeptide of type III procollagen (PIIINP), a marker of extracellular matrix turnover, was deter...
Abstract 1810: Stapled peptide inhibitors of mutant estrogen receptor/coactivator interactions
Authors: Thomas E. Speltz, Jeanne M. Danes, Sean W. Fanning, Christopher G. Mayne, Emad Tajkhorshid, Geoffrey L. Greene, Jonna M. Frasor, Terry W. Moore
Journal: Cancer Research (2018)

Abstract A current limitation in treating estrogen receptor-positive breast cancer is the development of resistance to endocrine therapy. Among the many possible mechanisms of resistance, mutations in the estrogen receptor ligand binding domain have been recently shown to be a contributing factor. Specifically, estrogen receptor mutations Y537S and D538G have been reported to contribute to resistance by decreasing the efficacy of the clinically used drug tamoxifen. A standing hypothesis in estrogen receptor pharmacology is that coactivator binding inhibitors can be used in place of traditional endocrine therapy to block cellular proliferation mediated by estrogen receptor. To validate the coactivator binding inhibitor hypothesis within a cellular context, we have prepared cell-permeable stapled peptides to function as inhibitors of the estrogen receptor/steroid receptor coactivator interaction in both wild-type and mutant estrogen receptors. Guided by x-ray crystallography, we have applied molecular dynamics and structure-based rational design to develop stapled peptides with high affinity for the estrogen receptor. In targeting the wild-type receptor, we have found that stapled peptides mimicking steroid receptor coactivators have even higher affinity against mutant receptors Y537S and D538G. In addition to inhibiting the estrogen receptor/coactivator interaction in biochemical assays, we find inhibition of estrogen receptor function within multiple breast cancer cell lines. The stapled peptides reported in this research support the coactivator binding inhibitor hypothesis and shed light on estrogen receptor coactivator interactions in cells expressing both wild-type and mutant receptors. Citation Format: Thomas E. Speltz, Jeanne M. Danes, Sean W. Fanning, Christopher G. Mayne, Emad Tajkhorshid, Geoffrey L. Greene, Jonna M. Frasor, Terry W. Moore. Stapled peptide inhibitors of mutant estrogen receptor/coactivator interactions [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 1810.
Distribution and Physiological Roles of ATP-Sensitive K+ Channels in the Vertebrobasilar System of the Rabbit
Authors: TetsuhikoNagao, SetsuroIbayashi, SeizoSadoshima, KojiFujii, KenichiroFujii, YusukeOhya, MasatoshiFujishima
Journal: Circulation Research (1996)

Abstract The effect of an opener (levcromakalim) and a blocker (glibenclamide) of ATP-sensitive K+ (KATP) channels was investigated in the vertebrobasilar system of the rabbit. Arterial tension and membrane potential were measured by the isometric tension recording method and the microelectrode technique, respectively. Glibenclamide (10−6 mol/L) depolarized the membrane and potentiated the contraction to histamine in vertebral arteries. The sensitivity to the relaxant effects of levcromakalim was in the following descending order: vertebral>proximal basilar>distal basilar>superior cerebellar arteries. Vertebral arteries were ≈50 times more sensitive to levcromakalim than were superior cerebellar arteries. The relaxation to levcromakalim was abolished by glibenclamide (10−6 mol/L). Glibenclamide attenuated vasorelaxation to adenosine in proximal arteries (vertebral and proximal basilar) but not in superior cerebellar arteries. Levcromakalim (7×10−8 mol/L) and adenosine (10−5 mol/L) induced glibenclamide-se...
Abstract 12371: The Association Between Urinary Calculi and Increased Future Cardiovascular Events
Authors: Chien-YiHsu, Po-HsunHuang, Hsin-BangLeu, Jaw-WenChen, Shing-JongLin
Journal: Circulation (2014)

Introduction: Although accumulating evidence suggests urinary calculi may increase the risk of cardiovascular disease (CVD), the number of longitudinal studies linking urolithiasis to cardiovascular events is limited. Hypothesis: We investigated the association between urinary calculi and the risk of development of myocardial infarction (MI) and/or stroke in a nationwide, population-based cohort database in Taiwan. Methods: Our analyses were conducted using information from a random sample of 1 million people enrolled in the nationally representative Taiwan National Health Insurance Research Database. A total of 81,546 subjects aged 18 years or above, including 40,773 subjects diagnosed with urinary calculi during the study period and a propensity score-matched 40,773 subjects without urinary calculi were enrolled in our study. Results: During a 10-year follow-up period, 501 MI events (0.61%) and 1,295 stroke events (1.59%) were identified. By comparison, the urinary calculi group had a higher incidence r...
An Integrative Analysis of Transcriptome and Epigenome Features of ASCL1–Positive Lung Adenocarcinomas
Authors: Naoya Miyashita, Masafumi Horie, Hiroshi I. Suzuki, Masahito Yoshihara, Dijana Djureinovic, Johan Persson, Hans Brunnström, Cecilia Lindskog, Hedvig Elfving, Patrick Micke, Akira Saito, Takahide Nagase
Journal: Journal of Thoracic Oncology (2018)
Abstract 470: p53 isoform delta133p53 in tumor senescence
Authors: Natalia Von Muhlinen, Jessica Beck, Curtis C. Harris
Journal: Cancer Research (2018)

Abstract The tumor suppressor gene TP53 expresses at least 12 isoforms due to alternative splicing, alternative initiation of translation, and alternative promoter usage. These isoforms include p53β and Δ133p53, which can modulate p53 transcriptional activity and apoptosis. The p53 isoform Δ133p53 is expressed in normal tissue, but is abnormally expressed in several cancer types. However, its role in tumor progression is still unclear. Normal somatic cells undergo a limited number of cell divisions, eventually leading to an irreversible proliferative growth arrest known as replicative senescence. Replicative senescence can act as a tumor suppressor mechanism, thus constituting a critical barrier to tumor progression in vivo. Previous studies showed that, p53β and Δ133p53 are endogenous regulators of replicative senescence in normal human fibroblasts. Interestingly, expression of Δ133p53 is upregulated in several cancer types. For instance, enhanced levels of Δ133p53 are associated with inhibition of cellular senescence in colon carcinoma as well as with progression of premalignant colon adenomas to colon carcinomas. However, little is known about the role of Δ133p53 in cancer. We are studying the roles of Δ133p53 in proliferation and senescence of cancer cell lines. We hypothesized that depletion of otherwise enhanced Δ133p53 isoform induces cellular growth arrest and increases the secretion of senescence-associated secretory phenotype (SASP) pro-inflammatory cytokines such as IL-6 and IL-8 of cancer cell lines, and thus Δ133p53 may be a therapeutic target to repress tumor cell growth. Citation Format: Natalia Von Muhlinen, Jessica Beck, Curtis C. Harris. p53 isoform delta133p53 in tumor senescence [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 470.