tbuckley/cabot-search huggingface dataset:
Abstract 3212: Nuclear-targeted gold nanoparticles as radiosensitizers
Authors: Sunil Krishnan, Maureen Aliru
Journal: Cancer Research (2018)

Abstract Purpose Intracellular localization of gold nanoparticles has been shown to enhance the effects of radiation. However, few studies have investigated the effect of subcellular localization of these particles on enhancing the radiosensitization effect in cells treated with radiation of varying energies and linear energy transfer (LET) levels. Herein, we evaluate the radiosensitization potential of nuclear-targeted gold nanoparticles across a spectrum of energies and LETs. Methods Gold nanospheres (AuNSs) were functionalized with a nuclear localization sequence (NLS) peptide to enhance the nuclear accumulation of these particles. Internalization of the particles into the cells was achieved using a cell penetrating peptide (CPP). Cellular and nuclear internalization were assessed in Panc-1 human pancreatic adenocarcinoma cancer cells using western blot (WB), transmission electron microscopy, dark field microscopy and inductively-coupled plasma mass spectrometry (ICP-MS). DNA damage due to radiation was evaluated through γH2AX and 53BP1 foci staining. Clonogenic cell survival assay was performed to evaluate the radiosensitization effect after irradiation with 250-kVp X-rays, Cs-137, Co-60, 6 MV and 100 MeV protons (LET 2.5 and 7.7 keV/µm). Results Nuclear-targeted particles (nAuNS) and non-targeted particles (PEGylated, pAuNS) demonstrated similar cellular internalization. However, enhanced uptake of nuclear-targeted particles was observed in the nucleus when compared to non-targeted particles. This was confirmed using dark field microscopy, WB and ICP-MS analysis. DNA double strand breaks through γH2AX and 53BP1 foci staining revealed significantly higher numbers of foci at early (1 hour) and late (24 hour) time points following radiation and nAuNS compared to radiation and pAuNS treatment. Clonogenic cell survival assay revealed significantly higher radiosensitization enhancement factor (REF) at 10% survival fraction for nAuNS compared to pAuNS for all beams assessed. Protons with higher LETs resulted in greater clonogenic cell death and nAuNS further increased radiosensitization whereas pAuNS did not. Conclusion Our data demonstrates that, across a spectrum of radiation energies and LETs, nuclear-targeted gold nanoparticles enhance radiosensitization beyond that achievable with strictly intracytoplasmic gold nanoparticles. Citation Format: Sunil Krishnan, Maureen Aliru. Nuclear-targeted gold nanoparticles as radiosensitizers [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 3212.
Cell Cycle-Dependent Expression of L- and T-Type Ca2+ Currents in Rat Aortic Smooth Muscle Cells in Primary Culture
Authors: TakeshiKuga, SeiKobayashi, YojiHirakawa, HideoKanaide, AkiraTakeshita
Journal: Circulation Research (1996)

The expression of L- and T-type Ca2+ channels has been reported to change during various biological events, including cellular differentiation and proliferation. The present study aimed to examine whether or not the expression of L- and T-type Ca2+ channels depends on the cell cycle in rat aortic smooth muscle cells in primary culture. Both the phase of the cell cycle and the functional expression of Ca2+ channels were determined in the same single cell, using an immunocytochemical analysis of cell cycle-specific nuclear antigens and a whole-cell voltage-clamp method, respectively. In the G0 (n=130) and M (n=75) phases, all cells showed only L-type Ca2+ currents. The cells showing a T-type Ca2+ current appeared in the G1 phase (37%, n=85) and increased in the S phase (90%, n=21). For L-type Ca2+ channels, the current density was significantly greater in the G1 phase than in the G0 and M phases. However, either the voltage-dependent properties or the dose-response relationships of Bay K 8644- and second me...
Abstract 2874: Benzaldehyde inhibits the multiple signals in cancer by suppressing the binding activity of overexpressed 14-3-3ζ and represses the pRb/E2F transcriptional pathway
Authors: Jun Saitoh, Hideyuki Saya
Journal: Cancer Research (2018)

Abstract Benzaldehyde (BA) is the simplest aromatic aldehyde composed of only benzene ring and aldehyde. It is constituents of many fruits and flavor essence. Anti-cancer effect of BA was first reported in 1980, and multi institutional clinical trials by using derivatives of BA were performed in 1980's in Japan. However, clinical study was aborted due to the policy and strategic change in the company. Only the safety of the compound was confirmed. Given that we had multiple effective clinical cases including pancreatic cancers and chemo-resistant non Hodgkin lymphoma, we attempted to elucidate the mechanism of anti-cancer effect of BA. We have previously reported that BA inhibits cancer-related multiple pathways such as PI3K/AKT/mTOR, STAT3, NFκB and ERK, leading to cell death and growth suppression in BA sensitive pancreatic cancer cell line BxPC3, but not in normal cells. We found that such mechanism is based on the BA-mediated inhibition of 14-3-3ζ binding to its client proteins. To further analyze the BA-mediated regulation of 14-3-3ζ, we generated HEK293 cells overexpressing 14-3-3ζ and confirmed that BA suppressed mTOR pathway in the 14-3-3ζ expressing HEK293 cells but not in parental HEK293 cells. Furthermore, we found that depletion of 14-3-3ζ suppresses mTOR signal in BxPC3 and BA-induced reduction of phosphorylation of mTOR signal proteins. Moreover, we performed microarray analysis on three pancreatic cancer cell lines (BxPC-3, AsPC1, PANC1) and found that stress response genes were upregulated in BxPC-3 cells by BA treatment. E2F2 and E2F targeted genes and histone cluster genes in 6p22 were suppressed in not only BxPC-3 but also BA low-sensitive PANC1. We confirmed that BA treatment suppresses the expression of E2F2 and E2F target genes. Of note, protein levels of pRb and cyclin D were also suppressed by BA treatment. Those data suggest that BA inhibits overexpressed 14-3-3ζ mediated multiple signaling pathway and consequently represses pRB/E2F and E2F target genes, resulting in inhibition of cell cycle progression, DNA replication and DNA repair. We propose that those mechanisms can explain why this safe compound is effective for refractory cancers. Citation Format: Jun Saitoh, Hideyuki Saya. Benzaldehyde inhibits the multiple signals in cancer by suppressing the binding activity of overexpressed 14-3-3ζ and represses the pRb/E2F transcriptional pathway [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 2874.
Abstract 4642: Personalized cancer-specific protein corona affects the therapeutic impact of nanoparticles
Authors: Claudia Corbo, Morteza Mahmoudi, Omid C. Farokhzad
Journal: Cancer Research (2018)

Abstract Despite recent progress in nanomedicine, there is still a lack of efficient nanotherapeutics for cancer treatment. When nanoparticles (NPs) are injected, they circulate the bloodstream and interact with biomolecules, creating a biomolecular shell. This shell of biomolecules surrounding the NPs consists mostly of proteins and is referred to as the protein corona (PC). The PC composition depends on various factors, including, but not limited to i) surface properties of NPs (e.g. surface chemistry and charge), and ii) experimental parameters (e.g. incubation time, pH, temperature). The impact of these factors on the formation of the PC has been widely investigated and is nowadays well known. However, the effects of the biological milieu (e.g. patient's health status, plasma vs serum) on the PC formation and composition have been underexamined and still need to be deeply clarified. Recently, it has been demonstrated that the protein pattern constituting the PC of NPs exposed to plasma of cancer patients is different than that of the PC formed by exposure of NPs to healthy plasma. These variations can be miniscule but crucial in the fate of NPs. In fact, NPs surrounded by a PC lose their synthetic identity and acquire a new biological identity responsible for their biological destiny (cell targeting, accumulation, immune response). In this work, we have studied the PCs formed around NPs using plasmas of patients with one of eight cancers to gain insights into the cancer-related variations of the PC composition and into their potential effects on the therapeutic efficacy of NPs. Our results confirmed that the same NPs incubated with plasmas of patients affected by different tumors have distinct PCs. Overall, this is the first wide study unveiling the specific PCs formed around NPs using plasmas of eight cancers. This comprehensive report acts as a tool for researchers in nanomedicine to design personalized nanotherapeutics in a cancer-specific manner for clinical applications. Methods: Silica NPs were incubated with plasma of healthy subjects and cancer patients. NPs in the study were 100 nm in size and the PCs in each subject's plasma were characterized and compared using SDS-PAGE and LC-MS/MS. Plasmas of patients with one of 8 cancers have been employed: breast, rectum, lung, kidney, thyroid, uterine, bladder, ovary. Citation Format: Claudia Corbo, Morteza Mahmoudi, Omid C. Farokhzad. Personalized cancer-specific protein corona affects the therapeutic impact of nanoparticles [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 4642.
Abstract 18043: Maladaptive Mitral Valve Changes After Myocardial Infarction Can Be Therapeutically Modulated
Authors: Philipp E Bartko, Luis Guerrero, Jesper Hjortnaes, Jonathan Beaudoin, Catherine Szymanski, Margo Seybolt, Mark Hanschumacher, Suzanne Sullivan, Michael Garcia, James Titus, Jill Wylie-Sears, Whitney Irvin, Emmanuel Messas, Albert Hagege, Alain Carpentier, Jacob Dal-Bianco, Elena Aikawa, Joyce Bischoff, Robert A Levine
Journal: Circulation (2016)

Introduction: In patients after myocardial infarction (MI), mitral valve (MV) tethering stimulates adaptive leaflet growth but also MV fibrosis that augments MV regurgitation (MR), doubling heart f...
Coexpression of P2Y and P2U Receptors on Aortic Endothelial Cells
Authors: DidierCommuni, EricRaspe, SabinePirotton, Jean-MarieBoeynaems
Journal: Circulation Research (1995)

Abstract Depending on the vascular bed considered, the actions of ATP on the endothelium are mediated by either P2Y or P2U receptors. The two types of receptors seem to coexist on bovine aortic endothelial cells, where they are both coupled to phospholipase C. In this study, we have investigated whether they are truly coexpressed on the same cells and whether their signaling pathways diverge beyond phospholipase C activation. Measurements of [Ca2+]i in single cells showed that almost all bovine aortic endothelial cells are responsive to both 2-methylthio-ATP (2MeSATP), an agonist of P2Y receptors, and UTP, an agonist of P2U receptors. UTP stimulated the release of prostacyclin from freshly isolated bovine aortic endothelial cells, even when they were exposed to cycloheximide at the time of their collection: this indicates that P2U receptors must already be expressed on endothelial cells in situ and do not appear during cell culture. The time course of inositol phosphate (InsP) accumulation and the relativ...
Abstract 3470: Ibrutinib and sorafenib synergistically inhibit HCC growth in preclinical models
Authors: Kalpana Ghoshal, Cho-hao Lin, Khadija Elkholy, Nissar A. Wani, Ding Li, Juan M. Barajas, Peng Hu, Xiaoli Zhang, Lianbo Yu, Tasneem Motiwala
Journal: Cancer Research (2018)

Abstract Hepatocellular carcinoma (HCC) is the second major cause of cancer-related death worldwide with limit therapeutic options. Thus, there is an urgent need to develop novel alternative therapies for HCC. In this study, we report that ibrutinib, recently approved for the treatment of B cell malignancies, and a covalent inhibitor of TEC (BTK, ITK etc.) and ERBB (EGFR, Her2 etc.) family of tyrosine kinases, inhibits tumorigenic functions of human HCC cells in vitro and in xenografts. More importantly, co-treatment with ibrutinib and sorafenib, an approved targeted therapy for advanced HCCs that marginally improve patients' survival, synergistically inhibited proliferation and clonogenic survival of HCC cells including those with acquired sorafenib resistance. Mechanistically, ibrutinib inhibits Akt and ERK signaling pathways through inactivating EGFR, its irreversible substrate in HCC cells. Besides, tumor sphere formation and expression of cancer stem cell markers were suppressed by ibrutinib and sorafenib co-treatment in HCC cells. Ectopic expression of the constitutively active Akt mutant abrogated the synergism of these two kinase inhibitors on HCC cell survival. Ibrutinib and sorafenib combination therapy significantly suppressed tumor growth of highly aggressive HCCLM3 subcutaneous xenografts in NSG mice. Collectively, these results demonstrate that ibrutinib could be a re-purposed anti-HCC drug, and our data provides the evidence for the therapeutic potential of ibrutinib and sorafenib combination as an effective and attractive strategy for treating HCCs including those with sorafenib resistance. Citation Format: Kalpana Ghoshal, Cho-hao Lin, Khadija Elkholy, Nissar A. Wani, Ding Li, Juan M. Barajas, Peng Hu, Xiaoli Zhang, Lianbo Yu, Tasneem Motiwala. Ibrutinib and sorafenib synergistically inhibit HCC growth in preclinical models [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 3470.
Abstract 1984: Cell fate reprogramming of liver tumor-initiating stem-like cells via phosphorylated NUMB and TBC1D15
Authors: Keigo Machida, Hifzur R. Siddique, Mengmei Zheng, Peleg Winer, Dinesh Babu Uthaya Kumar, Ahmed Rokan, Linda Sher, Stanley M. Tahara, Michael Elowitz, Chengyu Liang, Hidekazu Tsukamoto
Journal: Cancer Research (2018)

Abstract Tumor-initiating stem-like cells (TICs) are defective in their control of asymmetric division. Stem cells are maintained through asymmetric self-renewing divisions in which one daughter cell commits to a specific fate while the other retains the multipotent characteristics of its parent. The p53 interacting protein NUMB preserves this intrinsic cellular asymmetry and functions as a vital barrier against unchecked expansion as seen in TICs. How TICs overcome this control of asymmetric division to cause cancer is unknown. The hypothesis is that accentuated TLR4-NANOG-mediated NUMB phosphorylation and TBC1D15 upregulation promote self-renewal of TICs in liver oncogenesis caused by HCV and alcohol. Here, we determined the causal roles of NUMB phosphorylation and TBC1D15 oncoprotein in alcohol-induced liver tumorigenesis in HCV-Tg mice. Liver-specific TBC1D15 deficiency or non-phosphorylatable mutations of NUMB, reduce liver tumor incidence and tumor-associated NANOG+ TICs in HCV NS5A Tg mice fed alcohol Western diet. TICs lost asymmetric division capacity and overexpressed TBC1D15, which associated with NUMB to promote aPKCζ activity and NUMB phosphorylation. Thus, TIC self-renewal is dependent on TBC1D15 and NUMB phosphorylation. Similarly, aPKCζ-mediated NUMB phosphorylation and induced TBC1D15 are mutually required for self-renewal. Furthermore, TBC1D15 activated NOTCH via binding to NOTCH intracellular domain to trigger its proteolytic. TBC1D15 interacts with all NOTCH isoforms, activates NOTCH pathway, and induces Nanog and TIC self-renewal in a NOTCH-dependent manner. TBC1D15 cooperates with the NOTCH pathway to support TIC tumorigenic activity and an inhibitor of this interaction is potentially therapeutic. Candidate small molecule antagonists have been tested for their ability to block the interaction of TBC1D15-NOTCH/NICD. The originality of this findings lies within the discovery of the novel oncoprotein TBC1D15 and its unique oncogenic activities involving p53 degradation and cooperation with the NOTCH pathway in TICs and CD133+ Huh7 cells. These mechanistic findings have laid down the foundation for a new translational path for discovery of new therapeutic targets. Citation Format: Keigo Machida, Hifzur R. Siddique, Mengmei Zheng, Peleg Winer, Dinesh Babu Uthaya Kumar, Ahmed Rokan, Linda Sher, Stanley M. Tahara, Michael Elowitz, Chengyu Liang, Hidekazu Tsukamoto. Cell fate reprogramming of liver tumor-initiating stem-like cells via phosphorylated NUMB and TBC1D15 [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 1984.
Basic Control of Reperfusion Effectively Protects Against Reperfusion Injury in a Realistic Rodent Model of Acute Limb Ischemia
Authors: FlorianDick, JianhuiLi, Marie-NoëlleGiraud, ChristophKalka, JuergSchmidli, HendrikTevaearai
Journal: Circulation (2008)

Background— Reperfusion injury is insufficiently addressed in current clinical management of acute limb ischemia. Controlled reperfusion carries an enormous clinical potential and was tested in a new reality-driven rodent model. Methods and Results— Acute hind-limb ischemia was induced in Wistar rats and maintained for 4 hours. Unlike previous tourniquets models, femoral vessels were surgically prepared to facilitate controlled reperfusion and to prevent venous stasis. Rats were randomized into an experimental group (n=7), in which limbs were selectively perfused with a cooled isotone heparin solution at a limited flow rate before blood flow was restored, and a conventional group (n=7; uncontrolled blood reperfusion). Rats were killed 4 hours after blood reperfusion. Nonischemic limbs served as controls. Ischemia/reperfusion injury was significant in both groups; total wet-to-dry ratio was 159±44% of normal (P=0.016), whereas muscle viability and contraction force were reduced to 65±13% (P=0.016) and 45±3...
Effects of Aging on Angiogenesis
Authors: JohannaLähteenvuo, AnthonyRosenzweig
Journal: Circulation Research (2012)

Aging is a dominant risk factor for most forms of cardiovascular disease. Impaired angiogenesis and endothelial dysfunction likely contribute to the increased prevalence of both cardiovascular diseases and their adverse sequelae in the elderly. Angiogenesis is both an essential adaptive response to physiological stress and an endogenous repair mechanism after ischemic injury. In addition, induction of angiogenesis is a promising therapeutic approach for ischemic diseases. For these reasons, understanding the basis of age-related impairment of angiogenesis and endothelial function has important implications for understanding and managing cardiovascular disease. In this review, we discuss the molecular mechanisms that contribute to impaired angiogenesis in the elderly and potential therapeutic approaches to improving vascular function and angiogenesis in aging patients.
Abstract 12443: In-Beam PET Verification of Catheter-free Arrhythmia Ablation by Scanned Carbon-12 Ion Beam Irradiation
Authors: H. Immo Lehmann, Fine Fiedler, Stephan Helmbrecht, Christian Graeff, Anna Constantinescu, Patrick Lugenbiel, Matthias Prall, Robert Kaderka, Mitsuru Takami, Daniel Richter, Anna Eichhorn, Dierk Thomas, Hugo Katus, Susan Johnson, Kay Parker, Juergen Debus, Samuel Asirvatham, Christoph bert, Marco Durante, Douglas L Packer
Journal: Circulation (2015)

Introduction: Highly precise irradiation using carbon-12 (12C) ions is a new means for catheter-free ablation. Besides energy deposition leading to the dose distribution, nuclear interactions lead to by-product β+-activity that can be measured using positron-emission-tomography (PET). Hypothesis: In-beam PET scanning during focused myocardial irradiation using 12C can adequately depict 12C dose deposition. Methods: Pigs were irradiated with 25, 40, and 55 Gy for AV node (AVN), LA-PV junction, and local LV freewall ablations. PET measurement was performed by means of a double head camera system installed at irradiation site. Coincidences were captured in end-expiration during beam extraction pauses of the accelerator. Results: Evaluation of PET images was qualitatively performed using the coronal plane of the activity distribution superimposed on the contrast-CT in the center of the target contour. Strong β+-activities were measured in AVN and LV ablations. In AVN ablations, activity was localized to the target location, without target activity spreading to the level of the aortic root or coronary sinus (Figure A). Local LV irradiations revealed strong activity in the target location, slightly extending into left lung and chest wall (Figure B). In 55 Gy animals, the cardiac entry channel showed increased activity, decreasing in 40 Gy and more so in 25 Gy animals. Conclusion: This is the first study applying in-beam PET to track 12C dose-deposition into the target location for catheter-free ablation in intact animals. Correlation of β+-activity to electrophysiological outcome, lesion induction, and potential side-effects may be critically important in dosing therapy and predicting outcomes.
RIA: Randomized phase II study comparing induction (I) mFOLFOX6 with or without aflibercept followed by chemoradiation (CRT) and total mesorectal excision (TME) in high risk-rectal cancer. GEMCAD 14-02 trial.
Authors: Carlos Fernandez-Martos, Carles Pericay, Ferran Losa, Rocio Garcia-Carbonero, Laura Layos, Nuria Rodriguez Salas, Marta Martin, Vicente Alonso, Ruth Vera, Javier Gallego, Jaume Capdevila, Antonieta Salud, Miquel Nogue, Juan Maurel, Inmaculada Guasch, Clara Montagut Viladot, Carlos López-López, Mª Ángeles Cañas, Ismael Macias Declara, Xabier García-Albéniz
Journal: Journal of Clinical Oncology (2018)

3518 Background: Preclinical studies suggest that VEGF blockade can have a role in the preoperative treatment of rectal cancer but how to combine it with chemotherapy (CT) and/or CRT remains controversial. Increased risk of postoperative morbidity has been reported with preop anti VEGF/CRT combination. Aflibercept (Afli) acts as a soluble receptor that binds to human VEGF-A, VEGF-B, PlGF. We hypothesized that administering Afli/FOLFOX followed by CRT would improve pathological complete response (pCR) without compromising wound healing. Methods: Between 1/2015-3/2017, pts selected with centrally reviewed magnetic resonance (mr) imaging with middle or distal third, mrT3/T4/N2 rectal adenocarcinoma were randomly assigned (2:1, stratified by mr extra-mural venous invasion and mrT4) to mFOLFOX6 with (arm 1) or without Afli (arm 2) prior to standard CRT (capecitabine with 50.4 Gy in 28 fractions) and TME. The study was designed to perform a hypothesis testing with an alpha = .2 and beta = .2. Due to two planned interim analyses (O´Brien), the threshold for statistical significance was p < 0.1984 in the final analysis. We present primary (pCR) and early secondary endpoints: acute toxicity and compliance. Results: 115/65 pts were assigned to arm 1/arm 2. The pCR rate (ypT0N0) in pts who underwent curative surgery was achieved in 25/103: 24.2%; (95% CI 16.36-33.71) in arm 1 and in 9/62: 14.5% (CI 6.86-25.78) in arm 2. p = 0.1335 Preoperative grade 3-4 toxicity occurred in 50% in arm 1 and 23% in arm 2 during the I period (difference mostly due to hypertension). Overall postoperative complications were similar between both arms (14.7% and 12.3%). Six cycles of I CT were administered in 92% and 95% and 90% and 96% completed CRT in arm 1 and 2 respectively. R0 resection rate was 87.3% and 88.7%. Conclusions: The addition of aflibercept to I mFOLFOX6 led to a significantly greater pCR rate compared with mFOLFOX6 alone in patients with high-risk rectal cancer. The experimental arm showed higher toxicity during the I phase, with similar toxicity afterwards and no increase in surgical complications. Funding: Sanofi Clinical trial information: NCT02340949.