tbuckley/cabot-search huggingface dataset:
Abstract 17405: Small K+ Channel Activity Modulates Sinoatrial Node Pacemaker Rate and Explains the Abnormal Bursts of Sinoatrial Node Pacing in Atrial-Specific Na+/Ca2+ Exchange Knockout Mice
Authors: Angelo G Torrente, Rui Zhang, Heidy Wang, Audrey Zaini, Brian Y Kim, Kenneth D Philipson, Joshua I Goldhaber
Journal: Circulation (2016)

Rationale: Ca2+-sensitive small K+ (SK) channels have been implicated in abnormal atrial repolarization, automaticity and conduction in the heart. Despite their potential role in sinoatrial node (S...
Suppression of c-Cbl Tyrosine Phosphorylation Inhibits Neointimal Formation in Balloon-Injured Rat Arteries
Authors: ZhihuiTang, YingWang, YanboFan, YiZhu, ShuChien, NanpingWang
Journal: Circulation (2008)

Background— c-Cbl, a ubiquitously expressed protooncogene, is tyrosine phosphorylated in response to a variety of stimuli, including growth factors such as platelet-derived growth factor (PDGF), and consequently activates signaling proteins such as phosphatidylinositol-3 kinase (PI3K) and Akt. In the present study, we examined the role of c-Cbl tyrosine phosphorylation in vascular injury. Methods and Results— Western blotting showed that the tyrosine phosphorylation of c-Cbl was increased in balloon-injured rat carotid arteries and in cultured smooth muscle cells on stimulation by PDGF-BB, followed by the activations of Akt and the mammalian target of rapamycin. Adenovirus-mediated overexpression of a c-Cbl mutant that ablates the major tyrosine phosphorylation sites attenuated the Akt and the mammalian target of rapamycin activation and decreased the proliferation and migration of smooth muscle cells in response to PDGF-BB or fibroblast growth factor. These effects could be reversed by constitutively act...
Abstract 4669: Role of CD8+tissue-resident memory T (TRM) cells in anti-tumor T-cell response and cancer immunotherapy
Authors: Fathia Mami-Chouaib
Journal: Cancer Research (2018)

Abstract Tissue-resident memory T (TRM) cells, very often defined by the expression of CD103 integrin, correspond to a new subset of long-lived memory T lymphocytes that reside in tissues and are highly protective during localized reinfections. CD8+ TRM cells also frequently reside in human epithelial tumors and play an essential role in anti-tumor T-cell responses. In this context, our previous results indicated that the interaction of CD103 integrin with its ligand, the epithelial cell marker E-cadherin, favors adhesion of TRM cells to their specific epithelial cancer cells and participate to the potentiation of T-cell receptor (TCR)-mediated cytotoxic activity and cytokine production. We also demonstrated that an enhanced CD103+ tumor-infiltrating lymphocytes (TIL) subset correlates with improved early-stage non-small cell lung carcinoma (NSCLC) patient survival and increased intraepithelial T-lymphocyte infiltration. Notably, TRM cells are enriched with tumor-specific T cells and express high levels of inhibitory receptors, including PD-1 and Tim-3, making them an attractive target for cancer immunotherapy, such as checkpoint blockade. Moreover, we provided evidence that CD103 is involved in T-cell recruitment within epithelial tumor islets and in local early T-cell signaling. Our more recent results indicated that integrin-linked kinase (ILK) and paxillin adaptor protein are directly involved in CD103 bidirectional signaling events and defined the CD103 cytoplasmic domain that controls TRM adhesion, migratory behavior and TCR-mediated T-cell functions. Data emphasizing the contribution of CD8+/CD103+ TRM cells in promoting intra-tumoral cytotoxic T lymphocyte (CTL) responses and in success of cancer immunotherapy will be discussed. Citation Format: Fathia Mami-Chouaib. Role of CD8+ tissue-resident memory T (TRM) cells in anti-tumor T-cell response and 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 4669.
Abstract 4721: Combining STING agonists with an anti-PD-1 antagonist results in marked antitumor activity in immune-excluded tumors
Authors: Samanthi A. Perera, Johnny E. Kopinja, Yanhong Ma, Jason Laskey, Kalyan Chakravarthy, Yiping Chen, Long Cui, Jeremy Presland, Shuxia Zhao, Ellen Minnihan, Heidi Ferguson, Jennifer Piesvaux, Bo-Sheng Pan, Hyun Chong Woo, Ian Knemeyer, Saso Cemerski, Jared Cumming, Wesley Trotter, Archie Tse, George H. Addona, Brian J. Long
Journal: Cancer Research (2018)

Abstract The innate immune agonist STING (STimulator of INterferon Genes) binds its natural ligand 2'3'-cGAMP (cyclic guanosine-adenosine monophosphate) and initiates type I interferon production. This promotes systemic antigen-specific CD8+ T-cell priming that eventually provides potent anti-tumor activity. To exploit this mechanism we synthesized a novel STING agonist, MSA-1, that activates both mouse and human STING with higher in vitro potency than cGAMP. MSA-1 was administered to immune-competent mice bearing MC38 syngeneic tumors to monitor pharmacodynamics, pharmacokinetics and in vivo efficacy. Intratumoral (IT) dosed MSA-1 demonstrated robust tumor and plasma cytokine upregulation and effective anti-tumor activity. The highest tolerated doses provided complete responses (CRs) in 100% of MC38 tumors. Tumor models such as CT26 and B16-F10 that are intrinsically resistant to single-agent therapy with a fully murinized mouse anti-PD-1 antibody (mDX400) also demonstrated long-term tumor regressions or CRs. Mechanistic studies in immune-deficient mice suggested that anti-tumor activity of IT dosed STING agonists are in part due to cytotoxicity and/or innate immune responses rather than development of robust adaptive anti-tumor immunity. To enhance the adaptive immune response, we combined MSA-1 with mDX400 in mouse syngeneic tumor models previously characterized to be unresponsive to anti-PD-1 blockade. This combination restored T-cell responses in both blood and tumors of the treated mice and provided long-lived immunologic memory in a majority of the animals. Taken together, these data strongly support the development of STING agonists in combination with Keytruda for patients with tumors that are partially responsive or non-responsive to single agent anti-PD-1 therapy. Citation Format: Samanthi A. Perera, Johnny E. Kopinja, Yanhong Ma, Jason Laskey, Kalyan Chakravarthy, Yiping Chen, Long Cui, Jeremy Presland, Shuxia Zhao, Ellen Minnihan, Heidi Ferguson, Jennifer Piesvaux, Bo-Sheng Pan, Hyun Chong Woo, Ian Knemeyer, Saso Cemerski, Jared Cumming, Wesley Trotter, Archie Tse, George H. Addona, Brian J. Long. Combining STING agonists with an anti-PD-1 antagonist results in marked antitumor activity in immune-excluded tumors [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 4721.
Effects of Cell Density and Low K on Action Potentials of Cultured Chick Heart Cells
Authors: Melvynlieberman
Journal: Circulation Research (1967)

Hearts from 7-day-old chick embryos were separated by 0.05% trypsin and subsequently cultured in a medium containing low (1.4 mM) and normal (4.4 to 5.6 mM) potassium (K) concentration. A method was developed for controlling environmental conditions (pH, temperature, osmolarity) of 1- to 3-day. old cultured heart cells during intracellular recording with microelectrodes. No apparent differences were noted in the measurement of the several components of the action potential as a function of incubation time. Action potential configurations recorded from cells in dense areas of a culture were noticeably different from those potentials obtained in sparse areas of the same culture; the latter were similar to those of the slowly conducting cardiac junctional tissues. This difference was observed both in the presence of normal and low K. The transmembrane potential recorded from cells in densely populated areas in the normal K medium was characterized by large amplitude and steady, high resting potential whereas...
Silent infarcts in sickle cell disease occur in the border zone region and are associated with low cerebral blood flow
Authors: Andria L. Ford, Dustin K. Ragan, Slim Fellah, Michael M. Binkley, Melanie E. Fields, Kristin P. Guilliams, Hongyu An, Lori C. Jordan, Robert C. McKinstry, Jin-Moo Lee, Michael R. DeBaun
Journal: Blood (2018)
Abstract 4188: Preoperative supplementation of branched-chain amino acids suppresses Osteopontin expression in patients with hepatocellular carcinoma
Authors: Yukihiko Hiroshima, Yasuhiro Yabushita, Yutaro Kikuchi, Daisuke Kawagushi, Takashi Murakami, Yasushi Ichikawa, Itaru Endo, Kuniya Tanaka
Journal: Cancer Research (2018)

Abstract Background: Recently, the new effect of branched-chain amino acid (BCAA) on Osteopontin (OPN), which correlates with cancer progression, has been reported. The aim of this study was that preoperative administration of BCAA could improve prognosis via degradation of OPN expression in hepatocellular carcinoma (HCC). Methods: Human hepatocellular carcinoma cell lines were treated with BCAA (2nM), and investigated OPN expression, cell proliferation and invasion in vitro. Next, patients undergoing elective liver resections for HCC (n=72) were randomized to receive or not receive preoperative oral supplementation with BCAA. OPN protein levels in HCC patients were examined using immunohistochemistry and compared with the clinicopathologic features of the tumors. Results: Experimentally, the expression levels of OPN were significantly decreased in HCC cells treated with BCAA. BCAA treatment significantly decreased cell invasion. In the clinical setting, OPN expression correlated with HBV or HCV infection (p = 0.03), venous invasion (p = 0.02) and liver fibrosis (p = 0.07). There was no difference in both DFS and OS between OPN-positive and OPN-negative group, and preoperative BCAA administration did not improve prognosis, either. For the patients without late recurrence, OPN-positive group showed significantly poor outcome in DFS (p = 0.047), and preoperative BCAA administration improved DFS (p = 0.062). Conclusions: OPN expression was associated with cancer cell invasion and intrahepatic metastasis. BCAA treatment suppressed HCC cell invasion and preoperative BCAA administration prevented early intrahepatic recurrence by decreasing the expression level of OPN in HCC. Citation Format: Yukihiko Hiroshima, Yasuhiro Yabushita, Yutaro Kikuchi, Daisuke Kawagushi, Takashi Murakami, Yasushi Ichikawa, Itaru Endo, Kuniya Tanaka. Preoperative supplementation of branched-chain amino acids suppresses Osteopontin expression in patients with hepatocellular carcinoma [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 4188.
Abstract 1083: GAP43, a novel potential metastases promoter in non-small cell lung cancer
Authors: Fanrong Zhang, Jiaoyue Jin, Junzhou Wu, Kaiyan Chen, Minran Huang, Herbert Yu, Lisha Ying, Dan Su
Journal: Cancer Research (2018)

Abstract Metastasis is a serious sequela with dismal prognosis in non-small cell lung cancer (NSCLC). To identify novel biomarkers for predicting NSCLC metastasis, we performed high-throughput Luminex assays to profile the transcriptional level of 36 genes in 37 operable NSCLC patients who had distant metastases within 3 years after surgery and 33 paired patients without relapse after operation. Among the 36 genes, growth associated protein 43 (GAP43), an axonal membrane protein, was identified related to distant metastases. Multivariate cox regression analysis showed that NSCLC patients with elevated GAP43 had a 3.71-fold increase in risk for metastasis than those with low levels (95% confidence interval 1.69-8.14, P = 0.001). Analysis of a patient cohort of 1,926 NSCLC revealed that patients with high levels of GAP43 had worse progression-free and overall survival. In vitro experiments showed that GAP43 knockdown suppressed NSCLC cell migration and invasion, while GAP43 overexpression facilitated their migration and invasion. Immunofluorescence assay indicated that the linear polymer microfilament F-actin became cracked after GAP43 knockdown. Furthermore, animal studies using left ventrical injection demonstrated that GAP43 silenced NSCLC cells were less likely to metastasize to brain and bone than the controls. Together, our findings suggest that GAP43 may be an independent predictor for NSLCL metastasis, and it may facilitate distant metastasis through targeting F-actin. Citation Format: Fanrong Zhang, Jiaoyue Jin, Junzhou Wu, Kaiyan Chen, Minran Huang, Herbert Yu, Lisha Ying, Dan Su. GAP43, a novel potential metastases promoter in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1083.
Abstract 3565: T cell receptor signaling-responsive single chain IL-12 and IL-15 superagonist nanogel “backpacks” to enhance adoptive cell therapy in solid tumors
Authors: Michael Fichter
Journal: Cancer Research (2018)

Abstract Adoptive cell therapy (ACT) using patient-derived tumor-specific T cells is a promising approach for cancer treatment especially for the treatment of hematological malignancies. However, therapeutic approaches using ACT in patients with solid tumors, such as hepatocellular carcinoma (HCC), has not shown substantially improved clinical outcomes in particular due to immunosuppressive tumor microenvironments. Therefore, strategies to enhance ACT T cell functionality in vivo and to overcome the immunosuppressive microenvironments in solid tumors are strongly needed. We developed a strategy combining nanomedicine with ACT, based on the chemical conjugation of cytokine-loaded nanoparticles (NPs) as synthetic “backpacks” to the surfaces of live lymphocytes for adoptive therapy. Novel protein nanoparticles were synthesized by crosslinking of single chain IL-12 (scIL-12)- or IL-15 superagonist through disulfide-containing crosslinkers, forming nanogels that when bound to the surface of T cells, release the supporting cytokines in response to antigen receptor signaling-mediated changes in cell surface redox state. This TCR-mediated drug release allowed drug delivery to the T cells to be focused in tumors and tumor-draining lymph nodes. Coupling of cytokine nanogels to T cell membranes induced significant cell activation in terms of interferon-γ production or proliferation in a concentration-dependent manner. Antigen-specific CD8+ T cells “backpacked” with scIL-12 or IL-15SA nanogels were capable of substantial tumor cell killing in a B16F10 melanoma cancer model in vivo, while avoiding lethal systemic toxicities triggered by systemically-administered immunomodulatory cytokines. Ongoing studies are seeking to apply this approach in HCC, and this approach bears the potential for the development of successful immunotherapeutic strategies against this and other solid tumors where effective treatment options are still lacking. Citation Format: Michael Fichter. T cell receptor signaling-responsive single chain IL-12 and IL-15 superagonist nanogel “backpacks” to enhance adoptive cell therapy in solid tumors [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 3565.
Abstract 403: Analysis of the functional consequences of single nucleotide polymorphisms in CYP3A4 gene to prostate cancer in men of African ancestry
Authors: Solomon O. Rotimi, Chidiebere Ndukwe Ogo, Olubanke Olujoke Ogunlana, Shalom Nwodo Chinedu, Titi Akinremi, Omolara Fatiregun, Funlayo Buraimoh, Adewunmi Alabi, Kehinde Tijani, Ayo Salako, Emmanuel Omonisi, Ruth Agaba, Folakemi Odedina
Journal: Cancer Research (2018)

Abstract Prostate cancer (CaP) is the leading cause of cancer death among Black men and its pathogenesis is linked to testosterone metabolism. CYP3A4 deactivates testosterone and the polymorphisms of its gene are known to alter testosterone metabolism. In this study, computational techniques were used to investigate the effects of nonsynonymous single nucleotide polymorphisms (nsSNPs) in the CYP3A4 gene in African Americans exome sequence. A case-control study was also carried out on 100 prostate cancer patients and 100 controls, among Yoruba men in Nigeria, to investigate the allelic variants of CYP3A4*1B (rs2740574 A&amp;gt;G) using polymerase chain reaction restriction fragment length polymorphism. A total of 22 nsSNPs were found in CYP3A4 gene of African American; out of which, 13 mutations (Q472R, M445T, K421R, R403C, I396T, L373F, R372I, I335T, T309I, V191A, D174H, R162W and S134C) were predicted to have deleterious effects on the CYP3A4 protein. The protein structural analysis of these amino acid variants revealed that M445T mutation could result in an increased free energy with a significant (p&amp;lt;0.05) loss of allosteric site at M445, altered metal binding, and loss of catalytic site at R446. T309I mutation which also resulted in increase free energy was found to be associated with a loss of catalytic site at E308. All the Nigerian samples were homozygous for the variant CYP3A4*1B allele. Hence, the presence of GG homologous variant in the Yoruba population of Nigeria, coupled with the computationally predicted deleterious mutations, could contribute to the high prevalence and aggression of CaP in black men. These genetic variants identified through in silico analysis can provide a better understanding of the wide range of disease susceptibility associated with this gene in Black men and aid the development of new molecular diagnostic markers for CaP particularly in men of West African ancestry. Citation Format: Solomon O. Rotimi, Chidiebere Ndukwe Ogo, Olubanke Olujoke Ogunlana, Shalom Nwodo Chinedu, Titi Akinremi, Omolara Fatiregun, Funlayo Buraimoh, Adewunmi Alabi, Kehinde Tijani, Ayo Salako, Emmanuel Omonisi, Ruth Agaba, Folakemi Odedina. Analysis of the functional consequences of single nucleotide polymorphisms in CYP3A4 gene to prostate cancer in men of African ancestry [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 403.
Identification of a Novel 14-3-3ζ Binding Site Within the Cytoplasmic Domain of Platelet Glycoprotein Ibα That Plays a Key Role in Regulating the von Willebrand Factor Binding Function of Glycoprotein Ib-IX
Authors: YanhongYuan, WeilinZhang, RongYan, YiLiao, LiliZhao, ChanggengRuan, XiaopingDu, KeshengDai
Journal: Circulation Research (2009)

Rationale: The interaction between platelet glycoprotein (GP) Ib-IX and von Willebrand factor (VWF) is initiated by conformational changes in immobilized VWF and is also regulated by the intraplatelet proteins 14-3-3ζ and filamin A. Both 14-3-3ζ and filamin A associate with the cytoplasmic domain of GPIbα, whereas little is known about their relationship in regulating the VWF binding function of GPIb-IX. Objective: To explore the mechanism underlying the roles of 14-3-3ζ and filamin A in regulating the VWF binding function of GPIb-IX. Methods and Results: A truncation mutant of GPIbα (Δ565) deleting the C-terminal 14-3-3ζ binding sites retained 14-3-3ζ binding function, in contrast, deletion of the C-terminal residues 551 to 610 of GPIbα totally abolished 14-3-3ζ binding, indicating that the residues 551 to 564 of GPIbα are important in the interaction between 14-3-3ζ and GPIb-IX. An antibody recognizing phosphorylated R557GpSLP561 sequence reacted with GPIbα suggesting phosphorylation of a population of ...
One in seven children born to mothers who had Zika infection has health problems
Authors: Susan Mayor
Journal: BMJ (2018)

One in seven children born to women who had Zika virus infection when they were pregnant have Zika associated birth defects or neurodevelopmental abnormalities, an analysis that followed up children at one year old has found.1

“Careful monitoring and evaluation of children born to mothers with evidence of Zika infection during pregnancy is essential for ensuring early detection of possible disabilities and early referral …
Abstract 3785: Loss of vacuolar ATPase in hematopoietic stem cells promotes breast tumor progression and pathogenesis
Authors: Manoranjan Sahoo, Gajendra K. Katara, Mahamood Y. Bilal, Sara Fleetwood, Arpita Kulshrestha, Safaa A. Ibrahim, Kenneth D. Beaman
Journal: Cancer Research (2018)

Abstract Vacuolar ATPase (V-ATPase) is expressed intracellularly on vesicular membranes, and controls intracellular pH and acidification of various intracellular vesicles. Most cancer cells express V-ATPase on their cell surface where they appear to acidify the extracellular environment and help cancer cells to metastasize. We have previously demonstrated that the a2 isoform of V-ATPase (a2V) of mammary epithelial cells plays a key role during breast tumor progression and metastasis. However, the role of a2V of hematopoietic stem cells during breast tumor pathogenesis is not known. Therefore, to understand the role of a2V in hematopoietic stem cells during breast tumor progression, we conditionally knocked out a2V (cKO) from the hematopoietic stem cells of mice. We observed that deletion of a2V leads to a significant reduction of CD4+ and CD8+ T cells in the periphery and spleen of the a2V cKO mice compared to control mice. We hypothesized that reduction of helper CD4+ cells, or cytotoxic CD8+ T cells would result in larger and faster-growing tumors in the a2V-cKO mice. After implantation of a syngeneic tumor cell line (E0771) in the breast tissue of mice, we observed that deletion of a2V led to larger and faster-growing breast tumors compared to control mice. Further investigation of the tumor microenvironment revealed that there was a significant reduction in percentage of CD4+ and CD8+ T cells in the a2V-cKO mice compared to control mice. Targeted RNAseq of tumor microenvironment demonstrated that out of 499 genes that were analyzed, only 3 genes were significantly upregulated while 144 genes were significantly downregulated in the a2V cKO mice. The 144 downregulated genes included genes for pro-inflammatory cytokines, T cell specific genes, death receptors and proapoptotic genes. Collectively, these results demonstrate that deletion of a2V from the hematopoietic stem cells leads to a decrease in CD4+ and CD8+ T cells in the periphery, which results in a faster-growing and larger breast tumor. Further study is needed to understand the relative contribution of CD4+ or CD8+ T cells during breast tumor pathogenesis. Citation Format: Manoranjan Sahoo, Gajendra K. Katara, Mahamood Y. Bilal, Sara Fleetwood, Arpita Kulshrestha, Safaa A. Ibrahim, Kenneth D. Beaman. Loss of vacuolar ATPase in hematopoietic stem cells promotes breast tumor progression and pathogenesis [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 3785.