bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition of autotaxin alleviates inflammation and increases the expression of sodium-dependent glucose cotransporter 1 and Na+/H+ exchanger 3 in SAMP1/Fc mice
Authors: He Peijian , Haque Abedul , Lin Songbai , Cominelli Fabio , Yun C. Chris 
Published: August 2018

Crohn’s disease (CD) is a chronic, relapsing, inflammatory disease that is often associated with malnutrition because of inflammation in the small intestine. Autotaxin (ATX) is a secreted enzyme that produces extracellular lysophosphatidic acid. Increasing evidence suggests that ATX is upregulated during inflammation, and inhibition of ATX has been effective in attenuating chronic inflammatory conditions, such as arthritis and pulmonary fibrosis. This study aims to determine whether inhibition of ATX alleviates CD-associated inflammation and malnutrition by using SAMP1/Fc mice, a model of CD-like ileitis. SAMP1/Fc mice were treated the ATX inhibitor PF-8380 for 4 wk. Inhibition of ATX led to increased weight gain in SAMP1/Fc mice, decreased T helper 2 cytokine expression, including IL-4, IL-5, and IL-13, and attenuated immune cell migration. SAMP1/Fc mice have low expression of Na+-dependent glucose transporter 1 (SGLT1), suggesting impaired nutrient absorption associated with ileitis. PF-8380 treatment significantly enhanced SGLT1 expression in SAMP1/Fc mice, which could reflect the increased weight changes. However, IL-4 or IL-13 did not alter SGLT1 expression in Caco-2 cells, ruling out their direct effects on SGLT1 expression. Immunofluorescence analysis showed that the expression of sucrase-isomaltase, a marker for intestinal epithelial cell (IEC) differentiation, was decreased in inflamed regions of SAMP1/Fc mice, which was partially restored by PF-8380. Moreover, expression of Na+/H+ exchanger 3 was also improved by PF-8380, suggesting that suppression of inflammation by PF-8380 enhanced IEC differentiation. Our study therefore suggests that ATX is a potential target for treating intestinal inflammation and restoration of the absorptive function of the intestine. NEW & NOTEWORTHY This study is the first, to our knowledge, to determine whether autotoxin (ATX) inhibition improves inflammation and body weights in SAMP1/Fc mice, a mouse model of ileitis. ATX inhibition increased body weights of SAMP1/Fc mice and increased Na+-dependent glucose transporter 1 (SGLT1) expression. Increased SGLT1 expression in the inflamed regions was not a direct effect of cytokines but an indirect effect of increased epithelial cell differentiation upon ATX inhibition.
Periodontal therapy favorably modulates the oral-gut-hepatic axis in cirrhosis
Authors: Bajaj Jasmohan S. , Matin Payam , White Melanie B. , Fagan Andrew , Deeb Janina Golob , Acharya Chathur , Dalmet Swati S. , Sikaroodi Masoumeh , Gillevet Patrick M. , Sahingur Sinem E. 
Published: August 2018

Cirrhosis is associated with a systemic proinflammatory milieu, endotoxemia, and gut dysbiosis. The oral cavity could be an additional source of inflammation. We aimed to determine the effect of periodontal therapy in cirrhosis through evaluating endotoxemia, inflammation, cognition, and quality of life (QOL). Age-matched cirrhotic and noncirrhotic subjects exhibiting chronic gingivitis and/or mild or moderate periodontitis underwent periodontal therapy with follow-up at 30 days. Saliva/stool for microbial composition and serum for Model for End-stage Liver Disease (MELD) score, endotoxin and lipopolysaccharide binding protein (LBP) and immune-inflammatory markers (IL-1β; IL-6; histatins 1, 3, 5; and lysozyme) were collected at baseline and day 30. The cognitive function and QOL were also evaluated similarly. A separate group of cirrhotic patients were followed for the same duration without periodontal therapy. Cirrhotics, especially those with hepatic encephalopathy (HE), demonstrated improved dysbiosis in stool and saliva, and improved endotoxin, LBP, and salivary and serum inflammatory mediators following periodontal therapy. These parameters, which were higher in HE at baseline, became statistically similar posttherapy. Pretherapy vs. posttherapy QOL and cognition also improved in HE patients following oral interventions. On the other hand, LBP and endotoxin increased over time in cirrhotic patients not receiving therapy, but the rest of the parameters, including microbiota remained similar over time in the no-therapy group. This proof-of-concept study demonstrates that periodontal therapy in cirrhosis, especially in those with HE, is associated with improved oral and gut dysbiosis, systemic inflammation, MELD score, and cognitive function, which was not observed in those who did not receive therapy over the same time period. NEW & NOTEWORTHY Systematic periodontal therapy in cirrhotic outpatients improved endotoxemia, as well as systemic and local inflammation, and modulated salivary and stool microbial dysbiosis over 30 days. This was associated with improved quality of life and cognition in patients with prior hepatic encephalopathy. In a cirrhotic group that was not provided periodontal therapy, there was an increase in endotoxin and lipopolysaccharide binding protein in the same duration. The oral cavity could be an important underdefined source of inflammation in cirrhosis.
Linaclotide improves gastrointestinal transit in cystic fibrosis mice by inhibiting sodium/hydrogen exchanger 3
Authors: McHugh Daniel R. , Cotton Calvin U. , Moss Fraser J. , Vitko Megan , Valerio Dana M. , Kelley Thomas J. , Hao Shuyu , Jafri Anjum , Drumm Mitchell L. , Boron Walter F. , Stern Robert C. , McBennett Kimberly , Hodges Craig A. 
Published: August 2018

Gastrointestinal dysfunction in cystic fibrosis (CF) is a prominent source of pain among patients with CF. Linaclotide, a guanylate cyclase C (GCC) receptor agonist, is a US Food and Drug Administration-approved drug prescribed for chronic constipation but has not been widely used in CF, as the cystic fibrosis transmembrane conductance regulator (CFTR) is the main mechanism of action. However, anecdotal clinical evidence suggests that linaclotide may be effective for treating some gastrointestinal symptoms in CF. The goal of this study was to determine the effectiveness and mechanism of linaclotide in treating CF gastrointestinal disorders using CF mouse models. Intestinal transit, chloride secretion, and intestinal lumen fluidity were assessed in wild-type and CF mouse models in response to linaclotide. CFTR and sodium/hydrogen exchanger 3 (NHE3) response to linaclotide was also evaluated. Linaclotide treatment improved intestinal transit in mice carrying either F508del or null Cftr mutations but did not induce detectable Cl− secretion. Linaclotide increased fluid retention and fluidity of CF intestinal contents, suggesting inhibition of fluid absorption. Targeted inhibition of sodium absorption by the NHE3 inhibitor tenapanor produced improvements in gastrointestinal transit similar to those produced by linaclotide treatment, suggesting that inhibition of fluid absorption by linaclotide contributes to improved gastrointestinal transit in CF. Our results demonstrate that linaclotide improves gastrointestinal transit in CF mouse models by increasing luminal fluidity through inhibiting NHE3-mediated sodium absorption. Further studies are necessary to assess whether linaclotide could improve CF intestinal pathologies in patients. GCC signaling and NHE3 inhibition may be therapeutic targets for CF intestinal manifestations. NEW & NOTEWORTHY Linaclotide’s primary mechanism of action in alleviating chronic constipation is through cystic fibrosis transmembrane conductance regulator (CFTR), negating its use in patients with cystic fibrosis (CF). For the first time, our findings suggest that in the absence of CFTR, linaclotide can improve fluidity of the intestinal lumen through the inhibition of sodium/hydrogen exchanger 3. These findings suggest that linaclotide could improve CF intestinal pathologies in patients.
Hypercapnia-induced shear-mediated dilation in the internal carotid artery is blunted in healthy older adults
Authors: Iwamoto Erika , Bock Joshua M. , Casey Darren P. 
Published: August 2018

This study aimed to elucidate the effect of aging on shear-mediated dilation of the common and internal carotid arteries (CCA and ICA, respectively). Hypercapnia-induced shear-mediated dilation in the CCA and ICA were assessed in 10 young (5 women and 5 men, 23 ± 1 yr) and 10 older (6 women/4 men, 68 ± 1 yr) healthy adults. Shear-mediated dilation was induced by two levels of hypercapnia (target end-tidal Pco2, +5 and +10 mmHg from individual baseline values) and was calculated as the percent rise in peak diameter from baseline diameter. There were no differences in shear-mediated dilation between young and older adults in either artery under lower levels of hypercapnia (CCA: 2.8 ± 0.6 vs. 2.0 ± 0.3%, P = 0.35; ICA: 4.6 ± 0.8 vs 3.6 ± 0.4%, P = 0.37). However, shear-mediated dilation in response to higher levels of hypercapnia was attenuated in older compared with young adults in the ICA (4.5 ± 0.5 vs. 7.9 ± 1.2%, P < 0.01) but not in the CCA (3.7 ± 0.6 vs. 4.5 ± 0.8%, P = 0.35). Shear-mediated dilation was significantly correlated to the percent change in shear rate in the ICA (young: r = 0.55, P = 0.01; older: r = 0.49, P = 0.03) but not in the CCA in either young or older adults (young: r = −0.30, P = 0.90; older: r = 0.16, P = 0.50). These data indicate that aging attenuates shear-mediated dilation of the ICA in response to higher levels of hypercapnia, and shear rate is an important stimulus for hypercapnic vasodilation of the ICA in both young and older adults. The present results may provide insights into age-related changes in the regulation of cerebral circulation in healthy adults. NEW & NOTEWORTHY We explored the effect of aging on shear-mediated dilation in the common and internal carotid arteries (CCA and ICA, respectively) in healthy adults. Our findings suggest that 1) aging attenuates shear-mediated dilation of the ICA but not the CCA and 2) shear rate is an important stimulus for hypercapnic vasodilation of the ICA in young and older adults. These findings may provide insights into the age-related changes in cerebrovascular regulation of healthy adults.
Exacerbation of dystrophic cardiomyopathy by phospholamban deficiency mediated chronically increased cardiac Ca2+ cycling in vivo
Authors: Law Michelle L. , Prins Kurt W. , Olander Megan E. , Metzger Joseph M. 
Published: August 2018

Cardiomyopathy is a significant contributor to morbidity and mortality in Duchenne muscular dystrophy (DMD). Membrane instability, leading to intracellular Ca2+ mishandling and overload, causes myocyte death and subsequent fibrosis in DMD cardiomyopathy. On a cellular level, cardiac myocytes from mdx mice have dysregulated Ca2+ handling, including increased resting Ca2+ and slow Ca2+ decay, especially evident under stress conditions. Sarco(endo)plasmic reticulum Ca2+ ATPase and its regulatory protein phospholamban (PLN) are potential therapeutic targets for DMD cardiomyopathy owing to their key role in regulating intracellular Ca2+ cycling. We tested the hypothesis that enhanced cardiac Ca2+ cycling would remediate cardiomyopathy caused by dystrophin deficiency. We used a genetic complementation model approach by crossing dystrophin-deficient mdx mice with PLN knockout (PLNKO) mice [termed double-knockout (DKO) mice]. As expected, adult cardiac myocytes isolated from DKO mice exhibited increased contractility and faster relaxation associated with increased Ca2+ transient peak height and faster Ca2+ decay rate compared with control mice. However, compared with wild-type, mdx, and PLNKO mice, DKO mice unexpectedly had reduced in vivo systolic and diastolic function as measured by echocardiography. Furthermore, Evans blue dye uptake was increased in DKO hearts compared with control, mdx, and PLNKO hearts, demonstrating increased membrane damage, which subsequently led to increased fibrosis in the DKO myocardium in vivo. In conclusion, despite enhanced intracellular Ca2+ handling at the myocyte level, DMD cardiomyopathy was exacerbated owing to unregulated chronic increases in Ca2+ cycling in DKO mice in vivo. These findings have potentially important implications for ongoing therapeutic strategies for the dystrophic heart. NEW & NOTEWORTHY This study examined the effects of phospholamban ablation on the pathophysiology of cardiomyopathy in dystrophin-deficient mice. In this setting, contractility and Ca2+ cycling were enhanced in isolated myocytes; however, in vivo heart function was diminished. Additionally, sarcolemmal integrity was compromised and fibrosis was increased. This is the first study, to our knowledge, examining unregulated Ca2+ cycling in the dystrophin-deficient heart. Results from this study have implications for potential therapies targeting Ca2+ handling in dystrophic cardiomyopathy. Listen to this article's corresponding podcast at https://ajpheart.podbean.com/e/unregulated-ca2-cycling-exacerbates-dmd-cardiomyopathy/ .
Promoting Scientist–Advocate Collaborations in Cancer Research: Why and How
Authors: Salamone Jeannine M. , Lucas Wanda , Brundage Shelley B. , Holloway Jamie N. , Stahl Sherri M. , Carbine Nora E. , London Margery , Greenwood Naomi , Goyes Rosa , Chisholm Deborah Charles , Price Erin , Carlin Roberta , Winarsky Susan , Baker Kirsten B. , Maues Julia , Shajahan-Haq Ayesha N. 
Published: August 2018

Abstract
Advocates bring unique and important viewpoints to the cancer research process, ensuring that scientific and medical advances are patient-centered and relevant. In this article, we discuss the benefits of engaging advocates in cancer research and underscore ways in which both the scientific and patient communities can facilitate this mutually beneficial collaboration. We discuss how to establish and nurture successful scientist–advocate relationships throughout the research process. We review opportunities that are available to advocates who want to obtain training in the evaluation of cancer research. We also suggest practical solutions that can strengthen communication between scientists and advocates, such as introducing scientist–advocate interactions at the trainee level. Finally, we highlight the essential role social media can play in disseminating patient-supported cancer research findings to the patient community and in raising awareness of the importance of promoting cancer research. Our perspective offers a model that Georgetown Breast Cancer Advocates have found effective and which could be one option for those interested in developing productive, successful, and sustainable collaborations between advocates and scientists in cancer research. Cancer Res; 78(20); 5723–8. ©2018 AACR.
Abstract A142: Targeting FGFR to overcome EMT-related resistance in EGFR-mutated non-small cell lung cancer
Authors: Raoof Sana , Ruddy David , Timonia Daria , Damon Leah , Engelman Jeff , Hata Aaron 
Published: August 2018

Abstract
Epithelial-to-mesenchymal transition (EMT) has been identified as a mechanism of both adaptive and acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) in in vitro models and clinical samples of EGFR-mutated non-small cell lung cancer (NSCLC). However, a therapeutic strategy for targeting this mechanism remains unknown. In the setting of adaptive resistance early in the course of EGFR treatment, we observed that FGFR3 upregulation coincided with increased expression of mesenchymal genes, and a pooled shRNA dropout screen identified FGFR3 as a top sensitizer to EGFR inhibitor treatment. Dual FGFR (BGJ398) and EGFR (gefitinib) inhibition suppressed the outgrowth of drug-tolerant persister clones compared to EGFR TKI alone in vitro. Finally, we observed that the combination of BGJ398 and gefitinib prevented the development of in vivo resistance in PC9 xenograft mouse models. These results suggest that dual FGFR-EGFR blockade may be an effective strategy for preventing resistance associated with EMT in EGFR mutant NSCLC.
Citation Format: Sana Raoof, David Ruddy, Daria Timonia, Leah Damon, Jeff Engelman, Aaron Hata. Targeting FGFR to overcome EMT-related resistance in EGFR-mutated non-small cell lung cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A142.
Abstract A206: Small-molecule Cbl-b inhibitors as novel intracellular checkpoint inhibitors for cancer immunotherapy
Authors: Riling Christopher , Sokirniy Ivan , Cunnion Brigid , Todd Emily , Mattern Michael , Wu Jian , Kambayashi Taku , Kumar Suresh 
Published: August 2018

Abstract
Cancer cells evade destruction by co-opting checkpoint signaling in the immune system. Therapeutics aimed at preventing this, such as anti-PD1 and anti-CTLA4 antibodies, promote cytotoxic T lymphocyte (CTL)-mediated antitumor immune responses against advanced solid tumors. Harnessing the antitumor activity of CTLs, and that of their innate counterpart natural killer (NK) cells, is a promising approach. Activation of CTLs and NK cells is tightly regulated. CTLs require costimulatory signals, such as CD28, for robust activation. NK cell activation can be kept in check by a variety of inhibitory receptors, such as those of the TAM tyrosine kinase receptor family. Ultimately, these signaling events are orchestrated by the ubiquitin signaling system. One ubiquitin ligase in particular, Cbl-b (Casitas B-lineage lymphoma proto-oncogene b), is a negative regulator of both CTL and NK cell activation. In T cells, Cbl-b attenuates TCR signaling by negatively regulating several downstream signaling components, enforcing the requirement for costimulation. In NK cells, Cbl-b regulates TAM receptor internalization at the plasma membrane via ubiquitylation, and this process is important in enabling inhibitory signaling via the TAM receptors. Accordingly, mice deficient in active Cbl-b exhibit hyper-responsive immunity and reject a variety of implanted metastatic and nonmetastatic tumors. Outgrowth of spontaneous tumors in these mice is also significantly delayed. This tumor resistance is mediated by activated CD8+ T cells and NK cells. Thus, Cbl-b is a promising target for developing small-molecule cancer immunotherapy agents. Using proprietary HTS technologies, Progenra has discovered novel and selective Cbl-b inhibitors that decrease ubiquitylation of TAM receptor family members (Tyro3). These inhibitors also promote CD3-mediated activation of T cells in a CD28-independent manner, markedly increasing proliferation, IL-2 secretion, and TNFα production in T cells. Additionally, these Cbl-b inhibitors increase NK cell activation (as measured by IFNγ and degranulation) in ex vivo assays. ADME/DMPK as well as in vivo efficacy data will be discussed. These molecules are expected to synergize with other approved immunotherapy agents.
Citation Format: Christopher Riling, Ivan Sokirniy, Brigid Cunnion, Emily Todd, Michael Mattern, Jian Wu, Taku Kambayashi, Suresh Kumar. Small-molecule Cbl-b inhibitors as novel intracellular checkpoint inhibitors for cancer immunotherapy [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A206.
Abstract A207: Utilizing human OX40 knock-in mice (HuGEMMTM) to assess antitumor efficacy of OX40-agonistic antibodies
Authors: Huang Xuesong , Zheng Lei , Ouyang Wenyi , Zhang Mingkun , An Annie Xiaoyu , Zhao Jing , Gao Xiang , Wery Jean Pierre , Shi Qian 
Published: August 2018

Abstract
OX40 is a costimulatory molecule of TNF receptor family, primarily expressed on activated effector T cells and regulatory T cells. Engagement of OX40 by ligand leads to dramatic expansion, effector function, cytokine production, and survival of T cells. Several OX40-agonistic antibodies are in early stages of clinical development and some have shown promising antitumor immunity and improved tumor-free survival in the patients compared with standard-of-care therapies. Preclinical studies using surrogate OX40-agonistic antibodies have also shown robust tumor growth inhibition (TGI) efficacies, especially when combined with other checkpoint inhibitors like PD1 and CTLA-4 antibodies. However, we are lacking reliable preclinical models to assess the efficacy of human therapeutic antibodies. To address this need, we created a human OX40 knock-in GEMM (OX40 HuGEMM), where the entire 2.5 Kb mouse OX40 coding region is replaced by human OX40. We confirmed the expression of human OX40 in the 95% of activated T cells from the homozygous knock-in mice, while the mouse OX40 is completely eliminated. In the heterozygous knock-in mice, 58% of activated T cells express both mouse and human OX40. We then used both heterozygous and homozygous knock-in mice for efficacy studies of OX40 antibodies. In the heterozygous knock-in mice bearing MC38 syngeneic tumors, human and mouse OX40 antibody monotherapies led to 49% and 20% TGI, respectively, while their combination with PD1 antibody was synergistically effective, resulting in ~90% TGI with multiple complete tumor regressions. When we grafted the homozygous knock-in mice with B16F10 syngeneic tumors, single 5 mg/kg dose of an investigational human OX40 antibody led to 47% TGI. Tumor-killing efficacy of OX40 antibody is also correlated with significantly increased tumor infiltrated T cells and NK cells. Taken together, our OX40 HuGEMM provides an urgently needed tool for testing in vivo efficacy of human OX40 therapeutics, both as a single agent and as various combination strategies with other treatment modalities.
Citation Format: Xuesong Huang, Lei Zheng, Wenyi Ouyang, Mingkun Zhang, Annie Xiaoyu An, Jing Zhao, Xiang Gao, Jean Pierre Wery, Qian Shi. Utilizing human OX40 knock-in mice (HuGEMMTM) to assess antitumor efficacy of OX40-agonistic antibodies [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A207.