tbuckley/cabot-search huggingface dataset:
Deletion of Kir5.1 Impairs Renal Ability to Excrete Potassium during Increased Dietary Potassium Intake
Authors: Peng Wu, Zhong-Xiuzi Gao, Dan-Dan Zhang, Xiao-Tong Su, Wen-Hui Wang, Dao-Hong Lin
Journal: Journal of the American Society of Nephrology (2019)

Significance Statement In the distal convoluted tubule, the basolateral inwardly rectifying potassium channel, a heterotetramer of Kir4.1 and Kir5.1, plays an important role in the regulation of potassium excretion by determining the activity of the thiazide-sensitive sodium-chloride cotransporter (NCC). Previous research found that the deletion of Kir4.1 abolishes the effect of dietary potassium intake on NCC and impairs potassium homeostasis. In this study, the authors demonstrate that deleting Kir5.1 abolishes the inhibitory effect of high dietary potassium intake on NCC and impairs the renal ability to excrete potassium during increased dietary potassium intake. Their findings illustrate that like Kir4.1, Kir5.1 is also an essential component of the potassium-sensing mechanism in the distal convoluted tubule, and that Kir5.1 is indispensable for regulation of renal potassium excretion and maintaining potassium homeostasis. Background The basolateral potassium channel in the distal convoluted tubule (DCT), comprising the inwardly rectifying potassium channel Kir4.1/Kir5.1 heterotetramer, plays a key role in mediating the effect of dietary potassium intake on the thiazide-sensitive NaCl cotransporter (NCC). The role of Kir5.1 (encoded by Kcnj16 ) in mediating effects of dietary potassium intake on the NCC and renal potassium excretion is unknown. Methods We used electrophysiology, renal clearance, and immunoblotting to study Kir4.1 in the DCT and NCC in Kir5.1 knockout ( Kcnj16−/− ) and wild-type ( Kcnj16+/+ ) mice fed with normal, high, or low potassium diets. Results We detected a 40-pS and 20-pS potassium channel in the basolateral membrane of the DCT in wild-type and knockout mice, respectively. Compared with wild-type, Kcnj16−/− mice fed a normal potassium diet had higher basolateral potassium conductance, a more negative DCT membrane potential, higher expression of phosphorylated NCC (pNCC) and total NCC (tNCC), and augmented thiazide-induced natriuresis. Neither high- nor low-potassium diets affected the basolateral DCT’s potassium conductance and membrane potential in Kcnj16−/− mice. Although high potassium reduced and low potassium increased the expression of pNCC and tNCC in wild-type mice, these effects were absent in Kcnj16−/− mice. High potassium intake inhibited and low intake augmented thiazide-induced natriuresis in wild-type but not in Kcnj16−/− mice. Compared with wild-type, Kcnj16−/− mice with normal potassium intake had slightly lower plasma potassium but were more hyperkalemic with prolonged high potassium intake and more hypokalemic during potassium restriction. Conclusions Kir5.1 is essential for dietary potassium’s effect on NCC and for maintaining potassium homeostasis.
Abstract 14460: Sucrose Non-fermenting 1-related Kinasenrk Promotes Angiogenesis and Arteriogenesis in vivo
Authors: Qiulun Lu, Ye Ding, Zejun Ma, Ramani Ramchandran, Ming-Hui Zou
Journal: Circulation (2017)

Introduction: Sucrose non-fermenting 1 (Snf1)-related kinase (SNRK) is a serine/threonine kinase and a novel member of the AMP-activated protein kinase (AMPK)-related superfamily. Recent evidence s...
Abstract 5042: Folate and other B-vitamins and the risk of breast cancer in younger women
Authors: Serena C. Houghton, A Heather Eliassen, Shumin Zhang, Jacob Selhub, Bernard A. Rosner, Walter C. Willett, Susan E. Hankinson
Journal: Cancer Research (2019)

Abstract Purpose: Prior epidemiologic cohort studies have generally found no associations of folate and other B-vitamins with breast cancer overall, but differences by menopause status have been suggested. However, prior studies have been limited by small numbers to examine the relationship between different plasma measures and related polymorphisms and breast cancer risk among younger women. Therefore, we examined the association of plasma B-vitamins and metabolites, and related genetic variants, with risk of breast cancer among predominantly premenopausal women. Methods: We conducted a nested case-control study within the Nurses’ Health Study II. From blood samples collected in 1996-1999 and follow-up through 2007, plasma measures were available for 610 cases and 1,207 controls. Unconditional multivariable logistic regression was used to estimate relative risks (RR) of breast cancer and 95% confidence intervals (CIs). We examined whether associations varied by methylenetetrahydrofolate reductase (MTHFR) and dihydrofolate reductase polymorphisms, breast cancer risk factors, or tumor characteristics. Results: Plasma vitamin B12 was associated with a 71% increase in risk of breast cancer comparing the highest versus lowest quintile (95%CI=1.22-2.39, p-trend=0.02). Plasma folate (comparable RR=1.20, 95%CI=0.85-1.68), pyridoxal 5’-phosphate (RR=1.19, 95%CI=0.85-1.65), cysteine (RR=1.15, 95%CI=0.81-1.63), homocysteine (RR=0.90, 95%CI=0.65-1.25), and cysteinylglycine (RR=0.92, 95%CI=0.65-1.31) were not associated with overall breast cancer risk. Folate was significantly positively associated with invasive (RR highest tertile vs. lowest=1.48, 95%CI=1.09-2.01) and estrogen receptor-positive/progesterone receptor-positive breast cancer (RR T3 vs. T1= 1.59, 95%CI= 1.12-2.27) and the invasive association was suggestively stronger for bloods collected post-fortification (p-heterogeneity=0.19). Several nutrient/breast cancer associations varied across subgroups defined by age, smoking, alcohol, multivitamin use and MTHFR status (p-interaction&amp;lt;0.05). Conclusions: Overall, plasma B-vitamins and metabolites were not consistently associated with lower breast cancer risk. For increasing plasma folate and B12 levels higher risk of invasive breast cancer was observed. Additionally, there may be associations in subgroups defined by related genetic variants, breast cancer risk factors, and tumor factors. Future studies in younger women are needed to confirm findings. Citation Format: Serena C. Houghton, A Heather Eliassen, Shumin Zhang, Jacob Selhub, Bernard A. Rosner, Walter C. Willett, Susan E. Hankinson. Folate and other B-vitamins and the risk of breast cancer in younger women [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5042.
Abstract 20314: S100B Promotes Injury-Induced Vascular Remodeling Through Modulating Smooth Muscle Phenotype
Authors: Teng Cao, Lei Zhang, Junming Tang, Shiyou Chen, Jianing Wang
Journal: Circulation (2017)

Abstract S100B is a biomarker of nervous system injury, but it is unknown if it is also involved in vascular injury. In the present study, we investigated S100B function in vascular remodeling foll...
Abstract 1045: CRISPR/cas9 mediated generation of an EMT reporter cell line for metastatic breast cancer drug discovery and development
Authors: Metewo S. Enuameh, Weiguo Shu, Robert Newman
Journal: Cancer Research (2019)

Abstract Among women, breast cancer continues to be the most common cancer, with metastasis being the leading cause of mortality in cancer patients around the world (DIZON et al. 2016). Epithelial to mesenchymal transition (EMT) - the process by which epithelial cells shift to the mesenchymal state, has been implicated in many aspects of breast cancer tumorigenesis, metastasis and drug resistance ). The accumulation of a large body of data on the association of EMT with cancer over the years has not resulted in EMT being an active target for therapeutic development. This is due in part to the lack of appropriate in vitro models. Here we have exploited some of the basic biology of EMT, to create an advanced in vitro metastatic breast cancer reporter cell line model for use in both basic research and discovery of new EMT inhibitors. During EMT, E-cadherin protein expression is down regulated in cancer cells in association with the loss of cell-to-cell adhesion, apico-basal polarity and a change to a spindle-shaped morphology. By installing an emerald green fluorescent protein (EmGFP) tag on the C-terminus of the e-cadherin (ECAD) gene in the epithelial BT-474 breast cancer cell line via CRISPR/Cas9 genome editing, end-point or real-time EMT status of cells can be tracked under defined conditions. The EMT reporter cell line was verified at the nucleic acid (genomic and mRNA) and protein levels as well as in cell-based assays. Bio-functional evaluation of the BT-474 ECAD EmGFP cell line, shows that it responds to EMT induction. The subsequent EMT status of cells can be monitored in real time by observing and measuring ECAD EmGFP expression, in addition, the resulting mesenchymal cells have increased invasive capacities. Furthermore, this EMT reporter cell line shows sensitivity to the MEK1/2 inhibitor U0126 - thereby providing the basis for the use of this cell line in high-throughput screening (HTS) applications including the identification of new anti-EMT drugs for metastatic breast cancer. The BT-474 ECAD EmGFP reporter cell line is also a convenient and sensitive model for basic science research on the mechanisms of metastasis. References DIZON, D. S., L. KRILOV, E. COHEN, T. GANGADHAR, P. A. GANZ et al., 2016 Clinical Cancer Advances 2016: Annual Report on Progress Against Cancer From the American Society of Clinical Oncology. J Clin Oncol 34: 987-1011. HAY, E. D., 1995 An overview of epithelio-mesenchymal transformation. Acta Anat (Basel) 154: 8-20. Citation Format: Metewo S. Enuameh, Weiguo Shu, Robert Newman. CRISPR/cas9 mediated generation of an EMT reporter cell line for metastatic breast cancer drug discovery and development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1045.
Abstract 3219: <i>In vivo</i> efficacy and safety evaluation of anti-human PD-1 and CD40 mAbs using double humanized PD-1/CD40 mouse model
Authors: Yanan Guo
Journal: Cancer Research (2019)

Abstract In recent years, monoclonal antibodies have been successfully used in clinical trials to block or activate key mediators of immune checkpoint pathways, including CTLA4, PD-1, PD-L1, CD40 and others. Combination therapy can promote antigen release and T cell priming, T cell activation and homing, which helps to overcome tumor immune-evasive mechanisms and maximize efficacy, ultimately benefitting most patients. However, along the IO drug development process, in vivo efficacy models have always been a rate-limiting step, especially to test combination therapy using two IO antibodies. The transmembrane protein receptor CD40 is a member of the tumor necrosis factor (TNF) receptor super family and is involved in co-stimulation of immune cells. CD40 is expressed by antigen-presenting cells (APCs) including dendritic cells (DCs), B-cells, macrophages, and monocytes. It has the ability to "wake" DCs to prime effective cytotoxic T-cell responses. Thus, effective anti-CD40 antibodies provide an ideal therapy alternative in combination with other IO antibodies. To evaluate the in vivo efficacy and safety (immune-related adverse events) of CD40 and PD-1 combination antibodies, we developed a double humanized B-hPD-1/hCD40 mouse model. In this model, mouse PD-1 gene exon 2, and CD40 gene exons 2-7 were replaced with their human counterparts. Murine colon cancer MC38 cells were subcutaneously implanted into homozygous B-hPD-1/hCD40 mice. We compared the effect among single hPD-1 antibody Keytruda, single hCD40 antibody Selicrelumab and combination of the two. Combination treatment of Selicrelumab and Keytruda show higher inhibitory effects than single antibody treatments. The blood chemistry assays showed that the CD40 antibody had no toxicity effects compared with the control group. Based on these findings, we conclude that the B-hPD-1/hCD40 double-humanized mouse model is a powerful tool for in vivo efficacy and safety evaluation of hPD-1 and hCD40 antibodies for combination therapy. Citation Format: Yanan Guo. In vivo efficacy and safety evaluation of anti-human PD-1 and CD40 mAbs using double humanized PD-1/CD40 mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3219.
Abstract 316: Parallel activation of MEK as a mechanism of resistance to ALK inhibitor therapy
Authors: Vincent Huang, Yingjun Yan, Huan Qiao, Yunkai Zhang, Christine M. Lovly
Journal: Cancer Research (2019)

Abstract Chromosomal rearrangements of ALK can result in a fusion protein that serves as an oncogenic driver in non-small cell lung cancer (NSCLC). Although patients with ALK-positive (ALK+) lung cancer have significant response rates when treated with tyrosine kinase inhibitors (TKIs), resistance against ALK targeted therapy consistently develops. Here, we modeled acquired resistance to ALK TKI therapy using 5 different FDA-approved ALK TKIs, including crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib, using two distinct ALK+ lung cancer cell lines, H3122 and STE-1 (10 resistant cell lines total). Both of these cell lines harbor an EML4-ALK E13;A20 fusion and were derived from patients prior to ALK directed therapy. An ALK kinase domain mutation (F1174L) was detected in the H3122 ceritinib resistant cells, but none of the other resistant cell lines harbored mutations in the ALK kinase domain known to confer TKI resistance. For each of the cell lines tested, we found that ALK TKI treatment in TKI-resistant cells failed to inhibit MAP kinase pathway activity. We hypothesized that inhibition of the MAP kinase pathway, via MEK inhibition, could restore drug sensitivity. The allosteric MEK inhibitors, trametinib and binimetinib, did not effectively reduce cell viability as single agents. However, ALK TKI co-treatment with a MEK inhibitor resensitized these cells by reducing cell viability in a synergistic manner across all ALK TKI-resistant cell lines tested. Whole transcriptomic analysis of ALK TKI-resistant cell lines also revealed an upregulation in EGFR and HER2 mRNA levels. These results provide rationale for combined ALK+MEK inhibitor therapy in patients who have relapsed on first line ALK TKI therapy. Citation Format: Vincent Huang, Yingjun Yan, Huan Qiao, Yunkai Zhang, Christine M. Lovly. Parallel activation of MEK as a mechanism of resistance to ALK inhibitor therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 316.
Abstract 16026: Genetic Variation of Oxidative Phosphorylation Genes Associate With Right Ventricular Function in Patients With Pulmonary Arterial Hypertension
Authors: Reid W D'Amico, Rebecca Levinson, John H Newman, Tufik Assad, Stephen Halliday, Eric Farber-Eger, Quinn S Wells, Anna R Hemnes, Evan L Brittain
Journal: Circulation (2017)

Introduction: Genetic variation in the mitochondrial (mt) oxidative phosphorylation (Ox-phos) pathway influences exercise capacity and myocardial performance. Reduced exercise capacity and right ve...
Abstract 16808: Relationship of Kidney Injury Molecule-1 With Estimated Glomerular Filtration Rate and Blood Pressure in the General Population
Authors: Peter Egli, Stefanie Aeschbacher, Matthias Bossard, Lucien Eggimann, Laura Bargetzi, Joel Estis, John Todd, Martin Risch, Lorenz Risch, David Conen
Journal: Circulation (2016)

Background: Prior reports have shown that kidney injury molecule-1 (KIM-1) is increased among individuals with renal diseases. Currently, little is known about the role and function of KIM-1 in ind...
hPepT1-mediated epithelial transport of bacteria-derived chemotactic peptides enhances neutrophil-epithelial interactions.
Authors: D Merlin, A Steel, A T Gewirtz, M Si-Tahar, M A Hediger, J L Madara
Journal: Journal of Clinical Investigation (1998)

Intestinal epithelial cells express hPepT1, an apical transporter responsible for the uptake of a broad array of small peptides. As these could conceivably include n-formyl peptides, we examined whether hPepT1 could transport the model n-formylated peptide fMLP and, if so, whether such cellular uptake of fMLP influenced neutrophil-epithelial interactions. fMLP uptake into oocytes was enhanced by hPepT1 expression. In addition, fMLP competitively inhibited uptake of a known hPepT1 substrate (glycylsarcosine) in hPepT1 expressing oocytes. hPepT1 peptide uptake was further examined in a polarized human intestinal epithelial cell line (Caco2-BBE) known to express this transporter. Epithelial monolayers internalized apical fMLP in a fashion that was competitively inhibited by other hPepT1 recognized solutes, but not by related solutes that were not transported by hPepT1. Fluorescence analyses of intracellular pH revealed that fMLP uptake was accompanied by cytosolic acidification, consistent with the known function of hPepT1 as a peptide H+ cotransporter. Lumenal fMLP resulted in directed movement of neutrophils across epithelial monolayers. Solutes that inhibit hPepT1-mediated fMLP transport decreased neutrophil transmigration by approximately 50%. Conversely, conditions that enhanced the rate of hPepT1-mediated fMLP uptake (cytosolic acidification) enhanced neutrophil-transepithelial migration by approximately 70%. We conclude that hPepT1 transports fMLP and uptake of these peptide influences neutrophil-epithelial interactions. These data (a) emphasize the importance of hPepT1 in mediating intestinal inflammation, (b) raise the possibility that modulating hPepT1 activity could influence states of intestinal inflammation, and (c) provide the first evidence of a link between active transepithelial transport and neutrophil-epithelial interactions.
Abstract 290: Formulation of tolerable protocols for combination regimens to control triple-negative breast cancer cell-derived xenograft tumor development in animals
Authors: Pawat Pattarawat, Shelby Wallace, Agricola Odoi, Bianca Pfisterer, Hwa-Chain R. Wang
Journal: Cancer Research (2019)

Abstract Cumulative research and clinical results suggest an advantage to use a multiple drug combination over a single drug to control tumor growth and metastasis. In general, combination therapy may result in lower treatment failure rates, lower case fatality ratios, slower development of resistance, and fewer side effects than monotherapy, as well as reducing cost. Triple-negative breast cancer (TNBC) is aggressive, lethal, and heterogeneous. The molecular heterogeneity may account for the differential responses of TNBC to chemotherapies. TNBC is sensitive to conventional chemotherapies with initially high response rates; however, the prognosis is not optimal due to cancer recurrence and metastasis. Although recent advancements in drug development of targeted therapeutics and immunotherapy were somewhat effective in treating TNBC, these therapeutics still need extensive study. Although combination regimens are thought to have better therapeutic outcomes than single drug treatments, drug combinations may also come with overlapped toxicities. Thus, it is important to identify combination regimens that are safe and effectively treat cancers. Based on our in vitro results of combination regiments effective in the synergistic induction of TNBC cell death, we systemically investigated the toxicity and efficacy of combined triple and double agents at various doses and administration protocols to assess the treatment of mice bearing TNBC cell-derived xenograft tumors. We analyzed the adverse effects of combination regimens on the bone marrows, livers, and kidneys, as well as the blood cell profiles in immune-competent and -deficient mice. Our studies successfully identified tolerable protocols for triple and double combination regimens of gemcitabine, romidepsin, and cisplatin, which are FDA-approved anticancer agents, as well as the efficacy of these combination regimens in controlling TNBC xenograft tumors in immune-deficient mice. Our results indicated that the triple combination of gemcitabine plus romidepsin and cisplatin regimen was more effective than double combination regimens in the control of TNBC tumor development in vivo. In conclusion, our studies suggested that the triple combination regimens should be promptly considered as an advanced treatment of TNBC over the conventional gemcitabine and cisplatin regimen or the clinical trial romidepsin plus cisplatin regimen. Citation Format: Pawat Pattarawat, Shelby Wallace, Agricola Odoi, Bianca Pfisterer, Hwa-Chain R. Wang. Formulation of tolerable protocols for combination regimens to control triple-negative breast cancer cell-derived xenograft tumor development in animals [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 290.
Abstract 4069: Development of PSB205, a bifunctional MabPair product that targets PD-1 and CTLA-4
Authors: William C. Fanslow, Zhi Liu, Zhonghua Hu, Hua Liu, Min Shen, Yufeng Peng, Cristina Domeier, David Treiber, Ron Schoner, Wei Yan
Journal: Cancer Research (2019)

Abstract Here we describe a novel platform that enables the production of two full length IgG molecules from a single production cell line. This technology was achieved using a molecular engineering approach to precisely control the cognate pairing of antibody heavy chains and light chains during the assembly of two antibodies in the same cell line. This technology platform, which has been designated as MabPair, can be applied for the development of therapeutic antibody products that contain a mixture of two different antibodies. The antibody cocktail is produced by the same cell line in a predefined ratio and can be manufactured using a conventional antibody production process. When addressing multiple targets, MabPair products can offer significant advantages and flexibility over a bispecific antibody. MabPair technology represents a novel approach for developing antibody combination products. This approach is exemplified by the development of PSB205, our lead MabPair product candidate. PSB205 targets two immune checkpoint pathways, PD-1 and CTLA-4. The development of PSB205, as a potential anti-cancer immunotherapeutic, is discussed. Citation Format: William C. Fanslow, Zhi Liu, Zhonghua Hu, Hua Liu, Min Shen, Yufeng Peng, Cristina Domeier, David Treiber, Ron Schoner, Wei Yan. Development of PSB205, a bifunctional MabPair product that targets PD-1 and CTLA-4 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4069.