bluuebunny/crossref_metadata_2025_split huggingface dataset:
Can Less Be More: Evaluating the Synergistic Relationship between Chemotherapy Agents and NHE1 Inhibitors in Ovarian Cancer Cells
Authors: Larson Allie C. , Provost Joseph J. , Wallert Mark 
Published: June 2021

Ovarian cancer is the seventh most prevalent cancer found in women, resulting in over 200,000 new cases and close to 140,000 deaths annually. In order to combat the risk of mortality associated with this disease, extensive chemotherapy regimes are employed. These measures often include the use of therapeutic agents such as paclitaxel, rucaparib, olaparib, and cisplatin. The mechanisms of action for each of these oncogenic therapeutics differs substantially. Paclitaxel stabilizes microtubule polymerization, effectively preventing mitotic completion. Rucaparib and olaparib both inhibit PARP, an enzyme associated with repairing damaged DNA. Cisplatin also hinders DNA repair. However, it does so by crosslinking the purine bases on DNA to promote cellular apoptosis. Although the use of such chemotherapy agents has been instrumental in reducing cancer‐related deaths, the dosage intensity of these cytostatics can procure adverse side effects in the form of hair loss, anemia, nausea, and vomiting. Because of this reality, it has become of interest to investigate methodologies for reducing the required chemotherapy drug dosage, while still maintaining the same rate of cancer cell death. The Na+‐H+ Exchanger Isoform 1 (NHE1) is a plasma membrane protein that exchanges 1 extracellular Na+ for 1 intracellular H+, thus playing a primary role in pH regulation. It is hypothesized that such a synergistic effect can be produced through the pairing of chemotherapy agents with NHE1 inhibitors. In cancer cells, NHE1 is often hyperactivated leading to the development of a pH inversion. This dysregulation contributes to increased cancer cell proliferation, migration and invasion. Inhibition of this transport protein typically results in intracellular acidification, a mechanism that supports the progression of apoptosis. Applying this inhibition, with an accompanying cytostatic, has thus interested researchers as a possible therapeutic approach towards mitigating neoplastic development. The potential of these drug‐inhibitor pairs will be measured primarily via flow cytometry. Through the addition of a fluorescent dye, this instrument is able to differentiate viable cells from compromised cells within a single population. Such analysis allows for a quantitative assessment of each inhibitor‐drug combination.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Immunohistochemical study of the epithelial‐to‐mesenchymal transition phenotype in nonsmall cell lung cancer
Authors: Rodriguez‐Lopez Xavier Luis , Perez‐Morales Jaileene , Santiago‐Cardona Pedro 
Published: June 2021

Lung cancer is the leading cause of cancer death in both men and women in the United States. Lung cancer is divided into non‐small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). NSCLC accounts for 80% of all primary lung cancers and subdivided into adenocarcinoma (ADC), squamous cell carcinoma (SCC), and large cell carcinoma (LCC). Due to late diagnosis, only 16% of diagnosed patients live beyond 5 years, but this survival rate increases if the cancer has not yet metastasized. Recent developments in lung cancer therapies depend on precise histological subtyping of NSCLC. Accurate discrimination of SCC from the remaining NSCLCs is crucial for understanding the outcome and metastatic dissemination of lung cancer. The epithelial‐to‐mesenchymal transition (EMT) has been associated with an early proclivity for metastasis in lung cancer. We want to identify if N‐cadherin and E‐cadherin expression in tumor samples can be of clinical value for discriminating between SCC and ADC and in predicting the development of lung cancer metastasis. We performed immunohistochemistry analysis in two tissue microarrays that contained 24 lung cancer patients. An EMT phenotype was defined as a low expression of E‐cadherin and high expression of N‐cadherin. An EMT phenotype was observed in 58% cases of SCC and carried prognostic utility for lymph node metastasis. The EMT phenotype observed in SCC can be suggested as potential markers of malignant transformation.Support or Funding InformationR25GM096955, 2R25GM082406, 2U54CA163071‐06This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Src Family Kinase Tyrosine Phosphorylates Toll‐like Receptor 4 To Dissociate MyD88 And Mal/Tirap Suppressing LPS Induced Inflammatory Responses
Authors: Rhee Sang Hoon , Im Eunok , Mitchell Jonathon , Kim Su Jin 
Published: June 2021

Src family kinases (SFKs) are a family of protein tyrosine kinases containing nine members: Src, Lyn, Fgr, Hck, Lck, Fyn, Blk, Yes, and Ylk. Although SFK activation is a major immediate signaling event in LPS/Toll‐like receptor 4 (TLR4) signaling, its precise role has remained elusive due to various contradictory results obtained from a certain SFK member‐deficient mice or cells. The observed inconsistencies may be due to the compensation or redundancy by other SFKs upon a SFK deficiency. The chemical rescuing approach was suggested to induce temporal and precise SFK activation in living cells, thereby limiting the chance of cellular adaption to a SFK‐deficient condition.Using the rescuing approach, we demonstrate that restoring SFK activity not only induces tyrosine phosphorylation of TLR4, but also inhibits LPS‐induced NFkB and JNK1/2 activation and consequently suppresses LPS‐induced cytokine production. TLR4 normally recruits TIR domain‐containing adaptors in response to LPS, however, temporally restored SFK activation disrupts the LPS‐induced association of MyD88 and Mal/Tirap with TLR4. Additionally, using kinase‐dead SFK‐Lyn (Y397/508F) and constitutively active SFK‐Lyn (Y508F), we found that the kinase‐dead SFK inhibits TLR4 tyrosine phosphorylation with reduced binding affinity to TLR4, while the kinase‐active SFK strongly binds to TLR4 and promotes TLR4 tyrosine phosphorylation, suggesting that SFK kinase activity is required for TLR4 tyrosine phosphorylation and TLR4‐SFK interaction.Together, our results demonstrate that SFK activation induces TLR4 tyrosine phosphorylation, consequently dissociating MyD88 and Mal/Tirap from TLR4 and inhibiting LPS‐induced inflammatory responses, suggesting a negative feedback loop regulated by SFK‐induced tyrosine phosphorylation in TLR4.Support or Funding InformationSupported by a grant from Oakland University and the NIH (DK079015, S.H.R) and by Basic Science Research Program through the NRF of Korea (NRF) funded by the Ministry of Education (2016R1D1A1B03932222, E.I.)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Overcoming challenges in the diagnosis of Schistosoma mansoni infections using POC tests, recombinant protein and monoclonal antibody technologies.
Authors: Grenfell e Queiroz Rafaella Fortini , Harn Donald , Coelho Paulo Marcos 
Published: June 2021

Control constraints of Schistosomiasis include the lack of diagnostic methods with high sensitivity. We develop a prospective study in southeast Brazil to standardize new sensitive and rapid diagnostic methods for Schistosoma mansoni infection. Currently, we are investigating 6 endemic areas (>1000 individuals with chronic infection) and 84 travelers infected in a freshwater pool (with acute infection). Sera, urine, feces and saliva samples were used for the standardization/validation of innovative methods, including acute, chronic and post‐treatment patients. Comparisons are performed with eggs in feces by 24 Kato‐Katz slides and 2 analysis of Saline Gradient and clinical symptoms. With our new point‐of‐care methods using a selected recombinant protein called CCAr e other markers, we were able to detect the disease early as 10 days post‐infection and more than 95% of positive cases from chronic and low endemicity areas were obtained. Plus, POC‐CCA® test was improved with a urine concentration step that turned its sensibility from 6% to 56%. Monoclonal antibody and recombinant protein technologies allowed a superior detection method when comparing it to the conventional methods. In conclusion, data showed 100% of sensitivity of chronic patients and 98% of acute patients.Support or Funding InformationFapemig, CNPq, FIOCRUZ, PDTIS (Brazil). Fulbright, NIH, University of Georgia (USA).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Investigation of Lytic Activity of Melittin‐nNOS Chimeric Antimicrobial Peptides
Authors: Fujii Maria , Stevens‐Truss Regina 
Published: June 2021

Antibiotic resistance has become a growing problem in a world of prescription drug overuse and misuse. Antimicrobial peptides (AMPs) offer one possible solution. Melittin (Mel), isolated from bee venom, is a known AMP. It is active against a variety of microbes as well as cytotoxic towards eukaryotic cells. Previous work from our lab has demonstrated that the calmodulin‐binding sequence of the nNOS enzyme possesses selective activity against S. aureus. Our lab has been investigating the role that specific amino acid residues of Mel play in its lytic activities, and possibly what role these amino acids play in selectivity, by investigating the activities of a series of Mel‐nNOS chimeras. In this study, the chimeras were produced by replacing the middle 10 residues of one peptide with that of the other (nMel‐nNOS‐cMel and nnNOS‐Mel‐cnNOS). We also assessed the activity of Mel truncated peptides (nMel and cMel). All experimental peptides were tested for their ability to inhibit the growth of S. aureus and E. coli as well as their ability to lyse liposomes and red blood cells (RBCs). The results show that both truncated peptides were completely inactive. In addition, both chimeras were found to effectively cause liposome lysis at concentrations below 3 uM and have minimal effect on RBC lysis. Chimera nnNOS‐MelcnNOS was found to have IC50 values above 12 uM for both S. aureus and E. coli while chimera nMel‐nNOS‐cMel was found to be more selective for S. aureus (IC50 values between 4 uM and 8 uM), with IC50 for E. coli being greater than 16 uM. These results imply that the eight terminal residues of Mel are insufficient for bacterial growth inhibition. Further studies should focus on increasing the Mel to nNOS ratio of the chimeric AMPs.Support or Funding InformationThe Authors would like to acknowledge the American Society for Biochemistry and Molecular Biology, as well as the Kalamazoo College Chemistry Department and Faculty Development Committee for funding.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The Effect of Membrane Composition on PLCβ and Gαq‐mediated Activation
Authors: Hudson Brianna N. , Hyun Seok‐Hee , Thompson David H. , Lyon Angeline M. 
Published: June 2021

Phospholipase C β (PLCβ) enzymes are peripheral membrane proteins that are required for normal cardiovascular function and whose dysregulation results in cardiovascular disease. PLCβ hydrolyzes phosphatidylinositiol‐4,5‐bisphosphate (PIP2) to produce the potent second messengers inositol‐1,4,5‐triphosphate (IP3) and diacylglycerol (DAG), which increase intracellular Ca2+ and activate protein kinase C. PLCβ has low basal activity, but is activated downstream of G protein‐coupled receptors (GPCRs) through direct interactions with the heterotrimeric G protein subunits Gαq and Gβγ. While G proteins stimulate activity, they are insufficient for full activation. This suggests that the membrane is required for full activation. However, the molecular basis for how the membrane and its properties contribute to PLCβ adsorption, activity, and Gαq‐dependent activation are not well understood. We seek to understand how the membrane composition and its surface charge regulate adsorption of PLCβ to the membrane and promote interfacial activation, and the role of Gαq in this process. Using a model membrane system, we are applying an innovative combination of atomic force microscopy, Raman spectroscopy and biochemical assays to begin understanding how the membrane itself and Gαq regulate PLCβ activation. These studies provide the first structure‐based approach to understanding how the cell membrane regulates the activity of this essential effector enzyme.Support or Funding InformationAmerican Heart Association Scientist Development Grant (16SDG29920017) to A.M.L.; Purdue Doctoral Fellowship to B.N.H.; Purdue Center for Cancer ResearchThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Increased levels of FOXM1 transcription factor in bronchioalveolar stem cells promote epithelial cell repopulation in injured mouse airway
Authors: Wang I‐Ching , Chiu Yi‐Shiuan , Chen Wei‐Hsin , Li Chien‐Cheng , Lee Yun‐Ching 
Published: June 2021

Bronchioalveolar stem cells (BASCs) have been shown to maintain the bronchiolar and alveolar epithelial cell renewal upon lung injury. Previously we have shown Foxm1 transcription factors plays essential roles in cellular proliferation, migration, differentiation and tumorigenesis. Conditional deletion of Foxm1 from mouse respiratory epithelium during initial stages of lung development inhibited lung maturation and caused respiratory failure after birth, while deletion of Foxm1 from adult lung airway epithelium reduced club cell proliferation after naphthalene‐induced lung injury. Here, we show that premature expression of transgenic FOXM1accelerated airway epithelial cell proliferation after naphthalene induced lung injury in CCSP‐rtTA/tetO‐FOXM1 mouse (C/FOXM1), which is associated with increased numbers of CC10 and Ki‐67 positive cells in terminal bronchiolar epithelium and bronchioalveolar duct junction (BADJ), the stem cell niche. Lineage tracing experiment showed that FOXM1 promotes proliferation of LacZ or Brainbow labelled naphthalene‐resistant CCSP expressing cells that differentiated into bronchiolar epithelium in healing processes. Co‐immunofluorescent staining showed an increased number of proSPCposCCSPpos BASCs were found in in BADJ of C/FOXM1 lungs, which consistent to result that an increased number of CD45neg CD31neg Sca‐1hi EpCAMhi bronchiolar stem cells in C/FoxM1 lungs by FASC analysis. Our results indicated that increased expression of FOXM1 contributes to the increases proliferation of lung stem/progenitor cells, and facilitates bronchiolar epithelium repair from acute lung injury.Support or Funding InformationNational Health Research Institute, Taiwan (NHRI‐EX106‐10309BC); Ministry of Science and Technology, Taiwan (MOST 105‐2628‐B‐007‐003‐MY3); and National Tsing Hua University, Taiwan (106J00X9V8) to I‐C.W.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Marijuana, Crack and Cocaine Consumption in Undergraduate Brazilian Students
Authors: Miranda Renato Pricoli , Olcerenko Bianca Giovanna Batista , Rebecchi Cassio , Taricano Ingrid Dragan 
Published: June 2021

Drug addiction is one of the most prominent problems in many developing countries, including Brazil. Our study was aimed to investigate the relationship of the use of marijuana, the illicit drug with the biggest use prevalence in the world, with the use of crack/cocaine in undergraduate students from the city of São Paulo, covering samples from the north, south, east, west and center regions. The study sample comprised 907 undergraduate students. The group of respondents was chosen to represent undergraduate students of this city. Data on lifetime and recent frequency and intensity of use for alcohol, cannabis, amphetamines, ecstasy, LSD and cocaine was collected.METHODOLOGYThe instrument used for data collection was Google FormsTM. The instant addition of responses to the data set makes this tool appealing for research purposes. Additionally, the respondents involved in the study have been regularly using Google FormsTM, and it was therefore considered the most appropriate method for data collection. The results of the survey was statistically analyzed. Within the various areas the group of students from medical, biology, nursing, engineering, architecture, psychology, and other courses, were chosen because their experience using these tools. Data on lifetime and recent frequency and intensity of use for alcohol, cannabis, amphetamines, ecstasy, LSD and cocaine are presented.RESULTSParticipants already use illicit drugs. The greater consumption between the interviewed university population is marijuana, while the prevalence of cocaine use is 5% and crack 0.6%. According to the results obtained, 4.07% (37) of the participants had the use of marijuana associated with crack/cocaine, being that the marijuana/cocaine use relationship was 91.89% (34), the relationship of use marijuana/crack/cocaine was 8,11% (3), while the relationship of the use of marijuana associated only to the use of crack was not observed.CONCLUSIONThe relation of illicit drug use in undergraduate health area is the highest consumption indices. These results show some paradox, since the area in question is just formed by the professionals that will work with physical, psychological and social problems arising out of the use of drugs. This work was conducted in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration. CAAE(Br)67881517.1.0000.5511. All participants had full understanding and signed informed consent document.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Field Sobriety Test for Cannabis
Authors: Pabon Elisa , de Wit Harriet 
Published: June 2021

Cannabis and its active ingredient delta‐9‐tetrahydrocannabinol (THC) have been shown to impair memory, reaction time and attention. However, it is difficult to assess these impairments in the nonlaboratory setting. We have developed a prototype for a phone application called Am I Stoned?. As a first step, we tested the app in a within‐subjects double‐blind placebo‐controlled study with THC (0, 7.5, 15 mg). Participants completed both iPhone‐based and standard computer tests of cognitive speed, reaction time, fine motor ability, and memory. As a secondary aim we also assessed participants' ability to estimate their performance impairment. Twenty‐four healthy experienced non‐daily cannabis users completed a laboratory study, which included three 4‐hour experimental sessions in which participants consumed a capsule containing THC (7.5, 15 mg) or placebo. They completed all tasks at both two and three hours after taking the capsule. Performance was impaired by THC in three of the four computer tasks, but only one of the iPhone tasks. It is likely that the computer tasks were more sensitive to THC impairment than the app task because the computer tasks were longer (15–20 min compared to 5–7 min), providing more opportunity to detect a drug effect. With regard to self‐assessments, subjects were in general accurate in their awareness of impairments on the tasks. In a follow‐up study we will improve the tasks used in the phone application to increase their sensitivity to THC impairment. This research is likely to lead to sensitive field tests that will allow users to objectively evaluate their ability to perform psychomotor or cognitive tasks. The research will also identify conditions under which individuals are or are not aware of their impaired state.Support or Funding InformationThis research was supported by the National Institute on Drug Abuse Grant DA02812 (HdW)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
CYP2J2 inhibition: the arcane mechanism of dronedarone‐induced proarrhythmia
Authors: Chan Eric Chun Yong Yong , Karkhanis Aneesh , Mehta Ashish , Shim Winston 
Published: June 2021

BackgroundLike other Class III antiarrhythmic, dronedarone and amiodarone are potent human Ether‐à‐go‐go‐Related Gene (hERG) channel inhibitors.1–2 Although structurally and pharmacologically similar, dronedarone is known to worsen cardiac proarrhythmia3 and increase mortality in patients with permanent atrial fibrillation4 while amiodarone does not. Previously we demonstrated dronedarone is a more potent inhibitor of recombinant human cytochrome P4502J2 (CYP2J2)4 compared to amiodarone and yields negative perturbation of eicosatrienoic acid homeostasis5.ObjectivesWe aimed to investigate and compare the in vitro proarrhythmic potential of dronedarone and amiodarone and CYP2J2 inhibition in a cellular model.MethodsWe first measured the expression of CYP2J2 in human induced pluripotent stem cell derived cardiomyocytes (hiPSC‐CMs) using quantitative PCR. The extent of CYP2J2 inhibition in hiPSC‐CMs was measured using astemizole as a probe substrate. The electrophysiological changes in terms of field potential duration (FPD) and beat rate variability (BRV) were measured using multielectrode array.ResultsCYP2J2 is abundantly expressed in hiPSC‐CMs. Unlike amiodarone, dronedarone potently inhibited CYP2J2 activity (97%) at 1 μM. Both dronedarone and amiodarone yielded concentration‐dependent increase in FPD. Dronedarone showed 17‐fold and 2‐fold higher BRV compared to control and amiodarone at unbound plasma drug concentrations. Higher extent of CYP2J2 inhibition correlates with higher BRV.ConclusionDronedarone‐induced BRV corroborates its clinical proarrhythmia. For the first time, our study illuminates the currently arcane contribution of CYP2J2 inhibition to drug‐induced proarrhythmia.Support or Funding InformationSingapore Ministry of Education Tier 1 Funding (R‐148‐000‐193‐112) provided to Eric Chun Yong Chan.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.