bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of the most immunogenic regions in vaccine candidate P6 (948.7)
Authors: Bettinger John , Newman Emily , Mangan Anthony , Pichichero Michael , Michel Lea 
Published: June 2021

P6 is a leading protein vaccine candidate for protection against Nontypable Haemophilus influenzae (NTHi) infection. NTHi bacteria are a cause of middle ear infections, sinusitis, pneumonia, and chronic bronchitis. Vaccines that contain only the most immunogenic parts of the protein, often including the antibody binding sites or “epitopes,” can reduce production costs and can sometimes enhance effectiveness. Thus, identifying the most immunogenic part of P6 might be highly attractive to pharmaceutical companies who would like to use P6, or part of P6, in their next vaccine against NTHi. In this study, the P6 epitopes against monoclonal antibodies 4G4 and 7F3 were partially identified. P6 mutant T42R (threonine to arginine at residue 42) was prepared using recombinant DNA technologies, and mutated DNA was transformed into Escherichia coli cells for efficient overexpression. An Enzyme‐Linked Immunosorbent Assay (ELISA) showed decreased binding (compared to wild‐type P6) of the P6 T42R mutant for both the 4G4 and 7F3 antibodies, suggesting that 7F3 and 4G4 interact with residue 42. Nuclear Magnetic Resonance (NMR) spectroscopy was employed to assess structure changes in P6 due to the mutations.Grant Funding Source: This study was supported by NIH NIDCD RO1 08671 (to MEP) and the Rochester Institute of Technology.
Lkb1‐ a master tumor suppressor (LB108)
Authors: Aube Eric , Chan Rosanna , Maynard Alex , Ortbals Chloe , Paul Lindsey , Shome Ria , Wright Madison , Kessler Eric , Tuel Kelly , Whalen Joseph , Anant Shrikant 
Published: June 2021

The small intestine is remarkable in that 109 epithelial cells are produced every twenty minutes, but cancer rarely develops. This is possible due to the serine/threonine kinase tumor suppressor Liver Kinase B1 (LKB1). Mutations in LKB1 were first linked to the disease Peutz‐Jeghers syndrome in which polyps grow and have a 93% chance of becoming cancerous. Mutations in LKB1 have been linked to several forms of cancer including small intestine, breast, lung, liver, and pancreas. LKB1 forms an active heterotrimer with pseudokinase: STRAD, and scaffolding protein: MO25. LKB1’s primary function is to regulate energy homeostasis through the phosphorylation of the t‐loop structure on adenosine monophosphate protein kinase (AMPK), which mediates the production of ATP when cells enter a state of energy stress. AMPK detects and reacts to differences in the AMP:ATP ratio. AMPK has also been shown to impact several cancer‐related processes. For example, the AMPK‐mTOR signaling pathway is important for inducing cell death within cancer cells. Possible future research includes finding methods of inducing LKB1 activity, which would stimulate the AMPK‐mTOR pathway and diminishes cancer cell proliferation. The CAPS SMART Team (Students Modeling a Research Topic) created physical models of the tumor suppressor protein LKB1 and its target AMPK using 3D printing technology.Grant Funding Source: Supported by grants from the NIH‐SEPA and NIH‐CTSA.
The effect of food restriction on the expression of some placental proteins (LB24)
Authors: Harrath Abdel Halim , Mansour Lamjed , Al Omar Sulimen , Alwasel Saleh 
Published: June 2021

Fast food and ready meals may be an important determinant in the significant increases of numerous diseases, such as reproductive disorders, because these foods are low in macro and micronutrients. In this study, we aimed to investigate whether food restriction in pregnant mothers affects placental structure and function.The rat represents an excellent organism for studying human disease and the main source for testing new drugs and to increasing knowledge of the pathobiology of human disease. The placentas from pregnant females under food restriction and controls were removed on the day 6, 14 and 20 of pregnancy. A panel of Sulimen Y. Al Omar1differentially expressed proteins, specifically tumor necrosis factor (TNF) signaling, TNF receptor 1 (TNFR1) and transforming growth factor‐β (TGF‐β) have been subjected to immunohistochemistry and molecular analysis. Our observations suggest that the expressions of some of these proteins were affected by the food restriction, and thus placenta is affected by the lack of nutrition during pregnancy. We conclude that these differentially expressed proteins are an effective target for measuring placental defects and related risks to the fetus development. Results from a rat model may be extrapolated to other species including humans.Grant Funding Source: Supported by Deanship of Scientific Research at king Saud University
Effects of Calorie Restriction on Total and Heligmosomoides bakeri‐specific IgG1 in Mice of Differing Immune Phenotypes (LB307)
Authors: Jablanovic Jelena , Lang Samantha , Manibusan Pierre , Kristan Deborah 
Published: June 2021

Calorie restriction (CR) is currently being investigated in humans for therapeutic effects on longevity and age‐associated diseases. However, some preliminary animal studies have shown that CR can adversely affect the immune system in the presence of infection; therefore the risk of CR needs to be further evaluated. In this study we subjected 2 immunologically different strains of laboratory mice (C57BL/6, SJL) to CR, and then infected them with intestinal nematode Heligmosomoides bakeri. We then measured a non‐specific immunoglobulin response (total IgG1) and a pathogen‐specific immunoglobulin response (H. bakeri‐specific IgG1). Overall, our study showed that C57 had a more robust total IgG1 response, but H. bakeri‐specific IgG1 was similar in both strains. CR had an attenuating effect on total IgG1 in both C57 and SJL mice, but CR had no effect on the H. bakeri‐specific IgG1 response in either strain. Taken together, our study showed that CR can attenuate a non‐specific immunoglobulin response and have no effect on pathogen‐specific response. However, we caution that effects of CR on pathogen‐specific response should further be investigated during longer or repeated infections.Grant Funding Source: NIH 5SC3GM084806
Assessing the association between the methylenetetrahydrofolate reductase (MTHFR) 677C→T polymorphism on blood folate concentrations: a systematic review and meta‐analysis of trials and observational studies (LB311)
Authors: Tsang Becky , Cordero Amy , Marchetta Claire , Mulinare Joseph , Mersereau Patricia , Guo Jing , Qi Yan Ping , Berry Robert , Rosenthal Jorge , Crider Krista , Hamner Heather 
Published: June 2021

Background: The methylenetetrahydrofolate reductase (MTHFR) 677C→T polymorphism is a risk factor for neural tube birth defects (NTDs). The T allele produces an enzyme with reduced folate processing capacity, which has been shown to produce lower blood folate concentrations in some studies.Objective: To assess the association between MTHFR C677T genotypes (CC, CT, TT) and blood folate concentrations among women aged 12‐49 years.Design: We conducted a systematic review of literature published between 1/1992‐7/2013 to identify controlled trials and observational studies that reported serum, plasma, or red blood cell (RBC) folate concentrations and MTHFR C677T genotype. We applied a Bayesian random‐effects model to predict differences in blood folate concentrations between MTHFR C677T genotypes, stratified by folate assay.Results: Thirty‐eight studies met criteria for inclusion. Serum/plasma folate concentrations showed a consistent genotype trend with the highest concentrations for CC (CC > CT > TT) regardless of assay type. RBC folate concentrations measured by microbiologic assay also demonstrated this trend; however, this trend was reversed (CC < CT < TT) in studies using protein‐binding assays.Conclusions: Meta‐analyses results showed blood folate concentrations differed by assay type and genotype. Previous evidence has shown that RBC folate concentrations measured with a radioimmunoassay requires adjustment for genotype‐dependent folate recovery; our results suggest that other protein‐binding assays could have similar limitations. Compared to CC individuals, TT individuals have lower blood folate concentrations, which may increase a woman’s risk for an NTD‐affected pregnancy.
Circulating leptin and risk of pancreatic cancer: a pooled analysis of three cohorts (LB369)
Authors: Stolzenberg‐Solomon Rachael , Newton Christina , Silverman Debra , Pollak Michael , Nogueira Leticia , Albanes Demetrius , Männistö Satu , Tao Yuzhen , Jacobs Eric 
Published: June 2021

Background: Diabetes, overweight and obesity are consistently associated with increased pancreatic cancer risk; however the underlying mechanism(s) is uncertain. Leptin is an adipokine important in metabolic regulation.Methods: We conducted a pooled nested case‐control study of participants from the Prostate, Lung, Colorectal, and Ovarian Cancer Trial (PLCO), Alpha‐Tocopherol, Beta‐Carotene Cancer Prevention Study (ATBC), and Cancer Prevention Study II Nutrition (CPS‐II) cohorts to investigate whether pre‐diagnostic circulating leptin concentrations were associated with pancreatic cancer. In total, 759 incident pancreatic adenocarcinoma cases were included in this analysis (average follow‐up 8.3 years, up to 20 years). Incidence density selected controls (n=1069) were matched to cases by cohort, age, sex, race, and date of blood draw. We used conditional logistic regression analysis to calculate adjusted odds ratios (OR) and 95% confidence intervals (CI) and sex‐specific quintiles (Q) based on the distribution of the controls. Results: Overall, we did not observe an association between leptin and pancreatic cancer (compared to Q1, Q5 OR=1.13, 95% CI 0.75‐1.70, p‐trend=0.39). There was a statistically significant interaction by follow‐up time (p‐interaction=0.003) such that significantly elevated risk was apparent only among cases occurring 10 or more years after blood draw (compared to Q1, Q4 OR=2.21, 95% CI 1.18‐4.13, Q5 OR=2.55, 95% CI 1.23‐5.27, p‐trend=0.004). There were no significant interactions by cohort, sex, smoking, age, baseline BMI or diabetes.Conclusion: The lack of association during early follow‐up might be explained by subclinical disease. Our results support the hypothesis that leptin plays a role in pancreatic carcinogenesis, however long follow‐up is necessary to observe the association.
Thoracic Ultra Sound (TUS) integrated approach for FNAB‐US guided diagnosis and for monitoring environmental exposed subjects at risk of malignant pleural mesothelioma (MPM) and lung cancer (LC). Overview and preliminary report of TUS monitoring and screening approach. (LB498)
Authors: Sperandeo Marco , Dimitri Lucia , Trovato Francesca M. , Simeone Anna , Catalano Daniela , Pirri Clara , Trovato Guglielmo 
Published: June 2021

Thoracic Ultrasound (TUS) Image‐guided sampling of thickened pleura and of lung nodules is a valuable approach in patients with lung cancer (LC) and malignant pleural mesothelioma (MPM); moreover, we monitor by TUS imaging patients with occupational or environmental risk of MPM and LC addressing them more selectively to high resolution computerized tomography (HRCT), also with contrast CT for a further definition. A retrospective analysis of TUS imaging and of the diagnostic yield and complications of TUS‐guided fine needle aspirate biopsies (FNAB) was done. Results: the records of 133 patients with MPM and 801 patients with LC were analyzed. In 55/133 MPM and in 801/801 patients with LC (2008‐2013)TUS‐guided FNAB was performed using 20 G needles and a US transducer with a central passage. The specimens were of satisfactory size (length 1.0‐2.5 cm); in 20/801 LC patients a second FNAB was needed for further immunohistochemistry specimens. No significant complication was observed; 5 patient had partial pneumothorax following biopsies. The TUS signs observed in histologically confirmed MPM were irregular thickening of pleural line (above 5.0 mm) with associated micro‐nodules (5‐10 mm); a lower percentage showed plaque nodulations (5‐10 mm), all with slight or relevant pleural effusion. Patients at risk, without MPM/LG, under TUS monitoring, have irregular thickening of pleural line (above 3.0 mm), with associated micro‐nodules (2‐4 mm); a lower percentage have plaque nodulations (4‐7 mm). These early signs of lung involvement in subjects exposed to asbestos were observed in the absence of CXR findings, and with subsequent HRCT evidence without need of FNAB. Conclusion: TUS guided FNAB is a safe, affordable and reliable tool for the diagnosis of MPM and LC patients, provided that an adequate expertise of the operator and of the pathologist is available.TUS is currently used in our Institution as a complementary tool for screening patients with environmental or occupational risk for MPM and LC. They are preliminarily assessed by HRCT and TUS; this last is scheduled every six months thereafter. Diagnosing patients with pleural thickenings and/or subpleural nodes suspect for MPM is used to address to HRCT and/or contrast CT with the prospect of further focused indications to ultrasound‐guided FNAB.$graphic_00251AF2‐7D54‐4C2E‐BAF9‐980B59FD83CB$
Losartan protects the lung from chronic cellular damage induced by fat embolism (LB512)
Authors: Poisner Alan , Herndon Betty , Bass Devin , Jain Ashwin , Fletcher Amanda , Molteni Agostino 
Published: June 2021

In a model of triolein‐induced fat embolism (FE) in the rat, we have reported that the acute pulmonary histopathological changes were ameliorated by losartan (Los). The chronic pulmonary changes of FE persisted at 6 weeks and symptoms were exacerbated by a “second hit” at that time using LPS. The present experiment extended FE study to 10 weeks and examined whether the FE effects plus LPS would continue to be blocked by Los. Groups of rats were given FE (triolein i.v. or i.v. saline controls) followed 6 weeks later by LPS (3 mg/kg i.p). One‐hour after LPS rats were treated with saline or Los (2 mg/kg i.p. and then 0.1 mg/ml Los in the drinking water for 4 more weeks). In confirmation of our previous results, the FE group showed normal weight gain both at 6 and 10 weeks and appeared to be in no distress. However the lungs showed reduced lumen patency at 10 weeks, accompanied by inflammatory and fibrotic changes that were greater than what had been found previously at 6 weeks whether or not LPS was added. These changes were reduced or blocked by Los. In addition pulmonary arteries of all Los‐treated animals had increased lumen patency compared to their respective controls. The data suggest that the effect of FE continues to progress at 10 weeks. The involvement of the renin‐angiotensin system in the pathology of FE is supported by the action of the type 1 receptor blocker, Los. In addition, the enhanced effect of LPS on FE (second hit) was also blocked by Los. These results support the possibility of using angiotensin blockade in clinical situations where fat embolism is suspected .Grant Funding Source: Supported by Geldmacher Foundation
Small molecule Gβγ inhibition reduces pathologic activation of cardiac fibroblasts (LB563)
Authors: Travers Joshua , Kamal Fadia , Blaxall Burns 
Published: June 2021

Heart failure (HF) is a devastating disease characterized by cardiac hypertrophy, fibrosis and inflammation. Excess signaling through Gβγ subunits leads to chronic β‐adrenergic receptor (β‐AR) downregulation, mediated predominantly by β‐AR kinase 1 (GRK2) in complex with phosphoinositide 3 kinase γ (PI3Kγ). Our recent work has demonstrated the therapeutic potential of the small molecule Gβγ‐GRK2 inhibitor Gallein in limiting HF progression. Chronic activation of cardiac fibroblasts (CF), critical yet underappreciated myocardial cells, is a key contributor to pathologic cardiac remodeling. We hypothesized that Gβγ‐GRK2 inhibition may limit pathologic CF activation. CFs were stimulated with Isoproterenol (Iso, β‐AR agonist) or Angiotensin II +/‐ Gallein for 24hr. Gallein treatment attenuated the induction in the expression of α smooth muscle actin (αSMA), a marker of pathologic CF activation, several inflammatory cytokines and collagen, as assessed by qRT‐PCR. Gβγ inhibition also mitigated the induction in the phosphorylation of Akt, a kinase downstream of PI3Kγ, in both rodent and failing human CFs. We have recently demonstrated that the protease‐activated receptor 1 (PAR1), a GPCR we have implicated in cardiac hypertrophy, is pathologically transactivated via chronic β‐AR stimulation by induction of MMP‐13, a protease we have found to be elevated in HF. Interestingly, Gβγ inhibition reduced PAR1 cleavage in response to chronic Iso. In summary, small molecule Gβγ inhibition appears to reduce pathologic CF activation, and the reduction in β‐AR‐mediated PAR1 cleavage reveals an alternative mechanism for Gβγ inhibition. These data suggest a potential therapeutic role for small molecule Gβγ inhibition in limiting pathologic CF activation and HF progression.Grant Funding Source: Supported by the Pharmaceutical Research and Manufacturers of America Foundation
Sildenafil citrate attenuates acute renal injury in an animal model of contrast‐induced nephropathy (LB573)
Authors: Lauver D. , Lucchesi Benedict , Gurm Hitinder 
Published: June 2021

Contrast‐induced nephropathy (CIN) is defined as acute renal failure occurring within 48 hr of exposure to intravascular contrast agents. Although the exact etiology of CIN remains unclear, one hypothesis involves vasoconstriction of afferent arterioles resulting in renal ischemia. Increased renal blood flow, therefore, might represent an attractive target for the treatment of CIN. In this study we evaluated the effect of inhibition of cGMP‐specific phosphodiesterase type 5 (PDE5), a process resulting in renal vasodilation, in an animal model of CIN.New Zealand white rabbits were used due to their susceptibility to CIN. Contrast agent (ioxilan, 2.5‐10.0 g I/kg) was infused intravenously over 30 m. Another group of animals received an equiosmolar NaCl solution and served as the control. To evaluate the effects of PDE5 inhibition, a final group was treated with sildenafil citrate before contrast infusion and repeatedly throughout the remainder of the experiment (6 mg/kg, p.o., t.i.d.). The animals were sacrificed after 48 hr and the kidneys were prepared for histological evaluation.Intravenous administration of ioxilan produced marked kidney injury. Serum creatinine concentrations were elevated within two hr of the infusion and remained elevated for the duration of the experiment. Histological evaluation of the kidneys revealed significant tubular necrosis. The effects of the contrast agent were dose dependent, but absent in the animals that were administered NaCl solution. Notably, the effects of contrast infusion were attenuated by simultaneous treatment with sildenafil citrate.The conclusions of this study are two fold. First, the absence of deleterious effects in animals treated with equiosmolar NaCl solution suggests that the mechanism by which the contrast agent induced kidney injury was independent of osmolality. Second, selective PDE5 inhibition protected the kidney from CIN. The results suggest a possible role for PDE5 inhibitors in the treatment of CIN and warrant further evaluation to determine the exact mechanism of protection.
Vanillins relax isolated porcine coronary arterial smooth muscle by inhibiting L‐type Ca2+ channels (LB574)
Authors: Raffai Gábor , Kim Jihye , Khang Gilson , Lee Dongwon , Vanhoutte Paul 
Published: June 2021

Vanillin (VA) and vanillyl alcohol (VAA) are major components of natural vanilla, while ethyl vanillin (EtVA) is a synthetic vanillin analog with antioxidant and anti‐inflammatory properties. This study compared the relaxing effect of vanillins (VA, VAA, EtVA) and poly(vanillin) oxalate (PVO) nanoparticles (Ø 260nm) containing VA in porcine coronary artery rings by measuring isometric tension. Vanillins but not PVO caused concentration‐dependent, endothelium‐independent and complete relaxations during contractions to U46619, KCl or endothelin‐1 with an order of potency of VAA<VA<EtVA. The relaxations of U46619 contracted preparations were unaffected by inhibitors of NOS (L‐NAME), cyclooxygenases (indomethacin), soluble guanylyl cyclase (ODQ), KCa (TRAM‐34, UCL‐1684, iberiotoxin), KATP (glibenclamide), Kir (BaCl2), and TRPV3 channels (camphor) or by antioxidants (catalase, apocynin, tempol, N‐acetylcysteine, tiron). Vanillins inhibited contractions induced by both Ca2+ reintroduction in 40mM KCl solution and BayK8644. Both VA and PVOs caused partial relaxation of XO/XOD contracted rings. In conclusion, relaxation to vanillin(s) is solely due to the inhibition of L‐type Ca2+ channels in porcine coronary arteries. Both VA and PVO can prevent contractions induced by superoxide anions, and thus could be used to relieve coronary vasospasm associated with elevated oxidative stress.Grant Funding Source: Supported by Brain Korea 21 PLUS Project, NRF and NRF‐2012M3A9C6050204
The role of cardiac O‐linked β‐N‐acetylglucosamine (O‐GlcNAc) transferase (OGT) on endurance capacity and physical activity (LB681)
Authors: Duenwald Elizabeth , Miller Lindsey , Medford Heidi , Cox Emily , Marsh Susan 
Published: June 2021

The cardiovascular benefits obtained from endurance exercise are well established. Physiological cardiac hypertrophy occurs in response to the beneficial stress of exercise at both the cellular and transcriptional levels. The mechanisms triggering cardiac remodeling to induce a physiological or pathological hypertrophic phenotype remain largely unknown. The posttranslational attachment of O‐Linked β‐N‐acetylglucosamine (O‐GlcNAc) to serine or threonine residues of proteins is catalyzed by O‐GlcNAc transferase (OGT). O‐GlcNAcylation is an important mediator of signal transduction and protein‐protein interactions. However, the relevance of elevated O‐GlcNAc levels in the heart is complex as it is implicated in both cardiac dysfunction, and cardioprotection. Preliminary data and recent literature also suggests that inducible cardiomyocyte‐specific knockdown of OGT (OGT‐KD) alters gene transcription, which results in a heart failure phenotype. We investigated the impact of inducible, cardiomyocyte‐specific OGT‐KD on exercise capacity in a mouse model. Ten week old OGT‐KD mice were randomly assigned to a one‐time run to exhaustion treadmill (TM) cohort, or a 4 week voluntary wheel running (WR) cohort, or appropriate control groups. The TM cohort tolerated a decreased workload overall and exhibited increased ventricular heart weight with an increase in the ratio of heart weight (HW) to tibia length (TL). OGT‐KD mice in the WR cohort had decreased body weight, decreased overall activity, and increased HW:TL. These data suggest that inducible cardiac‐specific OGT‐KD in a mouse model significantly decreases endurance capacity and physical activity, while causing hypertrophy of the heart muscle as early as 11 weeks of age.Grant Funding Source: NIH/NHLBI HL104549