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  • Regulating oral biofilm from cariogenic state to non-cariogenic state via novel combination of bioactive therapeutic composite and gene-knockout

    Chen, Hong; Yang, Yingming; Weir, Michael D.; Dai, Quan; Lei, Lei; Homayounfar, Negar; Oates, Thomas W.; Yang, Kai; Zhang, Ke; Hu, Tao; et al. (MDPI AG, 2020-09-01)
    The objectives were to investigate a novel combination of gene-knockout with antimicrobial dimethylaminohexadecyl methacrylate (DMAHDM) composite in regulating oral biofilm from a cariogenic state toward a non-cariogenic state. A tri-species biofilm model included cariogenic Streptococcus mutans (S. mutans), and non-cariogenic Streptococcus sanguinis (S. sanguinis) and Streptococcus gordonii (S. gordonii). Biofilm colony-forming-units (CFUs), lactic acid and polysaccharide production were measured. TaqMan real-time-polymerase-chain reaction was used to determine the percentage of each species in biofilm. The rnc gene-knockout for S. mutans with DMAHDM composite reduced biofilm CFU by five logs, compared to control (p < 0.05). Using parent S. mutans, an overwhelming S. mutans percentage of 68.99% and 69.00% existed in biofilms on commercial composite and 0% DMAHDM composite, respectively. In sharp contrast, with a combination of S. mutans rnc knockout and DMAHDM composite, the cariogenic S. mutans percentage in biofilm was reduced to only 6.33%. Meanwhile, the non-cariogenic S. sanguinis + S. gordonii percentage was increased to 93.67%. Therefore, combining rnc-knockout with bioactive and therapeutic dental composite achieved the greatest reduction in S. mutans, and the greatest increase in non-cariogenic species, thereby yielding the least lactic acid-production. This novel method is promising to obtain wide applications to regulate biofilms and inhibit dental caries.
  • Expression of AR-V7 (Androgen receptor variant 7) protein in granular cytoplasmic structures is an independent prognostic factor in prostate cancer patients

    König, Paul; Eckstein, Markus; Jung, Rudolf; Abdulrahman, Amer; Guzman, Juan; Weigelt, Katrin; Serrero, Ginette; Hayashi, Jun; Geppert, Carol; Stöhr, Robert; et al. (MDPI AG, 2020-09-01)
    Prostate cancer (PCa) is the second most common cancer, causing morbidity and mortality among men world-wide. The expression of the androgen receptor (AR) and its splice variants is a crucial factor of prostate cancer biology that has not been comprehensively studied in PCa tumors. The aim of this study was to characterize the protein expression of the AR and its splice variant, AR-V7, and their subcellular distributions in PCa by immunohistochemistry and to correlate the results to the clinicopathological data and prognosis. Immunohistochemical staining for AR and AR-V7 was performed on a tissue microarray (TMA) with specimens from 410 PCa patients using an immunoreactive score (IRS) or only the percentage of AR-V7 staining in cytoplasmic granules. Nuclear or cytoplasmic AR staining was not associated with prognosis. AR-V7 staining was only occasionally observed in the nucleus. However, AR-V7 staining in the cytoplasm or in cytoplasmic granules was associated with relapse-free survival (RFS). AR-V7 staining of the cytoplasm was associated with a shorter RFS, whereas AR-V7 staining of cytoplasmic granules was associated with a longer RFS. In a multivariate Cox’s regression analysis, only negative (<5%) AR-V7 staining of cytoplasmic granules remained an independent prognostic factor for RFS (HR = 5.3; p = 0.006). In a further subgroup analysis by multivariate Cox’s regression analysis, AR-V7 was an independent prognostic factor in the following groups: age ≤ 65 (HR = 9.7; p = 0.029), negative CK20 staining (HR = 7.0; p = 0.008), and positive perineural invasion (HR = 3.7; p = 0.034). Altogether, AR-V7 protein in granular cytoplasmic structures is an independent prognostic factor for RFS in PCa patients.
  • Characterizing the complexity of weighted networks via graph embedding and point pattern analysis

    Chen, Shuo; Zhang, Zhen; Mo, Chen; Wu, Qiong; Kochunov, Peter; Hong, L. Elliot (MDPI AG, 2020-09-01)
    We propose a new metric to characterize the complexity of weighted complex networks. Weighted complex networks represent a highly organized interactive process, for example, co-varying returns between stocks (financial networks) and coordination between brain regions (brain connectivity networks). Although network entropy methods have been developed for binary networks, the measurement of non-randomness and complexity for large weighted networks remains challenging. We develop a new analytical framework to measure the complexity of a weighted network via graph embedding and point pattern analysis techniques in order to address this unmet need. We first perform graph embedding to project all nodes of the weighted adjacency matrix to a low dimensional vector space. Next, we analyze the point distribution pattern in the projected space, and measure its deviation from the complete spatial randomness. We evaluate our method via extensive simulation studies and find that our method can sensitively detect the difference of complexity and is robust to noise. Last, we apply the approach to a functional magnetic resonance imaging study and compare the complexity metrics of functional brain connectivity networks from 124 patients with schizophrenia and 103 healthy controls. The results show that the brain circuitry is more organized in healthy controls than schizophrenic patients for male subjects while the difference is minimal in female subjects. These findings are well aligned with the established sex difference in schizophrenia.
  • Gating and regulation of KCNH (ERG, EAG, and ELK) channels by intracellular domains

    Codding, Sara J; Johnson, Ashley A; Trudeau, Matthew C (MDPI AG, 2020-09-12)
    The KCNH family comprises the ERG, EAG, and ELK voltage-activated, potassium-selective channels. Distinct from other K channels, KCNH channels contain unique structural domains, including a PAS (Per-Arnt-Sim) domain in the N-terminal region and a CNBHD (cyclic nucleotide-binding homology domain) in the C-terminal region. The intracellular PAS domains and CNBHDs interact directly and regulate some of the characteristic gating properties of each type of KCNH channel. The PAS-CNBHD interaction regulates slow closing (deactivation) of hERG channels, the kinetics of activation and pre-pulse dependent population of closed states (the Cole-Moore shift) in EAG channels and voltage-dependent potentiation in ELK channels. KCNH channels are all regulated by an intrinsic ligand motif in the C-terminal region which binds to the CNBHD. Here, we focus on some recent advances regarding the PAS-CNBHD interaction and the intrinsic ligand.
  • Using Electronic Health Record Technology to Teach Inpatient Medication Order Verification to Pharmacy Students

    Ives, Amy L; Tucker, Shannon R; Trovato, James A (American Association of Colleges of Pharmacy, 2020-08)
    Objective. To measure Doctor of Pharmacy (PharmD) students' confidence and assess their performance when processing inpatient medication orders, and to determine students' opinions regarding electronic health record (EHR) technology. Methods. Using an EHR platform, students processed inpatient medication orders during two laboratory sessions and one assessment. Each student was assigned one unique patient per session and was given three inpatient orders to process. Medication errors were randomly imbedded in the medication orders. Students needed to determine if the order was acceptable or required flagging because of an identified error. Pre- and post-activity surveys were administered to assess students' level of confidence and perceptions regarding the simulated EHR activities. Aggregate performance scores were compared between a cohort of PharmD students that used an EHR for the activity versus those who completed the activity the previous year using a paper-based medication form. Results. One hundred eight of 158 students (68%) in the course had pre- and post-activity survey data that could be paired. Less than one quarter (24%) of students had prior work experience in a hospital setting. For the medication verification questions, the confidence levels of students who used the EHR doubled and in some cases tripled pre- and post-EHR implementation. In each of the areas surveyed, results for all medication order processing statements were significant. Student performance improved significantly compared with that of those who completed the activity the previous year using a paper-based medication form. Post-EHR implementation, a significantly lower number of students felt that learning to use EHR technology would prepare them for advanced pharmacy practice experiences. Conclusion. Exposure to EHR technology improved PharmD students' confidence and performance scores related to processing inpatient medication orders. These findings support the continued use of an EHR platform in skills-based activities.
  • Using Core Genome Alignments To Assign Bacterial Species

    Chung, Matthew; Munro, James B; Tettelin, Hervé; Dunning Hotopp, Julie C (American Society for Microbiology, 2018-12-04)
    With the exponential increase in the number of bacterial taxa with genome sequence data, a new standardized method to assign species designations is needed that is consistent with classically obtained taxonomic analyses. This is particularly acute for unculturable, obligate intracellular bacteria with which classically defined methods, like DNA-DNA hybridization, cannot be used, such as those in the Rickettsiales. In this study, we generated nucleotide-based core genome alignments for a wide range of genera with classically defined species, as well as those within the Rickettsiales. We created a workflow that uses the length, sequence identity, and phylogenetic relationships inferred from core genome alignments to assign genus and species designations that recapitulate classically obtained results. Using this method, most classically defined bacterial genera have a core genome alignment that is ≥10% of the average input genome length. Both Anaplasma and Neorickettsia fail to meet this criterion, indicating that the taxonomy of these genera should be reexamined. Consistently, genomes from organisms with the same species epithet have ≥96.8% identity of their core genome alignments. Additionally, these core genome alignments can be used to generate phylogenomic trees to identify monophyletic clades that define species and neighbor-network trees to assess recombination across different taxa. By these criteria, Wolbachia organisms are delineated into species different from the currently used supergroup designations, while Rickettsia organisms are delineated into 9 distinct species, compared to the current 27 species. By using core genome alignments to assign taxonomic designations, we aim to provide a high-resolution, robust method to guide bacterial nomenclature that is aligned with classically obtained results. IMPORTANCE With the increasing availability of genome sequences, we sought to develop and apply a robust, portable, and high-resolution method for the assignment of genera and species designations that can recapitulate classically defined taxonomic designations. Using cutoffs derived from the lengths and sequence identities of core genome alignments along with phylogenetic analyses, we sought to evaluate or reevaluate genus- and species-level designations for diverse taxa, with an emphasis on the order Rickettsiales, where species designations have been applied inconsistently. Our results indicate that the Rickettsia genus has an overabundance of species designations, that the current Anaplasma and Neorickettsia genus designations are both too broad and need to be divided, and that there are clear demarcations of Wolbachia species that do not align precisely with the existing supergroup designations.
  • Responding to preconditioned cues is devaluation sensitive and requires orbitofrontal cortex during cue-cue learning

    Hart, Evan E; Sharpe, Melissa J; Gardner, Matthew Ph; Schoenbaum, Geoffrey (eLife Sciences Publications, 2020-08-24)
    The orbitofrontal cortex (OFC) is necessary for inferring value in tests of model-based reasoning, including in sensory preconditioning. This involvement could be accounted for by representation of value or by representation of broader associative structure. We recently reported neural correlates of such broader associative structure in OFC during the initial phase of sensory preconditioning (Sadacca et al., 2018). Here, we used optogenetic inhibition of OFC to test whether these correlates might be necessary for value inference during later probe testing. We found that inhibition of OFC during cue-cue learning abolished value inference during the probe test, inference subsequently shown in control rats to be sensitive to devaluation of the expected reward. These results demonstrate that OFC must be online during cue-cue learning, consistent with the argument that the correlates previously observed are not simply downstream readouts of sensory processing and instead contribute to building the associative model supporting later behavior.
  • Cardioembolic stroke in a young male with cor triatriatum sinister: a case report

    Amara, Richard S; Lalla, Rakhee; Jeudy, Jean; Hong, Susie Nam (Oxford University Press (OUP), 2020-06)
    Background: Cor triatriatum sinister (CTS) is a rare congenital cardiac anomaly defined by a fibromuscular membrane which bisects the left atrium. Cor triatriatum sinister has been associated with cardioembolic stroke through mechanisms including stagnation of blood flow within the left atrium, an association with atrial fibrillation (AF), and/or an accompanying atrial septal defect (ASD) or patent foramen ovale. We describe a case highlighting the role that CTS may play in cardioembolic stroke, provide high-quality computed tomography angiography and two- and three-dimensional echocardiography of the CTS membrane, and outline management strategies for this uncommon clinical scenario. Case summary: A 35-year-old man with no prior medical history presented with acute onset weakness and aphasia. He was found to have an embolic stroke with left M1 and A1 occlusions and received tissue plasminogen activator followed by mechanical thrombectomy with successful recanalization. A thorough stroke workup revealed CTS with an associated ASD as well as potential protein C deficiency. He was managed with indefinite anticoagulation with apixaban. Discussion: This is the 13th reported case of CTS associated with stroke. In most previous cases evidence of blood stasis or frank thrombus was associated with the CTS membrane, and/or existing AF was noted. In this case, none of these were identified, particularly highlighting the surreptitious risk of CTS. In addition, the presence of potential protein C deficiency in this case compounded the risk for thromboembolism and factored into multidisciplinary management decisions.
  • Extensive coil embolization of a giant coronary artery aneurysm in an octogenarian: A case report

    Ahmed, Talha; Chahal, Diljon; Shkullaku, Melsjan; Gupta, Anuj (Oxford University Press, 2020-06-01)
    Background: Coronary artery aneurysms (CAA) are often diagnosed incidentally on coronary angiography or imaging modalities done for other reasons. 'Giant' CAA by definition exceeds 20 mm in diameter or four times the diameter of normal coronary artery. The management of patients with CAAs is challenging due to poorly understood mechanism, variable presentation, and lack of clear-cut societal recommendations. Though conservative management is preferred in asymptomatic patients, massive size or interval growth may make intervention necessary. Case summary: We describe a case of successful coil embolization of a giant coronary aneurysm in an elderly 84-year-old male. Patient, who presented for a follow-up computed tomography angiography to evaluate a previously repaired abdominal aortic aneurysm 2 years back, was found to have interval growth of right coronary artery aneurysm from 4 cm in diameter to 7 x 8 cm in its greatest dimensions. The rationale for treatment was to prevent sudden death from continued growth and eventual rupture of aneurysm in addition to potential risk of thromboembolism and compression of adjacent structures. Discussion: This case demonstrates the safe and successful use of extensive coil embolization technique to treat a 'giant' CAA in an elderly patient when surgical risks were prohibitive.
  • Brain-Selective Estrogen Therapy Prevents Androgen Deprivation-Associated Hot Flushes in a Rat Model

    Merchenthaler, Istvan; Lane, Malcolm; Stennett, Christina; Zhan, Min; Nguyen, Vien; Prokai-Tatrai, Katalin; Prokai, Laszlo (MDPI AG, 2020-06-10)
    Hot flushes are best-known for affecting menopausal women, but men who undergo life-saving castration due to androgen-sensitive prostate cancer also suffer from these vasomotor symptoms. Estrogen deficiency in these patients is a direct consequence of androgen deprivation, because estrogens (notably 17β-estradiol, E2) are produced from testosterone. Although estrogens alleviate hot flushes in these patients, they also cause adverse systemic side effects. Because only estrogens can provide mitigation of hot flushes on the basis of current clinical practices, there is an unmet need for an effective and safe pharmacotherapeutic intervention that would also greatly enhance patient adherence. To this end, we evaluated treatment of orchidectomized (ORDX) rats with 10β, 17β-dihydroxyestra-1,4-dien-3-one (DHED), a brain-selective bioprecursor prodrug of E2. A pilot pharmacokinetic study using oral administration of DHED to these animals revealed the formation of E2 in the brain without the appearance of the hormone in the circulation. Therefore, DHED treatment alleviated androgen deprivation-associated hot flushes without peripheral impact in the ORDX rat model. Concomitantly, we showed that DHED-derived E2 induced progesterone receptor gene expression in the hypothalamus without stimulating galanin expression in the anterior pituitary, further indicating the lack of systemic estrogen exposure upon oral treatment with DHED.
  • Revisiting the Protein C Pathway: An Opportunity for Adjunctive Intervention in COVID-19?

    Mazzeffi, Michael; Chow, Jonathan H; Amoroso, Anthony; Tanaka, Kenichi (Wolters Kluwer Health, 2020-09-01)
  • In Response

    Chow, Jonathan H; Mazzeffi, Michael A; Tanaka, Kenichi A (Wolters Kluwer Health, 2020-09-01)
  • Secreted Chaperones in Neurodegeneration

    Chaplot, Kriti; Jarvela, Timothy S.; Lindberg, Iris (Frontiers Media S.A., 2020-08-27)
    Protein homeostasis, or proteostasis, is a combination of cellular processes that govern protein quality control, namely, protein translation, folding, processing, and degradation. Disruptions in these processes can lead to protein misfolding and aggregation. Proteostatic disruption can lead to cellular changes such as endoplasmic reticulum or oxidative stress; organelle dysfunction; and, if continued, to cell death. A majority of neurodegenerative diseases involve the pathologic aggregation of proteins that subverts normal neuronal function. While prior reviews of neuronal proteostasis in neurodegenerative processes have focused on cytoplasmic chaperones, there is increasing evidence that chaperones secreted both by neurons and other brain cells in the extracellular – including transsynaptic – space play important roles in neuronal proteostasis. In this review, we will introduce various secreted chaperones involved in neurodegeneration. We begin with clusterin and discuss its identification in various protein aggregates, and the use of increased cerebrospinal fluid (CSF) clusterin as a potential biomarker and as a potential therapeutic. Our next secreted chaperone is progranulin; polymorphisms in this gene represent a known genetic risk factor for frontotemporal lobar degeneration, and progranulin overexpression has been found to be effective in reducing Alzheimer’s- and Parkinson’s-like neurodegenerative phenotypes in mouse models. We move on to BRICHOS domain-containing proteins, a family of proteins containing highly potent anti-amyloidogenic activity; we summarize studies describing the biochemical mechanisms by which recombinant BRICHOS protein might serve as a therapeutic agent. The next section of the review is devoted to the secreted chaperones 7B2 and proSAAS, small neuronal proteins which are packaged together with neuropeptides and released during synaptic activity. Since proteins can be secreted by both classical secretory and non-classical mechanisms, we also review the small heat shock proteins (sHsps) that can be secreted from the cytoplasm to the extracellular environment and provide evidence for their involvement in extracellular proteostasis and neuroprotection. Our goal in this review focusing on extracellular chaperones in neurodegenerative disease is to summarize the most recent literature relating to neurodegeneration for each secreted chaperone; to identify any common mechanisms; and to point out areas of similarity as well as differences between the secreted chaperones identified to date.
  • Covid-19: Do many people have pre-existing immunity?

    Doshi, Peter (BMJ Publishing Group, 2020-09-17)
  • Mass Drug Administration of Azithromycin to Reduce Child Mortality: Only for High-Mortality Settings?

    Tickell, Kirkby D; Deichsel, Emily L; Walson, Judd L (American Society of Tropical Medicine and Hygiene, 2020-09-01)
  • Minimizing pharmacotherapy-related healthcare worker exposure to SARS-CoV-2

    Barlow, Brooke; Barlow, Ashley; Thompson Bastin, Melissa L; Berger, Karen; Dixit, Deepali; Heavner, Mojdeh S (American Society of Health-System Pharmacists, 2020-09-04)
  • The Role of Eicosanoids in Gynecological Malignancies

    Smith, Paige G.; Roque, Dana; Ching, Mc Millan; Fulton, Amy; Rao, Gautam; Reader, Jocelyn C. (Frontiers Media S.A., 2020-08-26)
    Eicosanoids, bio-active lipid molecules, evoke a multitude of biological effects that directly affect cancer cells and indirectly affect tumor microenvironment. An emerging role has been shown for eicosanoids in the pathogenesis of gynecological malignancies which include cancers of the vulva, vagina, cervix, uterine, and ovary. Eicosanoid biosynthesis pathways start at the metabolism of phospholipids by phospholipase A2 then proceeding to one of three pathways: the cyclooxygenase (COX), lipoxygenase (LOX), or P450 epoxygenase pathways. The most studied eicosanoid pathways include COX and LOX; however, more evidence is appearing to support further study of the P450 epoxygenase pathway in gynecologic cancers. In this review, we present the current knowledge of the role of COX, LOX and P450 pathways in the pathogenesis of gynecologic malignancies. Vulvar and vaginal cancer, the rarest subtypes, there is association of COX-2 expression with poor disease specific survival in vulvar cancer and, in vaginal cancer, COX-2 expression has been found to play a role in mucosal inflammation leading to disease susceptibility and transmission. Cervical cancer is associated with COX-2 levels 7.4 times higher than in healthy tissues. Additionally, HPV elevates COX-2 levels through the EGFR pathway and HIV promotes elevated COX-2 levels in cervical tissue as well as increases PGE2 levels eliciting inflammation and progression of cancer. Evidence supports significant roles for both the LOX and COX pathways in uterine cancer. In endometrial cancer, there is increased expression of 5-LOX which is associated with adverse outcomes. Prostanoids in the COX pathway PGE2 and PGF2α have been shown to play a significant role in uterine cancer including alteration of proliferation, adhesion, migration, invasion, angiogenesis, and the inflammatory microenvironment. The most studied gynecological malignancy in regard to the potential role of eicosanoids in tumorigenesis is ovarian cancer in which all three pathways have shown to be associated or play a role in ovarian tumorigenesis directly on the tumor cell or through modulation of the tumor microenvironment. By identifying the gaps in knowledge, additional pathways and targets could be identified in order to obtain a better understanding of eicosanoid signaling in gynecological malignancies and identify potential new therapeutic approaches.
  • Intratumoral generation of photothermal gold nanoparticles through a vectorized biomineralization of ionic gold

    Schwartz-Duval, Aaron S; Konopka, Christian J; Moitra, Parikshit; Daza, Enrique A; Srivastava, Indrajit; Johnson, Elyse V; Kampert, Taylor L; Fayn, Stanley; Haran, Anand; Dobrucki, Lawrence W; et al. (Springer Nature, 2020-09-10)
    Various cancer cells have been demonstrated to have the capacity to form plasmonic gold nanoparticles when chloroauric acid is introduced to their cellular microenvironment. But their biomedical applications are limited, particularly considering the millimolar concentrations and longer incubation period of ionic gold. Here, we describe a simplistic method of intracellular biomineralization to produce plasmonic gold nanoparticles at micromolar concentrations within 30 min of application utilizing polyethylene glycol as delivery vector for ionic gold. We have characterized this process for intracellular gold nanoparticle formation, which progressively accumulates proteins as the ionic gold clusters migrate to the nucleus. This nano-vectorized application of ionic gold emphasizes its potential biomedical opportunities while reducing the quantity of ionic gold and required incubation time. To demonstrate its biomedical potential, we further induce in-situ biosynthesis of gold nanoparticles within MCF7 tumor mouse xenografts which is followed by its photothermal remediation. © 2020, The Author(s).
  • Computed Tomography-Based Radiomics Signature for the Preoperative Differentiation of Pancreatic Adenosquamous Carcinoma From Pancreatic Ductal Adenocarcinoma

    Ren, Shuai; Zhao, Rui; Cui, Wenjing; Qiu, Wenli; Guo, Kai; Cao, Yingying; Duan, Shaofeng; Wang, Zhongqiu; Chen, Rong (Frontiers Media S.A., 2020-08-25)
    Purpose: The purpose was to assess the predictive ability of computed tomography (CT)-based radiomics signature in differential diagnosis between pancreatic adenosquamous carcinoma (PASC) and pancreatic ductal adenocarcinoma (PDAC). Materials and Methods: Eighty-one patients (63.6 ± 8.8 years old) with PDAC and 31 patients (64.7 ± 11.1 years old) with PASC who underwent preoperative CE-CT were included. A total of 792 radiomics features were extracted from the late arterial phase (n = 396) and portal venous phase (n = 396) for each case. Significantly different features were selected using Mann–Whitney U test, univariate logistic regression analysis, and minimum redundancy and maximum relevance method. A radiomics signature was constructed using random forest method, the robustness and the reliability of which was validated using 10-times leave group out cross-validation (LGOCV) method. Results: Seven radiomics features from late arterial phase images and three from portal venous phase images were finally selected. The radiomics signature performed well in differential diagnosis between PASC and PDAC, with 94.5% accuracy, 98.3% sensitivity, 90.1% specificity, 91.9% positive predictive value (PPV), and 97.8% negative predictive value (NPV). Moreover, the radiomics signature was proved to be robust and reliable using the LGOCV method, with 76.4% accuracy, 91.1% sensitivity, 70.8% specificity, 56.7% PPV, and 96.2% NPV. Conclusion: CT-based radiomics signature may serve as a promising non-invasive method in differential diagnosis between PASC and PDAC.

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