Recent Submissions

  • Sensitivity to angiotensin II dose in patients with vasodilatory shock: a prespecified analysis of the ATHOS-3 trial

    Ham, K. (Springer Verlag, 2019-06-03)
    Background: Early clinical data showed that some patients with vasodilatory shock are responsive to low doses of angiotensin II. The objective of this analysis was to compare clinical outcomes in patients requiring ≤ 5 ng kg−1 min−1 angiotensin II at 30 min (≤ 5 ng kg−1 min−1 subgroup) to maintain mean arterial pressure (MAP) ≥ 75 mmHg versus patients receiving > 5 ng kg−1 min−1 angiotensin II at 30 min (> 5 ng kg−1 min−1 subgroup). Data from angiotensin II-treated patients enrolled in the ATHOS-3 trial were used. Results: The subgroup of patients whose angiotensin II dose was down-titrated from 20 ng kg−1 min−1 at treatment initiation to ≤ 5 ng kg−1 min−1 at 30 min (79/163) had significantly lower endogenous serum angiotensin II levels and norepinephrine-equivalent doses and significantly higher MAP versus the > 5 ng kg−1 min−1 subgroup (84/163). Patients in the ≤ 5 ng kg−1 min−1 subgroup were more likely to have a MAP response at 3 h versus those in the > 5 ng kg−1 min−1 subgroup (90% vs. 51%, respectively; odds ratio, 8.46 [95% CI 3.63–19.7], P < 0.001). Day 28 survival was also higher in the ≤ 5 ng kg−1 min−1 subgroup versus the > 5 ng kg−1 min−1 subgroup (59% vs. 33%, respectively; hazard ratio, 0.48 [95% CI 0.28–0.72], P = 0.0007); multivariate analyses supported the survival benefit in patients with lower angiotensin II levels. The ≤ 5 ng kg−1 min−1 subgroup had a more favorable safety profile and lower treatment discontinuation rate than the > 5 ng kg−1 min−1 subgroup. Conclusions: This prespecified analysis showed that down-titration to ≤ 5 ng kg−1 min−1 angiotensin II at 30 min is an early predictor of favorable clinical outcomes which may be related to relative angiotensin II insufficiency. © 2019, The Author(s).
  • The Integrative Human Microbiome Project

    Proctor, L. (Nature Publishing Group, 2019-05-30)
    The NIH Human Microbiome Project (HMP) has been carried out over ten years and two phases to provide resources, methods, and discoveries that link interactions between humans and their microbiomes to health-related outcomes. The recently completed second phase, the Integrative Human Microbiome Project, comprised studies of dynamic changes in the microbiome and host under three conditions: pregnancy and preterm birth; inflammatory bowel diseases; and stressors that affect individuals with prediabetes. The associated research begins to elucidate mechanisms of host–microbiome interactions under these conditions, provides unique data resources (at the HMP Data Coordination Center), and represents a paradigm for future multi-omic studies of the human microbiome. © 2019, The Author(s).
  • Variation in research designs used to test the effectiveness of dissemination and implementation strategies: A review

    Mazzucca, S.; Tabak, R.G.; Pilar, M. (Frontiers Media S. A, 2018)
    Background: The need for optimal study designs in dissemination and implementation (D & I) research is increasingly recognized. Despite the wide range of study designs available for D & I research, we lack understanding of the types of designs and methodologies that are routinely used in the field. This review assesses the designs and methodologies in recently proposed D & I studies and provides resources to guide design decisions. Methods: We reviewed 404 study protocols published in the journal Implementation Science from 2/2006 to 9/2017. Eligible studies tested the efficacy or effectiveness of D & I strategies (i.e., not effectiveness of the underlying clinical or public health intervention); had a comparison by group and/or time; and used ?1 quantitative measure. Several design elements were extracted: design category (e.g., randomized); design type [e.g., cluster randomized controlled trial (RCT)]; data type (e.g., quantitative); D & I theoretical framework; levels of treatment assignment, intervention, and measurement; and country in which the research was conducted. Each protocol was double-coded, and discrepancies were resolved through discussion. Results: Of the 404 protocols reviewed, 212 (52%) studies tested one or more implementation strategy across 208 manuscripts, therefore meeting inclusion criteria. Of the included studies, 77% utilized randomized designs, primarily cluster RCTs. The use of alternative designs (e.g., stepped wedge) increased over time. Fewer studies were quasi-experimental (17%) or observational (6%). Many study design categories (e.g., controlled pre-post, matched pair cluster design) were represented by only one or two studies. Most articles proposed quantitative and qualitative methods (61%), with the remaining 39% proposing only quantitative. Half of protocols (52%) reported using a theoretical framework to guide the study. The four most frequently reported frameworks were Consolidated Framework for Implementing Research and RE-AIM (n = 16 each), followed by Promoting Action on Research Implementation in Health Services and Theoretical Domains Framework (n = 12 each). Conclusion: While several novel designs for D & I research have been proposed (e.g., stepped wedge, adaptive designs), the majority of the studies in our sample employed RCT designs. Alternative study designs are increasing in use but may be underutilized for a variety of reasons, including preference of funders or lack of awareness of these designs. Promisingly, the prevalent use of quantitative and qualitative methods together reflects methodological innovation in newer D & I research. Copyright 2018 Mazzucca, Tabak, Pilar, Ramsey, Baumann, Kryzer, Lewis, Padek, Powell and Brownson.
  • Simulation models predict that school-age children are responsible for most human-to-mosquito Plasmodium falciparum transmission in southern Malawi

    Coalson, J.E.; Cohee, L.M.; Buchwald, A.G. (BioMed Central Ltd., 2018)
    Background: Malaria persists in some high-transmission areas despite extensive control efforts. Progress toward elimination may require effective targeting of specific human populations that act as key transmission reservoirs. Methods: Parameterized using molecular-based Plasmodium falciparum infection data from cross-sectional community studies in southern Malawi, a simulation model was developed to predict the proportions of human-to-mosquito transmission arising from (a) children under 5 years old (U5s), (b) school-age children (SAC, 5-15 years), (c) young adults (16-30 years), and (d) adults > 30 years. The model incorporates mosquito biting heterogeneity and differential infectivity (i.e. probability that a blood-fed mosquito develops oocysts) by age and gametocyte density. Results: The model predicted that SAC were responsible for more than 60% of new mosquito infections in both dry and rainy seasons, even though they comprise only 30% of this southern Malawi population. Young adults were the second largest contributors, while U5s and adults over 30 were each responsible for < 10% of transmission. While the specific predicted values are sensitive to the relative infectiousness of SAC, this group remained the most important contributor to mosquito infections under all realistic estimates. Conclusions: These results suggest that U5 children play a small role compared to SAC in maintaining P. falciparum transmission in southern Malawi. Models that assume biting homogeneity overestimate the importance of U5s. To reduce transmission, interventions will need to reach more SAC and young adults. This publicly available model can be used by others to estimate age-specific transmission contributions in epidemiologically similar sites with local parameter estimates of P. falciparum prevalence and bed net use. Copyright 2018 The Author(s).
  • Haemophilus influenzae genome evolution during persistence in the human airways in chronic obstructive pulmonary disease

    Pettigrew, M.M.; Ahearn, C.P.; Gent, J.F. (National Academy of Sciences, 2018)
    Nontypeable Haemophilus influenzae (NTHi) exclusively colonize and infect humans and are critical to the pathogenesis of chronic obstructive pulmonary disease (COPD). In vitro and animal models do not accurately capture the complex environments encountered by NTHi during human infection. We conducted whole-genome sequencing of 269 longitudinally collected cleared and persistent NTHi from a 15-y prospective study of adults with COPD. Genome sequences were used to elucidate the phylogeny of NTHi isolates, identify genomic changes that occur with persistence in the human airways, and evaluate the effect of selective pressure on 12 candidate vaccine antigens. Strains persisted in individuals with COPD for as long as 1,422 d. Slipped-strand mispairing, mediated by changes in simple sequence repeats in multiple genes during persistence, regulates expression of critical virulence functions, including adherence, nutrient uptake, and modification of surface molecules, and is a major mechanism for survival in the hostile environment of the human airways. A subset of strains underwent a large 400-kb inversion during persistence. NTHi does not undergo significant gene gain or loss during persistence, in contrast to other persistent respiratory tract pathogens. Amino acid sequence changes occurred in 8 of 12 candidate vaccine antigens during persistence, an observation with important implications for vaccine development. These results indicate that NTHi alters its genome during persistence by regulation of critical virulence functions primarily by slipped-strand mispairing, advancing our understanding of how a bacterial pathogen that plays a critical role in COPD adapts to survival in the human respiratory tract. Copyright 2018 National Academy of Sciences. All Rights Reserved.
  • L61H46 shows potent efficacy against human pancreatic cancer through inhibiting STAT3 pathway

    Bai, E.; Yang, L.; Xiang, Y. (Dove Medical Press Ltd, 2018)
    Background: Pancreatic cancer is the fourth leading cause of cancer-related death worldwide. The poor prognosis of this disease highlights the urgent need to develop more effective therapies. Activation of the STAT3 represents a potential drug target for pancreatic cancer therapy. Currently, clinically available small-molecule inhibitors targeting STAT3 are lacking. Methods: Through bioassay screening and molecular docking, we identified a small molecule L61H46 that can potently target constitutive STAT3 signaling and kill human pancreatic cancer cells in vitro and in vivo. Results: L61H46 effectively reduced colony formation and the viability of pancreatic cancer cells in a dose-dependent manner with half-maximal inhibitory concentration (IC 50 ) values in the range between 0.86 and 2.83 ?M. L61H46 significantly inhibited STAT3 phosphorylation (Tyr705) and the subsequent nucleus translocation but did not downregulate STAT1 phosphorylation. Moreover, L61H46 demonstrated a potent activity in suppressing pancreatic tumor growth in BXPC-3 xenograft model in vivo. Furthermore, L61H46 showed no signs of adverse effects on liver, heart, and kidney cells in vivo. Conclusion: Collectively, our results suggest that L61H46 could be further optimized into a highly potent STAT3 inhibitor for the treatment of pancreatic cancer. Copyright 2018 Bai et al.
  • Novel calcium phosphate cement with metformin-loaded chitosan for odontogenic differentiation of human dental pulp cells

    Qin, W.; Chen, J.-Y.; Guo, J. (Hindawi Limited, 2018)
    Metformin is an old and widely accepted first-line drug for treating type 2 diabetes. Our previous studies demonstrate that metformin can stimulate the osteo/odontogenic differentiation of human-induced pluripotent stem cell-derived mesenchymal stem cells and human dental pulp cells (DPCs). Due to the rapid dilution of metformin from the defect area, the aim of this study was to develop a drug delivery system with controlled release of metformin to promote cell viability and odontogenic differentiation of DPCs favoring dentin regeneration. Calcium phosphate cement (CPC) containing chitosan and metformin as a scaffold was synthesized. DPCs were seeded onto the scaffold, and the viability and proliferation were evaluated at several time points. For osteogenic differentiation analysis, alkaline phosphatase (ALP) activity was tested, cells were stained with Alizarin Red, and the expression of odontogenic markers was evaluated by real-time polymerase chain reaction. DPCs remained viable and attached well to the CPC-chitosan composite scaffold. Moreover, the addition of metformin to the CPC-chitosan composite did not adversely affect cell proliferation, compared to that of CPC control. Our data further revealed that the novel CPC-chitosan-metformin composite enhanced the odontogenic differentiation of DPCs, as evidenced by higher ALP activity, elevated expression of odontoblastic markers, and strong mineral deposition. These results suggest that the new CPC-chitosan-metformin composite is a highly promising scaffold with the potential for tissue engineering applications including dentin regeneration. Copyright Copyright 2018 Wei Qin et al. This is an open access article distributed under the Creative Commons Attribution.
  • Recommendations for toxicological investigation of drug-impaired driving and motor vehicle fatalities-2017 update

    Logan, B.K.; D'Orazio, A.L.; Mohr, A.L.A. (Society of Forensic Toxicologists, 2018)
    This report describes the outcomes of a process undertaken to review and update the National Safety Council's Alcohol, Drugs and Impairment Division's recommendations for the toxicological investigation of suspected alcohol and drug-impaired driving cases and motor vehicle fatalities. The updates to the recommendations are made based on a survey of practices in laboratories in the USA and Canada performing testing in these cases, consideration of existing epidemiological crash and arrest data, current drug use patterns, and practical considerations of widely available technology platforms in laboratories performing this work. The final recommendations updates are derived from a consensus meeting of experts recruited from survey respondents and the membership of the National Safety Council's Alcohol, Drug and Impairment Division. The principal changes in this round of recommendations include removal of butalbital, phenobarbital, and phencyclidine from Tier I (mandatory) to Tier II (optional) due to changes in prevalence. In addition, buprenorphine, fentanyl, tramadol, and their metabolites were moved from Tier II to Tier I due to increased prevalence and concerns about their potential for causing impairment. In addition, screening and confirmatory cutoffs for the oral fluid scope were further refined. Other additions were made to the list of Tier II compounds including fentanyl analogs (e.g., acetylfentanyl, butyrylfentanyl, furanylfentanyl, etc), mitragynine, novel opioids (e.g., MT-45, U- 47700), atypical antipsychotics, and novel benzodiazepines (e.g., clonazolam, flubromazolam, etc). Copyright The Author 2017. Published by Oxford University Press. All rights reserved.
  • Modifier variant of METTL13 suppresses human GAB1-associated profound deafness

    Yousaf, R.; Ahmed, Z.M.; Giese, A.P.J. (American Society for Clinical Investigation, 2018)
    A modifier variant can abrogate the risk of a monogenic disorder. DFNM1 is a locus on chromosome 1 encoding a dominant suppressor of human DFNB26 recessive, profound deafness. Here, we report that DFNB26 is associated with a substitution (p.Gly116Glu) in the pleckstrin homology domain of GRB2-associated binding protein 1 (GAB1), an essential scaffold in the MET proto-oncogene, receptor tyrosine kinase/HGF (MET/HGF) pathway. A dominant substitution (p.Arg544Gln) of METTL13, encoding a predicted methyltransferase, is the DFNM1 suppressor of GAB1-associated deafness. In zebrafish, human METTL13 mRNA harboring the modifier allele rescued the GAB1-associated morphant phenotype. In mice, GAB1 and METTL13 colocalized in auditory sensory neurons, and METTL13 coimmunoprecipitated with GAB1 and SPRY2, indicating at least a tripartite complex. Expression of MET-signaling genes in human lymphoblastoid cells of individuals homozygous for p.Gly116Glu GAB1 revealed dysregulation of HGF, MET, SHP2, and SPRY2, all of which have reported variants associated with deafness. However, SPRY2 was not dysregulated in normal-hearing humans homozygous for both the GAB1 DFNB26 deafness variant and the dominant METTL13 deafness suppressor, indicating a plausible mechanism of suppression. Identification of METTL13-based modification of MET signaling offers a potential therapeutic strategy for a wide range of associated hearing disorders. Furthermore, MET signaling is essential for diverse functions in many tissues including the inner ear. Therefore, identification of the modifier of MET signaling is likely to have broad clinical implications. Copyright 2018 American Society for Clinical Investigation. All rights reserved.
  • Insights into the evolutionary conserved regulation of Rio ATPase activity

    Kn�ppel, R.; Christensen, R.H.; Gray, F.C. (Oxford University Press, 2018)
    Eukaryotic ribosome biogenesis is a complex dynamic process which requires the action of numerous ribosome assembly factors. Among them, the eukaryotic Rio protein family members (Rio1, Rio2 and Rio3) belong to an ancient conserved atypical protein kinase/ATPase family required for the maturation of the small ribosomal subunit (SSU). Recent structure-function analyses suggested an ATPasedependent role of the Rio proteins to regulate their dynamic association with the nascent pre-SSU. However, the evolutionary origin of this feature and the detailed molecular mechanism that allows controlled activation of the catalytic activity remained to be determined. In this work we provide functional evidence showing a conserved role of the archaeal Rio proteins for the synthesis of the SSU in archaea. Moreover, we unravel a conserved RNA-dependent regulation of the Rio ATPases, which in the case of Rio2 involves, at least, helix 30 of the SSU rRNA and the Ploop lysine within the shared RIO domain. Together, our study suggests a ribosomal RNA-mediated regulatory mechanism enabling the appropriate stimulation of Rio2 catalytic activity and subsequent release of Rio2 from the nascent pre-40S particle. Based on our findings we propose a unified release mechanism for the Rio proteins. Copyright The Author(s) 2017.
  • Long-term effects of patiromer for hyperkalaemia treatment in patients with mild heart failure and diabetic nephropathy on angiotensin-converting enzymes/angiotensin receptor blockers: Results from AMETHYST-DN

    Pitt, B.; Bakris, G.L.; Weir, M.R. (Wiley-Blackwell, 2018)
    Aims: Chronic kidney disease (CKD) in heart failure (HF) increases the risk of hyperkalaemia (HK), limiting angiotensin‐converting enzyme inhibitor (ACE‐I) or angiotensin receptor blocker (ARB) use. Patiromer is a sodium‐free, non‐absorbed potassium binder approved for HK treatment. We retrospectively evaluated patiromer's long‐term safety and efficacy in HF patients from AMETHYST‐DN. Methods and results: Patients with Type 2 diabetes, CKD, and HK [baseline serum potassium >5.0–5.5 mmol/L (mild) or >5.5–<6.0 mmol/L (moderate)], with or without HF (New York Heart Association Class I and II, by investigator judgement), on ACE‐I/ARB, were randomized to patiromer 8.4–33.6 g to start, divided twice daily. Overall, 105/304 (35%) patients had HF (75%, Class II). Mean (standard deviation) ejection fraction (EF) was 44.9% (8.2) (n = 81) in patients with HF; 26 had EF ≤40%. In HF patients, mean serum potassium decreased by Day 3 through Week 52. At Week 4, estimated mean (95% confidence interval) change in serum potassium was −0.64 mmol/L (−0.72, −0.55) in mild and −0.97 mmol/L (−1.14, −0.80) in moderate HK (both P < 0.0001). Most HF patients with mild (>88%) and moderate (≥73%) HK had normokalaemia at each visit from Weeks 12 to 52. Three HF patients were withdrawn because of high (n = 1) or low (n = 2) serum potassium. The most common patiromer‐related adverse event was hypomagnesaemia (8.6%). Conclusions: In patients with a clinical diagnosis of HF, diabetes, CKD, and HK on ACE‐I/ARB, patiromer was well tolerated and effective for HK treatment over 52 weeks. Copyright 2018 The Authors.
  • Acute lung injury: How to stabilize a broken lung

    Nieman, G.F.; Andrews, P.; Satalin, J. (BioMed Central Ltd., 2018)
    The pathophysiology of acute respiratory distress syndrome (ARDS) results in heterogeneous lung collapse, edema-flooded airways and unstable alveoli. These pathologic alterations in alveolar mechanics (i.e. dynamic change in alveolar size and shape with each breath) predispose the lung to secondary ventilator-induced lung injury (VILI). It is our viewpoint that the acutely injured lung can be recruited and stabilized with a mechanical breath until it heals, much like casting a broken bone until it mends. If the lung can be "casted" with a mechanical breath, VILI could be prevented and ARDS incidence significantly reduced. Copyright 2018 The Author(s).
  • The Efficacy of liposomal bupivacaine in lumbar spine surgery

    Brown, L.; Weir, T.; Shasti, M. (ISASS, 2018)
    Background: Postoperative pain management in spine surgery holds unique challenges. The purpose of this study is to determine if the local anesthetic liposomal bupivacaine (LB) reduces the total opioid requirement in the first 3 days following posterior lumbar decompression and fusion (PLDF) surgery for degenerative spondylosis. Methods: Fifty patients underwent PLDF surgery in a prospective randomized control pilot trial between August 2015 and October 2016 and were equally allocated to either a treatment (LB) or a control (saline) group. Assessments included the 72-hour postoperative opioid requirement normalized to 1 morphine milligram equivalent (MME), visual analog scale (VAS), and hospital length of stay. Results: LB did not significantly alter the 72-hour postoperative opioid requirement compared to saline (11.6 vs. 13.4 MME, P = .40). In a subgroup analysis, there was also no significant difference in opioid consumption among narcotic-naive patients with either LB or saline. Among narcotic tolerant patients, however, opioid consumption was higher with saline than LB (20.6 MME vs. 13.3 MME, P=.048). Additionally, pre- and postoperative VAS scores and hospital length of stay were not significantly different with either LB or saline. Conclusions: In the setting of PLDF surgery, LB injections did not significantly reduce the consumption of opioids in the first 3 postoperative days, nor did the hospital length of stay or VAS pain scores, compared to saline. However, LB could be beneficial in reducing the consumption of opioids in narcotic-tolerant populations. Level of Evidence: 2. Copyright International Society for the Advancement of Spine Surgery.
  • Molecular characterization of Vibrio cholerae responsible for cholera epidemics in Uganda by PCR, MLVA and WGS

    Bwire, G.; Sack, D.A.; Almeida, M. (Public Library of Science, 2018)
    Background: For almost 50 years sub-Saharan Africa, including Uganda, has experienced several outbreaks due to Vibrio cholerae. Our aim was to determine the genetic relatedness and spread of strains responsible for cholera outbreaks in Uganda. Methodology/Principal findings: Sixty-three V. cholerae isolates collected from outbreaks in Uganda between 2014 and 2016 were tested using multiplex polymerase chain reaction (PCR), multi-locus variable number of tandem repeat analysis (MLVA) and whole genome sequencing (WGS). Three closely related MLVA clonal complexes (CC) were identified: CC1, 32% (20/63); CC2, 40% (25/63) and CC3, 28% (18/63). Each CC contained isolates from a different WGS clade. These clades were contained in the third wave of the 7thcholera pandemic strain, two clades were contained in the transmission event (T)10 lineage and other in T13. Analysing the dates and genetic relatedness revealed that V. cholerae genetic lineages spread between districts within Uganda and across national borders. Conclusion: The V. cholerae strains showed local and regional transmission within Uganda and the East African region. To prevent, control and eliminate cholera, these countries should implement strong cross-border collaboration and regional coordination of preventive activities. Copyright 2018 Bwire et al. http://creativecommons.org/licenses/by/4.0/
  • Exposure to concentrated ambient PM2.5 alters the composition of gut microbiota in a murine model

    Wang, W.; Zhou, J.; Chen, M. (BioMed Central Ltd., 2018)
    Background: Exposure to ambient fine particulate matter (PM2.5) correlates with abnormal glucose homeostasis, but the underlying biological mechanism has not been fully understood. The gut microbiota is an emerging crucial player in the homeostatic regulation of glucose metabolism. Few studies have investigated its role in the PM2.5 exposure-induced abnormalities in glucose homeostasis. Methods: C57Bl/6J mice were exposed to filtered air (FA) or concentrated ambient PM2.5 (CAP) for 12 months using a versatile aerosol concentration enrichment system (VACES) that was modified for long-term whole-body exposures. Their glucose homeostasis and gut microbiota were examined and analysed by correlation and mediation analysis. Results: Intraperitoneal glucose tolerance test (IPGTT) and insulin tolerance test (ITT) showed that CAP exposure markedly impaired their glucose and insulin tolerance. Faecal microbiota analysis demonstrated that the impairment in glucose homeostasis was coincided with decreased faecal bacterial ACE and Chao-1 estimators (the indexes of community richness), while there was no significant change in all faecal fungal alpha diversity estimators. The Pearson's correlation analyses showed that the bacterial richness estimators were correlated with glucose and insulin tolerance, and the mediation analyses displayed a significant mediation of CAP exposure-induced glucose intolerance by the alteration in the bacterial Chao-1 estimator. LEfSe analyses revealed 24 bacterial and 21 fungal taxa differential between CAP- and FA-exposed animals. Of these, 14 and 20 bacterial taxa were correlated with IPGTT AUC and ITT AUC, respectively, and 5 fungal taxa were correlated with abnormalities in glucose metabolism. Conclusions: Chronic exposure to PM2.5 causes gut dysbiosis and may subsequently contribute to the development of abnormalities in glucose metabolism. Copyright 2018 The Author(s).
  • Anti- HIV-1 activity of lactic acid in human cervicovaginal fluid

    Tyssen, D.; Wang, Y.-Y.; Hayward, J.A. (American Society for Microbiology, 2018)
    Women of reproductive age with a Lactobacillus-dominated vaginal microbiota have a reduced risk of acquiring and transmitting HIV and a vaginal pH of ~4 due to the presence of ~1% (wt/vol) lactic acid. While lactic acid has potent HIV virucidal activity in vitro, whether lactic acid present in the vaginal lumen inactivates HIV has not been investigated. Here we evaluated the anti-HIV-1 activity of native, minimally diluted cervicovaginal fluid obtained from women of reproductive age (n = 20) with vaginal microbiota dominated by Lactobacillus spp. Inhibition of HIVBa-L was significantly associated with the protonated form of lactic acid in cervicovaginal fluid. The HIVBa-L inhibitory activity observed in the &lt; 3-kDa acidic filtrate was similar to that of the corresponding untreated native cervicovaginal fluid as well as that of clarified neat cervicovaginal fluid subjected to protease digestion. These ex vivo studies indicate that protonated lactic acid is a major anti-HIV-1 metabolite present in acidic cervicovaginal fluid, suggesting a potential role in reducing HIV transmission by inactivating virus introduced or shed into the cervicovaginal lumen. Copyright 2018 Tyssen et al.
  • Chaperonology: The third eye on brain gliomas

    Graziano, F.; Bavisotto, C.C.; Gammazza, A.M. (MDPI AG, 2018)
    The European Organization for Research and Treatment of Cancer/National Cancer Institute of Canada Phase III trial has validated as a current regimen for high-grade gliomas (HGG) a maximal safe surgical resection followed by radiotherapy with concurrent temozolamide. However, it is essential to balance maximal tumor resection with preservation of the patient�s neurological functions. Important developments in the fields of pre-operative and intra-operative neuro-imaging and neuro-monitoring have ameliorated the survival rate and the quality of life for patients affected by HGG. Moreover, even though the natural history remains extremely poor, advancement in the molecular and genetic fields have opened up new potential frontiers in the management of this devastating brain disease. In this review, we aim to present a comprehensive account of the main current pre-operative, intra-operative and molecular approaches to HGG with particular attention to specific chaperones, also called heat shock proteins (Hsps), which represent potential novel biomarkers to detect and follow up HGG, and could also be therapeutic agents. Copyright 2018 by the authors. Licensee MDPI, Basel, Switzerland.
  • Sorafenib Dose Recommendation in Acute Myeloid Leukemia Based on Exposure-FLT3 Relationship

    Liu, T.; Ivaturi, V.; Sabato, P. (Blackwell Publishing Ltd, 2018)
    Sorafenib administered at the approved dose continuously is not tolerated long‐term in patients with acute myeloid leukemia (AML). The purpose of this study was to optimize the dosing regimen by characterizing the sorafenib exposure‐response relationship in patients with AML. A one‐compartment model with a transit absorption compartment and enterohepatic recirculation described the exposure. The relationship between sorafenib exposure and target modulation of kinase targets (FMS‐like tyrosine kinase 3 (FLT3)‐ITD and extracellular signal‐regulated kinase (ERK)) were described by an inhibitory maximum effect (Emax) model. Sorafenib could inhibit FLT3‐ITD activity by 100% with an IC50 of 69.3 ng/mL and ERK activity by 84% with an IC50 of 85.7 ng/mL (both adjusted for metabolite potency). Different dosing regimens utilizing 200 or 400 mg at varying frequencies were simulated based on the exposure‐response relationship. Simulations demonstrate that a 200 mg twice daily (b.i.d.) dosing regimen showed similar FLT3‐ITD and ERK inhibitory activity compared with 400 mg b.i.d. and is recommended in further clinical trials in patients with AML. Copyright 2018 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics
  • Feasibility of basic transesophageal echocardiography in hemorrhagic shock: Potential applications during resuscitative endovascular balloon occlusion of the aorta (REBOA)

    Teeter, W.A.; Conti, B.M.; Wasicek, P.J. (BioMed Central Ltd., 2018)
    Background: There are numerous studies in the cardiovascular literature that have employed transesophageal echocardiography (TEE) in swine models, but data regarding the use of basic TEE in swine models is limited. The primary aim of this study is to describe an echocardiographic method that can be used with relative ease to qualitatively assess cardiovascular function in a porcine hemorrhagic shock model using resuscitative endovascular balloon occlusion of the aorta (REBOA). Methods: Multiplane basic TEE exams were performed in 15 during an experimental hemorrhage model using REBOA. Cardiac anatomical structure and functional measurements were obtained. In a convenience sample (two animals from each group), advanced functional cardiovascular measurements were obtained before and after REBOA inflation for comparison with qualitative assessments. Results: Basic TEE exams were performed in 15 swine. Appropriate REBOA placement was confirmed using TEE in all animals and verified with fluoroscopy. Left ventricular volume was decreased in all animals, and left ventricular systolic function increased following REBOA inflation. Right ventricular systolic function and volume remained normal prior to and after hemorrhage and REBOA use. Mean ejection fraction (EF) decreased from 64% (S.D. 9.6) to 62.1 (S.D. 16.8) after hemorrhage and REBOA inflation (p = 0.76); fractional area of change (FAC) decreased from 49.8 (S.D. 9.0) to 48.5 (S.D. 13.6) after hemorrhage and REBOA inflation (p = 0.82). Conclusion: Basic TEE, which requires less training than advanced TEE, may be employed by laboratory investigators and practitioners across a wide spectrum of experimental and clinical settings. Copyright 2018 The Author(s).
  • A Supervised Learning Tool for Prostate Cancer Foci Detection and Aggressiveness Identification using Multiparametric magnetic resonance imaging/magnetic resonance spectroscopy imaging

    Kirlik, G.; Gullapalli, R.; D�Souza, W. (SAGE Publications Ltd, 2018)
    Prostate cancer is the most frequently diagnosed cancer in men in the United States. The current main methods for diagnosing prostate cancer include prostate-specific antigen test and transrectal biopsy. Prostate-specific antigen screening has been criticized for overdiagnosis and unnecessary treatment, and transrectal biopsy is an invasive procedure with low sensitivity for diagnosis. We provided a quantitative tool using supervised learning with multiparametric imaging to be able to accurately detect cancer foci and its aggressiveness. A total of 223 specimens from patients who received magnetic resonance imaging (MRI) and magnetic resonance spectroscopy imaging prior to the surgery were studied. Multiparametric imaging included extracting T2-map, apparent diffusion coefficient (ADC) using diffusion-weighted MRI, K trans using dynamic contrast-enhanced MRI, and 3-dimensional-MR spectroscopy. A pathologist reviewed all 223 specimens and marked cancerous regions on each and graded them with Gleason scores, which served as the ground truth to validate our prediction model. In cancer aggressiveness prediction, the average area under the receiver operating characteristic curve (AUC) value was 0.73 with 95% confidence interval (0.72-0.74) and the average sensitivity and specificity were 0.72 (0.71-0.73) and 0.73 (0.71-0.75), respectively. For the cancer detection model, the average AUC value was 0.68 (0.66-0.70) and the average sensitivity and specificity were 0.73 (0.70-0.77) and 0.62 (0.60-0.68), respectively. Our method included capability to handle class imbalance using adaptive boosting with random undersampling. In addition, our method was noninvasive and allowed for nonsubjective disease characterization, which provided physician information to make personalized treatment decision. Copyright The Author(s) 2018.

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