Recent Submissions

  • Phosphorylation of TRPV1 S801 Contributes to Modality-Specific Hyperalgesia in Mice

    Joseph, J.; Wang, S.; Kim, M.; Ro, J.; Chung, M.-K. (Society for Neuroscience, 2019)
    Transient receptor potential vanilloid subtype 1 (TRPV1) is a nonselective cationic channel activated by painful stimuli such as capsaicin and noxious heat, and enriched in sensory neurons of the pain pathway. During inflammation, chemical mediators activate protein kinases (such as PKC) that phosphorylate TRPV1 and thereby enhance its function, with consequent increases in nociceptor sensitization. However, the causal relationships between TRPV1 phosphorylation and pathological pain remain unexplored. To directly investigate the roles of one specific TRPV1 phosphorylation event in vivo, we genetically altered a major PKC phosphorylation site, mouse TRPV1 S801, to alanine. The TRPV1 expression pattern in sensory neurons of S801A knock-in (KI) mice was comparable to that in WT controls. However, sensitization of capsaicin-mediated currents after the activation of PKC was substantially impaired in sensory neurons from KI mice. Thermal hyperalgesia induced by PMA or burn injury in KI was identical to WT. Inflammatory thermal hyperalgesia was only marginally attenuated in KI mice. In contrast, PMA-evoked nocifensive responses and sensitization of capsaicin responses were significantly attenuated in the hindpaws of KI mice. Ongoing pain from inflamed masseter muscle was also reduced in KI mice, and was further inhibited by the TRPV1 antagonist AMG9810. These results suggest that PKC-mediated phosphorylation of TRPV1 S801 contributes to inflammation-mediated sensitization of TRPV1 to ligand, but not heat, in vivo Further, this suggests that interference with TRPV1 S801 phosphorylation might represent one potential way to attenuate inflammatory pain, yet spare basal sensitivity and produce fewer side effects than more general TRPV1 inhibition.SIGNIFICANCE STATEMENT Transient receptor potential vanilloid subtype 1 (TRPV1) has been considered a potential target for pain intervention. Global inhibitors of TRPV1 function, however, produce side effects which could compromise their clinical utility. By precisely removing a unique PKC phosphorylation site (TRPV1 S801) in mice through CRISPR/Cas9 editing, we provide in vivo evidence for a highly specific inhibition that leaves basal TRPV1 function intact, yet alleviates some forms of hyperalgesia. These findings support inhibition of TRPV1 S801 phosphorylation as a potential intervention for pain management. Copyright 2019 the authors.
  • Ventilator-Associated Pneumonia: Diagnostic Test Stewardship and Relevance of Culturing Practices

    O'Hara, L.M.; Kenaa, B.; Richert, M.E.; Claeys, K.C.; Shipper, A.; Sullivan, K.V.; Schrank, G.M.; Morgan, D.J.; Shanholtz, C.; Leekha, S. (Springer, 2019)
    Purpose of Review: Ventilator-associated pneumonia (VAP) is one of the most common infections in the ICU. Prompt diagnosis is vital as mortality increases with delayed antibiotic therapy. However, accurate diagnosis is challenging due to non-specific clinical features in a complicated patient cohort. Microbiological culture data remains a crucial aspect in confirming diagnosis. Recent Findings: Literature data comparing the benefit of invasive respiratory sampling to non-invasive is inconclusive. Differences in culturing practices translate in overidentification of organisms of unclear significance. Positive culture data in a low pre-test probability does not differentiate between true infection and colonization resulting in overtreatment. Furthermore, there are also opportunities for modifying the reporting of respiratory tract cultures that can better guide antimicrobial therapy. Summary: Under the umbrella of antimicrobial stewardship, diagnostic stewardship can be incorporated to create a systematic approach that would target culturing practices to match the right pre-test probability. Ideal outcome will be targeting cultures to the right patient population and minimizing unnecessary treatment.
  • Chronic oxidative stress and comorbidities in the HIV-1 transgenic rat

    Benedetti, F.; Curreli, S.; Zella, D.; Bryant, J. (Cambridge University Press, 2019)
  • Influence of the Maryland All-Payer Model on Primary Total Knee Arthroplasties

    Delanois, R.E.; Pollak, A.N.; Davila Castrodad, I.M.; Mohamed, M.S. (Lippincott Williams and Wilkins, 2019)
    Background: In 2014, Maryland received a waiver for the Global Budget Revenue (GBR) program. We evaluated GBR’s impact on patient and hospital trends for total knee arthroplasty (TKA) in Maryland compared with the U.S. Specifically, we examined (1) patient characteristics, (2) inpatient course, and (3) costs and charges associated with TKAs from 2014 through 2016. Methods: A comparative analysis of TKA-treated patients in the Maryland State Inpatient Database (n = 36,985) versus those in the National Inpatient Sample (n = 2,117,191) was performed. Patient characteristics included race, Charlson Comorbidity Index (CCI), morbid obesity, patient income status, and primary payer. Inpatient course included length of hospital stay (LOS), discharge disposition, and complications. Results: In the Maryland TKA cohort, the proportion of minorities increased from 2014 to 2016 while the proportion of whites decreased (p = 0.001). The proportion of patients with a CCI of ≥3 decreased (p = 0.014), that of low-income patients increased (p < 0.001), and that of patients covered by Medicare or Medicaid increased (p < 0.001). In the U.S. TKA cohort, the proportion of blacks increased (p < 0.001), that of patients with a CCI score of ≥3 decreased (p < 0.001), and the proportions of low-income patients (p < 0.001) and those covered by Medicare or Medicaid increased (p < 0.001). In both Maryland and the U.S., the LOS (p < 0.001) and complication rate (p < 0.001) decreased while home-routine discharges increased (p < 0.001). Costs and charges decreased in Maryland (p < 0.001 for both) whereas charges in the U.S. increased (p < 0.001) and costs decreased (p < 0.001). Conclusions: While the U.S. health reform and GBR achieved similar patient and hospital-specific outcomes and broader inclusion of minority patients, Maryland experienced decreased hospital charges while hospital charges increased in the U.S. Copyright 2019 The Authors
  • Cardiovascular risks impact human brain Nacetylaspartate in regionally specific patterns

    Chiappelli, J.; Rowland, L.M.; Wijtenburg, S.A.; Chen, H.; Maudsley, A.A.; Sheriff, S.; Chen, S.; Savransky, A.; Marshall, W.; Ryan, M.C.; et al. (National Academy of Sciences, 2019)
    Cardiovascular risk factors such as dyslipidemia and hypertension increase the risk for white matter pathology and cognitive decline. We hypothesize that white matter levels of N-acetylaspartate (NAA), a chemical involved in the metabolic pathway for myelin lipid synthesis, could serve as a biomarker that tracks the influence of cardiovascular risk factors on white matter prior to emergence of clinical changes. To test this, we measured levels of NAA across white matter and gray matter in the brain using echo planar spectroscopic imaging (EPSI) in 163 individuals and examined the relationship of regional NAA levels and cardiovascular risk factors as indexed by the Framingham Cardiovascular Risk Score (FCVRS). NAA was strongly and negatively correlated with FCVRS across the brain, but, after accounting for age and sex, the association was found primarily in white matter regions, with additional effects found in the thalamus, hippocampus, and cingulate gyrus. FCVRS was also negatively correlated with creatine levels, again primarily in white matter. The results suggest that cardiovascular risks are related to neurochemistry with a predominantly white matter pattern and some subcortical and cortical gray matter involvement. NAA mapping of the brain may provide early surveillance for the potential subclinical impact of cardiovascular and metabolic risk factors on the brain.
  • Male With Anterior Left Knee Pain

    Dubbs, S.B.; Richardson, A.C.; Blosser, K.M.; Tewelde, S.Z. (Elsevier, 2019)
  • Effect of fish oil supplement administration method on tolerability and adherence: A randomized pilot clinical trial

    Malinowski, S.S.; Barber, K.E.; Kishk, O.A. (BioMed Central Ltd., 2019)
    Objectives: Anecdotally, several strategies have been suggested in order to improve tolerability of fish oil supplements, but there is little evidence supporting any of these strategies. The aim of this study was to determine if there is a difference among four methods of oral administration of fish oil supplementation in terms of tolerability and adherence. Methods: A randomized, prospective, open-label, four-arm pilot study was conducted on 60 healthy adult subjects randomized to different fish oil supplement administration methods with (1) milk, (2) food, (3) an empty stomach, and (4) frozen capsules prior to ingestion. Each subject was instructed to take two capsules three times daily for 30 consecutive days. Adherence was assessed by pill counts. Adverse effects were assessed by survey and patient exit interview. Results: No apparent differences were demonstrated among the four administration groups in terms of adherence, reasons for non-adherence, or self-reported adverse effects. Conclusions: Method of administration did not affect rates of adherence or incidence of adverse effects in a small cohort of healthy adults taking fish oil supplement capsules for 30 days. Trial registration: ClinicalTrials.gov NCT01471366. Registered November 16, 2011. Copyright The Author(s).
  • Fixation using alternative implants for the treatment of hip fractures (FAITH-2): Design and rationale for a pilot multi-centre 2 x 2 factorial randomized controlled trial in young femoral neck fracture patients

    Slobogean, G.P.; Sprague, S.; Bzovsky, S. (BioMed Central Ltd., 2019)
    Background: Femoral neck fractures in patients . 60 years of age are often very different injuries compared to low-energy, hip fractures in elderly patients and are difficult to manage because of inherent problems associated with high-energy trauma mechanisms and increased functional demands for recovery. Internal fixation, with multiple cancellous screws or a sliding hip screw (SHS), is the most common treatment for this injury in young patients. However, there is no clinical consensus regarding which surgical technique is optimal. Additionally, there is compelling rationale to use vitamin D supplementation to nutritionally optimize bone healing in young patients. This pilot trial will determine feasibility and provide preliminary clinical data for a larger definitive trial. Methods: We will conduct a multicenter, concealed randomized controlled pilot study, using a 2 ~ 2 factorial design in 60 patients aged 18.60 years with a femoral neck fracture. Eligible patients will be randomized in equal proportions to one of four groups: 1) SHS and vitamin D supplementation (4000 international units (IU) daily dose) for 6 months, 2) cancellous screws and vitamin D supplementation (4000 IU daily dose) for 6 months, 3) SHS and placebo, and 4) cancellous screws and placebo. Participants will be followed for 12 months post-fracture. Feasibility outcomes include initiation of clinical sites, recruitment, follow-up, data quality, and protocol adherence. Clinical outcomes, for both the pilot and planned definitive trials, include a composite of patient-important outcomes (re-operation, femoral head osteonecrosis, severe femoral neck malunion, and nonunion), health-related quality of life and patient-reported function, fracture healing complications, and radiographic fracture healing. A priori success criteria have been established. If the pilot study is deemed successful, study participants will be included in the definitive trial and clinical outcomes for the pilot will not be analyzed. If the pilot study is not deemed successful, clinical outcome data will be analyzed. Discussion: Results of this study will inform the feasibility of a definitive trial. If clinical outcome data are analyzed, they will be disseminated through a publication and presentations. Trial registration: The FAITH-2 trial, described as a definitive trial, was registered at ClinicalTrials.gov (NCT01908751) prior to enrollment of the first participant. Copyright The Author(s).
  • Insights into the Experience of Liver Transplant Recipients with Alcoholic Liver Disease: A Descriptive Qualitative Study

    Hochheimer, M.; Moreland, M.L.; Tuten, M.; Lamattina, J.; Connelly, M.; Sacco, P. (Wolters Kluwer Health, 2019)
    Background. Alcoholic liver disease (ALD) due to alcohol use disorder (AUD) is the primary cause of liver transplantation (LT) in the United States. Studies have found that LT recipients experience a range of physical and emotional difficulties posttransplantation including return to alcohol use, depression, and anxiety. The aim of this study is to better understand the experiences of LT recipients with ALD because they recovered posttransplant to inform the development of a patient-centered intervention to assist patients during recovery. Methods. Using qualitative methods, researchers conducted semi-structured interviews with 16 ALD LT recipients. The primary topics of the interview were physical recovery, mental health, substance use including alcohol and tobacco use, and financial experiences. Common patient themes were identified and coded. Results. Within the domain of physical health, patients stressed that undergoing LT was a near-death experience, they were helpless, changes in weight influenced their perception of their illness, and they have ongoing medical problems. In the domain of mental health, patients described cognitive impairments during their initial recovery, difficulty in processing the emotions of having a terminal condition, ongoing depression, anxiety, and irritability. The patients also described their perception of having AUD, the last time they used alcohol and their attitude to AUD treatment posttransplant. Patients also described their reliance on one member of their social support network for practical assistance during their recovery and identified one member of their medical team as being of particular importance in providing emotional as well as medical support during recovery. Conclusions. The patient's description of their lived experience during the months following transplant informed the development of a patient-centered intervention that colocates behavioral health components with medical treatment that helps broaden their social network while addressing topics that emerged from this study. Copyright 2019 The Author(s).
  • A new bioinformatic pipeline allows the design of small, targeted gene panels for efficient TMB estimation

    Manca, P.; Mallona, I.; Rolfo, C.D. (Elsevier Ltd, 2019)
    Background: The tumor mutation burden (TMB) is emerging as a prognostic and predictive marker for the response to immune checkpoint blockade (ICB) drugs. We aimed to develop a new method for the definition of gene panels that can precisely estimate the TMB with a considerably lower amount of genome. Methods: We developed a bioinformatic pipeline which allows the design of gene panels suited for TMB estimation. The method is particularly efficient in optimizing the balance between the precision of the TMB estimate and the length of the gene panel created. We tested in silico the efficiency of different panels obtained with our method in an independent cohort of patients with lung adenocarcinoma (LUAD). We also compared in the same cohort of patients the performance of our panels with the performance of existing gene panels. Results: We designed a 0.080 Megabases (Mb) long gene panel which estimated TMB in an independent LUAD cohort with an acceptable precision (adjusted R2=0.745; Spearman ρ = 0.827, Pearson ρ = 0.864). The panel showed 0.89 accuracy in the identification of TMB-high patients (25/28 patients, CI: 0.73 – 0.96). Every unitary increase of our TMB estimate was associated with lower risk of disease progression (univariate analysis: HR = 0.78; CI: 0.65-0.93; p = 0.006; multivariate analysis: HR = 0.8; CI: 0.63-1.01; p = 0.0621). Different existing panels of less than 1 Mb long showed a lower adjusted R2 when compared to our gene panel (Table). Two other commercial panels of 1.9 Mb and 1.1 Mb showed a similar adjusted R2 to panels of the same lengths built with our method; nevertheless, they showed a lower accuracy in TMB-high patients definition (ROC curves AUC of 0.862, 0.870, 0.946 and 0.967 were observed, respectively, for the commercial 1.9 Mb panel, the commercial 1.1 Mb panel, our 0.080 Mb panel and our 2.0 Mb panel).
  • Blood Pressure and Living Kidney Donors: A Clinical Perspective

    Rastogi, A.; Bromberg, J.S.; Weir, M.R. (Wolters Kluwer Health, 2019)
    Elevated blood pressure (BP), or "hypertension," has been one of the main exclusion criteria for living kidney donation, as it is a risk factor for renal and cardiovascular disease. The effect of elevated BP in living kidney donors is not well studied or understood. The most current living kidney donation guidelines state that donors with a BP >140/90 mm Hg with 1-2 antihypertensive medications or evidence of end-organ damage should be excluded from living kidney donation. Yet, the definitions of "hypertension" have changed with the release of the American Heart Association (AHA)/American College of Cardiology (ACC) clinical practice guidelines suggesting that 120-129 mm Hg is elevated BP and Stage 1 hypertension is 130 mm Hg. However, the kidney function (in terms of estimated GFR) of "hypertensive" living kidney donors does not fare significantly worse postdonation compared with that of "normotensive" donors. In addition, even though living kidney donation itself is not considered to be a risk factor for developing hypertension, there exist certain risk factors (African American or Hispanic descent, obesity, age) that may increase the risk of living kidney donors developing elevated BP postdonation. The choice of BP targets and medications needs to be carefully individualized. In general, a BP <130/80 mm Hg is needed, along with lifestyle modifications. Copyright 2019 The Author(s).
  • Intra-Abdominal Heterotopic Cardiac Xenotransplantation: Pearls and Pitfalls

    DiChiacchio, L.; Singh, A.K.; Shockcor, N.M.; Zhang, T.; Lewis, B.G.; Mohiuddin, M.M. (Frontiers Media S.A., 2019)
    Heterotopic cardiac xenotransplantation in the intra-abdominal position has been studied extensively in a pig-to-baboon model to define the optimal donor genetics and immunosuppressive regimen to prevent xenograft rejection. Extensive investigation using this model is a necessary stepping stone toward the development of a life-supporting animal model, with the ultimate goal of demonstrating suitability for clinical cardiac xenotransplantation trials. Aspects of surgical technique, pre- and post-operative care, graft monitoring, and minimization of infectious risk have all required refinement and optimization of heterotopic cardiac xenotransplantation over time. This review details non-immunologic obstacles relevant to this model described by our group and in the literature, as well as strategies that have been developed to address these specific challenges. Copyright 2019 The Authors.
  • Current challenges in the management of sepsis in icus in resource-poor settings and suggestions for the future

    Schultz, M.J.; Papali, A.; Dünser, M.W. (Springer International Publishing, 2019)
    Sepsis is a major cause of critical illness worldwide, especially in resource-poor settings. Intensive care units (ICUs) in low- and middle-income countries (LMICs) face many challenges that could affect patient outcome. The aim of this review is to describe differences between resource-poor and resource-rich settings regarding the epidemiology, pathophysiology, economics, and research aspects of sepsis. We restricted this manuscript to the ICU setting although we are aware that many sepsis patients in LMICs are treated outside an ICU. Although many bacterial pathogens causing sepsis in LMICs are similar to those in high-income countries, resistance patterns to antimicrobial drugs can be very different; in addition, causes of sepsis in LMICs often include tropical diseases in which direct damaging effects of pathogens and their products can be more important than the host response. There are differences in ICU capacities around the world; not surprisingly the lowest capacities are found in LMICs with important heterogeneity within individual LMICs. Although many aspects of sepsis management developed in resource-rich countries are applicable in LMICs, implementation requires strong consideration of cost implications and important differences in resources. Addressing both disease-specific and setting-specific factors is important to improve performance of ICUs in LMICs. Although critical care for sepsis is likely cost-effective in LMIC setting, more detailed evaluation at both a macro- and micro-economy level is necessary. Sepsis management in resource-limited settings is a largely unexplored frontier with important opportunities for research, training, and other initiatives for improvement.
  • Infrastructure and organization of adult intensive care units in resource-limited settings

    Papali, A.; Adhikari, N.K.J.; Diaz, J.V. (Springer International Publishing, 2019)
    In this chapter, we provide guidance on some basic structural requirements, focusing on organization, staffing, and infrastructure. We suggest a closed-format intensive care unit (ICU) with dedicated physicians and nurses, specifically trained in intensive care medicine whenever feasible. Regarding infrastructural components, a reliable electricity supply is essential, with adequate backup systems. Facilities for oxygen therapy are crucial, and the choice between oxygen concentrators, cylinders, and a centralized system depends on the setting. For use in mechanical ventilators, a centralized piped system is preferred. Facilities for proper hand hygiene are essential. Alcohol-based solutions are preferred, except in the context of Ebola virus disease (chloride-based solutions) and Clostridium difficile infection (soap and water). Availability of disposable gloves is important for self-protection; for invasive procedures masks, caps, sterile gowns, sterile drapes, and sterile gloves are recommended. Caring for patients with highly contagious infectious diseases requires access to personal protective equipment. Basic ICU equipment should include vital signs monitors and mechanical ventilators, which should also deliver noninvasive ventilator modes. We suggest that ICUs providing invasive ventilatory support have the ability to measure end-tidal carbon dioxide and if possible can perform blood gas analysis. We recommend availability of glucometers and capabilities for measuring blood lactate. We suggest implementation of bedside ultrasound as diagnostic tool. Finally, we recommend proper administration of patient data; suggest development of locally applicable bundles, protocols, and checklists for the management of sepsis; and implement systematic collection of quality and performance indicators to guide improvements in ICU performance.
  • A single dose of modified vaccinia ankara expressing lassa virus-like particles protects mice from lethal intra-cerebral virus challenge

    Salvato, M.S.; Medina-Moreno, S.; Zapata, J.C.; Hsu, H.; Guzmán-Cardozo, C. (MDPI AG, 2019)
    Lassa fever surpasses Ebola, Marburg, and all other hemorrhagic fevers except Dengue in its public health impact. Caused by Lassa virus (LASV), the disease is a scourge on populations in endemic areas of West Africa, where reported incidence is higher. Here, we report construction, characterization, and preclinical efficacy of a novel recombinant vaccine candidate GEO-LM01. Constructed in the Modified Vaccinia Ankara (MVA) vector, GEO-LM01 expresses the glycoprotein precursor (GPC) and zinc-binding matrix protein (Z) from the prototype Josiah strain lineage IV. When expressed together, GP and Z form Virus-Like Particles (VLPs) in cell culture. Immunogenicity and efficacy of GEO-LM01 was tested in a mouse challenge model. A single intramuscular dose of GEO-LM01 protected 100% of CBA/J mice challenged with a lethal dose of ML29, a Mopeia/Lassa reassortant virus, delivered directly into the brain. In contrast, all control animals died within one week. The vaccine induced low levels of antibodies but Lassa-specific CD4+ and CD8+ T cell responses. This is the first report showing that a single dose of a replication-deficient MVA vector can confer full protection against a lethal challenge with ML29 virus. Copyright 2019 by the authors.
  • Real-world experience with ceftazidime-avibactam for multidrug-resistant gram-negative bacterial infections

    Jorgensen, S.C.J.; Trinh, T.D.; Claeys, K.C. (Oxford University Press, 2019)
    Background. We conducted this study to describe the clinical characteristics, microbiology, and outcomes of patients treated with ceftazidime-avibactam (CZA) for a range of multidrug-resistant Gram-negative (MDR-GN) infections. Methods. This is a multicenter, retrospective cohort study conducted at 6 medical centers in the United States between 2015 and 2019. Adult patients who received CZA (?72 hours) were eligible. The primary outcome was clinical failure defined as a composite of 30-day all-cause mortality, 30-day microbiological failure, and/or failure to resolve or improve signs or symptoms of infection on CZA. Results. In total, data from 203 patients were evaluated. Carbapenem-resistant Enterobacteriaceae (CRE) and Pseudomonas spp were isolated from 117 (57.6%) and 63 (31.0%) culture specimens, respectively. The most common infection sources were respiratory (37.4%), urinary (19.7%), and intra-abdominal (18.7%). Blood cultures were positive in 22 (10.8%) patients. Clinical failure, 30-day mortality, and 30-day recurrence occurred in 59 (29.1%), 35 (17.2%), and 12 (5.9%) patients, respectively. On therapy, CZA resistance developed in 1 of 62 patients with repeat testing. Primary bacteremia or respiratory tract infection and higher SOFA score were positively associated with clinical failure (adjusted odds ratio [aOR] = 2.270, 95% confidence interval [CI] = 1.115-4.620 and aOR = 1.234, 95% CI = 1.118–1.362, respectively). Receipt of CZA within 48 hours of infection onset was protective (aOR, 0.409; 95% CI, 0.180-0.930). Seventeen (8.4%) patients experienced a potential drug-related adverse effect (10 acute kidney injury, 3 Clostridioides difficile infection, 2 rash, and 1 each gastrointestinal intolerance and neutropenia) Conclusions. Ceftazidime-avibactam is being used to treat a range of MDR-GN infections including Pseudomonas spp as well as CRE. Copyright The Author(s) 2019.
  • Testosterone in Men With Chronic Hepatitis C Infection and After Hepatitis C Viral Clearance

    Chaudhury, C.S.; Mee, T.; Chairez, C.; McLaughlin, M.; Silk, R.; Gross, C.; Kattakuzhy, S.; Rosenthal, E.; Kottilil, S.; Hadigan, C. (Oxford University Press, 2019)
    BACKGROUND: Hepatitis C virus (HCV) and hepatic dysfunction are associated with low total and free testosterone (TT and FT) and high sex hormone-binding globulin (SHBG). However, little is known about changes in testosterone following successful HCV treatment. METHODS: We evaluated testosterone levels and the prevalence of low testosterone in a cohort of 327 men with chronic HCV infection (human immunodeficiency virus [HIV] coinfection = 150) and in a subset of 85 men with testosterone levels obtained pre-HCV treatment and after sustained virologic response (SVR). Median follow-up was 36 months. RESULTS: Participants with active HCV at baseline had higher TT (P < .0001) and SHBG (P < .0001) compared with participants who had achieved SVR, whereas FT did not differ. Low TT (<10.4 nmol/L) was more prevalent in participants with SVR compared with active HCV (P = .002); however, low FT (<0.1735 nmol/L) was common (50% active HCV, 43% SVR) and did not different between groups. For participants with longitudinal determinations, TT and SHBG decreased significantly (P < .0001) while FT remained unchanged post-SVR. Low FT persisted after SVR (pre-treatment 58%, post-SVR 54%, P = .72). HIV status and change in aspartate aminotrasferase-to-platelet ratio were significant independent predictors of change in FT following SVR. CONCLUSIONS: During active HCV infection, testosterone deficiency may be masked due to elevated SHBG. Despite improvements in SHBG following SVR, low FT was common and persisted after HCV clearance, indicating the need for enhanced awareness and screening using estimates of FT following successful treatment of chronic HCV. CLINICAL TRIALS REGISTRATION: NCT01350648.
  • Mesencephalic Astrocyte-Derived Neurotrophic Factor Inhibits Liver Cancer Through Small Ubiquitin-Related Modifier (SUMO)ylation-Related Suppression of NF-κB/Snail Signaling Pathway and Epithelial-Mesenchymal Transition

    Liu, J.; Wu, Z.; Fang, S. (John Wiley and Sons Inc., 2019)
    Background and Aims: Endoplasmic reticulum (ER) stress is associated with liver inflammation and hepatocellular carcinoma (HCC). However, how ER stress links inflammation and HCC remains obscure. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an ER stress-inducible secretion protein that inhibits inflammation by interacting with the key subunit of nuclear factor kappa light chain enhancer of activated B cells (NF-κB) p65. We hypothesized that MANF may play a key role in linking ER stress and inflammation in HCC. Approach and Results: Here, we found that MANF mRNA and protein levels were lower in HCC tissues versus adjacent noncancer tissues. Patients with high levels of MANF had better relapse-free survival and overall survival rates than those with low levels. MANF levels were also associated with the status of liver cirrhosis, advanced tumor-node-metastasis (TNM) stage, and tumor size. In vitro experiments revealed that MANF suppressed the migration and invasion of hepatoma cells. Hepatocyte-specific deletion of MANF accelerated N-nitrosodiethylamine (DEN)-induced HCC by up-regulating Snail1+2 levels and promoting epithelial-mesenchymal transition (EMT). MANF appeared in the nuclei and was colocalized with p65 in HCC tissues and in tumor necrosis factor alpha (TNF-α)-treated hepatoma cells. The interaction of p65 and MANF was also confirmed by coimmunoprecipitation experiments. Consistently, knockdown of MANF up-regulated NF-κB downstream target genes TNF-α, interleukin (IL)-6 and IL-1α expression in vitro and in vivo. Finally, small ubiquitin-related modifier 1 (SUMO1) promoted MANF nuclear translocation and enhanced the interaction of MANF and p65. Mutation of p65 motifs for SUMOylation abolished the interaction of p65 and MANF. Conclusions: MANF plays an important role in linking ER stress and liver inflammation by inhibiting the NF-κB/Snail signal pathway in EMT and HCC progression. Therefore, MANF may be a cancer suppressor and a potential therapeutic target for HCC. Copyright 2019 The Authors.
  • Benefit-risk assessment of nivolumab 240 mg flat dose relative to 3 mg/kg Q2W regimen in Japanese patients with advanced cancers

    Bei, D.; Osawa, M.; Gobburu, J. (Blackwell Publishing Ltd, 2019)
    Nivolumab 3 mg/kg every 2 weeks (Q2W) has been approved in Japan for various cancers; however, use of a flat dose is expected to simplify dosing and administration. A quantitative clinical pharmacology approach was used to assess the benefit-risk profile of nivolumab 240 mg Q2W relative to the approved dose of nivolumab 3 mg/kg Q2W in Japanese patients. Three exposure-response safety analyses were performed for adverse events that led to discontinuation/death, were grade 3 or higher, and were immune-mediated and grade 2 or higher for Japanese patients diagnosed with one of multiple tumor types. Exposure-response analyses of efficacy were evaluated for overall survival and objective response rate. Exposures of nivolumab 240 mg Q2W were 37% higher than those of nivolumab 3 mg/kg Q2W in Japanese patients across the tumor types analyzed. Predicted safety profiles at the two doses differed by less than 2% across tumor types for adverse events leading to discontinuation/death, adverse events of grade 3 or higher, or immune-mediated adverse events of grade 2 or higher. In addition, the predicted 1-year and 2-year overall survival rates, the mean overall survival and the objective response rates were comparable between the doses regardless of the tumor type analyzed. Overall, these results demonstrated that the benefit-risk of nivolumab 240 mg Q2W was comparable to that of the previously approved 3 mg/kg Q2W dosing regimen, and was the basis for the approval of the 240 mg Q2W as an alternative dosing regimen for treatment in Japanese patients across multiple tumor types. Copyright 2019 The Authors.
  • Late-onset renal hypertrophy and dysfunction in mice lacking CTRP1

    Rodriguez, S.; Little, H.C.; Woodward, O.M. (John Wiley and Sons Inc., 2019)
    Local and systemic factors that influence renal structure and function in aging are not well understood. The secretory protein C1q/TNF-related protein 1 (CTRP1) regulates systemic metabolism and cardiovascular function. We provide evidence here that CTRP1 also modulates renal physiology in an age- and sex-dependent manner. In mice lacking CTRP1, we observed significantly increased kidney weight and glomerular hypertrophy in aged male but not female or young mice. Although glomerular filtration rate, plasma renin and aldosterone levels, and renal response to water restriction did not differ between genotypes, CTRP1-deficient male mice had elevated blood pressure. Echocardiogram and pulse wave velocity measurements indicated normal heart function and vascular stiffness in CTRP1-deficient animals, and increased blood pressure was not due to greater salt retention. Paradoxically, CTRP1-deficient mice had elevated urinary sodium and potassium excretion, partially resulting from reduced expression of genes involved in renal sodium and potassium reabsorption. Despite renal hypertrophy, markers of inflammation, fibrosis, and oxidative stress were reduced in CTRP1-deficient mice. RNA sequencing revealed alterations and enrichments of genes in metabolic processes in CTRP1-deficient animals. These results highlight novel contributions of CTRP1 to aging-associated changes in renal physiology.

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