Investigational New Drugs

Drug repurposing using transcriptome sequencing and virtual drug screening in a patient with glioblastoma Summary Background Precision medicine and drug repurposing are attractive strategies, especially for tumors with worse prognosis. Glioblastoma is a highly malignant brain tumor with limited treatment options and short survival times. We identified novel BRAF (47-438del) and PIK3R1 (G376R) mutations in a glioblastoma patient by RNA-sequencing. Methods The protein expression of BRAF and PIK3R1 as well as the lack of EGFR expression as analyzed by immunohistochemistry corroborated RNA-sequencing data. The expression of additional markers (AKT, SRC, mTOR, NF-κB, Ki-67) emphasized the aggressiveness of the tumor. Then, we screened a chemical library of > 1500 FDA-approved drugs and > 25,000 novel compounds in the ZINC database to find established drugs targeting BRAF47-438del and PIK3R1-G376R mutated proteins. Results Several compounds (including anthracyclines) bound with higher affinities than the control drugs (sorafenib and vemurafenib for BRAF and PI-103 and LY-294,002 for PIK3R1). Subsequent cytotoxicity analyses showed that anthracyclines might be suitable drug candidates. Aclarubicin revealed higher cytotoxicity than both sorafenib and vemurafenib, whereas idarubicin and daunorubicin revealed higher cytotoxicity than LY-294,002. Liposomal formulations of anthracyclines may be suitable to cross the blood brain barrier. Conclusions In conclusion, we identified novel small molecules via a drug repurposing approach that could be effectively used for personalized glioblastoma therapy especially for patients carrying BRAF47-438del and PIK3R1-G376R mutations.

Simvastatin treatment varies the radiation response of human breast cells in 2D or 3D culture Summary Background Statins inhibit the cholesterol biosynthesis and are used as cholesterol-lowering agents in fat-metabolism disorders. Furthermore, several studies state that statins have supportive functions in breast cancer treatment. Therefore, simvastatin (SVA) as a potential radiosensitizer should be investigated on the basis of human breast cells. Methods First, an optimal concentration of SVA for normal (MCF10A) and cancer (MCF-7) cells was identified via growth and cytotoxicity assays that, according to the definition of a radiosensitizer in the narrower sense, enhances the effect of radiation therapy but has no cytotoxic effect. Next, in combination with radiation SVA's influence on DNA repair capacity and clonogenic survival in 2D and 3D was determined. Furthermore cell cycle distribution, expression of survivin and connective tissue growth factor (CTGF) as well as ERK1 map kinase were analysed. Results 1 μM SVA was identified as highest concentration without an influence on cell growth and cytotoxicity and was used for further analyses. In terms of early and residual γH2AX-foci, SVA affected the number of foci in both cell lines with or without irradiation. Different radiation responses were detected in 2D and 3D culture conditions. During the 2D cultivation, a radiosensitizing effect within the clonogenic survival was observable, but not in 3D. Conclusion The present study suggests that SVA may have potential for radiosensitization. Therefore, it is important to further investigate the role of SVA in relation to the extent of radiosensitization and how it could be used to positively influence the therapy of breast cancer or other entities.

Drug-repositioning screening identified fludarabine and risedronic acid as potential therapeutic compounds for malignant pleural mesothelioma Summary Objectives Malignant pleural mesothelioma (MPM) is an occupational disease mainly due to asbestos exposure. Effective therapies for MPM are lacking, making this tumour type a fatal disease. Materials and Methods In order to meet this need and in view of a future "drug repositioning" approach, here we screened five MPM (Mero-14, Mero-25, IST-Mes2, NCI-H28 and MSTO-211H) and one SV40-immortalized mesothelial cell line (MeT-5A) as a non-malignant model, with a library of 1170 FDA-approved drugs. Results Among several potential compounds, we found that fludarabine (F-araA) and, to a lesser extent, risedronic acid (RIS) were cytotoxic in MPM cells, in comparison to the non-malignant Met-5A cells. In particular, F-araA reduced the proliferation and the colony formation ability of the MPM malignant cells, in comparison to the non-malignant control cells, as demonstrated by proliferation and colony formation assays, in addition to measurement of the phospho-ERK/total-ERK ratio. We have shown that the response to F-araA was not dependent upon the expression of DCK and NT5E enzymes, nor upon their functional polymorphisms (rs11544786 and rs2295890, respectively). Conclusion This drug repositioning screening approach has identified that F-araA could be therapeutically active against MPM cells, in addition to other tumour types, by inhibiting STAT1 expression and nucleic acids synthesis. Further experiments are required to fully investigate this.

Correction to: The old CEACAMs find their new role in tumor immunotherapy Correction is needed to the original version of this article.

Correction to: Phase 1 dose-escalation study of a novel oral PI3K/mTOR dual inhibitor, LY3023414, in patients with cancer The article Phase 1 dose-escalation study of a novel oral PI3K/mTOR dual inhibitor, LY3023414, in patients with cancer, written by Shunsuke Kondo, Masaomi Tajimi, Tomohiko Funai, Koichi Inoue, Hiroya Asou, Vinay Kumar Ranka, Volker Wacheck, Toshihiko Doi, was originally published electronically on the publisher's internet portal on 23 June 2020 without open access.

The pan-Bcl-2 inhibitor obatoclax promotes differentiation and apoptosis of acute myeloid leukemia cells Summary One of the key features of acute myeloid leukemia (AML) is the arrest of differentiation at the early progenitor stage of myelopoiesis. Therefore, the identification of new agents that could overcome this differentiation block and force leukemic cells to enter the apoptotic pathway is essential for the development of new treatment strategies in AML. Regarding this, herein we report the pro-differentiation activity of the pan-Bcl-2 inhibitor, obatoclax. Obatoclax promoted differentiation of human AML HL-60 cells and triggered their apoptosis in a dose- and time-dependent manner. Importantly, obatoclax-induced apoptosis was associated with leukemic cell differentiation. Moreover, decreased expression of Bcl-2 protein was observed in obatoclax-treated HL-60 cells. Furthermore, differentiation of these cells was accompanied by the loss of their proliferative capacity, as shown by G0/G1 cell cycle arrest. Taken together, these findings indicate that the anti-AML effects of obatoclax involve not only the induction of apoptosis but also differentiation of leukemic cells. Therefore, obatoclax represents a promising treatment for AML that warrants further exploration.

A phase 1 study of PF-06840003, an oral indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor in patients with recurrent malignant glioma Summary Background PF-06840003 is a highly selective indoleamine 2, 3-dioxygenase (IDO1) inhibitor with antitumor effects in preclinical models. This first-in-human phase 1 study evaluated safety, pharmacokinetics/pharmacodynamics, and preliminary efficacy in recurrent malignant glioma to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D). Methods Patients (N = 17) received oral PF-06840003 in four dose-escalation groups: 125 mg once-daily (QD; n = 2); 250 mg QD (n = 4); 250 mg twice-daily (BID; n = 3); 500 mg BID (n = 8). A modified toxicity probability interval method determined the MTD. Results Four patients experienced serious adverse events (SAEs); one with treatment-related SAEs (grade 4 alanine and aspartate aminotransferase elevations). The dose-limiting toxicity (DLT) rate at 500 mg BID was 12.5% (n = 1/8); the MTD was not reached. Following PF-06840003 dosing, median time to maximum plasma concentration for the active enantiomer PF-06840002 was 1.5–3.0 hr and mean elimination half-life was 2 to 4 hr (Cycle 1 Day 1). Urinary recovery of PF-06840002 was low (< 1%). At 500 mg BID, maximum mean percentage inhibition of 13C10 kynurenine vs endogenous kynurenine was 75% vs 24%. PF-06840002 CSF-to-plasma ratio was 1.00. Disease control occurred in eight patients (47%). Mean duration of stable disease (SD) was 32.1 (12.1–72.3) weeks. Two patients with SD discontinued the study at 450 and 561 days and continued PF-06840003 on compassionate use. Conclusion PF‑06840003 up to 500 mg BID was generally well tolerated with evidence of a pharmacodynamic effect and durable clinical benefit in a subset of patients with recurrent malignant glioma. ClinicalTrials.gov, NCT02764151, registered April 2016.

A phase I study of the VEGFR kinase inhibitor vatalanib in combination with the mTOR inhibitor, everolimus, in patients with advanced solid tumors Summary Purpose Combining small-molecule inhibitors of different targets was shown to be synergistic in preclinical studies. Testing this concept in clinical trials is, however, daunting due to challenges in toxicity management and efficacy assessment. This study attempted to evaluate the safety and efficacy of vatalanib plus everolimus in patients with advanced solid tumors and explore the utility of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) studies as a predictive biomarker. Patients and Methods This single-center, phase I trial containing 70 evaluable patients consisted of a dose escalation proportion based on the traditional "3 + 3" design (cohort IA and IB) and a dose expansion proportion (cohort IIA and IIB). Toxicity was evaluated using the Common Terminology Criteria of Adverse Events. Antitumor activity was assessed using the Modified Response Evaluation Criteria in Solid Tumors. Results The maximum tolerated doses were determined to be vatalanib 1250 mg once daily or 750 mg twice daily in combination with everolimus 10 mg once daily. No treatment-related death occurred. The most common toxicities were hypertriglyceridemia, hypercholesterolemia, fatigue, vomiting, nausea and diarrhea. There was no complete response. Nine patients (12.9%) had partial response (PR) and 41 (58.6%) had stable disease (SD). Significant antitumor activity was observed in neuroendocrine tumors with a disease-control rate (PR + SD) of 66.7% and other tumor types including renal cancer, melanoma, and non-small-cell lung cancer. Conclusions The combination of vatalanib and everolimus demonstrated reasonable toxicity and clinical activity. Future studies combining targeted therapies and incorporating biomarker analysis are warranted based on this phase I trial.

A randomized, double-blind, placebo-controlled study of B-cell lymphoma 2 homology 3 mimetic gossypol combined with docetaxel and cisplatin for advanced non-small cell lung cancer with high expression of apurinic/apyrimidinic endonuclease 1 Summary Background Overexpression of apurinic/apyrimidinic endonuclease 1 (APE1) is an important cause of poor chemotherapeutic efficacy in advanced non-small cell lung cancer (NSCLC) patients. Gossypol, a new inhibitor of APE1, in combination with docetaxel and cisplatin is believed to improve the efficacy of chemotherapy for advanced NSCLC with high APE1 expression. Methods Sixty-two patients were randomly assigned to two groups. Thirty-one patients in the experimental group received 75 mg/m2 docetaxel and 75 mg/m2 cisplatin on day 1 with gossypol administered at 20 mg once daily on days 1 to 14 every 21 days. The control group received placebo with the same docetaxel and cisplatin regimen. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS), response rate, and toxicity. Results There were no significant differences in PFS and OS between the experimental group and the control group. The median PFS (mPFS) in the experimental and control groups was 7.43 and 4.9 months, respectively (HR = 0.54; p = 0.06), and the median OS (mOS) was 18.37 and 14.7 months, respectively (HR = 0.68; p = 0.27). No significant differences in response rate and serious adverse events were found between the groups. Conclusion The experimental group had a better mPFS and mOS than did the control group, though no significant difference was observed. Because the regimen of gossypol combined with docetaxel and cisplatin was well tolerated, future studies with larger sample sizes should be performed.

The old CEACAMs find their new role in tumor immunotherapy Summary Carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) contain 12 family members(CEACAM1、CEACAM3、CEACAM4、CEACAM5、CEACAM6、CEACAM7、CEACAM8、CEACAM16、CEACAM18、CEACAM19、CEACAM20 and CEACAM21)and are expressed diversely in different normal and tumor tissues. CEA (CEACAM5) has been used as a tumor biomarker since 1965. Here we review the latest research and development of the structures, expression, and function of CEACAMs in normal and tumor tissues, and their application in the tumor diagnosis, prognosis, and treatment. We focus on recent clinical studies of CEA targeted cancer immunotherapies, including bispecific antibody (BsAb) for radio-immuno-therapy and imaging, bispecific T cell engager (BiTE) and chimeric antigen receptor T cells (CAR-T). We summarize the promising clinical relevance and challenges of these approaches and give perspective view for future research. This review has important implications in understanding the diversified biology of CEACAMs in normal and tumor tissues, and their new role in tumor immunotherapy.

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Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,00306932607174,alsfakia@gmail.com,

Telephone consultation 11855 int 1193,

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Mechanical Ventilation With Moderate Tidal Volume Exacerbates Extrapulmonary Sepsis-Induced Lung Injury via IL33-WISP1 Signaling Pathway IL-33 and WISP1 play central roles in acute lung injury (ALI) induced by mechanical ventilation with moderate tidal volume (MTV) in the setting of sepsis. Here, we sought to determine the inter-relationship between IL-33 and WISP1 and the associated signaling pathways in this process. We used a two hit model of cecal ligation puncture (CLP) followed by MTV ventilation (4 h 10 ml/kg) in wildtype, IL-33-/- or ST2-/- mice or wildtype mice treated with intratracheal antibodies to WISP1. Macrophages (Raw 264.7 and alveolar macrophages from wildtype or ST2-/- mice) were used to identify specific signaling components. CLP + MTV resulted in ALI that was partially sensitive to genetic ablation of IL-33 or ST2 or antibody neutralization of WISP1. Genetic ablation of IL-33 or ST2 significantly prevented ALI after CLP + MTV and reduced levels of WISP1 in the circulation and BALF. rIL-33 increased WISP1 in alveolar macrophages in an ST2, PI3K/AKT and ERK dependent manner. This WISP1 upregulation and WNT β-catenin activation were sensitive to inhibition of the β-catenin/TCF/CBP/P300 nuclear pathway. We show that IL-33 drives WISP1 upregulation and ALI during MTV in CLP sepsis. The identification of this relationship and the associated signaling pathways reveals a number of possible therapeutic targets to prevent ALI in ventilated sepsis patients. Address reprint requests to Li-Ming Zhang, MD, Department of Anesthesiology and Perioperative Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, 200 Lothrop Street, UPMC MUH N467, Pittsburgh 15213, PA, USA. E-mail: zhangl1@anes.upmc.edu. Received 22 September, 2020 Revised 13 October, 2020 Accepted 14 December, 2020 Competing interests: The authors declare that they have no competing interest. Funding: This work was supported by National Institute of Health grants [R01-GM-108639, (LMZ)] for the design of the study, collection for analysis and interpretation of data, and writing the manuscript; National Institute of Health grants [R01-HL-22489, (HRT)] for his salary support. Ethics approval and consent to participate: Animal protocols were approved by the Animal Care and Use Committee of the University of Pittsburgh and experiments were performed in strict adherence to the National Institutes of Health Guidelines for the Use of Laboratory Animals. Consent for publication: Not applicable Availability of data and materials: The datasets generated and/or analyzed during the current study are available in the Dr. Billiar Lab of University of Pittsburgh, and the datasets are available from the corresponding author on reasonable request. Authors' contributions: Study concepts and design: SL, MHD, HRT, TRB, BRP, BHP, LMZ; data collection: SL, MHD.; writing up of the first of the paper: SL, TRB, BRP, LMZ; data analysis and interpretation: SL, MHD, HRT, BHP, TRB, BRP, LMZ; statistical analysis: SL, LMZ; manuscript preparation: SL, LMZ; manuscript revision: SL, MHD, HRT, BHP, TRB, BRP, LMZ; manuscript final version approval: SL, MHD, HRT, BHP, TRB, BRP, LMZ. All authors read and approved the final manuscript. Supplemental digital content is available for this article. Direct URL citation appears in the printed text and is provided in the HTML and PDF versions of this article on the journal's Web site (www.shockjournal.com). © 2020 by the Shock Society

Hypobaria Exposure Worsens Cardiac Function and Endothelial Injury in an Animal Model of Polytrauma: Implications for Aeromedical Evacuation Background: Aeromedical evacuation can expose traumatically injured patients to low pressure (hypobaria) and hypoxia. Here we sought to assess the impact of hypobaria on inflammation, organ injury, and mortality in a mouse model of polytrauma. Methods: Eight to 12 week-old male C57BL/6J mice were subjected to sham or polytrauma consisting of bowel ischemia by superior mesenteric artery (SMA) occlusion, hindlimb muscle crush, and tibia fracture. Two hours after injury, animals were randomized to undergo either 6 hours of hypobaria or sea-level, room air conditions. At 8 or 24 hours after injury, transthoracic echocardiography was performed. Acute kidney injury (AKI) biomarkers were measured by qRT-PCR. Plasma cytokine and endothelial injury markers were determined by ELISA. Results: Eight hours after traumatic injury, mice exhibited a marked increase in plasma IL-6 (57 vs. 1216 pg/ml), AKI with increased Ngal and Kim-1, and endothelial injury as evidenced by significantly increased plasma hyaluronic acid (96 vs.199 ng/ml), thrombomodulin (23.2 vs. 58.9 ng/ml), syndecan-1 (0.99 vs. 4.34 ng/ml), and E-selectin (38.6 vs. 62.7 ng/ml). The trauma mice also developed cardiac dysfunction with decreased cardiac output and stroke volume at 8 hours post-injury. Hypobaric exposure after polytrauma led to decreased ejection fraction (81.0 vs. 74.2%, p < 0.01) and increased plasma hyaluronic acid (199 vs. 260 ng/ml, p < 0.05), thrombomodulin (58.9 vs. 75.4 ng/ml, p < 0.05), and syndecan-1 (4.34 vs. 8.33 ng/ml, p < 0.001) at 8 hours post-injury. Conclusions: Hypobaria exposure appeared to worsen cardiac dysfunction and endothelial injury following polytrauma and thus may represent a physiological "second hit" following traumatic injury. Address reprint requests to Wei Chao, MD, PhD, Center for Shock, Trauma and Anesthesiology Research, University of Maryland School of Medicine, 660 W. Redwood St. Howard Hall #598A, Baltimore, MD, 21201, USA. E-mail: wchao@som.umaryland.edu Received 18 October, 2020 Revised 12 November, 2020 Accepted 17 December, 2020 Conflict of interest: All authors have declared no conflict of interest. Disclosures: This work was supported in part by the grants from the US Air Force Research (FA8650-17-2-6H12 and FA8650-18-2-6H17) and the National Institutes of Health (R01GM122908, R01GM117233, R35GM124775, R01NS110567, and T32HL007698). The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Air Force, the Department of Defense, or the U.S. Government. Author contribution: K.L. performed the majority of experiments, data analysis and interpretation, and wrote manuscript draft. A.S. contributed to study design, hypobaria chamber assembly, and polytrauma model creation. Y.Y. performed all echocardiography and data analysis. B.W. contributed to study design and direction. J.H. performed BAL collection and analysis. J.Z. assisted with animal husbandry, organ collection, and sample processing. S.W. contributed to technique supervision, data analysis, and figure preparation. G.F., A.C., R.K., and C.M. contributed to data interpretation and manuscript editing. W.C. designed the study, provided direction throughout the experiments, advised on data analysis and interpretation, and finalized the manuscript. © 2020 by the Shock Society

Low Microcirculatory Perfused Vessel Density and High Heterogeneity are Associated with Increased Intensity and Duration of Lactic Acidosis After Cardiac Surgery with Cardiopulmonary Bypass Introduction: Lactic acidosis after cardiac surgery with cardiopulmonary bypass is common and associated with an increase in postoperative morbidity and mortality. A number of potential causes for an elevated lactate after cardiopulmonary bypass including cellular hypoxia, impaired tissue perfusion, ischemic-reperfusion injury, aerobic glycolysis, catecholamine infusions, and systemic inflammatory response after exposure to the artificial cardiopulmonary bypass circuit. Our goal was to examine the relationship between early abnormalities in microcirculatory convective blood flow and diffusive capacity and lactate kinetics during early resuscitation in the intensive care unit. We hypothesized that patients with impaired microcirculation after cardiac surgery would have a more severe postoperative hyperlactatemia, represented by the lactate time-integral of an arterial blood lactate concentration greater than 2.0 mmol/L. Methods: We measured sublingual microcirculation using incident darkfield video microscopy in 50 subjects on ICU admission after cardiac surgery. Serial measurements of systemic hemodynamics, blood gas, lactate, and catecholamine infusions were recorded each hour for the first 6 hours after surgery. Lactate area under the curve (AUC) was calculated over the first 6 hours. The lactate AUC was compared between subjects with normal and low perfused vessel density (PVD < 18 mm/mm2), high heterogeneity index (MHI > 0.4), and low vessel-by-vessel microvascular flow index (MFIv < 2.6). Results: Thirteen (26%) patients had a low postoperative PVD, 20 patients (40%) had a high MHI, and 26 (52%) patients had a low MFIv. Patients with low perfused vessel density had higher lactate AUC compared to subjects with a normal PVD (22.3 [9.4–31.0] vs. 2.6 [0–8.8]; p < 0.0001). Patients with high microcirculatory heterogeneity had a higher lactate AUC compared to those with a normal MHI (2.5 [0.1–8.2] vs. 13.1 [3.7–31.1]; p < 0.001). We did not find a difference in lactate AUC when comparing high and low MFIv. Conclusion: Low perfused vessel density and high microcirculatory heterogeneity are associated with an increased intensity and duration of lactic acidosis after cardiac surgery with cardiopulmonary bypass. Address reprint requests to John C. Greenwood, MD, Department of Emergency Medicine, Hospital of the University of Pennsylvania. 3400 Spruce Street, Philadelphia, PA 19104, USA. E-mail: john.greenwood@pennmedicine.upenn.edu Received 28 October, 2020 Revised 13 November, 2020 Accepted 14 December, 2020 Ethics approval and consent to participate: This study was approved by our institutional review board (IRB # 829765) and informed consent was obtained prior to enrollment. All consent forms were copied in triplicate, one given to the subject, the second placed in the official medical record, the third kept in a secured location within the PI's office. Consent for publication: John C. Greenwood, MD (Corresponding author) consent to the publication of this work if accepted by the journal. Availability of data and materials: All original data and materials are kept in a locally managed REDCap database at the University of Pennsylvania. Deidentified microcirculation data is available online, uploaded to open access Zenodo database found here: https://doi.org/10.5281/zenodo.4106205. Competing interests: None. None of the authors have received any financial support or have a conflict of interest related to Cytocam or Braedius, BV. Funding: Not applicable Authors' contributions: JCG made substantial contributions to the conception or design of the work; the acquisition, analysis, or interpretation of data; drafted the work or substantively revised the manuscript. DHJ made substantial contributions to the conception or design of the work; the analysis and interpretation of data; substantively revised the manuscript. AES made substantial contributions to the acquisition, analysis, or interpretation of data; drafted the work or substantively revised the manuscript. JTG made substantial contributions to the conception or design of the work; drafted the work or substantively revised the manuscript. JH made substantial contributions to the conception or design of the work; drafted the work or substantively revised the manuscript. JH made substantial contributions to the conception or design of the work; drafted the work or substantively revised the manuscript. JH made substantial contributions to the conception or design of the work; drafted the work or substantively revised the manuscript. MAA made substantial contributions to the conception or design of the work; drafted the work or substantively revised the manuscript. TJK made substantial contributions to the conception or design of the work; the analysis, or interpretation of data; drafted the work or substantively revised the manuscript. FSS made substantial contributions to the conception or design of the work; the analysis, or interpretation of data; drafted the work or substantively revised the manuscript. JGTA made substantial contributions to the conception or design of the work; the analysis, or interpretation of data; drafted the work or substantively revised the manuscript. JB made substantial contributions to the conception or design of the work; the analysis, or interpretation of data; drafted the work or substantively revised the manuscript. BSA made substantial contributions to the conception or design of the work; the analysis, or interpretation of data; drafted the work or substantively revised the manuscript. Supplemental digital content is available for this article. Direct URL citation appears in the printed text and is provided in the HTML and PDF versions of this article on the journal's Web site (www.shockjournal.com). © 2020 by the Shock Society

Targeting Uric Acid Prevents Brain Injury and Anxiety in a Rat Model of Hemorrhagic Shock Secondary brain injury following hemorrhagic shock (HS) is a frequent complication in patients, even in absence of direct brain trauma, leading to behavioral changes and more specifically anxiety and depression. Despite pre-clinical studies showing inflammation and apoptosis in the brain after HS, none have addressed the impact of circulating mediators. Our group demonstrated an increased uric acid (UA) circulation in rats following HS. Since UA is implicated in endothelial dysfunction and inflammatory response, we hypothesized UA could alter the blood-brain barrier (BBB) and impact the brain. Male Wistar rats were randomly assigned to: SHAM, HS (hemorrhagic shock) and HS + U (hemorrhagic shock + 1.5 mg/kg of uricase). The uricase intervention, specifically targeting UA, was administered during fluid resuscitation. It prevented BBB dysfunction (fluorescein sodium salt permeability and expression of ICAM-1) following HS. As for neuroinflammation, all of the results obtained (MPO activity; Iba1 and GFAP expression) showed a significant increase after HS, also prevented by the uricase. The same pattern was observed after quantification of apoptosis (caspase-3 activity and TUNEL) and neurodegeneration (Fluoro-Jade). Finally, the forced swim, elevated plus maze and social interaction tests detected anxiety-like behavior after HS, which was blunted in rats treated with the uricase. In conclusion, we have identified UA as a new circulatory inflammatory mediator, responsible for brain alterations and anxious behavior after HS in a murine model. The ability to target UA holds the potential of an adjunctive therapeutic solution to reduce brain dysfunction related to hemorrhagic shock in human. Address reprint requests to Emmanuel Charbonney, MD, PhD, Centre de Recherche du Centre Hospitalier de, l'Université de Montréal (CRCHUM), Pavillon R 900, Rue Saint-Denis, Montréal Qc H2X 0A9, Canada. E-mail: emmanuel.charbonney@umontreal.ca Received 7 October, 2020 Revised 23 October, 2020 Accepted 7 December, 2020 Funding and Disclosures Part of the present work has been funded thanks to the Fondation NeuroTrauma Marie-Robert Dr. Emmanuel Charbonney had received financial support for his program of research from Sanofi Genzyme Canada The preliminary data of the present work have been presented as an abstract, at the International 2019 Brain Injury Association's 13th World Congress on Brain Injury, in Toronto AUTHOR CONTRIBUTION STATEMENT SLE, KG, GR and EC, designed the study, supervised and conducted the experiments, analyzed the data and drafted the manuscript. SLE, KG, BB, JB, CL, CB, MAG conducted the animal experiments, processed the molecular and IF experiments, with their analysis. SLE, JB and GR conducted the behavior experiment and their analysis. SLE, KG, FB, GR and EC conducted the analysis, verified the reproducibility of the results and reviewed the final version of the manuscript. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (www.shockjournal.com). © 2020 by the Shock Society

Circulating Syndecan-1 and Tissue Factor Pathway Inhibitor, Biomarkers of Endothelial Dysfunction, Predict Mortality in Burn Patients Objective: The aim of this study is to evaluate the association between burn injury and admission plasma levels of Syndecan-1 (SDC-1) and Tissue Factor Pathway Inhibitor (TFPI), and their ability to predict 30-day mortality. Background: SDC-1 and TFPI are expressed by vascular endothelium and shed into the plasma as biomarkers of endothelial damage. Admission plasma biomarker levels have been associated with morbidity and mortality in trauma patients, but this has not been well characterized in burn patients. Methods: This cohort study enrolled burn patients admitted to a regional burn center between 2013 and 2017. Blood samples were collected within 4 hours of admission and plasma SDC-1 and TFPI were quantified by ELISA. Demographics and injury characteristics were collected prospectively. The primary outcome was 30-day in-hospital mortality Results: Of 158 patients, 74 met inclusion criteria. Most patients were male with median age of 41.5 years and burn TBSA of 20.5%. The overall mortality rate was 20.3%. Admission SDC-1 and TFPI were significantly higher among deceased patients. Plasma SDC-1 >34 ng/mL was associated with a 32-times higher likelihood of mortality [OR: 32.65 (95% CI, 2.67–399.78); P = 0.006] and a strong predictor of mortality (AUROC 0.92). TFPI was associated with a 9-times higher likelihood of mortality [OR: 9.59 (95% CI, 1.02–89.75); P = 0.002] and a fair predictor of mortality (AUROC 0.68). Conclusions: SDC-1 and TFPI are associated with a higher risk of 30-day mortality. We propose the measurement of SDC-1 on admission to identify burn patients at high risk of mortality. However, further investigation with a larger sample size is warranted. Address reprint requests to Jeffrey W. Shupp, MD, MedStar Washington Hospital Center, The Burn Center, Department of Surgery, 110 Irving St. NW Suite 3B-55, Washington, DC 20010. E-mail: Jeffrey.w.shupp@medstar.net Received 5 October, 2020 Revised 27 October, 2020 Accepted 8 December, 2020 Disclosure of funding: This work was funded by the U.S. Department of Defense (DOD) (W911QY-15-C-0025, and W911NF-17-1-0594). This project was done in partnership with the Department of Health and Human Services; Office of the Assistant Secretary for Preparedness and Response; Biomedical Advanced Research and Development Authority and funding, in part, was provided through Interagency Agreement (750119PR2100075). SYSCOT Study Group Authorship: Melissa M. McLawhorn, RN BSN, Lauren T. Moffatt, PhD, Jeffrey W Shupp, MD, Rachael A Callcut, MD, MSPH, Mitchell J Cohen, MD, Linda R. Petzold, PhD, Jeffrey D. Varner, PhD, Maria Cristina Bravo, PhD, Kathleen E. Brummel-Ziedins, PhD, Kalev Freeman, MD, PhD, Kenneth G. Mann, PhD, Thomas Orfeo, PhD, Aarti Gautam, PhD, Rasha Hammamieh, PhD, Marti Jett, PhD, Anthony E. Pusateri, PhD Disclosure: This project was done in partnership with the Department of Health and Human Services; Office of the Assistant Secretary for Preparedness and Response; Biomedical Advanced Research and Development Authority and funding, in part, was provided through Interagency Agreement (750119PR2100075). The authors report no conflicts of interest. Research protocols were developed as part of the Systems Biology for Biological Responses to Severe Hemorrhage, conducted and supported by the Department of Defense. This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0 © 2020 by the Shock Society

Toll-Like Receptors, Associated Biochemical Signaling Networks, and S100 Ligands Host cells recognize molecules that signal danger using pattern recognition receptors (PRRs). Toll-Like Receptors (TLRs) are the most studied class of PRRs and detect pathogen associated molecular patterns and danger associated molecular patterns. Cellular TLR activation and signal transduction can therefore contain, combat and clear danger by enabling appropriate gene transcription. Here we review the expression, regulation and function of different TLRs, with an emphasis on TLR-4, and how TLR adaptor protein binding directs intracellular signaling resulting in activation or termination of an innate immune response. Finally, we highlight the recent progress of research on the involvement of S100 proteins as ligands for TLR-4 in inflammatory disease. Address reprint requests to John C. Marshall, MD, St. Michael's Hospital, 4th Floor Bond Wing, Room 4-007, 30 Bond Street, Toronto, Ontario, M5B 1W8, Canada. E-mail: john.marshall@unityhealth.to Received 25 October, 2020 Revised 12 November, 2020 Accepted 30 November, 2020 Conflicts of Interest: The authors have no conflicts of interest to declare. Grant Funding Source: Canadian Institutes of Health Research (MOP 129493) © 2020 by the Shock Society

Bone Marrow-Derived Mononuclear Cell Transplantation can Reduce Systemic Inflammation and Endothelial Glycocalyx Damage in Sepsis Bone marrow-derived mononuclear cells (BMMNCs) secrete anti-inflammatory mediators that protect against acute inflammation. Current evidence suggests that BMMNC transplantation can reduce acute tissue injury caused by systemic inflammation and lung dysfunction. This study evaluated the role of BMMNCs in reducing systemic inflammatory responses to vascular endothelial injury in sepsis. Bone marrow cells were harvested from the tibias and femurs of twelve-week-old male Wistar rats; BMMNCs were separated by density centrifugation. Additional rats underwent cecal ligation and puncture (CLP) or similar sham surgery. BMMNCs were injected intravenously 30 min after CLP. The Sham and CLP Control groups were administered PBS. The seven-day survival rate improved markedly in the CLP-BMMNC group compared with that in the Control group. BMMNCs markedly suppressed the serum levels of pro-inflammatory mediators such as tumor necrosis factor-alpha, interleukin-6, and histone H3 at 3, 6, and 12 h after CLP. In the CLP-BMMNC group, the serum levels of syndecan-1, the main component of the vascular endothelial glycocalyx layer, were notably lower than those in the Control group 6 h after CLP. Histological analysis revealed improvement of morphological damages in the CLP-BMMNC group. Ultrastructural analysis revealed that the glycocalyx structure was maintained and the continuity of the vascular endothelial glycocalyx layer was preserved in the BMMNC group, compared to the case for the Control group at 6 and 12 h. Therefore, BMMNC transplantation may provide reduced systemic inflammation and endothelial glycocalyx damage, dramatically improving the survival of rats. These findings provide insights into formulating potential therapeutic strategies against sepsis. Address reprint requests to Tsunehiro Matsubara, MD, Osaka University Graduate School of Medicine Department of Traumatology and Acute Critical Care Center, 2-15 Yamadaoka, Suita-city, Osaka 565-0871, Japan. E-mail: tsunehiro1231@live.jp Received 1 August, 2020 Revised 10 September, 2020 Accepted 9 December, 2020 Conflicts of Interest and Source of Funding: This study received a Grant-in-Aid for Young Scientists from The Ministry of Education, Culture, Sports, Science and Technology, Japan. The authors declare no conflicts of interest. © 2020 by the Shock Society

Neutrophil-To-Lymphocyte Ratio And Covid-19 No abstract available

Pharmacological and Genetic Inhibition of Translocator Protein 18 kDa Ameliorated Neuroinflammation in Murine Endotoxemia Model Sepsis-associated encephalopathy (SAE) is a diffuse brain dysfunction associated with sepsis. The development of an effective strategy for early diagnosis and therapeutic intervention is essential for the prevention of poor prognosis of SAE. Translocator protein 18 kDa (TSPO) is a mitochondrial protein implicated in steroidogenesis and inflammatory responses. Despite accumulating evidence that implicates TSPO in the neuroinflammatory response of the central nervous system, the possible role of TSPO in SAE remains unclear. Aim of this study is to address a role of TSPO in neuroinflammation using mice 24 h after systemic injection of lipopolysaccharide (LPS), which consistently demonstrated microglial activation and behavioral inhibition. Quantitative polymerase chain reaction analysis revealed that hippocampal TSPO expression was induced following the systemic LPS injection, associated with an increase in pro-inflammatory cytokines such as tumor necrosis factor-α and interleukin-1β. Interestingly, pretreatment with the TSPO antagonist, ONO-2952, or germ-line deletion of the TSPO gene exhibited an anti-inflammatory effect with significant suppression of LPS-induced production of those cytokines. These effects demonstrated by the ONO-2952 or TSPO knockout were associated with significant recovery from behavioral inhibition, as shown by improved locomotor activity in the open field analysis. Histological analysis revealed that ONO-2952 pretreatment suppressed the LPS-induced activation of TSPO-expressing microglia in the hippocampus of mice. Collectively, these results suggest that TSPO plays a critical role in the SAE mouse model. Based on this finding, monitoring TSPO activity, as well as the progress of endotoxemia and its sequelae in the animal model, would deepen our understanding of the underlying molecular mechanism of SAE. Address reprint requests to Hidenori Aizawa, MD, PhD, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553 Japan. E-mail: haizawa@hiroshima-u.ac.jp Received 24 September, 2020 Revised 12 October, 2020 Accepted 23 November, 2020 Disclosure: The authors declare that they have no conflicts of interest. Funding: This research was supported by a Grant-in-Aid for Scientific Research on Innovative Areas (JP19H05723) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) to HA; a Grant-in-Aid for 'Integrated Research on Depression, Dementia and Development Disorders (20dm0107093)' carried out under the Strategic Research Program for Brain Sciences by AMED to SY and a Grant-in-Aid for Scientific Research C (18K08888) to KH. © 2020 by the Shock Society

HIF-1α and Hypoxia Responsive Genes are Differentially Expressed in Leukocytes from Survivors and Non-Survivors Patients during Clinical Sepsis Hypoxia inducible factor 1 alpha (HIF-1α) is linked to the metabolic and immune alterations in septic patients. Stabilization of HIF-1α by hypoxia or inflammation promotes the expression of several genes related to glycolytic metabolism, angiogenesis, coagulation, cell proliferation and apoptosis. Here we analyzed public available blood transcriptome datasets from septic patients and evaluated by PCR array the expression of HIF-1α and other hypoxia responsive genes in peripheral blood mononuclear cells (PBMC) from patients with sepsis secondary to community acquired infections. Samples were collected at ICU admission (D0, n=29) and after 7 days follow-up (D7, n = 18); healthy volunteers (n = 10) were included as controls. Hypoxia and glycolysis were among the top scored molecular signatures in the transcriptome datasets. PCR array showed that 24 out of 78 analyzed genes were modulated in septic patients compared to healthy volunteers; most of them (23/24) were downregulated at admission. This same pattern was observed in surviving patients, while non-survivors presented more upregulated genes. EGLN1, EGLN2 and HIF1AN, inhibitors of HIF-1α activation were downregulated in patients, regardless of the outcome, while HIF-1α and other target genes, such as PDK1 and HMOX1, expression were higher in non-survivors than in survivors, mainly at D7. Non-survivor patients also presented a higher SOFA score and lower PaO2/FiO2 ratio. Our results indicate a differential modulation of hypoxia pathway in leukocytes between septic patients who survived and those who did not survive with an increased intensity at D7, which is possibly influenced by disease severity and may affect the immune response in sepsis. Address reprint requests to Reinaldo Salomao, MD, PhD, Division of Infectious Diseases, Escola Paulista de Medicina, Hospital São Paulo, Universidade Federal de São Paulo, Rua Pedro de Toledo, 669, 10th Floor, Sao Paulo, SP, 04039-032, Brazil. E-mail: rsalomao@unifesp.br Received 25 September, 2020 Revised 19 October, 2020 Accepted 6 November, 2020 Funding: This work was supported by FAPESP (Grant 2017/21052-0). RS is the recipient of a Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) fellowship. BLF has a scholarship from FAPESP (2016/13855-2). Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (www.shockjournal.com). © 2020 by the Shock Society

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Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,00306932607174,alsfakia@gmail.com,

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Fwd: New Articles From Journal of Translational Medicine

Translational Medicine

Journal of Translational Medicine The following new articles have just been published in Journal of Translational Medicine Correction Correction to: Systematic review of randomized controlled trials for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) Do-Young Kim, Jin-Seok Lee, Samuel-Young Park, Soo-Jin Kim and Chang-Gue Son Journal of Translational Medicine 2020, 18:492 | Published on: 23 December 2020 Full Text | PDF Correction Correction to: The long non-coding RNA TUG1 indicates a poor prognosis for colorectal cancer and promotes metastasis by affecting epithelial-mesenchymal transition Junfeng Sun, Chaohui Ding, Zhen Yang, Tao Liu, Xiefu Zhang, Chunlin Zhao and Jiaxiang Wang Journal of Translational Medicine 2020, 18:491 | Published on: 22 December 2020 Full Text | PDF Letter to the Editor COVID-19 biomarkers for severity mapped to polycystic ovary syndrome Abu Saleh Md Moin, Thozhukat Sathyapalan, Stephen L. Atkin and Alexandra E. Butler Journal of Translational Medicine 2020, 18:490 | Published on: 22 December 2020 Full Text | PDF Review May the analysis of 1918 influenza pandemic give hints to imagine the possible magnitude of Corona Virus Disease-2019 (COVID-19)? Raffaele Scarpa, Francesco Caso, Luisa Costa, Saverio Passavanti, Maria Grazia Vitale, Claudia Trojaniello, Antonio Del Puente and Paolo A. Ascierto Journal of Translational Medicine 2020, 18:489 | Published on: 22 December 2020 Full Text | PDF Research Evaluation of the diagnostic accuracy of a new point-of-care rapid test for SARS-CoV-2 virus detection Leonardo Miscio, Antonio Olivieri, Francesco Labonia, Gianfranco De Feo, Paolo Chiodini, Giuseppe Portella, Luigi Atripaldi, Roberto Parrella, Rodolfo Conenna, Franco Maria Buonaguro, Ernesta Cavalcanti, Paolo Ascierto, Gerardo Botti and Attilio Bianchi Journal of Translational Medicine 2020, 18:488 | Published on: 21 December 2020 Full Text | PDF Follow BMC on: This is how to ensure BMC's emails reach your inbox. You have received this message in a belief that it would be of interest to you, as a result of opting in to receive BMC Article Alerts. To modify your subscription (including adding or removing subjects), click here. Use this unsubscribe link to stop receiving any further Article Alerts like this. For further information or enquiries please use our contact page details. BMC respects your privacy and does not disclose, sell or rent your personal information to any non-affliated third parties with your consent. Privacy policy. BioMed Central Ltd The Campus, 4 Crinan Street, London, N1 9XW, United Kingdom © 2020 BioMed Central Limited unless otherwise stated. Part of Springer Nature.

Machine Learning Applied to Registry Data: Development of a Patient-Specific Prediction Model for Blood Transfusion Requirements During Craniofacial Surgery Using the Pediatric Craniofacial Perioperative Registry Dataset

xloma.fota13 shared this article with you from Inoreader Machine Learning Applied to Registry Data: Development of a Patient-Specific Prediction Model for Blood Transfusion Requirements During Craniofacial Surgery Using the Pediatric Craniofacial Perioperative Registry Dataset Via Anesthesia & Analgesia - Current Issue Background: Craniosynostosis is the premature fusion of ≥1 cranial sutures and often requires surgical intervention. Surgery may involve extensive osteotomies, which can lead to substantial blood loss. Currently, there are no consensus recommendations for guiding blood conservation or transfusion in this patient population. The aim of this study is to develop a machine-learning model to predict blood product transfusion requirements for individual pediatric patients undergoing craniofacial surgery. METHODS: Using data from 2143 patients in the Pediatric Craniofacial Surgery Perioperative Registry, we assessed 6 machine-learning classification and regression models based on random forest, adaptive boosting (AdaBoost), neural network, gradient boosting machine (GBM), support vector machine, and elastic net methods with inputs from 22 demographic and preoperative features. We developed classification models to predict an individual's overall need for transfusion and regression models to predict the number of blood product units to be ordered preoperatively. The study is reported according to the Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD) checklist for prediction model development. RESULTS: The GBM performed best in both domains, with an area under receiver operating characteristic curve of 0.87 ± 0.03 (95% confidence interval) and F-score of 0.91 ± 0.04 for classification, and a mean squared error of 1.15 ± 0.12, R-squared (R2) of 0.73 ± 0.02, and root mean squared error of 1.05 ± 0.06 for regression. GBM feature ranking determined that the following variables held the most information for prediction: platelet count, weight, preoperative hematocrit, surgical volume per institution, age, and preoperative hemoglobin. We then produced a calculator to show the number of units of blood that should be ordered preoperatively for an individual patient. CONCLUSIONS: Anesthesiologists and surgeons can use this continually evolving predictive model to improve clinical care of patients presenting for craniosynostosis surgery. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Analgesic Effect of Intraoperative Intravenous S-Ketamine in Opioid-Naïve Patients After Major Lumbar Fusion Surgery Is Temporary and Not Dose-Dependent: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial

xloma.fota13 shared this article with you from Inoreader Analgesic Effect of Intraoperative Intravenous S-Ketamine in Opioid-Naïve Patients After Major Lumbar Fusion Surgery Is Temporary and Not Dose-Dependent: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial Via Anesthesia & Analgesia - Current Issue Background: Severe pain often accompanies major spine surgery. Opioids are the cornerstone of postoperative pain management but their use can be limited by numerous side effects. Several studies claim that adjuvant treatment with intravenous (IV) ketamine reduces opioid consumption and pain after back surgery. However, the exact role of ketamine for this indication is yet to be elucidated. We compared 2 different doses of S-ketamine with placebo on postoperative analgesic consumption, pain, and adverse events in adult, opioid-naïve patients after lumbar fusion surgery. METHODS: One hundred ninety-eight opioid-naïve patients undergoing lumbar spinal fusion surgery were recruited to this double-blind trial and randomly assigned into 3 study groups: Group C (placebo) received a preincisional IV bolus of saline (sodium chloride [NaCl] 0.9%) followed by an intraoperative IV infusion of NaCl 0.9%. Both groups K2 and K10 received a preincisional IV bolus of S-ketamine (0.5 mg/kg); in group K2, this was followed by an intraoperative IV infusion of S-ketamine (0.12 mg/kg/h), while in group K10, it was followed by an intraoperative IV infusion of S-ketamine (0.6 mg/kg/h). Postoperative analgesia was achieved by an IV patient-controlled analgesia (IV PCA) device delivering oxycodone. The primary end point was cumulative oxycodone consumption at 48 hours after surgery. The secondary end points included postoperative pain up to 2 years after surgery, adverse events, and level of sedation and confusion in the immediate postoperative period. RESULTS: The median [interquartile range (IQR)] cumulative oxycodone consumption at 48 hours was 154.5 [120] mg for group K2, 160 [109] mg for group K10, and 178.5 [176] mg for group C. The estimated difference was −24 mg between group K2 and group C (97.5% confidence interval [CI], −73.8 to 31.5; P = .170) and −18.5 mg between group K10 and C (97.5% CI, 78.5–29.5; P = .458). There were no significant differences between groups. Postoperative pain scores were significantly lower in both ketamine treatment groups at the fourth postoperative hour but not later during the 2-year study period. The higher ketamine dose was associated with more sedation. Otherwise, differences in the occurrence of adverse events between study groups were nonsignificant. CONCLUSIONS: Neither a 0.12 nor a 0.6 mg/kg/h infusion of intraoperative IV S-ketamine was superior to the placebo in reducing oxycodone consumption at 48 hours after lumbar fusion surgery in an opioid-naïve adult study population. Future studies should assess ketamine's feasibility in specific study populations who most benefit from reduced opioid consumption. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.