TSPO acts as an immune resistance gene involved in the T cell mediated immune control of glioblastoma

Glioblastoma (GB) IDH-wildtype is the most malignant primary brain tumor. It is particularly resistant to current immunotherapies. Translocator protein 18 kDa (TSPO) is upregulated in GB and correlates with malignancy and poor prognosis, but also with increased immune infiltration. Here, we studied the role of TSPO in the regulation of immune resistance of human GB cells. The role of TSPO in tumor immune resistance was experimentally determined in primary brain tumor initiating cells (BTICs) and cell lines through genetic manipulation of TSPO expression and subsequent cocultures with antigen specific cytotoxic T cells and autologous tumor-infiltrating T cells. Death inducing intrinsic and extrinsic apoptotic pathways affected by TSPO were investigated. TSPO-regulated genes mediating apoptosis resistance in BTICs were identified through gene expression analysis and subsequent functional analyses. TSPO transcription in primary GB cells correlated with CD8+ T cell infiltration, cytotoxic activity of T cell infiltrate, expression of TNFR and IFNGR and with the activity of their downstream signalling pathways, as well as with the expression of TRAIL receptors. Coculture of BTICs with tumor reactive cytotoxic T cells or with T cell-derived factors induced TSPO up-regulation through T cell derived TNFα and IFNγ. Silencing of TSPO sensitized BTICs against T cell-mediated cytotoxicity. TSPO selectively protected BTICs against TRAIL-induced apoptosis by regulating apoptosis pathways. TSPO also regulated the expression of multiple genes associated with resistance against apoptosis. We conclude that TSPO expression in GB is induced through T cell-derived cytokines TNFα and IFNγ and that TSPO expression protects GB cells against cytotoxic T cell attack through TRAIL. Our data thereby provide an indication that therapeutic targeting of TSPO may be a suitable approach to sensitize GB to immune cell-mediated cytotoxicity by circumventing tumor intrinsic TRAIL resistance

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

Analyzing trends in HSV Western Blot results at a Reference Laboratory

Thesis (Master's)--University of Washington, 2021Objective: To better understand herpes simplex virus (HSV) Western Blot result trends over the past 20 years and to determine the proportion of Western Blot positivity for HSV-1 and HSV-2 and the proportion of results that are indeterminate. To examine the relationship between indeterminate results and age. Methods: We used de-identified HSV Western Blot data performed at the University of Washington Virology Laboratory between 1999-2020. We included all results collected between 1999-2020 from persons aged 18 to 99 with a result of negative, positive, or indeterminate. We excluded results from the oncology service with the label Seattle Cancer Care Alliance (“SCCA”) but included all other referral locations. We assessed overall total proportion of negative, positive, and indeterminate for both HSV-1 and HSV-2 in the sample. Linear regression was used assess the trends in positive and indeterminate results over time. We then analyzed the proportion of Western Blots done in the 5 year time period before and after the 2015 CDC guidelines. Linear regression was utilized to assess the association between indeterminate results and age. Results: Results from 188,342 samples collected from 1999 to 2020 were included in the analysis. 107,468 (57%) were HSV-1 positive while 35,294 (19%) were HSV-2 positive. There were 20,138 (11%) samples that were positive for both HSV-1 and HSV-2 and 61,533 (33%) that were negative for both types. Overall, 4,419 samples were indeterminate for HSV-2 (2%) and 2,152 (1%) for HSV-1. The proportion of HSV-1 positives decreased by 0.45% each year (p<0.001) while the proportion of indeterminates increased by 0.08% each additional year (p<0.001). For HSV-2, the proportion of positives decreased by 0.6% annually (p<0.001) and indeterminates increased by 0.15% each year (p<0.001). When looking at HSV-2 indeterminates by age category, the highest proportion was in the 56-65 age group with a total of 3.3% compared to the lowest at 1.7% in those 18-25 (p<0.003). Conclusion: HSV-1 and HSV-2 seropositivity has declined over the last twenty years, in parallel to national trends. The frequency of indeterminate results for both HSV-1 and HSV-2 may be rising possibly due to increased testing in the setting of declining seroprevalence leading to a decrease in the positive predictive value of testing and increase in false positives. Our analysis also showed that there was a statistically significant correlation between proportion of indeterminates and older age

An efficient parallel mixed method for flow simulations in heterogeneous geological media

International audienceThe permeability of a 3D geological fracture network is determined by triangulating the fractures and solving the 2D Darcy's equation in each fracture. Here, the numerical modelling aims to simulate a great number of networks made up of a great number of fractures i.e. from 10^3 to 10^6 fractures. Parallel computing allows us to solve very large linear systems improving the realism of simulations. Several algorithms to simulating fluid flow are proposed for the cases of signiccant matrix permeability. In the case of a weak permeability matrix, the flow is focused in the fractures having a strong permeability and fluids percolate through networks of interconnected fractures. In this paper, we present a complete parallel algorithm for solving flow equations in fracture networks. We consider an imprevious matrix. The different parts of the algorithm are detailed. Numerical examples using the mixed finite element (MFE) method for various fracture networks illustrate the efficiency and robustness of the proposed algorithm. To the best of our knowledge, results for parellel simulation of fluid flow in discrete-fractured media with impervious matrix using the MFE method are the first to appear in the literature

Urtica pilulifera leaves extract mitigates cadmium induced hepatotoxicity via modulation of antioxidants, inflammatory markers and Nrf-2 signaling in mice

Introduction: Cadmium (Cd) is a harmful heavy metal that results in many toxic issues. Urtica pilulifera showed potential pharmaceutical applications. This study investigated the possible ameliorative mechanism of Urtica pilulifera leaves extract (UPLE) against hepatotoxicity induced by cadmium chloride (CdCl2) in mice.Methods:In vitro phytochemical screening and the metal-chelating activity of UPLE were ascertained. Four groups of forty male mice were used (n = 10) as follows; Group 1 (G1) was a negative control. G2 was injected i.p., with UPLE (100 mg/kg b. wt) daily. G3 was injected i.p., with Cd (5 mg/kg b. wt) daily. G4 was injected with Cd as in G3 and with UPLE as in G2. On day 11, the body weight changes were evaluated, blood, and serum samples were collected for hematological and biochemical assessments. Liver tissues were used for biochemical, molecular, and histopathological investigations.Results: The results showed that UPLE contains promising secondary metabolites that considerably lessen the negative effects of Cd on liver. Furthermore, UPLE inhibited oxidative stress and inflammation; restored antioxidant molecules; and promoted nuclear-related factor-2 (Nrf-2) expression. Also, UPLE improved the histopathological alterations induced by Cd.Discussion: This study explored the beneficial role of UPLE treatment in Cd-induced liver injury through enhancing Nrf-2 signaling and antioxidant enzyme gene expression in the liver of mice. Therefore, UPLE could have valuable implications against hepatotoxicity induced by environmental cadmium exposure. Which can be used as a chelating agent against Cd