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Espensen Falk posted an update 6 months, 4 weeks ago
These results indicate that the intermediate domain is nonessential for UV-induced translesion replication in cultured mouse cells.
Immune-targeted therapies are being successfully implemented into cancer clinical practice. In particular checkpoint inhibitors are employed to modulate the immune microenvironment of solid tumors. We sought to determine the expression of PD-L1, HVEM, and B7H3 in human and canine osteosarcoma, and correlate expression with clinical features and tumor infiltrating lymphocytes in naturally-occurring canine osteosarcoma.
Flow cytometry was used to measure ligand surface expression of five human and three canine cell lines. Immunohistochemistry was utilized for expression of ligands and lymphocyte markers in thirty-seven treatment-naïve canine osteosarcoma patients.
All cell lines expressed all three ligands at variable levels in both species. Metastatic lesions were associated with higher expression of all three ligands in patient tumor samples. PD-L1 expression strongly correlated with B7H3 and HVEM expression, while HVEM and B7H3 were weakly correlated. Whereas peritumoral T-cell expression positively coand B7H3 were weakly correlated. Whereas peritumoral T-cell expression positively correlated with PD-L1 and HVEM tumor expression, the presence of T-cells intratumorally were rare. Furthermore, intratumor penetration by T-cells was greatest in metastatic lesions, despite log-fold increases in peritumoral T-cells. In summary, PD-L1, HVEM, and B7H3 are expressed in osteosarcoma, with metastatic disease lesions expressing higher levels. Metabolism inhibitor We show for the first time that these ligands expressed on osteosarcoma cells positively correlate with each other and the presence of peritumoral T cell infiltration. Furthermore, osteosarcoma appears to be an intratumoral immune desert with significant resistance to effector T cells. Multiple agents targeting checkpoints are in clinical practice, and may have immune modulating benefit in osteosarcoma.The purpose of this article is to review the many facets of central nervous system tuberculosis (CNS-TB). The entities described are tuberculous meningitis (TBM) and its complications, spinal cord disorders, tuberculomas and co-infection with the human immune-deficiency virus (HIV). The latter has become a common problem worldwide becoming a more fulminant disease. The accuracy of the conventional and the modern molecular techniques for the diagnosis of TBM have a high specificity but a low to moderate sensitivity. Computerised tomographic scans and magnetic resonance imaging have many characteristic features which have vastly improved the diagnostic accuracy of CNS-TB. The recommended therapeutic regimens are an extrapolation of the regimen used for pulmonary TB, hence the optimal composition, dosage and duration of the therapy are not yet established. Multidrug resistant TB is emerging as a global threat and the delay in recognition of drug resistance combined with the lack of data on appropriate drug regimen adds to its high mortality.Parkinson’s disease (PD) is characterized by both motor and nonmotor deficits. Among cardinal symptoms of this disorder, tremor is the least responsive to dopamine replacement therapy and is often undertreated. Zuranolone (SAGE-217) is an investigational oral neuroactive steroid (NAS) gamma-aminobutyric acid A (GABAA) receptor-positive allosteric modulator (PAM) that has been investigated for its safety and efficacy in patients with PD. In the current open-label study, zuranolone capsules (20 to 30 mg) were administered for 7 days in 14 patients (mean age, 65.1 years; mean time since PD diagnosis, 9 years). The primary efficacy endpoint was reduction in tremor symptoms, as assessed by change from baseline in Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part II/III Tremor Scores on Day 8. Additional endpoints included improvements in overall motor symptoms, and motor and nonmotor aspects of daily living. Adverse events (AEs) were also monitored. The MDS-UPDRS Part II/III Tremor Score improved by 40% (P less then 0.0001) from baseline on Day 8. The motor score, and nonmotor experiences of daily living (nM-EDL), and motor experiences of daily living (m-EDL) scores (MDS-UPDRS Parts I and II, respectively), also improved on Day 8. No serious AEs were reported, and no patients discontinued treatment. The most common AEs were dizziness, sedation, and somnolence. Zuranolone was generally well tolerated and improved tremor symptoms in patients with PD who were on stable doses of concurrent dopaminergic agents. These data support the further investigation of NAS GABAA receptor PAMs as adjunctive treatments for tremor in patients with PD.Microsporidiosis and cryptosporidiosis are associated with chronic diarrhea in immunocompromised patients. The objectives of this study were to i) assess a multiplex quantitative PCR assay targeting Cryptosporidium spp and the microsporidian Enterocytozoon bieneusi and Encephalitozoon spp, and ii) provide an update on the epidemiology of these pathogens. A prospective study was conducted from January 2017 to January 2019. Performance of the assay was assessed, and all cryptosporidia and microsporidia isolates were genotyped. The sensitivity of the multiplex PCR method reached 1 copy/μL for each targeted pathogen. The sensitivity of co-proantigen testing in the diagnosis of cryptosporidiosis was 73%. The sensitivity of microscopy in the diagnosis of cryptosporidiosis was 64%, and microsporidiosis, 50%. Among the 456 patients included, 14 were positive for Cryptosporidium spp (4 different species); 5, for E. bieneusi; and 2, for Encephalitozoon intestinalis. The overall prevalence of cryptosporidia was 3.1%, and of microsporidia, 1.5%; in kidney transplant recipients (n = 82), corresponding values were 7.3% and 2.4% (6 and 2 patients), respectively. Two cases of E. intestinalis infection were diagnosed in children who had traveled to the tropics. This study is the first to assess a multiplex quantitative PCR method for the simultaneous diagnosis of intestinal microsporidiosis and cryptosporidiosis. The highest prevalences of both pathogens were observed in kidney transplant recipients.
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