Viral load decrease in SARS‐CoV‐2 BA.1 and BA.2 Omicron sublineages infection after treatment with monoclonal antibodies and direct antiviral agents

alexandrossfakianakis shared this article with you from Inoreader Viral load decrease in SARS‐CoV‐2 BA.1 and BA.2 Omicron sublineages infection after treatment with monoclonal antibodies and direct antiviral agents via Journal of Medical Virology ABSTRACT Background The efficacy on the Omicron variant of the approved early- coronavirus disease 2019 (COVID-19) therapies, especially monoclonal antibodies, has been challenged by in vitro neutralization data, while data on in vivo antiviral activity are lacking. Materials and methods We assessed potential decrease from day1 to day7 viral load (VL) in nasopharyngeal swabs of outpatients receiving Sotrovimab, Molnupiravir, Remdesivir, or Nirmatrelvir/ritonavir for mild-to-moderate COVID-19 due to sublineages BA.1 or BA.2, and average treatment effect (ATE) by weighted marginal linear regression models. Results A total of 521 patients [378 BA.1 (73%),143 (27%) BA.2] received treatments (Sotrovimab 202, Molnupiravir 117, Nirmatrelvir/ritonavir 84, and Remdesivir 118): median age 66 years, 90% vaccinated, median time from symptoms onset 3 days. Day1 mean viral load was 4.12 log2 (4.16 for BA.1 and 4.01 for BA.2). The adjusted analysis showed that Nirmatrelvir/ritonavir significantly reduced VL compared to all the other drugs, except vs. Molnupiravir in BA.2. Molnupiravir was superior to Remdesivir in both BA.1 and BA.2, and to Sotrovimab in BA.2. Sotrovimab had better activity than Remdesivir only against BA.1. Conclusions Nirmatrelvir/ritonavir showed the greatest antiviral activity against Omicron variant, comparable to Molnupiravir only in the BA.2 subgroup. VL decrease could be a valuable surrogate of drug activity in the context of the high prevalence of vaccinated people and low probability of hospital admission. This article is protected by copyright. All rights reserved. View on Web

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Investigating a possible causal relationship between maternal serum urate concentrations and offspring birthweight: a Mendelian randomization study

alexandrossfakianakis shared this article with you from Inoreader Investigating a possible causal relationship between maternal serum urate concentrations and offspring birthweight: a Mendelian randomization study via International Journal of Epidemiology - Advance Access Abstract Background Higher urate levels are associated with higher systolic blood pressure (SBP) in adults, and in pregnancy with lower offspring birthweight. Mendelian randomization (MR) analyses suggest a causal effect of higher urate on higher SBP and of higher maternal SBP on lower offspring birthweight. If urate causally reduces birthweight, it might confound the effect of SBP on birthweight. We therefore tested for a causal effect of maternal urate on offspring birthweight. Methods We tested the association between maternal urate levels and offspring birthweight using multivariable linear regression in the Exeter Family Study of Childhood Health (EFSOCH; n = 872) and UK Biobank (UKB; n = 133 187). We conducted two-sample MR to test for a causal effect of maternal urate [114 single-nucleotide polymorphisms (SNPs); n = 288 649 European ancestry] on offspring birthweight (n = 406 063 European ancestry; maternal SNP effect estimates adjusted for fetal effects). We assessed a causal relationship between urate and SBP using one-sample MR in UKB women (n = 199 768). Results Higher maternal urate was associated with lower offspring birthweight with similar confounder-adjusted magnitudes in EFSOCH [22 g lower birthweight per 1-SD higher urate (95% CI: –50, 6); P = 0.13] and UKB [–28 g (95% CI: –31, –25); P = 1.8 × 10–75]. The MR causal effect estimate was directionally consistent, but smaller [–11 g (95% CI: –25, 3); PIVW = 0.11]. In women, higher urate was causally associated with higher SBP [1.7 mmHg higher SBP per 1-SD higher urate (95% CI: 1.4, 2.1); P = 7.8 × 10–22], consistent with that previously published in women and men. Conclusion The marked attenuation of the MR result of maternal urate on offspring birthweight compared with the multivariable regression result suggests previous observational associations may be confounded. The 95% CIs of the MR result included the null but suggest a possible small effect on birthweigh t. Maternal urate levels are unlikely to be an important contributor to offspring birthweight. View on Web

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CaPaBLE - Assessing the Patient Generated Index Methodology in High Grade Glioma Patients and Caregivers

alexandrossfakianakis shared this article with you from Inoreader CaPaBLE - Assessing the Patient Generated Index Methodology in High Grade Glioma Patients and Caregivers via # Neuro-Oncology Current Issue Abstract AIMS CaPaBLE tests the feasibility and acceptability of assessing quality of life (QoL) using the patient-, or caregiver-generated index (PGI/CaGI) methodology in patients with HGG and their caregivers. METHOD CaPaBLE, (https://www.isrctn.com/ISRCTN45555598), followed patients and/or their caregivers up to 6 months. Standard measures for patients were EORTC QLQ-C30/BN20, for caregivers the CarGOQOL questionnaire. The QoL topics raised through PGI/CaGI have been coded to the most relevant domain from their respective standard measure for an initial assessment of concordance. RESULTS 36 patients, 24 caregivers recruited to study; completing an average of 3 study assessment timepoints. PGI and CaGI generated 240 and 160 topics respectively. Patient concerns most frequently coded to EORTC domain of Ro le Functioning; Caregiver concerns mostly coded to CarGOQOL domain of Burden. Other topics frequently raised by patients such as the driving and sex life, and future planning by caregivers are not specifically raised in standard questionnaires. CONCLUSION Nearly all topics raised by patients and caregivers were mapped to the domains of their respective standard QoL measure. However, almost half of all topics raised by patients and caregivers mapped to a minority of the domains included in standard measures; whilst a notable number of topics are not specifically included in standard measures at all. This raises questions regarding the efficiency and relevance of such questionnaires to patient and caregivers' daily lives. View on Web

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Hull’s Magic Box: Keeping Brain Tumour Biopsies “Alive” in the Lab Brings Research Opportunities for New Therapies and Earlier Diagnosis of Brain Tumour

alexandrossfakianakis shared this article with you from Inoreader Hull's Magic Box: Keeping Brain Tumour Biopsies "Alive" in the Lab Brings Research Opportunities for New Therapies and Earlier Diagnosis of Brain Tumour via # Neuro-Oncology Current Issue Abstract AIMS Assess/evaluate apoptosis in GBM samples maintained on a microfluidics system in response to GSK3368715 and other PRMT inhibitors, currently in clinical trials, with the ultimate goal of synergising with personalised patient care and precision medicine. Investigate the effect of treating GBM biopsies on-chip with PRMT inhibitors at the molecular level, including RNA and protein modifications. METHOD GBM biopsies are received from Hull Royal Infirmary and maintained on-chip for 8-days. They are perfused with media, at a rate of 3 μl/min, mimicking the in vivo environment and allowing real-time analysis of tumour behaviour. PRMT inhibitors, such as GSK3368715, are added to the media, in conjunction with TMZ, to determine their efficacy ex vivo using a range of techniques, such as: immunohistochemistry, cell viability assays, protein analysis and RNA-sequencing. RESULTS We show that PRMT inhibition increases apoptos is five-fold above the control, untreated GBM-on-chip samples. This is compounded by cell viability assays, which have indicated that cell viability in these post-chip tissues is reduced by 30% upon treatment with 1μM GSK3368715. Additionally, western blot analysis has indicated that PRMT inhibition with GSK3368715 appears to switch the methylation status of fused-in-sarcoma (FUS) protein in GBM biopsies. CONCLUSION These results indicate that PRMT inhibition may not only be a viable target for GBM therapy, but could also highlight a mechanism for re-sensitising MGMT-negative GBM to TMZ. This data produces an exciting argument for further research into the use of this novel inhibitor for improving prognosis for patients diagnosed with this devastating disease. View on Web

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Carcinomatous Meningitis Management

alexandrossfakianakis shared this article with you from Inoreader Retrospective Review of Carcinomatous Meningitis Management at a Tertiary Centre: Reflections on Current and Future Management via # Neuro-Oncology Current Issue Abstract AIMS Carcinomatous meningitis (CM) arises following metastatic deposition of neoplastic cells in the meninges triggering a complex series of pathological changes, typically representing a terminal complication of underlying malignancy. No uniform management strategy exists for CM patients, despite research highlighting numerous treatment modalities. We present a single centre retrospective study of CM patients managed over a ten year period, along with analysis of current and future treatment modalities for CM. METHOD Patient datasets were identified using diagnostic codes. Inclusion criteria were patients with malignant cells identified in CSF, or those with radiological features consistent with CM with a background of cancer and supporting clinical features. Data regarding patient symptomatology, management, and outcome were then gathered from electronic patient records. RESULTS Ten cases of carcinomatous meningitis were identified. The most common primary tumour site was breast (30%). The most common presenting symptoms were headache (70%), weakness (60%), vomiting (50%), and confusion (50%). Radiological evidence of CM in the form of leptomeningeal enhancement was noted in 60% of cases. Management of CM cases was variable – six patients underwent no further anti-cancer treatment, two patients underwent chemotherapy, and two patients were planned for radiotherapy. Median length of survival from time of CM diagnosis was 30 days (IQR 15 – 63). CONCLUSION CM patients have a poor prognosis, and significant variability exists in management. New therapeutic options are emerging, particularly in the field of targeted biologic therapies, and engagement with specialist oncology teams is recommended. Early palliative care support is essential in the management of CM patients. View on Web

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Identification of an Inflammatory Biomarker Signature in Plasma-Derived Extracellular Vesicles of Glioblastoma Patients

alexandrossfakianakis shared this article with you from Inoreader Identification of an Inflammatory Biomarker Signature in Plasma-Derived Extracellular Vesicles of Glioblastoma Patients via # Neuro-Oncology Current Issue Abstract AIMS Description of effective biomarkers present in biofluids could prove invaluable in GBM diagnosis. Extracellular vesicles (EVs) are essential to intercellular crosstalk in the tumour bulk and circulating EVs have been described as a potential reservoir of GBM biomarkers. Therefore, EV-based liquid biopsies have been suggested as a promising tool for GBM METHOD Ethical approval was obtained for a prospective study of healthy donors and consenting GBM patients at the University Hospitals Sussex (Brighton). To identify GBM specific proteins, small EVs (sEVs) were isolated from plasma samples using differential ultracentrifugation and validated through Nanoparticles tracking analysis, transmission electron microscopy and detection of known sEVs markers such as CD9, CD63, CD81 and HSP70. sEVs content was characterised through mass spectrometry and bioinformatic tools. RESULTS Our data indicate the presence of a GBM infl ammatory biomarker signature comprising members of the complement and regulators of inflammation and coagulation including VWF, FCGBP, C3, PROS1, and SERPINA1. Bioinformatic analysis highlighted that all potential markers exclusively identified in patient samples had already been linked with either GBM diagnosis, prognosis or associated signalling, suggesting that sEVs protein cargo could mirror the landscape of the original tumour and that selective circulating sEV-derived proteins might be used as hallmarks for GBM patients. CONCLUSION this study is a step forward in the development of a non-invasive liquid biopsy approach for the identification of valuable biomarkers that could significantly improve GBM diagnosis and, consequently, patients' prognosis and quality of life. View on Web

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Development of Novel LAT1 Targeting Small Molecules for Boron Neutron Capture Therapy (BNCT) and Potential Application for Treating Glioblastoma

alexandrossfakianakis shared this article with you from Inoreader Development of Novel LAT1 Targeting Small Molecules for Boron Neutron Capture Therapy (BNCT) and Potential Application for Treating Glioblastoma via # Neuro-Oncology Current Issue Abstract AIMS to make molecules that deliver more Boron than BPA for boron neutron capture therapy BNCT METHOD Boronated compounds were designed based on known LAT-1 substrates, synthesized using boronation techniques and purified using preparative HPLC. The compounds were formulated to achieve high concentrations when compared to BPA-fructose (BPA-F). Boronated compounds were tested for boron uptake and retention in multiple cell lines expressing either LAT1 and/or PEPT1. Compounds were further tested in multiple human xenograft models representing the cancer indication currently treatable by BNCT as well as in one syngeneic colon tumor model that may have high PEPT1 expression. Intracellular and intra tumor boron concentration were measured by ICP OES. We also synthesized 2 dipeptides and tested them in BNCT experiments with our collaborators at Kyoto University in Japan. They were tested in a CT26 mouse syngeneic model using neutrons from KURR1. RESULTS We synthesized multiple boronated compounds with better solubility than BPA (100 mg/ml v 30mg/ml in fructose). They were readily taken up in multiple cell lines and one of these compounds had longer retention than others. In competition experiments we were able to show that this compound was a superior substrate for LAT1. We also showed better BNCT results with our molecules compared to BPA. CONCLUSION BPA works for BNCT but it has limitations such as poor solubility. We made several new boronated compounds with better solubility than BPA and showed that we could deliver 2-3 x more boron in vitro and in vivo and better BNCT outcomes at KURR1. View on Web

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