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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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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Management of Low-Grade Gliomas – Extent of Resection Matters But Not All Tumours Are Amenable to Surgery

alexandrossfakianakis shared this article with you from Inoreader Management of Low-Grade Gliomas – Extent of Resection Matters But Not All Tumours Are Amenable to Surgery via # Neuro-Oncology Current Issue Abstract AIMS To present and review our experience in the management of low-grade gliomas. METHOD Retrospective case note review of all patients with WHO grade 2 glioma from 2011 to 2018 (based on WHO criteria at time of diagnosis). Data collected on demographics, presentation, location, initial management, histology, treatment, progression free (PFS) and overall survival (OS). RESULTS 130 eligible patients. Median follow 4.6 years (up to 10.5). Median age 40 years (range: 18-83). There were 70 (53.8%) astrocytomas, 44 (33.8%) oligodenrogliomas, 16 (12.3%) oligoastrocytomas. 66%(n=86) presented with seizures, 10.7%(n=14) with sensory symptoms, 8.5%(n=11) with speech disturbance, 5.3%(n=4) with motor symptoms and 12.3%(n=16) were identified incidentally. 50.1%(n=65) were frontal, 27.7%(n=36) temporal and 9.2%(n=12) parietal. 1st line treatment was resection in 70.7%(n=92), biopsy in 23.8%(n=31) and observation in 4.6%(n=6). 15.4 %(n=20) received adjuvant radiotherapy alone and 6.1%(n=8) received adjuvant radiotherapy followed by chemotherapy . At first recurrence, 31.6%(n=12) received further surgery and 95%(n=38) received radiotherapy and/or chemotherapy . Median PFS from 1st line treatment 66, 44 and 33 months for gross total resection (GRT), subtotal resection (STR), and biopsy respectively. Overall survival was 95.1%, 79.3% and 69.% for GTR, STR and biopsy respectively. CONCLUSION Management of low-grade gliomas remains challenging. Extent of resection impacts prognosis but not all patients have gliomas amenable to surgery. The effects of chemoradiotherapy will be presented in future meetings as this is an ongoing project. View on Web

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Glioma Cell Invasion Is Dependent Upon the DNA Damage Response Kinase ATR

alexandrossfakianakis shared this article with you from Inoreader Glioma Cell Invasion Is Dependent Upon the DNA Damage Response Kinase ATR via # Neuro-Oncology Current Issue Abstract AIMS Gliomas have high levels of DNA replication stress and clinical trials of inhibitors of the key replication stress response protein ATR (ataxia telangiectasia and rad 3 related protein) as radiosensitisers are planned. We aimed to investigate the effect of ATR inhibition on the ability of glioma cells to infiltrate and invade the brain. METHOD Live cell imaging in a panel of primary glioma cultures following siRNA or pharmacological inhibition of ATR. Invasion following treatment of murine orthotopic gliomas was determined by immunohistochemistry. Intravital imaging of GFP expressing murine orthotopic xenografts via an intracranial window model of glioma was undertaken. RESULTS Invading margins of human glioma samples demonstrated increased pATR expression relative to core. Live cell imaging demonstrated reduced cell velocity following ATR inhibition (Berzosertib/BAY1895344) or siRNA. Cytoplasmic vacuolation occur red following ATRi or siRNA which were single walled structures which engulf high molecular weight dextran, compatible with blockade of macropinosome processing. Live cell imaging with GFP-integrin α5 and integrin recycling assays showed sequestration of integrins within macropinosomes and reduced integrin cycling. Intravital in vivo imaging of murine xenograft tumours confirmed vacuolation and dextran uptake following ATRi, whilst a further in vivo study demonstrated a reduction in invading tumour cells. CONCLUSION We demonstrate a novel role for ATR in facilitating macropinocytic vesicle trafficking and integrin recycling in GBM cells which results in a profound motility defect in vitro and in vivo. ATR inhibitors are entering early phase trials as radiation sensitisers and we propose that therapeutic benefit will extend beyond DNA damage potentiation. View on Web

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Stereotactic Radiosurgery for Brainstem Metastases

alexandrossfakianakis shared this article with you from Inoreader Stereotactic Radiosurgery for Brainstem Metastases via # Neuro-Oncology Current Issue Abstract AIMS Limited data exists on outcomes following SRS for brainstem metastases (BSM). The purpose of this audit was to explore the use of SRS using Cyberknife for BSM at a single centre; reporting rates of toxicity and survival outcomes. METHOD Patients undergoing SRS for BSM from 2013 to 2021 were identified from a prospective database. Clinical characteristics were collected including; gender, age, histology and KPS. The use of previous WBRT, the volume and the dose delivered to the BSM were also recorded. All target volumes were peer reviewed by a neuro-radiologist. RESULTS 41 patients with a BSM were identified. The median age was 62 years (range 35-78). Histology was lung 15 (36.6%), breast 13 (31.7%) and other 13(31.7%). The median brainstem target volume was 0.36cc (range 0.01 – 5.63cc). 32 patients had single fraction (dose range 14.5 to 18Gy) and 9 patients had 3 fractions (dose range 17-24Gy). 7 patients had p revious WBRT. Median overall survival was 242 days (range 19-1213). A radiological response or stable disease was seen in 26 out of 30 patients with post SRS imaging available for review. 2 patients developed a 6th nerve palsy. 12 patients required a prolonged course of dexamethasone. No statistically significant relationship was observed between patient age, brainstem lesion size or fractionation and the need for prolonged use of dexamethasone but there was a trend with lung cancer patients requiring prolonged dexamethasone (p=0.06). CONCLUSION Brainstem SRS is viable option with an acceptable late toxicity profile. Updated information on survival and local control will be presented. View on Web

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Exploring a Link Between Alzheimer’s and Glioma by Investigating SORL1 Network

alexandrossfakianakis shared this article with you from Inoreader Exploring a Link Between Alzheimer's and Glioma by Investigating SORL1 Network via # Neuro-Oncology Current Issue Abstract AIMS Use bioinformatics methods to identify and validate associated proteins and genes in the SORL1 network. Generate a bank of patient derived cells in association with the Royal Preston Hospital BTNW tissue bank. Explore identified targets from the bioinformatics in patient derived cells. METHOD Proteins and genes associated with SORL1 and SORLA were identified on GeneCards. Connectivity mapping of known and predicted interactions linked to SORL1 was explored in STRING. For clinical validation differential expression was investigated by comparing genomic data from GTEX and TCGA, available at Xenabrowser. For survival analysis Kaplan-Meier curves were generated on cBioPortal. The five most differently expressed novel targets are taken forward for laboratory experiments using western blots for protein quantification and immunocytochemistry to identify and visualise target proteins. RESULTS A total of 73 genes (30 from GeneCards and 43 from STRING) were obtained. 63 genes from the generated SORL1-related network were shown to be differentially expressed whilst 40 were significantly different between low-surviving patients and high-surviving patients. The top five associated proteins are CKAP4, CTNND1, FN1, HSPA12A and SORCS3. CKAP4, CTNND1 and FN1 are highly expressed in both glioma and glioblastoma, but low expressed in healthy tissue. HSPA12A is low expressed in cancerous brain tissue and highly expressed in healthy samples. SORCS3 is differentially expressed in healthy samples and glioma, but significantly low expressed glioblastoma. CONCLUSION This project provides insight into SORL1 molecular relationships and function in tissue, cultured cells and serum from a patient cohort including demographics, disease progression and site. View on Web

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Development of chemiluminescent lab‐on‐fiber immunosensor for rapid point‐of‐care testing of anti‐SARS‐CoV‐2 antibodies and evaluation of longitudinal immune response kinetics following three‐dose inactivation virus vaccination

alexandrossfakianakis shared this article with you from Inoreader Development of chemiluminescent lab‐on‐fiber immunosensor for rapid point‐of‐care testing of anti‐SARS‐CoV‐2 antibodies and evaluation of longitudinal immune response kinetics following three‐dose inactivation virus vaccination via Journal of Medical Virology Abstract Developing reliable, rapid, and quantitative point-of-care testing (POCT) technology of SARS-CoV-2 specific antibodies and understanding longitudinal vaccination response kinetics are highly required to restrain the ongoing Coronavirus Disease 2019 (COVID-19) pandemic. We demonstrate a novel portable, sensitive, and rapid chemiluminescent lab-on-fiber detection platform for detection of anti-SARS-CoV-2 antibodies: the c-LOFI. Using SARS-CoV-2 Spike S1 RBD protein functionalized fiber bio-probe, the c-LOFI can detect anti-SARS-CoV-2 IgG and IgM antibodies with high sensitivity based on their respective HRP labeled secondary antibodies. The limits of detection of anti-SARS-CoV-2 IgG and IgM antibodies were 0.6 ng/mL and 0.3 ng/mL, respectively. The c-LOFI was successfully applied for direct detection of anti-SARS-CoV-2 antibodies in whole blood samples with simple dilution, which can serve as a finger prick test to rapidly detect antibodies. Furthermore, the l ongitudinal immune response (>12 months) kinetics following three-dose inactivated virus vaccines was evaluated based on anti-SARS-CoV-2 IgG detection results, which can provide importance significance for understanding the immune mechanism against COVID-19 and identify individuals who may benefit from the vaccination and booster vaccination. The c-LOFI has great potential to become a sensitive, low-cost, rapid, high-frequency POCT tool for the detection of both SARS-CoV-2 specific antibodies and other biomarkers. This article is protected by copyright. All rights reserved. View on Web

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Partial laryngectomy for naïve pT3N0 laryngeal cancer: Systematic review on oncological outcomes

alexandrossfakianakis shared this article with you from Inoreader Partial laryngectomy for naïve pT3N0 laryngeal cancer: Systematic review on oncological outcomes via Head & Neck Abstract The first aim was to define the oncologic outcomes of open partial laryngectomy (OPL) in naïve pT3 laryngeal cancer. The second aim was to analyze the outcomes after OPL versus total laryngectomy (TL). A literature search was conducted in three databases (MEDLINE, EMBASE, and Cochrane Library) until January 2022. In 805 patients treated with OPL, 5-year OS, DSS, DFS and LFS were 80.5% (95% CI 70.6–87.6), 83.4% (95% CI 75.7–89), 77.4% (95% CI 66.3–85.7) and 77.9% (95% CI 68.7–85), respectively. Three articles compared TL versus OLP: 5-year OS, DSS and DFS risk difference were 0.100 (95% CI −0.092 to 0.291), 0.067 (95% CI −0.085 to 0.220) and 0.018 (95% CI −0.164 to 0.201) respectively. OPL for selected pT3 laryngeal cancer is able to guarantee a high percentage of oncological success. Accurate patient selection is of utmost importance to differentiate advanced disease amenable to conservative surgery. View on Web

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Molecular landscapes of longitudinal NF2/22q and non‐NF2/22q meningiomas show different life histories

alexandrossfakianakis shared this article with you from Inoreader Molecular landscapes of longitudinal NF2/22q and non‐NF2/22q meningiomas show different life histories via Brain Pathology Abstract Recurrence is a major complication of some meningiomas. Although there were many studies on biomarkers associated with higher grades or increased aggressiveness, few studies specifically examined longitudinal samples of primary meningiomas and recurrences from the same patients for molecular life history. We studied 99 primary and recurrent meningiomas from 42 patients by FISH for 22q, 1q, 1p, 3p, 5q, 6q, 10p, 10q, 14q, 18q, CDKN2A/B homozygous deletion, ALT (Alternative Lengthening of Telomere), TERT re-arrangement, targeted sequencing and TERTp sequencing. Although NF2 mutation and 22q were well known to be aetiological events in meningiomas, we found that in these paired meningiomas, combining the two events resulted in an NF2/22q group (57 tumors from 25 patients) which were almost mutually exclusive with those cases without these two changes (42 tumors from 17 patients) for NF2/22q. No other molecular changes were totally unique to NF2/22q or non-NF2/22q tumors. For molecular evolution, NF2/22q meningiomas had higher cytogenetic abnormalities than non-NF2/22q meningiomas (p = 0.003). Most of the cytogenetic changes in NF2/22q meningiomas were present from the outset whereas for non-NF2/22q meningiomas, cytogenetic events were uncommon in the primary tumors and most were acquired in recurrences. For non-NF2/22q tumors, CDKN2A/B homozygous deletion, 1q gain, 18p loss, 3p loss, and ALT were preferentially found in recurrences. Mutations were largely conserved between primary and recurrent tumors. Phylogenetic trees showed 11/11 patients with multiple recurrent tumors had a conserved evolutionary pattern. We conclude that for molecular life history, NF2 and 22q should be regarded as a group. NF2/22q recurring meningiomas showed more cytogenetic abnormalities in the primary tumors, whereas non-NF2/22q meningiomas showed C DKN2A/B deletion and other cytogenetic abnormalities and ALT at recurrences. Although chromosome 1p loss is a known poor prognostic marker in meningiomas, it was also associated with a shorter TBR (time between resection) in this cohort (p = 0.002). View on Web

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Genetic Polymorphism in the Tumor Necrosis Factor Alpha gene (G‐308A) is associated with Persistent Apical Periodontitis in Brazilians

alexandrossfakianakis shared this article with you from Inoreader Genetic Polymorphism in the Tumor Necrosis Factor Alpha gene (G‐308A) is associated with Persistent Apical Periodontitis in Brazilians via International Endodontic Journal Abstract Aim To investigate if there was an association between genetic polymorphisms in TNF-⍺ and its receptors TNFRSF1A and TNFRSF1B with persistent apical periodontitis (PAP) in Brazilian subjects. Methodology Patients who had pulpal necrosis and apical periodontitis installed at the time of treatment, with at least one-year of follow-up after non-surgical root canal treatment were recalled. 378 subjects were included, 150 subjects with signs/symptoms of PAP and 228 subjects with root canal–treated teeth exhibiting healthy perirradicular tissues (healed). Genomic DNA was extracted from saliva and used for TNF-⍺ (rs1800629), TNFRSF1A (rs1800693) and TNFRSF1B (rs1061622) genotyping by real-time PCR. Genotypes and alleles frequencies were evaluated by c2 or Fisher's exact tests and odds ratio were implemented (𝛂= 5%). Results The genetic polymorphism in TNF-α (rs1800629) was associated as a protective factor for the development of PAP (p<0.05), once subjects who presented at least one allele A (AA+AG X GG), had a higher chance to lesion repair (p<0.05). The polymorphisms rs1800693 and rs1061622 in TNF receptors (TNFRSF1A and TNFRSF1B respectively) were not associated with the development of PAP (p>0.05). Conclusions The observed results demonstrate that polymorphism in TNF-α but not in its receptors is associated with PAP. View on Web

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