The role of inflammation in subventricular zone cancer

The adult subventricular zone (SVZ) stem cell niche has proven vital for discovering neurodevelopmental mechanisms and holds great potential in medicine for neurodegenerative diseases. Yet the SVZ holds a dark side - it can become tumorigenic. Glioblastomas can arise from the SVZ via cancer stem cells (CSCs). Glioblastoma and other brain cancers often have dismal prognoses since they are resistant to treatment. In this review we argue that the SVZ is susceptible to cancer because it contains stem cells, migratory progenitors and unusual inflammation. Theoretically, SVZ stem cells can convert to CSCs more readily than can postmitotic neural cells. Additionally, the robust long-distance migration of SVZ progenitors can be subverted upon tumorigenesis to an infiltrative phenotype. There is evidence that the SVZ, even in health, exhibits chronic low-grade cellular and molecular inflammation. Its inflammatory response to brain injuries and disease differs from that of other brain regions. We hypothesize that the SVZ inflammatory environment can predispose cells to novel mutations and exacerbate cancer phenotypes. This can be studied in animal models in which human mutations related to cancer are knocked into the SVZ to induce tumorigenesis and the CSC immune interactions that precede full-blown cancer. Importantly inflammation can be pharmacologically modulated providing an avenue to brain cancer management and treatment. The SVZ is accessible by virtue of its location surrounding the lateral ventricles and CSCs in the SVZ can be targeted with a variety of pharmacotherapies. Thus, the SVZ can yield aggressive tumors but can be targeted via several strategies

Validation of plasma protein glycation and oxidation biomarkers for the diagnosis of autism

Autism Spectrum Disorder (ASD) is a common neurodevelopmental disorder in children. It is currently diagnosed by behaviour-based assessments made by observation and interview. In 2018 we reported a discovery study of a blood biomarker diagnostic test for ASD based on a combination of four plasma protein glycation and oxidation adducts. The test had 88% accuracy in children 5–12 years old. Herein, we present an international multicenter clinical validation study (N = 478) with application of similar biomarkers to a wider age range of 1.5–12 years old children. Three hundred and eleven children with ASD (247 male, 64 female; age 5.2 ± 3.0 years) and 167 children with typical development (94 male, 73 female; 4.9 ± 2.4 years) were recruited for this study at Sidra Medicine and Hamad Medical Corporation hospitals, Qatar, and Hospital Regional Universitario de Málaga, Spain. For subjects 5–12 years old, the diagnostic algorithm with features, advanced glycation endproducts (AGEs)—Nε-carboxymethyl-lysine (CML), Nω-carboxymethylarginine (CMA) and 3-deoxyglucosone-derived hydroimidazolone (3DG-H), and oxidative damage marker, o,o’-dityrosine (DT), age and gender had accuracy 83% (CI 79 – 89%), sensitivity 94% (CI 90–98%), specificity 67% (CI 57–76%) and area-under-the-curve of receiver operating characteristic plot (AUROC) 0.87 (CI 0.84–0.90). Inclusion of additional plasma protein glycation and oxidation adducts increased the specificity to 74%. An algorithm with 12 plasma protein glycation and oxidation adduct features was optimum for children of 1.5–12 years old: accuracy 74% (CI 70–79%), sensitivity 75% (CI 63–87%), specificity 74% (CI 58–90%) and AUROC 0.79 (CI 0.74–0.84). We conclude that ASD diagnosis may be supported using an algorithm with features of plasma protein CML, CMA, 3DG-H and DT in 5–12 years-old children, and an algorithm with additional features applicable for ASD screening in younger children. ASD severity, as assessed by ADOS-2 score, correlated positively with plasma protein glycation adducts derived from methylglyoxal, hydroimidazolone MG-H1 and Nε(1-carboxyethyl)lysine (CEL). The successful validation herein may indicate that the algorithm modifiable features are mechanistic risk markers linking ASD to increased lipid peroxidation, neuronal plasticity and proteotoxic stress.</p

Discovery of a novel cytokine signature for the diagnosis of autism spectrum disorder in young Arab children in Qatar

BackgroundAutism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder characterized by impaired social interaction and communication and the occurrence of stereotyped and repetitive behaviors. Several studies have reported altered cytokine profiles in ASD and hence may serve as potential diagnostic biomarkers of the disorder. This study aims to identify diagnostic biomarkers for ASD in a well-defined study cohort in Qatar.MethodsWe measured the protein levels of 45 cytokines in the plasma samples of age- and gender-matched children (2–4 years) with ASD (n = 100) and controls (n = 60) using a Luminex multiplex assay. We compared the differences in the levels of these cytokines between the two study groups and then fitted the significantly altered cytokines into a logistic regression model to examine their diagnostic potential for ASD.ResultsWe found elevated levels of IFN-γ, FGF-2, IL-1RA, and IL-13 and reduced levels of eotaxin, HGF, IL-1 alpha, IL-22, IL-9, MCP-1, SCF, SDF-1 alpha, VEGFA, and IP-10 in the plasma of children with ASD compared to controls. Furthermore, we observed that elevated levels of IFN-γ (odds ratio (OR) = 1.823; 95% (confidence interval) CI = 1.206, 2.755; p = 0.004) and FGF-2 (OR = 2.528; 95% CI = 1.457, 4.385; p &lt; 0.001) were significantly associated with increased odds of ASD, whereas reduced levels of eotaxin (OR = 0.350; 95% CI = 0.160, 0.765; p = 0.008) and HGF (OR = 0.220; 95% CI = 0.070, 0.696; p = 0.010) were significantly associated with lower odds of ASD relative to controls. The combination of these four cytokines revealed an area under the curve (ROC-AUC) of 0.829 (95% CI = 0.767, 0.891; p &lt; 0.001), which demonstrates the diagnostic accuracy of the four-cytokine signature.ConclusionsOur results identified a panel of cytokines that could discriminate between children with ASD and controls in Qatar. In addition, our findings support the predominance of a Th1 immune phenotype in ASD children and emphasize the need to validate these results in larger populations

DataSheet_1_In search of immune cellular sources of abnormal cytokines in the blood in autism spectrum disorder: A systematic review of case-control studies.zip

Abnormal cytokine levels in circulating blood have been repeatedly reported in autism; however, the underlying cause remains unclear. This systematic review aimed to investigate cytokine levels in peripheral blood compartments and identify their potential immune cellular sources in subjects with autism through comparison with controls. We conducted an electronic database search (PubMed, Scopus, ProQuest Central, Ovid, SAGE Journals, and Wiley Online Library) from inception (no time limits) to July 9, 2020, and identified 75 relevant articles. Our qualitative data synthesis focused on results consistently described in at least three independent studies, and we reported the results according to the PRISMA protocol. We found that compared with controls, in subjects with autism, cytokines IL-6, IL-17, TNF-α, and IL-1β increased in the plasma and serum. We also identified monocytes, neutrophils, and CD4+ T cells as potential sources of these elevated cytokines in autism. Cytokines IFN-γ, TGF-β, RANTES, and IL-8 were increased in the plasma/serum of subjects with autism, and IFN-γ was likely produced by CD4+ T cells and natural killer (NK) cells, although conflicting evidence is present for IFN-γ and TGF-β. Other cytokines—IL-13, IL-10, IL-5, and IL-4—were found to be unaltered in the plasma/serum and post-stimulated blood immune cells in autistic individuals as compared with controls. The frequencies of T cells, monocytes, B cells, and NK cells were unchanged in subjects with autism as opposed to controls, suggesting that abnormal cytokines were unlikely due to altered cell numbers but might be due to altered functioning of these cells in autism. Our results support existing studies of abnormal cytokines in autism and provide comprehensive evidence of potential cellular sources of these altered cytokines in the context of autism.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020205224, identifier [CRD42020205224].</p

Characterization of MXene as a Cancer Photothermal Agent Under Physiological Conditions

A growing interest has recently emerged in the use of nanomaterials in medical applications. Nanomaterials, such as MXene, have unique properties due to their 2D ultra-thin structure, which is potentially useful in cancer photothermal therapy. To be most effective, photothermal agents need to be internalized by the cancer cells. In this study, MXene was fabricated using chemical reactions and tested as a photothermal agent on MDA-231 breast cancer cells under static and physiological conditions. Fluid shear stress (∼0.1 Dyn/cm2) was applied using a perfusion system to mimic the physiological tumor microenvironment. The uptake of MXene was analyzed under fluid flow compared to static culture using confocal microscopy, scanning electron microscopy (SEM), energy dispersive spectrometer (EDS), and transmission electron microscopy (TEM). Furthermore, a viability assay was used to assess cell’s survival after exposing the treated cells to photothermal laser at different power densities and durations. We showed that when incubated with cancer cells, 2D MXene nanoparticles were successfully internalized into the cells resulting in increased intracellular temperatures when exposed to NIR laser. Interestingly, dynamic culture alone did not result in a significant increase in uptake suggesting the need for surface modifications for enhanced cellular uptake under shear stress.Qatar Universit

Table_1_Discovery of a novel cytokine signature for the diagnosis of autism spectrum disorder in young Arab children in Qatar.docx

BackgroundAutism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder characterized by impaired social interaction and communication and the occurrence of stereotyped and repetitive behaviors. Several studies have reported altered cytokine profiles in ASD and hence may serve as potential diagnostic biomarkers of the disorder. This study aims to identify diagnostic biomarkers for ASD in a well-defined study cohort in Qatar.MethodsWe measured the protein levels of 45 cytokines in the plasma samples of age- and gender-matched children (2–4 years) with ASD (n = 100) and controls (n = 60) using a Luminex multiplex assay. We compared the differences in the levels of these cytokines between the two study groups and then fitted the significantly altered cytokines into a logistic regression model to examine their diagnostic potential for ASD.ResultsWe found elevated levels of IFN-γ, FGF-2, IL-1RA, and IL-13 and reduced levels of eotaxin, HGF, IL-1 alpha, IL-22, IL-9, MCP-1, SCF, SDF-1 alpha, VEGFA, and IP-10 in the plasma of children with ASD compared to controls. Furthermore, we observed that elevated levels of IFN-γ (odds ratio (OR) = 1.823; 95% (confidence interval) CI = 1.206, 2.755; p = 0.004) and FGF-2 (OR = 2.528; 95% CI = 1.457, 4.385; p ConclusionsOur results identified a panel of cytokines that could discriminate between children with ASD and controls in Qatar. In addition, our findings support the predominance of a Th1 immune phenotype in ASD children and emphasize the need to validate these results in larger populations.</p

Genetic Variants and Protective Immunity against SARS-CoV-2

The novel coronavirus-19 (SARS-CoV-2), has infected numerous individuals worldwide, resulting in millions of fatalities. The pandemic spread with high mortality rates in multiple waves, leaving others with moderate to severe symptoms. Co-morbidity variables, including hypertension, diabetes, and immunosuppression, have exacerbated the severity of COVID-19. In addition, numerous efforts have been made to comprehend the pathogenic and host variables that contribute to COVID-19 susceptibility and pathogenesis. One of these endeavours is understanding the host genetic factors predisposing an individual to COVID-19. Genome-Wide Association Studies (GWAS) have demonstrated the host predisposition factors in different populations. These factors are involved in the appropriate immune response, their imbalance influences susceptibility or resistance to viral infection. This review investigated the host genetic components implicated at the various stages of viral pathogenesis, including viral entry, pathophysiological alterations, and immunological responses. In addition, the recent and most updated genetic variations associated with multiple host factors affecting COVID-19 pathogenesis are described in the study

Global economic burden of unmet surgical need for appendicitis

Background There is a substantial gap in provision of adequate surgical care in many low- and middle-income countries. This study aimed to identify the economic burden of unmet surgical need for the common condition of appendicitis. Methods Data on the incidence of appendicitis from 170 countries and two different approaches were used to estimate numbers of patients who do not receive surgery: as a fixed proportion of the total unmet surgical need per country (approach 1); and based on country income status (approach 2). Indirect costs with current levels of access and local quality, and those if quality were at the standards of high-income countries, were estimated. A human capital approach was applied, focusing on the economic burden resulting from premature death and absenteeism. Results Excess mortality was 4185 per 100 000 cases of appendicitis using approach 1 and 3448 per 100 000 using approach 2. The economic burden of continuing current levels of access and local quality was US $92 492 million using approach 1 and$73 141 million using approach 2. The economic burden of not providing surgical care to the standards of high-income countries was $95 004 million using approach 1 and$75 666 million using approach 2. The largest share of these costs resulted from premature death (97.7 per cent) and lack of access (97.0 per cent) in contrast to lack of quality. Conclusion For a comparatively non-complex emergency condition such as appendicitis, increasing access to care should be prioritized. Although improving quality of care should not be neglected, increasing provision of care at current standards could reduce societal costs substantially

Global economic burden of unmet surgical need for appendicitis

Background There is a substantial gap in provision of adequate surgical care in many low- and middle-income countries. This study aimed to identify the economic burden of unmet surgical need for the common condition of appendicitis. Methods Data on the incidence of appendicitis from 170 countries and two different approaches were used to estimate numbers of patients who do not receive surgery: as a fixed proportion of the total unmet surgical need per country (approach 1); and based on country income status (approach 2). Indirect costs with current levels of access and local quality, and those if quality were at the standards of high-income countries, were estimated. A human capital approach was applied, focusing on the economic burden resulting from premature death and absenteeism. Results Excess mortality was 4185 per 100 000 cases of appendicitis using approach 1 and 3448 per 100 000 using approach 2. The economic burden of continuing current levels of access and local quality was US $92 492 million using approach 1 and$73 141 million using approach 2. The economic burden of not providing surgical care to the standards of high-income countries was $95 004 million using approach 1 and$75 666 million using approach 2. The largest share of these costs resulted from premature death (97.7 per cent) and lack of access (97.0 per cent) in contrast to lack of quality. Conclusion For a comparatively non-complex emergency condition such as appendicitis, increasing access to care should be prioritized. Although improving quality of care should not be neglected, increasing provision of care at current standards could reduce societal costs substantially