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Effect of tumor genetics, pathology, and location on fMRI of language reorganization in brain tumor patients
Get PDFObjectives: Language reorganization may follow tumor invasion of the dominant hemisphere. Tumor location, grade, and genetics influence the communication between eloquent areas and tumor growth dynamics, which are drivers of language plasticity. We evaluated tumor-induced language reorganization studying the relationship of fMRI language laterality to tumor-related variables (grade, genetics, location), and patient-related variables (age, sex, handedness). Methods: The study was retrospective cross-sectional. We included patients with left-hemispheric tumors (study group) and right-hemispheric tumors (controls). We calculated five fMRI laterality indexes (LI): hemispheric, temporal lobe, frontal lobe, Broca’s area (BA), Wernicke’s area (WA). We defined LI ≥ 0.2 as left-lateralized (LL) and LI < 0.2 as atypical lateralized (AL). Chi-square test (p < 0.05) was employed to identify the relationship between LI and tumor/patient variables in the study group. For those variables having significant results, confounding factors were evaluated in a multinomial logistic regression model. Results: We included 405 patients (235 M, mean age: 51 years old) and 49 controls (36 M, mean age: 51 years old). Contralateral language reorganization was more common in patients than controls. The statistical analysis demonstrated significant association between BA LI and patient sex (p = 0.005); frontal LI, BA LI, and tumor location in BA (p < 0.001); hemispheric LI and fibroblast growth factor receptor (FGFR) mutation (p = 0.019); WA LI and O6-methylguanine-DNA methyltransferase promoter (MGMT) methylation in high-grade gliomas (p = 0.016). Conclusions: Tumor genetics, pathology, and location influence language laterality, possibly due to cortical plasticity. Increased fMRI activation in the right hemisphere was seen in patients with tumors in the frontal lobe, BA and WA, FGFR mutation, and MGMT promoter methylation. Key Points: • Patients harboring left-hemispheric tumors present with contralateral translocation of language function. Influential variables for this phenomenon included frontal tumor location, BA location, WA location, sex, MGMT promoter methylation, and FGFR mutation. • Tumor location, grade, and genetics may influence language plasticity, thereby affecting both communication between eloquent areas and tumor growth dynamics. • In this retrospective cross-sectional study, we evaluated language reorganization in 405 brain tumor patients by studying the relationship of fMRI language laterality to tumor-related variables (grade, genetics, location), and patient-related variables (age, sex, handedness). © 2023, The Author(s)
The Effect Of A Novel Homozygous Variant In RasGRP1 On Disease In A Patient With An Inborn Error Of Immunity
No full textBackground: Primary immunodeficiency diseases (PIDs) are a group of congenitally inherited heterogeneous disorders that result in the depletion or deficiency of one or more components of the immune system. RASGRP1 is a guanidine exchange factor involved in the development, differentiation, and function of lymphocytes. It regulates the activation and inactivation of RAS by adjusting the balance between GTP/GDP-bound forms. It is expressed in T cells, B cells, and innate cells, including natural killer (NK) cells. Recently, 11 patients have been reported to have inborn defects in RASGRP1 which caused severe illnesses. They presented with common clinical and laboratory features of Epstein–Barr virus (EBV) infection, EBV-related complications such as lymphoproliferative disease, lung infection, autoimmunity, decreased number of CD4+ T lymphocytes, impaired ERK/MAPK activation, and decreased T-cell proliferation in response to mitogens and antigens.
Case presentation: The patient under investigation is a 17-year-old male born to consanguineous parents with a history of Evans Syndrome. His earlier clinical history is indicative of autoimmune hemolytic anemia and decreased T-cell counts associated with recurrent infections. The early onset and severity of the clinical manifestations pointed towards an immunodeficiency.
Methods: Genomic DNA (gDNA) was purified and sequenced by Next Generation Sequencing and Sanger sequencing. Peripheral blood mononuclear cells (PBMCs) were isolated on a Ficoll-paque gradient by differential centrifugation. Immunophenotyping of PBMCs, Regulatory T cell staining, B and T cell proliferation, determination of intracellular cytokines, T-cell degranulation assay, and F-actin polymerization assay, were determined by flow cytometry. Expression of RASGRP1 and ERK phosphorylation were done by immunoblotting. Cytokine secretion was measured by Enzyme-Linked Immunosorbent Assay (ELISA). T cell function was determined using an EBV transformation assay.
Results: Immunophenotyping of PBMCs isolated from the patient revealed a very low T cell count, absent Recent Thymic Immigrants (RTEs), and normal to elevated numbers of B and NK cells. Next Generation Sequencing analysis identified a homozygous c.1396-1397insA in RASGRP1 coding sequence that resulted in the conversion of threonine to asparagine at position 466 on the RASGRP1 protein leading to a frameshift mutation (p.T466N fs*3). The c.1396-1397insA mutation abolished the expression of RASGRP1 and ERK phosphorylation downstream of TCR signaling, resulting in absent T cell activation in the form of upregulation of activation markers, proliferation and secretion of cytokines, F-actin polymerization, and inhibition of B cell transformation with EBV. B cell function was maintained.
Conclusion: We used genetic and functional approaches to identify a novel deleterious homozygous mutation in RASGRP1 and studied the effect of the mutation on protein expression and T cell development and function. Our work expands the spectrum of mutations in RASGRP1 in immunodeficiency and dysregulation
Comparative analysis of partial versus radical nephrectomy for renal cell carcinoma: Is oncologic safety compromised during nephron sparing in higher stage disease?
Get PDFObjectives: Over the past 20 years, the utility of partial nephrectomy (PN), compared to radical nephrectomy (RN), for the management of localized renal cell carcinoma (RCC) has progressively increased, particularly for larger and more complex masses. We sought to compare the recurrence-free survival (RFS) outcomes of PN versus RN in a single-institution cohort. Methods: Between 2002 and 2017, 228 patients underwent RN or PN for lcT1a-T2b, N0M0 RCC at a single tertiary referral center, performed by five surgeons. The clinical end point result was (local or distant) RFS. Univariate and multivariate (cox regression) models were used to evaluate the association between type of surgery (PN vs. RN) and RFS, in the overall cohort and in a subgroup of patients with cT1b. Results: The median age was 59 (interquartile range [IQR] 48-66), and the median tumor size was 4.5 cm (IQR 3-7). There were 128 PN and 100 RN. Over a median follow-up of 4.2 years (IQR 2.2-6.9), the Kaplan-Meier analysis showed no significant RFS difference between PN and RN (logrank P = 0.53). On multivariate analysis, pathologic stage ≥T2a, Fuhrman Grade ≥3, and chromophobe histology were associated with a worse RFS. PN was not significantly associated with diminished RFS (Hazard ratio [HR] 1.78, 95% confidence interval [CI] 0.74-4.3, P = 0.199) in the overall cohort compared to RN. However, in the cT1b subgroup, PN was associated with a significant increase in recurrence compared to RN (HR = 12.4, 95% CI 1.45-133.4, P = 0.038). Conclusions: Our institutional data highlight the possibility of compromise in RFS for clinically localized RCC treated with PN compared to RN, particularly for larger and more complex masses. These data raise concern, especially in light of the nonproven association of survival benefit of PN over RN, warranting future randomized prospective studies for further evaluation. © 2023 Wolters Kluwer Medknow Publications. All rights reserved
Spin wave excitations in a nanowire spin Hall oscillator with perpendicular magnetic anisotropy
Get PDFSpin torque oscillators (STOs) are emerging microwave devices that can potentially be used in spin-logic devices and the next-generation high-speed computing architecture. Thanks to their non-linear nature, STOs are easily tunable by the magnetic field and the dc current. Spin Hall nano-oscillators are promising types of STOs and most of the current studies focus on localized modes that can be easily excited. Here, we study using micromagnetic simulations, the nature of the spin-torque-induced excitations in nanowire devices made of perpendicular magnetic anisotropy (PMA) materials. Our results showed that, upon including PMA, the excitation of localized and propagating spin wave modes is feasible. We study the nature of the mode excitations as a function of the PMA strength (K u) and the current. Indeed, we estimate a critical value of K u to allow for the excitation of the propagating spin wave. We attribute this mode selectivity between localized and propagating modes to the magnitude and the change of the sign of the nonlinearity of the system from negative to positive at a non-zero K u, which is supported by analytical calculations. Our results provide deep insight into engineering microwave devices for future magnonic and computational applications. © 2023 Author(s)
Homocysteine levels, H-Hypertension, and the MTHFR C677T genotypes: A complex interaction
Get PDFBackground and objectives: High homocysteine levels are associated with increased risk of hypertension and stroke. Homocysteine is metabolized by the methylenetetrahydrofolate reductase (MTHFR). We aimed to investigate the levels of homocysteine and their association with hypertension, stroke, and antihypertensive medication usage in patients with different MTHFR C677T genotypes. Methods and results: Genotype frequency of MTHFR polymorphism was performed, and plasma homocysteine levels were measured in 2,640 adult Lebanese patients. Hypertension, history of stroke, and list of medications were documented, among other clinical and demographic parameters. The TT mutant genotype and the T mutant allele of MTHFR were more prevalent in hyperhomocysteinemia (HHcy) and H-hypertensive (H-HTN, defined as hypertension with hyperhomocysteinemia) patients when compared to non-HHcy subjects and non H-HTN patients respectively. Homocysteine levels were significantly higher in hypertensive patients specifically among those on diuretics. A higher level of homocysteine was found in hypertensive patients with the MTHFR T allele compared to patients carrying the C allele. Among the T allele carriers, the average plasma homocysteine level was 13.3 ± 0.193 μmol/L for hypertensive subjects compared to 11.9 ± 0.173 μmol/L (non-hypertensives). Furthermore, homocysteine levels significantly correlated with stroke risk in patients with the T alleles. Conclusions: We found an association of homocysteine with hypertension, hypertensive medication, and stroke risk among patients with the MTHFR T allele and the TT genotype. The association of diuretics therapy with higher homocysteine levels calls for routine measurements and therapeutic control of homocysteine in patients on diuretic, to improve health-related outcomes. © 2023 The Author
On Bender's orientation to models: Towards a philosophical debate on covering laws, theory, emergence and mechanisms in nursing science
No full textNursing scholars continuously refine nursing knowledge and the philosophical foundations of nursing practice. They advance nursing knowledge by creating new knowledge and weighing the relevance of developments in cognate sciences. Nurse philosophers go further by providing epistemological and ontological arguments for explanations of nursing phenomena. In this article, I engage with Bender's arguments about why mechanisms should have more primacy as carriers of nursing knowledge. Despite the careful scholarship involved, Bender's arguments need to be more convincing. Accordingly, this article encourages debate about Bender's arguments for reorientating nursing science to mechanisms. I begin by suggesting that the claim that the theory-practice divide can be overcome by reorientating to mechanisms is acceptable only if we accept Bender's depiction of the challenge. Then I question the ontology Bender relies on to justify reorientating nursing science. After that, I argue that mechanisms in models that parallel analytical sociology undermine the kind of nursing science Bender advocates. I illustrate my arguments with a social mechanism thought experiment. Then I explain why Bender's arguments cannot escape the received view of science or inform emancipatory nursing action without theory. Finally, I mention some caveats and implications for nursing science. © 2023 John Wiley & Sons Ltd
Use of Building Façade for Active Indoor Humidity Control
No full textRegulating indoor humidity levels to healthy ranges is important to provide occupants with acceptable thermal comfort and air quality conditions. Conventional techniques relied on the supply of dehumidified outdoor air to dilute the indoor generated moisture. They use vapor compression cooling either as standalone system or integrated with desiccant dehumidifiers to generate the dry air. Such systems are energy intensive and require large footprint areas, especially in hot and humid climates. This work proposes thus an energy-efficient alternative where the indoor humidity is pumped directly from the space and discharged outdoors. This system integrates a metal organic framework-based dehumidifier with the building breathable façade. The dehumidifier dries the outdoor air that is used to ventilate the façade and create the necessary driving gradient for the moisture transfer, irrespective of the outdoor air conditions. Mathematical models are developed to evaluate the system performance for an office space located in the extreme hot and humid climate of Jeddah, KSA. The proposed system resulted in 89 % and 90 % reduction in the system size and energy consumption compared to conventional systems over the peak humidity month. © 2023, European Association for the Development of Renewable Energy, Environment and Power Quality (EA4EPQ). All rights reserved
Biological applications of imiquimod analogues: An update (Review)
Get PDFThe last decade witnessed intensive efforts in drug discovery and the emergence of thousands of molecules with potential for use as therapeutic targets. However, only a few hundred of these molecules reached the stage of clinical trials, with only a handful being translated from the bench to bedside. One such example is imiquimod, an immune response modi‑ fier belonging to the imidazoquinoline family. Imiquimod was first approved by the US Food and Drug Administration for the topical treatment of anal and genital warts and actinic keratosis, and later exhibited a potent antitumor activity. This promising activity inspired the development of several imid‑ azoquinoxaline analogues and derivatives. The present review provides a comprehensive overview of the scientific literature on the chemical synthesis of imiquimod and several of its analogues, namely EAPB0203, EAPB0503 and EABP02303. The present review also discusses their preclinical proper‑ ties and mechanisms of action in the context of cancer and parasitic infections, highlighting the worthiness of translating these activities into therapeutic drugs. Copyright © 2023 Obeid et al. This work is licensed under a Creative Commons Attribution 4.0 International (CC BY 4.0) License
Assessment of Dietary Supplements Use among American University of Beirut Students: Prevalence, Knowledge, and Reasons for Supplementation
Get PDFThe purpose of this study was to evaluate the prevalence and type of supplements used among university students, level of knowledge in this respect, reasons to supplement their diet, and the sources for information about dietary supplements. A sample of 100 students at the American University of Beirut were surveyed through a questionnaire composed of 22 questions and divided into four sections: socio-demographic, anthropometric, dietary supplement (DS) knowledge, DS intake and reasons. Descriptive statistics were conducted to determine the frequency of respondents for each variable and appropriate statistical tests were used for associations according to variable type and data. A total of 100 participants were included in the study of which 49 (49.0%) were males and 51 (51.0%) were females. Sixty-eight participants were dietary supplement users, of which 27 (39.7%) were males and 41 (60.3%) were females. Supplementation reasons differed: 53 consumed supplements to improve energy and vitality, 22 to enhance cognitive performance, 22 to promote hair, skin and health, and 13 to prevent or treat cold. A significant association was observed between dietary supplements use and female gender (OR = 5.66, 95% CI: 1.60-20.10). No significance was found between consuming dietary supplements and smoking status, BMI, living conditions, medical condition, age, exercise, major, dietary knowledge, and side effects. More than half of the participants are dietary supplements users with females being more likely to use them. The main reason for both genders to resort to dietary supplement use is to improve their energy and vitality. © 2021 Taylor & Francis Group, LLC
Evaluation of the Anticancer, Anti-Inflammatory, and Antioxidant Properties of Various Extracts of Annona squamosa L
Get PDFBackground: Screening medicinal plants for their biological activities and phytochemicals is important for finding safe and potent new compounds for therapeutic use. The current investigation was conducted in extracts of Lebanese A. squamosa (leaves and bark) to evaluate the antioxidant, anticancer, and anti-inflammatory activities. Methods: Seven extracts were prepared by ultrasound-assisted extraction (UAE) or microwave-assisted extraction (MAE), and using various solvents. The evaluation of antioxidant activity was done using 2, 2-diphenyl-1-picrylhydrazyl (DPPH) assay, the anticancer activity assessed on the colon cancer HCT116 cell line was determined by water-soluble tetrazolium-1 (WST-1) viability assay. Finally, the anti-inflammatory activity was investigated by measuring the secreted amounts of prostaglandin E2 (PGE2) and interleukin 6 (IL-6) using. Results: The total phenolic contents were in the range between 27.3 to 179.5 mg GAE/g of plant extract, while total flavonoid contents were between 8.3 to 150.8 mg RE/g of plant extract. DPPH assay showed high antioxidant activity for the methanolic extracts obtained by UAE in both natural dried leaves and bark with IC50 values of 9.3 and 12.6 μg.mL-1, respectively. For WST-1 assay, methanolic extracts obtained by UAE showed a potent anti-proliferative effect against the HCT116 cell line with IC50 values ranged from 0.18 to 0.88 μg.mL-1. Also, the western blot assay suggested that these extracts may inhibit the proliferation of the HCT 116 cell line by causing cell cycle arrest through activation of the p21 pathway. Significant anti-inflammatory activity was observed due to the decrease in the secretion of IL-6 in lipopolysaccharide (LPS)-stimulated THP-1 cells. Conclusion: Therefore, the present study revealed that the dried leaves and bark of Lebanese A. squamosa methanolic extracts obtained by UAE possess effective bioactivities, and thus hold the potential application in the pharmacological field. © 2023 The Author(s). This is an open access article and applies the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/). Non-commercial uses of the work are permitted, provided the original work is properly cited