The current understanding of the inherited risk of colorectal cancer (CRC) started with an observational clinical era in the late 19
century, which was followed by a genetic era starting in the late ...20
century. Genome-wide linkage analysis allowed mapping several high-risk genes, which marked the beginning of the genetic era. The current high-throughput genomic phase includes genome-wide association study (GWAS) and genome-wide sequencing approaches which have revolutionized the conception of the inherited risk of CRC. On the one hand, GWAS has allowed the identification of multiple low risk loci correlated with CRC. On the other, genome-wide sequencing has led to the discovery of a second batch of high-to-moderate-risk genes that correlate to atypical familial CRC and polyposis syndromes. In contrast to other common cancers, which are usually dominated by a polygenic background, CRC risk is believed to be equally explained by monogenic and polygenic architectures, which jointly contribute to a quarter of familial clustering. Despite the fact that genome-wide approaches have allowed the identification of a continuum of responsible high-to-moderate-to-low-risk variants, much of the predisposition and familial clustering of CRC has not yet been explained. Other genetic, epigenetic and environmental factors might be playing important roles as well. In this review we aim to provide insights on the complementary roles played by different genomic approaches in allowing the current understanding of the genetic architecture of inherited CRC.
A founder variant is a genetic alteration, that is inherited from a common ancestor together with a surrounding chromosomal segment, and is observed at a high frequency in a defined population. This ...founder effect occurs as a consequence of long-standing inbreeding of isolated populations. For high-risk cancer predisposition genes, such as BRCA1/2, the identification of founder variants in a certain population could help designing customized cost-effective cancer screening panels. This advantage has been best utilized in designing a customized breast cancer BRCA screening panel for the Ashkenazi Jews (AJ) population, composed of the three BRCA founder variants which account for approximately 90% of identified BRCA alterations. Indeed, the high prevalence of pathogenic BRCA1/2 variants among AJ (~ 2%) has additionally contributed to make population-based screening cost-effective in comparison to family-history-based screening. In Jordan there are multiple demographic characteristics supporting the proposal of a founder effect. A high consanguinity rate of ~ 57% in the nineties of the last century and ~ 30% more recently is a prominent factor, in addition to inbreeding which is often practiced by different sub-populations of the country.This review explains the concept of founder effect, then applies it to analyze published Jordanian BRCA variants, and concludes that nine pathogenic (P) and likely pathogenic (LP) BRCA2 variants together with one pathogenic BRCA1 variant are potential founder variants. Together they make up 43% and 55% of all identified BRCA1/2 alterations in the two largest studied cohorts of young patients and high-risk patients respectively. These variants were identified based on being recurrent and either specific to ethnic groups or being novel. In addition, the report highlights the required testing methodologies to validate these findings, and proposes a health economic evaluation model to test cost-effectiveness of a population-based customized BRCA screening panel for the Jordanian population. The aim of this report is to highlight the potential utilization of founder variants in establishing customized cancer predisposition services, in order to encourage more population-based genomic studies in Jordan and similar populations.
In 2021, Suwala et al. described Primary Mismatch Repair Deficient IDH-mutant Astrocytoma (PMMRDIA) as a distinct group of gliomas. In unsupervised clustering, PMMRDIA forms distinct cluster, ...separate from other IDH-mutant gliomas, including IDH-mutant gliomas with secondary mismatch repair (MMR) deficiency. In the published cohort, three patients received treatment with an immune checkpoint blocker (ICB), yet none exhibited a response, which aligns with existing knowledge about the decreased immunogenicity of IDH-mutant gliomas in comparison to IDH-wildtype. In the case of PMMRDIA, the inherent resistance to the standard-of-care temozolomide caused by MMR deficiency is an additional challenge. It is known that a gain-of-function mutation of IDH1/2 genes produces the oncometabolite R-2-hydroxyglutarate (R-2-HG), which increases DNA and histone methylation contributing to the characteristic glioma-associated CpG island methylator phenotype (G-CIMP). While other factors could be involved in remodeling the tumor microenvironment (TME) of IDH-mutant gliomas, this systematic review emphasizes the role of R-2-HG and the subsequent G-CIMP in immune suppression. This highlights a potential actionable pathway to enhance the response of ICB, which might be relevant for addressing the unmet therapeutic challenge of PMMRDIA.
Abstract BACKGROUNDS Pediatric brain tumors (PBT) exhibit extensive heterogeneity, impacting treatment outcomes. While traditionally classified based on histopathological features, recent WHO ...classifications have integrated DNA methylation array profiling amongst other molecular characteristics, which improves diagnostic accuracy and thus treatment decisions. However, access to this technology is limited in low- and middle-income countries (LMICs) like Indonesia. As part of the MNP Outreach Consortium, we aimed to introduce methylation profiling in Indonesia to aid in diagnosing and stratifying PBT patients. METHODS In 2023, we conducted a case series involving seven challenging PBT cases from Cipto Mangunkusumo National General Hospital, re-assessing them with methylation profiling. RESULTS Through collaboration with the Institute of Neuropathology Heidelberg and the DKFZ, our centre adopted a discerning approach to re-evaluate histopathological samples from complex cases. This endeavour yielded notable results, reaffirming four initial diagnoses and altering three others Amongst the findings, one case initially diagnosed as anaplastic ependymoma, CNS WHO grade 3, was reclassified as a supratentorial ependymoma with YAP1 fusion gene, based on methylation class. Noteworthy within this latter group, one case initially categorized as low-grade pilocytic astrocytoma was reclassified as high-grade diffuse midline glioma, H3 K27 altered. Moreover identifying the copy number plot could indicate a KIAA1549::BRAF fusion to reclassify a case from diffuse pediatric glioma WHO grade 2 to pilocytic astrocytoma WHO grade 1. The recurrent pigmented neuroectodermal tumor of infancy (MNTI) was reclassified as Medulloblastoma, non-WNT/non-SHH, group 3 subtype II on methylation profiling, highlighting molecular similarities and potential treatment insights. These findings offer insights into genetic mechanisms and guide treatment strategies. CONCLUSION Accurate diagnosis, facilitated by advanced molecular profiling, enhances prognostication and enables personalized treatment plans, even in LMICs. This underscores the importance of expanding access to advanced diagnostic technologies in resource-limited settings.
Khdair-Ahmad F, Aladily T, Khdair-Ahmad O, Badran EF. Chelation therapy for secondary neonatal iron overload: Lessons learned from rhesus hemolytic disease. Turk J Pediatr 2018; 60: 335-339. ...Secondary neonatal iron overload occurs with intrauterine and post-natal blood transfusions. Treatment with intravenous Deferoxamine was reported only in four cases in the literature. Herein we report a case of a patient born at 36 weeks of gestation, who had rhesus hemolytic disease. He developed secondary iron overload, causing liver injury, after a total of six blood transfusions: four intrauterine and 2 post-natal transfusion therapies. Intravenous Deferoxamine treatment was started at the age of 45 days due to a ferritin level of 40,000 mg/L, progressive rise of liver enzymes, and worsening cholestasis. Treatment resulted in marked reduction in ferritin level (down to 829 mg/L at the age of 6 months), significant improvement in the liver enzymes, and resolution of cholestasis.
Constitutional Mismatch Repair Deficiency (CMMRD) is a cancer predisposition syndrome that presents with brain, gastrointestinal and haematological malignancies. We conducted a retrospective analysis ...of 9 pediatric patients (<18-years at diagnosis) who were diagnosed with biopsy-proven colorectal carcinoma (CRC) from June 2006 until February 2019 at our center. We reviewed these records for evidence of CMMRD association, and identified 3 patients with CMMRD and one patient with Lynch syndrome by immunohistochemistry (IHC). Five patients died after a median follow up of 15.5 months (range 5–35 months) and 3 moved out of the country and thus lost to follow up.
An organization's environmental performance is affected by its suppliers' environmental performance, and selecting green suppliers is a strategic decision in order to be more competitive in today's ...global market. The supplier selection problem involves several quantitative and qualitative criteria. In the supplier selection process, if suppliers have limited capacity or other constraints, it is necessary to determine the best supplier and order quantity of each supplier. In this paper, we present an integrated approach, of fuzzy multi attribute utility theory and multi-objective programming, for rating and selecting the best green suppliers according to economic and environmental criteria and then allocating the optimum order quantities among them. At first, the fuzzy analytic hierarchy process and fuzzy technique for order preference by similarity to ideal solution is applied in order to analyze the importance of multiple criteria by incorporating experts' opinion and to determine the best green suppliers. Next, multi-objective linear programming is used to consider and to formulate various constraints such as quality control, capacity, and other objectives. The objective of the mathematical model is simultaneously to maximize the total value of purchasing and to minimize the total cost of purchasing. To handle the subjectivity of decision makers' preferences, fuzzy logic has been applied. The efficiency and application of the proposed approach has been illustrated with a case study in an automobile manufacturing company. The obtained results help firms establish a systematic approach for tackling green supplier selection and order allocation problems in a realistic situation. Finally managerial implications, conclusions, and directions for additional research are introduced.
Riboflavin is an antioxidant: a review update Olfat, Nafisa; Ashoori, Marziyeh; Saedisomeolia, Ahmad
British journal of nutrition,
11/2022, Letnik:
128, Številka:
10
Journal Article
Recenzirano
Aerobic organisms need antioxidant defense systems to deal with free radicals which either are produced during aerobic respiration or may have an external origin. Oxidative stress, which is resulted ...from an imbalance between the production of free radicals and the ability of antioxidant defense mechanism to deactivate them, is involved in the development of many chronic diseases such as cancer, diabetes, CVD and some neurodegenerative diseases. Reinforcing the antioxidant potential of the body has been considered as a strategy that could prevent and manage such conditions. In the previous review article published by British Journal of Nutrition, in 2014, for the first time, we concluded that riboflavin could alleviate oxidative stress. Although riboflavin can serve as a prooxidant when exposed to ultraviolet irradiation, the literature is replete with studies that support its antioxidant properties. Furthermore, recent evidence suggests that riboflavin may have a therapeutic potential in many conditions in which oxidative stress is involved, although the therapeutic efficacy of riboflavin as an antioxidant requires further study under conditions of wellness and clinical disease.
Background: Critical thinking and self-confidence are imperative to success in clinical practice. Educators should use teaching strategies that will help students enhance their critical thinking and ...self-confidence in complex content such as electrocardiogram interpretation. Therefore, teaching electrocardiogram interpretation to students is important for nurse educators. Purpose: This study compares the effect of simulation-based and traditional teaching methods on the critical thinking and self-confidence of students during electrocardiogram interpretation sessions. Methods: Thirty undergraduate nursing students volunteered to participate in this study. The participants were divided into intervention and control groups, which were taught respectively using the simulation-based and traditional teaching programs. All of the participants were asked to complete the study instrument pretest and posttest to measure their critical thinking and self-confidence. Results: Improvement was observed in the control and experimental groups with respect to critical thinking and self-confidence, as evidenced by the results of the paired samples t test and the Wilcoxon signed-rank test (p ＜ .05). However, the independent t test and Mann-Whitney U test indicate that the difference between the two groups was not significant (p ＞ .05). Conclusions/Implications for Practice: This study evaluated an innovative simulation-based teaching method for nurses. No significant differences in outcomes were identified between the simulator-based and traditional teaching methods, indicating that well-implemented educational programs that use either teaching method effectively promote critical thinking and self-confidence in nursing students. Nurse educators are encouraged to design educational plans with clear objectives to improve the critical thinking and self-confidence of their students. Future research should compare the effects of several teaching sessions using each method in a larger sample.
This is a randomized, controlled, superiority, double-blinded, parallel-group, two-arms trial with an allocation ratio of 1:1. The aim of this trial was to compare the two-year clinical performance ...of partial indirect restorations fabricated from CAD/CAM nano-hybrid composite and ceramic lithium disilicate blocks using the modified USPHS criteria.
In two parallel groups (n = 50 restorations), fifty participants having mutilated vital teeth with a minimum of two remaining walls were randomly enrolled in this trial and received indirect restorations of either nano-hybrid composite resin blocks (Brilliant, Coltene, Switzerland) or Lithium Disilicate (IPS Emax CAD). The restorations were assessed using modified USPHS criteria by two independent blinded assessors at baseline, six months, one-year and two years follow-up visits. Categorical and ordinal data were presented as frequencies and percentages. Categorical data were analyzed using the chi-square test. Ordinal data were analyzed using the Mann-Whitney U test for intergroup comparisons and Freidman's test followed by the Nemenyi post hoc test for intragroup comparisons. Numerical data were presented as mean and standard deviation values. They were analyzed for normality using the Shapiro-Wilk test. Data were found to be normally distributed and were analyzed using the independent t-test. The significance level was set at p ≤ 0.05 within all tests.
Forty-eight participants received the allocated intervention and completed the follow-up periods. There was a statistically significant difference between both tested materials for all USPHS criteria regarding Marginal integrity and Marginal discoloration at six-months Follow-up, but with no statistically significant difference at one- and two-year follow-up.
Both materials showed an acceptable, successful clinical performance along the two-years follow-up period.
The CAD/CAM nano-hybrid composite blocks are as reliable as Lithium disilicate for restoring mutilated vital teeth.
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