Oncogenic transcription factors such as the leukemic fusion protein RUNX1/ETO, which drives t(8;21) acute myeloid leukemia (AML), constitute cancer-specific but highly challenging therapeutic ...targets. We used epigenomic profiling data for an RNAi screen to interrogate the transcriptional network maintaining t(8;21) AML. This strategy identified Cyclin D2 (CCND2) as a crucial transmitter of RUNX1/ETO-driven leukemic propagation. RUNX1/ETO cooperates with AP-1 to drive CCND2 expression. Knockdown or pharmacological inhibition of CCND2 by an approved drug significantly impairs leukemic expansion of patient-derived AML cells and engraftment in immunodeficient murine hosts. Our data demonstrate that RUNX1/ETO maintains leukemia by promoting cell cycle progression and identifies G1 CCND-CDK complexes as promising therapeutic targets for treatment of RUNX1/ETO-driven AML.
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•An RNAi screen identifies CCND2 as a crucial transcriptional target of RUNX1/ETO•RUNX1/ETO promotes CCND2 expression by binding to an upstream element•CCND2 knockdown inhibits RUNX1/ETO-driven leukemic expansion in vitro and in vivo•RUNX1/ETO-expressing leukemic cells are highly sensitive to a CDK4/6 inhibitor
Using in vitro and in vivo screens to identify essential RUNX1/ETO transcriptional targets in AML, Martinez-Soria identify CCND2 as required for leukemia maintenance and self-renewal. Targeting this dependency using the CDK4/6 inhibitor palbociclib prolongs the survival of AML PDX models.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The problem of the current paper arises from the individual’s need to hold himself accountable and reconsider his behaviors or actions when many situations passing him in daily in which he lives and ...keeps into contact with those around him. This situation is accompanied by either psychological pain or the individual’s feeling of relief, each according to the nature of the personality of this individual and his emotional state. The individual’s feeling of guilt is nothing but a necessity for the individual to discipline himself and address the mistakes and abusive actions in order to stop them once and for all, provided that the situation does not reach the feeling of imaginary guilt, which is considered obstructing his thinking and leads him to give errors greater than their normal size, which is what happens in patients having depression. Al-Ansari’s study (2001) maintained that university students suffer from situational guilt at a rate of (8.9%), while the percentage of university female students reached (17.4%). This gives an indication that female students are more likely to feel situational guilt than male students and that these percentages are serious and cannot be underestimated. Because the kindergarten students are part of the university students, their role as future teachers for an important segment of society is the focus, namely Kindergarten Dept. The kindergarten teacher should be more responsible and more psychologically and emotionally balanced in its dealings with the different situations that it brings together with the child and be alert to the conscience to achieve equality between children, taking into account the individual differences between them, so the problem of the current research was identified by the following question: Is there a relationship between situational guilt and conscientious awareness for kindergarten students? The current research aims to identify the relationship between situational guilt and conscientious awareness among female kindergarten students. The research sample consisted of (300) female students from the Kindergarten Department, and to achieve the goal of the research, two scales were prepared: the Situational Guilt Scale and the Conscientious Awareness Scale for the Kindergarten Department students. Through reviewing the literature and previous studies, the researcher identified (32) items for the Situational Guilt Scale and (24) to measure the final form of conscientious awareness, the validity, and reliability of the two scales were confirmed. After using the statistical methods, the research reached the following results: • The research sample has a high degree of situational guilt. • The research sample has a high degree of conscientious awareness. • There is a high correlation between situational guilt and conscientious awareness among female students of the Kindergarten Department.
Alzheimer’s is a neurodegenerative disorder affecting the central nervous system and cognitive processes, explicitly impairing detailed mental analysis. Throughout this condition, the affected ...individual’s cognitive abilities to process and analyze information gradually deteriorate, resulting in mental decline. In recent years, there has been a notable increase in endeavors aimed at identifying Alzheimer’s disease and addressing its progression. Research studies have demonstrated the significant involvement of genetic factors, stress, and nutrition in developing this condition. The utilization of computer-aided analysis models based on machine learning and artificial intelligence has the potential to significantly enhance the exploration of various neuroimaging methods and non-image biomarkers. This study conducts a comparative assessment of more than 80 publications that have been published since 2017. Alzheimer’s disease detection is facilitated by utilizing fundamental machine learning architectures such as support vector machines, decision trees, and ensemble models. Furthermore, around 50 papers that utilized a specific architectural or design approach concerning Alzheimer’s disease were examined. The body of literature under consideration has been categorized and elucidated through the utilization of data-related, methodology-related, and medical-fostering components to illustrate the underlying challenges. The conclusion section of our study encompasses a discussion of prospective avenues for further investigation and furnishes recommendations for future research activities on the diagnosis of Alzheimer’s disease.
Multiple myeloma (MM) is an incurable hematological malignancy in which MYC alterations contribute to the malignant phenotype. Nevertheless, MYC lacks therapeutic druggability. Here, we leveraged ...large-scale loss-of-function screens and conducted a small molecule screen to identify genes and pathways with enhanced essentiality correlated with MYC expression. We reported a specific gene dependency in glutaminase (GLS1), essential for the viability and proliferation of MYC overexpressing cells. Conversely, the analysis of isogenic models, as well as cell lines dataset (CCLE) and patient datasets, revealed GLS1 as a non-oncogenic dependency in MYC-driven cells. We functionally delineated the differential modulation of glutamine to maintain mitochondrial function and cellular biosynthesis in MYC overexpressing cells. Furthermore, we observed that pharmaceutical inhibition of NAMPT selectively affects MYC upregulated cells. We demonstrate the effectiveness of combining GLS1 and NAMPT inhibitors, suggesting that targeting glutaminolysis and NAD synthesis may be a promising strategy to target MYC-driven MM.
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•MYC overexpressing (MYC OE) cells are selectively dependent on glutaminase (GLS1)•GLS1 dependency in MYC-driven cells is non-oncogenic•CB-839 reduces OXPHOS and cellular biosynthesis and has anti-tumor effect in MM•GLS1 inhibition synergizes with NAMPT inhibition to block OXPHOS in MYC OE MM
Cancer; Metabolomics; Transcriptomics
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The noncoding genome presents a largely untapped source of new biological insights, including thousands of long noncoding RNA (lncRNA) loci. While lncRNA dysregulation has been reported in myeloid ...malignancies, their functional relevance remains to be systematically interrogated. We performed CRISPRi screens of lncRNA signatures from normal and malignant hematopoietic cells and identified MYNRL15 as a myeloid leukemia dependency. Functional dissection suggests an RNA-independent mechanism mediated by two regulatory elements embedded in the locus. Genetic perturbation of these elements triggered a long-range chromatin interaction and downregulation of leukemia dependency genes near the gained interaction sites, as well as overall suppression of cancer dependency pathways. Thus, this study describes a new noncoding myeloid leukemia vulnerability and mechanistic concept for myeloid leukemia. Importantly, MYNRL15 perturbation caused strong and selective impairment of leukemia cells of various genetic backgrounds over normal hematopoietic stem and progenitor cells in vitro, and depletion of patient-derived xenografts in vivo.
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•Long noncoding RNA locus MYNRL15 identified as a myeloid leukemia dependency•MYNRL15 function is RNA-independent, mediated by two regulatory elements in locus•Perturbation causes long-range looping, downregulation of cancer dependency genes•Perturbation is anti-leukemic in primary AML cells from different genetic backgrounds
Biochemistry; Cancer
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
يهدف هذا البحث إلى دراسة السلالم الحجاجية في آيات القتال الكريمة، وبيان فاعلية الإدراك التداولي في الوصول إلى مقاصد الخطاب القرآني؛ لأن إدراك المتلقي لقصد المتكلم هو غاية كل خطاب، وعليه يتوقف التأثير ...في المتلقي، وإقناعه، وتوجيهه. واقتضت طبيعة البحث، أن يصدر بتوطئة تبين طبيعة الخطاب القرآني السلمية، إذ يوصف بأنه متدرج يبدأ بمقدمات حجاجية، وينتهي بنتائج، وكيف يتدرج المتكلم في خطابه بشكل متدرج سلمي؛ ليكون أكثر تأثيرا في المتلقي، وبعدها يتناول البحث خاصية السلمية عند علماء العرب في مختلف تخصصاتهم؛ ليبين كيف تناولوا هذه الخاصية في علومهم، وإن لم يصطلحوا عليها اصطلاحات محددة، وبيان نقاط التلاقي بين ما ذهبوا إليه، وبين ما ذهب إليه الغربيون في دراستهم للسلالم الحجاجية على اعتبار أنهم المؤسسون لهذه النظرية. ثم ينتقل البحث إلى الجانب التطبيقي عبر تحليل آيات كريمات من مدونة البحث؛ ليبين كيف يرتقي الخطاب القرآني بحججه إلى أن يصل بالمتلقي إلى النتيجة المقصودة، وهي الغاية المنشودة من الخطاب؛ لتحصل عملية التأثير والإقناع. وتوصل البحث إلى أن الحجج في آيات القتال الكريمة رتبت بشكل متدرج سلمي، مكونة سلما حجاجيا رائعا؛ لأن القرآن الكريم بطبيعته لا يكتفي بعرض حجة واحدة، وإنما يتدرج في عرض الحجج؛ وصولا إلى التأثير في المتلقي وإقناعه، إما لدحض حجج الكافرين وإبطالها، وإما لرفع همم المؤمنين، وتشجيعهم على الجهاد في سبيل الله تعالى.
تُظهر التطورات الأخيرة في علم الاقتصاد ارتباطه الوثيق بالتطورات في تكنولوجيا الاتصالات والمعلومات, كما توسعت ارتباطاته بالعلوم الإقليمية "Regional Science", حيث تبنّت سياسات التخطيط الاستراتيجي في ...كثير من الدول هيكليات تخطيطية شاملة تربط بين مختلف القطاعات الاقتصادية والعمرانية والاجتماعية للوصول إلى تنمية مكانية متكاملة. يطرح البحث إشكالية الفجوة في التنمية الاقتصادية في الواقع المحلي, ويقدّم الاقتصاد الذكي, باعتباره أحد خصائص التخطيط الذكي, كحلّ يساهم في تغيير مسار التنمية والتخطيط لتحقيق تنمية متكاملة, وذلك من خلال التعريف بمفهوم الاقتصاد الذكي وتوضيح أهم ميزاته وذكر بعض تجاربه, للوصول إلى استنتاجات تساهم في توضيح رؤية مستقبل التنمية المحلي.
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