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كيف أصبحت أمل فتاة إيجابية مهتمة بمشكلات المجتمع ؟
من هو الشخص الإيجابي المهتم بقضايا عالمه ؟ لماذا تحتاج إلى مثل هؤلاء الأشخاص ؟ شارك أمل اكتشافها طرق التأثير الإيجابي في قضايا عالمية، مثل : التجارة العادلة ومساعدة اللاجئين... كل هذا في إطار مغامرة ممتعة حتى لو كنت صغيرا، يمكنك أن تساعد في جعل العالم مكانا أفضل.
Book
PRIMMO study protocol: a phase II study combining PD-1 blockade, radiation and immunomodulation to tackle cervical and uterine cancer
Background
Immunotherapeutic approaches have revolutionized oncological practice but are less evaluated in gynecological malignancies. PD-1/PD-L1 blockade in gynecological cancers showed objective responses in 13–17% of patients. This could be due to immunosuppressive effects exerted by gynecological tumors on the microenvironment and an altered tumor vasculature.
In other malignancies, combining checkpoint blockade with radiation delivers benefit that is believed to be due to the abscopal effect. Addition of immune modulation agents has also shown to enhance immune checkpoint blockade efficacy. Therefore we designed a regimen consisting of PD-1 blockade combined with radiation, and different immune/environmental-targeting compounds: repurposed drugs, metronomic chemotherapy and a food supplement.
We hypothesize that these will synergistically modulate the tumor microenvironment and induce and sustain an anti-tumor immune response, resulting in tumor regression.
Methods
PRIMMO is a multi-center, open-label, non-randomized, 3-cohort phase 2 study with safety run-in in patients with recurrent/refractory cervical carcinoma, endometrial carcinoma or uterine sarcoma.
Treatment consists of daily intake of vitamin D, lansoprazole, aspirin, cyclophosphamide and curcumin, starting 2 weeks before the first pembrolizumab dose. Pembrolizumab is administered 3-weekly for a total of 6 cycles. Radiation (3 × 8 Gy) is given on days 1, 3 and 5 of the first pembrolizumab dose.
The safety run-in consists of 6 patients. In total, 18 and 25 evaluable patients for cervical and endometrial carcinoma respectively are foreseen to enroll. No sample size is determined for uterine sarcoma due to its rarity.
The primary objective is objective response rate at week 26 according to immune-related response criteria.
Secondary objectives include safety, objective response rate at week 26 according to RECIST v1.1, best overall response, progression-free survival, overall survival and quality of life.
Exploratory, translational research aims to evaluate immune biomarkers, extracellular vesicles, cell death biomarkers and the gut microbiome.
Discussion
In this study, a combination of PD-1 blockade, radiation and immune/environmental-targeting compounds is tested, aiming to tackle the tumor microenvironment and induce anti-tumor immunity. Translational research is performed to discover biomarkers related to the mode of action of the combination.
Trial registration
EU Clinical Trials Register: EudraCT
2016-001569-97
, registered on 19-6-2017. Clinicaltrials.gov:
NCT03192059
, registered on 19-6-2017.
Journal Article
الموصل في مستهل القرن العشرين : مترجم عن كتاب وراء الحجاب في بلاد العرب العثمانية : سرد لتجارب ثمان سنوات عاشتها امرأة إنكليزية بين نساء الشرق 1908-1900
رواية عن إقامة امرأة إنجليزية لمدة ثماني سنوات بين نساء الشرق هي قصة كتبتها ماري هيوم جريفيث، زوجة الدكتور ألبرت هيوم جريفيث، وهو مبشر طبي بريطاني، عن حياتها وعمل في بلاد فارس (إيران) ومقاطعة الموصل التركية (في شمال العراق الحالي) في الأعوام من 1900 إلى 1908. بينما كان زوجها منخرطًا في العمل الطبي، أمضت ماري هيوم جريفيث الكثير من الوقت بصحبة النساء، اللاتي تصف ثقافتهن خلف الأبواب المغلقة في أندارون (أماكن النساء) بشكل عام بحساسية. هدفها هو \"تقديم بعض المعلومات عن الحياة الداخلية للشرق\". ينصب الاهتمام الرئيسي للكتاب على المدخل الذي استمتعت به للأسر من مختلف الطبقات الاجتماعية. قضت عائلة هيوم غريفيث ثلاث سنوات في مدن كرمان وأصفهان ويزد الإيرانية، حيث خصصت لها السيدة هيوم غريفيث عدة فصول تغطي موضوعات متنوعة مثل الفولكلور المحلي، والنصائح حول شراء السجاد، والتعامل مع الخدم. طوال عملها، تقدم أوصافًا وتعليقات على حالة المرأة. على الرغم من وصولها إلى الأندرون، تلتزم الكاتبة الصمت بشكل لائق بشأن معظم الأمور المتعلقة بالزواج وموضوعات الولادة ورعاية الأطفال. لكنها تدين الوضع غير الآمن للزوجات. وهي تولي اهتمامًا كبيرًا للأقليات الدينية والعرقية في إيران وشمال العراق، وتخصص فصولًا للبهائيين والبارسيين واليزيديين واليهود والأكراد والمسيحيين من مختلف الطوائف. الفصول المتعلقة بالصحة العامة والعلاج الطبي كتبها ألبرت هيوم-جريفيث، بناءً على خبرته كمبشر طبي. الكتاب مزود برسوم إيضاحية جيدة بصور فوتوغرافية التقطها زملاء أو من ملفات جمعية الكنيسة التبشيرية لأفريقيا والشرق، وهي المنظمة التي يوجد مقرها في لندن والتي رعت البعثة.
Book
Water, Sanitation, and Hygiene (WASH): A Critical Component for Sustainable Soil-Transmitted Helminth and Schistosomiasis Control
A second is that small sections of the population usually remain out of reach of chemotherapy programmes, subgroups that frequently have a disproportionately heavy burden of infection, thereby serving as a reservoir for reinfection. [...]longer-term effectiveness of chemotherapy in interrupting transmission is dependent on maintenance of regular retreatment. Other issues that are not yet resolved with regards to chemotherapy include potential teratogenic effects of benzimidazole drugs and associations with eczema in children following maternal chemotherapy during pregnancy [24]. [...]whilst chemotherapy is necessary to rapidly reduce the burden and morbidity of helminth infections, we argue that by itself it is an unsustainable strategy for helminth control and for reaching control and elimination targets.
Journal Article
مدخل إلى الفلسفة السياسية
تم نشر هذه المقدمة المؤثرة والكلاسيكية للفلسفة السياسية لأول مرة في عام 1953 لكل من طالب النظرية السياسية والقارئ العام يقدم لنا البروفيسور موراي أولا مقدمة توضح طبيعة الفلسفة والغرض منها، ثم يقوم بدراسة نقدية للنظريات الأساسية التي قدمها الفلاسفة السياسيون من أفلاطون إلى ماركس، مع إيلاء اهتمام خاص للقضايا المعاصرة يحاول الكتاب أيضا تحديد القضايا الأساسية ذات الأهمية الفلسفية في السياسة المعاصرة، مع الإشارة بشكل خاص إلى الصراع بين السلطة السياسية والحقوق الفردية، ولإظهار كيف أن الافتراضات الأخلاقية المختلفة الكامنة وراء أنظمة الحكم الاستبدادية والديمقراطية للحكومة تستند في النهاية إلى نظريات مختلفة من المنطق.
Book
O-GlcNAcylation modulates Bmi-1 protein stability and potential oncogenic function in prostate cancer
The Polycomb group transcriptional repressor Bmi-1 often overexpressed and participated in stem cells self-renewal and tumorigenesis initiating of prostate cancer. In this progression, Bmi-1 protein was regulated by transcription and post-translational modifications (PTMs). Nobly, the underlying PTMs regulation of Bmi-1 is poorly known. Here we use co-immunoprecipitation show that in C4-2 cell line, Bmi-1 directly interacted with OGT which is the only known enzyme catalyzed the O-GlcNAcylation in human. Furthermore, we identified that Ser255 is the site for Bmi-1 O-GlcNAcylation, and O-GlcNAcylation promoted Bmi-1 protein stability and its oncogenic activity. Finally, microarray analysis has characterized potential oncogenes associated pathway subject to repression via the OGT-Bmi-1 axis. Taken together, these results indicate that OGT-mediated O-GlcNAcylation at Ser255 stabilizes Bmi-1 and hence inhibits the TP53, PTEN and CDKN1A/CDKN2A pathway. The study not only uncovers a novel functional PTMs of Bmi-1 but also reveals a unique oncogenic role of O-GlcNAcylation in prostate cancer.
Journal Article
Distinct radiation responses after in vitro mtDNA depletion are potentially related to oxidative stress
Several clinically used drugs are mitotoxic causing mitochondrial DNA (mtDNA) variations, and thereby influence cancer treatment response. We hypothesized that radiation responsiveness will be enhanced in cellular models with decreased mtDNA content, attributed to altered reactive oxygen species (ROS) production and antioxidant capacity. For this purpose BEAS-2B, A549, and 143B cell lines were depleted from their mtDNA (ρ0). Overall survival after irradiation was increased (p<0.001) for BEAS-2B ρ0 cells, while decreased for both tumor ρ0 lines (p<0.05). In agreement, increased residual DNA damage was observed after mtDNA depletion for A549 and 143B cells. Intrinsic radiosensitivity (surviving fraction at 2Gy) was not influenced. We investigated whether ROS levels, oxidative stress and/or antioxidant responses were responsible for altered radiation responses. Baseline ROS formation was similar between BEAS-2B parental and ρ0 cells, while reduced in A549 and 143B ρ0 cells, compared to their parental counterparts. After irradiation, ROS levels significantly increased for all parental cell lines, while levels for ρ0 cells remained unchanged. In order to investigate the presence of oxidative stress upon irradiation reduced glutathione: oxidized glutathione (GSH:GSSG) ratios were determined. Irradiation reduced GSH:GSSG ratios for BEAS-2B parental and 143B ρ0, while for A549 this ratio remained equal. Additionally, changes in antioxidant responses were observed. Our results indicate that mtDNA depletion results in varying radiation responses potentially involving variations in cellular ROS and antioxidant defence mechanisms. We therefore suggest when mitotoxic drugs are combined with radiation, in particular at high dose per fraction, the effect of these drugs on mtDNA copy number should be explored.
Journal Article
زن و فن صيانة الدراجة النارية : بحث في القيم : رواية /
تدور هذه الرواية \"زن و فن صيانة الدراجة النارية\" بقالبها البسيط عن رحلة يقوم بها الراوي على متن دراجة نارية مع ابنه كريس عبر عدة ولايات في أميركا مستخدما الطرق الخلفية الثانوية ويرافقهما في بعض أجزاء الرحلة عائلة سذرلاند المكونة من جون وسيليفيا اللذين يرفضان معرفة أبسط قواعد التكنولوجيا بما فيها أساسيات صيانة الدراجة التي يمتطيانها على عكس الراوي.
Book
Dual-sgRNA CRISPR/Cas9 knockout of PD-L1 in human U87 glioblastoma tumor cells inhibits proliferation, invasion, and tumor-associated macrophage polarization
Programmed death ligand 1 (PD-L1) plays a key role in glioblastoma multiforme (GBM) immunosuppression, vitality, proliferation, and migration, and is therefore a promising target for treating GBM. CRISPR/Cas9-mediated genomic editing can delete both cell surface and intracellular PD-L1. This systemic deliverable genomic PD-L1 deletion system can be used as an effective anti-GBM therapy by inhibiting tumor growth and migration, and overcoming immunosuppression. To target PD-L1 for CRISPR/Cas9 gene editing, we first identified two single guide RNA (sgRNA) sequences located on PD-L1 exon 3. The first sgRNA recognizes the forward strand of human PD-L1 near the beginning of exon 3 that allows editing by Cas9 at approximately base pair 82 (g82). The second sgRNA recognizes the forward strand of exon 3 that directs cutting at base pair 165 (g165). A homology-directed repair template (HDR) combined with the dual-sgRNAs was used to improve PD-L1 knockout specificity and efficiency. sgRNAs g82 and g165 were cloned into the multiplex CRISPR/Cas9 assembly system and co-transfected with the HDR template in human U87 GBM cells (g82/165 + HDR). T7E1 analysis suggests that the dual-sgRNA CRISPR/Cas9 strategy with a repair template was capable of editing the genomic level of
PD-L1
. This was further confirmed by examining PD-L1 protein levels by western blot and immunofluorescence assays. Western blot analysis showed that the dual-sgRNAs with the repair template caused a 64% reduction of PD-L1 protein levels in U87 cells, while immunostaining showed a significant reduction of intracellular PD-L1. PD-L1 deletion inhibited proliferation, growth, invasion and migration of U87 cells, indicating intracellular PD-L1 is necessary for tumor progression. Importantly, U87 cells treated with g82/165 + HDR polarized tumor-associated macrophages (TAM) toward an M1 phenotype, as indicated by an increase in TNF-α and a decrease in IL-4 secretions. This was further confirmed with flow cytometry that showed an increase in the M1 markers Ly6C + and CD80 +, and a decrease in the M2 marker CD206 + both in vitro and in vivo. Utilizing dual-sgRNAs and an HDR template with the CRISPR/Cas9 gene-editing system is a promising avenue for the treatment of GBM.
Journal Article