The p110α and p110β Isoforms of Class I Phosphatidylinositol 3-Kinase Are Involved in Toll-Like Receptor 5 Signaling in Epithelial Cells

Background. Bacterial flagellin triggers inflammation in mammalian cells via Toll-like receptor (TLR) 5. Release of the chemokine IL-8 in response to flagellin involves NF-κB, p38 MAP kinase, and phosphatidylinositol 3-kinase (PI3K). However, PI3K has been reported to be either pro- or anti-inflammatory in different model systems. We hypothesized that this could be due to different activities of the p110α and β isoforms of PI3K. Results. PI3K and Akt were rapidly activated in Caco-2 colon carcinoma cells by flagellin. Using a plasmid-based shRNA delivery system and novel p110 isoform-specific inhibitors, we found that flagellin-induced IL-8 production was dependent on both p110α and p110β. However in the mouse, inhibition of p110β but not p110α reduced the increase of serum IL-6 levels induced by intraperitoneal injection of flagellin. Conclusions. These data demonstrate that the p110α and β isoforms of class IA PI3K are both required for the proinflammatory response to flagellin

Metabotyping of docosahexaenoic acid - Treated alzheimer's disease cell model

10.1371/journal.pone.0090123PLoS ONE92-POLN

ApoB100/LDLR-/- Hypercholesterolaemic Mice as a Model for Mild Cognitive Impairment and Neuronal Damage

Recent clinical findings support the notion that the progressive deterioration of cholesterol homeostasis is a central player in Alzheimer's disease (AD). Epidemiological studies suggest that high midlife plasma total cholesterol levels are associated with an increased risk of AD. This paper reports the plasma cholesterol concentrations, cognitive performance, locomotor activity and neuropathological signs in a murine model (transgenic mice expressing apoB100 but knockout for the LDL receptor [LDLR]) of human familial hypercholesterolaemia (FH). From birth, these animals have markedly elevated LDL-cholesterol and apolipoprotein B100 (apoB100) levels. These transgenic mice were confirmed to have higher plasma cholesterol concentrations than wild-type mice, an effect potentiated by aging. Further, 3-month-old transgenic mice showed cholesterol (total and fractions) concentrations considerably higher than those of 18-month-old wild-type mice. The hypercholesterolaemia of the transgenic mice was associated with a clear locomotor deficit (as determined by rotarod, grip strength and open field testing) and impairment of the episodic-like memory (determined by the integrated memory test). This decline in locomotor activity and cognitive status was associated with neuritic dystrophy and/or the disorganization of the neuronal microtubule network, plus an increase in astrogliosis and lipid peroxidation in the brain regions associated with AD, such as the motor and lateral entorhinal cortex, the amygdaloid basal nucleus, and the hippocampus. Aortic atherosclerotic lesions were positively correlated with age, although potentiated by the transgenic genotype, while cerebral β-amyloidosis was positively correlated with genetic background rather than with age. These findings confirm hypercholesterolaemia as a key biomarker for monitoring mild cognitive impairment, and shows these transgenic mice can be used as a model for cognitive and psycho-motor decline

Accumulation of neutral lipids in peripheral blood mononuclear cells as a distinctive trait of Alzheimer patients and asymptomatic subjects at risk of disease

<p>Abstract</p> <p>Background</p> <p>Alzheimer's disease is the most common progressive neurodegenerative disease. In recent years, numerous progresses in the discovery of novel Alzheimer's disease molecular biomarkers in brain as well as in biological fluids have been made. Among them, those involving lipid metabolism are emerging as potential candidates. In particular, an accumulation of neutral lipids was recently found by us in skin fibroblasts from Alzheimer's disease patients. Therefore, with the aim to assess whether peripheral alterations in cholesterol homeostasis might be relevant in Alzheimer's disease development and progression, in the present study we analyzed lipid metabolism in plasma and peripheral blood mononuclear cells from Alzheimer's disease patients and from their first-degree relatives.</p> <p>Methods</p> <p>Blood samples were obtained from 93 patients with probable Alzheimer's disease and from 91 of their first-degree relatives. As controls we utilized 57, cognitively normal, over-65 year-old volunteers and 113 blood donors aged 21-66 years, respectively. Data are reported as mean ± standard error. Statistical calculations were performed using the statistical analysis software Origin 8.0 version. Data analysis was done using the Student t-test and the Pearson test.</p> <p>Results</p> <p>Data reported here show high neutral lipid levels and increased ACAT-1 protein in about 85% of peripheral blood mononuclear cells freshly isolated (<it>ex vivo</it>) from patients with probable sporadic Alzheimer's disease compared to about 7% of cognitively normal age-matched controls. A significant reduction in high density lipoprotein-cholesterol levels in plasma from Alzheimer's disease blood samples was also observed. Additionally, correlation analyses reveal a negative correlation between high density lipoprotein-cholesterol and cognitive capacity, as determined by Mini Mental State Examination, as well as between high density lipoprotein-cholesterol and neutral lipid accumulation. We observed great variability in the neutral lipid-peripheral blood mononuclear cells data and in plasma lipid analysis of the subjects enrolled as Alzheimer's disease-first-degree relatives. However, about 30% of them tend to display a peripheral metabolic cholesterol pattern similar to that exhibited by Alzheimer's disease patients.</p> <p>Conclusion</p> <p>We suggest that neutral lipid-peripheral blood mononuclear cells and plasma high density lipoprotein-cholesterol determinations might be of interest to outline a distinctive metabolic profile applying to both Alzheimer's disease patients and asymptomatic subjects at higher risk of disease.</p

تفريق الجنسية في رواية بنات الرياض لرجاء الصانع بنظر قاسم أمين

مستخلص البحث أصبحت تفريق الجنسية وزرا ثقيلا تحذر النساء جميعهن. وهذا التفريق يجلب نشأة الجنسية التي تسيطر وتهيمن على الأخرى حتى ظهرت منها السلوك، القيم، النظم بل التأويلات المنحرفة عن النصوص الدينية بحيث يفهمون على قدر إمكانيتهم ويفتقد عن الإنسانية ويرفض على العدالة مثبتين تلك الانزلاقات لأجل الحفاظ على التقاليد الموجودة. وهذا السلوك لم يزل مألوفا حتى القرن الواحد الوعشرين. حكي في رواية بنات رياض تأليف رجاء الصانع أن هنالك النساء المعاناة لم يذقن العدالة. هن ينعزلن لأرملتهن، وحبهن يسود لأجل الاسم وولادتهن من الأمريكية، مهجورات لأجل الأخطاء المعية. ففي القرن السابق، يقلق قاسم أمين على حالة من حوله، حيث وجد الفراغات بين الرجال والنساء، فيحاول لمقاومتها ويعتز على عتق النساء. يهدف هذا البحث إلى وصف أشكال التفريقات الجنسية في رواية بنات رياض ووصف ردود الأشخاص اللاتي تصبن بالتفريق. هذا البحث يعتبر بحثا وصفيا كيفيا، ويستوعب البيانات من النصوص حتى تنتج البيانات الوصفية بوجود الكلمات المأخوذة من مصدرين. فالمصدر الأول هو المصدر الرئيسي وهو رواية بنات رياض، بينما المصدرالثانوي هو الكتب الجوهرية المتعلقة بهذه الدراسة. فطريقة جمع البيانات هي القراءة والتسجيل. ويستخدم الباحث طريقة التثليث لتصديق البيانات. وأما طريقة تحليل البيانات فيستخدم الباحث نموذج ميلس وهابرمان حيث يتناول على أربع مراحل، وهي: جمع البيانات، تقليل البينات، عرض البيانات والاستنتاج. فنتائج البينات تدل على أن: 1) أشكال التفريقات الجنسية في رواية بنات رياض تتمثل في صفد النساء في الأماكن العامة، السمة السلبية نحو الأرملة، تحديد حقوق التربية والموصول على العمل، تفضيل الأسباب النسلية بالنسبة إلى الفضائل من قبل النساء؛ 2) ردود النساء اللاتي تصبن بالتفريق نشأة الوعي لتكن نساء مدنية وتدعم بعضها ببعض ولم يسخرن على الرجال وتدعم على تجديد القيم القديمة المنحرفة والداعمة على الأفعال المفسدة ABSTRACT Gender discrimination is a very frightening specter for women. From there gave birth to one type of gender who felt most powerful and felt superior to other genders, so that behaviors, values, rules, and even one-sided interpretations of religious legitimacy were arranged in such a way, were exclusive, inhumane, and anti-equality, but they continued do it on the pretext of preserving existing traditions. Such behavior is still rampant even in the early 21st century. It is told in the novel Banat Riyadh by Raja al-Sanea of women who suffer and do not get justice. They were ostracized because they became widows, their love had to fail because their family name and birth from the womb of an American mother, were left unilaterally for mistakes made together. A century earlier Qasim Amin was nervous about the condition of his environment, where the gap between men and women became a plague, so he sought to suppress and free women for independence. The purpose of this study is to describe the forms of gender discrimination in the novel Banat Riyadh and describe the reactions of figures who are victims or affected by discriminatory behavior. This research uses descriptive qualitative research methods, data obtained sourced from texts, and research procedures produce descriptive data in the form of written words that take data from two sources. The first source uses primary data sources in the form of the novel "Banat Riyadh" and is supported by secondary data sources in the form of books that become references relating to this study. Data collection techniques in this study used the technique of reading and writing. Researchers used data validity testing techniques using triangulation. Data analysis techniques using the Milles and Huberman model which consists of four steps namely; data collection, data reduction, data presentation, and data verification. From the research conducted, the results obtained by researchers include: 1) Forms of gender discrimination in the Banat Riyadh novel include restrictions on women in public space, negative stigma against widows, education restrictions and access to the world of work, putting forward the big names of families rather than excess- the strengths women have. 2) The reaction of women to discriminatory behavior towards them is in the form of being a strong and independent woman, the birth of awareness to strengthen one another and not to submit to men, a revolutionary effort over old values which is considered as a justification for justification for mistakes. ABSTRAK Diskriminasi gender menjadi sebuah momok yang sangat mengerikan bagi wanita. Dari sana melahirkan satu jenis gender yang merasa paling berkuasa dan merasa lebih unggul dari gender lainnya, sehingga muncul perilaku, nilai, aturan, bahkan tafsir sepihak atas legitimasi agama yang diatur sedemikian rupa, bersifat eksklusif, tidak manusiawi, dan anti kesetaraan, namun terus mereka lakukan dengan dalih menjaga tradisi yang sudah ada. Perilaku demikian masih marak terjadi bahkan hingga pada awal abad 21. Diceritakan dalam novel Banat Riyadh karya Raja al-Sanea para wanita yang menderita dan tidak mendapatkan keadilan. Mereka dikucilkan sebab menjadi janda, cintanya harus kandas sebab nama keluarga dan terlahir dari rahim ibu seorang Amerika, ditinggalkan secara sepihak atas kesalahan yang dilakukan bersama. Seabad sebelumnya Qasim Amin gelisah atas kondisi lingkungannya, di mana kesenjangan antara laki-laki dan wanita menjadi sebuah wabah, maka dia berupaya memberangus dan memerdekakan kemerdekaan bagi kaum wanita. Tujuan penelitian ini adalah untuk mendeskripsikan bentuk-bentuk diskriminasi gender dalam novel Banat Riyadh serta mendeskripsikan reaksi para tokoh yang menjadi korban atau terdampak perilaku diskriminatif. Penelitian ini menggunakan metode penelitian deskriptif kualitatif, data-data yang diperoleh bersumber dari teks-teks, serta prosedur penelitian menghasilkan data deskriptif berupa kata-kata tertulis yang mengambil data dari dua sumber. Sumber yang pertama menggunakan sumber data primer berupa novel “Banat Riyadh” dan didukung oleh sumber data sekunder berupa buku-buku yang menjadi acuan yang berhubungan dengan kajian ini. Teknik pengumpulan data dalam penelitian ini menggunakan teknik baca-catat. Peneliti menggunakan teknik pengujian keabsahan data menggunakan triangulasi. Teknik analisis data menggunakan model Milles dan Huberman yang terdiri dari empat langkah yaitu; pengumpulan data, reduksi data, penyajian data, dan verifikasi data. Dari penelitian yang dilakukan, hasil yang diperoleh oleh peneliti antara lain: 1) Bentuk diskriminasi gender dalam novel Banat Riyadh meliputi pembatasan wanita di ruang publik, stigma negatif terhadap wanita janda, pembatasan pendidikan dan akses dunia kerja, lebih mengedepankan nama besar keluarga ketimbang kelebihan-kelebihan yang wanita punya. 2) Reaksi kaum wanita atas perilaku diskriminatif terhadap mereka berbentuk menjadi wanita kuat dan mandiri, lahirnya kesadaran saling menguatkan antar sesama dan tidak tunduk pada laki-laki, upaya revolusi atas nilai lama yang dianggap sebagai dalih pembenaran kesalahan-kesalahan

Clinical, Pathological, and Molecular Profiling of Radioactive Iodine Refractory Differentiated Thyroid Cancer

© Copyright 2019, Mary Ann Liebert, Inc., publishers 2019. Background: Six to 20% of thyroid cancer (TC) patients develop distant metastases, and one-Third become radioiodine refractory (RAIR). Available targeted therapies increase progression-free survival but are associated with toxicities. This study aims to characterize clinical, pathological, and molecular profiles of patients with RAIR TC. Methods: Data of TC patients seen during 2013-2017 at two tertiary care centers were retrospectively analyzed. Patients were considered RAIR according to American Thyroid Association guidelines. The control cohort was sex matched and age matched and had either regression or stable disease (by Response Evaluation Criteria in Solid Tumors) on follow-up at least three years after initial therapy. Molecular profiles on a subset of RAIR patients were reviewed. Results: Compared with 22 matched controls, 54 RAIR patients had an average age of 57 years (standard deviation [SD] = 13), 56% were male (41% in the control group); the average tumor size was 4 cm (SD = 2.5); tumors were multifocal in 54%, with involved surgical margins in 42%, focal invasion in 79%, and extrathyroidal extension (ETE) in 61%. Sixty-six percent had distant metastases at initial presentation with metastases to the lungs in 85%, bone in 56%, both sites in 43%, brain in 9%, and liver in 4%. There were no statistically significant differences between RAIR and controls in tumor size, focal invasion, ETE, and histology. The RAIR group received a higher cumulative radioactive iodine (RAI) dose and number of therapies compared with the controls (518 mCi vs. 302 mCi, p = 0.002 and 2.2 vs. 1.3 treatments, p = 0.001). Overall, patients \u3e46 years had 4.5 times higher odds ratio (OR) of being RAIR; white race/ethnicity was associated with a reduced OR of RAIR disease (OR 0.33, p = 0.079). Molecular profiling data in the RAIR subgroup indicated that 50% of patients harbored mutations in the RAS/RAF pathway (11/22). Among 19 patients with a more extensive molecular panel, median tumor mutational burden was 5 megabase (range 3-16) and 26% (5/19) exhibited strong PD-L1 positivity. Conclusion: Among patients with metastatic differentiated thyroid carcinomas, patients with RAIR have similar histopathological and clinical characteristics as patients with RAI avid cancer. The risk of having RAIR TC is increased at age ≥46 and reduced in Caucasians