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مقدمة في علم الاجتماع الثقافي
كان الحديث الأكبر في مناهج الدراسة في علم الاجتماع الأكاديمي، في النصف الثاني من القرن العشرين، هو دراسة الثقافة، لم يكن هذا الموضوع الجديد، قاصرا على علم الاجتماع، لكنه حظي بمراجعات كبيرة في عديد من المجالات داخل الدراسات الإنسانية، مثل الفلسفة ودراسة الفن، والأدب الإنجليزي، وغيرها ولقد خلق الموضوع أيضا مجالا خاص به في الدراسات الثقافية، ويبدو أن الفكرة التي تذهب بأن كل هذا كان بمثابة ابتكار فيها شيئا من التناقض ولأن الثقافة كانت محور العلوم الإنسانية وبصفة خاصة الأنثروبولوجيا، على الأقل لقرن من الزمان لذلك فنحن بحاجة إلى المعرفة كيف ولماذا؟ أعيد تشكيل المناهج الدراسية السوسيولوجية من خلال التحول إلى الثقافة، وأنا أرى أن التحول إلى الثقافة، نجح علماء الاجتماع وطوروا مشروعات سوسيولوجية أساسية لوصف الحداثة وأنه من الواضح الآن أن هذه المراجعات وصلت إلى بداية تأريخ الحياة المعاصرة.
Book
Three-Dimensional Microfluidic Tri-Culture Model of the Bone Marrow Microenvironment for Study of Acute Lymphoblastic Leukemia
Acute lymphoblastic leukemia (ALL) initiates and progresses in the bone marrow, and as such, the marrow microenvironment is a critical regulatory component in development of this cancer. However, ALL studies were conducted mainly on flat plastic substrates, which do not recapitulate the characteristics of marrow microenvironments. To study ALL in a model of in vivo relevance, we have engineered a 3-D microfluidic cell culture platform. Biologically relevant populations of primary human bone marrow stromal cells, osteoblasts and human leukemic cells representative of an aggressive phenotype were encapsulated in 3-D collagen matrix as the minimal constituents and cultured in a microfluidic platform. The matrix stiffness and fluidic shear stress were controlled in a physiological range. The 3-D microfluidic as well as 3-D static models demonstrated coordinated cell-cell interactions between these cell types compared to the compaction of the 2-D static model. Tumor cell viability in response to an antimetabolite chemotherapeutic agent, cytarabine in tumor cells alone and tri-culture models for 2-D static, 3-D static and 3-D microfluidic models were compared. The present study showed decreased chemotherapeutic drug sensitivity of leukemic cells in 3-D tri-culture models from the 2-D models. The results indicate that the bone marrow microenvironment plays a protective role in tumor cell survival during drug treatment. The engineered 3-D microfluidic tri-culture model enables systematic investigation of effects of cell-cell and cell-matrix interactions on cancer progression and therapeutic intervention in a controllable manner, thus improving our limited comprehension of the role of microenvironmental signals in cancer biology.
Journal Article
TMEM106B drives lung cancer metastasis by inducing TFEB-dependent lysosome synthesis and secretion of cathepsins
Metastatic lung cancer is the leading cause of cancer-associated mortality worldwide, therefore necessitating novel approaches to identify specific genetic drivers for lung cancer progression and metastasis. We recently performed an in vivo gain-of-function genetic screen to identify driver genes of lung cancer metastasis. In the study reported here, we identify
TMEM106B
as a primary robust driver of lung cancer metastasis. Ectopic expression of
TMEM106B
could significantly promote the synthesis of enlarged vesicular lysosomes that are laden with elevated levels of active cathepsins. In a
TFEB
-dependent manner,
TMEM106B
could modulate the expression of lysosomal genes of the coordinated lysosomal expression and regulation (CLEAR) pathway in lung cancer cells and patient samples. We also demonstrate that
TMEM106B
-induced lysosomes undergo calcium-dependent exocytosis, thereby releasing active lysosomal cathepsins necessary for
TMEM106B
-mediated cancer cell invasion and metastasis in vivo, which could be therapeutically prevented by pharmacological inhibition of cathepsins. Further, in TCGA LUAD data sets, 19% of patients show elevated expression of
TMEM106B
, which predicts for poor disease-free and overall-survival.
One of the major causes of cancer-related mortality is represented by metastatic lung cancer. Here the authors characterize the role of
TMEM106B
in driving metastatic lung adenocarcinoma and suggest that
TMEM106B
-mediated secretion of cathespin impacts cell migration and invasion of lung cancer cells, increasing metastatic spreading.
Journal Article
Congenital cytomegalovirus infection in pregnancy and the neonate: consensus recommendations for prevention, diagnosis, and therapy
Congenital cytomegalovirus is the most frequent, yet under-recognised, infectious cause of newborn malformation in developed countries. Despite its clinical and public health importance, questions remain regarding the best diagnostic methods for identifying maternal and neonatal infection, and regarding optimal prevention and therapeutic strategies for infected mothers and neonates. The absence of guidelines impairs global efforts to decrease the effect of congenital cytomegalovirus. Data in the literature suggest that congenital cytomegalovirus infection remains a research priority, but data are yet to be translated into clinical practice. An informal International Congenital Cytomegalovirus Recommendations Group was convened in 2015 to address these questions and to provide recommendations for prevention, diagnosis, and treatment. On the basis of consensus discussions and a review of the literature, we do not support universal screening of mothers and the routine use of cytomegalovirus immunoglobulin for prophylaxis or treatment of infected mothers. However, treatment guidelines for infected neonates were recommended. Consideration must be given to universal neonatal screening for cytomegalovirus to facilitate early detection and intervention for sensorineural hearing loss and developmental delay, where appropriate. The group agreed that education and prevention strategies for mothers were beneficial, and that recommendations will need continual updating as further data become available.
Journal Article
Daily longitudinal sampling of SARS-CoV-2 infection reveals substantial heterogeneity in infectiousness
The dynamics of SARS-CoV-2 replication and shedding in humans remain poorly understood. We captured the dynamics of infectious virus and viral RNA shedding during acute infection through daily longitudinal sampling of 60 individuals for up to 14 days. By fitting mechanistic models, we directly estimated viral expansion and clearance rates and overall infectiousness for each individual. Significant person-to-person variation in infectious virus shedding suggests that individual-level heterogeneity in viral dynamics contributes to ‘superspreading’. Viral genome loads often peaked days earlier in saliva than in nasal swabs, indicating strong tissue compartmentalization and suggesting that saliva may serve as a superior sampling site for early detection of infection. Viral loads and clearance kinetics of Alpha (B.1.1.7) and previously circulating non-variant-of-concern viruses were mostly indistinguishable, indicating that the enhanced transmissibility of this variant cannot be explained simply by higher viral loads or delayed clearance. These results provide a high-resolution portrait of SARS-CoV-2 infection dynamics and implicate individual-level heterogeneity in infectiousness in superspreading.
A longitudinal analysis of viral expansion and clearance rates in 60 individuals sampled daily during acute infection reveals high inter-individual variation in infectious virus shedding, which may contribute to superspreading.
Journal Article
Co-culture model of B-cell acute lymphoblastic leukemia recapitulates a transcription signature of chemotherapy-refractory minimal residual disease
B-cell acute lymphoblastic leukemia (ALL) is characterized by accumulation of immature hematopoietic cells in the bone marrow, a well-established sanctuary site for leukemic cell survival during treatment. While standard of care treatment results in remission in most patients, a small population of patients will relapse, due to the presence of minimal residual disease (MRD) consisting of dormant, chemotherapy-resistant tumor cells. To interrogate this clinically relevant population of treatment refractory cells, we developed an in vitro cell model in which human ALL cells are grown in co-culture with human derived bone marrow stromal cells or osteoblasts. Within this co-culture, tumor cells are found in suspension, lightly attached to the top of the adherent cells, or buried under the adherent cells in a population that is phase dim (PD) by light microscopy. PD cells are dormant and chemotherapy-resistant, consistent with the population of cells that underlies MRD. In the current study, we characterized the transcriptional signature of PD cells by RNA-Seq, and these data were compared to a published expression data set derived from human MRD B-cell ALL patients. Our comparative analyses revealed that the PD cell population is markedly similar to the MRD expression patterns from the primary cells isolated from patients. We further identified genes and key signaling pathways that are common between the PD tumor cells from co-culture and patient derived MRD cells as potential therapeutic targets for future studies.
Journal Article
Th17 cells contribute to combination MEK inhibitor and anti-PD-L1 therapy resistance in KRAS/p53 mutant lung cancers
Understanding resistance mechanisms to targeted therapies and immune checkpoint blockade in mutant KRAS lung cancers is critical to developing novel combination therapies and improving patient survival. Here, we show that MEK inhibition enhanced PD-L1 expression while PD-L1 blockade upregulated MAPK signaling in mutant KRAS lung tumors. Combined MEK inhibition with anti-PD-L1 synergistically reduced lung tumor growth and metastasis, but tumors eventually developed resistance to sustained combinatorial therapy. Multi-platform profiling revealed that resistant lung tumors have increased infiltration of Th17 cells, which secrete IL-17 and IL-22 cytokines to promote lung cancer cell invasiveness and MEK inhibitor resistance. Antibody depletion of IL-17A in combination with MEK inhibition and PD-L1 blockade markedly reduced therapy-resistance in vivo. Clinically, increased expression of Th17-associated genes in patients treated with PD-1 blockade predicted poorer overall survival and response in melanoma and predicated poorer response to anti-PD1 in NSCLC patients. Here we show a triple combinatorial therapeutic strategy to overcome resistance to combined MEK inhibitor and PD-L1 blockade.
Recent clinical trials combining MEK inhibitors with anti-PD-L1 in solid tumours show moderate responses. Here, the authors demonstrate that the combination of MEK inhibition and PD-L1 blockade in KRAS mutant lung cancer models leads to a transient tumour regressions and resistance due to increased infiltration of Th17 cells and that the triple therapy targeting MEK, PD-L1 and IL-17 produced better in vivo responses.
Journal Article
Autotaxin suppresses cytotoxic T cells via LPAR5 to promote anti–PD-1 resistance in non–small cell lung cancer
Non-small cell lung cancers that harbor concurrent KRAS and TP53 (KP) mutations are immunologically warm tumors with partial responsiveness to anti-PD-(L)1 blockade; however, most patients observe little or no durable clinical benefit. To identify novel tumor-driven resistance mechanisms, we developed a panel of KP murine lung cancer models with intrinsic resistance to anti-PD-1 and queried differential gene expression between these tumors and anti-PD-1-sensitive tumors. We found that the enzyme autotaxin (ATX), and the metabolite it produces, lysophosphatidic acid (LPA), were significantly upregulated in resistant tumors and that ATX directly modulated antitumor immunity, with its expression negatively correlating with total and effector tumor-infiltrating CD8+ T cells. Pharmacological inhibition of ATX, or the downstream receptor LPAR5, in combination with anti-PD-1 was sufficient to restore the antitumor immune response and efficaciously control lung tumor growth in multiple KP tumor models. Additionally, ATX was significantly correlated with inflammatory gene signatures, including a CD8+ cytolytic score in multiple lung adenocarcinoma patient data sets, suggesting that an activated tumor-immune microenvironment upregulates ATX and thus provides an opportunity for cotargeting to prevent acquired resistance to anti-PD-1 treatment. These data reveal the ATX/LPA axis as an immunosuppressive pathway that diminishes the immune checkpoint blockade response in lung cancer.
Journal Article
Valence of Media Coverage About Electronic Cigarettes and Other Tobacco Products From 2014 to 2017: Evidence From Automated Content Analysis
As media exposure can influence people's opinions and perceptions about vaping and smoking, analyzing the valence of media content about tobacco products (ie, overall attitude toward tobacco, cigars, electronic cigarettes, etc.) is an important issue. This study advances the field by analyzing a large amount of media content about multiple tobacco products across six different media sources.
From May 2014 to December 2017, we collected all English-language media items about tobacco products that U.S. young people might see from mass media and websites (long-form) and social media (Twitter and YouTube). We used supervised machine learning to develop validated algorithms to label the valence of these media items. Using the labeled results, we examined the impact of product type (e-cigarettes vs. other tobacco products), source (long-form vs. social media), and time (by month) on the valence of coverage.
We obtained 152 886 long-form media texts (20% with more than a passing mention), nearly 86 million tweets, and 12 262 YouTube videos about tobacco products. Most long-form media content opposed, while most social media coverage supported, the use of e-cigarettes and other tobacco products. Over time, within-source valence proportions were stable, though in aggregate, the amount of media coverage against the use of tobacco products decreased.
This study describes the U.S. public communication environment about vaping and smoking for young people and offers a novel big data approach to analyzing media content. Results suggest that content has gradually become less negative toward the use of e-cigarettes and other tobacco products.
This study is the first to examine how the valence of media coverage differs for e-cigarettes versus other tobacco products, across several media sources, and over time using a large corpus of media items. Unlike prior studies, these data allow us to draw conclusions about relative support and opposition for these two categories of products in a variety of media coverage because the same coding scheme was used across products and media sources.
Journal Article
Extensive Genome-Wide Variability of Human Cytomegalovirus in Congenitally Infected Infants
Research has shown that RNA virus populations are highly variable, most likely due to low fidelity replication of RNA genomes. It is generally assumed that populations of DNA viruses will be less complex and show reduced variability when compared to RNA viruses. Here, we describe the use of high throughput sequencing for a genome wide study of viral populations from urine samples of neonates with congenital human cytomegalovirus (HCMV) infections. We show that HCMV intrahost genomic variability, both at the nucleotide and amino acid level, is comparable to many RNA viruses, including HIV. Within intrahost populations, we find evidence of selective sweeps that may have resulted from immune-mediated mechanisms. Similarly, genome wide, population genetic analyses suggest that positive selection has contributed to the divergence of the HCMV species from its most recent ancestor. These data provide evidence that HCMV, a virus with a large dsDNA genome, exists as a complex mixture of genome types in humans and offer insights into the evolution of the virus.
Journal Article