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"Rodriguez, B."
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Molecular targeting of liposomal nanoparticles to tumor microenvironment
Liposomes are biodegradable and can be used to deliver drugs at a much higher concentration in tumor tissues than in normal tissues. Both passive and active drug delivery by liposomal nanoparticles can significantly reduce the toxic side effects of anticancer drugs and enhance the therapeutic efficacy of the drugs delivered. Active liposomal targeting to tumors is achieved by recognizing specific tumor receptors through tumor-specific ligands or antibodies coupled onto the surface of the liposomes, or by stimulus-sensitive drug carriers such as acid-triggered release or enzyme-triggered drug release. Tumors are often composed of tumor cells and nontumor cells, which include endothelial cells, pericytes, fibroblasts, stromal, mesenchymal cells, innate, and adaptive immune cells. These nontumor cells thus form the tumor microenvironment, which could be targeted and modified so that it is unfavorable for tumor cells to grow. In this review, we briefly summarized articles that had taken advantage of liposomal nanoparticles as a carrier to deliver anticancer drugs to the tumor microenvironment, and how they overcame obstacles such as nonspecific uptake, interaction with components in blood, and toxicity. Special attention is devoted to the liposomal targeting of anticancer drugs to the endothelium of tumor neovasculature, tumor associated macrophages, fibroblasts, and pericytes within the tumor microenvironment.
Journal Article
Holocene evolution of the western Louisiana-Texas Coast, USA : response to sea-level rise and climate change
\"The Western Louisiana and Texas coast is vulnerable to sea-level rise due to low gradients, high subsidence, and depleted sediment supply. This Memoir describes the response of coastal environments to variable rates of sea-level rise and sediment supply during Holocene to modern time. This volume is a wake-up call about the potential magnitude of coastal change over decadal to centennial time scales\"-- Provided by publisher.
Book
The precise determination of the window of implantation significantly improves ART outcomes
The human endometrium is receptive to the embryo for a specific period of time known as the window of implantation (WOI). During this period, the endometrium shows a specific gene expression profile suitable for endometrial function evaluation. ER Map is a molecular tool able to accurately predict endometrial receptivity status by transcriptomic analysis. In this retrospective study, including 2256 subfertile patients undergoing ART treatment, the clinical value of precise WOI determination is studied in detail. Results obtained when single embryo transfers (sET) were scheduled either within the WOI timeframe as established by ER Map, or deviating from this WOI, are assessed and compared. Data obtained showed that 34.18% (771/2256) of patients had a displaced WOI. Analysis of ART outcomes showed significantly higher pregnancy rates in transfers scheduled within the WOI predicted compared to transfers that deviated more than 12h from this WOI (44.35% vs 23.08%, p < 0.001). The deviation from the WOI had also an impact on the progression of pregnancy, with a significant increase in pregnancy loss (~ twofold) observed in transfers that deviated more than 12h from the WOI predicted. These results indicate that the precise determination of the WOI and personalised embryo transfer can significantly improve clinical outcomes.
Journal Article
شراكات المدرسة والأسرة والمجتمع : دليلك للعمل =
كتاب ثري وعملي يشجعك على البدء في بناء شراكة فاعلة بين المدرسة والأسرة والمجتمع ويقدم لك مختلف الأدوات التي تحتاجها لتبدأ ستجد نموذجا مميزا لمساعدة كل مدرسة على بناء خطة العام للشراكة مع الأسر والمجتمع بالتفصيل ستحصل على خطوات تكوين فرق الشراكة في داخل المدرسة ستحصل على نماذج جاهزة للعمل أيضا قوائم بأنشطة هادفة يمكن تنفيذها وأثبتت جدواها عبر دراسات.
BOOK
Mechanical fatigue in microtubules
Mechanical failure of biological nanostructures due to sustained force application has been studied in great detail. In contrast, fatigue failure arising from repeated application of subcritical stresses has received little attention despite its prominent role in engineering and potentially biology. Here, paclitaxel-stabilized microtubules are up to 256 times bent into sinusoidal shapes of varying wavelength and the frequency of breaking events are observed. These experiments allow the calculation of fatigue life parameters for microtubules. Repeated buckling due to 12.5% compression–equal to the compression level experienced by microtubules in contracting cardiomyocytes – results in failure after in average 5 million cycles, whereas at 20.0% compression failure occurs after in average one thousand cycles. The fatigue strength (Basquin) exponent B is estimated as − 0.054±0.009.
Journal Article
MeCP2-regulated miRNAs control early human neurogenesis through differential effects on ERK and AKT signaling
Rett syndrome (RTT) is an X-linked, neurodevelopmental disorder caused primarily by mutations in the methyl-CpG-binding protein 2 (MECP2) gene, which encodes a multifunctional epigenetic regulator with known links to a wide spectrum of neuropsychiatric disorders. Although postnatal functions of MeCP2 have been thoroughly investigated, its role in prenatal brain development remains poorly understood. Given the well-established importance of microRNAs (miRNAs) in neurogenesis, we employed isogenic human RTT patient-derived induced pluripotent stem cell (iPSC) and MeCP2 short hairpin RNA knockdown approaches to identify novel MeCP2-regulated miRNAs enriched during early human neuronal development. Focusing on the most dysregulated miRNAs, we found miR-199 and miR-214 to be increased during early brain development and to differentially regulate extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase and protein kinase B (PKB/AKT) signaling. In parallel, we characterized the effects on human neurogenesis and neuronal differentiation brought about by MeCP2 deficiency using both monolayer and three-dimensional (cerebral organoid) patient-derived and MeCP2-deficient neuronal culture models. Inhibiting miR-199 or miR-214 expression in iPSC-derived neural progenitors deficient in MeCP2 restored AKT and ERK activation, respectively, and ameliorated the observed alterations in neuronal differentiation. Moreover, overexpression of miR-199 or miR-214 in the wild-type mouse embryonic brains was sufficient to disturb neurogenesis and neuronal migration in a similar manner to Mecp2 knockdown. Taken together, our data support a novel miRNA-mediated pathway downstream of MeCP2 that influences neurogenesis via interactions with central molecular hubs linked to autism spectrum disorders.
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
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
MBIP (MAP3K12 binding inhibitory protein) drives NSCLC metastasis by JNK-dependent activation of MMPs
Metastasis is the cause for 90% of cancer-related mortalities. Identification of genetic drivers promoting dissemination of tumor cells may provide opportunities for novel therapeutic strategies. We previously reported an in vivo gain-of-function screen that identified ~30 genes with a functional role in metastasis promotion and characterized detailed mechanistic functions of two hits. In this study, we characterized the contribution of one of the identified genes, MBIP (MAP3K12 binding inhibitory protein), towards driving tumor invasion and metastasis. We demonstrate that expression of MBIP significantly enhances the cellular proliferation, migration and invasion of NSCLC cells in vitro and metastasis in vivo. We functionally characterized that MBIP mediates activation of the JNK pathway and induces expression of matrix metalloproteinases (MMPs), which are necessary for the invasive and metastatic phenotype. Our findings establish a novel mechanistic role of MBIP as a driver of NSCLC progression and metastasis.
Journal Article