Lung cancer remains a leading cause of mortality with 1.69 million deaths worldwide. Activating mutations in epidermal growth factor receptor (EGFR), predominantly exon 19 deletions and exon 21 L858R ...mutations, are known oncogenic drivers identified in 20-40% of non-small-cell lung cancers (NSCLC). 70% of EGFR-mutant NSCLC patients develop brain metastases (BM), compared to 38% in EGFR wild-type patients. First-generation tyrosine kinase inhibitors (TKIs), such as erlotinib and gefitinib have proven to be superior to chemotherapy in the front-line treatment of EGFR-mutant NSCLC, as has afatinib, a second-generation TKI. The most common acquired resistance mechanism is the development of a gatekeeper mutation in exon 20 T790M. Osimertinib has emerged as a third-generation EGFR TKI with proven activity in the front-line setting as well as in patients with a T790M acquired resistance mutation with remarkable CNS activity. As long-term survival outcomes in EGFR-mutant NSCLC continue to improve, the burden of BM becomes a greater challenge. Here, we review the literature related to the management of BM in EGFR-mutant NSCLC including the role of the three generations of EGFR TKIs, immunotherapy, and brain radiation.
Heat transfer is important in gas–solid flows that are encountered in many industrial applications such as energy generation. Computational fluid dynamics (CFD) simulations of heat transfer in ...gas–solid flow are based on statistical theories that result in averaged equations (e.g., the Eulerian–Eulerian two-fluid model). These averaged equations require accurate models for unclosed terms such as the average gas–solid heat transfer rate. The average gas–solid or interphase heat transfer rate is modeled in terms of the Nusselt number Nu, which is specified as a function of the solid volume fraction εs, mean slip Reynolds number Rem and Prandtl number Pr. In developing closure models for the average interphase heat transfer rate it is assumed that the gas–solid flow is locally homogeneous i.e., the effect of fluid heating (or cooling) on the average fluid temperature is negligible. However, continuous heating (or cooling) of the fluid along the flow direction causes the average fluid temperature to become inhomogeneous. In this work we develop a particle-resolved direct numerical simulation (PR-DNS) methodology to study heat transfer in steady flow past statistically homogeneous random assemblies of stationary particles. By using an analogy with thermally fully developed flow in pipes, we develop a thermal similarity condition that ensures a statistically homogeneous Nusselt number, even though the average fluid temperature field is inhomogeneous. From PR-DNS results we find that the effect of fluid heating (or cooling) cannot be neglected for gas–solid systems with high solid volume fractions and low mean slip Reynolds numbers. These results indicate that the assumption of scale separation implicit in two-fluid models is not always valid.
Invasive melanoma is the most lethal form of skin cancer. The treatment of melanoma-derived cell lines with 5-aza-2'-deoxycytidine (5-Aza-dC) markedly increases the expression of several miRNAs, ...suggesting that the miRNA-encoding genes might be epigenetically regulated, either directly or indirectly, by DNA methylation. We have identified a group of epigenetically regulated miRNA genes in melanoma cells, and have confirmed that the upstream CpG island sequences of several such miRNA genes are hypermethylated in cell lines derived from different stages of melanoma, but not in melanocytes and keratinocytes. We used direct DNA bisulfite and immunoprecipitated DNA (Methyl-DIP) to identify changes in CpG island methylation in distinct melanoma patient samples classified as primary in situ, regional metastatic, and distant metastatic. Two melanoma cell lines (WM1552C and A375 derived from stage 3 and stage 4 human melanoma, respectively) were engineered to ectopically express one of the epigenetically modified miRNA: miR-34b. Expression of miR-34b reduced cell invasion and motility rates of both WM1552C and A375, suggesting that the enhanced cell invasiveness and motility observed in metastatic melanoma cells may be related to their reduced expression of miR-34b. Total RNA isolated from control or miR-34b-expressing WM1552C cells was subjected to deep sequencing to identify gene networks around miR-34b. We identified network modules that are potentially regulated by miR-34b, and which suggest a mechanism for the role of miR-34b in regulating normal cell motility and cytokinesis.
Sterol regulatory element-binding proteins (SREBPs) have evolved as a focal point for linking lipid synthesis with other pathways that regulate cell growth and survival. Here, we have uncovered a ...polycistrionic microRNA (miRNA) locus that is activated directly by SREBP-2. Two of the encoded miRNAs, miR-182 and miR-96, negatively regulate the expression of Fbxw7 and Insig-2, respectively, and both are known to negatively affect nuclear SREBP accumulation. Direct manipulation of this miRNA pathway alters nuclear SREBP levels and endogenous lipid synthesis. Thus, we have uncovered a mechanism for the regulation of intracellular lipid metabolism mediated by the concerted action of a pair of miRNAs that are expressed from the same SREBP-2-regulated miRNA locus, and each targets a different protein of the multistep pathway that regulates SREBP function. These studies reveal an miRNA “operon” analogous to the classic model for genetic control in bacterial regulatory systems.
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•30 miRNAs are differentially regulated by lovastatin/ezetimibe versus cholesterol in mice•miR-182 targets Fbxw7 and miR-96 targets Insig2•Fbxw7 and Insig2 both negatively regulate nuclear SREBP levels•miR-96, miR-182, and miR-183 are expressed from an SREBP-2 regulated operon
Aberrant signaling pathway activity is a hallmark of tumorigenesis and progression, which has guided targeted inhibitor design for over 30 years. Yet, adaptive resistance mechanisms, induced by ...rapid, context-specific signaling network rewiring, continue to challenge therapeutic efficacy. Leveraging progress in proteomic technologies and network-based methodologies, we introduce Virtual Enrichment-based Signaling Protein-activity Analysis (VESPA)-an algorithm designed to elucidate mechanisms of cell response and adaptation to drug perturbations-and use it to analyze 7-point phosphoproteomic time series from colorectal cancer cells treated with clinically-relevant inhibitors and control media. Interrogating tumor-specific enzyme/substrate interactions accurately infers kinase and phosphatase activity, based on their substrate phosphorylation state, effectively accounting for signal crosstalk and sparse phosphoproteome coverage. The analysis elucidates time-dependent signaling pathway response to each drug perturbation and, more importantly, cell adaptive response and rewiring, experimentally confirmed by CRISPR knock-out assays, suggesting broad applicability to cancer and other diseases.
In this research, sulfonated chitosan (S-CS) was prepared by hydrothermal grafting reaction using 4-formyl-1,3-benzene disulfonate and glutaraldehyde as a cross-linker reagent. Batch adsorption ...experiments were performed to demonstrate the adsorptive properties of S-CS with a cationic dye (methylene blue; MB) as a model organic pollutant. The effect of the solution pH (3−12), initial dye concentration (50–200 mg L−1), contact time (0–24 h) and temperature (30–50 °C) on the relative removal of MB were studied. The kinetics of adsorption for MB showed a good correlation with the pseudo-second order kinetic model, while the adsorption isotherm at equilibrium was conformed to the Temkin model (R2 > 0.99). The maximum adsorption capacity, qm was 351.7, 326.1 and 302.4 mg g−1 at 303, 313 and 323 K, respectively. Owing to the simpler preparation method, relatively high adsorption capacity and regeneration ability, S-CS represents a promising adsorbent for the controlled MB removal and for other related organic dye pollutants from aqueous solution.
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•Sulfonated chitosan (S-CS) was prepared using N-benzyl disulfonated derivative•The hydrothermal synthesis technique has been adopted.•The new preparation procedure is environmentally friendly and cost-effective.•S-CS acted as an excellent adsorbent for the removal of methylene blue.•Pseudo-second order kinetic and Temkin isotherm models best fitted the adsorption.
► miR-375 is epigenetically regulated in human melanomas by hypermethylation. ► miR-375 methylation was observed in patient samples derived from primary, regional, distant, and nodular melanomas. ► ...miR-375 ectopic expression inhibited cell growth, invasion, and induced changes in cell morphology in melanoma cells. ► Gene expression changes suggest possible roles of miR-375 in cytoskeletal architecture, cell motility and migration.
To identify epigenetically regulated miRNAs in melanoma, we treated a stage 3 melanoma cell line WM1552C, with 5AzadC and/or 4-PBA. Several hypermethylated miRNAs were detected, one of which, miR-375, was highly methylated and was studied further. Minimal CpG island methylation was observed in melanocytes, keratinocytes, normal skin, and nevus but hypermethylation was observed in patient tissue samples from primary, regional, distant, and nodular metastatic melanoma. Ectopic expression of miR-375 inhibited melanoma cell proliferation, invasion, and cell motility, and induced cell shape changes, strongly suggesting that miR-375 may have an important function in the development and progression of human melanomas.
Dengue virus (DENV, family
, genus
) exists as four distinct serotypes. Generally, immunity after infection with one serotype is protective and lifelong, though exceptions have been described. ...However, secondary infection with a different serotype can result in more severe disease for a minority of patients. Host responses to the first DENV infection involve the development of both cross-reactive antibody and T cell responses, which, depending upon their precise balance, may mediate protection or enhance disease upon secondary infection with a different serotype. Abundant evidence now exists that responses elicited by DENV infection can cross-react with other members of the genus Flavivirus, particularly Zika virus (ZIKV). Cohort studies have shown that prior DENV immunity is associated with protection against Zika. Cross-reactive antibody responses may enhance infection with flaviviruses, which likely accounts for the cases of severe disease seen during secondary DENV infections. Data for T cell responses are contradictory, and even though cross-reactive T cell responses exist, their clinical significance is uncertain. Recent mouse experiments, however, show that cross-reactive T cells are capable of mediating protection against ZIKV. In this review, we summarize and discuss the evidence that T cell responses may, at least in part, explain the cross-protection seen against ZIKV from DENV infection, and that T cell antigens should therefore be included in putative Zika vaccines.
Background Prevalent non‐motor symptoms of Parkinson’s disease (PD) include gastrointestinal motor impairments and advanced stage PD displays pathological aggregates of α‐synuclein in colonic ...enteric neurons. We previously showed that 12 months old mice overexpressing human wild type (WT) α‐synuclein under the Thy1 promoter (Thy1‐aSyn) displayed colonic motor dysfunction. We investigated functional gut alterations at earlier ages and histological correlates.
Methods Defecation, gastric emptying (GE), and immunostaining for α‐synuclein, peripheral choline acetyltransferase (pChAT), tyrosine hydroxylase (TH), neuronal nitric oxide synthase (nNOS), and vasoactive intestinal peptide (VIP) in distal colon myenteric plexuses were assessed in male Thy1‐aSyn compared to littermate WT mice.
Key Results Thy1‐aSyn mice aged 2.5–3 or 7–8 months old had 81% and 55% reduction in fecal pellet output, respectively, in the first 15 min of exposure to a novel environment. The reduction remained significant in the older group for 2‐h, and subsequent refeeding resulted also in a 60% and 69% reduction of defecation in the first hour, respectively. Thy1‐aSyn mice (8–10 months) displayed increased α‐synuclein in the myenteric plexuses with abundant varicose terminals surrounding pChAT‐immunoreactive (ir) neurons, and only a few, nNOS‐ir neurons. There were no conspicuous changes in pChAT‐ and nNOS‐ir neurons, or TH‐ and VIP‐ir nerve fibers. Thy1‐aSyn mice aged 4–18 months had normal GE.
Conclusions & Inferences The occurrence of over‐production of pre‐synaptic α‐synuclein in colonic myenteric ganglia several months before the loss of striatal dopamine may provide an anatomical basis for interference with cholinergic neuronal activation, causing an early impairment in defecation to stimuli.
In WDM optical networks, the physical layer impairments (PLIs) and their significance depend on network type-opaque, translucent, or transparent; the reach-access, metro, or core/long-haul; the ...number and type of network elements-fiber, wavelengths, amplifiers, switching elements, etc.; and the type of applications-real-time, non-real time, missioncritical, etc. In transparent optical networks, PLIs incurred by non-ideal optical transmission media accumulate along an optical path, and the overall effect determines the feasibility of the lightpaths. If the received signal quality is not within the receiver sensitivity threshold, the receiver may not be able to correctly detect the optical signal and this may result in high bit-error rates. Hence, it is important to understand various PLIs and their effect on optical feasibility, analytical models, and monitoring and mitigation techniques. Introducing optical transparency in the physical layer on one hand leads to a dynamic, flexible optical layer with the possibility of adding intelligence such as optical performance monitoring, fault management, etc. On the other hand, transparency reduces the possibility of client layer interaction with the optical layer at intermediate nodes along the path. This has an impact on network design, planning, control, and management. Hence, it is important to understand the techniques that provide PLI information to the control plane protocols and that use this information efficiently to compute feasible routes and wavelengths. The purpose of this article is to provide a comprehensive survey of various PLIs, their effects, and the available modeling and mitigation techniques. We then present a comprehensive survey of various PLI-aware network design techniques, regenerator placement algorithms, routing and wavelength assignment algorithms, and PLI-aware failure recovery algorithms. Furthermore, we identify several important research issues that need to be addressed to realize dynamically reconfigurable next-generation optical networks. We also argue the need for PLI-aware control plane protocol extensions and present several interesting issues that need to be considered in order for these extensions to be deployed in real-world networks.
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