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Due to groundbreaking developments and continuous progress, the treatment of advanced and metastatic non-small cell lung cancer (NSCLC) has become an exciting, but increasingly challenging task. This applies, in particular, to the subgroup of NSCLC with oncogenic driver alterations. While the treatment of epidermal growth factor receptor (EGFR)-mutated and anaplastic lymphoma kinase (ALK)-rearranged NSCLC with various tyrosine kinase inhibitors (TKIs) is well-established, new targets have been identified in the last few years and new TKIs introduced in clinical practice. Even for KRAS mutations, considered for a long time as an “un-targetable” alteration, promising new drugs are emerging. The detection and in-depth molecular analysis of resistance mechanisms has further fueled the development of new therapeutic strategies. The objective of this review is to give a comprehensive overview on the current landscape of targetable oncogenic alterations in NSCLC.

Silicon dioxide (silica) nanoparticles (SDNPs) are widely used in nanotechnology and medicine, but these nanomaterials may carry a high risk for human health while little is known about their toxicity. We investigated the alterations in morphometry, biochemistry, hematology, histology of liver tissue and gene expression of drug-metabolizing enzymes induced by 10-nm SDNPs. Healthy male Wistar albino rats were exposed to 20, 35 and 50 repeated injections of SDNPs (2 mg/kg body weight). Whole blood, serum and plasma samples were used for hematological and biochemical analyses, whereas liver biopsies were processed for histopathological and gene expression alterations. In comparison with control rats, exposure to SDNPs lowered the body weight gain and liver index and increased the counts of white blood cells and platelets, but lowered the platelet larger cell ratio and plateletcrit. Levels of alkaline phosphatase, lactate dehydrogenase, low-density lipids, procalcitonin, aspartate aminotransferase and alanine aminotransferase, as well as potassium, phosphorus and iron concentrations, were increased. Histopathology revealed that SDNPs could induce hydropic degeneration, sinusoidal dilatation, hyperplasia of Kupffer cells, karyopyknosis and infiltration of inflammatory cells in the liver. SDNPs reduced the expression of 12 genes of drug-metabolizing enzymes significantly ( <0.05). These results suggest that SDNPs could cause alterations in morphometry, biochemistry, hematology, liver tissues and the expression of drug-metabolizing enzyme genes.

Letters to the editor

Water is a fundamental molecule in the star and planet formation process, essential for catalysing the growth of solid material and the formation of planetesimals within disks 1 , 2 . However, the water snowline and the HDO:H 2 O ratio within proto-planetary disks have not been well characterized because water only sublimates at roughly 160 K (ref. 3 ), meaning that most water is frozen out onto dust grains and that the water snowline radii are less than 10 AU (astronomical units) 4 , 5 . The sun-like protostar V883 Ori (M *  = 1.3  M ⊙ ) 6 is undergoing an accretion burst 7 , increasing its luminosity to roughly 200  L ⊙ (ref. 8 ), and previous observations suggested that its water snowline is 40–120 AU in radius 6 , 9 , 10 . Here we report the direct detection of gas phase water (HDO and H 2 18 O ) from the disk of V883 Ori. We measure a midplane water snowline radius of approximately 80 AU, comparable to the scale of the Kuiper Belt, and detect water out to a radius of roughly 160 AU. We then measure the HDO:H 2 O ratio of the disk to be (2.26 ± 0.63) × 10 −3 . This ratio is comparable to those of protostellar envelopes and comets, and exceeds that of Earth’s oceans by 3.1 σ . We conclude that disks directly inherit water from the star-forming cloud and this water becomes incorporated into large icy bodies, such as comets, without substantial chemical alteration. Direct detection of gas phase water from the disk of V883 Ori indicates that disks directly inherit water from the star-forming cloud that becomes incorporated into large icy bodies without notable chemical alteration.

Werner syndrome (WS) is a premature aging disorder caused by WRN protein deficiency. Here, we report on the generation of a human WS model in human embryonic stem cells (ESCs). Differentiation of WRN-null ESCs to mesenchymal stem cells (MSCs) recapitulates features of premature cellular aging, a global loss of H3K9me3, and changes in heterochromatin architecture. We show that WRN associates with heterochromatin proteins SUV39H1 and HP1α and nuclear lamina–heterochromatin anchoring protein LAP2β. Targeted knock-in of catalytically inactive SUV39H1 in wild-type MSCs recapitulates accelerated cellular senescence, resembling WRN-deficient MSCs. Moreover, decrease in WRN and heterochromatin marks are detected in MSCs from older individuals. Our observations uncover a role for WRN in maintaining heterochromatin stability and highlight heterochromatin disorganization as a potential determinant of human aging.

The Noachian terrain west of the Isidis basin hosts a diverse collection of alteration minerals in rocks comprising varied geomorphic units within a 100,000 km2 region in and near the Nili Fossae. Prior investigations in this region by the Observatoire pour l'Minéralogie, l'Eau, les Glaces, et l'Activité (OMEGA) instrument on Mars Express revealed large exposures of both mafic minerals and iron magnesium phyllosilicates in stratigraphic context. Expanding on the discoveries of OMEGA, the Compact Reconnaissance Imaging Spectrometer for Mars (CRISM) aboard the Mars Reconnaissance Orbiter (MRO) has found more spatially widespread and mineralogically diverse alteration minerals than previously realized, which represent multiple aqueous environments. Using CRISM near‐infrared spectral data, we detail the basis for identification of iron and magnesium smectites (including both nontronite and more Mg‐rich varieties), chlorite, prehnite, serpentine, kaolinite, potassium mica (illite or muscovite), hydrated (opaline) silica, the sodium zeolite analcime, and magnesium carbonate. The detection of serpentine and analcime on Mars is reported here for the first time. We detail the geomorphic context of these minerals using data from high‐resolution imagers onboard MRO in conjunction with CRISM. We find that the distribution of alteration minerals is not homogeneous; rather, they occur in provinces with distinctive assemblages of alteration minerals. Key findings are (1) a distinctive stratigraphy, in and around the Nili Fossae, of kaolinite and magnesium carbonate in bedrock units always overlying Fe/Mg smectites and (2) evidence for mineral phases and assemblages indicative of low‐grade metamorphic or hydrothermal aqueous alteration in cratered terrains. The alteration minerals around the Nili Fossae are more typical of those resulting from neutral to alkaline conditions rather than acidic conditions, which appear to have dominated much of Mars. Moreover, the mineralogic diversity and geologic context of alteration minerals found in the region around the Nili Fossae indicates several episodes of aqueous activity in multiple distinct environments.

Parkinson’s disease is a neurodegenerative disease whose progression and clinical characteristics have a close bidirectional and multilevel relationship with the process of neuroinflammation. In this context, it is necessary to understand the mechanisms involved in this neuroinflammation–PD link. This systematic search was, hereby, conducted with a focus on the four levels where alterations associated with neuroinflammation in PD have been described (genetic, cellular, histopathological and clinical-behavioral) by consulting the PubMed, Google Scholar, Scielo and Redalyc search engines, including clinical studies, review articles, book chapters and case studies. Initially, 585,772 articles were included, and, after applying the inclusion and exclusion criteria, 84 articles were obtained that contained information about the multilevel association of neuroinflammation with alterations in gene, molecular, cellular, tissue and neuroanatomical expression as well as clinical-behavioral manifestations in PD.

White mica and tourmaline are the dominant hydrothermal alteration minerals at the world-class Panasqueira W–Sn–Cu deposit in Portugal. Thus, understanding the controls on their chemical composition helps to constrain ore formation processes at this deposit and determine their usefulness as pathfinder minerals for mineralization in general. We combine whole-rock geochemistry of altered and unaltered metasedimentary host rocks with in situ LA-ICP-MS measurements of tourmaline and white mica from the alteration halo. Principal component analysis (PCA) is used to better identify geochemical patterns and trends of hydrothermal alteration in the datasets. The hydrothermally altered metasediments are enriched in As, Sn, Cs, Li, W, F, Cu, Rb, Zn, Tl, and Pb relative to unaltered samples. In situ mineral analyses show that most of these elements preferentially partition into white mica over tourmaline (Li, Rb, Cs, Tl, W, and Sn), whereas Zn is enriched in tourmaline. White mica has distinct compositions in different settings within the deposit (greisen, vein selvages, wall rock alteration zone, late fault zone), indicating a compositional evolution with time. In contrast, tourmaline from different settings overlaps in composition, which is ascribed to a stronger dependence on host rock composition and also to the effects of chemical zoning and microinclusions affecting the LA-ICP-MS analyses. Hence, in this deposit, white mica is the better recorder of the fluid composition. The calculated trace-element contents of the Panasqueira mineralizing fluid based on the mica data and estimates of mica-fluid partition coefficients are in good agreement with previous fluid-inclusion analyses. A compilation of mica and tourmaline trace-element compositions from Panasqueira and other W–Sn deposits shows that white mica has good potential as a pathfinder mineral, with characteristically high Li, Cs, Rb, Sn, and W contents. The trace-element contents of hydrothermal tourmaline are more variable. Nevertheless, the compiled data suggest that high Sn and Li contents are distinctive for tourmaline from W–Sn deposits.

Telomerase reverse transcriptase (TERT) is a catalytic subunit of telomerase. Telomerase complex plays a key role in cancer formation by telomere dependent or independent mechanisms. Telomere maintenance mechanisms include complex changes such as gene amplifications, structural variants, promoter germline and somatic mutations, epigenetic changes, and alternative lengthening of telomere. All of them are cancer specific at tissue histotype and at single cell level expression is regulated in tumors multiple genetic and epigenetic alterations which affect telomerase activity. Telomerase activity expression has an impact on telomere length and can be a useful marker in diagnosis and prognosis of various cancers and a new therapy approach. In this review we want to highlight the main roles of in different mechanisms of cancer development and regulation.

Altered gene expression is the primary molecular mechanism responsible for the pathological processes of human diseases, including cancer. MicroRNAs (miRNAs) are virtually involved at the post-transcriptional level and bind to 3′ UTR of their target messenger RNA (mRNA) to suppress expression. Dysfunction of miRNAs disturbs expression of oncogenic or tumor-suppressive target genes, which is implicated in cancer pathogenesis. As such, a large number of miRNAs have been found to be downregulated or upregulated in human cancers and to function as oncomiRs or oncosuppressor miRs. Notably, the molecular mechanism underlying the dysregulation of miRNA expression in cancer has been recently uncovered. The genetic deletion or amplification and epigenetic methylation of miRNA genomic loci and the transcription factor-mediated regulation of primary miRNA often alter the landscape of miRNA expression in cancer. Dysregulation of the multiple processing steps in mature miRNA biogenesis can also cause alterations in miRNA expression in cancer. Detailed knowledge of the regulatory mechanism of miRNAs in cancer is essential for understanding its physiological role and the implications of cancer-associated dysfunction and dysregulation. In this review, we elucidate how miRNA expression is deregulated in cancer, paying particular attention to the cancer-associated transcriptional and post-transcriptional factors that execute miRNA programs.