Patients with colorectal cancer (CRC) have a high incidence of regional and distant metastases. Although metastasis is the main cause of CRC-related death, its molecular mechanisms remain largely ...unknown.
Using array-CGH and expression microarray analyses, changes in DNA copy number and mRNA expression levels were investigated in human CRC samples. The mRNA expression level of RASAL2 was validated by qRT-PCR, and the protein expression was evaluated by western blot as well as immunohistochemistry in CRC cell lines and primary tumors. The functional role of RASAL2 in CRC was determined by MTT proliferation assay, monolayer and soft agar colony formation assays, cell cycle analysis, cell invasion and migration and in vivo study through siRNA/shRNA mediated knockdown and overexpression assays. Identification of RASAL2 involved in hippo pathway was achieved by expression microarray screening, double immunofluorescence staining and co-immunoprecipitation assays.
Integrated genomic analysis identified copy number gains and upregulation of RASAL2 in metastatic CRC. RASAL2 encodes a RAS-GTPase-activating protein (RAS-GAP) and showed increased expression in CRC cell lines and clinical specimens. Higher RASAL2 expression was significantly correlated with lymph node involvement and distant metastasis in CRC patients. Moreover, we found that RASAL2 serves as an independent prognostic marker of overall survival in CRC patients. In vitro and in vivo functional studies revealed that RASAL2 promoted tumor progression in both KRAS/NRAS mutant and wild-type CRC cells. Knockdown of RASAL2 promoted YAP1 phosphorylation, cytoplasm retention and ubiquitination, therefore activating the hippo pathway through the LATS2/YAP1 axis.
Our findings demonstrated the roles of RASAL2 in CRC tumorigenesis as well as metastasis, and RASAL2 exerts its oncogenic property through LATS2/YAP1 axis of hippo signaling pathway in CRC.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Pulmonary lymphoepithelioma-like carcinoma (LELC) is a subtype of non-small cell lung cancer (NSCLC) characterized by marked lymphocytic infiltration and association with Epstein–Barr virus (EBV). ...The molecular basis underlying the disease remains unclear. We sought to study the molecular landscape by multiple approaches including whole genomic sequencing, capture-based targeted sequencing, fluorescent in situ hybridization and immunohistochemistry. Tumor cells from 57 EBV-positive pulmonary LELCs were isolated by careful microdissection prior to genomic sequencing. Integrated analysis revealed a distinct genomic landscape of low TP53 mutation rate (11%), low incidence of known drivers in the RTK/RAS/RAF (11%) and PI3K/AKT/mTOR pathways (7%), but enriched for loss-of-function mutations in multiple negative regulators of the NF-κB pathway. High level programmed cell death ligand-1 (PD-L1) expression was shown with 47% and 79% of the cases showing positive PD-L1 immunoreactivity at ≥50% and ≥1% tumor proportion score, respectively. Subsets of the patients with actionable fibroblast growth factor receptor 3 (FGFR3) aberrations (4%) and mismatch repair deficiency (4%) were potentially eligible for precision medicine. Pulmonary LELC showed a distinct genomic landscape, different from major NSCLC subtypes but resembled that of EBV-associated nasopharyngeal carcinoma. Our work facilitated the understanding of molecular basis underlying pulmonary LELC to explore potential therapeutic options.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Nasopharyngeal carcinoma (NPC) is an Epstein‐Barr virus (EBV)‐associated epithelial malignancy. The high expression of BART‐miRNAs (miR‐BARTs) during latent EBV infection in NPC strongly supports ...their pathological importance in cancer progression. Recently, we found that several BART‐miRNAs work co‐operatively to modulate the DNA damage response (DDR) by reducing Ataxia‐telangiectasia‐mutated (ATM) activity. In this study, we further investigated the role of miR‐BARTs on DDR. The immunohistochemical study showed that the DNA repair gene, BRCA1, is consistently down‐regulated in primary NPCs. Using computer prediction programs and a series of reporter assays, we subsequently identified the negative regulatory role of BART2‐3p, BART12, BART17‐5p and BART19‐3p in BRCA1 expression. The ectopic expression of these four miR‐BARTs suppressed endogenous BRCA1 expression in EBV‐negative epithelial cell lines, whereas BRCA1 expression was enhanced by repressing endogenous miR‐BARTs activities in C666‐1 cells. More importantly, suppressing BRCA1 expression in nasopharyngeal epithelial cell lines using miR‐BART17‐5p and miR‐BART19‐3p mimics reduced the DNA repair capability and increased the cell sensitivity to the DNA‐damaging chemotherapeutic drugs, cisplatin and doxorubicin. Our findings suggest that miR‐BARTs play a novel role in DDR and may facilitate the development of effective NPC therapies.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Colorectal cancer (CRC) is a heterogeneous disease with complex mechanisms of pathogenesis. Classification systems have been proposed based on molecular features of tumors in clinical practice. Thus, ...more molecular markers associated with development and progression of CRC might serve as useful tools for early diagnosis even for providing more accurate molecular classification. Frequent gain of chromosome 8q was detected in CRC by array‐CGH and overexpression of exosome component 4 (EXOSC4) in this region was revealed by expression microarray analysis. Through qRT‐PCR and immunohistochemistry (IHC) analysis, EXOSC4 showed increased expression in CRC cell lines and clinical specimens. Higher expression of EXOSC4 was more often detected in left side, and correlated with BRAF wild type, MSI‐low or MSS, CIMP‐low, and MLH1‐no‐silence CRC patients. Functionally, EXOSC4 overexpression increased early tumorigenic capacity by promoting cell proliferation and monolayer colony formation, enhancing cell invasion and migration study and accelerating xenograft formation in nude mice. While EXOSC4 knockdown exhibited anti‐oncogenic role such as inhibiting cell proliferation and invasion. EXOSC4 inhibition also resulted in G1 phase cell cycle arrest. For the downstream signaling analysis, EXOSC4 was found to be involved in multiple signaling pathways such as cell cycle, p53 pathway and Wnt pathway. In summary, our findings demonstrated the oncogenic role of EXOSC4 in development and progression of CRC. Deep understanding of EXOSC4 as a potential diagnostic molecular biomarker will provide clinical translational potential for intervention therapy.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Whether EGFR mutation occurs in lung squamous cell carcinoma (SCC) remains a controversial issue. Although numerous trials have shown positive response to tyrosine kinase inhibitors in SCC, these ...observations have not been well correlated with presence or absence of EGFR mutation. A complicating issue is that adenosquamous carcinoma, a mimic of SCC, frequently harbours EGFR mutations. We evaluated the EGFR mutation status of 191 cases initially diagnosed as SCC of lung origin in years 2000–2011, and performed a panel of markers including p40, p63, CK5/6, TTF-1, mucicarmine on the tissue microarray or tissue blocks from each case, to ascertain the squamous differentiation of each case. Four cases were found to have EGFR mutations, with three showing typical squamous morphological features and immunohistochemical profile on all available tumour blocks, and one reclassified as adenosquamous carcinoma. Mixed responses were noted for two of the patients with EGFR-mutated SCC treated with tyrosine kinase inhibitors. In conclusion, we report that a small subset of rigorously proven SCC harbours EGFR mutation. It also appears in our cohort that EGFR-mutated tumours, in the context of SCC, may have relatively poor response to tyrosine kinase inhibitors.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Phenomenology and Human Experience is a volume of eleven essays generated from part of the works presented at "Border-Crossing: The 4th International Conference of P.E.A.CE (Phenomenology for ...East-Asian CirclE)" held in December 2010 at the National Sun Yatsen University, Taiwan. The themes treated include: interconnection between ethical space and space of truth, freedom in the biotechnologically enhanced world, wildnature facing the extension of urbanization, landscape as a way of thinking and living, Husserl's meditation on death, the subtle difference between Heidegger's and Gadamer's hermeneutics, Merleau-Ponty's reversibility thesis revisited, Pato?ka's phenomenology of body and subjective movement, and Edith Stein's phenomenology of education. They are original contributions or renewed reflections from East-Asian phenomenologists, joined by their Western colleagues, on the most divergent aspects of human experience. This is another concrete proof that more than a century since its emergence on German soil, phenomenology has spread across linguistic and geographical borders to become one of the most vibrant global philosophical movements. The editors: Chung-Chi Yu is Professor at the Institute of Philosophy, National Sun Yatsen University of Taiwan, and currently Director of the Institute. - Kwokying Lau is both Professor at the Department of Philosophy and Director of the Edwin Cheng Foundation Asian Centre for Phenomenology at The Chinese University of Hong Kong.
Abstract
Background
Clinical outcomes of the interaction between the co-circulating pandemic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and seasonal influenza viruses are unknown.
...Methods
We established a golden Syrian hamster model coinfected by SARS-CoV-2 and mouse-adapted A(H1N1)pdm09 simultaneously or sequentially. The weight loss, clinical scores, histopathological changes, viral load and titer, and serum neutralizing antibody titer were compared with hamsters challenged by either virus.
Results
Coinfected hamsters had more weight loss, more severe lung inflammatory damage, and tissue cytokine/chemokine expression. Lung viral load, infectious virus titers, and virus antigen expression suggested that hamsters were generally more susceptible to SARS-CoV-2 than to A(H1N1)pdm09. Sequential coinfection with A(H1N1)pdm09 one day prior to SARS-CoV-2 exposure resulted in a lower lung SARS-CoV-2 titer and viral load than with SARS-CoV-2 monoinfection, but a higher lung A(H1N1)pdm09 viral load. Coinfection also increased intestinal inflammation with more SARS-CoV-2 nucleoprotein expression in enterocytes. Simultaneous coinfection was associated with delay in resolution of lung damage, lower serum SARS-CoV-2 neutralizing antibody, and longer SARS-CoV-2 shedding in oral swabs compared to that of SARS-CoV-2 monoinfection.
Conclusions
Simultaneous or sequential coinfection by SARS-CoV-2 and A(H1N1)pdm09 caused more severe disease than monoinfection by either virus in hamsters. Prior A(H1N1)pdm09 infection lowered SARS-CoV-2 pulmonary viral loads but enhanced lung damage. Whole-population influenza vaccination for prevention of coinfection, and multiplex molecular diagnostics for both viruses to achieve early initiation of antiviral treatment for improvement of clinical outcome should be considered.
Coinfection of hamsters by 2020 pandemic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and 2009 pandemic influenza A(H1N1) virus given simultaneously or sequentially within 24 hours was associated with increased disease severity, delayed resolution of lung pathology, and suppressed neutralizing antibody response against SARS-CoV-2.
Abstract
Summary
The interaction between tumor and immune system plays a crucial role in both cancer development and treatment response. To facilitate comprehensive investigation of tumor–immune ...interactions, we have designed a user-friendly web portal TISIDB, which integrated multiple types of data resources in oncoimmunology. First, we manually curated 4176 records from 2530 publications, which reported 988 genes related to anti-tumor immunity. Second, genes associated with the resistance or sensitivity of tumor cells to T cell-mediated killing and immunotherapy were identified by analyzing high-throughput screening and genomic profiling data. Third, associations between any gene and immune features, such as lymphocytes, immunomodulators and chemokines, were pre-calculated for 30 TCGA cancer types. In TISIDB, biologists can cross-check a gene of interest about its role in tumor–immune interactions through literature mining and high-throughput data analysis, and generate testable hypotheses and high quality figures for publication.
Availability and implementation
http://cis.hku.hk/TISIDB
Supplementary information
Supplementary data are available at Bioinformatics online.
The COVID-19 pandemic is the third outbreak this century of a zoonotic disease caused by a coronavirus, following the emergence of severe acute respiratory syndrome (SARS) in 2003
and Middle East ...respiratory syndrome (MERS) in 2012
. Treatment options for coronaviruses are limited. Here we show that clofazimine-an anti-leprosy drug with a favourable safety profile
-possesses inhibitory activity against several coronaviruses, and can antagonize the replication of SARS-CoV-2 and MERS-CoV in a range of in vitro systems. We found that this molecule, which has been approved by the US Food and Drug Administration, inhibits cell fusion mediated by the viral spike glycoprotein, as well as activity of the viral helicase. Prophylactic or therapeutic administration of clofazimine in a hamster model of SARS-CoV-2 pathogenesis led to reduced viral loads in the lung and viral shedding in faeces, and also alleviated the inflammation associated with viral infection. Combinations of clofazimine and remdesivir exhibited antiviral synergy in vitro and in vivo, and restricted viral shedding from the upper respiratory tract. Clofazimine, which is orally bioavailable and comparatively cheap to manufacture, is an attractive clinical candidate for the treatment of outpatients and-when combined with remdesivir-in therapy for hospitalized patients with COVID-19, particularly in contexts in which costs are an important factor or specialized medical facilities are limited. Our data provide evidence that clofazimine may have a role in the control of the current pandemic of COVID-19 and-possibly more importantly-in dealing with coronavirus diseases that may emerge in the future.
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GEOZS, IJS, IMTLJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZAGLJ
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