A regulator of the protein phosphatase 2A (PP2A), α4, has been implicated in a variety of functions that regulate many cellular processes. To explore the role of α4 in human cell transformation and ...tumorigenesis, we show that α4 is highly expressed in human cells transformed by chemical carcinogens including benzo(a)pyrene, aflatoxin B(1), N-methyl-N'-nitro-N-nitrosoguanidine, nickel sulfate and in several hepatic and lung cancer cell lines. In addition, overexpression of α4 was detected in 87.5% (74/80) of primary hepatocellular carcinomas, 84.0% (21/25) of primary lung cancers and 81.8% (9/11) of primary breast cancers, indicating that α4 is ubiquitously highly expressed in human cancer. Functional studies revealed that elevated α4 expression results in an increase in cell proliferation, promotion of cell survival and decreased PP2A-attributable activity. Importantly, ectopic expression of α4 permits non-transformed human embryonic kidney cells (HEKTER) and L02R cells to form tumors in immunodeficient mice. Furthermore, we show that the highly expressed α4 in transformed cells or human tumors is not regulated by DNA hypomethylation. A microRNA, miR-34b, that suppresses the expression of α4 through specific binding to the 3'-untranslated region of α4 is downregulated in transformed or human lung tumors. Taken together, these observations identify that α4 possesses an oncogenic function. Reduction of PP2A activity due to an enhanced α4-PP2A interaction contributes directly to chemical carcinogen-induced tumorigenesis.
The edible mushroom Termitomyces is an agaric‐type basidiomycete fungus that has a symbiotic relationship with fungus‐growing termites. An understanding of the detailed development mechanisms ...underlying the adaptive responses of Termitomyces sp. to their growing environment is lacking. Here, we compared the transcriptome sequences of different Termitomyces sp. samples and link‐stipe grown on fungus combs in situ and monocultured in vitro. The assembled reads generated 8052 unigenes. The expression profiles were highly different for 2556 differentially expressed genes (DEGs) of the treated samples, where the expression of 1312 and 1244 DEGs was upregulated in the Mycelium and link‐stipe groups respectively. Functional classification of the DEGs based on both Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis revealed an expected shift in fungal gene expression, where stress response genes whose expression was upregulated in link‐stipe may adaptively be involved in cell wall hydrolysis and fusion, pathogenesis, oxidation‐reduction, transporter efflux, transposon efflux and self/non–self‐recognition. Urease has implications in the expression of genes involved in the nitrogen metabolism pathway, and its expression could be controlled by low‐level nitrogen fixation of fungus combs. In addition, the expression patterns of eleven select genes on the basis of qRT‐PCR were consistent with their changes in transcript abundance, as revealed by RNA sequencing. Taken together, these findings may be useful for enriching the knowledge concerning the Termitomyces adaptive response to in situ fungus combs compared with the response of monocultures in vitro.
Significance and Impact of the Study: The first study of the gene regulation from transcriptome can provide a theoretical basis for the subsequent further excavation of key developmental functional genes of Termitomyces sp. We found an important but not yet biologically defined Termitomyces tissue, link‐stipe. There are a lot of important developmental genes and stress response genes in the link‐stipe tissue, which can provide an important reference to analyse the development mechanism of Termitomyces sp. The important cohesion of link‐stipe tissue in the whole symbiotic system is demonstrated.
Aberrant activation of c-kit proto-oncogene contributes to abnormal cell proliferation by altering the tyrosine kinase signaling and constitutes a crucial impetus for leukemogenesis. Epigenetic ...silencing of tumor-suppressive microRNAs (miRNAs) is a key oncogenic mechanism for the activation of oncogenes in tumors. In this study, several miRNAs potentially binding to the 3'-untranslated region of human c-kit mRNA were screened by luciferase reporter assays. Among these miRNAs, miR-193a was embedded in a CpG island and epigenetically repressed by promoter hypermethylation in acute myeloid leukemia (AML) cell lines and primary AML blasts, but not in normal bone marrow cells. Importantly, miR-193a levels were inversely correlated with c-kit levels measured in 9 leukemia cell lines and 27 primary AML samples. Restoring miR-193a expression in AML cells harboring c-kit mutation and/or overexpression, either by synthetic miR-193a transfection or by DNA hypomethylating agent 5-azacytidine (5-aza) treatment, resulted in a significant reduction in c-kit expression at both RNA and protein levels and inhibition of cell growth. The growth-inhibitory activity of miR-193a was associated with apoptosis and granulocytic differentiation. Moreover, 5-aza-induced c-kit reduction could be partially blocked by miR-193a inhibitor, leading to a reversal of antiproliferative and proapoptotic effects of 5-aza. These data reveal a critical role for methylation-repressed miR-193a in myeloid leukemogenesis and the therapeutic promise of upregulating miR-193a expression for c-kit-positive AML.
We examined whether mucosal melanomas are different in their clinical course and patterns of metastases when arising from different anatomic sites. Our hypothesis was that metastatic behavior would ...differ from primary mucosal melanomas at different anatomical sites.
Clinical and pathological data from 706 patients were compared for their stage distribution, patterns of metastases, CKIT/BRAF mutation status, and overall survival for different anatomical sites.
The anatomic sites of the primary mucosal melanomas were from the lower GI tract (26.5%), nasal cavity and paranasal sinuses (23%), gynecological sites (22.5%), oral cavity (15%), urological sites (5%), upper GI tract (5%), and other sites (3.0%). At initial diagnosis, 14.5% were stage I disease, 41% Stage II, 21.5% Stage III, and 23.0% stage IV. Predominant metastatic sites were regional lymph nodes (21.5%), lung (21%), liver (18.5%), and distant nodes (9%). Oral cavity mucosal melanoma had a higher incidence of regional nodal metastases (31.7% versus 19.8%,P = 0.009), and a higher incidence of lung metastases (32.5% versus 18.5%,P = 0.007) compared to other primary mucosal melanomas. There was a 10% incidence of CKIT mutation and 12% BRAF mutation. Mucosal melanomas from nasal pharyngeal and oral, gastrointestinal, gynecological, and urological had a similar survival with a 1-year survival rate (88%, 83%, 86%), 2-year survival rate (66%, 57%, 61%), 5-year survival rate (27%, 16%, 20%), respectively.
The largest sample size allows, for the first time, a comparison of primary melanoma stage and patterns of metastases across anatomical sites. With few exceptions, the presenting stages, incidence of nodal and distant metastases, the site of predilection of distant metastases, or overall survival were similar despite different primary anatomic sites. These findings suggest that clinical trials involving mucosal melanomas and the administration of systemic therapy can be applied equally to mucosal melanomas regardless of their primary anatomic site.
Gentle remediation options (GROs) are risk management strategies or technologies involving plant (phyto-), fungi (myco-), and/or bacteria-based methods that result in a net gain (or at least no gross ...reduction) in soil function as well as effective risk management. GRO strategies can be customised along contaminant linkages, and can generate a range of wider economic, environmental and societal benefits in contaminated land management (and in brownfields management more widely). The application of GROs as practical on-site remedial solutions is still limited however, particularly in Europe and at trace element (typically metal and metalloid) contaminated sites. This paper discusses challenges to the practical adoption of GROs in contaminated land management, and outlines the decision support tools and best practice guidance developed in the European Commission FP7-funded GREENLAND project aimed at overcoming these challenges. The GREENLAND guidance promotes a refocus from phytoremediation to wider GROs- or phyto-management based approaches which place realisation of wider benefits at the core of site design, and where gentle remediation technologies can be applied as part of integrated, mixed, site risk management solutions or as part of “holding strategies” for vacant sites. The combination of GROs with renewables, both in terms of biomass generation but also with green technologies such as wind and solar power, can provide a range of economic and other benefits and can potentially support the return of low-level contaminated sites to productive usage, while combining GROs with urban design and landscape architecture, and integrating GRO strategies with sustainable urban drainage systems and community gardens/parkland (particularly for health and leisure benefits), has large potential for triggering GRO application and in realising wider benefits in urban and suburban systems. Quantifying these wider benefits and value (above standard economic returns) will be important in leveraging funding for GRO application and soft site end-use more widely at vacant or underutilized sites.
•Gentle Remediation Options (GROs) are evaluated as practical risk management methods.•Outputs and case studies are presented from the GREENLAND EC FP7 project.•Data are drawn from long-term (>5 years duration) GRO field trials across Europe.•GROs can effectively manage site contaminant risk while delivering wider benefits.
In order to solve the segregation and discontinuous precipitation of Cu–Ni–Sn alloys and explore the influence mechanism of solid soluble microelements on the microstructure and properties. Herein, ...based on the cluster-plus-glue-atom model, Zn or Co, with different solubilities in Cu, was selected as the fourth element in the way of replacing a small portion of Sn for the composition design of Cu–Ni–Sn–Zn (Co) series alloys. The solid solution forms and positions of Zn and Co solutes were revealed according to EPMA composition analysis and variation of the lattice parameter of the Cu matrix in solution treated alloys, and form atomic site occupation point of view, the influence of Zn or Co on solidus-liquidus temperature range were discussed. Furthermore, phase transformation and resistivity thermal stability with temperature rising were investigated and discussed utilizing results of variable temperature resistance. These results show that Zn solutes dissolve in the form of clusters, resulting in a strong solid solution strengthening, existing less effect on conductivity, and increasing comprehensive properties after long-term aging, which indicates that Zn can be a good candidate for the multi-component design of Cu–Ni–Sn alloys. These findings may offer new insights on composition optimization of Cu–Ni–Sn alloy.
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•Sn segregation and discontinuous precipitation in Cu–Ni–Sn alloys is ameliorated by Zn or Co solutes.•Effect of differential positions or solid solution forms of Zn and Co solutes on properties is systematic discussed.•Cu80Ni15Sn4·375Zn0.625 alloy with excellent comprehensive properties is obtained.
Embedding disasters into a general equilibrium model with heterogeneous firms induces strong nonlinearity in the pricing kernel, helping explain the empirical failure of the (consumption) CAPM. Our ...single-factor model reproduces the failure of the CAPM in explaining the value premium in finite samples without disasters and its relative success in samples with disasters. Due to beta measurement errors, the estimated beta-return relation is flat, consistent with the beta “anomaly,” even though the true beta-return relation is strongly positive. Finally, the consumption CAPM fails in simulations, even though a nonlinear model with the true pricing kernel holds exactly by construction.
No standard of care for mucosal melanoma (MM) in the adjuvant setting has been established. Meanwhile, relapse-free survival (RFS) is only ∼5 months after surgery alone. This phase II trial aimed to ...compare toripalimab versus high-dose interferon-α2b (HDI) as an adjuvant therapy for resected MM.
From July 2017 to May 2019, 145 patients with resected MM were randomized (1 : 1) to receive HDI (n = 72) or toripalimab (n = 73) for 1 year until disease relapse/distant metastasis, unacceptable toxicity, or withdrawal of consent. The primary endpoint was RFS. The secondary endpoints included distant metastasis-free survival (DMFS), overall survival (OS), and safety.
After a median follow-up of 26.3 months, the number of RFS, OS, and DMFS events was 51 versus 46, 33 versus 29, and 49 versus 44 in the toripalimab arm and the HDI arm, respectively. The median RFS was 13.6 95% confidence interval (CI) 8.31-19.02 months and 13.9 (95% CI 8.28-19.61) months in the toripalimab arm and the HDI arm, respectively. The DMFS was not significantly different between the two arms hazard ratio (HR) 1.00; 95% CI 0.65-1.54. The median OS was 35.1 months (95% CI 27.93 months-not reached) in the toripalimab arm, with no significant difference in all-cause death (HR 1.11, 95% CI 0.66-1.84) for the two arms. The median sums of the patients’ actual infusion doses were 3672 mg and 1054.5 MIU in the toripalimab arm and the HDI arm, respectively. The incidence of treatment-emergent adverse events with a grade ≥3 was much higher in the HDI arm than in the toripalimab arm (87.5% versus 27.4%).
Toripalimab showed a similar RFS and a more favorable safety profile than HDI, both better than historical data, suggesting that toripalimab might be the better treatment option. However, additional translational studies and better treatment regimens are still warranted to improve the clinical outcome of MM.
•This is the first study to compare toripalimab versus HDI as adjuvant therapy for resected MM.•In PD-L1-positive patients, the median RFS was ∼6 months longer in the toripalimab arm than in the HDI arm.•The incidence of TEAEs with a grade ≥3 was much higher in the HDI arm than in the toripalimab arm.•Both interventions have potential for MM; toripalimab might be the better treatment option.
To investigate the feasibility and safety of a fluoroscopy-assisted interventional technique for removal of bullet-shaped self-expanding covered metallic stents from bronchopleural fistulas (BPFs).
...Clinical data for 49 consecutive patients who underwent removal of bullet-shaped self-expanding covered metal stents from October 2010 to November 2019 were analysed retrospectively. Fifty-one stents were removed in all, including 29 large Y-shaped bullet stents, 10 small Y-shaped bullet stents, and 12 branched bullet-shaped stents. The average duration for which tracheal stents were in place was 99.4±8.5 days.
Fifty-one stents were removed successfully, of which 49 were directly removed on the first attempt. The time required for stent removal ranged from 7–60 minutes (median time, 22 minutes). In eight cases, the stent was removed by the conventional method (i.e., grasping the upper tip of the stent to collapse and adduct the proximal end), and in 43 by the eversion method (i.e., grasping the distal end of the stent to invert and peel out).
Interventional radiology is a simple, safe, and effective method to extract self-expanding covered metallic bullet-shaped stents, with no need for general anaesthesia and tracheal intubation. It has a short operation time, is well tolerated by patients, and is worthy of clinical application.
•We invented a technology for fluoroscopy-guided airway stent removal.•We applied this technique to remove 51 airway stents.•All stents were removed successfully, with no serious complications.•The technique is feasible and safe for fluoroscopy-guided airway stent removal.
Leptomeningeal metastases (LM) are more frequent in non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations. Due to limited access to leptomeningeal lesions, the ...purpose of this study was to explore the potential role of cerebrospinal fluid (CSF) as a source of liquid biopsy in patients with LM.
Primary tumor, CSF, and plasma in NSCLC with LM were tested by next-generation sequencing. In total, 45 patients with suspected LM underwent lumbar puncture, and those with EGFR mutations diagnosed with LM were enrolled.
A total of 28 patients were enrolled in this cohort; CSF and plasma were available in 26 patients, respectively. Driver genes were detected in 100% (26/26), 84.6% (22/26), and 73.1% (19/26) of samples comprising CSF cell-free DNA (cfDNA), CSF precipitates, and plasma, respectively; 92.3% (24/26) of patients had much higher allele fractions in CSF cfDNA than the other two media. Unique genetic profiles were captured in CSF cfDNA compared with those in plasma and primary tissue. Multiple copy number variations (CNVs) were mainly identified in CSF cfDNA, and MET copy number gain identified in 47.8% (11/23) of patients was the most frequent one, while other CNVs included ERBB2, KRAS, ALK, and MYC. Moreover, loss of heterozygosity (LOH) of TP53 was identified in 73.1% (19/26) CSF cfDNA, which was much higher than that in plasma (2/26, 7.7%; P<0.001). There was a trend towards a higher frequency of concomitant resistance mutations in patients with TP53 LOH than those without (70.6% versus 33.3%; P=0.162). EGFR T790M was identified in CSF cfDNA of 30.4% (7/23) of patients who experienced TKI progression.
CSF cfDNA could reveal the unique genetic profiles of LM and should be considered as the most representative liquid biopsy medium for LM in EGFR-mutant NSCLC.
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