Background. This work focused on investigating the role of programmed death ligand 2 (PD-L2) in the progression of breast cancer by utilizing breast cancer specimens and cells. Materials and Methods. ...The serum levels of soluble PD-L2 (sPD-L2) in breast cancer patients and healthy individuals were analyzed by means of the enzyme-linked immunosorbent assay, and the PD-L2 levels within 416 resected breast cancer specimens were assessed through immunohistochemistry. Concurrently, in vitro cell experiments and in vivo animal experiments were carried out to analyze the relationship between PD-L2 and the invasion and migration of breast cancer. Results. The concentration of sPD-L2 in breast cancer patients significantly increased compared to that in the control groups. Additionally, breast cancer patients with high concentrations of sPD-L2 had higher Ki67 values (≥30%) and tumor grades. PD-L2 was expressed in 79.09% of the cancer samples, which exhibited a positive correlation with the progesterone receptor (PR) and the human epidermal growth factor receptor 2 (HER2). Furthermore, we discovered that knockdown of PD-L2 inhibited the migratory and invasive abilities of both MCF-7 and MDA-MB231 cells. Conclusion. Our findings demonstrated that knockdown of PD-L2 suppressed tumor growth, providing novel insights into important biological functions.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Epstein-Barr virus (EBV) infection is associated with multiple malignancies, including pulmonary lymphoepithelioma-like carcinoma (pLELC), a particular subtype of primary lung cancer. However, the ...genomic characteristics of EBV related to pLELC remain unclear. Here, we obtained the whole-genome data set of EBV isolated from 78 pLELC patients and 37 healthy controls using EBV-captured sequencing. Compared with the reference genome (NC_007605), a total of 3,995 variations were detected across pLELC-derived EBV sequences, with the mutational hot spots located in latent genes. Combined with 180 published EBV sequences derived from healthy people in Southern China, we performed a genome-wide association study and identified 32 variations significantly related to pLELC (
2.56 × 10
, Bonferroni correction), with the top signal of single nucleotide polymorphism (SNP) coordinate T7327C (OR = 1.22,
2.39 × 10
) locating in the origin of plasmid replication (OriP). The results of population structure analysis of EBV isolates in East Asian showed the EBV strains derived from pLELC were more similar to those from nasopharyngeal carcinoma (NPC) than other EBV-associated diseases. In addition, typical latency type-II infection were recognized for EBV of pLELC at both transcription and methylation levels. Taken together, we defined the global view of EBV genomic profiles in pLELC patients for the first time, providing new insights to deepening our understanding of this rare EBV-associated primary lung carcinoma.
Pulmonary lymphoepithelioma-like carcinoma (pLELC) is a rare, distinctive subtype of primary lung cancer closely associated with Epstein-Barr virus (EBV) infection. Here, we gave the first overview of pLELC-derived EBV at the level of genome, methylation and transcription. We obtained the EBV sequences data set from 78 primary pLELC patients, and revealed the sequences diversity across EBV genome and detected variability in known immune epitopes. Genome-wide association analysis combining 217 healthy controls identifies significant variations related to the risk of pLELC. Meanwhile, we characterized the integration landscapes of EBV at the genome-wide level. These results provided new insight for understanding EBV's role in pLELC tumorigenesis.
The role of Fat Mass and Obesity-associated protein （FTO） and its substrate N6-methyladenosine （m6A） in mRNA processing and adipogenesis remains largely unknown. We show that FTO expression and m6A ...levels are inversely correlated during adipogenesis. FTO depletion blocks differentiation and only catalytically active FTO restores adi- pogenesis. Transcriptome analyses in combination with m6A-seq revealed that gene expression and mRNA splicing of grouped genes are regulated by FTO. M6A is enriched in exonic regions flanking 5＇- and 3＇-splice sites, spatially over- lapping with mRNA splicing regulatory serine/arginine-rich （SR） protein exonic splicing enhancer binding regions. Enhanced levels of m6A in response to FTO depletion promotes the RNA binding ability of SRSF2 protein, leading to increased inclusion of target exons. FTO controls exonic splicing of adipogenie regulatory factor RUNX1T1 by regulating m6A levels around splice sites and thereby modulates differentiation. These findings provide compelling evidence that FTO-dependent m6A demethylation functions as a novel regulatory mechanism of RNA processing and plays a critical role in the regulation of adipogenesis.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Alloying is one of the most effective means to confer superior properties to metal materials. For far too long, conventional W-based alloys were generally improved by the addition of minor elements. ...The exploitation of conventional W-based alloy is restricted to the corner of multielement phase diagrams with tiny compositional space. High-entropy alloys (HEAs) are a novel kind of alloys consisting of multi-principal alloying elements (usually more than 4) and have attracted increasing attention, since they were first reported in 2004. The emergence of HEAs filled the gap of the unexplored central region of multielement phase diagrams. Among them, tungsten-containing HEAs (TCHEAs) exhibit excellent mechanical properties, especially at extraordinarily elevated temperatures. Moreover, recent studies showed that TCHEAs had outstanding irradiation resistance properties. TCHEAs might serve as a promising candidate for plasma-facing materials in the fusion reactor. Many characteristics of TCHEAs are different from other HEAs due to the addition of tungsten with ultrahigh-melting temperature. Here, this paper aimed to introduce the manufacturing routes of TCHEAs; review the phase selection, mechanical properties, and irradiation resistance properties of TCHEAs; and propose the future prospects of TCHEAs.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The recepteur d’origine nantais (RON) receptor tyrosine kinase, belonging to the mesenchymal-to-epithelial transition proto-oncogene family, has been implicated in the pathogenesis of cancers derived ...from the colon, lung, breast, and pancreas. These findings lay the foundation for targeting RON for cancer treatment. However, development of RON-targeted therapeutics has not gained sufficient attention for the last decade. Although therapeutic monoclonal antibodies (TMABs) targeting RON have been validated in preclinical studies, results from clinical trials have met with limited success. This outcome diminishes pharmaceutical enthusiasm for further development of RON-targeted therapeutics. Recently, antibody–drug conjugates (ADCs) targeting RON have drawn special attention owing to their increased therapeutic activity. The rationale for developing anti-RON ADCs is based on the observation that cancer cells are not sufficiently addicted to RON signaling for survival. Thus, TMAB-mediated inhibition of RON signaling is ineffective for clinical application. In contrast, anti-RON ADCs combine a target-specific antibody with potent cytotoxins for cancer cell killing. This approach not only overcomes the shortcomings in TMAB-targeted therapies but also holds the promise for advancing anti-RON ADCs into clinical trials. In this review, we discuss the latest advancements in the development of anti-RON ADCs for targeted cancer therapy including drug conjugation profile, pharmacokinetic properties, cytotoxic effect in vitro, efficacy in tumor models, and toxicological activities in primates.
Zn–Al–Cu–TiB2 (ZA27–TiB2) in situ composites were fabricated via reactions between molten aluminum and mixed halide salts (K2TiF6 and KBF4) at temperature of 875 °C. The microstructure, mechanical ...properties and wear behavior of the composites were investigated. Microstructure analysis shows that fine and clean TiB2 particles distribute uniformly through the matrix. The mechanical properties of the composites increase with the increase in TiB2 content. As TiB2 content increases to 5% (mass fraction), an improvement of HB 18 in hardness and 49 MPa in ultimate tensile strength (UTS) is achieved. The overall results reveal that the composites possess low friction coefficients and the wear rate is reduced from 5.9×10−3 to 1.3×10−3 mm3/m after incorporating 5% TiB2. Friction coefficient and worn surface analysis indicate that there is a change in the wear mechanism in the initial stage of wear test after introducing in situ TiB2 particles into the matrix.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
N6-methyladenosine (m6A) RNA methylation is the most abundant modification on mRNAs and plays important roles in various biological processes. The formation of m6A is catalyzed by a methyltransferase ...complex including methyltransferase-like 3 (METTL3) as a key factor. However, the in vivo functions of METTL3 and m6A modification in mammalian development remain unclear. Here, we show that specific inactivation of Mettl3 in mouse nervous system causes severe developmental defects in the brain. Mettl3 conditional knockout (cKO) mice manifest cerebellar hypoplasia caused by drastically enhanced apoptosis of newborn cerebellar granule cells (CGCs) in the external granular layer (EGL). METTL3 depletion-induced loss of m6A modification causes extended RNA half-lives and aberrant splicing events, consequently leading to dysregulation of transcriptome-wide gene expression and premature CGC death. Our findings reveal a critical role of METTL3-mediated m6A in regulating the development of mammalian cerebellum.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
Several genome‐wide association studies (GWASs) have identified strong associations between genetic variants in the human leukocyte antigen (HLA) region and nasopharyngeal carcinoma (NPC). ...However, given the complex LD pattern in this region, the causal variants and the underlying mechanism of how genetic variants in HLA contribute to NPC development is yet to be understood.
Methods
To systematically characterize the HLA variants and their relationship to NPC susceptibility, we fine‐mapped the HLA genes based on the GWAS data of 1583 NPC cases and 972 healthy controls, using SNP2HLA with the Pan‐Asian panel as references. Stepwise conditional regression was used to identify independent association loci.
Results
Interestingly, the most significant association was the presence of Gln in HLA‐A amino acid position 62 (OR = 0.57, P = 1.41 × 10−16). The G allele of rs2894207 located between HLA‐B and HLA‐C showed protective effect of NPC development (OR = 0.52, P = 2.23 × 10−13). Additionally, amino acid Phe‐67 located in the peptide‐binding pocket of HLA‐DRB1 was identified as a novel functional variant with OR = 0.64 and P = 9.64 × 10−11. Another novel variant, Glu‐45 in HLA‐B pocket B, conferred a protective effect on NPC susceptibility (OR = 0.64, P = 5.23 × 10−8). These four variants explained 2.07% of the phenotypic variance for NPC risk.
Conclusion
In summary, by fine‐mapping the HLA region in south Chinese population, we reported additional loci missed in the GWAS studies and provided a better understanding of the relationship between HLA and NPC susceptibility.
Human leukocyte antigen (HLA) was identified as a susceptibility locus that was associated with NPC development; however, the causal variants remain to be found, and the underlying mechanism is yet to be understood. In this study, we identified two novel functional amino acid variants associated with lower NPC risk, one located in the peptide‐binding pocket of the DR β‐chain and one in HLA‐B pocket B, and provided a better understanding of the relationship between HLA and NPC susceptibility.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Rice source- and sink-associated traits are important for grain yield and are sensitive to environmental conditions. The continuing increase of CO
2
concentrations in the atmosphere will become a ...major challenge for rice growth and development in the future due to changes in our climate such as extremes in temperature. To guarantee food safety, novel genetic loci need to be identified for source- and sink-associated traits that are specifically expressed under elevated CO
2
conditions. Eighty chromosome segment substitution lines carrying
japonica
(Nipponbare) chromosome segments in the
indica
(9311) background were used in this study. QTL analysis was conducted for source- and sink-related traits, including flag leaf length, flag leaf width, flag leaf fresh weight, flag leaf dry weight, primary branch number, secondary branch number, grain number per panicle, panicle weight per plant, chlorophyll a, chlorophyll b, and carotenoid contents, under ambient CO
2
concentrations and free-air CO
2
enrichment. A total of 49 QTLs for these traits were detected on chromosomes 1, 3, 5, 6, 7, 9, and 12 under the two conditions; the variance explained by these QTLs varied from 6.22 to 38.15%. Among these QTLs, 19 of them were detected under the natural field conditions and 30 were detected in the elevated CO
2
conditions. In addition, 2 and 13 QTLs were specifically expressed in the natural and CO
2
-enriched conditions, respectively. Our findings have important implications on the utilization of germplasm resources for ensuring food security under elevated CO
2
levels, especially for QTLs that were specifically detected under the elevated CO
2
condition.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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