The presence of oral microbes in extra-oral sites is linked to gastrointestinal cancers. However, their potential ectopically colonization in the nasopharynx and impact on local cancer development ...remains uncertain. Our study involving paired nasopharyngeal-oral microbial samples from nasopharyngeal carcinoma (NPC) patients and controls unveils an aberrant oral-to-nasopharyngeal microbial translocation associated with increased NPC risk (OR = 4.51, P = 0.012). Thirteen species are classified as oral-translocated and enriched in NPC patients. Among these, Fusobacterium nucleatum and Prevotella intermedia are validated through culturomics and clonal strain identification. Nasopharyngeal biopsy meta-transcriptomes confirm these microbes within tumors, influencing local microenvironment and cytokine response. These microbes correlate significantly with the Epstein-Barr virus (EBV) loads in the nasopharynx, exhibiting an increased dose-response relationship. Collectively, our study identifies oral microbes migrating to the nasopharynx, infiltrating tumors, impacting microenvironments and linking with EBV infection. These results enhance our understanding of abnormal microbial communication and their roles in carcinogenesis.
Background
Nasopharyngeal carcinoma (NPC), an Epstein–Barr virus (EBV) associated cancer, exhibits an extremely high incidence in southern Chinese. Given that human leukocyte antigen (HLA) plays ...critical roles in antigen presentation and relates to NPC susceptibility, it is speculated that certain HLA variants may affect EBV reactivation, which is a key pathogenic factor of NPC. Therefore, we attempted to identify HLA alleles associated with the indicator of EBV reactivation, Zta‐IgA, in healthy males from NPC endemic area.
Methods
HLA alleles of 1078 healthy males in southern China from the 21‐RCCP study were imputed using genome‐wide single nucleotide polymorphism data. EBV Zta‐IgA in blood samples were measured using an enzyme‐linked immunosorbent assay. Multiple logistic regression analysis was used to evaluate the effect of HLA allele on Zta‐IgA serological status and its potential joint association with smoking. The binding affinity for Zta‐peptide was predicted using NetMHCIIpan 4.0.
Results
HLA‐DRB1*09:01 was found to be associated with a higher risk of Zta‐IgA seropositivity (odds ratio = 1.80, 95% confidence interval = 1.32–2.45; p = 1.82 × 10−4). Compared with non‐smokers without HLA‐DRB1*09:01, the effect size increased to 2.19‐ and 3.70‐fold for the light and heavy smokers carrying HLA‐DRB1*09:01, respectively. Furthermore, HLA‐DRB1*09:01 showed a stronger binding affinity to Zta peptide than other HLA‐DRB1 alleles.
Conclusions
Our study highlighted the pivotal role of genetic HLA variants in EBV reactivation and the etiology of NPC. Smokers with HLA‐DRB1*09:01 have a significantly higher risk of being Zta‐IgA seropositive, which indicates the necessity of smoking cessation in certain high‐risk populations and also provide clues for further research on the etiology of NPC.
We conducted an association study for human leukocyte antigen (HLA) alleles and Epstein–Barr virus Zta‐IgA serological status in healthy males from a nasopharyngeal carcinoma endemic area. We found that HLA‐DRB1*09:01 was associated with a high risk of Zta‐IgA seropositivity and the effect increased when combined with smoking. In silico prediction indicated that HLA‐DRB1*09:01 had a distinctive binding motif pattern and a stronger binding affinity to Zta peptide in comparison with other HLA‐DRB1 alleles.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Previous studies have demonstrated strong associations between host genetic factors and Epstein–Barr virus (EBV) VCA‐IgA with the risk of nasopharyngeal carcinoma (NPC). However, the specific ...interplay between host genetics and EBV VCA‐IgA on NPC risk is not well understood. In this two‐stage case–control study (N = 4804), we utilized interaction and mediation analysis to investigate the interplay between host genetics (genome‐wide association study‐derived polygenic risk score PRS) and EBV VCA‐IgA antibody level in the NPC risk. We employed a four‐way decomposition analysis to assess the extent to which the genetic effect on NPC risk is mediated by or interacts with EBV VCA‐IgA. We consistently found a significant interaction between the PRS and EBV VCA‐IgA on NPC risk (discovery population: synergy index SI = 2.39, 95% confidence interval CI = 1.85–3.10; replication population: SI = 3.10, 95% CI = 2.17–4.44; all pinteraction < 0.001). Moreover, the genetic variants included in the PRS demonstrated similar interactions with EBV VCA‐IgA antibody. We also observed an obvious dose–response relationship between the PRS and EBV VCA‐IgA antibody on NPC risk (all ptrend < 0.001). Furthermore, our decomposition analysis revealed that a substantial proportion (approximately 90%) of the genetic effects on NPC risk could be attributed to host genetic‐EBV interaction, while the risk effects mediated by EBV VCA‐IgA antibody were weak and statistically insignificant. Our study provides compelling evidence for an interaction between host genetics and EBV VCA‐IgA antibody in the development of NPC. These findings emphasize the importance of implementing measures to control EBV infection as a crucial strategy for effectively preventing NPC, particularly in individuals at high genetic risk.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
This study aimed to investigate the microstructure and mechanical properties of Ti
x
ZrVNb (
x
= 1, 1.5, 2) refractory high-entropy alloys at room and elevated temperatures. The TiZrVNb alloy ...consisted of the body-centered cubic (bcc) matrix with a small amount of V
2
Zr phase. The Ti
1.5
ZrVNb and Ti
2
ZrVNb alloys exhibited a single-phase bcc structure. At room temperature, the tensile ductility of the as-cast alloys increased from 3.5% to 12.3% with the increase in the Ti content. The Ti
x
ZrVNb alloys exhibited high yield strength at 600°C, and the ultimate yield strength was more than 900 MPa. Softening occurred at 800°C, but the ultimate yield strength could still exceed 200 MPa. Moreover, the Ti
x
ZrVNb alloys displayed low densities but high specific yield strengths (SYSs). The lowest density of Ti
x
ZrVNb alloys was only 6.12 g/cm
3
, but the SYS could reach about 180 MPa·cm
3
·g
−1
, which is better than those of most reported high-entropy alloys (HEAs).
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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
The development of an economic, environmental-friendly and energy-saving process for the selective depolymerization of lignin is an outstanding challenge. Herein, a novel and efficient ...visible-light-induced photocatalytic process for the selective depolymerization of lignin model compounds and organosolv lignin was first developed by using perylene diimide (PDI) as a metal-free organocatalyst. Interestingly, it can completely decompose the oxidized lignin models to phenolic and ketone fragmentation molecules with very high selectivity at room temperature under visible light illumination. Furthermore, the use of a home-made photocatalytic continuous-flow reactor efficiently shortened the reaction time within an hour. Even for organosolv lignin, nearly 86% mass ratio of lignin was degraded to low-molecular-mass monoaromatic or diaromatic products. We found that superior performances were realized by single-electron transfer (SET) from the photoexcited strongly reducing PDI&z.rad;
−
anion to the ketone groups of the β-O-4 linkage in the lignin.
A novel and efficient strategy for the selective depolymerization of lignin model compounds and organosolv lignin
via
a visible-light-induced photocatalytic continuous-flow reactor was first developed by using perylene diimide (PDI) as a organocatalyst.
Abstract
Advanced colorectal adenocarcinoma (CRAC), featured by distinctive histopathological appearance, distant organ metastasis, acquired chemoresistance, and tumorigenic stemness is a group of ...heterogeneous cancers with unique genetic signatures and malignant phenotypes. Treatment of CRAC is a daunting task for oncologists. Currently, various strategies including molecular targeting using therapeutic monoclonal antibodies, small molecule kinase inhibitors and immunoregulatory checkpoint therapy have been applied to combat this deadly disease. However, these therapeutic modalities and approaches achieve only limited success. Thus, there is a pharmaceutical need to discover new targets and develop novel therapeutics for CRAC therapy. MET and RON receptor tyrosine kinases have been implicated in CRAC pathogenesis. Clinical studies have revealed that aberrant MET and/or RON expression and signaling are critical in regulating CRAC progression and malignant phenotypes. Increased MET and/or RON expression also has prognostic value for CRAC progression and patient survival. These features provide the rationale to target MET and RON for clinical CRAC intervention. At present, the use of small molecule kinase inhibitors targeting MET for CRAC treatment has achieved significant progress with several approvals for clinical application. Nevertheless, antibody-based biotherapeutics, although under clinical trials for more than 8 years, have made very little progress. In this review, we discuss the importance of MET and/or RON in CRAC tumorigenesis and development of anti-MET, anti-RON, and MET and RON-dual targeting antibody-drug conjugates for clinical application. The findings from both preclinical studies and clinical trials highlight the potential of this novel type of biotherapeutics for CRAC therapy in the future.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Radiation-induced oral mucositis (OM) is one of the most common acute complications for head and neck cancer. Severe OM is associated with radiation treatment breaks, which harms successful tumor ...management. Radiogenomics studies have indicated that genetic variants are associated with adverse effects of radiotherapy.
A large-scale genome-wide scan was performed in 1467 nasopharyngeal carcinoma patients, including 753 treated with 2D-CRT from Genetic Architecture of the Radiotherapy Toxicity and Prognosis (GARTP) cohort and 714 treated with IMRT (192 from the GARTP and 522 newly recruited). Subgroup analysis by radiotherapy technique was further performed in the top associations. We also performed physical and regulatory mapping of the risk loci and gene set enrichment analysis of the candidate target genes.
We identified 50 associated genomic loci and 64 genes via positional mapping, expression quantitative trait locus (eQTL) mapping, chromatin interaction mapping and gene-based analysis, and 36 of these loci were replicated in subgroup analysis. Interestingly, one of the top loci located in TNKS, a gene relevant to radiation toxicity, was associated with increased OM risk with OR = 3.72 of the lead SNP rs117157809 (95% CI 2.10-6.57; P = 6.33 × 10
). Gene set analyses showed that the 64 candidate target genes were enriched in the biological processes of regulating telomere capping and maintenance and telomerase activity (Top P = 7.73 × 10
).
These results enhance the biological understanding of radiotherapy toxicity. The association signals enriched in telomere function regulation implicate the potential underlying mechanism and warrant further functional investigation and potential individual radiotherapy applications.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Although the pathogenesis of osteoarthritis (OA) is unclear, inflammatory cytokines are related to its occurrence. However, few studies focused on the therapeutic strategies of regulating joint ...homeostasis by simultaneously remodeling the anti‐inflammatory and immunomodulatory microenvironments. Fibroblast growth factor 18 (FGF18) is the only disease‐modifying OA drug (DMOAD) with a potent ability and high efficiency in maintaining the phenotype of chondrocytes within cell culture models. However, its potential role in the immune microenvironment remains unknown. Besides, information on an optimal carrier, whose interface and chondral‐biomimetic microenvironment mimic the native articular tissue, is still lacking, which substantially limits the clinical efficacy of FGF18. Herein, to simulate the cartilage matrix, chondroitin sulfate (ChS)‐based nanoparticles (NPs) are integrated into poly(D, L‐lactide)‐poly(ethylene glycol)‐poly(D, L‐lactide) (PLEL) hydrogels to develop a bionic thermosensitive sustainable delivery system. Electrostatically self‐assembled ChS and ε‐poly‐l‐lysine (EPL) NPs are prepared for the bioencapsulation of FGF18. This bionic delivery system suppressed the inflammatory response in interleukin‐1β (IL‐1β)‐mediated chondrocytes, promoted macrophage M2 polarization, and inhibited M1 polarization, thereby ameliorating cartilage degeneration and synovitis in OA. Thus, the ChS‐based hydrogel system offers a potential strategy to regulate the chondrocyte‐macrophage crosstalk, thus re‐establishing the anti‐inflammatory and immunomodulatory microenvironment for OA therapy.
A bionic thermosensitive sustainable delivery system is reported, which can suppress the inflammatory response in IL‐1β‐mediated chondrocytes, promote macrophage M2 polarization, and inhibit M1 polarization, thereby ameliorating cartilage degeneration and synovitis in osteoarthritis (OA). The ChS‐based hydrogel system offers a potential strategy to regulate the chondrocyte‐macrophage crosstalk, thus re‐establishing the anti‐inflammatory and immunomodulatory microenvironment for OA therapy.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Pancreatic ductal adenocarcinoma (PDAC) originates from normal pancreatic ducts where digestive juice is regularly produced. It remains unclear how PDAC can escape autodigestion by digestive enzymes. ...Here we show that human PDAC tumour cells use gasdermin E (GSDME), a pore-forming protein, to mediate digestive resistance. GSDME facilitates the tumour cells to express mucin 1 and mucin 13, which form a barrier to prevent chymotrypsin-mediated destruction. Inoculation of GSDME
PDAC cells results in subcutaneous but not orthotopic tumour formation in mice. Inhibition or knockout of mucin 1 or mucin 13 abrogates orthotopic PDAC growth in NOD-SCID mice. Mechanistically, GSDME interacts with and transports YBX1 into the nucleus where YBX1 directly promotes mucin expression. This GSDME-YBX1-mucin axis is also confirmed in patients with PDAC. These findings uncover a unique survival mechanism of PDAC cells in pancreatic microenvironments.
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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
Nasopharyngeal carcinoma (NPC), the most common head and neck cancer, is characterized by distinct geographic distribution and familial aggregation. Multiple risk factors, including host genetics, ...environmental factor, and EBV infection, have been linked to the development of NPC, particularly in the familial clustering cases. However, the cause of NPC endemicity remains enigmatic due possibly to the complicated interplay between these risk factors. Recently, positive Epstein‐Barr virus (EBV) DNA loads at nasopharyngeal (NP) cavity has been found to reflect NPC development and applied in NPC screening. To examine whether the increased NP EBV loads could aggregate in the families and be affected by host genetics and environmental factor, EBV loads were obtained by 510 NP brushing samples from eligible unaffected individuals, who have two or more relatives affected with NPC, in 116 high‐risk NPC families. The correlation of relative pairs was estimated using S.A.G.E. (version 6.4, 2016), and host heritability of NP EBV loads was calculated with variance component models using SOLAR (version 8.4.2, 2019). In result, significant correlations of EBV loads were observed between parent‐offspring pairs and sibling‐sibling pairs (P < .001), but not in distant kin relationship pairs. Interestingly, after excluding the shared environmental factor within families, host genetics contributes significantly to NP EBV loads with a heritability of 56.41% (P = 1.00 × 10−7), and its effect was slightly elevated (68.86%, P = 3.40 × 10−6) in families with more NPC cases (≥3). These findings indicate that additional host‐genetic variants involved in the EBV local NP mucosal behavior may be especially important for the development of NPC.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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