Genome-wide analysis of genomic signatures might reveal novel mechanisms for gastric cancer (GC) tumorigenesis. Here, we analysis structural variations (SVs) and mutational signatures via ...whole-genome sequencing of 168 GCs. Our data demonstrates diverse models of complex SVs operative in GC, which lead to high-level amplification of oncogenes. We find varying proportion of tandem-duplications (TDs) among individuals and identify 24 TD hotspots involving well-established cancer genes such as CCND1, ERBB2 and MYC. Specifically, we nominate a novel hotspot involving the super-enhancer of ZFP36L2 presents in approximately 10% GCs from different cohorts, the oncogenic role of which is further confirmed by experimental data. In addition, our data reveal a mutational signature, specifically occurring in noncoding region, significantly enriched in tumors with cadherin 1 mutations, and associated with poor prognoses. Collectively, our data suggest that TDs might serve as an important mechanism for cancer gene activation and provide a novel signature for stratification.
Atmospheric vapor pressure deficit (VPD) is a critical variable in determining plant photosynthesis. Synthesis of four global climate datasets reveals a sharp increase of VPD after the late 1990s. In ...response, the vegetation greening trend indicated by a satellite-derived vegetation index (GIMMS3g), which was evident before the late 1990s, was subsequently stalled or reversed. Terrestrial gross primary production derived from two satellite-based models (revised EC-LUE and MODIS) exhibits persistent and widespread decreases after the late 1990s due to increased VPD, which offset the positive CO
fertilization effect. Six Earth system models have consistently projected continuous increases of VPD throughout the current century. Our results highlight that the impacts of VPD on vegetation growth should be adequately considered to assess ecosystem responses to future climate conditions.
Cancers infiltrated with T-cells are associated with a higher likelihood of response to PD-1/PD-L1 blockade. Counterintuitively, a correlation between epithelial-mesenchymal transition (EMT)-related ...gene expression and T-cell infiltration has been observed across tumor types. Here we demonstrate, using The Cancer Genome Atlas (TCGA) urothelial cancer dataset, that although a gene expression-based measure of infiltrating T-cell abundance and EMT-related gene expression are positively correlated, these signatures convey disparate prognostic information. We further demonstrate that non-hematopoietic stromal cells are a major source of EMT-related gene expression in bulk urothelial cancer transcriptomes. Finally, using a cohort of patients with metastatic urothelial cancer treated with a PD-1 inhibitor, nivolumab, we demonstrate that in patients with T-cell infiltrated tumors, higher EMT/stroma-related gene expression is associated with lower response rates and shorter progression-free and overall survival. Together, our findings suggest a stroma-mediated source of immune resistance in urothelial cancer and provide rationale for co-targeting PD-1 and stromal elements.
Helicobacter pylori (H. pylori) is a common human pathogenic bacterium. Once infected, it is difficult for the host to clear this organism using the innate immune system. Increased antibiotic ...resistance further makes it challenging for effective eradication. However, the mechanisms of immune evasion still remain obscure, and novel strategies should be developed to efficiently eliminate H. pylori infection in stomachs. Here we uncovered desirable anti-H. pylori effect of vitamin D3 both in vitro and in vivo, even against antibiotic-resistant strains. We showed that H. pylori can invade into the gastric epithelium where they became sequestered and survived in autophagosomes with impaired lysosomal acidification. Vitamin D3 treatment caused a restored lysosomal degradation function by activating the PDIA3 receptor, thereby promoting the nuclear translocation of PDIA3-STAT3 protein complex and the subsequent upregulation of MCOLN3 channels, resulting in an enhanced Ca
2+
release from lysosomes and normalized lysosomal acidification. The recovered lysosomal degradation function drives H. pylori to be eliminated through the autolysosomal pathway. These findings provide a novel pathogenic mechanism on how H. pylori can survive in the gastric epithelium, and a unique pathway for vitamin D3 to reactivate the autolysosomal degradation function, which is critical for the antibacterial action of vitamin D3 both in cells and in animals, and perhaps further in humans.
Abbreviations: 1,25D3: 1α, 25-dihydroxyvitamin D3; ATG5: autophagy related 5; Baf A1: bafilomycin A
1
; BECN1: beclin 1; CagA: cytotoxin-associated gene A; CFU: colony-forming unit; ChIP-PCR: chromatin immunoprecipitation-polymerase chain reaction; Con A: concanamycin A; CQ: chloroquine; CRISPR: clustered regularly interspaced short palindromic repeats; CTSD: cathepsin D; GPN: Gly-Phe-β-naphthylamide; H. pylori: Helicobacter pylori; LAMP1: lysosomal associated membrane protein 1; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MCOLN1: mucolipin 1; MCOLN3: mucolipin 3; MCU: mitochondrial calcium uniporter; MOI: multiplicity of infection; NAGLU: N-acetyl-alpha-glucosaminidase; PDIA3: protein disulfide isomerase family A member 3; PMA: phorbol 12-myristate 13-acetate; PRKC: protein kinase C; SQSTM1: sequestosome 1; STAT3: signal transducer and activator of transcription 3; SS1: Sydney Strain 1; TRP: transient receptor potential; VacA: vacuolating cytotoxin; VD3: vitamin D3; VDR: vitamin D receptor
Abstract In the present study, a multivariate probabilistic framework is used to identify the meridional positions of regional tropical edges (RTEs), which are based on two variables: sea level ...pressure and precipitation minus evaporation. This new defined metric effectively captures inter-annual variability and long-term trend of the commonly adopted zonal mean tropical edge based on meridional mass stream function and near-surface winds. Besides, pronounced RTE trends are primarily located over the oceanic regions, and the terrestrial areas exhibit substantial inter-annual variability. These results are consistent among three modern reanalysis datasets. Moreover, the impacts of climate modes on RTE are investigated. The El Niño-Southern Oscillation, the Atlantic multi-decadal oscillation, and the Southern Annular Mode are important both on the inter-annual variations and long-term trends of RTE. The Pacific Decadal Oscillation is more inclined to affect long-term contribution rather than inter-annual relationship, and the Pacific–North American teleconnection, the North Atlantic Oscillation, and the Arctic oscillation highlight the inter-annual relationship with RTE in the specific regions, such as North Pacific, North Atlantic, and North Africa, respectively.
Abstract
The role of N
6
-methyladenosine (m
6
A) modification of host mRNA during bacterial infection is unclear. Here, we show that
Helicobacter pylori
infection upregulates host m
6
A methylases ...and increases m
6
A levels in gastric epithelial cells. Reducing m
6
A methylase activity via hemizygotic deletion of methylase-encoding gene
Mettl3
in mice, or via small interfering RNAs targeting m
6
A methylases, enhances
H. pylori
colonization. We identify LOX-1 mRNA as a key m
6
A-regulated target during
H. pylori
infection. m
6
A modification destabilizes LOX-1 mRNA and reduces LOX-1 protein levels. LOX-1 acts as a membrane receptor for
H. pylori
catalase and contributes to bacterial adhesion. Pharmacological inhibition of LOX-1, or genetic ablation of
Lox-1
, reduces
H. pylori
colonization. Moreover, deletion of the bacterial catalase gene decreases adhesion of
H. pylori
to human gastric sections. Our results indicate that m
6
A modification of host LOX-1 mRNA contributes to protection against
H. pylori
infection by downregulating LOX-1 and thus reducing
H. pylori
adhesion.
Autophagy is a conserved intracellular degradation process enclosing the bulk of cytosolic components for lysosomal degradation to maintain cellular homeostasis. Accumulating evidences showed that a ...specialized form of autophagy, known as xenophagy, could serve as an innate immune response to defend against pathogens invading inside the host cells. Correspondingly, infectious pathogens have developed a variety of strategies to disarm xenophagy, leading to a prolonged and persistent intracellular colonization. In this review, we first summarize the current knowledge about the general mechanisms of intracellular bacterial infections and xenophagy. We then focus on the ongoing battle between these two processes.
Single-cell sequencing is a powerful tool for delineating clonal relationship and identifying key driver genes for personalized cancer management. Here we performed single-cell sequencing analysis of ...a case of colon cancer. Population genetics analyses identified two independent clones in tumor cell population. The major tumor clone harbored APC and TP53 mutations as early oncogenic events, whereas the minor clone contained preponderant CDC27 and PABPC1 mutations. The absence of APC and TP53 mutations in the minor clone supports that these two clones were derived from two cellular origins. Examination of somatic mutation allele frequency spectra of additional 21 wholetissue exome-sequenced cases revealed the heterogeneity of clonal origins in colon cancer. Next, we identified a mutated gene SLC12A5 that showed a high frequency of mutation at the single-cell level but exhibited low prevalence at the population level. Functional characterization of mutant SLC12A5 revealed its potential oncogenic effect in colon cancer. Our study provides the first exome-wide evidence at single-cell level supporting that colon cancer could be of a biclonal origin, and suggests that low-prevalence mutations in a cohort may also play important protumorigenic roles at the individual level.
Background and Aims
During liver fibrosis, liver sinusoidal endothelial cells (LSECs) release angiocrine signals to recruit inflammatory cells into the liver. p300, a master regulator of gene ...transcription, is associated with pathological inflammatory response. Therefore, we examined how endothelial p300 regulates angiocrine signaling and inflammation related to portal hypertension and fibrogenesis.
Approach and Results
CCl4 or partial inferior vena cava ligation (pIVCL) was used to induce liver injury. Mice with LSEC‐specific p300 deletion (p300LSECΔ/Δ) or C‐C motif chemokine ligand 2 (Ccl2) deficiency, nuclear factor kappa B (NFκB)–p50 knockout mice, and bromodomain containing 4 (BRD4) inhibitors in wild‐type mice were used to investigate mechanisms of inflammation regulation. Leukocytes were analyzed by mass cytometry by time‐of‐flight. Epigenetic histone marks were modified by CRISPR endonuclease‐deficient CRISPR‐associated 9‐fused with the Krüppel associated box domain (CRISPR‐dCas9‐KRAB)–mediated epigenome editing. Portal pressure and liver fibrosis were reduced in p300LSECΔ/Δ mice compared to p300fl/fl mice following liver injury. Accumulation of macrophages was also reduced in p300LSECΔ/Δ mouse livers. Ccl2 was the most up‐regulated chemokine in injured LSECs, but its increase was abrogated in p300LSECΔ/Δ mice. While the macrophage accumulation was increased in NFκB‐p50 knockout mice with enhanced NFκB activity, it was reduced in mice with LSEC‐specific Ccl2 deficiency and mice treated with specific BRD4 inhibitors. In vitro, epigenome editing of CCL2 enhancer and promoter regions by CRISPR‐dCas9‐KRAB technology repressed TNFα‐induced CCL2 transcription through H3K9 trimethylation. In contrast, TNFα activated CCL2 transcription by promoting p300 interaction with NFκB and BRD4, leading to histone H3 lysine 27 acetylation at CCL2 enhancer and promoter regions.
Conclusions
In summary, endothelial p300 interaction with NFκB and BRD4 increases CCL2 expression, leading to macrophage accumulation, portal hypertension, and liver fibrosis. Inhibition of p300 and its binding partners might serve as therapy in the treatment of liver diseases.
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