Long noncoding RNAs (lncRNAs) are involved in the pathology of colorectal cancer (CRC). Current efforts to eradicate CRC predominantly focused on targeting the proliferation of rapidly growing cancer ...epithelial cells. This is largely ineffective with resistance arising in most tumors after exposure to chemotherapy. Despite the long‐standing recognition of the crosstalk between carcinoma‐associated fibroblasts (CAFs) and cancer cells in the tumor microenvironment, how CAFs may contribute to drug resistance in neighboring cancer cells is not well characterized. Here, we show that lncRNA CCAL (colorectal cancer‐associated lncRNA) promotes oxaliplatin (Oxa) resistance of CRC cells. RNA‐ISH shows higher CCAL expressed in the tumor stroma compared to cancer nests of CRC tissues. Functional studies reveal that CCAL is transferred from CAFs to the cancer cells via exosomes, where it suppresses CRC cell apoptosis, confers chemoresistance and activates β‐catenin pathway in vitro and in vivo. Mechanistically, CCAL interacts directly with mRNA stabilizing protein HuR (human antigen R) to increase β‐catenin mRNA and protein levels. Our findings indicate that CCAL expressed by CAFs of the colorectal tumor stroma contributes to tumor chemoresistance and CCAL may serve as a potential therapeutic target for Oxa resistance.
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Long noncoding RNA signatures of tumor‐derived exosomes have been identified in multiple tumor types, including colorectal cancer. The expression pattern of the lncRNA CCAL in CRC and its role in exosome‐derived chemoresistance remain to be elucidated, however. Here, the authors report that CCAL is located in the tumor stroma rather than cancer nests and can be delivered from cancer‐associated fibroblasts to cancer cells via exosomes, to promote oxaliplatin resistance in vitro and in vivo. The findings highlight the crucial role of CCAL in the interaction of cancer cells with the tumor microenvironment and offer potential targets for overcoming drug resistance.
In this letter, a modified hybrid coupler is employed to facilitate high isolation between its fundamental ( ω 0 ) and second harmonic (2 ω 0 ) operational bands at isolation (ISO) port, which ...establishes dual channels for both power delivery and harmonic backscattering ( ω 0 : IN→DIR/COU, 2 ω 0 : IN→ISO). Additionally, the λ 0 /8 open and short stubs are implemented in the coupler with an extended bandwidth centered at 2 ω 0 to avoid frequency offset. Agreements between simulated and measured (74.3%) RF-to-DC power conversion efficiency can be obtained by two subrectifiers from DIR/COU ports with an incident power of 19.5 dBm at the IN port while achieving low insertion loss (0.6 dB at 2 ω 0 ) and high isolation (28 dB at ω 0 ) from IN to ISO ports. For system validation, a pair of share-apertured dual-band dual-polarized antennas is employed for cross-polarized up ( ω 0 /2 ω 0 ) and down (2 ω 0 ) links. At the same time, an on/off keying modulation is implemented through the second harmonic channel (IN→ISO) for backscattering. According to the experimental results, such a system achieves high-isolated wireless power and information codelivery.
Long noncoding RNAs (lncRNAs) have emerged as a new class of regulatory molecules implicated in therapeutic resistance, yet the mechanisms underlying lncRNA-mediated oxaliplatin resistance in ...colorectal cancer (CRC) are poorly understood. In this study, lncRNA P53 inHibiting LncRNA (PiHL) was shown to be highly induced in oxaliplatin-resistant CRC cells and tumor tissues. In vitro and in vivo models clarified PiHL's role in conferring resistance to oxaliplatin-induced apoptosis. PiHL antagonized chemosensitivity through binding with EZH2, repressing location of EZH2 to HMGA2 promoter, and downregulating methylation of histone H3 lysine 27 (H3K27me3) level in HMGA2 promoter, thus activating HMGA2 expression. Furthermore, HMGA2 upregulation induced by PiHL promotes PI3K/Akt phosphorylation, which resulted in increased oxaliplatin resistance. We also found that transcription factor KLF4 was downregulated in oxaliplatin-resistant cells, and KLF4 negatively regulated PiHL expression by binding to PiHL promoter. In vivo models further demonstrated that treatment of oxaliplatin-resistant CRC with locked nucleic acids targeting PiHL restored oxaliplatin response. Collectively, this study established lncRNA PiHL as a chemoresistance promoter in CRC, and targeting PiHL/EZH2/HMGA2/PI3K/Akt signaling axis represents a novel choice in the investigation of drug resistance.
The relationship between gut microbial dysbiosis and acute or chronic kidney disease (CKD) is still unclear. Here, we show that oral administration of the probiotic Lactobacillus casei Zhang ...(L. casei Zhang) corrected bilateral renal ischemia-reperfusion (I/R)-induced gut microbial dysbiosis, alleviated kidney injury, and delayed its progression to CKD in mice. L. casei Zhang elevated the levels of short-chain fatty acids (SCFAs) and nicotinamide in the serum and kidney, resulting in reduced renal inflammation and damage to renal tubular epithelial cells. We also performed a 1-year phase 1 placebo-controlled study of oral L. casei Zhang use (Chinese clinical trial registry, ChiCTR-INR-17013952), which was well tolerated and slowed the decline of kidney function in individuals with stage 3–5 CKD. These results show that oral administration of L. casei Zhang, by altering SCFAs and nicotinamide metabolism, is a potential therapy to mitigate kidney injury and slow the progression of renal decline.
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•L. casei Zhang improves renal function and pathology in mouse models of AKI and CKD•L. casei Zhang ameliorates gut microbial dysbiosis in both AKI and CKD•L. casei Zhang reduces renal inflammation and damage via SCFAs and nicotinamide•L. casei Zhang slows the decline of kidney function in individuals with stage 3–5 CKD
Zhu et al. demonstrate that the probiotic L. casei Zhang slows kidney disease progression in mouse models and individuals with chronic kidney disease (CKD) through increasing the levels of short-chain fatty acids and via nicotinamide metabolism, which together modulate the inflammatory response of local macrophages and tubular epithelia cells. These findings suggest a potential therapeutic approach for acute kidney injury and CKD.
Point cloud upsampling has been extensively studied, however, the existing approaches suffer from the losing of structural information due to neglect of spatial dependencies between points. In this ...work, we propose PU-GAT, a novel 3D point cloud upsampling method that leverages graph attention networks to learn structural information over the baselines. Specifically, we first design a local–global feature extraction unit by combining spatial information and position encoding to mine the local spatial inter-dependencies across point features. Then, we construct an up-down-up feature expansion unit, which uses graph attention and GCN to enhance the ability of capturing local structure information. Extensive experiments on synthetic and real data have shown that our method achieves superior performance against previous methods quantitatively and qualitatively.
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•This is the first report of the co-administration of CoronaVac with IIV4 in adults aged 18–59 years.•The occurrence of adverse reactions (AR) in all groups was no more than 20% and 98.9% of the ARs ...were mild or moderate.•Both concomitant or separate administration of CoronaVac and IIV4 could induce sufficient immunogenicity.•A slight interference with the immune response to CoronaVac was observed in participants in C2 subgroup.•At least two doses of CoronaVac are needed to fulfill the primary immunization of inactivated COVID-19 vaccine.
Studies are needed for evidence of inactivated COVID-19 vaccine co-administered with influenza vaccine.
A randomized, open-label, controlled study was conducted in Zhejiang Province, China. Eligible healthy adults aged 18–59 years underwent randomization at a ratio of 1:1:2 to receive inactivated quadrivalent influenza vaccine (IIV4) either concomitantly with the first (C1 subgroup) or the second (C2 subgroup) dose of CoronaVac, or 14 days after the first dose of CoronaVac (S group). The primary purpose of the study was to prove the non-inferiority in seroconversion rate of antibody against SARS-CoV-2.
Overall, 480 participants were enrolled, with 120, 120, and 240 randomly assigned to the C1, C2, and S groups, respectively. As lower bound of the two-sided 95% confidence interval (CI) of the difference for the seroconversion rate of antibodies against SARS-CoV-2 was over −10%, the immune response for CoronaVac in the C group (93.1% 89.0, 96.0) was non-inferior to that in the S group (95.2% 91.5, 97.6) in the per-protocol set. A lower GMT of antibody against SARS-CoV-2 was observed in the C group as compared to the S group (27.5 vs. 38.1, P = 0.0001). Decrease of immune response to CoronaVac was mainly observed in participants received IIV4 concomitantly with their second dose of CoronaVac (C2 subgroup), with a seroconversion rate of 89.7% (95CI: 82.6%-94.5%) and a GMT of 23.3. The occurrences of vaccine related adverse reactions were no more than 20% and comparable among different groups. Most of the adverse reactions were mild and moderate.
Co-administration of inactivated COVID-19 vaccine and seasonal influenza vaccine, especially the administration regimen that the seasonal influenza vaccine co-administered with the first dose of the inactivated COVID-19 vaccine, would be feasible.
Individuals with Down syndrome have a low risk for many solid tumors, prompting the search for tumor suppressor genes on human chromosome 21 (HSA21). We aimed to identify and explore potential ...mechanisms of tumor suppressors on HSA21 in hepatocellular carcinoma (HCC).
We compared expression of HSA21 genes in 14 pairs of primary HCC and adjacent noncancer liver tissues using the Affymetrix HG-U133 Plus 2.0 array (Affymetrix, Santa Clara, CA). HCC tissues and adjacent normal liver tissues were collected from 108 patients at a hospital in China for real-time polymerase chain reaction and immunohistochemical analyses; expression levels of regulator of calcineurin 1 (RCAN1) isoform 4 (RCAN1.4) were associated with clinical features. We overexpressed RCAN1.4 from lentiviral vectors in MHCC97H and HCCLM3 cells and knocked expression down using small interfering RNAs in SMMC7721 and Huh7 cells. Cells were analyzed in proliferation, migration, and invasion assays. HCC cells that overexpressed RCAN1.4 or with RCAN1.4 knockdown were injected into livers or tail veins of nude mice; tumor growth and numbers of lung metastases were quantified. We performed bisulfite pyrosequencing and methylation-specific polymerase chain reaction analyses to analyze CpG island methylation. We measured phosphatase activity of calcineurin in HCC cells.
RCAN1.4 mRNA and protein levels were significantly decreased in primary HCC compared with adjacent noncancer liver tissues. Reduced levels of RCAN1.4 mRNA were significantly associated with advanced tumor stages, poor differentiation, larger tumor size, and vascular invasion. Kaplan-Meier survival analysis showed that patients with HCCs with lower levels of RCAN1.4 mRNA had shorter time of overall survival and time to recurrence than patients whose tumors had high levels of RCAN1.4 mRNA. In HCC cell lines, expression of RCAN1.4 significantly reduced proliferation, migration, and invasive activity. HCC cells that overexpressed RCAN1.4 formed smaller xenograft tumors, with fewer metastases and blood vessels, than control HCC cells. In HCC cells, RCAN1.4 inhibited expression of insulin-like growth factor 1 and vascular endothelial growth factor A by reducing calcineurin activity and blocking nuclear translocation of nuclear factor of activated T cells (NFAT1). HCC cells incubated with the calcineurin inhibitor cyclosporin A had decreased nuclear level of NFAT1. HCC cells had hypermethylation of a CpG island in the 5’ regulatory region of RCAN1.4, which reduced its expression.
RCAN1.4 is down-regulated in HCC tissues, compared with non-tumor liver tissues. RCAN1.4 prevents cell proliferation, migration, and invasion in vitro; overexpressed RCAN1.4 in HCC cells prevents growth, angiogenesis, and metastases of xenograft tumors by inhibiting calcineurin activity and nuclear translocation of NFAT1.
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•Root tuber had accumulated U and Cd, and would pose a health risk if consumed.•Both U and Cd significantly interfered with the mineral nutrient of the roots.•A total of 4865 root ...metabolites were identified using UPLC-MS analysis.•U and Cd induced the expression of plant hormones and cyclic nucleotides.•U and Cd had significant inhibitory effects on the pyrimidine metabolic pathway.
The purpose of this study was to reveal the absorption and interaction mechanisms of uranium (U) & cadmium (Cd) in corps. Purple sweet potato (Ipomoea batatas L.) was selected as the experimental material. The absorption behavior of U and Cd in this crop and the effects on mineral nutrition were analyzed in a pot experiment. The interactions between U and Cd in purple sweet potato were analyzed using UPLC-MS metabolome analysis. The pot experiment confirmed that the root tuber of the purple sweet potato had accumulated U (1.68–5.16 mg kg−1) and Cd (0.78–2.02 mg kg−1) and would pose a health risk if consumed. Both U and Cd significantly interfered with the mineral nutrient of the roots. Metabolomics revealed that a total of 4865 metabolites were identified in roots. 643 (419 up; 224 down), 526 (332 up; 194 down) and 634 (428 up; 214 down) different metabolites (DEMs) were identified in the U, Cd, and U + Cd exposure groups. Metabolic pathway analysis showed that U and Cd induced the expression of plant hormones (the first messengers) and cyclic nucleotides (cAMP and cGMP, second messengers) in cells and regulated the primary/secondary metabolism of roots to induce resistance to U and Cd toxicity.
To examine the effect of the triglyceride-glucose (TyG) index on longitudinal cognitive decline in a healthy middle-aged-to-elderly population.
We conducted a population-based longitudinal study. A ...total of 1774 participants without cognitive impairment were enrolled in the 4-year follow-up. They were divided into four groups according to the quartile of the TyG index. Multivariable-adjusted Cox proportional hazard models were performed to examine the association between the TyG index and cognitive decline. Discrimination tests were used to evaluate the incremental predictive value of the TyG index beyond conventional risk factors.
During the follow-up, compared with those in the bottom quartile group, participants in the top TyG quartile group presented a 51% increase in the risk of cognitive decline (OR 1.51 (95% CI: 1.06-2.14)). As shown by discrimination tests, adding the TyG index into the conventional model resulted in a slight improvement in predicting the risk of cognitive decline (NRI 16.00% (
= 0.004)).
This study demonstrated that increasing values of the TyG index were positively associated with the risk of cognitive decline. Monitoring the TyG index may help in the early identification of individuals at high risk of cognitive deterioration.
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