Pleiotropic phenotypic effects of the TaCYP78A family on multiple yield-related traits in wheat.

Increasing crop yield depends on selecting and utilizing pleiotropic genes/alleles to improve multiple yield-related traits (YRTs) during crop breeding. However, synergistic improvement of YRTs is challenging due to the trade-offs between YRTs in breeding practices. Here, the favourable haplotypes of the TaCYP78A family are identified by analysing allelic variations in 1571 wheat accessions worldwide, demonstrating the selection and utilization of pleiotropic genes to improve yield and related traits during wheat breeding. The TaCYP78A family members, including TaCYP78A3, TaCYP78A5, TaCYP78A16, and TaCYP78A17, are organ size regulators expressed in multiple organs, and their allelic variations associated with various YRTs. However, due to the trade-offs between YRTs, knockdown or overexpression of TaCYP78A family members does not directly increase yield. Favourable haplotypes of the TaCYP78A family, namely A3/5/16/17Ap-Hap II, optimize the expression levels of TaCYP78A3/5/16/17-A across different wheat organs to overcome trade-offs and improve multiple YRTs. Different favourable haplotypes have both complementary and specific functions in improving YRTs, and their aggregation in cultivars under strong artificial selection greatly increase yield, even under various planting environments and densities. These findings provide new support and valuable genetic resources for molecular breeding of wheat and other crops in the era of Breeding 4.0.

Improved dual-aggregation polyp segmentation network combining a pyramid vision transformer with a fully convolutional network.

Automatic and precise polyp segmentation in colonoscopy images is highly valuable for diagnosis at an early stage and surgery of colorectal cancer. Nevertheless, it still posed a major challenge due to variations in the size and intricate morphological characteristics of polyps coupled with the indistinct demarcation between polyps and mucosas. To alleviate these challenges, we proposed an improved dual-aggregation polyp segmentation network, dubbed Dua-PSNet, for automatic and accurate full-size polyp prediction by combining both the transformer branch and a fully convolutional network (FCN) branch in a parallel style. Concretely, in the transformer branch, we adopted the B3 variant of pyramid vision transformer v2 (PVTv2-B3) as an image encoder for capturing multi-scale global features and modeling long-distant interdependencies between them whilst designing an innovative multi-stage feature aggregation decoder (MFAD) to highlight critical local feature details and effectively integrate them into global features. In the decoder, the adaptive feature aggregation (AFA) block was constructed for fusing high-level feature representations of different scales generated by the PVTv2-B3 encoder in a stepwise adaptive manner for refining global semantic information, while the ResidualBlock module was devised to mine detailed boundary cues disguised in low-level features. With the assistance of the selective global-to-local fusion head (SGLFH) module, the resulting boundary details were aggregated selectively with these global semantic features, strengthening these hierarchical features to cope with scale variations of polyps. The FCN branch embedded in the designed ResidualBlock module was used to encourage extraction of highly merged fine features to match the outputs of the Transformer branch into full-size segmentation maps. In this way, both branches were reciprocally influenced and complemented to enhance the discrimination capability of polyp features and enable a more accurate prediction of a full-size segmentation map. Extensive experiments on five challenging polyp segmentation benchmarks demonstrated that the proposed Dua-PSNet owned powerful learning and generalization ability and advanced the state-of-the-art segmentation performance among existing cutting-edge methods. These excellent results showed our Dua-PSNet had great potential to be a promising solution for practical polyp segmentation tasks in which wide variations of data typically occurred.

Association of pro-inflammatory diet with increased risk of gallstone disease: a cross-sectional study of NHANES January 2017-March 2020.

Background and aim: Gallstone disease (GSD) is a major public health problem worldwide. The dietary inflammatory index (DII) and the energy-adjusted DII (E-DII) have been used to describe dietary inflammatory potential. The current study sought to investigate the pro-inflammatory role of diet on GSD among outpatients in the United States. Methods: Cross-sectional data from 7,334 individuals older than 20 years who participated in the National Health and Nutrition Examination Survey (NHANES) from January 2017 to March 2020 were obtained. The relationship between GSD and DII was assessed using self-reported data. An association between DII and the risk of GSD was determined using sample-weighted logistic regression and restricted cubic splines (RCS). Subgroup analyzes were conducted to assess the interaction between DII and related factors. Sensitivity analysis was further used to confirm the stability of the relationship. To control for the effect of total energy intake, E-DII was calculated and analyzed. Results: A total of 10.5% of the study participants had GSD. The DII ranged from -5.52 to 5.51, and the median DII was significantly higher for participants with GSD than those without (1.68 vs. 1.23, p < 0.001). There was a significant and stable positive relationship between DII and GSD in adjusted models (OR 1.10, 95% CI 1.00-1.20). In the fully adjusted model, subjects with DII scores in the highest tertile were more likely to have GSD than those in the lowest tertile (OR 1.52, 95% CI 1.19-1.93). An apparent dose-response association between DII and GSD was detected. The association between E-DII and GSD remained stable. Conclusion: Higher DII/E-DII scores linked to the intake of a pro-inflammatory diet were positively associated with a higher risk of GSD. These findings suggest that pro-inflammatory dietary patterns can promote the formation of gallstones.

Identification and characterization of a versatile keratinase, KerZJ, from Stenotrophomonas sp. LMY.

Keratinases have drawn increasing attention in recent decades owing to their catalytic versatility and broad applications from agriculture to medicine. In the present study, we isolated a highly keratinolytic and fibrinolytic bacterium from the campus soil and named it Stenotrophomonas sp. LMY based on genetic information. To identify the potential keratinase genes, the genome sequence of the strain was obtained and analyzed. Sequence alignment and comparison revealed that the protein 1_737 (KerZJ) had the highest sequence homology to a reported keratinase KerBL. We recombinantly expressed KerZJ in Escherichia coli Origami™ (DE) pLysS and purified it to homogeneity. KerZJ showed the highest activity at 40 °C and pH 9.0, and metal ions exhibited no significant effects on its activity. Although reducing agents would break the disulfide bonds in KerZJ and reduce its activity, KerZJ still exhibited the ability to hydrolyze feather keratin in the presence of ß-ME. KerZJ could efficiently digest human prion proteins. In addition, KerZJ showed fibrinolytic activity on fibrin plates and effectively eliminated blood clots in a thrombosis mouse model without side effects. Our results suggest that KerZJ is a versatile keratinase with significant potential for keratin treatment, decontamination of prions, and fibrinolytic therapy.

Construction and validation of a novel senescence-related risk score can help predict the prognosis and tumor microenvironment of gastric cancer patients and determine that STK40 can affect the ROS accumulation and proliferation ability of gastric cancer cells.

Background: In recent years, significant molecules have been found in gastric cancer research. However, their precise roles in the disease's development and progression remain unclear. Given gastric cancer's heterogeneity, prognosis prediction is challenging. This study aims to assess patient prognosis and immune therapy efficacy using multiple key molecules. Method: The WGCNA algorithm was employed to identify modules of genes closely related to immunity. A prognostic model was established using the Lasso-Cox method to predict patients' prognosis. Single-sample gene set enrichment analysis (ssGSEA) was conducted to quantify the relative abundance of 16 immune cell types and 13 immune functions. The relationship between risk score and TMB, MSI, immune checkpoints, and DNA repair genes was examined to predict the effectiveness of immune therapy. GO and KEGG analyses were performed to explore potential pathways and mechanisms associated with the genes of interest. Single-cell RNA sequencing was utilized to investigate the expression patterns of key genes in different cell types. Results: Through the WGCNA algorithm and Lasso-Cox algorithm selected KL, SERPINE1, and STK40 as key genes for constructing the prognostic model. The SSGSEA algorithm was employed to evaluate the infiltration of immune cells and immune functions in different patients, and their association with the risk score was investigated. The high-risk group exhibited lower TMB and MSI compared to the low-risk group. MMR and immune checkpoint analysis revealed a significant correlation between the risk score and multiple molecules. Finally, we also believe that STK40 is the most critical senescence-related gene affecting the progression of gastric cancer. In vitro experiments showed that ROS accumulation and cell proliferation ability of gastric cancer cells were impaired when STK40 was knocked down. Conclusion: In summary, we've constructed a prognostic model utilizing key genes for gastric cancer prognosis, while also showcasing its efficacy in predicting patient response to immunotherapy.

Use of non-canonical amino acids in genetic code expansion-based therapeutics: Effects on mouse gut microbiota.

Vaccines and cell therapeutics based on genetic code expansion are emerging. A crucial step in these therapeutic technologies is the oral administration of non-canonical amino acids (ncAAs) to control pathogen growth and therapeutic protein levels in vivo. Investigating the toxicity effects of ncAAs can help identify more suitable candidates for developing genetic code expansion-based vaccines and cell therapeutics. In this study, we determined the effects of three ncAAs, namely, 4-acetyl-phenylalanine (pAcF), 4-iodo-phenylalanine (pIoF), and 4-methoxy-phenylalanine (pMeoF), commonly used in genetic code expansion-based vaccines and cell therapeutics, on the main organs, serum biochemical parameters, and gut microbiota in mice. We observed that pIoF and pMeoF significantly altered serum biochemical parameters to some extent. Moreover, the alterations in the mouse gut microbial composition were considerably greater after the oral administration of pIoF and pMeoF than after that of pAcF, compared with that in the control mice. These findings suggest that pAcF is more suitable than pIoF and pMeoF for application in genetic code expansion-based vaccines and cell therapeutics as it disturbs the physiological and gut microecological balance in mice to a lesser extent.

The prognostic value and immunological role of angiogenesis-related patterns in colon adenocarcinoma.

Colon adenocarcinoma (COAD) is a malignant tumor with a high mortality rate. Angiogenesis plays a key role in the development and progression of cancer. However, in COAD, studies between angiogenesis and prognosis, immune cell infiltration, and personalized treatment guidance are currently lacking. In the present study, we comprehensively assessed 35 angiogenesis-related genes (ARG) and identified key ARGs affecting OS in COAD patients. The ARG Prognostic Index (ARGPI) was constructed based on a univariate Cox regression model and its prognostic value was evaluated in TCGA-COAD, GSE39582, GSE161158 and TRSJTUSM Cohort. We constructed ARGPI as an independent risk factor for OS in COAD patients and combined with clinical parameters to further construct an ARGPI-based nomogram, which showed a strong ability to predict overall survival in COAD patients. High ARGPI is associated with cancer-related and immune-related biological processes and signaling pathways; high TP53 mutation rate; high infiltration of MSC, pericytes, and stromal cells; and more CMS4 subtype. And low ARGPI benefited more from immune checkpoint inhibitor treatment. In addition, we also predicted the sensitivity of different ARGPI groups to common chemotherapeutic and targeted agents. In conclusion, this study constructed an ARGPI based on ARG, which robustly predicted the OS of COAD patients and provided a possible personalized treatment regime for COAD patients.

DLC1 inhibits colon adenocarcinoma cell migration by promoting secretion of the neurotrophic factor MANF.

DLC1 (deleted in liver cancer-1) is downregulated or deleted in colorectal cancer (CRC) tissues and functions as a potent tumor suppressor, but the underlying molecular mechanism remains elusive. We found that the conditioned medium (CM) collected from DLC1-overexpressed SW1116 cells inhibited the migration of colon adenocarcinoma cells HCT116 and SW1116, but had no effect on proliferation, which suggested DLC1-mediated secretory components containing a specific inhibitor for colon adenocarcinoma cell migration. Analysis by mass spectrometry identified mesencephalic astrocyte-derived neurotrophic factor (MANF) as a candidate. More importantly, exogenous MANF significantly inhibited the migration of colon adenocarcinoma cells HCT116 and SW1116, but did not affect proliferation. Mechanistically, DLC1 reduced the retention of MANF in ER by competing the interaction between MANF and GRP78. Taken together, these data provided new insights into the suppressive effects of DLC1 on CRC, and revealed the potential of MANF in the treatment of CRC.

Value of Artificial Neural Network Ultrasound in Improving Breast Cancer Diagnosis.

Ultrasound-guided needle biopsy based on artificial neural network, as a safe, effective, and simple preoperative pathological diagnosis technique, has been widely used in clinical practice. Ultrasound-guided needle biopsy based on artificial neural networks for suspicious breast lesions found in conventional ultrasound examinations is an effective method for preoperative diagnosis. The purpose of this article is to study the value of artificial neural network ultrasound in improving breast cancer diagnosis. This article summarizes the neuron model of PCNN by observing and studying its impulse synchronization phenomenon. Aiming at gray-scale images disturbed by mixed noise (impulse noise and the Gaussian noise), a comprehensive filtering algorithm based on the simplified PCNN model is proposed. In this paper, the benign and malignant breast masses were evaluated based on the two-dimensional and three-dimensional ultrasound imaging signs of the mass, and compared with the postoperative pathological results, a logistic regression model was established to analyze the shape, boundary, microcalcification, and posterior echo attenuation of the mass, values for keratinization or burrs, convergent signs, and blood flow classification in the differential diagnosis of benign and malignant. In this paper, a color ultrasound diagnostic device is used, Sonobi is used as a contrast medium, and the injection volume is 2.4 ml/dose. During the imaging process, the sound image performance of the lesion is dynamically observed, the original dynamic data are stored throughout the whole process, and the playback analysis is performed after the imaging is completed. Studies have shown that CDUS elastography (UE) combined with MRI can increase the sensitivity of breast cancer diagnosis, with a diagnostic accuracy rate of 92.4%.

Swimming Impedes Intestinal Microbiota and Lipid Metabolites of Tumorigenesis in Colitis-Associated Cancer.

Background: Accumulating data support that regular physical activity potentially inhibits chronic colitis, a risk factor for colitis-associated cancer (CAC). However, possible effects of physical activity on CAC and the underlying mechanisms remain poorly understood. Methods: A pretreatment of swimming on azoxymethane/dextran sodium sulfate (AOM/DSS)-induced CAC mice was implemented to determine its protective effect. Inflammation and tumorigenesis were assessed using colorectums from C57BL/6 mice. In order to determine how swimming alters colonic lipid metabolism and gene expression, a comparative analysis was conducted. Meanwhile, alterations in intestinal microbiota and short-chain fatty acids (SCFAs) were detected and analyzed. Finally, an integration analysis of colonic lipid metabolism with gene expression and intestinal microbiota was performed respectively. Result: Swimming pretreatment relieved bowel inflammation and minimized tumor formation. We demonstrated that prostaglandin E2 (PGE2)/PGE2 receptor 2 subtype (EP2) signaling as a potential regulatory target for swimming induces colonic lipid metabolites. Swimming-induced genera, Erysipelatoclostridium, Parabacteroides, Bacteroides, and Rikenellaceae_RC9_gut_group, induced intestinal SCFAs and affected the function of colonic lipid metabolites enriched in glycerophospholipid metabolism and choline metabolism in cancer. Conclusion: According to our experiments, swimming pretreatment can protect mice from CAC by intervention in the possible link between colonic lipid metabolites and PGE2/EP2 signaling. Further, swimming-induced genera and probiotics promoted glycerophospholipid metabolism and choline metabolism in cancer, the major constituents of colonic lipid metabolites, and increased SCFAs, which were also important mechanisms for the anti-inflammatory and anti-tumorigenic effects of swimming.

The long-circulating effect of pegylated nanoparticles revisited via simultaneous monitoring of both the drug payloads and nanocarriers.

The long-circulating effect is revisited by simultaneous monitoring of the drug payloads and nanocarriers following intravenous administration of doxorubicin (DOX)-loaded methoxy polyethylene glycol-polycaprolactone (mPEG-PCL) nanoparticles. Comparison of the kinetic profiles of both DOX and nanocarriers verifies the long-circulating effect, though of limited degree, as a result of pegylation. The nanocarrier profiles display fast clearance from the blood despite dense PEG decoration; DOX is cleared faster than the nanocarriers. The nanocarriers circulate longer than DOX in the blood, suggesting possible leakage of DOX from the nanocarriers. Hepatic accumulation is the highest among all organs and tissues investigated, which however is reversely proportionate to blood circulation time. Pegylation and reduction in particle size prove to extend circulation of drug nanocarriers in the blood with simultaneous decrease in uptake by various organs of the mononuclear phagocytic system. It is concluded that the long-circulating effect of mPEG-PCL nanoparticles is reconfirmed by monitoring of either DOX or the nanocarriers, but the faster clearance of DOX suggests possible leakage of a fraction of the payloads. The findings of this study are of potential translational significance in design of nanocarriers towards optimization of both therapeutic and toxic effects.

A prospective cohort study of the relationship between the withdrawal time and the detection rate of colorectal adenoma.

BACKGROUND AND AIMS: The effect of colonoscopy withdrawal time (WT) beyond 6 min on colorectal adenoma detection rate (ADR) is unclear. We focused on the relationship between WT and ADR. MATERIALS AND METHODS: This study was a prospective observational study involving 437 patients who underwent colonoscopy at Tongren Hospital in Shanghai from 1 July 2020 to 31 August 2020. Patients were divided into two groups according to whether the WT was >6 min. Age, sex, body mass index (BMI), defoaming rate score, Boston bowel preparation scale (BBPS), primary colonoscopy, hypertension, diabetes mellitus, dietary preparation 1 day before the examination, and abdominal surgery history factors were analysed by univariate and multivariable logistic regression to explore the odds ratios (ORs) of ADR in two WT groups. Restricted cubic spline regression was used to further analyze the relationship between WT and the ORs of adenoma detection. RESULTS: The ADR among 437 patients was 17.16% (75/437). Multivariable regression analysis showed that in the group with WT >6 min, patients aged ≥50 years old and male could have an increased risk of adenoma detection (OR 5.80, 95% CI 2.32-14.47; p < .001; OR 2.30, 95% CI 1.19-4.43; p = .013). The cubic spline curve showed that the ADR increased with time for WT of 6-8 min, and the highest ADR was achieved when the WT was controlled at 8 min (WT = 5.997, OR = 0.997; WT = 8.240 min, OR = 3.092). CONCLUSION: The highest ADR was achieved when the WT of colonoscopy was controlled at 8 min.

TaKLU Plays as a Time Regulator of Leaf Growth via Auxin Signaling.

The growth of leaves is subject to strict time regulation. Several genes influencing leaf growth have been identified, but little is known about how genes regulate the orderly initiation and growth of leaves. Here, we demonstrate that TaKLU/TaCYP78A5 contributes to a time regulation mechanism in leaves from initiation to expansion. TaKLU encodes the cytochrome P450 CYP78A5, and its homolog AtKLU has been described whose deletion is detrimental to organ growth. Our results show that TaKLU overexpression increases leaf size and biomass by altering the time of leaf initiation and expansion. TaKLU-overexpressing plants have larger leaves with more cells. Further dynamic observations indicate that enlarged wheat leaves have experienced a longer expansion time. Different from AtKLU inactivation increases leaf number and initiation rates, TaKLU overexpression only smooths the fluctuations of leaf initiation rates by adjusting the initiation time of local leaves, without affecting the overall leaf number and initiation rates. In addition, complementary analyses suggest TaKLU is functionally conserved with AtKLU in controlling the leaf initiation and size and may involve auxin accumulation. Our results provide a new insight into the time regulation mechanisms of leaf growth in wheat.

Analysis of transcript-wide profile regulated by microsatellite instability of colorectal cancer.

Background: Microsatellite instability-high (MSI-H) is a form of genomic instability present in 15% of colorectal cancer (CRC) cases. Several differential gene analyses have been conducted on CRC; however, none have specifically explored the differentially expressed genes in MSI-H CRC. Research on the different gene expressions between MSI-H CRC and microsatellite stable (MSS) CRC, and their different patterns of metastasis will provide invaluable insights for diagnosis, prognosis, and treatment. Methods: In this study, the differential expression of 46,602 genes were analyzed across 613 different tissue samples from The Cancer Genome Atlas (TCGA)-colon adenocarcinoma (COAD) and TCGA-rectum adenocarcinoma (READ) as part of a gene association analysis. R package TCGAbiolinks (version 2.18.0) was used to download the data set, and DESeq2 (version 1.30.1) was used for the differential gene analysis. The resulting genes were then analyzed for shared pathways with R package clusterProfiler (version 3.0.4). Results: A total of 237 significantly differentially expressed genes (Padj<0.05) were found between MSI-H and MSS CRC. Differentially expressed genes include insulin like growth factor 2 (IGF2) and fibroblast growth factor 3 (FGF3), and the enriched pathways mostly involve hearing, digestive regulation, and neurogenesis.463 differentially expressed genes were found between metastatic and non-metastatic CRC. Notably differentially expressed genes in metastatic CRC include DEAD-box helicase 53 (DDX53) and adiponectin, C1Q and collagen domain containing (ADIPOQ), and enriched pathways include the immune system, cell adhesion, and cell signaling. For MSI-H CRC, a total of 34 genes were significantly differently expressed between metastatic and non-metastatic CRC. These include notum, palmitoleoyl-protein carboxylesterase (NOTUM), serpin family B member 2 (SERPINB2), and several keratin (KRT) genes, and the pathway analysis showed the major enrichment of the hormonal and secretion and regulation pathways. Of the differentially expressed genes in metastatic CRC, 25 were immunity related and include fatty acid binding protein 4 (FABP4), and the pathway analysis showed the enrichment of humoral immunity and lymphocyte regulation. Conclusions: Of the biologically plausible differentially expressed genes, the most notable were NOTUM, KRT6A, KRT14, SERPINB2, and serum amyloid A1 (SAA1). NOTUM, KRT6A, and KRT14 are active in the Wnt pathway. All five are also involved in various inflammation pathways.

Ajuba transactivates N-cadherin expression in colorectal cancer cells through interaction with Twist.

Ajuba is a multiple LIM domain-containing protein and functions as a transcriptional coregulator to modulate many gene expressions in various cellular processes. Here, we describe that the LIM domain of Ajuba interacts with Twist, and the Twist box is a pivotal motif for the interaction. Biologically, Ajuba enhances transcription of target gene N-cadherin as an obligate coactivator of Twist. The enhancement is achieved by binding to the E-box element within N-cadherin promoter as revealed by luciferase reporter and chromatin immunoprecipitation assays. Mechanistic investigation demonstrates that Ajuba recruits CBP and Twist to form a ternary complex at the Twist target promoter region and concomitantly enhances histone acetylation at these sites. These findings identify that Twist is a new interacting protein of Ajuba and Ajuba/Twist/CBP ternary complex may be a potential treatment strategy for Twist-related tumour metastasis.

Snail enhances arginine synthesis by inhibiting ubiquitination-mediated degradation of ASS1.

Snail is a dedicated transcriptional repressor and acts as a master inducer of EMT and metastasis, yet the underlying signaling cascades triggered by Snail still remain elusive. Here, we report that Snail promotes colorectal cancer (CRC) migration by preventing non-coding RNA LOC113230-mediated degradation of argininosuccinate synthase 1 (ASS1). LOC113230 is a novel Snail target gene, and Snail binds to the functional E-boxes within its proximal promoter to repress its expression in response to TGF-ß induction. Ectopic expression of LOC113230 potently suppresses CRC cell growth, migration, and lung metastasis in xenograft experiments. Mechanistically, LOC113230 acts as a scaffold to facilitate recruiting LRPPRC and the TRAF2 E3 ubiquitin ligase to ASS1, resulting in enhanced ubiquitination and degradation of ASS1 and decreased arginine synthesis. Moreover, elevated ASS1 expression is essential for CRC growth and migration. Collectively, these findings suggest that TGF-ß and Snail promote arginine synthesis via inhibiting LOC113230-mediated LRPPRC/TRAF2/ASS1 complex assembly and this complex can serve as potential target for the development of new therapeutic approaches to treat CRC.

A KLF4/PiHL/EZH2/HMGA2 regulatory axis and its function in promoting oxaliplatin-resistance of colorectal cancer.

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.

Effect of particle size on the pharmacokinetics and biodistribution of parenteral nanoemulsions.

This study aims to investigate the effect of particle size on the pharmacokinetics and biodistributions of parenteral blank nanoemulsions (NEs). To monitor intact NEs in vivo, a near-infrared fluorescent dye is utilized to label NEs by exploiting its aggregation-caused quenching (ACQ) properties. After a single intravenous dose of NEs with mean sizes of 70, 200, 500 and 900 nm is administered to rats, the pharmacokinetic profiles are plotted based on semiquantification of the NE particles in blood by monitoring particle-bound fluorescence. All NE groups are cleared from the blood rapidly in a size-dependent manner. Reductions in particle size lead to prolonged residence times in blood which indicates size-dependent effect on the circulation time. Live imaging reveals pervasive distribution of NEs throughout the body in rats with an apparent size-dependency. Ex vivo bioimaging demonstrates the dynamic biodistribution of NEs in different organs and tissues with different patterns. The smallest NEs (70 nm) are prone to be taken up gradually by the liver, whereas the larger NEs are distributed in greater amounts in the spleen and lungs. The distribution in other tissues and organs is quite low. It is concluded that reductions in particle size lead to enhanced circulatory residence and hepatic exposure of NEs.

Long noncoding RNA PiHL regulates p53 protein stability through GRWD1/RPL11/MDM2 axis in colorectal cancer.

We identified a novel long noncoding RNA (lncRNA) upregulated in colorectal cancer (CRC). We elucidated its role and clinical significance in CRC carcinogenesis. Methods: LncRNA candidates were identified using TCGA database. LncRNA expression profiles were studied by qRT-PCR and microarray in paired tumor and normal tissues. The independence of the signature in survival prediction was evaluated by multivariable Cox regression analysis. The mechanisms of lncRNA function and regulation in CRC were examined using molecular biological methods. Results: We identified a novel long noncoding gene (PiHL, P53 inHibiting LncRNA) from 8q24.21 as a p53 negative regulator. PiHL is drastically upregulated in CRC and is an independent predictor of CRC poor prognosis. Further in vitro and in vivo models demonstrated that PiHL was crucial in maintaining cell proliferation and inducing 5-FU chemoresistance through a p53-dependent manner. Mechanistically, PiHL acts to promote p53 ubiquitination by sequestering RPL11 from MDM2, through enhancing GRWD1 and RPL11 complex formation. We further show that p53 can directly bind to PiHL promoter and regulating its expression. Conclusion: Our study illustrates how cancer cells hijack the PiHL-p53 axis to promote CRC progression and chemoresistance. PiHL plays an oncogenic role in CRC carcinogenesis and is an independent prognostic factor as well as a potential therapeutic target for CRC patients.

Long noncoding RNA CCAL transferred from fibroblasts by exosomes promotes chemoresistance of colorectal cancer cells.

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 ß-catenin pathway in vitro and in vivo. Mechanistically, CCAL interacts directly with mRNA stabilizing protein HuR (human antigen R) to increase ß-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.