PITPNC1 Suppress CD8+ T cell immune function and promote radioresistance in rectal cancer by modulating FASN/CD155.

BACKGROUND: Radioresistance is a primary factor contributing to the failure of rectal cancer treatment. Immune suppression plays a significant role in the development of radioresistance. We have investigated the potential role of phosphatidylinositol transfer protein cytoplasmic 1 (PITPNC1) in regulating immune suppression associated with radioresistance. METHODS: To elucidate the mechanisms by which PITPNC1 influences radioresistance, we established HT29, SW480, and MC38 radioresistant cell lines. The relationship between radioresistance and changes in the proportion of immune cells was verified through subcutaneous tumor models and flow cytometry. Changes in the expression levels of PITPNC1, FASN, and CD155 were determined using immunohistochemistry and western blotting techniques. The interplay between these proteins was investigated using immunofluorescence co-localization and immunoprecipitation assays. Additionally, siRNA and lentivirus-mediated gene knockdown or overexpression, as well as co-culture of tumor cells with PBMCs or CD8+ T cells and establishment of stable transgenic cell lines in vivo, were employed to validate the impact of the PITPNC1/FASN/CD155 pathway on CD8+ T cell immune function. RESULTS: Under irradiation, the apoptosis rate and expression of apoptosis-related proteins in radioresistant colorectal cancer cell lines were significantly decreased, while the cell proliferation rate increased. In radioresistant tumor-bearing mice, the proportion of CD8+ T cells and IFN-γ production within immune cells decreased. Immunohistochemical analysis of human and animal tissue specimens resistant to radiotherapy showed a significant increase in the expression levels of PITPNC1, FASN, and CD155. Gene knockdown and rescue experiments demonstrated that PITPNC1 can regulate the expression of CD155 on the surface of tumor cells through FASN. In addition, co-culture experiments and in vivo tumor-bearing experiments have shown that silencing PITPNC1 can inhibit FASN/CD155, enhance CD8+ T cell immune function, promote colorectal cancer cell death, and ultimately reduce radioresistance in tumor-bearing models. CONCLUSIONS: PITPNC1 regulates the expression of CD155 through FASN, inhibits CD8+ T cell immune function, and promotes radioresistance in rectal cancer.

Catalyst-free decarboxylative cross-coupling of N-hydroxyphthalimide esters with tert-butyl 2-(trifluoromethyl)acrylate and its application.

Here, we demonstrate a practical method toward the facile synthesis of CF3-containing amino acids through visible light promoted decarboxylative cross-coupling of a redox-active ester with tert-butyl 2-(trifluoromethyl)acrylate. The reaction was driven by the photochemical activity of electron donor-acceptor (EDA) complexes that were formed by the non-covalent interaction between a Hantzsch ester and a redox-active ester. The advantages of this protocol are its synthetic simplicity, rich functional group tolerance, and a cost-effective reaction system.

Catalyst-free inverse-electron-demand aza-Diels-Alder reaction of 4,4-dicyano-2-methylenebut-3-enoates and 1,3,5-triazinanes: access to polysubstituted tetrahydropyridines.

An inverse-electron-demand aza-Diels-Alder reaction between 4,4-dicyano-2-methylenebut-3-enoates and 1,3,5-triazinanes under catalyst-free and additive-free conditions was developed, which provided a highly convenient and straightforward method to construct a series of polyfunctionalized tetrahydropyridines in high yields. This strategy features numerous advantages, including high efficiency, good functional group tolerance, broad substrate scope, and environmentally friendly conditions.

Mucormycosis-induced upper gastrointestinal ulcer perforation in immunocompetent patients: a report of two cases.

BACKGROUND: Gastrointestinal mucormycosis (GIM) is a rare, opportunistic fungal infection with poor prognosis. Clinically, it is difficult to diagnose GIM owing to its nonspecific clinical symptoms and poor suspicion. The estimated incidence of GIM is inaccurate, and most cases are diagnosed accidentally during surgery or upon postmortem examination. GIM usually occurs in patients with immune deficiencies or diabetes. Here, we report two cases of immunocompetent young patients with GIM who had good prognosis after treatment. Compared to other case reports on GIM, our cases had unusual infection sites and no obvious predisposing factors, which make it important to highlight these cases. CASE PRESENTATION: The first case was that of a 16-year-old immunocompetent boy who was admitted with gastrointestinal bleeding and perforation due to a gastric ulcer. Strategies used to arrest bleeding during emergency gastroscopy were unsuccessful. An adhesive mass was then discovered through laparoscopy. The patient underwent type II gastric resection. Pathological examination of the mass revealed bacterial infection and GIM. The second case was of a 33-year-old immunocompetent woman with a recent history of a lower leg sprain. The patient subsequently became critically ill and required ventilatory support. After hemodynamic stabilization and extubation, she presented with hematemesis due to exfoliation and necrosis of the stomach wall. The patient underwent total gastrectomy plus jejunostomy. The pathology results revealed severe bacterial infection and fungal infection that was confirmed as GIM. The patient fully recovered after receiving anti-infective and antifungal treatments. CONCLUSIONS: Neither patient was immunosuppressed, and both patients presented with gastrointestinal bleeding. GIM was confirmed via pathological examination. GIM is not limited to immunocompromised patients, and its diagnosis mainly relies on pathological examination. Early diagnosis, timely surgical treatment, and early administration of systemic drug treatment are fundamental to improving its prognosis.

Identification, Expression and Evolution of Short-Chain Dehydrogenases/Reductases in Nile Tilapia (Oreochromis niloticus).

The short-chain dehydrogenases/reductases (SDR) superfamily is involved in multiple physiological processes. In this study, genome-wide identification and comprehensive analysis of SDR superfamily were carried out in 29 animal species based on the latest genome databases. Overall, the number of SDR genes in animals increased with whole genome duplication (WGD), suggesting the expansion of SDRs during evolution, especially in 3R-WGD and polyploidization of teleosts. Phylogenetic analysis indicated that vertebrates SDRs were clustered into five categories: classical, extended, undefined, atypical, and complex. Moreover, tandem duplication of hpgd-a, rdh8b and dhrs13 was observed in teleosts analyzed. Additionally, tandem duplications of dhrs11-a, dhrs7a, hsd11b1b, and cbr1-a were observed in all cichlids analyzed, and tandem duplication of rdh10-b was observed in tilapiines. Transcriptome analysis of adult fish revealed that 93 SDRs were expressed in more than one tissue and 5 in one tissue only. Transcriptome analysis of gonads from different developmental stages showed that expression of 17 SDRs were sexually dimorphic with 11 higher in ovary and 6 higher in testis. The sexually dimorphic expressions of these SDRs were confirmed by in situ hybridization (ISH) and qPCR, indicating their possible roles in steroidogenesis and gonadal differentiation. Taken together, the identification and the expression data obtained in this study contribute to a better understanding of SDR superfamily evolution and functions in teleosts.

Congenital asplenia due to a tlx1 mutation reduces resistance to Aeromonas hydrophila infection in zebrafish.

It is documented that tlx1, an orphan homeobox gene, plays critical roles in the regulation of early spleen developmental in mammalian species. However, there is no direct evidence supporting the functions of tlx1 in non-mammalian species, especially in fish. In this study, we demonstrated that tlx1 is expressed in the splenic primordia as early as 52 hours post-fertilization (hpf) in zebrafish. A tlx1-/- homozygous mutant line was generated via CRISPR/Cas9 to elucidate the roles of tlx1 in spleen development in zebrafish. In the tlx1-/- background, tlx1-/- cells persisted in the splenic primordia until 52 hpf but were no longer detectable after 53 hpf, suggesting perturbation of early spleen development. The zebrafish also exhibited congenital asplenia caused by the tlx1 mutation. Asplenic zebrafish can survive and breed normally under standard laboratory conditions, but the survival rate of animals infected with Aeromonas hydrophila was significantly lower than that of wild-type (WT) zebrafish. In asplenic zebrafish, the mononuclear phagocyte system was partially impaired, as demonstrated by retarded b7r expression and reduced ccr2 expression after injection with an inactivated A. hydrophila vaccine. Furthermore, the expression of MHCII/IgM was significantly reduced in the congenitally asplenic fish compared with that of the WT zebrafish. Taken together, our data suggest that tlx1 is a crucial regulator of spleen development in fish, as it is in mammals. We have also provided a new perspective for studying the role of the spleen during pathogen challenge in fish.

Study on vibration sensing performance of an equal strength cantilever beam based on an excessively tilted fiber grating.

An equal strength cantilever beam vibration sensor based on an excessively tilted fiber grating (Ex-TFG) with light intensity demodulation is proposed. The basic principles and sensing characteristics of vibration sensing of an equal strength cantilever beam and Ex-TFG, the combination of which is applied into vibration sensing, are analyzed. An Ex-TFG is attached to the middle axis of an equal strength cantilever beam. As the vibration of a piezoelectric ceramic causes the equal strength cantilever beam to deform, the same and uniform deformation also occurs on the Ex-TFG. Experimental results show that when the thickness of the equal strength cantilever beam is 0.3 mm and the Ex-TFG is at transverse electric (TE) polarization state, the sensing performance is the best, with the maximum acceleration sensitivity reaching 81.065 mv·m-1·s2, and the fast Fourier transform (FFT) main frequency components of the sensing signal accounting for more than 80%. In addition, this sensor is stable in sensing performance, easy in demodulation, simple in structure, high in sensitivity, and easy in manufacture, applicable for the sensing and on-line monitoring of low-frequency vibration signals.

Detection of FAM172A expressed in circulating tumor cells is a feasible method to predict high-risk subgroups of colorectal cancer.

Previous studies used to enumerate circulating tumor cells to predict prognosis and therapeutic effect of colorectal cancer. However, increasing studies have shown that only circulating tumor cells enumeration was not enough to reflect the heterogeneous condition of tumor. In this study, we classified different metastatic-potential circulating tumor cells from colorectal cancer patients and measured FAM172A expression in circulating tumor cells to improve accuracy of clinical diagnosis and treatment of colorectal cancer. Blood samples were collected from 45 primary colorectal cancer patients. Circulating tumor cells were enriched by blood filtration using isolation by size of epithelial tumor cells, and in situ hybridization with RNA method was used to identify and discriminate subgroups of circulating tumor cells. Afterwards, FAM172A expression in individual circulating tumor cells was measured. Three circulating tumor cell subgroups (epithelial/biophenotypic/mesenchymal circulating tumor cells) were identified using epithelial-mesenchymal transition markers. In our research, mesenchymal circulating tumor cells significantly increased along with tumor progression, development of distant metastasis, and vascular invasion. Furthermore, FAM172A expression rate in mesenchymal circulating tumor cells was significantly higher than that in epithelial circulating tumor cells, which suggested that FAM172A may correlate with malignant degree of tumor. This hypothesis was further verified by FAM172A expression in mesenchymal circulating tumor cells, which was strictly related to tumor aggressiveness factors. Mesenchymal circulating tumor cells and FAM172A detection may predict highrisk stage II colorectal cancer. Our research proved that circulating tumor cells were feasible surrogate samples to detect gene expression and could serve as a predictive biomarker for tumor evaluation.

[Comparison of different administration routes of saikosaponin in plasma pharmacokinetics and brain pharmacokinetics].

To evaluate the optimum administration routes of saikosaponin in the treatment of epilepsy by comparing the plasma pharmacokinetics and the brain pharmacokinetics after different administration routes of saikosaponin. After receiving saikosaponin in different administration routes, the mice were sacrificed to collect the blood and brain tissues. The acetonitrile and methanol (9∶1) were used to precipitate the plasma protein. The concentration of the SSa in mice plasma and brain was determined by UPLC-MS/MS, and the pharmacokinetic parameters, bioavailability, the brain targeting coefficient (Re) and the brain drug targeting index (DTI) were calculated with Kinetica software. The relative brain Re was 142.17% by intranasal administration, with DTI of 3.06, significantly higher than those by the injections; in addition, the brain DTI was 1.25 by gavage administration. The brain drug targeting of saikosaponin by intranasal administration was higher than that by injection and gavage administration, indicating the advantages of the intranasal administration on medicine absorption into the brain.

CPP2-p16MIS treatment-induced colon carcinoma cell death in vitro and prolonged lifespan of tumor-bearing mice.

BACKGROUND: Cell-penetrating peptides (CPPs) are a research hotspot due to their noninvasive delivery ability. Among the identified CPPs, the TAT and R8 peptides have been preferentially applied to transduction into different cells. However, this process is nonselective among various cells. Recent research suggested that CPP2 could selectively penetrate human colorectal cancer (CRC) cells. METHODS: Using in vitro experiments, the mean fluorescence intensity of fluorescein isothiocyanate-labeled CPPs (CPPs-FITC) incubated with different cell lines was compared to corroborate the colon tumor targeting ability of CPP2. The targeting ability of CPP2 was determined in the same way in tumor-bearing mice. We synthesized antitumor peptides by fusing CPP2 to the minimal inhibitory sequence of p16 (p16MIS), which had the ability to restore the function of lost p16, the expression of which was absent in tumor cell lines of various origins. The antitumor effect of the combined peptide was tested in both CRC cell lines and tumor-bearing mice. RESULTS: In each CRC cell line, the mean fluorescence intensity of CPP2-FITC was higher than that of the TAT-FITC (p < 0.001) and R8-FITC (p < 0.001) groups. CPP2-p16MIS, the targeting carrier, showed a higher antitumor response in the in vitro cell research. CPP2-p16MIS showed a prolonged mean lifespan of tumor-bearing mice, further characterizing its role in specific tumor-targeting ability in vivo. Survival analysis showed that the mice treated with CPP2-p16MIS had significantly longer survival than the mice treated with phosphate-buffered saline (p < 0.05) or those treated with control peptides, including the CPP2 (p < 0.05) and p16MIS (p < 0.05) groups. CONCLUSION: CPP2 could more selectively penetrate CRC cells than TAT or R8 as well as effectively deliver the p16MIS to the tumor.

Burden of ischemic stroke attributable to a high red meat diet in China, 1990-2019: analysis based on the 2019 Global Burden of Disease Study.

Background: The burden of ischemic stroke (IS) linked to high consumption of red meat is on the rise. This study aimed to analyze the mortality and disability-adjusted life years (DALYs) trends for IS attributed to high red meat intake in China between 1990 and 2019 and to compare these trends with global trends. Methods: This study extracted data on IS attributed to diets high in red meat in China from 1990 to 2019 from the Global Burden of Disease Study (GBD) database. Key measures, including mortality, DALYs, age-standardized mortality rates (ASMR), and age-standardized DALYs rates (ASDR), were used to estimate the disease burden. The estimated annual percentage change and joinpoint regression models were employed to assess the trends over time. An age-period-cohort analysis was used to assess the contribution of a diet high in red meat to the age, period, and cohort effects of IS ASMR and ASDR. Results: Between 1990 and 2019, deaths and DALYs from IS attributed to a diet high in red meat in China, along with corresponding age-standardized rates, significantly increased. The overall estimated annual percentage change for the total population and across sex categories ranged from 1.01 to 2.08. The average annual percentage changes for overall ASDR and ASMR were 1.4 and 1.33, respectively, with male ASDR and ASMR average annual percentage changes at 1.69 and 1.69, respectively. Contrastingly, female ASDR and ASMR average annual percentage changes were 1.07 and 0.87, respectively. Except for a few periods of significant decrease in females, all other periods indicated a significant increase or nonsignificant changes. Incidence of IS linked to a diet high in red meat rose sharply with age, displaying increasing period and cohort effects in ASDR. Female ASMR period and cohort effect ratios initially increased and then decreased, whereas the male ratio showed an upward trend. Conclusion: This study comprehensively analyzed epidemiological characteristics that indicated a marked increase in mortality and DALYs from IS attributable to high red meat consumption, contrasting with a global downtrend. This increase was more pronounced in males than females. This research provides valuable insights for enhancing IS prevention in China.

Congenital asplenia impairs heme-iron recycling during erythropoiesis in zebrafish.

The spleen is postulated to be a hematopoietic tissue in adult fish; however, clear evidence is still lacking to define its role in hematopoietic activity. In our previous study, a congenitally asplenic zebrafish was generated though gene editing, which provided a new perspective for studying the role of fish spleen in hematopoiesis. In this study, HSC-regulated and erythrocyte marker genes, such as gata1a, gata2, klf1, hbaa1, hbaa2, hbba1 and hbba2 were significantly reduced in congenitally asplenic zebrafish when compared with wild-type (WT). Subsequently, we conducted the transcriptome profiles of whole kidneys from WT and congenitally asplenic zebrafish to explore the possible molecular mechanisms underlying the impaired erythropoiesis caused by congenital asplenia. Our results demonstrated that congenital asplenia might impair heme-iron recycling during erythropoiesis, as evidenced by significant down-regulation of genes associated with iron acquisition (tfr1a, tfa, steap3 and slc25a37) and heme biosynthesis and transport (alas2, fech, uros, urod, copx, ppox and abcb10) in congenitally asplenic zebrafish. In addition, the down-regulation of hemopoiesis-related GO terms, including heme binding, tetrapyrrole binding, iron ion binding, heme metabolic process, heme biosynthetic process, erythrocyte differentiation, iron ion homeostasis and hemoglobin metabolic process confirmed the impaired erythropoiesis induced by congenital asplenia. Our study provides an in-depth understanding of spleen function in regulating heme-iron homeostasis during hematopoiesis, thereby providing valuable insights into pathological responses in splenectomized or congenitally asplenic patients.

Gut microbiota modulate CD8+ T cell immunity in gastric cancer through Butyrate/GPR109A/HOPX.

The gut microbiota and Short-chain fatty acids (SCFAs) can influence the progression of diseases, yet the role of these factors on gastric cancer (GC) remains uncertain. In this work, the analysis of the gut microbiota composition and SCFA content in the blood and feces of both healthy individuals and GC patients indicated that significant reductions in the abundance of intestinal bacteria involved in SCFA production were observed in GC patients compared with the controls. ABX mice transplanted with fecal microbiota from GC patients developed more tumors during the induction of GC and had lower levels of butyric acid. Supplementation of butyrate during the induction of gastric cancer along with H. pylori and N-methyl-N-nitrosourea (MNU) in WT in GPR109A-/-mice resulted in fewer tumors and more IFN-γ+ CD8+ T cells, but this effect was significantly weakened after knockout of GPR109A. Furthermore, In vitro GC cells and co-cultured CD8+ T cells or CAR-Claudin 18.2+ CD8+ T cells, as well as in vivo tumor-bearing studies, have indicated that butyrate enhanced the killing function of CD8+ T cells or CAR-Claudin 18.2+ CD8+ T cells against GC cells through G protein-coupled receptor 109A (GPR109A) and homologous domain protein homologous box (HOPX). Together, these data highlighted that the restoration of gut microbial butyrate enhanced CD8+ T cell cytotoxicity via GPR109A/HOPX, thus inhibiting GC carcinogenesis, which suggests a novel theoretical foundation for GC management against GC.

A deep learning algorithm with good prediction efficacy for cancer-specific survival in osteosarcoma: A retrospective study.

OBJECTIVE: Successful prognosis is crucial for the management and treatment of osteosarcoma (OSC). This study aimed to predict the cancer-specific survival rate in patients with OSC using deep learning algorithms and classical Cox proportional hazard models to provide data to support individualized treatment of patients with OSC. METHODS: Data on patients diagnosed with OSC from 2004 to 2017 were obtained from the Surveillance, Epidemiology, and End Results database. The study sample was then divided randomly into a training cohort and a validation cohort in the proportion of 7:3. The DeepSurv algorithm and the Cox proportional hazard model were chosen to construct prognostic models for patients with OSC. The prediction efficacy of the model was estimated using the concordance index (C-index), the integrated Brier score (IBS), the root mean square error (RMSE), and the mean absolute error (SME). RESULTS: A total of 3218 patients were randomized into training and validation groups (n = 2252 and 966, respectively). Both DeepSurv and Cox models had better efficacy in predicting cancer-specific survival (CSS) in OSC patients (C-index >0.74). In the validation of other metrics, DeepSurv did not have superiority over the Cox model in predicting survival in OSC patients. CONCLUSIONS: After validation, our CSS prediction model for patients with OSC based on the DeepSurv algorithm demonstrated satisfactory prediction efficacy and provided a convenient webpage calculator.

Distinct Neural Resource Involvements but Similar Hemispheric Lateralization Patterns in Pre-Attentive Processing of Speaker's Identity and Linguistic Information.

The speaker's identity (who the speaker is) and linguistic information (what the speaker is saying) are essential to daily communication. However, it is unclear whether and how listeners process the two types of information differently in speech perception. The present study adopted a passive oddball paradigm to compare the identity and linguistic information processing concerning neural resource involvements and hemispheric lateralization patterns. We used two female native Mandarin speakers' real and pseudo-Mandarin words to differentiate the identity from linguistic (phonological and lexical) information. The results showed that, in real words, the phonological-lexical variation elicited larger MMN amplitudes than the identity variation. In contrast, there were no significant MMN amplitude differences between the identity and phonological variation in pseudo words. Regardless of real or pseudo words, the identity and linguistic variation did not elicit MMN amplitudes differences between the left and right hemispheres. Taken together, findings from the present study indicated that the identity information recruited similar neural resources to the phonological information but different neural resources from the lexical information. However, the identity and linguistic information processing did not show a particular hemispheric lateralization pattern at an early pre-attentive speech perception stage. The findings revealed similarities and differences between linguistic and non-linguistic information processing, contributing to a better understanding of speech perception and spoken word recognition.

MOGS promotes stemness acquisition and invasion via enhancing NOTCH1-glycosylation dependent NOTCH pathway in colorectal cancer.

Colorectal cancer (CRC) ranks as the third most prevalent cancer globally, and about half of CRC patients eventually succumb to tumor metastasis. Despite this, treatment options for metastatic colon cancer remain severely limited, reflected by a 12% 5-year overall survival rate. Increasing evidence suggests that cancer stem cells (CSCs) are pivotal in driving CRC metastasis. Our study found a significant upregulation of MOGS in metastatic colorectal cancer, with high MOGS expression inversely correlating with patient prognosis. Additionally, MOGS enhances the NOTCH pathway, thus promoting stemness in CRC cells, both in vitro and in vivo. Mechanistically, MOGS may facilitate the maturation of NOTCH1 protein by promoting NOTCH1 glycosylation. Correspondingly, silencing MOGS markedly reduced invasion and stemness of CRC cells in vivo. In summary, our findings highlight the critical role of MOGS in fostering stemness and activating the NOTCH pathway in colorectal cancer cells. Disrupting the function of the MOGS/NOTCH could represent a feasible therapeutic strategy for CRC management.

FMO family may serve as novel marker and potential therapeutic target for the peritoneal metastasis in gastric cancer.

Objective: To explore the relationship between flavin-containing monooxygenases (FMOs) and peritoneal metastasis (PM) in gastric cancer (GC). Materials and methods: TIMER 2.0 was used to perform pan-cancer analysis and assess the correlation between the expression of FMOs and cancers. A dataset from The Cancer Genome Atlas (TCGA) was used to analyze the correlation between FMOs and clinicopathological features of GC. PM is well established as the most common mode of metastasis in GC. To further analyze the correlation between FMOs and PM of GC, a dataset was obtained from the National Center for Biotechnology Information Gene Expression Omnibus (GEO) database. The results were validated by immunohistochemistry. The relationship between FMOs and PM of GC was explored, and a novel PM risk signature was constructed by least absolute shrinkage and selection operator (LASSO) regression analysis. The regression model's validity was tested by multisampling. A nomogram was established based on the model for predicting PM in GC patients. The mechanism of FMOs in GC patients presenting with PM was assessed by conducting Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses in TCGA and GEO datasets. Finally, the potential relationship between FMOs and immunotherapy was analyzed. Results: The pan-cancer analysis in TCGA and GEO datasets showed that FMO1 was upregulated, while FMO2 and FMO4 were downregulated in GC. Moreover, FMO1 and FMO2 correlated positively with the T and N stage of GC in the TCGA dataset. FMO1 and FMO2 expression was a risk factor for GC (hazard ratio: 1.112 and 1.185). The overexpression of FMO1 was significantly correlated with worse disease-free-survival (DFS) and overall survival (OS). However, no relationship was found between FMO2 expression in GC and DFS and OS. PM was highly prevalent among GC patients and typically associated with a worse prognosis. FMO1 was highly expressed in GC with PM. FMO1 and FMO2 were positively correlated with PM in GC. We identified a 12-gene panel for predicting the PM risk signature by LASSO (Area Under Curve (AUC) = 0.948, 95%CI: 0.896-1.000). A 10-gene panel for PM prediction was identified (AUC = 0.932, 95%CI: 0.874-0.990), comprising FMO1 and FMO2. To establish a model for clinical application, a 7-gene panel was established (AUC = 0.927, 95% CI: 0.877-0.977) and successfully validated by multisampling. (AUC = 0.892, 95% CI: 0.878-0.906). GO and KEGG analyses suggest that FMO1 and FMO2 regulate the extracellular matrix and cell adhesion. FMO1 and FMO2 were positively correlated with the immune score of GC, and their expression was associated with the infiltration of immune cells. Conclusion: PM in GC is strongly correlated with FMOs. Overall, FMO1 and FMO2 have huge prospects for application as novel diagnostic and therapeutic targets.

Transcriptomics and Metabolomics Identify Drug Resistance of Dormant Cell in Colorectal Cancer.

Background: Tumor dormancy is an important way to develop drug resistance. This study aimed to identify the characteristics of colorectal cancer (CRC) cell dormancy. Methods: Based on the CRC cohorts, a total of 1,044 CRC patients were included in this study, and divided into a dormant subgroup and proliferous subgroup. Non-negative matrix factorization (NMF) was used to distinguish the dormant subgroup of CRC via transcriptome data of cancer tissues. Gene Set Enrichment Analysis (GSEA) was used to explore the characteristics of dormant CRC. The characteristics were verified in the cell model, which was used to predict key factors driving CRC dormancy. Potential treatments for CRC dormancy were also examined. Results: The dormant subgroup had a poor prognosis and was more likely to relapse. GSEA analysis showed two defining characteristics of the dormant subgroup, a difference in energy metabolism and synergistic effects of cancer-associated fibroblasts (CAFs), which were verified in a dormant cell model. Transcriptome and clinical data identified LMOD1, MAB21L2, and ASPN as important factors associated with cell dormancy and verified that erlotinib, and CB-839 were potential treatment options. Conclusion: Dormant CRC is associated with high glutamine metabolism and synergizes with CAFs in 5-FU resistance, and the key effectors are LMOD1, MAB21L2, and ASPN. Austocystin D, erlotinib, and CB-839 may be useful for dormant CRC.

Development and validation of a nomogram to predict B-cell primary thyroid malignant lymphoma-specific survival: A population-based analysis.

B cell primary thyroid malignant lymphoma (BC-PTML) accounts for 95% of all cases of PTML. However, development of effective treatment and management strategies for BC-PTML is challenging owing to the rarity of this disease. This study assessed data from 1,152 patients in the Surveillance, Epidemiology, and End Results (SEER) database who were diagnosed with BC-PTML during 2000-2015. Patients were randomly divided into a training group (n=806) and a test group (n=346) at a ratio of 7:3 using the hold-out method. Kaplan-Meier analysis and log-rank tests were used to calculate the survival rate of patients. Subsequently, a stepwise Cox regression model was established to screen the prognostic factors of patients with BC-PTML, and these variables were used to construct a nomogram to predict 5-, 10-, and 15-year BC-PTML cancer-specific survival (CSS). The discrimination and calibration of the new model were evaluated using the concordance index (C-index) and calibration curves, and the accuracy and benefits of the model were assessed through comparison with the traditional Ann Arbor staging system using decision curve analysis (DCA). After stepwise regression, the optimal model included radiotherapy, primary site surgery, Ann Arbor Stage, chemotherapy, histological subtype, and age at diagnosis. The C-index, area under the receiver operating characteristic curve, and DCA suggested that the nomogram had improved discriminatory ability and clinical benefit compared with the Ann Arbor staging system. In summary, this study established an effective nomogram to predict CSS in patients with BC-PTML and assist clinicians in developing effective individualized treatment strategies.

Effects of miR-939 and miR-376A on ulcerative colitis using a decoy strategy to inhibit NF-κB and NFAT expression.

The aim of this study was to explore the effects of miR-939 and miR-376A on the pathogenesis of ulcerative colitis (UC) by using a decoy strategy to regulate the expression of nuclear transcription factor kappa B (NF-κB) and nuclear factor of activated T cells (NFAT). Such strategies represent a potential novel treatment for UC. Quantitative polymerase chain reaction (qPCR) analysis was used to detect the differences between the expression of miR-939, miR-376a, NF-κB, NFAT in the tissue samples from the resting and active stages of UC and healthy controls, and analyzed the correlation. The electrophoretic mobility shift assay was used to validate the ability of miRNAs to bind to NF-κB and NFAT. The expression of components of the intestinal barrier in UC and changes in apoptosis-related factors were examined by western blotting, qPCR, and immunofluorescence. After a dextran sulfate sodium (DSS)-induced mouse model of UC was established, the morphological changes in the colonic tissues of mice, the changes in serum inflammatory factors, and the changes in urine protein or urine leukocytes, liver enzymes, and prothrombin time were measured to examine intestinal permeability. The expression of miR-939 and miR-376a in human UC tissue was significantly lower than that in the normal control tissue, and was negatively correlated with the expression of NF-κB and NFAT. miR-939 and miR-376a decoy strategies resulted in a beneficial increase in the expression of claudins, occludins, and ZO-1 protein and inhibited apoptosis in intestinal epithelial cells. The disease activity index of the UC model group was significantly higher than that of the normal control group. The expression of inflammatory factors in the decoy group was higher than that in the UC model group. Therefore, from the experimental results, it can be concluded that using miR-939 and miR-376a to trap NF-κB and NFAT inhibits the activation of transcription factors NF-κB and NFAT, which in turn inhibits the expression of inflammatory factors and results in partial recovery of the intestinal barrier in UC. The decoy strategy inhibited apoptosis in the target cells and had a therapeutic effect in the mice model of UC. This study provides new ideas for the development of future clinical therapies for UC.