The clinical value of artificial intelligence in assisting junior radiologists in thyroid ultrasound: a multicenter prospective study from real clinical practice.

BACKGROUND: This study is to propose a clinically applicable 2-echelon (2e) diagnostic criteria for the analysis of thyroid nodules such that low-risk nodules are screened off while only suspicious or indeterminate ones are further examined by histopathology, and to explore whether artificial intelligence (AI) can provide precise assistance for clinical decision-making in the real-world prospective scenario. METHODS: In this prospective study, we enrolled 1036 patients with a total of 2296 thyroid nodules from three medical centers. The diagnostic performance of the AI system, radiologists with different levels of experience, and AI-assisted radiologists with different levels of experience in diagnosing thyroid nodules were evaluated against our proposed 2e diagnostic criteria, with the first being an arbitration committee consisting of 3 senior specialists and the second being cyto- or histopathology. RESULTS: According to the 2e diagnostic criteria, 1543 nodules were classified by the arbitration committee, and the benign and malignant nature of 753 nodules was determined by pathological examinations. Taking pathological results as the evaluation standard, the sensitivity, specificity, accuracy, and area under the receiver operating characteristic curve (AUC) of the AI systems were 0.826, 0.815, 0.821, and 0.821. For those cases where diagnosis by the Arbitration Committee were taken as the evaluation standard, the sensitivity, specificity, accuracy, and AUC of the AI system were 0.946, 0.966, 0.964, and 0.956. Taking the global 2e diagnostic criteria as the gold standard, the sensitivity, specificity, accuracy, and AUC of the AI system were 0.868, 0.934, 0.917, and 0.901, respectively. Under different criteria, AI was comparable to the diagnostic performance of senior radiologists and outperformed junior radiologists (all P < 0.05). Furthermore, AI assistance significantly improved the performance of junior radiologists in the diagnosis of thyroid nodules, and their diagnostic performance was comparable to that of senior radiologists when pathological results were taken as the gold standard (all p > 0.05). CONCLUSIONS: The proposed 2e diagnostic criteria are consistent with real-world clinical evaluations and affirm the applicability of the AI system. Under the 2e criteria, the diagnostic performance of the AI system is comparable to that of senior radiologists and significantly improves the diagnostic capabilities of junior radiologists. This has the potential to reduce unnecessary invasive diagnostic procedures in real-world clinical practice.

Discovery of Ingenane Diterpenoids from Euphorbia hylonoma as Antiadipogenic Agents.

Thirteen new Euphorbia diterpenoids, euphylonanes A-M (1-13), and eight known ones were isolated from the whole plants of Euphorbia hylonoma. Compounds 1 and 2 are two rearranged ingenanes bearing a rare 6/6/7/3-fused ring system. Compound 3 represents the first example of a 9,10-epoxy tigliane, while 4-21 are typical ingenanes varying with substituents. Structures were elucidated using a combination of spectroscopic, computational, and chemical methods. Most ingenanes exerted a significant antiadipogenic effect in 3T3-L1 adipocytes, among which 4 was the most active with an EC50 value of 0.60 ± 0.27 µM. Mechanistic study revealed that 4 inhibited the adipogenesis and lipogenesis in adipocytes via activation of the AMPK signaling pathway.

Effectiveness of Enhanced Recovery After Surgery in the Perioperative Period for Patients with Ureteral Calculi.

Objective: This study aimed to investigate the effectiveness of enhanced recovery after surgery (ERAS) during the perioperative period for patients with ureteral stones. Methods: A total of 105 patients with ureteral stones who underwent holmium laser lithotripsy at our hospital between January 2020 and January 2021 were included in the study. They were randomly divided into two groups using a random number table: the research group (n = 53) received ERAS, while the control group (n = 52) received conventional care. Postoperative recovery parameters were compared between the two groups, including time to mobilization, time to void, time to rehydration, time to remove the urinary catheter, and length of hospital stay. Visual analogue scoring (VAS) scores were assessed at 12, 24, 36, and 48 hours postoperatively. The General Quality of Life Questionnaire (GQOLI-74) scores and complication rates were compared. Results: The research group exhibited significantly shorter postoperative time to mobilization, time to void, time to rehydration, time to remove the urinary catheter, and length of hospital stay compared to the control group (P < .05). VAS scores at 12, 24, 36, and 48 hours postoperatively were significantly lower in the research group than in the control group (P < .05). Furthermore, post-intervention, all GQOLI-74 scores were significantly higher in the research group than in the control group (P < .05). The complication rate in the research group was 5.66% lower than in the control group (25.00% vs. 30.66%, respectively, P < .05). Conclusions: The application of ERAS during the perioperative period for patients with ureteral stones is associated with improved postoperative recovery, reduced postoperative pain, lower complication rates, and enhanced quality of life. These findings suggest that ERAS is a valuable approach to be promoted for clinical use.

A case of esophageal neuromuscular choristoma.

BACKGROUND: Neuromuscular choristoma (NMC) is a rare peripheral nerve lesion that is composed of ectopic mature muscle fibers and nerve fascicles, typically involving major nerve roots or trunks, such as the cranial nerves, brachial plexus, and sciatic nerves. The onset of NMC frequently occurs in the first decade of life. Here, we present the first documented case of a case of esophageal NMC in an adult patient. CASE PRESENTATION: A 46-year-old male patient presented in 2018 with a submucosal tumor of the esophagus. Upon presentation, the tumor was approximately 10 mm in diameter, covered by normal mucosa, and located in the left posterior wall of the esophagus in a position that was 30 cm from the incisor. The tumor was discovered incidentally during gastroscopic examination. In March 2021, endoscopic re-examination revealed no significant changes in the tumor. Endoscopic ultrasound revealed an oval hypoechoic mass with a homogeneous internal echo that originated from the muscularis propria with a maximum cross section of 13 mm × 6 mm. Resection was performed under gastroscopy. The resection specimen was 12 mm × 5 mm in size and was a well-demarcated, elastic, hard, and tough with a gray section. Histologically, the specimen consisted of an abundance of smooth muscle fiber bundles intercalated among nerve fibers, but without malignancy. Immunohistochemical examinations revealed positivity for S-100 protein, caldesmon, NSE and desmin, but negativity for CD117, DOG-1, HMB45, and Melan A. There was also aberrant nuclear localization of beta-catenin. Collectively, these findings led to a diagnosis of esophageal NMC. CONCLUSIONS: NMC is extremely rare, especially esophageal NMC, and is very challenging to accurately diagnose prior to resection. It is important that we can differentiate NMC from other types of tumors.

Pseudolycorine chloride ameliorates Th17 cell-mediated central nervous system autoimmunity by restraining myeloid-derived suppressor cell expansion.

CONTEXT: The alkaloids of Narcissus tazetta L. var. Chinensis Roem (Amaryllidaceae) have antitumor and antiviral activities. However, the immunopharmacological effects of one of its constituents, pseudolycorine chloride (PLY), have not been reported yet. OBJECTIVE: We evaluated the effect of PLY on myeloid-derived suppressor cells (MDSCs) expansion and differentiation into monocyte-like MDSCs (M-MDSCs) and examined whether PLY alleviates Th17 cell-mediated experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis (MS). MATERIALS AND METHODS: In vitro, MDSCs were treated with PLY (0.67, 2 and 6 µM) or solcitinib (10 µM, positive control) for 48 or 96 h, and their proliferation, expansion, and differentiation into M-MDSCs were examined by flow cytometry. Myelin oligodendrocyte glycoprotein (MOG35-55) was used to induce EAE in female C57BL/6 mice, and the mice were treated with 40 mg/kg/d PLY or 1 mg/kg/d FK-506 (tacrolimus, positive control) for 21 days. Inflammatory infiltration, spinal cord demyelination, and MDSCs and Th17 cells infiltration into the spinal cord were examined using haematoxylin and eosin staining, Luxol fast blue staining, and immunofluorescence, respectively. RESULTS: In vitro, PLY (IC50/24 h = 6.18 µM) significantly inhibited IL-6 and GM-CSF-induced MDSCs proliferation, expansion and differentiation into M-MDSCs at all concentrations used. However, these concentrations did not show cytotoxicity. In mice, PLY (40 mg/kg) treatment alleviated EAE and inhibited inflammatory infiltration, demyelination, and MDSCs and Th17 cells infiltration into the spinal cord. DISCUSSION AND CONCLUSIONS: PLY may be an excellent candidate for the treatment of MS and other autoimmune diseases.

A Purified Glucomannan Oligosaccharide from Amorphophallus konjac Improves Colonic Mucosal Barrier Function via Enhancing Butyrate Production and Histone Protein H3 and H4 Acetylation.

A structurally defined konjac glucomannan oligosaccharide (KGMOS) with a relatively high molecular weight and narrow molecular weight distribution (molecular weight ranging from 3000 to 4000 Da, degree of polymerization (dp) 8-11) was prepared from native konjac glucomannan (KGM), and the beneficial effects and molecular mechanisms of KGMOS on colonic functions were investigated in C57BL/6 mice. The results are the first to reveal that KGMOS regulated intestinal microflora composition to facilitate the production of colonic butyrate. Elevated butyrate production further increased the acetylation of histone proteins H3 and H4 and thus enhanced the transcription of the major colonic mucin gene Muc2 and the secretion of mucin elements, which represents a new molecular mechanism of KGM oligosaccharide consumption. The findings indicate that KGM oligosaccharides with specific molecular sizes have highly desirable functional properties and potentially could improve gut health by promoting the barrier function of the colonic mucosa.

Alpinetin inhibits breast cancer growth by ROS/NF-κB/HIF-1α axis.

Alpinetin, the main active ingredient in the Chinese medicinal herb Alpinia katsumadai Hayata, has been found to have anticancer activity. However, the therapeutic efficacy of signalling cascades modulated by alpinetin remains unknown. Here, we showed that alpinetin provoked mitochondria-associated apoptosis in a dose-dependent manner in breast cancer cells. Mechanistic investigations revealed that alpinetin dampens hypoxia-inducible factor-1α (HIF-1α) signalling due to a lack of NF-κB activation through reduced mitochondrial reactive oxygen species (ROS) production, decreasing HIF-1α transcription. In vivo, we also found alpinetin led to significant tumour regression by inhibiting NF-κB pathway. Overall, our work uncovers a ROS/NF-κB/HIF-1α axis-dependent mechanism underlying the anticancer effects of alpinetin and suggests that alpinetin could act as a novel therapeutic agent against breast cancer.

MicroRNA-188-5p promotes apoptosis and inhibits cell proliferation of breast cancer cells via the MAPK signaling pathway by targeting Rap2c.

Breast cancer is a common malignancy that is highly lethal with poor survival rates and immature therapeutics that urgently needs more effective and efficient therapies. MicroRNAs are intrinsically involved in different cancer remedies, but their mechanism in breast cancer has not been elucidated for prospective treatment. The function and mechanism of microRNA-188-5p (miR-188) have not been thoroughly investigated in breast cancer. In our study, we found that the expression of miR-188 in breast cancer tissues was obviously reduced. Our findings also revealed the abnormal overexpression of miR-188 in 4T1 and MCF-7 cells significantly suppressed cell proliferation and migration and also enhanced apoptosis. miR-188 induced cell cycle arrest in the G1 phase. To illuminate the molecular mechanism of miR-188, Rap2c was screened as a single target gene by bioinformatics database analysis and was further confirmed by dual-luciferase assay. Moreover, Rap2c was found to be a vital molecular switch for the mitogen-activated protein kinase signaling pathway in tumor progression by decreasing apoptosis and promoting proliferation and migration. In conclusion, our results revealed that miR-188 is a cancer progression suppressor and a promising future target for breast cancer therapy.

Targeting the ROS/PI3K/AKT/HIF-1α/HK2 axis of breast cancer cells: Combined administration of Polydatin and 2-Deoxy-d-glucose.

It is well established that cancer cells depend upon aerobic glycolysis to provide the energy they need to survive and proliferate. However, anti-glycolytic agents have yielded few positive results in human patients, in part due to dose-limiting side effects. Here, we discovered the unexpected anti-cancer efficacy of Polydatin (PD) combined with 2-deoxy-D-glucose (2-DG), which is a compound that inhibits glycolysis. We demonstrated in two breast cell lines (MCF-7 and 4T1) that combination treatment with PD and 2-DG induced cell apoptosis and inhibited cell proliferation, migration and invasion. Furthermore, we determined the mechanism of PD in synergy with 2-DG, which decreased the intracellular reactive oxygen (ROS) levels and suppressed the PI3K/AKT pathway. In addition, the combined treatment inhibited the glycolytic phenotype through reducing the expression of HK2. HK2 deletion in breast cancer cells thus improved the anti-cancer activity of 2-DG. The combination treatment also resulted in significant tumour regression in the absence of significant morphologic changes in the heart, liver or kidney in vivo. In summary, our study demonstrates that PD synergised with 2-DG to enhance its anti-cancer efficacy by inhibiting the ROS/PI3K/AKT/HIF-1α/HK2 signalling axis, providing a potential anti-cancer strategy.

Sodium selenite induces apoptosis via ROS-mediated NF-κB signaling and activation of the Bax-caspase-9-caspase-3 axis in 4T1 cells.

Sodium selenite (SSE), a source of inorganic selenium, has been widely used as a clinical cancer treatment, but the precise molecular mechanisms of SSE remain to be elucidated. Our in vitro experiments have confirmed that SSE treatment causes a transient increase in intracellular reactive oxygen species (ROS) levels, resulting in the inhibition of nuclear transcription factor-κB (NF-κB) signaling and p65 and nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha phosphorylation levels in 4T1 cells. The inhibition of NF-κB subsequently increased the expression of the apoptosis gene B-cell lymphoma-2-associated X (Bax) and downregulated the transcription of antiapoptosis genes, such as B-cell lymphoma-2, cellular inhibitor of apoptosis 1, and X-linked inhibitor of apoptosis. Additionally, the accumulation of ROS caused mitochondrial dysfunction, leading to the activation of caspase-9 and -3, thereby resulting in apoptosis. However, modulation of the ROS level by the chemical inhibitor N-acetyl-cysteine reversed these events. Similarly, in vitro murine syngeneic breast tumor models showed that SSE inhibits tumor growth by promoting apoptosis. These results indicate that SSE induces apoptosis via ROS-mediated inhibition of NF-κB signaling and activation of the Bax-caspase-9-caspase-3 axis.

The combined effect of serum cystatin C and dyslipidemia on hypertension in a large health check-up population in China.

OBJECTIVE: Some studies have reported that both serum cystatin C (Cys C) and dyslipidemia are independently associated with hypertension. However, the combined effect of the two factors is still unknown. The present study was aimed at investigating the effect of Cys C combined with dyslipidemia on hypertension in a large health check-up population in China. METHODS: A total of 203 233 health check-up subjects from January 2011 to July 2016 were recruited into this cross-sectional study. A multivariate logistic regression model was used to evaluate the combined effect of Cys C and dyslipidemia on hypertension.RESULTS: In univariate analysis, Cys C, high-density lipoprotein cholesterol, low-density lipoprotein, total cholesterol, and triglycerides were independently correlated with hypertension (p < 0.001). A concentration-dependent combined effect of serum Cys C and dyslipidemia on hypertension was observed in multivariate regression analysis. When compared with Cys C of <0.82 mg/L, the risk of hypertension in Cys C of <0.82 mg/L with dyslipidemia, Cys C  of 0.82-0.94 mg/L with dyslipidemia, Cys C  of 0.94-1.08 mg/L with dyslipidemia, and Cys C  of ≥1.08 mg/L with dyslipidemia was increased 1.946 (95% confidence interval [CI]: 1.827-2.074), 1.973 (95% CI: 1.864-2.088), 2.047 (95% CI: 1.941-2.158), and 2.038 (95% CI: 1.937-2.143) folds, respectively, after adjustment.CONCLUSION: There was an association between hypertension and the combined effect of Cys C with dyslipidemia.

Hyperoside Induces Breast Cancer Cells Apoptosis via ROS-Mediated NF-κB Signaling Pathway.

Hyperoside (quercetin 3-o-ß-d-galactopyranoside) is one of the flavonoid glycosides with anti-inflammatory, antidepressant, and anti-cancer effects. But it remains unknown whether it had effects on breast cancer. Here, different concentrations of hyperoside were used to explore its therapeutic potential in both breast cancer cells and subcutaneous homotransplant mouse model. CCK-8 and wound healing assays showed that the viability and migration capability of Michigan Cancer Foundation-7 (MCF-7) and 4T1 cells were inhibited by hyperoside, while the apoptosis of cells were increased. Real-time quantitative PCR (qRT-PCR) and western blot analysis were used to detect mRNA and the protein level, respectively, which showed decreased levels of B cell lymphoma-2 (Bcl-2) and X-linked inhibitor of apoptosis (XIAP), and increased levels of Bax and cleaved caspase-3. After exploration of the potential mechanism, we found that reactive oxygen species (ROS) production was reduced by the administration of hyperoside, which subsequently inhibited the activation of NF-κB signaling pathway. Tumor volume was significantly decreased in subcutaneous homotransplant mouse model in hyperoside-treated group, which was consistent with our study in vitro. These results indicated that hyperoside acted as an anticancer drug through ROS-related apoptosis and its mechanism included activation of the Bax-caspase-3 axis and the inhibition of the NF-κB signaling pathway.

[Antibiotic resistance of Helicobacter pylori clinical isolates in Hebei Province].

OBJECTIVE: To evaluate the resistance of Helicobacter pylori (H.pylori) clinical isolates to various antibiotics, in order to guide rational drug use in Hebei Province. METHODS: From January 2014 to July 2015, 260 patients with H. pylori infection who had not received eradication treatment were enrolled in Third Hospital of Hebei Medical University. Gastric mucosa biopsy tissue samples were collected from these patients before treatment for isolation and culture of H. pylori. Kirby-Bauer method was used to detect drug-resistance rate of the H. pylori clinical isolates to metronidazole, clarithromycin, amoxicillin, levofloxacin, and furazolidone. RESULTS: A total of 155 H. pylori strains were isolated from tissue samples of the 260 patients (positive rate, 59.6%). The drug-resistance rate of H. pylori isolated to metronidazole, clarithromycin, amoxicillin, levofloxacin, and furazolidone was 94.2%(146/155), 21.3%(33/155), 2.6%(4/155), 5.8% (9/155), and 1.9%(3/155), respectively. There was no statistically significant difference in positive culture rate and drug-resistance rate between different sex, age, and disease category(all P>0.05). CONCLUSION: In Hebei Province, the resistance rates of H. pylori to metronidazole and clarithromycin appear to be higher than those to amoxicillin, levofloxacin, and furazolidone.

Design, synthesis, and biological evaluation of 3-phenyl substituted pyridine derivatives as potential dual inhibitors of XOR and URAT1.

Xanthine oxidoreductase (XOR) and uric acid transporter 1 (URAT1) are two most widely studied targets involved in production and reabsorption of uric acid, respectively. Marketed drugs almost target XOR or URAT1, but sometimes, single agents might not achieve aim of lowering uric acid to ideal value in clinic. Thus, therapeutic strategies of combining XOR inhibitors with uricosuric drugs were proposed and implemented. Based on our initial work of virtual screening, A and B were potential hits for dual-targeted inhibitors on XOR/URAT1. By docking A/B with XOR/URAT1 respectively, compounds I1-7 were designed to get different degree of inhibition effect on XOR and URAT1, and I7 showed the best inhibitory effect on XOR (IC50 = 0.037 ± 0.001 µM) and URAT1 (IC50 = 546.70 ± 32.60 µM). Further docking research on I7 with XOR/URAT1 led to the design of compounds II with the significantly improved inhibitory activity on XOR and URAT1, such as II11 and II15. Especially, for II15, the IC50 of XOR is 0.006 ± 0.000 µM, superior to that of febuxostat (IC50 = 0.008 ± 0.000 µM), IC50 of URAT1 is 12.90 ± 2.30 µM, superior to that of benzbromarone (IC50 = 27.04 ± 2.55 µM). In acute hyperuricemia mouse model, II15 showed significant uric acid lowering effect. The results suggest that II15 had good inhibitory effect on XOR/URAT1, with the possibility for further investigation in in-vivo models of hyperuricemia.

Effect of acupuncture on Hashimoto thyroiditis: A systematic review and meta-analysis.

BACKGROUND: Hashimoto thyroiditis (HT) is a common autoimmune thyroid disease for which there is no specific treatment. Oral levothyroxine sodium tablets significantly improved thyroid function but did not promote a reduction in thyroid-related antibody concentrations. Acupuncture can improve clinical symptoms and thyroid function in HT patients, reduce serum TPOAb and TGAb levels in HT patients, and improve patients' quality of life. METHODS: We conducted a systematic review and meta-analysis to evaluate the effect of acupuncture versus levothyroxine sodium tablets on Hashimoto thyroiditis. We searched Web of Science, Embase, China National Knowledge Infrastructure, WanFang, VIP, SinoMed and the Cochrane Central Registry of Controlled Trials to identify candidate randomized controlled trials (RCTs). RESULTS: A total of 1020 patients participated in 14 randomized controlled trials. The results of meta-analysis showed that acupuncture regulated TPOAb content (mean difference [MD] = -63.18, 95%CI = -91.73 to -34.62, P < .00001), TGAb content (MD = -68.56, 95%CI = -101.55 to -35.57, P < .00001), serum free triiodothyronine (FT3) content (MD = 0.74, 95%CI = 0.20 to 1.27, P < .00001), serum free thyroxine (FT4) content (MD = 1.10, 95%CI = 0.29 to 1.92, P < .00001), TSH content (MD = -2.16, 95%CI = -3.14 to -1.19, P < .00001) had a significant effect. CONCLUSION: Compared with levothyroxine sodium tablets alone, acupuncture can significantly regulate the contents of TPOAb, TGAb, FT3, FT4 and TSH.

Talaesthanes A-C, three new meroterpenoids from the endophytic fungus Talaromyces primulinus H21.

Three new meroterpenoids (1-3) and ten known ones (4-13) were obtained from the endophytic fungus Talaromyces primulinus H21 isolated from the plant of Euphorbia sikkimensis. Their structures including their absolute configurations were elucidated by extensive analysis of spectroscopic data such as HR-ESI-MS, 1D/2D NMR, and X-ray diffraction of single crystal together with comparison of experimental ECD with calculated ECD. All compounds were examined for their inhibitory effects on nitric oxide (NO) production induced by lipopolysaccharide (LPS) in RAW264.7 cells, and compounds 3, 9, 12, and 13 exhibited certain inhibition on NO production, with IC50 values of 27.19, 41.55, 25.23, and 24.71 µM, respectively.

The influence of perioperative nursing intervention in patients with ureteral calculi treated with URSL and its correlation to adverse event incidence: A retrospective study.

To evaluate the effectiveness of perioperative nursing intervention in patients undergoing ureteroscopic lithotripsy (URSL) for ureteral stones and its implications for the incidence of adverse events, a total of 144 patients with ureteral stones admitted to our hospital from January 2021 to December 2022 were selected for retrospective analysis. They were divided into 2 groups based on their different nursing methods, with 72 patients in each group. The control group (CG) received routine nursing intervention, while the study group (SD) received refined perioperative nursing intervention. The surgical situation, effective stone removal rate, postoperative pain, inflammatory factors, stress response, and incidence of adverse events were compared between the 2 groups. In comparison with the CG, the SD demonstrated a significant reduction in gastrointestinal recovery time, urinary catheter removal time, and hospitalization duration, all presenting statistically significant disparities (P < .05). Notably, the SD exhibited a one-time stone removal rate significantly superior to that of the CG (P < .05). Similarly, the postoperative pain index was significantly lower in the SD (P < .05). Pre- and post-surgical serotonin (5-HT) levels in the SD were markedly lower than in the CG (P < .05). Postoperative levels of Interleukin-10 (IL-10), C-reactive protein (CRP), and white blood cells (WBC) were elevated in both groups, and gradually declined as the patients recovered. However, postoperative levels of IL-10, CRP, and WBC were significantly lower in the SD (P < .05). The SD also showed significantly lower levels of malondialdehyde and higher levels of superoxide dismutase (P < .05). Postoperative levels of cortisol, adrenocorticotropic hormone, and norepinephrine were elevated and progressively returned to normal over time, and were significantly lower in the study group (P < .05). Furthermore, the SD experienced a significant reduction in adverse event incidence compared with the CG (P < .05). Implementing refined perioperative nursing interventions for patients undergoing URSL can effectively decrease the incidence of adverse events, diminish the surgical stimulation of inflammation markers and oxidative stress indicators, and foster patient recovery.

COL5A2 is a prognostic-related biomarker and correlated with immune infiltrates in gastric cancer based on transcriptomics and single-cell RNA sequencing.

BACKGROUND: There is still a therapeutic challenge in treating gastric cancer (GC) due to its high incidence and poor prognosis. Collagen type V alpha 2 (COL5A2) is increased in various cancers, yet it remains unclear how it contributes to the prognosis and immunity of GC. METHODS: The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets were used to download transcriptome profiling (TCGA-STAD; GSE84437), single-cell RNA sequencing (scRNA-seq) data (GSE167297) and clinical information. COL5A2 expression and its relationship with clinicopathological factors were analyzed. We conducted survival analysis and Cox regression analysis to evaluate the prognosis and independent factors of GC. Co-expressed analysis was also performed. To identify the underlying mechanism, we conducted analyses of differentially expressed genes (DEGs) and functional enrichment. The correlations between COL5A2 expression and immune cell infiltration levels and immune infiltrate gene marker sets were further explored. Additionally, we analyzed the association of COL5A2 expression with immunological checkpoint molecules. Furthermore, the relationship between COL5A2 expression and immunotherapy sensitivity was also investigated. RESULTS: COL5A2 expression was elevated in GC. More than this, the scRNA-seq analysis revealed that COL5A2 expression had a spatial gradient. The upregulated COL5A2 was associated with worse overall survival. A significant correlation was found between COL5A2 overexpression and age, T classification and clinical stage in GC. COL5A2 was found to be an independent factor for the unfortunate outcome in Cox regression analysis. The co-expressed genes of COL5A2 were associated with tumor stage or poor survival. Enrichment analysis revealed that the DEGs were mainly associated with extracellular matrix (ECM)-related processes, PI3K-AKT signaling pathway, and focal adhesion. GSEA analyses revealed that COL5A2 was associated with tumor progression-related pathways. Meanwhile, COL5A2 expression was correlated with tumor-infiltrating immune cells. Moreover, immunophenoscore (IPS) analysis and PRJEB25780 cohorts showed that patients with low COL5A2 expression were highly sensitive to immunotherapy. CONCLUSIONS: COL5A2 might act as a prognostic biomarker of GC prognosis and immune infiltration and may provide a therapeutic intervention strategy.

The potential use and experimental validation of genomic instability-related lncRNA in pancreatic carcinoma.

This study explored the potential role of long noncoding RNA (lncRNAs) associated with genomic instability in the diagnosis and treatment of pancreatic adenocarcinoma (PAAD). Transcriptome and single-nucleotide variation data of PAAD samples were downloaded from the cancer genome atlas database to explore genomic instability-associated lncRNAs. We constructed a genomic instability-associated lncRNA prognostic signature. Then gene ontology and Kyoto encyclopedia of genes and genomes enrichment analyses were used to explore the physiological role of lncRNAs involved in genomic instability. Tumor microenvironments, immunotherapy response, immune cell infiltration, immune checkpoint, and drug sensitivity were compared between high-risk and low-risk groups. In vitro experiments were performed for external validation. Six lncRNAs associated with genomic instability were identified, capable of predicting the prognosis of PAAD. Patients were assigned to low-risk or high-risk groups using these biomarkers, with better or worse prognosis, respectively. The tumor immune score, immune cell infiltration, and efficacy of immunotherapy were worse in the high-risk group. A drug sensitivity analysis revealed the high- and low-risk groups had different half-maximal inhibitory concentrations. The expression of cancer susceptibility candidate 8 was significantly higher in tumor tissues than in normal tissues, while the expression of LYPLAL1-AS1 exhibited an opposite pattern. They may be potential diagnostic or prognostic biomarkers for patients with pancreatic cancer. Genomic instability-associated lncRNAs were explored in this study and predicted the prognosis of PAAD and stratified patients risk in PAAD. These lncRNAs also predicted the efficacy of immunotherapy and potential therapeutic targets in PAAD.

Discovery of a highly potent and orally available importin-ß1 inhibitor that overcomes enzalutamide-resistance in advanced prostate cancer.

Nuclear transporter importin-ß1 is emerging as an attractive target by virtue of its prevalence in many cancers. However, the lack of druggable inhibitors restricts its therapeutic proof of concept. In the present work, we optimized a natural importin-ß1 inhibitor DD1 to afford an improved analog DD1-Br with better tolerability (>25 folds) and oral bioavailability. DD1-Br inhibited the survival of castration-resistant prostate cancer (CRPC) cells with sub-nanomolar potency and completely prevented tumor growth in resistant CRPC models both in monotherapy (0.5 mg/kg) and in enzalutamide-combination therapy. Mechanistic study revealed that by targeting importin-ß1, DD1-Br markedly inhibited the nuclear accumulation of multiple CRPC drivers, particularly AR-V7, a main contributor to enzalutamide resistance, leading to the integral suppression of downstream oncogenic signaling. This study provides a promising lead for CRPC and demonstrates the potential of overcoming drug resistance in advanced CRPC via targeting importin-ß1.