RFC3 drives the proliferation, migration, invasion and angiogenesis of colorectal cancer cells by binding KIF14.

Colorectal cancer (CRC) is a deadly and aggressive type of cancer that has a high fatality rate. The expression levels of replication factor C subunit 3 (RFC3) and kinesin family member 14 (KIF14) have been reported to be increased in CRC. The current study aimed to explore the effects of RFC3 on the malignant behaviors of CRC cells and its possible underlying mechanism involving KIF14. RFC3 and KIF14 expression levels in CRC tissues were analyzed using TNMplot database and Gene Expression Profiling Interactive Analysis database bioinformatics tools. RFC3 and KIF14 levels in CRC cells were examined using reverse transcription-quantitative PCR and western blotting. Cell Counting Kit-8 and 5-ethynyl-2'-deoxyuridine assays were performed to assess cell proliferation. Cell apoptosis was determined using flow cytometric analysis. Wound healing and Transwell assays were adopted for the evaluation of cell migration and invasion. Tube formation assay in human umbilical vein endothelial cells was used to measure angiogenesis. Western blotting analysis was performed to determine the expression of apoptosis-, migration- and angiogenesis-associated proteins. Additionally, bioinformatics tools predicted the co-expression and interaction of RFC3 and KIF14, which was verified by a co-immunoprecipitation assay. RFC3 displayed elevated expression in CRC tissues and cells, and depletion of RFC3 halted the proliferation, migration, invasion and angiogenesis, while increasing the apoptosis of CRC cells; this was accompanied by changes in the expression levels of related proteins. In addition, RFC3 bound to KIF14 and interference with RFC3 reduced KIF14 expression. Moreover, KIF14 upregulation reversed the effects of RFC3 depletion on the aggressive cellular behaviors in CRC. In conclusion, RFC3 might interact with KIF14 to function as a contributor to the malignant development of CRC.

Mechanism Exploration on the Immunoregulation of Allogeneic Heart Transplantation Rejection in Rats With Exosome miRNA and Proteins From Overexpressed IDO1 BMSCs.

Immunoregulation and indoleamine 2,3-dioxygenase 1 (IDO1) play pivotal roles in the rejection of allogeneic organ transplantation. This study aims to elucidate the immune-related functional mechanisms of exosomes (Exos) derived from bone marrow-derived mesenchymal stem cells (BMSCs) overexpressing IDO1 in the context of allogeneic heart transplantation (HTx) rejection. A rat model of allogeneic HTx was established. Exos were extracted after transfection with oe-IDO1 and oe-NC from rat BMSCs. Exos were administered via the caudal vein for treatment. The survival of rats was analyzed, and reverse transcription qualitative PCR (RT-qPCR) and immunohistochemistry (IHC) were employed to detect the expression of related genes. Histopathological examination was conducted using hematoxylin and eosin (HE) staining, and flow cytometry was utilized to analyze T-cell apoptosis. Proteomics and RNA-seq analyses were performed on Exos. The data were subjected to functional enrichment analysis using the R language. A protein interaction network was constructed using the STRING database, and miRWalk, TargetScan, and miRDB databases predicted the target genes, differentially expressed miRNAs, and transcription factors (TFs). Exos from BMSCs overexpressing IDO1 prolonged the survival time of rats undergoing allogeneic HTx. These Exos reduced inflammatory cell infiltration, mitigated myocardial damage, induced CD4 T-cell apoptosis, and alleviated transplantation rejection. The correlation between Exos from BMSCs overexpressing IDO1 and immune regulation was profound. Notably, 13 immune-related differential proteins (Anxa1, Anxa2, C3, Ctsb, Hp, Il1rap, Ntn1, Ptx3, Thbs1, Hspa1b, Vegfc, Dcn, and Ptpn11) and 10 significantly different miRNAs were identified. Finally, six key immune proteins related to IDO1 were identified through common enrichment pathways, including Thbs1, Dcn, Ptpn11, Hspa1b, Il1rap, and Vegfc. Thirteen TFs of IDO1-related key miRNAs were obtained, and a TF-miRNA-mRNA-proteins regulatory network was constructed. Exosome miRNA derived from BMSCs overexpressing IDO1 may influence T-cell activation and regulate HTx rejection by interacting with mRNA.

TMEM16A inhibits autophagy and promotes the invasion of hypopharyngeal squamous cell carcinoma through mTOR pathway.

Previous studies have indicated that transmembrane protein 16A (TMEM16A) plays a crucial role in the pathogenesis and progression of various tumors by influencing multiple signaling pathways. However, the role of TMEM16A in regulating autophagy via the mammalian target of rapamycin (mTOR) pathway and its impact on the development of hypopharyngeal squamous cell carcinoma (HSCC) remain unclear. Immunohistochemistry and western blotting were used to assess the expression of TMEM16A in HSCC tissues and metastatic lymph nodes. Manipulation of TMEM16A expression levels was achieved in the FaDu cell line through overexpression or knockdown, followed by assessment of its biological effects using cell colony formation, wound healing, transwell, and invasion assays. Additionally, apoptosis and autophagy-related proteins, as well as autophagosome formation, were evaluated through western blotting, transmission electron microscopy, and immunofluorescence following TMEM16A knockdown or overexpression in FaDu cells. Our study revealed significantly elevated levels of TMEM16A in both HSCC tissues and metastatic lymph nodes compared to normal tissues. In vitro experiments demonstrated that silencing TMEM16A led to a notable suppression of HSCC cell proliferation, invasion, and migration. Furthermore, TMEM16A silencing effectively inhibited tumor growth in xenografted mice. Subsequent investigations indicated that knockdown of TMEM16A in HSCC cells could suppress mTOR activation, thereby triggering autophagic cell death by upregulating sequestosome-1 (SQSTM1/P62) and microtubule-associated protein light chain 3 II (LC3II). This study highlights the crucial role of TMEM16A in modulating autophagy in HSCC, suggesting its potential as a therapeutic target for the treatment of this malignancy.

EIF4A3-Bound hsa_circ_0006847 Exerts a Tumor-Suppressive Role in Gastric Cancer.

Numerous studies have shown that circular RNAs are associated with the occurrence and development of various cancers, but the biological functions and mechanisms of hsa_circ_0006847 (circASPHD1) in gastric cancer (GC) remain unclear. The expression of hsa_circ_0006847 in GC cell lines, tissue, and plasma from GC patients was assayed by quantitative real-time reverse transcription-polymerase chain reaction. Hsa_circ_0006847 expression in cells was downregulated or upregulated by transfected small interfering RNA (siRNA) or overexpression plasmid. The role of hsa_circ_0006847 in GC was investigated with Cell Counting Kit-8, EdU, Transwell, flow cytometry assays, and in a subcutaneous xenograft tumor model. In addition, the interaction of eukaryotic translation initiation factor 4A3 (EIF4A3) and hsa_circ_0006847 was determined with western blot, biotin-labeled RNA pull-down, and RNA immunoprecipitation assays. Co-immunoprecipitation and mass spectrometry were used to validate the combination of EIF4A3 and synaptopodin-2 (SYNPO2). The expression of hsa_circ_0006847 was decreased in GC tissues and cells and indicated poor survival and prognosis. Overexpression of hsa_circ_0006847 inhibited cell proliferation, migration, and invasion. Flow cytometry showed that upregulation of hsa_circ_0006847 resulted in promotion of apoptosis of GC cells and inhibited their progression through the G0/G1 phase. Downregulation of hsa_circ_0006847 expression had the opposite effects. Overexpression of hsa_circ_0006847 in subcutaneous tumor xenografts inhibited tumor growth. Mechanically, hsa_circ_0006847 promoted the binding of EIF4A3 to SYNPO2 by recruiting EIF4A3, which inhibited the growth of GC. The tumor suppressor activity of hsa_circ_0006847, inhibition of the occurrence and development of GC, was mediated by promotion of EIF4A3 and the binding of EIF4A3 to SYNPO2. The results support the study of hsa_circ_0006847 as a novel therapeutic target for the treatment of GC.

Circular RNA CircSLC22A23 Promotes Gastric Cancer Progression by Activating HNRNPU Expression.

BACKGROUND: Circular RNAs (CircRNAs) play essential roles in cancer occurrence as regulatory RNAs. However, circRNA-mediated regulation of gastric cancer (GC) remains poorly understood. AIM: The purpose of this study was to investigate the molecular mechanism of circSLC22A23 (hsa_circ_0075504) underlying GC occurrence. METHODS: CircSLC22A23 levels were first quantified by quantitative real-time reverse transcription-polymerase chain reaction in GC cell lines, 80 paired GC tissues and adjacent normal tissues, and 27 pairs of plasma samples from preoperative and postoperative patients with GC. Then circSLC22A23 was knocked-down with short hairpin RNA to analyze its oncogenic effects on the proliferation, migration, and invasion of GC cells. Finally, circRNA-binding proteins and their downstream target genes were identified by RNA pulldown, mass spectrometry, RNA immunoprecipitation, quantitative real-time reverse transcription-polymerase chain reaction, and Western blot assays. RESULTS: CircSLC22A23 was found to be highly expressed in GC cells, GC tissues, and plasma from GC patients. Knockdown of circSLC22A23 inhibited GC cell proliferation, migration and invasion. RNA pulldown and RNA immunoprecipitation assays verified the interaction between circSLC22A23 and heterogeneous nuclear ribonucleoprotein U (HNRNPU). Knockdown of circSLC22A23 decreased HNRNPU protein levels. Moreover, rescue assays showed that the tumor suppressive effect of circSLC22A23 knockdown was reversed by HNRNPU overexpression. Finally, epidermal growth factor receptor (EGFR) was found to be one of the downstream target genes of HNRNPU that was up regulated by circSLC22A23. CONCLUSION: CircSLC22A23 regulated the transcription of EGFR through activation of HNRNPU in GC cells, suggesting that circSLC22A23 may serve as a potential therapeutic target for the treatment of GC.

The therapeutic efficacy and mechanism action of Si Cao formula in the treatment of psoriasis: A pilot clinical investigation and animal validation.

ETHNOPHARMACOLOGICAL RELEVANCE: Psoriasis is a chronic inflammation and relapsing disease that affected approximately 100 million individuals worldwide. In previous clinical study, it was observed that the topical application of Si Cao Formula (SCF) ameliorated psoriasis skin lesions and reduced the recurrence rate of patients over a period of three months. However, the precise mechanism remains unclear. AIM OF THE STUDY: The objective of this study was to assess the effectiveness and safety of SCF in patients diagnosed with psoriasis and explore the molecular mechanisms that contribute to SCF's therapeutic efficacy in psoriasis treatment. MATERIALS AND METHODS: A randomized, controlled, and pilot clinical study was performed. This study assessed 30 individuals diagnosed with mild to moderate plaque psoriasis. 15 of them underwent local SCF treatment, the others received calcipotriol intervention. The outcome measure focused on Psoriasis Area and Severity Index (PASI), Dermatology Life Quality Index (DLQI), and recurrence rate. In addition, IMQ-induced psoriasis-like mice model were used to assess the impact of SCF on ameliorating epidermal hyperplasia, suppressing angiogenesis, and modulating immune response. Furthermore, we performed bioinformatics analysis on transcriptome data obtained from skin lesions of mice model. This analysis allowed us to identify the targets and signaling pathways associated with the action of SCF. Subsequently, we conducted experimental validation to confirm the core targets. RESULTS: Our clinical pilot study demonstrated that SCF could ameliorate skin lesions in psoriasis patients with comparable efficacy of calcipotriol in drop of PASI and DLQI scores. SCF exhibited a significantly reduced recurrence rate within 12 weeks (33.3%). Liquid Chromatography Mass Spectrometry (LC-MS) identified 41 active constituents of SCF (26 cations and 15 anions). Animal experiments showed SCF ameliorates the skin lesions of IMQ-induced psoriasis like mice model and suppresses epidermal hyperkeratosis and angiogenesis. There were 845 up-regulated and 764 down-regulated DEGs between IMQ and IMQ + SCF groups. GO analysis revealed that DEGs were linked to keratinization, keratinocyte differentiation, organic acid transport epidermal cell differentiation, and carboxylic acid transport interferon-gamma production. KEGG pathway analysis showed that SCF may play a vital part through IL-17 and JAK/STAT signaling pathway. In addition, SCF could reduce the number of positive cells expressing PCNA, CD31, pSTAT3, CD3, and F4/80 within the epidermis of psoriatic lesions, as well as the expression of Il-17a and Stat3 in IMQ-induced psoriasis mice. CONCLUSIONS: Our research suggests that SCF serves as a reliable and efficient local approach for preventing and treating psoriasis. The discovery of plausible molecular mechanisms and therapeutic targets associated with SCF may support its broad implementation in clinical settings.

Potent Half-Sandwich 16-/18-Electron Iridium(III) and Ruthenium(II) Anticancer Complexes with Readily Available Amine-Imine Ligands.

The synthesis and biological evaluation of stable 16-electron half-sandwich complexes have remained scarce. We herein present the different coordination modes (16-electron or 18-electron) between half-sandwich iridium(III) complexes and ruthenium(II) complexes derived from the same amine-imine ligands chelating hybrid sp3-N/sp2-N donors. The 16-electron iridium(III) and 18-electron ruthenium(II) complexes with different counteranions were obtained and identified by various techniques. The promising cytotoxicity of these complexes against A549 lung cancer cells, cisplatin-resistant A549/DPP cells, cervical carcinoma HeLa cells, and human hepatocellular liver carcinoma HepG2 cells was observed with IC50 values ranging from 5.4 to 16.3 µM. Moreover, these complexes showed a certain selectivity (selectivity index: 2.1-3.7) toward A549 cells and BEAS-2B normal cells. The variation of metal center, counteranion, 16/18-electron coordination mode, and ligand substituents showed little influence on the cytotoxicity and selectivity of these complexes. The mechanism of action study showed that these complexes could target mitochondria, induce the depolarization of the mitochondrial membrane, and promote the generation of intracellular reactive oxygen species (ROS). Further, the induction of cell apoptosis and the perturbation of the cell cycle in the G0/G1 phase were also observed for these complexes. Overall, it seems that the redox mechanism dominated the anticancer efficacy of these complexes.

pH-Sensitive Biomimetic Nanosystem Based on Large-Pore Mesoporous Silica Nanoparticles with High Hyaluronidase Loading for Tumor Deep Penetration.

Loading hyaluronidase (Hyal) in a nanocarrier is a potent strategy to degrade the tumor extracellular matrix for tumor deep penetration and enhanced tumor therapy. Herein, a pH-sensitive biomimicking nanosystem with high Hyal loading, effective tumor targeting, and controllable release is constructed. Specifically, cationic mesoporous silica nanoparticles (CMSNs) with large pores 13.52 nm in diameter were synthesized in a one-pot manner by adding N-[3-trimethoxysilylpropyl]-N,N,N-trimethylammonium to a reversed microemulsion reaction system. The Hyal loading rate was as high as 19.47% owing to matched pore size and the cationic surface charge. Subsequently, a pH-sensitive biomimetic hybrid membrane (pHH) composed of pH-sensitive liposome (pHL), red blood cell membrane, and pancreatic cancer cell membrane was camouflaged on the pHL-coated and doxorubicin/Hyal-loaded CMSNs (shortened as DHCM). The DHCM@pHL@pHH is stable at neutral pH while it releases the payloads smoothly in the tumor acidic microenvironment. Consequently, it can escape from macrophage clearance, be specifically taken up by pancreatic cancer cells, and efficiently accumulate at the tumor site. More importantly, it can penetrate deeply in pancreatic tumors with a tumor growth inhibition ratio of 80.46%. The nanosystem is biocompatible and has potential for clinical transformation, and the nanocarrier is promisingly applicable as a platform for encapsulation of various macromolecules for smart and tumor-targeted delivery.

Linc-ROR Regulates POU5F1 and SOX2 by Competitively Binding miR-145-5p to Affect the Proliferation and Migration of Gastric Cancer Cells.

Gastric cancer is the third leading cause of cancer-related deaths worldwide, and research on gastric cancer pathogenesis is fundamental. Long intergenic non-coding RNAs (lincRNAs) control cancer initiation and progression through several mechanisms, with the competitive endogenous RNA (ceRNA) regulatory network being the most common. In this study, in situ hybridization revealed that long intergenic non-protein coding RNA-regulator of reprogramming (linc-ROR) was highly expressed in gastric cancer cells and was mainly cytoplasmic-positive. Cell counting kit-8 (CCK-8), plate colony formation, wound healing, and Transwell assay revealed that linc-ROR knockdown impedes the growth, proliferation, and migration of gastric cancer cells, while linc-ROR overexpression promoted gastric cancer cell growth, migration, and colony formation ability. Combined with previous studies, the molecular mechanism axis of linc-ROR/miR-145-5-5p/POU5F1/SOX2 was verified. The expression of linc-ROR knockdown significantly suppressed the protein expression of POU5F1 and SOX2. Co-transfection with linc-ROR siRNA reverses the carcinogenic effect of the miR-145-5p inhibitor on gastric cancer cell proliferation, cloning, and migration. These findings lay a foundation for developing novel targets for gastric cancer treatment.

Increasing global precipitation whiplash due to anthropogenic greenhouse gas emissions.

Precipitation whiplash, including abrupt shifts between wet and dry extremes, can cause large adverse impacts on human and natural systems. Here we quantify observed and projected changes in characteristics of sub-seasonal precipitation whiplash and investigate the role of individual anthropogenic influences on these changes. Results show that the occurrence frequency of global precipitation whiplash is projected to be 2.56 ± 0.16 times higher than in 1979-2019 by the end of the 21st Century, with increasingly rapid and intense transitions between two extremes. The most dramatic increases of whiplash show in the polar and monsoon regions. Changes in precipitation whiplash show a much higher percentage change than precipitation totals. In historical simulations, anthropogenic greenhouse gas (GHG) and aerosol emissions have increased and decreased precipitation whiplash occurrences, respectively. By 2079, anthropogenic GHGs are projected to increase 55 ± 4% of the occurrences risk of precipitation whiplash, which is driven by shifts in circulation patterns conducive to precipitation extremes.

Mechanisms of JinHong Formula on treating sepsis explored by randomized controlled trial combined with network pharmacology.

ETHNOPHARMACOLOGICAL RELEVANCE: JinHong Formula (JHF) was derived from the famous Rhubarb and Moutan Decoction which was prescribed for appendicitis. It was originally recorded in the classic of "Jingui Yaolve" written by Zhang Zhongjing. It is a kind of traditional Chinese medicine, widely used in the treatment of inflammation. However, the clinical effect of JHF for sepsis and its comprehensive mechanism in sepsis remained largely unknown. RESEARCH PURPOSE: The aim of our study was to evaluate the clinical effect of JHF in the treatment of sepsis, and to explore its mechanism from the perspective of network pharmacology. RESEARCH METHODS: The single-center randomized clinical trial was conducted to assess the effect of JHF in the treatment of sepsis. Additionally, we used the Chinese herbal medicine pharmacology database and analysis platform to identify the active components and therapeutic target of JHF. Numerous well-known disease target databases have been used to screen therapeutic target proteins for sepsis. Furthermore, we have established a Protein-Protein Interaction (PPI) network and carried out Gene Onotology/Kyoto Encyclopedia of Genes and Genomes (GO/KEGG) enrichment analysis. In order to conclude which active compounds from JHF may be responsible for signaling pathway, we performed network analysis. RESEARCH RESULTS: The study included 114 patients. By comparing participants with and without JHF, the results suggested that JHF significantly reduced all-cause mortality on 28 and 60 days after intervention, and improved Sequential Organ Failure Assessment (SOFA) on 7th day after intervention as well as. JHF had an effect of anti-inflammatories and antioxidants (SOD). By using network pharmacological analysis, we identified 72 active components and 426 target genes of JHF, and successfully constructed a "JHF-compound target-sepsis" network. 116 mentioned targets revealed by GO/KEGG enrichment analysis played a significant role in the inflammatory reaction and immunoregulation via interleukin-17 (IL-17) and tumor necrosis factor (TNF) signaling pathway. Moreover, the analysis of "pathway target-active component" revealed that Sennidin A, Rheidin A, Rheidin B, Rheidin C, (E)-4-Phenyl-3-Buten-2-One, Osmanthuside H, Esculetin, and Caffeicacid were responsible for IL-17, TNF signaling pathways. CONCLUSION: JHF contains potential active substance of anti-inflammatory and antioxidant. These active compounds may come into play through IL-17 and TNF signaling pathways. For sepsis, JHF may be a promising and effective treatment strategy.

Heat shock protein 90 inhibitors induce cell differentiation via the ubiquitin-dependent aurora kinase A degradation in a MPLW515L mouse model of primary myelofibrosis.

Primary myelofibrosis (PMF) is characterized by immature megakaryocytic hyperplasia, splenomegaly, extramedullary hematopoiesis and bone marrow fibrosis. Our preclinical study had demonstrated that aurora kinase A (AURKA) inhibitor MLN8237 reduced the mutation burden of PMF by inducing differentiation of immature megakaryocytes. However, it only slightly alleviated splenomegaly, reduced tissue fibrosis, and normalized megakaryocytes in PMF patients of the preliminary clinical study. So enhancing therapeutic efficacy of PMF is needed. In this study, we found that AURKA directly interacted with heat shock protein 90 (HSP90) and HSP90 inhibitors promoted the ubiquitin-dependent AURKA degradation. We demonstrated that HSP90 inhibitors 17-allylamino-17-demethoxygeldanamycin (17-AAG) and 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), normalized peripheral blood counts, improved splenomegaly, attenuated extramedullary hematopoiesis, decreased tissue fibrosis and reduced mutant burden in a MPLW515L mouse model of PMF. Importantly, both 17-AAG and 17-DMAG treatment at effective doses in vivo did not influence on hematopoiesis in healthy mice. Collectively, the study demonstrates that HSP90 inhibitors induce cell differentiation via the ubiquitin-dependent AURKA and also are safe and effective for the treatment of a MPLW515L mouse model of PMF, which may provide a new strategy for PMF therapy. Further, we demonstrate that combined therapy shows superior activity in acute megakaryocytic leukemia mouse model than single therapy.

Cadmium-Tolerant Bacterium Strain Cdb8-1 Contributed to the Remediation of Cadmium Pollution through Increasing the Growth and Cadmium Uptake of Chinese Milk Vetch (Astragalus sinicus L.) in Cadmium-Polluted Soils.

Cadmium (Cd) pollution has attracted global attention because it not only jeopardizes soil microbial ecology and crop production, but also threatens human health. As of now, microbe-assisted phytoremediation has proven to be a promising approach for the revegetation of Cd-contaminated soil. Therefore, it is important to find such tolerant microorganisms. In the present study, we inoculated a bacteria strain tolerant to Cd, Cdb8-1, to Cd-contaminated soils and then explored the effects of Cdb8-1 inoculation on the performance of the Chinese milk vetch. The results showed plant height, root length, and fresh and dry weight of Chinese milk vetch grown in Cdb8-1-inoculated soils increased compared to the non-inoculated control group. The inoculation of Cd-contaminated soils with Cdb8-1 also enhanced their antioxidant defense system and decreased the H2O2 and malondialdehyde (MDA) contents, which alleviated the phytotoxicity of Cd. The inoculation of Cdb8-1 in Cd-contaminated soils attenuated the contents of total and available Cd in the soil and augmented the BCF and TF of Chinese milk vetch, indicating that the combined application of Cd-tolerant bacteria Cdb8-1 and Chinese milk vetch is a potential solution to Cd-contaminated soils.

Case report: TP53 and RB1 loss may facilitate the transformation from lung adenocarcinoma to small cell lung cancer by expressing neuroendocrine markers.

Introduction: Transformation from lung adenocarcinoma (LUAD) to small cell lung cancer (SCLC) is one of the mechanisms responsible for acquired EGFR-TKIs resistance. Although it rarely happens this event determines a rapid disease deterioration and needs specific treatment. Patient and method: We report a case of 75-year-old LUAD female with a p.L858R mutation in Epidermal Growth Factor Receptor (EGFR) who presented with SCLC transformation after responding to first line osimertinib treatment for only 6 months. To understand the underlying molecular mechanism, we retrospectively sequenced the first (LUAD) and the second (SCLC) biopsy using a 56 multi-gene panel. Immunohistochemistry (IHC) staining and Fluorescence In Situ Hybridization (FISH) was applied to confirm the genetic aberrations identified. Results: EGFR p.E709A and p.L858R, Tumor Protein p53 (TP53) p.A159D and Retinoblastoma 1 (RB1) c.365-1G>A were detected in both the diagnostic LUAD and transformed SCLC samples. A high copy number gain for Proto-Oncogene C-Myc (MYC) and a Phosphoinositide 3-Kinase Alpha (PIK3CA) p.E545K mutation were found in the transformed sample specifically. Strong TP53 staining and negative RB1 staining were observed in both LUAD and SCLC samples, but FISH only identified MYC amplification in SCLC tissue. Conclusion: We consider the combined presence of MYC amplification with mutations in TP53 and RB1 as drivers of SCLC transformation. Our results highlight the need to systematically evaluate TP53 and RB1 status in LUAD patients to offer a different therapeutic strategy.

Primary resistance to first- and second-generation ALK inhibitors in a non-small cell lung cancer patient with coexisting ALK rearrangement and an ALK F1174L-cis-S1189C de novo mutation: A case report.

The effectiveness of the tyrosine kinase inhibitor ALK (TKI) for non-small cell lung cancer has been confirmed. However, resistance to ALK-TKIs seems inevitable. Mutations in the ALK kinase domain have been reported as an important mechanism of acquired resistance to ALK therapy. However, patients with de novo ALK kinase domain mutations and ALK rearrangements who were not treated with ALK inhibitors have rarely been reported. Here, we report a case of primary drug resistance to first- and second-generation ALK inhibitors in a NSCLC patient with ALK-rearrangement. The next-generation sequencing test of the pathological biopsy showed that the de novo ALK kinase domain mutation F1174L-cis-S1189C may be the cause of primary drug resistance.

The roles and mechanisms of circular RNAs related to mTOR in cancers.

BACKGROUND: Circular RNAs (circRNAs) are stable molecules with covalently closed structures that have an irreplaceable role in the occurrence, progression, and even treatment of plenty of cancers. Mammalian/mechanistic target of rapamycin (mTOR) is a key regulator in cancers and plays several biological functions, such as proliferation, migration, invasion, autophagy, and apoptosis. METHODS: All data were collected through PubMed and CNKI, using terms including "circRNA," "mTOR," "caner," "signaling pathway," "biomarker," "diagnosis," "treatment." Articles published in Chinese and English were included. RESULTS: In this review, the expression, function, and mechanism of circRNA-associated mTOR in cancers were described. CircRNA-associated-mTOR can regulate the progression and therapy of a variety of cancers in multiple signaling pathways, such as phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt)/mTOR, mitogen-activated protein kinase (MAPK)/mTOR, and AMP-activated protein kinase (AMPK)/mTOR axis. These cancers including esophageal carcinoma (circLPAR3, ciRS-7), gastric cancer (circNRIP1, hsa_circ_0010882, hsa_circ_0000117, hsa_circ_0072309, and circST3GAL6), colorectal cancer (hsa_circ_0000392, hsa_circ_0084927, hsa_circ_0104631, and circFBXW7), liver cancer (circC16orf62, hsa_circ_100338, hsa_circ_0004001, hsa_circ_0004123, hsa_circ_0075792, hsa_circ_0079299, and hsa_circ_0002130), pancreatic cancer (circ-IARS and circRHOBTB3), renal carcinoma (ciRS-7), bladder cancer (circUBE2K), prostate cancer (circMBOAT2 and circ-ITCH), ovarian cancer (circEEF2, circRAB11FIP1, circMYLK, and circTPCN), endometrial cancer (hsa_circ_0002577 and circWHSC1), lung cancer (circHIPK3, hsa_circ_0001666), thyroid cancer (hsa_circ_0007694 and hsa_circ_0008274), glioma (circGFRA1, circ-MAPK4, circPCMTD1, and hsa_circ_0037251), osteosarcoma (circTCF25), leukemia (circ-PRKDC), and breast cancer (hsa_circ_0000199, circUBAP2, and circWHSC1).

Radiomics Analysis of Computed Tomography for Prediction of Thyroid Capsule Invasion in Papillary Thyroid Carcinoma: A Multi-Classifier and Two-Center Study.

Objective: To investigate the application of computed tomography (CT)-based radiomics model for prediction of thyroid capsule invasion (TCI) in papillary thyroid carcinoma (PTC). Methods: This retrospective study recruited 412 consecutive PTC patients from two independent institutions and randomly assigned to training (n=265), internal test (n=114) and external test (n=33) cohorts. Radiomics features were extracted from non-contrast (NC) and artery phase (AP) CT scans. We also calculated delta radiomics features, which are defined as the absolute differences between the extracted radiomics features. One-way analysis of variance and least absolute shrinkage and selection operator were used to select optimal radiomics features. Then, six supervised machine learning radiomics models (k-nearest neighbor, logistic regression, decision tree, linear support vector machine [L-SVM], Gaussian-SVM, and polynomial-SVM) were constructed. Univariate was used to select clinicoradiological risk factors. Combined models including optimal radiomics features and clinicoradiological risk factors were constructed by these six classifiers. The prediction performance was evaluated using the receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis (DCA). Results: In the internal test cohort, the best combined model (L-SVM, AUC=0.820 [95% CI 0.758-0.888]) performed better than the best radiomics model (L-SVM, AUC = 0.733 [95% CI 0.654-0.812]) and the clinical model (AUC = 0.709 [95% CI 0.649-0.783]). Combined-L-SVM model combines 23 radiomics features and 1 clinicoradiological risk factor (CT-reported TCI). In the external test cohort, the AUC was 0.776 (0.625-0.904) in the combined-L-SVM model, showing that the model is stable. DCA demonstrated that the combined model was clinically useful. Conclusions: Our combined model based on machine learning incorporated with CT radiomics features and the clinicoradiological risk factor shows good predictive ability for TCI in PTC.

Extrathyroidal Extension Prediction of Papillary Thyroid Cancer With Computed Tomography Based Radiomics Nomogram: A Multicenter Study.

Objectives: To develop and validate a Computed Tomography (CT) based radiomics nomogram for preoperative predicting of extrathyroidal extension (ETE) in papillary thyroid cancer (PTC) patients. Methods: A total of 153 patients were randomly assigned to training and internal test sets (7:3). 46 patients were recruited to serve as an external test set. A radiologist with 8 years of experience segmented the images. Radiomics features were extracted from each image and Delta-radiomics features were calculated. Features were selected by using one way analysis of variance and the least absolute shrinkage and selection operator in the training set. K-nearest neighbor, logistic regression, decision tree, linear-support vector machine (linear -SVM), gaussian-SVM, and polynomial-SVM were used to build 6 radiomics models. Next, a radiomics signature score (Rad-score) was constructed by using the linear combination of selected features weighted by their corresponding coefficients. Finally, a nomogram was constructed combining the clinical risk factors with Rad-scores. Receiver operating characteristic (ROC) curve, decision curve analysis (DCA), and calibration curve were performed on the three sets to evaluate the nomogram's performance. Results: 4 radiomics features were selected. The six models showed the certain value of radiomics, with area under the curves (AUCs) from 0.642 to 0.701. The nomogram combining the Rad-score and clinical risk factors (radiologists' interpretation) showed good performance (internal test set: AUC 0.750; external test set: AUC 0.797). Calibration curve and DCA demonstrated good performance of the nomogram. Conclusion: Our radiomics nomogram incorporating the radiomics and radiologists' interpretation has utility in the identification of ETE in PTC patients.

Radiomics Model for Predicting TP53 Status Using CT and Machine Learning Approach in Laryngeal Squamous Cell Carcinoma.

Objective: We aim to establish and validate computed tomography (CT)-based radiomics model for predicting TP53 status in patients with laryngeal squamous cell carcinoma (LSCC). Methods: We divided all patients into a training set 1 (n=66) and a testing set 1 (n=30) to establish and validate radiomics model to predict TP53. Radiomics features were selected by analysis of variance (ANOVA) and the least absolute shrinkage and selection operator (Lasso) regression analysis. Five radiomics models were established by using K-Nearest Neighbor, logistics regressive, linear-support vector machine (SVM), gaussian-SVM, and polynomial-SVM in training set 1. We also divided all patients into a training set 2 and a testing set 2 according to different CT equipment to establish and evaluate the stability of the radiomics models. Results: After ANOVA and subsequent Lasso regression analysis, 22 radiomics features were selected to build the radiomics model in training set 1. The radiomics model based on linear-SVM has the best predictive performance of the five models, and the area under the receiver operating characteristic curve in training set 1 and testing set 1 were 0.831(95% confidence interval [CI] 0.692-0.970) and 0.797(95% CI 0.632-0.957) respectively. The specificity, sensitivity, and accuracy were 0.971(95% CI 0.834-0.999), 0.714(95% CI 0.535-0.848), and 0.843(95% CI 0.657-0.928) in training set 1 and 0.750(95% CI 0.500-0.938), 0.786(95% CI 0.571-1.000), and 0.667(95% CI 0.467-0.720) in testing set 1, respectively. In addition, the radiomics model also achieved stable prediction results even in different CT equipment. Decision curve analysis showed that the radiomics model for predicting TP53 status could benefit LSCC patients. Conclusion: We developed and validated a relatively optimal radiomics model for TP53 status prediction by trying five different machine learning methods in patients with LSCC. It shown great potential of radiomics features for predicting TP53 status preoperatively and guiding clinical treatment.

Artificial Intelligence-Assisted Microcatheter Shaping for Intracranial Aneurysm Coiling: A Preliminary Study.

BACKGROUND: To evaluate the efficacy of artificial intelligence (AI) technology-assisted microcatheter shaping for coil embolization of intracranial aneurysms. METHODS: From June 2019 to May 2021, 30 aneurysms in 24 patients were treated with coiling embolization using computer software-assisted microcatheter shaping at our institution. All patients underwent digital subtraction angiography (DSA) before coiling embolization. After three-dimensional (3D) rotational angiography, digital imaging and communications in medicine (DICOM) data were extracted and imported into computer software based on an AI algorithm. 3D images of the parent artery and aneurysm were constructed with the software and data including the central axis of the parent artery, aneurysm location, aneurysm size, and 3D structure were automatically obtained. The optimal microcatheter path was calculated and the shape of the mandrel was automatically generated. Surgeons shaped the mandrel and microcatheter following the AI-generated template and completed the endovascular procedure. RESULTS: All patients successfully completed the endovascular procedure without perioperative complications. The microcatheters shaped as per the AI template accurately entered the aneurysm sacs in 1 attempt; 15 aneurysms required no microguidewire assistance in catheterizing the aneurysm sac and 15 did. The stability of the microcatheters during the procedures was satisfactory. No rebound incidence was observed and no reshaping was necessary. CONCLUSIONS: The AI-assisted microcatheter shaping technology provides a new method to generate the optimal shape for the mandrel and microcatheter during endovascular procedures. The technology facilitates microcatheter accuracy and stability during coiling embolization and provides technical support for surgeons.