Elucidating molecular mechanisms and therapeutic synergy: irreversible HER2-TKI plus T-Dxd for enhanced anti-HER2 treatment of gastric cancer.

BACKGROUND: HER2-targeted therapies have improved the outcomes of HER2-positive gastric cancer (GC), yet resistance remains a challenge. We sought to explore the effects of reversible and irreversible HER2 tyrosine kinase inhibitors (TKIs) alone or in combination with the HER2-targeting antibody drug conjugate trastuzumab deruxtecan (T-Dxd). METHODS: The effects of HER2-TKIs on HER2 and downstream signaling were evaluated via Western blotting. Proteasomal inhibitors and co-immunoprecipitation assays were performed to explore the role of proteasomal degradation in HER2 expression modulation, and immunofluorescence assays were employed to explore mechanisms of HER2 internalization. The synergistic potential of the irreversible HER2-TKI pyrotinib in combination with T-Dxd was validated using growth and viability assays in anti-HER2-positive GC cell cultures and tumor growth and immunohistochemical staining assays in a mouse xenograft model. RESULTS: Our study revealed that reversible HER2-TKIs elevated HER2 protein levels, whereas irreversible HER2-TKIs decreased them. Pyrotinib triggered HER2 degradation within the proteasome by promoting ubiquitination and dissociation from HSP90. Furthermore, pyrotinib substantially induced HER2 internalization, which led to improved cellular uptake of T-Dxd. The increased T-Dxd uptake was accompanied by greater efficacy in suppressing the growth of GC cells and enhanced anti-tumor effects in an animal model. CONCLUSION: In summary, our research reveals the molecular mechanisms of irreversible HER2-TKIs in regulating HER2 protein expression by promoting HER2 internalization. These findings advance our comprehension of targeted therapy for GC and provide a promising therapeutic combination strategy with enhanced efficacy against HER2-positive GC.

Association between novel anthropometric indices and prevalence of kidney stones in US adults.

BACKGROUND: Our aim is to evaluate the relationship between prevalence of kidney stones (KS) and novel anthropometric indices (AHIs). METHODS: Participants who participated in the KS questionnaire was extracted from the National Health and Nutrition Examination Survey (NHANES) from 2007 to 2018.A series of covariates were also obtained. The novel AHIs include a body shape index (ABSI) and body roundness index (BRI). Weighted multivariable-adjusted logistic regression was performed to investigate the association of KS with AHIs. RESULTS: After relative covariates were adjusted, a greater risk of KS for each z score increase in ABSI (OR = 1.13, 95%CI 1.05-1.22), and the risk of KS augmented by 19% for every 1 BRI z score added (OR = 1.19, 95%CI 1.11-1.27). The results from subgroup analysis showed that among adults aged 20-39 (OR = 1.31, 95%CI 1.04-1.65), male (OR = 1.14, 95%CI 1.02-1.28), the risk of KS is higher with the increase of each ABSI z score. Raising each BRI z score in those who were male aged 20-39 and 40-59 resulted in a higher risk of KS (aged 20-39: OR = 1.34, 95%CI 1.06-1.69; aged 40-59: OR = 1.29, 95%CI 1.09-1.53). In female aged 40-59, increasing each BRI z score led to a higher risk of KS (OR = 1.23, 95%CI 1.07-1.41). A linear association of ABSI z score with the risk of KS and a non-linear relationship between BRI z score and the risk of KS were discovered. CONCLUSION: This study found that the novel AHIs was related to the risk of kidney stones, and can be used as important indicators to evaluate the risk of KS.

Pyrotinib shows a potent antitumor effect on HER2-positive esophageal cancer cells by promoting HER2 proteasomal degradation.

Pan-HER TKIs (pyrotinib, lapatinib) are potent HER2 inhibitors, however, their anti-tumor efficacy on esophageal cancer remains to be elucidated. Using two HER2-positive esophageal cancer cell lines, we observed that both pyrotinib and lapatinib could significantly suppress the activation of HER2 and its downstream signaling. However, pyrotinib showed a potent inhibitory effect at 0.1 µM treatment relative to 1 µM of lapatinib. Moreover, treatment with pyrotinibm, but not lapatinib, markedly reduced the protein level of HER2 through enhancing HER2 ubiquitination level and proteasomal degradation. In vitro and in vivo experiments further revealed that pyrotinib effectively suppresses cancer cell invasion and migration, as well as the growth of tumors in nude mice. Overall, our results suggest that pyrotinib is a superior TKI over lapatinib in inhibiting esophageal cancer cell proliferation and tumorigenic potential, and can be chosen as a neo-adjuvant for esophageal cancer treatment.

Rhomboid domain containing 1 promotes the growth of non-small cell lung cancer through the activation of EGFR and regulation of the BIK-mediated apoptosis.

RHBDD1 overexpression is found in various malignancies, including non-small cell lung cancer (NSCLC), and it is correlated with NSCLC patients' poor overall survival. This study aims to explore the function of RHBDD1 in regulating the progression of NSCLC and its potential molecular basis. qPCR, immunohistochemistry, and/or western blotting were used to evaluate the expression of RHBDD1 in NSCLC tissues and cell lines. RHBDD1 knockdown and overexpression were performed, CCK-8 assay and cell clone formation were applied to study the function of RHBDD1 in cell proliferation in vitro. Flow cytometry and immunofluorescence tests were employed to determine the regulation of apoptosis, cell cycle, and endoplasmic reticulum stress by RHBDD1. As a result, RHBDD1 was found significantly upregulated in NSCLC tissues and cells and associated with pathological tumor staging. RHBDD1 knockdown inhibited the proliferation of NSCLC cells both in vitro and in vivo, promoted their apoptosis, caused cell cycle arrest at G0/G1 phase, characterized with reduced CDK2, suppressed TGF-α secretion, and inhibited the EGFR/Raf/MEK/ERK signaling pathway. In contrast, RHBDD1 overexpression showed the opposite effects. These effects of the manipulated expression of RHBDD1 on NSCLC were restored by EGFR or MEK inhibitor. Additionally, RHBDD1 knockdown and overexpression resulted in decreased and increased BIK cleavage, respectively, but the effects could be blocked by a proteasome inhibitor. In conclusion, our research shows that RHBDD1 promotes the progression of NSCLC through enhancement of proliferation and induction of apoptosis by regulating the EGFR/Raf/MEK/ERK signaling pathway and the level of BIK protein level.

Involvement of SLC39A6 in gastric adenocarcinoma and correlation of the SLC39A6 polymorphism rs1050631 with clinical outcomes after resection.

BACKGROUND: The single-nucleotide polymorphism SLC39A6 rs1050631 is strongly implicated in esophageal squamous cell carcinoma, leading us to question whether it may also play a role in gastric adenocarcima (GA). METHODS: We genotyped the SLC39A6 rs1050631 in 512 patients who underwent GA resection. All study subjects lived in an area of China with high GA incidence. Genotypes were examined for possible correlation with survival and recurrence. The potential involvement of SLC39A6 in gastric cancer was explored in clinical samples and cell culture studies. RESULTS: Multivariable analysis showed that patients with the CT + TT genotype at SLC39A6 rs1050631 were at greater risk of recurrence (hazard ratio, HR 1.387, p = 0.004) and death (HR 1.429, p = 0.002) than patients with CC genotype. Median recurrence-free and overall survival were significantly shorter in patients with the CT + TT genotype (20, 27 months) than in patients with the CC genotype (36, 43 months, p = 0.001, p < 0.001). Patients with the CT + TT genotype who were male or ≥ 60 years, or who had a tumor ≥5 cm or a moderately differentiated tumor were at significantly higher risk of recurrence and death. SLC39A6 was overexpressed in tissues from GA patients and in GA cell lines, and SLC39A6 knockdown in GA cell lines inhibited their proliferation, migration and invasion. CONCLUSION: SLC39A6 rs1050631 correlates with post-resection prognosis of GA patients and SLC39A6 may participate in GA onset or progression.

The rs2839698 Single Nucleotide Polymorphism of lncRNA H19 is Associated with Post-Operative Prognosis in T3 Gastric Adenocarcinoma.

BACKGROUND: It has been widely demonstrated that long non-coding RNA H19 (lncRNA H19) plays an important role in the progression of various human cancers. However, the associations of common genetic variations with recurrence and survival in gastric adenocarcinoma in this lncRNA remain largely unknown. METHODS: The rs2839698 single nucleotide polymorphism (SNP) of H19 was genotyped in tissue samples from 441 patients with T3 gastric adenocarcinoma who had surgical operations between 2004 to 2009, and the relationships between the different genotypes and recurrence and survival after surgery alone (n = 156) or surgery plus chemotherapy (n = 285) were assessed using 3 different statistical-methods. RESULTS: Based on the final day of investigation (November 2014), the GA genotype was significantly associated with recurrence and survival in patients treated with surgery alone, but not in patients treated with surgery plus chemotherapy. In patients treated with surgery alone, individuals with the GA genotype had significantly lower risks of recurrence and death [adjusted hazard ratio (HR) 0.57, 95% CI 0.37 - 0.88; adjusted HR: 0.58, 95% CI 0.38 - 0.88] than the GG genotype (p = 0.010 and p = 0.010), respectively. More importantly, patients treated with surgery alone who carried the GA genotype achieved significantly longer median disease-free survival time and overall survival than carriers of the GG genotype (45 vs. 26 months, p = 0.010; 44 vs. 23 months, p = 0.013). CONCLUSIONS: The rs2839698 SNP of H19 may have potential as a novel prognostic factor for survival in T3 gastric adenocarcinoma after surgery alone; these finding have special relevance to patients who are not suitable for postoperative chemotherapy.

Squalene monooxygenase facilitates bladder cancer development in part by regulating PCNA.

Bladder cancer (BC) is one of the most common cancers worldwide. Although the treatment and survival rate of BC are being improved, the risk factors and the underlying mechanisms causing BC are incompletely understood. Squalene monooxygenase (SQLE) has been associated with the occurrence and development of multiple cancers but whether it contributes to BC development is unclear. In this study, we performed bioinformatics analysis on paired BC and adjacent non-cancerous tissues and found that SQLE expression is significantly upregulated in BC samples. Knockdown of SQLE impairs viability, induces apoptosis, and inhibits the migration and invasion of BC cells. RNA-seq data reveals that SQLE deficiency leads to dysregulated expression of genes regulating proliferation, migration, and apoptosis. Mass spectrometry-directed interactome screening identifies proliferating cell nuclear antigen (PCNA) as an SQLE-interacting protein and overexpression of PCNA partially rescues the impaired viability, migration, and invasion of BC cells caused by SQLE knockdown. In addition, we performed xenograft assays and confirmed that SQLE deficiency inhibits BC growth in vivo. In conclusion, these data suggest that SQLE promotes BC development and SQLE inhibition may be therapeutically useful in BC treatment.

Corrigendum: LncRNA-AC02278.4 is a novel prognostic biomarker that promotes tumor growth and metastasis in lung adenocarcinoma.

[This corrects the article DOI: 10.3389/fonc.2022.860961.].

The function and clinical implication of YTHDF1 in the human system development and cancer.

YTHDF1 is a well-characterized m6A reader protein that is essential for protein translation, stem cell self-renewal, and embryonic development. YTHDF1 regulates target gene expression by diverse molecular mechanisms, such as promoting protein translation or modulating the stability of mRNA. The cellular levels of YTHDF1 are precisely regulated by a complicated transcriptional, post-transcriptional, and post-translational network. Very solid evidence supports the pivotal role of YTHDF1 in embryonic development and human cancer progression. In this review, we discuss how YTHDF1 influences both the physiological and pathological biology of the central nervous, reproductive and immune systems. Therefore we focus on some relevant aspects of the regulatory role played by YTHDF1 as gene expression, complex cell networking: stem cell self-renewal, embryonic development, and human cancers progression. We propose that YTHDF1 is a promising future cancer biomarker for detection, progression, and prognosis. Targeting YTHDF1 holds therapeutic potential, as the overexpression of YTHDF1 is associated with tumor resistance to chemotherapy and immunotherapy.

HS6ST1 overexpressed in cancer-associated fibroblast and inhibited cholangiocarcinoma progression.

BACKGROUD: Fibroblasts turn into cancer associated fibroblasts (CAFs) in the tumor microenvironment, which play an important role in tumor progression. However, the mechanism is unclear. AIMS: To investigate the role of CAFs with HS6ST1-overexpression in cell migration and invasion effects. METHODS: Human primary CAFs were isolated and identified from intrahepatic cholangiocarcinoma. mRNA profiles differences between CAFs and NFs were examined by using transcriptome sequencing. Using Transwell® migration assays, ICCA cells (RBE and HUCCT1) with NF-CM, CAF-CM, CAFsNC-CM, and CAFsHS6ST1-CM were analyzed. Immunohistochemical staining were used to analyze the expression of HS6ST1 in CAF in 152 patients with ICCA. Overall survival (OS) was compared based on CAF HS6ST1 expression were analysed. The relationship between clinicopathological parameters and survival was also examined. RESULTS: Successfully isolated CAFs is positive staining with αSMA, FSP-1, FAP, and PDGFR-ß. Transcriptome sequencing showed that differently expressed genes were enriched in the function of the extracellular matrix and chemokine signaling pathway. HS6ST1 is differentially expressed between CAFs and NFs, and associated with the migration and invasion of ICCA cells. Moreover, HS6ST1 positive expression of CAFs predicted unfavorable prognosis in patients with intrahepatic cholangiocarcinoma and showed correlation with the presence of lymph node metastasis. CONCLUSION: HS6ST1 is new possibilities for targeting the CAFs to reduce cholangiocarcinoma growth and metastasis.

Knockdown of miR-19a suppresses gastrointestinal dysmotility diarrhea after TBI by regulating VIP expression.

BACKGROUND AND AIMS: Traumatic brain injury (TBI) is the main cause of death and can lead to a variety of physiological complications, including gastrointestinal dysfunction. The present study aimed to confirm the miR-19a-mediated suppression of diarrhea after TBI through the regulation of VIP expression. METHODS: A rat model of TBI induced by controlled cortical injury was used to observe gastrointestinal morphology by opening the abdomen after TBI. After 72 h of injury, the fecal water content of the rats was measured. The end ileal segments were removed, and HE staining was used to observe the histopathological changes in the intestine. The levels of serum miR-19a and VIP mRNA were detected by qRT-PCR. ELISA was performed to detect VIP levels in serum. Immunohistochemistry was used to detect the level of VIP in ileal tissues, and immunofluorescence was used to detect c-kit expression in ileal tissue. CCK-8 assay was used to detect the cell viability of interstitial cells of Cajal (ICCs), and TUNEL assay was used to detect apoptosis of ICCs. RESULTS: miR-19a and VIP were highly expressed in the serum of TBI rats, and the knockdown of miR-19a alleviated TBI-induced diarrhea. In addition, the overexpression of miR-19a or VIP inhibited the proliferation of ICCs, promoted apoptosis, and suppressed intracellular Ca2+ levels, whereas miR-19a suppression had the opposite effects. A nonselective nitric oxide synthase inhibitor (L-NA), PKG inhibitors (KT-5823 and RP-8CPT-cGMPS), and a guanylate cyclase inhibitor (ODQ) restored the inhibitory effects of VIP on ICC proliferation, anti-apoptosis effects, and Ca2+ concentrations. CONCLUSION: Knockdown of miR-19a inhibits activation of the VIP-NO-cGMP-PKG pathway through suppression of VIP expression, which in turn inhibits diarrhea after TBI.

Impacts of Surgeons' Experience on Patients with Epiretinal Membrane: A Retrospective Study from 2015 to 2020 in Wenzhou Eye Hospital.

Background: To explore the impacts of surgeons' experience in patients with epiretinal membrane (ERM). Methods: Patients with idiopathic ERM (334 eyes) who underwent PPV and membrane peeling were included in this study. The surgeries were performed by 9 surgeons. Patients were categorized into the experienced group (surgeons who had performed more than 5000 cases of PPV) and the regular group (surgeons who had performed less than 1000 cases of PPV). The patients were also categorized into five groups according to different preoperative best corrected visual acuity (BCVA): 20/100 or worse, 20/70-20/50, 20/40-20/30, 20/25 and 20/20. Impacts of preoperative BCVA, surgeons' experience, lens status, and internal limiting membrane (ILM) peeling on postoperative BCVA were analyzed. Results: The postoperative BCVA was significantly better at 1 week and 1 month in the experienced group compared to the regular group (p = 0.022 and 0.045, respectively). There were no significant differences in postoperative BCVA at 3 months and 6 months between the two groups (p = 0.268 and 0.233, respectively). Postoperative BCVA at 6 months was similar in the 20/25 group and 20/20 group (p = 0.063); both groups had better BCVA compared to the other three groups. The 20/100 or worse group had the greatest visual improvement among the 5 groups at 6 months. Conclusion: This study suggested that although the experience of surgeons had no significant impact on the final BCVA following PPV and ERM removal, the BCVA during the early postoperative phase appeared to be better in the experienced group.

The function and clinical implication of circular RNAs in lung cancer.

Lung cancer is the leading cause of cancer-related deaths worldwide. Despite the recent advent of promising new targeted therapies, lung cancer diagnostic strategies still have difficulty in identifying the disease at an early stage. Therefore, the characterizations of more sensible and specific cancer biomarkers have become an important goal for clinicians. Circular RNAs are covalently close, endogenous RNAs without 5' end caps or 3'poly (A) tails and have been characterized by high stability, abundance, and conservation as well as display cell/tissue/developmental stage-specific expressions. Numerous studies have confirmed that circRNAs act as microRNA (miRNA) sponges, RNA-binding protein, and transcriptional regulators; some circRNAs even act as translation templates that participate in multiple pathophysiological processes. Growing evidence have confirmed that circRNAs are involved in the pathogenesis of lung cancers through the regulation of proliferation and invasion, cell cycle, autophagy, apoptosis, stemness, tumor microenvironment, and chemotherapy resistance. Moreover, circRNAs have emerged as potential biomarkers for lung cancer diagnosis and prognosis and targets for developing new treatments. In this review, we will summarize recent progresses in identifying the biogenesis, biological functions, potential mechanisms, and clinical applications of these molecules for lung cancer diagnosis, prognosis, and targeted therapy.

miR-425-5p is negatively associated with atrial fibrosis and promotes atrial remodeling by targeting CREB1 in atrial fibrillation.

BACKGROUND: Progression of atrial fibrosis is vital for atrial remodeling in atrial fibrillation (AF). The main objective of the present study was to explore the association between miR-425-5p and atrial fibrosis as well as the resultant impact on atrial remodeling in AF. METHODS: Firstly, miRNAs sequencing and quantitative real-time polymerase chain reaction was used to screen and verify the miRNAs expression level in plasma and atrial tissue in AF patients. The left atrial fibrosis was evaluated with the left atrial low voltage area by using left atrial voltage matrix mapping. Cell counting kit-8 was used to detect fibroblasts proliferation. The AF mouse model was established using acetylcholine-CaCl2 injection for 7 days. Target gene prediction software, luciferase assay, and western blotting were employed to confirm the direct targets of miR-425-5p. RESULTS: Firstly, we demonstrated that miR-425-5p was downregulated in plasma and atrial tissue among the patients who suffered from AF. We then confirmed that the plasma's miR-425-5p level was negatively correlated with left atrial fibrosis in persistent AF, and catheter ablation could restore the decreased plasma miR-425-5p. Besides, receiver operating characteristic curve analysis revealed the miR-425-5p not only could differentiate AF from healthy control wit area under the curve (AUC) 0.921, but also discriminated persistent AF from paroxysmal AF with AUC 0.888. Furthermore, downregulation of miR-425-5p could promote atrial remodeling, and overexpression of miR-425-p could improve atrial remodeling and decrease susceptibility to atrial fibrillation. Finally, CREB1 was verified to be a direct target for miR-425-5p. CONCLUSIONS: Our findings suggested that miR-425-5p could serve as novel atrial fibrosis biomarker and contributed to atrial remodeling in AF.

Over-Expression of Long Non-Coding RNA-AC099850.3 Correlates With Tumor Progression and Poor Prognosis in Lung Adenocarcinoma.

Lung adenocarcinoma (LUAD) is the most common histological lung cancer, and it is the leading cause of cancer-related deaths worldwide. Long noncoding RNAs (lncRNAs) have been implicated in the initiation and progression of various cancers. LncRNA-AC099850.3 is a novel lncRNA that is abnormally expressed in diverse cancer types including LUAD. However, the clinical significance, prognostic value, diagnostic value, immune role, and potential biological function of AC099850.3 LUAD remain elusive. In this study, we found that AC099850.3 was highly expressed in LUAD and associated with an advanced tumor stage, poor prognosis, and immune infiltration. Receiver operating curve analysis revealed the significant diagnostic ability of AC099850.3 (AUC=0.888). Functionally, the knockdown of AC099850.3 restrained LUAD cell proliferation and migration in vitro. Finally, we constructed a competitive endogenous RNAs (ceRNA) network that included hsa-miR-101-3p and 4 mRNAs (ESPL1, AURKB, BUB3, and FAM83D) specific to AC099850.3 in LUAD. Kaplan-Meier survival analysis showed that a lower expression of miR-101-3p and a higher expression of ESPL1, AURKB, BUB3, and FAM83D, were associated with adverse clinical outcomes in patients with LUAD. This finding provided a comprehensive view of the AC099850.3-mediated ceRNA network in LUAD, thereby highlighting its potential role in the diagnosis and prognosis of LUAD.

LncRNA-AC02278.4 Is a Novel Prognostic Biomarker That Promotes Tumor Growth and Metastasis in Lung Adenocarcinoma.

LncRNA-AC02278.4 (ENSG00000248538) is a long non-coding RNA (lncRNA) found to be highly expressed in multiple human cancers including lung adenocarcinoma (LUAD). However, the underlying biological function and potential mechanisms of AC02278.4 driving the progression of LUAD remain unclear. In this study, we investigated the role of AC02278.4 in LUAD and found that AC02278.4 expression was significantly increased in datasets extracted from The Cancer Genome Atlas. Increased expression of lncRNA-AC02278.4 was correlated with advanced clinical parameters. Receiver operating characteristic (ROC) curve analysis revealed the significant diagnostic ability of AC02278.4 [area under the ROC curve (AUC) = 0.882]. In addition, gene set enrichment analysis (GSEA) enrichment showed that AC02278.4 expression was correlated with immune response-related signaling pathways. Finally, we determined that AC02278.4 regulated cell proliferation and migration of LUAD in vitro. Our clinical sample results also confirmed that AC02278.4 was highly expressed in LUAD and correlated with adverse clinical outcomes. In conclusion, our data demonstrated that AC02278.4 was correlated with progression and immune infiltration and could serve as a prognostic biomarker for LUAD.

LncRNA-AL035458.2/hsa-miR-181a-5p Axis-Mediated High Expression of NCAPG2 Correlates With Tumor Immune Infiltration and Non-Small Cell Lung Cancer Progression.

Lung adenocarcinoma (LUAD) is the most common histological lung cancer, and it is the leading cause of cancer-related deaths worldwide. NCAPG2 (non-SMC condensin II complex subunit G2) has been shown to be upregulated in various human cancers. Nevertheless, the underlying biological function and potential mechanisms of NCAPG2 driving the progression of LUAD remain unclear. In this study, we investigated the role of NCAPG2 in LUAD and found that the expression of NCAPG2 in LUAD tissues was significantly higher than that of NCAPG2 expression in adjacent normal tissues. Kaplan-Meier survival analysis showed that patients with higher NCAPG2 expression correlated with unfavorable clinical outcomes. Receiver operating characteristic (ROC) curve analysis showed that the AUC value of NCAPG2 was 0.914. Correlation analysis showed that NCAPG2 expression was associated with immune infiltration in LUAD. Finally, we found that AL139385.1 was upregulated in LUAD cancer tissues and cell lines. Knockdown of NCAPG2 inhibited cell proliferation, cell migration, and cell invasion of LUAD in vitro. More importantly, we established the AL035458.2/hsa-miR-181a-5p axis as the most likely upstream ncRNA-related pathway of NCAPG2 in LUAD. In conclusion, our data demonstrated that ncRNA-mediated high expression of NCAPG2 was correlated with progression and immune infiltration, and could serve as a prognostic biomarker for LUAD.

Long Non-Coding RNA AL139385.1 as a Novel Prognostic Biomarker in Lung Adenocarcinoma.

Lung adenocarcinoma (LUAD) is the most common histological lung cancer, and it is the leading cause of cancer-related deaths worldwide. LncRNA-AL139385.1 (ENSG00000275880) is a novel lncRNA that is abnormally expressed in various cancer types including LUAD. However, the underlying biological function and potential mechanisms of AL139385.1 driving the progression of LUAD remain unclear. In this study, we investigated the role of AL139385.1 in LUAD and found that DNA hypomethylation was positively correlated with AL139385.1 expression in LUAD. Moreover, we uncover that the expression of AL139385.1 in LUAD tissues was significantly higher than that of AL139385.1 expression in adjacent normal tissues. Kaplan-Meier survival analysis showed that patients with higher AL139385.1 expression correlated with adverse overall survival and progression-free survival. Receiver operating characteristic (ROC) curve analysis showed that the area under the curve (AUC) value of AL139385.1 was 0.808. Correlation analysis showed that AL139385.1 expression was associated with immune infiltration in LUAD. We also found that AL139385.1 was upregulated in LUAD cancer tissues and cell lines. Knockdown of AL139385.1 significantly inhibited cell proliferation and migration abilities of LUAD. Finally, we constructed a ceRNA network that includes hsa-miR-532-5p and four mRNAs (GALNT3, CYCS, EIF5A, and ITGB4) specific to AL139385.1 in LUAD. Subsequent Kaplan-Meier survival analysis suggested that polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3), cytochrome c, somatic (CYCS), eukaryotic translation initiation factor 5A (EIF5A), and integrin subunit beta 4 (ITGB4), were potential prognostic biomarkers for patients with LUAD. In conclusion, this finding provides possible mechanisms underlying the abnormal upregulation of AL139385.1 as well as a comprehensive view of the AL139385.1-mediated competing endogenous RNAs (ceRNA) network in LUAD, thereby highlighting its potential role in diagnosis and therapy.

Pan-Cancer Integrated Analysis Identification of SASH3, a Potential Biomarker That Inhibits Lung Adenocarcinoma Progression.

Sterile alpha motif (SAM) and Src homology-3 (SH3) domain-containing 3 (SASH3) is an adaptor protein expressed mainly in lymphocytes, and plays significant roles in T-cell proliferation and cell survival. However, its expression level, clinical significance, and correlation with tumor-infiltrating immune cells across cancers remain unclear. In this study, we comprehensively examined the expression, dysregulation, and prognostic significance of SASH3, and the correlation with clinicopathological parameters and immune infiltration in pan-cancer. The mRNA and protein expression status of SASH3 were determined by TCGA, GTEx, and UALCAN. Kaplan-Meier analysis utilized the prognostic values of SASH3 in diverse cancers. The association between SASH3 expression and gene mutation, DNA methylation, immune cells infiltration, immune checkpoints, tumor mutation burden (TMB), and microsatellite instability (MSI) were analyzed using data from the TCGA database. High expression of SASH3 was not only linked to poor OS in ESCC, LAML, LGG, and UVM, but also associated with better OS in CESC, HNSC, LUAD, SARC, SKCM, THYM, and UCEC. As for DSS, a high level of SASH3 correlated with adverse DSS in ESCC, LGG, and UVM, and lowly expressed SASH3 was associated with shorter OS in CESC, HNSC, LUAD, SARC, SKCM, and UCEC. The results of Cox regression and nomogram analyses confirmed that SASH3 was an independent factor for LUAD prognosis. Gene Ontology (GO), the Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA) results showed that SASH3 was involved in natural killer cell-mediated cytotoxicity, Th17 cell differentiation, PD-L1 expression and PD-1 checkpoint pathway in cancer, NF-kappa B signaling pathway, B-cell receptor signaling pathway, and Toll-like receptor signaling pathway. SASH3 expression was correlated with TMB in 28 cancer types and associated with MSI in 22 cancer types, while there was a negative correlation between SASH3 expression and DNA methylation in diverse human cancer. The high DNA methylation level of SASH3 was correlated with better OS in KIRC and UVM, and associated with poor OS in SKCM. Moreover, we uncover that SASH3 expression was positively associated with the stroma score in 27 cancer types, the microenvironment score, and immune score in 32 cancer types, 38 types of immune cells in 32 cancer types, the 45 immune stimulators, 24 immune inhibitors, 41 chemokines, 18 receptors, and 21 major histocompatibility complex (MHC) molecules in 33 cancer types. Finally, forced SASH3 expression inhibited lung adenocarcinoma (LUAD) cell proliferation and cell migration. Our findings confirmed that SASH3 may be a biomarker for the prognosis and diagnosis of human cancer.

The Role of Different Tear Volume Detection Methods in the Evaluation and Diagnosis of Mild Dry Eye Disease.

Purpose: To compare the diagnostic power of strip meniscometry (SM), Schirmer test (ST), and tear meniscus (TM) in mild dry eye disease (DED) and to evaluate the association with DED-related parameters. Methods: Forty left eyes with mild DED and 40 left eyes of control participants were investigated. All participants underwent a comprehensive ocular surface examination, including the Ocular Surface Disease Index (OSDI), fluorescein tear film break-up time (FTBUT), ocular surface staining grades, meiboscores, and tear film volume examinations, including SM, ST, tear meniscus height (TMH), and tear meniscus cross-sectional area (TMA) measurements, respectively, by optical coherence tomography (OCT) and Keratograph 5M (K5M). The correlation between these parameters was evaluated, and the receiver operating characteristic (ROC) curve was used to verify the diagnostic power by the area under the curve (AUC). Results: All tear film volume examinations significantly correlated with DED parameters. Among them, the most relevant factor to OSDI scores and FTBUT was SM. In addition, SM (AUC = 0.992), TMH-OCT (AUC = 0.978), and TMA-OCT (AUC = 0.960) showed better diagnostic power than ST (AUC = 0.650) in DED, in which the cutoff value of SM was 3.5 mm (sensitivity, 97.5%; specificity, 95.0%). Conclusions: Compared with ST, SM and TM parameters obtained by OCT were more relevant to ocular surface parameters and can provide a more valuable approach to discriminate mild DED from control participants. Translational Relevance: This study made a comprehensive comparison of the existing tear volume detection methods and provided a basis for the clinical selection of appropriate detection methods and the diagnosis of mild DED.