Efficient treatment and pre-exposure prophylaxis in rhesus macaques by an HIV fusion-inhibitory lipopeptide.

Two HIV fusion-inhibitory lipopeptides (LP-97 and LP-98) were designed with highly potent, long-acting antiviral activity. Monotherapy using a low dose of LP-98 sharply reduced viral loads and maintained long-term viral suppression in 21 SHIVSF162P3-infected rhesus macaques. We found that five treated monkeys achieved potential posttreatment control (PTC) efficacy and had lower viral DNA in deep lymph nodes, whereas monkeys with a stable viral rebound had higher viral DNA in superficial lymph nodes. The tissues of PTC monkeys exhibited significantly decreased quantitative viral outgrowth and fewer PD-1+ central memory CD4+ T cells, and CD8+ T cells contributed to virologic control efficacy. Moreover, LP-98 administrated as a pre-exposure prophylaxis (PrEP) provided complete protection against SHIVSF162P3 and SIVmac239 infections in 51 monkeys via intrarectal, intravaginal, or intravenous challenge. In conclusion, our lipopeptides exhibit high potential as an efficient HIV treatment or prevention strategy.

Targeted pseudouridylation: An approach for suppressing nonsense mutations in disease genes.

Nonsense mutations create premature termination codons (PTCs), activating the nonsense-mediated mRNA decay (NMD) pathway to degrade most PTC-containing mRNAs. The undegraded mRNA is translated, but translation terminates at the PTC, leading to no production of the full-length protein. This work presents targeted PTC pseudouridylation, an approach for nonsense suppression in human cells. Specifically, an artificial box H/ACA guide RNA designed to target the mRNA PTC can suppress both NMD and premature translation termination in various sequence contexts. Targeted pseudouridylation exhibits a level of suppression comparable with that of aminoglycoside antibiotic treatments. When targeted pseudouridylation is combined with antibiotic treatment, a much higher level of suppression is observed. Transfection of a disease model cell line (carrying a chromosomal PTC) with a designer guide RNA gene targeting the PTC also leads to nonsense suppression. Thus, targeted pseudouridylation is an RNA-directed gene-specific approach that suppresses NMD and concurrently promotes PTC readthrough.

CRISPR-free, programmable RNA pseudouridylation to suppress premature termination codons.

Nonsense mutations, accounting for >20% of disease-associated mutations, lead to premature translation termination. Replacing uridine with pseudouridine in stop codons suppresses translation termination, which could be harnessed to mediate readthrough of premature termination codons (PTCs). Here, we present RESTART, a programmable RNA base editor, to revert PTC-induced translation termination in mammalian cells. RESTART utilizes an engineered guide snoRNA (gsnoRNA) and the endogenous H/ACA box snoRNP machinery to achieve precise pseudouridylation. We also identified and optimized gsnoRNA scaffolds to increase the editing efficiency. Unexpectedly, we found that a minor isoform of pseudouridine synthase DKC1, lacking a C-terminal nuclear localization signal, greatly improved the PTC-readthrough efficiency. Although RESTART induced restricted off-target pseudouridylation, they did not change the coding information nor the expression level of off-targets. Finally, RESTART enables robust pseudouridylation in primary cells and achieves functional PTC readthrough in disease-relevant contexts. Collectively, RESTART is a promising RNA-editing tool for research and therapeutics.

Mutations in TSPAN12 gene causing familial exudative vitreoretinopathy.

BACKGROUND: To report newly found TSPAN12 mutations with a unique form of familial exudative vitreoretinopathy (FEVR) and find out the possible mechanism of a repeated novel intronic variant in TSPAN12 led to FEVR. RESULTS: Nine TSPAN12 mutations with a unique form of FEVR were detected by panel-based NGS. MINI-Gene assay showed two splicing modes of mRNA that process two different bands A and B, and mutant-type shows replacement with the splicing mode of Exon11 hopping. Construction of wild-type and mutant TSPAN12 vector showed the appearance of premature termination codons (PTC). In vitro expression detection showed significant down-regulated expression level of TSPAN12 mRNAs and proteins in cells transfected with mutant vectors compared with in wild-type group. On the contrary, translation inhibitor CHX and small interfering RNA of UPF1 (si-UPF1) significantly increased mRNA or protein expression of TSPAN12 in cells transfected with the mutant vectors. CONCLUSIONS: Nine mutations in TSPAN12 gene are reported in 9 FEVR patients with a unique series of ocular abnormalities. The three novel TSPAN12 mutations trigger NMD would cause the decrease of TSPAN12 proteins that participate in biosynthesis and assembly of microfibers, which might lead to FEVR, and suggest that intronic sequence analysis might be a vital tool for genetic counseling and prenatal diagnoses.

METTL16 inhibits papillary thyroid cancer tumorigenicity through m6A/YTHDC2/SCD1-regulated lipid metabolism.

Papillary thyroid carcinoma (PTC) stands as the leading cancer type among endocrine malignancies, and there exists a strong correlation between thyroid cancer and obesity. However, the clinical significance and molecular mechanism of lipid metabolism in the development of PTC remain unclear. In this study, it was demonstrated that the downregulation of METTL16 enhanced lipid metabolism and promoted the malignant progression of PTC. METTL16 was expressed at lower levels in PTC tissues because of DNMT1-mediated hypermethylation of its promoter. Loss- and gain-of-function studies clarified the effects of METTL16 on PTC progression. METTL16 overexpression increased the abundance of m6A in SCD1 cells, increasing RNA decay via the m6A reader YTHDC2. The SCD1 inhibitor A939572 inhibited growth and slowed down lipid metabolism in PTC cells. These results confirm the crucial role of METTL16 in restraining PTC progression through SCD1-activated lipid metabolism in cooperation with YTHDC2. This suggests that the combination of METTL16 and anti-SCD1 blockade might constitute an effective therapy for PTC.

Graphene Oxide Membrane Reactor for Electrochemical Deuteration Reactions.

The deuteration of organic molecules is considerably important in organic and medicinal chemistry. An electrochemical membrane reactor using proton-conducting graphene oxide (GO) nanosheets was developed to synthesize valuable deuterium-labeled products via an efficient hydrogen-to-deuterium (H/D) exchange under mild conditions at ambient temperature and atmospheric pressure. Deuterons (D+) formed by the anodic oxidation of heavy water (D2O) at the Pt/C anode permeate through the GO membrane to the Pt/C cathode, where organic molecules with functional groups (C≡C and C═O) are deuterated with adsorbed atomic D species. Deuteration occurs in outstanding yields with high levels of D incorporation. We also achieved the electrodeuteration of a drug molecule, ibuprofen, demonstrating the promising feasibility of the GO membrane reactor in the pharmaceutical industry.

Mechanism of DAPK1 for Regulating Cancer Stem Cells in Thyroid Cancer.

Death-associated protein kinase 1 (DAPK1) is a calcium/calmodulin (Ca2+/CaM)-dependent serine/threonine (Ser/Thr) protein kinase and is characteristically downregulated in metastatic cancer. Several studies showed that DAPK1 is involved in both the early and late stages of cancer. DAPK1 downregulation is elaborately controlled by epigenetic, transcriptional, posttranscriptional, and posttranslational processes. DAPK1 is known to regulate not only cancer cells but also stromal cells. Recent studies showed that DAPK1 was involved not only in tumor suppression but also in epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) formation in colon and thyroid cancers. CSCs are major factors in determining cancer aggressiveness in cancer metastasis and treatment prognosis by influencing EMT. However, the molecular mechanism involved in the regulation of cancer cells by DAPK1 remains unclear. In particular, little is known about the existence of CSCs and how they are regulated in papillary thyroid carcinoma (PTC) among thyroid cancers. In this review, we describe the molecular mechanism of CSC regulation by DAPK1 in PTC progression.

Interaction of BANCR in the relationship between Hashimoto's thyroiditis and papillary thyroid carcinoma expression patterns and possible molecular mechanisms.

BACKGROUND: Previous studies have established a connection between Hashimoto's thyroiditis (HT) and an increased risk of papillary thyroid carcinoma (PTC). However, the molecular mechanisms driving this association are not well understood. The long non-coding RNA (lncRNA) BRAF-activated non-coding RNA (BANCR) has been implicated in various cancers, suggesting a potential role in the HT-PTC linkage. METHODS: This study investigated the expression levels of BANCR in PTC and HT samples, compared to control tissues. We also examined the association between BANCR expression and clinicopathological features, including lymph node metastasis. Furthermore, we explored the molecular mechanisms of BANCR in PTC pathogenesis and its potential as a therapeutic target. RESULTS: BANCR expression was significantly lower in PTC samples than in controls, while it was moderately increased in HT samples. In PTC cases with concurrent HT, BANCR expression was markedly reduced compared to normal tissues. Our analysis revealed BANCR's role as an oncogene in PTC, influencing various cancer-related signaling pathways. Interestingly, no significant correlation was found between BANCR expression and lymph node metastasis. CONCLUSION: Our findings underscore the involvement of BANCR in the connection between HT and PTC. The distinct expression patterns of BANCR in PTC and HT, especially in PTC with concurrent HT, provide new insights into the molecular interplay between these conditions. This study opens avenues for the development of innovative diagnostic and therapeutic strategies targeting BANCR in PTC and HT.

Circ_0004851 regulates the molecular mechanism of miR-296-3p/FGF11 in the influence of high iodine on PTC.

The prevalence of papillary thyroid cancer (PTC) has been rising in recent years. Despite its relatively low mortality, PTC frequently metastasizes to lymph nodes and often recurs, posing significant health and economic burdens. The role of iodine in the pathogenesis and advancement of thyroid cancer remains poorly understood. Circular RNAs (circRNAs) are recognized to function as competing endogenous RNAs (ceRNAs) that modulate gene expression and play a role in various cancer stages. Consequently, this research aimed to elucidate the mechanism by which circRNA influences the impact of iodine on PTC. Our research indicates that high iodine levels can exacerbate the malignancy of PTC via the circ_0004851/miR-296-3p/FGF11 axis. These insights into iodine's biological role in PTC and the association of circRNA with the disease could pave the way for novel biomarkers and potentially effective therapeutic strategies to mitigate PTC progression.

Impact of radioiodine therapy on recurrence and survival outcomes in intermediate-risk papillary thyroid carcinoma -A systematic review and meta-analysis.

OBJECTIVE: The utility of radioiodine (RAI) therapy in intermediate-risk papillary thyroid carcinoma (PTC) remains a topic of ongoing discussion. This systematic review and meta-analysis aimed to consolidate existing evidence on the impact of postoperative RAI therapy on recurrence and survival outcomes in intermediate-risk PTC. METHODS: A literature search was performed using relevant keywords in PubMed, Scopus, and EMBASE. Articles from January 2008 to March 2023 were included. Odds ratios (ORs) and hazard ratios (HRs) were extracted from the individual articles, and pooled estimates were generated using meta-analysis. RESULTS: Eleven articles comprising 56,266 intermediate-risk PTC patients were included. 41,530 (73.8%) patients underwent postoperative RAI therapy, while 14,736 (26.2%) patients were kept on no-RAI (NOI) follow-up. No significant reduction in rates of structural disease recurrence was noted with RAI therapy in comparison to NOI follow-up (pooled univariate OR, 0.73, 95% confidence interval [CI], 0.29-1.87, I2 = 75%). RAI therapy was not a significant predictor of better recurrence-free survival (pooled multivariate HR, 0.21; 95% CI, 0.01-3.74, I2 = 94%). Interestingly, RAI therapy was associated with an overall survival benefit compared to NOI follow-up (pooled multivariate HR, 0.63; 95% CI, 0.48-0.82, I2 = 79%). CONCLUSIONS: This meta-analysis did not establish a conclusive benefit of RAI therapy in preventing structural disease recurrence or improving recurrence-free survival in intermediate-risk PTC. However, these results need to be interpreted with caution owing to significant heterogeneity in the existing literature. A prospective, randomised clinical trial is the need of the hour to better understand the effect of RAI therapy on long-term outcomes.

Phonon transport in vacancy induced defective stanene/hBN van der Waals heterostructure.

In this study, Non-Equilibrium Molecular Dynamics (NEMD) simulation is employed to investigate the phonon thermal conductivity (PTC) of Sn/hBN van der Waals heterostructures with different vacancy-induced defects. We deliberately introduce three types of vacancies in Sn/hBN bilayer point vacancies, bivacancies, and edge vacancies at various concentrations ranging from 0.25% to 2%, to examine their effects on PTC across temperatures from 100 K to 600 K. The key findings of our work are (i) PTC declines monotonically with increasing vacancy concentration for all types of vacancies, with a maximum reduction of ∼62% observed at room temperature compared to its pristine form. (ii) The position of defects has an impact on PTC, with a larger decrease observed when defects are present in the hBN layer and a smaller decrease when defects are in the Sn layer. (iii) The type of vacancy also influences PTC, with point vacancies causing the most substantial reduction, followed by bivacancies, and edge vacancies having the least effect. A 2% defect concentration results in a ∼62% decrease in PTC for point vacancies, ∼51% for bivacancies, and ∼32% for edge vacancies. (iv) Finally, our results indicate that for a given defect concentration, PTC decreases as temperature increases. The impact of temperature on thermal conductivity is less pronounced compared to the effect of vacancies for the defective Sn/hBN bilayer. The presence of vacancies and elevated temperatures enhance phonon-defect and phonon-phonon scattering, leading to changes in the phonon density of states (PDOS) profile and the distribution of phonons across different frequencies of Sn/hBN bilayer, thus affecting its thermal conductivity. This work offers new insights into the thermal behavior of vacancy-filled Sn/hBN heterostructures, suggesting potential pathways for modulating thermal conductivity in bilayer van der Waals heterostructures for applications in thermoelectric, optoelectronics, and nanoelectronics in future.

Hypoxic papillary thyroid carcinoma cells-secreted exosomes deliver miR-221-3p to normoxic tumor cells to elicit a pro-tumoral effect by regulating the ZFAND5.

Papillary thyroid cancer (PTC) has seen a worldwide expansion in incidence in the past three decades. Tumor-derived exosomes have been associated with the metastasis of cancer cells and are present within the local hypoxic tumor microenvironment, where they mediate intercellular communication by transferring molecules including microRNAs (miRNAs) between cells. Although miRNAs have been shown to serve as non-invasive biomarkers for cancer diagnosis, the role of hypoxia-induced tumor-derived exosomes in PTC progression remains unclear. Herein, we investigated the differentially expressed miRNA expression profiles from GEO datasets (GSE191117 and GSE151180) by using the DESeq package in R and identified a novel role for miR-221-3p as an oncogene in PTC development. In vivo and in vitro loss and gain assays were used to clarify the mechanism of hypoxic PTC cells derived exosomal-miR-221-3p in PTC. miR-221-3p was upregulated in human PTC plasma exosomes, tissues and cell lines. We found that hypoxic PTC cells derived exosomal-miR-221-3p promoted normoxic PTC cells proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) in vitro, while inhibition of miR-221-3p limited PTC tumor growth in our PTC xenograft model in nude mice. We finally identified ZFAND5, to be a miR-221-3p target. Mechanistically, hypoxic PTC cell lines-derived exosomes carrying miR-221-3p promoted PTC tumorigenesis by regulating ZFAND5. Our findings further the understanding of the underlying mechanisms associated with PTC progression and identify exosomal-miR-221-3p as a potential biomarker for the diagnosis and prognosis of PTC patients. Our study also suggests that miR-221-3p inhibitors could be a potential treatment strategy for PTC.

Prevalence and diagnostic significance of non-invasive follicular thyroid neoplasm with papillary-like nuclear features in Japan-A multi-institutional study.

This multi-institutional study investigated non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) frequency and its diagnostic significance in Japan. We reviewed 4008 thyroid nodules resected in six institutions before NIFTP was proposed. Overall, 26 cases diagnosed as non-invasive encapsulated follicular variant of papillary thyroid carcinoma (PTC) and 145 cases of follicular thyroid adenoma (FTA) were included. Of these nodules, 80.8% and 31.0%, respectively, were NIFTPs. In five institutions, NIFTPs were more commonly found in FTA than in PTC nodules. When NIFTP was included with PTC, the overall prevalence was 2.3%, with rates in five institutions below 5.0% (0.8%-4.4%). One NIFTP case with nuclear score 3 revealed nodal metastasis 2.5 years post-resection, and the carcinoma cells were immunohistochemically positive for BRAF. FTAs or NIFTPs with nuclear score 2 did not metastasize. NIFTP was more common among FTA than among PTC nodules, possibly due to underdiagnosis of PTC on nuclear findings. Considering the clinical findings, molecular pathogenesis, and therapeutic strategy in Japan, NIFTP with nuclear score 2 is not different from FTA, and use of this entity terminology is not meaningful. In contrast, NIFTP with nuclear score 3 has potential for metastasis and BRAFV600E mutation. Therefore, in NIFTP cases, nuclear scores 2 and 3 should be separately reported.

HYPOXIA induces lncRNA HOTAIR for recruiting RELA in papillary thyroid cancer cells to upregulate miR-181a and promote angiogenesis.

BACKGROUND: Papillary thyroid carcinoma (PTC) is one of the most common subtypes of thyroid carcinoma. Exosomal miR-181a plays an important role in the development of PTC. This study examined the regulatory mechanism of miR-181a under conditions of hypoxia and its impact on angiogenesis. METHODS: A ribonucleoprotein immunoprecipitation (RIP) experiment was conducted to verify the interaction between HOTAIR and RELA. The relationship between RELA and the miR-181a promoter was detected by ChIP-qPCR. Short hairpin (sh) RNA was designed to knock down HOTAIR in TPC cells. The underlying mechanism of miR-181a was verified by use of dual-luciferase assays and rescue experiments. The regulatory effect of GATA6 on angiogenesis was studied using CCK8, EdU, Transwell, and western blot assays. RESULTS: A RIP assay showed that HOTAIR could bind to RELA under hypoxic conditions. ChIP-qPCR and dual luciferase assays showed RELA could interact with the miR181a promoter and upregulate miR-181a. Knockdown of HOTAIR downregulated miR-181a in TPC-1 cells, and the downregulation could be rescued by RELA overexpression. MiR-181a downregulated GATA6 in HUVEC cells. Overexpression of GATA6 inhibited HUVEC proliferation, migration, tube formation, and EGFR expression. Exosomal miR-181a promoted angiogenesis by downregulating GATA6 expression. CONCLUSION: HOTAIR activated RELA to upregulate miR-181a during hypoxia. Exosomal miR-181a promotes tumor angiogenesis by downregulating GATA6.

The ABC's of Alzheimer risk gene ABCA7.

Alzheimer's disease (AD) is a growing problem worldwide. Since ABCA7's identification as a risk gene, it has been extensively researched for its role in the disease. We review its recently characterized structure and what the mechanistic insights teach us about its function. We furthermore provide an overview of identified ABCA7 mutations, their presence in different ancestries and protein domains and how they might cause AD. For ABCA7 PTC variants and a VNTR expansion, haploinsufficiency is proposed as the most likely mode-of-action, although splice events could further influence disease risk. Overall, the need to better understand expression of canonical ABCA7 and its isoforms in disease is indicated. Finally, ABCA7's potential functions in lipid metabolism, phagocytosis, amyloid deposition, and the interplay between these three, is described. To conclude, in this review, we provide a comprehensive overview and discussion about the current knowledge on ABCA7 in AD, and what research questions remain. HIGHLIGHTS: Alzheimer's risk-increasing variants in ABCA7 can be found in up to 7% of AD patients. We review the recently characterized protein structure of ABCA7. We present latest insights in genetics, expression patterns, and functions of ABCA7.

Hedgehog signaling mechanism and role in cancer.

Cell-cell communication through evolutionarily conserved signaling pathways governs embryonic development and adult tissue homeostasis. Deregulation of these signaling pathways has been implicated in a wide range of human diseases including cancer. One such pathway is the Hedgehog (Hh) pathway, which was originally discovered in Drosophila and later found to play a fundamental role in human development and diseases. Abnormal Hh pathway activation is a major driver of basal cell carcinomas (BCC) and medulloblastoma. Hh exerts it biological influence through a largely conserved signal transduction pathway from the activation of the GPCR family transmembrane protein Smoothened (Smo) to the conversion of latent Zn-finger transcription factors Gli/Ci proteins from their repressor (GliR/CiR) to activator (GliA/CiA) forms. Studies from model organisms and human patients have provided deep insight into the Hh signal transduction mechanisms, revealed roles of Hh signaling in a wide range of human cancers, and suggested multiple strategies for targeting this pathway in cancer treatment.

ALKBH5-induced circular RNA NRIP1 promotes glycolysis in thyroid cancer cells by targeting PKM2.

Although circular RNAs (circRNAs) are involved in cell proliferation, differentiation, apoptosis, and invasion, the underlying regulatory mechanisms of circRNAs in thyroid cancer have not been fully elucidated. This article aimed to study the role of circRNA regulated by N6-methyladenosine modification in papillary thyroid cancer (PTC). Quantitative real-time PCR, western blotting, and immunohistochemistry were used to investigate the expressions of circRNA nuclear receptor-interacting protein 1 (circNRIP1) in PTC tissues and adjacent noncancerous thyroid tissues. In vitro and in vivo assays were carried out to assess the effects of circNRIP1 on PTC glycolysis and growth. The N6-methyladenosine mechanisms of circNRIP1 were evaluated by methylated RNA immunoprecipitation sequencing, luciferase reporter gene, and RNA stability assays. Results showed that circNRIP1 levels were significantly upregulated in PTC tissues. Furthermore, elevated circNRIP1 levels in PTC patients were correlated with high tumor lymph node metastasis stage and larger tumor sizes. Functionally, circNRIP1 significantly promoted glycolysis, PTC cell proliferation in vitro, and tumorigenesis in vivo. Mechanistically, circNRIP1 acted as a sponge for microRNA (miR)-541-5p and miR-3064-5p and jointly upregulated pyruvate kinase M2 (PKM2) expression. Knockdown of m6 A demethylase α-ketoglutarate-dependent dioxygenase alkB homolog 5 (ALKBH5) significantly enhanced circNRIP1 m6 A modification and upregulated its expression. These results show that ALKBH5 knockdown upregulates circNRIP1, thus promoting glycolysis in PTC cells. Therefore, circNRIP1 can be a prognostic biomarker and therapeutic target for PTC by acting as a sponge for oncogenic miR-541-5p and miR-3064-5p to upregulate PKM2 expression.

Colchicine inhibits the proliferation and promotes the apoptosis of papillary thyroid carcinoma cells likely due to the inhibitory effect on HDAC1.

Although the prognosis for papillary thyroid carcinoma (PTC) is generally good, a certain proportion of patients show recurrent or advanced disease, indicating the need for further development of targeted medications. The purpose of this study was to explore the interventional effects of colchicine on PTC and the potential mechanisms or targets. We obtained PTC-related targets from the database and colchicine targets by predicting them. We screened the common targets of colchicine and the PTC-related target histone deacetylase 1 (HDAC1) and verified through molecular docking that colchicine has a good affinity for HDAC1, i.e., colchicine may act on PTC by affecting HDAC1. We then used CCK-8, colony formation, mitochondrial membrane potential and apoptosis assays to confirm that colchicine could inhibit the proliferation and promote the apoptosis of PTC cells and verified by RT‒qPCR, Western blot, and cellular immunofluorescence assays that colchicine could inhibit the expression of HDAC1 in PTC cells. The cytotoxicity and inhibitory effect of colchicine on HDAC1 in PTC cells was stronger than that in normal thyroid cells. We then applied an HDAC1 inhibitor, pyroxamide, to verify that inhibition of HDAC1 inhibits proliferation and promotes apoptosis in PTC cells. Therefore, we conclude that colchicine can inhibit the proliferation and promote the apoptosis of PTC cells likely due to its inhibitory effect on HDAC1. This finding implies that colchicine may be helpful for therapeutic intervention in PTC and that HDAC1 may be a promising clinical therapeutic target.

Novel LncRNA AK023507 inhibits cell metastasis and proliferation in Papillary Thyroid Cancer through ß-catenin/Wnt Signaling Pathway.

INTRODUCTION: Papillary Thyroid Cancer (PTC) represents a commonly encountered type of thyroid malignancy whose occurrence and development is influenced by long non-coding RNA (LncRNA). A novel lncRNA (LncRNA AK023507), known to have tumor suppressive functions, was shown to prevent breast cancer cells from proliferating and metastasizing, but its mechanism in PTC is unclear. METHODS: Using PTC tissues and cell lines, the expression of LncRNA AK023507 was investigated by quantitative Real-time Polymerase Chain Reaction (qRT-PCR). The effects of knockdown or overexpression of LncRNA AK023507 on cell growth and movement were investigated through various cell experiments in vitro. The presence of important functional proteins was determined by Western blotting, with the recovery experiment used for verification. RESULTS: LncRNA AK023507 was found to have low expression in both the PTC cell lines and tissue samples. Knockdown of LncRNA AK023507 in PTC cells significantly promoted cell proliferation, migration, and invasion, while overexpression of LncRNA AK023507 resulted in the opposite effects. Furthermore, LncRNA AK023507 could regulate the expression of ß-catenin/Wnt signaling pathway as confirmed by recovery experiment. CONCLUSION: By acting through the ß-catenin/Wnt signaling pathway, LncRNA AK023507 prevented PTC cells from proliferating and metastasizing. These novel findings indicate that LncRNA AK023507 could be of prognostic and diagnostic value as a potential biomarker of PTC.

NTRK Fusion in a Cohort of BRAF p. V600E Wild-Type Papillary Thyroid Carcinomas.

Owing to the availability of a potent tropomyosin receptor kinase (TRK) inhibitor, it is necessary to develop an effective strategy to identify an enriched population of NTRK fusions in papillary thyroid carcinoma (PTC) in routine diagnostic practice. The reported prevalence of NTRK fusion in a large cohort of PTC is ∼3%. We performed an analysis to refine the characteristic histologic features of PTCs harboring NTRK fusions and further validate the diagnostic utility of pan-TRK immunohistochemistry as a screening tool. In this study, 450 PTCs known to harbor no BRAF p. V600E mutations were screened by pan-TRK immunohistochemistry, and the cases with TRK expression were confirmed by RNA-based next-generation sequencing assay. Eleven NTRK fusion cases were detected (2.4%), and all PTCs were classical subtypes. NTRK1 and NTRK3 were involved in the fusion with 9 different partner genes. Most cases showed similar characteristic histologic findings. Nodular permeative border, multinodular growth with a predominantly follicular pattern, extensive lymphatic invasion, and prominent internodular and intratumoral fibrosis were the characteristic histologic features of NTRK-rearranged PTCs. The ill-defined margins in the ultrasonography findings, which could not be clearly distinguished from the adjacent nontumorous thyroid tissue, were nodular permeative margins in histologic findings. Therefore, preoperative ultrasonographic findings in nodule margins were consistent with the final histologic findings. NTRK1/3 fusion in PTCs showed an overall sensitivity of 100% (95% CI, 71.51%-100%) and specificity of 100% (95% CI, 71.51%-100%) in the 22 cases examined, as confirmed with next-generation sequencing. Our study provides an integrative report of the preoperative ultrasonographic, histologic, immunohistochemical, and molecular features of NTRK-rearranged PTCs. Based on these findings, we propose an algorithmic approach for the stepwise assessment of NTRK fusions in PTCs.