Feasibility of the enhanced neuromuscular blockade recovery protocol with selective use of sugammadex in thyroid surgery with intraoperative neuromonitoring.

BACKGROUND: To investigate feasibility of utilizing enhanced neuromuscular blocking agents with selective recovery protocol during thyroid surgery with intraoperative neuromonitoring (IONM). METHODS: Two-hundred and ninety patients were randomized into two groups: group A 0.3 mg/kg rocuronium and group B 0.6 mg/kg. Sugammadex 2 mg/kg was injected if needed followed initial vagal stimulation (V0). Electromyography signals from vagus and recurrent laryngeal nerves before and after resection were recorded as V1, V2, R1, and R2. RESULTS: In group B, 30 patients (20.7%) had V0 signals <100 µV, compared to 9 (6.2%) in group A. After sugammadex administration, 144 patients (99.3%) in both groups achieved positive V1 signals. Group B demonstrated a shorter surgical time from rocuronium injection to V2 stimulation compared to group A, accompanied by a significantly lower incidence of intraoperative body movement (0 vs. 16 patients). CONCLUSIONS: 0.6 mg/kg rocuronium with selective use 2 mg/kg sugammadex for IONM in thyroid surgery can meet both anesthesia and surgery demands.

Evolution of blockchain accounting literature from the perspective of CiteSpace (2013-2023).

Against the backdrop of the Industrial Revolution 4.0, the advantages of blockchain technology in traceability, transparency, safety improvement, and efficiency improvement have made it possible to reduce the work of accounting personnel by 50 %, thus saving billions of dollars for global companies by combining this technology with accounting. However, the blockchain technology associated with accounting is in the experimental stage and has several problems to be solved including limited data processing capacity, information confidentiality, and regulatory difficulties. This innovation and progress in science and technology has provided more abundant, efficient, and professional technical support for the research of blockchain accounting documents. Among these advances, CiteSpace software has promoted the development of blockchain and accounting in the direction of visualization, comprehensiveness, security, and relevance. In this study, we used the knowledge map drawn by CiteSpace to search the core Blockchain Accounting database from 2013 to 2023 on the Web of Science (WoS). We obtained 1414 documents measured according to co-citation analysis, log-likelihood ratio (LLR) network clustering, co-occurrence keywords, and emergent time zone diagram method. We analyzed and summarized the important documents, research keywords, key research fields, and knowledge evolution related to "blockchain accounting" by network, literature integration, and popular research topics. We found that adopting blockchain technology in accounting information systems is expected to improve recordkeeping and reporting. Blockchain, as an innovative technology, provides a tamper-proof, traceable, and shareable platform for accounting information by using a distributed ledger system. By implementing blockchain, artificial intelligence can improve safety, transparency, and accuracy, and also may completely change the way we manage financial records. With its ability to improve overall efficiency and reduce errors, blockchain technology may change our familiar accounting methods. In addition, blockchain technology, intelligent contract, artificial intelligence, the Internet, information systems, and supply chain are the most important keywords, while blockchain technology, intelligent contract, and artificial intelligence are important components of blockchain accounting knowledge system. This research provided an important opportunity to advance the understanding of the crucial contribution of blockchain to the accounting field.

De novo transcriptome assembly database for 100 tissues from each of seven species of domestic herbivore.

Domesticated herbivores are an important agricultural resource that play a critical role in global food security, particularly as they can adapt to varied environments, including marginal lands. An understanding of the molecular basis of their biology would contribute to better management and sustainable production. Thus, we conducted transcriptome sequencing of 100 to 105 tissues from two females of each of seven species of herbivore (cattle, sheep, goats, sika deer, horses, donkeys, and rabbits) including two breeds of sheep. The quality of raw and trimmed reads was assessed in terms of base quality, GC content, duplication sequence rate, overrepresented k-mers, and quality score distribution with FastQC. The high-quality filtered RNA-seq raw reads were deposited in a public database which provides approximately 54 billion high-quality paired-end sequencing reads in total, with an average mapping rate of ~93.92%. Transcriptome databases represent valuable resources that can be used to study patterns of gene expression, and pathways that are related to key biological processes, including important economic traits in herbivores.

Graphiumisides A-D, Monoterpene Glycosides from an Animal-Derived Endophytic Fungus Graphium sp. GD-11.

 Four new monoterpene rhamnosides, graphiumisides A-D (1-4), along with four known steroid compounds (5-8) were isolated from the fermentation extract of animal-derived endophytic fungus, Graphium sp. GD-11. The chemical structures of all compounds were elucidated using 1D and 2D NMR, HRESIMS spectroscopic analyses, and other spectroscopic methods. Compounds 1-4 exhibit a distinctive structure connected by one p-menthane type monoterpene and one L-rhamnose. This is the first report of monoterpene glycosides from Graphium sp. All compounds (1-8) were tested for cytotoxic activities against four cancer cell lines (HepG2, SMMC7721, SW480, and A549), and only compound 1 showed weak anti-tumor activity against SMMC7721 cells.

Postpartum life interventions to prevent type 2 diabetes in women with gestational diabetes: A systematic review and meta-analysis.

AIMS/INTRODUCTION: Type 2 diabetes mellitus is a major metabolic disease that seriously endangers life and health, but women with gestational diabetes mellitus are at increased risk for developing type 2 diabetes mellitus. This study aimed to evaluate the effectiveness of postpartum lifestyle intervention on the prevention of type 2 diabetes mellitus, and the effect of lifestyle intervention on glycemic outcomes and anthropometric measures. MATERIALS AND METHODS: We searched PubMed and other databases to retrieve articles published before May 21, 2023, on randomized controlled trials of postnatal lifestyle interventions (diet and/or physical activity) in women with gestational diabetes mellitus. We estimated the pooled odds ratios using fixed or random effects models and conducted a subgroup analysis of the different intervention methods to explore differences in the different lifestyle interventions. RESULTS: The review included 17 randomized controlled trials. Overall, lifestyle changes started after a pregnancy complicated by gestational diabetes mellitus an 11% (RR = 0.89; 95% CI: 0.74-1.07) reduction in diabetes risk; significant differences were found for weight (MD = -1.33; 95% CI: [-1.76; -0.89], P < 0.00001) body mass index (MD = -0.53; 95% CI: [-0.74, -0.32], P < 0.00001), and waist circumference change (MD = -1.38; 95% CI: [-2.12; -0.64], P = 0.0002) but not for fasting glucose (MD = -0.06; 95% CI: [-0.19; 0.06], P = 0.32), 2 h glucose (MD = -0.12; 95% CI: [-0.30; 0.06], P = 0.19), and hemoglobin A1c (MD = -0.11; 95% CI: [-0.23; 0.02], P = 0.09). Subgroup analyses showed no significant differences in the effects of different lifestyle interventions on the incidence of type 2 diabetes, blood glucose levels, and anthropometric parameters. CONCLUSION: Our comprehensive meta-analysis of lifestyle interventions can improve modifiable anthropometric measures in women with gestational diabetes. We need further research to provide more intensive lifestyle intervention, more scientific intervention methods, and to reduce the incidence of type 2 diabetes in patients with gestational diabetes.

Survival outcome and optimal candidates of primary tumor resection for patients with metastatic medullary thyroid cancer.

CONTEXT: Medullary thyroid cancer (MTC) often exhibits aggressive growth with distant organ metastasis, leading to poor survival. OBJECTIVE: The question of whether primary tumor resection (PTR) is beneficial for patients with metastatic MTC remains a subject of debate. In this study, we evaluated the prognostic significance of organ-specific metastases and the number of metastatic organs in these patients, and we also conducted an analysis to determine the therapeutic value of PTR in managing this rare malignancy. MATERIALS AND METHODS: Patients initially diagnosed with metastatic MTC were identified within the Surveillance, Epidemiology, and End Results (SEER) database. Univariable and multivariable Cox proportional hazards regression models were performed to identify survival predictors. Survival outcomes were calculated using the Kaplan-Meier method and compared using the log-rank tests. RESULTS: A total of 186 patients with metastatic MTC at initial diagnosis from 2010 to 2020 were included. Bone, lung and liver were the most common metastatic organs. Patients with brain metastasis had significantly worse overall survival (OS) (p = 0.007) and cancer-specific survival (CSS) (p = 0.0013). Among all patients, 105 (56.45%) underwent PTR, and this group showed reduced overall mortality (OM) and cancer-specific mortality (CSM) (all p < 0.05). When analyzing different metastatic patterns, PTR significantly lowered the risk of OM and CSM for patients with bone, lung, liver, or distant lymph node (DLN) involvement (all p < 0.05). Additionally, among patients with one or two metastases, those undergoing surgical resection were significantly associated with favorable OS (p = 0.008) and CSS (p = 0.0247). CONCLUSIONS: PTR may confer therapeutic benefits for carefully selected individuals with metastatic MTCs. To integrate these insights into clinical decision-making settings, it is imperative to undertake multicenter prospective studies in the future.

Generation of arbitrarily structured optical vortex arrays based on the epicycle model.

Optical vortex arrays (OVAs) are complex light fields with versatile structures that have been widely studied in large-capacity optical communications, optical tweezers, and optical measurements. However, generating OVAs with arbitrary structures without explicit analytical expressions remains a challenge. To address this issue, we propose an alternative scheme for customizing OVAs with arbitrary structures using an epicycle model and vortex localization techniques. This method can accurately generate an OVA with an arbitrary structure by pre-designing the positions of each vortex. The influence of the number and coordinates of the locating points on customized OVAs is discussed. Finally, the structures of the OVA and each vortex are individually shaped into specifically formed fractal shapes by combining cross-phase techniques. This unique OVA will open up novel potential applications, such as the complex manipulation of multiparticle systems and optical communication based on optical angular momentum.

A distinct tumor microenvironment makes anaplastic thyroid cancer more lethal but immunotherapy sensitive than papillary thyroid cancer.

Both anaplastic thyroid cancer (ATC) and papillary thyroid cancer (PTC) originate from thyroid follicular epithelial cells, but ATC has a significantly worse prognosis and shows resistance to conventional therapies. However, clinical trials found that immunotherapy works better in ATC than late-stage PTC. Here, we used single-cell RNA sequencing (scRNA-Seq) to generate a single-cell atlas of thyroid cancer. Differences in ATC and PTC tumor microenvironment components (including malignant cells, stromal cells, and immune cells) leading to the polarized prognoses were identified. Intriguingly, we found that CXCL13+ T lymphocytes were enriched in ATC samples and might promote the development of early tertiary lymphoid structure (TLS). Last, murine experiments and scRNA-Seq analysis of a treated patient's tumor demonstrated that famitinib plus anti-PD-1 antibody could advance TLS in thyroid cancer. We displayed the cellular landscape of ATC and PTC, finding that CXCL13+ T cells and early TLS might make ATC more sensitive to immunotherapy.

YAP/Aurora A-mediated ciliogenesis regulates ionizing radiation-induced senescence via Hedgehog pathway in tumor cells.

Primary cilia are antenna-like organelles that play critical roles in sensing and responding to various signals. Nevertheless, the function of primary cilia in cellular response to ionizing radiation (IR) in tumor cells remains unclear. Here, we show that primary cilia are frequently expressed in tumor cells and tissues. Notably, IR promotes cilia formation and elongation in time- and dose-dependent manners. Mechanistic study shows that the suppression of YAP/Aurora A pathway contributes to IR-induced ciliogenesis, which is diminished by Aurora A overexpression. The ciliated tumor cells undergo senescence but not apoptosis in response to IR and the abrogation of cilia formation is sufficient to elevate the lethal effect of IR. Furthermore, we show that IR-induced ciliogenesis leads to the activation of Hedgehog signaling pathway to drive senescence and resist apoptosis, and its blockage enhances cellular radiosensitivity by switching senescence to apoptosis. In summary, this work shows evidence of primary cilia in coordinating cellular response to IR in tumor cells, which may help to supply a novel sensitizing target to improve the outcome of radiotherapy.

Two New Isospirostanol-Type Saponins from the Bulbs of Lilium Brownii and Their Anti-Hepatocarcinogenic Activity.

Bulbs of Lilium brownii, commonly known as "Bai-he" in China, serve both edible and medicinal purposes in clinical practice. In this study, two new isospirostanol-type saponins were isolated from L. brownii, and their structures were identified by spectroscopic method, and absolute configurations were elucidated by comprehensive analysis of spectral data obtained from combined acid hydrolysis. Two compounds were finally identified as 3-O-[α-L-rhamnopyranosyl-(1→2)-ß-D-glucopyranoside]-(22R,25R)-5α-spirosolane-3ß-ol (1) and 3-O-{α-L-rhamnopyranosyl-(1→2)-[ß-D-glucopyranosyl-(1→4)]-ß-D-glucopyranoside}-(22R,25R)-5α-spirosolane-3ß-ol (2), respectively. Further, we found that compound 2 significantly suppressed the proliferation of SMMC-7721 and HepG2 cells with IC50 values of 26.3±1.08 µM and 30.9±1.59 µM, whereas compound 1 didn't inhibit both of the two hepatocellular carcinoma. Subsequently, compound 2 effectively decreased the levels of interleukin-1ß and tumor necrosis factor-α and the expression of Bcl-2, and increased the expression of Bax and Caspase-3 proteins. Which indicated that the anti-hepatocellular carcinoma effect of compound 2 involves reducing the level of inflammation and inducing apoptosis.

Integrated metabolomic and transcriptomic dynamic profiles of endopleura coloration during fruit maturation in three walnut cultivars.

BACKGROUND: The color of endopleura is a vital factor in determining the economic value and aesthetics appeal of nut. Walnuts (Juglans) are a key source of edible nuts, high in proteins, amino acids, lipids, carbohydrates. Walnut had a variety endopleura color as yellow, red, and purple. However, the regulation of walnut endopleura color remains little known. RESULTS: To understand the process of coloration in endopleura, we performed the integrative analysis of transcriptomes and metabolomes at two developmental stages of walnut endopleura. We obtained total of 4,950 differentially expressed genes (DEGs) and 794 metabolites from walnut endopleura, which are involved in flavonoid and phenolic biosynthesis pathways. The enrichment analysis revealed that the cinnamic acid, coniferyl alcohol, naringenin, and naringenin-7-O-glucoside were important metabolites in the development process of walnut endopleura. Transcriptome and metabolome analyses revealed that the DEGs and differentially regulated metabolites (DRMs) were significantly enriched in flavonoid biosynthesis and phenolic metabolic pathways. Through co-expression analysis, CHS (chalcone synthase), CHI (chalcone isomerase), CCR (cinnamoyl CoA reductase), CAD (cinnamyl alcohol dehydrogenase), COMT (catechol-Omethyl transferase), and 4CL (4-coumaroyl: CoA-ligase) may be the key genes that potentially regulate walnut endopleura color in flavonoid biosynthesis and phenolic metabolic pathways. CONCLUSIONS: This study illuminates the metabolic pathways and candidate genes that underlie the endopleura coloration in walnuts, lay the foundation for further study and provides insights into controlling nut's colour.

A Review on Chemical Structures and Biological Activities of Dopamine Derivatives from Medicinal Insects.

Medicinal insects play an important role in the treatment of refractory diseases due to their unique and rich pharmacological activities. However, compared to plants, microorganisms, and marine organisms, medicinal insects have been largely ignored. Some small molecules isolated from insects are known to have defensive effects, but their majority roles remain unknown. In-depth research on the small molecules of medicinal insects has been conducted in recent years. Then alkaloids, dopamine derivatives, nucleoside derivatives, and other components are obtained. Among them, dopamine derivatives are a unique class of components from medicinal insects. Thus, we present a comprehensive overview of chemical structures and biological activities of dopamine derivatives from some medicinal insects, which will bring more attention to other researchers for further chemical and biological investigations on the unique dopamine derivatives as well as medicinal insects.

Induction Toripalimab and Chemotherapy for Organ Preservation in Locally Advanced Laryngeal and Hypopharyngeal Cancer: A Single-Arm Phase II Clinical Trial.

PURPOSE: The aim of this study was to assess the efficacy, toxicities, and potential role of larynx preservation of induction chemotherapy combined with programmed cell death protein 1 (PD-1) inhibitor in locally advanced laryngeal and hypopharyngeal cancer. PATIENTS AND METHODS: This is a single-arm phase II study. Patients with histopathologically confirmed, resectable locally advanced laryngeal/hypopharyngeal squamous cell carcinoma and Eastern Cooperative Oncology Group Performance Status 0-1 were eligible. Three cycles of induction chemotherapy (paclitaxel 175 mg/m2 d1, cisplatin 25 mg/m2 d1-3) combined with PD-1 inhibitor (toripalimab 240 mg d0) were administered. Response assessment was performed after induction chemoimmunotherapy using RECIST 1.1 criteria. Patients with a complete/partial response of the primary tumor received concurrent chemoradiation, followed by maintenance therapy of toripalimab. Otherwise, patients were referred to surgery, followed by adjuvant (chemo) radiation and maintenance therapy of toripalimab. The primary endpoint is a larynx preservation rate at 3 months postradiation. RESULTS: Twenty-seven patients were enrolled. Most cases exhibited stage IV disease (81.5%), with T4 representing 37.0%. Five patients underwent pretreatment tracheostomy because of impaired larynx function. Overall response rate of induction chemoimmunotherapy was 85.2%. At 3 months postradiation, the larynx preservation rate was 88.9%. With a median follow-up of 18.7 months, the 1-year overall survival rate, progression-free survival rate, and larynx preservation rate were 84.7%, 77.6%, and 88.7%, respectively. When excluding those with pretreatment tracheostomy, the 1-year larynx preservation rate was 95.5%. Exploratory analysis revealed that relapse correlated with enrichment of RNA signature of hypoxia and M2 macrophage-associated genes. CONCLUSIONS: Induction toripalimab combined with chemotherapy provided encouraging activity, promising larynx preservation rate and acceptable toxicity in this cohort of extensively locally advanced laryngeal and hypopharyngeal cancer.

Comprehensive DNA Methylation Profiling of Medullary Thyroid Carcinoma: Molecular Classification, Potential Therapeutic Target, and Classifier System.

PURPOSE: Medullary thyroid carcinoma (MTC) presents a distinct biological context from other thyroid cancers due to its specific cellular origin. This heterogeneous and rare tumor has a high prevalence of advanced diseases, making it crucial to address the limited therapeutic options and enhance complex clinical management. Given the high clinical accessibility of methylation information, we construct the largest MTC methylation cohort to date. EXPERIMENTAL DESIGN: Seventy-eight fresh-frozen MTC samples constituted our methylation cohort. The comprehensive study process incorporated machine learning, statistical analysis, and in vitro experiments. RESULTS: Our study pioneered the identification of a three-class clustering system for risk stratification, exhibiting pronounced epigenomic heterogeneity. The elevated overall methylation status in MTC-B, combined with the "mutual exclusivity" of hypomethylated sites displayed by MTC-A and MTC-C, distinctively characterized the MTC-specific methylation pattern. Integrating with the transcriptome, we further depicted the features of these three clusters to scrutinize biological properties. Several MTC-specific aberrant DNA methylation events were emphasized in our study. NNAT expression was found to be notably reduced in poor-prognostic MTC-C, with its promoter region overlapping with an upregulated differentially methylated region. In vitro experiments further affirmed NNAT's therapeutic potential. Moreover, we built an elastic-net logistic regression model with a relatively high AUC encompassing 68 probes, intended for future validation and systematic clinical application. CONCLUSIONS: Conducting research on diseases with low incidence poses significant challenges, and we provide a robust resource and comprehensive research framework to assist in ongoing MTC case inclusion and facilitate in-depth dissection of its molecular biological features.

Primary cilium participates in radiation-induced bystander effects through TGF-ß1 signaling.

Many studies have indicated that tumor growth factor-beta (TGF-ß) signaling mediates radiation-induced bystander effects (RIBEs). The primary cilium (PC) coordinates several signaling pathways including TGF-ß signaling to regulate diverse cellular processes. But whether the PC participates in TGF-ß induced RIBEs remains unclear. The cellular levels of TGF-ß1 were detected by western blot analysis and the secretion of TGF-ß1 was measured by ELISA kit. The ciliogenesis was altered by CytoD treatment, STIL siRNA transfection, IFT88 siRNA transfection, or KIF3a siRNA transfection, separately, and was detected by western blot analysis and immunofluorescence staining. G0 /G1 phase cells were arrested by serum starvation and S phase cells were induced by double thymidine block. The TGF-ß1 signaling was interfered by LY2109761, a TGF-ß receptor 1 (TßR1) inhibitor, or TGF-ß1 neutral antibody. The DNA damages were induced by TGF-ß1 or radiated conditional medium (RCM) from irradiated cells and were reflected by p21 expression, 53BP1 foci, and γH2AX foci. Compared with unirradiated control, both A549 and Beas-2B cells expressed and secreted more TGF-ß1 after carbon ion beam or X-ray irradiation. RCM collected from irradiated cells or TGF-ß1 treatment caused an increase of DNA damage in cocultured unirradiated Beas-2B cells while blockage of TGF-ß signaling by TßR1 inhibitor or TGF-ß1 neutral antibody alleviates this phenomenon. IFT88 siRNA or KIF3a siRNA impaired PC formation resulted in an aggravated DNA damage in bystander cells, while elevated PC formation by CytoD or STIL siRNA resulted in a decrease of DNA damage. Furthermore, TGF-ß1 induced more DNA damages in S phases cells which showed lower PC formation rate and less DNA damages in G0 /G1 phase cells which showed higher PC formation rate. This study demonstrates the particular role of primary cilia during RCM induced DNA damages through TGF-ß1 signaling restriction and thereby provides a functional link between primary cilia and RIBEs.

A multicenter prospective study of lateral neck lymph node mapping in papillary thyroid cancer.

Background: Despite the high incidence of lateral neck lymph node (LN) metastasis in papillary thyroid cancer (PTC), the management of the lateral neck remains controversial. We aimed to map the draining LNs in the lateral neck using carbon nanoparticles and explore its potential in neck evaluation. Methods: We conducted a multicenter, prospective study in PTC patients who had non-palpable yet suspicious metastatic lateral LNs on ultrasound and/or computed tomography (CT) but could not be confirmed by fine needle aspiration. Carbon nanoparticle suspension was injected peritumorally into the thyroid and modified lateral neck dissection was subsequently performed. Results: A total of 154 patients were enrolled for analysis. And 5,070 lateral LNs were removed, of which 1,079 (21.3%) were dyed. The median of dyed LNs was 6 per case (range, 1-33). The distribution of dyed LNs in neck compartments was IV > III > IIA > IIB/V, independent of tumor size, location, multifocality or microscopic extra-thyroidal extension (ETE). Compared with undyed LNs, the probabilities of metastasis in dyed LNs were significantly increased in compartment III, IV, V, and II-V (III: 29.3% vs. 15.4%, P<0.001; IV: 26.3% vs. 14.5%, P<0.001; V: 16.7% vs. 3.3%, P=0.005; II-V: 26.3% vs. 10.0%, P<0.001). The relative risks of metastasis in dyed LNs compared with undyed LNs were 1.90, 1.82, 5.04 and 2.62 in compartment III, IV, V, and II-V, respectively. Conclusions: It was the first prospective multicenter study to map the lateral neck LNs with carbon nanoparticles, which could help surgeons visualize the suspicious LNs during surgery. Instead of unguided LN biopsy, this method has a potential role in lateral neck assessment for indeterminate lateral LNs in PTC.

Regulation of Circulating miR-342-3p Alleviates the Radiation-Induced Immune System Injury.

Ionizing radiation in space, radiation devices or nuclear disasters are major threats to human health and public security. Expanding countermeasures for dealing with accidental or occupational radiation exposure is crucial for the protection of radiation injuries. Circulating microRNAs (miRNAs) have emerged as promising radiation biomarkers in recent years. However, the origin, distribution and functions of radiosensitive circulating miRNAs remain unclear, which obstructs their clinical applications in the future. In this study, we found that mmu-miR-342-3p (miR-342) in mouse serum presents a stable and significant decrease after X-ray total-body irradiation (TBI). Focusing on this miRNA, we investigated the influences of circulating miR-342 on the radiation-induced injury. Through tail vein injection of Cy5-labeled synthetic miR-342, we found the exogenous miR-342-Cy5 was mainly enriched in metabolic and immune organs. Besides, the bioinformatic analysis predicted that miR-342 might involve in immune-related processes or pathways. Further, mice were tail vein injected with synthetic miR-342 mimetics (Ago-miR-342) after irradiation to upregulate the level of miR-342 in circulating blood. The results showed that the upregulation of circulating miR-342 alleviated the radiation-induced depletion of CD3+CD4+ T lymphocytes and influenced the levels of IL-2 and IL-6 in irradiated mice. Moreover, the injection of Ago-miR-342 improved the survival rates of mice with acute radiation injury. Our findings demonstrate that upregulation of circulating miR-342 alleviates the radiation-induced immune system injury, which provides us new insights into the functions of circulating miRNAs and the prospect as the targets for mitigation of radiation injuries.

Identification of the Kupffer cell-derived circulating IGFBP-3 as a universal radiation biomarker for heavy ion, proton, and X-ray exposure.

The minimally invasive biomarkers that can facilitate a rapid dose assessment are valuable for the early medical treatment when accidental or occupational radiation exposure happens. Our previous proteomic research identified one kind of circulating protein, Insulin-like Growth Factor Binding Protein 3 (IGFBP-3), which showed a significant increase after total body exposure of mice to carbon ions and X-rays. However, several critical issues such as the responses to diverse radiation, the origin and underlying mechanism in radiation response obstruct the utilization of circulating IGFBP-3 as a reliable radiation biomarker. In this study, mice were subjected to total or partial body irradiation with carbon ions, protons or X-rays, or treated with chloroform as a comparison. The level of IGFBP-3 in serum and different organs were measured via Enzyme Linked Immunosorbent Assay (ELISA), Western blot (WB) and Immunohistochemistry (IHC). A significant increase of IGFBP-3 was discovered in serum and liver tissue post-irradiation with three kinds of radiation, but absent when challenged with chloroform. Likewise, a similar response was also observed in blood samples from patients receiving radiotherapy. Moreover, the effect of radiation on three main hepatic cells was investigated, the findings indicated that IGFBP-3 could be detected in the culture medium of Kupffer cells (MKC) alone and was elevated in cells and cultured medium of MKC post-irradiation. Additionally, we observed a co-expression effect between P53 and IGFBP-3 in liver tissues and MKC post-irradiation. Along with down-regulation of Trp53 by siRNA, the response of IGFBP-3 to radiation was attenuated. The present study demonstrated that circulating IGFBP-3 could be a promising universal biomarker for complex environmental radiation exposure, and the upregulation of IGFBP-3 is attributed to the MKC in a P53-dependent manner. Circulating IGFBP-3 assays would offer rapid, convenient and effective dose and toxicity assessment methods in occupational exposure or radiation disaster management.

The Efficacy and Safety of Surufatinib Combined with Anti PD-1 Antibody Toripalimab in Neoadjuvant Treatment of Locally Advanced Differentiated Thyroid Cancer: A Phase II Study.

BACKGROUND: Surgery is the primary treatment for locally advanced differentiated thyroid cancer (DTC). However, some locally advanced patients are not candidates for R0/1 resection. There is limited evidence of neoadjuvant treatment in locally advanced DTC. Surufatinib targets multiple kinases, which is efficient, tolerable, and safe in patients with radioiodine-refractory DTC. In addition, surufatinib plus toripalimab (an anti-PD-1 antibody) showed encouraging antitumor activity in advanced solid tumors. This study was designed to evaluate the efficacy and safety of surufatinib plus toripalimab in locally advanced DTC in the neoadjuvant setting. METHODS: In this single-arm, phase II study, patients with pathologically confirmed unresectable or borderline resectable DTC were eligible and received a combination of 250 mg of surufatinib (orally daily) with 240 mg of toripalimab (intravenous, every 3 weeks). Treatment continued until satisfied for curative surgery, disease progression, withdrawal of consent, unacceptable toxicity, or investigator decision. Primary endpoint was objective response rate (ORR). Secondary endpoints included R0/1 resection rate, adverse events (AEs), etc. RESULTS: Ten patients were enrolled and received at least 4 cycles of treatment. The ORR was 60%. Nine patients received R0/1 resections after neoadjuvant treatment. The median best percentage change in the sum of the target lesion diameter was 32%. Most adverse events (AEs) were grade 1 or 2. CONCLUSIONS: Surufatinib in combination with toripalimab as neoadjuvant therapy for locally advanced DTC was feasible, and the majority of patients achieved R0/1 resection. It represents a new option for locally advanced DTC and needs further investigation.

TERT accelerates BRAF mutant-induced thyroid cancer dedifferentiation and progression by regulating ribosome biogenesis.

TERT reactivation occurs frequently in human malignancies, especially advanced cancers. However, in vivo functions of TERT reactivation in cancer progression and the underlying mechanism are not fully understood. In this study, we expressed TERT and/or active BRAF (BRAF V600E) specifically in mouse thyroid epithelium. While BRAF V600E alone induced papillary thyroid cancer (PTC), coexpression of BRAF V600E and TERT resulted in poorly differentiated thyroid carcinoma (PDTC). Spatial transcriptome analysis revealed that tumors from mice coexpressing BRAF V600E and TERT were highly heterogeneous, and cell dedifferentiation was positively correlated with ribosomal biogenesis. Mechanistically, TERT boosted ribosomal RNA (rRNA) expression and protein synthesis by interacting with multiple proteins involved in ribosomal biogenesis. Furthermore, we found that CX-5461, an rRNA transcription inhibitor, effectively blocked proliferation and induced redifferentiation of thyroid cancer. Thus, TERT promotes thyroid cancer progression by inducing cancer cell dedifferentiation, and ribosome inhibition represents a potential strategy to treat TERT-reactivated cancers.