Hierarchical self-recognition and response in CSC and non-CSC micro-niches for cancer therapy.

Cancer stem cells (CSCs) characterized by self-renewal, invasiveness, tumorigenicity and resistance to treatment are regarded as the thorniest issues in refractory tumors. We develop a targeted and hierarchical controlled release nano-therapeutic platform (SEED-NPs) that self-identifies and responds to CSC and non-CSC micro-niches of tumors. In non-CSC micro-niche, reactive oxygen species (ROS) trigger the burst release of the chemotherapeutic drug and photosensitizer to kill tumor cells and reduce tumor volume by combining chemotherapy and photodynamic therapy (PDT). In CSC micro-niche, the preferentially released differentiation drug induces CSC differentiation and transforms CSCs into chemotherapy-sensitive cells. SEED-NPs exhibit an extraordinary capacity for downregulating the stemness of CD44+/CD24- SP (side population) cell population both in vitro and in vivo, and reveal a 4-fold increase of tumor-targeted accumulation. Also, PDT-generated ROS promote the formation of tunneling nanotubes and facilitate the divergent network transport of drugs in deep tumors. Moreover, ROS in turn promotes CSC differentiation and drug release. This positive-feedback-loop strategy enhances the elimination of refractory CSCs. As a result, SEED-NPs achieve excellent therapeutic effects in both 4T1 SP tumor-bearing mice and regular 4T1 tumor-bearing mice without obvious toxicities and eradicate half of mice tumors. SEED-NPs integrate differentiation, chemotherapy and PDT, which proved feasible and valuable, indicating that active targeting and hierarchical release are necessary to enhance antitumor efficacy. These findings provide promising prospects for overcoming barriers in the treatment of CSCs.

Light-Activated Nanodiamond-Based Drug Delivery Systems for Spatiotemporal Release of Antisense Oligonucleotides.

Nanodiamonds (NDs) are considered promising delivery platforms, but inaccurate and uncontrolled release of drugs at target sites is the biggest challenge of NDs in precision medicine. This study presents the development of phototriggerable ND-based drug delivery systems, utilizing ortho-nitrobenzyl (o-NB) molecules as photocleavable linkers between drugs and nanocarriers. UV irradiation specifically cleaved o-NB molecules and then was followed by releasing antisense oligonucleotides from ND-based carriers in both buffer and cellular environments. This ND system carried cell nonpermeable therapeutic agents for bypassing lysosomal trapping and degradation. The presence of fluorescent nitrogen-vacancy centers also allowed NDs to serve as biological probes for tracing in cells. We successfully demonstrated phototriggered release of antisense oligonucleotides from ND-based nanocarriers, reactivating their antisense functions. This highlights the potential of NDs, photocleavable linkers, and light stimuli to create advanced drug delivery systems for controlled drug release in disease therapy, opening possibilities for targeted and personalized treatments.

CoO/Co-graphene quantum dots as an oxidative mimetic nanozyme for the colorimetric detection of L-cysteine.

The preparation of cobalt-based nanozymes with high oxidase-like activity still needs more efforts. In this paper, we report the synthesis of a CoO/Co-tryptophan-functional graphene quantum dot hybrid (CoO/Co-Try-GQD). Firstly, cobalt ions coordinate with the indole nitrogen on Try-GQD to form a complex, followed by thermal reduction and oxidation. The resulting hybrid presents a three-dimensional network structure, and CoO/Co nanoparticles are uniformly dispersed on the graphene sheet with an average size of 10 ± 0.24 nm. This unique structure improved the oxidase-like activity of the hybrid, enabling it to catalyze the oxidation of colorless 3,3',5,5'-tetramethylbenzidine (TMB) to rapidly produce deep blue ox-TMB with a strong absorbance at 652 nm (A652). A colorimetric method was developed for the highly sensitive determination of L-cysteine (L-cys) based on the inhibition of the hybrid's oxidase-like activity and low A652 caused by the binding of L-cys with Co atoms on CoO/Co via the Co-S bond. The A652 linearly decreased with increasing L-cys concentration in the range of 0.05-2 µM, and the detection limit was 0.032 µM. Further, the established method has been successfully applied to the determination of L-cys in milk.

Advances in Metabolism and Metabolic Toxicology of Quinoxaline 1,4-Di-N-oxides.

Quinoxaline 1,4-di-N-Oxides (QdNOs) have been used as synthetic antimicrobial agents in animal husbandry and aquaculture. The metabolism and potential toxicity have been also concerns in recently years. The metabolism investigations showed that there were 8 metabolites of Carbadox (CBX), 34 metabolites of Cyadox (CYA), 33 metabolites of Mequindox (MEQ), 35 metabolites of Olaquindox (OLA), and 56 metabolites of Quinocetone (QCT) in different animals. Among them, Cb3 and Cb8, M6, and O9 are metabolic residual markers of CBX, MEQ and OLA, which are associated with N → O reduction. Toxicity studies revealed that QdNOs exhibited severe tumorigenicity, cytotoxicity, and adrenal toxicity. Metabolic toxicology showed that toxicity of QdNOs metabolites might be related to the N → O group reduction, and some metabolites exhibited higher toxic effects than the precursor, which could provide guidance for further research on the metabolic toxicology of QdNOs and provide a wealth of information for food safety evaluation.

Reinforced Immunogenic Endoplasmic Reticulum Stress and Oxidative Stress via an Orchestrated Nanophotoinducer to Boost Cancer Photoimmunotherapy.

Cancer progression and treatment-associated cellular stress impairs therapeutic outcome by inducing resistance. Endoplasmic reticulum (ER) stress is responsible for core events. Aberrant activation of stress sensors and their downstream components to disrupt homeostasis have emerged as vital regulators of tumor progression as well as response to cancer therapy. Here, an orchestrated nanophotoinducer (ERsNP) results in specific tumor ER-homing, induces hyperthermia and mounting oxidative stress associated reactive oxygen species (ROS), and provokes intense and lethal ER stress upon near-infrared laser irradiation. The strengthened "dying" of ER stress and ROS subsequently induce apoptosis for both primary and abscopal B16F10 and GL261 tumors, and promote damage-associated molecular patterns to evoke stress-dependent immunogenic cell death effects and release "self-antigens". Thus, there is a cascade to activate maturation of dendritic cells, reprogram myeloid-derived suppressor cells to manipulate immunosuppression, and recruit cytotoxic T lymphocytes and effective antitumor response. The long-term protection against tumor recurrence is realized through cascaded combinatorial preoperative and postoperative photoimmunotherapy including the chemokine (C-C motif) receptor 2 antagonist, ERsNP upon laser irradiation, and an immune checkpoint inhibitor. The results highlight great promise of the orchestrated nanophotoinducer to exert potent immunogenic cell stress and death by reinforcing ER stress and oxidative stress to boost cancer photoimmunotherapy.

Synthetic self-adjuvanted multivalent Mucin 1 (MUC1) glycopeptide vaccines with improved in vivo antitumor efficacy.

The tumor-associated glycoprotein Mucin 1 (MUC1) is aberrantly glycosylated on cancer cells and is considered a promising target for antitumor vaccines. The weak immunogenicity and low sequence homology of mouse mucins and human MUC1 are the main obstacles for the development of vaccines. Herein, a self-adjuvanted strategy combining toll-like receptor 2 lipopeptide ligands and T-cell epitopes and the multivalent effect were used to amplify the immune response and evade the unpredictable immunogenicity, generating two self-adjuvanted three-component MUC1 vaccines (mono- and trivalent MUC1 vaccines). To simulate the aberrantly glycosylated MUC1 glycoprotein, the MUC1 tandem repeat peptide was bounded with Tn antigens at T9, S15, and T16, and served as B-cell epitopes. Results showed that both vaccines elicited a robust antibody response in wild-type mice compared with a weaker response in MUC1 transgenic mice. The trivalent vaccine did not elevate the antibody response level compared with the monovalent vaccine; however, a more delayed tumor growth and prolonged survival time was realized in wild-type and transgenic mouse models treated with the trivalent vaccine. These results indicate that the self-adjuvanted three-component MUC1 vaccines, especially the trivalent vaccine, can trigger robust antitumor effects regardless of sequence homology, and, therefore, show promise for clinical translation.

Aerobic glycolysis of bronchial epithelial cells rewires Mycoplasma pneumoniae pneumonia and promotes bacterial elimination.

The immune response to Mycoplasma pneumoniae infection plays a key role in clinical symptoms. Previous investigations focused on the pro-inflammatory effects of leukocytes and the pivotal role of epithelial cell metabolic status in finely modulating the inflammatory response have been neglected. Herein, we examined how glycolysis in airway epithelial cells is affected by M. pneumoniae infection in an in vitro model. Additionally, we investigated the contribution of ATP to pulmonary inflammation. Metabolic analysis revealed a marked metabolic shift in bronchial epithelial cells during M. pneumoniae infection, characterized by increased glucose uptake, enhanced aerobic glycolysis, and augmented ATP synthesis. Notably, these metabolic alterations are orchestrated by adaptor proteins, MyD88 and TRAM. The resulting synthesized ATP is released into the extracellular milieu via vesicular exocytosis and pannexin protein channels, leading to a substantial increase in extracellular ATP levels. The conditioned medium supernatant from M. pneumoniae-infected epithelial cells enhances the secretion of both interleukin (IL)-1ß and IL-18 by peripheral blood mononuclear cells, partially mediated by the P2X7 purine receptor (P2X7R). In vivo experiments confirm that addition of a conditioned medium exacerbates pulmonary inflammation, which can be attenuated by pre-treatment with a P2X7R inhibitor. Collectively, these findings highlight the significance of airway epithelial aerobic glycolysis in enhancing the pulmonary inflammatory response and aiding pathogen clearance.

Development and validation of a multimorbidity risk prediction nomogram among Chinese middle-aged and older adults: a retrospective cohort study.

OBJECTIVES: The aim of this study is to establish a self-simple-to-use nomogram to predict the risk of multimorbidity among middle-aged and older adults. DESIGN: A retrospective cohort study. PARTICIPANTS: We used data from the Chinese Longitudinal Healthy Longevity Survey, including 7735 samples. MAIN OUTCOME MEASURES: Samples' demographic characteristics, modifiable lifestyles and depression were collected. Cox proportional hazard models and nomogram model were used to estimate the risk factors of multimorbidity. RESULTS: A total of 3576 (46.2%) participants have multimorbidity. The result showed that age, female (HR 0.80, 95% CI 0.72 to 0.89), chronic disease (HR 2.59, 95% CI 2.38 to 2.82), sleep time (HR 0.78, 95% CI 0.72 to 0.85), regular physical activity (HR 0.88, 95% CI 0.81 to 0.95), drinking (HR 1.27 95% CI 1.16 to 1.39), smoking (HR 1.40, 95% CI 1.26 to 1.53), body mass index (HR 1.04, 95% CI 1.03 to 1.05) and depression (HR 1.02, 95% CI 1.01 to 1.03) were associated with multimorbidity. The C-index of nomogram models for derivation and validation sets were 0.70 (95% CI 0.69 to 0.71, p=0.006) and 0.71 (95% CI 0.70 to 0.73, p=0.008), respectively. CONCLUSIONS: We have crafted a user-friendly nomogram model for predicting multimorbidity risk among middle-aged and older adults. This model integrates readily available and routinely assessed risk factors, enabling the early identification of high-risk individuals and offering tailored preventive and intervention strategies.

Tolperisone induces UPR-mediated tumor inhibition and synergizes with proteasome inhibitor and immunotherapy by targeting LSD1.

BACKGROUND: Drug repurposing is an attractive strategy for extending the arsenal of oncology therapies. Tolperisone is an old centrally acting muscle relaxant used for treatment of chronic pain conditions. In this study, we investigated the therapeutic effect and mechanism of tolperisone in human cancers and explored the combination strategy with proteasome inhibitor and immunotherapy. RESEARCH DESIGN AND METHODS: The antitumor effect of tolperisone was evaluated by measuring half maximal inhibitory concentration, cell death, and cell growth. RNA sequencing, western blotting, molecular docking, enzyme activity assay, and ChIP-qPCR were performed to reveal the underlying mechanism. Xenograft models were used to evaluate the efficacy of tolperisone alone or in combination with proteasome inhibitor or immunotherapy. RESULTS: Tolperisone inhibited cell growth and induced cell death in human cancer cell lines. Unfolded protein responses (UPR) pathway was hyperactivated in tolperisone-treated cells. We further identified histone lysine-specific demethylase 1 (LSD1) as a potential target of tolperisone, which directly demethylates UPR-related genes in H3K4me2. Tolperisone synergistically improved the efficacy of MG132 by enhancing UPR and sensitized tumors to immunotherapy by reprogramming M2 macrophages into M1 phenotype.Tolperisone inhibits human cancer by targeting LSD1. Repurposing tolperisone in cancer therapy by a combination strategy implies clinical potential.

STAG2 inactivation reprograms glutamine metabolism of BRAF-mutant thyroid cancer cells.

STAG2, an important subunit in cohesion complex, is involved in the segregation of chromosomes during the late mitosis and the formation of sister chromatids. Mutational inactivation of STAG2 is a major cause of the resistance of BRAF-mutant melanomas to BRAF/MEK inhibitors. In the present study, we found that STAG2 was frequently down-regulated in thyroid cancers compared with control subjects. By a series of in vitro and in vivo studies, we demonstrated that STAG2 knockdown virtually had no effect on malignant phenotypes of BRAF-mutant thyroid cancer cells such as cell proliferation, colony formation and tumorigenic ability in nude mice compared with the control. In addition, unlike melanoma, STAG2 knockdown also did not affect the sensitivity of these cells to MEK inhibitor. However, we surprisingly found that STAG2-knockdown cells exhibited more sensitive to glutamine deprivation or glutaminase inhibitor BPTES compared with control cells. Mechanistically, knocking down STAG2 in BRAF-mutant thyroid cancer cells decreases the protein stability of c-Myc via the ERK/AKT/GSK3ß feedback pathway, thereby impairing glutamine metabolism of thyroid cancer cells by down-regulating its downstream targets such as SCL1A5, GLS and GLS2. Our data, taken together, demonstrate that STAG2 inactivation reprograms glutamine metabolism of BRAF-mutant thyroid cancer cells, thereby improving their cellular response to glutaminase inhibitor. This study will provide a potential therapeutic strategy for BRAF-mutant thyroid cancers.

PSMD8 can serve as potential biomarker and therapeutic target of the PSMD family in ovarian cancer: based on bioinformatics analysis and in vitro validation.

BACKGROUND: The ubiquity-proteasome system is an indispensable mechanism for regulating intracellular protein degradation, thereby affecting human antigen processing, signal transduction, and cell cycle regulation. We used bioinformatics database to predict the expression and related roles of all members of the PSMD family in ovarian cancer. Our findings may provide a theoretical basis for early diagnosis, prognostic assessment, and targeted therapy of ovarian cancer. METHODS: GEPIA, cBioPortal, and Kaplan-Meier Plotter databases were used to analyze the mRNA expression levels, gene variation, and prognostic value of PSMD family members in ovarian cancer. PSMD8 was identified as the member with the best prognostic value. The TISIDB database was used to analyze the correlation between PSMD8 and immunity, and the role of PSMD8 in ovarian cancer tissue was verified by immunohistochemical experiments. The relationship of PSMD8 expression with clinicopathological parameters and survival outcomes of ovarian cancer patients was analyzed. The effects of PSMD8 on malignant biological behaviors of invasion, migration, and proliferation of ovarian cancer cells were studied by in vitro experiments. RESULTS: The expression levels of PSMD8/14 mRNA in ovarian cancer tissues were significantly higher than those in normal ovarian tissues, and the expression levels of PSMD2/3/4/5/8/11/12/14 mRNA were associated with prognosis. Up-regulation of PSMD4/8/14 mRNA expression was associated with poor OS, and the up-regulation of PSMD2/3/5/8 mRNA expression was associated with poor PFS in patients with ovarian serous carcinomas. Gene function and enrichment analysis showed that PSMD8 is mainly involved in biological processes such as energy metabolism, DNA replication, and protein synthesis. Immunohistochemical experiments showed that PSMD8 was mainly expressed in the cytoplasm and the expression level was correlated with FIGO stage. Patients with high PSMD8 expression had poor prognosis. Overexpression of PSMD8 significantly enhanced the proliferation, migration, and invasion abilities in ovarian cancer cells. CONCLUSION: We observed different degrees of abnormal expression of members of PSMD family in ovarian cancer. Among these, PSMD8 was significantly overexpressed in ovarian malignant tissue, and was associated with poor prognosis. PSMDs, especially PSMD8, can serve as potential diagnostic and prognostic biomarkers and therapeutic targets in ovarian cancer.

Metastatic differentiated thyroid cancer with negative serum stimulated Tg but positive post-therapeutic 131I-SPECT/CT scintigraphy: a single-center retrospective study.

PURPOSE: This study aimed to describe the characteristics of patients with metastatic differentiated thyroid carcinoma (DTC) who had positive 131I-scintigraphy but negative stimulated thyroglobulin (sTg), and to evaluate their short-term response to radioiodine therapy (RAI). METHODS: A total of 2250 consecutive postoperative DTC patients, who underwent RAI treatment from July 2019 to June 2022, were analyzed retrospectively. The target group was defined as stimulated Tg < 2 ng/mL with TgAb < 100 IU/mL but with post-therapeutic 131I-SPECT/CT metastases. The characteristics of these patients were analyzed and the metastatic profiles were compared with TgAb positive or sTg positive ones. A cross-sectional efficacy was evaluated 6-12 months after the RAI therapy and the treatment course until the end of the study was recorded. RESULTS: 105 (4.67%) DTC patients were post-therapeutic 131I-SPECT/CT positive and sTg negative (target group). Metastatic profiles were found significant differences between sTg negative and sTg positive ones (P < 0.001). Excellent response (ER) was achieved in 72.4% of the target group between 6-12 months of cross-sectional efficacy assessment, compared with only 12.8% in sTg positive ones (P < 0.001). The majority of the target group didn't require aggressive treatment in short-term follow-up compared with sTg positive group (P < 0.001). CONCLUSION: The percentage of DTCs with negative sTg but positive post-therapeutic 131I-SPECT/CT was relatively low, but still significant. Moreover, the majority of these patients showed an ER to RAI and may not require the next course of therapy. Long-term follow-up is still necessary to assess recurrence and adapt surveillance in these patients.

Oxidative Stress Response Biomarkers of Ovarian Cancer Based on Single-Cell and Bulk RNA Sequencing.

Background: The occurrence and development of ovarian cancer (OV) are significantly influenced by increased levels of oxidative stress (OS) byproducts and the lack of an antioxidant stress repair system. Hence, it is necessary to explore the markers related to OS in OV, which can aid in predicting the prognosis and immunotherapeutic response in patients with OV. Methods: The single-cell RNA-sequencing (scRNA-seq) dataset GSE146026 was retrieved from the Gene Expression Omnibus (GEO) database, and Bulk RNA-seq data were obtained from TCGA and GTEx databases. The Seurat R package and SingleR package were used to analyze scRNA-seq and to identify OS response-related clusters based on ROS markers. The "limma" R package was used to identify the differentially expressed genes (DEGs) between normal and ovarian samples. The risk model was constructed using the least absolute shrinkage and selection operator (LASSO) regression analysis. The immune cell infiltration, genomic mutation, and drug sensitivity of the model were analyzed using the CIBERSORT algorithm, the "maftools," and the "pRRophetic" R packages, respectively. Results: Based on scRNA-seq data, we identified 12 clusters; OS response-related genes had the strongest specificity for cluster 12. A total of 151 genes were identified from 2928 DEGs to be significantly correlated with OS response. Finally, nine prognostic genes were used to construct the risk score (RS) model. The risk score model was an independent prognostic factor for OV. The gene mutation frequency and tumor immune microenvironment in the high- and low-risk score groups were significantly different. The value of the risk score model in predicting immunotherapeutic outcomes was confirmed. Conclusions: OS response-related RS model could predict the prognosis and immune responses in patients with OV and provide new strategies for cancer treatment.

Disulfiram/Cu Kills and Sensitizes BRAF-Mutant Thyroid Cancer Cells to BRAF Kinase Inhibitor by ROS-Dependently Relieving Feedback Activation of MAPK/ERK and PI3K/AKT Pathways.

BRAFV600E, the most common genetic alteration, has become a major therapeutic target in thyroid cancer. Vemurafenib (PLX4032), a specific inhibitor of BRAFV600E kinase, exhibits antitumor activity in patients with BRAFV600E-mutated thyroid cancer. However, the clinical benefit of PLX4032 is often limited by short-term response and acquired resistance via heterogeneous feedback mechanisms. Disulfiram (DSF), an alcohol-aversion drug, shows potent antitumor efficacy in a copper (Cu)-dependent way. However, its antitumor activity in thyroid cancer and its effect on cellular response to BRAF kinase inhibitors remain unclear. Antitumor effects of DSF/Cu on BRAFV600E-mutated thyroid cancer cells and its effect on the response of these cells to BRAF kinase inhibitor PLX4032 were systematically assessed by a series of in vitro and in vivo functional experiments. The molecular mechanism underlying the sensitizing effect of DSF/Cu on PLX4032 was explored by Western blot and flow cytometry assays. DSF/Cu exhibited stronger inhibitory effects on the proliferation and colony formation of BRAFV600E-mutated thyroid cancer cells than DSF treatment alone. Further studies revealed that DSF/Cu killed thyroid cancer cells by ROS-dependent suppression of MAPK/ERK and PI3K/AKT signaling pathways. Our data also showed that DSF/Cu strikingly increased the response of BRAFV600E-mutated thyroid cancer cells to PLX4032. Mechanistically, DSF/Cu sensitizes BRAF-mutant thyroid cancer cells to PLX4032 by inhibiting HER3 and AKT in an ROS-dependent way and subsequently relieving feedback activation of MAPK/ERK and PI3K/AKT pathways. This study not only implies potential clinical use of DSF/Cu in cancer therapy but also provides a new therapeutic strategy for BRAFV600E-mutated thyroid cancers.

Academic Performance and Peer or Parental Tobacco Use among Non-Smoking Adolescents: Influence of Smoking Interactions on Intention to Smoke.

BACKGROUND: Intention to smoke is an important predictor of future smoking among adolescents. The purpose of our study was to examine the interaction between academic performance and parents/peer tobacco use on adolescents' intention to smoke. METHODS: A multi-stage stratified sampling was used to select participants, involving 9394 students aged between 9-16 years in Changchun city, northeastern China. Multiple logistic regression analyses were conducted to examine the individual effect of academic performance and peer/parental smoking behavior. Stratified logistic regressions were conducted to examine the protective effect of academic performance based on peer or parental smoking. Interaction effects of academic performance × peer/parental smoking on adolescents' intention to smoke were tested. RESULTS: Of all the non-smoking students sampled, 11.9% intended to smoke within the next five years. The individual effect of academic performance and peer/parental smoking was significant. The protective effect of academic performance on the intention to smoke was significant regardless of whether peers smoked or not. However, the protective effect was not significant among adolescents with only maternal smoking and both parental smoking. The current study found the significant interaction effects of academic performance × peer smoking and the academic performance × both parents' smoking. Students with poor academic performance were more likely to intend to smoke if their peers or both parents smoked. CONCLUSION: These preliminary results suggest that peer smoking or smoking by both parents reinforces the association between low academic performance and the intention to smoke among adolescents. Enhancing school engagement, focusing on social interaction among adolescents with low academic performance, and building smoke-free families may reduce adolescents' intention to smoke.

The role of [99mTc]Tc-HFAPi SPECT/CT in patients with malignancies of digestive system: first clinical experience.

BACKGROUND: Recently, PET/CT imaging with radiolabelled FAP inhibitors (FAPIs) has been widely evaluated in diverse diseases. However, rare report has been published using SPECT/CT, a more available imaging method, with [99mTc]Tc-labelled FAPI. In this study, we evaluated the potential effect of [99mTc]Tc-HFAPi in clinical analysis for digestive system tumours. METHODS: This is a single-centre prospective diagnostic efficiency study (Ethic approved No.: XJTU1AF2021LSK-021 of the First Affiliated Hospital of Xi'an Jiaotong University and ChiCTR2100048093 of the Chinese Clinical Trial Register). Forty patients with suspected or confirmed digestive system tumours underwent [99mTc]Tc-HFAPi SPECT/CT between January and June 2021. For dynamic biodistribution and dosimetry estimation, whole-body planar scintigraphy was performed at 10, 30, 90, 150, and 240 min post-injection in four representative patients. Optimal acquisition time was considered in all the patients at 60-90 min post-injection, then quantified or semi-quantified using SUVmax and T/B ratio was done. The diagnostic performance of [99mTc]Tc-HFAPi was calculated and compared with those of contrast-enhanced CT (ceCT) using McNemar test, and the changes of tumour stage and oncologic management were recorded. RESULTS: Physiological distribution of [99mTc]Tc-HFAPi was observed in the liver, pancreas, gallbladder, and to a lesser extent in the kidneys, spleen and thyroid. Totally, 40 patients with 115 lesions were analysed. The diagnostic sensitivity of [99mTc]Tc-HFAPi for non-operative primary lesions was similar to that of ceCT (94.29% [33/35] vs 100% [35/35], respectively; P = 0.5); in local relapse detection, [99mTc]Tc-HFAPi was successfully detected in 100% (n = 3) of patients. In the diagnosis of suspected metastatic lesions, [99mTc]Tc-HFAPi exhibited higher sensitivity (89.66% [26/29] vs 68.97% [20/29], respectively, P = 0.03) and specificity (97.9% [47/48] vs 85.4% [41/48], respectively, P = 0.03) than ceCT, especially with 100% (24/24) specificity in the diagnosis of liver metastases, resulting in 20.0% (8/40) changes in TNM stage and 15.0% (6/40) changes in oncologic management. CONCLUSION: [99mTc]Tc-HFAPi demonstrates a greater diagnostic efficiency than ceCT in the detection of distant metastasis, especially in identifying liver metastases.

Case report: The effective response to pembrolizumab in combination with bevacizumab in the treatment of a recurrent glioblastoma with multiple extracranial metastases.

Multiple extracranial metastases of recurrent glioblastoma are rare and often indicate a very poor prognosis. The main conventional treatments are chemotherapy, radiotherapy, chemoradiotherapy or antiangiogenic therapy. Median overall survival is 2.3 to 6 months after the detection of extracranial metastases, and to date, there is no effective treatment for these patients. Herein, we report a recurrent glioblastoma patient with lung metastasis treated with a combination therapy containing bevacizumab and pembrolizumab due to overexpression of PD-L1 and the absence of driver mutations. The progression-free survival was 11 months from lung metastases to bone metastases. This combination treatment was further used as maintenance therapy for another 11 months after bone metastasis and secondary dorsal metastasis because there was no suitable treatment alternative. The overall survival was 27 months after lung metastases, which is much longer than previously reported cases. To our knowledge, this was the first effective use of bevacizumab plus pembrolizumab in a glioblastoma patient with extracranial metastases. Furthermore, this was the first time that bevacizumab plus pembrolizumab was used as a maintenance treatment in glioblastoma, with 11 months of response. Importantly, we showed that such combination therapy may be a novel and effective therapy for glioblastoma patients with extracranial metastases.

Sinomenine Hydrochloride Promotes TSHR-Dependent Redifferentiation in Papillary Thyroid Cancer.

Radioactive iodine (RAI) plays an important role in the diagnosis and treatment of papillary thyroid cancer (PTC). The curative effects of RAI therapy are not only related to radiosensitivity but also closely related to the accumulation of radionuclides in the lesion in PTC. Sinomenine hydrochloride (SH) can suppress tumor growth and increase radiosensitivity in several tumor cells, including PTC. The aim of this research was to investigate the therapeutic potential of SH on PTC cell redifferentiation. In this study, we treated BCPAP and TPC-1 cells with SH and tested the expression of thyroid differentiation-related genes. RAI uptake caused by SH-pretreatment was also evaluated. The results indicate that 4 mM SH significantly inhibited proliferation and increased the expression of the thyroid iodine-handling gene compared with the control group (p < 0.005), including the sodium/iodide symporter (NIS). Furthermore, SH also upregulated the membrane localization of NIS and RAI uptake. We further verified that upregulation of NIS was associated with the activation of the thyroid-stimulating hormone receptor (TSHR)/cyclic adenosine monophosphate (cAMP) signaling pathway. In conclusion, SH can inhibit proliferation, induce apoptosis, promote redifferentiation, and then increase the efficacy of RAI therapy in PTC cells. Thus, our results suggest that SH could be useful as an adjuvant therapy in combination with RAI therapy in PTC.