Osteosarcoma is a highly malignant bone tumor, and a subset of cases is closely associated with hereditary syndromes. These syndrome-related osteosarcomas exhibit unique clinical features, molecular mechanisms, and therapeutic challenges. This review summarizes the current understanding of specific types of syndrome-related osteosarcomas, including those associated with Rothmund-Thomson syndrome, Li-Fraumeni syndrome, secondary osteosarcoma in retinoblastoma survivors, Werner syndrome, and Bloom syndrome. These syndromes are typically characterized by specific gene mutations or chromosomal instability, significantly increasing the risk of osteosarcoma development. However, the rarity and heterogeneity of syndrome-related osteosarcomas pose significant challenges for diagnosis and treatment, including difficulties in early detection, incomplete elucidation of molecular mechanisms, and limitations of conventional therapeutic approaches. This article aims to systematically review the clinical characteristics, molecular mechanisms, and therapeutic challenges of these syndromes, providing a comprehensive reference for clinicians and directions for future research.

ABSTRACT Purpose The objective of this study was retrospectively to compare the efficacy and safety of hypofractionated radiotherapy (HFRT) with a simultaneous integrated boost (SIB) or with a sequential boost (SB) after breast‐conserving surgery in patients diagnosed with early breast cancer. Methods This study enrolled a total of 343 patients diagnosed with T1‐2N0‐1 breast cancer who had undergone breast‐conserving surgery followed by whole‐breast irradiation (WBI) without nodal irradiation, between March 2018 and April 2021. Out of 343 patients, 176 (51.3%) received HFRT‐SIB treatment, totaling 15 sessions, while the remaining 167 (48.7%) received HFRT‐SB treatment, totaling 18 sessions. Demographic characteristics, skin toxicity, radiation pneumonia, and myelosuppression, were compared in the two groups. Three‐year local progression free survival (LPFS) rates were determined using the Kaplan–Meier method and compared using the log‐rank test. Results The median follow‐up time was 39.7 months (range 24.3–61.3 months). Toxicities rates did not differ significantly in the HFRT‐SIB and HFRT‐SB groups, including rates of grade 2 skin toxicity (14.8% vs. 13.8%, p = 0.721), Grade 2 radiation pneumonia (2.8% vs. 3.6%, p = 0.355), grades 1, 2 and 3 myelosuppression (12.5%, 5.7% and 1.1%, respectively, vs. 9.6%, 7.8%, and 1.2%, respectively; p = 0.744). Three‐year cumulative LPFS rates were similar in the HFRT‐SIB and HFRT‐SB groups (99.3% vs. 98.6%, p = 0.52). Regional nodal recurrences were observed in one patient in the HFRT‐SIB group (after 27.4 months) and in two patients in the HFRT‐SB group (after 29.4 and 56.4 months), and a local recurrence was observed in one patient in the latter group after 36.0 months. One patient in the HFRT‐SIB group was diagnosed with distant metastases to bone, and one patient in the HFRT‐SB group was diagnosed with distant metastases to the liver. Conclusion Similar efficacy and safety of HFRT‐SIB and HFRT‐SB after breast‐conserving surgery in patients with early‐stage (T1‐2N0‐1) breast cancer. Longer‐term follow‐up is required to further compare their efficacy.

Neurodegenerative diseases are age-associated disorders characterized by distinctive pathological features. Microglia are essential for brain development and function. Modulating microglial activation in neurodegenerative diseases may provide novel therapeutic strategies. Ulinastatin (UTI), an intrinsic serine protease inhibitor, is widely used to treat acute inflammatory disorders. Although the anti-inflammatory effects of UTI have been studied, the mechanisms by which it affects microglial activation remain incompletely understood. In this study, we investigated the effects of UTI on lipopolysaccharide (LPS)-induced microglial activation in both rats and BV2 mouse microglial cells, with a focus on the MAPK and JAK-STAT signaling pathways. We employed Morris water maze, ELISA, MTT assay, immunohistochemistry, immunofluorescence, and western blotting to evaluate the impact of UTI. Our results showed that LPS induced microglial activation via MAPK and JAK-STAT signaling, resulting in elevated TNF-α and IL-1β expression and spatial learning deficits in rats. UTI treatment suppressed LPS-induced microglial activation by modulating these pathways, reduced pro-inflammatory cytokine production, and attenuated spatial memory impairment. Notably, our findings provide new evidence that UTI exerts anti-inflammatory and neuroprotective effects by targeting MAPK/JAK-STAT-mediated microglial activation, suggesting its potential as a therapeutic agent for neuroinflammatory and neurodegenerative diseases. Graphical abstract illustrating the experimental design and key findings. In the in vivo study, rats received intraperitoneal injections of PBS or LPS, followed by UTI administration 3 h later. One hour after UTI injection, cognitive function was assessed using the Morris water maze, and hippocampal tissues were subsequently collected for immunohistochemistry, ELISA, and western blot analysis. In the in vitro model, BV2 microglial cells were treated with LPS, followed by MTT assay, ELISA, and western blot experiments. The results demonstrate that UTI improves memory and cognitive function in rats, and suppresses the production of inflammatory cytokines by activated microglia, potentially via the MAPK and JAK-STAT signaling pathways.

Lead (Pb) exposure poses a significant public health concern due to its neurotoxic effects. While mitochondrial dysfunction is implicated in lead neurotoxicity, the precise molecular mechanisms, particularly the role of non-coding RNA-mediated competing endogenous RNA networks, remain underexplored. SH-SY5Y neuroblastoma cells were treated with 10 μM lead acetate. Cell viability was assessed by Cell Counting Kit-8 (CCK-8). Mitochondrial ultrastructure and quantity were analyzed via transmission electron microscopy (TEM). Key mitochondrial dynamics proteins were examined by Western blot. Comprehensive transcriptome sequencing, including long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), microRNAs (miRNAs) and mRNAs, was performed followed by functional enrichment and ceRNA network construction. Selected RNAs and hub genes were validated using quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR). Lead exposure significantly reduced SH-SY5Y cell viability and induced mitochondrial damage (decreased quantity, swelling, fragmentation). Western blot confirmed an imbalance in mitochondrial dynamics, as indicated by decreased mitofusin 2 (MFN2), increased total and phosphorylated dynamin-related protein 1 (DRP1). Transcriptomic analysis revealed widespread differential expression of lncRNAs, circRNAs, miRNAs, and mRNAs. Enrichment analysis highlighted mitochondrial function and oxidative stress pathways. A ceRNA network identified five key hub genes: SLC7A11, FOS, HMOX1, HGF, and NR4A1. All validated RNA and hub gene expression patterns were consistent with sequencing results. Our study demonstrates that lead exposure significantly impairs mitochondrial quantity and morphology in SH-SY5Y cells, likely via disrupted mitochondrial dynamics. We reveal the potential regulatory mechanisms of lead-induced neurotoxicity involving ceRNA networks, identifying hub genes crucial for cellular stress response. This research provides a foundational framework for developing therapeutic strategies against lead-induced neurotoxicity.

Immunosuppressive regulatory cells (IRCs) play important roles in negatively regulating immune response, and are mainly divided into myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs). Large numbers of preclinical and clinical studies have shown that inhibition or reduction of IRCs could effectively elevate antitumor immune responses. However, several studies also reported that excessive inhibition of IRCs function is one of the main reasons causing the side effects of cancer immunotherapy. Therefore, the reasonable regulation of IRCs is crucial for improving the safety and efficiency of cancer immunotherapy. In this review, we summarised the recent research advances in the cancer immunotherapy by regulating the proportion of IRCs, and discussed the roles of IRCs in regulating tumour immune evasion and drug resistance to immunotherapies. Furthermore, we also discussed how to balance the potential opportunities and challenges of using IRCs to improve the safety of cancer immunotherapies.

Background:Osteoporosis is a highly prevalent disease that causes fractures and loss of motor function. Current drugs targeted for osteoporosis often have inevitable side effects. Bone marrow mesenchymal stem cell (BMSCs)-derived apoptotic extracellular vesicles (ApoEVs) are nanoscale extracellular vesicles, which has been shown to promote bone regeneration with low immunogenicity and high biological compatibility. However, natural ApoEVs cannot inherently target bones, and are often eliminated by macrophages in the liver and spleen. Thus, our study aimed to reconstruct ApoEVs to enhance their bone-targeting capabilities and bone-promoting function and to provide a new method for osteoporosis treatment. Methods:We conjugated a bone-targeting peptide, (Asp-Ser-Ser)6 ((DSS)6), onto the surface of ApoEVs using standard carbodiimide chemistry with DSPE-PEG-COOH serving as the linker. The bone-targeting ability of (DSS)6-ApoEVs was determined using an in vivo imaging system and confocal laser scanning microscopy (CLSM). We then loaded ubiquitin ligase RING finger protein146 (RNF146) into BMSCs via adenovirus transduction to obtain functional ApoEVs. The bone-promoting abilities of (DSS)6-ApoEVs and (DSS)6-ApoEVsRNF146 were measured in vitro and in vivo. Results:Our study successfully synthesized bone-targeting and gained functional (DSS)6-ApoEVsRNF146 and found that engineered ApoEVs could promote osteogenesis in vitro and exert significant bone-targeting and osteogenesis-promoting effects to alleviate osteoporosis in a mouse model. Conclusion:To promote the bone-targeting ability of natural ApoEVs, we successfully synthesized engineered ApoEVs, (DSS)6-ApoEVsRNF146 and found that they could significantly promote osteogenesis and alleviate osteoporosis compared with natural ApoEVs, which holds great promise for the treatment of osteoporosis.

Low viability of seed cells and the concern about biosafety restrict the application of cell-based tissue-engineered bone (TEB). Exosomes that bear similar bioactivities to donor cells display strong stability and low immunogenicity. Human umbilical cord mesenchymal stem cells-derived exosomes (hUCMSCs-Exos) show therapeutic efficacy in various diseases. However, little is known whether hUCMSCs-Exos can be used to construct TEB to repair bone defects. Herein, PM-Exos and OM-Exos were separately harvested from hUCMSCs which were cultured in proliferation medium (PM) or osteogenic induction medium (OM). A series of in-vitro studies were performed to evaluate the bioactivities of human bone marrow mesenchymal stem cells (hBMSCs) when co-cultured with PM-Exos or OM-Exos. Differential microRNAs (miRNAs) between PM-Exos and OM-Exos were sequenced and analyzed. Furthermore, PM-Exos and OM-Exos were incorporated in 3D printed tricalcium phosphate scaffolds to build TEBs for the repair of critical-sized calvarial bone defects in rats. Results showed that PM-Exos and OM-Exos bore similar morphology and size. They expressed representative surface markers of exosomes and could be internalized by hBMSCs to promote cellular migration and proliferation. OM-Exos outweighed PM-Exos in accelerating the osteogenic differentiation of hBMSCs, which might be attributed to the differentially expressed miRNAs. Furthermore, OM-Exos sustainably released from the scaffolds, and the resultant TEB showed a better reparative outcome than that of the PM-Exos group. Our study found that exosomes isolated from osteogenically committed hUCMSCs prominently facilitated the osteogenic differentiation of hBMSCs. TEB grafts functionalized by OM-Exos bear a promising application potential for the repair of large bone defects.

Osteoarthritis (OA) is a chronic degenerative joint disease characterized by cartilage degeneration and subchondral bone remodelling. Currently, conservative treatment strategies cannot effectively alleviate the progression of OA. In this study, we used computer network analysis to show that Nitisinone (NTBC) is closely related to extracellular matrix degradation in OA and mainly interferes with the TNF-α signaling pathway. NTBC is an orphan drug used to treat hereditary type I tyrosinemia by altering phenylalanine/tyrosine metabolic flow. In this study, we found that NTBC effectively reduced chondrocyte inflammation and extracellular matrix degradation induced by TNF-α. Mechanistically, NTBC inhibited the cGAS/STING signaling pathway and reduced activation of the STING-dependent NF-κB pathway to alleviate inflammation. In addition, NTBC inhibited osteoclastogenesis and delayed the occurrence of subchondral bone remodelling. In mice with ACLT-induced osteoarthritis, intra-articular injection of NTBC significantly reduced cartilage degradation and subchondral bone remodelling. NTBC showed impressive therapeutic efficacy as a potential pharmaceutical intervention for the treatment of OA.

BACKGROUND:Oxaliplatin (OXA) is easy to cause sinusoidal obstruction syndrome (SOS), leading to liver injury. Isolinderalactone (ILL), one of the main components of Lindera aggregate, has been reported to have a protecting effect on the liver. However, it is unclear whether ILL has a therapeutic effect on liver injury caused by OXA. This study aims to determine the effect of ILL on the prevention and treatment of OXA-induced liver injury and to provide a basis for the chemotherapy of gastrointestinal tumors.METHODS:Intraperitoneal injection of folinic acid, 5-fluorouracil, and OXA was administered on the SOS rat model for 7 weeks. The indexes of liver function were measured by biochemical kit. The ratio of liver weight to body weight was calculated. The pathological analysis of the liver was scored with the SOS scoring standard, fibrosis was evaluated with a four-point scale. The expression of inflammation factors was detected by Real-Time PCR, and the related indexes of IL-6/STAT3 were examined by Western blot analysis.RESULTS:ILL down-regulated the portal vein pressure and alleviated the abnormal liver function of SOS rats and improved the liver lesions. ILL inhibited the SOS by inhibiting IL-6/STAT3.CONCLUSION:ILL resistance to liver injury through inhibiting IL-6/STAT3 signal pathway.

Immune checkpoint inhibitors, a type of immunotherapy, have demonstrated optimal treatment efficacy in inducing durable antitumor responses in various cancers. Cytokine-release syndrome is a rare immune-related adverse event induced by immune checkpoint inhibitors. In our case, a patient with hypopharyngeal squamous cell carcinoma received toripalimab combined with chemotherapy. On the fourth day post treatment, the patient developed fever and hypotension. Laboratory examination indicated myelosuppression, acute kidney injury and disseminated intravascular coagulation. Meanwhile, serum cytokine levels of IL-6, IL-8, IL-10, IL-1β, IFN-γ and the level of hypersensitive C-reactive protein were markedly elevated. The patient was diagnosed with cytokine release syndrome, which progressed rapidly and led to the patient's demise on the fifth day post treatment.

Objective: Gestational diabetes mellitus (GDM) affects 7% of pregnant women worldwide. How to effectively treat GDM has always been a concern of people.Research methods: In this study, a diabetes model was established by drug-induced mice. Subsequently, the blood glucose levels and serum insulin changes of the mice after N-acetyl-l-cysteine (NAC) treatment were observed. At the same time, the effect of NAC on reproduction of GDM mice was recorded.Results of the study: Mice fed NAC showed significantly improved glucose tolerance and insulin sensitivity compared to Diabetic/Control. Total serum cholesterol, serum triglycerides, and serum low-density lipoprotein were significantly reduced, and atherosclerosis index was much lower than in control mice. In addition, Diabetic/Control mice had lower litter sizes and higher birth weights. NAC treatment significantly restored litter size and reduced birth weight in Diabetic/Control mice. It was found in WB assay that the NAC-fed group significantly increased nuclear Nrf2 and HO-1 expression levels.Conclusion: NAC can improve blood glucose tolerance in GDM mice; NAC effectively relieves the symptoms of hyperlipidemia caused by GDM; NAC enhances the expression of Nrf2/HO-1 in the liver, thereby restoring redox homeostasis. NAC can reduce gestational diabetes-related disease indicators by oral administration, and has a beneficial effect on the offspring of pregnant mice (reduces its diabetes disease indicators).

Rationale: Vulvar melanoma is a rare and aggressive tumor with a high risk of local recurrence and distant metastasis. The prognosis is poor with a 5-year overall survival rate of only 46.6%. Management of vulvar melanoma remains a clinical challenge. Recent evidences have shown that immune checkpoint inhibitors are effective in the treatment of vulvar melanoma. Patient concerns and diagnoses: A 63-year-old woman with vulvar malignant melanoma suffered inguinal lymph node metastasis after vulvectomy and chemotherapy. She underwent inguinal lymph node dissection and inguinal radiotherapy. The tumor progressed again and she received immunotherapy. Interventions: The tumor progressed again, and she was admitted to our hospital and received toripalimab combined with apatinib and abraxane. Outcomes: After 6 cycles of immunotherapy, the efficacy achieved partial remission. And with toripalimab as maintenance therapy, the patient achieved durable antitumor efficacy and good safety. Lessons: In this rare case, the patient with metastatic vulvar malignant melanoma had durable antitumor efficacy and good safety when receiving toripalimab.

Abstract The authors have requested that this preprint be removed from Research Square.

Background: Clinical application of stem cell-based tissue-engineered bone (TEB) has been severely hindered by a low viability of seed cells, slow osteogenesis and biosafety. Mesenchymal stem cells-derived small extracellular vesicles (sEVs) possess similar properties to donor cells and have low immunogenicity, strong stability and favorable biosafety. It’s validated that h uman umbilical cord mesenchymal stem cells-derived sEVs (hUCMSCs-sEVs) exert therapeutic effects on various diseases. However, little is known whether hUCMSCs-sEVs can effectively be used to construct TEB. This study aimed to investigate whether hUCMSCs-sEVs bore positive effects on bone regeneration and elucidate the underlying mechanisms. Methods: PM-sEVs and OM-sEVs were separately harvested from proliferation medium (PM) and osteogenic medium (OM) cultured hUCMSCs and identified. The effects of PM-sEVs and OM-sEVs on the bioactivities and osteogenic differentiation of human bone marrow stromal cells (hBMSCs) were evaluated. The differential microRNAs (miRNAs) expressions between PM-sEVs and OM-sEVs were screened by miRNA sequencing. Furthermore, PM-sEVs and OM-sEVs were separately incorporated in tricalcium phosphate (TCP) scaffolds to build TEBs, which were used to repair critical-sized calvarial bone defects of rats. Results: Both PM-sEVs and OM-sEVs had similar morphology, size and expressed specific surface markers of exosomes while didn’t have the surface marker from donor cells. Both PM-sEVs and OM-sEVs could be internalized by hBMSCs, thus significantly promoting the migration, proliferation and osteogenic differentiation of hBMSCs. Remarkably, OM-sEVs outweighed PM-sEVs in accelerating hBMSCs ’ migration and osteogenic differentiation. Besides, miRNA sequencing analysis revealed that several differentially expressed miRNAs might be responsible for sEVs ’ bioactivities. Furthermore, OM-sEVs could sustainably release from TCP scaffolds, and the resultant TEB had better reparative outcome than that of PM-sEVs group and pure TCP. Conclusion: sEVs isolated from osteogenically induced hUCMSCs (OM-sEVs) could prominently facilitate osteogenic differentiation of hBMSCs by unique miRNAs signature. TEB graft derived from OM-sEVs provided a promising alternative for clinical transplantation. and negative markers in PM-sEVs, OM-sEVs and the respective donor cells PM-cells, OM-cells; (C), NTA of PM-sEVs and OM-sEVs. PM: proliferation medium without FBS and penicillin-streptomycin; OM: osteogenic medium without FBS and penicillin-streptomycin; NTA: nanoparticle tracking analysis (NTA).

Immune checkpoint inhibitors (ICIs) have achieved prominent efficacy in the treatment of numerous cancers, which is the most significant breakthrough in cancer therapy in recent years. However, ICIs are associated with a series of immune-related adverse events (irAEs). Pneumonitis is an uncommon but potentially fatal irAE. In the case reported here, a patient with advanced small cell lung cancer (SCLC) had rapid progression of disease following chemotherapy and received ICIs. The patient experienced severe immune-related hyperthermia followed by immune-related pneumonitis. Fortunately, a good clinical response was achieved after the patient received corticosteroids and tocilizumab.

Background: Human epidermal growth factor receptor 2 (HER2) is an overexpressed antigen in esophageal squamous cell carcinomas (ESCCs) but with limited expression levels in normal esophageal tissues. Therefore, employing the adoptive transfer of T cells genetically modified to express chimeric antigen receptor (CAR) targeting HER2 could be a promising therapeutic strategy against ESCC. Methods: Two different second-generation CAR-T cells expressing antibodies for HER2 and CD19 antigens were developed using retroviral vector transduction. The expression of HER2 antigen in ESCC tissue and cell lines was examined by immunohistochemistry and flow cytometry, respectively. The tumor killing efficacy of the CAR-T cells in mice model and ESCC cell lines and its potential for the treatment of ESCC was evaluated by determining tumor size in mice xenograft, and by crystal violet staining, MTS assay, and cytokine release. Results: In vitro, HER2.CAR-T cells efficiently recognized and killed HER2-positive tumor cells as evidenced by the secretion of proinflammatory cytokines, interferon-γ, and interleukin 2 and by cytotoxicity assays. In vivo, intratumor injection of HER2.CAR-T cells resulted in a significant suppression of established ESCCs in a subcutaneous xenograft BALB/c nude mouse model. In contrast, the injection of CD19.CAR-T cells did not affect the tumor growth pattern. Conclusions: An effective HER2 CAR targeting ESCC was developed successfully. The HER2.CAR-T cell showed promising immunotherapeutic potential for the treatment of HER2-positive esophageal cancer.

OBJECTIVES:Mesenchymal stem cells (MSCs) based therapy for bone regeneration has been regarded as a promising method in the clinic. However, hBMSCs with invasive harvesting process and undesirable proliferation rate hinder the extensive usage. HUCMSCs of easier access and excellent performances provide an alternative for the fabrication of tissue-engineered bone construct. Evidence suggested the osteogenesis ability of hUCMSCs was weaker than that of hBMSCs. To address this issue, a co-culture strategy of osteogenically and angiogenically induced hUCMSCs has been proposed since thorough vascularization facilitates the blood-borne nutrition and oxygen to transport in the scaffold, synergistically expediting the process of ossification.MATERIALS AND METHODS:Herein, we used osteogenic- and angiogenic-differentiated hUCMSCs for co-culture in screened culture medium to elevate the osteogenic capacity with in vitro studies and finally coupled with 3D TCP scaffold to repair rat's critical-sized calvarial bone defect. By dual-directional induction, hUCMSCs could differentiate into osteoblasts and endothelial cells, respectively. To optimize the co-culture condition, gradient ratios of dual-directional differentiated hUCMSCs co-cultured under different medium were studied to determine the appropriate condition.RESULTS:It revealed that the osteogenic- and angiogenic-induced hUCMSCs mixed with the ratio of 3:1 co-cultured in the mixed medium of osteogenic induction medium to endothelial cell induction medium of 3:1 possessed more mineralization nodules. Similarly, ALP and osteogenesis/angiogenesis-related genes expressions were relatively higher. Further evidence of bone defect repair with 3D printed TCP of 3:1 group exhibited better restoration outcomes.CONCLUSIONS:Our work demonstrated a favourable and convenient approach of dual-directional differentiated hUCMSCs co-culture to improve the osteogenesis, establishing a novel way to fabricate tissue-engineered bone graft with 3D TCP for large bone defect augmentation.

Objective: (1) to investigate the expression of long non-coding RNA (lncRNA) H19 in OVCAR3 and cisplatin-resistant OVCAR3/DDP cells; (2) to explore the effects of lncRNA H19 on cisplatin-resistance in ovarian cancer (OC) cells; (3) to determine the roles of lncRNA H19 on OC cell migration and epithelial to mesenchymal transition (EMT)-related factors. Methods: The human ovarian cancer OVCAR3 cell line was obtained from ATCC; the cisplatinresistant OVCAR3/DDP cell line was induced from OVCAR3 cells through a progressive cisplatin concentration; OVCAR3 cells that overexpress lncRNA H19 and OVCAR3/DDP cells that silence the lncRNA H19 expression were established by the transfection of a recombinant lentivirus. A cell counting kit-8 (CCK-8) assay was used to determine the cell viability of OVCAR3 and OVCAR3/DDP. A reverse transcription-quantitative polymerase chain reaction (RT-qPCR) demonstrated the expressions of lncRNA H19, E-cadherin, twist, slug, and snail mRNA in OVCAR3 and OVCAR3/DDP cells. A Transwell assay was used to investigate the migration of OVCAR3 and OVCAR3/DDP cells. The expressions of E-cadherin, twist, slug, and snail proteins were determined by Western blot. Results: The cisplatinresistant OVCAR3/DPP cells were successfully established. The level of lncRNA H19 in the OVCAR3/DDP cells was significantly elevated compared with the OVCAR3 cells (P <0.05). The overexpression of lncRNA in the OVCAR3 cells improved the cisplatin-resistance, and the inhibition of lncRNA H19 expression in OVCAR3/DDP cells eliminated the cisplatin resistance. Furthermore, the migration ability and the expressions of the EMT positive regulator, twist, slug, snail mRNA, and protein in OVCAR3/DDP were dramatically up-regulated compared with the OVCAR3 group, and the expressions of the EMT negative regulator, E-cadherin mRNA, and protein were decreased compared with the OVCAR3 group, suggesting an increase of migration and EMT ability was observed in the OVCAR3/DDP cells. A gain of lncRNA expression in the OVCAR3 cells promoted migration and EMT-related activity; the loss of lncRNA H19 expression eliminated the enhanced ability of migration and EMT in the OVCAR3/DDP cells. Conclusions: LncRNA H19 is responsible for the cisplatin-resistance, migration, and MET regulation in OVCAR3 cells.

The long non-coding RNA (lncRNA) H19 is reported to be involved in invasion and metastasis of ovarian cancer (OC). In addition, the epithelial-mesenchymal transition (EMT) plays a role in the progression and metastasis of OC. However, whether lncRNA H19 involvement in OC invasion and metastasis is associated with EMT remains unclear. Eight cases of OC tissues and the corresponding adjacent normal (AN) tissues were included. The expressions of lncRNA H19 and EMT-related proteins (E-cadherin, TWIST1, Slug, and Snail) were detected by RT-qPCR and immunohistochemistry. Human OC cell lines (SKOv3, OVCAR3, CoC1, A2780, and HO-8910PM) and human normal ovarian surface epithelial HOSEpiC cells were obtained from ATCC. SKOv3 cells that silence the lncRNA H19 expression (silncRNA H19) were established via a transfection of recombinant lentivirus. The expression of lncRNA H19 and EMT-related proteins were significantly increased in human OC tissues compared with relative AN tissues (except for a decline in the level of E-cadherin) assessed through RT-qPCR and western blot. The lncRNA H19 and both EMT-related protein and mRNA levels (TWIST1, Slug, and Snail) in OC cell lines including SKOv3, OVCAR3, CoC1, A2780, and HO-8910PM were dramatically elevated compared with HOSEpiC cells (SKOv3 and OVCAR3: P < 0.01; CoC1, A2780, and HO-8910PM: P < 0.05); however, the expression of E-cadherin protein and mRNA were decreased, which is consistent with the results in vivo. Inhibition of lncRNA H19 expression in SKOv3 cells abolished the effects of lncRNA H19 on EMT-associated protein regulation. Importantly, Transwell assay suggested that invasion and metastasis ability were significantly reduced in SKOv3+silncRNA H19 group compared with SKOv3 group (P < 0.01). This study demonstrates a novel mechanism by which lncRNA H19 modulates OC cell invasion and metastasis, and this mechanism is involved in the regulation of EMT-related proteins.

The aim of the present study was to investigate the cytotoxic and antitumour effects of baicalin in human chondrosarcoma both in vivo and in vitro. We examined the effects of baicalin on the growth and apoptosis of human chondrosarcoma cells. Baicalin inhibited the growth of SW1353 and CH2879 cells in a dose- and time-dependent manner, but did not inhibit the growth of normal chondrocytes. Baicalin reduced tumour growth and induced apoptotic death in SW1353-transplanted nude mice without reducing their body weight. Further studies showed that baicalin reduced the mitochondrial membrane potential, upregulated the expression of Bax and cytoplasmic cytochrome c, downregulated the expression of Bcl-2 and mitochondrial cytochromes, and activated caspase-3 and caspase-9. Baicalin inhibited the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin pathway by decreasing the expression of phosphorylated phosphoinositide 3-kinase, phosphorylated protein kinase B, and phosphorylated mammalian target of rapamycin both in vivo and in vitro. Moreover, the mice that received SC79 and baicalin exhibited a greater tumour size compared with the mice that received baicalin. The mice that received LY294002 and baicalin showed a smaller tumour size compared with the mice that received baicalin. In the in vitro study, SC79 and LY294002 affected the baicalin-induced cytotoxic effects on chondrosarcoma cells in the same manner. Our data suggest baicalin has therapeutic efficacy in human chondrosarcoma through the induction of apoptosis and inhibition of the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin pathway. Baicalin can be considered a potential therapeutic agent for treating chondrosarcomas.