Learnable PM diffusion coefficients and reformative coordinate attention network for low dose CT denoising.

Objective.Various deep learning methods have recently been used for low dose CT (LDCT) denoising. Aggressive denoising may destroy the edge and fine anatomical structures of CT images. Therefore a key issue in LDCT denoising tasks is the difficulty of balancing noise/artifact suppression and edge/structure preservation.Approach.We proposed an LDCT denoising network based on the encoder-decoder structure, namely the Learnable PM diffusion coefficient and efficient attention network (PMA-Net). First, using the powerful feature modeling capability of partial differential equations, we constructed a multiple learnable edge module to generate precise edge information, incorporating the anisotropic image processing idea of Perona-Malik (PM) model into the neural network. Second, a multiscale reformative coordinate attention module was designed to extract multiscale information. Non-overlapping dilated convolution capturing abundant contextual content was combined with coordinate attention which could embed the spatial location information of important features into the channel attention map. Finally, we imposed additional constraints on the edge information using edge-enhanced multiscale perceptual loss to avoid structure loss and over-smoothing.Main results.Experiments are conducted on simulated and real datasets. The quantitative and qualitative results show that the proposed method has better performance in suppressing noise/artifacts and preserving edges/structures.Significance.This work proposes a novel edge feature extraction method that unfolds partial differential equation into neural networks, which contributes to the interpretability and clinical application value of neural network.

CAIR: Combining integrated attention with iterative optimization learning for sparse-view CT reconstruction.

Sparse-view CT is an efficient way for low dose scanning but degrades image quality. Inspired by the successful use of non-local attention in natural image denoising and compression artifact removal, we proposed a network combining integrated attention and iterative optimization learning for sparse-view CT reconstruction (CAIR). Specifically, we first unrolled the proximal gradient descent into a deep network and added an enhanced initializer between the gradient term and the approximation term. It can enhance the information flow between different layers, fully preserve the image details, and improve the network convergence speed. Secondly, the integrated attention module was introduced into the reconstruction process as a regularization term. It adaptively fuses the local and non-local features of the image which are used to reconstruct the complex texture and repetitive details of the image, respectively. Note that we innovatively designed a one-shot iteration strategy to simplify the network structure and reduce the reconstruction time while maintaining image quality. Experiments showed that the proposed method is very robust and outperforms state-of-the-art methods in terms of both quantitative and qualitative, greatly improving the preservation of structures and the removal of artifacts.

Effects of Exercise on Extracellular Vesicles in Patients with Metabolic Dysfunction: a Systematic Review.

The aim of this study was to investigate the effect of exercise on extracellular vesicles (EVs) in patients with metabolic dysfunction. The literatures were searched until Apr 28, 2022, and 16 studies that met inclusion criteria were included in this review. The results showed that the concentrations of platelet-derived extracellular vesicles (PEVs) and endothelial cell-derived extracellular vesicles (EEVs) decreased after long-term exercise, especially for CD62E+ EEVs and CD105+ EEVs. Simultaneously, exercise improved the concentration of clinical evaluation indicators of metabolic diseases, and the changes in these indicators were positively correlated with the changes of EEVs and PEVs. The concentration of skeletal muscle-derived extracellular vesicles (SkEVs) increased after a single bout of exercise. The aforementioned results indicated that long-term exercise might improve endothelial function and hypercoagulability in patients with metabolic dysfunction. The changes in concentrations of EVs could assist in assessing effect of exercise on patients with metabolic dysfunction.

Abnormalities of hippocampus and frontal lobes in heart failure patients and animal models with cognitive impairment or depression: A systematic review.

AIMS: This systematic review aimed to study the hippocampal and frontal changes of heart failure (HF) patients and HF animal models with cognitive impairment or depression. METHODS: A systematic review of the literature was conducted independently by reviewers using PubMed, Web of Science, Embase, and the Cochrane Library databases. RESULTS AND CONCLUSIONS: 30 studies were included, involving 17 pieces of clinical research on HF patients and 13 studies of HF animal models. In HF patients, the hippocampal injuries were shown in the reduction of volume, CBF, glucose metabolism, and gray matter, which were mainly observed in the right hippocampus. The frontal damages were only in reduced gray matter and have no difference between the right and left sides. The included HF animal model studies were generalized and demonstrated the changes in inflammation and apoptosis, synaptic reduction, and neurotransmitter disorders in the hippocampus and frontal lobes. The results of HF animal model studies complemented the clinical observations by providing potential mechanistic explanations of the changes in the hippocampus and frontal lobes.

Case report: Mycobacterium neoaurum infection during ICI therapy in a hepatocellular carcinoma patient with psoriasis.

We report here a patient with advanced hepatocellular carcinoma (HCC) and psoriasis treated with immune checkpoint inhibitor (ICI) therapy who experienced tumor partial response and psoriatic exacerbation. Meanwhile, the patient contracted mycobacterium neoaurum during the treatment period, while it was an opportunistic infection and mainly happened in immunosuppressed patients. We discussed the possibility that this infection was an ICI-associated infection independent of immunosuppression due to dysregulated immunity, which was the result of the effects of immunotherapy and autoimmune disease (AID), and the characteristics and treatment of M. neoaurum, which was rarely reported in China. This case highlights the fact that some infections can be precipitated by ICIs in the absence of immunosuppressive treatment, especially the patients with AID.

Effect of Extracellular Vesicles From Multiple Cells on Vascular Smooth Muscle Cells in Atherosclerosis.

Atherosclerosis (AS)-related diseases are still the main cause of death in clinical patients. The phenotype switching, proliferation, migration, and secretion of vascular smooth muscle cells (VSMCs) have a pivotal role in atherosclerosis. Although numerous research studies have elucidated the role of VSMCs in AS, their potential functional regulations continue to be explored. The formation of AS involves various cells, such as endothelial cells, smooth muscle cells, and macrophages. Therefore, intercellular communication of blood vessels cannot be ignored due to closely connected endothelia, media, and adventitia. Extracellular vesicles (EVs), as the vectors of cell-to-cell communication, can deliver proteins and nucleic acids of parent cells to the recipient cells. EVs have emerged as being central in intercellular communication and play a vital role in the pathophysiologic mechanisms of AS. This review summarizes the effects of extracellular vesicles (EVs) derived from multiple cells (endothelial cells, macrophages, mesenchymal stem cells, etc.) on VSMCs in AS. The key findings of this review are as follows: 1) endothelial cell-derived EVs (EEVs) have anti- or pro-atherogenic effects on VSMCs; 2) macrophage-derived EVs (MEVs) aggravate the proliferation and migration of VSMCs; 3) mesenchymal stem cells can inhibit VSMCs; and 4) the proliferation and migration of VSMCs can be inhibited by the treatment of EVs with atherosclerosis-protective factors and promoted by noxious stimulants. These results suggested that EVs have the same functional properties as treated parent cells, which might provide vital guidance for treating AS.

Efficacy and Safety for the Use of Half-Dosed Pegylated Granulocyte Colony-Stimulating Factors in Preventing Febrile Neutropenia During Chemotherapy in Patients With Malignant Tumors: A Multicenter, Open-Labeled, Single-Arm Phase 2 Trial.

Background: Prophylactic granulocyte-colony stimulating factor (G-CSF) has been shown to effectively prevent febrile neutropenia (FN) and grade 3/4 neutropenia during myelosuppressive treatment. The present study reports the clinical efficacy and safety of the prophylactic use of G-CSF with a half dose for cancer patients with an intermediate risk of FN combined with ≥1 patient-specific risk during multiple chemotherapy. Methods: This multicenter, one-arm, and open-label clinical study involved 151 patients [median age, 54 years old (range, 46.0-62.5); 38.4% female] with malignant tumors, including >20 different cancers. These patients underwent a total of 604 cycles of chemotherapy and received a half dose of PEG-rhG-CSF administration prior to each cycle. Results: The incidence rate of FN was 3.3% for this cohort during chemotherapy. Chemotherapy delay occurred in 6 (4.0%) patients for 12 (2.0%) cycles. Early termination of cancer treatment occurred in 14 (9.3%) patients. In this cohort, 23 (15.2%) patients required antibiotic use during courses of chemotherapy. A total of 28 (18.5%) patients experienced clear adverse effects during cancer treatment. Conclusion: The prophylactic PEG-rhG-CSF with a half dose can both efficaciously and safely prevent neutropenia for patients of diverse cancers with an intermediate risk of FN combined with ≥1 patient-specific risk during chemotherapy.

Differential early diagnosis of benign versus malignant lung cancer using systematic pathway flux analysis of peripheral blood leukocytes.

Early diagnosis of lung cancer is critically important to reduce disease severity and improve overall survival. Newer, minimally invasive biopsy procedures often fail to provide adequate specimens for accurate tumor subtyping or staging which is necessary to inform appropriate use of molecular targeted therapies and immune checkpoint inhibitors. Thus newer approaches to diagnosis and staging in early lung cancer are needed. This exploratory pilot study obtained peripheral blood samples from 139 individuals with clinically evident pulmonary nodules (benign and malignant), as well as ten healthy persons. They were divided into three cohorts: original cohort (n = 99), control cohort (n = 10), and validation cohort (n = 40). Average RNAseq sequencing of leukocytes in these samples were conducted. Subsequently, data was integrated into artificial intelligence (AI)-based computational approach with system-wide gene expression technology to develop a rapid, effective, non-invasive immune index for early diagnosis of lung cancer. An immune-related index system, IM-Index, was defined and validated for the diagnostic application. IM-Index was applied to assess the malignancies of pulmonary nodules of 109 participants (original + control cohorts) with high accuracy (AUC: 0.822 [95% CI: 0.75-0.91, p < 0.001]), and to differentiate between phases of cancer immunoediting concept (odds ratio: 1.17 [95% CI: 1.1-1.25, p < 0.001]). The predictive ability of IM-Index was validated in a validation cohort with a AUC: 0.883 (95% CI: 0.73-1.00, p < 0.001). The difference between molecular mechanisms of adenocarcinoma and squamous carcinoma histology was also determined via the IM-Index (OR: 1.2 [95% CI 1.14-1.35, p = 0.019]). In addition, a structural metabolic behavior pattern and signaling property in host immunity were found (bonferroni correction, p = 1.32e - 16). Taken together our findings indicate that this AI-based approach may be used for "Super Early" cancer diagnosis and amend the current immunotherpay for lung cancer.

The Improvement of Cardiac and Endothelial Functions of Xue-Fu-Zhu-Yu Decoction for Patients with Acute Coronary Syndrome: A Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Xue-Fu-Zhu-Yu decoction (XFZYD) is a traditional Chinese prescription that has been used to treat patients with blood stasis in China for many years. The present study aimed to evaluate the improvement of cardiac and endothelial functions of XFZYD for patients with acute coronary syndrome (ACS) through a systematic review and meta-analysis. METHODS: Six databases were searched to collect RCTs related to the treatment of XFZYD for ACS. The primary outcomes were cardiac and endothelial functions, including the levels of left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVEDD), and left ventricular end-systolic diameter (LVESD) in echocardiography, as well as the changes in the levels of nitric oxide (NO), endothelin-1 (ET-1), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) in the serum. The secondary outcomes were the blood levels of oxidative damage markers (including superoxide dismutase (SOD) and malondialdehyde (MDA)), C-reactive protein (CRP), brain natriuretic peptide (BNP), creatine kinase-MB (CK-MB), and cardiac troponin I (cTnI) as well as the incidence of adverse drug reactions (ADRs). Weighted mean difference (WMD) was estimated for all the outcomes with the random effects model. This type of analysis was conducted in the subgroups of the ACS subtypes, and the methodological quality was assessed using the handbook of Cochrane Collaboration. RESULTS: A total of 1,658 records were identified, and 16 randomized controlled trials (1,171 patients) were included. The primary outcomes suggested that XFZYD combined with routine treatment improved LVEF, reduced LVEDD and LVESD, and also improved the serum levels of NO, and reduced the levels of ET-1 and ICAM-1. XFZYD combination therapy significantly ameliorated the blood levels of SOD, MDA, BNP, CK-MB, and cTnI. However, the results indicated no significant difference between XFZYD plus routine treatment and routine treatment for the levels of VCAM-1 and CRP. Moreover, all the ADRs reported in the included studies were slight and the patients recovered soon. CONCLUSIONS: The present study suggested that XFZYD may improve the cardiac and endothelial functions of ACS patients without serious ADRs. However, based on the mediocre methodological quality, the aforementioned conclusion should be confirmed in a multicenter, large-scale, and accurately designed clinical trial.

Mesenchymal Stem Cell Exosomes in the Treatment of Myocardial Infarction: a Systematic Review of Preclinical In Vivo Studies.

Several prior studies have highlighted the promise of mesenchymal stem cells (MSCs) as tools for treating myocardial infarction (MI) patients. While MSCs were initially thought to mediate post-MI repair through differentiation and replacement of injured cells, they are now thought to function by releasing exosomes carrying important cargos which can prevent apoptosis and facilitate revascularization in the context of MI. Herein, we comprehensively survey prior preclinical studies examining MSC-derived exosomes (MSC-Exos) utility for the repair of MI-related tissue injury. In total, 24 relevant studies were identified in the PubMed, Web of Science, Embase, and Cochrane Library databases as per the PRISMA guidelines. In most studies, exosome-treated rodents exhibited improved cardiac function and angiogenesis together with decreased apoptotic cell death. MSC-Exos thus offer beneficial therapeutic efficacy when treating MI injury. However, further work will be necessary to standardize experimental preclinical models and to validate these results. This systematic review provides a comprehensive overview of previous preclinical studies on the utility of exosomes derived from mesenchymal stem cells (MSCs) in the repair of myocardial infarction (MI) injury.

Atheroprotective Effects and Mechanisms of Postmarketing Chinese Patent Formulas in Atherosclerosis Models: A Systematic Review.

BACKGROUND: Some postmarketing Chinese patent formulas have been widely used to treat atherosclerosis (AS) and play critical roles in Chinese healthcare. However, the usage of these herbs is yet controversial due to unclear effects and lack of understanding of the mechanism of action. With the modernization of traditional Chinese formulas, we are to elucidate the atheroprotective properties of these remedies from successful postmarketing experiments in vivo. METHODS: In this systematic review, we critically searched the databases, applied stringent criteria, assessed the methodological quality, and examined the current evidence in vivo. RESULTS: Consequently, 60 studies were included in the present qualitative synthesis. Data on models, high-fat diet, intervention time, outcome measures, efficacy, and mechanisms were collected. Finally, 23 formulas that could alleviate AS were correlated to the amelioration of plaques, improvement of plaque stability, modification of lipid level and lipid metabolism, and the effects of anti-inflammation and antioxidant stress with multiple components and targets. However, the methodological quality was low and incomplete among the included literature. CONCLUSIONS: Thus, taken together, the studies on postmarketing Chinese patent formulas would provide a novel approach to improve the treatment of AS, and rigorously designed studies would provide high-quality evidence.

Comprehensive Analysis of Key mRNAs and lncRNAs in Osteosarcoma Response to Preoperative Chemotherapy with Prognostic Values.

OBJECTIVE: Osteosarcoma is one of the most common types of bone sarcoma with a poor prognosis. However, identifying the predictive factors that contribute to the response to neoadjuvant chemotherapy remains a significant challenge. METHODS: A public data series (GSE87437) was downloaded to identify differentially expressed genes (DEGs) and differentially expressed lncRNAs (DElncRNAs) between osteosarcoma patients that do and do not respond to preoperative chemotherapy. Subsequently, functional analysis of the transcriptome expression profile, regulatory networks of DEGs and DElncRNAs, competing endogenous RNAs (ceRNA) and protein-protein interaction networks were performed. Furthermore, the function, pathway, and survival analysis of hub genes was performed and drug and disease relationship prediction of DElncRNA was carried out. RESULTS: A total of 626 DEGs, 26 DElncRNAs, and 18 hub genes were identified. However, only one gene and two lncRNAs were found to be suitable as candidate gene and lncRNAs respectively. CONCLUSION: The DEGs, hub genes, candidate gene, and candidate lncRNAs screened out in this context were considered as potential biomarkers for the response to neoadjuvant chemotherapy of osteosarcoma.

Complement C3 identified as a unique risk factor for disease severity among young COVID-19 patients in Wuhan, China.

Given that a substantial proportion of the subgroup of COVID-19 patients that face a severe disease course are younger than 60 years, it is critical to understand the disease-specific characteristics of young COVID-19 patients. Risk factors for a severe disease course for young COVID-19 patients and possible non-linear influences remain unknown. Data were analyzed from COVID-19 patients with clinical outcome in a single hospital in Wuhan, China, collected retrospectively from Jan 24th to Mar 27th. Clinical, demographic, treatment and laboratory data were collected from patients' medical records. Uni- and multivariable analysis using logistic regression and random forest, with the latter allowing the study of non-linear influences, were performed to investigate the clinical characteristics of a severe disease course. A total of 762 young patients (median age 47 years, interquartile range [IQR] 38-55, range 18-60; 55.9% female) were included, as well as 714 elderly patients as a comparison group. Among the young patients, 362 (47.5%) had a severe/critical disease course and the mean age was statistically significantly higher in the severe subgroup than in the mild subgroup (59.3 vs. 56.0, Student's t-test: p < 0.001). The uni- and multivariable analysis suggested that several covariates such as elevated levels of serum amyloid A (SAA), C-reactive protein (CRP) and lactate dehydrogenase (LDH), and decreased lymphocyte counts influence disease severity independently of age. Elevated levels of complement C3 (odds ratio [OR] 15.6, 95% CI 2.41-122.3; p = 0.039) are particularly associated with the risk of developing severe COVID-19 specifically in young patients, whereas no such influence seems to exist for elderly patients. Additional analysis suggests that the influence of complement C3 in young patients is independent of age, gender, and comorbidities. Variable importance values and partial dependence plots obtained using random forests delivered additional insights, in particular indicating non-linear influences of risk factors on disease severity. This study identified increased levels of complement C3 as a unique risk factor for adverse outcomes specific to young COVID-19 patients.

Neocarzilin A Is a Potent Inhibitor of Cancer Cell Motility Targeting VAT-1 Controlled Pathways.

The natural product neocarzilin A (NCA) was discovered decades ago, and despite its potent cytotoxic effects no mode of action studies have been performed up to date. Synthesis of neocarzilins A, B, and C and a stereoisomer of NCA provided insights into structural preferences as well as access to probes for functional studies. NCA turned out to be the most active member and was not only effective against cell proliferation but also migration, a novel and so far overlooked activity. To decipher the molecular mode of action, we applied chemical proteomics for target discovery and revealed that NCA targets cancer cell migration via irreversible binding to the largely uncharacterized synaptic vesicle membrane protein VAT-1. A corresponding knockout of the protein confirmed the phenotype, and pull-down studies showed the interaction with an intricate network of key migration mediators such as Talin-1. Overall, we introduce VAT-1 as a promising novel target for the development of selective migration inhibitors with the perspective to limit toxicity in the absence of antiproliferative effects.

Tanshinone IIA ameliorates oxaliplatin-induced neurotoxicity via mitochondrial protection and autophagy promotion.

Peripheral neurotoxicity is a common adverse reaction in cancer patients undergoing chemotherapy. The neuropathologic changes were partly associated with mitochondrial dysfunction and autophagy. Tanshinone IIA, a compound extracted from the medicinal herb Salvia miltiorrhiza, has been shown to exhibit neuroprotective effects. The present study investigated the effects of tanshinone IIA on chemotherapy-induced neurotoxicity and to study the underlying mechanism. Neuroma cell line N2a and rats were treated with oxaliplatin and/or tanshinone IIA. The effects on neurotoxicity were evaluated using cell viability assay, flow cytometry detection of apoptosis, measurement of intracellular reactive oxygen species (ROS) and mitochondrial membrane potential (Ψm), autophagy detection, nerve function assessment, and behavior assessment. The results showed that tanshinone IIA prevented oxaliplatin-induced inhibition of cell viability and reduced apoptosis. Tanshinone IIA also prevented excessive oxidative stress, as demonstrated by decreased ROS levels and reduced Ψm loss. Lastly, treatment with tanshinone IIA promoted autophagy through the PI3K/Akt/mTOR signaling pathway. The in vivo experiment showed that tanshinone IIA ameliorated oxaliplatin-induced allodynia and sciatic nerve dysfunction. An increase in serum nerve growth factor level was observed. In conclusion, the results of the study suggested a protective role of tanshinone IIA in neurotoxicity induced by oxaliplatin via mitochondrial protection and autophagy promotion.

HDAC6 inhibition suppresses chondrosarcoma by restoring the expression of primary cilia.

Chondrosarcoma is a bone tumor characterized by the secretion of a cartilage-like extracellular matrix. It has been proved to lack extracellular sensor primary cilia. This study aimed to illustrate a feasible therapeutic method for chondrosarcoma by regulating primary cilia assembly through inhibiting histone deacetylases 6 (HDAC6) activation. In order to detect the interaction between primary cilia and HDAC6 in human chondrosarcoma, Tubastatin A and small interfering RNA (siRNA) were used to inhibit the endogenous expression of HDAC6. Cell viability test and Transwell assay were applied to evaluate the effects of malignant biological properties. Primary cilia staining and related proteins were detected. The abnormal expression of HDAC6 and cilia intraflagellar transport protein 88 (IFT88) was found in chondrosarcoma tissues. The inhibition of HDAC6 could downregulate the proliferation of chondrosarcoma cells in a concentration- and time-dependent manner and suppress the invasion capacity of tumor cells. Besides, the downregulation of HDAC6 exhibited a negative effect on the proliferation of relevant proteins but a positive effect on the primary cilia-related expression of IFT88 and acetylated α-tubulin. Primary cilia restoration could be observed after HDAC6 siRNA transfection. The Aurora A-HDAC6 cascade was involved in regulating primary cilia resorption by affecting α-tubulin deacetylation and Tubastatin A could inhibit chondrosarcoma cell growth in vivo. These results indicate that restricting HDAC6 can restore primary cilia assembly accompanied with suppressed chondrosarcoma cell proliferation and invasion capacities. Thus, promoting primary cilia restoration by targeting HDAC6 may be a feasible potential therapeutic method for chondro-sarcoma treatment.

[Effect of Tanshinone IIA in Preventing and Treating Oxaliplatin Induced Peripheral Neuropathy].

OBJECTIVE: To observe preventive and therapeutic effects of Tanshinone IIA (T II A) on oxaliplatin induced peripheral neuropathy (OlPN) and to explore its effects on the expression of calcitonin gene related peptide (CGRP) and never growth factor (NGF). METHODS: Totally 36 phase II - III patients with malignant tumor of digestive tract undergoing chemotherapy program with oxaliplatin, were equally assigned to the T II A group (using THA at 80 mg/day 1 day before oxaliplatin chemotherapy for 3 successive days) and the control group (using chemotherapy program with oxaliplatin alone) by segmented randomization. After 4 cycles of chemotherapy, the incidence degree and incidence of OlPN were evaluated. Sensory nerve conduction velocity (SNCV) and motor nerve conduction velocity ( MNCV) were tested by EMG evoked potential device. Serum levels of CGRP and NGF were also detected in the two groups before and after chemotherapy. The correlation of serum levels of CGRP and NGF to OIPN was assessed using linear correlation analysis. RESULTS: After chemotherapy the OlPN incidence was 27.8% (5/18 cases) in the T II A group, obviously lower than that in the control group (55.6%, 10/18 cases; P < 0.05). Compared with before treatment in the same group, SNCV and MNCV of common peroneal nerve were slowed down, serum NGF levels decreased, and serum CGRP levels obviously increased in the two groups (all P < 0.05). Compared with the control group after treatment, SNCV and MNCV of common peroneal nerve were obviously accelerated, serum NGF levels increased, and serum CGRP levels obviously decreased in the THA group (all P < 0.05). Results of linear correlation analysis indicated serum NGF level was negatively correlated with peripheral neuropathy (PN), serum CGRP expression was positively correlated with neurotoxicity (P < 0.05). CONCLUSION: T II A could reduce the incidence of OlPN, which might be associated with inhibiting the expression of CGRP and up-regulating NGF activities.

Evaluating the role of PTH in promotion of chondrosarcoma cell proliferation and invasion by inhibiting primary cilia expression.

Chondrosarcoma is characterized by secretion of a cartilage-like matrix, with high proliferation ability and metastatic potential. Previous studies have shown that parathyroid hormone-related protein (PTHrP) has a close relationship with various tumor types. The objectives of this study were to research the function played by PTHrP in human chondrosarcoma, especially targeting cell proliferation and invasion, and to search for the potential interaction between PTHrP and primary cilia in tumorigenesis. Surgical resection tissues and the human chondrosarcoma cell line SW1353 were used in the scientific research. Cells were stimulated with an optimum concentration of recombinant PTH (1-84), and siRNA was used to interfere with internal PTHrP. Cell proliferation and invasion assays were applied, including MTS-8 cell proliferation assay, Western blot, RT-PCR, Transwell invasion assay, and immunohistochemistry and immunofluorescence assays. A high level of PTHrP expression was found in human chondrosarcoma tissues, and recombinant PTH exhibited positive promotion in tumor cell proliferation and invasion. In the meantime, PTHrP could inhibit the assembly of primary cilia and regulate downstream gene expression. These findings indicate that PTHrP can regulate tumor cell proliferation and invasion ability, possibly through suppression of primary cilia assembly. Thus, restricting PTHrP over-expression is a feasible potential therapeutic method for chondrosarcoma.

Hedgehog pathway inhibitor-4 suppresses malignant properties of chondrosarcoma cells by disturbing tumor ciliogenesis.

Chondrosarcoma is a type of malignant bone tumor secreting cartilage-like matrix. In clinical treatment, there is no frequently used drug treatment option except for surgical resection. Hedgehog (HH) pathway is a classical signaling pathway that regulates normal cartilage cell development. In order to detect the role that HH pathway plays in chondrosarcoma, we used immunohistochemistry and found this tumor clearly expressed HH pathway-related proteins. Treatment with HH pathway inhibitor-4 (HPI-4) could significantly decrease human chondrosarcoma cell proliferation, invasion and migration ability. Furthermore, HPI-4 could distinctly disturb HH pathway-mediated ciliogenesis and suppress primary cilia-related protein intraflagellar transport protein IFT88 expression. HH downstream effect molecular GLI2 was restrained to block parathyroid hormone-related protein and affect MAPK/ERK-regulated matrix metalloproteinases (MMP2 and MMP9). These results indicated that activated HH pathway existed in chondrosarcoma and HPI-4 could be a new therapeutic option specific to chondrosarcoma expressing elevated levels of HH pathway.