Comprehensive analyses of the cancer-associated fibroblast subtypes and their score system for prediction of outcomes and immunosuppressive microenvironment in prostate cancer.

BACKGROUND: Cancer-associated fibroblasts (CAFs) drive cancer progression and treatment failure on one hand, while their tumor-restraining functions are also observed on the other. Recent single cell RNA sequencing (scRNA-seq) analyses demonstrates heterogeneity of CAFs and defines molecular subtypes of CAFs, which help explain their different functions. However, it remains unclear whether these CAF subtypes have the same or different biological/clinical implications in prostate cancer (PCa) or other malignancies. METHODS: PCa cells were incubated with supernatant from normal fibroblasts and CAFs to assess their effects on cell behaviors. Sequencing, genomic, and clinical data were collected from TCGA, MSKCC, CPGEA and GEO databases. CAF molecular subtypes and total CAF scores were constructed and grouped into low and high groups based on CAF-specific gene expression. Progression free interval (PFI), clinicopathological features, telomere length, immune cell infiltration, drug treatment and somatic mutations were compared among CAF molecular subtypes and low/high score groups. RESULTS: The PCa CAF-derived supernatant promoted PCa cell proliferation and invasion. Based on differentially expressed genes identified by scRNA-seq analyses, we classified CAFs into 6 molecular subtypes in PCa tumors, and each subtype was then categorized into score-high and low groups according to the subtype-specific gene expression level. Such score models in 6 CAF subtypes all predicted PFI. Telomeres were significantly shorter in high-score tumors. The total CAF score from 6 CAF subtypes was also associated with PFI in PCa patients inversely, which was consistent with results from cellular experiments. Immunosuppressive microenvironment occurred more frequently in tumors with a high CAF score, which was characterized by increased CTLA4 expression and indicated better responses to CTLA4 inhibitors. Moreover, this model can also serve as a useful PFI predictor in pan-cancers. CONCLUSION: By combining scRNA-seq and bulk RNA-seq data analyses, we develop a CAF subtype score system as a prognostic factor for PCa and other cancer types. This model system also helps distinguish different immune-suppressive mechanisms in PCa, suggesting its implications in predicting response to immunotherapy. Thus, the present findings should contribute to personalized PCa intervention.

Cancer-associated fibroblasts promote enzalutamide resistance and PD-L1 expression in prostate cancer through CCL5-CCR5 paracrine axis.

Cancer-associated fibroblasts (CAFs) have been shown to play a key role in prostate cancer treatment resistance, but the role of CAFs in the initial course of enzalutamide therapy for prostate cancer remains unclear. Our research revealed that CAFs secrete CCL5, which promotes the upregulation of androgen receptor (AR) expression in prostate cancer cells, leading to resistance to enzalutamide therapy. Furthermore, CCL5 also enhances the expression of tumor programmed death-ligand 1 (PD-L1), resulting in immune escape. Mechanistically, CCL5 binds to the receptor CCR5 on prostate cancer cells and activates the AKT signaling pathway, leading to the upregulation of AR and PD-L1. The CCR5 antagonist maraviroc to inhibit the CAFs mediated CCL5 signaling pathway can effectively reduce the expression of AR and PD-L1, and improve the efficacy of enzalutamide. This study highlights a promising therapeutic approach targeting the CCL5-CCR5 signaling pathway to improve the effectiveness of enzalutamide.

SYTL2 promotes metastasis of prostate cancer cells by enhancing FSCN1-mediated pseudopodia formation and invasion.

BACKGROUND: Metastatic prostate cancer (mPCa) has a poor prognosis with limited treatment options. The high mobility of tumor cells is the key driving characteristic of metastasis. However, the mechanism is complex and far from clarified in PCa. Therefore, it is essential to explore the mechanism of metastasis and discover an intrinsic biomarker for mPCa. METHODS: Transcriptome sequencing data and clinicopathologic features of PCa from multifarious public databases were used to identify novel metastatic genes in PCa. The PCa tissue cohort containing 102 formalin-fixed paraffin-embedded (FFPE) samples was used to evaluate the clinicopathologic features of synaptotagmin-like 2 (SYTL2) in PCa. The function of SYTL2 was investigated by migration and invasion assays and a 3D migration model in vitro and a popliteal lymph node metastasis model in vivo. We performed coimmunoprecipitation and protein stability assays to clarify the mechanism of SYTL2. RESULTS: We discovered a pseudopodia regulator, SYTL2, which correlated with a higher Gleason score, worse prognosis and higher risk of metastasis. Functional experiments revealed that SYTL2 promoted migration, invasion and lymph node metastasis by increasing pseudopodia formation in vitro and in vivo. Furthermore, SYTL2 induced pseudopodia formation by enhancing the stability of fascin actin-bundling protein 1 (FSCN1) by binding and inhibiting the proteasome degradation pathway. Targeting FSCN1 enabled rescue and reversal of the oncogenic effect of SYTL2. CONCLUSIONS: Overall, our study established an FSCN1-dependent mechanism by which SYTL2 regulates the mobility of PCa cells. We also found that the SYTL2-FSCN1-pseudopodia axis may serve as a pharmacological and novel target for treating mPCa.

HMMR promotes prostate cancer proliferation and metastasis via AURKA/mTORC2/E2F1 positive feedback loop.

Although dysregulated HMMR is linked to prostate cancer (PCa) prognosis, the precise mechanisms remain unclear. Here, we sought to elucidate the role of HMMR in PCa progression as well as underlying mechanism. Herein, we found that upregulation of HMMR frequently observed in PCa samples and was associated with poor prognosis. Additionally, HMMR significantly promoted PCa proliferation and metastasis through gain- and loss-of function approaches in vitro and in vivo. Mechanistically, HMMR may interact with AURKA and elevated AURKA protein level through inhibiting ubiquitination-mediated degradation, which subsequently activated mTORC2/AKT pathway to ensure the reinforcement of PCa progression. Moreover, upregulated E2F1 caused from sustained activation of mTORC2/AKT pathway in turn function as transcription factor to promote HMMR transcription, thereby forming a positive feedback loop to trigger PCa progression. Importantly, administration of the mTOR inhibitor partially antagonised HMMR-mediated PCa progression in vivo. In summary, we not only reveal a novel possible post-translation mechanism mediated by HMMR involved in AURKA regulation, but also describe a positive feedback loop that contributes to PCa deterioration, suggesting HMMR may serve as a potential promising therapeutic target in PCa.

Capn4 regulates Snail to promote the epithelial-mesenchymal transition of nasopharyngeal carcinoma by mediating the transcriptional activity of claudin-11.

The metastasis and recurrence of nasopharyngeal carcinoma (NPC) contribute to the poor prognosis of patients. Inhibiting epithelial-mesenchymal transition (EMT) is an effective strategy to obstruct metastasis. Therefore, this study aimed to explore the effects of Capn4 on the EMT of NPC cells and its specific mechanism of action. The mRNA and protein expression levels of objective genes in NPC cell lines (5-8F and CNE-2) were evaluated by qRT-PCR and western blotting methods. The subcellular localization of Capn4 was detected by immunofluorescence (IF). Migration and invasion abilities of NPC cells were examined via wound-healing and trans-well methods, and the linkage between Snail and its downstream effector gene (claudin-11) was validated by chromatin immunoprecipitation (ChIP), dual-luciferase, and the yeast one-hybrid assays in series. Over-expression of Capn4 activated the PI3K/AKT signaling pathway and improved the expression of Snail, thus promoting the migration and invasion abilities of NPC cells. Mechanically, claudin-11 is one of the target genes in NPC cells that Snail regulates in a transcriptional regulatory manner. By blocking the regulatory axis of CAPN4/AKT/Snail/claudin-11 can significantly inhibit the invasion and metastasis of NPC cells. Capn4 promoted the EMT of NPC cells by activating the PI3K/AKT/Snail/claudin-11 axis, thereby promoting the malignant development of NPC. The Capn4/PI3K/AKT/Snail/claudin-11 axis might be a novel target to prevent NPC progression.

Delivery of enzalutamide via nanoparticles for effectively inhibiting prostate cancer progression.

Androgen deprivation therapy has been used as a standard clinical treatment for prostate cancer, but the disease generally progresses to castration-resistant prostate cancer in a very short time. Enzalutamide (ENZ) is an emerging second-generation androgen receptor (AR) antagonist used for the treatment of patients with nonmetastatic castration-resistant prostate cancer (CRPC). However, due to the rapid onset of drug resistance, it provides only a modest increase in survival. Here, we propose a convenient and effective androgen receptor antagonist drug delivery strategy, that is, the use of a biocompatible nanoparticle (NP) drug delivery system for drug delivery to improve its bioavailability and therapeutic performance. Although the particle size of the phenylpropyl polymer (8P4) nanoparticles is small, it has a high drug-carrying capacity. ENZ-8P4 NPs can increase drug delivery efficiency, enhance drug cytotoxicity, and reduce the half-inhibitory concentration (IC50) of the drug. In addition, in vivo experiments confirmed that ENZ-8P4 preferentially accumulates in the tumor and significantly inhibits tumor growth. Hence, the 8P4 drug delivery system loaded with enzalutamide has excellent potential for the treatment of prostate cancer.

Functional Differentiation of BMP7 Genes in Zebrafish: bmp7a for Dorsal-Ventral Pattern and bmp7b for Melanin Synthesis and Eye Development.

Bone morphogenetic protein 7 (BMP7) belongs to the transforming growth factor ß (TGF-ß) family, which not only induces cartilage and bone formation, but also regulates eye development and melanoma tumorigenesis in mammals. In teleosts, BMP7 differentiates into two subtypes, bmp7a and bmp7b, which have clearly differentiated structures. To fully understand the functional differentiation of bmp7a and bmp7b in fish species, we successfully constructed bmp7a and bmp7b gene deletion mutants in zebrafish using CRISPR/Cas9-mediated gene editing technology. Our results showed that bmp7a mutation caused abnormal development of the embryo's dorsal-ventral pattern that led to death; bmp7b mutation induced growth inhibition and increased melanin production in the skin and eye of mutants. Histological analysis revealed that melanin in the retina of the eyes in bmp7b mutants increased, and behavioral observation showed that the vision and sensitivity to food of the mutants were reduced. Transcriptome analysis of the skin and eye tissues showed that the expression changes of wnt7ba and gna14 in bmp7b mutants might promote the increase of melanin. Additionally, the eye transcriptome analysis indicated that changes in the structure of the eyes in bmp7b mutants led to defects in phototransduction, and seven DEGs (rgs9a, rgs9b, rcvrn2, guca1d, grk1b, opn1mw4, and gc2) were identified as key candidate genes that affected the photonic response of the eyes. The study revealed the functional differentiation of bmp7a and bmp7b in teleosts and the first report about the inhibitory effect of bmp7b on melanogenesis may provide useful information for the future research on human melanoma-related diseases.

Enhanced solubility of curcumin by complexation with fermented cyclic ß-1,2-glucans.

Curcumin (CUR) is a low-solubility polyphenolic compound with many physiological functions. Cyclic ß-1,2-glucans (cyclosophoraoses [Cys]), which contain rings of different sizes with degrees of polymerization ranging from 17 to 23, were obtained from Rhizobium radiobacter ATCC 1333, a soil microorganism. The complexation ability and solubility enhancement of cyclic ß-1,2-glucans with insoluble curcumin were investigated. Phase-solubility analysis revealed that the stoichiometric ratio of the inclusion complexes was 1:1. The stability constant of Cys was 930 M-1, which was 7.68 times that of α-cyclodextrin (α-CD) and 2.09 times that of ß-cyclodextrin (ß-CD). The characteristics of the curcumin/Cys inclusion complexes were successfully determined by using Fourier transform infrared (FTIR) spectrometry, differential scanning calorimetry (DSC), nuclear magnetic resonance (1H NMR) spectroscopy, and scanning electron microscopy (SEM). Moreover, a 1:1 molecular model of the curcumin/Cys inclusion complexes was established through molecular docking analysis. These findings indicated that cyclic ß-1,2-glucans successfully formed complexes with curcumin, which suggested that they could be used as solubility-increasing agents. To the best of our knowledge, this is the first report in which curcumin has been embedded into cyclic ß-1,2-glucans resulting in an increase in its aqueous solubility.

CT-Based Classification Systems for Intra-Articular Calcaneal Fractures: The Inter- and Intraobserver Variations as well as Integrality.

The aim of this study was to measure the inter- and intraobserver variations as well as integrality of the Zwipp, Crosby-Fitzgibbons, Sanders, and Eastwood-Atkins classification systems based on more accurate CT scans. Five hundred and forty-nine patients with intra-articular calcaneal fractures from January 2018 to December 2019 taken from a database in our level-I trauma center (3 affiliated hospitals) were included. For each case, normative CT (1 mm slices) scans were available. Four different observers reviewed all CT scans 2 times according to these 4 most prevalent fracture classification systems (FCSs) within a 2-month interval. For these 4 FCSs, the kappa [κ] coefficient was used to evaluate interobserver reliability and intraobserver reproducibility, and the percentage that can be classified was used to indicate integrality. The κ values were measured for Zwipp (κ = 0.38 interobserver, κ = 0.61 intraobserver), Crosby-Fitzgibbons (κ = 0.48 interobserver, κ = 0.79 intraobserver), Sanders (κ = 0.40 interobserver, κ = 0.57 intraobserver), and Eastwood-Atkins (κ = 0.44 interobserver, κ = 0.72 intraobserver). Furthermore, the integralities were calculated for Zwipp (100%), Crosby-Fitzgibbons (100%), Sanders (92%) as well as Eastwood-Atkins (89.6%). Compared with previous literatures, CT scanning with higher accuracy can significantly improve intraobserver reproducibility of Zwipp and Eastwood-Atkins FCSs, but it has no positive effect on variability of Sanders FCS and interobserver reliability of Crosby-Fitzgibbons FCS. In terms of integrality, Zwipp and Crosby-Fitzgibbons FCSs appear to be superior to the other 2 FCSs.

Girdin influences pancreatic cancer progression by regulating c-MYC expression.

Pancreatic ductal adenocarcinoma is a complex gastrointestinal tumor with high metastatic potential and poor prognosis. Actin-binding protein Girdin is highly expressed in a variety of tumors and promotes tumorigenesis and progression. However, the mechanisms underlying the involvement of Girdin in pancreatic cancer have not been clarified. In this study, we observed that the expression of Girdin was upregulated in pancreatic cancer cells. The siRNA-mediated gene knockdown experiments showed that reduced expression of Girdin in pancreatic cancer cells inhibited cell proliferation, migration, and invasion while promoting cell apoptosis. Functional assays revealed that c-MYC overexpression in pancreatic cancer cells could significantly increase the cell proliferation ability and rates of cell migration and invasion while decreasing the apoptosis rate. It has been shown that phosphorylation plays a role in the functional regulation of the c-MYC gene. Subsequently, we examined the expression level of c-MYC in cells with manipulated expression of Girdin and identified a positive correlation between Girdin expression and c-MYC expression. Moreover, we found that Girdin knockdown in c-MYC-overexpressing pancreatic cancer cells slowed cell growth, blocked the cell cycle progression, significantly promoted apoptosis, and markedly decreased the cell migration and invasion. This finding indicated that silencing Girdin could mitigate the effect of c-MYC on promoting proliferation and metastasis of pancreatic cancer. Overall, this study provided evidence that Girdin promoted pancreatic cancer development presumably by regulating the c-MYC overexpression.

Chrysin inhibits hepatocellular carcinoma progression through suppressing programmed death ligand 1 expression.

BACKGROUNDS: The aberrant PD-L1 expression on cancer cells was confirmed to participate in immune evasion of hepatocellular carcinoma (HCC). Previous studies had documented that there were anti-tumorigenic effects of chrysin on HCC. However, whether chrysin can act on the over-expressed PD-L1 on HCC cells to exert the therapeutic effectiveness and the involved mechanisms has not yet been deciphered. PURPOSE: Herein, we aimed to explore the regulatory effects of chrysin on the PD-1/PD-L1 immune checkpoint and investigate its possible mechanisms in vivo and in vitro. METHODS: H22 xenograft mouse model was used to investigate the effects of chrysin on tumor growth and PD-L1 expression in tumors. In interferon-gamma (IFN-γ)-induced HepG2 cells, the cytotoxicity of chrysin was detected by MTT assay. Flow cytometry, ELISA and RT-PCR were carried out to evaluate the expression of PD-L1, and the expression of proteins in STAT3 and NF-κB pathways was also determined by Western blot. In HepG2 cells and Jurkat T cell co-culture system, ELISA kit was used to detect the level of IL-2, and T cell proliferation was further evaluated by CCK-8 method. RESULTS: Our data suggested that chrysin could effectively inhibit the progression of tumor, and promote the anti-tumor immunity of mice concomitant with enhanced CD4/CD8-positive T cell proportion in tumor tissues of H22 xenograft mouse model. Additionally, chrysin significantly down-regulated the expression of PD-L1 in vivo and in vitro, which was closely associated with the blockage of STAT3 and NF-κB pathways. Moreover, in the co-culture system, chrysin could increase the proliferation of T cells and the concentration of IL-2. CONCLUSION: These results indicate that chrysin may have the potential to be an immune checkpoint inhibitor for preventive or as an adjunctive curative agent for HCC.

The treatment effect of posterior lumbar fusion surgery on patients suffering from lumbar disc herniation concurrent with peroneal nerve paralysis.

Purpose: The purpose of this study is to investigate the clinical effect of posterior lumbar fusion surgery on patients who suffer from lumbar disc herniation concurrent with peroneal nerve paralysis. Methods: The patients suffering from peroneal nerve paralysis and undergoing posterior lumbar fusion surgery between January 2012 and December 2019 were retrospectively reviewed. The data of the identified patients were then collected and processed. All patients were followed up post-operatively after discharge from the hospital. The data was analyzed in terms of Oswestry disability index (ODI), visual analogue scale (VAS) score, and relative lower-limb muscle strength. Results: A total of 87 patients (52 males and 35 females) aged 54 ± 11 years met the inclusion criteria for this study. These patients stayed in hospital for 16 ± 6 days and were followed up for 81 ± 24 months. Data analysis showed that muscle strength of the tibialis anterior and extensor digitorum significantly recovered at the last follow-up with a grade of 3 (median), compared to grade 0 at admission (p < 0.001). Furthermore, the median VAS score decreased to 1 at the last follow-up from 6 at admission (p < 0.001), and the ODI greatly improved with 10% (median) at the last follow-up, while it was 58% at admission (p < 0.001). The ODI improvement rate was 60% on average at the last follow-up. Multivariate regression analysis regarding the ODI and muscle strength improvement rates showed that advanced age was a risk factor for postoperative recovery. Conclusions: Most of the patients suffering from lumbar disc herniation concurrent with peroneal nerve paralysis can improve after undergoing posterior lumbar fusion surgery, but few can reach full recovery. Advanced age might be a risk factor that affects the prognosis of these patients after surgery.

Immune Signatures Combined With BRCA1-Associated Protein 1 Mutations Predict Prognosis and Immunotherapy Efficacy in Clear Cell Renal Cell Carcinoma.

Immunotherapy is gradually emerging in the field of tumor treatment. However, because of the complexity of the tumor microenvironment (TME), some patients cannot benefit from immunotherapy. Therefore, we comprehensively analyzed the TME and gene mutations of ccRCC to identify a comprehensive index that could more accurately guide the immunotherapy of patients with ccRCC. We divided ccRCC patients into two groups based on immune infiltration activity. Next, we investigated the differentially expressed genes (DEGs) and constructed a prognostic immune score using univariate Cox regression analysis, unsupervised cluster analysis, and principal component analysis (PCA) and validated its predictive power in both internal and total sets. Subsequently, the gene mutations in the groups were investigated, and patients suitable for immunotherapy were selected in combination with the immune score. The prognosis of the immune score-low group was significantly worse than that of the immune score-high group. The patients with BRCA1-associated protein 1 (BAP1) mutation had a poor prognosis. Thus, this study indicated that establishing an immune score model combined with BAP1 mutation can better predict the prognosis of patients, screen suitable ccRCC patients for immunotherapy, and select more appropriate drug combinations.

Multiple-mRNA-controlled and heat-driven drug release from gold nanocages in targeted chemo-photothermal therapy for tumors.

Multifunctional drug delivery systems enabling effective drug delivery and comprehensive treatment are critical to successful cancer treatment. Overcoming nonspecific release and off-target effects remains challenging in precise drug delivery. Here, we design triple-interlocked drug delivery systems to perform specific cancer cell recognition, controlled drug release and effective comprehensive therapy. Gold nanocages (AuNCs) comprise a novel class of nanostructures possessing hollow interiors and porous walls. AuNCs are employed as a drug carrier and photothermal transducer due to their unique structure and photothermal properties. A smart triple-interlocked I-type DNA nanostructure is modified on the surface of the AuNCs, and molecules of the anticancer drug doxorubicin (DOX) are loaded as molecular cargo and blocked. The triple-interlocked nanostructure can be unlocked by binding with three types of tumor-related mRNAs, which act as "keys" to the triple locks, sequentially, which leads to precise drug release. Additionally, fluorescence-imaging-oriented chemical-photothermal synergistic treatment is achieved under illumination with infrared light. This drug delivery system, which combines the advantages of AuNCs and interlocked I-type DNA, successfully demonstrates effective and precise imaging, drug release and photothermal therapy. This multifunctional triple-interlocked drug delivery system could be used as a potential carrier for effective cancer-targeting comprehensive chemotherapy and photothermal therapy treatments.

Comparative Transcriptome Analysis Revealed Genes Involved in Sexual and Polyploid Growth Dimorphisms in Loach (Misgurnus anguillicaudatus).

Sexual and polyploidy size dimorphisms are widespread phenomena in fish, but the molecular mechanisms remain unclear. Loach (Misgurnus anguillicaudatus) displays both sexual and polyploid growth dimorphism phenomena, and are therefore ideal models to study these two phenomena. In this study, RNA-seq was used for the first time to explore the differentially expressed genes (DEGs) between both sexes of diploid and tetraploid loaches in four tissues (brain, gonad, liver, and muscle). Results showed that 21,003, 17, and 1 DEGs were identified in gonad, liver, and muscle tissues, respectively, between females and males in both diploids and tetraploids. Regarding the ploidy levels, 4956, 1496, 2187, and 1726 DEGs were identified in the brain, gonad, liver, and muscle tissues, respectively, between tetraploids and diploids of the same sex. When both sexual and polyploid size dimorphisms were considered simultaneously in the four tissues, only 424 DEGs were found in the gonads, indicating that these gonadal DEGs may play an important regulatory role in regulating sexual and polyploid size dimorphisms. Regardless of the sex or ploidy comparison, the significant DEGs involved in glycolysis/gluconeogenesis and oxidative phosphorylation pathways were upregulated in faster-growing individuals, while steroid hormone biosynthesis-related genes and fatty acid degradation and elongation-related genes were downregulated. This suggests that fast-growing loaches (tetraploids, females) have higher energy metabolism levels and lower steroid hormone synthesis and fatty acid degradation abilities than slow-growing loaches (diploids, males). Our findings provide an archive for future systematic research on fish sexual and polyploid dimorphisms.

GADD45B Is a Potential Diagnostic and Therapeutic Target Gene in Chemotherapy-Resistant Prostate Cancer.

BACKGROUND: Chemoresistance is the major cause of death in advanced prostate cancer (PCa), especially in metastatic PCa (mPCa). However, the molecular mechanisms underlying the chemoresistance of PCa remain unclear. Understanding the reason behind the drug resistance would be helpful in developing new treatment approaches. METHODS: The Cancer Genome Atlas, Gene Expression Omnibus datasets, and clinical samples were used to examine the correlation between growth arrest and DNA damage-inducible 45 beta (GADD45B) with clinical characteristics and prognosis. Lentiviral transfection was used to construct GADD45B overexpression cell lines. Hypoxic incubator, low serum medium, or docetaxel was used to build environmental stress model or chemotherapy cell model. The MTS assay and colony formation assay were used to test cell viability. Apoptosis and cell cycle were detected by flow cytometry. The RNA and protein levels of related biomarkers were tested by Western blotting and quantitative polymerase chain reaction. Bioinformatics analysis after RNA sequencing was performed to identify the possible mechanism of how GADD45B regulates chemotherapy resistance. RESULTS: GADD45B was related to distant metastasis but not to Gleason score, prostate-specific antigen level, T stage, or lymph node metastasis and indicated a good prognosis. The level of GADD45B increased significantly in PCa cells that faced environmental stress. It was found that a high level of GADD45B significantly enhanced the chemosensitivity. Furthermore, high GADD45B promoted cell apoptosis via mitogen-activated protein kinase (MAPK) pathway. CONCLUSION: GADD45B promoted chemosensitivity of prostate cancer through MAPK pathway. GADD45B could serve as a diagnostic biomarker and therapeutic target for mPCa or chemotherapy-resistant patients.

Failed reduction of posterior hip dislocation accompanied by femoral head fracture: causes and resolving strategy.

BACKGROUND: We investigated the causes of failure of the Allis manoeuvre for posterior hip dislocations with an associated Pipkin type I femoral head fractures. The effectiveness of a modified Allis manoeuvre was also evaluated. METHODS: From January 2013 to December 2016, we enrolled five patients with a posterior hip dislocation associated by a Pipkin type I femoral head fracture who were treated initially with the Allis manoeuvre that subsequently failed. Radiographic evaluations were performed to determine the cause of failure, and then a modified Allis manoeuvre was performed. During this procedure, the hip and knee joints of the injured lower limb were both flexed to 90°, and the leg was pulled posteriorly following an upward force to reduce the dislocation. Reduction was assessed by radiographic evaluation. RESULTS: In all patients, the fractured femoral head was incarcerated on the superior edge of the posterior rim of the acetabulum, resulting in failure of the conventional Allis manoeuvre. Satisfactory reduction was achieved with a modified Allis manoeuvre. The mean follow-up duration was 31 months. The femoral head fracture healed after four months on average. The mean Harris score was 91 at the final follow-up. Re-dislocation or femoral head necrosis was not observed. CONCLUSIONS: For posterior hip dislocations associated with a Pipkin type I femoral head fracture, failed reduction is often caused by incarceration of the fractured femoral head on the superior edge of the posterior rim of the acetabulum. The modified Allis manoeuvre can effectively reduce the combined injury in a closed fashion.

The metastatic promoter DEPDC1B induces epithelial-mesenchymal transition and promotes prostate cancer cell proliferation via Rac1-PAK1 signaling.

Metastasis is the major cause of prostate cancer (PCa)-related mortality. Epithelial-mesenchymal transition (EMT) is a vital characteristic feature that empowers cancer cells to adapt and survive at the beginning of metastasis. Therefore, it is essential to identify the regulatory mechanism of EMT in metastatic prostate cancer (mPCa) and to develop a novel therapy to block PCa metastasis. Here, we discovered a novel PCa metastasis oncogene, DEP domain containing 1B (DEPDC1B), which was positively correlated with the metastasis status, high Gleason score, advanced tumor stage, and poor prognosis. Functional assays revealed that DEPDC1B enhanced the migration, invasion, and proliferation of PCa cells in vitro and promoted tumor metastasis and growth in vivo. Mechanistic investigations clarified that DEPDC1B induced EMT and enhanced proliferation by binding to Rac1 and enhancing the Rac1-PAK1 pathway. This DEPDC1B-mediated oncogenic effect was reversed by a Rac1-GTP inhibitor or Rac1 knockdown. In conclusion, we discover that the DEPDC1B-Rac1-PAK1 signaling pathway may serve as a multipotent target for clinical intervention in mPCa.

Sinapic Acid Inhibits IL-1ß-Induced Apoptosis and Catabolism in Nucleus Pulposus Cells and Ameliorates Intervertebral Disk Degeneration.

BACKGROUND: Low back pain (LBP) is a very common condition and leads to serious pain, disability, and price tag all over the world. Intervertebral disk degeneration (IDD) is one of the major reasons that contributed to LBP. The levels of interleukin 1 beta (IL-1ß) increase significantly in degenerative disks. IL-1ß also accelerates IDD. Sinapic acid (SA) has the effect of anti-inflammatory, antioxidant and antimicrobial. However, the effect of SA on IDD has never been studied. Therefore, the aim of this study was to figure out whether SA has protective effect on nucleus pulposus (NP) cells and further explore the possible underlying mechanism. METHODS: The nucleus pulposus (NP) tissues of rats were collected and cultured into NP cells. The NP cells were stimulated by IL-1ß and treated with SA. In vitro treatment effects were evaluated by ELISA, Western blot assay, immunofluorescence, TUNEL method and real-time PCR. We conducted percutaneous needle puncture in the rat tail to build intervertebral disk degeneration model and treated rats with SA. In vivo treatment effects were evaluated by hematoxylin and eosin (HE) and safranin O (SO) staining and magnetic resonance imaging (MRI) method. RESULTS: Our results showed that SA not only inhibited apoptosis but also suppressed inflammatory mediators including nitric oxide (NO), prostaglandin E2 (PGE2), cyclooxygenase 2 (COX-2), inducible nitric oxide synthase (iNOS) interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) in IL-1ß-stimulated NP cells. As to extracellular matrix (ECM), SA could increase collagen II and aggrecan levels and reduce the expression of MMP13 and ADAMTS5 during the stimulation of IL-1ß. Furthermore, SA could activate nuclear factor-erythroid 2-related factor-2 (Nrf2) to inhibit nuclear factor κB (NF-κB) induced by IL-1ß. Nrf2 knockdown partly reduced the protective effect of SA on NP cells. Correspondingly, SA ameliorated IDD by promoting Nrf2 expression. In vivo results also showed that SA could delay the progression of IDD. CONCLUSION: In conclusion, we demonstrated that SA could protect the degeneration of NP cells and revealed the underlying mechanism of SA on Nrf2 activation in NP cells.

Immune Cytolytic Activity as an Indicator of Immune Checkpoint Inhibitors Treatment for Prostate Cancer.

Immune checkpoint inhibitors (ICIs) treatment is becoming a new hope for cancer treatment. However, most prostate cancer (PCa) patients do not benefit from it. In order to achieve the accuracy of ICIs treatment in PCa and reduce unnecessary costs for patients, we have analyzed the data from TCGA database to find a indicator that can assist the choice of treatment. By analyzing the data of PCa patients with TMB analysis and immune infiltration analysis, we found the expression of immune cells in different immune infiltration groups. Commonly used markers of ICIs, expressed on CD8+ T cell, were highly expressed in the high immune group. Then we used the forimmune cytolytic activity (CYT) to determine its relationship with the target of ICIs treatment. Through the analysis of CYT score and the ligands of immune checkpoints, we found that there was a significant correlation between them. With the increase of CYT score, the expression of CD80/86, PD-L1/L2, TNFSF14, and LGALS9 also increased gradually. Similarly, CD8+ T cells were significantly increased in the CYT high group compared with the CYT low group in PRAD. The present research provides novel insights into the immune microenvironment of PRAD and potential immunotherapies. The proposed CYT score is a clinically promising indicator that can serve as a marker to assist anti-PD-L1 or other ICIs treatment. At the same time, it also provides a basis for the selection of other immune checkpoint drugs.