Novel pyridazinone derivatives bind to KSRP: Synthesis, anti-tumor biological evaluations and modelling insights.

Pyridazinone derivatives have been extensively used as anticancer agents. IMB5036 is a structure specific pyridazinone compound with potential antitumor activity via targeting KSRP protein which controls gene expression at multiple levels. In this study, fifteen IMB5036 analogues were synthesized and preliminary structure-activity relationships were explored. Among them, compounds 8 and 10 exhibited remarkably anti-proliferation of various cancer cells and a good cancer cell selectivity (against human fetal hepatocyte L02 cells). More detailed investigation was included that both 8 and 10 inhibited colony formation and migration in concentration-dependent mode against MCF-7 cells. Additionally, 8 and 10 induced apoptosis and cell cycle arrest, decreased mitochondrial membrane potential, damaged DNA, and increased reactive oxygen species. Moreover, 8 displayed a potent antitumor efficacy (TGI = 74.2 %, at a dose of 30 mg/kg) in MCF-7 xenograft model by i.p. injection. Further, we synthesized a biotinylated probe 16 for identifying the detail domain of KSRP. Through pull down assay and molecular docking study, we validated that the KH23 domain functioned as the binding pocket for the compounds. Thus, compound 8 was identified as a novel targeting KSRP pyridazinone-based compound and exhibited excellent antitumor activity both in vitro and in vivo.

Liquiritin targeting Th17 cells differentiation and abnormal proliferation of keratinocytes alleviates psoriasis via NF-κB and AP-1 pathway.

Psoriasis is a common immune-mediated inflammatory skin disease, caused by disturbed interactions between keratinocytes and immune cells. Chinese medicine shows potential clinical application for its treatment. Liquiritin is a flavone compound extracted from licorice and shows potential antitussive, antioxidant and antiinflammatory effects, and therefore may have potential as a psoriasis therapeutic. The aim of this work was to examine the possible roles that liquiritin may have in treating psoriasis. HaCaT cells were stimulated by TNF-α with or without liquiritin, harvested for analysis by western blots and RT-qPCR, and the cellular supernatants were collected and analyzed by ELISA for cytokines. In addition, 4 groups of mice were examined: Normal, Vehicle, LQ-L and LQ-H. The mice were sacrificed after 6 days and analyzed using IHC, ELISA, RT-qPCR and flow cytometry. The results showed that liquiritin could significantly inhibit the progression of psoriasis both in vitro and in vivo. Liquiritin strongly suppressed the proliferation of HaCaT keratinocytes but did not affect cell viability. Moreover, liquiritin alleviated imiquimod-induced psoriasis-like skin inflammation and accumulation of Th17 cells and DCs in vivo. In TNF-α-induced HaCaT keratinocytes, both protein and mRNA expression levels of inflammatory cytokines were sharply decreased. In imiquimod-induced mice, the activation of NF-κB and AP-1 was reduced after treatment with liquiritin. Collectively, our results show that liquiritin might act as a pivotal regulator of psoriasis via modulating NF-κB and AP-1 signal pathways.

GATA2 co-opts TGFß1/SMAD4 oncogenic signaling and inherited variants at 6q22 to modulate prostate cancer progression.

BACKGROUND: Aberrant somatic genomic alteration including copy number amplification is a hallmark of cancer genomes. We previously profiled genomic landscapes of prostate cancer (PCa), yet the underlying causal genes with prognostic potential has not been defined. It remains unclear how a somatic genomic event cooperates with inherited germline variants contribute to cancer predisposition and progression. METHODS: We applied integrated genomic and clinical data, experimental models and bioinformatic analysis to identify GATA2 as a highly prevalent metastasis-associated genomic amplification in PCa. Biological roles of GATA2 in PCa metastasis was determined in vitro and in vivo. Global chromatin co-occupancy and co-regulation of GATA2 and SMAD4 was investigated by coimmunoprecipitation, ChIP-seq and RNA-seq assays. Tumor cellular assays, qRT-PCR, western blot, ChIP, luciferase assays and CRISPR-Cas9 editing methods were performed to mechanistically understand the cooperation of GATA2 with SMAD4 in promoting TGFß1 and AR signaling and mediating inherited PCa risk and progression. RESULTS: In this study, by integrated genomics and experimental analysis, we identified GATA2 as a prevalent metastasis-associated genomic amplification to transcriptionally augment its own expression in PCa. Functional experiments demonstrated that GATA2 physically interacted and cooperated with SMAD4 for genome-wide chromatin co-occupancy and co-regulation of PCa genes and metastasis pathways like TGFß signaling. Mechanistically, GATA2 was cooperative with SMAD4 to enhance TGFß and AR signaling pathways, and activated the expression of TGFß1 via directly binding to a distal enhancer of TGFß1. Strinkingly, GATA2 and SMAD4 globally mediated inherited PCa risk and formed a transcriptional complex with HOXB13 at the PCa risk-associated rs339331/6q22 enhancer, leading to increased expression of the PCa susceptibility gene RFX6. CONCLUSIONS: Our study prioritizes causal genomic amplification genes with prognostic values in PCa and reveals the pivotal roles of GATA2 in transcriptionally activating the expression of its own and TGFß1, thereby co-opting to TGFß1/SMAD4 signaling and RFX6 at 6q22 to modulate PCa predisposition and progression.

Benzoylaconitine Alleviates Progression of Psoriasis via Suppressing STAT3 Phosphorylation in Keratinocytes.

Psoriasis is a chronic and multifactorial skin disease which is caused by inflammatory infiltrates, keratinocyte hyperproliferation, and accumulation of immune cells. As part of the Aconitum species, Benzoylaconitine (BAC) shows potential antiviral, anti-tumor, and anti-inflammatory effects. In this study, we investigated the effects and mechanisms of BAC on tumor necrosis factor-alpha (TNF-α)/LPS-induced HaCaT keratinocytes in a imiquimod(IMQ)-induced mice model. The results showed that BAC could relieve the symptoms of psoriasis by inhibiting cell proliferation, the release of inflammatory factors, and the accumulation of Th17 cells, while no obvious effect on cell viability and safety was observed both in vitro and in vivo. Additionally, BAC can markedly inhibit the protein and mRNA levels of inflammatory cytokines in TNF-α/LPS-induced HaCaT keratinocytes by inhibiting the phosphorylation of STAT3. In brief, our data indicated that BAC could alleviate the progression of psoriasis and may be a potential therapeutic agent for treating psoriasis in clinical practice.

Hypoxia-inducible factor 1α/IL-6 axis in activated hepatic stellate cells aggravates liver fibrosis.

Hepatic stellate cells (HSCs) upregulate hypoxia inducible factor 1 alpha (HIF-1α) expression in response to fibrosis-induced hypoxia. The mechanism by which HIF-1α promotes liver fibrosis in HSCs is not fully understood. In this study, we found that increased expression of α-SMA, HIF-1α and IL-6, as well as colocalization of α-SMA and HIF-1α, and HIF-1α and IL-6, were observed in liver fibrotic tissues of patients and a mouse model. HIF-1α expression induced IL-6 secretion in activated HSCs and the increase could be abolished by HIF-1α suppression or HIF1A gene knockdown. HIF-1α directly bound to the hypoxia response element (HRE) region in HSC IL6/Il6 promoters. Additionally, culturing naïve CD4 T cells with supernatant from HSCs in which HIF-1α is highly expressed increased IL-17A expression, and the expression could be abolished by HIF1A knockdown in LX2. In turn, the IL-17A-enriched supernatant induced IL-6 secretion in HSCs. Together, these results show that HIF-1α upregulates IL-6 expression in HSCs and induces IL-17A secretion through directly binding to the HRE of IL6 promoter.

Bioinformatic analysis of differentially expressed profiles of lncRNAs and miRNAs with their related ceRNA network in endometrial cancer.

Increasing evidence suggests that long non-coding riboneucleic acids (lncRNAs), as competing endogenous RNA (ceRNA), play a key role in the initiation, invasion, and metastasis of cancer. As a new hypothesis, the lncRNA-micro RNA (miRNA)-messenger RNA (mRNA), ceRNA regulatory network has been successfully constructed in a variety of cancers. However, lncRNA, which plays a ceRNA function in endometrial cancer (EC), is still poorly understood. In this study, we downloaded EC expression profiling from The Cancer Genome Atlas database and used the R software "edgeR" package to analyze the differentially expressed genes between EC and normal endometrium samples. Then, differentially expressed (DE) lncRNAs, miRNAs and mRNAs were selected to construct a lncRNA-miRNA-mRNA prognosis-related regulatory network based on interaction information. The Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were performed on the genes in the network to predict the potential underlying mechanisms and functions of lncRNAs in EC. Kaplan-Meier method and the log-rank test were used for survival analysis. Based on the "ceRNA hypothesis," we constructed a co-expression network of mRNA and lncRNA genes mediated by miRNA in the process of tumor genesis. Furthermore, we successfully constructed a dysregulated lncRNA-associated ceRNA network containing 96 DElncRNAs, 27 DEmiRNAs, and 74 DEmRNAs. Through Kaplan-Meier curve analysis, we found that 9 lncRNAs, 3 miRNAs, and 12 mRNAs were significantly correlated with the overall survival rate of patients among all lncRNAs, miRNAs, and mRNAs involved in ceRNA (P < .05). Our research provides a new perspective for the interaction among lncRNAs, miRNAs, and mRNA and lays the foundation for further research on the mechanism of lncRNAs in the occurrence of EC.

Pharmacological agents for defatting livers by normothermic machine perfusion.

BACKGROUND: Ex-vivo normothermic machine perfusion (NMP) preserves the liver metabolism at 37°C and has rapidly developed as a promising approach for assessing the viability and improving the performance of organs from expanded criteria donors, including fatty liver grafts. NMP is an effective method for defatting fatty livers when combined with pharmaceutical therapies. Pharmacological agents have been shown to facilitate liver defatting by NMP. OBSERVATIONS: This systematic review summarizes available pharmacological therapies for liver defatting, with a particular emphasis on defatting agents that can be employed clinically as defatting components during liver NMP as an ex vivo translational paradigm. CONCLUSION: NMP provides an opportunity for organ treatment and can be used as a defatting platform in the future with defatting agents. Nagrath's cocktail is the most commonly used defatting cocktail in NMP; however, its carcinogenic components may limit its clinical application. Thus, the combination of a defatting cocktail with a new clinically applicable component, for example, a polyphenolic natural compound, may be a novel pharmacological option.

Nuclear localization signal peptides enhance genetic transformation of Dunaliella salina.

BACKGROUND: Dunaliella salina (D. salina) expression system shows a very attractive application prospect, but it currently has a technical bottleneck, namely the low or unstable expression of recombinant proteins. Given the characteristics of cell-penetrating peptides or/and nuclear localization signal (NLS) peptides, this study is the first attempt to improve the transformation rate of foreign gene with trans-activating transcriptional (TAT) protein or/and NLS peptides. METHODS AND RESULTS: Using salt gradient method, exogenous plasmids were transferred into D. salina cells with TAT or TAT/NLS complexes simultaneously. The ß-glucuronidase gene expression was identified by means of histochemical stain and RT-qPCR detection. Through observation with light microscope, TAT-mediating cells exhibit an apparent cytotoxicity even at ratios of 0.5, no significant toxicity was noted in the TAT/plasmid/NLS complex group. It is obvious that with the addition of peptides the toxicity decreases significantly. Histochemical staining showed that the transformants presented blue color under light microscope, but the negative control and blank control are not. Furthermore, based on a TAT/plasmids ratio of 4 with 10 µg NLS peptides mediation, RT-qPCR results demonstrated that the transcripts of target gene were increased by 269 times than that of control group. CONCLUSIONS: This study demonstrated that combination of TAT and NLS peptides can significantly improve the transformation rate and expression level of foreign gene in D. salina system. It offers a promising way for promoting the application and development of D. salina bioreactor.

Numerical Study for the Performance of Viscoelastic Fluids on Displacing Oil Based on the Fractional-Order Maxwell Model.

In the study of polymer flooding, researchers usually ignore the genetic stress properties of viscoelastic fluids. In this paper, we investigate the process of viscoelastic fluid flooding the remaining oil in the dead end. This work uses the fractional-order Maxwell in the traditional momentum equation. Furthermore, a semi-analytic solution of the flow control equation for fractional-order viscoelastic fluids is derived, and the oil-repelling process of viscoelastic fluids is simulated by a secondary development of OpenFOAM. The results show that velocity fractional-order derivative α significantly affects polymer solution characteristics, and increasing the elasticity of the fluid can significantly improve the oil repelling efficiency. Compared to the Newtonian fluid flow model, the fractional order derivative a and relaxation time b in the two-parameter instanton equation can accurately characterize the degree of elasticity of the fluid. The smaller the a, the more elastic the fluid is and the higher the oil-repelling efficiency. The larger the b, the less elastic the fluid is and the lower the cancellation efficiency. Moreover, the disturbance of the polymer solution to the dead end is divided into two elastic perturbation areas. The stronger the elasticity of the polymer solution, the higher the peak value of the area in the dead end and the higher the final oil displacement efficiency.

Feasible management of median arcuate ligament syndrome in orthotopic liver transplantation recipients.

BACKGROUND: In orthotopic liver transplantation (OLT) recipients, median arcuate ligament syndrome (MALS) is considered a risk factor for hepatic arterial thrombosis (HAT), which is dreadful for OLT recipients. Different alternative surgical procedures have been proposed to overcome the impact of MALS on transplantation, but clinical evidence is still scarce. AIM: To evaluate the feasible surgical management of MALS to reduce complications in OLT patients. METHODS: Data for 288 consecutive patients who underwent OLT at The First Hospital of Jilin University between January 2017 and July 2020 were retrospectively reviewed. The surgical management of median arcuate ligament (MAL) and modifications to the arterial anastomosis were recorded. The perioperative and long-term prognosis of MALS recipients were noted. Detailed preoperative and postoperative data of patients were analyzed in a descriptive manner. RESULTS: Eight patients with MALS were included in this study. The first patient with MALS received no intervention during the primary surgery and developed postoperative HAT. Salvage liver transplantation with MAL division was successfully performed. Gastroduodenal artery (GDA) preservation with splenic artery ligation was performed on three patients, only GDA preservation was performed on two patients, and no intervention was performed on two patients. No patient developed HAT after surgery and postoperative recovery was satisfactory. CONCLUSION: The preservation of collateral circulation between the superior mesenteric artery and celiac trunk via the GDA with or without splenic artery ligation is a safe and feasible alternative to MAL division.

Pediatric living donor liver transplantation using liver allograft after ex vivo backtable resection of hemangioma: A case report.

BACKGROUND: Use of liver allograft with hepatic hemangioma after in vivo resection of hemangioma in living donor liver transplantation (LDLT) has been previously reported. However, there are few reports describing ex vivo backtable resection of hemangioma from liver allografts in LDLT. CASE SUMMARY: A 55-year-old male was evaluated as a donor for an 8-month-year old patient with acute hepatic failure due to biliary atresia. Pre-operative contrast enhanced computed tomography revealed a 9 cm hemangioma in segment 4 with vascular variations in the donor. During LDLT, an intra-operative intrahepatic cholangiography was performed to ensure no variation in the anatomy of the intrahepatic bile duct. After intra-operative pathological diagnosis, ex vivo backtable resection of the hemangioma was performed and the liver allograft was transplanted into the recipient. The donor's and recipient's post-operative course were uneventful. At the 2-year follow-up, the liver allograft showed good regeneration without any recurrence of hemangioma. CONCLUSION: Liver allografts with hemangiomas are an acceptable alternative strategy for LDLT. Ex vivo backtable resection of hemangioma from the donor liver during pediatric LDLT is safe and feasible, and can effectively reduce the operative time and intra-operative bleeding for the donor.

Targeting lectin-like oxidized low-density lipoprotein receptor-1 triggers autophagic program in esophageal cancer.

Autophagy is a highly conserved catabolic process to maintain cellular homeostasis. However, dysfunctional autophagy contributes to a context-dependent role in cancer. Here, we clarified the exact role of autophagy modulated by the scavenger receptor lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) in esophageal cancer (EC). A comprehensive analysis in various cancers displayed that LOX-1 was upregulated the most in EC tissues and associated with poor prognosis of patients. Deletion of LOX-1 ex vivo and in vivo suppresses EC development by inducing autophagic cell death. Receptor for activated C kinase 1 (RACK1) was identified as a signal adapter of LOX-1, which incented RAS/MEK/ERK pathway and TFEB nuclear export signal and safeguarded tumorigenesis. A sulfated polysaccharide fucoidan extracted from brown seaweed was found to bind with LOX-1 and mediate its proteasomal degradation but not the lysosome pathway, leading to autophagy-related cell death in EC. These results reveal a central contribution of LOX-1 to EC development and provide genetic ablation or bioactive polysaccharide as an effective intervention for EC therapy.

Laparoscopic treatment of a recurrent biliary stone forming around a Hem-o-lok clip in a patient with previous gastrectomies: Case report.

RATIONALE: A history of gastrectomy is associated with an increased incidence of gallstones requiring surgery. Endoscopic retrograde cholangiopancreatography is challenging for patients who undergo total or Billroth II gastrectomy. Laparoscopic common bile duct exploration (LCBDE) has been attempted in such cases. Herein, we report a case of choledocholithiasis in which a stone formed around a migrated Hem-o-lok clip. PATIENT CONCERNS: A 67-year-old man was admitted to the hospital for acute right upper abdominal pain. He had a history of 2 open gastric cancer surgeries in the previous seven years and had undergone LCBDE 12 months prior to this admission. Postoperative examination revealed recurrence of bile duct stones. INTERVENTIONS: The patient underwent repeat LCBDE plus primary closure with an evaluation of abdominal adhesion. A stone had formed around a Hem-o-lok clip in the common bile duct was removed. OUTCOMES: The patient had an uneventful recovery with no stone recurrence or movement of the remaining Hem-o-lok clips after a 1-year follow-up. LESSONS: LCBDE with primary closure should be carefully considered in patients with certain gallstone diseases after complicated upper abdominal surgery.Postoperative clip migration is a rare complication; hence care must be taken in placing the clip appropriately to ensure that it is not too close to the common bile duct.

Sclerosing angiomatoid nodular transformation of the spleen: A case report and literature review.

BACKGROUND: Sclerosing angiomatoid nodular transformation (SANT) is a rare disease of the spleen. It has unique pathological features and mimics splenic tumor on radiological imaging. CASE SUMMARY: A 47-year-old woman was incidentally found to have a splenic mass on abdominal ultrasound. She had a 10-cm postoperative scar in the lower abdomen due to previous cesarean sections. The patient had a past history of anemia of unknown etiology for 20 years. The patient underwent laparoscopic splenectomy. The postoperative course was uneventful, with a hospital stay of 7 d. The histopathological examination of the spleen revealed SANT. At the 6-mo follow-up, the patient remained disease-free. CONCLUSION: SANT is a rare benign disease mimicking a malignant tumor. A definitive diagnosis can be made only on histopathology.

Hepatic epithelioid hemangioendothelioma: Update on diagnosis and therapy.

With an estimated incidence of only 1-2 cases in every 1 million people, hepatic epithelioid hemangioendothelioma (HEHE) is a rare vascular endothelial cell tumor occurring in the liver and consisting of epithelioid and histiocyte-like vascular endothelial cells in mucus or a fibrotic matrix. HEHE is characterized as a low-to-moderate grade malignant tumor and is classified into three types: solitary, multiple, and diffuse. Both the etiology and characteristic clinical manifestations of HEHE are unclear. However, HEHE has a characteristic appearance on imaging including ultrasound, magnetic resonance imaging, and positron emission tomography/computerized tomography. Still, its diagnosis depends mainly on pathological findings, with immunohistochemical detection of endothelial markers cluster of differentiation 31 (CD31), CD34, CD10, vimentin, and factor VIII antigen as the basis of diagnosis. Hepatectomy and/or liver transplantation are the first choice for treatment, but various chemotherapeutic drugs are reportedly effective, providing a promising treatment option. In this review, we summarize the literature related to the diagnosis and treatment of HEHE, which provides future perspectives for the clinical management of HEHE.

Fast-growing epithelioid hemangioendothelioma of the liver: A case report.

RATIONALE: Hepatic epithelioid hemangioendothelioma (HEH) is a rare vascular tumor of the liver with malignant potential. It can be of solitary type, multifocal type, or diffuse type. Although there are some characteristic features on radiologic imaging, the definitive diagnosis of HEH is based on histopathology. The surgical treatment of HEH includes liver resection and transplant. PATIENT CONCERNS: A middle-aged woman presented with easy fatiguability and anorexia for 1 month was found to have multifocal lesions on radiological imaging. DIAGNOSIS: HEH was diagnosed by needle biopsy. It can be seen from imaging that this case is a multifocal form. The largest lesion increased from 3 to 3.3 cm within 2 months, with an increase of 9.45%; no other relevant literatures have been reported. INTERVENTIONS: The possibility of liver transplantation was suggested to the patient. However, the patient refused transplantation and was successfully treated by radical right hepatectomy and resection of the left lobe lesion. OUTCOMES: She remained disease-free throughout a year follow-up period. CONCLUSION: HEH is a rare disease with characteristic radiological and pathological features. Although liver transplantation is the preferred treatment for multifocal HEH, surgical excision represents one alternative when the lesions can be guaranteed to be completely excised.

Wnt/ß-Catenin Signaling Axis Is Required for TFEB-Mediated Gastric Cancer Metastasis and Epithelial-Mesenchymal Transition.

Gastric cancer remains the third leading cause of cancer-related death, and tumor metastasis is the main risk factor for poor prognosis of patients with gastric cancer. Transcription factor EB (TFEB) is a MiT family member and has been found to drive tumorigenesis in a number of tissues, whereas few studies were focused on investigating its prometastasis role and mechanism in gastric cancer. Here, we found TFEB was upregulated in gastric cancer tissues compared with adjacent normal gastric epithelial tissues. IHC analysis from gastric cancer tissue microarray revealed that TFEB in gastric cancer was correlated with depth of tumor invasion, lymph node or distant metastasis, tumor tumor-node-metastasis stage, and overall survival. Gastric cancer cells with TFEB overexpression presented an increased cell migration or invasion, and epithelial-mesenchymal transition (EMT). Furthermore, gene correlation analysis and gene set enrichment analysis enriched Wnt/ß-catenin signaling pathway members in TFEB high-expression group, and the TOP/FOPflash assay verified the effect of TFEB on ß-catenin transcription activity. Besides, we found that TFEB could trigger the aggregation of ß-catenin in nucleus and activate its transcription, as well as facilitate the expression of Wnt/ß-catenin target genes and EMT-related markers, which could be reversed by the Wnt/ß-catenin inhibitor XAV-939. Collectively, TFEB enhances gastric cancer metastatic potential by activating Wnt/ß-catenin signaling pathway and may become a promising therapeutic target for gastric cancer metastasis. IMPLICATIONS: Overexpressed TFEB predicts a higher rate of metastasis and worse survival in patients with gastric cancer. Mechanistically, TFEB activates Wnt/ß-catenin signaling to fuel migratory and invasive activities of gastric cancer cells, as well as EMT.

Crowe Type IV Hip Dysplasia Treated by THA Comebined with Osteotomy to Balance Functional Leg Length Discrepancy: A Prospective Observational Study.

OBJECTIVE: To measure the factors that affect functional leg length of Crowe type IV Developmental dysplasia of the hip (DDH) patients and to review our own methods to balance leg length discrepancy (LLD) in Crowe type IV DDH patients. METHODS: This was a prospective observational study which started in June 2017 and ended in August 2019. Inclusion criteria included: (i) Crowe type I or Crowe type IV hip dysplasia patients who underwent total hip arthroplasty (THA) in the Department of Orthopaedics at our institution between July 2017 and June 2018; (ii) the patients were treated with our specific leg length balance strategy; and (iii) the related outcomes of patients were completely recorded. Finally, 18 consecutive Crowe type I patients (20 hips) and 14 consecutive Crowe type IV patients (18 hips) were selected and divided into two groups according to Crowe types. All patients received THA, and patients with a longer affected side and inferior anatomical acetabular positions in Crowe type IV group also received subtrochanteric osteotomy. During operation and after hip reduction, leg lengths were compared while two legs were in an extended position and the operative leg was on top of the non-operative one. Additional leg length adjustment was applied when leg length was considered to be unequal. Prior to surgery, subluxation height of the femoral head on the affected side, functional LLD, bony length of lower limbs, and distance from teardrops to the lowest point line of the sacroiliac joint were recorded. After surgery, cup sizes, functional LLD, and height of hip rotational centers were measured. Clinical evaluations, such as Harris Hip Score (HHS) and SF-12 scale, were also obtained before and after surgery for all patients. RESULTS: At the last follow-up, functional LLD and clinical measurements of both Crowe type IV group and Crowe type I group were significantly improved. Compared with Crowe type I patients, Crowe type IV patients had a significantly lower MCS, a significantly longer leg lengthening length and a significantly lower hip center height after surgery. Significant differences of tibia length, leg length, and teardrop position were found between affected side and healthy side of Crowe type IV patients. Only three of 14 Crowe type IV patients remained under 1 cm functional LLD. Five patients in the Crowe type IV group developed lower limb numbness immediately following surgery, and they all recovered within 6 months. The average follow-up period for either group was 14 months, and all patients were followed-up at 1, 3, 6, and 12 months then yearly after surgery until the final follow-up. CONCLUSION: After detailed leg length balance process, THA combined with transverse sub-trochanter osteotomy could be an effective method to achieve equal function leg length with most Crowe type IV patients.

Fucoidan suppresses the gastric cancer cell malignant phenotype and production of TGF-ß1 via CLEC-2.

The sulfated polysaccharide fucoidan displays excellent anticancer properties with low toxicity in many kinds of cancers. However, its detailed pharmacological effect and mechanism of action in gastric carcinoma remains unclear. In this study, we found that fucoidan could suppress gastric cancer (GC) cell growth, as well as cell migration and invasion. A cytokine expression screen demonstrated that transforming growth factor beta 1 (TGF-ß1) secretion was decreased in fucoidan-treated cells. Fucoidan has been reported to be a platelet agonist for the C-type lectin-like receptor 2 (CLEC-2), and our previous research found that upregulation of CLEC-2 inhibited GC progression. Here, we confirmed that fucoidan, combined with CLEC-2, significantly increased CLEC-2 expression in GC cells via the transcription factor caudal type homeobox transcription factor 2, an important regulator of gut homeostasis. In addition, the inhibitory effect of fucoidan on the GC cell malignant phenotype and TGF-ß1 secretion could be restored by knocking down CLEC-2. Thus, our data suggest that fucoidan targets CLEC-2 to exert antitumorigenesis and antimetastatic activity, suggesting that fucoidan is a promising treatment for gastric carcinoma.

Total Hip Arthroplasty for Crowe Type IV Hip Dysplasia: Surgical Techniques and Postoperative Complications.

Total hip arthroplasty (THA) of Crowe type IV developmental dysplasia of the hip (DDH) is challenging. Although traditional (lateral, posterolateral, and posterior) THA approaches have been used with great anatomic success, they damage periarticular muscles, which are already quite weak in type IV DDH. The recently developed direct anterior approach (DAA) can provide an inter-nerve and inter-muscle approach for THA of type IV dysplasia hips. However, femur exposure with the DAA could be difficult during surgery and it is hard to apply femoral shortening osteotomy. THA techniques used for type IV DDH include anatomic hip center techniques (true acetabular reconstruction) and high hip center techniques, wherein an acetabulum is reconstructed above the original one. Although anatomic construction of the hip center is considered "the gold standard" treatment, it is impossible if the anatomical acetabular is too small and shallow. Procedures used to support type IV DDH reduction with anatomic hip center techniques include greater trochanter osteotomy, lesser trochanter osteotomy, and subtrochanteric osteotomy. However, these techniques have yet to be standardized, and it is unclear which is best for type IV DDH. One-state and two-state non-osteotomy reduction techniques have also been introduced to treat type IV DDH. Potential complications of THA performed in patients with type IV DDH include leg length discrepancy (LLD), peri-operative femur fracture, nonunion of the osteotomy site, and nerve injury. It is worth noting that nowadays an increasing number of Crowe type IV DDH patients are more sensitive to postoperative LLD.