A patient with tumor necrosis factor receptor-associated periodic syndrome misdiagnosed as Kawasaki disease: A case report and literature review.

This article reports a case of tumor necrosis factor receptor-associated periodic syndrome (TRAPS) misdiagnosed as Kawasaki disease and summarizes the clinical features and therapeutic progress of TRAPS and the relationship between its clinical manifestations and gene mutations. We retrospectively analyzed a patient with tumor necrosis factor receptor superfamily member 1A (TNFRSF1A) -mutated auto-inflammatory disease who was misdiagnosed with Kawasaki disease in another hospital. The clinical features and therapeutic progress of TRAPS were analyzed by combining clinical features and gene reports of this case and literature review. TRAPS onset occurred in a female pediatric patient at the age of 4 months. The child and in his father at the age of 6 years, both of whom manifested periodic fever, and recurrent rash, as well as elevated leukocytes, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) during episodes but normal between episodes. This child carried a heterozygous mutation in TNFRSF1A located in the region 6442923-6442931 on chromosome 12. The nucleic acid alteration was: c.298 (exon3) _c.306 (exon3) 291 delCTCAGCTGC, resulting in a 3 amino acid deletion p.L100_C 102del 292 (p.Leu100_Cys102del) (NM_001065). After etanercept treatment, the symptoms of fever and rash disappeared, and the levels of ESR, CRP, interleukin (IL)-1, IL-6, and TNF-α levels were normal. Subsequently, no liver, kidney, or cardiac amyloidosis and severe etanercept-related adverse events were observed at 1-year follow-up. TRAPS pathogenesis is associated with TNFRSF1A mutation, which is characterized by periodic episodes of fever, mostly accompanied by recurrent rashes, periorbital edema, abdominal pain, and serious complications of organ amyloidosis. Moreover, etanercept can effectively alleviate the clinical symptoms and high inflammation level of TRAPS.

An autopsy case of unexpected death due to Addison's disease caused by adrenal tuberculosis.

BACKGROUND: Adrenal tuberculosis is difficult to diagnose due to non-specific symptom. Unexpected death due to adrenal insufficiency after trauma surgery is rare. CASE PRESENTATION: A 45-year-old man, who was admitted to hospital because of trauma to the right hand, died unexpectedly on the 13th day after replantation of amputated fingers. He was diagnosed with brain edema and diluted hyponatremia. Autopsy and histopathologic examination revealed severe brain edema combined with cerebellar tonsillar hernia, extensive destruction of adrenal gland caused by bilateral adrenal tuberculosis and right lung invasive pulmonary tuberculosis. CONCLUSIONS: Trauma and pulmonary tuberculosis complicated with adrenal tuberculosis induced the adrenal crisis, which eventually lead to severe cerebral edema and hernia, and finally death from respiratory and circulatory failure. This autopsy and histopathologic examination suggested a possible pathophysiologic mechanism of sudden death due to diluted hyponatremia after trauma surgery.

Propofol mediates pancreatic cancer cell activity through the repression of ADAM8 via SP1.

Propofol is a commonly used anesthetic with controversial effects on cancer cells. A growing number of studies have demonstrated that low concentrations of propofol are associated with tumor suppression and when used as an intravenous anesthesia improved recurrence­free survival rates for many cancers, but deeper insights into its underlying mechanism are needed. The study detailed herein focused upon the effect of propofol on pancreatic cancer cells and the mechanism by which propofol reduces A disintegrin and metalloproteinase 8 (ADAM8) expression. The ability of propofol to impact the proliferation, migration and cell cycle of pancreatic cancer cell lines was assessed in vitro. This was mechanistically explored following the identification of SP1 binding sites within ADAM8, which enabled the regulatory effects of specificity protein 1 (SP1) on ADAM8 following propofol treatment to be further explored. Ultimately, this study was able to show that propofol significantly inhibited the proliferation, migration and invasion of pancreatic cancer cells and decreased the percentage of cells in S­phase. Propofol treatment was also shown to repress ADAM8 and SP1 expression, but was unable to affect ADAM8 expression following knockdown of SP1. Moreover, a direct physical interaction between SP1 and ADAM8 was verified using co­immunoprecipitation and dual­luciferase reporter assays. Cumulatively, these results suggest that propofol represses pathological biological behaviors associated with pancreatic cancer cells through the suppression of SP1, which in turn results in lower ADAM8 mRNA expression and protein levels.

Inhibiting Monoacylglycerol Lipase Suppresses RANKL-Induced Osteoclastogenesis and Alleviates Ovariectomy-Induced Bone Loss.

Osteoporosis is a common chronic metabolic bone disease characterized by reduced trabecular bone and increased bone fragility. Monoacylglycerol lipase (MAGL) is a lipolytic enzyme to catalyze the hydrolysis of monoglycerides and specifically degrades the 2-arachidonoyl glycerol (2-AG). Previous studies have identified that 2-AG is the mainly source for arachidonic acid and the most abundant endogenous agonist of cannabinoid receptors. Considering the close relationship between inflammatory mediators/cannabinoid receptors and bone metabolism, we speculated that MAGL may play a role in the osteoclast differentiation. In the present study, we found that MAGL protein expression increased during osteoclast differentiation. MAGL knockdown by adenovirus-mediated shRNA in bone marrow-derived macrophages demonstrated the suppressive effects of MAGL on osteoclast formation and bone resorption. In addition, pharmacological inhibition of MAGL by JZL184 suppressed osteoclast differentiation, bone resorption, and osteoclast-specific gene expression. Activation of the Mitogen-activated protein kinase (MAPK) and nuclear factor κB (NF-κB) pathways was inhibited by JZL184 and deletion of MAGL. Our in vivo study indicated that JZL184 ameliorated bone loss in an ovariectomized mouse model. Furthermore, overexpressing H1 calponin partially alleviated the inhibition caused by JZL184 or MAGL deletion on osteoclastogenesis. Therefore, we conclude that targeting MAGL may be a novel therapeutic strategy for osteoporosis.

Enalapril inhibits inflammatory osteolysis induced by wear debris in a mouse model.

OBJECTIVE: Aseptic loosening, the most frequent complication after total joint replacement, is probably caused by an inflammatory response to the shedding of wear debris from the implant. The only effective treatment is surgical revision. Using a mouse model, we investigated whether enalapril inhibits wear debris-induced inflammatory osteolysis. METHODS: Titanium (Ti) alloy particles were introduced, and calvarial bone from syngeneic mice was implanted into air pouches established in BALB/c mice. Histological and molecular analyses were performed with inflammatory tissue samples obtained from mice treated with and without enalapril. RESULTS: Enalapril inhibited tissue inflammation and inflammatory osteolysis induced by Ti particles, reducing pouch membrane thickness and decreasing inflammatory cell infiltration. In addition, enalapril inhibited the expression of the inflammatory cytokines vascular endothelial growth factor and tumor necrosis factor-α. CONCLUSIONS: Our study provides evidence that enalapril inhibits Ti particle-induced inflammatory osteolysis, and it may be a potentially useful treatment for aseptic loosening.

An integrated RNA-Seq and network study reveals the effect of nicotinamide on adrenal androgen synthesis.

Acne vulgaris is a chronic inflammatory disease of the skin resulting from androgen-induced increased sebum production and altered keratinization. Nicotinamide (NAM), an amide form of vitamin B3 with a well-established safety profile, has shown good therapeutic potential in treating acne and its complications. NAM has anti-inflammatory effects and reduces sebum but its function in androgen biosynthesis remains unknown. In this study, we used a widely used cell model, starved human adrenal NCI-H295R cells, to examine the effects of NAM in androgen production and its mediated network changes. By treating NCI-H295R cells with 1-25 mmol/L of NAM, we found that cell viability was only slightly inhibited at the highest dose (25 mmol/L). NAM reduced testosterone production in a dose-dependent manner. Transcriptomic analysis demonstrated that key enzymes of androgen biosynthesis were significantly decreased under NAM treatment. In addition, gene set enrichment analysis (GSEA) showed that gene sets of cell cycle, steroid biosynthesis, TGFß signalling, and targets of IGF1 or IGF2 were enriched in NAM-treated cells. Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway and Gene ontology (GO) analysis of the differentially expressed genes also suggested that steroidogenesis and SMAD signalling were affected by NAM. Overall, these crucial genes and pathways might form a complex network in NAM-treated NCI-H295R cells and result in androgen reduction. These findings help explain the potential molecular actions of NAM in acne vulgaris, and position NAM as a candidate for the treatment of other hyperandrogenic disorders.

Propofol inhibits pancreatic cancer progress under hypoxia via ADAM8.

BACKGROUND: To investigate the potential anti-tumoral properties of propofol in pancreatic cancer and elucidate the underlying mechanisms. METHODS: The relative expression of ADAM metallopeptidase domain 8 (ADAM8) in response to hypoxia in Panc1 cells was analyzed by western blotting. The enzymatic activity was determined by fluorescence release from PEPDAB013 decomposition. Cell growth was measured via cell counting and cell viability was measured using CCK-8 kit. Cell migrative capacity was evaluated by transwell and adhesion assay. The relative abundance of angiogenesis-related markers including platelet-derived growth factor AA, angiogenin, endothelin-1 and vascular endothelial growth factor were determined by real-time polymerase chain reaction and western blotting. The anti-tumoral activity of propofol was investigated with Panc1-derived xenograft mice model. RESULTS: ADAM8 was significantly induced by hypoxia and efficiently inhibited by co-treatment with propofol. Propofol suppressed proliferation and compromised viability of Panc1 cells. In addition, the migrative capacity was greatly inhibited by propofol dosage. Comprehensive profiling of angiogenesis-related markers demonstrated that propofol remarkably suppressed neovascularization response in Panc1 cells under hypoxia. We further uncovered that propofol administration via subcutaneous injection delayed xenograft tumor progression. CONCLUSION: Propofol specifically inhibited ADAM8 expression and activation in response to hypoxia in pancreatic cancer, and held great value for therapeutic effects.

Propofol inhibits pancreatic cancer proliferation and metastasis by up-regulating miR-328 and down-regulating ADAM8.

Propofol is commonly used for anaesthesia during surgery, and accumulating evidence has demonstrated that propofol is associated with tumour suppression. For example, propofol down-regulates the expression of vascular endothelial growth factor to inhibit pancreatic cancer malignancy. However, deeper insights into its underlying mechanism are needed. In this study, we treated pancreatic cell lines Panc1 and Bxpc3 with or without propofol. Cell proliferation, migration and invasion were evaluated using 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and transwell assays. Real-time polymerase chain reaction was used to measure RNA expression levels. Luciferase assay was performed to determine the transcriptional activity of microRNAs (miRNAs). We found that propofol significantly reduced the proliferation, migration and invasion of pancreatic cancer cells compared to untreated cells. By testing the changes in miRNAs after propofol treatment, propofol was shown to strikingly enhance the expression of miR-328. Luciferase assays demonstrated that propofol repressed the transcriptional activity of miR-328, while a disintegrin and metalloproteinase 8 (ADAM8) was a direct target of miR-328. Knockdown of miR-328 or ADAM8 led to significantly decreased cell growth and viability. Our results implicate that propofol inhibits pancreatic cancer growth and metastasis by enhancing miR-328 which targets ADAM8.

Extraperiosteal segmental excision for osteofibrous dysplasia of tibia with reconstruction by liquid nitrogen-treated recycled autograft.

BACKGROUND: Osteofibrous dysplasia usually progresses until ten years of age and occasionally regresses spontaneously after puberty. Patients with osteofibrous dysplasia usually require close observation. Surgery is an option considered only for extensive, deforming lesions and those with pathological fractures and rapid progression prior to puberty. If surgery is indicated, the traditional intra-lesional curettage or subperiosteal resection usually leads to high recurrence. Hence, extraperiosteal wide excision and various methods of reconstruction after resection have been advocated for this lesion. We reviewed the clinical results of patients managed with extraperiosteal segmental excision and reconstruction by liquid nitrogen-treated tumor-bearing autograft combined with allograft. METHODS: From January 2010 to December 2014, twelve patients with final diagnosis of tibial osteofibrous dysplasia were studied retrospectively. All these patients were treated with extraperiosteal segmental excision and reconstruction by liquid nitrogen-treated tumor-bearing autograft combined with allograft. RESULTS: The patient group consisted of 5 males and 7 females, with a median age of 13 years (6-24 years). 3 lesions were located in left tibia and 9 in right. The median length of resected segment was 8 cm (5-11 cm). The patients were followed for 36-84 months (median 52 months). Follow-up radiographs showed that the median time for complete union of the grafted bone was 9 months (6-15 months). There was no evidence of recurrence. All patients had full range of motion in the knee and ankle joints after surgery. CONCLUSIONS: Extraperiosteal segmental excision for osteofibrous dysplasia of tibia with reconstruction by liquid nitrogen-treated recycled autograft and allograft is a good surgical option to prevent recurrence and fill bone defects in this rare lesion.

Hesperetin suppresses RANKL-induced osteoclastogenesis and ameliorates lipopolysaccharide-induced bone loss.

Destructive bone diseases caused by osteolysis are increasing in incidence. They are characterized by an excessive imbalance of osteoclast formation and activation. During osteolysis, the activation of nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways are triggered by receptor activator of NF-κB ligand (RANKL), inflammatory factors, and oxidative stress. Previous studies have indicated that the common flavanone glycoside compound hesperetin exhibits anti-inflammatory and antioxidant activity by inhibition of NF-κB and MAPK signaling pathways. However, the direct relationship between hesperetin and osteolysis remain unclear. In the present study, we investigated the effects of hesperetin on lipopolysaccharide (LPS)-induced osteoporosis and elucidated the related mechanisms. Hesperetin effectively suppressed RANKL-induced osteoclastogenesis, osteoclastic bone resorption, and F-actin ring formation in a dose-dependent manner. It also significantly suppressed the expression of osteoclast-specific markers including tartrate-resistant acid phosphatase, matrix metalloproteinase-9, cathepsin K, c-Fos, and nuclear factor of activated T-cells cytoplasmic 1. Furthermore, it inhibited osteoclastogenesis by inhibiting activation of NF-κB and MAPK signaling, scavenging reactive oxygen species, and activating the nuclear factor E2 p45-related factor 2/heme oxygenase 1 (Nrf2/HO-1) signaling pathway. Consistent with in vitro results, hesperetin effectively ameliorated LPS-induced bone loss, reduced osteoclast numbers, and decreased the RANKL/OPG ratio in vivo. As such, our results suggest that hesperetin may be a great candidate for developing a novel drug for destructive bone diseases such as periodontal disease, tumor bone metastasis, rheumatoid arthritis, and osteoporosis.

Antitumor and immunomodulatory activities of total flavonoids extract from persimmon leaves in H22 liver tumor-bearing mice.

Persimmon (Diospyros kaki L.) leaves are commonly used in Asia as tea infusion and as an agent in traditional medicine. The present study aims to explore the antitumor and immunomodulatory effects of total flavonoids extract from persimmon leaves (PLF) in H22 liver tumor-bearing mice. We found that the PLF showed significant inhibition on the liver tumor growth in mice with a tumor inhibition rate of up to 49.35%. In contrast to the severe side effects of cyclophosphamide (CTX), the PLF exhibited anti-cachexia effect and showed no alternation in the body weight and food intake in mice. Moreover, compared with the vehicle control and CTX group, the PLF significantly enhanced the thymus and spleen indices, level of serum interleukin-18 (IL-18), monocyte/macrophage phagocytosis, level of serum hemolysin, and activity of natural killer (NK) cells. This study demonstrated that the PLF could effectively inhibit liver tumor growth in vivo via enhancement of the immune function in mice, and it displayed the potential to be a safe and effective anticancer agent or functional immune-enhancing agent.

Flavonoids Active Against Osteosarcoma: A Review of the Molecular Mechanisms Involved.

Osteosarcoma is the most frequent primitive malignant bone tumor affecting adolescents and young adults worldwide. The tumor exhibits aggressive growth in the primary site and readily metastasizes to other organs. There has been no significant improvement in the 5-year survival rate since the 1970s and the figure remains at 60-70%. In addition, the side effects of chemotherapeutic drugs and resistance to chemotherapy compromise the effects of treatment for osteosarcoma. In recent years, the development of flavonoids drugs inhibiting carcinogenesis is attracting great interest in the scientific community. Flavonoids are one kind of polyphenolic compounds widely found in vegetables and fruits. Moreover, flavonoids have become popular compounds, exhibiting comprehensive antitumor activities, while being safe and inexpensive. Here, the literature on the benefits afforded by flavonoids in terms of osteosarcoma treatment is reviewed and certain flavonoids and their effects on osteosarcoma are discussed. These compounds can perturb the cell cycle, induce apoptosis, inhibit tumor cell invasion and metastasis, potentiate the actions of chemotherapeutic agents, trigger autophagy, and stimulate antitumor activity in vivo. In summary, we highlight the currently well-accepted flavonoid compounds and detail the molecular mechanisms by which flavonoids may treat osteosarcoma, and thus the flavonoids exhibit great promise as anti-osteosarcoma agents.

The Fascinating Effects of Baicalein on Cancer: A Review.

Cancer is one of the leading causes of death worldwide and a major global health problem. In recent decades, the rates of both mortality and morbidity of cancer have rapidly increased for a variety of reasons. Despite treatment options, there are serious side effects associated with chemotherapy drugs and multiple forms of drug resistance that significantly reduce their effects. There is an accumulating amount of evidence on the pharmacological activities of baicalein (e.g., anti-inflammatory, antioxidant, antiviral, and antitumor effects). Furthermore, there has been great progress in elucidating the target mechanisms and signaling pathways of baicalein's anti-cancer potential. The anti-tumor functions of baicalein are mainly due to its capacities to inhibit complexes of cyclins to regulate the cell cycle, to scavenge oxidative radicals, to attenuate mitogen activated protein kinase (MAPK), protein kinase B (Akt) or mammalian target of rapamycin (mTOR) activities, to induce apoptosis by activating caspase-9/-3 and to inhibit tumorinvasion and metastasis by reducing the expression of matrix metalloproteinase-2/-9 (MMP-2/-9). In this review, we focused on the relevant biological mechanisms of baicalein involved in inhibiting various cancers, such as bladder cancer, breast cancer, and ovarian cancer. Moreover, we also summarized the specific mechanisms by which baicalein inhibited the growth of various tumors in vivo. Taken together, baicalein may be developed as a potential, novel anticancer drug to treat tumors.

[ANALYSIS OF IMPLANT-RELATED COMPLICATIONS AFTER HINGE KNEE REPLACEMENT FOR TUMORS AROUND THE KNEE].

OBJECTIVE: To investigate the reasons and managements of implant-related complications after hinge knee replacement for tumors around the knee. METHODS: A retrospective analysis was made on the clinical data of 96 patients undergoing hinge knee replacement between January 2000 and December 2012. There were 64 males and 32 females with the mean age of 31.0 years (range, 15-72 years). The most common tumor type was osteosarcoma (72 cases), and the second was giant cell tumor (15 cases). The tumor located at the distal femurs in 52 cases and at the proximal tibias in 44 cases. Fifteen hinge and 81 rotating hinge prostheses were used. The recurrence, metastasis, and survival were recorded. The implant-related complications were observed. RESULTS: The median follow-up time was 43.5 months (range, 10-156 months). Complications were observed in 21 patients (25 implant-related complications); 13 complications located at the femur and 12 complications at the tibia. The complications included aseptic loosening (8 cases), deep infection (7 cases), prosthetic breakage (4 cases), peri-prosthetic fracture (2 cases), and dislocation (4 cases). Most deep infection occurred within 12 months after operation (6/7), and most aseptic loosening after 40 months of operation (6/8). The rate of limb salvage was 90.6% (87/96) and the amputation rate was 9.4% (9/96). The overall survival rate of the prosthesis was 76.7% (5-year) and 47.2% (10-year). The 5-year survival rate was 82.9% for femoral prosthesis and 71.0% for tibial prosthesis, showing no significant difference (P = 0.954). CONCLUSION: Hinge knee prosthesis still has a high rate of complications. Deep infection is main reason to decrease short-term prosthetic survival rate, and aseptic loosening shortens the long-short prosthetic survival time.

[Correlation of vasculogenic mimicry with clinicopathologic features and prognosis of ovarian carcinoma].

OBJECTIVE: To explore the existence of vasculogenic mimicry (VM) in ovarian carcinoma and its correlationship with the clinicopathologic features and prognosis of the tumor. METHODS: A total of 84 ovarian carcinoma cases were collected with complete clinical and prognostic data. CD31 immunohistochemistry and PAS special stain were used to investigate VM in the tumor tissue. Immunohistochemical staining of VEGF, MMP-2, MMP-9, E-cadherin, beta-catenin, and Vimentin were used to explore the pathogenesis of VM. RESULTS: Totally 36 of 84 cases exhibited evidence of VM. FIGO classification, pathologic grades and histological types were significantly different between the VM and non-VM groups. Expression of VEGF, MMP-2, MMP-9, E-cadherin and beta-catenin were higher in the VM group than in the non-VM group. Kaplan-Meier survival curve analysis showed that cases of the VM group had a lower survival rate than that of the non-VM group (P = 0.04). CONCLUSIONS: Vasculogenic mimicry exists in ovarian carcinoma. Ovarian carcinomas with a high grade malignancy have a high incidence of VM formation, a higher incidence of metastases and a lower survival rate. High expression of MMP-2 and MMP-9 may contribute to the formation of VM in the ovarian cancer.

The effect of increased peripheral suture purchase on the strength of flexor tendon repairs.

PURPOSE: Previous studies have hypothesized unequal load sharing between peripheral and core sutures in flexor tendon repairs. Most commonly peripheral sutures are placed very near the repair site and characteristically fail before the core strands. We hypothesized that placement of the peripheral sutures farther from the repair site would better optimize load sharing and resist suture pullout, yielding a stronger overall repair. METHODS: To test the hypothesis we developed a mathematical model of the load sharing between core and peripheral sutures. By using this model we predicted that placement of peripheral sutures 2 mm from the repair site would optimize the balance of load between core and peripheral sutures. We then divided and repaired 27 flexor digitorum profundus tendons in 6 ways (core plus peripheral or peripheral sutures only at 1 mm, 2 mm, or 3 mm from the repair site). Tendons were clamped to a custom-built linear loading machine and distracted to failure. RESULTS: There was a clinically and statistically significant increase in strength with an increased distance of the peripheral suture from the repair site showing that core sutures augmented by a 2-mm peripheral repair were stronger than those performed with 1-mm peripheral repairs (50.8 vs 37.1 N). CONCLUSIONS: A peripheral stitch placement approximately 2 mm from the repair site represents a simple modification that can significantly increase the ultimate strength of flexor tendon repairs.