Two naturally derived small molecules disrupt the sineoculis homeobox homolog 1-eyes absent homolog 1 (SIX1-EYA1) interaction to inhibit colorectal cancer cell growth.

BACKGROUND: Emerging evidence indicates that the sineoculis homeobox homolog 1-eyes absent homolog 1 (SIX1-EYA1) transcriptional complex significantly contributes to the pathogenesis of multiple cancers by mediating the expression of genes involved in different biological processes, such as cell-cycle progression and metastasis. However, the roles of the SIX1-EYA1 transcriptional complex and its targets in colorectal cancer (CRC) are still being investigated. This study aimed to investigate the roles of SIX1-EYA1 in the pathogenesis of CRC, to screen inhibitors disrupting the SIX1-EYA1 interaction and to evaluate the efficiency of small molecules in the inhibition of CRC cell growth. METHODS: Real-time quantitative polymerase chain reaction and western blotting were performed to examine gene and protein levels in CRC cells and clinical tissues (collected from CRC patients who underwent surgery in the Department of Integrated Traditional and Western Medicine, West China Hospital of Sichuan University, between 2016 and 2018, n = 24). In vivo immunoprecipitation and in vitro pulldown assays were carried out to determine SIX1-EYA1 interaction. Cell proliferation, cell survival, and cell invasion were determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, clonogenic assay, and Boyden chamber assay, respectively. The Amplified Luminescent Proximity Homogeneous Assay Screen (AlphaScreen) method was used to obtain small molecules that specifically disrupted SIX1-EYA1 interaction. CRC cells harboring different levels of SIX1/EYA1 were injected into nude mice to establish tumor xenografts, and small molecules were also injected into mice to evaluate their efficiency to inhibit tumor growth. RESULTS: Both SIX1 and EYA1 were overexpressed in CRC cancerous tissues (for SIX1, 7.47 ±â€Š3.54 vs.1.88 ±â€Š0.35, t = 4.92, P = 0.008; for EYA1, 7.61 ±â€Š2.03 vs. 2.22 ±â€Š0.45, t = 6.73, P = 0.005). The SIX1/EYA1 complex could mediate the expression of two important genes including cyclin A1 (CCNA1) and transforming growth factor beta 1 (TGFB1) by binding to the myocyte enhancer factor 3 consensus. Knockdown of both SIX1 and EYA1 could decrease cell proliferation, cell invasion, tumor growth, and in vivo tumor growth (all P < 0.01). Two small molecules, NSC0191 and NSC0933, were obtained using AlphaScreen and they could significantly inhibit the SIX1-EYA1 interaction with a half-maximal inhibitory concentration (IC50) of 12.60 ±â€Š1.15 µmol/L and 83.43 ±â€Š7.24 µmol/L, respectively. Administration of these two compounds could significantly repress the expression of CCNA1 and TGFB1 and inhibit the growth of CRC cells in vitro and in vivo. CONCLUSIONS: Overexpression of the SIX1/EYA1 complex transactivated the expression of CCNA1 and TGFB1, causing the pathogenesis of CRC. Pharmacological inhibition of the SIX1-EYA1 interaction with NSC0191 and NSC0933 significantly inhibited CRC cell growth by affecting cell-cycle progression and metastasis.

Modified Van Assche magnetic resonance imaging-based score for assessing the clinical status of anal fistulas.

The modified Van Assche magnetic resonance imaging (MRI)-based score is a feasible system to assess the clinical status of anal fistulas in Crohn disease. In this study, we evaluated this score's association with clinical status in patients with anal fistulas (AFs).We included all patients with AF who underwent contrast-enhanced pelvic MRI and surgery between January 2011 and December 2016. The score was evaluated retrospectively preoperatively and 1, 3, and 6 months postoperatively. Univariate and multivariate analyses of the risk factors for AF recurrence were also performed.We retrospectively analyzed data for 104 patients. Twelve (11.5%) patients developed AF recurrence. We classified patients' preoperative clinical status into three grades: 52 (50.0%) grade A, 31 (29.8%) grade B, and 21 (20.2%) grade C. The preoperative MRI-based score was significantly correlated with patients' preoperative clinical status grade (Pearson correlation: 0.547; P < .001). The 3 preoperative clinical status grades showed significant (F = 23.303, P < .001) tendencies for associations with lower respective MRI-based scores. The incidence of AF recurrence decreased with the MRI-based score to 1-month postoperatively, then gradually increased (F = 60.863, P = .000). Long duration of disease, prior interventions, and high MRI-based score were independent risk factors for AF recurrence.The MRI-based score objectively assessed the clinical status and disease activity of patients with AFs, with a high score being associated with severe clinical status and long recovery time.

Epiphyseal distraction and hybrid reconstruction using polymethyl methacrylate construct combined with free non-vascularized fibular graft in pediatric patients with osteosarcoma around knee: A case report.

BACKGROUND: In children with osteosarcoma around the knee joint without epiphysis involvement, joint-sparing surgery seems to be an ideal way to retain knee joint function. However, there are two points of debate with regard to the technique: How to accurately achieve a safe surgical margin, and how to achieve intercalary reconstruction of the massive bone defect following resection of the tumor. CASE SUMMARY: We present the case of an 8-year-old girl with osteosarcoma of the distal femur without involvement of the epiphysis. Epiphyseal distraction was applied to separate the epiphysis and metaphysis, and this provided a safe surgical margin. The massive bone defect was reconstructed with a custom-made antibiotic-loaded polymethyl methacrylate (PMMA) construct combined with a free non-vascularized fibular graft. Six months after surgery, bone union between the autograft and host bone was confirmed in both the proximal and distal femur by computer tomography (CT) examination. Moreover, considerable callus formation was found around the PMMA construct. After 28 mo of follow-up, there was no sign of recurrence or metastasis. The patient could walk without any aid and carry out her daily life activities satisfactorily. CONCLUSION: In cases of osteosarcoma without epiphysis involvement, epiphyseal distraction can be easily applied to obtain a safe margin. Hybrid reconstruction with an antibiotic-loaded PMMA construct combined with a free non-vascularized fibular graft has the advantages of being easy to manufacture, less time-consuming to place, and less likely to get infected, while also ensuring bone union. Our case provides an alternative technique for biological reconstruction after joint-sparing surgery in patients with osteosarcoma around the knee without epiphyseal involvement.

Prescription practices in the treatment of agitation in newly hospitalized Chinese schizophrenia patients: data from a non-interventional naturalistic study.

BACKGROUND: Data on the pharmacological management of acute agitation in schizophrenia are scarce. The aim of this study is to investigate the prescription practices in the treatment of agitation in Chinese patients with schizophrenia. METHODS: We conducted a large, multicenter, observational study in 14 psychiatry hospitals in China. Newly hospitalized schizophrenia patients with the PANSS-EC total score ≥ 14 and a value ≥4 on at least one of its five items were included in the study. Their drug treatments of the first 2 weeks in hospital were recorded by the researchers. RESULTS: Eight hundred and 53 patients enrolled in and 847 (99.30%) completed the study. All participants were prescribed antipsychotics, 40 (4.72%) were prescribed benzodiazepine in conjunction with antipsychotics and 81 were treated with modified electric convulsive therapy (MECT). Four hundred and 12 (48.64%) patients were prescribed only one antipsychotic, in the order of olanzapine (120 patients, 29.13%), followed by risperidone (101 patients, 24.51%) and clozapine (41 patients, 9.95%). About 435 (51.36%) participants received antipsychotic polypharmacy, mostly haloperidol + risperidone (23.45%), haloperidol+ olanzapine (17.01%), olanzapine+ ziprasidone (5.30%), haloperidol + clozapine (4.37%) and haloperidol + quetiapine (3.90%). Binary logistic regression analysis suggests that a high BARS score (OR 2.091, 95%CI 1.140-3.124), severe agitation (OR 1.846, 95%CL 1.266-2.693), unemployment or retirement (OR 1.614, 95%CL 1.189-2.190) and aggressiveness on baseline (OR 1.469, 95%CL 1.032-2.091) were related to an increased antipsychotic polypharmacy odds. Male sex (OR 0.592, 95%CL 0.436-0.803) and schizophrenia in older persons (age ≥ 55 years, OR 0.466, 95%CL 0.240-0.902) were less likely to be associated with antipsychotic polypharmacy. CONCLUSION: The present study demonstrates that monotherapy and polypharmacy display equally common patterns of antipsychotic usage in managing agitation associated with schizophrenia in China. The extent and behavioral activities of agitation and several other factors were associated with polypharmacy.

Angiogenesis Process in Osteosarcoma: An Updated Perspective of Pathophysiology and Therapeutics.

In this review, we discuss the pathologic mechanism of the angiogenesis process in osteosarcoma (OS) and the therapeutic use of angiogenesis inhibitors in OS treatment. The activation of endothelial cells by angiogenic factors leads to the production of proteolytic enzymes, which degrade the extracellular matrix. The degradation of the underlying basement membrane enables endothelial cells to proliferate and migrate to the surrounding tissue to form new vessels. These new vessels provide cancer cells with oxygen and nutrition and play an important role in cancer cell survival and metastasis. Thus, antiangiogenic therapies might be an interesting approach in OS therapeutics.

The possible role of insulin-like growth factor-1 in osteosarcoma.

Osteosarcoma (OS) is a common malignant tumor of bone, of which clear understanding of molecular pathologic process is not yet possible. Insulin-like growth factor-1 (IGF-1) is a hormone that plays vital role in development and function of many tissues. Unfortunately, IGF-1 and its receptor (IGF-1R)'s over-expression have been implicated in carcinogenesis, and indicated to constitute a risk factor for the development of multiple human cancers, including OS. Increased levels of IGF-1 and IGF-1R have been reported in OS, leading to cancer progression through transformation, proliferation, pro-metastasis, and decreased susceptibility to apoptosis. Over-expression of IGF-1/IGF-1R signaling also contributes to tumor cell survival, metastasis, and resistance to chemotherapeutic drugs. IGF-1 has been included as an OS marker recently, and targeting IGF-1 is an interesting and promising approach in OS therapeutics. However more investigations with clinical trials are necessary to validate the use of drugs against IGF-1 that may provide a basis for new therapeutic approaches to treat this devastating disease. This review article focused on the role of IGF-1/IGF-1R in OS progression and therapeutic aspects of OS targeting IGF-1.

Surgical treatment for shepherd's crook deformity in fibrous dysplasia: THERE IS NO BEST, ONLY BETTER.

BACKGROUND: The optimal strategy for shepherd's crook deformity correction remains technically challenging. In particular, it is difficult to perform an accurate osteotomy based on the pre-operative correction plan. Moreover, the choice of ideal hardware remains unclear. In addition, when combined with the deformity of knee joint, the sequence of deformity correction is another overlooked factor when making a correction strategy. METHODS: From February 2012 to March 2014, we retrospectively examined a cases series in our department involving the creation of three-dimensional (3D) printing osteotomy templates and inner fixation for shepherd's crook deformity in fibrous dysplasia. RESULTS: A total of ten patients of shepherd's crook deformity were enrolled in this study. The neck shaft angle was corrected from a mean value of 88.1° (range, 73-105°) pre-operatively to a mean value of 128.5° (range, 120-135°) post-operatively; no marked loss in the value was observed (mean, 123.7°; range, 115-130°) at the final follow-up. In addition, compared with patients using dynamic hip screw (DHS), longer operation time and additional blood loss were recorded in patients using intramedullary nail (IN). Moreover, after correction of shepherd's crook deformity, two patients were observed more predominant on their pre-existing valgus knee deformity. CONCLUSIONS: 3D printing osteotomy templates facilitate the correction of shepherd's crook deformity. Dynamic hip screw (DHS), combined with polymethylmethacrylate (PMMA) augmentation, yields excellent outcomes and ensures easy placement and non-intramedullary manipulation, lower bleeding volume, and reduced operation time. Prior to the correction of shepherd's crook deformity, the mechanical axis of the lower limb should be carefully examined, and any evidence of valgus knee deformity should be addressed in advance.

Distraction-suppression effect on osteosarcoma.

Osteosarcoma is the most common primary malignant bone tumor. It occurs mainly in children and adolescents. In patients with open growth plate, epiphyseal distraction is used to separate the uninvolved epiphysis from adjacent tumor. This helps preserve the growth potential and restore joint and limb function to a great extent. Interestingly, epiphyseal distraction also appears to inhibit the proliferation of osteosarcoma tumor cells and to increase sensitivity to chemotherapy. Tumor interstitial pressure (TIP) is often elevated in the microenvironment of most solid tumors, including osteosarcoma. Elevated TIP can promote the proliferation, invasion, and migration ability of osteosarcoma cells and also decrease the uptake and distribution of chemotherapeutic agents. Studies have confirmed that the sustained volumetric strain produced in distracted tissue decreases TIP; it stretches extracellular matrix, decreases interstitial density, and increases vessel diameter. We hypothesize that lowering of TIP during the period of epiphyseal distraction inhibits the proliferation and invasion of osteosarcoma cell and, at the same time, increases blood perfusion in the tumor and thus enhances uptake and distribution of chemotherapy agents. If the hypothesis is proved to be true, distraction of tumor segment could be a novel supplementary treatment for osteosarcoma by manipulation of TIP.

Use of Clavien-Dindo classification in evaluating complications following pancreaticoduodenectomy in 1,056 cases: A retrospective analysis from one single institution.

The Clavien-Dindo (C-D) classification is a simple and feasible grading system of postoperative complications. The aim of the present study was to apply this system to retrospectively classify all types of post-pancreaticoduodenectomy (PD) complications (PPCs) and to systematically identify associated risk factors. Between January 2009 and December 2014, the C-D classification was applied to retrospectively classify PPCs for 1,056 patients who had undergone PD at the West China Hospital. Univariate and multivariate analyses were performed to link perioperative parameters and mortality with the severity of PPCs, which were subdivided into overall PPCs (Grade I-V), severe PPCs (Grade III-V) and mortality (Grade V). The number of patients with Clavien-Dindo grade I, II, IIIa, IIIb, IVa, IVb and V complications was 185 (17.5%), 128 (12.1%), 50 (4.7%), 25 (2.4%), 35 (3.3%), 19 (1.8%) and 33 (3.1%), respectively. A total of 475 (45.0%) patients experienced overall PPCs; 168 (15.9%) patients experienced severe PPCs; and 33 patients succumbed to mortality following PD. The following risk factors were identified following PD: Preoperative hypoproteinemia was correlated with all three subdivisions; obstructive jaundice was associated with severe PPCs and mortality; and older age was revealed to be an independent risk factor of mortality. A large retrospective study was performed in the present study and PD was correlated with a high occurrence of PPCs. The Clavien-Dindo system represents a broad applicable and feasible approach to evaluating PPCs in patients following PD. The independent risk factors of PPCs that were identified in the present study require further validation using the Clavien-Dindo classification in additional prospective studies.

Is double-approach surgery and tenodesis without a gastrocnemius flap better for dealing with proximal fibular osteosarcoma?

BACKGROUND: Resection of proximal fibular osteosarcoma involving the posteromedial aspect of the fibula is challenging. Reconstruction using a gastrocnemius flap may result in significant lateral instability and abnormal knee movement. Furthermore, postoperative gait may be disturbed by foot drop resulting from scarification of the common peroneal nerve. METHODS: Between January 2011 and December 2013, five patients with proximal fibular osteosarcoma were treated via the double-approach procedure using en bloc resection without a gastrocnemius flap. Simultaneously, all patients received one-stage tenodesis of the anterior tibial and toe extensor tendons. Clinical outcomes, including local tumor recurrence, complications, and functional outcomes, were evaluated. RESULTS: The mean follow-up duration was 47.2 months (range 42-52 months). No patients experienced local recurrence. The patients' Enneking functional scores were excellent (80%) or good (20%) at the final follow-up. CONCLUSIONS: In patients with proximal fibular osteosarcoma, the double-approach procedure allows easier and safer en bloc tumor resection with vessel and nerve protection. One-stage tenodesis without a gastrocnemius flap is associated with good functional outcomes.

MiR-96 regulates bone metabolism by targeting osterix.

MicroRNAs (miRNAs) play important roles in bone metabolism and aging. Here we show that miR-96 was markedly up-regulated in serum of elderly patients with osteoporosis by miRNA microarray analysis and qRT-PCR. Moreover miR-96 was also up-regulated in bone marrow mesenchymal stem cells (BMSCs) of aged humans and mice. Our results show that the over-expression of miR-96 reduced osteogenic differentiation of BMSCs, whereas the inhibition of miR-96 increased osteogenic differentiation of BMSCs. At the molecular level, miR-96 regulated osteogenesis by targeting osterix. Interestingly, over-expression of miR-96 in young mice by intravenous injection of agomiR-96 developed a low bone mass due to impaired osteogenesis. However, inhibition of miR-96 in aged mice attenuated the age-related bone loss. Thus, our data suggest that miR-96 regulates osteogenesis and may represent a potential diagnostic marker or therapeutic target for age-related bone loss.

MiR-497∼195 cluster regulates angiogenesis during coupling with osteogenesis by maintaining endothelial Notch and HIF-1α activity.

A specific bone vessel subtype, strongly positive for CD31 and endomucin (CD31hiEmcnhi), is identified as coupling angiogenesis and osteogenesis. The abundance of type CD31hiEmcnhi vessels decrease during ageing. Here we show that expression of the miR-497∼195 cluster is high in CD31hiEmcnhi endothelium but gradually decreases during ageing. Mice with depletion of miR-497∼195 in endothelial cells show fewer CD31hiEmcnhi vessels and lower bone mass. Conversely, transgenic overexpression of miR-497∼195 in murine endothelium alleviates age-related reduction of type CD31hiEmcnhi vessels and bone loss. miR-497∼195 cluster maintains the endothelial Notch activity and HIF-1α stability via targeting F-box and WD-40 domain protein (Fbxw7) and Prolyl 4-hydroxylase possessing a transmembrane domain (P4HTM) respectively. Notably, endothelialium-specific activation of miR-195 by intravenous injection of aptamer-agomiR-195 stimulates CD31hiEmcnhi vessel and bone formation in aged mice. Together, our study indicates that miR-497∼195 regulates angiogenesis coupled with osteogenesis and may represent a potential therapeutic target for age-related osteoporosis.

MicroRNA-379 inhibits the proliferation, migration and invasion of human osteosarcoma cells by targetting EIF4G2.

Osteosarcoma (OS) is an aggressive malignant mesenchymal neoplasm amongst adolescents. The aim of the present study was to explore the various modes of action that miR-379 has on the proliferation, migration, and invasion of human OS cells. miR-379 achieves this by targetting eukaryotic initiation factor 4GII (EIF4G2). Human OS cell lines U2OS and MG-63 were selected and assigned into blank, miR-379 mimics, miR-379 mimic negative control (NC), miR-379 inhibitors, miR-379 inhibitor NC, EIF4G2 shRNA, control shRNA, and miR-379 inhibitor + EIF4G2 shRNA group. The miR-379 expression and EIF4G2 mRNA expression were detected utilising quantitative real-time PCR (qRT-PCR) and the EIF4G2 protein expression using Western blotting. MTT assay, scratch test, Transwell assay, and flow cytometry were performed to determine the proliferation, migration, invasion, and cell cycle, respectively. In comparison with the miR-379 mimic NC group, the miR-379 mimics group had decreased EIF4G2 expression; the miR-379 inhibitors group indicated an increased EIF4G2 expression. Compared with the control shRNA group, the EIF4G2 expression was lower in the EIF4G2 shRNA group and the miR-379 expression was dropped in the miR-379 inhibitor + EIF4G2 shRNA group. The proliferation, migration, and invasion abilities of OS cells were reduced in the miR-379 mimics and EIF4G2 shRNA groups. The percentage of OS cells at the G0/G1 stage was increased, and the percentage at the S-stage was decreased in the miR-379 mimics and EIF4G2 shRNA groups. miR-379 may inhibit the proliferation, migration and invasion of OS cells through the down-regulation of EIF4G2.

GDF8 inhibits bone formation and promotes bone resorption in mice.

Growth Differentiation Factor 8 (GDF8), also called myostatin, is a member of the transforming growth factor (TGF)-ß super-family. As a negative regulator of skeletal muscle growth, GDF8 is also associated with bone metabolism. However, the function of GDF8 in bone metabolism is not fully understood. Our study aimed to investigate the role of GDF8 in bone metabolism, both in vitro and in vivo. Our results showed that GDF8 had a negative regulatory effect on primary mouse osteoblasts, and promoted receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclastogenesis in vitro. Intraperitoneal injection of recombinant GDF8 repressed bone formation and accelerated bone resorption in mice. Furthermore, treatment of aged mice with a GDF8 neutralizing antibody stimulated new bone formation and prevented bone resorption. Thus, our study showed that GDF8 plays a significant regulatory role in bone formation and bone resorption, thus providing a potential therapeutic pathway for osteoporosis.

An atypical monomelic presentation of Mazabraud syndrome.

Mazabraud syndrome is a rare condition characterized by a combination of fibrous dysplasia and intramuscular myxomas. In Mazabraud syndrome, the distribution of fibrous dysplasia is mostly polyomelic and frequently located in the femur, with myxomas adjacent to the fibrous dysplasia lesion of bone (mostly in the quadriceps muscle). However, when presented as atypical clinical features, patients of Mazabraud syndrome is either misdiagnosed or difficult to diagnose. We report an atypical monomelic case of Mazabraud syndrome in the right upper arm and discuss the difficulties in making an accurate diagnosis.

[Influence of acupuncture and moxibustion on defecation in postoperative patients of anal fissure: a randomized controlled trial].

OBJECTIVE: To verify the clinical efficacy of acupuncture and moxibustion on defecating and pain symptoms in postoperative patient of anal fissure. METHODS: Two hundred cases of postoperation of anal fissure were randomly divided into an acupuncture-moxibustion group and a medication group, 100 cases in each one. The basic treatment after the surgery was the same in two groups, besides, acupuncture was applied at Zhongliao (BL 33) and Xialiao (BL 34) in the morning of first 5 days of postoperative 24 h in the acupuncture-moxibustion group, and suspended moxibusiton was applied at Changqiang (GV 1) within 5 to 10 min after defecation; while two bags of forlax was orally administrated in the morning of first 5 days of postoperative 24 h in the medication group. The pain intensity, defecation willingness, defecation difficulty and stool texture during postoperative defecation were observed. RESULTS: The defecation pain on the first two days after the treatment was not statistically significant between two groups (both P > 0.05). From the third day of treatment, the improvements of defecation pain in acupuncture-moxibustion group were more obvious than those in the medication group (all P < 0.05). The patients in the acupuncture-moxibustion group had more positive defecation willingness than those in the medication group (all P < 0.05). The differences of defecation difficulty and stool properties in two groups had no statistical significance (both P > 0.05). CONCLUSION: The intervention treatment of acupuncture and moxibustion has clinical significance on relieving pain symptoms and improving defecation willingness in postoperative patient of anal fissure.

Relationship between serum TGF-ß1, OPG levels and osteoporotic risk in native Chinese women.

BACKGROUND: Cytokines including transforming growth factor beta 1 (TGF-ß1) and osteoprotegerin (OPG) are closely related to bone metabolism. However, the relationships between TGF-ß1, OPG and risk of osteoporosis in native Chinese women are unknown. Our research indicated that there is a positive correlation between TGF-ß1 and bone mineral density (BMD) T-score, and a negative correlation between OPG and T-score. The risk of osteoporosis is reduced as TGF-ß1 increases and increases as OPG was raised. We investigated correlations of BMD T-scores with circulating TGF-ß1 and BMD T-scores with circulating OPG in healthy native Chinese women, and to study the effects of changes in TGF-ß1 and OPG on osteoporosis. METHODS: This was a cross-sectional study of 691 healthy native Chinese women aged 20-80 years. Concentrations of serum TGF-ß1 and OPG were determined. BMD T-scores at the posteroanterior spine, left hip, and forearm were measured by dual-energy X-ray absorptiometry. RESULTS: There were positive correlations between serum TGF-ß1 and T-scores at the various skeletal sites (r=0.167-0.285, all P=0.000) and negative correlations between serum OPG and T-scores (r=-0.179 to -0.270, all P=0.007-0.000). After adjusting for age and BMI, correlations between TGF-ß1 and T-score at the lumbar vertebrae and ultradistal forearm, and between OPG and T-score at the ultradistal forearm in premenopausal subjects, remained statistically significant. Multivariate linear stepwise analysis showed that TGF-ß1 could explain 1.9-8.3% of T-score variation at each skeletal site. OPG could explain 2.4-4.4% of T-score variation. When TGF-ß1 and OPG concentrations were grouped according to quartile intervals, T-score and the prevalence and risk of osteoporosis varied with changes in the cytokines. CONCLUSIONS: The risk of osteoporosis in native Chinese women increased as circulating TGF-ß1 was reduced and OPG was raised.

Alterations of CSF cystatin C levels and their correlations with CSF Αß40 and Αß42 levels in patients with Alzheimer's disease, dementia with lewy bodies and the atrophic form of general paresis.

Immunohistochemical studies have revealed that cystatin C (CysC) co-localizes with amyloid-ß (Αß) in amyloid-laden vascular walls and in the senile plaque cores of amyloid. In vitro and in vivo animal studies suggest that CysC protects against neurodegeneration by inhibition of cysteine proteases, inhibition of Αß aggregation, induction of autophagy and induction of cell division. CysC levels may be altered and may have a potential link with cerebrospinal fluid (CSF) Aß levels in various types of dementia with characteristic amyloid deposits, such as Alzheimer's disease (AD), dementia with Lewy bodies (DLB) and the atrophic form of general paresis (AF-GP). We assessed the serum and CSF levels of CysC and the CSF levels of Aß40 and Aß42 in patients with AD (n = 51), DLB (n = 26) and AF-GP (n = 43) and normal controls (n = 30). Using these samples, we explored the correlation between CSF CysC and CSF Aß levels. We found that in comparison to the normal control group, both CSF CysC and CSF Aß42 levels were significantly lower in all three dementia groups (all p<0.001); serum CysC levels were the same in the AD and DLB groups, and were lower in the AF-GP group (p = 0.008). The CSF CysC levels were positively correlated with both the CSF Aß40 and Aß42 levels in the AD, AF-GP and normal control groups (r = 0.306∼0.657, all p<0.05). Lower CSF CysC levels might be a common feature in dementia with characteristic amyloid deposits. Our results provide evidence for the potential role of CysC involvement in Aß metabolism and suggest that modulation of the CysC level in the brain might produce a disease-modifying effect in dementia with characteristic amyloid deposits.

miR-148a regulates osteoclastogenesis by targeting V-maf musculoaponeurotic fibrosarcoma oncogene homolog B.

MicroRNAs (miRNAs) play crucial roles in bone metabolism. In the present study, we found that miR-148a is dramatically upregulated during osteoclastic differentiation of circulating CD14+ peripheral blood mononuclear cells (PBMCs) induced by macrophage colony stimulating factor (M-CSF) and receptor activator of nuclear factor-κB ligand (RANKL). Overexpression of miR-148a in CD14+ PBMCs promoted osteoclastogenesis, whereas inhibition of miR-148a attenuated osteoclastogenesis. V-maf musculoaponeurotic fibrosarcoma oncogene homolog B (MAFB) is a transcription factor negatively regulating RANKL-induced osteoclastogenesis. miR-148a directly targeted MAFB mRNA by binding to the 3' untranslated region (3'UTR) and repressed MAFB protein expression. In vivo, our study showed that silencing of miR-148a using a specific antagomir-inhibited bone resorption and increased bone mass in mice receiving ovariectomy (OVX) and in sham-operated control mice. Furthermore, our results showed that miR-148a levels significantly increased in CD14+ PBMCs from lupus patients and resulted in enhanced osteoclastogenesis, which contributed to the lower bone mineral density (BMD) in lupus patients compared with normal controls. Thus, our study provides a new insight into the roles of miRNAs in osteoclastogenesis, and contributes to a new therapeutic pathway for osteoporosis.