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Nile tilapia(Oreochromis niloticus) fingerlings (average weight and length: 20.20 ± 0.20 g, 10 ±0.25 cm)cultivated at reusing water from systems with biofloc technology (BFT) under three treatments: T1: Control, T2: tilapia cultured in reused water biofloc (RW) with adding carbohydrate and T3: tilapia cultured in reused water biofloc (RW) without adding carbohydrate. Nine rectangular tanks (66 x 47 x 44 cm, 75L) were used with stocking densities (400 Fish/m3) for 60 days to investigate fish growth performance, feed utilization, body composition, survival, water quality and also economic evaluation was done. Fish were fed a commercial diet containing 30% crude protein. Growth performance of tilapia was recorded biweekly. Water temperature, dissolved oxygen and pH, were recorded daily, while NO2–, NO3–N; total hardness, carbonate hardness and total suspended solids were recorded biweekly. The body composition of the whole fish was determined at the end of the experiment. Results showed that the best water quality parameters, finial body weight, weight gain, daily weight gain, specific growth rate, final biomass, net yield, PER, FCR, FE, feed intake and economic evaluation were significantly(P 0.05). The present study recommended rearing Nile tilapia in reusing water from systems with biofloc technology (BFT) without adding carbon source for best growth performance and prolonged the useful life, quality of water and reduced overall water consumption.

Aim: This study was designed to evaluate immediate implant placement combined with sticky bone and enriched fibrin membrane for teeth exhibiting periapical pathosis clinically, radiographically and resonance frequency analysis. Subjects and methods: Thirteen immediate implant combined with sticky bone and CGF membrane were inserted in 13 patients suffering from teeth with periapical pathosis indicated for extraction. Preoperative cone beam CT (CBCT were taken for every patient to determine alveolar bone height, width and bone defects The change in the implant stability and bone density readings were measured using ostel device and (CBCT) immediatly, and after 6 months of healing. Results: the mean values of ISQ was 48, 02 1ry stability . After 6 months, the mean value was increased to 72. Increasing of ISQ was observed with the time with significant statistical difference in the value of ISQ in whole time of evaluation and There was statistically significant increase of bone density readings after 6 months. Conclusion: The Immediate implant placement combined with sticky bone and enriched fibrin membrane for teeth exhibiting periapical pathosis is a successful technique

Synovial sarcoma is an aggressive malignancy with no effective treatments for patients with metastasis. The synovial sarcoma fusion SS18-SSX, which recruits the SWI/SNF-BAF chromatin remodeling and polycomb repressive complexes, results in epigenetic activation of FGF receptor (FGFR) signaling. In genetic FGFR-knockout models, culture, and xenograft synovial sarcoma models treated with the FGFR inhibitor BGJ398, we show that FGFR1, FGFR2, and FGFR3 were crucial for tumor growth. Transcriptome analyses of BGJ398-treated cells and histological and expression analyses of mouse and human synovial sarcoma tumors revealed prevalent expression of two ETS factors and FGFR targets, ETV4 and ETV5. We further demonstrate that ETV4 and ETV5 acted as drivers of synovial sarcoma growth, most likely through control of the cell cycle. Upon ETV4 and ETV5 knockdown, we observed a striking upregulation of DUX4 and its transcriptional targets that activate the zygotic genome and drive the atrophy program in facioscapulohumeral dystrophy patients. In addition to demonstrating the importance of inhibiting all three FGFRs, the current findings reveal potential nodes of attack for the cancer with the discovery of ETV4 and ETV5 as appropriate biomarkers and molecular targets, and activation of the embryonic DUX4 pathway as a promising approach to block synovial sarcoma tumors.

Stocking density is considered a priority topic in aquaculture research due to its bearing on the welfare of farmed fish and the need for future recommendations governing stocking density management on fish farms. The aim of this study was to evaluate the influence of stocking density (10, 20, 30 and 40 fry/L3) on growth performance, Feed utilization and survival rate of fry gilthead seabream (Sparus aurata). The results showed that the group of fry stocked at density 30 fry/ L3 was significantly the highest final weight, weight gain, daily gain, SGR and insignificant differences in survival rate. Growth performance parameters were the highest with stocking density 30 fry/ L3 compared with stocking density (10, 20 and 40 fry/ L3), respectively. The results indicated that the best FCR, PER and FE group of fry stocked at 30 fry/ L3 than the rest of experimental groups. Stocking density also did not affect the crude protein and moisture content in body composition. But ash content was significantly highest at density 30 fry/ L3 than the rest of other stocking density (10. 20 and 40 fry/L3) groups. In contrast, total lipid was significantly highest at density 10 fry/L3 than the rest of experimental groups (20, 30 and 40 fry/L3). From the aforementioned results, it could be concluded that stocking density 30 fry/L3 had the best growth performance and feed utilization under experimental conditions.

Astudy was undertaken to determine the effect of the dietary lipid levels on growth performance , feed utilization and body composition of Nile tilapia larvae. Four isonitrogenous diets (40% crude protein) and dietary lipid levels (4, 6, 8 and 10% DM) were fed to satiation Nile tilapia larvae for 9 weeks. The best survival, weight gain, specific growth rate (SGR), protein efficiency ratio (PER), feed conversion ratio (FCR) and feed efficiency were observed for larvae fed 8% lipid level. While the poorest survival, specific growth rate (SGR), protein efficiency ratio (PER), lowest weight gain, specific growth rate (SGR), feed efficiency and highest feed conversion ratio (FCR), were observed with larvae fed 4% lipid level. The lipid content of fish were positively correlated with dietary lipid level. The body protein content increased with increasing the protein levels in the diet. It could be concluded that the requirement of lipid for Nile tilapia fry was 8% lipid under the present experimental condition.

The present study was performed to investigate the influence of feeding diets contained three levels of yellow corn (YC) without or with enzymes and/or prebiotics on the nutrient digestibility and blood parameters of growing New Zealand White (NZW ) rabbits. A feeding trial (3x4) with factorial arrangement of treatment was carried out. The chemical analyses for experimental diets and faces and blood constituents were run. One hundred and eight, 6 weeks old weaning NZW rabbits were used in this study. Rabbits were randomly distributed into 12 equal experimental groups; each contained three equal replicates. The digestibility coefficients of dry matter (DM), organic matter (OM), crude fiber (CF), ether extract (EE), nitrogen free extract (NFE), non-ditrgant fiber (NDF), ADF and hemicellulose were increased with feeding on 15 % YC diets than those of rabbits fed on 5 % or 10 % YC rations, but there was no significant effect of dietary treatments on DMI and CP digestibility. Rabbits fed enzyme-supplemented diets displayed significantly lower DM, OM, CF, EE, NFE, NDF, ADF and hemicellulose than those of other dietary treatments. There was no significant effect of these supplements on DMI (g/d) and CP digestibility, compared with the control diet (without supplements). The digestible DCP (%), TDN% and DEI (kcal/d) were significantly higher (P≤0.05) for animals fed diets containing 15 % YC than feeding on 5 or 10 % YC diets, while there were no significant effect on TDNI (g/d), CPI (g/d) and DEI (kcal/d). Rabbits fed the enzyme-supplemented diets exhibited significantly lower TDN (%) and DE (kcal/kg) than did those fed other experimental diets. Similarly, significantly lower means of DEI (kcal/d) were recorded by rabbits fed enzyme- or enzyme plus prebiotics-supplemented diets compared with other experimental groups of rabbits, but DCP % and CPI (g/d) were not affected. The plasma levels of triglycerides and total cholesterol were significantly lower for rabbits fed diets with 10 % or 15 % YC than those of rabbits fed the lowest level of YC,, while there was no significant effect on ALT, AST, total protein or urea concentration. Rabbits fed the diets fortified with enzymes plus prebiotics exhibited significantly lower (P≤0.05) levels of plasma urea and triglycerides and significantly higher cholesterol concentration than did the control group. In conclusion, using YC to partially replace wheat bran in growing rabbits diets had no negative effect on the nutritive value of diets. The nutritive value of the experimental diets for growing rabbits could increase by supplementing enzymes plus prebiotics. The present study showed that feeding growing rabbits on diets contained 10 % YC without supplements or feeding on diets contained 15 % YC with enzymes and prebiotics are effective for nutrient digestibility, nutritive value and health status of rabbits.

One hundred and eight, 6 weeks of age weaning New Zealand White (NZW) rabbits were used in this study to investigate the impact of feeding three levels of yellow corn diets without or with enzymes or prebiotics or both. Rabbits were distributed in a completely randomized experimental design in a 3×4 factorial arrangements, with the variables being supplementation or not with enzymes (500 g / ton feed) or prebiotics (500 g / ton feed) or both (500 g enzymes +500 g prebiotics) / ton feed. The experimental groups of rabbits were fed their respective experimental rations in pelleted form. Three basal rations were used in this study; the first containing 5% corn (R1), the second one contained 10% corn (R5) and the third one contained 15% corn (R9). The composition and calculated analysis of the basal diets were done according to NRC (1977). The basal ration (R1) was supplemented with enzymes or prebiotics or both for R2, R3 and R4, respectively. While the basal ration (R5) was supplemented with enzymes or prebiotics or both for R6, R7 and R8, respectively, and the basal ration (R9) was supplemented with enzymes or prebiotics or both for R10, R11 and R12, respectively. Apart from the effect of feed rations which were contained 5% or 15% corn, were significantly (P 0.05) on live body weight of rabbits at different ages of the experimental period, from 6 to 15 weeks of age. Apart from the effect of corn levels and dietary supplements had no significant effect (P< 0.05) on daily feed intake (DFI) of rabbits during the period from 6 to 15 weeks. The daily feed intake (DFI) of rabbits fed rations contained 5%, 10% and 15% corn were 89.88, 89.03 and 89.62 g / d, respectively. The interaction between dietary corn levels and added supplements on feed conversion ratio (FCR) duringthe whole experimental period (from 6-15 weeks) showed that, the FCR of the growing rabbits were better(P

The effect of dietary protein levels (35%, 40% and 45%) on growth, survival, feed utilization and body composition of mono sex and mixed sex of Nile tilapia; Oreochromis niloticus L. fry was investigated. Fish were fed frequently to satiation for 7 days a week for 56 days. Results showed that fish growth was significantly affected by protein level. The highest growth performance of fry were obtained with 45% protein diet and the poorest one was obtained with 35% protein diet in both mono and mixed sex Nile tilapia, Oreochromis niloticus fry. Mono sex tilapia were reared in hap in earthen pond showed the highest weight gain, specific growth rate, feed conversion ratio, feed efficiency and protein efficiency ratio, while mixed-sex tilapia showed the lowest weight gain, specific growth rate, feed conversion ratio, feed efficiency and protein efficiency ratio. In conclusion, it was found that 45% crude protein had the highest growth performance parameters, feed utilization and economical evaluation for mono sex Nile tilapia (O. niloticus) fry under this experimental condition.

Objective:Postoperative renal dysfunction necessitating hemodialysis after implantation of ventricular assist devices presents a challenge with respect to establishment of hemodialysis access. Lack of pulsatile flow has led to concerns that arteriovenous fistulas will not mature. This study aims to evaluate arteriovenous fistula as a method of hemodialysis.Methods:Consecutive patients who underwent implantation of a ventricular assist device between 1988 and 2016 with a subsequent need for hemodialysis were identified. Retrospective data were collected for patients requiring hemodialysis through an arteriovenous fistula or arteriovenous graft. Access flow rates and duration of patency are reported.Results:Sixty-four patients were identified (10 required long-term hemodialysis, 5 via arteriovenous fistula, 1 via arteriovenous graft). All six patients receiving long-term hemodialysis access were on continuous-flow ventricular assist devices. Brachiocephalic arteriovenous fistulas were performed in all arteriovenous fistula patients, and the average preoperative vein diameter was 4.1 ± 0.9 mm. On 30-day follow-up, the average flow rate was 1262 ± 643 mL/min (880–2220). In arteriovenous fistula patients, one died at 30 days, one arteriovenous fistula required ligation for steal syndrome at 5 months, and one was abandoned after 10.7 months for low flow. Of remaining fistulas, one was converted to an arteriovenous graft at 1.7 years for malfunction (with 5.3 month patency), and one remains open at 4.0 years.Conclusion:Arteriovenous fistulas should be considered in selected patients with ventricular assist devices as a means of long-term hemodialysis access to avoid use of catheters. Maturation and usage of primary arteriovenous fistulas is possible despite lack of pulsatile flow.

Objectives: To evaluate the prevalence of occult hepatitis B viral infections (OBIs) among blood donors considering the clinical and epidemiological importance of identifying OBIs. Methods: A cross-sectional study conducted at King Khalid University Hospital, Riyadh, Saudi Arabia between January 2011 and January 2012. Blood donors (n=8501) were screened for Hepatitis B virus surface antigen (HBsAg) and hepatitis B core antibodies (HBcAb). All HBsAg-negative and HBcAb-positive samples were tested further for hepatitis B surface antibodies (HBsAb), hepatitis B virus (HBV)-DNA, and HBV genotyping. Results: Of the 8501 serum samples tested, 56 (0.7%) were positive and 8445 (99.3%) were negative for HBsAg. Among the HBsAg-negative samples, 198 (2.3%) were positive for HBcAb and these patients were suspected to have OBIs. Among the HBcAb-positive samples, 119 (60.1%) were positive while 79 (39.9%) were negative for HBsAb. Analysis of HBV-DNA for the suspected OBIs showed that 17 out of 198 samples (8.6%) yielded positive results, and all of them were HBsAb-negative. The viral load was low (less than 20-186 IU/mL) in all OBIs. Hepatitis B virus genotyping showed that 15 out of 17 samples (88.2%) were genotype D, and the other 2 samples (11.8%) were genotype E. Conclusion: The prevalence of OBIs among blood donors in Riyadh was 0.2%. Therefore, it is recommended that HBV molecular testing should be incorporated with serological assays for screening of blood donors. Saudi Med J 2016; Vol. 37 (10): 1114-1119 doi: 10.15537/smj.2016.10.14708 How to cite this article: Alshayea AI, Eid GE, El-Hazmi MM, Alhetheel AF. Prevalence and characterization of occult hepatitis B infection among blood donors in central Saudi Arabia. Saudi Med J . 2016 Oct;37(10):1114-9. doi: 10.15537/smj.2016.10.14708.

Chondrosarcomas are a heterogeneous group of malignant bone tumors that produce hyaline cartilaginous matrix. Mutations in isocitrate dehydrogenase enzymes (IDH1/2) were recently described in several cancers, including conventional and dedifferentiated chondrosarcomas. These mutations lead to the inability of IDH to convert isocitrate into &alpha, ketoglutarate (&alpha, KG). Instead, &alpha, KG is reduced into D-2-hydroxyglutarate (D-2HG), an oncometabolite. IDH mutations and D-2HG are thought to contribute to tumorigenesis due to the role of D-2HG as a competitive inhibitor of &alpha, KG-dependent dioxygenases. However, the function of IDH mutations in chondrosarcomas has not been clearly defined. In this study, we knocked out mutant IDH1 (IDH1mut) in two chondrosarcoma cell lines using the CRISPR/Cas9 system. We observed that D-2HG production, anchorage-independent growth, and cell migration were significantly suppressed in the IDH1mut knockout cells. Loss of IDH1mut also led to a marked attenuation of chondrosarcoma formation and D-2HG production in a xenograft model. In addition, RNA-Seq analysis of IDH1mut knockout cells revealed downregulation of several integrin genes, including those of integrin alpha 5 (ITGA5) and integrin beta 5 (ITGB5). We further demonstrated that deregulation of integrin-mediated processes contributed to the tumorigenicity of IDH1-mutant chondrosarcoma cells. Our findings showed that IDH1mut knockout abrogates chondrosarcoma genesis through modulation of integrins. This suggests that integrin molecules are appealing candidates for combinatorial regimens with IDH1mut inhibitors for chondrosarcomas that harbor this mutation.

The objective of this study was to apply a biological control program on cucumber crop under greenhouse conditions, using biological control agents compared with insecticides to control the cotton aphid, Aphis gossypii Glover. The treatments were conducted at Dokki, Giza, Egypt, through two cucumber summer plantations in 2015 and 2016. Inspection was made once a week to determine the population density of A. gossypii, one of the major pests on cucumber. Aphid infestation occurred from week 6 to week 12 in 2015 and from week 4 to week 11 in 2016. Adults of the aphid parasitoid Aphidius colemani Viereck and larvae of the predatory coccinellid, Coccinella septempunctata L., were released in the biological greenhouse in weeks 8, 9, and 10 in season 2015 and 7, 8, and 9 in season 2016. In the insecticide greenhouse, the recommended insecticide program was used. The cost of control in the biological control greenhouses was more than that in the insecticide one, but the yield was much higher, recording 63.88% increase in 2015 and 64.91% in 2016.

Introduction Considering the large number of patients undergoing anterior cruciate ligament (ACL) surgery, it is important for radiologists to be familiar with these procedures, the normal imaging findings as well as the appearances of common complications that can occur in these patients. Symptomatic patients might present with complications related to the graft itself or due to other causes not related to the graft. Aim of the work Evaluate the MRI findings in symptomatic patients following ACL surgery. Patients and methods The study included 26 symptomatic patients following anterior cruciate ligament surgery. The examination was done on 1.5 Tesla magnet MRI machines. Results Twenty-five patients had reconstruction surgery (96%) and 1 patient had fixation of tibial attachment (4%). Among 25 cases of ACL reconstruction 21 patients had semi-membranosus/semi-tendinosus graft (84%) and 4 patients had Bone-patellar tendon-Bone graft (16%). The most common finding was complete graft tear (32%); followed by abnormal tunnel position (24%); screw failure (16%); graft impingement and partial graft tear (12% each); tibial tunnel and femoral tunnel cysts (8% each); arthrofibrosis (4%). Conclusions MRI is the modality of choice in evaluating the causes of symptomatic patients following ACL reconstruction surgery.

Cellular metabolism reprogramming is an emerging hallmark of cancer, which provides tumor cells with not only necessary energy but also crucial materials to support growth. Exploiting the unique features of cancer metabolism is promising in cancer therapies. The growing interest in this field has led to numerous inhibitors being developed against key molecules in metabolic pathways, though most of them are still in preclinical development. Potential targeted cancer cell metabolic pathways under investigation include glycolysis, tricarboxylic acid (TCA) cycle, oxidative phosphorylation (OXPHOS), glutaminolysis, pentose phosphate pathway (PPP), lipid synthesis, amino acid and nucleotide metabolism. Sarcoma is a type of cancer that arises from transformed cells of mesenchymal origin, in contrast to carcinoma which originates from epithelial cells. Compared with carcinoma, progress towards harnessing the therapeutic potential of targeting sarcoma cell metabolism has been relatively slow. Recently however, with the discovery of cancer-specific mutations in metabolic enzymes such as isocitrate dehydrogenase (IDH) and succinate dehydrogenase (SDH) in certain sarcoma types, cancer cellular metabolism has been considered more as a source of new targets for treating sarcoma. In this article, we review metabolic enzymes currently tested for cancer therapies and describe the therapeutic potential of targeting IDH mutations and SDH deficiency in sarcomas.

In this experiment, fifty four, 6-week-old weaned New Zealand White rabbits were used to investigate the impact of dietary supplementation with nano-selenium or glutamine on growth performance and carcass characteristics of growing rabbits fed diets containing two crude protein levels. A factorial experiment (2x3), being two levels of dietary crude protein (16 and 14 %) without or with organic nano-Se (0.1 mg/kg feed) and glutamine (10 g/kg feed) were performed. Rabbits were randomly distributed into 6 equal experimental groups; each contained three equal replications. Each replicate group was housed in a separate cage and fed their respective experimental diets from 6 to 15 weeks of age. Feed and water were offered ad libitum throughout the experimental period. Apart from the effect of feed supplements, rabbits fed the normal crude protein level (16%) achieved significantly better growth performance (final live body weight, daily weight gain, daily feed intake and feed conversion ratio) while carcass traits were not affected compared with those of rabbits fed the low crude protein level. But dietary supplements (nano-Se or glutamine) did not significantly affect criteria of growth performance or dressing-out percentage of rabbits. Dietary protein by added supplements interaction did not significantly affect traits, investigated in the present study, the whole experimental period. Based on the present results, it can concluded that the crude protein level (14%) is inadequate for attaining normal growth of post-weaning New Zealand White rabbits. However, dietary supplementation with nano-selenium or glutamine proved to be ineffective.

Avian oncogenic viruses include Marek’s disease virus (MDV), a highly contagious herpesvirus, as well as retroviruses such as avian leukosis virus (ALV) subgroups A to J and reticuloendotheliosis virus (REV). In this study, we are surveying the incidence of these viruses during 2011-2015. A total of 64 flocks were vaccinated against MDV by using bivalent vaccine (HVT FC-126 + Rispens CVI988) (45 commercial Brown, white layers and 19 broiler breeder flocks) suffering from increase mortality with high No. of culling birds, bad uniformity and the post mortem examination revealed the presence of tumor lesions in different visceral organs. The age of birds varied from 11-24week, located in eight different governorates; [El-Sharkia, El-Dakahlia, El-Behera, Ismailia, Damietta, El-Monofia, El-Giza, Alexandria] .The total mortality reached 32.6% in brown commercial layers, 25.2% in white commercial layers (with average 28.9%) , 35.7% and 25.2% in females and males of broiler breeders respectively. Samples were collected from a total number of 20 out of 64 examined flocks, the twenty flocks representive 8, 6 and 6 commercial brown, white layer and broiler breeders respectively from tumor organs (liver, spleen, kidney, Bursa of Fabricious, heart, nerve, brain, mesentery and proventriculus). The histopathology-positive tissue sections were identified and further con-firmed by RT-PCR in addition to a blood samples were also collected for serological test using ELISA for ALV and REV. PCR using primers specific to (MDV, ALV, REV) appeared to be the method of choice for rapid and accurate diagnosis of these viruses. PCR and ELISA tests demonstrated the presence of MDV only in all collected samples except one sample was positive for both MDV and REV virus but all samples were negative for ALV.

Synovial sarcoma is an aggressive soft-tissue malignancy of children and young adults, with no effective systemic therapies. Its specific oncogene, SYT–SSX (SS18–SSX), drives sarcoma initiation and development. The exact mechanism of SYT–SSX oncogenic function remains unknown. In an SYT–SSX2 transgenic model, we show that a constitutive Wnt/β-catenin signal is aberrantly activated by SYT–SSX2, and inhibition of Wnt signaling through the genetic loss of β-catenin blocks synovial sarcoma tumor formation. In a combination of cell-based and synovial sarcoma tumor xenograft models, we show that inhibition of the Wnt cascade through coreceptor blockade and the use of small-molecule CK1α activators arrests synovial sarcoma tumor growth. We find that upregulation of the Wnt/β-catenin cascade by SYT-SSX2 correlates with its nuclear reprogramming function. These studies reveal the central role of Wnt/β-catenin signaling in SYT–SSX2-induced sarcoma genesis, and open new venues for the development of effective synovial sarcoma curative agents. Significance: Synovial sarcoma is an aggressive soft-tissue cancer that afflicts children and young adults, and for which there is no effective treatment. The current studies provide critical insight into our understanding of the pathogenesis of SYT–SSX-dependent synovial sarcoma and pave the way for the development of effective therapeutic agents for the treatment of the disease in humans. Cancer Discov; 3(11); 1286–1301. ©2013 AACR. This article is highlighted in the In This Issue feature, p. 1207

Summary Background We aimed to assess efficacy and tolerability of vorinostat in combination with bortezomib for treatment of patients with relapsed or refractory multiple myeloma. Methods In our randomised, double-blind, placebo-controlled, phase 3 trial, we enrolled adults (≥18 years) at 174 university hospitals in 31 countries worldwide. Eligible patients had to have non-refractory multiple myeloma that previously responded to treatment (one to three regimens) but were currently progressing, ECOG performance statuses of 2 or less, and no continuing toxic effects from previous treatment. We excluded patients with known resistance to bortezomib. We randomly allocated patients (1:1) using an interactive voice response system to receive 21 day cycles of bortezomib (1·3 mg/m 2 intravenously on days 1, 4, 8, and 11) in combination with oral vorinostat (400 mg) or matching placebo once-daily on days 1–14. We stratified patients by baseline tumour stage (International Staging System stage 1 or stage ≥2), previous bone-marrow transplantation (yes or no), and number of previous regimens (1 or ≥2). The primary endpoint was progression-free survival (PFS) in the intention-to-treat population. We assessed adverse events in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number 00773747. Findings Between Dec 24, 2008, and Sept 8, 2011, we randomly allocated 317 eligible patients to the vorinostat group (315 of whom received at least one dose) and 320 to the placebo group (all of whom received at least one dose). Median PFS was 7·63 months (95% CI 6·87–8·40) in the vorinostat group and 6·83 months (5·67–7·73) in the placebo group (hazard ratio [HR] 0·77, 95% CI 0·64–0·94; p=0·0100). 312 (99%) of 315 patients in the vorinostat group and 315 (98%) of 320 patients in the placebo group had adverse events (300 [95%] adverse events in the vorinostat group and 282 [88%] in the control group were regarded as related to treatment). The most common grade 3–4 adverse events were thrombocytopenia (143 [45%] patients in the vorinostat group vs 77 [24%] patients in the placebo group), neutropenia (89 [28%] vs 80 [25%]), and anaemia (53 [17%] vs 40 [13%]). Interpretation Although the combination of vorinostat and bortezomib prolonged PFS relative to bortezomib and placebo, the clinical relevance of the difference in PFS between the two groups is not clear. Different treatment schedules of bortezomib and vorinostat might improve tolerability and enhance activity. Funding Merck.

Purpose Aberrant mammalian target of rapamycin (mTOR) signaling is common in sarcomas and other malignancies. Drug resistance and toxicities often limit benefits of systemic chemotherapy used to treat metastatic sarcomas. This large randomized placebo-controlled phase III trial evaluated the mTOR inhibitor ridaforolimus to assess maintenance of disease control in advanced sarcomas. Patients and Methods Patients with metastatic soft tissue or bone sarcomas who achieved objective response or stable disease with prior chemotherapy were randomly assigned to receive ridaforolimus 40 mg or placebo once per day for 5 days every week. Primary end point was progression-free survival (PFS); secondary end points included overall survival (OS), best target lesion response, safety, and tolerability. Results A total of 711 patients were enrolled, and 702 received blinded study drug. Ridaforolimus treatment led to a modest, although significant, improvement in PFS per independent review compared with placebo (hazard ratio [HR], 0.72; 95% CI, 0.61 to 0.85; P = .001; median PFS, 17.7 v 14.6 weeks). Ridaforolimus induced a mean 1.3% decrease in target lesion size versus a 10.3% increase with placebo (P < .001). Median OS with ridaforolimus was 90.6 weeks versus 85.3 weeks with placebo (HR, 0.93; 95% CI, 0.78 to 1.12; P = .46). Adverse events (AEs) more common with ridaforolimus included stomatitis, infections, fatigue, thrombocytopenia, noninfectious pneumonitis, hyperglycemia, and rash. Grade ≥ 3 AEs were more common with ridaforolimus than placebo (64.1% v 25.6%). Conclusion Ridaforolimus delayed tumor progression to a small statistically significant degree in patients with metastatic sarcoma who experienced benefit with prior chemotherapy. Toxicities were observed with ridaforolimus, as expected with mTOR inhibition. These data provide a foundation on which to further improve control of sarcomas.

Dendritic cells (DCs) are potent antigen-presenting cells critical in regulating the adaptive immune response. The role of DCs is dichotomous; they may both present antigens and the appropriate stimulatory molecules to initiate an adaptive immune response, or they may induce tolerance and release anti-inflammatory signals. The activation of immature DCs, required for the expression of the necessary costimulatory T cell molecules, is dependent on pattern recognition receptors. In addition to the pathogen-derived ligands of pattern recognition receptors, several damage-associated molecular patterns (DAMPs) have recently been shown to interact with DCs and dramatically affect their ultimate function. The complex interplay of DAMPs on DCs is clinically important, with implications for transplantation, tumor immunity, autoimmunity, chronic inflammation and other conditions of sterile inflammation such as ischemia reperfusion injury. In this review, we will focus on the role of DAMPs in DC function.

Purpose: A phase I study was conducted to evaluate the pharmacokinetics, pharmacodynamics, safety, and tolerability of R1507—a fully human IgG1 type monoclonal antibody directed against the human insulin-like growth factor-I receptor. Experimental design: Patients with advanced solid tumors were assigned to receive i.v. R1507 weekly (qW), starting with 1 mg/kg. Subsequent cohorts were dosed at 3 and then 9 mg/kg. An additional 12 patients received 9 mg/kg R1507 qW. Patients remained on the study until the development of a dose-limiting toxicity or progressive disease. Results: In total, 37 patients were treated with R1507 qW. No dose-limiting toxicities were identified and the maximum tolerated dose was not reached. The pharmacokinetics of R1507 were characterized by a slow clearance and limited volume of distribution, with an estimated elimination half-life justifying weekly administration. Serum IGF-I ligand levels increased proportionally to dose during the first 72 hours in all cohorts. R1507 was well tolerated. Two patients diagnosed with Ewing's sarcoma had partial responses of 11.5 and >26 months (ongoing at time of submission); 13 patients had stable disease; and 16 had progressive disease as best response by the Response Evaluation Criteria in Solid Tumors. Conclusion: R1507 is well tolerated and shows antitumor activity in patients with solid neoplasms, in particular Ewing's sarcoma. The recommended dose for the weekly schedule is 9 mg/kg qW. Clin Cancer Res; 16(8); 2458–65. ©2010 AACR.

Introduction Total knee arthroplasty (TKA) may be the only effective treatment available to reduce pain and restore joint mobility and function in case of advanced osteoarthritis of the knee. The major benefit of TKA with the use of tourniquet is operating in a bloodless field. A possible secondary benefit is a better cement bone interface for fixation. However, the use of tourniquet in TKA is associated with multiple risk factors both local and systemic. The aim of this work To compare between the use or nonuse of tourniquet on patients operated for TKA. Patients and methods This study included 30 TKA in 30 patients. The comparison was made between 15 TKA done with the use of tourniquet in 15 patients (group A) and 15 TKA done without the use of tourniquet in the next consecutive 15 patients (group B). Full preoperative assessment including clinical, laboratorial, and radiological examination with routine investigations was done for every patient. The intraoperative blood loss and the need for and amount of blood transfusion were estimated. Immediate postoperative assessment included the estimation of hemoglobin level, blood loss, and need for and amount of blood transfusion. The 3-month postoperative evaluation included the pain by visual analog scale, range of knee flexion, and time to straight leg raising. Results There was no major operative complication during the procedures. Intraoperative blood loss was higher in group B (1273.3±430.1 ml), and postoperative blood loss was higher in group A (623.3±161.0 ml). Overall, 60% of group B patients had increased need for blood transfusion. Moreover, 26.7% of patients in group A compared with 6.7% of patients in group B had severe postoperative pain on the visual analog scale. The mean time to straight leg raising was 6.67±1.18 weeks in group A and 4.73±0.70 weeks in group B. The mean range of knee flexion was 118.33±5.56° in group A and 124.80±3.91° in group B after 3 months. Conclusion TKA done without the use of tourniquet is accompanied by more intraoperative blood loss and increased need for both intraoperative and postoperative blood transfusion. TKA without the use of tourniquet accelerates the recovery of knee flexion range and shortens the time for straight leg raising.

Background— Atherosclerosis is an inflammatory disease in which interferon (IFN)-γ, the signature cytokine of Th1 cells, plays a central role. We investigated whether interleukin (IL)-17, the signature cytokine of Th17 cells, is also associated with human coronary atherosclerosis. Methods and Results— Circulating IL-17 and IFN-γ were detected in a subset of patients with coronary atherosclerosis and in referent outpatients of similar age without cardiac disease but not in young healthy individuals. IL-17 plasma levels correlated closely with those of the IL-12/IFN-γ/CXCL10 cytokine axis but not with known Th17 inducers such as IL-1β, IL-6, and IL-23. Both IL-17 and IFN-γ were produced at higher levels by T cells within cultured atherosclerotic coronary arteries after polyclonal activation than within nondiseased vessels. Combinations of proinflammatory cytokines induced IFN-γ but not IL-17 secretion. Blockade of IFN-γ signaling increased IL-17 synthesis, whereas neutralization of IL-17 responses decreased IFN-γ synthesis; production of both cytokines was inhibited by transforming growth factor-β1. Approximately 10-fold fewer coronary artery–infiltrating T helper cells were IL-17 producers than IFN-γ producers, and unexpectedly, IL-17/IFN-γ double producers were readily detectable within the artery wall. Although IL-17 did not modulate the growth or survival of cultured vascular smooth muscle cells, IL-17 interacted cooperatively with IFN-γ to enhance IL-6, CXCL8, and CXCL10 secretion. Conclusions— Our findings demonstrate that IL-17 is produced concomitantly with IFN-γ by coronary artery–infiltrating T cells and that these cytokines act synergistically to induce proinflammatory responses in vascular smooth muscle cells.

Interleukin (IL) 1α produced by human endothelial cells (ECs), in response to tumor necrosis factor (TNF) or to co-culture with allogeneic T cells in a TNF-dependent manner, can augment the release of cytokines from alloreactive memory T cells in vitro. In a human–mouse chimeric model of artery allograft rejection, ECs lining the transplanted human arteries express IL-1α, and blocking IL-1 reduces the extent of human T cell infiltration into the artery intima and selectively inhibits IL-17 production by infiltrating T cells. In human skin grafts implanted on immunodeficient mice, administration of IL-17 is sufficient to induce mild inflammation. In cultured cells, IL-17 acts preferentially on vascular smooth muscle cells rather than ECs to enhance production of proinflammatory mediators, including IL-6, CXCL8, and CCL20. Neutralization of IL-17 does not reduce T cell infiltration into allogeneic human artery grafts, but markedly reduces IL-6, CXCL8, and CCL20 expression and selectively inhibits CCR6+ T cell accumulation in rejecting arteries. We conclude that graft-derived IL-1 can promote T cell intimal recruitment and IL-17 production during human artery allograft rejection, and suggest that targeting IL-1 in the perioperative transplant period may modulate host alloreactivity.

Atherosclerosis and graft arteriosclerosis are characterized by leukocytic infiltration of the vessel wall that spares the media. The mechanism(s) for medial immunoprivilege is unknown. In a chimeric humanized mouse model of allograft rejection, medial immunoprivilege was associated with expression of IDO by vascular smooth muscle cells (VSMCs) of rejecting human coronary artery grafts. Inhibition of IDO by 1-methyl-tryptophan (1-MT) increased medial infiltration by allogeneic T cells and increased VSMC loss. IFN-γ-induced IDO expression and activity in cultured human VSMCs was considerably greater than in endothelial cells (ECs) or T cells. IFN-γ-treated VSMCs, but not untreated VSMCs nor ECs with or without IFN-γ pretreatment, inhibited memory Th cell alloresponses across a semipermeable membrane in vitro. This effect was reversed by 1-MT treatment or tryptophan supplementation and replicated by the absence of tryptophan, but not by addition of tryptophan metabolites. However, IFN-γ-treated VSMCs did not activate allogeneic memory Th cells, even after addition of 1-MT or tryptophan. Our work extends the concept of medial immunoprivilege to include immune regulation, establishes the compartmentalization of immune responses within the vessel wall due to distinct microenvironments, and demonstrates a duality of stimulatory EC signals versus inhibitory VSMC signals to artery-infiltrating T cells that may contribute to the chronicity of arteriosclerotic diseases.

Synovial sarcoma is a soft tissue cancer associated with a recurrent t(X:18) translocation that generates one of two fusion proteins, SYT-SSX1 or SYT-SSX2. In this study, we demonstrate that SYT-SSX2 is a unique oncogene. Rather than confer enhanced proliferation on its target cells, SYT-SSX2 instead causes a profound alteration of their architecture. This aberrant morphology included elongation of the cell body and formation of neurite-like extensions. We also observed that cells transduced with SYT-SSX2 often repulsed one another. Notably, cell repulsion is a known component of ephrin signaling. Further analysis of SYT-SSX2–infected cells revealed significant increases in the expression and activation of Eph/ephrin pathway components. On blockade of EphB2 signaling SYT-SSX2 infectants demonstrated significant reversion of the aberrant cytoskeletal phenotype. In addition, we discovered, in parallel, that SYT-SSX2 induced stabilization of the microtubule network accompanied by accumulation of detyrosinated Glu tubulin and nocodazole resistance. Glu tubulin regulation was independent of ephrin signaling. The clinical relevance of these studies was confirmed by abundant expression of both EphB2 and Glu tubulin in SYT-SSX2–positive synovial sarcoma tissues. These results indicate that SYT-SSX2 exerts part of its oncogenic effect by altering cytoskeletal architecture in an Eph-dependent manner and cytoskeletal stability through a concurrent and distinct pathway.

Background and Objectives Continuous erythropoietin receptor activator (C.E.R.A.) is an innovative agent with unique erythropoietin receptor activity and a prolonged half-life, which has the potential for administration at extended dosing intervals. The objectives of this dose-finding study were to evaluate the hemoglobin (Hb) dose-response, pharmacokinetics, and safety of repeated doses of C.E.R.A. given once every 3 weeks to anemic patients with multiple myeloma (MM) receiving chemotherapy.Design and Methods This was an exploratory two-stage, open-label, parallel-group, multicenter study. Patients received C.E.R.A. doses of 1.0, 2.0, 3.5, 4.2, 5.0, 6.5, or 8.0 μg/kg once every 3 weeks by subcutaneous injection initially for 6 weeks, followed by a 12-week optional extension period. The primary outcome measures were the average Hb level and its change from baseline over the initial 6-week period, based on values of the slope of the linear regression analysis and the area under the curve. Rates of Hb response (defined as an increase in Hb of ≥2 g/dL without transfusion) and blood transfusion were also evaluated.Results Sixty-four patients entered the study. Dose-related increases in Hb levels were observed during the initial 6-week treatment period for C.E.R.A. doses of 1.0–4.2 μg/kg, with a similar response observed at higher doses. At least 70% of patients receiving 2.0–8.0 μg/kg of C.E.R.A. had Hb responses during the 18-week study. The elimination half-life of C.E.R.A. was found to be long (6.3–9.7 days [151.2–232.8 hours]). All doses were generally well tolerated.Interpretation and Conclusions Based on its unique, long elimination half-life, C.E.R.A. has been demonstrated to be an effective and well-tolerated treatment of anemia given once every 3 weeks to patients with multiple myeloma receiving chemotherapy.

Localization of beta-catenin in the cell is a key determinant in its decision to function as a critical mediator of cell adhesion at the surface or a transcription activator in the nucleus. SYT-SSX2 is the fusion product of the chromosomal translocation, t(X;18)(p11.2;q11.2), which occurs in synovial sarcoma, a soft tissue tumor. SYT-SSX2 is known to associate with chromatin remodeling complexes and is proposed to be involved in controlling gene expression. We report that SYT-SSX2 plays a direct role in beta-catenin regulation. When expressed in mammalian cells, SYT-SSX2-induced beta-catenin recruitment to the nucleus. Interestingly, known target genes of canonical Wnt were not activated as a result of SYT-SSX2 expression, nor was the nuclear localization of beta-catenin due to one of the signaling pathways normally implicated in this event. beta-Catenin accumulation in the nucleus led to the formation of a transcriptionally active nuclear complex that contained SYT-SSX2 and beta-catenin. More importantly, depletion of SYT-SSX2 in primary synovial sarcoma cells resulted in loss of nuclear beta-catenin signal and a significant decrease in its signaling activity. These results unravel a novel pathway in the control of beta-catenin cellular transport and strongly suggest that SYT-SSX2 contributes to tumor development, in part through beta-catenin signaling.

The treatment outcomes of ruptured visceral artery aneurysms (rVAAs) have been sparsely characterized, with no clear comparison between different treatment modalities. The purpose of this paper was to review the perioperative and long-term outcomes of open and endovascular interventions for intact visceral artery aneurysms (iVAAs) and rVAAs.This was a retrospective review of all treated VAAs at one institution from 2003 to 2013. Patient demographics, aneurysm characteristics, management, and subsequent outcomes (technical success, mortality, reintervention) and complications were recorded.The study identified 261 patients; 181 patients were repaired (77 ruptured, 104 intact). Pseudoaneurysms were more common in rVAAs (81.8% vs 35.3% for iVAAs; P.001). The rVAAs were smaller than the iVAAs (20.7 mm vs 27.5 mm; P = .018), and their most common presentation was abdominal pain; 29.7% were hemodynamically unstable. Endovascular intervention was the initial treatment modality for 67.4% (75.3% for rVAAs, 61.5% for iVAAs). The perioperative complication rate was higher for rVAAs (13.7% vs 1% for iVAAs; P = .003), as was mortality at 30 days (13% vs 0% for iVAAs; P = .001), 1 year (32.5% for rVAAs vs 4.1% for iVAAs; P.001), and 3 years (36.4% for rVAAs vs 8.3% for iVAAs; P.001). Lower 30-day mortality was noted with endovascular repair for rVAAs (7.4% vs 28.6% open; P = .025). Predictors of mortality for rVAAs included age (odds ratio, 1.04; P = .002), whereas endovascular repair was protective (odds ratio, 0.43; P = .037). Mean follow-up was 26.2 months, and Kaplan-Meier estimates of survival were higher for iVAAs at 3 years (88% vs 62% for rVAAs; P = .045). The 30-day reintervention rate was higher for rVAAs (7.7% vs 19.5% for iVAAs; P = .019) but was similar between open and endovascular repair (8.2% vs 15%; P = NS).rVAAs have significant mortality. Open and endovascular interventions are equally durable for elective repair of VAAs, but endovascular interventions for rVAAs result in lower morbidity and mortality. Aggressive treatment of pseudoaneurysms is electively recommended at diagnosis regardless of size.

Summary Patients with acute myeloid leukaemia (AML) or myelodysplastic syndrome (MDS) may respond to treatment with epigenetic-modifying agents. Histone deacetylase inhibitors may synergize with hypomethylating agents. This phase 1 dose-escalation study was designed to determine the maximum tolerated dose, recommended phase 2 dose, safety and tolerability of vorinostat plus decitabine in patients with relapsed/refractory AML, newly-diagnosed AML, or intermediate- to high-grade MDS. Thirty-four patients received concurrent therapy with decitabine plus vorinostat and 37 received sequential therapy with decitabine followed by vorinostat. Twenty-nine patients had relapsed/refractory AML, 31 had untreated AML and 11 had MDS. The target maximum administered dose (MAD) of decitabine 20 mg/m2 daily for 5 d plus vorinostat 400 mg/d for 14 d was achieved for concurrent and sequential schedules, with one dose-limiting toxicity (Grade 3 QTc prolongation) reported in the sequential arm. Common toxicities were haematological and gastrointestinal. Responses were observed more frequently at the MAD on the concurrent schedule compared with the sequential schedule in untreated AML (46% vs. 14%), relapsed/refractory AML (15% vs. 0%) and MDS (60% vs. 0%). Decitabine plus vorinostat given concurrently or sequentially appears to be safe and well-tolerated. Concurrent therapy shows promising clinical activity in AML or MDS, warranting further investigation.

OBJECTIVE Intractable hyperemesis gravidarum remains a serious cause of morbidity among pregnant women. If not controlled, hyperemesis gravidarum can lead to severe disability, electrolyte and acid base imbalance, and even various organ system dysfunctions. From the successful use of steroids for chemotherapy-induced emesis, corticosteroids might prove useful in hyperemesis gravidarum. The purpose of this study was to compare the efficacy of pulsed hydrocortisone therapy with that of metoclopramide for the management of intractable hyperemesis gravidarum. DESIGN Prospective, double-blind study. SETTING Intensive care unit of Ain Shams University Maternity Hospital. PATIENTS Forty patients aged 19-34 yrs having a normal appearing intrauterine pregnancy, of < or =16 wks gestation, admitted to the intensive care unit with intractable hyperemesis meeting the study criteria. INTERVENTIONS Patients were randomly assigned to receive either intravenous hydrocortisone 300 mg as a daily dose or intravenous metoclopramide 10 mg 3 times daily. After 3 days the hydrocortisone was tapered completely during the course of 1 wk, whereas the metoclopramide was continued without change for 1 wk. Patients were followed up daily during the therapy course and for 2 wks following intensive care unit discharge. MEASUREMENTS AND MAIN RESULTS There was a significant reduction in vomiting episodes in the hydrocortisone group compared with the metoclopramide group (p < .0001). Within-patient analyses showed a significant reduction in mean vomiting episodes in the hydrocortisone group within the first 3 days (p < .0001). No patients from the hydrocortisone group but six of the patients receiving metoclopramide were readmitted for intractable vomiting within 1 wk from discharge. Five of them showed improvement on intravenous hydrocortisone therapy. CONCLUSIONS A short course of hydrocortisone is an effective treatment for intractable hyperemesis gravidarum.

Purpose To determine the effectiveness of Nd:YAG laser membranectomy for reopening blocked glaucoma tube shunts and maintaining the patency over time. Methods We reviewed retrospectively the records of 13 patients (13 eyes) who, during the period January 1990 through June 1996, underwent Nd:YAG laser membranectomy in an attempt to reopen a blocked glaucoma tube shunt. Intraocular pressure and tube patency were evaluated at each follow-up visit. Results Nd:YAG laser membranectomy effectively opened the blocked glaucoma tube shunts in 11 (84.6%) of 13 eyes. Two tubes could not be reopened. Reblockage occurred in seven eyes (53.8%) within the first 11 weeks; four tubes (30.8%) remained patent through follow-up periods of 39, 82, 106, and 169 weeks. Postlaser complications were moderate anterior chamber reaction in four eyes (30.8%), hyphema in two eyes (15.4%), corneal edema in two eyes (15.4%), pressure spike in one eye (7.7%), and shallow anterior chamber in one eye (7.7%). Conclusions Nd:YAG laser membranectomy is effective in reopening blocked glaucoma tube shunts but is associated with a relatively high rate of subsequent reblockage in the initially successful cases.

Purpose: The authors evaluated the long-term results of tube-shunt surgery in management of childhood glaucoma. Methods: The results of tube-shunt surgery in children who had glaucoma refractory to medical or alternative surgical treatment in the Glaucoma Service of wills Eye Hospital during the period 1986 through 1993 were reviewed. Eighteen eyes of 15 patients were included in the analysis. Follow-up ranged from 14 to 80 months (mean ± standard deviation, 47.3 ± 25.1 months). Results: In the early postoperative course (6 months after surgery), the intraocular pressure (10P) was between 6 and 21 mmHg in 13 eyes (72.2%) with or without glaucoma medication. Two or more years later, IOP was between 6 and 21 mmHg in four eyes without further glaucoma medication (22.2%) and four eyes (22.2%) with the addition of anti hypertensive therapy. Five eyes (27.8%) lost light perception, whereas seven (38.9%) remained within one line of preoperative vision or improved. Twelve eyes underwent 28 additional surgical procedures after the tube-shunt operation, mostly to control IOP or manage tube-related complications. Conclusion: The limited success rate, relatively high complication rate, and need for frequent surgical intervention suggest caution regarding the prognosis of tube-shunt surgery in children with glaucoma.

This article introduces a new surgical method for one-stage reconstruction of the penis. It is applied to the reconstruction of the microphallus as well as to traumatic cases with the residual stump of the amputated penis not less than 3 cm long. By transferring the original glans or the residual penile stump to the anterior portion of the newly reconstructed penile body with microsurgical techniques, we have thus rebuilt a penis with more satisfactory results in both appearance and erotic sensation. Seven patients are reported here who were operated on by this method and who have been followed up for 18 months to 10 years. The good results achieved and the method's advantages over other methods are demonstrated and discussed.

Ischemia-reperfusion (I/R) injury is a process whereby an initial hypoxic insult and subsequent return of blood flow leads to the propagation of innate immune responses and organ injury. The necessity of the pattern recognition receptor, toll-like receptor (TLR)-4, for this innate immune response has been previously shown. However, TLR4 is present on various cell types of the liver, both immune and non-immune cells. Therefore, we sought to determine the role of TLR4 in individual cell populations, specifically parenchymal hepatocytes, myeloid cells including Kupffer cells, and dendritic cells following hepatic I/R. When hepatocyte specific (Alb-TLR4-/-) and myeloid cell specific (Lyz-TLR4-/-) TLR4 knockout mice were subjected to warm hepatic ischemia there was significant protection in these mice compared to wild-type (WT). However, the protection afforded in these two strains was significantly less than global TLR4 specific TLR4 knockout (TLR4-/-) mice. Dendritic cell specific TLR4-/- (CD11c-TLR4-/-) mice had significantly increased hepatocellular damage compared to WT mice. Circulating levels of high mobility group box-1 (HMGB1) were significantly reduced in the Alb-TLR4-/- mice compared to WT, Lyz-TLR4-/-, CD11c-TLR4-/- mice and equivalent to global TLR4-/- mice, suggesting that TLR4 mediated HMGB1 release from hepatocytes may be a source of HMGB1 after I/R. Hepatocytes exposed to hypoxia responded by rapidly phosphorylating the mitogen-activated protein kinases JNK and p38 in a TLR4-dependent manner; inhibition of JNK decreased the release of HMGB1 after both hypoxia in vitro and I/R in vivo. Conclusion These results provide insight into the individual cellular response of TLR4. It was found that the parenchymal hepatocyte is an active participant in the sterile inflammatory response after I/R through TLR4-mediated activation of pro-inflammatory signaling and release of danger signals such as HMGB1.

Our experience in reconstructive surgery of the penis in 136 cases is reported. The postoperative complication rate was 13.24 percent. Five methods were used: the radial forearm free flap, the superficial inferior epigastric artery flap, the superficial circumflex iliac artery flap, the anterolateral thigh flap, and the combined cutaneous flap. The choice of the method had to be made depending on the patient's condition and prediction of the operative results. The penis not only should have a good appearance with normal size but also should have good sensation and function. The keys to success of this operation are considered to be correct preoperative planning, careful manipulation, and excellent anastomoses.

Background The present global, open-label, single-arm, multicenter, phase IIb study was designed to determine the efficacy and tolerability of oral vorinostat combined with standard doses of bortezomib in patients with multiple myeloma considered refractory to novel myeloma agents. Patients and Methods Eligible patients were age ≥ 18 years, had received ≥ 2 previous regimens, had disease refractory to ≥ 1 previous bortezomib-containing regimen, and had received ≥ 1 dose of an immunomodulatory drug (thalidomide or lenalidomide)-based regimen. The patients received 21-day cycles of bortezomib (1.3 mg/m 2 intravenously on days 1, 4, 8, and 11) plus oral vorinostat (400 mg/d on days 1-14). Oral dexamethasone, 20 mg, on the day of and the day after each dose of bortezomib could be added for patients with progressive disease after 2 cycles or no change after 4 cycles. The primary endpoint was the objective response rate. Results The objective response rate was 11.3% (95% confidence interval, 6.6%-17.7%), and the median duration of response was 211 days (range, 64-550 days). The median overall survival duration was 11.2 months (95% confidence interval, 8.5-14.4 months), with a 2-year survival rate of 32%. The frequently reported adverse events were thrombocytopenia (69.7%), nausea (57.0%), diarrhea (53.5%), anemia (52.1%), and fatigue (48.6%); the overall safety profile was consistent with that of bortezomib and vorinostat. Conclusion The combination of vorinostat and bortezomib is active in patients with multiple myeloma refractory to novel treatment modalities and offers a new therapeutic option for this difficult-to-treat patient population (ClinicalTrials.gov identifier, NCT00773838).

BackgroundSYT-SSX is the oncogene associated with synovial sarcoma (SS), a stem cell disease. SYT-SSX is thought to be responsible for sarcoma initiation and development. It interacts with components of Polycomb and SWI/SNF complexes, the two epigenetic controllers that maintain the heritable status of differentiation-specific genes in the stem/progenitor cell. Through these associations SYT-SSX is thought to alter gene expression programs by epigenetic mechanisms. Recently, we reported that SYT-SSX2 reprograms mesenchymal stem cells and myoblasts by dictating their commitment to the neural lineage while disrupting their normal differentiation. This reprogramming was due to the direct occupancy of proneural genes by the SYT-SSX2 nuclear complex. To gain a clear understanding of SYT-SSX2 control of gene expression networks, we conducted a thorough genome-wide analysis to determine the mechanism of its recruitment and identify signature sets of epigenetic markers that would predict its targeting and transcriptional activity.ResultsSYT-SSX2 was recruited to distinct loci across all chromosomes, and an overwhelming number of Polycomb-modified sites enriched with the trimethylated histone H3 on lysine 27 (H3K27me3) formed the main recruiting module for SYT-SSX2. Not all SYT-SSX2/H3K27me3-occupied genes had altered expression, denoting the requirement for additional signals upon oncogene binding. Differential binding and epigenetic patterns distinguished upregulated and downregulated genes. Most activated genes had SYT-SSX2 sites enriched with H3K27me3 within their body or near their transcription start site (TSS) whereas a majority of downregulated genes were characterized by SYT-SSX2/H3K27me3-rich regions at long-range, or by modifications associated with transcription activation within the gene body or near the TSS. Hierarchical and functional clustering identified H3K27me3 as the dominant epigenetic marker associated with SYT-SSX2 binding and gene expression. Notably, this analysis revealed a cluster of upregulated neuronal genes densely covered by H3K27me3, consistent with programming toward the neural lineage by SYT-SSX2 observed previously.ConclusionsThe data analysis revealed that Polycomb complexes or their modified chromatin and their stably silenced differentiation programs seem to be the main target for SYT-SSX2, suggesting that their perturbation is at the center of tumorigenesis driven by the oncogene. Further research into this mechanism is crucial to the full understanding of SS biology.

Review on SSX2 (synovial sarcoma, X breakpoint 2), with data on DNA, on the protein encoded, and where the gene is implicated.

Cell identity is determined by its gene expression programs. The ability of a cell to change its identity and produce cell types outside its lineage is achieved by the activity of transcription controllers capable of reprogramming differentiation gene networks. The synovial sarcoma (SS)-associated protein, SYT–SSX2, reprograms myogenic progenitors and human bone marrow-derived mesenchymal stem cells (BMMSCs) by dictating their commitment to a pro-neural lineage. It fulfills this function by directly targeting an extensive array of neural-specific genes as well as genes of developmental pathway mediators. Concomitantly, the ability of both myoblasts and BMMSCs to differentiate into their normal myogenic and adipogenic lineages was compromised. SS is believed to arise in mesenchymal stem cells where formation of the t(X/18) translocation product, SYT–SSX, constitutes the primary event in the cancer. SYT–SSX is therefore believed to initiate tumorigenesis in its target stem cell. The data presented here allow a glimpse at the initial events that likely occur when SYT–SSX2 is first expressed, and its dominant function in subverting the nuclear program of the stem cell, leading to its aberrant differentiation, as a first step toward transformation. In addition, we identified the fibroblast growth factor receptor gene, Fgfr2, as one occupied and upregulated by SYT–SSX2. Knockdown of FGFR2 in both BMMSCs and SS cells abrogated their growth and attenuated their neural phenotype. These results support the notion that the SYT–SSX2 nuclear function and differentiation effects are conserved throughout sarcoma development and are required for its maintenance beyond the initial phase. They also provide the stem cell regulator, FGFR2, as a promising candidate target for future SS therapy.

Objective Secondary interventions after endovascular aneurysm repair (EVAR) remain a concern. Most are simple catheter-based procedures, but in some instances, open conversions (OCs) are required and carry a worse outcome. We reviewed our experience to characterize these OCs. Methods A retrospective review was conducted of all patients who underwent an OC after a previous EVAR for an aneurysm-related indication from 2001 to 2010. Clinical outcomes are reported. Results Data were reviewed for 44 patients (77% men) with a mean age of 74 years (range, 55-90 years). The average time from EVAR to the first OC was 45 months (range, 2-190 months). In six patients (14%), the initial EVAR was at another institution. The endografts used were Ancure in 16, Excluder in 13, AneuRx in eight, Zenith in three, Lifepath in one, Renu in one, and undetermined in two. Twenty-two patients had previously undergone a total of 32 endovascular reinterventions before their index OC. Indications for OC were aneurysm expansion in 28 (64%), rupture in 12 (27%), and infection in four (9%). The endograft was preserved in situ in 10 patients (23%). Explantation was partial in 18 (41%) or complete in 16 (36%). Endograft preservation was used for type II endoleak in all but one patient by selective ligation of the culprit arteries (lumbar in four, inferior mesenteric artery in five, and middle sacral in one). Proximal neck banding was performed in one type Ia endoleak. Overall morbidity was 55%, and mortality was 18%. No deaths occurred in a subgroup of patients who underwent endograft preservation with selective ligation of culprit vessels for type II endoleak. Intraoperative complications included bowel injury in two, bleeding in two, splenectomy in one, and ureteral injury in one. At a mean follow-up of 20 months, two patients underwent additional procedures after the index OC: one after endograft preservation and one after partial explantation. None of the patients who underwent elective OC with endograft preservation required subsequent endograft explantation. Conclusions Most OCs after EVAR are associated with significant morbidity and mortality, except when electively treating an isolated type II endoleak with ligation of branches and preservation of the endograft.

This study demonstrates deregulation of polycomb activity by the synovial sarcoma-associated SYT-SSX2 oncogene, also known as SS18-SSX2. Synovial sarcoma is a soft tissue cancer associated with a recurrent t(X:18) translocation event that generates one of two fusion proteins, SYT-SSX1 or SYT-SSX2. The role of the translocation products in this disease is poorly understood. We present evidence that the SYT-SSX2 fusion protein interacts with the polycomb repressive complex and modulates its gene silencing activity. SYT-SSX2 causes destabilization of the polycomb subunit Bmi1, resulting in impairment of polycomb-associated histone H2A ubiquitination and reactivation of polycomb target genes. Silencing by polycomb complexes plays a vital role in numerous physiological processes. In recent years, numerous reports have implicated gain of polycomb silencing function in several cancers. This study provides evidence that, in the appropriate context, expression of the SYT-SSX2 oncogene leads to loss of polycomb function. It challenges the notion that cancer is solely associated with an increase in polycomb function and suggests that any imbalance in polycomb activity could drive the cell toward oncogenesis. These findings provide a mechanism by which the SYT-SSX2 chimera may contribute to synovial sarcoma pathogenesis.