Cytotoxic effects of bortezomib in myelodysplastic syndrome/acute myeloid leukemia depend on autophagy-mediated lysosomal degradation of TRAF6 and repression of PSMA1

Bortezomib (Velcade) is used widely for the treatment of various human cancers; however, its mechanisms of action are not fully understood, particularly in myeloid malignancies. Bortezomib is a selective and reversible inhibitor of the proteasome. Paradoxically, we find that bortezomib induces proteasome-independent degradation of the TRAF6 protein, but not mRNA, in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) cell lines and primary cells. The reduction in TRAF6 protein coincides with bortezomib-induced autophagy, and subsequently with apoptosis in MDS/AML cells. RNAi-mediated knockdown of TRAF6 sensitized bortezomib-sensitive and -resistant cell lines, underscoring the importance of TRAF6 in bortezomib-induced cytotoxicity. Bortezomib-resistant cells expressing an shRNA targeting TRAF6 were resensitized to the cytotoxic effects of bortezomib due to down-regulation of the proteasomal subunit α-1 (PSMA1). To determine the molecular consequences of loss of TRAF6 in MDS/AML cells, in the present study, we applied gene-expression profiling and identified an apoptosis gene signature. Knockdown of TRAF6 in MDS/AML cell lines or patient samples resulted in rapid apoptosis and impaired malignant hematopoietic stem/progenitor function. In summary, we describe herein novel mechanisms by which TRAF6 is regulated through bortezomib/autophagy-mediated degradation and by which it alters MDS/AML sensitivity to bortezomib by controlling PSMA1 expression.     

CD44 enhances tumor formation and lung metastasis in experimental osteosarcoma and is an additional predictor for poor patient outcome

Formation of metastases in the lungs is the major cause of death in patients suffering from osteosarcoma (OS). Metastases at presentation and poor response to preoperative chemotherapy are strong predictors for poor patient outcome. The elucidation of molecular markers that promote metastasis formation and/or chemoresistance is therefore of importance. CD44 is a plasma membrane glycoprotein that binds to the extracellular matrix component hyaluronan (HA) and has been shown to be involved in metastasis formation in a variety of other tumors. Here we investigated the role of CD44 expression on OS tumor formation and metastasis. High CD44 expression, evaluated with a tissue microarray including samples from 53 OS patients and stained with a pan‐CD44 antibody (Hermes3), showed a tendency (p < 0.08) to shortened overall survival. However, nonresponders and patients with lung metastases and high CD44 expression had significantly poorer prognosis than patients with low CD44 expression. Overexpression of the standard CD44 isoform (CD44s) and its HA‐binding defective mutant R41A in osteoblastic SaOS‐2 cells resulted in HA‐independent higher migration rates and increased chemoresistance, partially dependent on HA. In an orthotopic mouse model of OS, overexpression of CD44s in SaOS‐2 cells resulted in an HA‐dependent increased primary tumor formation and increased numbers of micrometastases and macrometastases in the lungs. In conclusion, although CD44 failed to be an independent predictor for patient outcome in this limited cohort of OS patients, increased CD44 expression was associated with even worse survival in patients with chemoresistance and with lung metastases. CD44‐associated chemoresistance was also observed in vitro, and increased formation of lung metastases was found in vivo in SCID mice. © 2013 American Society for Bone and Mineral Research.     

Postoperative Outcomes After Robotic Versus Abdominal Myomectomy

Background and Objectives:

Differences in postoperative outcomes comparing robotic-assisted laparoscopic myomectomy (RALM) with abdominal myomectomy (AM) have rarely been reported. The objective of this study was to compare surgical, quality-of-life, and residual fibroid outcomes after RALM and AM.

Methods:

Consecutive patients who underwent RALM (n = 16) were compared with AM patients (n = 23) presenting with a uterine size of <20 weeks. Study patients participated in a telephone interview at 6 weeks and underwent a no-cost ultrasonographic examination at 12 weeks after surgery to obtain quality-of-life and residual fibroid outcomes. Medical records were reviewed to obtain surgical outcomes.

Results:

Longer operative times (261.1 minutes vs 124.8 minutes, P < .001) and a 3-fold unfavorable difference in operative efficiency (73.7 g vs 253.0 g of specimen removed per hour, P < .05) were observed with RALM compared with AM. Patients undergoing RALM had shorter lengths of hospital stay (1.5 days vs 2.7 days, P < .001). Reduction of patient symptoms and overall satisfaction were equal. RALM patients were more likely to be back to work within 1 month (85.7% vs 45.0%, P < .05). Residual fibroid volume in the RALM group was 5 times greater than that in the AM group (17.3 cm³ vs 3.4 cm³, P < .05).

Conclusion:

RALM and AM were equally efficacious in improving patient symptoms. Although operative times were significantly longer with RALM, patients had a quicker recovery, demonstrated by shortened lengths of stay and less time before returning to work. However, greater residual fibroid burden was observed with RALM when measured 12 weeks after surgery.     

Use of antibiotic prophylaxis in elective inguinal hernia repair in adults in London and south-east England: a cross-sectional survey

Purpose

Evidence regarding whether or not antibiotic prophylaxis is beneficial in preventing post-operative surgical site infection in adult inguinal hernia repair is conflicting. A recent Cochrane review based on 17 randomised trials did not reach a conclusion on this subject. This study aimed to describe the current practice and determine whether clinical equipoise is prevalent.

Methods

Surgeons in training were recruited to administer the Survey of Hernia Antibiotic Prophylaxis usE survey to consultant-level general surgeons in London and the south-east of England on their practices and beliefs regarding antibiotic prophylaxis in adult elective inguinal hernia repair. Local prophylaxis guidelines for the participating hospital sites were also determined.

Results

The study was conducted at 34 different sites and received completed surveys from 229 out of a possible 245 surgeons, a 93 % response rate. Overall, a large majority of hospital guidelines (22/28) and surgeons’ personal beliefs (192/229, 84 %) supported the use of single-dose pre-operative intravenous antibiotic prophylaxis in inguinal hernia repair, although there was considerable variation in the regimens in use. The most widely used regimen was intravenous co-amoxiclav (1.2 g). Less than half of surgeons were adherent to their own hospital antibiotic guidelines for this procedure, although many incorrectly believed that they were following these.

Conclusion

In the south-east of England, there is a strong majority of surgical opinion in favour of the use of antibiotic prophylaxis in this procedure. It is therefore likely to be extremely difficult to conduct further randomised studies in the UK to support or refute the effectiveness of prophylaxis in this commonly performed procedure.     

Feasibility of real-time echocardiographic evaluation during patient transport.

Echocardiography is a key diagnostic tool in evaluating patients with cardiac emergencies and chest trauma. The lack of qualified real-time interpretation limits its use by emergency first responders. Early diagnosis of cardiac emergencies has the potential to facilitate triage and medical intervention to improve outcomes. We investigated the feasibility of remote, real-time interpretation of echocardiograms during patient transport. Echocardiograms using a hand-carried ultrasound device were transmitted from an ambulance in transit to a tertiary care facility using a distributed mobile local area network. Transmitted studies were reviewed by a cardiologist for ability to interpret predefined features. Transmission quality and reliability were assessed. Echocardiographic images were successfully transmitted greater than 88% of transport time. The evaluation of left-ventricular size and function, and presence of pericardial effusion were greater than 90% concordant, but only 66% of all echocardiographic features were concordant. Most transmission losses were brief (相似文献