Myosin II isoform switching mediates invasiveness after TGF-β-induced epithelial-mesenchymal transition

Despite functional significance of nonmuscle myosin II in cell migration and invasion, its role in epithelial-mesenchymal transition (EMT) or TGF-β signaling is unknown. Analysis of normal mammary gland expression revealed that myosin IIC is expressed in luminal cells, whereas myosin IIB expression is up-regulated in myoepithelial cells that have more mesenchymal characteristics. Furthermore, TGF-β induction of EMT in nontransformed murine mammary gland epithelial cells results in an isoform switch from myosin IIC to myosin IIB and increased phosphorylation of myosin heavy chain (MHC) IIA on target sites known to regulate filament dynamics (S1916, S1943). These expression and phosphorylation changes are downstream of heterogeneous nuclear ribonucleoprotein-E1 (E1), an effector of TGF-β signaling. E1 knockdown drives cells into a migratory, invasive mesenchymal state and concomitantly up-regulates MHC IIB expression and MHC IIA phosphorylation. Abrogation of myosin IIB expression in the E1 knockdown cells has no effect on 2D migration but significantly reduced transmigration and macrophage-stimulated collagen invasion. These studies indicate that transition between myosin IIC/myosin IIB expression is a critical feature of EMT that contributes to increases in invasive behavior.     

High expression of BMP pathway genes distinguishes a subset of atypical teratoid/rhabdoid tumors associated with shorter survival

Molecular profiling of tumors has proven to be a valuable tool for identification of prognostic and diagnostic subgroups in medulloblastomas, glioblastomas, and other cancers. However, the molecular landscape of atypical teratoid/rhabdoid tumors (AT/RTs) remains largely unexplored. To address this issue, we used microarrays to measure the gene expression profiles of 18 AT/RTs and performed unsupervised hierarchical clustering to determine molecularly similar subgroups. Four major subgroups (clusters) were identified. These did not conform to sex, tumor location, or presence of monosomy 22. Clusters showed distinct gene signatures and differences in enriched biological processes, including elevated expression of some genes associated with choroid plexus lineage in cluster 4. In addition, survival differed significantly by cluster, with shortest survival (mean, 4.7 months) in both clusters 3 and 4, compared with clusters 1 and 2 (mean, 28.1 months). Analysis showed that multiple bone morphogenetic protein (BMP) pathway genes were upregulated in the short survival clusters, with BMP4 showing the most significant upregulation (270-fold). Thus, high expression of BMP pathway genes was negatively associated with survival in this dataset. Our study indicates that molecular subgroups exist in AT/RTs and that molecular profiling of these comparatively rare tumors may be of diagnostic, prognostic, and therapeutic value.     

Training vs practice: A tale of opposition in acute cholecystitis

Acute cholecystitis is one of the most common surgical diagnoses encountered by general surgeons. Despite its high incidence there remains a range of treatment of approaches. Current practices in biliary surgery vary as to timing, intraoperative utilization of biliary imaging, and management of bile duct stones despite growing evidence in the literature defining best practice. Management of patients with acute cholecystitis with early laparoscopic cholecystectomy (LC) results in better patient outcomes when compared with delayed surgical management techniques including antibiotic therapy or percutaneous cholecystostomy. Regardless of this data, many surgeons still prefer to utilize antibiotic therapy and complete an interval LC to manage acute cholecystitis. The use of intraoperative biliary imaging by cholangiogram or laparoscopic ultrasound has been demonstrated to facilitate the safe completion of cholecystectomy, minimizing the risk for inadvertent injury to surrounding structures, and lowering conversion rates, however it is rarely utilized. Choledocholithiasis used to be a diagnosis managed exclusively by surgeons but current practice favors referral to gastroenterologists for performance of preoperative endoscopic removal. Yet, there is evidence that intraoperative laparoscopic stone extraction is safe, feasible and may have added advantages. This review aims to highlight the differences between existing management of acute cholecystitis and evidence supported in the literature regarding best practice with the goal to change surgical practice to adopt these current recommendations.     

Manual small-incision cataract surgery and glaucoma – A dilemma of the duo

Both cataract and glaucoma significantly affect the quality of life of an individual and they are often found to coexist, either primarily or secondary to one another. Clear-cut guidelines are not available for this subgroup of coexistent morbidities. Through this article, we attempt to discuss the risks and benefits of staged and combined surgery, their short- and long-term effects on the intraocular pressure and pre and postoperative management. The indication and type of surgery will depend on the type, severity and control of glaucoma, and the clinical significance of cataract; and the surgical outcome on the surgical technique used, site of surgery, use of anti-fibrotic agents, and most importantly, the surgeon’s skill and experience.     

Pharmacokinetics and disposition of the kavalactone kawain: interaction with kava extract and kavalactones in vivo and in vitro.

Reported adverse drug interactions with the popular herb kava have spurred investigation of the mechanisms by which kava could mediate these effects. In vivo and in vitro experiments were conducted to examine the effects of kava extract and individual kavalactones on cytochrome P450 (P450) and P-glycoprotein activity. The oral pharmacokinetics of the kavalactone, kawain (100 mg/kg), were determined in rats with and without coadministration of kava extract (256 mg/kg) to study the effect of the extract on drug disposition. Kawain was well absorbed, with >90% of the dose eliminated within 72 h, chiefly in urine. Compared with kawain alone, coadministration with kava extract caused a tripling of kawain AUC(0-8 h) and a doubling of C(max). However, a 7-day pretreatment with kava extract (256 mg /kg/day) had no effect on the pharmacokinetics of kawain administered on day 8. The 7-day pretreatment with kava extract only modestly induced hepatic P450 activities. The human hepatic microsomal P450s most strongly inhibited by kava extract (CYP2C9, CYP2C19, CYP2D6, CYP3A4) were inhibited to the same degree by a "composite" kava formulation composed of the six major kavalactones contained in the extract. K(i) values for the inhibition of CYP2C9 and CYP2C19 activities by methysticin, dihydromethysticin, and desmethoxyyangonin ranged from 5 to 10 microM. Kava extract and kavalactones (< or =9 microM) modestly stimulated P-glycoprotein ATPase activities. Taken together, the data indicate that kava can cause adverse drug reactions via inhibition of drug metabolism.     

Management of the primary tumor in patients with metastatic pancreatic neuroendocrine tumor: a contemporary single-institution review

Background

Pancreatic nonfunctioning neuroendocrine tumors (PNFNETs) are an uncommon malignancy and often present with metastatic disease. There is a lack of information on the management of the primary tumor in patients who present with unresectable synchronous hepatic metastases.

Methods

A retrospective review (2001-2008) of PNFNETs was conducted. Patients were divided into 3 groups: PNFNET without evidence of hepatic metastasis (group A), PNFNET with metastatic disease involving less than 50% of the liver (group B), and PNFNET with metastatic disease involving more than 50% of the liver (group C). Clinical data and outcomes were analyzed.

Results

Thirty-five patients with PNFNET were identified (group A = 15, group B = 11, group C = 9). Resection of the pancreatic tumor was performed in 26 patients. With a mean follow-up period of 30 months, death from disease progression occurred in 1 patient in group A, none in group B, and in 7 in group C.

Conclusions

In selected patients, resection of the primary pancreatic tumor even in the setting of unresectable but limited hepatic metastases may be indicated.     

Pancreatectomy risk calculator: an ACS-NSQIP resource

Background

The morbidity of pancreatoduodenectomy remains high and the mortality may be significantly increased in high-risk patients. However, a method to predict post-operative adverse outcomes based on readily available clinical data has not been available. Therefore, the objective was to create a ‘Pancreatectomy Risk Calculator’ using the American College of Surgeons-National Surgical Quality Improvement Program (ACS-NSQIP) database.

Methods

The 2005–2008 ACS-NSQIP data on 7571 patients undergoing proximal (n =4621), distal (n =2552) or total pancreatectomy (n =177) as well as enucleation (n =221) were analysed. Pre-operative variables (n =31) were assessed for prediction of post-operative mortality, serious morbidity and overall morbidity using a logistic regression model. Statistically significant variables were ranked and weighted to create a common set of predictors for risk models for all three outcomes.

Results

Twenty pre-operative variables were statistically significant predictors of post-operative mortality (2.5%), serious morbidity (21%) or overall morbidity (32%). Ten out of 20 significant pre-operative variables were employed to produce the three mortality and morbidity risk models. The risk factors included age, gender, obesity, sepsis, functional status, American Society of Anesthesiologists (ASA) class, coronary heart disease, dyspnoea, bleeding disorder and extent of surgery.

Conclusion

The ACS-NSQIP ‘Pancreatectomy Risk Calculator’ employs 10 easily assessable clinical parameters to assist patients and surgeons in making an informed decision regarding the risks and benefits of undergoing pancreatic resection. A risk calculator based on this prototype will become available in the future as on online ACS-NSQIP resource.     

Compressive properties of commercially available polyurethane foams as mechanical models for osteoporotic human cancellous bone

Background  

Polyurethane (PU) foam is widely used as a model for cancellous bone. The higher density foams are used as standard biomechanical test materials, but none of the low density PU foams are universally accepted as models for osteoporotic (OP) bone. The aim of this study was to determine whether low density PU foam might be suitable for mimicking human OP cancellous bone.