Meta-analysis of randomized controlled trials and individual patient data comparing minimally invasive with open oesophagectomy for cancer.

BACKGROUND: Minimally invasive oesophagectomy (MIO) for oesophageal cancer may reduce surgical complications compared with open oesophagectomy. MIO is, however, technically challenging and may impair optimal oncological resection. The aim of the present study was to assess if MIO for cancer is beneficial. METHODS: A systematic literature search in MEDLINE, Web of Science and CENTRAL was performed and randomized controlled trials (RCTs) comparing MIO with open oesophagectomy were included in a meta-analysis. Survival was analysed using individual patient data. Random-effects model was used for pooled estimates of perioperative effects. RESULTS: Among 3219 articles, six RCTs were identified including 822 patients. Three-year overall survival (56 (95 per cent c.i. 49 to 62) per cent for MIO versus 52 (95 per cent c.i. 44 to 60) per cent for open; P = 0.54) and disease-free survival (54 (95 per cent c.i. 47 to 61) per cent versus 50 (95 per cent c.i. 42 to 58) per cent; P = 0.38) were comparable. Overall complication rate was lower for MIO (odds ratio 0.33 (95 per cent c.i. 0.20 to 0.53); P < 0.010) mainly due to fewer pulmonary complications (OR 0.44 (95 per cent c.i. 0.27 to 0.72); P < 0.010), including pneumonia (OR 0.41 (95 per cent c.i. 0.22 to 0.77); P < 0.010). CONCLUSION: MIO for cancer is associated with a lower risk of postoperative complications compared with open resection. Overall and disease-free survival are comparable for the two techniques. LAY SUMMARY: Oesophagectomy for cancer is associated with a high risk of complications. A minimally invasive approach might be less traumatic, leading to fewer complications and may also improve oncological outcome. A meta-analysis of randomized controlled trials comparing minimally invasive to open oesophagectomy was performed. The analysis showed that the minimally invasive approach led to fewer postoperative complications, in particular, fewer pulmonary complications. Survival after surgery was comparable for the two techniques.

Oesophagectomy for cancer is associated with a high risk of complications. A minimally invasive approach might be less traumatic, leading to fewer complications and may also improve oncological outcome. A meta-analysis of randomized controlled trials comparing minimally invasive to open oesophagectomy was performed. The analysis showed that the minimally invasive approach led to fewer postoperative complications, in particular, fewer pulmonary complications. Survival after surgery was comparable for the two techniques.

[Current standards of abdominal wall closure techniques : Conventional suture techniques]. / Aktuelle Studienlage zum Bauchdeckenverschluss : Klassische Nahttechniken.

BACKGROUND: The most frequent complications following midline abdominal laparotomy include incisional hernias, which develop in 10-15 % of patients and surgical site infections in 15-25 % of cases; however, the risk of these complications can be reduced by the surgical technique and the use of special suture materials. In 2010, the INLINE meta-analysis performed by the Study Centre of the German Society of Surgery (SDGC) revealed that a continuous suture technique using slowly absorbable suture material resulted in the lowest risk of developing postoperative incisional hernia after elective midline laparotomy. OBJECTIVE: The aim of this study was to perform a systematic literature search to identify all randomized controlled trials (RCTs) that have been published since 2010 concerning conventional abdominal wall closure in order to update the 2010 INLINE meta-analysis and summarize current evidence. MATERIAL AND METHODS: On 28 January 2016, a systematic literature search was performed in MEDLINE and the Cochrane Central Register of Controlled Trials (CENTRAL). All RCTs dealing with abdominal wall closure after midline laparotomy were identified and included for further analysis. RESULTS: Since 2010 a total of 9 RCTs comparing different techniques of abdominal wall closure have been published. Three monocentric RCTs comparing different suture materials, showed no significant differences to the INLINE meta-analysis regarding incisional hernia development; therefore, slowly absorbable sutures using a continuous suture technique are still recommended for abdominal wall closure in elective cases. Furthermore, six RCTs were identified which investigated antimicrobial suture materials but failed to show an overall advantage for Triclosan-coated suture material with respect to surgical site infections. CONCLUSION: Current evidence shows that slowly absorbable monofilament suture material using a continuous suture technique provides the best results with regard to incisional hernia rates after elective midline laparotomy. Triclosan-coated sutures cannot be recommended as a standard suture material as they failed to reduce surgical site infections. For emergency laparotomies no evidence exists to recommend a specific kind of suture technique or a special suture material.

Long-term toxicity studies in dogs support the safety of the special extract ERr 731 from the roots of Rheum rhaponticum.

The special extract ERr 731 from the roots of rhapontic rhubarb has been regularly prescribed for women with menopausal symptoms since 1993. As its constituents belong to the class of natural hydroxystilbenes, concerns have been raised about possible health risks similar to those known for the estrogenic diethylstilbestrol. To demonstrate the safety of the medical use of ERr 731, the extract was tested in long-term toxicity studies in dogs. In two independent studies, male and female beagle dogs were treated with 100, 300 and 1000 mg ERr 731/kg body weight (bw)/day and observed for 4 and 13 weeks followed by recovery periods. A histopathological examination of a full set of organs of all animals was examined. In both studies, all animals survived the scheduled treatment and recovery periods. The administration of ERr 731 resulted in increased incidences of feces with white particles due to an incomplete absorption of the extract. In the 13-week study, a slight decrease in glucose levels was recorded in both sexes at 1000 mg/kg bw/day. All other clinical changes were marginal and not related to ERr 731. Importantly, there was no increase in weight of organs of the genital tract due to ERr 731 intake. Based on these results, the no-observed-adverse-effect-level is 1000 mg/kg bw/day. No pathological findings where detected following ERr 731 treatment demonstrating that the toxicological risk for women taking ERr 731 regularly is extremely low.

Universal finite-size scaling behavior and universal dynamical scaling behavior of absorbing phase transitions with a conserved field.

We analyze numerically three different models exhibiting an absorbing phase transition. We focus on the finite-size scaling as well as the dynamical scaling behavior. An accurate determination of several critical exponents allows one to validate certain hyperscaling relations. Using these hyperscaling relations it is possible to express the avalanche exponents of a self-organized critical system in terms of the ordinary exponents of a continuous absorbing phase transition.

Universal scaling behavior at the upper critical dimension of nonequilibrium continuous phase transitions.

In this work we analyze the universal scaling functions and the critical exponents at the upper critical dimension of a continuous phase transition. The consideration of the universal scaling behavior yields a decisive check of the value of the upper critical dimension. We apply our method to a nonequilibrium continuous phase transition. By focusing on the equation of state of the phase transition it is easy to extend our analysis to all equilibrium and nonequilibrium phase transitions observed numerically or experimentally.

Qualitative highly divergent nuclear export signals can regulate export by the competition for transport cofactors in vivo.

Nucleo-cytoplasmic transport of proteins is mediated by nuclear export signals, identified in various proteins executing heterologous biological functions. However, the molecular mechanism underlying the orchestration of export is only poorly understood. Using microinjection of defined recombinant export substrates, we now demonstrate that leucine-rich nuclear export signals varied dramatically in determining the kinetics of export in vivo. Thus, nuclear export signals could be kinetically classified which correlated with their affinities for CRM1-containing export complexes in vitro. Strikingly, cotransfection experiments revealed that proteins containing a fast nuclear export signal inhibited export and the biological activity of proteins harboring a slower nuclear export signal in vivo. The affinity for export complexes seems therefore predominantly controlled by the nuclear export signal itself, even in the context of the complete protein in vivo. Overexpression of FG-rich repeats of nucleoporins affected a medium nuclear export signal containing protein to the same extent as a fast nuclear export signal containing protein, indicating that nucleoporins appear not to contribute significantly to nuclear export signal-specific export regulation. Our results imply a novel mode for controlling the biological activity of shuttle proteins already by the composition of the nuclear export signal itself.

The adenovirus type 5 E1B-55K oncoprotein is a highly active shuttle protein and shuttling is independent of E4orf6, p53 and Mdm2.

The E1B-55K and E4orf6 oncoproteins of adenovirus type 5 are involved in the export of viral mRNAs. Previously, it was suggested that a complex composed of E1B-55K and E4orf6 serves as a nucleocytoplasmic transporter for viral mRNAs in which the E4orf6 protein directs both nuclear import and export. We now demonstrate that the E1B-55K protein itself shuttles efficiently in the absence of E4orf6. In addition, E1B-55K trafficking was independent of the defined shuttle proteins Mdm2 or p53, which interacts with E1B-55K. The identified N-terminal E1B-55K leucine-rich nuclear-export signal (NES) conferred rapid nuclear export even in a heterologous system in contrast to the postulated E4orf6NES. Interestingly, although shuttling was blocked by inhibitors of the CRM1 mediated export pathway, E1B-55K inhibited neither the activity nor the trafficking of the retroviral shuttle proteins HIV-1 Rev and HTLV-1 Rex. In contrast, Rev or Rex blocked the nuclear export of E1B-55K, most likely by competing for essential export factors. Our results provide new insights into the regulation of the adenovirus mRNA export system and the processes of adenovirus mediated transformation. Oncogene (2000) 19, 850 - 857.

Titration of cellular export factors, but not heteromultimerization, is the molecular mechanism of trans-dominant HTLV-1 rex mutants.

The HTLV-1 Rex protein is an essential shuttle protein required for nuclear export of unspliced and incompletely-spliced viral RNAs. Several trans-dominant (TD) mutant Rex proteins have been reported, however, the mechanism of trans-dominance is not known. We compared TD Rex mutants and found that a natural occurring Rex mutant, Rexp21, lacking the RNA binding domain, was highly TD and inhibited also HIV-1 Rev function. Using fusions to the green fluorescent protein (GFP) we observed that Rexp21-GFP displayed a cytoplasmic localization but was actively shuttling between the nucleus and the cytoplasm in live human cells. The presence of Rexp21-GFP inhibited the nuclear export of Rex and HIV-1 Rev as assayed by cotransfection and microinjection experiments. However, Rex-GFP or Rexp21-GFP did not form heteromultimers with nuclear Rex mutants in vivo. In contrast, shuttling was essential for trans-dominance. Thus, we propose that TD Rex mutants do not function by retaining WT Rex in the nucleus by protein-protein interactions, as demonstrated for Rev, but to titrate factors essential for Rex/Rev export. Our findings demonstrate differences between the regulatory proteins Rex and Rev and implicate a novel strategy to generate highly TD Rex mutants also applicable to other proteins.

Direct observation of nucleocytoplasmic transport by microinjection of GFP-tagged proteins in living cells.

We established a straightforward experimental system to investigate directly the requirements for nucleocytoplasmic transport in live cells. For this purpose, substrates were created containing nuclear localization signals (NLS) or nuclear export signals (NES) linked to a chimeric protein composed of the glutathione S-transferase (GST) fused to the green fluorescent protein (GFP). The combination of GST/GFP-tagging allowed us to control protein expression in bacteria and to monitor protein purification during chromatography. Following microinjection into somatic cells, nuclear export/import of the highly fluorescent substrates could be observed directly by fluorescence microscopy. This system sets the stage to quantitate, in real time, the kinetics of nuclear import/export in living cells and to evaluate qualitative differences in various NLS/NES signals and pathways.

Nuclear pore localization and nucleocytoplasmic transport of eIF-5A: evidence for direct interaction with the export receptor CRM1.

Eukaryotic initiation factor 5A (eIF-5A) is the only cellular protein known to contain the unusual amino acid hypusine. The exact in vivo function of eIF-5A, however, is to date unknown. The finding that eIF-5A is an essential cofactor of the human immunodeficiency virus type 1 (HIV-1) Rev RNA transport factor suggested that eIF-5A is part of a specific nuclear export pathway. In this study we used indirect immunofluorescence and immunogold electron microscopy to demonstrate that eIF-5A accumulates at nuclear pore-associated intranuclear filaments in mammalian cells and Xenopus oocytes. We are able to show that eIF-5A interacts with the general nuclear export receptor, CRM1. Furthermore, microinjection studies in somatic cells revealed that eIF-5A is transported from the nucleus to the cytoplasm, and that this nuclear export is blocked by leptomycin B. Our data demonstrate that eIF-5A is a nucleocytoplasmic shuttle protein.

Multimer formation is not essential for nuclear export of human T-cell leukemia virus type 1 Rex trans-activator protein.

The Rex trans-regulatory protein of human T-cell leukemia virus type 1 (HTLV-1) is required for the nuclear export of incompletely spliced and unspliced viral mRNAs and is therefore essential for virus replication. Rex is a nuclear phosphoprotein that directly binds to its cis-acting Rex response element RNA target sequence and constantly shuttles between the nucleus and cytoplasm. Moreover, Rex induces nuclear accumulation of unspliced viral RNA. Three protein domains which mediate nuclear import-RNA binding, nuclear export, and Rex oligomerization have been mapped within the 189-amino-acid Rex polypeptide. Here we identified a different region in the carboxy-terminal half of Rex which is also required for biological activity. In inactive mutants with mutations that map within this region, as well as in mutants that are deficient in Rex-specific multimerization, Rex trans activation could be reconstituted by fusion to a heterologous leucine zipper dimerization interface. The intracellular trafficking capabilities of wild-type and mutant Rex proteins reveal that biologically inactive and multimerization-deficient Rex mutants are still efficiently translocated from the nucleus to the cytoplasm. This observation indicates that multimerization is essential for Rex function but is not required for nuclear export. Finally, we are able to provide an improved model of the HTLV-1 Rex domain structure.

Functional analysis of the human immunodeficiency virus type 1 Rev protein oligomerization interface.

The expression of human immunodeficiency virus type 1 (HIV-1) structural proteins requires the action of the viral trans-regulatory protein Rev. Rev is a nuclear shuttle protein that directly binds to its cis-acting Rev response element (RRE) RNA target sequence. Subsequent oligomerization of Rev monomers on the RRE and interaction of Rev with a cellular cofactor(s) result in the cytoplasmic accumulation of RRE-containing viral mRNAs. Moreover, Rev by itself is exported from the nucleus to the cytoplasm. Although it has been demonstrated that Rev multimerization is critically required for Rev activity and hence for HIV-1 replication, the number of Rev monomers required to form a trans-activation-competent complex on the RRE is unknown. Here we report a systematic analysis of the putative multimerization domains within the Rev trans-activator protein. We identify the amino acid residues which are part of the proposed single hydrophobic surface patch in the Rev amino terminus that mediates intermolecular interactions. Furthermore, we show that the expression of a multimerization-deficient Rev mutant blocks HIV-1 replication in a trans-dominant (dominant-negative) fashion.