Histopathological Determinants of Survival in Resected Cases of Pancreas Cancer

We have examined the histopathological factors affecting the degree of local spread, regional lymph node (RLN) metastases, and overall survival (O.S.) in a group of 39 cases of resected carcinoma of the exocrine pancreas. Although the mean O.S. for the group was 14.3 months, resected patients without RLN involvement had a mean survival of 24 months. In contrast the mean O.S. rate was 8 months for patients with RLNs involved. Size, tumor location, and histological grade were compared to RLN involvement and O.S. The mean size of primary tumor did not differ significantly between patients with or without RLN's (r.1 versus 4.6cms). However, 7 or 8 T1 tumors were <4cm and 35% of tumors <4cm were T1 lesions. In contrast, only of 17 tumors (6%) >4cm was T1. Histological grade was correlated with nodal status and O.S. There was a significant difference between histological grade and the presence of metastatic lymph nodes (G1, 37% positive, G2-4.50% positive). Patients with well differentiated tumors had a mean survival of 21 months compared to a mean survival of 10 months for less differentiated tumors (p<0.05). This difference was even more significant when stratified for nodal status. The patients with well differentiated tumors and no RLN involvement had a mean survival of 32.5 months compared to 8.6 months for well differentiated tumors with RLN involvement. In summary, we have shown that size, histological grade, and local spread predict for nodal status. However, specific patient subsets (G1, node negative) may exhibit an excellent survival when curative pancreas resection is successful

Water and molecular chaperones act as weak links of protein folding networks: energy landscape and punctuated equilibrium changes point towards a game theory of proteins

Water molecules and molecular chaperones efficiently help the protein folding process. Here we describe their action in the context of the energy and topological networks of proteins. In energy terms water and chaperones were suggested to decrease the activation energy between various local energy minima smoothing the energy landscape, rescuing misfolded proteins from conformational traps and stabilizing their native structure. In kinetic terms water and chaperones may make the punctuated equilibrium of conformational changes less punctuated and help protein relaxation. Finally, water and chaperones may help the convergence of multiple energy landscapes during protein-macromolecule interactions. We also discuss the possibility of the introduction of protein games to narrow the multitude of the energy landscapes when a protein binds to another macromolecule. Both water and chaperones provide a diffuse set of rapidly fluctuating weak links (low affinity and low probability interactions), which allow the generalization of all these statements to a multitude of networks.Comment: 9 pages, 1 figur

miR-93, miR-98, and miR-197 Regulate Expression of Tumor Suppressor Gene FUS1

FUS1 is a tumor suppressor gene located on human chromosome 3p21, and expression of Fus1 protein is highly regulated at various levels, leading to lost or greatly diminished tumor suppressor function in many lung cancers. Here we show that selected microRNAs (miRNAs) interact with the 3’ untranslated region (3’ UTR) of FUS1, leading to down-regulation of protein expression. Using computational methods, we first predicted that FUS1 is a target of three miRNAs, miR-93, miR-98 and miR-197, and then showed that exogenous over-expression of these miRNAs inhibited Fus1 protein expression. We then confirmed that the three miRNAs target the 3’UTR region of the FUS1 transcript, and that individual deletion of the three miRNA target sites in the FUS1 3’UTR restores the expression level of Fus1 protein. We further found that miR-93 and miR-98 are expressed at higher levels in small cell lung cancer cell lines (SCLC) than in non-small cell lung cancer cell lines (NSCLC) and immortalized human bronchial epithelial cells (HBECs), and that miR-197 is expressed at higher levels in both SCLC and NSCLC than in HBECs. Finally, we found that elevated miR-93 and miR-197 expression is correlated with reduced Fus1 expression in NSCLC tumor specimens. These results suggest that the three miRNAs are negative regulators of Fus1 expression in lung cancers

ZEB1 drives prometastatic actin cytoskeletal remodeling by downregulating miR-34a expression

Metastatic cancer is extremely difficult to treat, and the presence of metastases greatly reduces a cancer patient’s likelihood of long-term survival. The ZEB1 transcriptional repressor promotes metastasis through downregulation of microRNAs (miRs) that are strong inducers of epithelial differentiation and inhibitors of stem cell factors. Given that each miR can target multiple genes with diverse functions, we posited that the prometastatic network controlled by ZEB1 extends beyond these processes. We tested this hypothesis using a mouse model of human lung adenocarcinoma metastasis driven by ZEB1, human lung carcinoma cells, and human breast carcinoma cells. Transcriptional profiling studies revealed that ZEB1 controls the expression of numerous oncogenic and tumor-suppressive miRs, including miR-34a. Ectopic expression of miR-34a decreased tumor cell invasion and metastasis, inhibited the formation of promigratory cytoskeletal structures, suppressed activation of the RHO GTPase family, and regulated a gene expression signature enriched in cytoskeletal functions and predictive of outcome in human lung adenocarcinomas. We identified several miR-34a target genes, including Arhgap1, which encodes a RHO GTPase activating protein that was required for tumor cell invasion. These findings demonstrate that ZEB1 drives prometastatic actin cytoskeletal remodeling by downregulating miR-34a expression and provide a compelling rationale to develop miR-34a as a therapeutic agent in lung cancer patients.Young-Ho Ahn, Don L. Gibbons, Deepavali Chakravarti, Chad J. Creighton, Zain H. Rizvi, Henry P. Adams, Alexander Pertsemlidis, Philip A. Gregory, Josephine A. Wright, Gregory J. Goodall, Elsa R. Flores and Jonathan M. Kuri

Complete Genome Viral Phylogenies Suggests the Concerted Evolution of Regulatory Cores and Accessory Satellites

We consider the concerted evolution of viral genomes in four families of DNA viruses. Given the high rate of horizontal gene transfer among viruses and their hosts, it is an open question as to how representative particular genes are of the evolutionary history of the complete genome. To address the concerted evolution of viral genes, we compared genomic evolution across four distinct, extant viral families. For all four viral families we constructed DNA-dependent DNA polymerase-based (DdDp) phylogenies and in addition, whole genome sequence, as quantitative descriptions of inter-genome relationships. We found that the history of the polymerase gene was highly predictive of the history of the genome as a whole, which we explain in terms of repeated, co-divergence events of the core DdDp gene accompanied by a number of satellite, accessory genetic loci. We also found that the rate of gene gain in baculovirus and poxviruses proceeds significantly more quickly than the rate of gene loss and that there is convergent acquisition of satellite functions promoting contextual adaptation when distinct viral families infect related hosts. The congruence of the genome and polymerase trees suggests that a large set of viral genes, including polymerase, derive from a phylogenetically conserved core of genes of host origin, secondarily reinforced by gene acquisition from common hosts or co-infecting viruses within the host. A single viral genome can be thought of as a mutualistic network, with the core genes acting as an effective host and the satellite genes as effective symbionts. Larger virus genomes show a greater departure from linkage equilibrium between core and satellites functions

A Probabilistic Model of Local Sequence Alignment That Simplifies Statistical Significance Estimation

Sequence database searches require accurate estimation of the statistical significance of scores. Optimal local sequence alignment scores follow Gumbel distributions, but determining an important parameter of the distribution (λ) requires time-consuming computational simulation. Moreover, optimal alignment scores are less powerful than probabilistic scores that integrate over alignment uncertainty (“Forward” scores), but the expected distribution of Forward scores remains unknown. Here, I conjecture that both expected score distributions have simple, predictable forms when full probabilistic modeling methods are used. For a probabilistic model of local sequence alignment, optimal alignment bit scores (“Viterbi” scores) are Gumbel-distributed with constant λ = log 2, and the high scoring tail of Forward scores is exponential with the same constant λ. Simulation studies support these conjectures over a wide range of profile/sequence comparisons, using 9,318 profile-hidden Markov models from the Pfam database. This enables efficient and accurate determination of expectation values (E-values) for both Viterbi and Forward scores for probabilistic local alignments

Intraoperative assessment of biliary anatomy for prevention of bile duct injury: a review of current and future patient safety interventions

Background Bile duct injury (BDI) is a dreaded complication of cholecystectomy, often caused by misinterpretation of biliary anatomy. To prevent BDI, techniques have been developed for intraoperative assessment of bile duct anatomy. This article reviews the evidence for the different techniques and discusses their strengths and weaknesses in terms of efficacy, ease, and cost-effectiveness. Method PubMed was searched from January 1980 through December 2009 for articles concerning bile duct visualization techniques for prevention of BDI during laparoscopic cholecystectomy. Results Nine techniques were identified. The critical-view-of-safety approach, indirectly establishing biliary anatomy, is accepted by most guidelines and commentaries as the surgical technique of choice to minimize BDI risk. Intraoperative cholangiography is associated with lower BDI risk (OR 0.67, CI 0.61-0.75). However, it incurs extra costs, prolongs the operative procedure, and may be experienced as cumbersome. An established reliable alternative is laparoscopic ultrasound, but its longer learning curve limits widespread implementation. Easier to perform are cholecystocholangiography and dye cholangiography, but these yield poor-quality images. Light cholangiography, requiring retrograde insertion of an optical fiber into the common bile duct, is too unwieldy for routine use. Experimental techniques are passive infrared cholangiography, hyperspectral cholangiography, and near-infrared fluorescence cholangiography. The latter two are performed noninvasively and provide real-time images. Quantitative data in patients are necessary to further evaluate these techniques. Conclusions The critical-view-of-safety approach should be used during laparoscopic cholecystectomy. Intraoperative cholangiography or laparoscopic ultrasound is recommended to be performed routinely. Hyperspectral cholangiography and near-infrared fluorescence cholangiography are promising novel techniques to prevent BDI and thus increase patient safety