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The PTTG1-binding factor (PBF) is a transforming gene capable of eliciting tumor formation in xenograft models. However, the precise role of PBF in tumorigenesis and its prognostic value as a cancer biomarker remain largely uncharacterised, particularly in malignancies outside the thyroid. Here, we provide the first evidence that PBF represents a promising prognostic marker in colorectal cancer. Examination of a total of 39 patients demonstrated higher PBF expression at both the mRNA (P = 0.009) and protein (P0.0001) level in colorectal tumors compared to matched normal tissue. Critically, PBF was most abundant in colorectal tumors associated with Extramural Vascular Invasion (EMVI), increased genetic instability (GI) and somatic TP53 mutations, all features linked with recurrence and poorer patient survival. We further demonstrate by glutathione-S-transferase (GST) pull-down and coimmunoprecipitation that PBF binds to the tumor suppressor protein p53, as well as to p53 mutants (Δ126-132, M133K, V197E, G245D, I255F and R273C) identified in the colorectal tumors. Importantly, overexpression of PBF in colorectal HCT116 cells interfered with the transcriptional activity of p53-responsive genes such as mdm2, p21 and sfn. Diminished p53 stability (90%; P0.01) was also evident with a concurrent increase in ubiquitinated p53. Human colorectal tumors with wild-type TP53 and high PBF expression also had low p53 protein levels (P0.05), further emphasizing a putative interaction between these genes in vivo. Overall, these results demonstrate an emerging role for PBF in colorectal tumorigenesis through regulating p53 activity, with implications for PBF as a prognostic indicator for invasive tumors.

Study Type – Prognosis (case series) Level of Evidence 4 OBJECTIVE To investigate the rate of pathologically confirmed unfavourable prostate cancers among Korean men who fulfilled the contemporary Epstein criteria for clinically insignificant prostate cancer. PATIENTS AND METHODS This was a retrospective study of 131 Korean men who underwent radical prostatectomy (RP) for clinically insignificant prostate cancer as defined by contemporary Epstein criteria. We assessed the percentage of unfavourable prostate cancer (pathological Gleason sum ≥7 and/or extraprostatic extension [EPE]) among these men and tried to identify useful predictors for such unfavourable tumour profiles using uni- and multivariate analyses. RESULTS Among 131 men with clinically insignificant prostate cancer, 40 (30.5%) had pathological Gleason ≥7 tumours after RP. Of these 40 men, four (3.1%) also had EPE on examination of RP specimen. All those who did not have Gleason score upgrading after RP had organ-confined disease from examination of RP specimen. Overall, 40 (30.5%) of the 131 men who fulfilled the contemporary Epstein criteria for clinically insignificant prostate cancer before RP had pathologically unfavourable disease. Among our patients, no significant preoperative predictor of pathologically unfavourable disease was identified using uni- and multivariate analyses. CONCLUSION Our results showed that a significant proportion of contemporary Korean patients who meet all the conditions of the contemporary Epstein criteria for prediction of clinically insignificant prostate cancer might actually harbour prostate cancer with unfavourable pathological features. Such findings should be considered when treatment options are contemplated based upon the Epstein criteria among Asian patients.

This paper describes the development and performance evaluation of multi-nozzle virtual impactors used in concentrating aerosol particles. Four virtual impactors were designed: one single-nozzle and three multi-nozzle virtual impactors with 4, 12 and 18 nozzles, respectively. For each of the four designs, two kinds of nozzles were implemented, one that had a flat surface and the other a cut-out nozzle designed with consideration of airflow streamlines inside the impactor. Thus, a total of 8 models of virtual impactors were designed and fabricated to study the internal particle loss and concentration performance. Multi-nozzle devices were provided primarily for applications involving high-volume air sampling. Virtual impactors with cut-out nozzles yielded higher fractional collection efficiencies and lower internal losses than virtual impactors with flat nozzles. It is expected that significant flow turbulence will occur in the space between the acceleration nozzles and the collection probes. This may increase the internal losses arising from back-impaction on the acceleration nozzles and particle deposition on the collection probes with flat nozzles.

Expression of HMGI(Y), a nucleoprotein that binds to A/T rich sequences in the minor groove of the DNA helix, is observable in neoplastically transformed cells but not in normal cells. We have analyzed HMGI(Y) expression in colorectal cancer and evaluated its clinicopathologic significance. HMGI(Y) mRNA was measured by CRT-PCR (competitive reverse transcription-polymerase chain reaction). Immunohistochemical staining for HMGI(Y), p53 and Ki-67 was performed in the same colon cancer tissues, and the results in colorectal tissues were similar to those of RT-PCR. HMGI(Y) expression evidenced by RT-PCR was observed in 63 of 64 (98.4%) colorectal cancer samples, and 2 of 5 (40%) adenomatous polyps, whereas 21 normal colon samples were negative (p

At the elbow, the ulnar nerve is compressed most commonly either in the epicondylar groove or at the cubital tunnel. While conventional electrodiagnosis may localize an ulnar neuropathy to the elbow, separating epicondylar syndrome (tardy ulnar nerve palsy) from cubital tunnel syndrome is more difficult. We describe a new method using a near-nerve needle technique for distinguishing these two types of ulnar neuropathy at the elbow. We placed three active needle electrodes across the elbow: the first was 4 cm above, and the second and third were 1.5 cm and 6 cm below the medial epicondyle, respectively. The latter two points were chosen because of the presence of the cubital tunnel in this segment. Sensory, motor, and mixed nerve conduction studies (NCS) were performed on these two segments (elbow segment and cubital tunnel segment) in 26 normal nerves and normal data were established. We also present 7 cases of epicondylar ulnar nerve palsy and 1 case of cubital tunnel syndrome in which we were able to confirm the diagnosis with the present method. In 3 cases of epicondylar ulnar nerve palsy, the present method accurately localized the lesion when other methods failed. We believe that this method will be helpful in distinguishing cubital tunnel syndrome from epicondylar ulnar nerve palsy, especially in early ulnar neuropathy in which only sensory fibers are involved.

Guanidine hydrochloride is known to be highly effective in the symptomatic treatment of the Lambert-Eaton myasthenic syndrome (LEMS). However, because of its potentially dangerous side reactions of hematologic abnormalities and renal insufficiency, 3,4-diaminopyridine, which is not readily available in the United States, is recommended as the preferred drug for LEMS. We used low-dose guanidine and pyridostigmine combination therapy in 9 patients with LEMS and analyzed its long-term safety and effectiveness. In all patients, a liberal amount of pyridostigmine was used, while daily guanidine dose was kept below 1000 mg a day, and guanidine was given between pyridostigmine dosings. This combination therapy was used for 3-102 months (mean: 34.1 months) and improved clinical status in all patients. Although guanidine had to be discontinued due to severe gastrointestinal symptoms in 3 cases, no serious side reactions such as bone marrow suppressions or signs of renal insufficiency developed in any case. Thus, we conclude that low-dose guanidine therapy is relatively safe and effective for long-term symptomatic treatment of LEMS when it is combined with pyridostigmine.

Although AKT ⁄ protein kinase B is constitutively active in nonsmall cell lung cancer (NSCLC) cells and is an attractive target for enhancing the cytotoxicity of therapeutic agents, the distinct roles of the AKT isoforms in NSCLC are largely unknown. In the present study, we investigated the roles of AKT1 and AKT2 in NSCLC cells using RNAi. The siRNA targeting of AKT1 or AKT2 effectively decreased protein levels of AKT1 and AKT2, respectively, in A549 and H460 cells. Cisplatin treatment of these cells increased apoptotic cell death compared with control. The siRNA-induced knockdown of AKT1 in H460 cells significantly decreased basal MEK⁄ ERK1 ⁄ 2 activity, resulting in nuclear factor-κB activation, whereas knockdown of AKT2 resulted in anti-apoptotic Bcl-2 family protein MCL-1 (MCL-1) cleavage, the collapse of mitochondrial membrane potential, cytochrome c release, and activation of the caspase cascade. Consequently, both siRNA treatments enhanced the chemosensitivity of H460 cells to cisplatin. However, neither AKT1 nor AKT2 siRNA treatment had any effect of p27 expression, and although both treatments tended to induced G₂ ⁄M phase arrest, the effect was not statistically significant. Treatment with AKT1 siRNA markedly decreased colony formation growth and migration, but AKT2 siRNA had no significant effects on these parameters. These data suggest that AKT1 and AKT2 both contribute to cell survival, albeit via different mechanisms, and that the effects on cell growth and migration are predominantly regulated by AKT1. These findings may aid in refining targeted strategies for the inhibition of AKT isoforms towards the sensitization of NSCLC cells to therapeutic agents.

XML processing programs play an important role in the achievement of XML data querying, manipulation, and construction operations to compose XML data structures for very diverse purposes regarding information representation, storing and exchange on XML-based systems. Testing of XML processing programs is a challenging task since the test input and output data involved in the test executions may be complex and large in volume, which makes it difficult to determine the correctness of the execution results. However, existing approaches on XML-based testing pay scarce attention to the specification and automation of so-called test oracles in charge of judging the execution results from XML processing programs. This paper deals with the definition of an automated test oracle for XML processing programs which operates with differentiated levels of specification. The oracle automation is achieved by transforming these specification levels into program code, and the resulting oracle implementation is evaluated through an experimental study that reveals promising results.

To investigate the rate of pathologically confirmed unfavourable prostate cancers among Korean men who fulfilled the contemporary Epstein criteria for clinically insignificant prostate cancer.This was a retrospective study of 131 Korean men who underwent radical prostatectomy (RP) for clinically insignificant prostate cancer as defined by contemporary Epstein criteria. We assessed the percentage of unfavourable prostate cancer (pathological Gleason sumor = 7 and/or extraprostatic extension [EPE]) among these men and tried to identify useful predictors for such unfavourable tumour profiles using uni- and multivariate analyses.Among 131 men with clinically insignificant prostate cancer, 40 (30.5%) had pathological Gleasonor = 7 tumours after RP. Of these 40 men, four (3.1%) also had EPE on examination of RP specimen. All those who did not have Gleason score upgrading after RP had organ-confined disease from examination of RP specimen. Overall, 40 (30.5%) of the 131 men who fulfilled the contemporary Epstein criteria for clinically insignificant prostate cancer before RP had pathologically unfavourable disease. Among our patients, no significant preoperative predictor of pathologically unfavourable disease was identified using uni- and multivariate analyses.Our results showed that a significant proportion of contemporary Korean patients who meet all the conditions of the contemporary Epstein criteria for prediction of clinically insignificant prostate cancer might actually harbour prostate cancer with unfavourable pathological features. Such findings should be considered when treatment options are contemplated based upon the Epstein criteria among Asian patients.

A partial test oracle is proposed to verify the actual outputs in access testing on XML data. The considered software under test is a query program which receives as input an XML document obtained from an XML repository of any kind, and produces XML data as output. To deal with the actual outputs from this testing process, the partial oracle evaluates the correctness of the test executions according to: (1) a loose specification provided by the tester, and (2) a set of predefined constraints that describe invariant properties of the expected outputs. By means of the loose specification, the oracle can particularize the constraints to the concrete behaviour of the query program to test. This approach enables the oracle to give automatically a response about the correctness of the program under test with a certain precision at feasible cost. To illustrate the usefulness of the approach a case study is presented.

Objectives: There are many reports of experience with Goode T-tubes and Per-Lee tubes in the literature, although there are only 3 studies with Paparella II grommets. In addition to the relative lack of Paparella II studies, we believe there are 2 other areas of deficiency. The aim of the present study was to provide comprehensive 5-year follow-up data on the use of Paparella II grommets in children with refractory glue ear. Methods: Retrospective case study of all children who underwent Paparella II grommet insertions at the ENT department, Burton district general hospital between 1992 and 1997. Results: A total of 102 grommets placed in 53 children were analyzed. All children had at least 1 previous grommet treatment for glue ear. The mean functional period of the grommets was 3.73 years and 53 (52.0%) grommets remained in situ for the whole 5-year duration of follow-up. Overall infection rate was 55.9% and perforation rate was 49%. Other complications included blockage (n = 1) and dislocation into middle ear (n = 4). There was no cholesteatoma development. There was increased morbidity (infection and perforation rates) associated with increased duration of grommet in situ. This was most notable after 36 months. Conclusions: This long-term follow-up study presents data that establish the functional duration and complications associated with the Paparella II grommet, when used to treat refractory childhood OME. For grommets that have remained in situ for over 3 years, a high rate of infection and persistent tympanic membrane perforation is demonstrated.

Problem: Angiogenesis is the rate-limiting step in tumor progression and metastatic spread. Both promoters and inhibitors of angiogenesis have been implicated in thyroid tumorigenesis. We have reported PTTG overexpression in thyroid cancer, and PTTG upregulation of the angiogenic factors FGF-2 and VEGF. This study was conducted to investigate whether PTTG also transactivates other downstream angiogenic effectors. Methods: To investigate whether PTTG also transactivates other downstream angiogenic effectors, we used angiogenesis-specific cDNA arrays. Primary thyroid cells and PTTG-null HCT113 cells were transiently transfected with wild-type-PTTG. Angiogenic factors that demonstrated more than 2-fold changes in expression averaged over 3 cDNA consecutive arrays were selected for further investigation. Results: Thrombospondin-1 (TSP-1), an anti-angiogenic factor, showed a mean 2.7-fold downregulation in response to PTTG overexpression. Conversely, the pro-angiogenic factor ID3 showed a 3.8-fold induction. We subsequently validated these candidate genes using TaqMan RT-PCR. PTTG downregulated TSP-1 86% (P < 0.001) in primary thyroid cells and 73% (P < 0.05) in HCT113 cells compared to vector-only cells. By contrast, PTTG upregulated ID3 62% in primary thyroid cells (P = 0.0053), and transfection studies in FTC133 thyroid follicular cells further supported PTTG upregulation of ID3 (4.35-fold, P < 0.01). In addition, we validated our findings at the protein level. We next examined expression in our thyroid cancer cohort. In keeping with our in vitro data, TSP-1 was reduced in cancers compared to normal thyroids. ID3, however, was significantly raised in tumors compared to normal tissue (5.57 fold, P = 0.025). Conclusion: We conclude that PTTG promotion of angiogenesis may be via altered regulation of several genes with both pro-(ID3) and anti-angiogenic (TSP-1) properties. Significance: We have identified PTTG, ID3, and thrombospondin as potentially important anti-angiogenic targets. It is hoped that this will improve the future treatment of the more aggressive thyroid cancers that are associated with very poor prognosis. Support: None reported.

The Calman reforms have led to a reduction in the length of all surgical training. Before the reforms, dental graduates had a shorter pathway than medical graduates to achieve maxillofacial consultant status, with exemptions from primary FRCS and 3-year medical courses. Now that 3-year dentistry courses for medical graduates have been established, medical graduates and dental graduates can complete their second degrees in the same length of time. Furthermore, medical graduates with the MRCS diploma are exempted from parts A and B of the MFDS, whereas dental graduates with MFDS have no exemptions from the MRCS examinations. Dental graduates may need more time as senior house officers to take these extra examinations. This could lead to dental graduates taking longer time than medical graduates to achieve consultant status. Traditionally, maxillofacial surgery has recruited the overwhelming majority of its trainees from dental graduates and has had close links with dental surgery. However, these recent developments in training make maxillofacial surgery far more attractive to medical graduates. Whether maxillofacial surgery continues to recruit the majority of its trainees form a dental background remains to be seen.