A Granulin-Like Growth Factor Secreted by the Carcinogenic Liver Fluke, Opisthorchis viverrini, Promotes Proliferation of Host Cells

The human liver fluke, Opisthorchis viverrini, infects millions of people throughout south-east Asia and is a major cause of cholangiocarcinoma, or cancer of the bile ducts. The mechanisms by which chronic infection with O. viverrini results in cholangiocarcinogenesis are multi-factorial, but one such mechanism is the secretion of parasite proteins with mitogenic properties into the bile ducts, driving cell proliferation and creating a tumorigenic environment. Using a proteomic approach, we identified a homologue of human granulin, a potent growth factor involved in cell proliferation and wound healing, in the excretory/secretory (ES) products of the parasite. O. viverrini granulin, termed Ov-GRN-1, was expressed in most parasite tissues, particularly the gut and tegument. Furthermore, Ov-GRN-1 was detected in situ on the surface of biliary epithelial cells of hamsters experimentally infected with O. viverrini. Recombinant Ov-GRN-1 was expressed in E. coli and refolded from inclusion bodies. Refolded protein stimulated proliferation of murine fibroblasts at nanomolar concentrations, and proliferation was inhibited by the MAPK kinase inhibitor, U0126. Antibodies raised to recombinant Ov-GRN-1 inhibited the ability of O. viverrini ES products to induce proliferation of murine fibroblasts and a human cholangiocarcinoma cell line in vitro, indicating that Ov-GRN-1 is the major growth factor present in O. viverrini ES products. This is the first report of a secreted growth factor from a parasitic worm that induces proliferation of host cells, and supports a role for this fluke protein in establishment of a tumorigenic environment that may ultimately manifest as cholangiocarcinoma

Whole genome identification of Mycobacterium tuberculosis vaccine candidates by comprehensive data mining and bioinformatic analyses

<p>Abstract</p> <p>Background</p> <p><it>Mycobacterium tuberculosis</it>, the causative agent of tuberculosis (TB), infects ~8 million annually culminating in ~2 million deaths. Moreover, about one third of the population is latently infected, 10% of which develop disease during lifetime. Current approved prophylactic TB vaccines (BCG and derivatives thereof) are of variable efficiency in adult protection against pulmonary TB (0%–80%), and directed essentially against early phase infection.</p> <p>Methods</p> <p>A genome-scale dataset was constructed by analyzing published data of: (1) global gene expression studies under conditions which simulate intra-macrophage stress, dormancy, persistence and/or reactivation; (2) cellular and humoral immunity, and vaccine potential. This information was compiled along with revised annotation/bioinformatic characterization of selected gene products and <it>in silico </it>mapping of T-cell epitopes. Protocols for scoring, ranking and prioritization of the antigens were developed and applied.</p> <p>Results</p> <p>Cross-matching of literature and <it>in silico</it>-derived data, in conjunction with the prioritization scheme and biological rationale, allowed for selection of 189 putative vaccine candidates from the entire genome. Within the 189 set, the relative distribution of antigens in 3 functional categories differs significantly from their distribution in the whole genome, with reduction in the Conserved hypothetical category (due to improved annotation) and enrichment in Lipid and in Virulence categories. Other prominent representatives in the 189 set are the PE/PPE proteins; iron sequestration, nitroreductases and proteases, all within the Intermediary metabolism and respiration category; ESX secretion systems, resuscitation promoting factors and lipoproteins, all within the Cell wall category. Application of a ranking scheme based on qualitative and quantitative scores, resulted in a list of 45 best-scoring antigens, of which: 74% belong to the dormancy/reactivation/resuscitation classes; 30% belong to the Cell wall category; 13% are classical vaccine candidates; 9% are categorized Conserved hypotheticals, all potentially very potent T-cell antigens.</p> <p>Conclusion</p> <p>The comprehensive literature and <it>in silico</it>-based analyses allowed for the selection of a repertoire of 189 vaccine candidates, out of the whole-genome 3989 ORF products. This repertoire, which was ranked to generate a list of 45 top-hits antigens, is a platform for selection of genes covering all stages of <it>M. tuberculosis </it>infection, to be incorporated in rBCG or subunit-based vaccines.</p

Wearable inertial sensors and pressure MAT detect risk factors associated with ACL graft failure that are not possible with traditional return to sport assessments

Introduction Anterior cruciate ligament reconstruction (ACLR) is associated with poor return to sport and high graft re-rupture rates. This study explored the use of a wearable inertial sensor (ViMove) that incorporates an accelerometer and gyroscope, and MatScan pressure sensing mat (TekScan, South Boston, Massachusetts, USA) to provide objective return-to-sport measures. Methods Three cohorts' ACLR patients, non-athletic controls and elite athletes (Australian seven's rugby Olympic Gold medallist). Patients performed biometric and functional tests (thigh circumference and triple hop) and the ViMove knee module (consisting of single and double leg squats, hops and box drops) for lower limb alignment assessment, concurrently with force plate. Results Elite athletes had less varus/valgus (VV) movement during ViMove exercises compared with the ACLR cohort, who in turn had less VV malalignment than controls. When analysing side-to-side differences, single leg squats and box drop were asymmetrical in the ACL group, with greater malalignment in the reconstructed leg (p<0.05). Subgroup analysis failed to differentiate who passed or failed current return to sport assessment. TekScan pressure plate detected differences in double leg landing and flight time while hopping not detected with ViMove, suggesting ACL patients compensate by offloading the reconstructed leg to improve coronal alignment during double leg activity. Conclusion The inertial sensor detected differences in motion for patients following ACLR, which are known to be associated with graft rupture and were not detected with functional return to sport testing. Coupling the device with data from a pressure plate provides a powerful assessment tool detecting alignment differences known to be associate with graft failure only previously detected in formal gait analysis

Adjuvant Therapy for the Reduction of Postoperative Intra-abdominal Adhesion Formation

To review currently available evidence on the use of adjuvant therapy to reduce the formation of postoperative intra-abdominal adhesions. Methods: A search on Pubmed and the Cochrane library was undertaken using the keywords “abdominal”, “adhesion”, “postoperative”, “prevention” and “reduction”. Only randomised controlled trials, prospective non-randomised controlled studies and review articles published in the English language between 1990 and 2006 were included. Results: Two prospective non-randomised controlled studies and 18 randomised controlled trials were included in this review. Adjuvant therapies reviewed included pharmacological agents (streptokinase, recombinant tissue plasminogen activator, vitamin E antioxidant molecules), and mechanical barriers (hyaluronic acid barriers, oxidised regenerated cellulose barriers, nanofibrous barriers and collagen foils). Hyaluronate/carboxymethylcellulose-based bioresorbable membrane (Seprafilm) appeared to be the most efficacious in reducing adhesion formation as well as decreasing the incidence of adhesion obstruction requiring reoperation in clinical studies. Drawbacks to the use of Seprafilm include high cost and complications such as haemorrhage and poor wound healing. Conclusions: Only a limited number of adjuvant treatment methods are currently available for the reduction of postoperative adhesions. Seprafilm has been proven to be the efficacious method to reduce adhesions. Investigations into the novel therapies are showing promising results in experimental studies and clinical studies before their wider application

The performance characteristics of prostate-specific antigen and prostate-specific antigen density in Chinese men

We investigated the performance characteristics of prostate-specific antigen (PSA) and PSA density (PSAD) in Chinese men. All Chinese men who underwent transrectal ultrasound-guided prostate biopsy (TRUS-PB) from year 2000 to 2013 were included. The receiver operating characteristic (ROC) curves for both PSA and PSAD were analyzed. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) at different cut-off levels were calculated. A total of 2606 Chinese men were included. For the ROC, the area under curve was 0.770 for PSA (P < 0.001) and 0.823 for PSAD (P < 0.001). PSA of 4.5 ng ml−1 had sensitivity of 94.4%, specificity of 14.1%, PPV of 29.5%, and NPV of 86.9%; PSAD of 0.12 ng ml−1 cc−1 had sensitivity of 94.5%, specificity of 26.6%, PPV of 32.8%, and NPV of 92.7%. On multivariate logistic regression analyses, PSA cut-off at 4.5 ng ml−1 (OR 1.61, 95% CI 1.05-2.45, P= 0.029) and PSAD cut-off at 0.12 ng ml−1 cc−1 (OR 6.22, 95% CI 4.20-9.22, P< 0.001) were significant predictors for prostate cancer detection on TRUS-PB. In conclusion, the performances of PSA and PSAD at different cut-off levels in Chinese men were very different from those in Caucasians. PSA of 4.5 ng ml−1 and PSAD of 0.12 ng ml−1 cc−1 had near 95% sensitivity and were significant predictors of prostate cancer detection in Chinese men

Association of time to prostate-specific antigen nadir and logarithm of prostate-specific antigen velocity after progression in metastatic prostate cancer with prior primary androgen deprivation therapy

We investigated the association of time to prostate-specific antigen nadir (TTPN) and logarithm of prostate-specific antigen velocity after progression Log(PSAVAP) in metastatic prostate cancer with prior primary androgen deprivation therapy (ADT). All metastatic prostate cancer patients treated with primary ADT from 2000 to 2009 were reviewed. Patients who developed disease progression were included in the subsequent analyses. Patients were categorized into three groups according to their TTPN: TTPN of 17 months. We compared the Log(PSAVAP) between the different TTPN groups using Mann-Whitney U-test and Kruskal-Wallis test. Further multiple linear regression analyses on Log(PSAVAP) were performed to adjust for other potential confounding factors. Among 419 patients who were treated with primary ADT, 306 patients developed disease progression with a median follow-up of 28 months. Longer TTPN was associated with lower Log(PSAVAP) (P = 0.008) within all subgroup analyses (TTPN of 17 months, P= 0.009; and TTPN of 17 months, P= 0.001). Upon multiple linear regression analyses, baseline PSA (regression coefficient 0.001, P= 0.045), PSA nadir (regression coefficient 0.002, P= 0.040), and TTPN (regression coefficient −0.030, P= 0.001) were the three factors that were significantly associated with Log(PSAVAP). In conclusion, a longer TTPN was associated with lower Log(PSAVAP) in metastatic prostate cancer patients following primary ADT. TTPN cut-offs at 3 months and 17 months appeared to have prognostic significance in predicting Log(PSAVAP). TTPN may serve as a good prognostic indicator in deciding the treatment strategy in patients with disease progression