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1.  Application of the multicellular tumour spheroid model to screen PET tracers for analysis of early response of chemotherapy in breast cancer 
Positron emission tomography (PET) is suggested for early monitoring of treatment response, assuming that effective anticancer treatment induces metabolic changes that precede morphology alterations and changes in growth. The aim of this study was to introduce multicellular tumour spheroids (MTS) to study the effect of anticancer drugs and suggest an appropriate PET tracer for further studies.
MTS of the breast cancer cell line MCF7 were exposed to doxorubicin, paclitaxel, docetaxel, tamoxifen or imatinib for 7 days for growth pattern studies and for 3 or 5 days for PET tracer studies. The effect on growth was computed using the semi-automated size determination method (SASDM). The effect on the uptake of PET tracers [18F]3'-deoxy-3'-fluorothymidine (FLT), [1-11C]acetate (ACE), [11C]choline (CHO), [11C]methionine (MET), and 2-[18F]fluoro-2-deoxyglucose (FDG) was calculated in form of uptake/viable volume of the MTS at the end of the drug exposures, and finally the uptake was related to effects on growth rate.
The drugs paclitaxel, docetaxel and doxorubicin gave severe growth inhibition, which correlated well with inhibition of the FLT uptake. FLT had, compared with ACE, CHO, MET and FDG, higher sensitivity in monitoring the therapy effects.
SASDM provides an effective, user-friendly, time-saving and accurate method to record the growth pattern of the MTS, and also to calculate the effect of the drug on PET tracer uptake. This study demonstrate the use of MTS and SASDM in combination with PET tracers as a promising approach to probe and select PET tracer for treatment monitoring of anticancer drugs and that can hopefully be applied for optimisation in breast cancer treatment.
PMCID: PMC2206720  PMID: 17659092
2.  Heterogeneous response of individual multicellular tumour spheroids to immunotoxins and ricin toxin. 
British Journal of Cancer  1995;72(3):607-614.
The cytoreductive effects of anti-transferrin receptor (anti-TfnR) immunotoxins (ITs) and of ricin toxin against tumour micromasses have been evaluated in a multicellular tumour spheroid (MTS) model. More than 600 (656) MTSs obtained with human breast carcinoma (MCF7) or rat glioblastoma (9L) cell lines were treated individually with ITs or toxin and the effects induced by the treatment were measured for each MTS as volume variation vs time by applying the Gompertz growth model. Two dose-dependent patterns of MTS growth were observed in MTSs of both cell lines in response to IT or toxin treatment: (1) complete inhibition of MTS growth ('sterilisation'); and (2) partial/complete inhibition ('heterogeneous response'). Within the range of IT or toxin concentrations resulting in partial inhibition of MTS growth, the sensitivity of treated MTSs was extremely heterogeneous (the cytoreductive effects varying between 0.1 and 4 logs of cells killed for a given IT or toxin concentration). Analysis of the post-treatment regrowth kinetics indicated that treated non-sterilised and control MTSs reached the same final limiting volumes. However, the doubling time estimated for the surviving cells of treated MCF7 and 9L MTSs ranged between 15 and 50 h, indicating that each MTS had individual growing potential. In conclusion, our results indicate that at substerilising IT concentrations individual heterogenicity of MTSs may greatly influence the cytoreductive potential of ITs. An implication of our study is that the efficacy of an IT treatment in eradicating disseminated micrometastases may not be predictable a priori. The MTS model that we describe in this paper may help in dissecting out factors limiting the effect of ITs in three-dimensional tumours.
PMCID: PMC2033892  PMID: 7669569
3.  The impact of Metastasis Suppressor-1, MTSS1, on oesophageal squamous cell carcinoma and its clinical significance 
Metastasis suppressor-1 (MTSS1) has been proposed to function as a cytoskeletal protein with a role in cancer metastasis. Recent studies have demonstrated the clinical significance of MTSS1 in certain type of cancers, yet the clinical relevance of MTSS1 in oesophageal squamous cell carcinoma (ESCC) has not been reported.
In this study, we assessed the expression levels of MTSS1 in tumours and its matched adjacent non-tumour tissues obtained from 105 ESCC patients. We also used ESCC cells with differing MTSS1 expression and assessed the influence of MTSS1 on ESCC cells.
Down-regulation of MTSS1 expression was observed both in oesophageal tumour tissues and ESCC cancer cell lines. We also reported that MTSS1 expression was associated with tumour grade (p = 0.024), lymph node metastasis (p = 0.010) and overall survival (p = 0.035). Patients with high levels of MTSS1 transcripts had a favorable prognosis in comparison with those who had reduced or absent expression levels. Using over-expression and knockdown approach, we created sublines from ESCC cells and further demonstrated that MTSS1 expression in ESCC cells significantly influenced the aggressiveness of the oesophageal cancer cells, by reducing their cellular migration and in vitro invasiveness.
MTSS1 serves as a potential prognostic indicator in human ESCC and may be an important target for cancer therapy.
PMCID: PMC3131255  PMID: 21696600
metastasis suppressor-1; MTSS1; MIM; oesophageal squamous cell carcinoma; metastasis
4.  Risk factors associated with medial tibial stress syndrome in runners: a systematic review and meta-analysis 
Medial tibial stress syndrome (MTSS) affects 5%–35% of runners. Research over the last 40 years investigating a range of interventions has not established any clearly effective management for MTSS that is better than prolonged rest. At the present time, understanding of the risk factors and potential causative factors for MTSS is inconclusive. The purpose of this review is to evaluate studies that have investigated various risk factors and their association with the development of MTSS in runners.
Medical research databases were searched for relevant literature, using the terms “MTSS AND prevention OR risk OR prediction OR incidence”.
A systematic review of the literature identified ten papers suitable for inclusion in a meta-analysis. Measures with sufficient data for meta-analysis included dichotomous and continuous variables of body mass index (BMI), ankle dorsiflexion range of motion, navicular drop, orthotic use, foot type, previous history of MTSS, female gender, hip range of motion, and years of running experience. The following factors were found to have a statistically significant association with MTSS: increased hip external rotation in males (standard mean difference [SMD] 0.67, 95% confidence interval [CI] 0.29–1.04, P<0.001); prior use of orthotics (risk ratio [RR] 2.31, 95% CI 1.56–3.43, P<0.001); fewer years of running experience (SMD −0.74, 95% CI −1.26 to −0.23, P=0.005); female gender (RR 1.71, 95% CI 1.15–2.54, P=0.008); previous history of MTSS (RR 3.74, 95% CI 1.17–11.91, P=0.03); increased body mass index (SMD 0.24, 95% CI 0.08–0.41, P=0.003); navicular drop (SMD 0.26, 95% CI 0.02–0.50, P=0.03); and navicular drop >10 mm (RR 1.99, 95% CI 1.00–3.96, P=0.05).
Female gender, previous history of MTSS, fewer years of running experience, orthotic use, increased body mass index, increased navicular drop, and increased external rotation hip range of motion in males are all significantly associated with an increased risk of developing MTSS. Future studies should analyze males and females separately because risk factors vary by gender. A continuum model of the development of MTSS that links the identified risk factors and known processes is proposed. These data can inform both screening and countermeasures for the prevention of MTSS in runners.
PMCID: PMC3873798  PMID: 24379729
medial tibial stress syndrome; injury prevention; risk factors; running injuries
5.  Multicellular Tumour Spheroid as a model for evaluation of [18F]FDG as biomarker for breast cancer treatment monitoring 
In order to explore a pre-clinical method to evaluate if [18F]FDG is valid for monitoring early response, we investigated the uptake of FDG in Multicellular tumour spheroids (MTS) without and with treatment with five routinely used chemotherapy agents in breast cancer.
The response to each anticancer treatment was evaluated by measurement of the [18F]FDG uptake and viable volume of the MTSs after 2 and 3 days of treatment.
The effect of Paclitaxel and Docetaxel on [18F]FDG uptake per viable volume was more evident in BT474 (up to 55% decrease) than in MCF-7 (up to 25% decrease).
Doxorubicin reduced the [18F]FDG uptake per viable volume more noticeable in MCF-7 (25%) than in BT474 MTSs.
Tamoxifen reduced the [18F]FDG uptake per viable volume only in MCF-7 at the highest dose of 1 μM.
No effect of Imatinib was observed.
MTS was shown to be appropriate to investigate the potential of FDG-PET for early breast cancer treatment monitoring; the treatment effect can be observed before any tumour size changes occur.
The combination of PET radiotracers and image analysis in MTS provides a good model to evaluate the relationship between tumour volume and the uptake of metabolic tracer before and after chemotherapy. This feature could be used for screening and selecting PET-tracers for early assessment of treatment response.
In addition, this new method gives a possibility to assess quickly, and in vitro, a good preclinical profile of existing and newly developed anti-cancer drugs.
PMCID: PMC1459213  PMID: 16556298
6.  Downregulation of metastasis suppressor 1(MTSS1) is associated with nodal metastasis and poor outcome in Chinese patients with gastric cancer 
BMC Cancer  2010;10:428.
The putative tumor metastasis suppressor 1(MTSS1) is an actin-binding scaffold protein that has been implicated to play an important role in carcinogenesis and cancer metastasis, yet its role in the development of gastric cancer has not been well illustrated. In this study, we detected MTSS1 expression and explored its clinical significance in gastric cancer.
Immunohistochemistry was performed using tissue microarrays containing gastric adenocarcinoma specimens from 1,072 Chinese patients with normal adjacent mucosa, primary gastric cancer and lymph node (LN) metastasis and specific antibody against MTSS1. MTSS1 mRNA and protein expression were detected by reverse transcription-polymerase chain reaction and Western blotting. The clinical follow-up was done in the 669 patients living in Shanghai that was chose from the 1072 cases.
Complete loss of MTSS1 expression was observed in 751 cases (70.1%) of the 1,072 primary tumors and 103 (88%) of 117 nodal metastases; and loss of MTSS1 expression was significantly associated with poorly differentiated tumors, large tumor size, deep invasion level, the presence of nodal metastases and advanced disease stage. Moreover, multivariate analysis demonstrated that loss of MTSS1 expression correlated significantly with poor survival rates (RR = 0.194, 95% CI = 0.144-0.261, P < 0.001).
MTSS1 expression decreased significantly as gastric cancer progressed and metastasized, suggesting MTSS1 may serve as a useful biomarker for the prediction of outcome of gastric cancer.
PMCID: PMC2928798  PMID: 20712855
7.  Effect of different imputation approaches on the evaluation of radiographic progression in patients with psoriatic arthritis: results of the RAPID-PsA 24-week phase III double-blind randomised placebo-controlled study of certolizumab pegol 
Annals of the Rheumatic Diseases  2013;73(1):233-237.
To report the effect of different imputation methodologies on the assessment of radiographic progression in clinical trials.
The 216-week RAPID-psoriatic arthritis (PsA) (NCT01087788) trial of certolizumab pegol (CZP) in patients with active PsA was double-blind and placebo-controlled until week 24. A primary end point was change from baseline in modified Total Sharp Score(s) (mTSS). Prespecified imputation methodology in patients with fewer than two analysable mTSS used minimum observed baseline score for missing baseline values and maximum observed week 24 score for missing week 24 values. Post hoc analyses used alternative methods of imputation in patients with fewer than two analysable mTSS. mTSS non-progressors were defined as patients with ≤0 (predefined) or ≤0.5 (post hoc) change in mTSS from baseline to week 24. Baseline mTSS and C-reactive protein levels as predictors of radiographic progression were investigated.
409 patients were randomised. Baseline demographics were similar between groups. Prespecified imputation analysis inappropriately overestimated radiographic progression (least squares mean placebo, 28.9; CZP, 18.3; p≥0.05). Multiple post hoc analyses demonstrated that CZP inhibited radiographic progression compared with placebo, particularly in patients with high baseline mTSS and C-reactive protein levels. mTSS non-progression rate was higher in CZP than placebo groups in all analyses.
Inappropriate prespecified imputation methodology resulted in an unrealistic assessment of progression in all arms. Methodologies for imputing missing radiographic data can greatly affect assessment and reporting of mTSS progression.
PMCID: PMC3888591  PMID: 23942869
Anti-TNF; Psoriatic Arthritis; Outcomes research
8.  Metastasis tumour suppressor-1 and the aggressiveness of prostate cancer cells 
Previous studies have suggested that metastasis tumour suppressor-1 (MTSS1) plays a key role in cancer metastasis. Firstly, in this study we assessed MTSS1 expression levels in prostate cancer cell lines to reveal any changes in cell properties. Secondly, we aimed to clarify the cellular function of MTSS1 in prostate cancer cells. MTSS1 expression levels were assessed in different types of cancer cell lines through the RT-PCR analysis technique. The influence of MTSS1 was further examined via biological overexpression and knockdown in the prostate cancer cell lines. Two prostate cell lines were chosen for either knockdown or overexpression of the MTSS1 gene. The overexpression of MTSS1 in PC-3 human prostate cancer cells significantly suppressed the migratory, growth and adherence properties of the cells (p<0.01). By contrast, the knockdown of MTSS1 in DU-145 human prostate cancer cells dramatically enhanced these properties (p<0.001). We concluded that MTSS1 demonstrates the ability to play a role in controlling the metastatic nature of prostate cancer cells.
PMCID: PMC3440677  PMID: 22977484
metastasis tumour suppressor-1; ribozyme transgenes; cell growth; cell migration; prostate cancer
9.  Mtss1 regulates epidermal growth factor signaling in head and neck squamous carcinoma cells 
Oncogene  2011;31(14):1781-1793.
Mtss1 is located within chromosomal region 8q23-24, which is one of the three most commonly amplified regions in HNSCC. Mtss1 is lost in metastatic cells but confusingly is commonly overexpressed in primary tumors. Here we address possible reasons why Mtss1 is positively selected for in primary tumors. We find that Mtss1 enhances the localization of the EGF receptor to the plasma membrane, prolonging EGF signaling and resulting in enhanced proliferation in HNSCC. Depletion of Mtss1 results in decreased EGF receptor levels and decreased phosphorylation of Erk1/2 and Akt. However, when cells are at high density and adherent to each other, analogous to conditions in a solid tumor, Mtss1 does not confer any growth advantage, either in basal conditions or following EGF stimulation. This could indicate why Mtss1 might be lost in metastases, but preserved in early primary tumors. This is supported by an organotypic assay showing that Mtss1 expressing cells display a less proliferative more epithelial-like morphology on top of a collagen matrix. Furthermore, xenograft tumors expressing Mtss1 initially grow more rapidly, but later show less proliferation and more differentiation. Mtss1 positively modulates EGF signaling at low cell densities to promote proliferation and, therefore, may be beneficial for the early stages of primary HNSCC tumor growth. However, at high cell densities, Mtss1 impacts negatively on EGF signaling and this suggests why it inhibits metastasis.
PMCID: PMC3245856  PMID: 21927027
Mtss1; HNSCC; epidermal growth factor receptor
10.  Developmental expression and differentiation-related neuron-specific splicing of metastasis suppressor 1 (Mtss1) in normal and transformed cerebellar cells 
Mtss1 encodes an actin-binding protein, dysregulated in a variety of tumors, that interacts with sonic hedgehog/Gli signaling in epidermal cells. Given the prime importance of this pathway for cerebellar development and tumorigenesis, we assessed expression of Mtss1 in the developing murine cerebellum and human medulloblastoma specimens.
During development, Mtss1 is transiently expressed in granule cells, from the time point they cease to proliferate to their synaptic integration. It is also expressed by granule cell precursor-derived medulloblastomas. In the adult CNS, Mtss1 is found exclusively in cerebellar Purkinje cells. Neuronal differentiation is accompanied by a switch in Mtss1 splicing. Whereas immature granule cells express a Mtss1 variant observed also in peripheral tissues and comprising exon 12, this exon is replaced by a CNS-specific exon, 12a, in more mature granule cells and in adult Purkinje cells. Bioinformatic analysis of Mtss1 suggests that differential exon usage may affect interaction with Fyn and Src, two tyrosine kinases previously recognized as critical for cerebellar cell migration and histogenesis. Further, this approach led to the identification of two evolutionary conserved nuclear localization sequences. These overlap with the actin filament binding site of Mtss1, and one also harbors a potential PKA and PKC phosphorylation site.
Both the pattern of expression and splicing of Mtss1 is developmentally regulated in the murine cerebellum. These findings are discussed with a view on the potential role of Mtss1 for cytoskeletal dynamics in developing and mature cerebellar neurons.
PMCID: PMC2194783  PMID: 17925019
11.  The relationship between lower extremity alignment and Medial Tibial Stress Syndrome among non-professional athletes 
To determine the relationship between lower extremity alignment and MTSS amongst non-professional athletes
In a prospective Study, sixty six subjects were evaluated. Bilateral navicular drop test, Q angle, Achilles angle, tibial angle, intermalleolar and intercondylar distance were measured. In addition, runner's height, body mass, history of previous running injury, running experience was recorded. Runners were followed for 17 weeks to determine occurrence of MTSS.
The overall injury rate for MTSS was 19.7%. The MTSS injury rate in girls (22%) was not significantly different from the rate in boys (14.3%). Most MTSS injuries were induced after 60 hours of exercise, which did not differ between boys and girls. There was a significant difference in right and left navicular drop (ND) in athletes with MTSS. MTSS had no significant correlation with other variables including Quadriceps, Tibia and Achilles angles, intercondylar and intermaleolar lengths and lower extremity lengths.
All measurements performed in this study were uniplanar and static. The small sample size deemed our main limitation. The accurate assessment of participants with previous history of anterior leg pain for MTSS was another limitation.
Although a significant relationship between navicular drop and MTSS was found in this study; there was not any significant relationship between lower extremity alignment and MTSS in our sample study.
PMCID: PMC2700791  PMID: 19519909
12.  Tumor slices as a model to evaluate doxorubicin in vitro treatment and expression of trios of genes PRSS11, MTSS1, CLPTM1 and PRSS11, MTSS1, SMYD2 in canine mammary gland cancer 
In women with breast cancer submitted to neoadjuvant chemotherapy based in doxorubicin, tumor expression of groups of three genes (PRSS11, MTSS1, CLPTM1 and PRSS11, MTSS1, SMYD2) have classified them as responsive or resistant. We have investigated whether expression of these trios of genes could predict mammary carcinoma response in dogs and whether tumor slices, which maintain epithelial-mesenchymal interactions, could be used to evaluate drug response in vitro.
Tumors from 38 dogs were sliced and cultured with or without doxorubicin 1 μM for 24 h. Tumor cells were counted by two observers to establish a percentage variation in cell number, between slices. Based on these results, a reduction in cell number between treated and control samples ≥ 21.7%, arbitrarily classified samples, as drug responsive. Tumor expression of PRSS11, MTSS1, CLPTM1 and SMYD2, was evaluated by real time PCR. Relative expression results were then transformed to their natural logarithm values, which were spatially disposed according to the expression of trios of genes, comprising PRSS11, MTSS1, CLPTM1 and PRSS11, MTSS1, SMYD2. Fisher linear discrimination test was used to generate a separation plane between responsive and non-responsive tumors.
Culture of tumor slices for 24 h was feasible. Nine samples were considered responsive and 29 non-responsive to doxorubicin, considering the pre-established cut-off value of cell number reduction ≥ 21.7%, between doxorubicin treated and control samples. Relative gene expression was evaluated and tumor samples were then spatially distributed according to the expression of the trios of genes: PRSS11, MTSS1, CLPTM1 and PRSS11, MTSS1, SMYD2. A separation plane was generated. However, no clear separation between responsive and non-responsive samples could be observed.
Three-dimensional distribution of samples according to the expression of the trios of genes PRSS11, MTSS1, CLPTM1 and PRSS11, MTSS1, SMYD2 could not predict doxorubicin in vitro responsiveness. Short term culture of mammary gland cancer slices may be an interesting model to evaluate chemotherapy activity.
PMCID: PMC2474627  PMID: 18601734
13.  SCFβ-TRCP targets MTSS1 for ubiquitination-mediated destruction to regulate cancer cell proliferation and migration 
Oncotarget  2013;4(12):2339-2353.
Metastasis suppressor 1 (MTSS1) is an important tumor suppressor protein, and loss of MTSS1 expression has been observed in several types of human cancers. Importantly, decreased MTSS1 expression is associated with more aggressive forms of breast and prostate cancers, and with poor survival rate. Currently, it remains unclear how MTSS1 is regulated in cancer cells, and whether reduced MTSS1 expression contributes to elevated cancer cell proliferation and migration. Here we report that the SCFβ-TRCP regulates MTSS1 protein stability by targeting it for ubiquitination and subsequent destruction via the 26S proteasome. Notably, depletion of either Cullin 1 or β-TRCP1 led to increased levels of MTSS1. We further demonstrated a crucial role for Ser322 in the DSGXXS degron of MTSS1 in governing SCFβ-TRCP-mediated MTSS1 degradation. Mechanistically, we defined that Casein Kinase Iδ (CKIδ) phosphorylates Ser322 to trigger MTSS1's interaction with β-TRCP for subsequent ubiquitination and degradation. Importantly, introducing wild-type MTSS1 or a non-degradable MTSS1 (S322A) into breast or prostate cancer cells with low MTSS1 expression significantly inhibited cellular proliferation and migration. Moreover, S322A-MTSS1 exhibited stronger effects in inhibiting cell proliferation and migration when compared to ectopic expression of wild-type MTSS1. Therefore, our study provides a novel molecular mechanism for the negative regulation of MTSS1 by β-TRCP in cancer cells. It further suggests that preventing MTSS1 degradation could be a possible novel strategy for clinical treatment of more aggressive breast and prostate cancers.
PMCID: PMC3926831  PMID: 24318128
tumor suppressor; MTSS1; ubiquitination; phosphorylation; migration
14.  The treatment of medial tibial stress syndrome in athletes; a randomized clinical trial 
The only three randomized trials on the treatment of MTSS were all performed in military populations. The treatment options investigated in this study were not previously examined in athletes. This study investigated if functional outcome of three common treatment options for medial tibial stress syndrome (MTSS) in athletes in a non-military setting was the same.
The study design was randomized and multi-centered. Physical therapists and sports physicians referred athletes with MTSS to the hospital for inclusion. 81 athletes were assessed for eligibility of which 74 athletes were included and randomized to three treatment groups. Group one performed a graded running program, group two performed a graded running program with additional stretching and strengthening exercises for the calves, while group three performed a graded running program with an additional sports compression stocking. The primary outcome measure was: time to complete a running program (able to run 18 minutes with high intensity) and secondary outcome was: general satisfaction with treatment.
74 Athletes were randomized and included of which 14 did not complete the study due a lack of progress (18.9%). The data was analyzed on an intention-to-treat basis. Time to complete a running program and general satisfaction with the treatment were not significantly different between the three treatment groups.
This was the first randomized trial on the treatment of MTSS in athletes in a non-military setting. No differences were found between the groups for the time to complete a running program.
Trial registration
CCMO; NL23471.098.08
PMCID: PMC3352296  PMID: 22464032
Running program; Exercises; Compression sleeve; Shin splints
15.  MicroRNA-182 downregulates metastasis suppressor 1 and contributes to metastasis of hepatocellular carcinoma 
BMC Cancer  2012;12:227.
miR-182 is one of the most significantly up-regulated miRNAs in hepatocellular carcinoma (HCC). Metastasis suppressor 1 (MTSS1), one target gene of miR-182, plays an important role in the metastasis of cancers. However, it remains unclear what role does function and mechanism of miR-182 and MTSS1play in HCC.
miR-182 expression was tested in 86 cases of paired HCC and normal tissues by real-time PCR and the relationships between miR-182 expression and clinicopathological parameters were analyzed. The expression of MTSS1 was evaluated by immunohistochemistry and western blot in the above tissues and its correlation with miR-182 expression was analyzed. Moreover, western blot and invasion assays were performed after transfection of pre-miR-182 or anti-miR-182 to HCC cell lines. In addition, luciferase assays was performed to confirm the regulation of miR-182 on MTSS1.
Compared with normal tissue, miR-182 was up-regulated and MTSS1 was down-regulated in HCC tissues. Moreover, the over-expression of miR-182 was correlated with intrahepatic metastasis (p = 0.034) and poor prognosis (p = 0.039) of HCC patients. There was a negative correlation between miR-182 and MTSS1 expression in both HCC tissues (r = −0.673, p < 0.01) and HCC cell lines (r = −0.931, p = 0.021). Furthermore, the up-regulation of miR-182 resulted in the down-regulation of MTSS1 and increased invasive potential of HUH-1, and reverse results were also confirmed when the expression of miR-182 was inhibited. In addition, the results of the luciferase assay demonstrated the targeted regulation of miR-182 on MTSS1.
miR-182 could promote metastasis of HCC and inhibit the expression of MTSS1. miR-182 and MTSS1 are potential prognostic markers and/or therapeutic targets in HCC.
PMCID: PMC3492170  PMID: 22681717
Hepatocellular carcinoma; miR-182; Metastasis suppressor 1; Metastasis
16.  An Advanced System of the Mitochondrial Processing Peptidase and Core Protein Family in Trypanosoma brucei and Multiple Origins of the Core I Subunit in Eukaryotes 
Genome Biology and Evolution  2013;5(5):860-875.
Mitochondrial processing peptidase (MPP) consists of α and β subunits that catalyze the cleavage of N-terminal mitochondrial-targeting sequences (N-MTSs) and deliver preproteins to the mitochondria. In plants, both MPP subunits are associated with the respiratory complex bc1, which has been proposed to represent an ancestral form. Subsequent duplication of MPP subunits resulted in separate sets of genes encoding soluble MPP in the matrix and core proteins (cp1 and cp2) of the membrane-embedded bc1 complex. As only α-MPP was duplicated in Neurospora, its single β–MPP functions in both MPP and bc1 complexes. Herein, we investigated the MPP/core protein family and N-MTSs in the kinetoplastid Trypanosoma brucei, which is often considered one of the most ancient eukaryotes. Analysis of N-MTSs predicted in 336 mitochondrial proteins showed that trypanosomal N-MTSs were comparable with N-MTSs from other organisms. N-MTS cleavage is mediated by a standard heterodimeric MPP, which is present in the matrix of procyclic and bloodstream trypanosomes, and its expression is essential for the parasite. Distinct Genes encode cp1 and cp2, and in the bloodstream forms the expression of cp1 is downregulated along with the bc1 complex. Phylogenetic analysis revealed that all eukaryotic lineages include members with a Neurospora-type MPP/core protein family, whereas cp1 evolved independently in metazoans, some fungi and kinetoplastids. Evolution of cp1 allowed the independent regulation of respiration and protein import, which is essential for the procyclic and bloodstream forms of T. brucei. These results indicate that T. brucei possesses a highly derived MPP/core protein family that likely evolved in response to its complex life cycle and does not appear to have an ancient character proposed earlier for this eukaryote.
PMCID: PMC3673636  PMID: 23563972
mitochondrial processing peptidase; bc1 complex; mitochondrial targeting sequence; trypanosome; evolution
17.  Adalimumab for long-term treatment of psoriatic arthritis: 2-year data from the Adalimumab Effectiveness in Psoriatic Arthritis Trial (ADEPT) 
Annals of the Rheumatic Diseases  2008;68(5):702-709.
To evaluate the long-term effectiveness and tolerability of adalimumab in the treatment of psoriatic arthritis (PsA).
Patients with PsA who completed a 24-week, double-blind study of adalimumab versus placebo were eligible to enroll in an open-label extension study and receive adalimumab 40 mg subcutaneously every other week for up to an additional 120 weeks. At the time of this analysis, available efficacy evaluations throughout 2 years of treatment (n  =  245) included American College of Rheumatology (ACR) 20%, 50% and 70% improvement scores, measures of joint disease and skin disease, disability and quality of life; modified total Sharp scores (mTSS) were available for 2.75 years of treatment for patients who received adalimumab in the 24-week study.
After 24 weeks of double-blind treatment, the mean change in mTSS was −0.2 for the adalimumab group (N  =  144) and 1.0 for the placebo group (N  =  152; p<0.001), and outcomes for all individual ACR component variables were significantly improved in adalimumab compared with placebo-treated patients. Compared with 24-week responses, inhibition of radiographic progression and improvements in joint disease were maintained in most patients during long-term, open-label adalimumab treatment. Also, improvements in skin disease were maintained, with >20% of patients achieving the strict criterion of psoriasis area and severity index 100. The nature and frequency of adverse events during long-term adalimumab treatment were consistent with the safety profile during short-term treatment.
The clinical and radiographic efficacy of adalimumab demonstrated during short-term treatment was sustained during long-term treatment. Adalimumab has a favourable risk–benefit profile in patients with PsA.
Trial registration number:
PMCID: PMC2663711  PMID: 18684743
18.  Prevalence of Toxic Shock Syndrome Toxin 1-Producing Staphylococcus aureus and the Presence of Antibodies to This Superantigen in Menstruating Women 
Journal of Clinical Microbiology  2005;43(9):4628-4634.
Menstrual toxic shock syndrome (mTSS) is thought to be associated with colonization with toxic shock syndrome toxin 1 (TSST-1)-producing Staphylococcus aureus in women with insufficient antibody titers. mTSS has been associated with menstruation and tampon use, and although it is rare, the effects can be life threatening. It remains of interest because of the widespread use of tampons, reported to be about 70% of women in the United States, Canada, and much of Western Europe. This comprehensive study was designed to determine S. aureus colonization and TSST-1 serum antibody titers in 3,012 menstruating women in North America between the ages of 13 and 40, particularly among age and racial groups that could not be assessed reliably in previous small studies. One out of every four subjects was found to be colonized with S. aureus in at least one of three body sites (nose, vagina, or anus), with approximately 9% colonized vaginally. Eighty-five percent of subjects had antibody titers (≥1:32) to TSST-1, and the vast majority (81%) of teenaged subjects (13 to 18 years) had already developed antibody titers. Among carriers of toxigenic S. aureus, a significantly lower percentage of black women than of white or Hispanic women were found to have antibody titers (≥1:32) to TSST-1 (89% versus 98% and 100%). These findings demonstrate that the majority of teenagers have antibody titers (≥1:32) to TSST-1 and are presumed to be protected from mTSS. These findings also suggest that black women may be more susceptible to mTSS than previously thought.
PMCID: PMC1234102  PMID: 16145118
19.  Medial Tibial Stress Syndrome: Evidence-Based Prevention 
Journal of Athletic Training  2008;43(3):316-318.
Thacker SB, Gilchrist J, Stroup DF, Kimsey CD. The prevention of shin splints in sports: a systematic review of literature. Med Sci Sports Exerc. 2002;34(1):32–40.
Clinical Question:
Among physically active individuals, which medial tibial stress syndrome (MTSS) prevention methods are most effective to decrease injury rates?
Data Sources:
Studies were identified by searching MEDLINE (1966–2000), Current Contents (1996–2000), Biomedical Collection (1993–1999), and Dissertation Abstracts. Reference lists of identified studies were searched manually until no further studies were identified. Experts in the field were contacted, including first authors of randomized controlled trials addressing prevention of MTSS. The Cochrane Collaboration (early stage of Cochrane Database of Systematic Reviews) was contacted.
Study Selection:
Inclusion criteria included randomized controlled trials or clinical trials comparing different MTSS prevention methods with control groups. Excluded were studies that did not provide primary research data or that addressed treatment and rehabilitation rather than prevention of incident MTSS.
Data Extraction:
A total of 199 citations were identified. Of these, 4 studies compared prevention methods for MTSS. Three reviewers independently scored the 4 studies. Reviewers were blinded to the authors' names and affiliations but not the results. Each study was evaluated independently for methodologic quality using a 100-point checklist. Final scores were averages of the 3 reviewers' scores.
Main Results:
Prevention methods studied were shock-absorbent insoles, foam heel pads, Achilles tendon stretching, footwear, and graduated running programs. No statistically significant results were noted for any of the prevention methods. Median quality scores ranged from 29 to 47, revealing flaws in design, control for bias, and statistical methods.
No current evidence supports any single prevention method for MTSS. The most promising outcomes support the use of shock-absorbing insoles. Well-designed and controlled trials are critically needed to decrease the incidence of this common injury.
PMCID: PMC2386425  PMID: 18523568
shin splints; injury prevention methods; stress injuries; running injuries; tibial injuries
20.  Discontinuation of infliximab after attaining low disease activity in patients with rheumatoid arthritis: RRR (remission induction by Remicade in RA) study 
Annals of the Rheumatic Diseases  2010;69(7):1286-1291.
Tumour necrosis factor (TNF) inhibitors enable tight control of disease activity in patients with rheumatoid arthritis (RA). Discontinuation of TNF inhibitors after acquisition of low disease activity (LDA) is important for safety and economic reasons.
To determine whether infliximab might be discontinued after achievement of LDA in patients with RA and to evaluate progression of articular destruction during the discontinuation.
114 patients with RA who had received infliximab treatment, and whose Disease Activity Score, including a 28-joint count (DAS28) was <3.2 (LDA) for 24 weeks, were studied.
The mean disease duration of the 114 patients was 5.9 years, mean DAS28 5.5 and mean modified total Sharp score (mTSS) 63.3. After maintaining LDA for >24 weeks by infliximab treatment, the drug was discontinued and DAS28 in 102 patients was evaluated at year 1. Fifty-six patients (55%) continued to have DAS28<3.2 and 43% reached DAS<2.6 at 1 year after discontinuing infliximab. For 46 patients remission induction by Remicade in RA (RRR) failed: disease in 29 patients flared within 1 year and DAS28 was >3.2 at year 1 in 17 patients. Yearly progression of mTSS (ΔTSS) remained <0.5 in 67% and 44% of the RRR-achieved and RRR-failed groups, respectively. The estimated ΔmTSS was 0.3 and 1.6 and Health Assessment Questionnaire-Disability Index was 0.174 and 0.614 in the RRR-achieved and RRR-failed groups, respectively, 1 year after the discontinuation.
After attaining LDA by infliximab, 56 (55%) of the 102 patients with RA were able to discontinue infliximab for >1 year without progression of radiological articular destruction.
PMCID: PMC3015067  PMID: 20360136
21.  Tissue-Based Microarray Expression of Genes Predictive of Metastasis in Uveal Melanoma and Differentially Expressed in Metastatic Uveal Melanoma 
To screen the microarray expression of CDH1, ECM1, EIF1B, FXR1, HTR2B, ID2, LMCD1, LTA4H, MTUS1, RAB31, ROBO1, and SATB1 genes which are predictive of primary uveal melanoma metastasis, and NFKB2, PTPN18, MTSS1, GADD45B, SNCG, HHIP, IL12B, CDK4, RPLP0, RPS17, RPS12 genes that are differentially expressed in metastatic uveal melanoma in normal whole human blood and tissues prone to metastatic involvement by uveal melanoma.
We screened the GeneNote and GNF BioGPS databases for microarray analysis of genes predictive of primary uveal melanoma metastasis and those differentially expressed in metastatic uveal melanoma in normal whole blood, liver, lung and skin.
Microarray analysis showed expression of all 22 genes in normal whole blood, liver, lung and skin, which are the most common sites of metastases. In the GNF BioGPS database, data for expression of the HHIP gene in normal whole blood and skin was not complete.
Microarray analysis of genes predicting systemic metastasis of uveal melanoma and genes differentially expressed in metastatic uveal melanoma may not be used as a biomarker for metastasis in whole blood, liver, lung, and skin. Their expression in tissues prone to metastasis may suggest that they play a role in tropism of uveal melanoma metastasis to these tissues.
PMCID: PMC3957035  PMID: 24653816
Eye; Uvea; Melanoma; Cancer; Metastasis; Microarray; Gene Expression Profiling
22.  Sustained inhibition of progressive joint damage with rituximab plus methotrexate in early active rheumatoid arthritis: 2-year results from the randomised controlled trial IMAGE 
Annals of the Rheumatic Diseases  2011;71(3):351-357.
In the IMAGE study, rituximab plus methotrexate (MTX) inhibited joint damage and improved clinical outcomes at 1 year in MTX-naïve patients with early active rheumatoid arthritis.
The aim of this study was to assess joint damage progression and clinical outcomes over 2 years.
Patients (n=755) were randomised to receive rituximab 2×500 mg+MTX, 2×1000 mg+MTX or placebo+MTX. The placebo-controlled period continued to week 104. Two-year end points were defined as secondary or exploratory and included change in total Genant-modified Sharp score (mTSS), total erosion score and joint space narrowing score from baseline to week 104. Clinical efficacy and physical function end points were also assessed.
At 2 years, rituximab 2×1000 mg+MTX maintained inhibition of progressive joint damage versus MTX alone (mTSS change 0.41 vs 1.95; p<0.0001 (79% inhibition)), and a higher proportion of patients receiving rituximab 2×1000 mg+MTX had no radiographic progression over 2 years compared with those receiving MTX alone (57% vs 37%; p<0.0001). Contrary to 1-year results, exploratory analysis of rituximab 2×500 mg+MTX at 2 years showed that progressive joint damage was slowed by ∼61% versus placebo+MTX (mTSS, exploratory p=0.0041). Improvements in clinical signs and symptoms and physical function seen after 1 year in rituximab-treated patients versus those receiving placebo were maintained at year 2. Safety profiles were similar between groups.
Treatment with rituximab 2×1000 mg+MTX was associated with sustained improvements in radiographic, clinical and functional outcomes over 2 years.
Clinical identifier NCT00299104.
PMCID: PMC3277723  PMID: 22012969
23.  Endoscopic Approach to Middle Turbinate Squeeze Syndrome 
Middle turbinate squeeze syndrome (MTSS) refers to sino-nasal headache due to intense contact between the middle turbinate and the nasal septum and/or between middle turbinate and other structures in the lateral nasal wall. This study was intended to evaluate the efficacy of precise endoscopic surgical treatment of MTSS. This is a prospective study of 126 patients with refractory cephalgia due to endoscopically confirmed MTSS who underwent functional endoscopic naso-sinus surgery (FENS) wherein the contact points and ostio-meatal complex obstruction were endoscopically relieved. 91% of cases reported improvement/resolution of headache and 95% of cases had relieved contact points as documented endoscopically. This surgery was also found to facilitate resolution of sinus disease, both radiologically (in 64% of cases) and endoscopically (in 94% of cases). Cephalgia caused by MTSS can be effectively treated by an ultra-conservative endoscopic approach.
PMCID: PMC3392353  PMID: 23730579
Cephalgia; Naso-sinus headache; Middle turbinate syndrome; Contact neuralgia; Uncinate process; Supra-bullar approach; Endoscopic sinus surgery
24.  Increased nanoparticle penetration in collagenase-treated multicellular spheroids 
The extracellular matrix of solid tumors presents a transport barrier that restricts nanoparticle penetration, thereby limiting the efficacy of nanosized delivery vehicles for cancer imaging and therapy. In this study, the effect of nanoparticle size and collagenase treatment on penetration of carboxylated polystyrene nanoparticles was systematically assessed in a multicellular spheroid model. Penetration of the nanoparticles into the spheroid core was limited to particles smaller than 100 nm. Collagenase treatment of spheroids resulted in significantly increased penetration of nanoparticles up to 100 nm with only a minor increase in particle penetration observed for particles larger than 100 nm. Collagenase was immobilized onto the surface of nanoparticles for site-specific degradation of ECM proteins. Collagenase-coated, 100 nm nanoparticles demonstrated a 4-fold increase in the number of particles delivered to the spheroid core compared with control nanoparticles. Thus, nanoparticle delivery to solid tumors may be substantially improved by the incorporation of ECM-modulating enzymes in the delivery formulation.
PMCID: PMC2673974  PMID: 17722554
nanoparticles; collagenase; cancer treatment; spheroids; solid tumors
25.  AlgiMatrix™ Based 3D Cell Culture System as an In-Vitro Tumor Model for Anticancer Studies 
PLoS ONE  2013;8(1):e53708.
Three-dimensional (3D) in-vitro cultures are recognized for recapitulating the physiological microenvironment and exhibiting high concordance with in-vivo conditions. Taking the advantages of 3D culture, we have developed the in-vitro tumor model for anticancer drug screening.
Cancer cells grown in 6 and 96 well AlgiMatrix™ scaffolds resulted in the formation of multicellular spheroids in the size range of 100–300 µm. Spheroids were grown in two weeks in cultures without compromising the growth characteristics. Different marketed anticancer drugs were screened by incubating them for 24 h at 7, 9 and 11 days in 3D cultures and cytotoxicity was measured by AlamarBlue® assay. Effectiveness of anticancer drug treatments were measured based on spheroid number and size distribution. Evaluation of apoptotic and anti-apoptotic markers was done by immunohistochemistry and RT-PCR. The 3D results were compared with the conventional 2D monolayer cultures. Cellular uptake studies for drug (Doxorubicin) and nanoparticle (NLC) were done using spheroids.
IC50 values for anticancer drugs were significantly higher in AlgiMatrix™ systems compared to 2D culture models. The cleaved caspase-3 expression was significantly decreased (2.09 and 2.47 folds respectively for 5-Fluorouracil and Camptothecin) in H460 spheroid cultures compared to 2D culture system. The cytotoxicity, spheroid size distribution, immunohistochemistry, RT-PCR and nanoparticle penetration data suggested that in vitro tumor models show higher resistance to anticancer drugs and supporting the fact that 3D culture is a better model for the cytotoxic evaluation of anticancer drugs in vitro.
The results from our studies are useful to develop a high throughput in vitro tumor model to study the effect of various anticancer agents and various molecular pathways affected by the anticancer drugs and formulations.
PMCID: PMC3548811  PMID: 23349734

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