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author:("circos, T")
1.  The association of statins and taxanes: an efficient combination trigger of cancer cell apoptosis 
British Journal of Cancer  2012;106(4):685-692.
Cancer cell killing might be achieved by the combined use of available drugs. Statins are major anti-hypercholesterolemia drugs, which also trigger apoptosis of many cancer cell types, while docetaxel is a potent microtubule-stabilising agent.
Here, we looked at the combined effects of lovastatin and docetaxel in cancer cells.
Whole transcriptome microarrays in HGT-1 gastric cancer cells demonstrated that lovastatin strongly suppressed expression of genes involved in cell division, while docetaxel had very little transcriptional effects. Both drugs triggered apoptosis, and their combination was more than additive. A marked rise in the cell-cycle inhibitor p21, together with reduction of aurora kinases A and B, cyclins B1 and D1 proteins was induced by lovastatin alone or in combination with docetaxel. The drug treatments induced the proteolytic cleavage of procaspase-3, a drop of the anti-apoptotic Mcl-1 protein, Poly-ADP-Ribose Polymerase and Bax. Strikingly, docetaxel-resistant HGT-1 cell derivatives overexpressing the MDR-1 gene were much more sensitive to lovastatin than docetaxel-sensitive cells.
These results suggest that the association of lovastatin and docetaxel, or lovastatin alone, shows promise as plausible anticancer strategies, either as a direct therapeutic approach or following acquired P-glycoprotein-dependent resistance.
PMCID: PMC3322964  PMID: 22294184
statins; taxanes; gastric cancer
2.  Adaptation to statins restricts human tumour growth in Nude mice 
BMC Cancer  2011;11:491.
Statins have long been used as anti-hypercholesterolemia drugs, but numerous lines of evidence suggest that they may also bear anti-tumour potential. We have recently demonstrated that it was possible to isolate cancer cells adapted to growth in the continuous presence of lovastatin. These cells grew more slowly than the statin-sensitive cells of origin. In the present study, we compared the ability of both statin-sensitive and statin-resistant cells to give rise to tumours in Nude mice.
HGT-1 human gastric cancer cells and L50 statin-resistant derivatives were injected subcutaneously into Nude mice and tumour growth was recorded. At the end of the experiment, tumours were recovered and marker proteins were analyzed by western blotting, RT-PCR and immunohistochemistry.
L50 tumours grew more slowly, showed a strong decrease in cyclin B1, over-expressed collagen IV, and had reduced laminin 332, VEGF and CD34 levels, which, collectively, may have restricted cell division, cell adhesion and neoangiogenesis.
Taken together, these results showed that statin-resistant cells developed into smaller tumours than statin-sensitive cells. This may be reflective of the cancer restricting activity of statins in humans, as suggested from several retrospective studies with subjects undergoing statin therapy for several years.
PMCID: PMC3254125  PMID: 22107808
Statins, Gastric cancer; Nude mice; Apoptosis, Angiogenesis
3.  CELF proteins regulate CFTR pre-mRNA splicing: essential role of the divergent domain of ETR-3 
Nucleic Acids Research  2010;38(20):7273-7285.
Cystic fibrosis is a prominent genetic disease caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Among the many disease-causing alterations are pre-mRNA splicing defects that can hamper mandatory exon inclusion. CFTR exon 9 splicing depends in part on a polymorphic UG(m)U(n) sequence at the end of intron 8, which can be bound by TDP-43, leading to partial exon 9 skipping. CELF proteins, like CUG-BP1 and ETR-3, can also bind UG repeats and regulate splicing. We show here that ETR-3, but not CUG-BP1, strongly stimulates exon 9 skipping, although both proteins bind efficiently to the same RNA motif as TDP-43 and with higher affinity. We further show that the skipping of this exon may be due to the functional antagonism between U2AF65 and ETR-3 binding onto the polymorphic U or UG stretch, respectively. Importantly, we demonstrate that the divergent domain of ETR-3 is critical for CFTR exon 9 skipping, as shown by deletion and domain-swapping experiments. We propose a model whereby several RNA-binding events account for the complex regulation of CFTR exon 9 inclusion, with strikingly distinct activities of ETR-3 and CUG-BP1, related to the structure of their divergent domain.
PMCID: PMC2978352  PMID: 20631008
4.  Caspase-2, a Novel Lipid Sensor under the Control of Sterol Regulatory Element Binding Protein 2†  
Molecular and Cellular Biology  2005;25(21):9621-9631.
Caspases play important roles in apoptotic cell death and in some other functions, such as cytokine maturation, inflammation, or differentiation. We show here that the 5′-flanking region of the human CASP-2 gene contains three functional response elements for sterol regulatory element binding proteins (SREBPs), proteins that mediate the transcriptional activation of genes involved in cholesterol, triacylglycerol, and fatty acid synthesis. Exposure of several human cell lines to statins, lipid-lowering drugs that drive SREBP proteolytic activation, induced the CASP-2 gene to an extent similar to that for known targets of SREBP proteins. Adenoviral vector-mediated transfer of active SREBP-2 also induced expression of the CASP-2 gene and the caspase-2 protein and increased the cholesterol and triacylglycerol cellular content. These rises in lipids were strongly impaired following small interfering RNA-mediated silencing of the CASP-2 gene. Taken together, our results identify the human CASP-2 gene as a member of the SREBP-responsive gene battery that senses lipid levels in cells and raise the possibility that caspase-2 participates in the control of cholesterol and triacylglycerol levels.
PMCID: PMC1265809  PMID: 16227610
5.  Neural reconstruction methods of restoring bladder function 
Nature reviews. Urology  2015;12(2):100-118.
During the past century, diverse studies have focused on the development of surgical strategies to restore function of a decentralized bladder after spinal cord or spinal root injury via repair of the original roots or by transferring new axonal sources. The techniques included end-to-end sacral root repairs, transfer of roots from other spinal segments to sacral roots, transfer of intercostal nerves to sacral roots, transfer of various somatic nerves to the pelvic or pudendal nerve, direct reinnervation of the detrusor muscle, or creation of an artificial reflex pathway between the skin and the bladder via the central nervous system. All of these surgical techniques have demonstrated specific strengths and limitations. The findings made to date already indicate appropriate patient populations for each procedure, but a comprehensive assessment of the effectiveness of each technique to restore urinary function after bladder decentralization is required to guide future research and potential clinical application.
PMCID: PMC4324509  PMID: 25666987
6.  Unconstrained reaching modulates eye-hand coupling 
Experimental brain research  2014;232(1):211-223.
Eye-hand coordination is a crucial element of goal-directed movements. However, few studies have looked at the extent to which unconstrained movements of the eyes and hand made to targets influence each other. We studied human participants who moved either their eyes, or both their eyes and hand to one of three static or flashed targets presented in 3D space. The eyes were directed and hand located at a common start position on either the right or left side of the body. We found that the velocity and scatter of memory-guided saccades (flashed targets) differed significantly when produced in combination with a reaching movement than when produced alone. Specifically, when accompanied by a reach, peak saccadic velocities were lower than when the eye moved alone. Peak saccade velocities, as well as latencies, were also highly correlated with those for reaching movements, especially for the briefly flashed targets compared to the continuous visible target. The scatter of saccade endpoints was greater when the saccades were produced with the reaching movement than when produced without, and the size of the scatter for both saccades and reaches were weakly correlated. These findings suggest that the saccades and reaches made to 3D targets are weakly to moderately coupled both temporally and spatially, and that this is partly the result of the arm movement influencing the eye movement. Taken together this study provides further evidence that the oculomotor and arm motor systems interact above and beyond any common target representations shared by the two motor systems.
PMCID: PMC3945424  PMID: 24121521
eye-hand coordination; human; motor control; kinematics
7.  Tissue Engineering of Rat Bladder Using Marrow-Derived Mesenchymal Stem Cells and Bladder Acellular Matrix 
PLoS ONE  2014;9(12):e111966.
Bladder replacement or augmentation is required in congenital malformations or following trauma or cancer. The current surgical solution involves enterocystoplasty but is associated with high complication rates. Strategies for bladder tissue engineering are thus actively sought to address this unmet clinical need. Because of the poor efficacy of synthetic polymers, the use of bladder acellular matrix (BAM) has been proposed. Indeed when cellular components are removed from xenogenic or allogeneic bladders, the extracellular matrix scaffold thus obtained can be used alone or in combination with stem cells. In this study, we propose the use of BAM seeded with marrow-derived mesenchymal stem cells (MSCs) for bladder tissue engineering. We optimized a protocol for decellularization of bladder tissue from different species including rat, rabbit and swine. We demonstrate the use of non-ionic detergents followed by nuclease digestion results in efficient decellularization while preserving the extracellular matrix. When MSCs were seeded on acellular matrix scaffold, they remained viable and proliferative while adopting a cellular phenotype consistent with their microenvironment. Upon transplantation in rats after partial cystectomy, MSC-seeded BAM proved superior to unseeded BAM with animals recovering nearly 100% normal bladder capacity for up to six months. Histological analyses also demonstrated increased muscle regeneration.
PMCID: PMC4249849  PMID: 25437001
8.  Diffusion Tensor Imaging of Parkinson’s Disease, Atypical Parkinsonism and Essential Tremor 
Diffusion tensor imaging could be useful in characterizing movement disorders because it non-invasively examines multiple brain regions simultaneously. We report a multi-target imaging approach focused on the basal ganglia and cerebellum in Parkinson’s disease, parkinsonian variant of multiple system atrophy, progressive supranuclear palsy, essential tremor, and healthy controls. Seventy-two subjects were studied with a diffusion tensor imaging protocol at 3 Tesla. Receiver operating characteristics analysis was performed to directly compare groups. Sensitivity and specificity values were quantified for control vs. movement disorder (92% sensitivity, 88% specificity), control vs. parkinsonism (93% sensitivity, 91% specificity), Parkinson’s disease vs. atypical parkinsonism (90% sensitivity, 100% specificity), Parkinson’s disease vs. multiple system atrophy (94% sensitivity, 100% specificity), Parkinson’s disease vs. progressive supranuclear palsy (87% sensitivity, 100% specificity), multiple system atrophy vs. progressive supranuclear palsy (90% sensitivity, 100% specificity), and Parkinson’s disease vs. essential tremor (92% sensitivity, 87% specificity). The brain targets varied for each comparison, but the substantia nigra, putamen, caudate, and middle cerebellar peduncle were the most frequently selected brain regions across classifications. These results indicate that using diffusion tensor imaging of the basal ganglia and cerebellum accurately classifies subjects diagnosed with Parkinson’s disease, atypical parkinsonism, and essential tremor and clearly distinguishes them from control subjects.
PMCID: PMC3748146  PMID: 23674400
DTI; Parkinsonism; essential tremor; basal ganglia; cerebellum
9.  Study in Parkinson Disease of Exercise (SPARX): Translating high-intensity exercise from animals to humans 
Contemporary clinical trials  2013;36(1):90-98.
A burgeoning literature suggests that exercise has a therapeutic benefit in persons with Parkinson disease (PD) and in animal models of PD, especially when animals exercise at high intensity. If exercise is to be prescribed as “first-line” or “add-on” therapy in patients with PD, we must demonstrate its efficacy and dose-response effects through testing phases similar to those used in the testing of pharmacologic agents. The SPARX Trial is a multicenter, randomized, controlled, single-blinded, Phase II study that we designed to test the feasibility of using high-intensity exercise to modify symptoms of PD and to simultaneously test the nonfutility of achieving a prespecified change in patients’ motor scores on the Unified Parkinson Disease Rating Scale (UPDRS). The trial began in May 2102 and is in the process of screening, enrolling, and randomly assigning 126 patients with early-stage PD to 1 of 3 groups: usual care (wait-listed controls), moderate-intensity exercise (4 days/week at 60%–65% maximal heart rate [HRmax]), or high-intensity exercise (4 days/week at 80%–85% HRmax). At 6-month follow-up, the trial is randomly reassigning usual care participants to a moderate-intensity or high-intensity exercise group for the remaining 6 months. The goals of the Phase II trial are to determine if participants can exercise at moderate and high intensities; to determine if either exercise yields benefits consistent with meaningful clinical change (nonfutility); and to document safety and attrition. The advantage of using a non-futility approach allows us to efficiently determine if moderate- or high-intensity exercise warrants further large-scale investigation in PD.
PMCID: PMC3769494  PMID: 23770108
Parkinson disease; exercise; futility; Phase II; randomized controlled trial; Unified Parkinson Disease Rating Scale
10.  Dabigatran etixilate and traumatic brain injury: Evolving anticoagulants require evolving care plans 
AIM: To investigate the outcomes of trauma patients with traumatic brain injury (TBI) on Dabigatran Etexilate (DE).
METHODS: Following IRB approval, all patients taking DE who were admitted to our level 1 trauma service were enrolled in the study. Injury complexity, length of stay (LOS), intensive care length of stay, operative intervention, therapeutic interventions and outcomes were analyzed retrospectively.
RESULTS: Twenty-eight of 4310 admissions were taking DE. Eleven patients were excluded on concurrent antiplatelet therapy. Average age was 77.14 years (64-94 years), and average LOS was 4.7 d (1-35 d). Thirty-two percent were admitted with intracranial hemorrhage. Eighteen percent received factor VII, and 22% received dialysis in attempts to correct coagulopathy. Mortality was 21%.
CONCLUSION: The low incidence, absence of reversal agents, and lack of practice guidelines makes managing patients with TBI taking DE frustrating and provider specific. Local practice guidelines may be helpful in managing such patients.
PMCID: PMC4133427  PMID: 25133148
Dabigatran; Brain injury; Anticoagulation; Dabigatran reversal
11.  A Two Year Randomized Controlled Trial of Progressive Resistance Exercise for Parkinson’s Disease 
The effects of progressive resistance exercise (PRE) on the motor signs of Parkinson’s disease have not been studied in controlled trials. Our aim was to compare 6, 12, 18, and 24 month outcomes of patients with Parkinson’s disease who received PRE to a stretching, balance, and strengthening exercise program.
We conducted a randomized controlled trial between September 2007 and July 2011. Pairs of patients, matched by sex and off-medication Unified Parkinson’s Disease Rating Scale, motor subscale (UPDRS-III), were randomly assigned to the interventions with a 1:1 allocation ratio. The PRE group performed a weight lifting program. The Modified Fitness Counts (mFC) group performed a stretching, balance, and strengthening exercise program. Patients exercised two days per week for 24 months at a gym. A personal trainer directed both weekly sessions for the first six months and one weekly session after six months. The primary outcome was the off-medication UPDRS-III score. Patients were followed for 24 months at six-month intervals.
Of 51 patients, 20 in PRE and 18 in mFC completed the trial. At 24 months, the mean off-medication UPDRS-III score decreased more with PRE than with mFC (mean difference: - 7·3 points; 95% CI: -11·3 to -3·6; P < 0·001). The PRE group had ten adverse events. The mFC group had seven adverse events.
PRE demonstrated a statistically and clinically significant reduction in UPDRS-III scores compared to mFC and is recommended as a useful adjunct therapy to improve Parkinsonian motor signs.
PMCID: PMC3701730  PMID: 23536417
Parkinson’s disease; progressive resistance exercise; strength training; randomized controlled trial; Unified Parkinson’s Disease Rating Scale motor subscale (UPDRS-III)
12.  Incontinence after radical prostatectomy: Anything new in its management? 
With the increasing number of radical prostatectomies (RP) performed, male stress urinary incontinence (SUI) has become common. The artificial urinary sphincter (AUS) is the gold standard to treat SUI post-RP, but new devices have recently been developed. We review the recent studies on the treatment of SUI post-RP; we also describe the surgical techniques, mechanisms of action and results of these new procedures.
We conducted a literature review search in the PubMed/Medline and Embase databases. Our search was restricted to recent articles. We included studies even if the urinary incontinence was due to sphincter deficiency after RP in non-neurologic patients.
We found 8 cohort studies for the surgical procedure: 3 studies concerning slings, 1 involving balloons adjustable implant, and 4 involving new devices. The only randomized controlled trial (RCT) was a pharmacologic clinical trial comparing duloxetine to placebo. The social continence rates were analyzed for 6 studies and were up to 66%.
New minimally invasive surgical procedures have emerged as the main alternative to AUS, with social continence rates up to 60% despite just 1 RCT studying the pharmacologic approach. There is an urgent need for well-designed clinical trials to clarify the role of new surgical alternatives in the management of SUI post-RP. New technologies should continue to be evaluated and compared with the AUS, which remains the gold standard.
PMCID: PMC4081251  PMID: 25024791
13.  A Gene Expression and Pre-mRNA Splicing Signature That Marks the Adenoma-Adenocarcinoma Progression in Colorectal Cancer 
PLoS ONE  2014;9(2):e87761.
It is widely accepted that most colorectal cancers (CRCs) arise from colorectal adenomas (CRAs), but transcriptomic data characterizing the progression from colorectal normal mucosa to adenoma, and then to adenocarcinoma are scarce. These transition steps were investigated using microarrays, both at the level of gene expression and alternative pre-mRNA splicing. Many genes and exons were abnormally expressed in CRAs, even more than in CRCs, as compared to normal mucosae. Known biological pathways involved in CRC were altered in CRA, but several new enriched pathways were also recognized, such as the complement and coagulation cascades. We also identified four intersectional transcriptional signatures that could distinguish CRAs from normal mucosae or CRCs, including a signature of 40 genes differentially deregulated in both CRA and CRC samples. A majority of these genes had been described in different cancers, including FBLN1 or INHBA, but only a few in CRC. Several of these changes were also observed at the protein level. In addition, 20% of these genes (i.e. CFH, CRYAB, DPT, FBLN1, ITIH5, NR3C2, SLIT3 and TIMP1) showed altered pre-mRNA splicing in CRAs. As a global variation occurring since the CRA stage, and maintained in CRC, the expression and splicing changes of this 40-gene set may mark the risk of cancer occurrence from analysis of CRA biopsies.
PMCID: PMC3916340  PMID: 24516561
14.  A dedicated microarray for in-depth analysis of pre-mRNA splicing events: application to the study of genes involved in the response to targeted anticancer therapies 
Molecular Cancer  2014;13:9.
Alternative pre-mRNA splicing (AS) widely expands proteome diversity through the combinatorial assembly of exons. The analysis of AS on a large scale, by using splice-sensitive microarrays, is a highly efficient method to detect the majority of known and predicted alternative transcripts for a given gene. The response to targeted anticancer therapies cannot easily be anticipated without prior knowledge of the expression, by the tumor, of target proteins or genes. To analyze, in depth, transcript structure and levels for genes involved in these responses, including AKT1-3, HER1-4, HIF1A, PIK3CA, PIK3R1-2, VEGFA-D and PIR, we engineered a dedicated gene chip with coverage of an average 185 probes per gene and, especially, exon-exon junction probes. As a proof of concept, we demonstrated the ability of such a chip to detect the effects of over-expressed SRSF2 RNA binding protein on the structure and abundance of mRNA products in H358 lung cancer cells conditionally over-expressing SRSF2. Major splicing changes were observed, including in HER1/EGFR pre-mRNA, which were also seen in human lung cancer samples over-expressing the SRSF2 protein. In addition, we showed that variations in HER1/EGFR pre-mRNA splicing triggered by SRSF2 overexpression in H358 cells resulted in a drop in HER1/EGFR protein level, which correlated with increased sensitivity to gefitinib, an EGFR tyrosine kinase inhibitor. We propose, therefore, that this novel tool could be especially relevant for clinical applications, with the aim to predict the response before treatment.
PMCID: PMC3899606  PMID: 24428911
DNA chip; Targeted anticancer therapies; Pre-mRNA splicing; SRSF2
15.  Botulinum neurotoxin–A treatment of lower urinary tract symptoms in multiple sclerosis 
Multiple sclerosis (MS) is the most common neuroinflammatory disease of the central nervous system and a leading cause of disability in young adults. Symptoms related to vesicourethral dysfunction are very prevalent, but not specific to underlying urodynamic abnormalities. Detrusor overactivity and detrusor external sphincter dysynergia are the most frequent findings and are usually linked. Botulinum neurotoxin-A injection represents a significant advance in the management of voiding dysfunction among MS patients failing first-line therapy. It significantly improves patients’ urodynamic parameters and quality of life, with efficacy sustained by repeated injections and minimal risk of adverse events.
PMCID: PMC3896564  PMID: 24454606
16.  Living from Day to Day – Qualitative Study on Borderline Personality Disorder in Adolescence 
The purpose of this study was to assess how far identity and self-image disturbances are features of borderline personality disorder (BPD) in adolescence.
Face-to-face interviews were carried out with a total of 50 adolescents with BPD and 50 controls, with a median age of 16 (SD 1.1; range 13 to 18) years. Data was analysed using a qualitative methodology, interpretative phenomenological analysis (IPA). Thematic statements representative of adolescents’ lived experience were extracted from the interviews.
Four main themes representing the day-to-day experiences of adolescents with BPD were identified: emotional experiences characterised by the feelings of fear, sadness and pessimism; interpersonal relationships characterised by the feelings of solitude and hostility from others; a conformist self-image characterised by a feeling of normality and difficulty in projecting into time; and, a structuring of discourse characterised by discontinuity in the perception of experiences.
This qualitative study suggests that the day-to-day experiences of adolescents with borderline personality disorder is centred on the experience of the present. Discontinuity in self-image, alongside marked dysphoric manifestations, leads to distress and hinders compliance with care. These issues are highly relevant in psychotherapy and could lead to more effective treatment of the disorder in adolescents.
PMCID: PMC3825468  PMID: 24223047
borderline personality disorder; adolescence; qualitative research; self-image; trouble de la personnalité borderline; adolescence; recherche qualitative; image de soi
17.  Intratumor heterogeneity characterized by textural features on baseline 18F-FDG PET images predicts response to concomitant radiochemotherapy in esophageal cancer 
Journal of Nuclear Medicine  2011;52(3):369-378.
18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) is often used in clinical routine for diagnosis, staging and response to therapy assessment or prediction. The Standardized Uptake Value (SUV) in the primary or regional area is the most common quantitative measurement derived from PET images used for those purposes. The aim of this study was to propose and evaluate new parameters obtained by textural analysis of baseline PET scans for the prediction of therapy response in esophageal cancer. Methods: 41 patients with a newly diagnosed esophageal cancer treated with combined radio-chemotherapy were included in this study. All patients underwent a pretreatment whole-body 18F-FDG PET scan. Patients were treated with radiotherapy and alkylatin-like agents (5FU-cisplatin or 5FU-carboplatin). Patients were classified as non-responders (NR: progressive or stable disease), partial-responders (PR) or complete-responders (CR) according to RECIST criteria. Different image derived indices obtained from the pretreatment PET tumor images were considered. These included usual indices such as SUVmax, SUVpeak, SUVmean, and a total of 38 features (such as for example entropy, size and magnitude of local and global heterogeneous and homogeneous tumor regions) extracted from the five different textures considered. The capacity of each parameter to classify patients with respect to response to therapy was assessed using the Kruskal-Wallis test (p-value < 0.05). Specificity and sensitivity (including 95% confidence intervals) for each of the studied parameters were derived using Receiver Operating Characteristic (ROC) curves. Results: Relationships between pairs of voxels, characterizing local tumor metabolic non-uniformities, were able to significantly differentiate all three patient groups (p<0.0006). Regional measures of tumor characteristics, such as size of non-uniform metabolic regions and corresponding intensity non-uniformities within these regions, were also significant factors for prediction to therapy (p=0.0002). ROC curve analysis showed that tumor textural analysis can provide NR, PR and CR patient identification with higher sensitivity (76%–92%) than any SUV measurement.
Textural features of tumor metabolic distribution extracted from baseline 18F-FDG PET images allow for the best stratification of esophageal carcinoma patient in the context of therapy response prediction.
PMCID: PMC3789272  PMID: 21321270
Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; therapeutic use; Carboplatin; administration & dosage; Cisplatin; administration & dosage; Combined Modality Therapy; Esophageal Neoplasms; radionuclide imaging; therapy; Female; Fluorodeoxyglucose F18; diagnostic use; Fluorouracil; administration & dosage; Humans; Image Enhancement; methods; Image Interpretation, Computer-Assisted; Male; Middle Aged; Positron-Emission Tomography; Prognosis; Radiopharmaceuticals; diagnostic use; Radiotherapy, Conformal; Reproducibility of Results; Sensitivity and Specificity; Treatment Outcome; 18F-FDG PET; esophageal cancer; texture analysis; predictive value; response to therapy
18.  Reproducibility of tumor uptake heterogeneity characterization through textural feature analysis in 18F-FDG PET 
Journal of Nuclear Medicine  2012;53(5):693-700.
18F-FDG PET measurement of standardized uptake values (SUV) is increasingly used for monitoring therapy response or predicting outcome. Alternative parameters computed through textural analysis were recently proposed to quantify the tumor tracer uptake heterogeneity as significant predictors of response. The primary objective of this study was the evaluation of the reproducibility of these heterogeneity measurements.
Double-baseline 18F-FDG PET scans of 16 patients acquired within a period of 4 days prior to any treatment were considered. A Bland-Altman analysis was carried out on six parameters based on histogram measurements and 17 heterogeneity parameters based on textural features obtained after discretization with values between 8 and 128.
SUVmax and SUVmean reproducibility were similar to previously reported studies with a mean percentage difference of 4.7±19.5% and 5.5±21.2% respectively. By comparison better reproducibility was measured for some of the textural features describing tumor tracer local heterogeneity, such as entropy and homogeneity with a mean percentage difference of −2±5.4% and 1.8±11.5% respectively. Several of the tumor regional heterogeneity parameters such as the variability in the intensity and size of homogeneous tumor activity distribution regions had similar reproducibility to the SUV measurements with 95% confidence intervals of −22.5% to 3.1% and −1.1% to 23.5% respectively. These parameters were largely insensitive to the discretization range values.
Several of the parameters derived from textural analysis describing tumor tracer heterogeneity at local and regional scales had similar or better reproducibility as simple SUV measurements. These reproducibility results suggest that these FDG PET image derived parameters which have already been shown to have a predictive and prognostic value in certain cancer models, may be used within the context of therapy response monitoring or predicting patient outcome.
PMCID: PMC3779464  PMID: 22454484
Biological Transport; Esophageal Neoplasms; metabolism; radionuclide imaging; therapy; Fluorodeoxyglucose F18; diagnostic use; metabolism; Image Processing, Computer-Assisted; methods; Positron-Emission Tomography; methods; Reproducibility of Results; Retrospective Studies; Treatment Outcome
19.  A urological challenge: Voiding dysfunction in multiple sclerosis 
Canadian Urological Association Journal  2013;7(9-10 Suppl 4):S181-S182.
Patients with multiple sclerosis (MS) have a very high prevalence of lower urinary tract symptoms. This summary provides a brief overview of MS epidemiology, pathophysiology, the impact of the disease on patient quality of life, and the particular kinds of urinary tract abnormalities and symptoms that can present among patients with MS. Strategies to help diminish the impact of these symptoms are also discussed.
PMCID: PMC3919189  PMID: 24523839
20.  Toward a universal treatment for cancer: cell inflation assisted chemotherapy 
Cancer Medicine  2013;2(4):421-426.
Cancers show considerable genetic and functional heterogeneity, preventing the development of a universal anticancer drug. Here, I argue that it is nevertheless possible to elaborate a therapeutic strategy that can be used in almost every cancer, exploiting the negative feedback effect of normal cells on the proliferation of their precursors. This method, termed cell inflation assisted chemotherapy, is aimed at blocking normal cell division prior to high-dose antimitotic chemotherapy. Evidence for a negative feedback effect on granulocyte production suggests that it is possible to prevent neutropenia by transfusion of autologous granulocytes. In a first step, this protocol will be devised to protect neutrophils and to prevent granulopenia in patients treated with intensive chemotherapy. In its simplest form, it will consist of a leukapheresis–storage–reinjection sequence just prior to drug administration. Then, if the proof of concept is established, a more systematic use of intensive cell cycle-specific chemotherapy, together with protection of other lineages through temporary mitotic blockade might be a treatment applicable for most cancers.
Negative feedback effect of normal cells on the proliferation of their precursors may be used to protect them from high-dose antimitotic chemotherapy, preventing myelosuppression. In its simplest form, cell inflation assisted chemotherapy will consist of a leukapheresis-storage-reinjection sequence just prior to drug administration.
PMCID: PMC3799276  PMID: 24156014
Cancer chemotherapy; granulocytes; myelosuppression; negative feedback
21.  Thalamic projection fiber integrity in de novo Parkinson’s disease 
Background and Purpose
Post-mortem studies of advanced Parkinson’s disease (PD) have revealed disease-related pathology in the thalamus with an apparent predilection for specific thalamic nuclei. In the present study, we used diffusion tensor imaging (DTI) to investigate in vivo the microstructural integrity of six thalamic regions in de novo PD patients relative to healthy controls.
Materials and Methods
Forty subjects (20 with early-stage, untreated PD and 20 age- and sex-matched controls) were studied with a high-resolution DTI protocol at 3 Tesla to investigate the integrity of thalamic nuclei projection fibers. Two blinded, independent raters drew regions of interest (ROIs) in the following six thalamic regions: anterior nucleus (AN), ventral anterior nucleus (VA), ventral lateral nucleus (VL), dorsomedial nucleus (DM), ventral posterior lateral nucleus (VPL)/ventral posterior medial nucleus (VPM), and pulvinar (PU). Fractional anisotropy (FA) values were then calculated from the projection fibers in each region.
FA values were reduced significantly in the fibers projecting from the AN, VA, and DM, but not the VPL/VPM and PU, in the PD group compared to the control group. In addition, there was a reduction in FA values that approached significance in the VL of PD patients. These findings were consistent across both raters.
The present study provides preliminary in vivo evidence of thalamic projection fiber degeneration in de novo PD and sheds light on the extent of disrupted thalamic circuitry as a result of the disease itself.
PMCID: PMC3669594  PMID: 22766668
Parkinson’s disease; thalamus; diffusion tensor imaging; tractography; fractional anisotropy; magnetic resonance imaging
22.  Glucose-Reducing Effect of the ORMD-0801 Oral Insulin Preparation in Patients with Uncontrolled Type 1 Diabetes: A Pilot Study 
PLoS ONE  2013;8(4):e59524.
The unpredictable behavior of uncontrolled type 1 diabetes often involves frequent swings in blood glucose levels that impact maintenance of a daily routine. An intensified insulin regimen is often unsuccessful, while other therapeutic options, such as amylin analog injections, use of continuous glucose sensors, and islet or pancreas transplantation are of limited clinical use. In efforts to provide patients with a more compliable treatment method, Oramed Pharmaceuticals tested the capacity of its oral insulin capsule (ORMD-0801, 8 mg insulin) in addressing this resistant clinical state. Eight Type I diabetes patients with uncontrolled diabetes (HbA1c: 7.5–10%) were monitored throughout the 15-day study period by means of a blind continuous glucose monitoring device. Baseline patient blood glucose behavior was monitored and recorded over a five-day pretreatment screening period. During the ensuing ten-day treatment phase, patients were asked to conduct themselves as usual and to self-administer an oral insulin capsule three times daily, just prior to meal intake. CGM data sufficient for pharmacodynamics analyses were obtained from 6 of the 8 subjects. Treatment with ORMD-0801 was associated with a significant 24.4% reduction in the frequencies of glucose readings >200 mg/dL (60.1±7.9% pretreatment vs. 45.4±4.9% during ORMD-0801 treatment; p = 0.023) and a significant mean 16.6% decrease in glucose area under the curve (AUC) (66055±5547 mg/dL/24 hours vs. 55060±3068 mg/dL/24 hours, p = 0.023), with a greater decrease during the early evening hours. In conclusion, ORMD-0801 oral insulin capsules in conjunction with subcutaneous insulin injections, well tolerated and effectively reduced glycemia throughout the day.
Trial Registration NCT00867594.
PMCID: PMC3622027  PMID: 23593142
23.  Force Control Deficits in Individuals with Parkinson’s Disease, Multiple Systems Atrophy, and Progressive Supranuclear Palsy 
PLoS ONE  2013;8(3):e58403.
This study examined grip force and cognition in Parkinson’s disease (PD), Parkinsonian variant of multiple system atrophy (MSAp), progressive supranuclear palsy (PSP), and healthy controls. PD is characterized by a slower rate of force increase and decrease and the production of abnormally large grip forces. Early-stage PD has difficulty with the rapid contraction and relaxation of hand muscles required for precision gripping. The first goal was to determine which features of grip force are abnormal in MSAp and PSP. The second goal was to determine whether a single variable or a combination of motor and cognitive measures would distinguish patient groups. Since PSP is more cognitively impaired relative to PD and MSAp, we expected that combining motor and cognitive measures would further distinguish PSP from PD and MSAp.
We studied 44 participants: 12 PD, 12 MSAp, 8 PSP, and 12 controls. Patients were diagnosed by a movement disorders neurologist and were tested off anti-Parkinsonian medication. Participants completed a visually guided grip force task wherein force pulses were produced for 2 s, followed by 1 s of rest. We also conducted four cognitive tests.
PD, MSAp, and PSP were slower at contracting and relaxing force and produced longer pulse durations compared to controls. PSP produced additional force pulses during the task and were more cognitively impaired relative to other groups. A receiver operator characteristic analysis revealed that the combination of number of pulses and Brief Test of Attention (BTA) discriminated PSP from PD, MSAp, and controls with a high degree of sensitivity and specificity.
Slowness in contracting and relaxing force represent general features of PD, MSAp, and PSP, whereas producing additional force pulses was specific to PSP. Combining motor and cognitive measures provides a robust method for characterizing behavioral features of PSP compared to MSAp and PD.
PMCID: PMC3594313  PMID: 23505500
24.  Faecal D/L Lactate Ratio Is a Metabolic Signature of Microbiota Imbalance in Patients with Short Bowel Syndrome 
PLoS ONE  2013;8(1):e54335.
Our objective was to understand the functional link between the composition of faecal microbiota and the clinical characteristics of adults with short bowel syndrome (SBS).
Sixteen patients suffering from type II SBS were included in the study. They displayed a total oral intake of 2661±1005 Kcal/day with superior sugar absorption (83±12%) than protein (42±13%) or fat (39±26%). These patients displayed a marked dysbiosis in faecal microbiota, with a predominance of Lactobacillus/Leuconostoc group, while Clostridium and Bacteroides were under-represented. Each patient exhibited a diverse lactic acid bacteria composition (L. delbrueckii subsp. bulgaricus, L. crispatus, L. gasseri, L. johnsonii, L. reuteri, L. mucosae), displaying specific D and L-lactate production profiles in vitro. Of 16 patients, 9/16 (56%) accumulated lactates in their faecal samples, from 2 to 110 mM of D-lactate and from 2 to 80 mM of L-lactate. The presence of lactates in faeces (56% patients) was used to define the Lactate-accumulator group (LA), while absence of faecal lactates (44% patients) defines the Non lactate-accumulator group (NLA). The LA group had a lower plasma HCO3− concentration (17.1±2.8 mM) than the NLA group (22.8±4.6 mM), indicating that LA and NLA groups are clinically relevant sub–types. Two patients, belonging to the LA group and who particularly accumulated faecal D-lactate, were at risk of D-encephalopathic reactions. Furthermore, all patients of the NLA group and those accumulating preferentially L isoform in the LA group had never developed D-acidosis. The D/L faecal lactate ratio seems to be the most relevant index for a higher D- encephalopathy risk, rather than D- and L-lactate faecal concentrations per se. Testing criteria that take into account HCO3− value, total faecal lactate and the faecal D/L lactate ratio may become useful tools for identifying SBS patients at risk for D-encephalopathy.
PMCID: PMC3553129  PMID: 23372709
25.  Specific cerebellar regions are related to force amplitude and rate of force development 
NeuroImage  2011;59(2):1647-1656.
The human cerebellum has been implicated in the control of a wide variety of motor control parameters, such as force amplitude, movement extent, and movement velocity. These parameters often covary in both movement and isometric force production tasks, so it is difficult to resolve whether specific regions of the cerebellum relate to specific parameters. In order to address this issue, the current study used two experiments and SUIT normalization to determine whether BOLD activation in the cerebellum scales with the amplitude or rate of change of isometric force production or both. In the first experiment, subjects produced isometric pinch-grip force over a range of force amplitudes without any constraints on the rate of force development. In the second experiment, subjects varied the rate of force production, but the target force amplitude remained constant. The data demonstrate that BOLD activation in separate sub-areas of cerebellar regions lobule VI and Crus I/II scale with both force amplitude and force rate. In addition, BOLD activation in cerebellar lobule V and vermis VI was specific to force amplitude, whereas BOLD activation in lobule VIIb was specific to force rate. Overall, cerebellar activity related to force amplitude was located superior and medial, whereas activity related to force rate was inferior and lateral. These findings suggest that specific circuitry in the cerebellum may be dedicated to specific motor control parameters such as force amplitude and force rate.
PMCID: PMC3230677  PMID: 21963915
BOLD; Cerebellum; fMRI; Isometric

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