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PDF file - 119K, TRPM7 expression measurements on TRPM7 knockdown MDA-MB-231 and MCF7 cells and TRPM7 rescued cells

PDF file - 92K, Patient- and tumor characteristics in discovery and validation cohort

PDF file - 114K, Uncropped immunoblots and autoradiograms

PDF file - 54K, TRPM7 shRNA#2 treatment reduces malignant phenotype of MDA-MB-231 cells

PDF file - 643K, Rho-kinase inhibition rescues contractile and migratory phenotype of TRPM7 shRNA cells

PDF file - 3.9MB, TRPM7 knockdown does not affect MDA-MB-231 cell proliferation but impairs metastasis formation in vivo

TRPM7 encodes a Ca2+-permeable nonselective cation channel with kinase activity. TRPM7 has been implicated in control of cell adhesion and migration, but whether TRPM7 activity contributes to cancer progression has not been established. Here we report that high levels of TRPM7 expression independently predict poor outcome in breast cancer patients and that it is functionally required for metastasis formation in a mouse xenograft model of human breast cancer. Mechanistic investigation revealed that TRPM7 regulated myosin II–based cellular tension, thereby modifying focal adhesion number, cell–cell adhesion and polarized cell movement. Our findings therefore suggest that TRPM7 is part of a mechanosensory complex adopted by cancer cells to drive metastasis formation. Cancer Res; 72(16); 4250–61. ©2012 AACR.

PDF file - 96K, TRPM7 expression levels and clinical parameters

This non-interventional post-authorisation safety study (PASS) assessed the long-term safety of everolimus in patients with tuberous sclerosis complex (TSC) who participated in the TuberOus SClerosis registry to increase disease Awareness (TOSCA) clinical study and received everolimus for the licensed indications in the European Union. The rate of adverse events (AEs), AEs that led to dose adjustments or treatment discontinuation, AEs of potential clinical interest, treatment-related AEs (TRAEs), serious AEs (SAEs), and deaths were documented. One hundred seventy-nine patients were included in the first 5 years of observation; 118 of 179 patients had an AE of any grade, with the most common AEs being stomatitis (7.8%) and headache (7.3%). AEs caused dose adjustments in 56 patients (31.3%) and treatment discontinuation in nine patients (5%). AEs appeared to be more frequent and severe in children. On Tanner staging, all patients displayed signs of age-appropriate sexual maturation. Twenty-two of 106 female (20.8%) patients had menstrual cycle disorders. The most frequent TRAEs were stomatitis (6.7%) and aphthous mouth ulcer (5.6%). SAEs were reported in 54 patients (30.2%); the most frequent SAE was pneumonia (>3% patients; grade 2, 1.1%, and grade 3, 2.8%). Three deaths were reported, all in patients who had discontinued everolimus for more than 28 days, and none were thought to be related to everolimus according to the treating physicians. The PASS sub-study reflects the safety and tolerability of everolimus in the management of TSC in real-world routine clinical practice.

Background: Knowledge is increasing about TSC-Associated Neuropsychiatric Disorders (TAND), but little is known about the potentially confounding effects of intellectual ability (IA) on the rates of TAND across age, sex, and genotype. We evaluated TAND in (a) children vs. adults, (b) males vs. females, and (c) TSC1 vs. TSC2 mutations, after stratification for levels of IA, in a large, international cohort. Methods: Individuals of any age with a documented visit for TSC in the 12 months prior to enrolment were included. Frequency and percentages of baseline TAND manifestations were presented by categories of IA (no intellectual disability [ID, intelligence quotient (IQ)>70]; mild ID [IQ 50-70]; moderate-to-profound ID [IQ

Renal angiomyolipomas are one of the most common renal manifestations in patients with tuberous sclerosis complex (TSC), with potentially life-threatening complications and a poor prognosis. Despite the considerable progress in understanding TSC-associated renal angiomyolipomas, there are no large scale real-world data. The aim of our present study was to describe in detail the prevalence and outcome of renal angiomyolipomas in patients with TSC, enrolled into the TuberOus SClerosis registry to increase disease Awareness (TOSCA) from 170 sites across 31 countries worldwide. We also sought to evaluate the relationship of TSC-associated renal angiomyolipomas with age, gender and genotype. The potential risk factors for renal angiomyolipoma-related bleeding and chronic kidney disease (CKD) were studied in patients who participated in the TOSCA renal angiomyolipoma substudy. Of the 2,211 eligible patients, 1,062 (48%) reported a history of renal angiomyolipomas. The median age of TSC diagnosis for the all subjects (n = 2,211) was 1 year. The median age of diagnosis of renal angiomyolipoma in the 1,062 patients was 13 years. Renal angiomyolipomas were significantly more prevalent in female patients (p < 0.0001). Rates of angiomyolipomas >3 cm (p = 0.0119), growing lesions (p = 0.0439), and interventions for angiomyolipomas (p = 0.0058) were also higher in females than males. Pre-emptive intervention for renal angiomyolipomas with embolisation, surgery, or mammalian target of rapamycin (mTOR) inhibitor may have abolished the gender difference in impaired renal function, hypertension, and other complications. The rate of interventions for angiomyolipomas was less common in children than in adults, but interventions were reported in all age groups. In the substudy of 76 patients the complication rate was too low to be useful in predicting risk for more severe CKD. In addition, in this substudy no patient had a renal hemorrhage after commencing on an mTOR inhibitor. Our findings confirmed that renal angiomyolipomas in subjects with TSC1 mutations develop on average at the later age, are relatively smaller in size and less likely to be growing; however, by age 40 years, no difference was observed in the percentage of patients with TSC1 and TSC2 mutations needing intervention. The peak of appearance of new renal angiomyolipomas was observed in patients aged between 18 and 40 years, but, given that angiomyolipomas can occur later, lifelong surveillance is necessary. We found that pre-emptive intervention was dramatically successful in altering the outcome compared to historical controls; with high pre-emptive intervention rates but low rates of bleeding and other complications. This validates the policy of surveillance and pre-emptive intervention recommended by clinical guidelines. © Copyright © 2020 Kingswood, Belousova, Benedik, Carter, Cottin, Curatolo, Dahlin, D'Amato, Beaure d'Augères, de Vries, Ferreira, Feucht, Fladrowski, Hertzberg, Jozwiak, Lawson, Macaya, Marques, Nabbout, O'Callaghan, Qin, Sander, Shah, Takahashi, Touraine, Youroukos, Zonnenberg, Jansen and Sauter.

The onset and growth of subependymal giant cell astrocytoma (SEGA) in tuberous sclerosis complex (TSC) typically occurs in childhood. There is minimal information on SEGA evolution in adults with TSC. Of 2,211 patients enrolled in TOSCA, 220 of the 803 adults (27.4%) ever had a SEGA. Of 186 patients with SEGA still ongoing in adulthood, 153 (82.3%) remained asymptomatic, and 33 (17.7%) were reported to ever have developed symptoms related to SEGA growth. SEGA growth since the previous scan was reported in 39 of the 186 adults (21%) with ongoing SEGA. All but one patient with growing SEGA had mutations in TSC2. Fourteen adults (2.4%) were newly diagnosed with SEGA during follow-up, and majority had mutations in TSC2. Our findings suggest that surveillance for new or growing SEGA is warranted also in adulthood, particularly in patients with mutations in TSC2. © 2019 Jansen, Belousova, Benedik, Carter, Cottin, Curatolo, D'Amato, Beaure d'Augères, de Vries, Ferreira, Feucht, Fladrowski, Hertzberg, Jozwiak, Lawson, Macaya, Marques, Nabbout, O'Callaghan, Qin, Sander, Sauter, Shah, Takahashi, Touraine, Youroukos, Zonnenberg and Kingswood.

Summary Objective To present the baseline data of the international TuberOus SClerosis registry to increase disease Awareness (TOSCA) with emphasis on the characteristics of epilepsies associated with tuberous sclerosis complex (TSC). Methods Retrospective and prospective patients’ data on all aspects of TSC were collected from multiple countries worldwide. Epilepsy variables included seizure type, age at onset, type of treatment, and treatment outcomes and association with genotype, seizures control, and intellectual disability. As for noninterventional registries, the study protocol did not specify any particular clinical instruments, laboratory investigations, or intervention. Evaluations included those required for diagnosis and management following local best practice. Results Epilepsy was reported in 83.6% of patients (1852/2216) at baseline; 38.9% presented with infantile spasms and 67.5% with focal seizures. The mean age at diagnosis of infantile spasms was 0.4 year (median

OBJECTIVES: To investigate whether a low peripheral blood lymphocyte count is associated with increased mortality risk in older persons and to determine whether this association could be ascribed to ill health. DESIGN: A cohort study with a total follow-up period of 1,602 person years. SETTING: Leiden, the Netherlands. PARTICIPANTS: Four hundred thirty-six community-dwelling residents aged 85 and older. MEASUREMENTS: Health status and leukocyte total and differential counts were assessed at baseline. Lymphocyte subsets were measured with a fluorescence-activated cell sorter. Age- and sex-adjusted mortality risks were estimated using Cox proportional hazard regression analysis. RESULTS: There was no association between lymphocyte count and mortality in persons with ill health (mortality risk lowest vs highest quartile = 1.16; 95% confidence interval (CI) = 0.85-1.58, P = .35), but mortality was dependent on lymphocyte count if disease was excluded (mortality risk lowest vs highest quartile = 2.14; 95% CI = 1.08-4.23, P = .03). A similar increase in mortality risk was found when the cluster designation (CD)4(+), CD8(+), and CD16(+) lymphocyte subsets were analyzed. Within individuals, low values of the lymphocyte subsets were related and there was no compensatory increase in CD16(+) lymphocyte counts. A low lymphocyte count was not associated with specific causes of death. CONCLUSION: A low lymphocyte count was associated with an increased mortality risk in older persons without apparent disease. This association was not only found for the total lymphocyte count but also for the CD4(+), CD8(+), and CD16(+) lymphocyte subset counts.

Although structural brain alterations in schizophrenia have been demonstrated extensively, their quantitative distribution has not been studied over the last 14 years despite advances in neuroimaging. Moreover, a volumetric meta-analysis has not been conducted in antipsychotic-naive patients. Therefore, meta-analysis on cross-sectional volumetric brain alterations in both medicated and antipsychotic-naive patients was conducted. Three hundred seventeen studies published from September 1, 1998 to January 1, 2012 comprising over 9000 patients were selected for meta-analysis, including 33 studies in antipsychotic-naive patients. In addition to effect sizes, potential modifying factors such as duration of illness, sex composition, current antipsychotic dose, and intelligence quotient matching status of participants were extracted where available. In the sample of medicated schizophrenia patients (n = 8327), intracranial and total brain volume was significantly decreased by 2.0% (effect size d = -0.17) and 2.6% (d = -0.30), respectively. Largest effect sizes were observed for gray matter structures, with effect sizes ranging from -0.22 to -0.58. In the sample of antipsychotic-naive patients (n = 771), volume reductions in caudate nucleus (d = -0.38) and thalamus (d = -0.68) were more pronounced than in medicated patients. White matter volume was decreased to a similar extent in both groups, while gray matter loss was less extensive in antipsychotic-naive patients. Gray matter reduction was associated with longer duration of illness and higher dose of antipsychotic medication at time of scanning. Therefore, brain loss in schizophrenia is related to a combination of (early) neurodevelopmental processes-reflected in intracranial volume reduction-as well as illness progression.

The long-standing notion of schizophrenia as a disorder of connectivity is supported by emerging evidence from recent neuroimaging studies, suggesting impairments of both structural and functional connectivity in schizophrenia. However, investigations are generally restricted to supratentorial brain regions, thereby excluding the cerebellum. As increasing evidence suggests that the cerebellum contributes to cognitive and affective processing, aberrant connectivity in schizophrenia may include cerebellar dysconnectivity. Moreover, as schizophrenia is highly heritable, unaffected family members of schizophrenia patients may exhibit similar connectivity profiles. The present study applies resting-state functional magnetic resonance imaging to determine cerebellar functional connectivity profiles, and the familial component of cerebellar connectivity profiles, in 62 schizophrenia patients and 67 siblings of schizophrenia patients. Compared to healthy control subjects, schizophrenia patients showed impaired functional connectivity between the cerebellum and several left-sided cerebral regions, including the hippocampus, thalamus, middle cingulate gyrus, triangular part of the inferior frontal gyrus, supplementary motor area, and lingual gyrus (all p< 0.0025, whole-brain significant). Importantly, siblings of schizophrenia patients showed several similarities to patients in cerebellar functional connectivity, suggesting that cerebellar dysconnectivity in schizophrenia might be related to familial factors. In conclusion, our findings suggest that dysconnectivity in schizophrenia involves the cerebellum and that this defect may be related to the risk to develop the illness.

Large scale scientific applications are frequently modeled as a workflow that is executed under the control of a workflow management system. One crucial requirement is the validation of the generated results, e.g. The trace ability of the experiment execution path. The automated tracking and storage of provenance information during workflow execution could satisfy this requirement.. To collect provenance data using the grid-enabled scientific workflow management system WS-VLAM, experimentations were made with two different implementations of the provenance concepts. The first one, adopts the Open Provenance Model (OPM) using the Provenance Layer Infrastructure for e-Science Resources (PLIER). The second one is the history-tracing XML (HisT). This paper describes how these two provenance models are integrated into WS-VLAM.

BPEL4People and WS-HumanTask (WS-HT) specify models to integrate human resources into business processes. The emerging use of these standards will result in more challenging authorization decisions in the context of the execution of workflows. Compared to a classical scenario where a workflow management system controls the mapping of tasks to a specific set of resources, human interaction introduces an additional mapping scheme in which humans were separately mapped to tasks. Basically the authorization framework needs to be adapted from a push-based model to a push-/pull-based approach. This short paper introduces the concepts of a security framework for a WS-HT implementation. It presents a generic framework that supports a pull-based work distribution strategy in distributed environments with the help of a task repository that mediates tasks between resources and workflow instances.

Currently, most workflow management systems (WfMS) in Grid environments provide push-oriented task distribution strategies, where tasks are directly bound to suitable resources. In those scenarios the dedicated resources execute the submitted tasks according to the request of a WfMS or sometimes by support of a Meta-Scheduling service. This approach has specific problems, especially because of various conditions and constrains that have to be taken into account like local policies or the sites’ autonomy. To deal with such issues, this paper takes a closer look to the task distribution strategies. The established Grid WfMSs essentially support control-flow and data perspectives. However, they neglect the resource perspective. This paper exposes the advantages to deal with this perspective and demonstrates its feasability by a prototype implementation that integrates the missing resource patterns into UNICORE.

The tumor suppressor gene TP53 and its regulator MDM2 are both important players in the DNA-damage repair "TP53 response pathway". Common germline polymorphisms in these genes may affect outcome in patients with tumors characterized by additional somatic changes in the same or a related pathway. To evaluate this hypothesis, we determined the effect of the common germline TP53 R72P and MDM2 SNP309 polymorphisms on breast cancer survival in a consecutive cohort of breast cancer patients (age at diagnosis

Although schizophrenia is characterized by impairments in intelligence and the loss of brain volume, the relationship between changes in IQ and brain measures is not clear.To investigate the association between IQ and brain measures in patients with schizophrenia across time.Case-control longitudinal study at the Department of Psychiatry at the University Medical Center Utrecht, Utrecht, the Netherlands, comparing patients with schizophrenia and healthy control participants between September 22, 2004, and April 17, 2008. Magnetic resonance imaging of the brain and IQ scores were obtained at baseline and the 3-year follow-up. Participants included 84 patients with schizophrenia (mean illness duration, 4.35 years) and 116 age-matched healthy control participants.Associations between changes in IQ and the total brain, cerebral gray matter, cerebral white matter, lateral ventricular, third ventricles, cortical, and subcortical volumes; cortical thickness; and cortical surface area.Cerebral gray matter volume (P = .006) and cortical volume (P = .03) and thickness (P = .02) decreased more in patients with schizophrenia across time compared with control participants. Patients showed additional loss in cortical volume and thickness of the right supramarginal, posterior superior temporal, left supramarginal, left postcentral, and occipital regions (P values were between.001 and .03 after clusterwise correction). Although IQ increased similarly in patients with schizophrenia and control participants, changes in IQ were negatively correlated with changes in lateral ventricular volume (P = .05) and positively correlated with changes in cortical volume (P = .007) and thickness (P = .004) only in patients with schizophrenia. Positive correlations between changes in IQ and cortical volume and thickness were found globally and in widespread regions across frontal, temporal, and parietal cortices (P values were between.001 and .03 after clusterwise correction). These findings were independent of symptom severity at follow-up, cannabis use, and the use of cumulative antipsychotic medications during the 3 years of follow-up.Progressive brain tissue loss in schizophrenia is related to relative cognitive decline during the early course of illness.

To investigate whether a low peripheral blood lymphocyte count is associated with increased mortality risk in older persons and to determine whether this association could be ascribed to ill health.A cohort study with a total follow-up period of 1,602 person years.Leiden, the Netherlands.Four hundred thirty-six community-dwelling residents aged 85 and older.Health status and leukocyte total and differential counts were assessed at baseline. Lymphocyte subsets were measured with a fluorescence-activated cell sorter. Age- and sex-adjusted mortality risks were estimated using Cox proportional hazard regression analysis.There was no association between lymphocyte count and mortality in persons with ill health (mortality risk lowest vs highest quartile=1.16; 95% confidence interval (CI)=0.85-1.58, P=.35), but mortality was dependent on lymphocyte count if disease was excluded (mortality risk lowest vs highest quartile=2.14; 95% CI=1.08-4.23, P=.03). A similar increase in mortality risk was found when the cluster designation (CD)4+, CD8+, and CD16+ lymphocyte subsets were analyzed. Within individuals, low values of the lymphocyte subsets were related and there was no compensatory increase in CD16+ lymphocyte counts. A low lymphocyte count was not associated with specific causes of death.A low lymphocyte count was associated with an increased mortality risk in older persons without apparent disease. This association was not only found for the total lymphocyte count but also for the CD4+, CD8+, and CD16+ lymphocyte subset counts.

Purpose:\ud \ud To define the phenotypic and mutational spectrum of epilepsies related to DEPDC5, NPRL2 and NPRL3 genes encoding the GATOR1 complex, a negative regulator of the mTORC1 pathway.\ud \ud Methods:\ud \ud We analyzed clinical and genetic data of 73 novel probands (familial and sporadic) with epilepsy-related variants in GATOR1-encoding genes and proposed new guidelines for clinical interpretation of GATOR1 variants.\ud \ud Results:\ud \ud The GATOR1 seizure phenotype consisted mostly in focal seizures (e.g., hypermotor or frontal lobe seizures in 50%), with a mean age at onset of 4.4 years, often sleep-related and drug-resistant (54%), and associated with focal cortical dysplasia (20%). Infantile spasms were reported in 10% of the probands. Sudden unexpected death in epilepsy (SUDEP) occurred in 10% of the families. Novel classification framework of all 140 epilepsy-related GATOR1 variants (including the variants of this study) revealed that 68% are loss-of-function pathogenic, 14% are likely pathogenic, 15% are variants of uncertain significance and 3% are likely benign.\ud \ud Conclusion:\ud \ud Our data emphasize the increasingly important role of GATOR1 genes in the pathogenesis of focal epilepsies (>180 probands to date). The GATOR1 phenotypic spectrum ranges from sporadic early-onset epilepsies with cognitive impairment comorbidities to familial focal epilepsies, and SUDEP.