Career perspectives for young cardiologists in the Netherlands: a steady increase in temporary positions.

In the Netherlands, concerns have been raised regarding the high unemployment rates and the lack of permanent positions for young medical specialists. In the current study, we present data on contemporary early career perspectives in the field of cardiology. We conducted a survey among 304 young cardiologists who completed their training between 2015 and 2020; the response rate was 91%. Our analysis revealed a low unemployment rate (0.3%). One, 3 and 5 years after registration, 81%, 41% and 18% of the respondents, respectively, had not gained a permanent position. Having conducted a fellowship significantly delayed the time to permanent position (hazard ratio (HR): 0.48; 95% confidence interval (CI): 0.34-0.67). For those who had conducted a fellowship, holding a PhD degree (HR: 1.95; 95% CI: 1.10-3.44), age (per year increase, HR: 0.90; 95% CI: 0.82-0.99) and training in an academic hospital (HR: 1.97; 95% CI: 1.10-3.52) were of significant influence on the likelihood of having a permanent position at 3 years of follow-up. These results showed a disturbing increase in time to permanent position compared with an earlier analysis. This trend justifies close monitoring of the labour market in the coming years. Solutions for this multifactorial problem in the field of cardiology and across the entire medical specialty spectrum should be explored.

Career perspectives for young cardiologists in the Netherlands: a steady increase in temporary positions.

In the Netherlands, concerns have been raised regarding the high unemployment rates and the lack of permanent positions for young medical specialists. In the current study, we present data on contemporary early career perspectives in the field of cardiology. We conducted a survey among 304 young cardiologists who completed their training between 2015 and 2020; the response rate was 91%. Our analysis revealed a low unemployment rate (0.3%). One, 3 and 5 years after registration, 81%, 41% and 18% of the respondents, respectively, had not gained a permanent position. Having conducted a fellowship significantly delayed the time to permanent position (hazard ratio (HR): 0.48; 95% confidence interval (CI): 0.34-0.67). For those who had conducted a fellowship, holding a PhD degree (HR: 1.95; 95% CI: 1.10-3.44), age (per year increase, HR: 0.90; 95% CI: 0.82-0.99) and training in an academic hospital (HR: 1.97; 95% CI: 1.10-3.52) were of significant influence on the likelihood of having a permanent position at 3 years of follow-up. These results showed a disturbing increase in time to permanent position compared with an earlier analysis. This trend justifies close monitoring of the labour market in the coming years. Solutions for this multifactorial problem in the field of cardiology and across the entire medical specialty spectrum should be explored. Supplementary Information: The online version of this article (10.1007/s12471-022-01736-1) contains supplementary material, which is available to authorized users.

Care and referral patterns in a large, dedicated nurse-led atrial fibrillation outpatient clinic.

INTRODUCTION: Atrial fibrillation (AF) is the most common arrhythmia and imposes a high burden on the healthcare system. A nurse-led AF outpatient clinic may alleviate the burden on the cardiology outpatient clinic by triaging patients who need care by a cardiologist or general practitioner (GP). However, care and referral patterns after initial assessment in a nurse-led AF outpatient clinic are unknown. We examined the proportion of AF patients assessed in a nurse-led clinic without outpatient follow-up by a cardiologist. METHODS: All patients with AF referred to our tertiary medical centre underwent cardiac work-up in the nurse-led AF outpatient clinic and were prospectively followed. Data on patient characteristics, rhythm monitoring and echocardiography were collected and described. Odds ratio (OR) for continuing care in the nurse-led AF outpatient clinic was calculated. RESULTS: From 2014 to 2018, 478 consecutive individual patients were referred to the nurse-led AF outpatient clinic. After the initial cardiac work-up, 139 patients (29.1%) remained under nurse-led care and 121 (25.3%) were referred to a cardiologist and 218 (45.6%) to a GP. Patients who remained under nurse-led care were significantly younger, were more symptomatic, more often had paroxysmal AF and had less comorbidities than the other two groups. After multivariable testing, CHA2DS2-VASc score ≥ 2 was associated with discontinued nurse-led care (OR 0.57, 95% confidence interval 0.34-0.95). CONCLUSION: After initial cardiac assessment in the nurse-led outpatient clinic, about half of the newly referred AF patients were referred back to their GP. This strategy may reduce the burden of AF patients on secondary or tertiary cardiology outpatient clinics.

Early career perspectives of young Dutch cardiologists.

BACKGROUND: There are nationwide concerns about the unemployment rate among young Dutch cardiologists and the increase in temporary positions. Therefore, the aim of this study was to investigate the unemployment rate in this subgroup as well as the length of time between the end of their training and the acquisition of a permanent position. METHODS: All cardiologists who completed their training between January 2015 and December 2018 were invited to fill in an online questionnaire about their demographic characteristics, professional profile and employment status. The unemployment rate was calculated and Kaplan-Meier curves were used to determine the time between the end of training and the first permanent contract. RESULTS: In total, 174 participants were included (mean age 35 ± 3 years, 64% male, median follow-up 2.3 years (interquartile range 1.4-3.2 years)). The unemployment rate was 0.6% (n = 1). Only 12 participants (7%) started their career with a permanent position. The percentage of cardiologists with a temporary position was 82%, 61% and 33% at 1, 2 and 3 years, respectively. The percentage of cardiologists with a temporary position did not differ with regard to age, gender, holding a PhD degree or type of teaching institution attended (academic vs non-academic). Forty-four per cent of participants perceived the current job market to be problematic. CONCLUSIONS: The unemployment rate among young cardiologists in the Netherlands was low between 2015 and 2018. The vast majority of cardiologists start their career on a temporary contract. Three years later, 33% still hold temporary positions. Due to the resultant job insecurity, many young cardiologists describe the job market as problematic.

Dutch cardiology residents and the COVID-19 pandemic: Every little thing counts in a crisis.

The COVID-19 pandemic has overwhelmed healthcare systems worldwide, and a large part of regular cardiology care came to a quick halt. A Dutch nationwide survey showed that 41% of cardiology residents suspended their training and worked at COVID-19 cohort units for up to 3 months. With tremendous flexibility, on-call schedules were altered and additional training was provided in order for residents to be directly available where needed most. These unprecedented times have taught them important lessons on crisis management. The momentum is used to incorporate novel tools for patient care. Moreover, their experience of pandemic and crisis management has provided future cardiologists with unique skills. This crisis will not be wasted; however, several challenges have to be overcome in the near future including, but not limited to, a second pandemic wave, a difficult labour market due to an economic recession, and limitations in educational opportunities.

Loss of CUL4A expression is underlying cisplatin hypersensitivity in colorectal carcinoma cells with acquired trabectedin resistance.

BACKGROUND: Colorectal carcinoma (CRC) is the third most common cancer worldwide. Platinum-based anticancer compounds still constitute one mainstay of systemic CRC treatment despite limitations due to adverse effects and resistance development. Trabectedin has shown promising antitumor effects in CRC, however, again resistance development may occur. In this study, we aimed to develop strategies to circumvent or even exploit acquired trabectedin resistance in novel CRC treatment regimens. METHODS: Human HCT116 CRC cells were selected for acquired trabectedin resistance in vitro and characterised by cell biological as well as bioinformatic approaches. In vivo xenograft experiments were conducted. RESULTS: Selection of HCT116 cells for trabectedin resistance resulted in p53-independent hypersensitivity of the selected subline against cisplatin. Bioinformatic analyses of mRNA microarray data suggested deregulation of nucleotide excision repair and particularly loss of the ubiquitin ligase CUL4A in trabectedin-selected cells. Indeed, transient knockdown of CUL4A sensitised parental HCT116 cells towards cisplatin. Trabectedin selected but not parental HCT116 xenografts were significantly responsive towards cisplatin treatment. CONCLUSIONS: Trabectedin selection-mediated CUL4A loss generates an Achilles heel in CRC cancer cells enabling effective cisplatin treatment. Hence, inclusion of trabectedin in cisplatin-containing cancer treatment regimens might cause profound synergism based on reciprocal resistance prevention.

Can we spice up our Christmas dinner? : Busting the myth of the 'Chinese restaurant syndrome'.

BACKGROUND: Monosodium glutamate (MSG), also referred to as Vetsin or E621, is a flavour enhancer frequently used in Asian cuisine and abundantly present in the famous Chinese dish Peking duck. MSG is notorious for triggering the onset of the so-called 'Chinese restaurant syndrome' (CRS), a complex of unpleasant symptoms, which might include flushing, sweating and the onset of atrial fibrillation (AF). This study aims to determine the effects of MSG on the occurrence of AF. METHODS: We conducted a placebo self-controlled single-arm study in the Academic Medical Centre in Amsterdam. We included paroxysmal AF patients who reported a consistent onset of AF upon MSG intake. During three admissions, participants were subsequently administered: placebo, 1.5 g and 3 g MSG. If AF was recorded after the dose of 1.5 g MSG, patients were given another placebo instead of 3 g MSG. The primary outcome was the onset of AF registered by 24-hour Holter monitoring. The secondary outcomes were any other arrhythmia and the onset of CRS defined as two or more symptoms of CRS after MSG intake. RESULTS: Six men participated in the study. Both 1.5 g and 3 g MSG were unrelated to CRS, arrhythmias or AF occurrence. CONCLUSION: Peking duck can be put on the Christmas menu without risking guests to be admitted to the emergency department with new episodes of AF.

MP-AzeFlu is more effective than fluticasone propionate for the treatment of allergic rhinitis in children.

The objective was to evaluate the efficacy of MP-AzeFlu (Dymista(®) ) vs fluticasone propionate (FP), (both 1 spray/nostril bid), in children with allergic rhinitis (AR). MP-AzeFlu combines azelastine hydrochloride, FP and a novel formulation in a single spray. Children were randomized in a 3 : 1 ratio to MP-AzeFlu or FP in this open-label, 3-month study. Efficacy was assessed in children aged ≥ 6 to <12 years (MP-AzeFlu: n = 264; FP: n = 89), using a 4-point symptom severity rating scale from 0 to 3 (0 = no symptoms; 3 = severe symptoms). Over the 3-month period, MP-AzeFlu-treated children experienced significantly greater symptom relief than FP-treated children (Diff: -0.14; 95% CI: -0.28, -0.01; P = 0.04), noted from the first day (particularly the first 7 days) and sustained for 90 days. More MP-AzeFlu children achieved symptom-free or mild symptom severity status, and did so up to 16 days faster than FP. MP-AzeFlu provides significantly greater, more rapid and clinically relevant symptom relief than FP in children with AR.

Localizing the RPGR protein along the cilium: a new method to determine efficacies to treat RPGR mutations.

Retinal dystrophies constitute a group of clinically and genetically heterogeneous diseases that cause visual impairment. As treatments are not readily available, readout assays performed in patient-derived cells can aid in the development and comparative analysis of therapeutic approaches. We describe a new method with which the localization of the retinitis pigmentosa GTPase regulator (RPGR) protein along the cilium can be used as a measure for treatment efficacy. In a patient-derived fibroblast cell line, we found that the RPGR protein is mislocalized along the ciliary axoneme. The patient carried a point mutation that leads to skipping of RPGR exon 10. We confirmed that this skipping is causative for the impaired localization of RPGR using a U7 small nuclear RNA (U7snRNA)-based antisense approach in control cells. Treatment of the patient-derived fibroblasts with therapeutic U1snRNA significantly corrected the proteins' mislocalization. In this proof of principle study, we show that detecting the RPGR protein along the cilium provides a reliable and quantifiable readout assay to evaluate the efficacy of therapies intended to correct or silence RPGR gene mutations. This method opens the possibility to compare different therapeutic agents, and thus facilitate the identification of treatment options for the clinically and molecularly complex RPGR-associated diseases.

Ki67 index is an independent prognostic factor in epithelioid but not in non-epithelioid malignant pleural mesothelioma: a multicenter study.

BACKGROUND: Estimating the prognosis in malignant pleural mesothelioma (MPM) remains challenging. Thus, the prognostic relevance of Ki67 was studied in MPM. METHODS: Ki67 index was determined in a test cohort of 187 cases from three centres. The percentage of Ki67-positive tumour cells was correlated with clinical variables and overall survival (OS). The prognostic power of Ki67 index was compared with other prognostic factors and re-evaluated in an independent cohort (n=98). RESULTS: Patients with Ki67 higher than median (>15%) had significantly (P<0.001) shorter median OS (7.5 months) than those with low Ki67 (19.1 months). After multivariate survival analyses, Ki67 proved to be-beside histology and treatment-an independent prognostic marker in MPM (hazard ratio (HR): 2.1, P<0.001). Interestingly, Ki67 was prognostic exclusively in epithelioid (P<0.001) but not in non-epithelioid subtype. Furthermore, Ki67 index was significantly lower in post-chemotherapy samples when compared with chemo-naive cases. The prognostic power was comparable to other recently published prognostic factors (CRP, fibrinogen, neutrophil-to-leukocyte ratio (NLR) and nuclear grading score) and was recapitulated in the validation cohort (P=0.048). CONCLUSION: This multicentre study demonstrates that Ki67 is an independent and reproducible prognostic factor in epithelioid but not in non-epithelioid MPM and suggests that induction chemotherapy decreases the proliferative capacity of MPM.

[Cost Effectiveness of Aftercare in the Cardiovascular Rehabilitation: A Five Years Follow-up Analysis]. / Kosteneffektive Langzeitnachsorge in der kardiovaskulären Rehabilitation: Fünf-Jahres-Follow-up der SeKoNa-Studie (ISRCTN 15954342).

OBJECTIVE: In Germany, the rehabilitative approaches towards patients with coronary artery events are not adequately sustainable despite the high costs. Both sustainability and cost effectiveness are the subjects of this 5-year analysis. METHODS: The study was initiated in 2004. One year recruiting phase was followed by 3 years aftercare with telephone as an intervention. This unicentric randomised controlled trial included 600 patients of rehabilitative aftercare (intervention group [IG] 271; control group [CG] 329). Data on (i) mortality, (ii) duration of retirement, (iii) type of retirement and (iv) status of retirement were obtained from the German Retirement Insurance.The analyses for cost-effectiveness are conducted for the intention-to-treat (ITT) approach. The general assessment basis of retirements (partial and full disability pensions) are average values for the year 2013 (year of the measurement). RESULTS: On the reporting date (31.12.2013), the values of the IG in part (early) retirement and full (early) retirement are higher than the CG (1.5 and 2.7%, n. s. and 7.4 and 13.4%, respectively n. s.). The same applies for mortality (8.1 and 9.4%, respectively n. s.).The savings through lower pension payments amount to € 1.55 million for the adjusted ITT approach. From this, € 130 080, which represents the cost of the aftercare (intervention), must be deducted. CONCLUSIONS: The results of the 5-year follow-up show that a part of pension payment could be reduced. The evidence of cost effectiveness, independently of the methodological approach, is strong. The saving potential is reached by half in both approaches.

Circulating fibrinogen is a prognostic and predictive biomarker in malignant pleural mesothelioma.

BACKGROUND: To investigate the clinical utility of pretreatment plasma fibrinogen levels in malignant pleural mesothelioma (MPM) patients. METHODS: A retrospective multicenter study was performed in histologically proven MPM patients. All fibrinogen levels were measured at the time of diagnosis and clinical data were retrospectively collected after approval of the corresponding ethics committees. RESULTS: In total, 176 MPM patients (mean age: 63.5 years ± 10.4 years, 38 females and 138 males) were analysed. Most patients (n=154, 87.5%) had elevated (≥ 390 mg dl(-1)) plasma fibrinogen levels. When patients were grouped by median fibrinogen, patients with low level (≤ 627 mg dl(-1)) had significantly longer overall survival (OS) (19.1 months, confidence interval (CI) 14.5-23.7 months) when compared with those with high level (OS 8.5; CI 6.2-10.7 months). In multivariate survival analyses, fibrinogen was found to be an independent prognostic factor (hazard ratio 1.81, CI 1.23-2.65). Most interestingly, fibrinogen (cutoff 75th percentile per 750 mg dl(-1)) proved to be a predictive biomarker indicating treatment benefit achieved by surgery within multimodality therapy (interaction term: P=0.034). Accordingly, only patients below the 75th percentile benefit from surgery within multimodality therapy (31.3 vs 5.3 months OS). CONCLUSIONS: Fibrinogen is a novel independent prognostic biomarker in MPM. Most importantly, fibrinogen predicted treatment benefit achieved by surgery within multimodality therapy.

Up-regulation of 12(S)-lipoxygenase induces a migratory phenotype in colorectal cancer cells.

12(S)-Lipoxygenase (LOX) and its product 12(S)-hydroxyeicosatetraenic (HETE) acid have been implicated in angiogenesis and tumour invasion in several tumour types while their role in colorectal cancer progression has not yet been studied. We have analysed 12(S)-LOX expression in colorectal tumours and found gene expression up-regulated in colorectal cancer specimens for which the pathology report described involvement of inflammation. Using cell line models exposed to 12(S)-HETE or over-expressing 12(S)-LOX malignant cell growth as well as tumour cell migration was found to be stimulated. Specifically, Caco2 and SW480 cells over-expressing 12(S)-LOX formed fewer colonies from sparse cultures, but migrated better in filter-migration assays. SW480 LOX cells also had higher anchorage-independent growth capacity and a higher tendency to metastasise in vivo. Knock-down or inhibition of 12(S)-LOX inhibited cell migration and anchorage-independent growth in both 12(S)-LOX transfectants and SW620 cells that express high endogenous levels of 12(S)-LOX. On the cell surface E-cadherin and integrin-ß1 expression were down-regulated in a 12(S)-LOX-dependent manner disturbing cell-cell interactions. The results demonstrate that 12(S)-LOX expression in inflammatory areas of colorectal tumours has the capacity to induce an invasive phenotype in colorectal cancer cells and could be targeted for therapy.

A new therapy (MP29-02) is effective for the long-term treatment of chronic rhinitis.

BACKGROUND AND OBJECTIVE: MP29-02 (Dymista), a novel intranasal formulation of azelastine hydrochloride (AZE) and fluticasone propionate (FP), is significantly better than first-line therapy for the treatment of moderate-to-severe seasonal allergic rhinitis (SAR), and is well tolerated following 52 weeks of continuous use in chronic rhinitis. The aim of this study was to evaluate the long-term efficacy of MP29-02 versus FP in patients with chronic rhinitis. PATIENTS AND METHODS: In total, 612 chronic rhinitis patients (perennial allergic rhinitis [PAR], n = 424; nonallergic rhinitis, n=188) aged 12 years or older were enrolled into this open-label, parallel-group study and randomized to MP29-02 (1 spray/nostril bid) or FP nasal spray (2 sprays/nostril qd) for 52 weeks. Efficacy was assessed by change from baseline in PM reflective total nasal symptom score (rTNSS), time to first achieve 100% PM rTNSS reduction from baseline, and percentage of symptom-free days in the total and PAR populations posthoc. RESULTS: MP29-02 reduced patients' PM rTNSS from baseline significantly more than FP, from Day 1 up to and including week 28 (-2.88 vs -2.53; P = .0048), with treatment difference maintained for 52 weeks. Fluctuation in significance after week 28 might be explained, at least in part, by decreasing sample size, permitted according to ICH guidelines. By Day 1 almost twice as many MP29-02-patients were symptom free. After 1 month, 71.1% of MP29-02 patients experienced 100% rTNSS reduction (60.3% for FP), and did on a median of 9 days faster (P=.0024). Over 52 weeks MP29-02 patients experienced 8.4% more symptom-free days (P = .0005). These results were mirrored in the PAR subpopulation. CONCLUSION: These results confirm MP29-02's wide therapeutic spectrum and assert its consistent superiority over an intranasal corticosteroid.

Norrie disease is caused by mutations in an extracellular protein resembling C-terminal globular domain of mucins.

A candidate gene for Norrie disease, an X-linked disorder characterized by blindness, deafness and mental disturbances, was recently isolated and found to contain microdeletions in numerous patients. No strong homologies were identified. By studying the number and spacing of cysteine residues, we now detect homologies between the Norrie gene product and a C-terminal domain which is common to a group of proteins including mucins. Three newly-characterized missense mutations, replacing evolutionarily conserved cysteines or creating new cysteine codons, emphasize the functional importance of these sites. These findings and the clinical features of this disorder suggest a possible role for the Norrie gene in neuroectodermal cell-cell interaction.

Isolation of a candidate gene for Norrie disease by positional cloning.

The gene for Norrie disease, an X-linked disorder characterized by progressive atrophy of the eyes, mental disturbances and deafness, has been mapped to chromosome Xp11.4 close to DXS7 and the monoamine oxidase (MAO) genes. By subcloning a YAC with a 640 kilobases (kb) insert which spans the DXS7-MAOB interval we have generated a cosmid contig which extends 250 kb beyond the MAOB gene. With one of these cosmids, microdeletions were detected in several patients with Norrie disease. Screening of cDNA libraries has enabled us to isolate and sequence a likely candidate gene for Norrie disease which is expressed in retina, choroid and fetal brain. No homologous sequences were found in DNA and protein databases indicating that this cDNA is part of a gene encoding a 'pioneer' protein.

The complete form of X-linked congenital stationary night blindness is caused by mutations in a gene encoding a leucine-rich repeat protein.

X-linked congenital stationary night blindness (XLCSNB) is characterized by impaired scotopic vision with associated ocular symptoms such as myopia, hyperopia, nystagmus and reduced visual acuity. Genetic mapping in families with XLCSNB revealed two different loci on the proximal short arm of the X chromosome. These two genetic subtypes can be distinguished on the basis of electroretinogram (ERG) responses and psychophysical testing as a complete (CSNB1) and an incomplete (CSNB2) form. The CSNB1 locus has been mapped to a 5-cM linkage interval in Xp11.4 (refs 2,5-7). Here we construct and analyse a contig between the markers DXS993 and DXS228, leading to the identification of a new gene mutated in CSNB1 patients. It is partially deleted in 3 families and mutation analysis in a further 21 families detected another 13 different mutations. This gene, designated NYX, encodes a protein of 481 amino acids (nyctalopin) and is expressed at low levels in tissues including retina, brain, testis and muscle. The predicted polypeptide is a glycosylphosphatidylinositol (GPI)-anchored extracellular protein with 11 typical and 2 cysteine-rich, leucine-rich repeats (LRRs). This motif is important for protein-protein interactions and members of the LRR superfamily are involved in cell adhesion and axon guidance. Future functional analysis of nyctalopin might therefore give insight into the fine-regulation of cell-cell contacts in the retina.

Positional cloning of the gene for X-linked retinitis pigmentosa 2.

X-linked retinitis pigmentosa (XLRP) results from mutations in at least two different loci, designated RP2 and RP3, located at Xp11.3 and Xp21.1, respectively. The RP3 gene was recently isolated by positional cloning, whereas the RP2 locus was mapped genetically to a 5-cM interval. We have screened this region for genomic rearrangements by the YAC representation hybridization (YRH) technique and detected a LINE1 (L1) insertion in one XLRP patient. The L1 retrotransposition occurred in an intron of a novel gene that consisted of five exons and encoded a polypeptide of 350 amino acids. Subsequently, nonsense, missense and frameshift mutations, as well as two small deletions, were identified in six additional patients. The predicted gene product shows homology with human cofactor C, a protein involved in the ultimate step of beta-tubulin folding. Our data provide evidence that mutations in this gene, designated RP2, are responsible for progressive retinal degeneration.

Opitz G/BBB syndrome, a defect of midline development, is due to mutations in a new RING finger gene on Xp22.

Opitz syndrome (OS) is an inherited disorder characterized by midline defects including hypertelorism, hypospadias, lip-palate-laryngotracheal clefts and imperforate anus. We have identified a new gene on Xp22, MID1 (Midline 1), which is disrupted in an OS patient carrying an X-chromosome inversion and is also mutated in several OS families. MID1 encodes a member of the B-box family of proteins, which contain protein-protein interaction domains, including a RING finger, and are implicated in fundamental processes such as body axis patterning and control of cell proliferation. The association of MID1 with OS suggests an important role for this gene in midline development.

Suppression of activin A signals inhibits growth of malignant pleural mesothelioma cells.

BACKGROUND: Activins control the growth of several tumour types including thoracic malignancies. In the present study, we investigated their expression and function in malignant pleural mesothelioma (MPM). METHODS: The expression of activins and activin receptors was analysed by quantitative PCR in a panel of MPM cell lines. Activin A expression was further analysed by immunohistochemistry in MPM tissue specimens (N=53). Subsequently, MPM cells were treated with activin A, activin receptor inhibitors or activin-targeting siRNA and the impact on cell viability, proliferation, migration and signalling was assessed. RESULTS: Concomitant expression of activin subunits and receptors was found in all cell lines, and activin A was overexpressed in most cell lines compared with non-malignant mesothelial cells. Similarly, immunohistochemistry demonstrated intense staining of tumour cells for activin A in a subset of patients. Treatment with activin A induced SMAD2 phosphorylation and stimulated clonogenic growth of mesothelioma cells. In contrast, treatment with kinase inhibitors of activin receptors (SB-431542, A-8301) inhibited MPM cell viability, clonogenicity and migration. Silencing of activin A expression by siRNA oligonucleotides further confirmed these results and led to reduced cyclin D1/3 expression. CONCLUSION: Our study suggests that activin A contributes to the malignant phenotype of MPM cells via regulation of cyclin D and may represent a valuable candidate for therapeutic interference.