Transforming growth factor-β in breast cancer: too much, too late

The contribution of transforming growth factor (TGF)β to breast cancer has been studied from a myriad perspectives since seminal studies more than two decades ago. Although the action of TGFβ as a canonical tumor suppressor in breast is without a doubt, there is compelling evidence that TGFβ is frequently subverted in a malignant plexus that drives breast cancer. New knowledge that TGFβ regulates the DNA damage response, which underlies cancer therapy, reveals another facet of TGFβ biology that impedes cancer control. Too much TGFβ, too late in cancer progression is the fundamental motivation for pharmaceutical inhibition

Therapeutic approach to FSGS in children

Therapy of primary focal segmental glomerulosclerosis (FSGS) in children incorporates conservative management and immunosuppression regimens to control proteinuria and preserve kidney function. In long-term cohort studies in adults and children with primary FSGS, renal survival has been directly associated with degree of proteinuria control. This educational article reviews the current therapeutic approach toward children with primary FSGS

Long-term cerebral imaging after pre-eclampsia

Please cite this paper as: Aukes A, De Groot J, Wiegman M, Aarnoudse J, Sanwikarja G, Zeeman G. Long-term cerebral imaging after pre-eclampsia. BJOG 2012;119:11171122. Objective Formerly eclamptic women demonstrate cerebral white matter lesions (WMLs) several years following the index pregnancy. The pathophysiology is unclear and may be related to the predisposition for cerebrovascular/cardiovascular disease in such women and/or the occurrence of posterior reversible encephalopathy syndrome whilst pregnant. The aim of this study was to assess the presence and severity of WMLs and their relationship with the severity of the neurological symptoms during the index pregnancy and several current cardiovascular risk factors in formerly pre-eclamptic women. Design This was a retrospective cohort study. Setting The Neuroimaging Centre at the School for Behavioural and Cognitive Neurosciences, Groningen, the Netherlands. Population Seventy-three formerly pre-eclamptic women were matched for age (37 +/- 6 years) and elapsed time since index pregnancy (5.1 +/- 3.7 years) with parous control women. Methods Cerebral magnetic resonance imaging scans were performed on cases and controls. Scans were rated by a neuroradiologist blind to the patient category. Main outcome measures The presence and severity of cerebral WMLs. Results Formerly pre-eclamptic women had WMLs significantly more often (37%) and more severely (mean, 0.11; median, 0.00; range, 02.34 ml) than controls (21%, P = 0.04; mean, 0.015; median, 0.00; range, 00.13 ml; P = 0.02). Current hypertension and a history of early-onset pre-eclampsia (<37 weeks) were independently associated with the presence of WMLs (beta = 1.34, P = 0.02 and beta = 1.73, P = 0.01, respectively). Conclusions Our findings indicate that pre-eclampsia might be a risk marker for early cerebrovascular damage. The predisposition of formerly pre-eclamptic women to later cardiovascular and cerebrovascular disease may be an important factor for the development of cerebral WMLs. Whether a history of posterior reversible encephalopathy syndrome may be an additive risk factor for the development of these lesions remains unknown

Sputum transcriptomics reveal upregulation of IL-1 receptor family members in patients with severe asthma

BACKGROUND: Sputum analysis in asthmatic patients is used to define airway inflammatory processes and might guide therapy. OBJECTIVE: We sought to determine differential gene and protein expression in sputum samples from patients with severe asthma (SA) compared with nonsmoking patients with mild/moderate asthma. METHODS: Induced sputum was obtained from nonsmoking patients with SA, smokers/ex-smokers with severe asthma, nonsmoking patients with mild/moderate asthma (MMAs), and healthy nonsmoking control subjects. Differential cell counts, microarray analysis of cell pellets, and SOMAscan analysis of sputum analytes were performed. CRID3 was used to inhibit the inflammasome in a mouse model of SA. RESULTS: Eosinophilic and mixed neutrophilic/eosinophilic inflammation were more prevalent in patients with SA compared with MMAs. Forty-two genes probes were upregulated (>2-fold) in nonsmoking patients with severe asthma compared with MMAs, including IL-1 receptor (IL-1R) family and nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain containing 3 (NRLP3) inflammasome members (false discovery rate < 0.05). The inflammasome proteins nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain containing 1 (NLRP1), NLRP3, and nucleotide-binding oligomerization domain (NOD)-like receptor C4 (NLRC4) were associated with neutrophilic asthma and with sputum IL-1β protein levels, whereas eosinophilic asthma was associated with an IL-13-induced TH2 signature and IL-1 receptor-like 1 (IL1RL1) mRNA expression. These differences were sputum specific because no activation of NLRP3 or enrichment of IL-1R family genes in bronchial brushings or biopsy specimens in patients with SA was observed. Expression of NLRP3 and of the IL-1R family genes was validated in the Airway Disease Endotyping for Personalized Therapeutics cohort. Inflammasome inhibition using CRID3 prevented airway hyperresponsiveness and airway inflammation (both neutrophilia and eosinophilia) in a mouse model of severe allergic asthma. CONCLUSION: IL1RL1 gene expression is associated with eosinophilic SA, whereas NLRP3 inflammasome expression is highest in patients with neutrophilic SA. TH2-driven eosinophilic inflammation and neutrophil-associated inflammasome activation might represent interacting pathways in patients with SA