Prenatal Diagnosis of Agenesis of the Corpus Callosum and Cerebellar Vermian Hypoplasia Associated with a Microdeletion on Chromosome 1p32

We present the prenatal detection of a 1p32.1p31.3 microdeletion (3.46 Mb) by array comparative genomic hybridization (CGH) associated with fetal agenesis of the corpus callosum (ACC) and cerebellar vermian hypoplasia. Analysis of cultured amniocytes showed a normal karyotype. Our observations strengthen the association between this locus and central nervous system development. In addition, the fetus reported herein underscores the importance of array CGH analysis when ACC is detected prenatally, especially when there are additional central nervous system anomalies, to search for submicroscopic imbalances which can facilitate further management and parental counselling. Moreover, the presence of urinary tract anomalies should alert the clinician to the possibility of a 1p interstitial deletion, although the absence of such does not exclude it. Further reports will help to provide more information on the long-term outcomes of individuals with such microdeletion as there are only limited data.published_or_final_versio

The clinical impact of chromosomal microarray on paediatric care in Hong Kong

Objective To evaluate the clinical impact of chromosomal microarray (CMA) on the management of paediatric patients in Hong Kong. Methods We performed NimbleGen 135k oligonucleotide array on 327 children with intellectual disability (ID)/developmental delay (DD), autism spectrum disorders (ASD), and/or multiple congenital anomalies (MCAs) in a university-affiliated paediatric unit from January 2011 to May 2013. The medical records of patients were reviewed in September 2013, focusing on the pathogenic/likely pathogenic CMA findings and their “clinical actionability” based on established criteria. Results Thirty-seven patients were reported to have pathogenic/likely pathogenic results, while 40 had findings of unknown significance. This gives a detection rate of 11% for clinically significant (pathogenic/likely pathogenic) findings. The significant findings have prompted clinical actions in 28 out of 37 patients (75.7%), while the findings with unknown significance have led to further management recommendation in only 1 patient (p<0.001). Nineteen out of the 28 management recommendations are “evidence-based” on either practice guidelines endorsed by a professional society (n = 9, Level 1) or peer-reviewed publications making medical management recommendation (n = 10, Level 2). CMA results impact medical management by precipitating referral to a specialist (n = 24); diagnostic testing (n = 25), surveillance of complications (n = 19), interventional procedure (n = 7), medication (n = 15) or lifestyle modification (n = 12). Conclusion The application of CMA in children with ID/DD, ASD, and/or MCAs in Hong Kong results in a diagnostic yield of ∼11% for pathogenic/likely pathogenic results. Importantly the yield for clinically actionable results is 8.6%. We advocate using diagnostic yield of clinically actionable results to evaluate CMA as it provides information of both clinical validity and clinical utility. Furthermore, it incorporates evidence-based medicine into the practice of genomic medicine. The same framework can be applied to other genomic testing strategies enabled by next-generation sequencing.published_or_final_versio

The Role of PPARβ/δ in Melanoma Metastasis.

Peroxisome proliferator⁻activated receptor (PPAR) β/δ, a ligand-activated transcription factor, is involved in diverse biological processes including cell proliferation, cell differentiation, inflammation and energy homeostasis. Besides its well-established roles in metabolic disorders, PPARβ/δ has been linked to carcinogenesis and was reported to inhibit melanoma cell proliferation, anchorage-dependent clonogenicity and ectopic xenograft tumorigenicity. However, PPARβ/δ's role in tumour progression and metastasis remains controversial. In the present studies, the consequence of PPARβ/δ inhibition either by global genetic deletion or by a specific PPARβ/δ antagonist, 10h, on malignant transformation of melanoma cells and melanoma metastasis was examined using both in vitro and in vivo models. Our study showed that 10h promotes epithelial-mesenchymal transition (EMT), migration, adhesion, invasion and trans-endothelial migration of mouse melanoma B16/F10 cells. We further demonstrated an increased tumour cell extravasation in the lungs of wild-type mice subjected to 10h treatment and in Pparβ/δ &lt;sup&gt;-/-&lt;/sup&gt; mice in an experimental mouse model of blood-borne pulmonary metastasis by tail vein injection. This observation was further supported by an increased tumour burden in the lungs of Pparβ/δ &lt;sup&gt;-/-&lt;/sup&gt; mice as demonstrated in the same animal model. These results indicated a protective role of PPARβ/δ in melanoma progression and metastasis

Prognostic model to predict postoperative acute kidney injury in patients undergoing major gastrointestinal surgery based on a national prospective observational cohort study.

Background: Acute illness, existing co-morbidities and surgical stress response can all contribute to postoperative acute kidney injury (AKI) in patients undergoing major gastrointestinal surgery. The aim of this study was prospectively to develop a pragmatic prognostic model to stratify patients according to risk of developing AKI after major gastrointestinal surgery. Methods: This prospective multicentre cohort study included consecutive adults undergoing elective or emergency gastrointestinal resection, liver resection or stoma reversal in 2-week blocks over a continuous 3-month period. The primary outcome was the rate of AKI within 7 days of surgery. Bootstrap stability was used to select clinically plausible risk factors into the model. Internal model validation was carried out by bootstrap validation. Results: A total of 4544 patients were included across 173 centres in the UK and Ireland. The overall rate of AKI was 14·2 per cent (646 of 4544) and the 30-day mortality rate was 1·8 per cent (84 of 4544). Stage 1 AKI was significantly associated with 30-day mortality (unadjusted odds ratio 7·61, 95 per cent c.i. 4·49 to 12·90; P < 0·001), with increasing odds of death with each AKI stage. Six variables were selected for inclusion in the prognostic model: age, sex, ASA grade, preoperative estimated glomerular filtration rate, planned open surgery and preoperative use of either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Internal validation demonstrated good model discrimination (c-statistic 0·65). Discussion: Following major gastrointestinal surgery, AKI occurred in one in seven patients. This preoperative prognostic model identified patients at high risk of postoperative AKI. Validation in an independent data set is required to ensure generalizability

LRG1 Promotes Metastatic Dissemination of Melanoma through Regulating EGFR/STAT3 Signalling.

Although less common, melanoma is the deadliest form of skin cancer largely due to its highly metastatic nature. Currently, there are limited treatment options for metastatic melanoma and many of them could cause serious side effects. A better understanding of the molecular mechanisms underlying the complex disease pathophysiology of metastatic melanoma may lead to the identification of novel therapeutic targets and facilitate the development of targeted therapeutics. In this study, we investigated the role of leucine-rich α-2-glycoprotein 1 (LRG1) in melanoma development and progression. We first established the association between LRG1 and melanoma in both human patient biopsies and mouse melanoma cell lines and revealed a significant induction of LRG1 expression in metastatic melanoma cells. We then showed no change in tumour cell growth, proliferation, and angiogenesis in the absence of the host Lrg1. On the other hand, there was reduced melanoma cell metastasis to the lungs in Lrg1-deficient mice. This observation was supported by the promoting effect of LRG1 in melanoma cell migration, invasion, and adhesion. Mechanistically, LRG1 mediates melanoma cell invasiveness in an EGFR/STAT3-dependent manner. Taken together, our studies provided compelling evidence that LRG1 is required for melanoma metastasis but not growth. Targeting LRG1 may offer an alternative strategy to control malignant melanoma

A newborn with a 790 kb chromosome 17p13.3 microduplication presenting with aortic stenosis, microcephaly and dysmorphic facial features - Is cardiac assessment necessary for all patients with 17p13.3 microduplication?

While deletion of chromosome 17p13.3 (encompassing PAFAH1B1 and YWHAE genes) is known to result in Miller-Dieker syndrome (OMIM 247200), 17p13.3 microduplication gives rise to a condition commonly associated with developmental delay and autism spectrum disorder. We report a Chinese newborn presenting with dysmorphic features, microcephaly and valvar aortic stenosis, who was confirmed to have a 790 kb microduplication in chromosome 17p13.3 by array comparative genomic hybridization (aCGH). The patient passed away at 4 months of age with presumably life-threatening event associated with his cardiac condition. From literature review, congenital heart diseases of various kinds were identified in up to 20% of patients with 17p13.3 microduplication. We propose cardiac assessment should be part of the comprehensive evaluation of these patients. © 2012 Elsevier Masson SAS.link_to_subscribed_fulltex

Collaborative Regulation of LRG1 by TGF-β1 and PPAR-β/δ Modulates Chronic Pressure Overload-Induced Cardiac Fibrosis.

Despite its established significance in fibrotic cardiac remodeling, clinical benefits of global inhibition of TGF (transforming growth factor)-β1 signaling remain controversial. LRG1 (leucine-rich-α2 glycoprotein 1) is known to regulate endothelial TGFβ signaling. This study evaluated the role of LRG1 in cardiac fibrosis and its transcriptional regulatory network in cardiac fibroblasts. Pressure overload-induced heart failure was established by transverse aortic constriction. Western blot, quantitative reverse transcription polymerase chain reaction, immunofluorescence, and immunohistochemistry were used to evaluate the expression level and pattern of interested targets or pathology during fibrotic cardiac remodeling. Cardiac function was assessed by pressure-volume loop analysis. LRG1 expression was significantly suppressed in left ventricle of mice with transverse aortic constriction-induced fibrotic cardiac remodeling (mean difference, -0.00085 [95% CI, -0.0013 to -0.00043]; P=0.005) and of patients with end-stage ischemic-dilated cardiomyopathy (mean difference, 0.13 [95% CI, 0.012-0.25]; P=0.032). More profound cardiac fibrosis (mean difference, -0.014% [95% CI, -0.029% to -0.00012%]; P=0.048 for interstitial fibrosis; mean difference, -1.3 [95% CI, -2.5 to -0.2]; P=0.016 for perivascular fibrosis), worse cardiac dysfunction (mean difference, -2.5 ms [95% CI, -4.5 to -0.4 ms]; P=0.016 for Tau-g; mean difference, 13% [95% CI, 2%-24%]; P=0.016 for ejection fraction), and hyperactive TGFβ signaling in transverse aortic constriction-operated Lrg1-deficient mice (mean difference, -0.27 [95% CI, -0.47 to -0.07]; P&lt;0.001), which could be reversed by cardiac-specific Lrg1 delivery mediated by adeno-associated virus 9. Mechanistically, LRG1 inhibits cardiac fibroblast activation by competing with TGFβ1 for receptor binding, while PPAR (peroxisome proliferator-activated receptor)-β/δ and TGFβ1 collaboratively regulate LRG1 expression via SMRT (silencing mediator for retinoid and thyroid hormone receptor). We further demonstrated functional interactions between LRG1 and PPARβ/δ in cardiac fibroblast activation. Our results established a highly complex molecular network involving LRG1, TGFβ1, PPARβ/δ, and SMRT in regulating cardiac fibroblast activation and cardiac fibrosis. Targeting LRG1 or PPARβ/δ represents a promising strategy to control pathological cardiac remodeling in response to chronic pressure overload