Biliary atresia (BA) is characterized by the progressive fibrosclerosing obliteration of the extrahepatic biliary system during the first few weeks of life. Despite early diagnosis and prompt ...surgical intervention, the disease progresses to cirrhosis in many patients. The current theory for the pathogenesis of BA proposes that during the perinatal period, a still unknown exogenous factor meets the innate immune system of a genetically predisposed individual and induces an uncontrollable and potentially self-limiting immune response, which becomes manifest in liver fibrosis and atresia of the extrahepatic bile ducts. Genetic factors that could account for the disease, let alone for its high incidence in Chinese, are to be investigated. To identify BA susceptibility loci, we carried out a genome-wide association study (GWAS) using the Affymetrix 5.0 and 500 K marker sets. We genotyped nearly 500 000 single-nucleotide polymorphisms (SNPs) in 200 Chinese BA patients and 481 ethnically matched control subjects. The 10 most BA-associated SNPs from the GWAS were genotyped in an independent set of 124 BA and 90 control subjects. The strongest overall association was found for rs17095355 on 10q24, downstream XPNPEP1, a gene involved in the metabolism of inflammatory mediators. Allelic chi-square test P-value for the meta-analysis of the GWAS and replication results was 6.94 × 10−9. The identification of putative BA susceptibility loci not only opens new fields of investigation into the mechanisms underlying BA but may also provide new clues for the development of preventive and curative strategies.
Our laboratory has recently demonstrated a melatonin MT1 receptor-mediated antiproliferative signaling mechanism in androgen receptor (AR)-positive prostate epithelial cells which involves ...up-regulation of p27(Kip1) through dual activation of Gα(s)/protein kinase A (PKA) and Gα(q)/protein kinase C (PKC) in parallel, and down-regulation of activated AR signaling via PKC stimulation. The aim of the present investigation was to identify the transcription factor that mediates melatonin's up-regulatory effect on p27(Kip1) in LNCaP and 22Rv1 prostate cancer cells. Deletion mapping and reporter assays of the p27(Kip1) promoter revealed that the putative melatonin-responsive transcription factor binds to a 116 base-pair region of the promoter sequence, which contains a potential nuclear factor kappa B (NF-κB) binding site. When the NF-κB binding site was abolished by site-directed mutagenesis, the stimulatory effect of melatonin on p27(Kip1) promoter activity was mitigated. Notably, melatonin inhibited the DNA binding of activated NF-κB via MT1 receptor-induced PKA and PKC stimulation. Furthermore, melatonin's up-regulatory effect on p27(Kip1) transcription and consequent cell antiproliferation were abrogated by NF-κB activator but mimicked by NF-κB inhibitor. The results indicate that inhibition of constitutively active NF-κB via melatonin MT1 receptor-induced dual activation of (Gα(s)) PKA and (Gα(q)) PKC can de-repress the p27(Kip1) promoter leading to transcriptional up-regulation of p27(Kip1). MT1 receptor-mediated inhibition of activated NF-κB signaling provides a novel mechanism supporting the use of melatonin in prostate cancer chemoprevention and therapy.
Hirschsprung disease (HSCR, congenital colon aganglionosis) is a relatively common complex genetic condition caused by abnormal development of the enteric nervous system (ENS). Through a recent ...genome-wide association study conducted on Chinese HSCR patients, we identified a new HSCR contributing locus, neuregulin 1 (
NRG1
; 8p12), a gene known to be involved in the development of the ENS. As genes in which disease-associated common variants are found are to be considered as candidates for the search of deleterious rare variants (RVs) in the coding sequences, we sequenced the
NRG1
exons of 358 sporadic HSCR patients and 333 controls. We identified a total of 13 different heterozygous RVs including 8 non-synonymous (A28G, E134K, V266L, H347Y, P356L, V486M, A511T, P608A) and 3 synonymous amino acid substitutions (P24P, T169T, L483L), a frameshift (E239
fs
X10), and a c.503-4insT insertion. Functional analysis of the most conserved non-synonymous substitutions, H347Y and P356L, showed uneven intracellular distribution and aberrant expression of the mutant proteins. Except for T169T and V486M, all variants were exclusive to HSCR patients. Overall, there was a statistically significant over-representation of
NRG1
RVs in HSCR patients (
p
= 0.008). We show here that not only common, but also rare variants of the
NRG1
gene contribute to HSCR. This strengthens the role of
NRG1
.
In this study, we investigated the effects of a mindfulness-based family psychoeducation (MBFPE) program on the mental-health outcomes of both caregivers and young adults with first-episode psychosis ...with an onset in the past three years through a multi-site randomized controlled trial. We also studied the outcomes of three potential mediating effects of interpersonal mindfulness, expressed emotions, and non-attachment on the program.
We randomly assigned 65 caregivers of young adults with psychosis to MBFPE (
= 33) or an ordinary family psychoeducation (FPE) program (
= 32); among them, 18 young adults in recovery also participated in the evaluation of outcomes.
Intent-to-treat analyses were conducted. No significant time × group interaction effects of MBFPE and FPE programs were found in any of the caregivers' outcomes. However, the young adults with psychosis reported higher levels of recovery after the MBFPE program than after the ordinary FPE program (
= 8.268,
= 0.012,
= 1.484). They also reported a larger reduction in over-involvement of their caregivers (
= 4.846,
= 0.044,
= 1.136), showing that MBFPE had a superior effect to FPE in promoting recovery and reducing over-involvement.
A brief psychoeducation program may not reduce the burden on or improve the mental-health outcome of caregivers of individuals with recent-onset psychosis. However, integrating mindfulness into a conventional family psychoeducation program may reduce the expressed emotions of caregivers, especially over-involvement. Further studies should explore how psychoeducation programs can reduce the impact of psychosis on family through sustainable effects in terms of reducing their burden and expressed emotions, using a rigorous study and adequate sample size.
Background
Gliomas are the most common primary brain tumour. They are graded using the WHO classification system, with Grade II‐IV astrocytomas, oligodendrogliomas and oligoastrocytomas. Low‐grade ...gliomas (LGGs) are WHO Grade II infiltrative brain tumours that typically appear solid and non‐enhancing on magnetic resonance imaging (MRI) scans. People with LGG often have little or no neurologic deficit, so may opt for a watch‐and‐wait‐approach over surgical resection, radiotherapy or both, as surgery can result in early neurologic disability. Occasionally, high‐grade gliomas (HGGs, WHO Grade III and IV) may have the same MRI appearance as LGGs. Taking a watch‐and‐wait approach could be detrimental for the patient if the tumour progresses quickly. Advanced imaging techniques are increasingly used in clinical practice to predict the grade of the tumour and to aid clinical decision of when to intervene surgically. One such advanced imaging technique is magnetic resonance (MR) perfusion, which detects abnormal haemodynamic changes related to increased angiogenesis and vascular permeability, or "leakiness" that occur with aggressive tumour histology. These are reflected by changes in cerebral blood volume (CBV) expressed as rCBV (ratio of tumoural CBV to normal appearing white matter CBV) and permeability, measured by Ktrans.
Objectives
To determine the diagnostic test accuracy of MR perfusion for identifying patients with primary solid and non‐enhancing LGGs (WHO Grade II) at first presentation in children and adults. In performing the quantitative analysis for this review, patients with LGGs were considered disease positive while patients with HGGs were considered disease negative.
To determine what clinical features and methodological features affect the accuracy of MR perfusion.
Search methods
Our search strategy used two concepts: (1) glioma and the various histologies of interest, and (2) MR perfusion. We used structured search strategies appropriate for each database searched, which included: MEDLINE (Ovid SP), Embase (Ovid SP), and Web of Science Core Collection (Science Citation Index Expanded and Conference Proceedings Citation Index). The most recent search for this review was run on 9 November 2016.
We also identified 'grey literature' from online records of conference proceedings from the American College of Radiology, European Society of Radiology, American Society of Neuroradiology and European Society of Neuroradiology in the last 20 years.
Selection criteria
The titles and s from the search results were screened to obtain full‐text articles for inclusion or exclusion. We contacted authors to clarify or obtain missing/unpublished data.
We included cross‐sectional studies that performed dynamic susceptibility (DSC) or dynamic contrast‐enhanced (DCE) MR perfusion or both of untreated LGGs and HGGs, and where rCBV and/or Ktrans values were reported. We selected participants with solid and non‐enhancing gliomas who underwent MR perfusion within two months prior to histological confirmation. We excluded studies on participants who received radiation or chemotherapy before MR perfusion, or those without histologic confirmation.
Data collection and analysis
Two review authors extracted information on study characteristics and data, and assessed the methodological quality using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS‐2) tool. We present a summary of the study characteristics and QUADAS‐2 results, and rate studies as good quality when they have low risk of bias in the domains of reference standard of tissue diagnosis and flow and timing between MR perfusion and tissue diagnosis.
In the quantitative analysis, LGGs were considered disease positive, while HGGs were disease negative. The sensitivity refers to the proportion of LGGs detected by MR perfusion, and specificity as the proportion of detected HGGs. We constructed two‐by‐two tables with true positives and false negatives as the number of correctly and incorrectly diagnosed LGG, respectively, while true negatives and false positives are the number of correctly and incorrectly diagnosed HGG, respectively.
Meta‐analysis was performed on studies with two‐by‐two tables, with further sensitivity analysis using good quality studies. Limited data precluded regression analysis to explore heterogeneity but subgroup analysis was performed on tumour histology groups.
Main results
Seven studies with small sample sizes (4 to 48) met our inclusion criteria. These were mostly conducted in university hospitals and mostly recruited adult patients. All studies performed DSC MR perfusion and described heterogeneous acquisition and post‐processing methods. Only one study performed DCE MR perfusion, precluding quantitative analysis.
Using patient‐level data allowed selection of individual participants relevant to the review, with generally low risks of bias for the participant selection, reference standard and flow and timing domains. Most studies did not use a pre‐specified threshold, which was considered a significant source of bias, however this did not affect quantitative analysis as we adopted a common rCBV threshold of 1.75 for the review. Concerns regarding applicability were low.
From published and unpublished data, 115 participants were selected and included in the meta‐analysis. Average rCBV (range) of 83 LGGs and 32 HGGs were 1.29 (0.01 to 5.10) and 1.89 (0.30 to 6.51), respectively. Using the widely accepted rCBV threshold of <1.75 to differentiate LGG from HGG, the summary sensitivity/specificity estimates were 0.83 (95% CI 0.66 to 0.93)/0.48 (95% CI 0.09 to 0.90). Sensitivity analysis using five good quality studies yielded sensitivity/specificity of 0.80 (95% CI 0.61 to 0.91)/0.67 (95% CI 0.07 to 0.98). Subgroup analysis for tumour histology showed sensitivity/specificity of 0.92 (95% CI 0.55 to 0.99)/0.42 (95% CI 0.02 to 0.95) in astrocytomas (6 studies, 55 participants) and 0.77 (95% CI 0.46 to 0.93)/0.53 (95% CI 0.14 to 0.88) in oligodendrogliomas+oligoastrocytomas (6 studies, 56 participants). Data were too sparse to investigate any differences across subgroups.
Authors' conclusions
The limited available evidence precludes reliable estimation of the performance of DSC MR perfusion‐derived rCBV for the identification of grade in untreated solid and non‐enhancing LGG from that of HGG. Pooled data yielded a wide range of estimates for both sensitivity (range 66% to 93% for detection of LGGs) and specificity (range 9% to 90% for detection of HGGs). Other clinical and methodological features affecting accuracy of the technique could not be determined from the limited data. A larger sample size of both LGG and HGG, preferably using a standardised scanning approach and with an updated reference standard incorporating molecular profiles, is required for a definite conclusion.
Background: While statin induces plaque regression, its effects, particularly with different doses on plaque virtual histology composition, remain unknown. Methods and Results: In this prospective, ...randomized, double-blinded study, 40 consecutive statin-naive patients with stable angina requiring percutaneous coronary intervention (PCI) were randomized to 2 arms (20 patients each) receiving 6 months of atorvastatin 10mg or 40mg daily. The primary end-point was (VH-IVUS) changes from baseline to 6 months, as assessed by a core laboratory. Fifty-four VH-IVUS lesions were analyzed from the 10mg group and 57 from the 40mg group. Overall, plaque volume was reduced by 4.28% (–5.10±14.93mm3, P<0.001), absolute VH-IVUS fibrous volume by 10.54% (–4.87±10.74mm3, P<0.001), and relative percentage fibrous component by 3.29±7.84% (P<0.001), while relative percentage dense calcium increased by 1.50±3.08% (P<0.001), and necrotic core by 3.19±7.82% (P<0.001). Beneficial changes were more substantial in the higher dose (40mg) group, with significantly more percentage plaque volume regression (–1.50±3.85% vs. 0.38±4.05% increase in the 10mg group, P=0.014), less relative percentage necrotic core expansion (1.68±7.57% vs. 4.78±7.82% in the 10mg group, P=0.037), and without occurrence of major adverse cardiac events (vs. 6 patients in the 10mg group, P=0.020). Conclusions: In statin-naive patients requiring PCI, 6 months of atorvastatin induced a significant percentage of plaque volume reduction and substantial modification of VH-IVUS composition. In addition, these effects appeared to vary with different doses of atorvastatin, showing significantly better limitation of relative percentage necrotic core expansion at a higher dose. (Circ J 2012; 76: 2662–2672)
OBJECTIVE: To investigate short term effects of concentrations of pollutants in ambient air on hospital admissions for cardiovascular and respiratory diseases in Hong Kong. METHODS: Retrospective ...ecological study. A Poisson regression was performed of concentrations of daily air pollutant on daily counts of emergency hospital admissions in 12 major hospitals. The effects of time trend, season, and other cyclical factors, temperature, and humidity were accounted for. Autocorrelation and overdispersion were corrected. Daily concentrations of nitrogen dioxide (NO2), sulphur dioxide (SO2), ozone (O3), and particulate matter < 10 microns in aerodynamic diameter (PM10) were obtained from seven air monitoring stations in Hong Kong in 1994 and 1995. Relative risks (RR) of respiratory and cardiovascular disease admissions (for an increase of 10 micrograms/m3 in concentration of air pollutant) were calculated. RESULTS: Significant associations were found between hospital admissions for all respiratory diseases, all cardiovascular diseases, chronic obstructive pulmonary diseases, and heart failure and the concentrations of all four pollutants. Admissions for asthma, pneumonia, and influenza were significantly associated with NO2, O3, and PM10. Relative risk (RR) for admissions for respiratory disease for the four pollutants ranged from 1.013 (for SO2) to 1.022 (for O3), and for admissions for cardiovascular disease, from 1.006 (for PM10) to 1.016 (for SO2). Those aged > or = 65 years were at higher risk. Significant positive interactions were detected between NO2, O3, and PM10, and between O3 and winter months. CONCLUSIONS: Adverse health effects are evident at current ambient concentrations of air pollutants. Further reduction in air pollution is necessary to protect the health of the community, especially that of the high risk group.
Despite the established role of EGFR tyrosine kinase inhibitors (TKIs) in
-mutated NSCLC, drug resistance inevitably ensues, with a paucity of treatment options especially in
-negative resistance.
We ...performed whole-exome and transcriptome analysis of 59 patients with first- and second-generation EGFR TKI-resistant metastatic
-mutated NSCLC to characterize and compare molecular alterations mediating resistance in T790M-positive (T790M
) and -negative (T790M
) disease.
Transcriptomic analysis revealed ubiquitous loss of adenocarcinoma lineage gene expression in T790M
tumors, orthogonally validated using multiplex IHC. There was enrichment of genomic features such as
alterations, 3q chromosomal amplifications, whole-genome doubling and nonaging mutational signatures in T790M
tumors. Almost half of resistant tumors were further classified as immune
, with clinical outcomes conditional on immune cell-infiltration state and T790M status. Finally, using a Bayesian statistical approach, we explored how T790M
and T790M
disease might be predicted using comprehensive genomic and transcriptomic profiles of treatment-naïve patients.
Our results illustrate the interplay between genetic alterations, cell lineage plasticity, and immune microenvironment in shaping divergent TKI resistance and outcome trajectories in
-mutated NSCLC. Genomic and transcriptomic profiling may facilitate the design of bespoke therapeutic approaches tailored to a tumor's adaptive potential.
Omphalocele and gastroschisis are the most common types of abdominal wall defects. Comprehensive local experience helps parents to make decisions on the pregnancy and foresee the disease journey. A ...retrospective review of abdominal wall defect patients in all three pediatric surgical centers in Hong Kong between January 2003 and February 2023 was conducted. All patients consecutively diagnosed with omphalocele and gastroschisis were included, excluding other forms. Data of demographics and short- and long-term outcome parameters were collected. A total of 99 cases were reviewed and 85 patients met the inclusion criteria. Diagnoses include omphalocele major (
n
= 49, 57.6%), omphalocele minor (
n
= 22, 25.9%) and gastroschisis (
n
= 14, 16.5%), with mean gestational age 37 weeks (SD 2.2) and birth weight 2.7 kg (SD 0.6). Omphalocele is most commonly associated with cardiovascular (
n
= 28, 39.4%) and chromosomal defects (
n
= 11, 15.5%). Surgical procedures including primary repair (
n
= 38, 53.5%), staged closure (
n
= 30, 42.3%) with average 8.6 days (SD 4.7) of silo reduction, and conservative management (
n
= 3, 4.2%) were performed. The mortality rate was 14.1% (
n
= 10) and the complication rate was 36.6% (
n
= 26). The majority of patients had normal intellectual development (92.5%) and growth (79.2%) on the latest follow-up. For gastroschisis, one patient (7.1%) had intestinal atresia. Surgical procedures included primary repair (
n
= 9, 64.3%) and staged closure (
n
= 5, 35.7%) with average 8 days (SD 3.5) of silo reduction. Complication rate was 21.4% (
n
= 3), with one mortality (7.1%). All patients had normal intellectual development and growth. The mean follow-up time of this series is 76.9 months (SD 62.9). Most abdominal wall defects in our series were managed surgically with a good overall survival rate and long-term outcome. This information is essential during antenatal and postnatal counseling for parents.
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