No abstract

The cardiac T-box transcription factor TBX5 is crucial for proper cardiovascular development, and mutations in TBX5 have been associated with various congenital heart diseases and arrhythmias in humans. However, whether mutated TBX5 contributes to dilated cardiomyopathy (DCM) remains unclear. In this study, the coding exons and flanking introns of the TBX5 gene were sequenced in 190 unrelated patients with idiopathic DCM. The available family members of the index patient carrying an identified mutation and 200 unrelated ethnically matched healthy individuals used as controls were genotyped for TBX5. The functional characteristics of the mutant TBX5 were explored in contrast to its wild-type counterpart by using a dual-luciferase reporter assay system. As a result, a novel heterozygous TBX5 mutation, p.S154A, was identified in a family with DCM inherited in an autosomal dominant pattern, which co-segregated with DCM in the family with complete penetrance. The missense mutation was absent in 400 control chromosomes and the altered amino acid was completely conserved evolutionarily across various species. Functional assays revealed that the mutant TBX5 had significantly decreased transcriptional activity. Furthermore, the mutation markedly diminished the synergistic activation of TBX5 with NKX2-5 or GATA4, other two transcription factors causatively linked to DCM. This study firstly associates TBX5 loss-of-function mutation with enhanced susceptibility to DCM, providing novel insight into the molecular mechanisms of DCM, and suggesting the potential implications in the development of new treatment strategies for this common form of myocardial disorder.

Purpose: To assess whether measuring the pattern of pancreatic enhancement on gadolinium chelate dynamic magnetic resonance imaging (MRI) is helpful for diagnosis of suspected early or mild chronic pancreatitis. Materials and Methods:In this retrospective study, 24 patients with suspected early or mild chronic pancreatitis, classified by imaging criteria of equivocal chronic pancreatitis (ultrasound, computed tomography [CT] or ERCP) grading, had dynamic MRI that included unenhanced, arterial dominant, early venous, and late venous phases of contrast enhancement. Twenty patients without pancreatic diseases also had the dynamic sequence as a control group. The signal intensity was measured at the pancreatic head, body, and tail on all phases, and for each, the signal intensity ratio (SIR, the signal intensity in postcontrast divided by that in precontrast) was calculated. Two radiologists independently reviewed the images of the patients with suspected early or mild chronic pancreatitis for pancreatic morphologic abnormalities without knowing the results of signal intensity measurements.Results: On unenhanced images, there was no significant difference of signal intensity between control and pancreatitis groups (P Ͻ 0.05). In the pancreatitis group, but not in the control group, the unenhanced signal intensity of the pancreatic head and body were significantly higher than that of the tail (P Ͻ 0.05). In the control group, the greatest enhancement (highest SIR) after injection was in the arterial phase (1.89 Ϯ 0.31), significantly higher than that in the early venous phase (1.68 Ϯ 0.17, P Ͻ 0.01) and in the late venous phase (1.61 Ϯ 0.15, P Ͻ 0.001). The pancreatitis group, however, had an arterial phase SIR (1.65 Ϯ 0.23) that was significantly lower than its early venous phase SIR (1.75 Ϯ 0.22, P Ͻ 0.05) and lower than the arterial phase SIR of the control group (P Ͻ 0.01). The presence of an SIR less than 1.73 in the arterial phase and/or a delayed peak enhancement after contrast agent administration had a sensitivity and specificity of diagnosing early or mild chronic pancreatitis of 92% and 75%, respectively. This sensitivity was significantly higher than the sensitivity of 50% for diagnosis based on morphologic abnormalities (P Ͻ 0.05). Conclusion:Measuring pancreatic signal intensity on gadolinium chelate dynamic MRI is helpful for diagnosing early or mild chronic pancreatitis, especially before apparent pancreatic morphologic or signal intensity changes are present.

Intracoronary transfer of autologous BMC in patients with healed MI did not lead to significant improvement of cardiac systolic function, infarct size or myocardial perfusion, but did lead to improvement in diastolic function.

Background: Acute xerostomia is the most common side effect of radiation therapy (RT) for head and neck (H&N) malignancies. Investigating radiation-induced changes of computed tomography (CT) radiomics in parotid glands (PGs) and saliva amount (SA) can predict acute xerostomia during the RT for nasopharyngeal cancer (NPC).Methods: CT and SA data from 35 patients with stages I-IVB were randomly collected from an NPC clinical trial registered on the clinicaltrials.gov (ID: NCT01762514). All patients received radical treatment based on intensity-modulated RT (IMRT) with a prescription dose of 68.1 Gy in 30 fractions. The patients' ages ranged 24-72 years, and each patient had five CT sets acquired at treatment position: at the 0 th , 10 th , 20 th , 30 th fractions during the RT, and at 3-month later after the RT. The PGs for each CT set were delineated by a radiation oncologist and verified independently by another. Patients' saliva was collected every other 10 days during the RT. Acute xerostomia was evaluated based on the RTOG acute toxicity scoring and the SA. In total, 1,703 radiomics features were calculated for PGs from each CT set, including feature value at 0 th fraction (FV 0F ), FV 10F , and delta FV (ΔFV 10F-0F ), respectively. Extensive experiments were conducted to achieve the optimal results. RidgeCV and Recursive Feature Elimination (RFE) were used for feature selection, while linear regression was used for predicting SA 30F . Four more patients were added for independent testing.Results: Substantial changes in various radiomics metrics of PGs were observed during the RT. Eight normalized feature value (NFV), selected from NFV 0F , predicted SA 10F with a mean square error (MSE) of 0.9042 and a R 2 score of 0.7406. Fourteen NFV, selected from ΔNFV 10F-0F , NFV 0F , and NFV 10F to predict SA 30F , showed the best predictive ability with an MSE of 0.0569. The model predicted the level of acute xerostomia with a precision of 0.9220 and a sensitivity of 100%, compared to the clinical observed SA. For the independent test, the MSE of PSA 30F was 0.0233. Conclusions:This study demonstrated that radiation-induced acute xerostomia level could be early predicted based on the SA and radiomics changes of the PGs during IMRT delivery. SA, NFV 0F , NFV 10F , and especially ΔNFV 10F-0F provided the best performance on acute xerostomia prediction for individual patient based on RidgeCV_RFE_LinearRegression method of delta radiomics.

No abstract

Molecular-based classifications of gastric cancer (GC) were recently proposed, but few of them robustly predict clinical outcomes. While mutation and expression signature of protein-coding genes were used in previous molecular subtyping methods, the noncoding genome in GC remains largely unexplored. Here, we developed the fast long-noncoding RNA analysis (FLORA) method to study RNA sequencing data of GC cases, and prioritized tumor-specific long-noncoding RNAs (lncRNAs) by integrating clinical and multi-omic data. We uncovered 1235 tumor-specific lncRNAs, based on which three subtypes were identified. The lncRNA-based subtype 3 (L3) represented a subgroup of intestinal GC with worse survival, characterized by prevalent TP53 mutations, chromatin instability, hypomethylation, and over-expression of oncogenic lncRNAs. In contrast, the lncRNA-based subtype 1 (L1) has the best survival outcome, while LINC01614 expression further segregated a subgroup of L1 cases with worse survival and increased chance of developing distal metastasis. We demonstrated that LINC01614 over-expression is an independent prognostic factor in L1 and network-based functional prediction implicated its relevance to cell migration. Over-expression and CRISPR-Cas9-guided knockout experiments further validated the functions of LINC01614 in promoting GC cell growth and migration. Altogether, we proposed a lncRNA-based molecular subtype of GC that robustly predicts patient survival and validated LINC01614 as an oncogenic lncRNA that promotes GC proliferation and migration.

Congenital heart disease (CHD), the most common form of developmental abnormality in humans, remains a leading cause of morbidity and mortality in neonates. Genetic defects have been recognized as the predominant causes of CHD. Nevertheless, CHD is of substantial genetic heterogeneity and the genetic defects underlying CHD in most cases remain unclear. In the current study, the coding regions and splicing junction sites of the TBX20 gene, which encodes a T-box transcription factor key to cardiovascular morphogenesis, were sequenced in 175 unrelated patients with CHD, and a novel heterozygous TBX20 mutation, p.K274X, was identified in an index patient with tetralogy of Fallot (TOF). Genetic analysis of the proband's available family members showed that his father, elder brother and son had also TOF. In addition, his father and elder brother had also atrial septal defect, and his niece had persistent truncus arteriosus and ventricular septal defect. Analysis of the pedigree revealed that the mutation co-segregated with CHD transmitted in an autosomal dominant fashion, with complete penetrance. The nonsense mutation, which was absent in the 800 control chromosomes, was predicted to produce a truncated protein with only the amino terminus and partial T-box domain left. Functional analyses by using a dual-luciferase reporter assay system showed that the mutant TBX20 lost the ability to transactivate the target gene ANF. Furthermore, the mutation reduced the synergistic activation between TBX20 and NKX2.5 as well as GATA4, two other transcriptional factors previously associated with various CHD, encompassing TOF. This study firstly links TBX20 loss-of-function mutation to familial TOF or sporadic persistent truncus arteriosus, providing novel insight into the molecular pathogenesis of CHD.