We evaluated the ability of various grading scales including platelet-albumin-bilirubin (PALBI) and albumin-bilirubin (ALBI) grades to predict overall survival (OS) according to treatment modality in ...patients with hepatocellular carcinoma (HCC).
The cohort of 6,669 patients with HCC was selected randomly from the 2008-2012 national cohort of the Korean Central Cancer Registry. The OS of 6,507 of these patients was evaluated using the Child-Turcotte-Pugh (CTP) class, Model for End-stage Liver Disease (MELD) score, and ALBI and PALBI grades.
The patient's mean age was 59.7 years. The most patients were hepatitis B virus (63.4%) and CTP class A (71.8%). The median OS durations of PALBI grade1 (38.4%), grade2 (33.2%), and grade3 (28.4%) patients were 81, 30, and 5 months, respectively (P<0.001). The PALBI grade had a larger area under the receiver operator characteristic curve (AUC) than did the CTP class, MELD score, and ALBI grade (overall AUC: 0.675 vs. 0.633, 0.645, and 0.642, respectively; P < 0.001). Moreover, the PALBI and ALBI grades enabled sub-classification of CTP A patients (P < 0.001). In a multivariate analysis, the PALBI and ALBI grades were significant risk factors for OS (P < 0.05). According to treatment modality, the PALBI grade was predictive of OS in patients receiving transarterial chemoembolization or supportive care. The ALBI grade was predictive of OS in patients undergoing surgical resection or radiofrequency ablation.
The PALBI and ALBI grades are more reliable for accessing liver function and predicting OS in patients with HCC. Moreover, according to treatment modality, appropriate use of the ALBI and PALBI grades will enable accurate determination of the prognosis of patients with HCC.
Unintended genetic modifications that occur during the differentiation and proliferation of human induced pluripotent stem cells (hiPSCs) can lead to tumorigenicity. This is a crucial concern in the ...development of stem cell-based therapies to ensure the safety and efficacy of the final product. Moreover, conventional genetic stability testing methods are limited by low sensitivity, which is an issue that remains unsolved. In this study, we assessed the genetic stability of hiPSCs and hiPSC-derived cardiomyocytes using various testing methods, including karyotyping, CytoScanHD chip analysis, whole-exome sequencing, and targeted sequencing. Two specific genetic mutations in
and
were selected from the 17 gene variants identified by whole-exome and targeted sequencing methods, which were validated using droplet digital PCR. The applicability of this approach to stem cell-based therapeutic products was further demonstrated with associated validation according to the International Council for Harmonisation (ICH) guidelines, including specificity, precision, robustness, and limit of detection. Our droplet digital PCR results showed high sensitivity and accuracy for quantitatively detecting gene mutations, whereas conventional qPCR could not avoid false positives. In conclusion, droplet digital PCR is a highly sensitive and precise method for assessing the expression of mutations with tumorigenic potential for the development of stem cell-based therapeutics.
Radioresistance is a challenge in the treatment of esophageal squamous cell carcinoma (ESCC). MicroRNAs (miRNAs) are known to play an important role in the functional modification of cancer cells and ...recent studies have reported miRNA-mediated radiotherapy resistance. However, further research is necessary to reveal the regulation mechanisms, and treatment strategies using miRNA are yet to be established for ESCC. We compared the miRNA expression profiles of ESCC parental (TE-4) and acquired radioresistance (TE-4R) cell lines using a miRNA microarray and qRT-PCR. Our data showed that miR-338-5p, one of the target miRNA biomarkers, was significantly downregulated in TE-4R. Ectopic overexpression of miR-338-5p induced apoptosis and sensitivity to radiation treatment by interfering with survivin, which is a known inhibitor of apoptosis. Overexpression of survivin reversed miR-338-5p-induced apoptosis. Tumor xenograft experiments indicated that therapeutic delivery of the miR-338-5p mimics via direct injection into tumor mass increased sensitivity to radiation therapy. In conclusion, our findings suggest that miR-338-5p is a potential radiosensitizer and may be a therapeutic biomarker for radioresistant in ESCC.
Sjogren's syndrome (SS) is a heterogenous disease with various phenotypes. We aimed to provide a relevant subclassification based on symptom-based clustering for patients with primary (p) SS.
Data ...from patients in a prospective pSS cohort in Korea were analysed. Latent class analysis (LCA) was performed using patient reported outcomes, including pain, fatigue, dryness, and anxiety/depression. Clinical and laboratory differences between the classes were analysed. Latent transition analysis (LTA) was applied to the longitudinal data (annually for up to 5 years) to assess temporal stability of the classifications.
LCA identified three classes among 341 patients with pSS (i.e., 'high symptom burden', 'dryness dominant', 'low symptom burden'). Each group had distinct laboratory and clinical phenotypes. LTA revealed that class membership remained stable over time. Baseline class predicted future salivary gland function and damage accrual represented by a Sjogren's syndrome disease damage index.
Symptom-based clustering of heterogenous patients with primary Sjogren's syndrome provided a relevant classification supported by temporal stability over time and distinct phenotypes between the classes. This clustering strategy may provide more homogenous groups of pSS patients for novel treatment development and predict future phenotypic evolvement.
Solid-pseudopapillary neoplasm is an uncommon pancreatic tumor with distinct clinicopathologic features. Solid-pseudopapillary neoplasms are characterized by mutations in exon 3 of CTNNB1. However, ...little is known about the gene and microRNA expression profiles of solid-pseudopapillary neoplasms. Thus, we sought to characterize solid-pseudopapillary neoplasm-specific gene expression and identify the signaling pathways activated in these tumors. Comparisons of gene expression in solid-pseudopapillary neoplasm to pancreatic ductal carcinomas, neuroendocrine tumors, and non-neoplastic pancreatic tissues identified solid-pseudopapillary neoplasm-specific mRNA and microRNA profiles. By analyzing 1686 (1119 upregulated and 567 downregulated) genes differentially expressed in solid-pseudopapillary neoplasm, we found that the Wnt/β-catenin, Hedgehog, and androgen receptor signaling pathways, as well as genes involved in epithelial mesenchymal transition, are activated in solid-pseudopapillary neoplasms. We validated these results experimentally by assessing the expression of β-catenin, WIF-1, GLI2, androgen receptor, and epithelial–mesenchymal transition-related markers with western blotting and immunohistochemistry. Our analysis also revealed 17 microRNAs, especially the miR-200 family and miR-192/215, closely associated with the upregulated genes associated with the three pathways activated in solid-pseudopapillary neoplasm and epithelial mesenchymal transition. Our results provide insight into the molecular mechanisms underlying solid-pseudopapillary neoplasm tumorigenesis and its characteristic less epithelial cell differentiation than the other common pancreatic tumors.
We investigated the clinical course of patients with prolonged disorders of consciousness (PDoC), predictors of emergence from PDoC (EDoC), and the temporal dynamics of six neurobehavior domains ...based on the JFK Coma Recovery Scale-Revised (CRS-R) during the recovery.
A total of 50 traumatic and non-traumatic patients with PDoC were enrolled between October 2014 and February 2017. A retrospective analysis of the clinical findings and neurobehavioral signs was conducted using standardized methodology such as CRS-R. The findings were used to investigate the incidence and predictors of EDoC and determine the cumulative pattern of neurobehavioral recovery at 6 months, 1 year, and 2 years post-injury.
The results showed that 46% of the subjects emerged from PDoC after 200 median days (64-1197 days) of injury onset. The significant predictors of EDoC included minimally conscious state (MCS) (vs. vegetative state), higher auditory, communication, arousal, total CRS-R scores, shorter lag time post-injury, and the absence of intra-axial lesions. In terms of cumulative recovery of motor and communication signs in patients who emerged from PDoC, 39 and 32% showed EDoC at 6 months post-injury, and 88 and 93% exhibited EDoC at 2 years post-injury, respectively.
Nearly half of the patients with PDoC recovered consciousness during inpatient rehabilitation. MCS, shorter lag time, the absence of intra-axial lesions, higher auditory, communication, arousal, and total CRS-R scores were important predictors for EDoC. Motor scores in the early stage of recovery and communication scores after prolonged intervals contributed to the higher levels of cumulative EDoC.
Abstract
β
1
-adrenergic receptors (β
1
ARs) mediate catecholamine actions in cardiomyocytes by coupling to both Gs/cAMP-dependent and Gs-independent/growth-regulatory pathways. Structural studies of ...the β
1
AR define ligand-binding sites in the transmembrane helices and effector docking sites at the intracellular surface of the β
1
AR, but the extracellular N-terminus, which is a target for post-translational modifications, typically is ignored. This study identifies β
1
AR N-terminal O-glycosylation at Ser
37
/Ser
41
as a mechanism that prevents β
1
AR N-terminal cleavage. We used an adenoviral overexpression strategy to show that both full-length/glycosylated β
1
ARs and N-terminally truncated glycosylation-defective β
1
ARs couple to cAMP and ERK-MAPK signaling pathways in cardiomyocytes. However, a glycosylation defect that results in N-terminal truncation stabilizes β
1
ARs in a conformation that is biased toward the cAMP pathway. The identification of O-glycosylation and N-terminal cleavage as novel structural determinants of β
1
AR responsiveness in cardiomyocytes could be exploited for therapeutic advantage.
Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), which are collectively called pluripotent stem cells (PSCs), have emerged as a promising source for regenerative medicine. ...Particularly, human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) have shown robust potential for regenerating injured heart. Over the past two decades, protocols to differentiate hPSCs into CMs at high efficiency have been developed, opening the door for clinical application. Studies further demonstrated therapeutic effects of hPSC-CMs in small and large animal models and the underlying mechanisms of cardiac repair. However, gaps remain in explanations of the therapeutic effects of engrafted hPSC-CMs. In addition, bioengineering technologies improved survival and therapeutic effects of hPSC-CMs in vivo. While most of the original concerns associated with the use of hPSCs have been addressed, several issues remain to be resolved such as immaturity of transplanted cells, lack of electrical integration leading to arrhythmogenic risk, and tumorigenicity. Cell therapy with hPSC-CMs has shown great potential for biological therapy of injured heart; however, more studies are needed to ensure the therapeutic effects, underlying mechanisms, and safety, before this technology can be applied clinically.
Gain-of-function mutations and KIT overexpression are well-known tumorigenesis mechanisms in gastrointestinal stromal tumors (GIST). This study aimed to discover microRNAs (miRNA) that target KIT and ...reveal the relationship between the discovered miRNAs and KIT expression in GISTs.
Fresh-frozen GISTs from 31 patients were used to confirm the relationship between miR-494 and KIT expression using quantitative reverse transcription-PCR to assess miR-494 expression levels and Western blotting to assess KIT protein expression levels. A luciferase assay was conducted for the target evaluation. The functional effects of miR-494 on GIST882 cells (GIST cell line with activating KIT mutation) were validated by a cell proliferation assay and fluoresce-activated cell sorting analysis.
An inverse relationship was found between the expression levels of miR-494 and KIT in GISTs (r = -0.490, P = 0.005). The direct targeting of KIT by miR-494 was shown by the reduction in KIT expression after miR-494 overexpression and the increase in KIT expression after inhibiting endogenous miR-494 expression. We showed that miR-494 regulates KIT by binding two different seed match sites. Induced miR-494 overexpression in GIST882 reduced the expression of downstream molecules in KIT signaling transduction pathways, including phospho-AKT and phospho-STAT3. Finally, miR-494 overexpression provoked apoptosis and inhibited GIST cell growth, which were accompanied by changes in G(1) and S phase content.
Our findings indicate that miR-494 is a negative regulator of KIT in GISTs and overexpressing miR-494 in GISTs may be a promising approach to GIST treatment.
PDF
