Overexpression of metastatic tumor antigen 1 (MTA1) was correlated with poor prognosis of hepatitis B virus (HBV)‐associated hepatocellular carcinoma (HBV‐HCC). The aim of this study was to examine ...the clinical significance of the expression of MTA1 and its exon 4‐excluded form (MTA1dE4), the most abundant spliced variant of MTA1, in patients receiving curative resection for HBV‐HCC. We collected 102 patients with HBV‐HCC and received curative resection retrospectively and examined the expressions level of total MTA1/MTA1dE4 in their paired nontumor and tumor liver tissues by using RT‐qPCR. The association between MTA1/MTA1dE4 expression and various tumor features as well as tumor recurrence was analyzed. During the median follow‐up period of 4 years, 25 patients (24.5%) showed early recurrence (within 12 months postresection) and 42 (54.5%) showed late recurrence. In Kaplan‐Meier analysis, MTA1dE4 overexpression in tumor, but not MTA1, was associated with early recurrence (P = 0.0365), but not late recurrence. In multivariate analysis, only alpha‐fetoprotein (AFP) ≥200 ng/mL (P = 0.006) and large tumor size (P = 0.027) were correlated with early recurrence. In the subgroup of patients with AFP <200 ng/mL, high MTA1dE4, but not total MTA1, expression could help predict early recurrence (P = 0.0195). In vitro, wound healing and invasion assays were performed in HCC cells, and MTA1dE4 was found to exhibit a higher ability in promoting migration and invasion of hepatoma cells than full‐length MTA1. Conclusion: MTA1dE4 expression is correlated with more aggressive tumor characteristics and might serve as a more sensitive marker for early recurrence of HBV‐HCC, especially for low‐AFP patients.
Both nuclear and cytoplasmic overexpression of metastatic tumor antigen 1 (MTA1) contributes to tumorigenesis of HCC. Most studies have focused on nuclear MTA1 whose function is mainly a chromatin ...modifier regulating the expression of various cancer-promoting genes. By contrast, the molecular mechanisms of cytoplasmic MTA1 in carcinogenesis remain elusive. Here, we reveal a role of MTA1 in posttranscriptional gene regulation.
We conducted the in vitro and in vivo RNA-protein interaction assays indicating that MTA1 could bind directly to the 3'-untranslated region of MYC RNA. Mutation at the first glycine of the conserved GXXG loop within a K-homology II domain-like structure in MTA1 (G78D) resulted in the loss of RNA-binding activity. We used gain- and loss-of-function strategy showing that MTA1, but not the G78D mutant, extended the half-life of MYC and protected it from the lethal -7-mediated degradation. The G78D mutant exhibited lower activity in promoting tumorigenesis than wild-type in vitro and in vivo. Furthermore, RNA-immunoprecipitation sequencing analysis demonstrated that MTA1 binds various oncogenesis-related mRNAs besides MYC . The clinical relevance of cytoplasmic MTA1 and its interaction with MYC were investigated using HBV-HCC cohorts with or without early recurrence. The results showed that higher cytoplasmic MTA1 level and MTA1- MYC interaction were associated with early recurrence.
MTA1 is a generic RNA-binding protein. Cytoplasmic MTA1 and its binding to MYC is associated with early recurrence in patients with HBV-HCC. This function enables it to regulate gene expression posttranscriptionally and contributes to hepatocarcinogenesis.
Hemophilia is a genetic disorder linked to the sex chromosomes, resulting in impaired blood clotting due to insufficient intrinsic coagulation factors. There are approximately one million individuals ...worldwide with hemophilia, with hemophilia A being the most prevalent form. The current treatment for hemophilia A involves the administration of clotting factor VIII (FVIII) through regular and costly injections, which only provide temporary relief and pose inconveniences to patients. In utero transplantation (IUT) is an innovative method for addressing genetic disorders, taking advantage of the underdeveloped immune system of the fetus. This allows mesenchymal stromal cells to play a role in fetal development and potentially correct genetic abnormalities. The objective of this study was to assess the potential recovery of coagulation disorders in FVIII knockout hemophilia A mice through the administration of human amniotic fluid mesenchymal stromal cells (hAFMSCs) via IUT at the D14.5 fetal stage. The findings revealed that the transplanted human cells exhibited fusion with the recipient liver, with a ratio of approximately one human cell per 10,000 mouse cells and produced human FVIII protein in the livers of IUT-treated mice. Hemophilia A pups born to IUT recipients demonstrated substantial improvement in their coagulation issues from birth throughout the growth period of up to 12 weeks of age. Moreover, FVIII activity reached its peak at 6 weeks of age, while the levels of FVIII inhibitors remained relatively low during the 12-week testing period in mice with hemophilia. In conclusion, the results indicated that prenatal intrahepatic therapy using hAFMSCs has the potential to improve clotting issues in FVIII knockout mice, suggesting it as a potential clinical treatment for individuals with hemophilia A.
The development of security-aware mobile devices using wide-input-output (IO) nonvolatile memory (NVM) is hindered by high peak current, large area overhead for high read bandwidth (BWR), and ...considerable energy consumption for data movement between NVM and logic blocks. Furthermore, data stored in NVM are vulnerable to reverse-engineering attacks. This work presents a high BWR security-aware near-memory-computing spin-transfer torque magnetic random-access memory (STT-MRAM) macro using a multi-bit current-mode sense amplifier (MB-CSA) to reduce peak current and energy consumption for wide-IO access, a near-memory shift-and-rotate functionality (NSRF) in conjunction with the MB-CSA to reduce area overhead and enable the completion of read and logic operations within a single cycle, and a reverse-engineering-proof XOR-based memory data protector to protect data stored in NVM against reverse-engineering attacks. A 1-Mb 1024-b read STT-MRAM macro with data protector fabricated using foundry embedded 22-nm STT-MRAM. This work achieved 42.67 GB/s for BWR and 0.23 pJ/b. Inclusion of the NSRF circuit reduced area overhead by 33.3% while increasing latency by only 170 ps.
The development of alcohol-associated liver disease (ALD) is influenced by the amount and duration of alcohol consumption. The resulting liver damage can range from reversible stages, such as ...steatosis, steatohepatitis and alcoholic fibrosis, to the advanced and irreversible stage of cirrhosis. Aldo-keto reductase family 1 member A1 (AKR1A1) is a member of the aldo-keto reductase family that catalyzes the reduction of aldehyde groups to their corresponding alcohols in an NADPH-dependent manner. AKR1A1 was found to be downregulated in patients diagnosed with ALD. This study aims to interpret the protective effects of AKR1A1 on the development of ALD.
A 5% alcohol-fed (AF) Akr1a1 knockout (Akr1a1
) mouse model and an AML12 hepatocyte model were used. The effects of AKR1A1 on liver function, inflammation, oxidative stress, lipid accumulation, and fibrosis were assessed by ELISA, western blotting, RT‒PCR, and a variety of histological staining methods in AF-induced wild-type (WT) and Akr1a1
mice compared to control liquid diet-fed (PF) WT and Akr1a1
mice.
The results demonstrated that AF-WT mice expressed higher levels of AKR1A1 than WT mice fed a control diet, and they did not show any noticeable liver steatosis. However, AF-Akr1a1
mice displayed a lower survival rate and more severe liver injury than AF-WT mice, as demonstrated by increased proinflammatory cytokines, oxidative stress, lipid accumulation, fibrosis, and reduced antioxidant enzymes in their livers. Additionally, elevated levels of 4-HNE and p53 phosphorylation were observed in AF-Akr1a1
mice, suggesting that the loss of AKR1A1 led to increased 4-HNE accumulation and subsequent activation of p53, which contributed to the progression of ALD. Furthermore, in AML12 hepatocytes, Akr1a1 knockdown aggravated oxidative stress and steatosis induced by palmitic acid/oleic acid (P/O) inflammation induced by lipopolysaccharide (LPS), and fibrosis induced by TGF-β1.
This loss-of-function study suggests that AKR1A1 plays a liver-protective role during chronic alcohol consumption by reducing the accumulation of 4-HNE and inhibiting 4-HNE-mediated p53 activation.
The association between type 1 diabetes mellitus (T1DM) and asthma remains controversial and has led to new interest in these 2 disorders. The purpose of this study was to examine the associations ...among young people with T1DM and asthma and offer a clinical demonstration of the balance between Th1 and Th2 responses.We conducted a retrospective cohort study by using data from the National Health Insurance (NHI) system of Taiwan. The cohort consisted of 3545 T1DM cases and 14,180 controls established during the 1998 to 2011 period. Of the 3545 T1DM patients, 55.1% were girls and 26.5% were in the age group <8 years.The overall incidence of asthma was 47% higher in the T1DM cohort than in the control cohort (6.49 vs 4.42 per 1000 person-y), with an adjusted hazard ratio (HR) of 1.34 (95% confidence interval CI = 1.11-1.62). Moreover, T1DM patients who visited the emergency room (ER) more than twice for diabetes had a higher adjusted HR of 17.4 (95% CI = 12.9-23.6) of developing asthma. The adjusted HR of asthma was 38.6 (95% CI = 28.5-52.2) in T1DM patients who had been hospitalized more than twice for diabetes.We observed a significantly higher incidence of asthma in young patients with T1DM than in the general population. Among young people of T1DM with more ER visits or frequent hospitalization because of diabetes mellitus were associated with risk of asthma, may indicate that poor glycemic control significantly contributes to asthma risk.
Osteoporosis is a clinically prevalent comorbidity in patients with hemophilia. A preventive effect of kefir peptides (KPs) on postmenopausal osteoporosis has been proved. The aim of this study was ...to evaluate the therapeutic effect of KPs for the treatment of osteoporosis in coagulation factor VIII (
) gene knockout mice (F8KO), a model of hemophilia A. In this study, male F8KO mice at 20 weeks of age were orally administered different doses of KPs for 8 weeks. The therapeutic effects of KPs were shown in the femoral trabeculae and the 4
lumbar vertebrae, which increased the trabecular bone mineral density (BMD), bone volume (Tb.BV/TV), and trabecular number (Tb.N) and decreased the trabecular separation (Tb.Sp), and they were also observed in the femoral cortical bones, in which the mechanical properties were enhanced in a dose-dependent manner. Characterization of receptor activator of nuclear factor κB ligand (RANKL), osteoprotegerin (OPG), and interleukin 6 (IL-6) demonstrated that the serum RANKL/OPG ratio and IL-6 levels were significantly decreased in the F8KO mice after the KP treatment. Tartrate-resistant acid phosphatase (TRAP) staining of mature osteoclasts indicated that the therapeutic effect of KPs in F8KO mice was associated with the functions of KPs to inhibit RANKL-induced osteoclastogenesis by reducing serum RANKL/OPG ratio and IL-6 secretion. The present study is the first to address the potentials of KPs for the treatment of hemophilia-induced osteoporosis in mice and it also provides useful information for the application of KPs as a complementary therapy for the treatment of osteoporosis in hemophilic patients.
Hemophilia A is a bleeding disease caused by loss of coagulation factor VIII (FVIII) function. Although prophylactic FVIII infusion prevents abnormal bleeding, disability and joint damage in ...hemophilia patients are common. The cost of treatment is among the highest for a single disease, and the adverse effects of repeated infusion are still an issue that has not been addressed. In this study, we established a nonviral gene therapy strategy to treat FVIII knockout (FVIII KO) mice. A novel gene therapy approach was developed using dipalmitoylphosphatidylcholine formulated with iron oxide (DPPC-Fe3O4) to carry the B-domain-deleted (BDD)-FVIII plasmid, which was delivered into the FVIII KO mice via tail vein injection. Here, a liver-specific albumin promoter-driven BDD-FVIII plasmid was constructed, and the binding ability of circular DNA was confirmed to be more stable than that of linear DNA when combined with DPPC-Fe3O4 nanoparticles. The FVIII KO mice that received the DPPC-Fe3O4 plasmid complex were assessed by staining the ferric ion of DPPC-Fe3O4 nanoparticles with Prussian blue in liver tissue. The bleeding of the FVIII KO mice was improved in a few weeks, as shown by assessing the activated partial thromboplastin time (aPTT). Furthermore, no liver toxicity, thromboses, deaths, or persistent changes after nonviral gene therapy were found, as shown by serum liver indices and histopathology. The results suggest that this novel gene therapy can successfully improve hemostasis disorder in FVIII KO mice and might be a promising approach to treating hemophilia A patients in clinical settings.
This work proposes (1) an auto-forming (AF) scheme to shorten the macro forming time (\text{T}_{\text{FM}-\text{M}}) and testing costs; (2) an auto-RESET (ARST) scheme to shorten page-RESET time ...(\text{T}_{\text{W}-\text{PAGE}-\text{RST}}) for expanding the applications of hidden-RESET operation in standby mode, and (3) an auto-SET (ASET) scheme to shorten page-write time (\text{T}_{\text{W}-\text{PAGE}}) combined with hidden-RESET scheme. A fabricated 40nm 2Mb ReRAM macro achieved 85+% reduction in T FM - M , and 99+\% reduction in \text{T}_{\text{W}}-\text{PAGE} for a page. For the first time, AF, ARST, and ASET schemes are demonstrated in silicon for ReRAM. Keywords: ReRAM, forming, page-write
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