Chronic hepatitis B patients with high viral loads are at increased risk of cirrhosis and hepatocellular carcinoma (HCC). In patients with low viral loads, higher hepatitis B surface antigen (HBsAg) ...levels have been shown to predict HCC development. However, little is known about the difference in risk for other hepatitis B virus (HBV)‐related adverse outcomes with varying HBsAg levels. A total of 1,068 Taiwanese hepatitis B e antigen (HBeAg)‐negative HBV carriers with serum HBV DNA level <2,000 IU/mL at baseline were followed for a mean duration of 13.0 years. Patients were categorized based on their HBsAg levels, and the relationships between HBsAg level and development of HBeAg‐negative hepatitis, hepatitis flare, and cirrhosis were investigated. Of the 1068 patients with low viral loads, 280 developed HBeAg‐negative hepatitis, with an annual incidence rate of 2.0%. HBsAg level, but not HBV DNA level, was found to be a risk factor for HBeAg‐negative hepatitis. Multivariate analysis showed that the adjusted hazard ratio in patients with an HBsAg level ≥1,000 versus <1000 IU/mL was 1.5 (95% confidence interval, 1.2–1.9). The positive correlation was present when evaluating other endpoints, including hepatitis flare and cirrhosis, and remained consistent when the study population was restricted to those with normal alanine aminotransferase (ALT) level at baseline. The annual incidence rate of HBeAg‐negative hepatitis was lowered to 1.1% in patients with low levels of HBV DNA, HBsAg, and ALT. Conclusion: In HBeAg‐negative patients with low viral loads and genotype B or C virus infection, a higher HBsAg level can predict disease progression. HBsAg <1,000 IU/mL in combination with low levels of HBV DNA and ALT help define minimal‐risk HBV carriers. (HEPATOLOGY 2013)
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality in Taiwan. The Taiwan Liver Cancer Association and the Gastroenterological Society of Taiwan had established a management ...consensus guideline in 2016. The current recommendations focus on updating critical issues regarding the management of HCC, including surveillance, diagnosis, and systemic treatment. For surveillance, the updated guideline suggests the role of dynamic computed tomography or magnetic resonance imaging and contrast-enhanced ultrasound (CEUS) in selected patients. For diagnosis, this update incorporates CEUS and recognizes the role of gadoxetic acid–enhanced magnetic resonance imaging. For systemic therapy, the updated guideline summarizes the multiple choices of targeted therapy, immune checkpoint inhibitors, and the combination of both. Through this update of the management consensus guideline, patients with HCC can benefit from receiving optimal diagnostic and therapeutic modalities.
Multilineage tissue-source mesenchymal stem cells (MSCs) possess strong immunomodulatory properties and are excellent therapeutic agents, but require constant isolation from donors to combat ...replicative senescence. The differentiation of human induced pluripotent stem cells (iPSCs) into MSCs offers a renewable source of MSCs; however, reports on their immunomodulatory capacity have been discrepant. Using MSCs differentiated from iPSCs reprogrammed using diverse cell types and protocols, and in comparison to human embryonic stem cell (ESC)-MSCs and bone marrow (BM)-MSCs, we performed transcriptome analyses and assessed for functional immunomodulatory properties. Differentiation of MSCs from iPSCs results in decreased c-Myc expression and its downstream pathway along with a concomitant downregulation in the DNA replication pathway. All four lines of iPSC-MSCs can significantly suppress in vitro activated human peripheral blood mononuclear cell (PBMC) proliferation to a similar degree as ESC-MSCs and BM-MSCs, and modulate CD4 T lymphocyte fate from a type 1 helper T cell (Th1) and IL-17A-expressing (Th17) cell fate to a regulatory T cell (Treg) phenotype. Moreover, iPSC-MSCs significantly suppress cytotoxic CD8 T proliferation, activation, and differentiation into type 1 cytotoxic T (Tc1) and IL-17-expressing CD8 T (Tc17) cells. Coculture of activated PBMCs with human iPSC-MSCs results in an overall shift of secreted cytokine profile from a pro-inflammatory environment to a more immunotolerant milieu. iPSC-MSC immunomodulation was also validated in vivo in a mouse model of induced inflammation. These findings support that iPSC-MSCs possess low oncogenicity and strong immunomodulatory properties regardless of cell-of-origin or reprogramming method and are good potential candidates for therapeutic use. Stem Cells 2018;36:903-914.
Background
We aimed to assess the latest prevalence and secular trend of Helicobacter pylori infection and its association with the incidence and mortality of gastric cancer in Taiwan.
Materials and ...Methods
Adults naive to H. pylori eradication received 13C‐urea breath test (13C‐UBT), H. pylori stool antigen test, and serology test during 2019–2020 in this prospective screening program. Children and adolescent aged between 7 and 19 years received 13C‐UBT for H. pylori screening. We also conducted a systematic review and meta‐analysis to assess the secular trend of prevalence of H. pylori from 1990 to 2020 in Taiwan. The secular trends of age‐standardized incidence and mortality of gastric cancer were obtained from the Taiwan Cancer Registry.
Results
A total of 1494 participants were enrolled, including 294 children or adolescents and 1200 adults. The overall prevalence of active H. pylori infection by 13C‐UBT was 26.6% (397/1494), which was 30.8% in adults and 9.5% in adolescents/children. The age‐standardized prevalence of active H. pylori infection was 32.3% in adults after adjustment of the population structure in Taiwan. Of the 29 studies including 38,597 subjects eligible for the meta‐analysis, the pooled prevalence of H. pylori infection decreased from 63.8% (95% CI: 55.9%–71%) in 1990–2000 to 28.2% (95% CI:21.8%–35.6%) in 2016–2020. The age‐standardized incidence and mortality of gastric cancer have also declined from 15.2 to 10.75 per 100,000, respectively, in 1999 to 9.29 and 5.4 per 100,000, respectively, in 2019.
Conclusions
The prevalence of H. pylori infection has declined in Taiwan, which correlates with the declining trends of age‐standardized incidence and mortality of gastric cancer in Taiwan.
Gallic acid (3,4,5-trihydroxybenzoic acid, GA), a phenolic acid, is ubiquitous in almost all parts of the plant. In the present study, a neuroinflammatory rat model using intranigral infusion of ...lipopolysaccharides (LPS, 4 μg/μL) was employed to study the neuroprotective effect of GA which was orally administered daily. Compared with the vehicle-treated rats, systemic administration of GA (100 mg/kg) significantly attenuated LPS-induced increases in glial fibrillary acidic protein (a biomarker of activated astrocytes) and ED-1 (a biomarker of activated microglia), as well as inducible nitric oxide synthase (iNOS, a proinflammatory enzyme) and interleukin-1β (a proinflammatory cytokine), in the LPS-infused substantia nigra (SN) of rat brain. At the same time, GA attenuated LPS-induced elevation in heme oxygenase-1 level (a redox-regulated protein) and α-synuclein aggregation (a hallmark of CNS neurodegeneration), suggesting that GA is capable of inhibiting LPS-induced oxidative stress and protein conjugation. Furthermore, GA prevented LPS-induced caspase 3 activation (a biomarker of programmed cell death) and LPS-induced increases in receptor-interacting protein kinase (RIPK)-1 and RIPK-3 levels (biomarkers of necroptosis), indicating that GA inhibited LPS-induced apoptosis and necroptosis in the nigrostriatal dopaminergic system of rat brain. Moreover, an in vitro study was employed to investigate the anti-inflammatory effect of GA on BV2 microglial cells which were subjected to LPS (1 μg/mL) treatment. Consistently, co-incubation of GA diminished LPS-induced increases in
iNOS
mRNA and iNOS protein expression in the treated BV-2 cells as well as NO production in the culture medium. The anti-oxidative activity of GA was evaluated using iron-induced lipid peroxidation of brain homogenates. After 3-h incubation at 37 °C, GA was more potent than glutathione and less potent than trolox in inhibiting iron-induced lipid peroxidation. Conclusively, the present study suggests that GA is anti-inflammatory via attenuating LPS-induced neuroinflammation, oxidative stress, and protein conjugation. Furthermore, GA prevented LPS-induced programmed cell deaths of nigrostriatal dopaminergic neurons of the rat brain, suggesting that GA may be neuroprotective by attenuating neuroinflammation in CNS neurodegenerative diseases.
Endoplasmic reticulum (ER) stress is an adaptive response to various stress conditions and plays emerging roles in cancer. Activating transcription factor 6 (ATF6), one of the three major ER stress ...transducers, has been shown to contribute to chemoresistance by altering cancer cell survival. Cancerous inhibitor of protein phosphatase 2A (CIP2A) is an oncogene, and its expression has been correlated with the prognosis of patients with cancer. In this study, we aimed to explore the relationship between ER stress‐related ATF signaling and CIP2A. We found that CIP2A expression was positively correlated with ATF6 expression by analyzing publicly available RNA sequence data of patients with colorectal cancer (The Cancer Genome Atlas, TCGA). In addition, we demonstrated that tunicamycin‐induced ER stress in vitro upregulated ATF6 and CIP2A. Mechanistically, we found that ATF6 directly bound to the CIP2A promoter and induced CIP2A gene expression, which contributed to colon cancer cell survival. Furthermore, knockdown of CIP2A reduced the viability of cells under ER stress. Most importantly, immunohistochemical analysis of a tissue microarray from a colon cancer patient cohort showed that higher expression levels of ATF6 and CIP2A were associated with a trend toward poor prognosis. Taken together, our results show that ER stress‐related ATF6 upregulates CIP2A and contributes to the prognosis of colon cancer. Targeting CIP2A may disrupt ER stress‐mediated colon cancer cell survival and thus improve the prognosis of patients with colon cancer.
Endoplasmic reticulum (ER) stress induces activating transcription factor 6 (ATF6) that translocates from the ER to the Golgi membrane to release active form of ATF6. The active ATF6 directly binds to the cancerous inhibitor of protein phosphatase 2A (CIP2A) promoter and elicits CIP2A gene expression, which contributes to colon cancer cell survival and the prognosis of colon cancer.
Aromatic l‐amino acid decarboxylase deficiency (AADCD), attributed to mutations in the dopa decarboxylase (DDC) gene, is a rare neurometabolic disease resulting from a defect in the biosynthesis of ...dopamine and serotonin. The DDC c.714+4A>T mutation is the most prevalent mutation among patients with AADCD, and is also a founder mutation among Taiwanese patients. In this study, the molecular consequences and function of this mutation were examined in AADCD patient‐derived lymphoblastoid cells. We identified novel DDC mRNA isoforms spliced with a new exon (exon 6a) in normal and c.714+4A>T lymphoblastoid cells. In addition, we identified the SR proteins (SRSF9 and SRSF6), as well as cis‐elements involved in modulating the splicing of this mutated transcript. Notably, we demonstrated that antisense oligonucleotides (ASOs) were able to restore the normal mRNA splicing and increase the level of DDC protein, as well as its downstream product serotonin, in lymphoblastoid cells derived from the patient with AADCD, suggesting that these ASOs might represent a feasible alternative strategy for gene therapy of AADCD in patients with the common c.714+4A>T mutation.
Antisense oligonucleotides (ASOs) were able to modulate the mRNA splicing errors and increase the level of DDC protein, as well as its downstream product serotonin, in lymphoblastoid cells derived from AADCD patient bearing with founder splicing mutation.
Triple negative breast cancer (TNBC) lacks specific drug targets and remains challenging. Palbociclib, a cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor is approved for metastatic estrogen ...receptor (ER)-positive and human epithermal growth factor 2 (HER2)-negative breast cancer. The nature of cell cycle inhibition by palbociclib suggests its potential in TNBC cells. Retinoblastoma (RB, a known substrate of CDK4/6) pathway deregulation is a frequent occurrence in TNBC and studies have revealed that pharmacological CDK4/6 inhibition induces a cooperative cytostatic effect with doxorubicin in RB-proficient TNBC models. In addition, recent studies reported that anti-androgen therapy shows preclinical efficacy in androgen-receptor (AR)-positive TNBC cells. Here we examined the effect of palbociclib in combination with an anti-androgen enzalutamide in TNBC cells.
MDA-MB-453, BT-549, MDA-MB-231 and MDA-MB-468 TNBC cell lines were used for in vitro studies. Protein expressions were assessed by Western blot analysis. Cytostatic effect was examined by MTT assay. Cell cycle and apoptosis were examined by flow cytometry.
Palbociclib showed inhibitory effect in RB-proficient TNBC cells, and enzalutamide inhibited cell viability in AR-positive TNBC cells. Enzalutamide treatment could enhance the palbociclib-induced cytostatic effect in AR-positive/RB-proficient TNBC cells. In addition, palbociclib-mediated G1 arrest in AR-positive/RB-proficient TNBC cells was attenuated by RB knockdown.
Our study provided a preclinical rationale in selecting patients who might have therapeutic benefit from combining CDK4/6 inhibitors with AR antagonists.
Primary pulmonary meningioma Hsu, Chia‐Chi; Tsai, Ying‐Ming; Yang, Sheau‐Fang ...
The Kaohsiung journal of medical sciences,
11/2023, Volume:
39, Issue:
11
Journal Article
Peer reviewed
Open access
Radiologically, a PPM typically presents as an isolated, well-defined solid nodule 1; however, some PPMs may present as ground-glass density nodules or multiple solid nodules. 1,3 PPMs have various ...enhancement CT manifestations, and the pattern of lesion enhancement might not help to determine whether the PPM is benign or malignant. 1 Additionally, one recent study reported increased glucose uptake in synchronous benign and malignant PPMs. 4 This result suggested that the malignancy of PPM might not be correlated with 18F-FDG uptake. CONFLICT OF INTEREST The authors declare no conflict of interest.
To prospectively compare the efficacy of intra-articular injections of platelet-rich plasma (PRP) and hyaluronic acid (HA) with a sham control group (normal saline solution NS) for knee ...osteoarthritis in a randomized, dose-controlled, placebo-controlled, double-blind, triple-parallel clinical trial.
A total of 87 osteoarthritic knees (53 patients) were randomly assigned to 1 of 3 groups receiving 3 weekly injections of either leukocyte-poor PRP (31 knees), HA (29 knees), or NS (27 knees). The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score and International Knee Documentation Committee (IKDC) subjective score were collected at baseline and at 1, 2, 6, and 12 months after treatment. Data were analyzed using generalized estimating equations.
All 3 groups showed statistically significant improvements in both outcome measures at 1 month; however, only the PRP group sustained the significant improvement in both the WOMAC score (63.71 ± 20.67, increased by 21%) and IKDC score (49.93 ± 17.74, increased by 40%) at 12 months. For the intergroup comparison, except for the first month, there was a statistically significant difference between the PRP and NS groups in both scores throughout the study duration (regression coefficients of 8.72 P = .0015, 7.94 P = .0155, and 11.92 P = .0014 at 2, 6, and 12 months, respectively, for WOMAC score, and 9.1 P = .0001, 10.28 P = .0002, and 13.97 P < .0001, respectively, for IKDC score). There was no significant difference in both functional outcomes between the HA and NS groups at any time point. Only the PRP group reached the minimal clinically important difference in the WOMAC score at every evaluation (15%, 21%, 18%, and 21% at 1, 2, 6, and 12 months, respectively) and the minimal clinically important difference in the IKDC score at 6 months (improvement of 11.6).
Intra-articular injections of leukocyte-poor PRP can provide clinically significant functional improvement for at least 1 year in patients with mild to moderate osteoarthritis of the knee.
Level I, randomized controlled single-center trial.
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