Neonatal outcomes of preterm infants with pulmonary hypertension: clustering based on prenatal risk factors.

BACKGROUND: To investigate association of prenatal risk factors and neonatal outcomes of preterm infants with pulmonary hypertension (PH). METHODS: A prospective cohort study of very-low-birth-weight infants born at 22-29 weeks' gestation who received PH-specific treatment during hospitalization. Infants were classified using a two-step cluster analysis based on gestational age (GA), small-for-gestational-age (SGA), exposure to antenatal corticosteroids (ACS), histologic chorioamnionitis (HCA), and oligohydramnios. RESULTS: Among 910 infants, six clusters were identified: cluster A (HCA, n = 240), cluster B (oligohydramnios, n = 79), cluster C (SGA, n = 74), cluster D (no-ACS, n = 109), cluster E (no dominant parameter, n = 287), and cluster F (HCA and oligohydroamnios, n = 121). Cluster A was used as a reference group for comparisons among clusters. Compared to cluster A, cluster C (aHR: 1.63 [95% CI: 1.17-2.26]) had higher risk of overall in-hospital mortality. Clusters B (aHR: 1.52 [95% CI: 1.09-2.11]), D (aHR: 1.71 [95% CI: 1.28-2.30]), and F (aHR: 1.51 [95% CI: 1.12-2.03]) had higher risks of receiving PH-specific treatment within the first week of birth compared to cluster A. CONCLUSION: These findings may provide a better understanding of prenatal risk factors contributing to the development of PH. IMPACT: Pulmonary hypertension (PH), presenting as hypoxic respiratory failure, has complex etiologies in preterm infants. Although multifactorial risks for the development of PH in preterm infants are known, few studies have classified infants with similar etiologies for PH. Each cluster has distinct patterns of prenatal condition and neonatal outcome.

Apoptotic Effect of Isoimpertorin via Inhibition of c-Myc and SIRT1 Signaling Axis.

Though Isoimperatorin from Angelicae dahuricae is known to have antiviral, antidiabetic, anti-inflammatory and antitumor effects, its underlying antitumor mechanism remains elusive so far. Hence, the apoptotic mechanism of Isoimperatorin was explored in hepatocellular carcinomas (HCCs). In this study, Isoimperatorin inhibited the viability of Huh7 and Hep3B HCCs and increased the subG1 apoptotic portion and also abrogated the expression of pro-poly-ADP ribose polymerase (pro-PARP) and pro-caspase 3 in Huh7 and Hep3B cells. Also, Isoimperatorin abrogated the expression of cyclin D1, cyclin E1, CDK2, CDK4, CDK6 and increased p21 as G1 phase arrest-related proteins in Huh7 and Hep3B cells. Interestingly, Isoimperatorin reduced the expression and binding of c-Myc and Sirtuin 1 (SIRT1) by Immunoprecipitation (IP), with a binding score of 0.884 in Huh7 cells. Furthermore, Isoimperatorin suppressed the overexpression of c-Myc by the proteasome inhibitor MG132 and also disturbed cycloheximide-treated c-Myc stability in Huh7 cells. Overall, these findings support the novel evidence that the pivotal role of c-Myc and SIRT1 is critically involved in Isoimperatorin-induced apoptosis in HCCs as potent molecular targets in liver cancer therapy.

Astragalus membranaceus Extract Induces Apoptosis via Generation of Reactive Oxygen Species and Inhibition of Heat Shock Protein 27 and Androgen Receptor in Prostate Cancers.

Although Astragalus membranaceus is known to have anti-inflammatory, anti-obesity, and anti-oxidant properties, the underlying apoptotic mechanism of Astragalus membranaceus extract has never been elucidated in prostate cancer. In this paper, the apoptotic mechanism of a water extract from the dried root of Astragalus membranaceus (WAM) was investigated in prostate cancer cells in association with heat shock protein 27 (HSP27)/androgen receptor (AR) signaling. WAM increased cytotoxicity and the sub-G1 population, cleaved poly (ADP-ribose) polymerase (PARP) and cysteine aspartyl-specific protease 3 (caspase 3), and attenuated the expression of B-cell lymphoma 2 (Bcl-2) in LNCaP cells after 24 h of exposure. Consistently, WAM significantly increased the number of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive LNCaP cells. WAM decreased the phosphorylation of HSP27 on Ser82 and inhibited the expression of the AR and prostate-specific antigen (PSA), along with reducing the nuclear translocation of p-HSP27 and the AR via the disturbed binding of p-HSP27 with the AR in LNCaP cells. WAM consistently inhibited the expression of the AR and PSA in dihydrotestosterone (DHT)-treated LNCaP cells. WAM also suppressed AR stability, both in the presence and absence of cycloheximide, in LNCaP cells. Taken together, these findings provide evidence that WAM induces apoptosis via the inhibition of HSP27/AR signaling in prostate cancer cells and is a potent anticancer candidate for prostate cancer treatment.

Inhibition of glycolysis and SIRT1/GLUT1 signaling ameliorates the apoptotic effect of Leptosidin in prostate cancer cells.

Since the silent information regulation 2 homolog-1 (sirtuin, SIRT1) and glucose transporter 1 (GLUT1) are known to modulate cancer cell metabolism and proliferation, the role of SIRT1/GLUT1 signaling was investigated in the apoptotic effect of Leptosidin from Coreopsis grandiflora in DU145 and PC3 human prostate cancer (PCa) cells. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, cell cycle analysis, Western blotting, cBioportal correlation analysis, and co-immunoprecipitation were used in this work. Leptosidin showed cytotoxicity, augmented sub-G1 population, and abrogated the expression of pro-poly (ADP-ribose) polymerase (pro-PARP) and pro-cysteine aspartyl-specific protease (pro-caspase3) in DU145 and PC3 cells. Also, Leptosidin inhibited the expression of SIRT1, GLUT1, pyruvate kinase isozymes M2 (PKM2), Hexokinase 2 (HK2), and lactate dehydrogenase A (LDHA) in DU145 and PC3 cells along with disrupted binding of SIRT1 and GLUT1. Consistently, Leptosidin curtailed lactate, glucose, and ATP in DU145 and PC3 cells. Furthermore, SIRT1 depletion enhanced the decrease of GLUT1, LDHA, and pro-Cas3 by Leptosidin in treated DU145 cells, while pyruvate suppressed the ability of Leptosidin in DU145 cells. These findings suggest that Leptosidin induces apoptosis via inhibition of glycolysis and SIRT1/GLUT1 signaling axis in PCa cells.

Carbon footprint and cost reduction by endoscopic grading of gastric intestinal metaplasia using narrow-band imaging.

BACKGROUND AND AIM: Gastric intestinal metaplasia (GIM) is a high-risk factor for the development of gastric cancer. Narrow-band imaging (NBI) enables endoscopic grading of GIM (EGGIM). In the era of climate change, gastrointestinal endoscopists are expected to reduce greenhouse gas emissions and medical waste. Based on the diagnostic performance of NBI endoscopy, this study measured the environmental impact and reduced cost of implementing EGGIM during gastroscopy. METHODS: Using NBI endoscopy in 242 patients, EGGIM classification and operative link on GIM (OLGIM) staging were prospectively performed in five different areas (lesser and greater curvatures of the corpus and antrum, and the incisura angularis). We estimated the environmental impact and cost reduction of the biopsy procedures and pathological processing if EGGIM were used instead of OLGIM. RESULTS: The diagnostic accuracy of NBI endoscopy for GIM was 93.0-97.1% depending on the gastric area. When a high EGGIM score ≥ 5 was the cut-off value for predicting OLGIM stages III-IV, the area under the curve was 0.862, sensitivity was 81.9%, and specificity was 90.4%. The reduction in the carbon footprint by EGGIM was -0.4059 kg carbon dioxide equivalents per patient, equivalent to 1 mile driven by a gasoline-powered car. The cost savings were calculated to be $47.36 per patient. CONCLUSIONS: EGGIM is a reliable method for identifying high-risk gastric cancer patients, thereby reducing the carbon footprint and medical costs in endoscopy practice.

Conversion to colistin susceptibility by tigecycline exposure in colistin-resistant Klebsiella pneumoniae and its implications to combination therapy.

OBJECTIVES: This study investigated the effect of tigecycline exposure on susceptibility of colistin-resistant Klebsiella pneumoniae isolates to colistin and explored the possibility of antibiotic combination at low concentrations to treat colistin-resistant K. pneumoniae isolates. METHODS: Twelve tigecycline-resistant (TIR) mutants were induced in vitro from wild-type, colistin-resistant, and tigecycline-susceptible K. pneumoniae isolates. Antibiotic susceptibility was determined using the broth microdilution method. The deduced amino acid alterations were identified for genes associated with colistin resistance, lipid A biosynthesis, and tigecycline resistance. Expression levels of genes were compared between wild-type stains and TIR mutants using quantitative real-time polymerase chain reaction (PCR). Lipid A modification was explored using MALDI-TOF mass spectrometry. Time-killing assay was performed to assess the efficiency of combination therapy using low concentrations of colistin and tigecycline. RESULTS: All TIR mutants except one were converted to be susceptible to colistin. These TIR mutants had mutations in the ramR gene and increased expression levels of ramA. Three genes associated with lipid A biosynthesis, lpxC, lpxL, and lpxO, were also overexpressed in TIR mutants, although no mutation was observed. Additional polysaccharides found in colistin-resistant, wild-type strains were modified in TIR mutants. Colistin-resistant K. pneumoniae strains were eliminated in vitro by combining tigecycline and colistin at 2 mg/L. In this study, we found that tigecycline exposure resulted in reduced resistance of colistin-resistant K. pneumoniae to colistin. Such an effect was mediated by regulation of lipid A modification involving ramA and lpx genes. CONCLUSION: Because of such reduced resistance, a combination of colistin and tigecycline in low concentrations could effectively eradicate colistin-resistant K. pneumoniae strains.

The microRNA-193a-5p induced ROS production and disturbed colocalization between STAT3 and androgen receptor play critical roles in cornin induced apoptosis.

Though cornin is known to induce angiogenic, cardioprotective, and apoptotic effects, the apoptotic mechanism of this iridoid monoglucoside is not fully understood in prostate cancer cells to date. To elucidate the antitumor mechanism of cornin, cytotoxicity assay, cell cycle analysis, Western blotting, RT-qPCR, RNA interference, immunofluorescence, immunoprecipitation, reactive oxygen species (ROS) measurement, and inhibitor assay were applied in this work. Cornin exerted cytotoxicity, increased sub-G1 population, and cleaved PARP and caspase3 in LNCaP cells more than in DU145 cells. Consistently, cornin suppressed phosphorylation of signal transducer and activator of transcription 3 (STAT3) and disrupted the colocalization of STAT3 and androgen receptor (AR) in LNCaP and DU145 cells, along with suppression of AR, prostate-specific antigen (PSA), and 5α-reductase in LNCaP cells. Furthermore, cornin increased ROS production and the level of miR-193a-5p, while ROS inhibitor N-acetylcysteine disturbed the ability of cornin to attenuate the expression of AR, p-STAT3, PSA, pro-PARP, and pro-caspase3 in LNCaP cells. Notably, miR-193a-5p mimics the enhanced apoptotic effect of cornin, while miR-193a-5p inhibitor reverses the ability of cornin to abrogate AR, PSA, and STAT3 in LNCaP cells. Our findings suggest that ROS production and the disturbed crosstalk between STAT3 and AR by microRNA-193a-5p are critically involved in the apoptotic effect of cornin in prostate cancer cells.

The Correlations between the Intensity of Histopathological Ubiquitin-Specific Protease 11 Staining and Progression of Prostate Cancer.

BACKGROUND: Ubiquitin-specific protease 11 (USP11), one of the principal phosphatase and tensin homolog (PTEN) deubiquitinases, can reserve PTEN polyubiquitination to maintain PTEN protein integrity and inhibit PI3K/AKT pathway activation. The aim of the current study was to investigate the associations between immunohistochemical USP11 staining intensities and prognostic indicators in individuals with prostate cancer. METHODS: Tissue microarrays (TMAs) were performed for human prostate cancer and normal tissue (control) samples. Data on patient's age, Gleason score, plasma prostate-specific antigen (PSA) titer, disease stage, and presence of seminal vesicles, lymph nodes, and surgical margin involvement were collected. A pathologist who was blinded to the clinical outcome data scored the TMA for USP11 staining intensity as either positive or negative. RESULTS: Cancerous tissues exhibited lower USP11 staining intensity, whereas the neighboring benign peri-tumoral tissues showed higher USP11 staining intensity. The degree of USP11 staining intensity was lower in patients with a higher PSA titer, higher Gleason score, or more advanced disease stage. Patients who showed positive USP11 staining were more likely to have more optimal clinical and biochemical recurrence-free survival statistics. CONCLUSIONS: USP11 staining intensity in patients with prostate cancer is negatively associated with several prognostic factors such as an elevated PSA titer and a high Gleason score. It also reflects both biochemical and clinical recurrence-free survival in such patients. Thus, USP11 staining is a valuable prognostic factor in patients with prostate cancer.

Long-Term Outcome of Unilateral Acoustic Neuromas With or Without Hearing Loss: Over 10 Years and Beyond After Gamma Knife Radiosurgery.

BACKGROUND: Since the long-term outcomes of 162 patients who underwent gamma knife radiosurgery (GKS) as an initial or adjuvant treatment for acoustic neuromas (ANs) with unilateral hearing loss were first reported in 1998, there has been no report of a comprehensive analysis of what has changed in GKS practice. METHODS: We performed a retrospective study of the long-term outcomes of 106 patients with unilateral sporadic ANs who underwent GKS as an initial treatment. The mean patient age was 50 years, and the mean initial tumor volume was 3.68 cm3 (range, 0.10-23.30 cm3). The median marginal tumor dose was 12.5 Gy (range, 8.0-15.0 Gy) and the median follow-up duration was 153 months (range, 120-216 months). RESULTS: The tumor volume increased in 11 patients (10.4%), remained stationary in 27 (25.5%), and decreased in 68 patients (64.2%). The actuarial 3, 5, 10, and 15-year tumor control rates were 95.3 ± 2.1%, 94.3 ± 2.2%, 87.7 ± 3.2%, and 86.6 ± 3.3%, respectively. The 10-year actuarial tumor control rate was significantly lower in the patients with tumor volumes of ≥ 8 cm3 (P = 0.010). The rate of maintaining the same Gardner-Robertson scale grade was 28.6%, and that of serviceable hearing was 46.4%. The rates of newly developed facial and trigeminal neuropathy were 2.8% and 4.7%, respectively. The patients who received marginal doses of less than 12 Gy revealed higher tumor control failure rates (P = 0.129) and newly occurred facial or trigeminal neuropathy rates (P = 0.040 and 0.313, respectively). CONCLUSION: GKS as an initial treatment for ANs could be helpful in terms of tumor control, the preservation of serviceable hearing, and the prevention of cranial neuropathy. It is recommended to perform GKS as soon as possible not only for tumor control in unilateral ANs with hearing loss but also for hearing preservation in those without hearing loss.

Application of Static Headspace GC-MS Method for Selective 1,4-Dioxane Detection in Food Additives.

Efficient detection methods must be developed for 1,4-dioxane due to its suspected status as a human carcinogen, which is highly mobile in food and environmental resources. In this regard, this experiment has been conducted to develop reliable and selective detection and measurement methods by using static headspace (SH) isolation, followed by gas chromatography-mass spectrometry (GC-MS). A new method was developed for determining the spiked 1,4-dioxane contents in a polyethylene glycol 600 (PEG 600). The optimal condition for SH-GC-MS was discussed. The representative ions of 1,4-dioxane and 1,4-dioxane-d8 in the SIM mode of MS are 88 and 96, respectively, and the peaks of the SIM mode were separated and confirmed. The linear range for the method covers 0.25 to 100 mg/L with a coefficient of determination (R2) ≥ 0.999. The method applicability was demonstrated by spike recovery across a variety of food additives (i.e., chlorine bitartrate, choline chloride, polysorbate 20 and 60, and PEG 1000). All spike recovery from the tested samples was in the range of 89.50-102.68% with a precision of 0.44-11.22%. These findings suggest a new analytical method for food safety inspection, and could be applicable for ensuring the safety of foods and environmental and public health on a broad scale.

Postoperative cervical length to predict success of repeat cerclage in singleton pregnancies with prolapsed membranes after prior cerclage.

Background: This study aimed to evaluate the outcome of repeat cerclage (RC) in singleton pregnancies with prolapsed membranes following a prior cerclage and analyze predictive factors for delivery at ≥26 weeks of gestation following RC. Materials and methods: Patients who underwent RC between 2010 and 2020 at the Hallym University Medical Center were reviewed. Women with singleton pregnancies with prolapsed membranes following prior cerclage were candidates for RC. We analyzed the characteristics, pregnancy outcomes, perioperative clinical and laboratory findings, and postoperative cervical length (CL) to identify the factors for predicting delivery at ≥26 weeks following RC. Results: Thirty-five women with RC were identified; the median gestational age (GA) at a prior cerclage was 14 weeks, the average GA at RC was 21 + 3 weeks, and the median GA at delivery following RC was 26 + 2 weeks. Patients were divided into two groups based on their delivery status at 26 weeks: 17 women delivered at <26 weeks (range, 18 + 4-25 + 6 weeks) (Group A) and 18 women delivered at ≥26 weeks (range, 26 + 2-40 + 3 weeks) (Group B). The median GA at delivery in group A was 22 + 4 weeks, whereas that in group B was 33 + 4 weeks (p < 0.001). No differences in preoperative clinical and laboratory findings were observed between the two groups. However, the postoperative CL in group A was significantly shorter than that in group B (12 mm vs. 21.5 mm, p < 0.001). The ROC curve of postoperative CL predicting delivery at ≥26 weeks showed an AUC of 0.843; a CL of 20 mm showed a sensitivity of 61.1% and a specificity of 100%. Conclusion: RC may prolong singleton pregnancies with prolapsed membranes following prior cerclage. A postoperative CL ≥20 mm may predict the success of RC.

The Apoptotic and Anti-Warburg Effects of Brassinin in PC-3 Cells via Reactive Oxygen Species Production and the Inhibition of the c-Myc, SIRT1, and ß-Catenin Signaling Axis.

Though Brassinin is known to have antiangiogenic, anti-inflammatory, and antitumor effects in colon, prostate, breast, lung, and liver cancers, the underlying antitumor mechanism of Brassinin is not fully understood so far. Hence, in the current study, the apoptotic mechanism of Brassinin was explored in prostate cancer. Herein, Brassinin significantly increased the cytotoxicity and reduced the expressions of pro-Poly ADP-ribose polymerase (PARP), pro-caspase 3, and B-cell lymphoma 2 (Bcl-2) in PC-3 cells compared to DU145 and LNCaP cells. Consistently, Brassinin reduced the number of colonies and increased the sub-G1 population and terminal deoxynucleotidyl transferase (TdT) dUTP Nick-End Labeling (TUNEL)-positive cells in the PC-3 cells. Of note, Brassinin suppressed the expressions of pyruvate kinase-M2 (PKM2), glucose transporter 1 (GLUT1), hexokinase 2 (HK2), and lactate dehydrogenase (LDH) as glycolytic proteins in the PC-3 cells. Furthermore, Brassinin significantly reduced the expressions of SIRT1, c-Myc, and ß-catenin in the PC-3 cells and also disrupted the binding of SIRT1 with ß-catenin, along with a protein-protein interaction (PPI) score of 0.879 and spearman's correlation coefficient of 0.47 being observed between SIRT1 and ß-catenin. Of note, Brassinin significantly increased the reactive oxygen species (ROS) generation in the PC-3 cells. Conversely, ROS scavenger NAC reversed the ability of Brassinin to attenuate pro-PARP, pro-Caspase3, SIRT1, and ß-catenin in the PC-3 cells. Taken together, these findings support evidence that Brassinin induces apoptosis via the ROS-mediated inhibition of SIRT1, c-Myc, ß-catenin, and glycolysis proteins as a potent anticancer candidate.

Apoptotic and anti-Warburg effect of Morusin via ROS mediated inhibition of FOXM1/c-Myc signaling in prostate cancer cells.

Though Morusin is known to induce apoptotic, antiprolifertaive, and autophagic effects through several signaling pathways, the underlying molecular mechanisms of Morusin still remain unclear until now. To elucidate antitumor mechanism of Morusin, cytotoxicity assay, cell cycle analysis, Western blotting, TUNEL assay, RNA interference, immunofluorescense, immunoprecipitation, reactive oxygen species (ROS) measurement, and inhibitor study were applied in this study. Morusin enhanced cytotoxicity, increased the number of TUNEL positive cells, sub-G1 population and induced the cleavages of PARP and caspase3, attenuated the expression of HK2, PKM2, LDH, c-Myc, and Forkhead Box M1 (FOXM1) along with the reduction of glucose, lactate, and ATP in DU145 and PC3 cells. Furthermore, Morusin disrupted the binding of c-Myc and FOXM1 in PC-3 cells, which was supported by String and cBioportal database. Notably, Morusin induced c-Myc degradation mediated by FBW7 and suppressed c-Myc stability in PC3 cells exposed to MG132 and cycloheximide. Also, Morusin generated ROS, while NAC disrupted the capacity of Morusin to reduce the expression of FOXM1, c-Myc, pro-PARP, and pro-caspase3 in PC-3 cells. Taken together, these findings provide scientific evidence that ROS mediated inhibition of FOXM1/c-Myc signaling axis plays a critical role in Morusin induced apoptotic and anti-Warburg effect in prostate cancer cells. Our findings support scientific evidence that ROS mediated inhibition of FOXM1/c-Myc signaling axis is critically involved in apoptotic and anti-Warburg effect of Morusin in prostate cancer cells.

Utility of accelerated T2-weighted turbo spin-echo imaging with deep learning reconstruction in female pelvic MRI: a multi-reader study.

OBJECTIVES: To determine the clinical feasibility of T2-weighted turbo spin-echo (T2-TSE) imaging with deep learning reconstruction (DLR) in female pelvic MRI compared with conventional T2 TSE in terms of image quality and scan time. METHODS: Between May 2021 and September 2021, 52 women (mean age, 44 years ± 12) who underwent 3-T pelvic MRI with additional T2-TSE using a DLR algorithm were included in this single-center prospective study with patient's informed consents. Conventional, DLR, and DLR T2-TSE images with reduced scan times were independently assessed and compared by four radiologists. The overall image quality, differentiation of anatomic details, lesion conspicuity, and artifacts were evaluated using a 5-point scale. Inter-observer agreement of the qualitative scores was compared and reader protocol preferences were then evaluated. RESULTS: In the qualitative analysis of all readers, fast DLR T2-TSE showed significantly better overall image quality, differentiation of anatomic regions, lesion conspicuity, and lesser artifacts than conventional T2-TSE and DLR T2-TSE, despite approximately 50% reduction in scan time (all p < 0.05). The inter-reader agreement for the qualitative analysis was moderate to good. All readers preferred DLR over conventional T2-TSE regardless of scan time and preferred fast DLR T2-TSE (57.7-78.8%), except for one who preferred DLR over fast DLR T2-TSE (53.8% vs. 46.1%). CONCLUSION: In female pelvic MRI, image quality and accelerated image acquisition for T2-TSE can be significantly improved by using DLR compared to conventional T2-TSE. Fast DLR T2-TSE was non-inferior to DLR T2-TSE in terms of reader preference and image quality. CLINICAL RELEVANCE STATEMENT: DLR of T2-TSE in female pelvic MRI enables fast imaging along with maintaining optimal image quality compared with parallel imaging-based conventional T2-TSE. KEY POINTS: • Conventional T2 turbo spin-echo based on parallel imaging has limitations for accelerated image acquisition while maintaining good image quality. • Deep learning image reconstruction showed better image quality in both images obtained using the same or accelerated image acquisition parameters compared with conventional T2 turbo spin-echo in female pelvic MRI. • Deep learning image reconstruction enables accelerated image acquisition while maintaining good image quality in the T2-TSE of female pelvic MRI.

Anti-Warburg effect via generation of ROS and inhibition of PKM2/ß-catenin mediates apoptosis of lambertianic acid in prostate cancer cells.

To elucidate the underlying antitumor mechanism of lambertianic acid (LA) derived from Pinus koraiensis, the role of cancer metabolism related molecules was investigated in the apoptotic effect of LA in DU145 and PC3 prostate cancer cells. MTT assay for cytotoxicity, RNA interference, cell cycle analysis for sub G1 population, nuclear and cytoplasmic extraction, lactate, Glucose and ATP assay by ELISA, Measurement of reactive oxygen species (ROS) generation, Western blotting, and immunoprecipitation assay were conducted in DU145 and PC3 prostate cancer cells. Herein LA exerted cytotoxicity, increased sub G1 population and attenuated the expression of pro-Caspase3 and pro-poly (ADP-ribose) polymerase (pro-PARP) in DU145 and PC3 cells. Also, LA reduced the expression of lactate dehydrogenase A (LDHA), glycolytic enzymes such as hexokinase 2 and pyruvate kinase M2 (PKM2) with reduced production of lactate in DU145 and PC3 cells. Notably, LA decreased phosphorylation of PKM2 on Tyr105 and inhibited the expression of p-STAT3, cyclin D1, C-Myc, ß-catenin, and p-GSK3ß with the decrease of nuclear translocation of p-PKM2. Furthermore, LA disturbed the binding of p-PKM2 and ß-catenin in DU145 cells, which was supported by Spearman coefficient (0.0463) of cBioportal database. Furthermore, LA generated ROS in DU145 and PC3 cells, while ROS scavenger NAC (N-acetyl L-cysteine) blocked the ability of LA to reduce p-PKM2, PKM2, ß-catenin, LDHA, and pro-caspase3 in DU145 cells. Taken together, these findings provide evidence that LA induces apoptosis via ROS generation and inhibition of PKM2/ß-catenin signaling in prostate cancer cells.

Serum zinc deficiency could be associated with dementia conversion in Parkinson's disease.

Background: Association between heavy metals and Parkinson's disease (PD) is well noted, but studies regarding heavy metal levels and non-motor symptoms of PD, such as PD's dementia (PD-D), are lacking. Methods: In this retrospective cohort study, we compared five serum heavy metal levels (Zn, Cu, Pb, Hg, and Mn) of newly diagnosed PD patients (n = 124). Among 124 patients, 40 patients were later converted to Parkinson's disease dementia (PD-D), and 84 patients remained without dementia during the follow-up time. We collected clinical parameters of PD and conducted correlation analysis with heavy metal levels. PD-D conversion time was defined as the initiation time of cholinesterase inhibitors. Cox proportional hazard models were used to identify factors associated with dementia conversion in PD subjects. Results: Zn deficiency was significant in the PD-D group than in the PD without dementia group (87.53 ± 13.20 vs. 74.91 ± 14.43, p < 0.01). Lower serum Zn level was significantly correlated with K-MMSE and LEDD at 3 months (r = -0.28, p < 0.01; r = 0.38, p < 0.01). Zn deficiency also contributed to a shorter time to dementia conversion (HR 0.953, 95% CI 0.919 to 0.988, p < 0.01). Conclusion: This clinical study suggests that a low serum Zn level can be a risk factor for developing PD-D and could be used as a biological marker for PD-D conversion.

Honokiol inhibits epithelial-mesenchymal transition and hepatic fibrosis via activation of Ecadherin/GSK3ß/JNK and inhibition of AKT/ERK/p38/ß-catenin/TMPRSS4 signaling axis.

Though Honokiol was known to have anti-inflammatory, antioxidant, anticancer, antithrombotic, anti-viral, metabolic, antithrombotic, and neurotrophic activities, the underlying mechanisms of Honokiol on epithelial-mesenchymal transition (EMT) mediated liver fibrosis still remain elusive so far. Anti-EMT and antifibrotic effects of Honokiol were explored in murine AML-12 hepatocyte cells by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, wound healing assay, Western blotting and also in CCl4-induced liver injury mouse model by immunohistochemistry. Honokiol significantly suppressed transforming growth factor ß1 (TGF-ß1)-induced EMT and migration of AML-12 cells along with decreased EMT phenotypes such as loss of cell adhesion and formation of fibroblast like mesenchymal cells in TGF-ß1-treated AML-12 cells. Consistently, Honokiol suppressed the expression of Snail and transmembrane protease serine 4 (TMPRSS4), but not p-Smad3, and activated E-cadherin in TGF-ß1-treated AML-12 cells. Additionally, Honokiol reduced the expression of ß-catenin, p-AKT, p-ERK, p-p38 and increased phosphorylation of glycogen synthase kinase 3 beta (GSK3ß) and JNK in TGF-ß1-treated AML-12 cells via TGF-ß1/nonSmad pathway. Conversely, GSK3ß inhibitor SB216763 reversed the ability of Honokiol to reduce Snail, ß-catenin and migration and activate E-cadherin in TGF-ß1-treated AML-12 cells. Also, Honokiol suppressed hepatic steatosis and necrosis by reducing the expression of TGF-ß1 and α-SMA in liver tissues of CCl4 treated mice. These findings provide scientific evidence that Honokiol suppresses EMT and hepatic fibrosis via activation of E-cadherin/GSK3ß/JNK and inhibition of AKT/ERK/p38/ß-catenin/TMPRSS4 signaling axis.

Longitudinal changes in shoulder arthroplasty stratified by age groups, types of surgical facilities, and geographical regions in Korea from 2010 to 2020.

BACKGROUND: Shoulder arthroplasty (SA), including hemiarthroplasty, reverse and anatomical total SA (TSA), improves quality of life by reducing shoulder pain and restoring function in patients not only with irreparable rotator cuff tears and/or cuff tear arthropathy but also with osteoarthritis posttraumatic arthritis, proximal humeral fractures, etc. Given the rapid developments in artificial joints and improvements in postoperative outcomes, the number of SA surgeries is increasing worldwide. Therefore, we investigated changes in trends over time in Korea. METHODS: We analyzed the longitudinal changes in the incidence of SA including anatomic and reverse TSA, hemiarthroplasty, and shoulder revision arthroplasty (SRA) by changes in the Korean age profile, surgical facilities, and geographical regions using the Korean Health Insurance Review and Assessment Service database from 2010 to 2020. Data were also collected from the National Health Insurance Service and the Korean Statistical Information Service. RESULTS: From 2010 to 2020, the TSA rate per 1,000,000 person-years increased from 10.571 to 101.372 (time trend = 1.252; 95% CI 1.233-1.271, P < .001). The shoulder hemiarthroplasty (SH) rate per 1,000,000 person-years decreased from 6.414 to 3.685 (time trend = 0.933; 95% CI 0.907-0.960, P < .001). The SRA rate per 1,000,000 person-years increased from 0.792 to 2.315; the increase was significant (time trend = 1.133; 95% CI 1.101-1.166, P < .001). DISCUSSION: Overall, TSA and SRA are increasing and SH is decreasing. For both total TSA and SRA, steep increases are evident in the numbers of patients in their 70s and older than 80 years. The SH trend is decreasing regardless of differences in age groups, surgical facilities, and geographical regions. SRA is preferentially performed in Seoul.

Visual Scoring of Sacroiliac Joint/Sacrum Ratios of Single-Photon Emission Computed Tomography/Computed Tomography Images Affords High Sensitivity and Negative Predictive Value in Axial Spondyloarthritis.

Spondyloarthritis (SpA) is characterized by inflammatory back pain. Magnetic resonance imaging (MRI) was the earlier gold standard technique for detecting early inflammatory change. We reassessed the diagnostic utility of sacroiliac joint/sacrum (SIS) ratios of single-photon emission computed tomography/computed tomography (SPECT/CT) for identifying sacroiliitis. We aimed to investigate of SPECT/CT in diagnosing SpA using a rheumatologist's visual scoring of SIS ratios assessment. We conducted a single-center, medical records review study of patients with lower back pain who underwent bone SPECT/CT from August 2016 to April 2020. We employed semiquantitative visual bone scoring methods of SIS ratio. The uptake of each sacroiliac joint was compared to that of the sacrum (0-2). A score of 2 for the sacroiliac joint of either side was considered diagnostic of sacroiliitis. Of the 443 patients assessed, 40 had axial SpA (axSpA), 24 being radiographic axSpA and 16 being nonradiographic axSpA. The sensitivity, specificity, and positive and negative predictive values of SIS ratio of SPECT/CT for axSpA were 87.5%, 56.5%, 16.6%, and 97.8%, respectively. In receiver operating curve analysis, MRI better diagnosed axSpA than did SIS ratio of SPECT/CT. Although the diagnostic utility of SIS ratio of SPECT/CT was inferior to MRI, visual scoring of SPECT/CT affords high sensitivity and negative predictive value in axSpA. When MRI is inappropriate for certain patients, SIS ratio of SPECT/CT is an alternative tool for identifying axSpA in real practice.