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Catharanthus roseus (L.) G. Don is a herbal plant traditionally used by local populations in India, South Africa, China and Malaysia to treat diabetes. The present study reports the in vitro antioxidant and antidiabetic activities of the major alkaloids isolated from Catharanthus roseus (L.) G. Don leaves extract. Four alkaloids—vindoline I, vindolidine II, vindolicine III and vindolinine IV—were isolated and identified from the dichloromethane extract (DE) of this plant’s leaves. DE and compounds I–III were not cytotoxic towards pancreatic β-TC6 cells at the highest dosage tested (25.0 µg/mL). All four alkaloids induced relatively high glucose uptake in pancreatic β-TC6 or myoblast C2C12 cells, with III showing the highest activity. In addition, compounds II–IV demonstrated good protein tyrosine phosphatase-1B (PTP-1B) inhibition activity, implying their therapeutic potential against type 2 diabetes. III showed the highest antioxidant potential in ORAC and DPPH assays and it also alleviated H2O2-induced oxidative damage in β-TC6 cells at 12.5 µg/mL and 25.0 µg/mL.

Impression management refers to controlling or shaping the information disclosed to affect readers’ interpretations. Managers may manipulate the tone and length of financial reports to manage stakeholders’ expectations. This exploratory study examines the impact of managerial ownership on impression management using Management Discussion and Analysis (MD&A) reports contained in annual reports for all A-shares listed in China from 2018 to 2021. In total, 5279 firm-year observations were collected from China. The results suggest that managerial ownership has a significantly inverted U-shaped relationship with impression management, indicating that executives who hold ownership in a company are more likely to engage in impression management. However, beyond 31% of managerial ownership, the effectiveness of oversight quality on impression management is strengthened, leading to decreased levels of impression management. This relationship is more prevalent during the COVID-19 pandemic (2020 and 2021). The findings of this study provide policy implications not only for China but also for Asian countries with similar institutional backgrounds. For example, managerial ownership should not be restricted to below 31%. Additionally, the findings provide additional mechanisms for investors to identify impression management during unstable financial periods.

Objectives: Cryptococcus neoformans is an opportunistic fungus that causes fatal meningoencephalitis especially in AIDS patients. There is an increasing need for discovery of new anti-cryptococcal drugs due to emergence of resistance cases in recent years. In this study, we aim to elucidate the antifungal effect of triclosan against C. neoformans.Methods: Minimal inhibitory concentration (MIC) of triclosan in different C. neoformans strains was first examined. The in vitro interactions between triclosan and two standard anti-fungal drugs (amphotericin B and fluconazole) were further evaluated by microdilution checkerboard assay. Mechanism of triclosan fungicidal activity was then investigated by viewing the cell morphology under transmission electron microscope.Results: We reported that triclosan potently inhibited the growth of C. neoformans. A combination of triclosan with amphotericin B or with fluconazole enhanced their fungicidal effects. Triclosan-treated C. neoformans displayed characteristics such as nuclear chromatin condensation, extensive intracellular vacuolation and mitochondrial swelling, indicating that triclosan triggered apoptosis-like cell death.Conclusion: In summary, our report suggests triclosan as an independent drug or synergent for C. neoformans treatment.

Plants in the Meliaceae family are known to possess interesting biological activities, such as antimalaral, antihypertensive and antitumour activities. Previously, our group reported the plant-derived compound cycloart-24-ene-26-ol-3-one isolated from the hexane extracts of Aglaia exima leaves, which shows cytotoxicity towards various cancer cell lines, in particular, colon cancer cell lines. In this report, we further demonstrate that cycloart-24-ene-26-ol-3-one, from here forth known as cycloartane, reduces the viability of the colon cancer cell lines HT-29 and CaCO-2 in a dose- and time-dependent manner. Further elucidation of the compound's mechanism showed that it binds to tumour necrosis factor-receptor 1 (TNF-R1) leading to the initiation of caspase-8 and, through the activation of Bid, in the activation of caspase-9. This activity causes a reduction in mitochondrial membrane potential (MMP) and the release of cytochrome-C. The activation of caspase-8 and -9 both act to commit the cancer cells to apoptosis through downstream caspase-3/7 activation, PARP cleavage and the lack of NFkB translocation into the nucleus. A molecular docking study showed that the cycloartane binds to the receptor through a hydrophobic interaction with cysteine-96 and hydrogen bonds with lysine-75 and -132. The results show that further development of the cycloartane as an anti-cancer drug is worthwhile.

The infection of Cryptococcus neoformans is acquired through the inhalation of desiccated yeast cells and basidiospores originated from the environment, particularly from bird's droppings and decaying wood. Three environmental strains of C. neoformans originated from bird droppings (H4, S48B and S68B) and C. neoformans reference clinical strain (H99) were used for intranasal infection in C57BL/6 mice. We showed that the H99 strain demonstrated higher virulence compared to H4, S48B and S68B strains. To examine if gene expression contributed to the different degree of virulence among these strains, a genome-wide microarray study was performed to inspect the transcriptomic profiles of all four strains. Our results revealed that out of 7,419 genes (22,257 probes) examined, 65 genes were significantly up-or down-regulated in H99 versus H4, S48B and S68B strains. The up-regulated genes in H99 strain include Hydroxymethylglutaryl-CoA synthase (MVA1), Mitochondrial matrix factor 1 (MMF1), Bud-site-selection protein 8 (BUD8), High affinity glucose transporter 3 (SNF3) and Rho GTPase-activating protein 2 (RGA2). Pathway annotation using DAVID bioinformatics resource showed that metal ion binding and sugar transmembrane transporter activity pathways were highly expressed in the H99 strain. We suggest that the genes and pathways identified may possibly play crucial roles in the fungal pathogenesis.

Phytochemicals from Pseuduvaria species have been reported to display a wide range of biological activities. In the present study, a known benzopyran derivative, (6E,10E) isopolycerasoidol (1), and a new benzopyran derivative, (6E,10E) isopolycerasoidol methyl ester (2), were isolated from a methanol extract of Pseuduvaria monticola leaves. The structures of the isolated compounds were elucidated by spectroscopic methods including 1D and 2D NMR, IR, UV, and LCMS-QTOF, and by comparison with previously published data. The anti-proliferative and cytotoxic effects of these compounds on human breast cancer cell-lines (MCF-7 and MDA-MB-231) and a human normal breast epithelial cell line (MCF-10A) were investigated. MTT results revealed both (1) and (2) were efficient in reducing cell viability of breast cancer cells. Flow cytometry analysis demonstrated that (1) and (2) induced cell death via apoptosis, as demonstrated by an increase in phosphotidylserine exposure. Both compounds elevated ROS production, leading to reduced mitochondrial membrane potential and increased plasma membrane permeability in breast cancer cells. These effects occurred concomitantly with a dose-dependent activation of caspase 3/7 and 9, a down-regulation of the anti-apoptotic gene BCL2 and the accumulation of p38 MAPK in the nucleus. Taken together, our data demonstrate that (1) and (2) induce intrinsic mitochondrial-mediated apoptosis in human breast cancer cells, which provides the first pharmacological evidence for their future development as anticancer agents.

The cytotoxic potential of ammonium-based deep eutectic solvents (DESs) with four hydrogen bond donors, namely glycerine (Gl), ethylene glycol (EG), triethylene glycol (TEG) and urea (U) were investigated. The toxicity of DESs was examined using In Vitro cell lines and In Vivo animal model. IC50 and selectivity index were determined for the DESs, their individual components and their combinations as aqueous solutions for comparison purposes. The cytotoxicity effect of DESs varied depending on cell lines. The IC50 for the GlDES, EGDES, UDES and TEGDES followed the sequence of TEGDES< GlDES< EGDES< UDES for OKF6, MCF-7, A375, HT29 and H413, respectively. GlDES was selective against MCF-7 and A375, EGDES was selective against MCF-7, PC3, HepG2 and HT29, UDES was selective against MCF-7, PC3, HepG2 and HT29, and TEGDES was selective against MCF-7 and A375. However, acute toxicity studies using ICR mice showed that these DESs were relatively toxic in comparison to their individual components. DES did not cause DNA damage, but it could enhance ROS production and induce apoptosis in treated cancer cells as evidenced by marked LDH release. Furthermore, the examined DESs showed less cytotoxicity compared with ionic liquids. To the best of our knowledge, this is the first time that combined In Vitro and In Vivo toxicity profiles of DESs were being demonstrated, raising the toxicity issue of these neoteric mixtures and their potential applicability to be used for therapeutic purposes.

BackgroundCinnamomum cassia bark is a popular culinary spice used for flavoring and in traditional medicine. C. cassia extract (CE) induces apoptosis in many cell lines. In the present study, particular differences in the mechanism of the anti-proliferative property of C. cassia on two breast cancer cell lines, MCF-7 and MDA-MB-231, were elucidated.Methodology/principal findingsThe hexane extract of C. cassia demonstrated high anti-proliferative activity against MCF-7 and MDA-MB-231 cells (IC50, 34 ± 3.52 and 32.42 ± 0.37 μg/ml, respectively). Oxidative stress due to disruption of antioxidant enzyme (SOD, GPx and CAT) activity is suggested as the probable cause for apoptosis initiation. Though the main apoptosis pathway in both cell lines was found to be through caspase-8 activation, caspase-9 was also activated in MDA-MB-231 cells but suppressed in MCF-7 cells. Gene expression studies revealed that AKT1, the caspase-9 suppressor, was up-regulated in MCF-7 cells while down-regulated in MDA-MB-231 cells. Although, AKT1 protein expression in both cell lines was down-regulated, a steady increase in MCF-7 cells was observed after a sharp decrease of suppression of AKT1. Trans-cinnamaldehyde and coumarin were isolated and identified and found to be mainly responsible for the observed anti-proliferative activity of CE (Cinnamomum cassia).ConclusionActivation of caspase-8 is reported for the first time to be involved as the main apoptosis pathway in breast cancer cell lines upon treatment with C. cassia. The double effects of C. cassia on AKT1 gene expression in MCF-7 cells is reported for the first time in this study.

BackgroundThe biological properties of thiosemicarbazone have been widely reported. The incorporation of some transition metals such as Fe, Ni and Cu to thiosemicarbazone complexes is known to enhance its biological effects. In this study, we incorporated nickel(II) ions into thiosemicarbazone with N4-substitution groups H3L (H; H3L1, CH3; H3L2, C6H5; H3L3 and C2H5; H3L4) and examined its potential anti-inflammatory activity.Methodology/principal findingsFour ligands (1-4) and their respective nickel-containing complexes (5-8) were synthesized and characterized. The compounds synthesized were tested for their effects on NF-κB nuclear translocation, pro-inflammatory cytokines secretion and NF-κB transactivation activity. The active compound was further evaluated on its ability to suppress carrageenan-induced acute inflammation in vivo. A potential binding target of the active compound was also predicted by molecular docking analysis.Conclusions/significanceAmong all synthesized compounds tested, we found that complex [Ni(H2L1)(PPh3)]Cl (5) (complex 5), potently inhibited IκBα degradation and NF-κB p65 nuclear translocation in LPS-stimulated RAW264.7 cells as well as TNFα-stimulated HeLa S3 cells. In addition, complex 5 significantly down-regulated LPS- or TNFα-induced transcription of NF-κB target genes, including genes that encode the pro-inflammatory cytokines TNFα, IFNβ and IL6. Luciferase reporter assays confirmed that complex 5 inhibited the transactivation activity of NF-κB. Furthermore, the anti-inflammatory effect of complex 5 was also supported by its suppressive effect on carrageenan-induced paw edema formation in wild type C57BL/6 mice. Interestingly, molecular docking study showed that complex 5 potentially interact with the active site of IKKβ. Taken together, we suggest complex 5 as a novel NF-κB inhibitor with potent anti-inflammatory effects.

In this study, a new apoptotic monoterpenoid indole alkaloid, subditine (1), and four known compounds were isolated from the bark of Nauclea subdita. Complete (1)H- and (13)C- NMR data of the new compound were reported. The structures of isolated compounds were elucidated with various spectroscopic methods such as 1D- and 2D- NMR, IR, UV and LCMS. All five compounds were screened for cytotoxic activities on LNCaP and PC-3 human prostate cancer cell-lines. Among the five compounds, the new alkaloid, subditine (1), demonstrated the most potent cell growth inhibition activity and selective against LNCaP with an IC50 of 12.24±0.19 µM and PC-3 with an IC50 of 13.97±0.32 µM, compared to RWPE human normal epithelial cell line (IC50 = 30.48±0.08 µM). Subditine (1) treatment induced apoptosis in LNCaP and PC-3 as evidenced by increased cell permeability, disruption of cytoskeletal structures and increased nuclear fragmentation. In addition, subditine (1) enhanced intracellular reactive oxygen species (ROS) production, as reflected by increased expression of glutathione reductase (GR) to scavenge damaging free radicals in both prostate cancer cell-lines. Excessive ROS could lead to disruption of mitochondrial membrane potential (MMP), release of cytochrome c and subsequent caspase 9, 3/7 activation. Further Western blot analyses showed subditine (1) induced down-regulation of Bcl-2 and Bcl-xl expression, whereas p53 was up-regulated in LNCaP (p53-wild-type), but not in PC-3 (p53-null). Overall, our data demonstrated that the new compound subditine (1) exerts anti-proliferative effect on LNCaP and PC-3 human prostate cancer cells through induction of apoptosis.

Two new synthesized and characterized quinazoline Schiff bases 1 and 2 were investigated for anticancer activity against MCF-7 human breast cancer cell line. Compounds 1 and 2 demonstrated a remarkable antiproliferative effect, with an IC50 value of 6.246 × 10−6 mol/L and 5.910 × 10−6 mol/L, respectively, after 72 hours of treatment. Most apoptosis morphological features in treated MCF-7 cells were observed by AO/PI staining. The results of cell cycle analysis indicate that compounds did not induce S and M phase arrest in cell after 24 hours of treatment. Furthermore, MCF-7 cells treated with 1 and 2 subjected to apoptosis death, as exhibited by perturbation of mitochondrial membrane potential and cytochrome c release as well as increase in ROS formation. We also found activation of caspases-3/7, -8, and -9 in compounds 1 and 2. Moreover, inhibition of NF-κB translocation in MCF-7 cells treated by compound 1 significantly exhibited the association of extrinsic apoptosis pathway. Acute toxicity results demonstrated the nontoxic nature of the compounds in mice. Our results showed significant activity towards MCF-7 cells via either intrinsic or extrinsic mitochondrial pathway and are potential candidate for further in vivo and clinical breast cancer studies.

Metal-based drugs with extensive clinical applications hold great promise for the development of cancer chemotherapeutic agents. In the last few decades, Schiff bases and their complexes have become well known for their extensive biological potential. In the present study, we examined the antiproliferative effect of a copper (II) complex on HT-29 colon cancer cells. The Cu(BrHAP)2 Schiff base compound demonstrated a potent antiproliferative effect in HT-29 cells, with an IC50 value of 2.87 μg/ml after 72 h of treatment. HT-29 cells treated with Cu (II) complexes underwent apoptosis death, as exhibited by a progressive elevation in the proportion of the G1 cell population. At a concentration of 6.25 μg/ml, the Cu(BrHAP)2 compound caused significant elevation in ROS production following perturbation of mitochondrial membrane potential and cytochrome c release, as assessed by the measurement of fluorescence intensity in stained cells. Furthermore, the activation of caspases 3/7 and 9 was part of the Cu (II) complex-induced apoptosis, which confirmed the involvement of mitochondrial-mediated apoptosis. Meanwhile, there was no significant activation of caspase-8. Taken together, these results imply that the Cu(BrHAP)2 compound is a potential candidate for further in vivo and clinical colon cancer studies to develop novel chemotherapeutic agents derived from metal-based agents.

Curcuma zedoaria also known as Temu putih is traditionally used in food preparations and treatment of various ailments including cancer. The cytotoxic activity of hexane, dichloromethane, ethyl acetate, methanol, and the methanol-soxhlet extracts of Curcuma zedoaria rhizomes was tested on two human cancer cell lines (Ca Ski and MCF-7) and a noncancer cell line (HUVEC) using MTT assay. Investigation on the chemical components in the hexane and dichloromethane fractions gave 19 compounds, namely, labda-8(17),12 diene-15,16 dial (1), dehydrocurdione (2), curcumenone (3), comosone II (4), curcumenol (5), procurcumenol (6), germacrone (7), zerumbone epoxide (8), zederone (9), 9-isopropylidene-2,6-dimethyl-11-oxatricyclo[6.2.1.01,5]undec-6-en-8-ol (10), furanodiene (11), germacrone-4,5-epoxide (12), calcaratarin A (13), isoprocurcumenol (14), germacrone-1,10-epoxide (15), zerumin A (16), curcumanolide A (17), curcuzedoalide (18), and gweicurculactone (19). Compounds (1–19) were evaluated for their antiproliferative effect using MTT assay against four cancer cell lines (Ca Ski, MCF-7, PC-3, and HT-29). Curcumenone (3) and curcumenol (5) displayed strong antiproliferative activity (IC50=8.3±1.0 and 9.3±0.3 μg/mL, resp.) and were found to induce apoptotic cell death on MCF-7 cells using phase contrast and Hoechst 33342/PI double-staining assay. Thus, the present study provides basis for the ethnomedical application of Curcuma zedoaria in the treatment of breast cancer.

BACKGROUND: Centratherum anthelminticum (L.) seeds (CA) is a well known medicinal herb in Indian sub-continent. We recently reported anti-oxidant property of chloroform fraction of Centratherum anthelminticum (L.) seeds (CACF) by inhibiting tumor necrosis factor-α (TNF-α)-induced growth of human breast cancer cells. However, the active compounds in CACF have not been investigated previously. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we showed that CACF inhibited growth of MCF-7 human breast cancer cells. CACF induced apoptosis in MCF-7 cells as marked by cell size shrinkage, deformed cytoskeletal structure and DNA fragmentation. To identify the cytotoxic compound, CACF was subjected to bioassay-guided fractionation which yielded 6 fractions. CACF fraction A and B (CACF-A, -B) demonstrated highest activity among all the fractions. Further HPLC isolation, NMR and LC-MS analysis of CACF-A led to identification of vernodalin as the cytotoxic agent in CACF-A, and -B. 12,13-dihydroxyoleic acid, another major compound in CACF-C fraction was isolated for the first time from Centratherum anthelminticum (L.) seeds but showed no cytotoxic effect against MCF-7 cells. Vernodalin inhibited cell growth of human breast cancer cells MCF-7 and MDA-MB-231 by induction of cell cycle arrest and apoptosis. Increased of reactive oxygen species (ROS) production, coupled with downregulation of anti-apoptotic molecules (Bcl-2, Bcl-xL) led to reduction of mitochondrial membrane potential (MMP) and release of cytochrome c in both human breast cancer cells treated with vernodalin. Release of cytochrome c from mitochondria to cytosol triggered activation of caspase cascade, PARP cleavage, DNA damage and eventually cell death. CONCLUSIONS/SIGNIFICANCE: To the best of our knowledge, this is the first comprehensive study on cytotoxic and apoptotic mechanism of vernodalin isolated from the Centratherum anthelminticum (L.) seeds in human breast cancer cells. Overall, our data suggest a potential therapeutic value of vernodalin to be further developed as new anti-cancer drug.

Abstract Background Cardiovascular disease is the chief cause of death in Taiwan and many countries, of which myocardial infarction (MI) is the most serious condition. Hyperlipidemia appears to be a significant cause of myocardial infarction, because it causes atherosclerosis directly. In recent years, copy number variation (CNV) has been analyzed in genomewide association studies of complex diseases. In this study, CNV was analyzed in blood samples and SNP arrays from 31 myocardial infarction patients with hyperlipidemia. Results We identified seven CNV regions that were associated significantly with hyperlipidemia and myocardial infarction in our patients through multistage analysis (PCDC73), 1q42.2 (DISC1), 3p21.31 (CDCP1), 10q11.21 (RET) 12p12.3 (PIK3C2G) and 16q23.3 (CDH13), respectively. In particular, the CNV region at 10q11.21 was examined by quantitative real-time PCR, the results of which were consistent with microarray findings. Conclusions Our preliminary results constitute an alternative method of evaluating the relationship between CNV regions and cardiovascular disease. These susceptibility CNV regions may be used as biomarkers for early-stage diagnosis of hyperlipidemia and myocardial infarction, rendering them valuable for further research and discussion.

BACKGROUND:Lnk plays a non-redundant role by negatively regulating cytokine signaling of TPO, SCF or EPO. Retroviral expression of Lnk has been shown to suppress hematopoietic leukemic cell proliferation indicating its therapeutic value in cancer therapy. However, retroviral gene delivery carries risks of insertional mutagenesis. To circumvent this undesired consequence, we fused a cell permeable peptide octa-arginine to Lnk and evaluated the efficacy of inhibition of leukemic cell proliferation in vitro. METHODOLOGY/PRINCIPAL FINDINGS:In this study, proliferation assays, flow cytometry, Western Blot analyses were performed on wild-type (WT), mutant Lnk R8 or BSA treated M-MOK cells. We found that delivered WT, but not mutant Lnk R8 blocked TPO-induced M-MOK megakaryoblastic leukemic cell proliferation. In contrast, WT Lnk R8 showed no growth inhibitive effect on non-hematopoietic HELA or COS-7 cell. Moreover, we demonstrated that TPO-induced M-MOK cell growth inhibition by WT Lnk R8 was dose-dependent. Penetrated WT Lnk R8 induced cell cycle arrest and apoptosis. Immunoprecipitation and Western blots data indicated WT Lnk R8 interacted with endogeneous Jak2 and downregulated Jak-Stat and MAPK phosphorylation level in M-MOK cells after TPO stimulation. Treatment with specific inhibitors (TG101348 and PD98059) indicated Jak-Stat and MAPK pathways were crucial for TPO-induced proliferation of M-MOK cells. Further analyses using TF-1 and HEL leukemic cell-lines showed that WT Lnk R8 inhibited Jak2-dependent cell proliferation. Using cord blood-derived CD34+ stem cells, we found that delivered WT Lnk R8 blocked TPO-induced megakaryopoiesis in vitro. CONCLUSIONS/SIGNIFICANCE:Intracellular delivery of WT Lnk R8 fusion protein efficiently inhibited TPO-induced M-MOK leukemic cell growth by promoting apoptosis. WT Lnk R8 protein delivery may provide a safer and more practical approach to inhibit leukemic cell growth worthy of further development.

Abstract Background The full extent of chromosomal alterations and their biological implications in early breast carcinogenesis has not been well examined. In this study, we aimed to identify chromosomal alterations associated with poor prognosis in early-stage breast cancers (EBC). Methods A total of 145 EBCs (stage I and II) were examined in this study. We analyzed copy number alterations in a discovery set of 48 EBCs using oligoarray-comparative genomic hybridization. In addition, the recurrently altered regions (RARs) associated with poor prognosis were validated using an independent set of 97 EBCs. Results A total of 23 RARs were defined in the discovery set. Six were commonly detected in both stage I and II groups (> 50%), suggesting their connection with early breast tumorigenesis. There were gains on 1q21.2-q21.3, 8q24.13, 8q24.13-21, 8q24.3, and 8q24.3 and a loss on 8p23.1-p22. Among the 23 RARs, copy number gains on 16p11.2 (NUPR1) and 17q12 (ERBB2) showed a significant association with poor survival (P = 0.0186 and P = 0.0186, respectively). The patients simultaneously positive for both gains had a significantly worse prognosis (P = 0.0001). In the independent replication, the patients who were double-positive for NUPR1-ERBB2 gains also had a significantly poorer prognosis on multivariate analysis (HR = 7.31, 95% CI 2.65-20.15, P = 0.0001). Conclusions The simultaneous gain of NUPR1 and ERBB2 can be a significant predictor of poor prognosis in EBC. Our study will help to elucidate the molecular mechanisms underlying early-stage breast cancer tumorigenesis. This study also highlights the potential for using combinations of copy number alterations as prognosis predictors for EBC.

Abstract Background Cell transdifferentiation is characterized by loss of some phenotypes along with acquisition of new phenotypes in differentiated cells. The differentiated state of a given cell is not irreversible. It depends on the up- and downregulation exerted by specific molecules. Results We report here that HCCR-1, previously shown to play an oncogenic role in human cancers, induces epithelial-to-mesenchymal transition (EMT) and mesenchymal-to-epithelial transition (MET) in human and mouse, respectively. The stem cell factor receptor CD117/c-Kit was induced in this transdifferentiated (EMT) sarcoma tissues. This MET occurring in HCCR-1 transfected cells is reminiscent of the transdifferentiation process during nephrogenesis. Indeed, expression of HCCR-1 was observed during the embryonic development of the kidney. This suggests that HCCR-1 might be involved in the transdifferentiation process of cancer stem cell. Conclusions Therefore, we propose that HCCR-1 may be a regulatory factor that stimulates morphogenesis of epithelia or mesenchyme during neoplastic transformation.

Abstract Background Since hepatocellular carcinoma (HCC) is one of the leading causes of cancer death worldwide, it is still important to understand hepatocarcinogenesis mechanisms and identify effective markers for tumor progression to improve prognosis. Amplification and overexpression of Tropomyosin3 (TPM3) are frequently observed in HCC, but its biological meanings have not been properly defined. In this study, we aimed to elucidate the roles of TPM3 and related molecular mechanisms. Methods TPM3-siRNA was transfected into 2 HCC cell lines, HepG2 and SNU-475, which had shown overexpression of TPM3. Knockdown of TPM3 was verified by real-time qRT-PCR and western blotting targeting TPM3. Migration and invasion potentials were examined using transwell membrane assays. Cell growth capacity was examined by colony formation and soft agar assays. Results Silencing TPM3 resulted in significant suppression of migration and invasion capacities in both HCC cell lines. To elucidate the mechanisms behind suppressed migration and invasiveness, we examined expression levels of Snail and E-cadherin known to be related to epithelial-mesenchymal transition (EMT) after TPM3 knockdown. In the TPM3 knockdown cells, E-cadherin expression was significantly upregulated and Snail downregulated compared with negative control. TPM3 knockdown also inhibited colony formation and anchorage independent growth of HCC cells. Conclusions Based on our findings, we formulate a hypothesis that overexpression of TPM3 activates Snail mediated EMT, which will repress E-cadherin expression and that it confers migration or invasion potentials to HCC cells during hepatocarcinogenesis. To our knowledge, this is the first evidence that TPM3 gets involved in migration and invasion of HCCs by modifying EMT pathway.

Abstract Background Oncoprotein HCCR-1 functions as a negative regulator of the p53 and contributes breast tumorigenesis. The serum HCCR-1 assay is useful in diagnosing breast cancer and mice transgenic for HCCR developed breast cancers. But it is unknown how HCCR-1 contributes to human breast tumorigenesis. Methods Oncogene HCCR-1 expression levels were determined in normal breast tissues, breast cancer tissues and cancer cell lines. We examined whether HCCR-1 protein expression in breast cancer is related to different biological characteristics, including ER, PR, p53 genotype, and HER2 status in 104 primary breast cancer tissues using immunohistochemical analyses. Results HCCR-1 was upregulated in breast cancer cells and tissues compared with normal breast tissues. In this study, overexpression of HCCR-1 was well correlated with known breast cancer prognostic markers including the presence of steroid receptors (ER and PR), p53 mutation and high HER2 overexpression. HCCR-1 was not detected in the ER-negative, PR-negative, p53 negative and low HER2 breast cancer tissues. These data indicate that the level of HCCR-1 in breast cancer tissues is relatively well correlated with known breast cancer factors, including the HER2 overexpression, p53 mutation, and ER/PR status. Conclusion Determination of HCCR-1 levels as options for HER2 testing is promising although it needs further evaluation.

Abstract Background Gene clustering has been widely used to group genes with similar expression pattern in microarray data analysis. Subsequent enrichment analysis using predefined gene sets can provide clues on which functional themes or regulatory sequence motifs are associated with individual gene clusters. In spite of the potential utility, gene clustering and enrichment analysis have been used in separate platforms, thus, the development of integrative algorithm linking both methods is highly challenging. Results In this study, we propose an algorithm for discovery of molecular functions and elucidation of transcriptional logics using two kinds of gene information, functional and regulatory motif gene sets. The algorithm, termed gene set expression coherence analysis first selects functional gene sets with significantly high expression coherences. Those candidate gene sets are further processed into a number of functionally related themes or functional clusters according to the expression similarities. Each functional cluster is then, investigated for the enrichment of transcriptional regulatory motifs using modified gene set enrichment analysis and regulatory motif gene sets. The method was tested for two publicly available expression profiles representing murine myogenesis and erythropoiesis. For respective profiles, our algorithm identified myocyte- and erythrocyte-related molecular functions, along with the putative transcriptional regulators for the corresponding molecular functions. Conclusion As an integrative and comprehensive method for the analysis of large-scaled gene expression profiles, our method is able to generate a set of testable hypotheses: the transcriptional regulator X regulates function Y under cellular condition Z. GSECA algorithm is implemented into freely available software package.

AIM: To compare the diagnostic performances of gadoxetic acid-enhanced magnetic resonance imaging (MRI) and multiphasic multidetector computed tomography (MDCT) in the detection of hepatocellular carcinoma (HCC) in patients with chronic liver disease. MATERIALS AND METHODS: Institutional review board approval was obtained for this study and informed consent was obtained from all patients. Fifty-one patients (43 men, eight women; age range 32-80 years) with 73 HCCs underwent gadoxetic acid-enhanced MRI and multiphasic MDCT. Two readers independently analysed each image in three separate reading sessions. The alternative free-response receiver operating characteristic (AFROC) method was used to analyse the diagnostic accuracy. Positive and negative predictive values and sensitivity were evaluated. RESULTS: A total of 73 HCCs were detected in 51 patients. Although not significant (p>0.05), the areas under the receiver operating characteristic curves were 0.877 and 0.850 for MDCT, 0.918 and 0.911 for dynamic MRI, and 0.905 and 0.918 for combined interpretation of dynamic and hepatobiliary phase MR images. Differences in sensitivity, specificity, and positive and negative predictive values between the readers were not statistically significant (p>0.05). Combined interpretation of dynamic and hepatobiliary phase MRI images was more useful than MDCT in the detection of HCC lesions <=1cm in diameter for one reader (p=0.043). CONCLUSION: Gadoxetic acid-enhanced MRI and MDCT show similar diagnostic performances for the detection of HCC in patients with chronic liver disease. However, the combined interpretation of dynamic and hepatobiliary phase MRI images may improve diagnostic accuracy in the detection of HCC lesions <=1cm in diameter. [ABSTRACT FROM AUTHOR]

Background & Aims: This study aimed to compare ultrasonography (US) and noncontrast magnetic resonance imaging (MRI) in the surveillance of hepatic malignancy., Methods: We conducted a randomized, nonblinded, single-center trial at a single center in South Korea. Eligible individuals were aged 20 to 70 years with liver cirrhosis, Child-Pugh class A, and no history of liver cancer or other recent malignancy. Participants were randomized 1:1 to receive up to 10 semiannual surveillance using US or noncontrast MRI with serum alpha-fetoprotein testing. The primary endpoints were the detection rates of Barcelona Clinic Liver Cancer (BCLC) stage 0 or A tumors, stage distribution at initial diagnosis, and false-positive referral rates., Results: From June 2015 to November 2017, 416 patients were screened, and 414 were enrolled and assigned to the US (n = 207) or MRI (n = 207) group. In total, 23 participants in the US group and 25 in the MRI group were diagnosed with liver cancer by November 2022. The detection rates of BCLC stage 0 or A tumors were not different between the US and MRI groups (8%; [95% confidence interval (CI), 5%-13%] vs 12% [8%-17%]). BCLC stage 0 tumors were more prevalent in the MRI group than in the US group (8% vs 3%). The MRI group had earlier BCLC stage (P = .014) and lower false-positive referral rate (0.7% [95% CI, 0.4%-1.2%] vs 3.1% [2.3%-4.1%], P < .001) compared with the US group., Conclusions: Noncontrast MRI is a better alternative to US for the surveillance of cirrhotic patients offering earlier stage at initial diagnosis and lower false-positive referral rate. (ClincalTrials.gov, Number: NCT02514434.)., (Copyright © 2025 AGA Institute. Published by Elsevier Inc. All rights reserved.)

The accurate and early detection of vertebral metastases is crucial for improving patient outcomes. Although deep-learning models have shown potential in this area, their lack of prediction reliability and robustness limits their clinical utility. To address these challenges, we propose a novel technique called Ensemble Monte Carlo Dropout (EMCD) for uncertainty quantification (UQ), which combines the Monte Carlo dropout and deep ensembles. In this retrospective study, we analyzed 11,468 abdominal computed tomography images from 116 patients diagnosed with vertebral metastases and 957 images from 11 healthy controls. Uncertainty was quantified and visualized using single number, predictive probability interval, posterior distribution and uncertainty class activation maps to provide a detailed understanding of prediction confidence. The EMCD model demonstrated superior performance compared with traditional UQ methods, achieving an area under the receiver operating characteristic curve (AUC) of 0.93 and an expected calibration error of 0.09, indicating high predictive accuracy and reliability. In addition, the model exhibited strong performance in handling out-of-distribution data. When data retention was applied based on uncertainty values, the AUC of the model improved to 0.96, highlighting the potential of uncertainty-driven data selection to enhance performance. The EMCD model represents a significant advancement in the automated detection of vertebral metastases, providing superior diagnostic accuracy and introducing a robust UQ framework to aid clinicians in making informed decisions., Competing Interests: Declarations. Ethical Approval: This study was approved by the Institutional Review Board at Yonsei University College of medicine Severance Hospital (IRB no. 4–2024-0646). Conflict of Interest: The authors declare no competing interests., (© 2024. The Author(s) under exclusive licence to Society for Imaging Informatics in Medicine.)

Background: One key population related to achieving the global goal of hepatitis C virus (HCV) elimination is people who inject drugs (PWID). By surveying opioid agonist treatment (OAT) programs nationwide in Taiwan, this study aimed to examine (1) the current status of HCV care cascade provision by OAT programs and (2) the opinions of the programs' directors on integrating the HCV care cascade into OAT programs., Methods: From September to November 2022, questionnaires were sent via administrative networks to case managers for information on daily operation and routine booking and to directors for information on the HCV care cascade of 185 OAT programs. The responses of the 125 OAT programs that provided information from both case managers and directors were included for subsequent analyses., Results: Among the 125 OAT programs, 91 (73 %) offered HCV antibody testing, and 69 (55 %) offered HCV treatment services. The provision of HCV antibody testing was associated with being general hospital- or psychiatric hospital-based and having more care team personnel, whereas the provision of HCV treatment was associated with being general hospital-based. However, on-site HCV treatment was found to be rarely offered, and the future willingness to do so remained low., Conclusion: Our survey revealed that the provision of HCV screening and treatment in OAT programs in Taiwan has substantial room for improvement. Increasing the number of care personnel for satellite-dispensing OAT programs is key to expanding the service for HCV screening, as more issues related to multidisciplinary medical resources are involved in the provision of HCV treatment. Our results point to some options that might help accomplish these goals., Competing Interests: Declaration of competing interest We declare that we have no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Purpose: To investigate the relationship between contrast medium administration and long-term mortality and renal function in patients with septic acute kidney injury (AKI)., Materials and Methods: We performed a retrospective, propensity-matched cohort study involving 1521 adult patients admitted with septic shock. Patients with septic AKI who underwent contrast or non-contrast CT scans were enrolled. The primary outcomes were the rates of 90-day mortality and dialysis within 90 days. The secondary outcomes included worsening of AKI, in-hospital mortality, and maintenance of dialysis after 90 days., Results: During the study period, 609 patients with septic AKI were identified; 220 (36.1%) underwent contrast CT and 389 (63.9%) underwent non-contrast CT. After propensity score matching, 133 pairs were obtained. There were no significant differences between the contrast and non-contrast CT groups in 90-day mortality (54.9% vs. 58.6%, P = 0.579), dialysis within 90 days (6.8% vs. 8.3%, P = 0.655), worsening AKI (2.3% vs. 3.0%, P = 0.706), in-hospital mortality (10.6% vs. 14.4%, P = 0.369), or maintenance of dialysis after 90 days (0.0% vs. 0.8%, P > 0.99)., Conclusions: The administration of intravenous contrast medium was not associated with long-term mortality, deterioration of renal function, or dialysis in patients with septic AKI., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: We aimed to assess imaging findings and detection sensitivity for melanoma liver metastases on gadoxetic acid-enhanced magnetic resonance imaging (MRI)., Methods: This retrospective study included patients with melanoma liver metastasis who underwent gadoxetic acid-enhanced MRI. Two abdominal radiologists independently evaluated signal characteristics of liver metastases on morphologic imaging (precontrast T1- and T2-weighted imaging), diffusion-weighted imaging (DWI), dynamic imaging, and hepatobiliary phase (HBP). Imaging findings were compared according to detection on HBP and the primary site of the melanoma using logistic regression with the generalized estimating equation (GEE). Detection sensitivity for metastases was compared among different MR imaging sets using logistic regression with GEE., Results: A total of 67 patients with 254 liver metastases were included (44 women; mean age ± standard deviation, 65.6 ± 13.0 years). On HBP, 76.0% of metastases were detected, and 55.5% (141/254) showed hypointensity. Most of the metastases that were not detected on HBP originated from ocular melanomas (98.4%, 60/61), ≤1 cm (90.2%, 55/61) and showed T1 hyperintensity (98.4%, 60/61). Metastases from non-ocular melanomas more frequently showed T1 hypointensity, T2 hyperintensity, diffusion restriction, arterial enhancement, and HBP hypointensity than those from ocular melanomas (Ps ≤ 0.019). The detection sensitivity of HBP (76.0%) was significantly higher than DWI (65.7%, P = 0.006), but lower than morphologic imaging (98.8%, P < 0.001) and dynamic imaging (97.6%, P < 0.001)., Conclusion: The detection sensitivity of HBP for melanoma liver metastasis was 76.0%, which was lower than that of morphologic or dynamic imaging. HBP of gadoxetic acid-enhanced MRI has little advantage in detecting melanoma liver metastases., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Chung et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Abstract: Hemorrhagic shock (HS) is a life-threatening condition with high mortality rates despite current treatments. This study investigated whether targeted temperature management (TTM) could improve outcomes by modulating inflammation and protecting organs following HS. Using a rat model of HS, TTM was applied at 33°C and 36°C after fluid resuscitation. Surprisingly, TTM at 33°C increased mortality, while TTM at 36°C significantly improved survival rates. It also reduced histological damage in lung and kidney tissues, lowered serum lactate levels, and protected against apoptosis and excessive reactive oxygen species production. TTM at 36°C inhibited the release of high mobility group box 1 protein (HMGB1), a key mediator of inflammation, and decreased proinflammatory cytokine levels in the kidneys and lungs. Moreover, it influenced macrophage behavior, suppressing the harmful M1 phenotype while promoting the beneficial M2 polarization. Cytokine array analysis confirmed reduced levels of proinflammatory cytokines with TTM at 36°C. These results collectively highlight the potential of TTM at 36°C as a therapeutic approach to improve outcomes in HS. By addressing multiple aspects of injury and inflammation, including modulation of macrophage responses and cytokine profiles, TTM at 36°C offers promising implications for critical care management after HS, potentially reducing mortality and improving patient recovery., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Shock Society.)

Background: The COVID-19 pandemic resulted in a rapid accumulation of novel vaccine research evidence. As a means to monitor this evidence, the Public Health Agency of Canada (PHAC) created the E vidence e X traction T eam for R esearch A nalysis ( EXTRA ), which contributed to situational awareness in Canada through a bibliographic repository used to support decision-making by the National Advisory Committee on Immunization. We describe the process by which this literature was identified and catalogued, and provide an overview of characteristics in the identified literature., Methods: To expedite the process, PHAC leveraged an artificial intelligence (AI) tool to assist in the screening and selection of relevant articles. Literature search results were initially screened by AI, then manually reviewed for relevance. Relevant articles were tagged using controlled vocabulary and stored in a bibliographic repository. This repository was analyzed to identify trends in vaccine research over time according to several key characteristics., Results: As of December 31, 2023, EXTRA's repository contained 19,050 articles relevant to PHAC's immunization mandate. The majority of these articles (63.9 %) were identified between August 2021 and January 2023, with an average of 20 relevant articles added daily during this period. Nearly 14,000 articles reported on mRNA vaccines. Safety outcomes were most frequently reported (n = 8,289), followed by immunogenicity (n = 7,269) and efficacy/effectiveness (n = 3,246). COVID-19 vaccine literature output started to decrease in mid-2023, two years after the initial dramatic increase in mid-2021., Conclusions: This hybrid (AI and human) approach was critical for PHAC situational awareness and the development of timely vaccine guidance in Canada during the COVID-19 pandemic. Given the volume of data and analyses required, the AI-augmented processes made this massive undertaking manageable. Analysis of COVID-19 vaccine research patterns supports projections of research volume, type, and rate that will help predict resourcing and information needs to plan future emergency vaccine guidance activities., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Matthew Tunis reports financial support was provided by Public Health Agency of Canada. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Crown Copyright © 2024 Published by Elsevier Ltd.)

This multi-center, retrospective study focused on periampullary cancer patients undergoing MRI for hepatic metastasis and abscess differentiation. T1-weighted, T2-weighted, and arterial phase images were utilized to create radiomics models. In the training-set, 112 lesions in 54 patients (median age [IQR, interquartile range], 73 [63-80]; 38 men) were analyzed, and 123 lesions in 55 patients (72 [66-78]; 34 men) comprised the validation set. The T1-weighted + T2-weighted radiomics model showed the highest AUC (0.82, 95% CI 0.75-0.89) in the validation set. Notably, < 30% T1-T2 size discrepancy in MRI findings predicted metastasis (Ps ≤ 0.037), albeit with AUCs of 0.64-0.68 for hepatic metastasis. The radiomics model enhanced radiologists' performance (AUCs, 0.85-0.87 vs. 0.80-0.84) and significantly increased diagnostic confidence (P < 0.001). Although the performance increase lacked statistical significance (P = 0.104-0.281), the radiomics model proved valuable in differentiating small hepatic lesions and enhancing diagnostic confidence. This study highlights the potential of MRI-based radiomics in improving accuracy and confidence in the diagnosis of periampullary cancer-related hepatic lesions., (© 2024. The Author(s).)

Importance: Long-acting injectable antipsychotics (LAIs) can help decrease the rate of nonadherence to medications in patients with schizophrenia, but these drugs are underutilized in clinical practice, especially in Asian countries. One strategy for the early prescription of LAIs is to administer the drugs during patients' first admission, when they have more time to absorb medication-related knowledge., Objective: To estimate the prevalence of and risk factors for in-hospital use of LAIs among first-admission patients with schizophrenia in Taiwan and to examine the association of early discontinuation with readmission risk among patients receiving LAIs., Design, Setting, and Participants: This cohort study included data from a claims database for patients with a first admission for schizophrenia at psychiatric wards in Taiwan from 2004 to 2017. Eligible patients were diagnosed with schizophrenia or schizoaffective disorder at discharge and aged between 15 and 64 years. Data analysis was performed from April to September 2022., Exposure: In-hospital use of LAIs with or without early discontinuation., Main Outcome and Measures: Readmission for any psychotic disorder following discharge from first admission, with risk estimated via multivariable survival regression analysis, including the Cox proportional hazards (CPH) model and accelerated failure time (AFT) model., Results: Of the 56 211 patients with a first admission for schizophrenia (mean [SD] age, 38.1 [12.1] years; 29 387 men [52.3%]), 46 875 (83.4%) did not receive any LAIs during admission, 5665 (10.1%) received LAIs with early discontinuation, and 3671 (6.5%) received LAIs without early discontinuation. The prevalence of receiving LAIs increased by 4%, from 15.3% (3863 of 25 251 patients) to 19.3% (3013 of 15 608 patients) between 2004-2008 and 2013-2017. After controlling for sex, year, prior antipsychotic use, age at first admission, and length of stay, the CPH regression analysis revealed that the readmission risk increased among patients receiving LAIs with early discontinuation (adjusted hazard ratio [aHR], 1.25; 95% CI, 1.21-1.30) but decreased among patients receiving LAIs without early discontinuation (aHR, 0.88; 95% CI, 0.84-0.92) compared with patients not receiving LAIs. Results remained similar for the AFT model., Conclusions and Relevance: The incidence of in-hospital use of LAIs among patients with a first admission for schizophrenia has remained low. In this study, early discontinuation of LAIs was associated with readmission risk-specifically, early discontinuation with a higher risk while the lack of early discontinuation with a lower risk compared with treatment with oral antipsychotics alone-which suggests our results have implications for improving the efficacy of LAI administration among patients with a first admission for schizophrenia.

Backgrounds/aims: Reported incidence of extrahepatic bile duct cancer is higher in Asians than in Western populations. Korea, in particular, is one of the countries with the highest incidence rates of extrahepatic bile duct cancer in the world. Although research and innovative therapeutic modalities for extrahepatic bile duct cancer are emerging, clinical guidelines are currently unavailable in Korea. The Korean Society of Hepato-Biliary-Pancreatic Surgery in collaboration with related societies (Korean Pancreatic and Biliary Surgery Society, Korean Society of Abdominal Radiology, Korean Society of Medical Oncology, Korean Society of Radiation Oncology, Korean Society of Pathologists, and Korean Society of Nuclear Medicine) decided to establish clinical guideline for extrahepatic bile duct cancer in June 2021., Methods: Contents of the guidelines were developed through subgroup meetings for each key question and a preliminary draft was finalized through a Clinical Guidelines Committee workshop., Results: In November 2021, the finalized draft was presented for public scrutiny during a formal hearing., Conclusions: The extrahepatic guideline committee believed that this guideline could be helpful in the treatment of patients.

Objective: To investigate molecular and functional consequences of additional exposures to iodine- or gadolinium-based contrast agents within 24 hours from the initial intravenous administration of iodine-based contrast agents through an animal study., Materials and Methods: Fifty-six Sprague-Dawley male rats were equally divided into eight groups: negative control, positive control (PC) with single-dose administration of CT contrast agent, and additional administration of either CT or MR contrast agents 2, 4, or 24 hours from initial CT contrast agent injection. A 12 µL/g of iodinated contrast agent or a 0.47 µL/g of gadolinium-based contrast agent were injected into the tail vein. Serum levels of blood urea nitrogen, creatinine, cystatin C (Cys C), and malondialdehyde (MDA) were measured. mRNA and protein levels of kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) were evaluated., Results: Levels of serum creatinine (SCr) were significantly higher in repeated CT contrast agent injection groups than in PC (0.21 ± 0.02 mg/dL for PC; 0.40 ± 0.02, 0.34 ± 0.03, and 0.41 ± 0.10 mg/dL for 2-, 4-, and 24-hour interval groups, respectively; P < 0.001). There was no significant difference in the average Cys C and MDA levels between PC and repeated CT contrast agent injection groups (Cys C, P = 0.256-0.362; MDA, P > 0.99). Additional doses of MR contrast agent did not make significant changes compared to PC in SCr ( P > 0.99), Cys C ( P = 0.262), and MDA ( P = 0.139-0.771) levels. mRNA and protein levels of KIM-1 and NGAL were not significantly different among additional CT or MR contrast agent groups ( P > 0.05)., Conclusion: A sufficient time interval, probably more than 24 hours, between repeated contrast-enhanced CT examinations may be necessary to avoid deterioration in renal function. However, conducting contrast-enhanced MRI on the same day as contrast-enhanced CT may not induce clinically significant kidney injury., Competing Interests: The authors have no potential conflicts of interest to disclose., (Copyright © 2024 The Korean Society of Radiology.)

Objective: Geriatric patients requiring gynecological surgery is increasing worldwide. However, older patients are at higher risk of postoperative morbidity and mortality, particularly cardiopulmonary complications. Laparoscopic surgery is widely used as a minimally invasive method for reducing postoperative morbidities. We compared the outcomes of open and laparoscopic gynecologic surgeries in patients older than 55 years., Methods: We included patients aged >55 years who underwent gynecological surgery at a single tertiary center between 2010 and 2020, excluding vaginal or ovarian cancer surgeries were excluded. Surgical outcomes were compared between the open surgery and laparoscopic groups, with age cutoff was set at 65 years for optimal discriminative power. We performed linear or logistic regression analyses to compare the surgical outcomes according to age and operation type., Results: Among 2,983 patients, 28.6% underwent open surgery and 71.4% underwent laparoscopic surgery. Perioperative outcomes of laparoscopic surgery were better than those of open surgery in all groups. In both the open and laparoscopic surgery groups, the older patients showed worse overall surgical outcomes. However, age-related differences in perioperative outcomes were less severe in the laparoscopic group. In the linear regression analysis, the differences in estimated blood loss, transfusion, and hospital stay between the age groups were smaller in the laparoscopy group. Similar restuls were observed in cancer-only and benign-only cohorts., Conclusion: Although the surgical outcomes were worse in the older patients, the difference between age groups was smaller for laparoscopic surgery. Laparoscopic surgery offers more advantages and safety in patients aged >65 years.

Background: Given the steady decline in patient numbers at methadone maintenance treatment (MMT) clinics in Taiwan since 2013, the government initiated Patients' Medical Expenditure Supplements (PMES) in January 2019 and the MMT Clinics Accessibility Maintenance Program (MCAM) in September 2019. This study aims to evaluate the impact of the PMES and MCAM on the enrollment and retention of patients attending MMT clinics and whether there are differential impacts on MMT clinics with different capacities., Methods: The monthly average number of daily participants and 3-month retention rate from 2013 to 2019 were extracted from MMT databases and subjected to single interrupted time series analysis. Pre-PMES (from February 2013 to December 2018) was contrasted with post-PMES, either from January 2019 to December 2019 for clinics funded solely by the PMES or from January 2019 to August 2019 for clinics with additional MCAM. Pre-MCAM (from January 2019 to August 2019) was contrasted with post-MCAM (from September 2019 to December 2019). Based on the monthly average number of daily patients in 2018, each MMT clinic was categorized as tiny (1-50), small (51-100), medium (101-150), or large (151-700) for subsequent stratification analysis., Results: In terms of participant numbers after the PMES intervention, a level elevation and slope increase were detected in the clinics at every scale except medium in MMT clinics funded solely by PMES. In MMT clinics with subsequent MCAM, a level elevation was only detected in small-scale clinics, and a slope increase in the participant numbers was detected in tiny- and small-scale clinics. The slope decrease was also detected in medium-scale clinics. In terms of the 3-month retention rate, a post-PMES level elevation was detected at almost every scale of the clinics, and a slope decrease was detected in the overall and tiny-scale clinics for both types of clinics., Conclusions: Supplementing the cost of a broad treatment repertoire enhances the enrollment of people with heroin use in MMTs. Further funding of human resources is vital for MMT clinics to keep up with the increasing numbers of participants and their retention., (© 2024. The Author(s).)

Background: Antidepressants, specifically selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), are commonly prescribed for depression treatment. Animal studies have shown that antidepressants can influence gut microbiota composition and specific bacterial taxa. We aimed to investigate the association between antidepressant use and human gut microbiota composition and functional pathway., Methods: We collected information on antidepressant use, demographic, food patterns, and clinical characteristics through questionnaires and medical records. The gut microbiota profiles of 271 depressive patients were carried out through 16S rRNA gene sequencing. Patients were categorized based on different types of antidepressant use groups for gut microbiota comparisons. MaAsLin2 was performed to evaluate microbiota composition across groups. PICRUSt2 was used to predict microbiota functional pathways., Results: Patients taking SSRIs or SNRIs had a lower microbiota diversity. We found seven taxa abundances (Turicibacter, Barnesiella, Lachnospiraceae&#95;ND3007&#95;group, Romboutia, Akkermansia, Dialister, Romboutia and Fusicatenibacter) differed in patients with various types of antidepressants compared with those without antidepressant treatments (p < 0.05). Turicibacter inversely correlated with depression severity in SSRIs or SNRI users (r = -0.43, p < 0.05). Top identified pathways were related to compound fermentation and biosynthesis in microbiota function., Conclusion: Antidepressant usage, especially SSRIs and SNRIs, associates with changes in gut microbiota composition and specific taxa. Given our study's preliminary cross-sectional nature, further research is warranted to comprehend the relationship between antidepressant use, treatment response, and gut microbiota, aiming to enhance therapeutic interventions in the future., Competing Interests: Declaration of competing interest No conflicts of interest exist, according to the authors, with the publishing of this article., (Copyright © 2023 Elsevier B.V. All rights reserved.)