A Novel Synthesized Cyclohexane-Hydroxytyrosol Derivative Suppresses Ovarian Cancer Cell Growth Through Inducing Reactive Oxidative Species and Blocking Autophagic Flux.

Aims: Drug resistance in ovarian cancer (OC) cells often leads to recurrence, metastasis, and high mortality rates among OC patients. Hydroxytyrosol (HT) has been reported to inhibit the proliferation of ovarian and other types of cancer cells. Here we synthesized a novel cyclohexane-hydroxytyrosol derivative (Chx-HT) for enhanced anticaner efficacy. We examined the growth-suppressing effect of Chx-HT on OC cells in vitro and in a xenograft mouse model and investigated the underlying mechanism. Results: We demonstrated that Chx-HT inhibits proliferation, promotes apoptosis, and remodels glucose and lipid metabolism by reducing fatty acid ß-oxidation while increasing glycolysis, de novo fatty acid synthesis (FAS), and lipid droplet (LD) accumulation, impairs mitochondrial respiration, and induces oxidative stress both in vitro and in vivo. In addition, Chx-HT blocks autophagic flux by obstructing the maturation of lysosomal cathepsins in the late stage, but also activates autophagy through the p-AMPK/p-mTOR/p-ULK1 pathway in response to energy deficit. Innovation and Conclusion: Reactive oxidative species (ROS) play a critical role in mediating the effects of Chx-HT on proliferation, apoptosis, autophagy, tricarboxylic acid (TCA) cycle, fatty acid ß-oxidation, and mitochondrial respiration, and the autophagic activation underlies the effects of Chx-HT on glycolysis, de novo FAS, and LD accumulation in OC cells. Cotreating OC cells with Chx-HT and autophagic inhibitor or glycolytic inhibitor results in an additive inhibition of proliferation. Our study indicates that Chx-HT stands for a promising OC therapeutic by ROS and autophagy blockade-mediated metabolic remodeling.

An empirical investigation of the nexus among renewable energy, financial openness, economic growth, and environmental degradation in selected ASEAN economies.

This study investigates the relationship between economic growth, renewable energy consumption, financial openness, and environmental degradation in selected ASEAN (Association of Southeast Asian Nations) countries (Cambodia, Indonesia, Malaysia, Philippines, Singapore, Thailand, and Vietnam) from 1996 to 2018. We aim to analyze how macroeconomic situation, energy-related factors, and financial determinants contribute to environmental deprivation in selected countries whose growth has recently been substantial. To address this issue, we employ second-generation panel data regression models and quantiles with fixed-effects estimators. Initially, the cointegration analysis supports a long-run association between the variables of our interest. Empirical findings confirm the environmental Kuznets curve hypothesis, but it seems valid only for Singapore. Moreover, results highlight the ecological role of renewable energy for ASEAN countries to achieve Sustainable Development Goals, such as transitioning to a low-carbon economy and reducing air pollution. On the contrary, financial openness is a cause that positively influences CO2 emissions. This research offers practical policy recommendations for many countries, including the ASEAN economies, to attain sustainable development.

Synthesis and Biological Evaluation of 2-Substituted Quinazolin-4(3H)-Ones with Antiproliferative Activities.

Sixteen new 2-substituted quinazolines were synthesized using a straightforward methodology starting from 2-methoxybezoic acid or 3-methoxy-2-naphthoic acid. The anti-proliferative activity of the target compounds was evaluated against nine cancer cell lines. Additionally, all the compounds were screened for their potency and selectivity against a panel of 109 kinases and four bromodomains, using Differential Scanning Fluorimetry (DSF). Compound 17 bearing a 2-methoxyphenyl substitution along with a basic side chain displayed a remarkable profile against the majority of the tested cell lines.

Next-generation sequencing reveals altered gene expression and enriched pathways in triple-negative breast cancer cells treated with oleuropein and oleocanthal.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer characterized by poor prognosis and limited treatment options. Oleuropein and oleocanthal are bioactive chemicals found in extra-virgin olive oil; they have been shown to have anti-cancer potential. In this study, we examined the inhibitory effects of these two natural compounds, on MDA-MB-231 and MDA-MB-468 TNBC cell lines. The human TNBC MDA-MB-231 and MDA-MB-468 cell lines were treated with oleuropein or oleocanthal at ranging concentrations for 48 h. After determining the optimum concentration to reach IC50, using the sulforhodamine B assay, total RNA was extracted after 12, 24, and 48 h from treated and untreated cells. Poly(A)-RNA selection was conducted, followed by library construction and RNA sequencing. Differential gene expression (DEG) analysis was performed to identify DEGs between treated and untreated cells. Pathway analysis was carried out using the KEGG and GO databases. Oleuropein and oleocanthal considerably reduced the proliferation of TNBC cells, with oleocanthal having a slightly stronger effect than oleuropein. Furthermore, multi-time series RNA sequencing showed that the expression profile of TNBC cells was significantly altered after treatment with these compounds, with temporal dynamics and groups of genes consistently affected at all time points. Pathway analysis revealed several significant pathways associated with TNBC, including cell death, apoptotic process, programmed cell death, response to stress, mitotic cell cycle process, cell division, and cancer progression. Our findings suggest that oleuropein and oleocanthal have potential therapeutic benefits for TNBC and can be further investigated as alternative treatment options.

Exploring the Interaction of New Pyridoquinazoline Derivatives with G-Quadruplex in the c-MYC Promoter Region.

Novel amino-substituted pyridoquinazolinone derivatives have been designed and synthesized as potential c-MYC G-quadruplex (G4) ligands, employing an efficient methodology. All the new compounds exhibited moderate to good antiproliferative activity against the human osteosarcoma U2OS cell line. NMR and docking experiments revealed that the recently synthesized compounds interact with the Pu22 G-quadruplex in the c-MYC promoter region, establishing a 2:1 complex, with each molecule positioned over the tetrads at the 3'- and 5'-ends.

Bridging locoregional treatment prior to liver transplantation for cirrhotic patients with hepatocellular carcinoma within the Milan criteria: a systematic review and meta-analysis.

Background: We performed a meta-analysis to assess the benefit of bridging locoregional treatment (LRT) before liver transplantation for cirrhotic patients with hepatocellular carcinoma (HCC) already within the Milan criteria at diagnosis. Methods: We included original studies with HCC cases within the Milan criteria at diagnosis, comparing patients with and without bridging LRT before liver transplantation. Results: Twenty-six retrospective original studies were included. Out of the 9068 patients within the Milan criteria, 6435 (71%) received bridging LRT and 2633 (29%) did not. The most frequent LRTs were transarterial chemoembolization, radiofrequency ablation, and microwave ablation. Most of the patient and tumor characteristics were similar between the 2 groups. Maximum tumor diameter on scans was slightly larger in the LRT arm (mean difference: 0.36 cm, 95% confidence interval [CI] 0.11-0.61; I2=79%). The LRT group also had multifocal disease slightly more frequently (risk ratio [RR] 1.21, 95%CI 1.04-1.41; I2=0%) and disease extent outside the Milan criteria (RR 1.3, 95%CI 1.03-1.66; I2=0%) on pathological examination of explanted livers. There was no difference between the 2 arms in the waiting time for transplant, dropout rates, disease-free survival at 1, 3, 5 years after transplant, or overall survival at 3 and 5 years after transplant. However, cases with LRT had better overall survival at 1 year after transplant (hazard ratio 0.54, 95%CI 0.35-0.86; I2=0%). Conclusions: The precise benefit of bridging LRT for cirrhotic patients with HCC within the Milan criteria at diagnosis is unclear. There may be an advantage regarding short-term overall survival after liver transplantation.

Xanthone synthetic derivatives with high anticandidal activity and positive mycostatic selectivity index values.

With the current massive increases in drug-resistant microbial infection as well as the significant role of fungal infections in the death toll of COVID-19, discovering new antifungals is extremely important. Natural and synthetic xanthones are promising derivatives, although only few reports have demonstrated their antifungal mechanism of action in detail. Newly synthetized by us xanthone derivative 44 exhibited strong antifungal activity against reference and fluconazole resistant C. albicans strains. Our results indicate that the most active compounds 42 and 44 are not substrates for fungal ABC transporters (Cdr1p and Cdr2p) and Mdr1p, the main representative of the major facilitator superfamily efflux pumps, membrane proteins that are responsible for the development of resistance. Moreover, fungicidal mode of action reduces the probability of persistent or recurrent infections and resistance development. In this light, the demonstrated killing activity of the examined derivatives is their undoubted advantage. Novel synthesized compounds exhibited moderate cytotoxicity against human cell lines, although the selectivity index value for human pathogenic strains remained favourable. Our results also indicate that novel synthetized compounds 42 and 44 with antifungal activity target yeast topoisomerase II activity. In summary, further validation of xanthones applicability as antifungals is highly valuable.

Synthesis and Biological Evaluation of Resveratrol Methoxy Derivatives.

Resveratrol, a naturally occurring stilbene, exhibits numerous beneficial health effects. Various studies have demonstrated its diverse biological actions, including anti-oxidant, anti-inflammatory, and anti-platelet properties, thereby supporting its potential for cardio protection, neuroprotection, and anti-cancer activity. However, a significant limitation of resveratrol is its weak bioavailability. To overcome this challenge, multiple research groups have investigated the synthesis of new resveratrol derivatives to enhance bioavailability and pharmacological activities. Nevertheless, there are limited data on the effects of resveratrol derivatives on platelet function. Therefore, the objective of this study was to synthesize resveratrol methoxy derivatives and evaluate their anti-platelet and anti-proliferative activity. Platelet-rich plasma (PRP) obtained from healthy volunteers was utilized to assess the derivatives' ability to inhibit platelet aggregation induced by platelet activating factor (PAF), adenosine diphosphate (ADP), and thrombin receptor activating peptide (TRAP). Additionally, the derivatives' anti-tumor activity was evaluated against the proliferation of PC-3 and HCT116 cells. The results revealed that some methoxy derivatives of resveratrol exhibited comparable or even superior anti-platelet activity compared to the original compound. The most potent derivative was the 4'-methoxy derivative, which demonstrated approximately 2.5 orders of magnitude higher anti-platelet activity against TRAP-induced platelet aggregation, indicating its potential as an anti-platelet agent. Concerning in silico studies, the 4'-methyl group of 4'-methoxy derivative is oriented similarly to the fluorophenyl-pyridyl group of Vorapaxar, buried in a hydrophobic cavity. In terms of their anti-tumor activity, 3-MRESV exhibited the highest potency in PC-3 cells, while 3,4'-DMRESV and TMRESV showed the greatest efficacy in HCT116 cells. In conclusion, methoxy derivatives of resveratrol possess similar or improved anti-platelet and anti-cancer effects, thereby holding potential as bioactive compounds in various pathological conditions.

Time-Related Evidence of Intestinal Oxidative Stress in Obstructive Jaundice-Induced Rats.

INTRODUCTION: Obstructive jaundice is known to affect intestinal permeability and facilitate bacterial translocation through related mechanisms. This study was conducted to evaluate the alterations concerning blood biochemistry and levels of several markers of oxidative stress (OS) in blood and intestinal mucosa caused by obstructive jaundice and how these fluctuate over time, in order to further explore the possibility of intervening in the OS path in future experiments. METHODS: A total of 54 albino Wistar rats were randomly divided into three groups (control, sham operated, and bile duct ligation) and sacrificed at specific time intervals (12 h and 2, 7, and 14 days). The intestinal barrier function was evaluated by measuring endotoxin levels in portal, aortic, and peripheral blood. Also, basic biochemical parameters were simultaneously measured in peripheral blood. Tissue samples collected from the terminal ileum were homogenized for determining the OS markers, lipid peroxidation, and protein-free radical-induced oxidation. RESULTS: We designed this experiment to examine the alterations in enteric mucosa primarily in relation to OS in a period of 14 days. During this time period, we investigated in specific time intervals not only OS fluctuations but also other liver function parameters, as well as CRP and endotoxin levels. The alterations were monitored in relation to time after bile duct ligation. CONCLUSION: Bile duct ligation in rats causes OS versus post-ligation time progression of the common bile duct. OS was increased by ∼50% compared to control/sham and peaked at 7 days and at least up to 14 days post-ligation. This phenomenon was accompanied with a deranging of liver function after ligation, as anticipated, but not in all measured parameters; biochemical and endotoxin levels followed the same pattern.

Disaggregated energy use and socioeconomic sustainability within OECD countries.

This study investigates the relationship between disaggregated energy use, human development, trade openness, economic growth, urbanization, and sustainability index in OECD countries from 2014 to 2019. Static, quantile, and dynamic panel data approaches are employed. The findings reveal that fossil fuels such as petroleum, solid fuels, natural gas, and coal decrease sustainability. On the contrary, alternative sources such as renewable and nuclear energy seem to contribute positively to sustainable socioeconomic development. It is also interesting to note that alternative energy sources strongly influence socioeconomic sustainability in the lower and upper quantiles. Also, the human development index and trade openness improve sustainability, while urbanization seems to be an obstacle in complying with sustainability goals within OECD countries. Policymakers should revisit their strategies toward sustainable development by mitigating fossil fuels and urbanization and promoting human development, trade openness, and alternative energy sources as drivers of economic progress.

Mitochondria-Targeted Triphenylphosphonium-Hydroxytyrosol Prevents Lipotoxicity-Induced Endothelial Injury by Enhancing Mitochondrial Function and Redox Balance via Promoting FoxO1 and Nrf2 Nuclear Translocation and Suppressing Inflammation via Inhibiting p38/NF-кB Pathway.

Hyperlipidemia results in endothelial dysfunction, which is intimately associated with disturbed mitochondrial homeostasis, and is a real risk factor for cardiovascular diseases (CVDs). Triphenylphosphonium (TPP+)-HT, constructed by linking a mitochondrial-targeting moiety TPP+ to hydroxytyrosol (HT), enters the cell and accumulates in mitochondria and is thus an important candidate drug for preventing hyperlipidemia-induced endothelial injury. In the present study, we found that TPP-HT has a better anti-inflammatory effect than HT. In vivo, TPP-HT significantly prevented hyperlipidemia-induced adverse changes in the serological lipid panel, as well as endothelial and mitochondrial dysfunction of the thoracic aorta. Similarly, in vitro, TPP-HT exhibited similar protective effects in palmitate (PA)-induced endothelial dysfunction, particularly enhanced expression of the mitochondrial ETC complex II, recovered FoxO1 expression in PA-injured human aorta endothelial cells (HAECs) and promoted FoxO1 nuclear translocation. We further demonstrated that FoxO1 plays a pivotal role in regulating ATP production in the presence of TPP-HT by using the siFoxO1 knockdown technique. Simultaneously, TPP-HT enhanced Nrf2 nuclear translocation, consistent with the in vivo findings of immunofluorescence, and the antioxidant effect of TPP-HT was almost entirely blocked by siNrf2. Concomitantly, TPP-HT's anti-inflammatory effects in the current study were primarily mediated via the p38 MAPK/NF-κB signaling pathway in addition to the FoxO1 and Nrf2 pathways. In brief, our findings suggest that mitochondria-targeted TPP-HT prevents lipotoxicity induced endothelial dysfunction by enhancing mitochondrial function and redox balance by promoting FoxO1 and Nrf2 nuclear translocation.

Pediatric renal transplantation-A UNOS database analysis of donor-recipient size mismatch.

BACKGROUND: We used the BSAi (Donor BSA/Recipient BSA) to assess whether transplanting a small or large kidney into a pediatric recipient relative to his/her size influences renal transplant outcomes. METHODS: We included 14 322 single-kidney transplants in pediatric recipients (0-17 years old) (01/2000-02/2020) from the United Network for Organ Sharing database. We divided cases into four BSAi groups (BSAi ≤ 1, 1 < BSAi ≤ 2, 2 < BSAi ≤ 3, BSAi > 3). RESULTS: There were no differences concerning delayed graft function (DGF) or primary non-function (PNF) rates, whether the grafts were from living or brain-dead donors. In both transplants coming from living donors and brain-dead donors, cases with BSAi > 3 and cases with 2 < BSAi ≤ 3 had similar graft survival (p = .13 for transplants from living donors, p = .413 for transplants from brain-dead donors), and both groups had longer graft survival than cases with 1 < BSAi ≤ 2 and cases with BSAi ≤ 1 (p < .001). The difference in 10-year graft survival rates between cases with BSAi > 3 and cases with BSAi ≤ 1 reached around 25% in both donor types. The better graft survival in transplants with BSAi > 2 was confirmed in multivariable analysis. CONCLUSIONS: There is no significant impact of donor-recipient size mismatch on DGF and PNF rates in pediatric renal transplants. However, graft survival is significantly improved when the donor's size is more than twice the pediatric recipient's size.

Donor-Recipient Body Surface Area Mismatch and the Outcome of Liver Transplantation in the UK.

Introduction: Too small or too big liver grafts for recipient's size has detrimental effects on transplant outcomes. Research Questions: The purpose was to correlate donor-recipient body surface area ratio or body surface area index with recipient survival, graft survival, hepatic artery or portal vein, or vena cava thrombosis. High and low body surface area index cut-off points were determined. Design: There were 11,245 adult recipients of first deceased donor whole liver-only grafts performed in the UK from January 2000 until June 2020. The transplants were grouped according to the body surface area index and compared to complications, graft and recipient survival. Results: The body surface area index ranged from 0.491 to 1.691 with a median of 0.988. The body surface area index > 1.3 was associated with a higher rate of portal vein thrombosis within the first 3 months (5.5%). This risk was higher than size-matched transplants (OR: 2.878, 95% CI: 1.292-6.409, P = 0.01). Overall graft survival was worse in transplants with body surface area index ≤ 0.85 (HR: 1.254, 95% CI: 1.051-1.497, P = 0.012) or body surface area index > 1.4 (HR: 3.704, 95% CI: 2.029-6.762, P < 0.001) than those with intermediate values. The graft survival rates were reduced by 2% for cases with body surface area index ≤ 0.85 but were decreased by 20% for cases with body surface area index > 1.4. These findings were confirmed by bootstrap internal validation. No statistically significant differences were detected for hepatic artery thrombosis, occlusion of hepatic veins/inferior vena cava or recipient survival. Conclusions: Donor-recipient size mismatch affects the rates of portal vein thrombosis within the first 3 months and overall graft survival in deceased-donor liver transplants.

Policies for supporting the regional circular economy and sustainability.

The Circular Economy and Sustainability are among the greatest challenges faced by policymakers, producers, and consumers. Circular Economy processes demand less from the environment since they can minimize waste generation and, hence, can be powerful tools to combat the negative effects of climate change. Additionally, following subsidiarity principles, public policies supporting the Circular Economy should be designed at the lowest levels of public administrations-this provides huge opportunities for regional governments to design, implement and monitor these policies. This editorial of the special issue explores and discusses implications for those policies before introducing the five papers published in the special issue dedicated to policies for regional economy and sustainability. While some of the papers attempt to conceptualize sustainable development through a microeconomic perspective, others have a clear macroeconomic empirical focus. In consequence, this special issue provides a rich body of work for further Circularity and Sustainability nexus studies.

Chemometrically Assisted Optimization of Pregabalin Fluorescent Derivatization Reaction with a Novel Xanthone Analogue and Validation of the Method for the Determination of Pregabalin in Bulk via a Plate Reader.

Quantitation of chromophore-free analytes is always a challenge. To this purpose, derivatization of the analyte constitutes a common strategy, leading to a product with a strong signal. In the current study, a novel xanthone analogue was utilized for the first time for the derivatization of pregabalin, a model analyte with a primary amine moiety that lacks a chromophore. The fact that only the xanthene-based derivative, formed after the derivatization reaction fluoresces, enables avoiding its chromatographic separation from the reagent and thus reducing the analysis time of a series of samples in 1-2 min via a plate reader. The reaction conditions were optimized via a central composite design (CCD), with fluorescence signal as the measure of the yield. The following factors that affect the derivatization reaction were chosen: (a) temperature, (b) reaction time, and (c) triethylamine solution volume used to drive the reaction to completion. After the identification of the optimal conditions, the method was validated according to ICH guidelines, using a fluorescence plate reader for signal measurement (λex = 540, λem = 615 nm). Finally, the newly developed high-throughput method was applied to the determination of drug content in pregabalin bulk.

Residential demand for electricity: empirical evidence from Greece using pseudo-panels.

This study investigates the behaviour of residential demand for electricity, employing a pseudo-panel methodology. The case of Greece, over the period 2009-2018, is taken as an example for our empirical investigation. The empirical analysis uses annual household panel data for the construction of 330 cohorts. The specification of cohorts is based on the date of birth, education level and geographical location of the head of the household. The econometric analysis is carried out using static and dynamic specifications and a quantile regression model. The results show that residential demand for electricity is price and income inelastic, both in the short and the long run. Electricity and heating oil appear to be complementary energy sources, while the household size and the education level are important determinants of residential demand for electricity. Income status has a marginal effect on demand for electricity, and the impact of urbanisation is insignificant. The quantile regression results show that, as the level of electricity use increases, demand for electricity becomes less income responsive and more price responsive. Our results show that a mix of structural energy measures along with economic policies could result in a decrease in electricity use and improve energy efficiency.

Solid Pseudopapillary Neoplasms of the Pancreas: a Single-Center Experience and Review of the Literature.

PURPOSE: Pancreatic solid pseudopapillary neoplasms (SPNs) are rare borderline tumours mainly affecting young female patients. The number of patients diagnosed with SPNs has increased significantly in the last decades owing to the increased use of cross-sectional imaging investigating different abdominal symptoms, whilst a significant proportion are incidentally discovered during the process of evaluating other pathologies. We herein present our institutional experience of patients with SPN who underwent curative resection focusing on clinical, pathological features, and the long-term outcomes. METHODS: All patients undergoing pancreatectomy in our institution for SPN from January 2010 until December 2018 were included. Clinical, perioperative, histological, and long-term outcomes were collected and analysed. RESULTS: During the inclusion period, a total of 19 patients had a pathological diagnosis of SPNs after surgical resection. Sixteen of them were female (84%), while the median patient age was 30 (range 16-66) years. Nine patients (47%) underwent distal pancreatectomy and splenectomy, 2 (11%) underwent spleen preserving distal pancreatectomy, 6 (32%) underwent pancreatoduodenectomy, one (5%) underwent total pancreatectomy, and one (5%) central pancreatectomy. Seventeen patients underwent R0 resection. During a median follow-up of 23 months, no tumour recurrence or death was recorded. CONCLUSION: In our experience, SPNs are rare tumours with low malignant potentials. Surgical resection remains the gold standard treatment and is associated with good prognosis.

Molecular investigation of artificial and natural sweeteners as potential anti-inflammatory agents.

Repurposing existing drugs, as well as natural and artificial sweeteners for novel therapeutic indications could speed up the drug discovery process since numerous associated risks and costs for drug development can be surpassed. In this study, natural and artificial sweeteners have been evaluated by in silico and experimental studies for their potency to inhibit lipoxygenase enzyme, an enzyme participating in the inflammation pathway. A variety of different methods pinpointed that aspartame inhibits the lipoxygenase isoform 1 (LOX-1). In particular, "LOX-aspartame" complex, that was predicted by docking studies, was further evaluated by Molecular Dynamics (MD) simulations in order to assess the stability of the complex. The binding energy of the complex has been calculated after MD simulations using Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) method. Furthermore, Quantum Mechanics/Molecular Mechanics (QM/MM) calculations have been applied for geometry optimization of the "enzyme-ligand" complex. After having fully characterized the "LOX-aspartame" complex in silico, followed in vitro biological assays confirmed that aspartame inhibits LOX-1 (IC50=50 ± 3.0 µΜ) and blocks its biological response. The atomic details of aspartame's interaction profile with LOX-1 were revealed through Saturation Transfer Difference (STD) NMR (Nuclear Magnetic Resonance). Finally, aspartame was also tested with Molecular Docking and Molecular Dynamics studies for its potent binding to a number of different LOX isoforms of many organisms, including human. The in silico methods indicated that aspartame could serve as a novel starting point for drug design against LOX enzyme. Communicated by Ramaswamy H. Sarma.

Adrenocortical Cancer: A 20-Year Experience of a Single Referral Center in Prognosis and Outcomes.

Adrenocortical carcinoma (ACC) is a rare but very aggressive endocrine malignancy with poor survival. Histopathology is important for diagnosis, while in some cases immunohistochemical markers and gene profiling of the resected tumor may be superior to current staging systems to determine prognosis. We aimed to present the 20-year experience at a tertiary hospital in patients with ACCs and correlate the immunohistochemical characteristics of ACCs with the clinical and morphological characteristics of the tumors and the survival of the patients. Forty-five patients with ACC were included in the study. All the resections were R0. The tumor size and weight, the disease stage (ENSAT classification), Weiss score and Helsinki score were examined along with immunohistochemical expression of inhibin-A, melan A, calretinin, Ki67, synaptophysin, p53, vimentin, CKAE1/AE3. The male to female ratio was 1:1.37. The median age at diagnosis was 55.5 years (IQR 19-77). The median size of ACCs was 9 cm (IQR 3.5-22 cm) and the median weight 127 g (IQR 18-1400 g). The median follow up period was 18 months (IQR 1-96). Ki67 varied from<1% to 75% (median: 16.4%). The expression of melan-A and lower expression of Ki-67 (≤4) were independently associated with longer OS time (p=0.01 and p=0.04, respectively). In multivariable analysis, tumor volume>400 cm3 (p=0.046), Weiss score>5 (p=0.007) and overexpression of p53 (p=0.036) were independent risk factors for shorter survival. Adrenocortical carcinoma is a rare and very aggressive endocrine malignancy. The most important factors that determine long-term prognosis of ACC are the disease stage at diagnosis, the Weiss score, and the Ki67 index. Immunohistochemical markers such as melan A could also serve as prognostic factors.

Combining Donor and Recipient Age With Preoperative MELD and UKELD Scores for Predicting Survival After Liver Transplantation.

OBJECTIVES: The end-stage liver disease scoring systems MELD, UKELD, and D-MELD (donor age × MELD) have had mediocre results for survival assessment after orthotopic liver transplant. Here, we introduced new indices based on preoperative MELD and UKELDscores and assessed their predictive ability on survival posttransplant. MATERIALS AND METHODS: We included 1017 deceased donor orthotopic liver transplants that were performed between 2008 (the year UKELD was introduced) and 2019. Donor and recipient characteristics, liver disease scores, transplant characteristics, and outcomes were collected for analyses. D-MELD, D-UKELD (donor age × UKELD),DR-MELD[(donor age + recipient age) × MELD], and DR-UKELD [(donor age + recipient age) × UKELD] were calculated. RESULTS: No score had predictive value for graft survival. For patient survival,DR-MELD and DR-UKELD provided the best results but with low accuracy. The highest accuracy was observed at 1 year posttransplant (areas under the curve of 0.598 [95% CI, 0.529-0.667] and 0.609 [95% CI, 0.549-0.67]forDR-MELDandDR-UKELD). Addition of donor and recipient age significantly improved the predictive abilities of MELD and UKELD for patient survival, but addition of donor age alone did not. For 1-year mortality (using receiver operating characteristic curves), optimal cut-off points were DR-MELD>2345 and DR-UKELD>5908. Recipients with DR-MELD >2345 (P < .001) and DR-UKELD >5908 (P = .002) had worse patient survival within the first year, but only DR-MELD >2345 remained significant after multivariable analysis (P = .007). CONCLUSIONS: DR-MELD and DR-UKELD scores provided the best, albeit mediocre, predictive ability among the 6 tested models, especially at 1 year after posttransplant, although only for patient but not for graft survival. A DR-MELD >2345 was considered to be an additional independent risk factor for worse recipient survival within the first postoperative year.