Synthesis of scaberol C amino acid ester derivatives with anti-cancer activity.

A series of amino acid ester trifluoroacetate derivatives was synthesized from scaberol C. They were screened for their inhibitory activity against Non-Small Cell Lung Cancer (NSCLC) cells. Among them, compound 2 l showed significant cytotoxicity against A549 and H460 cells (IC50), and was more active than cisplatin (DDP). The epidermal growth factor receptor (EGFR) was overexpressed in NSCLC, which was the target of multiple cancer therapies and a strong prognostic indicator. Our previous studies reported that the target of scaberol C derivatives against NSCLC cells was EGFR. And then molecular docking analysis and molecular dynamics (MD) simulations indicated that 2 l can stably and covalently bind to the EGFR target protein.

13-Oxyingenol-dodecanoate inhibits the growth of non-small cell lung cancer cells by targeting ULK1.

Lung cancer is the leading cause of cancer deaths worldwide. Non-small cell lung cancer (NSCLC) accounts for 80-85% of all lung cancers. Euphorbia kansui yielded 13-oxyingenol-dodecanoate (13OD), an ingenane-type diterpenoid, which had a strong cytotoxic effect on NSCLC cells. The underlying mechanism and potential target, however, remained unknown. The study found that 13OD effectively inhibited the cell proliferation and colony formation of NSCLC cells (A549 and H460 cells), with less toxicity in normal human lung epithelial BEAS-2B cells. Moreover, 13OD can cause mitochondrial dysfunction, and apoptosis in NSCLC cells. Mechanistically, the transcriptomics results showed that differential genes were mainly enriched in the mTOR and AMPK signaling pathways, which are closely related to cellular autophagy, the related indicators were subsequently validated. Additionally, bafilomycin A1 (Baf A1), an autophagy inhibitor, reversed the mitochondrial damage caused by 13OD. Furthermore, the Omics and Text-based Target Enrichment and Ranking (OTTER) method predicted ULK1 as a potential target of 13OD against NSCLC cells. This hypothesis was further confirmed using molecular docking, the cellular thermal shift assay (CETSA), and Western blot analysis. Remarkably, ULK1 siRNA inhibited 13OD's toxic activity in NSCLC cells. In line with these findings, 13OD was potent and non-toxic in the tumor xenograft model. Our findings suggested a possible mechanism for 13OD's role as a tumor suppressor and laid the groundwork for identifying targets for ingenane-type diterpenoids.

13-oxyingenol dodecanoate derivatives induce mitophagy and ferroptosis through targeting TMBIM6 as potential anti-NSCLC agents.

Ingenol diterpenoids continue to attract the attention for their extensive biological activity and novel structural features. To further explore this type of compound as anti-tumor agent, 13-oxyingenol dodecanoate (13-OD) was prepared by a standard chemical transformation from an Euphorbia kansui extract, and 29 derivatives were synthesized through parent 13-OD. Their inhibition activities against different types of cancer were screened and some derivatives showed superior anti-non-small cell lung cancer (NSCLC) cells cytotoxic potencies than oxaliplatin. In addition, TMBIM6 was identified as a crucial cellular target of 13-OD using ABPP target angling technique, and subsequently was verified by pull down, siRNA interference, BLI and CETSA assays. With modulating the function of TMBIM6 protein by 13-OD and its derivatives, Ca2+ release function was affected, causing mitochondrial Ca2+ overload, depolarisation of membrane potential. Remarkably, 13-OD, B6, A2, and A10-2 induced mitophagy and ferroptosis. In summary, our results reveal that 13-OD, B6, A2, and A10-2 holds great potential in developing anti-tumor agents for targeting TMBIM6.

New daphnane diterpenoidal 1,3,4-oxdiazole derivatives as potential anti-hepatoma agents: Synthesis, biological evaluation and molecular modeling studies.

Hepatocellular carcinoma (HCC) is a major challenge for human healthy. Daphnane-type diterpenes have attracted increasingly attention due to remarkable pharmaceutical potential including anti-HCC activity. To further develop this class of compounds as inhibitors of HCC, the daphnane diterpenoids 12-O-debenzoyl-Yuanhuacine (YHC) and 12-hydroxydaphnetoxin (YHE) were prepared by a standard chemical transformation from dried flower buds of the Daphne genkwa plant. Subsequently, 22 daphnane diterpenoidal 1,3,4-oxdiazole derivatives were rationally designed and synthesized based on YHC and YHE. The assessment of the target compound's anti-hepatocellular carcinoma activity revealed that YHC1 exhibited comparable activity to sorafenib in the Hep3B cell line, while demonstrating higher selectivity. The mechanistic investigation demonstrates that compound YHC1 induces cell cycle arrest at the G0/G1 phase, cellular senescence, apoptosis, and elevates cellular reactive oxygen species levels. Moreover, molecular docking and CETSA results confirm the interaction between YHC1 and YAP1 as well as TEAD1. Co-IP experiments further validated that YHC1 can effectively inhibit the binding of YAP1 and TEAD1. In conclusion, YHC1 selectively targets YAP1 and TEAD1, exhibiting its anti-hepatocellular carcinoma effects through the inhibition of their interaction.

Exploring the mechanism of daphne-type diterpenes against gastric cancer cells.

Gastric cancer is one of the common malignant tumors. It is reported that daphne-type diterpenes have inhibitory effects on gastric cancer cells, but the mechanism is still unknown. To explore the detailed mechanism of the anticancer effect of daphne-type diterpenes, we carried out an integrated network pharmacology prediction study and selected an effective component (yuanhuacine, YHC) for the following validation in silico and in vitro. The result showed that daphne-type diterpenes exerted an anti-tumor effect by targeting proto-oncogene tyrosine-protein kinase SRC as well as regulating the Ras/MAPK signaling pathway, which caused the apoptosis and mitochondrial damage in gastric cancer cells.

SESN2-Mediated AKT/GSK-3ß/NRF2 Activation to Ameliorate Adriamycin Cardiotoxicity in High-Fat Diet-Induced Obese Mice.

Aims: Obese patients are highly sensitive to adriamycin (ADR)-induced cardiotoxicity. However, the potential mechanism of superimposed toxicity remains to be elucidated. Sestrin 2 (SESN2), a potential antioxidant, could attenuate stress-induced cardiomyopathy; therefore, this study aims to explore whether SESN2 enhances cardiac resistance to ADR-induced oxidative damage in high-fat diet (HFD)-induced obese mice. Results: The results revealed that obesity decreased SESN2 expression in ADR-exposed heart. And, HFD mice may predispose to ADR-induced cardiotoxicity, which was probably associated with inhibiting protein kinase B (AKT), glycogen synthase kinase-3 beta (GSK-3ß) phosphorylation and subsequently blocking nuclear localization of nuclear factor erythroid-2 related factor 2 (NRF2), ultimately resulting in cardiac oxidative damage. However, these destructive cascades and cardiac oxidative damage effects induced by HFD/sodium palmitate combined with ADR were blocked by overexpression of SESN2. Moreover, the antioxidant effect of SESN2 could be largely abolished by sh-Nrf2 or wortmannin. And sulforaphane, an NRF2 agonist, could remarkably reverse cardiac pathological and functional abnormalities caused by ADR in obese mice. Innovation and Conclusion: This study demonstrated that SESN2 might be a promising therapeutic target for improving anthracycline-related cardiotoxicity in obesity by upregulating activity of NRF2 via AKT/GSK-3ß/Src family tyrosine kinase signaling pathway. Antioxid. Redox Signal. 40, 598-615.

Ingenane-type diterpenoids inhibit non-small cell lung cancer cells by regulating SRC/PI3K/Akt pathway.

Ingenane-type diterpenoids (ITDs) are distinct components of plants belonging to the genus Euphorbia. These compounds have significant cytotoxic effects on non-small cell lung cancer (NSCLC) cells. However, the underlying molecular mechanism has yet to be reported. To explore the mechanism of the anticancer effect of ITDs, we carried out a network pharmacology prediction study. PPI network suggested that SRC and PI3K had high levels of interaction. In addition, KEGG analysis revealed that these common targets were significantly enriched in the PI3K/Akt signalling pathway. 13-oxyingenol-dodecanoate (13OD) was used for validation after the biological evaluation of some ITDs against NSCLC cells. It demonstrated that 13OD could significantly inhibit the growth of NSCLC cells by inducing apoptosis. The results from molecular docking and Western blotting showed that 13OD interacted with SRC and PI3K and down-regulated the SRC/PI3K/Akt signalling pathway in NSCLC cells. This study provided the underlying mechanism of ITDs against NSCLC.

Multi-omics integrated analyzed the origin of intrahepatic mucinous cholangiocarcinoma: a case report.

Intrahepatic mucinous cholangiocarcinoma (IMCC) is a rare subtype of intrahepatic cholangiocarcinoma (IHCC). Limited data describe the genetic characteristics of IMCC and insights on its pathogenesis are lacking. Here, we employed a multi-omics approach to analyze somatic mutations, transcriptome, proteome and metabolome of tumor tissue obtained from a case of IMCC in order to clarify the pathogenesis of IMCC. A total of 54 somatic mutations were detected, including a G12D mutation in KRAS that is likely to be involved in the onset of IMCC. The genes consistently up-regulated at the transcription level and in the proteome were enriched for mucin and mucopolysaccharide biosynthesis, for cell cycle functions and for inflammatory signaling pathways. The consistently down-regulated genes were enriched in bile synthesis and fatty acid metabolism pathways. Further multi-omics analysis found that mucin synthesis by MUC4 and MUC16 was elevated by up-regulated expression of mesothelin (MSLN). Moreover, transcription factor ONECUT3 was identified that possibly activates the transcription of mucin and mucopolysaccharide biosynthesis in IMCC.

Disulfidptosis: a new form of programmed cell death.

Disulfidptosis, a new form of cell death triggered by disulfide stress, is characterized by the collapse of cytoskeleton proteins and F-actin due to the intracellular accumulation of disulfides. This discovery will eventually aid in the development of therapeutic strategies against cancer.

Biclonal lymphoplasmacytic lymphoma/Waldenström macroglobulinemia associated with POEMS syndrome: A case report and literature review.

Due to its unique clinical, immunological and molecular genetic characteristics, biclonal lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM) with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein and skin changes (POEMS) syndrome is extremely rare in clinical practice, and there is no standard treatment for patients afflicted with this condition. In the present case report, a rare case of double LPL/WM with POEMS syndrome is described. The patient, a 65-year-old male, exhibited significant renal impairment and polylymphadenopathy. The patient was treated with rituximab and his symptoms were resolved following two courses of treatment. A review of the literature was performed, comparing the present case with previous cases. It is hoped that this case report will enable clinicians to gain a better understanding of this disease.

Synthesis and Structure-Activity Analysis of Icaritin Derivatives as Potential Tumor Growth Inhibitors of Hepatocellular Carcinoma Cells.

The prenylated flavonoid icaritin (ICT, 1), a new drug for treating advanced hepatocellular carcinoma (HCC), was selected as a template to develop more potent inhibitors. An initial semisynthetic modification of ICT was performed to obtain a structure-activity relationship (SAR), which indicated that the cytotoxicity is enhanced by OH-3 rhamnosylation and that OH-7 is an important modification site. Based on the results of the SAR study, 46 N-containing ICT derivatives were synthesized and evaluated as the anti-HCC inhibitors. The results showed that most of the derivatives produced inhibited three HCC cell lines used (Hep3B, HepG2 and SMMC-7721). The modification strategy was validated by 3D-QSAR, which provided information for the further design and optimization of ICT. The most potent compound, 11c, exhibited IC50 values of 7.6 and 3.1 µM against HepG2 and SMMC-7721 cells, respectively, which were more potent than those of ICT and sorafenib, respectively. Further mechanistic studies indicated that 11c caused arrest at the G0/G1 phase in the cell cycle and induced cell apoptosis in HepG2 and SMMC-7721 cells.

Flavonoid-Rich Extract of Oldenlandia diffusa (Willd.) Roxb. Inhibits Gastric Cancer by Activation of Caspase-Dependent Mitochondrial Apoptosis.

OBJECTIVE: To evaluate the apoptosis and cycle arrest effects of Oldenlandia diffusa flavonoids on human gastric cancer cells, determine the action mechanisms in association with the mitochondrial dependent signal transduction pathway that controls production of reactive oxygen species (ROS), and evaluate the pharmacodynamics of a mouse xenotransplantation model to provide a reference for the use of flavonoids in prevention and treatment of gastric cancer. METHODS: Flavonoids were extracted by an enzymatic-ultrasonic assisted method and purified with D-101 resin. Bioactive components were characterized by high-performance liquid chromatography. Cell lines MKN-45, AGS, and GES-1 were treated with different concentrations of flavonoids (64, 96, 128, 160 µg/mL). The effect of flavonoids on cell viability was evaluated by MTT method, and cell nuclear morphology was observed by Hoechst staining. The apoptosis rate and cell cycle phases were measured by flow cytometry, the production of ROS was detected by laser confocal microscope, the mitochondrial membrane potential (MMP) were observed by fluorescence microscope, and the expression of apoptotic proteins related to activation of mitochondrial pathway were measured by immunoblotting. MKN-45 cells were transplanted into BALB/c nude mice to establish a xenograft tumor model. Hematoxylin and eosin staining was used to reveal the subcutaneous tumor tissue. The tumor volume and tumor weight were measured, the expression levels of proliferation markers proliferating cell nuclear antigen (PCNA) and Ki-67 were detected by immunohistochemistry, and the expression levels of CA72-4 were measured by enzyme linked immunosorbent assay. RESULTS: Oldenlandia diffusa flavonoids inhibited proliferation of MKN-45 and AGS human gastric cancer cells, arrested the cell cycle in G1/S phase, induced accumulation of ROS in the process of apoptosis, and altered MMP. In addition, flavonoids increased Apaf-1, Cleaved-Caspase-3, and Bax, and decreased Cyclin A, Cdk2, Bcl-2, Pro-Caspase-9, and Mitochondrial Cytochrome C (P<0.05). The MKN-45 cell mouse xenotransplantation model further clarified the growth inhibitory effect of flavonoids towards tumors. The expression levels of PCNA and Ki-67 decreased in each flavonoid dose group, the expression level of CA72-4 decreased (P<0.05). CONCLUSION: Flavonoids derived from Oldenlandia diffusa can inhibit proliferation and induce apoptosis of human gastric cancer cells by activating the mitochondrial controlled signal transduction pathway.

Deoxyelephantopin, a germacrane-type sesquiterpene lactone from Elephantopus scaber, induces mitochondrial apoptosis of hepatocarcinoma cells by targeting Hsp90α in vitro and in vivo.

Hepatocellular carcinoma has been known as the most frequent subtype of liver cancer with a high rate of spread, metastases, and recurrence, also dismal treatment effects. However, effective therapies for HCC are still required. Nowadays, natural products have been known as a valuable source for drug discovery. In this research, 44 sesquiterpene lactones isolated from the Elephantopus scaber Linn. (Asteraceae) were tested by MTT assay for the antitumor activities. Deoxyelephantopin (DET) was found to exert significant cytotoxicity on HepG2 and Hep3B cells. Moreover, we found that DET treatment markedly reduced the growth of HCC cells in a concentration-dependent manner, which was better than sorafenib. Furthermore, DET induced mitochondrial dysfunction, oxidative stress, and cellular apoptosis. Additionally, we found that DET and sorafenib synergistically induced apoptosis and mitochondrial dysfunction in HCC cells. DET combined with sorafenib was also efficacious in tumor xenograft model. Molecular docking experiments revealed that DET had a potentially high binding affinity with Hsp90α. Moreover, Drug Affinity Responsive Target Stability assay suggested that DET could directly target Hsp90α. Additionally, the expression of Hsp90α was both decreased in vitro and in vivo. Altogether, this study revealed that DET might be a promising agent for HCC therapy by targeting Hsp90α.

Resveratrol and FGF1 Synergistically Ameliorates Doxorubicin-Induced Cardiotoxicity via Activation of SIRT1-NRF2 Pathway.

Doxorubicin (DOX) has received attention due to dose-dependent cardiotoxicity through abnormal redox cycling. Native fibroblast growth factor 1 (FGF1) is known for its anti-oxidative benefits in cardiovascular diseases, but possesses a potential tumorigenic risk. Coincidentally, the anti-proliferative properties of resveratrol (RES) have attracted attention as alternatives or auxiliary therapy when combined with other chemotherapeutic drugs. Therefore, the purpose of this study is to explore the therapeutic potential and underlying mechanisms of co-treatment of RES and FGF1 in a DOX-treated model. Here, various cancer cells were applied to determine whether RES could antagonize the oncogenesis effect of FGF1. In addition, C57BL/6J mice and H9c2 cells were used to testify the therapeutic potential of a co-treatment of RES and FGF1 against DOX-induced cardiotoxicity. We found RES could reduce the growth-promoting activity of FGF1. Additionally, the co-treatment of RES and FGF1 exhibits a more powerful cardio-antioxidative capacity in a DOX-treated model. The inhibition of SIRT1/NRF2 abolished RES in combination with FGF1 on cardioprotective action. Further mechanism analysis demonstrated that SIRT1 and NRF2 might form a positive feedback loop to perform the protective effect on DOX-induced cardiotoxicity. These favorable anti-oxidative activities and reduced proliferative properties of the co-treatment of RES and FGF1 provided a promising therapy for anthracycline cardiotoxicity during chemotherapy.

Co-Treatment With Resveratrol and FGF1 Protects Against Acute Liver Toxicity After Doxorubicin Treatment via the AMPK/NRF2 Pathway.

Doxorubicin (DOX), an anthracycline type of chemotherapy, is an effective therapy for several types of cancer, but serious side effects, such as severe hepatotoxicity, limit its use currently. Accordingly, an effective therapeutic strategy to prevent DOX-related hepatotoxicity is urgently needed. Through the inhibition of oxidative stress, fibroblast growth factor 1 (FGF1) is an effect therapy for a variety of liver diseases, but its use is limited by an increased risk of tumorigenesis due to hyperproliferation. Resveratrol (RES), a natural product, inhibits the growth of many cancer cell lines, including liver, breast, and prostate cancer cells. Therefore, this study explored whether and how RES in combination with FGF1 can alleviate DOX-induced hepatotoxicity. The results showed that RES or FGF1 alone improved DOX-induced hepatic inflammation, apoptosis and oxidative stress, and these adverse effects were further attenuated after treatment with both RES and FGF1. Mechanistically, both in vivo and in vitro results showed that RES/FGF1 reduced oxidative stress and thereby alleviated liver injury by promoting nuclear translocation of nuclear factor erythroid 2-related factor 2 (NRF2) and subsequently upregulating expression of antioxidant proteins in an adenosine monophosphate-activated protein kinase (AMPK)-dependent manner. Together, our results not only demonstrate that co-treatment with RES and FGF1 significantly inhibited DOX-induced hepatic inflammation and apoptosis, but also that co-treatment with RES and FGF1 markedly suppressed DOX-induced hepatic oxidative stress, via targeting the AMPK/NRF2 pathway and subsequently ameliorating hepatic dysfunction. Thus, the combination of RES and FGF1 may provide a new therapeutic strategy for limiting DOX-induced hepatotoxicity.

SHARPIN promotes cell proliferation of cholangiocarcinoma and inhibits ferroptosis via p53/SLC7A11/GPX4 signaling.

SHARPIN is a tumor-associated gene involved in the growth and proliferation of many tumor types. A function of SHARPIN in cholangiocarcinoma (CCA) is so far unclear. Here, we studied the role and function of SHARPIN in CCA and revealed its relevant molecular mechanism. The expression of SHARPIN was analyzed in cholangiocarcinoma tissues from patients using immunohistochemistry, quantitative PCR, and western blot analysis. Expression of SHARPIN was suppressed/overexpressed by siRNA silencing or lentiviral overexpression vector, and the effect on cell proliferation was determined by the CCK-8 assay and flow cytometry. Accumulation of reactive oxygen species was measured with MitoTracker, and JC-1 staining showed mitochondrial fission/fusion and mitochondrial membrane potential changes as a result of the silencing or overexpression. The ferroptosis marker solute carrier family 7 member 11 (SLC7A11), glutathione peroxidase 4 (GPX4), and the antioxidant enzymes superoxide dismutase 1 (SOD-1) and SOD-2 were analyzed by western blot. The results showed that SHARPIN expression was increased in CCA tissue, and this was involved in cell proliferation. SHARPIN silencing resulted in accumulated reactive oxygen species, reduced mitochondrial fission, and a reduced mitochondrial membrane potential. Silencing of SHARPIN inhibited the ubiquitination and degradation of p53, and downregulated levels of SLC7A11, GPX4, SOD-1, and SOD-2, all of which contributed to excessive oxidative stress that leads to ferroptosis. Overexpression of SHARPIN would reverse the above process. The collected data suggest that in CCA, SHARPIN-mediated cell ferroptosis via the p53/SLC7A11/GPX4 signaling pathway is inhibited. Targeting SHARPIN might be a promising approach for the treatment of CCA.

SCP-7, a germacrane-type sesquiterpene lactone derivative, induces ROS-mediated apoptosis in NSCLC cells in vitro and in vivo.

Scabertopin (SCP), an abundant germacrane-type sesquiterpene lactone (SLC) isolated from Elephantopus scaber, was selected as a reference compound for modification and evaluation as anticancer agents for non-small cell lung cancer (NSCLC) treatment. All derivatives (SCP-1-SCP-13) except for SCP-3 showed potential inhibitory effect (IC50 5.2-9.7 µM) against A549 cells. The most promising compound SCP-7 also showed good cytotoxic activity against another two NSCLC cell lines (H1299 and H460), with IC50 value of 4.4 and 8.9 µM, respectively. Furthermore, SCP-7 could induce apoptotic cell death that was associated with the increased reactive oxygen species (ROS) generation, the loss of mitochondrial membrane potential, Bcl-2 family proteins modulation, caspases-3 and PARP cleavage. In addition, SCP-7 also inhibited cell growth by increasing Bax expression and reducing the Ki-67 positive cells in vivo, but there were no obvious toxic and side effects on internal organs. Mechanistically, PharmMapper, molecular docking and Western blot analysis revealed that SCP-7 might interact with the epidermal growth factor receptor (EGFR) and inhibit its expression in lung cancer cells. Together, above results suggest further effective application of SCP-7 as a potential anti-tumor agent in the treatment of NSCLC.

A new FGF1 variant protects against adriamycin-induced cardiotoxicity via modulating p53 activity.

A cumulative and progressively developing cardiomyopathy induced by adriamycin (ADR)-based chemotherapy is a major obstacle for its clinical application. However, there is a lack of safe and effective method to protect against ADR-induced cardiotoxicity. Here, we found that mRNA and protein levels of FGF1 were decreased in ADR-treated mice, primary cardiomyocytes and H9c2 cells, suggesting the potential effect of FGF1 to protect against ADR-induced cardiotoxicity. Then, we showed that treatment with a FGF1 variant (FGF1ΔHBS) with reduced proliferative potency significantly prevented ADR-induced cardiac dysfunction as well as ADR-associated cardiac inflammation, fibrosis, and hypertrophy. The mechanistic study revealed that apoptosis and oxidative stress, the two vital pathological factors in ADR-induced cardiotoxicity, were largely alleviated by FGF1ΔHBS treatment. Furthermore, the inhibitory effects of FGF1ΔHBS on ADR-induced apoptosis and oxidative stress were regulated by decreasing p53 activity through upregulation of Sirt1-mediated p53 deacetylation and enhancement of murine double minute 2 (MDM2)-mediated p53 ubiquitination. Upregulation of p53 expression or cardiac specific-Sirt1 knockout (Sirt1-CKO) almost completely abolished FGF1ΔHBS-induced protective effects in cardiomyocytes. Based on these findings, we suggest that FGF1ΔHBS may be a potential therapeutic agent against ADR-induced cardiotoxicity.

Semisynthesis and Non-Small-Cell Lung Cancer Cytotoxicity Evaluation of Germacrane-Type Sesquiterpene Lactones from Elephantopus scaber.

Two series of germacrane-type sesquiterpene lactones were produced by semisynthetic modulation of scaberol C, which was prepared by a standard chemical transformation from an Elephantopus scaber extract. Their inhibition activities against non-small-cell lung cancer cells were screened, and preliminary structure-activity relationships were also established. Among them, monomeric analog 1u and dimeric analog 3d exhibited superior anti-non-small-cell lung cancer cytotoxic potencies with IC50 values of 4.3 and 0.7 µM against A549 cells, respectively, and were more active than cisplatin and the standard sesquiterpene lactones, parthenolide and scabertopin. Further studies revealed that compounds 1u and 3d cause G2/M phase arrest and induce apoptosis through the activation of mitochondrial pathways in A549 cells. Collectively, the results obtained suggest that compounds 1u and 3d are promising anti-non-small-cell lung cancer lead compounds.

Development and Validation of Prognostic Nomograms for Hepatocellular Carcinoma After Hepatectomy Based on Inflammatory Markers.

Background: The value of lactate dehydrogenase (LDH) compared with other inflammation-based scores in predicting the outcomes of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) patients after curative resection remains unknown. This study aims to evaluate the predictive value of LDH and develop novel nomograms to predict postoperative recurrence and survival in these patients. Methods: This study retrospectively collected 1560 patients with HBV-related HCC who underwent curative resection from four institutions in China. In total, 924 patients were recruited from our center and randomly divided into the training cohort (n = 616) and internal validation (n = 308) cohorts. Additionally, 636 patients were selected from three other centers as the external validation cohort. The C index of inflammation-based scores was calculated and compared in the training cohort. Novel models were developed according to multivariable Cox regression analysis in the training cohort and validated in the internal and external validation cohorts. Results: LDH showed a higher C-index than other inflammation-based scores for recurrence survival (RFS, 0.60, 95% CI, 0.58-0.61) and overall survival (OS, 0.65, 95% CI, 0.63-0.68). The nomograms of RFS and OS were developed based on tumor diameter, macrovascular invasion, AFP, operative hemorrhage, tumor differentiation, tumor number and LDH and achieved a high C-index (0.78, 95% CI, 0.76-0.79 and 0.81, 95% CI, 0.79-0.83), which were remarkably higher than the C-indexes of the five conventional HCC staging systems (0.52-0.62 for RFS and 0.53-0.67 for OS). The nomograms were validated in the internal validation cohort (0.77 for RFS, 0.78 for OS) and external validation cohort (0.80 for RFS, 0.81 for OS) and performed well-fitted calibration curves. Conclusion: The two nomograms based on inflammatory markers achieved optimal prediction for RFS and OS of patients with HBV-related HCC after hepatectomy.