Unusual cadinane-involved sesquiterpenoid dimers from Artemisia annua and their antihepatoma effect.

Artemisia annua L. ("Qinghao" in Chinese) is a famous traditional Chinese medicinal herb and has been used to treat malaria and various tumors. Our preliminary screening indicated that the EtOAc extract of A. annua manifested activity against HepG2, Huh7, and SK-Hep-1 cell lines with inhibitory ratios of 53.2%, 52.1%, and 59.6% at 200 µg/mL, respectively. Bioassay-guided isolation of A. annua afforded 14 unusual cadinane-involved sesquiterpenoid dimers, artemannuins A‒N (1-14), of which the structures were elucidated by extensive spectral analyses, ECD calculations, and single-crystal X-ray diffraction. Structurally, these compounds were classified into five different types based on the coupled modes of two monomeric sesquiterpenoids. Among them, compounds 1-9 represented the first examples of sesquiterpenoid dimers formed via the C-3‒C-3' single bond of two 5(4 â†’ 3)-abeo-cadinane sesquiterpenoid monomers, while compounds 13 and 14 were dimers fused by cadinane and humulane sesquiterpenoids via an ester bond. Methylated derivatives of 1, 4, 6, and 8 showed antihepatoma activity against HepG2, Huh7, and SK-Hep-1 cell lines with IC50 values ranging from 30.5 to 57.2 µM.

Syringic Acid Attenuates the IL-1ß-Induced Akt Pathway in Chondrocyte ATDC5 Cells.

BACKGROUND: Osteoarthritis (OA) is a chronic progressive joint ailment that is largely predominant worldwide. However, it typically gets worse over time, occurs more frequently, and becomes more crippling. OBJECTIVES: Syringic acid (SA) is a well-known phenolic compound reported to suppress inflammation, cell proliferation, and apoptosis of various cancer cells. Since the role of SA in OA remains unknown, there is a need to hypothesize the anti-inflammatory activities of SA on IL- 1ß-induced ATDC5 chondrocyte­like cells and to elucidate its protective action against OA. METHODS: The cytotoxicity, inflammatory mediators, mRNA expression of MMPs, ADAMTS, COX-2, and Akt/NF-κB protein expression of SA activity on ATDC5 cells were examined through CCK-8 assay, ELISA, RT-qPCR, and western blot. It was found that SA (10, 20, and 30 µM) did not show any inhibitory effects on the viability of the ATDC5 cells in a concentrationdependent manner. RESULTS: SA markedly reduced the inflammatory mediators, cytokines, PGE2, MMPs, COX-2, and ADAMTS in a concentration-dependent manner. Likewise, SA expressively attenuated IL- 1ß-stimulated Akt phosphorylation and NF-κB activation as well as IL-1ß- induced ATDC5 chondrocytes. CONCLUSION: This study revealed that SA is a novel candidate applicable for the treatment of OA.

Transarterial Chemoembolization with Epirubicin-Loaded Microspheres for Hepatocellular Carcinoma: A Prospective, Single-Arm, Multicenter, Phase 2 Study (STOPPER Trial).

PURPOSE: While the role of drug-eluting beads transarterial chemoembolization (DEB-TACE) for hepatocellular carcinoma (HCC) is established, questions regarding appropriate bead size for use in patients remain. This trial evaluated the effectiveness and safety of DEB-TACE using small-size (≤ 100 µm) microspheres loaded with epirubicin. MATERIALS AND METHODS: This prospective, single-arm, multicenter study enrolled patients diagnosed with HCC who underwent DEB-TACE using 40 (range, 30-50), 75 (range, 60-90), or 100 (range, 75-125) µm epirubicin-loaded microspheres (TANDEM microspheres, Varian Medical). Bead size was at the discretion of treating physicians and based on tumor size and/or vascular structure. The primary outcome measure was 6-month objective response rate (ORR). Secondary outcome measures were 30-day and 3-month ORR, time to tumor progression and extrahepatic spread, proportion of progression-free survival and overall survival (OS) at one year, and incidence of treatment-associated adverse events. RESULTS: Data from 108 patients from ten centers was analyzed. Six-month ORR was 73.3 and 71.3% based on European association for the study of the liver (EASL) and modified response evaluation criteria in solid tumors (mRECIST) criteria, respectively. Thirty-day ORR was 79.6% for both EASL and mRECIST criteria with 3-month ORR being 80.0 and 81.0%, respectively, for each criteria. One-year PPF and OS rate were 60.3 and 94.3%. There was a total of 30 SAEs reported to be likely to definitely associated with microsphere (n = 9), epirubicin (n = 9), or procedure (n = 12) with none resulting in death. CONCLUSION: DEB-TACE using epirubicin-loaded small-sized (≤ 100 µm) microspheres demonstrates promising local tumor control and acceptable safety in patients with HCC. TRIAL REGISTRATION: Clinicaltrials.gov NCT03113955; registered April 14, 2017. Trial Registration Clinicaltrials.gov NCT03113955; registered April 14, 2017. LEVEL OF EVIDENCE: 2, Prospective, Non-randomized, Single-arm, study.

Highly oxygenated guaiane-type sesquiterpene lactones from Artemisia sacrorum and their antihepatoma activity.

The ethanol and EtOAc extracts of Artemisia sacrorum exhibited inhibitory effect against HepG2, Huh7, and SK-Hep-1 cell lines with inhibitory ratios of 65.5%, 28.1%, 84.6%, and 93.5%, 82.0%, 89.0% at 200 µg/mL. Twenty-three undescribed guaiane-type sesquiterpene lactones, artemisacrolides A‒W, were isolated from A. sacrorum under the guidance of antihepatoma activity. Their structures were elucidated by spectral data (HRESIMS, IR, UV, 1D and 2D NMR), ECD calculations, and a single-crystal X-ray diffraction. Artemisacrolides A‒U were guaiane-type sesquiterpene lactones possessing α-methylene-γ-lactone and containing acetoxyl groups at C-8, and artemisacrolides V and W represented the first report from the genus Artemisia with a 1,10-rearranged guaiane-type sesquiterpene lactone. Antihepatoma assay suggested that artemisacrolides A‒U demonstrated better inhibitory activity in Huh7 and SK-Hep-1 cells than those of HepG2 cells. Among them, nine compounds exhibited significant inhibitory activity against Huh7 cells with IC50 values of 8.2-14.3 µM, superior or equal to that of sorafenib; seven compounds demonstrated obvious activity against SK-Hep-1 cells with IC50 values of 13.5-19.2 µM, which were equivalent to that of sorafenib. Artemisacrolides B and E were the most active ones in three human hepatoma cell lines with IC50 values of 21.9, 8.2, 16.9 and 22.6, 9.0, 17.3 µM.

Association between the ESR1 and ESR2 polymorphisms and osteoporosis risk: An updated meta-analysis.

BACKGROUND: Gene polymorphisms of estrogen receptor (ESR) 1 PvuII (rs2234693), XbaI (rs9340799), G2014A (rs2228480), ESR2 AluI (rs4986938), and RsaI (rs1256049) had been reported to be associated with the risk of osteoporosis. However, these conclusions were inconsistent, therefore, an updated meta-analysis was conducted to further explore these issues. OBJECTIVE: To evaluate the association between gene polymorphisms of ESR1 PvuII (rs2234693), XbaI (rs9340799), G2014A (rs2228480), ESR2 AluI (rs4986938), RsaI (rs1256049), and osteoporosis risk. MATERIALS AND METHODS: PubMed, Medline, Ovid, Embase, CNKI, and China Wanfang databases were searched. Association was assessed using odds ratio with 95% confidence interval. Moreover, the false-positive reporting probability, Bayesian false-finding probability, and Venetian criteria were used to assess the credibility of statistically significant associations. RESULTS: Overall, ESR1 PvuII (rs2234693) and XbaI (rs9340799) were associated with the risk of osteoporosis in Indians. Moreover, ESR1 G2014A (rs2228480) was associated with the decreased risk of osteoporosis in East Asians. Moreover, ESR2 Alul (rs4986938) was associated with the increased risk of osteoporosis in East Asians and Caucasians. There was a significant association between ESR2 Rsal (rs1256049) and osteoporosis risk in overall population. When only high-quality and Hardy-Weinberg equilibrium studies were included in the sensitivity analysis, all results did not change in the present study. When the credibility was evaluated applying false-positive reporting probability, Bayesian false-finding probability, and Venetian criteria, all significant associations were considered as false positive results. CONCLUSIONS: In summary, this study shows that all substantial associations between gene polymorphisms of ESR1 (PvuII, XbaI, and G2014A) and ESR 2 (AluI and RsaI) and osteoporosis risk are possibly false positive results instead of real associations or biological variables.

Mapping research trends of transarterial chemoembolization for hepatocellular carcinoma from 2012 to 2021: A bibliometric analysis.

BACKGROUND: Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the second leading cause of cancer-related deaths. Transcatheter arterial chemoembolization (TACE) is a therapy where drugs aimed to slow or halt tumor development are injected into the artery supplying for HCC tissues. A comprehensive analysis of all the articles on TACE for HCC can give us a general understanding of the progress in this field and provide guidance for future research. AIM: To analyze and visualize scientific results and research trends in TACE treatment for HCC. METHODS: The "Web of Science" database was used to identify articles regarding TACE for the treatment of HCC from 2012 to 2021. VOSviewer and CiteSpace were used to analyze the publications trends, collaboration between countries/insti-tutions/authors, and the co-occurrence of keywords, keyword bursts, and references. RESULTS: A total of 5728 original articles on TACE for HCC were retrieved. Regarding the volume of publications, the total number of yearly publications showed a generally increasing trend. China had the highest number of articles, while the United States achieved the highest Hirsch index and highest number of citations. The Sun Yat-sen University in China was most prolific institution. The most active author was Park, J.W from South Korea. The Journal of Vascular and Interventional Radiology (234 articles) was the most productive journal. There is a growing trend toward international collaboration in TACE for HCC. Cluster networks of co-cited references suggested that practice guidelines and targeted therapies are an essential theme in this field. In addition, cluster analysis based on keyword co-occurrence identified the research topic "prediction of TACE treatment" as a hotspot, and propensity score matching can be used to help investigators conduct innovative studies in the future. CONCLUSION: The results of our bibliometric analysis provide the latest trends and hot topics in TACE therapy for HCC.

Artemongolins A-K, undescribed germacrane-guaiane sesquiterpenoid dimers from Artemisia mongolica and their antihepatoma activities.

Artemongolins A-K (1-11), which are undescribed sesquiterpenoid dimers, were obtained from Artemisia mongolica and characterized through comprehensive spectral data, including HRESIMS, IR, 1D and 2D NMR, and ECD calculations. The absolute configurations of compounds 1, 4, and 7 were undoubtedly determined by a single-crystal X-ray crystallography. Artemongolins A-K (1-11) featured a rare 5/7/5/5/5/10 hexacyclic system composed of a germacrene and a guaianolide by a fused 2-oxaspiro[4,4]nonane-1-one ring system. Antihepatoma evaluation against three human hepatoma cell lines demonstrated that the most active compounds 5 and 6 displayed inhibitory activity with IC50 values of 88.6 and 57.0 (HepG2), 59.1 and 26.4 (Huh7), and 67.5 and 32.5 (SK-Hep-1) µM, respectively.

Artemeriosides A-F, the first examples of natural sesquiterpenoids substituted by a 6'-O-crontonyl ß-glucopyranoside from Artemisia annua.

Artemeriosides A-F (1-6), six novel sesquiterpenoids containing a 6'-O-crontonyl ß-glucopyranoside, were isolated from Artemisia annua L. Their structures were determined by spectral data including HRESIMS, IR, UV, 1D and 2D NMR, and ECD calculations. Compounds 1-6 represented the first examples of natural sesquiterpenoid substituted by 6'-O-crontonyl ß-glucopyranoside. By antihepatoma assay, compounds 1 and 2 demonstrated inhibitory effect against both HepG2 and SK-Hep-1 cells with inhibitory ratios of 77.0%, 88.8%, and 86.8%, 83.9% at 200.0 µM, and compound 1 showed inhibitory activity against Huh7 cells with inhibitory ratio of 56.8%.

Artemannuols A-C, novel sesquiterpenoid-flavonol hybrids with antihepatoma activity from Artemisia annua.

Artemisia annua, also known as "Qinghao" in Chinese, is a famous traditional Chinese medicine and has been used for the treatment of malaria and various tumors. In this study, three novel sesquiterpenoid-flavonol hybrids, artemannuols A-C (1-3), were isolated and elucidated by extensive spectral data and ECD calculations. Structurally, artemannuols A-C (1-3) are the first examples of sesquiterpenoid-flavonol hybrids fused by an ether bond, among which artemannuols A and B (1 and 2) are composed of bisabolane-type sesquiterpenoid and flavonol moieties, and artemannuol C (3) is composed of humulane-type sesquiterpenoid and flavonol moieties. The antihepatoma assay suggested that compounds 1-3 showed inhibitory effects against HepG2, Huh7, and SK-Hep-1 cell lines with IC50 values in the range of 32.7 to 70.4 µM.

Artemiprinolides A-M, thirteen undescribed sesquiterpenoid dimers from Artemisia princeps and their antihepatoma activity.

Bioassay-guided investigation of the active fraction of Artemisia princeps led to 13 undescribed sesquiterpenoid dimers, artemiprinolides A-M (1-13), together with 11 known ones (14-24). Their structures were elucidated by comprehensive spectroscopic data and absolute configurations were assigned based on single crystal X-ray diffraction data and ECD calculations. Structurally, all compounds were postulated to be derived from the Diels-Alder cycloaddition. The isolated dimers except 11 and 15 were assayed for their cytotoxicity against HepG2, Huh7, and SK-Hep-1 cell lines, of which four compounds (3, 13, 17, 18) exhibited obvious cytotoxicity with IC50 values ranging from 8.8 to 20.1 µM. Interestingly, the most active compounds 1 and 16 manifested significant cytotoxicity on the three tested hepatoma cell lines with IC50 values of 5.4, 4.1 (HepG2), 7.7, 5.6 (Huh7), and 11.8, 15.7 µM (SK-Hep-1), respectively, which were better than sorafenib. Compound 1 dose-dependently inhibited cell migration and invasion, and significantly induced the HepG2 cell arrest in G2/M phase by downregulating cdc2 and pcdc2 and upregulating cyclinB1; and induced apoptosis by downregulating Bcl-2 expression and upregulating Bax level. The molecular docking study implied that the carbonyl at the C-12' of 1 had a strong binding affinity with PRKACA.

New eudesmanolides from Artemisia verlotorum and their potential targets of hepatocellular carcinoma by network pharmacology.

Fractionation of the ethanol extract of Artemisia verlotorum led to the identification of eight undescribed eudesmane-type sesquiterpenoids, artemverlolides A-H (1-8). Their structures were determined by spectral analyses (HRESIMS, 1D and 2D NMR, IR, and ECD). Network pharmacology predicted that compounds 1-8 might be target on AURKA, CCNA2, CYP2C19, and EPHX2 with possibly antihepatoma effect from Swiss TargetPrediction and Gene Expression Omnibus database. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses showed that the targets significantly enriched in FoxO signaling pathway. The molecular docking suggested that compound 8 had high binding affinity with AURKA. Furthermore, the interaction between compound 8 and AURKA was determined by Surface Plasmon Resonance (SPR) assay. The result suggested that compound 8 bound to AURKA with KD value of 68.0µM and was consistent with the predicted data, demonstrating that AURKA might be one of acting targets of 8.

Artemongolides A-F, undescribed sesquiterpenoid dimers from Artemisia mongolica and their antihepatic fibrosis activities.

Artemongolides A-E (1-5), an unusual class of diseco-guaianolides featuring a rare fused 7-methylbicyclo[2.2.1]-2-ene-7-heptanol ring system, and artemongolide F (6), the first example of [4 + 2] Diels-Alder type adducts presumably incorporating a chain farnesane sesquiterpene and a guaianolide diene, were isolated from the whole plant of Artemisia mongolica. Their structures were elucidated based on the spectroscopic analyses of UV, IR, MS, and 1D and 2D NMR spectra. The absolute configurations of artemongolides A (1) and F (6) were determined by single-crystal X-ray crystallography, and those of artemongolides B-E (2-5) were established by ECD calculations. Cytotoxicity evaluation suggested that compound 1 exhibited activity against HSC-LX2 cells with an IC50 value of 165.0 µM, equivalent to that of the positive control silybin (IC50, 146.4 µM). Preliminary mechanism studies revealed that compound 1 could inhibit the deposition of human collagen type I (Col I), human hyaluronic acid (HA), and human laminin (HL) with IC50 values of 123.8, 160.4, and 139.20 µM.

Artemleucolides A-L, eudesmane-type sesquiterpenoids from Artemisia leucophylla and their antihepatoma cytotoxicity.

Twelve undescribed and 13 known eudesmane-type sesquiterpenoids were obtained from Artemisia leucophylla, and structurally elucidated based on comprehensive analyses of spectral data, including HRESIMS, IR, 1D and 2D NMR, and ECD calculation. The absolute configuration of compound 1 was determined by a single X-ray single crystal diffraction. Chemically, compounds 1-5 featured unprecedented 1,2-seco-1-nor-eudesmane-type skeleton with a cis-fused 6/5 bicyclic system. Antihepatoma evaluation against three human hepatoma cell lines (HepG2, Huh7, and SK-Hep-1) for all compounds demonstrated that compound 7 displayed the most active cytotoxicity with IC50 values of 35.1, 35.0, and 32.7 µΜ.

[Terpenoids from fruits of Amomum villosum and their hypoglycemic activity].

Eight terpenoids were isolated from the fruits of Amomum villosum by silica gel, Sephadex LH-20, Rp-C_(18), MCI GEL CHP20 P column chromatography, preparative TLC, and HPLC. Their structures were identified by HR-ESI-MS, ~1H and ~(13)C-NMR, IR, UV, [α]_D, and ECD spectroscopic data as kravanhin A 3-O-ß-D-glucopyranoside(1), kravanhin B(2), 6-eudesmene-1ß,4ß-diol(3), oplodiol(4), vicodiol(5),(1R,2S,4R,7S)-vicodiol 9-O-ß-D-glucopyranoside(6),(1R,2S,4S,5R)-angelicoidenol 2-O-ß-D-glucopyranoside(7), and(1S,2S,4R,6S)-bornane-2,6-diol 2-O-ß-D-glucopyranoside(8). Compound 1 was a new compound, and compounds 2-5 were isolated from A. villosum for the first time. Their hypoglycemic activity was tested based on STC-1 cell model and two enzymatic models(GPa and PTP1 B). The results showed that compounds 1, 7, and 8 could stimulate GLP-1 with the secretion rates of 692.8%, 398.6%, and 483.3% at 25.0 µmol·L~(-1), and compound 6 showed inhibitory activity against GPa with an IC_(50) value of 78.6 µmol·L~(-1).

Association between OPG polymorphisms and osteoporosis risk: An updated meta-analysis.

Background: Numerous studies have demonstrated an association between osteoprotegerin (OPG) polymorphisms (A163G (rs3102735), T245G (rs3134069), T950C (rs2073617), G1181C (rs2073618)) and osteoporosis risk. However, their conclusions are inconsistent. In addition, some new studies have been updated, and more importantly, previous meta-analyses have not tested for false-positive results. In order to further explore these associations, we recently conducted a meta-analysis. Objectives: To study the relationship between OPG polymorphisms A163G, T245G, T950C, G1181C and the risk of osteoporosis. Methods: PubMed, Medline, International Statistical Institute (ISI), China National Knowledge Infrastructure (CNKI) and China Wanfang Database were used for research searches. Associations were assessed with five genetic models using odds ratios (ORs) with 95% confidence intervals (CIs). In addition, confidence in statistically significant associations was assessed using false-positive report probability (FPRP), Bayesian probability of False discovery (BFDP), and Venice criteria. Results: On the whole, the OPG A163G polymorphism was not significantly associated with risk of osteoporosis. However, in a subgroup analysis, we found that the OPG A163G polymorphism increased the risk of osteoporosis in Caucasians (AG + GG vs AA: OR = 1.35, 95% CI = 1.06-1.73; AA + GG vs AG: OR = 0.64, 95% CI = 0.49-0.82) and the female (G vs A: OR = 1.30, 95% CI = 1.03-1.64; AG + GG vs AA: OR = 1.42, 95% CI = 1.18-1.71). At the same time, the OPG G1181C polymorphism reduces the risk of osteoporosis (C vs G: OR = 0.84, 95% CI = 0.74-0.95; CC vs GG: OR = 0.75, 95% CI = 0.60-0.93; GC + CC vs GG: OR = 0.80, 95% CI = 0.67-0.95; CC vs GG + GC: OR = 0.84, 95% CI = 0.70-1.00). Moreover, a significantly decreased risk of osteoporosis was also discovered in Asian (C vs G: OR = 0.80, 95% CI = 0.66-0.98; CC vs GG: OR = 0.67, 95% CI = 0.47-0.95; GC + CC vs GG: OR = 0.74, 95% CI = 0.58-0.95) and the female (C vs G: OR = 0.85, 95% CI = 0.75-0.97; CC vs GG: OR = 0.77, 95% CI = 0.61-0.96; GC + CC vs GG: OR = 0.79, 95% CI = 0.66-0.95). Finally, we did not find a close association between OPG T245G and T950C polymorphisms and osteoporosis risk. However, when we retained only studies in the control group that was consistent with Hardy-Weinberg equilibrium (HWE) and high-quality scores, we observed that the OPG A163G polymorphism increased the risk of osteoporosis in the overall analysis (G vs A: OR = 1.40, 95% CI = 1.16-1.68; GG vs AA: OR = 1.96, 95% CI = 1.20-3.21; AG + GG vs AA: OR = 1.45, 95% CI = 1.22-1.72). Finally, after the credibility assessment, we concluded that all statistically significant association results in the meta-analysis in this study and those in the previous study were 'positive results with low confidence'. Conclusion: In conclusion, our study concluded that all meaningful results between OPG A163G and G1181C polymorphisms and osteoporosis risk were false-positive results rather than true associations.

Individual and combined effects of the GSTM1, GSTT1, and GSTP1 polymorphisms on leukemia risk: An updated meta-analysis.

Background: Several meta-analyses have analyzed the association of GSTM1 present/null, GSTT1 present/null, and GSTP1 IIe105Val polymorphisms with leukemia risk. However, the results of these meta-analyses have been conflicting. Moreover, they did not evaluate the combined effects of the three aforementioned gene polymorphisms. Furthermore, they did not appraise the credibility of the positive results. Finally, many new studies have been published. Therefore, an updated meta-analysis was conducted. Objectives: To further explore the relationship of the three aforementioned gene polymorphisms with leukemia risk. Methods: The crude odds ratios (ORs) and 95% confidence intervals (CIs) were applied to evaluate the association of the individual and combined effects of the three aforementioned genes. Moreover, the false-positive report probability (FPRP) and Bayesian false discovery probability (BFDP) were applied to verify the credibility of these statistically significant associations. Results: Overall, the individual GSTM1, GSTT1, and GSTP1 IIe105Val polymorphisms added leukemia risk. On combining GSTM1 and GSTT1, GSTM1 and GSTP1, and GSTT1 and GSTP1 polymorphisms, positive results were also observed. However, no significant association was observed between the combined effects of these three polymorphisms with leukemia risk in the overall analysis. Moreover, when only selecting Hardy-Weinberg equilibrium (HWE) and medium- and high-quality studies, we came to similar results. However, when the FPRP and BFDP values were applied to evaluate the credibility of positive results, the significant association was only observed for the GSTT1 null genotype with leukemia risk in Asians (BFDP = 0.367, FPRP = 0.009). Conclusion: This study strongly suggests a significant increase in the risk of leukemia in Asians for the GSTT1 null genotype.

Individual and combined effects of the GSTM1, GSTT1, and GSTP1 polymorphisms on type 2 diabetes mellitus risk: A systematic review and meta-analysis.

Backgrounds: Compared with previously published meta-analyses, this is the first study to investigate the combined effects of glutathione-S-transferase polymorphisms (GSTM1, GSTT1 and GSTP1 IIe105Val) and type 2 diabetes mellitus (T2DM) risk; moreover, the credibility of statistically significant associations was assessed; furthermore, many new original studies were published. Objectives: To determine the relationship between GSTM1, GSTT1, and GSTP1 polymorphisms with T2DM risk. Methods: PubMed, Embase, Wanfang, and China National Knowledge Infrastructure Databases were searched. We quantify the relationship using crude odds ratios and their 95% confidence intervals Moreover, the Venice criteria, false-positive report probability (FPRP), and Bayesian false discovery probability (BFDP) were used to validate the significance of the results. Results: Overall, significantly increased T2DM risk was found between individual and combined effects of GSTM1, GSTT1, and GSTP1 polymorphisms on T2DM risk, but, combined effects of the GSTT1 and GSTP1 polymorphisms was not statistically significant. GSTT1 gene polymorphism significantly increases the risk of T2DM complications, while GSTM1 and GSTP1 polymorphisms had no statistical significance. The GSTM1 null genotype was linked to a particularly increased risk of T2DM in Caucasians; the GSTT1 null genotype was connected to a significantly higher risk of T2DM in Asians and Indians; and the GSTP1 IIe105Val polymorphism was related to a substantially increased T2DM risk in Indians. Moreover, the GSTM1 and GSTT1 double null genotype was associated with substantially increased T2DM risk in Caucasians and Indians; the combined effects of GSTM1 and GSTP1 polymorphisms was associated with higher T2DM risk in Caucasians. However, all significant results were false when the Venice criteria, FPRP, and BFDP test were used (any FPRP >0.2 and BFDP value >0.8). Conclusion: The current analysis strongly suggests that the individual and combined effects of GSTM1, GSTT1 and GSTP1 polymorphisms might not be connected with elevated T2DM risk.

Tumor-feeding artery diameter reduction is associated with improved short-term effect of hepatic arterial infusion chemotherapy plus lenvatinib treatment.

BACKGROUND: Recently, hepatic arterial infusion chemotherapy (HAIC) plus lenvatinib has been frequently used to treat unresectable hepatocellular carcinoma (uHCC) in China. In the clinic, the hepatic arteries of some patients shrink significantly during this treatment, leading to improved short-term efficacy. AIM: To investigate the relationship between the shrinkage of hepatic arteries and the short-term effect of HAIC plus lenvatinib treatment. METHODS: Sixty-seven participants with uHCC were enrolled in this retrospective study. The patients received HAIC every 3 wk, followed by oral lenvatinib after the first HAIC course. Hepatic artery diameters were measured on CT before treatment and after 1 and 2 mo of treatment. Meanwhile, the changes in tumor capillaries were also examined on pathological specimens before and after 1 mo of treatment. The antitumor response after 1, 3, and 6 mo of treatment was assessed using the modified Response Evaluation Criteria in Solid Tumors (mRECIST). The relationship between the changes in vessel diameters and the short-term effect of the combination treatment was evaluated by receiver-operating characteristic and logistic regression analyses. RESULTS: The hepatic artery diameters were all significantly decreased after 1 and 2 mo of treatment (P < 0.001), but there was no difference in the vessel diameters between 1 and 2 mo (P > 0.05). The microvessel density in the tumor lesions decreased significantly after 1 mo of combination treatment (P < 0.001). According to mRECIST, 46, 41, and 24 patients had complete or partial responses after 1, 3, and 6 mo of treatment, respectively, whereas 21, 21, and 32 patients had a stable or progressive disease at these times, respectively. Shrinkage of the tumor-feeding artery was significantly associated with the tumor response after 1, 3, and 6 mo of treatment (P < 0.001, P = 0.004, and P = 0.023, respectively); however, changes in other hepatic arteries were not significantly associated with the tumor response. Furthermore, shrinkage of the tumor-feeding artery was an independent factor for treatment efficacy (P = 0.001, P = 0.001, and P = 0.002 and 1, 3, and 6 mo, respectively). CONCLUSION: The hepatic arteries shrank rapidly after treatment with HAIC plus lenvatinib, and shrinkage of the tumor-feeding artery diameter was closely related to improved short-term efficacy.

A Nomogram Based on Preoperative Lipiodol Deposition after Sequential Retreatment with Transarterial Chemoembolization to Predict Prognoses for Intermediate-Stage Hepatocellular Carcinoma.

(1) Background: Conventional transarterial chemoembolization (cTACE) is the mainstay treatment for patients with Barcelona Clinic Liver Cancer (BCLC) B-stage hepatocellular carcinoma (HCC). However, BCLC B-stage patients treated with cTACE represent a prognostically heterogeneous population. We aim to develop and validate a lipiodol-deposition-based nomogram for predicting the long-term survival of BCLC B-stage HCC patients after sequential cTACE. (2) Methods: In this retrospective study, 229 intermediate-stage HCC patients from two hospitals were separately allocated to a training cohort (n = 142) and a validation cohort (n = 87); these patients underwent repeated TACE (≥4 TACE sessions) between May 2010 and May 2017. Lipiodol deposition was assessed by semiautomatic volumetric measurement with multidetector computed tomography (MDCT) before cTACE and was characterized by two ordinal levels: ≤50% (low) and >50% (high). A clinical lipiodol deposition nomogram was constructed based on independent risk factors identified by univariate and multivariate Cox regression analyses, and the optimal cutoff points were obtained. Prediction models were assessed by time-dependent receiver-operating characteristic curves, calibration curves, and decision curve analysis. (3) Results: The median number of TACE sessions was five (range, 4−7) in both cohorts. Before the TACE-3 sessions, the newly constructed nomogram based on lipiodol deposition achieved desirable diagnostic performance in the training and validation cohorts with AUCs of 0.72 (95% CI, 0.69−0.74) and 0.71 (95% CI, 0.68−0.73), respectively, and demonstrated higher predictive ability compared with previously published prognostic models (all p < 0.05). The prognostic nomogram obtained good clinical usefulness in predicting the patient outcomes after TACE. (4) Conclusions: Based on each pre-TACE lipiodol deposition, two sessions are recommended before abandoning cTACE or combining treatment for patients with intermediate-stage HCC. Furthermore, the nomogram based on pre-TACE-3 lipiodol deposition can be used to predict the prognoses of patients with BCLC B-stage HCC.