Vasculogenic mimicry:a pivotal mechanism contributing to drug resistance in antiangiogenic therapy

The growth of solid tumors relies on establishing a robust blood supply,with angiogenesis playing a key role in this intricate process.Based on this understanding,therapeutic strategies targeting tumor angiogenesis have been developed.However,the clinical effectiveness of antiangiogenic therapy(AAT)in treating tumors has not lived up to expectations.In recent years,vasculogenic mimicry(VM)has attracted increasing attention from the academic community as a longstanding but often overlooked mechanism of nonangiogenic tumor vascularization.Within the tumor microenvironment,neoplastic cells can autonomously form vessel-like structures,creating a blood supply that does not rely on endothelial cells.This phenomenon,known as VM,is a critical marker of aggressive tumors and may play a significant role in conferring resistance to AAT.In this review,we thoroughly examine the evidence,clinical characteristics,and mechanisms of VM across various tumor types and explore its potential role and importance in resistance to AAT and the development of new antitumor therapies.

Antiangiogenic therapy for portal hypertension in liver cirrhosis: Current progress and perspectives

Developing medicines for hemodynamic disorders that are characteristic of cirrhosis of the liver is a relevant problem in modern hepatology. The increase in hepatic vascular resistance to portal blood flow and subsequent hyperdynamic circulation underlie portal hypertension(PH) and promote its progression, despite the formation of portosystemic collaterals. Angiogenesis and vascular bed restructurization play an important role in PH pathogenesis as well. In this regard, strategic directions in the therapy for PH in cirrhosis include selectively decreasing hepatic vascular resistance while preserving or increasing portal blood flow, and correcting hyperdynamic circulation and pathological angiogenesis. The aim of this review is to describe the mechanisms of angiogenesis in PH and the methods of antiangiogenic therapy. The Pub Med database, the Google Scholar retrieval system, and the reference lists from related articles were used to search for relevant publications. Articles corresponding to the aim of the review were selected for 2000-2017 using the keywords: "liver cirrhosis", "portal hypertension", "pathogenesis", "angiogenesis", and "antiangiogenic therapy". Antiangiogenic therapy for PH was the inclusion criterion. In this review, we have described angiogenesis inhibitors and their mechanism of action in relation to PH. Although most of them were studie donly in animal experiments, this selective therapy for abnormally growing newly formed vessels is pathogenetically reasonable to treat PH and associated complications.

Antioxidant and antiangiogenic activities of the essential oils of Myristica fragrans and Morinda citrifolia

Objective:Toinvestigate the anti-angiogenic activity and antioxidant properties of Myristica fragrans（M.fragrans）（nutmeg） and Morinda citrifolia（M.citrifolia）（mengkudu） oils. Methods:The nutmeg and megkudu essential oils were obtained by steam distillation. The antioxidant activities of both essenlial oils were delermined by beta-carotene/ linoleic acid bleaching assay and reducing power while the anti-angiogenic activity was investigated using rat aortic ring assay using various concentrations.Results:The results showed that nutmeg oil has higher antioxidant activity than mengkudu oil.The nutmeg oil effectively inhibited the oxidation of linoleic acid with（88.68±0.1）%while the inhibition percentage of oxidation of linoleic acid of the mengkudu oil is（69.44±0.4）%.The nutmeg oil and mengkudu oil showed reducing power with an EC50 value of 181.4μg/mL and 3 043.0μg/mL,respectively.The anliangiogenic activity of nutmeg oil showed significant antiangiogenic activity with IC50 of 77.64μg/mL comparing to mengkudu oil which exhibits IC50 of 109.30μg/mL.Conclusion:Bioactive compound（s） will be isolated from the nutmeg essential oil to be developed as antiangiogenic drugs.

Degarelix as a new antiangiogenic agent for metastatic colon cancer?

Recently,follicle stimulating hormone receptor was found to be selectively expressed by endothelial cells on tumor-associated blood vessels in a wide range of human cancers.In this context,we hypothesized that degarelix,a new gonadotropin-releasing hormone receptor antagonist developed for patients with prostate cancer,may have antiangiogenic effects via its capacity to block follicle stimulating hormone(FSH)production. We report the case of a patient with metastatic colon cancer exhibiting tumor progression after failure of all conventional chemotherapeutic regimens.The addition of degarelix to the last chemotherapeutic regimen was proposed as compassionate treatment.Degarelix induced a rapid decrease in FSH level.This treatment induced radiological stabilization and carcinoembryonic antigen stabilization during 1 year.Contrast-enhanced ultrasonography demonstrated reduction of tumor vas-clature.This case represents the first report of an antitumoral effect of degarelix in metastatic colon cancer and suggests an antiangiogenic property of this drug.

Evaluation of antiangiogenic efficacy in advanced hepatocellular carcinoma: Biomarkers and functional imaging

Many years after therapeutic wilderness, sorafenib finally showed a clinical benefit in patients with advanced hepatocellular carcinoma. After the primary general enthusiasm worldwide, some disappointments emerged particularly since no new treatment could exceed or at least match sorafenib in this setting. Without these new drugs, research focused on optimi-zing care of patients treated with sorafenib. One challenging research approach deals with identifying prognostic and predictive biomarkers of sorafenib in this population. The task still seems difficult; however appropriate investigations could resolve this dilemma, as observed for some malignancies where other drugs were used.

Synthesis and antiangiogenic activities of 5-amino-1,3-dihydro-1,3-dioxo-2H-isoindole-2-propanoic acid derivatives

Based on the structure-activity relationships and antiangiogenic mechanism of RGD-containing peptides, a series of 5-amino- 1,3-dihydro-1,3-dioxo-2H-isoindole derivatives were synthesized. The structures were characterized by ^1H NMR, MS and elementary analysis. There ability to inhibit angiogenesis were evaluated by chick embryo chorioallantoic membrane assay at 10^-5 mol/L. Compounds 7a and 7b displayed obvious antiangiogenic activity.

Evaluation of tumor response to antiangiogenic therapy in patients with recurrent gliomas using contrast-enhanced perfusion-weighted magnetic resonance imaging techniques:A meta-analysis

BACKGROUND It is of vital importance to find radiologic biomarkers that can accurately predict treatment response. Usually, the initiation of antiangiogenic therapy causes a rapid decrease in the contrast enhancing tumor. However, the treatment response is observed only in a fraction of patients due to the partial radiological response secondary to stabilization of abnormal vessels which does not essentially indicate a true antitumor effect. Perfusion-weighted magnetic resonance imaging(PWMRI) techniques have shown implicitness as a strong imaging biomarker for gliomas since they give hemodynamic information of blood vessels. Hence, there is a rapid expansion of PW-MRI related studies and clinical applications.AIM To determine the diagnostic performance of PW-MRI techniques including:(A)dynamic contrast-enhanced magnetic resonance imaging(DCE-MRI); and(B)dynamic susceptibility contrast magnetic resonance imaging(DSC-MRI) for evaluating response to antiangiogenic therapy in patients with recurrent gliomas.METHODS Databases such as PubMed(MEDLINE included), EMBASE, and Google Scholar were searched for relevant original articles. The included studies were assessed for methodological quality with the Quality Assessment of Diagnostic Accuracy Studies 2 tool. Medical imaging follow-up or histopathological analysis was used as the reference standard. The data were extracted by two reviewers independently, and then the sensitivity, specificity, summary receiver operating characteristic curve, area under the curve(AUC), and heterogeneity were calculated using Meta-Disc 1.4 software.RESULTS This study analyzed a total of six articles. The overall sensitivity for DCE-MRI and DSC-MRI was 0.69 [95% confidence interval(CI): 0.53-0.82], and the specificity was 0.99(95%CI: 0.93-1) by a random effects model(DerSimonianeeLaird model). The likelihood ratio(LR) +, LR-, and diagnostic odds ratio(DOR)were 12.84(4.54-36.28), 0.35(0.22-0.53), and 24.44(7.19-83.06), respectively. The AUC(± SE) was 0.9921(± 0.0120), and the Q* index(± SE) was 0.9640(± 0.0323).For DSC-MRI, the sensitivity was 0.73, the specificity was 0.98, the LR+ was 7.82,the LR-was 0.32, the DOR was 31.65, the AUC(± SE) was 0.9925(± 0.0132), and the Q* index was 0.9649(± 0.0363). For DCE-MRI, the sensitivity was 0.41, the specificity was 0.97, the LR+ was 5.34, the LR-was 0.71, the DOR was 8.76, the AUC(± SE) was 0.9922(± 0.2218), and the Q* index was 0.8935(± 0.3037).CONCLUSION This meta-analysis demonstrated a beneficial value of PW-MRI(DSC-MRI and DCE-MRI) in monitoring the response of recurrent gliomas to antiangiogenic therapy, with reasonable sensitivity, specificity, +LR, and-LR.

Safety of endoscopy in patients undergoing treatments with antiangiogenic agents: A 5-year retrospective review

BACKGROUND Antiangiogenic agents(AAs)are increasingly used to treat malignant tumors and have been associated with gastrointestinal(GI)bleeding and perforation.Elective surgeries and endoscopy are recommended to be delayed for 31 d until after AAs treatment.Data regarding the safety of endoscopy while on antiangiogenic agents is extremely limited.No guidelines are in place to address the concern about withholding these anti-angiogenic drugs.AIM To evaluate the risks of endoscopy in patients on antiangiogenic agents from 2015 to 2020 at our institution.METHODS This is a single centered retrospective study approved by the institutional review board statement of the institution.Patients that underwent endoscopy within 28 d of antiangiogenic agents’treatment were included in the study.Primary outcome of interest was death,and secondary outcomes included perforation and GI bleeding.Data were analyzed utilizing descriptive statistics.Fifty-nine patients were included in the final analysis and a total of eighty-five procedures were performed that were characterized as low risk and high risk.RESULTS Among the 59 patients a total of 85 endoscopic procedures were performed with 24(28.2%)categorized as high-risk and 61(71.8%)procedures as low-risk.Of the total number of patients,(50%)were on bevacizumab and the rest were on imatinib(11.7%),lenvatinib(6.7%)and,ramucirumab(5%).The average duration between administration of AAs and the performance of endoscopic procedures was 9.9 d.No procedure-related adverse events were noted among our study population.We did observe two deaths with one patient,on lenvatinib for metastatic hepatocellular carcinoma,who had persistent bleeding despite esophageal variceal banding and died 4 d later from hemorrhagic shock.Another patient was diagnosed with acute myeloid leukemia died 24 d after an esophagogastroduodenoscopy with biopsy after transition to comfort care.CONCLUSION As per this single center retrospective study,the rate of endoscopic procedure-related adverse events and death within 28 d of AA administration appears to be low.

Reversibly size-switchable polyion complex micelles for antiangiogenic cancer therapy

Size is one of the most important characteristics of nanoparticles to influence their biodistribution and antitumoral efficacy.Particles with large sizes have difficulty in deep tumor penetration,while small particles are easily removed from tumor tissues due to the high tumor interstitial fluid pressure.To address these issues,an intelligent core-crosslinked polyion complex micelle(cPCM)with a reversibly sizeswitchable feature was engineered in this study.The micelles are consisting of methoxy poly(ethylene glycol)-poly(D,L-lactide)copolymer(mPEG-PLA),mPEG-PLA-(HE)6CC,and mPEG-PLA-(RG)6CC at an optimal mass ratio of 6:1:1 with an antiangiogenic compound,dabigatran etexilate(DE),encapsulated.The net charge inside the micelles is switchable when exposed to different pH conditions,thereby leading to revisable size-change of micelles.DE-loaded micelles(DE@cPCM)can swell and release drugs at the tumor sites with a mildly acidic pH,while they shrink and protect the cargo from leaking into the blood circulation with a neutral pH.Results indicated that DE@cPCM can inhibit tumor angiogenesis in vitro and in vivo,thereby efficiently restraining tumor growth in a 4T1-bearing mouse model.Collectively,the sizeswitchable cPCM is a promising nanoplatform for targeting delivery of anticarcinogens into the matrix of tumor tissues.

OPA3 overexpression modulates lipid droplet production and sensitizes colorectal cancer cells to bevacizumab treatment

Background:Colorectal cancer(CRC)represents a substantial risk to public health.Bevacizumab,thefirst US FDA-approved antiangiogenic drug(AAD)for human CRC treatment,faces resistance in patients.The role of lipid metabolism,particularly through OPA3-regulated lipid droplet production,in overcoming this resistance is under investigation.Methods:The protein expression pattern of OPA3 in CRC primary/normal tissues was evaluated by bioinformatics analysis.OPA3-overexpressed SW-480 and HCT-116 cell lines were established,and bevacizumab resistance and OPA3 effects on cell malignancy were examined.OPA3 protein/mRNA expression and lipid droplet-related genes were measured with Western blot and qRT-PCR.OPA3 subcellular localization was detected using immunofluorescence.Proliferation and apoptosis were assessed via colony formation andflow cytometry.Tube formation assays were conducted to assess the angiogenic potential of human umbilical vein endothelial cells(HUVECs).Lipid analysis was used to measure the phosphatidylcholine(PC)and lysophosphatidylcholine(LPC)levels in CRC cells.Results:Bioinformatics analysis revealed that OPA3 was downregulated in CRC.Overexpression of OPA3 inhibited CRC cell proliferation,stimulated apoptosis,and suppressed the angiogenic ability of HUVECs.OPA3 effectively reversed the resistance of CRC cells to bevacizumab and decreased lipid droplet production in CRC cells.Additionally,OPA3 reversed the bevacizumab-induced lipid droplet production in CRC cells,thereby increasing CRC cell sensitivity to bevacizumab treatment.Conclusion:This study suggests that OPA3 modulates lipid metabolism in CRC cells and reduces resistance to bevacizumab in CRC cells.Therefore,OPA3 may be a potential therapeutic target against the AAD resistance in CRC.

Three novel rare TP53 fusion mutations in a patient with multiple primary cancers:a case report

As survival rates improve and detection technologies advance,the occurrence of multiple primary cancers(MPCs)has been increasing.Approximately 16%of cancer survivors develop a subsequent malignancy,with lung cancer often developing after esophageal cancer due to potential“field cancerization”effects.Despite this observation,the genetic heterogeneity underlying MPCs remains understudied.However,the recent emergence of genetic testing has expanded the scope of investigations into MPCs to investigate signatures underlying cancer predisposition.This report reveals 3 unprecedented TP53 fusion mutations in a Chinese patient afflicted by MPCs,namely,AP1M2–TP53(A1;T11)fusion,TP53–ILF3(T10;I13)fusion,and SLC44A2–TP53(S5;T11)fusion.This patient exhibited an extended period of survival after diagnosis of extensive-stage small cell lung cancer,which occurred 6 years after the diagnosis of esophageal squamous cell cancer.This unique reportmay provide supplementary data that enhance our understanding of the genetic landscape ofMPCs.

Antiangiogenic therapy with bevacizumab in recurrent malignant gliomas： analysis of the response and core pathway aberrations

Background Bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor, has shown promising activity in recurrent malignant gliomas. We reported the treatment response for the combination of bevacizumab and chemotherapy in a series of six patients with recurrent malignant glioma and investigated the molecular alterations in cancer pathways using the surgical biopsies from these patients. Methods Standard therapy with primary resection followed by adjuvant chemoradiotherapy had failed in all patients. Bevacizumab was administered at a dose of 10 mg/kg every 2 weeks. Concomitantly, four patients received temozolomide （50 mg·m^-2·d^-1）, one patient irinotecan （125 mg/m^2 every 2 weeks） and one patient topotecan （1.2 mg·m^-2·d^-1）. Response to therapy was mainly determined by magnetic resonance imaging. The expression of Ras, phosphorylated mitogen activated protein kinase （p-MAPK）, phosphorylated AKT （p-AKT）, phosphorylated mammalian target of rapamycin （p-mTOR） and phosphorylated signal transducer and activator of transcription 3 （p-STAT3） were semiquantitatively assessed by immunohistochemistry using surgical biopsies before the initial treatment. Results Five of the six patients had a radiographic response. Three were complete response, and two were partial response. Only one patient had progressive disease. The 6-month progession-free survival （PFS） was 33% and the median PFS was 15 weeks, with a range of 6 to more than 60 weeks. Of the three core pathways analyzed in this study, the Ras/MAPK and phosphatidylinositol-3-kinase （PI3K）/AKT/mTOR pathways were more likely to be associated with the treatment response to bevacizumab. In two younger patients （ages 〈50） with complete response, simultaneous overexpression of p-MAPK, p-AKT and p-mTOR might be the crucial feature. Conclusions Bevacizumab in combination with chemotherapeutic agents may be an effective strategy for patients with recurrent malignant glioma. Activated MAPK and AKT might be possible biomarkers for selecting suitable patients for this targeted therapy.

Evaluation,partial characterization and purification of acetylcholine esterase enzyme and antiangiogenic activity from marine sponges

Objective:To test three marine sponges Halichondria glabrata Keller,1891;Spirastrellapachyspira(S.pachyspira)Levi,1958 and Cliona lobata Hancock,1849 for the presence of the acetylcholinesterase(AChE)in both young and developed samples from western coastal area of India.S.pachyspira methanolic extract was selected for anti/pro angiogenic activity.Methods:They were evaluated for AChE activity using Ellman’s assay based on production of yellow colored 5-thio-2-nitrobenzoate.Purification of the enzyme was planned using ammonium sulphate precipitation and characterization by sodium dodecyl sulfate polyacrylamide gel electrophoresis.Chorioallantoic membrane(ChAM)assay model was used for angiogenic/antiangiogenic testing.Results:All the three sponges showed good specific enzyme activity and S.pachyspira contained maximum specific enzyme activity.Sixty percent of ammonium sulphate precipitation of crude protein sample gave single band at 66 kDa corresponding to the true AChE.ChAM assay was performed at 62.5,125.0 and 250.0μg/mL.Dosage beyond 250μg/mL extract showed toxic response with anti angiogenic activity at all the concentrations.Conclusions:AChE activity was detected in all samples.Extract showed good anti-angiogenic response at 62.5μg/mL.Extract was highly toxic affecting microvasculature of ChAM as well as normal growth and development of the embryo at 500μg/mL.With further characterization of bioactive compounds from the extract of S.pachyspira,the compounds can be developed for anti tumor activity.

Immunotherapy for mucosal melanoma

Mucosal melanoma(MM)is extremely rare in Caucasians,whereas it is the second predominant melanoma subtype in Asian and other non-Caucasian populations.Distinct from cutaneous melanoma in terms of epidemiology,biology,and molecular characteristics,MM is characterized by more aggressive biological behavior,lower mutational burden,more chromosomal structure variants,and poorer prognosis.Because of the rarity of MM,its biological features are not fully understood,and potential novel therapies are less well depicted.Whereas immunotherapy has shown encouraging efficacy for cutaneous melanoma,its efficacy in MM is unclear due to limited sample sizes in clinical trials.Thus,in this review,we describe the epidemiological,clinical,and molecular features of MM and summarize the efficacies of different immunotherapies for MM,including immune checkpoint inhibitors,vaccines,oncolytic virus therapy,adoptive T-cell therapy,and various combination therapies.

Efficacy and safety of ranibizumab for wet age-related macular degeneration in Chinese patients

AIM： To evaluate the clinical efficacy and safety of ranibizumab for wet age-related macular degeneration （wAMD） in Chinese patients and to determine the mean number of injections administered over one year of follow-up. METHODS： This single centre, retrospective observational case series study included data from 121 patients with wAMD （121 eyes） who were diagnosed by indirect ophthalmoscopy, fluorescence fundus angiography （FFA）, indocyanine green angiography, and optical coherence tomography. Ranibizumab was injected into the vitreous cavities once per month for 3mo and as needed afterwards. Changes in visual acuity and central foveal thickness （CFT） during the follow-up period were compared, and the mean number of injections over the year was calculated. Patients with one or more adverse events related to the drugs and injections were recorded for further adverse events analysis.RESULTS： The study population included 70 males and 51 females aged between 50 and 87y （mean： 71.32±9.41y）. The mean number of injections over the first year was 5±1 （range： 3-9）. The mean best-corrected visual acuity by Early Treatment Diabetic Retinopathy Study increased from 43.2±19.3 （95%CI： 39.8-46.7） at baseline to 51.7±20.1 （95%CI： 48.1-55.3）, and central foveal thickness （CFT） decreased from 526.5±277.0 μm （95%CI： 476.6-576.4） to 258.2±161.6 μm （95%CI： 229.2-287.3） at 12mo. The differences were statistically significant （P〈0.001）. Visual acuity significantly improved in 34.1% of the patients （38 eyes）, stabilized in 66.1% of the patients （80 eyes）, and significantly decreased in 2.5% of the patients （3 eyes）. CFT at baseline was an independent risk factor of decreased CFT and increased visual acuity. None of the patients had severe adverse events during the follow-up period.CONCLUSION： Ranibizumab can effectively control disease progression and improve visual acuity in patients with wAMD. The disease conditions of most patients stabilized after a one-year treatment with an average of 5 injections.

Angiogenesis of hepatocellular carcinoma: An immunohistochemistry study

BACKGROUND Although hepatocellular carcinoma(HCC) is one of the most vascular solid tumors, antiangiogenic therapy has not induced the expected results.AIM To uncover immunohistochemical(IHC) aspects of angiogenesis in HCC.METHODS A retrospective cohort study was performed and 50 cases of HCC were randomly selected. The angiogenesis particularities were evaluated based on the IHC markers Cyclooxygenase-2(COX-2), vascular endothelial growth factor(VEGF) A and the endothelial area(EA) was counted using the antibodies CD31 and CD105.RESULTS The angiogenic phenotype evaluated with VEGF-A was more expressed in small tumors without vascular invasion(pT1), whereas COX-2 was rather expressed in dedifferentiated tumors developed in non-cirrhotic liver. The CD31-related EA value decreased in parallel with increasing COX-2 intensity but was higher in HCC cases developed in patients with cirrhosis. The CD105-related EA was higher in tumors developed in patients without associated hepatitis.CONCLUSION In patients with HCC developed in cirrhosis, the newly formed vessels are rather immature and their genesis is mediated via VEGF. In patients with non-cirrhotic liver, COX-2 intensity and number of mature neoformed vessels increases in parallel with HCC dedifferentiation.

The 150 most important questions in cancer research and clinical oncology series:questions 57-66

Since the beginning of 2017,Chinese Journal of Cancer has published a series of important questions in cancer research and clinical oncology,which sparkle diverse thoughts,interesting communications,and potential collaborations among researchers all over the world.In this article,10 more questions are presented as followed.Question 57.What are the major stresses that drive the formation,progression,and metastasis of a cancer? Question 58.What is the mechanism responsible for altering an acidic intracellular pH and a basic extracellular pH in normal tissue cells to a basic intracellular pH and an acidic extracellular pH in cancer cells,a fundamental and yet largely ignored phenomenon? Question 59.Where are the tumor-associated plasma microRNAs from in cancer patients? Question 60.Can we identify mechanisms employed by tumor subpopulations to evade standard therapies and seed relapse/metastatic tumors before treatment? Question 61.Why are mutation rates in epidermal growth factor receptor(EGFR) and erb-b2 receptor tyrosine kinase 2(ERBB2) higher in lung cancer from never smokers than that from smokers? Question 62.Does tumor vasculogenic mimicry contribute to the resistance against antiangiogenic therapy in renal cancer? Question 63.What molecular targeted drugs would be effective for non-clear cell renal cell carcinoma(RCC),especially metastatic papillary RCC and chromophobe RCC? Question 64.Can it be more effective by targeting both the vascular endothelial growth factor receptor(VEGFR) and MET signaling pathways in sporadic metastatic papillary renal cell carcinoma(RCC)? Question 65.What are the predictive biomarkers that may be used to identify the renal cell carcinoma(RCC) patients who can benefit from immune checkpoint inhibitor treatment? Question 66.How do we identify predictive molecular biomarkers to stratify clear cell renal cell carcinoma patients for targeted therapies?

The 150 most important questions in cancer research and clinical oncology series:questions 76-85

Since the beginning of 2017, Chinese Journal of Cancer has published a series of important questions in cancer research and clinical oncology to promote cancer research and accelerate collaborations. In this article, 10 questions are presented as followed. Question 76. How to develop effective therapeutics for cancer cachexia? Question 77.How can we develop preclinical animal models to recapitulate clinical situations of cancer patients for more effective anti-cancer drug development? Question 78. How can we develop novel effective therapeutics for pancreatic cancer and hepatocellular carcinoma? Question 79. What are the true beneficial mechanisms of antiangiogenic therapy in cancer patients? Question 80. How to approach the complex mechanisms of interplay among various cellular and molecular components in the tumor microenvironment? Question 81. Can tissue oxygenation improve the efficacy of conventional chemotherapy on cancer? Question 82. Can tissue oxygenation improve the efficacy of radiotherapy on digestive system tumors including liver cancer? Question 83. Can we integrate metabolic priming into multimodal management of liver cancer? Question 84. Has the limit of anti-androgen strategy in prostate cancer treatment been reached by the new generation of anti-androgen drugs? Question 85. Can we identify individuals with early-stage cancers via analyzing their clinical and non-clinical information collected from social media, shopping history, and clinical, pathological, and molecular traces?

Chemical constituents from Munronia sinica and their bioactivities

Two new minor constituents,musinisins A(1)and B(2),together with five known compounds(3-7),were isolated from the aerial parts of Munronia sinica.Their structures were established by means of spectroscopic methods and the absolute stereochemistry of 1 was determined by single crystal X-ray experiment.Compound 4 showed antiangiogenic activity evaluated by a zebrafish model and apoptosis-inducing effect on A549 lung cancer cells.