Recent advances of sonodynamic therapy in cancer treatment

Sonodynamic therapy(SDT) is an emerging approach that involves a combination of low-intensity ultrasound and specialized chemical agents known as sonosensitizers. Ultrasound can penetrate deeply into tissues and can be focused into a small region of a tumor to activate a sonosensitizer which offers the possibility of non-invasively eradicating solid tumors in a site-directed manner.In this article, we critically reviewed the currently accepted mechanisms of sonodynamic action and summarized the classification of sonosensitizers. At the same time, the breath of evidence from SDT-based studies suggests that SDT is promising for cancer treatment.

Novel method for extracting exosomes of hepatocellular carcinoma cells

AIM: To develop a novel method for the rapid and efficient extraction of exosomes secreted by tumor cells.

Identification of biomarkers for hepatocellular carcinoma by semiquantitative immunocytochemistry

AIM: To investigate the expression of key biomarkers in hepatoma cell lines, tumor cells from patients’ blood samples, and tumor tissues.

Clinical significance of serum expression of GROβ in esophageal squamous cell carcinoma

AIM:To determine the association between serum levels of growth-related gene product β(GROβ) and clinical parameters in esophageal squamous cell carcinoma(ESCC).METHODS:Using enzyme-linked immunosorbent assay,serum GROβ levels were measured in ESCC patients(n = 72) and healthy volunteers(n = 83).The association between serum levels of GROβ and clinical parameters of ESCC was analyzed statistically.RESULTS:The serum GROβ levels were much higher in ESCC patients than in healthy controls(median:645 ng/L vs 269 ng/L,P < 0.05).Serum GROβ levels were correlated positively with tumor size,lymph node metastasis,and tumor-node-metastasis(TNM) staging,but not with gender or the histological grade of tumors in ESCC patients.The sensitivity and specificity of the assay for serum GROβ were 73.61% and 56.63%,respectively.CONCLUSION:GROβ may function as an oncogene product and contribute to tumorigenesis and metastasis of ESCC.

Quantitative proteomic analysis for high-throughput screening of differential glycoproteins in hepatocellular carcinoma serum

Objective： Hepatocellular carcinoma （HCC） is a leading cause of cancer-related deaths. Novel serum biomarkers are required to increase the sensitivity and specificity of serum screening for early HCC diagnosis. This study employed a quantitative proteomic strategy to analyze the differential expression of serum glycoproteins between HCC and normal control serum samples. Methods： Lectin affinity chromatography （LAC） was used to enrich glycoproteins from the serum samples. Quantitative mass spectrometric analysis combined with stable isotope dimethyl labeling and 2D liquid chromatography （LC） separations were performed to examine the differential levels of the detected proteins between HCC and control serum samples. Western blot was used to analyze the differential expression levels of the three serum proteins. Results： A total of 2,280 protein groups were identified in the serum samples from HCC patients by using the 2D LC-MS/MS method. Up to 36 proteins were up-regulated in the HCC serum, whereas 19 proteins were down-regulated. Three differential glycoproteins, namely, fibrinogen gamma chain （FGG）, FOS-like antigen 2 （FOSL2）, and a-l, 6-mannosylglycoprotein 6-^-N-acetylglucosaminyltransferase B （MGATSB） were validated by Western blot. All these three proteins were up-regulated in the HCC serum samples. Conclusion： A quantitative glycoproteomic method was established and proven useful to determine potential novel biomarkers for HCC.

Efficacy and Immune Mechanisms of Cetuximab for the Treatment of Metastatic Colorectal Cancer

Cetuximab is a chimeric immunoglobulin G1 mono-clonal antibody that targets the ligand-binding domain of the epidermal growth factor receptor and inhibits downstream intra-cellular signals. Research has shown that cetuximab can stimulate the autoimmune system and produce antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity reactions, which can recruit cytotoxic lymphocytes to attack and kill cancer cells. Cetuximab is mainly indicated for patients with epidermal growth factor receptor-positive metastatic colorectal cancer who fail to respond to both irinotecan-and oxaliplatin-based regimens. The efficacy and safety of cetuximab as monotherapy or in combination with other treatment options were evaluated in a series of phase II and phase III trials. Identifying the clinical and molecular markers that can predict which patient groups may best benefit from cetuximab treatment is key to improving patient outcomes and avoiding unnecessary toxicities and costs. Herein, we discuss the mechanisms of action by which cetuximab exerts its antitumor effects, as well as the possible clinical and molecular markers that may help predict therapeutic benefits for patients with metastatic colorectal cancer.

Fast infectious diseases diagnostics based on microfuidic biochip system

Molecular diagnostics is one of the most important tools currently in use for clinical pathogen detection due to its high sensitivity,specificity,and low consume of sample and reagent is keyword to low cost molecular diagnostics.In this paper,a sensitive DNA isothermal amplifi-cation method for fast clinical infectious diseases diagnostics at aM concentrations of DNA was developed using a polycarbonate(PC)microfuidic chip.A portable confocal optical fuo-rescence detector was specifically developed for the microfuidic chip that was capable of highly sensitive real-time detection of amplified products for sequence-specific molecular identification near the optical diffraction limit with low background.The molecular diagnostics of Listeria monocytogenes with nucleic acid extracted from stool samples was performed at a minimum DNA template concentration of 3.65 aM,and a detection limit of less than five copies of genomic DNA.Contrast to the general polymerase chain reaction(PCR)at eppendorf(EP)tube,the detection time in our developed method was reduced from 1.5h to 45 min for multi-target parallel detection,the consume of sample and reagent was dropped from 25μL to 1.45μL.This novel microfuidic chip system and method can be used to develop a micro total analysis system as a clinically relevant pathogen molecular diagnostics method via the amplification of targets,with potential applications in biotechnology,medicine,and clinical molecular diagnostics.

PD-1/PD-L1 pathway blockade works as an effective and practical therapy for cancer immunotherapy

Cancer immunotherapy has greatly advanced in recent years,and PD-1/PD-L1 blocking therapy has become a major pillar of immunotherapy.Successful clinical trials of PD-1/PD-L1 blocking therapies in cancer treatments have benefited many patients,which promoted the Food and Drug Administration(FDA)approval of PD-1/PD-L1 blocking drugs.In this review,we provide a detailed introduction of five PD-1/PD-L1 blocking drugs,with indications and studies,as a valuable reference for doctors and medical investigators.Moreover,the characteristics of PD-1/PD-L1 blocking therapies,including their universality and sustainability,are discussed in this review.Furthermore,we also discuss and predict the possibility of PD-L1 as an indication marker of PD-1/PD-L1 blocking therapy for pan-cancer treatment,and the current status of combination therapies.

Two new terpenes from Tripterygium wilfordii

Two new terpenes,wilfornine H(1) and triptobenzene Q(2) were isolated from Tripterygium wilfordii,as well as 11 terpenes. Their structures were elucidated by spectroscopic methods.Compounds 5,9-13 showed significant immunosuppressive activities.

Two new triterpenes from Duchesnea indica

Two new triterpenes, 2α,3β-dihydroxyurs- 12-en- 18,19-epoxy-28-oic acid （1） and 18,19-seco, 2α, 2α-dihydroxyl-19-oxo-urs- 11,13（18）-dien-28-oic acid （2） were isolated from the herbaceous part of Duchesnea indica. Their structures were elucidated by spectroscopic analysis, including 2D NMR technique. The isolated compounds exhibited moderate cytotoxic activities against HeLa and L929 cell lines.

Cytosolic Phospholipase A2 and Its Role in Cancer

Cytosolic phospholipase A2α （cPLA2α） catalyzes the release of arachidonic acid （AA） and lysophosphoglyceride from membrane phospholipids. Although the roles of AA and eicosanoids in cellular viability, the processes of inflammation and cancer cell development have been extensively studied, the function of cPLA2α in the processes of inflammation and cancer cell development is not clear. This review summarizes published evidences for the biochemical properties and regulatory mechanisms of cPLA2α. The potential for use of cPLA2α as a novel diagnostic target and predictive biomarker for tumors is also discussed.

Cellular Anchorage Sensing and Anoikis

Normal epithelial cells that lose the integrindependent anchorage to their extracellular matrix trigger anoikis,while metastatic tumor cells bypass anoikis pathway, which is one of the key events to achieve the metastasis. Physiological role of anoikis is also involved during embryonic development and tissue homeostasis, suggesting that anoikis must be strictly regulated at some level. Despite its importance, the molecular pathways involved in the regulation of anoikis and the proximal signals reporting loss of anchorage are poorly understood. Recent studies suggest an adaptor protein p66Shc, localizing at focal adhesions,mediates anoikis through activation of RhoA. However, expression of p66Shc is inadequate in metastatic cancer cells, failing to initiate anoikis and promoting tumor metastasis. Reexpression of proapoptotic protein p66Shc can restore the susceptibility to anoikis.Thus, p66Shc may be a potential target molecule for diagnosis of tumor metastasis and for tumor treatment.

Association between HER-2 Over-Expression and Prognosis in Human Osteosarcoma:a Meta-Analysis

OBJECTIVE Various studies examining the relationship be-tween HER-2 over-expression and the response to chemotherapy and clinical outcome in patients with osteosarcoma have yielded inconclusive results.The purpose of the current study was to evaluate the relation of HER-2 status with the response to chemo-therapy and clinical outcome in osteosarcoma.METHODS We conducted a meta-analysis of 6 studies that evaluated the correlation between HER-2 status and histologic response to chemotherapy and 2-year survival.Data were syn-thesized in summary receiver operating characteristic curves and with summary likelihood ratios(LRs) and relative risk.RESULTS The quantitative synthesis showed that HER-2 status is not a prognostic factor for the response to chemotherapy.The positive LR was 1.27(95% conf idence interval,0.91～1.77),and the negative LR was 0.68(95% confidence interval,0.38～1.22).There was no significant between-study heterogeneity.HER2-positive status tended to be associated with a worse 2-year survival,but the overall results were not formally statistically signif icant.CONCLUSION HER-2 status is not associated with the histo-logic response to chemotherapy in patients with osteosarcoma,whereas HER-2 positive patients may be associated with decreased survival.

NK cell-based cancer immunotherapy: from basic biology to clinical application

Natural killer(NK) cells, which recognize and kill target cells independent of antigen specificity and major histocompatibility complex(MHC) matching, play pivotal roles in immune defence against tumors. However, tumor cells often acquire the ability to escape NK cell-mediated immune surveillance. Thus, understanding mechanisms underlying regulation of NK cell phenotype and function within the tumor environment is instrumental for designing new approaches to improve the current cell-based immunotherapy. In this review, we elaborate the main biological features and molecular mechanisms of NK cells that pertain to regulation of NK cell-mediated anti-tumor activity. We further overview current clinical approaches regarding NK cell-based cancer therapy, including cytokine infusion, adoptive transfer of autologous or allogeneic NK cells, applications of chimeric antigen receptor(CAR)-expressing NK cells and adoptive transfer of memory-like NK cells. With these promising clinical outcomes and fuller understanding the basic questions raised in this review, we foresee that NK cell-based approaches may hold great potential for future cancer immunotherapy.

Progress and prospects in chitosan derivatives:Modification strategies and medical applications

Chitosan(CS)is the only natural alkaline polysaccharide originated from deacetylation of chitin that is the main component of shell from marine organisms.It has great potential medical application due to its broad-spectrum antimicrobial activity and good water solubility originated from its protonated amino groups under acidic condition and abundant hydroxyl groups.However,unprotonated NH_(2)group of CS leads to its poor solubility under physiological condition and limits its diverse applications.Therefore,it is highly necessary to summarize the modification strategies of CS derivatives systematically to help researchers select the most appropriate strategies for their specific applications.Herein,we have summarized the modification strategies of CS derivatives for improving their antimicrobial activity,water solubility,biocompatibility,and mechanical property by chemical reaction and physical integration.And then we have reviewed the CS derivatives in hydrogels,nanoparticles,or coatings for medical application in wound dressing,drug delivery,medical implant.Last but not the least,we have put forward the future perspectives of deep studies about structure-activity relationship and clinical applications of CS derivatives.

Identification of p100 target promoters by chromatin immunoprecipitation-guided ligation and selection (ChIP-GLAS)

The multifunctional protein p100 is a vital transcriptional regulator that increases gene transcription by forming a physical bridge between promoter-specific transcription factors and the basal transcription machinery.To identify potential signal transduction pathways in which human p100 acts as a coregulator and to find target promoter regions that may interact with p100,we performed a promoter microarray assay called chromatin immunoprecipitation-guided ligation and selection(ChIP-GLAS).From this assay,we determined that a set of promoter fragments,including several factors in the transforming growth factor beta(TGF-β)signaling pathway,exhibited interaction with p100.The ChIP-GLAS data were validated by RT-PCR assessing the mRNA expression of various factors in the TGF-b signaling pathway in cell lines.

The prognostic value of clinical and pathologic features in nonmetastatic operable male breast cancer

Compared with female breast cancer, male breast cancer is a rare disease, and the relationship between clinical/pathologic features and prognosis is controversial, or even largely unknown. In this study, we performed a retrospective analysis using clinical and pathologic data from 109 nonmetastatic operable male breast cancer patients treated from January 1996 to December 2011 at Tianjin Medical University Cancer Institute and Hospital. Log-rank test showed that lower tumor stage, no lymph node involvement, and positive estrogen/progesterone receptor status were good predictors of both disease-free survival and overall survival on univariate analysis. However, hormonotherapy is only a good predictive factor of disease-free survival, and not of overall survival. In addition, based on a Cox proportional hazard regression model, only lymph node involvement, and estrogen/progesterone receptor status were statistically significant predictive factors on multivariate analysis. Our results demonstrated that although adjuvant systemic therapy is used extensively in male breast cancer patients and prognosis has improved over the last few decades, lymph node involvement, and estrogen/progesterone receptor status are still the most important prognostic factors. A prospective multi-center study with a larger sample size is urgently needed to further understand male breast cancer.

Dual inhibition of EGFR at protein and activity level via combinatorial blocking of PI4KIla as anti-tumor strategy

Our previous studies indicate that phosphatidylinositol 4-kinase Ila can promote the growth of multi-malignant tumors via HER-2/PI3K and MAPK pathways. However, the molecular mechanisms of this pathway and its potential for clinical application remain unknown. In this study, we found that PI4KIla could be an ideal combinatorial target for EGFR treatment via regulating EGFR degradation. Results showed that PI4KIla knockdown reduced EGFR protein level, and the expression of Pi4KIla shows a strong correlation with EGFR in human breast cancer tissues （r= 0.77, P 〈 0.01）. PI4KIla knockdown greatly prolonged the effects and decreased the effective dosage of AG-1478, a specific inhibitor of EGFR. In addition, it significantly enhanced AG1478-induced inhibition of tumor cell survival and strengthened the effect of the EGFR-targeting anti-cancer drug Iressa in xenograft tumor models. Mechanistically, we found that PI4KIla suppression increased EGFR ligand-independent degradation. Quantitative proteomic analysis by stable isotope labeling with amino acids in cell culture （SlLAC） and LC-MS/MS suggested that HsPg0 mediated the effect of PI4KIla on EGFR. Furthermore, we found that combined inhibition of PI4KIla and EGFR suppressed both PI3K/AKT and MAPK/ERK pathways, and resulted in downregulation of multiple oncogenes like PRDX2, FASN, MTA2, ultimately leading to suppression of tumor growth. Therefore, we conclude that combined inhibition of PI4KIla and EGFR exerts a multiple anti-tumor effect. Dual inhibition of EGFR at protein and activity level via combinatorial blocking of PI4KIla presents a novel strategy to combat EGFR-dependent tumors.

Use of copper-cysteamine nanoparticles to simultaneously enable radiotherapy,oxidative therapy and immunotherapy for melanoma treatment

Dear Editor,Melanoma,squamous cell carcinoma(SCC),and basal cell carcinoma(BCC)are three major types of skin cancer.Among them,melanoma is the most severe form and accounts for~4%of all newly diagnosed cancers annually in the United States.It is estimated that approximately 9500 people are diagnosed with skin cancer every day,and more than 1 million Americans are living with melanoma.Melanoma treatment is still a major challenge in the clinic.Photodynamic therapy(PDT)is composed of targeted ablation and immune activation,is less invasive than other therapies and has been widely used in the treatment of various cancers.

Increased Soluble Epoxide Hydrolase Activity Positively Correlates with Mortality in Heart Failure Patients with Preserved Ejection Fraction:Evidence from Metabolomics

Epoxyeicosatrienoic acids(EETs)have pleiotropic endogenous cardiovascular protective effects and can be hydrolyzed to the corresponding dihydroxyeicosatrienoic acids by soluble epoxide hydrolase(sEH).Heart failure with preserved ejection fraction(HFpEF)has shown an increased prevalence and worse prognosis over the decades.However,the role of sEH activ-ity in HFpEF remains unclear.We enrolled 500 patients with HFpEF and 500 healthy controls between February 2010 and March 2016.Eight types of sEH-related eicosanoids were measured according to target metabolomics,and their correlation with clinical endpoints was also analyzed.The primary endpoint was cardiac mortality,and the secondary endpoint was a composite of cardiac events,including heart failure(HF)readmission,cardiogenic hospitalization,and all-cause mortal-ity.Furthermore,the effect of sEH inhibitors on cardiac diastolic function in HFpEF was investigated in vivo and in vitro.Patients with HFpEF showed significantly enhanced EET degradation by the sEH enzyme compared with healthy controls.More importantly,sEH activity was positively correlated with cardiac mortality in patients with HFpEF,especially in older patients with arrhythmia.A consistent result was obtained in the multiple adjusted models.Decreased sEH activity by the sEH inhibitor showed a significant effective effect on the improvement of cardiac diastolic function by ameliorating lipid disorders in cardiomyocytes of HFpEF mouse model.This study demonstrated that increased sEH activity was associated with cardiac mortality in patients with HFpEF and suggested that sEH inhibition could be a promising therapeutic strategy to improve diastolic cardiac function.Clinical trial identifier:NCT03461107(https://clini caltr ials.gov).