Comparative Molecular Field Analysis(CoMFA) of Curcumin-related Compounds for Anticancer Activity

Three-dimensional （3D） quantitative structure-activity relationship （QSAR） studies of 44 curcumin-related compounds have been carried out based on our previously reported result for their anticancer activity against pancreas cancer Panc-I cells and colon cancer HT-29 cells. The established 3D-QSAR models from the comparative molecular field analysis （CoMFA） in training set showed not only significant statistical quality, but also satisfying predictive ability, with high correlation coefficient values （R12= 0.911, R22= 0.985） and cross-validation coefficient values （q2= 0.580, q22= 0.722）. Based on the CoMFA contour maps, some key structural factors responsible for anticancer activity of these series of compounds were revealed. The results provide some useful theoretical references for understanding the mechanism of action, designing new curcumin-related compounds with anticancer activity and predicting their activities prior to synthesis.

Expert Consensus on the Diagnosis and Treatment of Anticancer Drug-Induced Interstitial Lung Disease

Drug-induced interstitial lung disease(DILD)is the most common pulmonary adverse event of anticancer drugs.In recent years,the incidence of anticancer DILD has gradually increased with the rapid development of novel anticancer agents.Due to the diverse clinical manifestations and the lack of specific diagnostic criteria,DILD is difficult to diagnose and may even become fatal if not treated properly.Herein,a multidisciplinary group of experts from oncology,respiratory,imaging,pharmacology,pathology,and radiology departments in China has reached the“expert consensus on the diagnosis and treatment of anticancer DILD”after several rounds of a comprehensive investigation.This consensus aims to improve the awareness of clinicians and provide recommendations for the early screening,diagnosis,and treatment of anticancer DILD.This consensus also emphasizes the importance of multidisciplinary collaboration while managing DILD.

PROGRESS OF RESEARCH IN THE PREPARATION OF CHINESE TRADITIONAL AND HERBAL DRUGS WITH ANTICANCER ACTIVITY

Research into anticancer substances madefrom Chinese herbal drugs and their clinicalapplication is gaining international attention bythe medical profession of the more than 20analogues of camptothecine isolated from Camp-totheca tree in China, most exhibited anticanceractivity. Among them, 10-hydroxycamptothe-cine has a wide anticancer spectrum and is lesstoxic. In suspension, it exhibits some therapeu-tic effects on primary hepatic cancer, gastriccarcinoma, cancer of the urinary bladder andleukemia.

Preparation, characterization, pharmacokinetics and anticancer effects of PEGylated β-elemene liposomes

Objective:This study aimed to develop a new polyethylene glycol(PEG)ylatedβ-elemene liposome(PEG-Lipo-β-E)and evaluate its characterization,pharmacokinetics,antitumor effects and safety in vitro and in vivo.Methods:The liposomes were prepared by ethanol injection and high-pressure micro-jet homogenization.Characterization of the liposomes was conducted,and drug content,entrapment efficiency(EE),in vitro release and stability were studied by ultra-fast liquid chromatography(UFLC)and a liquid surface method.Blood was drawn from rats to establish the pharmacokinetic parameters.The anticancer effect was evaluated in a KU-19-19 bladder cancer xenograft model.Histological analyses were performed to evaluate safety.Results:The PEG-Lipo-β-E showed good stability and was characterized as 83.31±0.181 nm in size,0.279±0.004 in polydispersity index(PDI),-21.4±1.06 mV in zeta potential,6.65±0.02 in pH,5.024±0.107 mg/mL inβ-elemene(β-E)content,and 95.53±1.712%in average EE.The Fourier transform infrared spectroscopy(FTIR)and differential scanning calorimetry(DSC)indicated the formation of PEG-Lipo-β-E.Compared to elemene injection,PEG-Lipo-β-E demonstrated a 1.75-fold decrease in clearance,a 1.62-fold increase in half-life,and a 1.76-fold increase in area under the concentration-time curves(AUCs)from 0 hour to 1.5 hours(P<0.05).PEG-Lipo-β-E also showed an enhanced anticancer effect in vivo.Histological analyses showed that there was no evidence of toxicity to the heart,kidney,liver,lung or spleen.Conclusions:The present study demonstrates PEG-Lipo-β-E as a new formulation with ease of preparation,high EE,good stability,improved bioavailability and antitumor effects.

Synthesis and anticancer effects of 6-nitro-4-anilinoquinazolines and 6-amino-4-ani-linoquinazolines

Objective: To synthesize inhibitors of the epidermal growth factor receptor tyrosine kinase such as 6-nitro-4-anilinoquinazolines and 6-amino-4-anilinoquinazolines,and to compare their anticancer effects in vitro. Methods: The 4-anilinoquinazolines compounds were prepared by hydrolyzed, ringed, halagenated, substituded in turn from 2-amino-5-nitrobenzylcarbonitril. The synthesized 4- anilinoquinazoline compounds has been rudimentarily screened by using A431 tumor cell line which overexpresses epidermal growth factor receptor as model adopted MTT method. Results: Five 6-nitro-4-halo-sbstituted anilinoquinazolines and five 6-amino-4-halo-substituted anilinoquinazolines have been obtained,and all of them had anticancer activity. The anticancer activity of 6-amino substituted inhibitors was higher than that of 6-nitro substituted inhibitors. However, the difference of anticancer activity between two series of quinazoline was much less than that of their inhibiting EGFR tyrosine kinase activity. Conclusion: The probable reason for 6-nitro-4-anilinoquinazolines having anticancer activity in vitro was that they had been partially transformed to 6-amino-4-anilinoquinazolines through endocellular cytochrome oxidation-reduction system.

Call for papers-Proceedings of Anticancer Research

Dear Researchers,Proceedings of Anticancer Research is an international peer-reviewed and open access journal,which is devoted to the rapid publication of high quality original articles,reviews,case reports,short communication and letters on all aspects of experimental and clinical oncology.

Approaches and challenges in cancer immunotherapy pathways

Cancer immunotherapy is an effective with critical approaches in the treatment of oncological patients.Whilst numerous research and clinical trials are underway to develop endogenous immunotherapy approaches,it is necessary to focus on fundamental issues and identify barriers to basic clinical progress.Addressing these challenges and the new pathways will require researchers and clinicians to join forces to accelerate the understanding of the complex interactions between cancer and the immune system and focus resources on developing better treatments for patients.

A Single-Cell Landscape of Human Liver Transplantation Reveals a Pathogenic Immune Niche Associated with Early Allograft Dysfunction

Liver transplantation(LT)is the standard therapy for individuals afflicted with end-stage liver disease.Despite notable advancements in LT technology,the incidence of early allograft dysfunction(EAD)remains a critical concern,exacerbating the current organ shortage and detrimentally affecting the prognosis of recipients.Unfortunately,the perplexing hepatic heterogeneity has impeded characterization of the cellular traits and molecular events that contribute to EAD.Herein,we constructed a pioneering single-cell transcriptomic landscape of human transplanted livers derived from non-EAD and EAD patients,with 12 liver samples collected from 7 donors during the cold perfusion and portal reperfusion stages.Comparison of the 75231 cells of non-EAD and EAD patients revealed an EAD-associated immune niche comprising mucosal-associated invariant T cells,granzyme B^(+)(GZMB^(+))granzyme K^(+)(GZMK^(+))natural killer cells,and S100 calcium binding protein A12^(+)(S100A12^(+))neutrophils.Moreover,we verified this immune niche and its association with EAD occurrence in two independent cohorts.Our findings elucidate the cellular characteristics of transplanted livers and the EAD-associated pathogenic immune niche at the single-cell level,thus,offering valuable insights into EAD onset.

Guidelines for application of high-content screening in traditional Chinese medicine:concept,equipment,and troubleshooting

High-content screening(HCS)technology combines automated high-speed imaging hardware and single-cell quantitative analysis.It can greatly accelerate data acquisition in cellular fluorescence imaging and is a powerful research technique in traditional Chinese medicine(TCM).An increasing number of laboratories and platforms,including TCM laboratories,have begun utilizing HCS systems.However,this technology is still in its infancy in TCM research and there is a lack of sufficient experience with the associated concepts,instrument configurations,and analysis methods.To improve the understanding of HCS among researchers in the field of TCM,this paper summarizes the concept of HCS,software and hardware configuration,the overall research process,as well as common problems and related solutions of HCS in TCM research based on our team’s previous research experience,providing several research examples and an outlook on future perspectives,aiming to provide a technical guide for HCS in TCM research.

重组蛋氨酸酶在猕猴体内的药动学、免疫原性及系统毒性

目的重组蛋氨酸酶(rMETase)对于人系外源性蛋白酶,该酶在人肿瘤裸鼠模型中表现出广泛的抑瘤作用。本实验以灵长类动物猕猴为研究对象,测定了rMETase的药动学、免疫原性及系统毒性。方法与结果rMETase单次静脉注射1000u/kg、2000u/kg和4000u/kg时,猕猴血浆蛋氨酸水平在30min内可降低至无法检测的水平(小于0.5μmol/L),且持续4h;给药剂量4000u/kg时,血浆蛋氨酸低于1μmol/L的水平,可维持8h。rMETase在猕猴体内的t1/2为2.49h,给药2000u/kg和4000u/kg时的CL分别为11.28ml/h和30.77ml/h;rMETase以4000u/(kg.8h)重复给药2周时,可使血浆蛋氨酸水平在给药期间维持在2μmol/L以下;重复大剂量给药的主要系统毒性表现为食量减少、体重轻微下降,血浆白蛋白和红细胞水平呈可逆性降低。当rMETase重复给药2周后的28d再次给药时,出现过敏性休克,其中有1只动物死亡;及时给予激素抢救可避免死亡,或给药前给予氢化可的松可预防过敏性休克发生。在实验后的66、86和116d时再次给药,首次给药后抗rMETase抗体水平为10-3,第4次给药后增加到10-6;在以后的2个月内抗体水平降低至10-2。抗rMETase抗体类型主要是IgG,体外检测系中和性抗体;但在体内对rMETase降低血浆蛋氨酸作用的影响较小。结论系统研究表明,rMETase在猕猴模型中能有效地降低血浆中蛋氨酸水平,出现的系统毒性反应很小;rMETase是一具良好前景的广谱抗肿瘤新药,但应重视其免疫原性,如能进行化学修饰或其它处理则可增加药物的作用时间并降低其免疫原性,增加用药安全性。

Overexpressed NEDD8 as a potential therapeutic target in esophageal squamous cell carcinoma

Objective:The hyperactivated neddylation pathway plays an important role in tumorigenesis and is emerging as a promising anticancer target.We aimed to study whether NEDD8(neural precursor cell expressed,developmentally down-regulated 8)might serve as a therapeutic target in esophageal squamous cell carcinoma(ESCC).Methods:The clinical relevance of NEDD8 expression was evaluated by using The Cancer Genome Atlas(TCGA)database and tissue arrays.NEDD8-knockdown ESCC cells generated with the CRISPR/Cas9 system were used to explore the anticancer effects and mechanisms.Quantitative proteomic analysis was used to examine the variations in NEDD8 knockdown-induced biological pathways.The cell cycle and apoptosis were assessed with fluorescence activated cell sorting.A subcutaneous-transplantation mouse tumor model was established to investigate the anticancer potential of NEDD8 silencing in vivo.Results:NEDD8 was upregulated at both the mRNA and protein expression levels in ESCC,and NEDD8 overexpression was associated with poorer overall patient survival(mRNA level:P=0.028,protein level:P=0.026,log-rank test).Downregulation of NEDD8 significantly suppressed tumor growth both in vitro and in vivo.Quantitative proteomic analysis revealed that downregulation of NEDD8 induced cell cycle arrest,DNA damage,and apoptosis in ESCC cells.Mechanistic studies demonstrated that NEDD8 knockdown led to the accumulation of cullin-RING E3 ubiquitin ligases(CRLs)substrates through inactivation of CRLs,thus suppressing the malignant phenotype by inducing cell cycle arrest and apoptosis in ESCC.Rescue experiments demonstrated that the induction of apoptosis after NEDD8 silencing was attenuated by DR5 knockdown.Conclusions:Our study elucidated the anti-ESCC effects and underlying mechanisms of NEDD8 knockdown,and validated NEDD8 as a potential target for ESCC therapy.

减毒鼠沙门氏菌抗肿瘤的研究进展

近年来,细菌治疗肿瘤研究成为科学家日益关注的热点.细菌作为活的抗肿瘤生物制剂存在多重的优势,具有肿瘤靶向能力,能在肿瘤内生存和繁殖,且具有生物敏感传感器及自主运动能力,可以进入肿瘤内坏死及血管损伤区域,同时释放毒素进入外围肿瘤组织等,克服了药物治疗被动地随血流分布的障碍,为肿瘤治疗带来新途径.通过对鼠沙门氏菌等多种细菌进行改造和抗肿瘤效果的评价,减毒鼠沙门氏细菌因其有效靶向和杀伤肿瘤,抑制转移和延长荷瘤动物的生存期,而被广泛深入研究.本文综述了鼠沙门氏菌的抗肿瘤活性及其效应机制研究的新进展.

Role of radiation therapy in neoadjuvant era in patients with locally advanced rectal cancer

Surgery remains the primary determinant of cure in patients with localized rectal cancer, and total mesorectal excision is now widely accepted as standard of care. The widespread implementation of neoadjuvant shortcourse radiotherapy (RT) or long-course chemoradiotherapy (CRT) has reduced local recurrence rates from 25% to 40% to less than 10%; Preoperative RT in resectable rectal cancer has a number of potential advantages, most importantly reducing local recurrence, and down-staging effect. In this article making a comprehensive literature review searching the reliable medical data bases of PubMed and Cochrane we present all available information on the role of radiation therapy alone or in combination with chemotherapy in preoperative setting of rectal cancer. Data reported show that in locally advanced rectal cancer the addition of radiation therapy or CRT pre surgically has significantly improved sphincter prevention surgery. Moreover, the addition of chemotherapy to radiation therapy in preoperative setting has significantly improved pathologic complete response rate and loco-regional control rate without improvement in sphincter preserving surgery. Finally, the results of recently published randomized trials have shown a significant improvement of prevs postoperative CRT on local control; however, there was no effect on overall survival.

Multiplex RT-PCR-based detections of CEA, CK20 and EGFR in colorectal cancer patients

AIM: To develop a multiplex reverse transcription polymerase chain reaction (RT-PCR) method detecting cir-culating tumor cells in the peripheral blood of colorectal cancer (CRC) patients. METHODS: Peripheral blood samples were collected from 88 CRC patients and 40 healthy individuals from the blood donors' clinic and subsequently analyzed by multiplex RT-RCR for the expression of carcinoembryonic antigen (CEA), cytokeratin 20 (CK20) and epidermal growth factor receptor (EGFR) mRNA. The analysis involved determining the detection rates of CEA, CK20 and EGFR transcripts vs disease stage and overall survival. Median follow-up period was 19 mo (range 8-28 mo). RESULTS: Rates of CEA, CK20 and EGFR detection in CRC patients were 95.5%, 78.4% and 19.3%, respectively. CEA transcripts were detected in 3 healthy volunteer samples (7.5%), whereas all control samples were tested negative for CK20 and EGFR transcripts. The increasing number of positive detections for CEA, CK20 and EGFR transcripts in each blood sample was positively correlated with Astler-Coller disease stage (P< 0.001) and preoperative serum levels of CEA (P=0.029) in CRC patients. Data analysis using Kaplan-Meier estimator documented signif icant differences in the overall survival of the different CRC patient groups as formed according to the increasing number of positivity for CEA, CK20 and EGFR transcripts. CONCLUSION: These data suggest that multiplex RTPCR assay can provide useful information concerning disease stage and overall survival of CRC patients.

Autologous hematopoietic stem cell transplantation in chemotherapy-sensitive lymphoblastic lymphoma: treatment outcome and prognostic factor analysis

Objective： The study evaluated the effectiveness of autologous hematopoietic stem cell transplantation （AHSCT） in the treatment of lymphoblastic lymphoma （LL）. Methods： We relxospectively analyzed the data from 41 patients with chemotherapy-sensitive LL who underwent hematopoietic stem cell transplantation （HSCT） from December 1989 to December 2009 in a single institution. Results： HSCT was conducted as first-line consolidation therapy and salvage therapy in 36 and 5 patients, respectively. The median follow-up was 97.1 months （range, 24.6-173.1 months）. The 5-year overall survival （OS） and event-free survival （EFS） rate were 64% and 47% for the initially treated patients, respectively, and were both 20% for the relapsed ones. Bone marrow （BM） involvement and chemotherapy cycles prior to transplantation were identified as significant prognostic factors for EFS in multivariate analysis. Conclusions These results confirm that AHSCT is a reasonable option for chemotherapy-sensitive LL patients in first complete remission （CR1）.

Clinical features and outcomes of diffuse large B-cell lymphoma based on nodal or extranodal primary sites of origin:Analysis of 1,085 WHO classified cases in a single institution in China

Objective: To explore the clinicobiologic features and outcomes of diffuse large B-cell lymphoma(DLBCL)patients in China according to the primary site.Methods: A total of 1,085 patients diagnosed with DLBCL in National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College during a 6-year period were enrolled. Their clinical characteristics and outcomes were analyzed according to the primary site.Results: In the 1,085 patients, 679(62.6%) cases were nodal DLBCL(N-DLBCL) and 406 cases(37.4%) were extranodal DLBCL(EN-DLBCL). The most common sites of N-DLBCL were lymphonodus(64.8%), Waldeyer's ring(19.7%), mediastinum(12.8%) and spleen(2.7%), while in EN-DLBCL, stomach(22.4%), intestine(16.0%),nose and sinuses(8.9%), testis(8.4%), skin(7.9%), thyroid(6.9%), central nervous system(CNS)(6.4%), breast(5.7%), bone(3.4%), and salivary gland(2.7%) were most common. N-DLBCL patients tend to present B symptoms, bulky disease, and elevated LDH more often, while age >60 years, extranodal sites >1, Ann Arbor stage I or II, bone marrow involvement, and Ki-67 index >90% were usually seen in EN-DLBCL. The 5-year overall survival(OS) rate and progression-free survival(PFS) rate for all patients were 62.5% and 54.2%. The 5-year OS rate for patients with N-DLBCL and EN-DLBCL were 65.5% and 56.9%(P=0.008), and the 5-year PFS were57.0% and 49.0%(P=0.020). Waldeyer's ring originated DLBCL possessed the highest 5-year OS rate(83.6%) and PFS rate(76.9%) in N-DLBCL. The top five EN-DLBCL subtypes with favorable prognosis were stomach,breast, nose and sinuses, lung, salivary gland, with 5-year OS rate: 70.3%, 69.6%, 69.4%, 66.7% and 63.6%,respectively. While CNS, testis, oral cavity and kidney originated EN-DLBCL faced miserable prognosis, with 5-year OS rate of 26.9%, 38.2%, and 42.9%.Conclusions: In our study, primary sites were associated with clinical characteristics and outcomes. Compared with EN-DLBCL, N-DLBCL had better prognosis.

Effect of percutaneous endoscopic gastrostomy on gastroesophageal reflux in mechanically-ventilated patients

AIM： To investigate the effect of percutaneous endoscopic gastrostomy （PEG） on gastroesophageal reflux （GER） in mechanically-ventilated patients. METHODS ： In a prospective, randomized, controlled study 36 patients with recurrent or persistent ventilatorassociated pneumonia （VAP） and GER 〉 6% were divided into PEG group （n=16） or non-PEG group （n = 20）. Another 11 ventilated patients without reflux （GER 〈 3%） served as control group. Esophageal pH-metry was performed by the ＂pull through＂ method at baseline, 2 and 7 d after PEG. Patients were strictly followed up for semi-recumbent position and control of gastric nutrient residue. RESULTS： A significant decrease of median （range） reflux was observed in PEG group from 7.8 （6.2-15.6） at baseline to 2.7 （0-10.4） on d 7 post-gastrostomy （P 〈 0.01）, while the reflux increased from 9 （6.2-22） to 10.8 （6.3-36.6） （P〈 0.01） in non-PEG group. A significant correlation between GER （%） and the stay of nasogastric tube was detected （r= 0.56, P〈 0.01）. CONCLUSION： Gastrostomy when combined with semi- recumbent position and absence of nutrient gastric residue reduces the gastroesophageal reflux in ventilated patients.

PhaseⅠdose-finding study of sorafenib with FOLFOX4 as firstline treatment in patients with unresectable locally advanced or metastatic gastric cancer

Objective： To determine the maximum tolerated dose（MTD）, dose-limiting toxicity（DLT） and efficacy of sorafenib in combination with FOLFOX4（oxaliplatin/leucovorin（LV）/5-fluorouracil） as first-line treatment for advanced gastric cancer, we performed a phase I dose-finding study in nine evaluable patients with unresectable locally advanced or metastatic gastric cancer or gastroesophageal junction adenocarcinoma. Methods： According to modified Fibonacci method, the design of this study was to guide elevation of the sorafenib dosage to the next level（from 200 mg twice daily to 400 mg twice daily and then, if tolerated, 600 mg twice daily）. If the patient achieved complete response（CR）, partial response（PR） or stable disease（SD） after eight cycles of treatment, combination chemotherapy was scheduled to be discontinued and sorafenib monotherapy continued at the original dose until either disease progression or unacceptable toxicity. Results： In sorafenib 200 mg twice daily group, DLT was observed in 1 of 6 patients, and in 400 mg twice daily group, it was observed in 2 of 3 patients. Seven of 9（77.8%） evaluable patients achieved PR, with a median overall survival（OS） of 11.8 [95% confidence interval（CI）： 8.9-14.7] months. Common adverse effects include hand-foot syndrome, leukopenia, neutropenia, anorexia, and nausea.Conclusions： Twice-daily dosing of sorafenib 200 mg in combination with FOLFOX4 was proven effective and safe for the treatment of advanced gastric cancer, and could be an appropriate dosage for subsequent phase II clinical studies.

Autologous peripheral blood stem cell mobilization following dose-adjusted cyclophosphamide, doxorubicin, vincristine and prednisolone chemotherapy alone or in combination with rituximab in treating high-risk non-Hodgkin's lymphoma

Background: The regimen of cyclophosphamide, doxorubicin, vincristine, and prednisolone(CHOP) is an eicient treatment of non-Hodgkin's lymphoma(NHL). This study aimed to assess the eicacy and toxicity of dose-adjusted CHOP alone or in combination with rituximab(R-CHOP) by examining the stem cell mobilization in NHL patients. Factors afecting the collection of CD34+ cells were also explored.Methods: Our retrospective study included 39 patients eligible for autologous stem cell transplantation: 14 patients who expressed CD20 and were inancially eligible received R-CHOP for autologous peripheral blood stem cell(APBSC) mobilization; the remaining 25 patients received CHOP.Results: The median CD34+ cell yield was 7.01 × 106 cells/kg body weight(range 1.49–28.39 × 106 cells/kg body weight), with only two patients failing to meet the target CD34+ cell harvest of ber of apheresis procedures per patient was 1(range 1–3). The≥2.0 APBS× 106 cells/kg body weight. The median numC mobilization yield of the CHOP group appeared to be higher than that of the R-CHOP group(P response(CR) rate in = 0.005), whereas the success rate was similar between groups. R-CHOP elevated the completeB cell lymphoma patients as compared with CHOP(P = 0.01). No signiicant diferences in toxicity or engraftment were observed between the two groups.Conclusion: The present study demonstrated that dose-adjusted CHOP chemotherapy efectively mobilized APBSCs in NHL patients and that the addition of rituximab to dose-adjusted CHOP chemotherapy elevated the CR rate for patients with B-cell lymphoma.