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.

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.

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.

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.

Chidamide combined with cyclophosphamide,doxorubicin,vincristine and prednisone in previously untreated patients with peripheral T-cell lymphoma

Objective:Chidamide is an oral histone deacetylase subtype-selective inhibitor approved for relapsed or refractory peripheral T-cell lymphoma(PTCL).This phase 1 b study evaluated the safety,pharmacokinetics,and preliminary efficacy of chidamide in combination with cyclophosphamide,doxorubicin,vincristine and prednisone(CHOP)for treatment-na?ve PTCL patients.Methods:This study was an open-label,multicenter trial composed of dose escalation and dose expansion.Patients received CHOP for six 21-d cycles and chidamide on d 1,4,8 and 11 in each cycle.Four dose levels of chidamide(20,25,30 and 35 mg)were evaluated.The primary objective was to evaluate the safety and tolerability of the combination regimen.Results:A total of 30 patients were evaluated in this study:15 in the dose-escalation part and 15 in the doseexpansion part.In the dose-escalation study,three patients were enrolled in the 35 mg chidamide cohort.One had dose-limiting toxicity with grade 3 vascular access complications,and one had grade 2 neutropenia with a sustained temperature>38°C.Dose escalation was stopped at this chidamide dose level.The most common(≥10%)grade 3 or 4 adverse events(AEs)were leukopenia(90.0%),neutropenia(83.3%),vomiting(13.3%),thrombocytopenia(10.0%)and febrile neutropenia(10.0%).No significant changes in chidamide pharmacokinetic properties were observed before and after combination treatment.The objective response rate for the 28 patients evaluable for preliminary efficacy was 89.3%(25/28),with 16(57.1%)achieving complete response or unconfirmed complete response.The estimated median progression-free survival was 14.0 months.In summary,we chose chidamide 30 mg as the recommended dose for phase 2.Conclusions:The addition of chidamide to standard CHOP chemotherapy was tolerable with promising preliminary efficacy in previously untreated PTCL patients,which supports further clinical studies with this combination regimen for the frontline treatment of PTCL.

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.

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.

Oxidative imbalance increases the risk for colonic polyp and colorectal cancer development

BACKGROUND The role of oxidative stress in the pathogenesis of colorectal carcinoma(CRC)has garnered considerable interest recently.Specific oxidative factors have been implicated in the pathogenesis of adenomatous polyps and ultimately adenocarcinoma.AIM To evaluate the effect of oxidative imbalance as quantified by specific serological markers in the development of sporadic colon adenocarcinoma.METHODS A total of 170 patients that underwent endoscopy of the lower gastrointestinal tract in a tertiary center within 3 years were included in the study.They were allocated in three groups;those with sporadic colon adenocarcinoma(n=56,32.9%),those with colonic polyps(n=33,19.4%)and healthy controls(n=81,47.7%).All patients were evaluated for oxidant activity and antioxidant capacity with serum measurements of specific markers such as vitamins A,25(OH)D3,E,C,B12,folic acid,glutathione,selenium(Se),zinc(Zn),free iron(Fe^(2+)),and malondialdehyde and results were compared between groups.RESULTS Serum levels of vitamins C,E,D,Se,Zn,vitamin B12 and total antioxidant capacity were significantly lower in the combined neoplasia/polyp group than in the control group(P=0.002,P=0.009,P<0.001,P<0.001,P<0.001,P=0.020 and P<0.001,correspondingly).Increased levels of vitamin E(P=0.004),vitamin D(P<0.001),Se(P<0.001)and Zn(P<0.001)seem to bestow a protective effect on the development of CRC.For vitamin D(P<0.001)and Zn(P=0.036),this effect seems to extend to the development of colon polyps as well.On the other hand,elevated serum levels of malondialdehyde are associated with a higher risk of CRC(OR=2.09 compared to controls,P=0.004).Regarding colonic polyp development,increased concentrations of vitaminΑand Fe^(2+) are associated with a higher risk,whereas lower levels of malondialdehyde with a lower risk.CONCLUSION Increased oxidative stress may play an important role in the pathogenesis and progression of CRC.Antioxidants’presence may exert a protective effect in the very early stages of colon carcinogenesis.

Incidence,Survival Outcome,and Prognostic Nomogram of Patients with Angioimmunoblastic T-cell Lymphoma:a Population-based Analysis

Objective Due to the rarity of angioimmunoblastic T-cell lymphoma(AITL),very limited data concerning its incidence patterns and prognostic factors are available.This study aimed to explore the incidence,characteristics,survival outcomes,and prognostic factors of AITL.Methods Age-adjusted incidence and temporal trends were calculated based on 1247 AITL patients from the National Cancer Institute’s Surveillance,Epidemiology,and End Results(SEER)-13 database.A total of 1525 AITL patients from the SEER-18 database and 43 patients from our single center were included for survival analysis and nomogram construction.Results The age-adjusted incidence for overall cohort was 0.123[95%confidence interval(CI),0.117–0.131)per 100000 during 1992–2017.The overall incidence increased steeply at the rate of 15.3%(95%CI 11.0%–19.8%,P<0.001)per year during 1992–2004,but remained stable during 2004–2017(P=0.200).Similar incidence trends were observed in age,sex,and stage subgroups.The final nomograms consisted of four variables:age at diagnosis,sex,Ann Arbor stage,and primary site.The concordance index(C-index)of the nomogram for 5-year overall survival prediction was 0.717,0.690 and 0.820 in the training cohort,validation cohort-1 and cohort-2,respectively.Regarding the disease-specific survival(DSS),the nomogram also demonstrated a good discrimination level,with the C-index for predicting the probability of DSS at 5 years of 0.716,0.682 and 0.813 for the three cohorts,respectively.The calibration displayed good concordance between the nomogram-predicted and actual observed outcomes.Conclusion The age-adjusted incidence for AITL was low during 1992–2017.The incidence continuously increased during 1992–2004,but remained stable during 2004–2017.The nomograms as proposed may provide a favorable and accurate prognostic survival prediction in AITL.

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.

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.

HOXB8 contributed to oxaliplatin chemo-resistance in colon cancercells by activating STAT3

Background:Homeobox B8(HOXB8),a member of HOX family,plays a key role in the development of colorectal cancer(CRC).However,the function of HOXB8 in oxaliplatin(OXA)resistance in CRC is still unclear.This study investigated the role and precise molecular mechanism of HOXB8 in OXA-resistant CRC cells.Methods:The cell viability was measured by the 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide(MTT)assay,and the colony forming ability was determined by colony formation assay.The silencing RNA(siRNA)approach was used to knockdown HOXB8 in CRC cells while the lentiviral transfection system was used to establish stable HOXB8 overexpressing CRC cells.The protein and mRNA levels were evaluated by western blot and real-time reverse transcription-polymerase chain reaction.Results:HOXB8 expression was upregulated in OXA-resistant HCT116 cells(HCT116/OXA)compared to its level in the parent HCT116 cells.Knockdown of HOXB8 significantly inhibited CRC cell growth by suppressing the signal transducer and activator of transcription 3(STAT3)pathway.HOXB8 knockdown also potentiated cytotoxicity of OXA in CRC cells.Inversely,HOXB8 overexpression attenuated OXAinduced growth inhibition of HCT116 cells and RKO cells by activating STAT3 signaling.HOXB8 knockdown effectively inhibited HCT116/OXA cell viability regardless of OXA treatment by suppressing STAT3 signaling.Conclusions:These results shed light on the important functions of HOXB8 in OXA-resistant CRC and suggested that targeting HOXB8 might be an effective therapeutic strategy for select OXA-resistant CRC patients.

Single-cell RNA sequencing reveals the dynamics of hepatic non-parenchymal cells in autoprotection against acetaminophen-induced hepatotoxicity

Gaining a better understanding of autoprotection against drug-induced liver injury(DILI)may provide new strategies for its prevention and therapy.However,little is known about the underlying mechanisms of this phenomenon.We used single-cell RNA sequencing to characterize the dynamics and functions of hepatic non-parenchymal cells(NPCs)in autoprotection against DILI,using acetaminophen(APAP)as a model drug.Autoprotection was modeled through pretreatment with a mildly hepatotoxic dose of APAP in mice,followed by a higher dose in a secondary challenge.NPC subsets and dynamic changes were identified in the APAP(hepatotoxicity-sensitive)and APAP-resistant(hepatotoxicity-resistant)groups.A chemokine(C-C motif)ligand 2^(+)endothelial cell subset almost disappeared in the APAP-resistant group,and an R-spondin 3^(+)endothelial cell subset promoted hepatocyte proliferation and played an important role in APAP autoprotection.Moreover,the dendritic cell subset DC-3 may protect the liver from APAP hepatotoxicity by inducing low reactivity and suppressing the autoimmune response and occurrence of inflammation.DC-3 cells also promoted angiogenesis through crosstalk with endothelial cells via vascular endothelial growth factor-associated ligand-receptor pairs and facilitated liver tissue repair in the APAP-resistant group.In addition,the natural killer cell subsets NK-3 and NK-4 and the Sca-1^(-)CD62L^(+)natural killer T cell subset may promote autoprotection through interferon-γ-dependent pathways.Furthermore,macrophage and neutrophil subpopulations with anti-inflammatory phenotypes promoted tolerance to APAP hepatotoxicity.Overall,this study reveals the dynamics of NPCs in the resistance to APAP hepatotoxicity and provides novel insights into the mechanism of autoprotection against DILI at a high resolution.

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。

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.