温热体外对人胃癌细胞株生物学行为的影响

目的:探讨温热对人胃癌细胞株增殖、生存以及黏附、侵袭能力的影响．方法:对人胃癌细胞株(AGS,MKN45, SGC7901,NCI-N87,SNU-1和SNU-16)行43℃ 2h的温热处理,以37℃常温培养为对照．处理后用MTT法绘制生长曲线并比较增殖抑制情况;光镜下动态观察细胞生长情况和形态学变化;Hoechst33342/PI荧光染色观察细胞核染色等形态学变化:透射电镜(transmission electron microscopy,TEM)观察细胞超微结构和死亡的具体形式;流式细胞术(flow cytometry,FCM)定量分析细胞的凋亡和坏死比例;黏附和侵袭试验观察胃癌细胞的黏附和侵袭能力．结果:MTT提示,温热对SNU-1有显著的增殖抑制作用(P<0．01),对SNU-16则无显著影响(P>0．05),对4株贴壁细胞则表现为暂时性的增殖抑制(d1-d2,P<0．05);光镜观察发现温热处理后SNU-1细胞出现死亡,而其他细胞无;荧光染色和透射电镜未发现AGS在温热处理后24h有显著的形态学改变,而SNU-1则出现凋亡和坏死;FCM提示温热处理不增加 AGS的自然死亡率(t=0．45,P=0．678 8),但能诱导SNU-1发生凋亡和坏死,增加细胞死亡率(9．7％±1．1％vs 20．1％±2．5％,t=6．54, P=0．002 8);黏附试验表明温热能不同程度降低4株贴壁细胞的黏附能力[AGS(t=4．86, P=0．008 3),MKN45(t=4．50,P=0．0108), SGC7901(t=6．83,P=0．002 4),N87(t=4．16, P=0．014 1)1;侵袭试验表明温热能不同程度降低6株细胞的侵袭能力[AGS(t=2．94, P=0．042 5),MKN45(t=3．60,P=0．022 7), SGC7901(t=4．70,P=0．0093),N87(t=12．41, P=0．0002),SNU-1(t=3．63,P=0．022 2), SNU-16(t=4．13,P:0．0145)]．结论:大多数的胃癌细胞株表现对短时间温热的耐受,除了暂时性的增殖抑制作用外,温热并无细胞杀伤作用,SNU-1是一个例外,温热能导致SNU-1细胞的凋亡和坏死;同时,温热处理能降低细胞的黏附和侵袭能力．     

硫代修饰端粒酶反义核酸联合顺铂、阿霉素对胃癌细胞作用的研究

目的：探讨应用硫代修饰人端粒酶RNA（hTR)反义核酸后胃癌细胞对顺铂（DDP）和阿霉素（ADM）敏感性的变化。方法：采用脂质体将针对hTR模版区设计的13相碱基硫代磷酸修饰的反义寡核苷酸CAGTTAGGGTTAG导入胃癌细胞SGC7901，应用四甲基偶氮唑蓝（MTT）法，流式细胞仪和TRAP－PCR－ELISA法测定联合应用化疗药后对细胞增殖，凋亡和端粒酶活性的影响。结果：化疗药物ADM和DDP地端粒酶活性抑制作用不同，而且有明显依赖趋势。hTR反义PS－ODN可增加ADR和DDP抑制胃癌细胞系SGC7901端粒酶活性，诱导细胞凋亡和抑制细胞增殖的作用。结论：hTR反义PS－ODN在体外能增加胃癌细胞系SGC701对化疗药ADR、DDP敏感性，其机制可能与其抑制细胞端粒酶活性，诱导细胞凋亡有关。     

高温对SGC7901/ADM细胞多药耐药蛋白表达的影响和意义

目的:研究高温43℃对多药耐药基因表达产物P-gp、MRP、LRP在蛋白水平上的影响及其生物学意义,更深入地了解热效应逆转耐药的机制.方法:采用免疫细胞化学染色法、RT-PCR以及Western blot方法,检测在不同温度和不同药物作用下,人胃癌耐药细胞株SGC7901/ADM和对照的人胃癌敏感细胞SGC7901株中,与人胃癌多药耐药相关的分子MDR1、P-gp、MRP、LRP在蛋白水平上的表达差异.结果:采用免疫细胞化学染色法检测人胃癌耐药株SGC7901/ADM细胞,发现高温43℃60 min处理可使P-gp蛋白表达下调率(down-regulated rate,DRR)31.78%(P=0.016),而MRP表达DRR为20.22%(P=0.037),差异有统计学意义,LRP未表达.采用Western blot法在SGC7901细胞中未检测出P-gp蛋白表达,而SGC7901/ADM细胞中P-gp高表达;在ADM和CDDP处理组细胞中,高温43℃时P-gp的表达量较37℃时DRR分别为45.65%(P=0.007)、17.95%(P=0.021),差异有显著学意义;TAX处理组DRR为11.90%,差异无显著学意义(P=0.065).结论:高温43℃的短期处理对人胃癌SGC7901/ADM细胞中P-gp和MRP多药耐药蛋白的表达有一定的抑制作用,可能是逆转耐药的机制之一.     

顺铂结合CIK细胞对裸鼠人胃癌模型体内的抗肿瘤作用

目的:探讨顺铂、CIK细胞以及顺铂联合CIK对裸鼠人胃癌移植瘤生长的抑制作用,为临床上联合应用顺铂和CIK细胞治疗胃癌提供实验依据.方法:应用淋巴细胞分离液分离外周血单个核细胞,给予多种细胞因子(rhIFN-g、CD3mcAb、rh1L-1、rhlL-2),诱导生成CIK细胞;培养人胃癌细胞株SGC-7901,接种至80只裸鼠右腋皮下,10 d后取移植瘤直径基本一致的裸鼠随机分4组:NS对照组、顺铂组、CIK细胞组和顺铂+CIK细胞组,每组16只.连续5 d在接种肿瘤细胞部位处给予相应注射治疗,观察其对胃癌移植瘤模型的抗肿瘤疗效.结果:与NS对照组相比,顺铂组、CIK细胞组、顺铂+CIK细胞组裸鼠人胃癌移植瘤模型治疗后肿块质量均减轻,生存期均明显延长,尤以顺铂+CIK组效果显著(P<0.01).裸鼠体内实验表明,顺铂+CIK细胞联合应用能够显著抑制胃癌细胞的生长,其抑瘤率可达57.8%,明显高于NS对照组(P<0.01).免疫功能检测显示红细胞C3b反应受体明显升高,红细胞免疫复合物受体明显降低(P<0.01).结论:顺铂联合CIK细胞对人胃癌移植瘤生长的抑制作用大于单独应用顺铂或CIK细胞.     

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in gastric cancer

Gastric cancer associated peritoneal carcinomatosis(GCPC) has a poor prognosis with a median survival of less than one year. Systemic chemotherapy including targeted agents has not been found to significantly increase the survival in GCPC. Since recurrent gastric cancer remains confined to the abdominal cavity in many patients, regional therapies like aggressive cytoreductive surgery( CRS) and hyperthermic intraperitoneal chemotherapy(HIPEC) have been investigated for GCPC. HIPEC has been used for three indications in GC- as an adjuvant therapy after a curative surgery, HIPEC has been shown to improve survival and reduce peritoneal recurrences in many randomised trials in Asian countries; as a definitive treatment in established PC, HIPEC along with CRS is the only therapeutic modality that has resulted in longterm survival in select groups of patients; as a palliative treatment in advanced PC with intractable ascites, HIPEC has been shown to control ascites and reduce the need for frequent paracentesis. While the results of randomised trials of adjuvant HIPEC from western centres are awaited, the role of HIPEC in the treatment of GCPC is still evolving and needs larger studies before it is accepted as a standard of care.     

反义端粒酶基因与顺铂诱导原代胃癌细胞凋亡作用的研究

目的　探讨端粒酶反义寡核苷酸 (PS- ASODN)与顺铂 (DDP)联合应用对原代胃癌细胞凋亡作用的影响。方法　常规组织块培养法进行胃癌细胞原代纯化培养 ,取第 3代对数生长期细胞分六组进行实验。其中四组在培养 2 4小时及 4 8小时分别加入相同剂量的培养液 ,终浓度为 PS- ASODN3μM,N- ASODN3μM,DDP2 .0μg/ ml。作用 2 4小时后分别在 PS- ASODN组及 N- ASODN组加入终浓度为 2 .0 μg/ ml的 DDP;分别于培养后 2 4、4 8、72及 96小时收集各组细胞。以台盼蓝拒染法计算各组细胞生长抑制率 ,观察 PS- ASODN联合 DDP对原代胃癌细胞生长的影响 ;流式细胞学观察细胞凋亡率及细胞周期变化。结果　终浓度为 3μM的 PS- ASODN作用于原代胃癌细胞 2 4小时后加入 DDP 2 .0μg/ m l,能明显抑制胃癌细胞增殖 ,流式细胞学可检测到凋亡峰 ,细胞受阻于G0 / G1 期 ,作用 4 8及 72小时的凋亡细胞百分率 (35 .1%、4 5 .7% )明显高于 N- ASODN组、PS- ASODN组、DDP组及 N- ASODN+DDP组 ,差异有显著性 (P<0 .0 5 )。其作用呈时间依赖性及序列特异性。结论　以端粒酶 RNA模板区为靶点的 PS- ASODN可促进 DDP诱导的胃癌细胞凋亡 ,对胃癌具有治疗价值     

Immunotherapy-based novel nanoparticles in the treatment of gastrointestinal cancer: Trends and challenges

Gastrointestinal cancer (GIC) is the most common cancer with a poor prognosis. Currently, surgery is the main treatment for GIC. However, the high rate of postoperative recurrence leads to a low five-year survival rate. In recent years, immunotherapy has received much attention. As the only immunotherapy drugs approved by the Food and Drug Administration (FDA), immune checkpoint blockade (ICB) drugs have great potential in cancer therapy. Nevertheless, the efficacy of ICB treatment is greatly limited by the low immunogenicity and immunosuppressive microenvironment of GIC. Therefore, the targets of immunotherapy have expanded from ICB to increasing tumor immunogenicity, increasing the recruitment and maturation of immune cells and reducing the proportion of inhibitory immune cells, such as M2-like macrophages, regulatory T cells and myeloid-derived suppressor cells. Moreover, with the development of nanotechnology, a variety of nanoparticles have been approved by the FDA for clinical therapy, so novel nanodrug delivery systems have become a research focus for anticancer therapy. In this review, we summarize recent advances in the application of immunotherapy-based nanoparticles in GICs, such as gastric cancer, hepatocellular carcinoma, colorectal cancer and pancreatic cancer, and described the existing challenges and future trends.     

Pancreatic cancer in 2021: What you need to know to win

Pancreatic cancer is one of the solid tumors with the worst prognosis. Five-year survival rate is less than 10%. Surgical resection is the only potentially curative treatment, but the tumor is often diagnosed at an advanced stage of the disease and surgery could be performed in a very limited number of patients. Moreover, surgery is still associated with high post-operative morbidity, while other therapies still offer very disappointing results. This article reviews every aspect of pancreatic cancer, focusing on the elements that can improve prognosis. It was written with the aim of describing everything you need to know in 2021 in order to face this difficult challenge.     

Regional but fatal: Intraperitoneal metastasis in gastric cancer

Peritoneal carcinomatosis appears to be the most common pattern of metastasis or recurrence and is associated with poor prognosis in gastric cancer patients. Many efforts have been made to improve the survival in patients with peritoneal metastasis. Hyperthermic intraperitoneal chemotherapy remains a widely accepted strategy in the treatment of peritoneal dissemination. Several phase Ⅱ-Ⅲ studies confirmed that the combined cytoreducitve surgery and hyperthermic intraperitoneal chemotherapy resulted in longer survival in patients with peritoneal carcinomatosis. In addition,proper selection and effective regional treatment in patients with high risk of peritoneal recurrence after resection will further improve prognosis in local advanced gastric cancer patients.     

ABO blood type, diabetes and risk of gastrointestinal cancer in northern China

AIM: To explore the potential risk factors related to gastrointestinal cancer in northern China.METHODS: A total of 3314 cases of gastrointestinal cancer (esophageal, gastric, pancreatic and biliary) and 2223 controls (including healthy individuals, glioma and thyroid cancer) were analyzed by case-control study. Multivariable logistic regression analysis was applied to evaluate the association between different cancers and hepatitis B surface antigen, sex, age, blood type, diabetes, or family history of cancer.RESULTS: Type 2 diabetes was significantly associated with gastric, biliary and pancreatic cancer with an OR of 2.0-3.0. Blood type B was significantly associated with esophageal cancer [odd ratio (OR) = 1.53, 95% confidence interval (CI) = 1.10-2.14] and biliary cancer (OR = 1.49, 95% CI = 1.09-2.05). The prevalence of type 2 diabetes was significantly higher in gastric, biliary and pancreatic cancers compared with other groups, with ORs ranging between 2.0 and 3.0. Family history of cancer was strongly associated with gastrointestinal compared with other cancers.CONCLUSION: Blood type B individuals are susceptible to esophageal and biliary cancer. Type 2 diabetes is significantly associated with gastric, biliary and especially pancreatic cancer.     

紫杉醇脂质体联合顺铂方案在晚期宫颈癌诱导化疗中的应用

目的评价紫杉醇脂质体联合顺铂方案作为诱导化疗在宫颈癌治疗中的抗肿瘤作用及毒性。方法选择晚期宫颈癌患者73例,按照住院单、双号分为TP方案组（41例）和FP方案组（32例）。TP方案组采用紫杉醇联合铂类药物诱导化疗;FP方案组采用5．氟尿嘧啶联合铂类药物诱导化疗。化疗均为2个疗程,配合后装妮Ir放疗,然后评价两组抗肿瘤效果,再进行手术治疗。结果两组治疗总有效率分别为75．6％和46．9％,TP方案组总有效率高于FP方案组（P〈0．05）。两组化疗毒副反应强度差异无统计学意义（P均〉0．05）。结论紫杉醇脂质体联合顺铂是一种非常有效的诱导化疗方案,有助于控制肿瘤,达到术前治疗的目的。     

Role of ABCG2 expression driven by cisplatin in platinumcontaining chemotherapy for gastric cancer

AIM:To investigate the relationship between increases in expression time of ABCG2 mRNA driven by cisplatin and efficacy of platinum-containing chemotherapy for gastric cancer.METHODS:Tumor specimens and normal control tissues were collected from 78 patients with gastric cancer treated from January 2008 to December 2011.Fresh tumor tissue obtained from the surgically resected specimens was tested within 6 h.Polymerase chain reaction products were run on 2%agarose gels and analyzed under ultraviolet light after ethidium bromide staining.Increases in ABCG2 mRNA expression time cisplatin,and were divided into terciles and compared in relation to clinical outcomes.RESULTS:Among groups classified by expression time of ABCG2 mRNA,no significant differences in baseline clinical characteristics and pathological findings were detected.The median overall time was 14.2(95%CI:9.7-18.6),11.4(95%CI:6.3-16.5)and 8.1(95%CI:5.4-10.8)in patients with low,intermediate and high increases in ABCG2 mRNA expression times(P<0.05),respectively.Median survival associated with performance status and tumor node metastasis(TNM)stage showed a similar trend,with longer survival and higher risk for mortality associated with lower performance status score and TNM stage.In a multivariate analysis for survival with Cox proportional-hazards model,increased ABCG2 mRNA expression time was an independent predictor for overall survival.Overall survival was longer with increased ABCG2 mRNA expression times≤0.71 than increased ABCG2 mRNA expression times>0.71,with a hazard ratio for death of 0.855(95%CI:0.615-0.962,P=0.038).CONCLUSION:Increased ABCG2 mRNA expression time driven by cisplatin is associated with survival of gastric cancer patients,and this may help modify the therapeutic strategies.     

Pilot study of postoperative adjuvant chemoradiation for advanced gastric cancer： Adjuvant 5-FU/cisplatin and chemoradiation with capecitabine

AIM:To evaluate the efficacy and toxicity of postopera-tive chemoradiation using FP chemotherapy and oralcapecitabine during radiation for advanced gastric cancerfollowing curative resection.METHODS:Thirty-one patients who had underwent apotentially curative resection for Stage Ⅲ and Ⅳ(MO)gastric cancer were enrolled.Therapy consists of onecycle of FP(continuous infusion of 5-FU 1000 mg/m~2on d 1 to 5 and cisplatin 60 mg/m~2 on d 1)followed by4500 cGy(180 cGy/d)with capecitabine(1650 mg/m~2daily throughout radiotherapy).Four wk after completionof the radiotherapy,patients received three additionalcycles of FP every three wk.The median follow-up dura-tion was 22.2 mo.RESULTS:The 3-year disease free and overall survivalin this study were 82.7% and 83.4%,respectively.Fourpatients(12.9%)showed relapse during follow-up.Eightpatients did not complete all planned adjuvant therapy.Grade 3/4 toxicities included neutropenia in 50.2%,ane-mia in 12.9%,thrombocytopenia in 3.2% and nausea/vomiting in 3.2%.Neither grade 3/4 hand foot syndromenor treatment related febrile neutropenia or death wereobserved.CONCLUSION:These preliminary results suggest thatthis postoperative adjuvant chemoradiation regimen ofFP before and after capecitabine and concurrent radio-therapy appears well tolerated and offers a comparable toxicity profile to the chemoradiation regimen utilized inINT-0116.This treatment modality allowed successfulloco-regional control rate and 3-year overall survival.     

Pressurized intraperitoneal aerosol chemotheprapy after misdiagnosed gastric cancer: case report and review of the literature

We report the first application of pressurized intraperitoneal aerosol chemotherapy(PIPAC) as a rescue therapy before palliative D2 gastrectomy combined with liver metastasectomy performed in a 49-yearold woman with peritoneal carcinomatosis who was primarily diagnosed with and underwent surgery for a Krukenberg tumor. The PIPAC procedure was performed with the use of cisplatin at 7.5 mg/m2 and doxorubicin at 1.5 mg/m2 for 30 min at 37 ℃. Eight weeks after the PIPAC procedure, the patient underwent open classic D2 gastrectomy with the creation of a Roux-en-Y anastomosis(RNY) combined with liver metastasectomy. The patient underwent the classic protocol for chemotherapy combined with Xeloda. The patient felt better and returned to her daily activities. Multicenter data should be gathered to confirm the usefulness of PIPAC as a rescue or neoadjuvant supportive therapy in a very select group of patients who have been recently qualified to undergo classic chemotherapy or standard oncologic surgical procedures.     

Role of ion channels in gastrointestinal cancer

In their seminal papers Hanahan and Weinberg described oncogenic processes a normal cell undergoes to be transformed into a cancer cell.The functions of ion channels in the gastrointestinal(GI) tract influence a variety of cellular processes,many of which overlap with these hallmarks of cancer.In this review we focus on the roles of the calcium(Ca~(2+)),sodium(Na~+),potassium(K~+),chloride(Cl~-) and zinc(Zn~(2+)) transporters in GI cancer,with a special emphasis on the roles of the KCNQ1 K~+ channel and CFTR Cl channel in colorectal cancer(CRC).Ca~(2+)is a ubiquitous second messenger,serving as a signaling molecule for a variety of cellular processes such as control of the cell cycle,apoptosis,and migration.Various members of the TRP superfamily,including TRPM8,TRPM7,TRPM6 and TRPM2,have been implicated in GI cancers,especially through overexpression in pancreatic adenocarcinomas and down-regulation in colon cancer.Voltage-gated sodium channels(VGSCs) are classically associated with the initiation and conduction of action potentials in electrically excitable cells such as neurons and muscle cells.The VGSC Na_v1.5 is abundantly expressed in human colorectal CRC cell lines as well as being highly expressed in primary CRC samples.Studies have demonstrated that conductance through Na_v1.5 contributes significantly to CRC cell invasiveness and cancer progression.Zn~(2+)transporters of the ZIP/SLC39 A and ZnT/SLC30 A families are dysregulated in all major GI organ cancers,in particular,ZIP4 up-regulation in pancreatic cancer(PC).More than 70 K~+ channel genes,clustered in four families,are found expressed in the GI tract,where they regulate a range of cellular processes,including gastrin secretion in the stomach and anion secretion and fluid balance in the intestinal tract.Several distinct types of K~+ channels are found dysregulated in the GI tract.Notable are hERG1 upregulation in PC,gastric cancer(GC) and CRC,leading to enhanced cancer angiogenesis and invasion,and KCNQ1 down-regulation in CRC,where KCNQ1 expression is associated with enhanced disease-free survival in stage Ⅱ,Ⅲ,and Ⅳ disease.Cl~-channels are critical for a range of cellular and tissue processes in the GI tract,especially fluid balance in the colon.Most notable is CFTR,whose deficiency leads to mucus blockage,microbial dysbiosis and inflammation in the intestinal tract.CFTR is a tumor suppressor in several GI cancers.Cystic fibrosis patients are at a significant risk for CRC and low levels of CFTR expression are associated with poor overall disease-free survival in sporadic CRC.Two other classes of chloride channels that are dysregulated in GI cancers are the chloride intracellular channels(CLIC1,3 4) and the chloride channel accessory proteins(CLCA1,2,4).CLIC1 4 are upregulated in PC,GC,gallbladder cancer,and CRC,while the CLCA proteins have been reported to be down-regulated in CRC.In summary,it is dear,from the diverse influences of ion channels,that their aberrant expression and/or activity can contribute to malignant transformation and tumor progression.Further,because ion channels are often localized to the plasma membrane and subject to multiple layers of regulation,they represent promising clinical targets for therapeutic intervention including the repurposing of current drugs.