Prognostic and predictive role of immune microenvironment in colorectal cancer

Colorectal cancer(CRC)represents a molecularly heterogeneous disease and one of the most frequent causes of cancer-related death worldwide.The traditional classification of CRC is based on pathomorphological and molecular character-istics of tumor cells(mucinous,ring-cell carcinomas,etc.),analysis of mechanisms of carcinogenesis involved(chromosomal instability,microsatellite instability,CpG island methylator phenotype)and mutational statuses of commonly altered genes(KRAS,NRAS,BRAF,APC,etc.),as well as expression signatures(CMS 1-4).It is also suggested that the tumor microenvironment is a key player in tumor progression and metastasis in CRC.According to the latest data,the immune microenvironment can also be predictive of the response to immune checkpoint inhibitors.In this review,we highlight how the immune environment influences CRC prognosis and sensitivity to systemic therapy.

To explore the pathogenesis of anterior resection syndrome by magnetic resonance imaging rectal defecography

BACKGROUND Over 90%of rectal cancer patients develop low anterior resection syndrome(LARS)after sphincter-preserving resection.The current globally recognized evaluation method has many drawbacks and its subjectivity is too strong,which hinders the research and treatment of LARS.AIM To evaluate the anorectal function after colorectal cancer surgery by quantifying the index of magnetic resonance imaging(MRI)defecography,and pathogenesis of LARS.METHODS We evaluated 34 patients using the standard LARS score,and a new LARS evaluation index was established using the dynamic images of MRI defecography to verify the LARS score.RESULTS In the LARS score model,there were 10(29.41%)mild and 24(70.58%)severe cases of LARS.The comparison of defecation rate between the two groups was 29.36±14.17%versus 46.83±18.62%(P=0.004);and MRI-rectal compliance(MRI-RC)score was 3.63±1.96 versus 7.0±3.21(P=0.001).Severe and mild LARS had significant differences using the two evaluation methods.There was a significant negative correlation between LARS and MRI-RC score(P<0.001),and they had a negative correlation with defecation rate(P=0.028).CONCLUSION MRI defecography and standard LARS score can both be used as an evaluation index to study the pathogenesis of LARS.

Prioritizing the efforts:lived experiences of family when taking care of people with cancer

Objective:Cancer has one of the highest disease mortality rates.Families are very important in the treatment of people with cancer.By using a phenomenological design,this study aimed to explore the experience of families in caring for a person with cancer and to identify the needs of these families.Methods:First,eight interviews were under taken with family members selected through a purposive sampling method.Then,another three interviews were conducted for data validation.The collected data were analyzed using the framework method of analysis.Results:The core theme,“Prioritizing the efforts:Being aware of the best we could do for our family,”reflected family’s experiences of caring for a person with cancer and was underpinned by five themes:“Decisions to make,”“Keeping up the good support,”“Acknowledging the others’contributions,”“Assisting my family to alleviate the disease,”and“Adapting to the current situation.”Conclusions:The results suggest that building mutual trust and communication between family and healthcare professionals is vital in decision-making for people with cancer.Family may also work with the person in fulfilling their needs,without disregarding the needs of the family.When suppor ting the needs of people with diabetes,the family requires appropriate information,and thus,healthcare professionals wisely select which information can help the family make a decision regarding the treatment.After administering the treatment and providing information for people with cancer and their family,asking for feedback is required for evaluation.

Chloroquine enhances the cytotoxicity of topotecan by inhibiting autophagy in lung cancer cells

Although the anti-malaria drug chloroquine(CQ) has been shown to enhance chemotherapy and radiation sensitivity in clinical trials,the potential mechanisms underlying this enhancement are still unclear.Here,we examined the relevant mechanisms by which the multipotent CQ enhanced the cytotoxicity of topotecan(TPT).The lung cancer cell line A549 was treated with TPT alone or TPT combined with CQ at non-cytotoxic concentrations.Cell viability was assessed using the MTT assay.The percentage of apoptotic cells and the presence of a side population of cells were both determined by flow cytometry.Autophagy and the expression of Bcl-2 family proteins were examined by Western blotting.The accumulation of YFP-LC3 dots and the formation of acidic vesicular organelles were examined by confocal microscopy.CQ sensitized A549 cells to TPT and enhanced TPT-induced apoptosis in a Bcl-2 family protein-independent fashion.CQ inhibited TPT-induced autophagy,which modified the cytotoxicity of TPT.However,CQ failed to modify the transfer of TPT across the cytoplasmic membrane and did not increase lysosomal permeability.This study showed that CQ at non-cytotoxic concentrations potentiated the cytotoxicity of TPT by interfering with autophagy,implying that CQ has significant potential as a chemotherapeutic enhancer.

Dynamic alterations in the gut microbiota and metabolome during the development of methionine-choline-deficient diet-induced nonalcoholic steatohepatitis

AIM To investigate changes in gut microbiota and metabolism during nonalcoholic steatohepatitis(NASH) development in mice fed a methionine-choline-deficient(MCD) diet. METHODS Twenty-four male C57 BL/6 J mice were equally divided into four groups and fed a methionine-choline-sufficient diet for 2 wk(Control 2 w group,n = 6) or 4 wk(Control 4 w group,n = 6) or the MCD diet for 2 wk(MCD 2 w group,n = 6) or 4 wk(MCD 4 w group,n = 6). Liver injury,fibrosis,and intestinal barrier function were evaluated after 2 and 4 wk of feeding. The fecal microbiome and metabolome were studied using 16 s r RNA deep sequencing and gas chromatography-mass spectrometry. RESULTS The mice fed the MCD diet presented with simple hepatic steatosis and slight intestinal barrier deterioration after 2 wk. After 4 wk of feeding with the MCD diet,however,the mice developed prominent NASH with liver fibrosis,and the intestinal barrier was more impaired. Compared with the control diet,the MCD diet induced gradual gut microbiota dysbiosis,as evidenced by a marked decrease in the abundance of Alistipes and the(Eubacterium) coprostanoligenes group(P < 0.001 and P < 0.05,respectively) and a significant increase in Ruminococcaceae UCG 014 abundance(P < 0.05) after 2 wk. At 4 wk,the MCD diet significantly reduced the promising probiotic Bifidobacterium levels and markedly promoted Bacteroides abundance(P < 0.05,and P < 0.01,respectively). The fecal metabolomic profile was also substantially altered by the MCD diet: At 2 wk,arachidic acid,hexadecane,palmitic acid,and tetracosane were selected as potential biomarkers that were significantly different in the corresponding control group,and at 4 wk,cholic acid,cholesterol,arachidic acid,tetracosane,and stearic acid were selected. CONCLUSION The MCD diet induced persistent alterations in the gut microbiota and metabolome.

Promoter methylation of tumor suppressor genes in esophageal squamous cell carcinoma

Esophageal squamous cell carcinoma(ESCC) is a prevalent and fatal cancer in China and other Asian countries.Epigenetic silencing of key tumor suppressor genes(TSGs) is critical to ESCC initiation and progression.Recently,many novel TSGs silenced by promoter methylation have been identified in ESCC,and these genes further serve as potential tumor markers for high-risk group stratification,early detection,and prognosis prediction.This review summarizes recent discoveries on aberrant promoter methylation of TSGs in ESCC,providing better understanding of the role of disrupted epigenetic regulation in tumorigenesis and insight into diagnostic and prognostic biomarkers for this malignancy.

Prognostic factors of refractory NSCLC patients receiving anlotinib hydrochloride as the third-or further-line treatment

Objective:Anlotinib hydrochloride is a multitarget tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor,fibroblast growth factor receptor,platelet-derived growth factor receptor,c-Kit,and c-MET;therefore,it exhibits both antitumor and anti-angiogenetic activities.A phase III trial has shown that anlotinib improved progression-free survival(PFS)and overall survival(OS)in patients with advanced non-small cell lung cancer(NSCLC),who presented with progressive disease or intolerance after standard chemotherapy.This study aimed to analyze the characteristics of patients receiving anlotinib treatment to determine the dominant populations who are fit for the treatment.Methods:Data were collected from March 2015 to January 2017 from a randomized,double-blind,placebo-controlled,multicenter,phase III trial of anlotinib(ALTER0303).A total of 437 patients were enrolled and randomly allocated(2:1)to the anlotinib and placebo groups.Kaplan–Meier analysis and log-rank test were performed to compare PFS and OS.Cox proportional hazards model was adopted for multivariate prognostic analysis.Results:Multivariate analysis indicated that high post-therapeutic peripheral blood granulocyte/lymphocyte ratio and elevated alkaline phosphatase levels were independent risk factors for PFS.Meanwhile,elevated thyroid-stimulating hormone,blood glucose,and triglyceride levels;hypertension;and hand–foot syndrome were independent protective factors of PFS.High posttherapeutic peripheral blood granulocyte/lymphocyte ratio,an Eastern Cooperative Oncology Group(ECOG)score≥2,and the sum of the maximal target lesion length at baseline were independent risk factors of OS,and hypertriglyceridemia was an independent protective factor of OS.Conclusions:This study preliminarily explored the possible factors that affected PFS and OS after anlotinib treatment in patients with advanced refractory NSCLC,and the baseline characteristics of the therapeutically dominant populations were then identified.

Polymorphisms of interleukin-10 promoter are not associated with prognosis of advanced gastric cancer

AIM: To evaluate the association between of the interleukin-10 (IL-10) promoter polymorphisms and survival of advanced gastric cancer (GC) patients. METHODS: The IL-10 (-1082, rs1800896; -819, rs1800871; and-592, rs1800896) genotypes in 234 patients with advanced gastric cancer and in 243 healthy controls were determined by polymerase chain reaction-restriction fragment length polymorphism assay. Odds ratios (OR) and 95% confidence intervals (CI) were calculated by unconditional logistic regression for the associations between IL-10 genotypes and the risk of GC. The Kaplan-Meier method with log-rank testing was used to evaluate the association between genotype and survival of the patients.RESULTS: The IL-10 -1082 G allele and GCC (-1082, -819 and -592) haplotype were associated with increased gastric cancer risks (OR 1.2, 95% CI 0.6-3.2, P = 0.007, for -1082 G allele, OR = 2.3, 95% CI, 1.2-4.1, P = 0.005, for GCC haplotype, respectively). However, none of the three IL-10 gene polymorphisms (-1082, -819 and -592) was correlated with gastric cancer survival (P > 0.05), and none of the genotypes of the three IL-10 sites was found as independent prognostic risk factors in the multivariate test. CONCLUSION: IL-10 gene promoter polymorphisms may not be associated with the prognosis of advanced gastric cancer.

Cyclooxygenase-2 expression is associated with initiation of hepatocellular carcinoma, while prostaglandin receptor-1 expression predicts survival

AIM to determine whether cyclooxygenase-2(COX-2) and prostaglandin E1 receptor(EP1) contribute to disease and whether they help predict prognosis.METHODS We retrospectively reviewed the records of 116 patients with hepatocellular carcinoma(HCC) who underwent surgery between 2008 and 2011 at our hospital. Expression of COX-2 and EP1 receptor was examined by immunohistochemistry of formalin-fixed, paraffinembedded tissues using polyclonal antibodies. Possible associations between immunohistochemical scores and survival were determined.RESULTS Factors associated with poor overall survival(OS) were alpha-fetoprotein > 400 ng/m L, tumor size ≥ 5 cm, and high EP1 receptor expression, but not high COX-2 expression. Disease-free survival was not significantly different between patients with low or high levels of COX-2 or EP1. COX-2 immunoreactivity was significantly higher in well-differentiated HCC tissues(Edmondson grade Ⅰ-Ⅱ) than in poorly differentiated tissues(Edmondson grade Ⅲ-Ⅳ)(P = 0.003). EP1 receptor immunoreactivity was significantly higher in poorly differentiated tissue than in well-differentiated tissue(P = 0.001).CONCLUSION COX-2 expression appears to be linked to early HCC events(initiation), while EP1 receptor expression may participate in tumor progression and predict survival.

Significance of Bcl-xL in human colon carcinoma

AIM:To investigate the clinical significance of Bcl-xL gene in the pathogenesis of human colon carcinoma. METHODS:Fifty-six pair tissue samples from patients with colon cancer were collected, and protein level of the Bcl-xL gene was measured by immunohistochemistry method. The correlation of Bcl-xL expression with clinical index was evaluated. After human colon cancer cell line HT29 was transfected with Bcl-xL small interfering RNA (siRNA), the anchorage-independent growth of cancer cells was detected by colony formation in soft agar and invasion ability of cancer cells was determined by a transwell model. RESULTS:The Bcl-xL expression was higher in cancerous tissue samples than in normal tissue samples (38.78 ± 11.36 vs 0.89 ± 0.35, P < 0.001), and was associated with the pathological grade, lymphnode metastasis and Duke’s stage of colorectal carcinoma. Transfection with Bcl-xL siRNA inhibited the colony formation and invasion ability of human colon cancer cell line HT29 in vitro. CONCLUSION:Bcl-xL gene plays an important role in carcinogenesis of human colorectal carcinoma and is associated with malignant biological behaviors of human colorectal carcinoma.

Expression of ornithine decarboxylase in precancerous and cancerous gastric lesions

AIM: To investigate the expression of ornithine decarboxylase (ODC) in precancerous and cancerous gastric lesions. METHODS: We studied the expression of ODC in gastric mucosa from patients with chronic superficial gastritis (CSG,n = 32),chronic atrophic gastritis CAG,n = 43; 15 with and 28 without intestinal metaplasia (IM),gastric dysplasia (DYS,n = 11) and gastric cancer (GC,n = 48) tissues using immunohistochemical staining. All 134 biopsy specimens of gastric mucosa were collected by gastroscopy. METHODS: The positive rate of ODC expression was 34.4%,42.9%,73.3%,81.8% and 91.7% in cases with CSG,CAG without IM,CAG with IM,DYS and GC,respectively (P < 0.01),The positive rate of ODC expression increased in the order of CSG < CAG (without IM) < CAG (with IM) < DYS and finally,GC. In addition,ODC positive immunostaining rate was lower in well-differentiated GC than in poorly-differentiated GC (P < 0.05). CONCLUSION: The expression of ODC is positively correlated with the degree of malignity of gastric mucosa and development of gastric lesions. This finding indicates that ODC may be used as a good biomarker in the screening and diagnosis of precancerous lesions.

Postoperative chemotherapy with S-1 plus oxaliplatin versus S-1alone in locally advanced gastric cancer(RESCUE-GC study): a protocol for a phase Ⅲ randomized controlled trial

Background： The ACTS-GC study had shown postoperative adiuvant therapy with S-1 improved survival of patients with locally advanced gastric cancer. Addition of oxaliplatin to S-1 is considered to be acceptable as one of the treatment options for gastric cancer patients after radical gastrectomy with D2 lymph node excision. Methods： We have commenced a randomized phase III trial in December 2016 to evaluate S-I plus oxaliplatin compared with S-1 alone in the adjuvant setting for locally advanced gastric cancer. A total of 564 patients will be accrued from 13 Chinese institutions in two years. The primary endpoint is 3-year relapse-free survival. The secondary endpoints are 5-year overall survival, proportion of patients who complete the postoperative chemotherapy and incidence of adverse events. Ethic and dissemination： The trial has been approved by the institutional review board of each participating institution and it was activated on December, 2016. The enrollment will be finished in December, 2018. Patient＇s follow-up will be ended until December, 2023. Trial registration： ClinicalTrials.gov, identifier： NCT02867839. Registered on August 4, 2016.

Comparison of efficacy and toxicity between gemcitabine plus cisplatin and plus carboplatin in first-line treatment of advanced non-small cell lung cancer

Objective: To compare the efficacy and toxicity between gemcitabine plus cisplatin and plus carboplatin in first-line treatment of advanced non-small cell lung cancer (NSCLC). Methods: Gemcitabine 1000 mg/m2 iv, d1, 8; cisplatin 75 mg/m2 iv, d1, or 25 mg/m2 iv, d1-3; carboplatin AUC = 5 iv, d1; repeated every 21 days. Results: All 76 cases were available for objective response. Gemcitabine + cisplatin (GCis) group: among 33 cases, CR 1 case, PR 13 cases, MR 3 cases, SD 7 cases, PD 9 cases, response rate, disease control rate, time to progress (TTP), median survival time (MST) and 1-, 2-year survival rates were 42.42% (14/33), 72.73% (24/33), 5 months, 14 months and 66.67% (22/33), 12.12% (4/33), respectively; Gemcitabine + carboplatin (GCarb) group: among 43 cases, PR 13 cases, MR 11 cases, SD 7 cases, PD 12 cases, the results while comparing with those of GCis group were 30.23% (13/43), 72.09% (31/43), 4 months, 11 months and 48.84% (21/43), 2.33% (1/43), respectively. Among them, only MST between the two groups had significant statistic difference (χ2 = 2.45, P = 0.017). Mild to modest myelo-suppression as well as nausea and vomiting were observed. Conclusion: Both GCis and GCarb regimens had active and well-tolerated toxicity for advanced NSCLC. Cisplatin-based chemotherapy yields a substantial effective advantage over carboplatin-based regimens. Therefore, carboplatin and cisplatin are not equal-active and that cisplatin-based doublet regimens should remain the standard first-line therapy for patients with advanced NSCLC with good performance status.

Analysis of Lymph Node Metastases of 1,526 Cases with Thoracic Esophageal and Cardiac Carcinomas: A Random Sampling Report froni the Fourth Hospital of Hebei Medical University from 1996 to 2004

OBJECTIVE To summarize the regular pattern and state oflymph node metastasis of patients with esophageal and cardiaccarcinomas,so as to analyze factors influencing lymph nodemetastasis.METHODS Clinical data collected from 1,526 thoracicesophageal and cardiac carcinoma patients who were admitted inthe Fourth Hospital of Hebei Medical University during a periodfrom January 1996 to December 2004,were randomly selectedand an Access Database of the patient's information was set up.Eight clinico-pathologic factors,including the patient's age,tumorlocation and size,pathological classification,the depth of tumorinvasion,vascular tumor embolus (VTE),the state of surroundingorgan encroachment and the status of tumor residues,wereidentified.A correlation between these factors and metastases wasstatistically analyzed using SPSS13.0 software.RESULTS Lymph node metastatic sites from esophagealcarcinomas included the thoracic and abdominal cavity.Lymphnode metastasis from the superior esophageal carcinomasmainly occurred in the neck and thoracic cavity.There was atwo-way lymph node metastasis in the patients with the middleesophageal carcinoma.The inferior esophageal carcinomas mainlymetastasized to the paraesophageal,paragastric cardia,and leftgastric artery lymph nodes.The rate and degree of the metastasisfrom the inferior esophageal carcinomas were significantly highercompared to those of the superior and the middle esophagealcarcinomas (P<0.0125).The degree of abdominal lymph node metastasis fromcarcinomas of the gastric cardia was significantly higher comparedwith that of esophageal carcinomas.In the group with carcinomaof the gastric cardia,the rate and degree of the lymph nodemetastases in the paragastric cardia and left gastric artery weresignificantly higher compared to the group with esophagealcarcinoma (P<0.05).Paraesophageal lymph node metastasis fromcarcinomas of the gastric cardia in the thoracic cavity frequentlyoccurred,too,and the degree of the metastasis was similar to thatof esophageal carcinoma.There was no significant difference inthe rate and degree of the paraesophageal lymph-node metastasisbetween the group with carcinoma of the gastric cardia comparedto those with esophageal carcinoma (P>0.05).Multifactoriallogistic regression analysis showed that the tumor size,depth oftumor encroachment,VTE,and tumor residues could all bringabout obvious impact on lymph-node metastases (P<0.05).CONCLUSION Lymph node metastasis from superioresophageal carcinomas mainly occurs in the neck and thoraciccavity.The middle esophageal carcinomas presented a two-waylymph-node metastasis (both the upwards and the downwards),and the lymph node metastasis from inferior esophagealcarcinomas mainly occurred in the thoracic and abdominal cavities.The metastases of carcinoma of the gastriccardia were most commonly found in the abdominalcavity,with frequent paraesophageal lymph-nodemetastasis.The sufficient attention should be paidto neck lymph node clearance in cases of esophagealcarcinoma.What is of the greatest concern is theclearance of the left gastric artery lymph nodes,andalso in cases of gastric cardia carcinoma,clearance,the paraesophageal lymph nodes.With an increasein the tumor size and depth of tumor encroachment,and occurrence of VTE and tumor residual cells,therisk of lymph node metastasis is significantly raised (P<0.05).

Prevalence of Family History of Cancer among Gastric Cancer Patients at Brazilian National Cancer Institute

Background: Gastric cancer is the third most incident malignancy and the fifth leading cause of death in the world. In Brazil, it is the fourth most common tumour in men and the fifth in women. Familial aggregation of this tumour is being studied and discussed by experts. Aim: Determine the frequency of family history of cancer in patients with gastric cancer, suggesting familial aggregation or increased risk for hereditary cancer syndromes. Methods: This is a retrospective cross-sectional study carried out from January 2011 to March 2015 at the Department of Abdominal and Pelvic Surgery of the Brazilian National Cancer Institute (INCA). Data were collected from electronic medical records and analyzed using SPSS Statistics? version 20. Results: 873 patients with gastric adenocarcinoma were analyzed. A family history of cancer was reported by 451 patients (51.6%), which reported cancer in 878 relatives, of which 110 (12.6%), reported having more than three relatives with any type of cancer. The most prevalent malignancies among these relatives were gastric cancer (21.3%) and breast cancer (9.5%). Conclusion: Most of the patients had cancer family history, being gastric cancer the most common. The high percentage of cancer family history confirms the importance of collecting this information, whose lack reflects professional negligence, as family history study can serve as a low-cost tool, favoring prevention and early diagnosis, situations where morbidity and mortality are smaller, thus reducing health costs and assistance and preserving lives.

MULTIVARIATE ANALYSIS OF BONE METASTASES IN BREAST CARCINOMA

Objective： To investigate the risk factors of bone metastases in breast carcinoma. Methods： By cross sectional study, the data of 225 breast cancer patients who were inpatients in four hospitals in Hangzhou were analyzed. All patients underwent total body bone scan with single photon emission computed tomography （SPECT） at least once during 1995 to 2000. Results： All patients were followed-up to 294 months after operation, bone metastases were found in 113 cases, suspected bone metastases 3 cases, with a bone metastases rate of 50.9% （113/222）. Multivariate analysis by Cox＇s proportional hazards regression model showed that there were four risk factors of bone metastases in breast cancer： （1） clinical stage, Ⅰ～Ⅳ stages with a hazard ratio of bone metastases of 1.945, 95% confidence interval 1.396～2.710; （2） number of invaded axillary lymph nodes, with a hazard ratio of 1.039, 95% confidence interval 1.0142～1.068; （3） skeletal complications （yes vs. no）, with a hazard ratio of bone metastases of 1.722, 95% confidence interval 1.060～2.796; （4） age at the time of surgery or diagnosis, with a hazard ratio of 2.048, 95% confidence interval 1.123～3.876 for patients of age 40～50 y versus patients bellow 40 y of age and 2.837, 95% confidence interval 1.473～5.465 for patients of age above 50 y versus patients of ages between 40 and 50. Kaplan-Meier curves showed that for patients with more than 5 invasive axillary lymph nodes, compared with those with 1～5, the bone metastasis rates increased significantly （x^2 =6.3319, P=0.012）. Conclusion： The clinical stage, number of metastatic axillary lymph nodes, age at the time of operation and skeletal complications are essential risk factors of bone metastases.

Nomogram for preoperative estimation of liver cirrhosis in hepatitis B virus-related hepatocellular carcinoma patients

Objective:The degree of liver cirrhosis is one of the most important diagnostic and prognostic assessments in chronic liver disease.Among the etiologies of liver cirrhosis,hepatitis B virus(HBV)infection-induced liver damage is most common in Asia-Pacific regions,particularly in China.Many current conventionally used preoperative estimation of liver cirrhosis models.

Role of the STAT3/survivin signaling pathway in the EML4-ALK-positive lung adenocarcinoma cell line H2228 before and after crizotinib-induced resistance

Objective This study investigated the role of the STAT3/survivin signaling pathway in the EML4-ALK- positive lung adenocarcinoma cell line H2228 before and after crizotinib-induced resistance. The mecha- nism of resistance was studied. Methods Cell viability was determined using the MTT assay. Crizotinib-induced apoptosis in H2228 and H2228 crizotinib-resistant cells treated with the indicated doses of crizotinib was measured at different times （24 h, 48 h, 72 h） using flow cytometry. The levels of p-ALK, ALK, p-STAT3, STAT3, and survivin after treatment of cells with 0, 0.3, and 1 pM crizotinib for 72 h were determined using Western blot analysis. DNA sequencing was used to identify mutations in H2228 crizotinib-resistant cells. Results The crizotinib IC50 values in H2228 and H2228 crizotinib-resistant cells at 72 h were 334.5 nM and 3418 nM, respectively. The resistance index of 1-12228 crizotinib-resistant cells was 10.20. Crizotinib induced apoptosis in H2228 cells and reduced the levels of p-ALK, p-STAT3, and survivin. In contrast, no changes in the levels of p-ALK, p-STAT3, and survivin were observed in H2228 crizotinib-resistant cells. The mutations 2067G--,A and 2182G--,C in EML4-ALK were present in the H2228 crizotinib-resistant cells. Conclusion Crizotinib decreased the viability of H2228 cells in a dose- and time-dependent manner. In the STAT3/survivin pathway, downregulation of p-ALK, p-STAT3, and survivin might contribute to crizo- tinib-induced apoptosis in H2228 ceils. However, the STAT3/survivin pathway in H2228 crizotinib-resistant cells was unaffected by crizotinib treatment. Acquired resistance in H2228 cells might be related to ALK mutations.

Informal caregivers'quality of life and management strategies following the transformation of their cancer caregiving role:A qualitative systematic review

Objectives:Globally,informal caregivers caring for cancer patients meet challenges within their caregiving role,which significantly influence their quality of life.This qualitative systematic review aimed to analyze how cancer caregiving influence the quality of life of informal caregivers and the management strategies of informal caregivers for their role as cancer caregivers.Methods:Following the enhancing transparency in reporting the synthesis of qualitative research(ENTREQ)statement,Wanfang database,the China National Knowledge Infrastructure(CNKI),CINAHL,MEDLINE,PubMed,Cochrane Library,PsycARTICLES and PsycINFO,and grey literature in English and Chinese from 1 May 2009 to 31 December 2019 were searched.Quality of included studies was assessed by the Critical Appraisal Skills Programme(2018)Qualitative Checklist and thematic synthesis was conducted.Results:Of the 8,945 studies identified,6 studies met the inclusion criteria.One analytical theme relating to the QoL of informal caregivers following cancer caregiving was identified:"challenges of caregiving".In terms of the management strategies to the role of cancer caregivers,two analytical themes were identified:"self-adjustment"and"seeking for formal and informal support".Conclusions:Cancer caregiving influences informal caregivers'QoL significantly and informal caregivers develop diverse coping strategies to deal with the difficulties occurred while balancing the relationship between their own lives and caregiving.However,professional and policy support remain inadequate for informal caregivers that require the need for improvement in terms of health care professionals and policymakers.

P53 Regulation of Leukemia Cells with the Blockage of MDM2 by Antisense Oligonucleotides

Summary： The changes of expression and function of MDM2 and P53 by MDM2 specific antisense oligonucleotides were investigated in HL60 cells. Cells were divided into control group, AS group （MDM2 specific antisense oligonucleotides group）, cisplatin group, and combined treatment group. FCM analysis and Western blot and RT-PCR were used to estimate apoptosis and the expression of MDM2 and P53. Our results showed that the transfection of MDM2 specific antisense oligonucleotides obviously inhibited MDM2 expression （P〈0.01） and increased the expression of P53 （P〈0.05）. Apoptosis rate were reduced by MDM2 specific antisense oligonucletides and cisplatin （P〈0.01）. It is concluded that MDM2 specific antisense oligonucletides can inhibit the expression of MDM2, induce the expression of P53 and increase the apoptosis of leukemia cells after chemotherapy.