Unraveling links between aging,circadian rhythm and cancer:Insights from evidence-based analysis

Aging and circadian rhythms have been connected for decades,but their molecular interaction has remained unknown,especially for cancers.In this situation,we summarized the current research actuality and problems in this field using the bibliometric analysis.Publications in the PubMed and Web of Science databases were retrieved.Overall,there is a rising trend in the publication volume regarding aging and circadian rhythms in the field of cancer.Researchers from USA,Germany,Italy,China and England have greater studies than others.Top three publication institutions are University of California System,UDICE-French Research Universities and University of Texas System.Current research hotspots include oxidative stress,breast cancer,melatonin,cell cycle,calorie restriction,prostate cancer and NF-κB.In conclusion,results generated by bibliometric analysis indicate that many approaches involve in the complex interactions between aging and circadian rhythm in cancer.These established and emerging research directions guide our exploration of the regulatory mechanisms of aging and circadian rhythms in cancer and provide a reference for developing new research avenues.

MUTAGENICITY AND CARCINOGENICITY OF FISH SAUCE FROM A COUNTY WITH THE HIGH RISK FOR GASTRIC CANCER IN CHINA

The mutagenicity and carcinogenicity of fish sauce (FS) sample from Changle County, a high gastric cancer mortality (113.20/105) area, were investigated with the biologic short-term tests and laboratory animal experiment. The results showed that the extract of FS was markedly direct mutagenic toward S. typhimurium TA100, induced high sister chromatid exchanges (SCE) and micronucleus (MN) in V79 cells after nitrosation with sodium nitrite. But the non-nitrosated FS did not. The nitrosated fish sauce (NFS) also induced SOS in E. coli PQ37 and alkylation of calfthymus DNA. The potency of NFS to induce unscheduled DNA synthesis (UDS) in human normal gastric mucosal cells was increased about fivefold compared with FS. When the NFS extract was given to newborn rats by gavage, dys-plasia and adenocaroinoma were induced in the glandular stomach in the 4th and 16th experimental week, respectively. N-nitrosamides were also found in NFS, which may account for the mutagenicity and carcinogenicity of NFS. It is indicated that FS, a traditional daily eaten seasoning, may contribute to the causes of the high gastric cancer mortality for the local residents.

Laparoscopy-assisted transanal total mesorectal excision for lower rectal cancer:A feasible and innovative technique

BACKGROUND Transanal total mesorectal excision(taTME)is a new technique with many potential technical advantages.Laparoscopy-assisted taTME is a combination of transabdominal taTME and transluminal endoscopic surgery taTME.Laparoscopy-assisted taTME is a combination of techniques such as minimally invasive surgery,intersphincter-assisted resection,natural orifice extraction,ta minimally invasive surgery,and ultralow-level preservation of the anus.AIM To verify the feasibility and safety of an innovative technique of taTME for treatment of cancer located in the lower rectum.METHODS From January 2016 to March 2018,we attempted to perform laparoscopy-assisted taTME surgery in 24 patients with lower rectal cancer.RESULTS The new technique of laparoscopy-assisted taTME was successfully performed in all 24 patients.Mean operating time was 310.0 min and mean intraoperative blood loss was 69.1 mL.The mean time to passing of first flatus was 3.1 d,and mean postoperative hospital stay was 9.2 d.Two patients were given postoperative analgesics due to anal pain.Twenty-three patients were able to walk in first 2 d,and five patients had postoperative complications.CONCLUSION Laparoscopy-assisted taTME is suitable for selected patients with lower rectal cancer,and this technique is worthy of further recommendation.

The bad and the good of mesenchymal stem cells in cancer: Boosters of tumor growth and vehicles for targeted delivery of anticancer agents

In cancer biology,mesenchymal stem cells(MSCs)display aspects that can appear contradictory.On one hand,these cells possess several features which give them the ability to specifically target and then sustain cancer cells in their ability to survive the multifaceted host response against cancer.On the other hand,due to this excellent aptitude to home-in on tumor tissues,regardless their location in the host’s body,MSCs are considered to be extremely selective vehicles to reach cancer cells specifically.Recently,MSC sustainment of cancer cell growth is a hot research topic.Indeed,these cells are known to sustain tumor angiogenesis and metastasis formation,to create a microenvironment favorable for cancer cell growth and to down-modulate the immune system capabilities in the host organism.On the other hand,since scientists became able to take advantage of their extremely selective capability to target cancer cells,MSCs are now also thought of in a different light.Indeed,MSCs are now considered a promising vehicle for local expression or delivery of even particularly toxic anticancer agents,ranging from Herpes Simplex Virus to locally-acting antineoplastic drugs.On this basis,investigation is now focused on how to impair the pro-neoplastic features of MSCs on one hand whilst taking advantage of their specific tropism toward cancer cells,on the other.As with the two faces of Janus,this review will concisely explore the research activity in these two apparently conflicting fields.

Targeting Enhancer of Zeste Homolog 2 as a promising strategy for cancer treatment

Polycomb group proteins represent a global silencing system involved in development regulation.In specific,they regulate the transition from proliferation to differentiation,contributing to stem-cell maintenance and inhibiting an inappropriate activation of differentiation programs.Enhancer of Zeste Homolog 2(EZH2) is the catalytic subunit of Polycomb repressive complex 2,which induces transcriptional inhibition through the tri-methylation of histone H3,an epigenetic change associated with gene silencing.EZH2 expression is high in precursor cells while its level decreases in differentiated cells.EZH2 is upregulated in various cancers with high levels associated with metastatic cancer and poor prognosis.Indeed,aberrant expression of EZH2 causes the inhibition of several tumor suppressors and differentiation genes,resulting in an uncontrolled proliferation and tumor formation.This editorial explores the role of Polycomb repressive complex 2 in cancer,focusing in particular on EZH2.The canonical function of EZH2 in gene silencing,the non-canonical activities as the methylation of other proteins and the role in gene transcriptional activation,were summarized.Moreover,mutations of EZH2,responsible for an increased methyltransferase activity in cancer,were recapitulated.Finally,various drugs able to inhibit EZH2 with different mechanism were described,specifically underscoring the effects in several cancers,in order to clarify the role of EZH2 and understand if EZH2 blockade could be a new strategy for developing specific therapies or a way to increase sensitivity of cancer cells to standard therapies.

Palliative Endoscopic Therapy for Cancer Patients with Esophageal Fistula

Objective： To find an effective treatment for advanced cancer patients with esophageal fistula. Methods： From 1998 to 2006, we studied 42 patients with advanced esophageal cancer and 5 lung cancer patients with carcinomatous esophageal fistula （3 females, 44 males, aged 29-92 years）. Ten patients with both esophageal cancer stricture and fistula were first dilated under endoscope, then a memory stent with a membrane was placed in the esophageal lumen. Others were treated only with a memory stent with a membrane, three of them with a large fistula （diameter 〉1.5 cm） were treated with bio-protein glue after placement of an esophageal metal stent. Results： The fistulas were covered by a stent and the patients could eat and drink immediately. Their quality of life was improved and their survival was prolonged, 44 out of 47 patients survived for 〉3 mo. Conclusion： Placement of esophageal stent with membrane or in combination with bio-protein glue through endoscope is an effective method for treating the bronchoesophageal fistula.

PROGNOSTIC FACTORS ANALYSIS FOR STAGEⅠ RECTAL CANCER

Objective: To explore the death-related factors of stageⅠrectal cancer patients. Methods: 89 cases of stage I rectal cancer patients between 1985 and 2000 were retrospectively studied for prognostic factors. Factors including age, gender, tumor size, circumferential occupation, gross type, pathological type, depth of tumor invasion, surgical procedure, adjuvant chemotherapy and postoperative complication were chosen for cox multivariate analysis (forward procedure) using Spss software (10.0 version). Results: multivariate analysis demonstrated that muscular invasion was an independent negative prognostic factor for stageⅠrectal cancer patients (P=0.003). Conclusion: Muscular invasion is a negative prognostic factor for stage I rectal cancer patients.

TUMOR UPTAKE AND THERAPEUTIC EFFECT OF ASTATINATED INTACT McAb 3H11 AND ITS Fab FRAGMENT FOR HUMAN GASTRIC CANCER XENOGRAFT IN NUDE MICE

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EPIDEMIOLOGICAL FEATURES FOR LUNG CANCER IN BEIJING

The epidemioiogical features of lung cancer in Beijing during 1977 ?1986 were analysed. The data collected showed that lung cancer ncidence and mortality rates ranks first among all other malignant tumor and had been on the increase from year to year. The mortality rate in urban area was higher than that in its suburbs. While the male incidence was higher than that of the female. The sex ratio of the male to female incidence rates was 1.56. The incidence rate rises with age. The lung cancer is one of the lesser prevised cancer and the five-year relative survival rate is 6.5% for both sexes in 19S2 ?1983. The lung cancer mortality rate in Beijing urban area is compared in this report with other countries in the world, and it is found that the female mortality rate of lung cancer in Beijing is among the highest.

Changing patterns of colorectal cancer in China over a period of 20 years

AIM： To determine whether any changes have occurred on the patterns of colorectal cancer in China. METHODS： Data from 21 Chinese articles published from 1980 to 1999, were used to analyze the time trend of colorectal cancer according to the patients＇age at diagnosis, sex, the site of the tumor, stage, and the pathology. RESULTS： From 1980s to 1990s, the mean age of the colorectal cancer patients has increased. The percentage of the female patients rose. The distribution of colorectal carcinoma shows a predominance of rectal cancer. However, the proportion of proximal colon cancer （induding transverse and ascending colon） increased significantly accompanied by a decline in the percentage of rectal cancer. Similarity in the percentage of distal colon cancer between two decades was revealed. In the 1990s, statistically more Stage B patients were found than those in 1980s. In addition, databases show a significant decrease in the Stage D cases. The proportion of adenocarcinoma increased, but the mucinous adenocarcinoma decreased during two decades. CONCLUSION： These findings indicate that the pattern of colorectal cancer in China has been changing. Especially, a proximal shift due to the increasing proportion of ascending and transverse colon cancer has occurred in China.

Therapeutic targeting of epidermal growth factor receptor in human cancer: successes and limitations

Epidermal growth fac tor receptor (EGFR) is one of the most commonly altered genes in human cancer by way of over-expression, amplification, and mutation. Targeted inhibition of EGFR activity suppresses signal transduction pathways which control tumor cell growth, proliferation, and resistance to apoptosis. Small molecule tyrosine kinase inhibitors and monoclonal antibodies are among the most common EGFR-targeting agents and have been used clinically for treating various malignancies. This review discusses the successes and challenges of targeting EGFR in human cancer. The genetic alterations of EGFR tend to occur more often in some solid tumors than others, as do the mechanisms of resistance to targeted inhibition. The clinical and basic science experiences with these agents thus far have important implications for the future of therapeutic targeting of EGFR.

Overcoming endocrine resistance in metastatic breast cancer: Current evidence and future directions

About 75% of all breast cancers are estrogen receptor(ER)-positive. They generally have a more favorable clinical behavior, prognosis, and pattern of recurrence, and endocrine therapy forms the backbone of treatment. Anti-estrogens(such as tamoxifen and fulvestrant) and aromatase inhibitors(such as anastrozole, letrozole, and exemestane) can effectively control the disease and induce tumor responses in a large proportion of patients. However, the majority of patients progress during endocrine therapy(acquired resistance) and a proportion of patients may fail to respond to initial therapy(de novo resistance). Endocrine resistance is therefore of clinical concern and there is great interest in strategies that delay or circumvent it. A deeper knowledge of the molecular mechanisms that drive endocrine resistance has recently led to development of new strategies that have the promise to effectivelyovercome it. Many resistance mechanisms have been described, and the crosstalk between ER and growth factor receptor signaling pathways seems to represent one of the most relevant. Compounds that are able to inhibit key elements of these pathways and restore endocrine sensitivity have been studied and more are currently under development. The aim of this review is to summarize the molecular pathophysiology of endocrine resistance in breast cancer and its impact on current clinical management.

Molecular mechanisms of metastasis in prostate cancer

Prostate cancer （PCa） preferentially metastasizes to the bone marrow stroma of the axial skeleton. This activity is the principal cause of PCa morbidity and mortality. The exact mechanism of PCa metastasis is currently unknown, although considerable progress has been made in determining the key players in this process. In this review, we present the current understanding of the molecular processes driving PCa metastasis to the bone.

Using induced pluripotent stem cells as a tool for modelling carcinogenesis

Cancer is a highly heterogeneous group of diseases that despite improved treatments remain prevalent accounting for over 14 million new cases and 8.2 million deaths per year. Studies into the process of carcinogenesis are limited by lack of appropriate models for the development and pathogenesis of the disease based on human tissues. Primary culture of patient samples can help but is difficult to grow for a number of tissues. A potential opportunity to overcome these barriers is based on the landmark study by Yamanaka which demonstrated the ability of four factors;Oct4, Sox2, Klf4, and c-Myc to reprogram human somatic cells in to pluripotency. These cells were termed induced pluripotent stem cells(i PSCs) and display characteristic properties of embryonic stem cells. This technique has a wide range of potential uses including disease modelling, drug testing and transplantation studies. Interestingly i PSCs also share a number of characteristics with cancer cells including self-renewal and proliferation, expression of stem cell markers and altered metabolism. Recently, i PSCs have been generated from a number of human cancer cell lines and primary tumour samples from a range of cancers in an attempt to recapitulate the development of cancer and interrogate the underlying mechanisms involved. This review will outline the similarities between the reprogramming process and carcinogenesis, and how these similarities have been exploited to generate i PSC models for a number of cancers.

Endoscopic mucosal resection for high-grade dysplasia and intramucosal carcinoma in Barrett's esophagus: An Italian experience

AIM： To evaluate endoscopic mucosal resection （EMR） in patients with high-grade dysplasia （HGD） and/or intramucosal cancer （IMC） in Barrett＇s esophagus （BE）. METHODS： Between June 2000 and December 2003, 39 consecutive patients with HGD （35） and/or IMC （4） underwent EMR. BE 〉30 mm was present in 27 patients. In three patients with short segment BE （25.0%）, HGD was detected in a normal appearing BE. Lesions had a mean diameter of 14.8＋10.3 ram. Mucosal resection was carried out using the cap method. RESULTS： The average size of resections was 19.7± 9.4×14.6＋8.2 mm. Histopathologic assessment postresection revealed 5 low-grade dysplasia （LGD） （12.8%）, 27 HGD （69.2%）, 2 IMC （5.1%）, and 5 SMC （-12.8%）. EMR changed the pre-treatment diagnosis in 10 patients （25.6%）. Three patients with SMC underwent surgery. Histology of the surgical specimen revealed 1 TON0 and 2 TIN0 lesions. The remaining two patients were cancer free at 32.5 and 45.6 mo, respectively. A metachronous lesion was detected after 25 mo in one patient with HGD. Intra-procedural bleeding, controlled at endoscopy, occurred in four patients （10.3%）. After a median follow-up of 34.9 mo, all patients remained in remission. CONCLUSION： In the medium term, EMR is effective and safe to treat HGD and/or IMC within BE and is a valuable staging method. It could become an alternative to surgery.

DIAGNOSTIC VALUE OF SERUM PROGRP31-98 IN PATIENTS WITH SMALL-CELL LUNG CANCER

Objective To explore the clinical significance of serum level of pro gastrin releasing peptide 31 98 (ProGRP31 98) for small cell lung cancer (SCLC), in comparison with neuron specific enolase (NSE). Methods Serum level of ProGRP31 98 and NSE was measured by ELISA respectively in 30 patients with SCLC, 30 with non small cell lung cancer (NSCLC), 15 with benign lung diseases and 15 normal subjects, additionally, 10 SCLC patients after having treatment with chemotherapy were included. The receiver operating characteristic (ROC) curve was used to set the cut off value and evaluate the diagnostic accuracy. Results The serum level of ProGRP31 98 was higher in patients with SCLC than that in other groups. The SCLC patients with extensive disease had a higher value than the patients with limited disease. In SCLC patients with distant metastases, it was also higher than in those without. Increase in serum ProGRP31 98 and NSE was both seen in SCLC patients, but for the former one, the increase was of much greater compared to the normal controls. Given the cut off value for ProGRP31 98 was 40ng·L -1 and for NSE 8μg·L -1 , their sensitivity of diagnosis in SCLC was 73% and 60%, respectively. The area under ROC curve of ProGRP31 98 was significantly larger than that of NSE. All patients responded to chemotherapy showed marked decrease in ProGRP31 98. Conclusion ProGRP31 98 is a more specific and sensitive marker than NSE in the diagnosis of SCLC.

Therapeutic resistance in cancer: microRNA regulation of EGFR signaling networks

Receptor tyrosine kinases(RTKs)such as the epidermal growth factor receptor(EGFR)regulate cellular homeostatic processes.EGFR activates downstream signaling cascades that promote tumor cell survival,proliferation and migration.Dysregulation of EGFR signaling as a consequence of overexpression,amplification and mutation of the EGFR gene occurs frequently in several types of cancers and many become dependent on EGFR signaling to maintain their malignant phenotypes.Consequently,concerted efforts have been mounted to develop therapeutic agents and strategies to effectively inhibit EGFR.However,limited therapeutic benefits to cancer patients have been derived from EGFR-targeted therapies.A well-documented obstacle to improved patient survival is the presence of EGFR-inhibitor resistant tumor cell variants within heterogeneous tumor cell masses.Here,we summarize the mechanisms by which tumors resist EGFR-targeted therapies and highlight the emerging role of microRNAs(miRs)as downstream effector molecules utilized by EGFR to promote tumor initiation,progression and that play a role in resistance to EGFR inhibitors.We also examine evidence supporting the utility of miRs as predictors of response to targeted therapies and novel therapeutic agents to circumvent EGFR-inhibitor resistance mechanisms.

The emerging role of probiotics in neurodegenerative diseases:new hope for Parkinson’s disease?

Neurodegenerative disease etiology is still unclear,but different contributing factors,such as lifestyle and genetic factors are involved.Altered components of the gut could play a key role in the gut-brain axis,which is a bidirectional system between the central nervous system and the enteric nervous system.Variations in the composition of the gut microbiota and its function between healthy people and patients have been reported for a variety of human disorders comprising metabolic,autoimmune,cancer,and,notably,neurodegenerative disorders.Diet can alter the microbiota composition,affecting the gutbrain axis function.Different nutraceutical interventions have been devoted to normalizing gut microbiome dysbiosis and to improving biological outcomes in neurological conditions,including the use of probiotics.Preclinical and clinical investigations discussed in this review strengthen the correlation between intestinal microbiota and brain and the concept that modifying the microbiome composition may improve brain neurochemistry,modulating different pathways.This review will discuss the potential use of probiotics for Parkinson’s disease prevention or treatment or as adjuvant therapy,confirming that gut microbiota modulation influences different pro-survival pathways.Future investigations in Parkinson’s disease should consider the role of the gut-brain axis and additional comprehension of the underlying mechanisms is extremely necessary.

RELATIONSHIP AMONG CEA EXPRESSION IN TUMOR, CEA SERUM LEVEL AND RADIOIMMUNOGUIDED SURGERY IN COLORECTAL CANCER

Objective: To research the relationship among CEA expression in tumor, CEA serum level and Radioimmunoguided Surgery (RIGS) in Colorectal Cancer. Methods: twenty-nine patients with colorectal cancer wer administered radiolabeled McAb CL58 submucosally via endoscope, and all underwent surgical intervention 3 to 14 days later. Intraoperative radioimmunodetection was performed using a portable gamma-detecting probe (GDP). The counts of tumors were obtained, and tumor-to-normal tissue (T/NT) ratio was calculated. The T/NT ratio of 3:1 was taken as the lowest threshold value of positiveness. Anti-CEA immunohistochemical for all the samples were performed. The CEA serum levels of all the patients before operations were also recorded. Results: The sensitivity for RIGS in detecting primary lesions was 93.1% (27/29). 28 patients (96.6%) had CEA expressions to a greater or less extent. 5 patients (17.2%) had elevated CEA serum. There was no correlation between the CEA serum levels and results of RIGS (P>0.5), and no correlation between the CEA serum levels and CEA expression in tumor (P>0.5). The CEA expression in tumor correlated significantly with the RIGS results (P<0.05). Conclusion: This study indicates that immunostaining can be used to select the patients as candidates who will benefit most from RIGS.

Carboxyl Terminus Truncated Human Papillomavirus Type 58 L1 Protein Maintains Its Bioactivity and Ability to Form Virus-like Particles

Summary: To prepare carboxyl terminus truncated human papillomavirus type 58 L1(HPV58L1) protein and evaluate its ability to form virus-like particles, the baculovirus and Sf-9 insect cells was used to express HPV58L1 protein, and pFastBac-Htb containing HPV58L1 gene sequence of carboxyl terminus truncation was generated. Then Sf-9 cells were infected with recombinant baculovirus. After being cultured, the post-infected cells expressing-HPV58L1 protein-were harvested and analyzed by SDS-PAGE and Western blot. The ProBond~TM purification system was used for protein purification. The bio-activity of purified protein was identified by mouse erythrocyte hemagglutination assay, and the VLP formation was examined with transmission electron microscope. Our results showed that the recombinant baculovirus was generated and the Sf-9 cells was infected with the recombinant baculovirus, and after collecting, total cellular proteins were extracted. Truncated HPV58L1 protein with MW 58KD was revealed by SDS-PAGE and confirmed by Western blot. The purified L1 proteins under native condition could cause mouse erythrocytes to agglutinate and form VLP. It is concluded that HPV58L1 protein with carboxyl terminus truncation could be efficiently expressed. In baculovirus Sf-9 cells expression system, the purified protein could self-assemble into virions in vitro, and induce agglutination of mouse erythrocytes, indicating that carboxyl terminus truncation does not interfere with the bioactivity of HPV58L1 protein.