Research Advances in the Role of Keratins in Gastrointestinal Cancer.

The incidence and mortality rates of gastrointestinal (GI) cancer remain high. Despite constant improvements in diagnostic and therapeutic techniques, the early diagnosis, mid- and late-stage treatment, drug tolerance, and cancer recurrence and metastasis in GI cancer remain challenging. In this review article we summarize the recent research advance in the roles of keratins in GI cancer, with the hope that they will become efficient biomarkers for the prediction, diagnosis, or treatment of these malignancies.

NUCKS1 promotes gastric cancer cell aggressiveness by upregulating IGF-1R and subsequently activating the PI3K/Akt/mTOR signaling pathway.

The effects of nuclear ubiquitous casein and cyclin-dependent kinase substrate 1 (NUCKS1) on tumor cells and the relevant mechanisms are less well defined. This study aimed to explore the role and mechanism of action of NUCKS1 in gastric cancer (GC) progression. The expression dynamics of NUCKS1 were examined using microarray-based immunohistochemistry (IHC) in a group of carcinomatous and adjacent non-tumor specimens. Various in vitro and in vivo assays were performed to clarify the function of NUCKS1 in GC and its underlying mechanisms. In our research, NUCKS1 overexpression was identified by IHC in 86/200 (43%) GC patients, was significantly related to the invasive phenotype of GC and was an indisputable predictor of shortened survival. Depleting NUCKS1 in GC cells significantly induced apoptosis and reduced cell proliferation and invasiveness in vitro and inhibited tumor growth in vivo. Additionally, ectopic overexpression of NUCKS1 in GC cells enhanced proliferation and invasion in vitro and promoted tumor growth in vivo. Importantly, PI3K/Akt/mTOR signaling pathway activity was inhibited upon downregulation of NUCKS1 expression and enhanced by ectopic overexpression of NUCKS1. Subsequently, the insulin-like growth factor 1 receptor (IGF-1R) gene was found to be a potential downstream target of NUCKS1 in GC cells, and knockdown of IGF-1R eliminated the augmentation of GC cell migration, invasion and proliferation as well as PI3K/Akt/mTOR signaling pathway activity by ectopic NUCKS1. The data suggested that NUCKS1 enhanced GC aggressiveness via the PI3K/Akt/mTOR signaling pathway in an IGF-1R-dependent manner. NUCKS1 or its respective signaling pathways could hold immense promise as potent anticancer targets for GC treatment.

[Immunotherapy of Gastrointestinal Stromal Tumors].

Gastrointestinal stromal tumors(GISTs)are the most common mesenchymal tumors of the gastrointestinal tract and respond poorly to conventional radiochemotherapy.Complete excision is the only possible way to cure GISTs.Although targeted therapy is effective for GISTs,multiple and/or secondary mutations of KIT or PDGFRA gene have lead to increased drug resistance and disease relapse.A variety of tumor infiltrating immune cells and complex immune microenvironments have been found in GISTs.Many immune cells participate in the occurrence and development of GISTs and play key roles in targeted therapy.The feasibility and effectiveness of immunotherapy for GISTs have been well demonstrated in preclinical and clinical studies.

[Predictive Factors of Early Weight Loss after Laparoscopic Sleeve Gastrectomy].

Objective To explore the clinical factors that can be used to predict the early weight loss after laparoscopic sleeve gastrectomy(LSG).Methods The clinical data of 64 obese patients undergoing LSG in Peking Union Medical College Hospital from August 2015 to January 2018 were retrospectively analyzed.We analyzed the relationship between different clinical factors and early weight loss,determined the independent predictors based on Logistic models,and estimated their test power by using the receiver operating characteristic(ROC)curves.Results Correlation analysis indicated that preoperative body mass index(P=0.000,P=0.000,P=0.000),waist circumference(WC)(P=0.000,P=0.000,P=0.000),whole body fat volume(P=0.000,P=0.006,P=0.003),homeostatic model assessment for insulin resistance(HOMA-IR)(P=0.000,P=0.000,P=0.002),and hypersensitive C-reactive protein(hsCRP)(P=0.004,P=0.002,P=0.025)were negatively correlated with excess weight loss percentage(EWL %) after 3,6 and 12 months.Also,hsCRP after 6 months showed negative correlation with EWL % after 1 year(P=0.029).Binary Logistic regression analysis showed that WC was an independent predictor of early weight loss(P=0.018).ROC analysis showed that when the optimal cutoff value is 142.5 cm for WC,Youden index was highest,with a sensitivity of 80% and a specificity of 87%.Patients were further divided into low WC group and high WC group based on this optimal cutoff value.The low WC group had significantly higher EWL% than the high WC group 3 months(t=6.677,P=0.000),6 months(t=6.157,P=0.000),and 1 year(t=4.006,P=0.000)after surgery.The low WC group also had significantly lower hsCRP than high WC group 6 months after surgery(z=-3.510,P=0.000).HOMA-IR showed no significant difference between these two groups(z=-0.821,P=0.412).Conclusions WC is an independent predictor of weight loss early after LSG.The patients with low WC have better weight loss effectiveness.

[History, Recent Advancements, and Prospects in Bariatric/Metabolic Surgery].

Bariatric/metabolic surgery is the most effective method to treat morbid obesity and its complications. Tracing its origin back to jejunoileal bypass in 1950s, bariatric/metabolic surgery has been continuously improved after more than 60 years of development. At present, the mainstream surgical procedures include sleeve gastrectomy, Roux-en-Y gastric bypass, biliopancreatic diversion/duodenal switch, and mini gastric bypass. In addition, new procedures such as single-anastomosis duodenal switch, duodenal-jejunal bypass with sleeve gastrectomy, laparoscopic greater curvature plication and endoscopic surgeries have been developed. This article reviews the history, status quo, and prospects of bariatric/metabolic surgery.

[Relationship between Depression and Quality of Life in Patients with Severe Obesity].

Objective To investigate the depression status and quality of life (QoL) of patients with severe obesity who have undergone bariatric surgery and to evaluate their potential correlation.Methods A total of 50 patients with severe obesity who had undergone elective bariatric surgery in the general surgical ward of Peking Union Medical College from January 2013 to December 2017 were enrolled in this study. The general data were collected. The patient's depression status and QoL were assessed by the Zung's Depression Self-Assessment Scale and the SF-36 Quality of Life Scale,respectively.Results The depression score was (44.85±9.07) scores in these 50 patients,including 38 patients (76%) without depression and 12 (24%) with mild depression. The scores of the mental-emotional,physical,psychomotor,and psychological barrier dimensions of patients with severe obesity were (3.70±1.25),(18.65±4.10),(4.25±1.35),and (18.75±5.46)scores,respectively. The physiological function score of patients with mild depression was (95.83±10.21)scores,which was significantly higher than those without depression (68.42±38.95) scores(F=6.209,P=0.011). The vitality and mental health scores were (46.67±14.72) and (57.33±14.68) scores in patients with mild depression,which were significantly lower than those [(65.79±21.94) (F=4.867,P=0.030) and (75.16±17.21) scores (F=0.212,P=0.032)] in patients without depression. Correlation analysis showed that the mental-emotional score was positively correlated with physical score in patients with severe obesity (r=0.503,P=0.015),whereas the depression score was negatively correlated with the general health status (r=-0.430,P=0.032),vitality (r=-0.594,P=0.002),social functioning (r=-0.455,P=0.022),mental health (r=-0.562,P=0.003),and QoL score (r=-0.439,P=0.028).Conclusions The QoL is remarkably affected by depression in patients with severe obesity before surgery. Assessment of the mental status of patients with severe obesity may help to identify this problem and thus improve the QoL.

[Effectiveness of Laparoscopic Sleeve Gastrectomy in Treating Obesity and Its Co-morbidities].

Objective To analyze the effectiveness and safety of laparoscopic sleeve gastrectomy (LSG) in treating obesity and its co-morbidities.Methods The clinical data of obese patients undergoing LSG in Peking Union Medical College Hospital from August 2012 to August 2017 were retrospectively analyzed. Medium-term outcome measures included excess weight loss (%EWL),co-morbidity improvement,and complications.Results Seventy-five obese patients comprising 28 men[ body mass index(BMI):(47.3±7.5)kg/m 2) ] and 47 women [BMI (41.1±7.0) kg/m 2] were enrolled in this analysis. The common co-morbidities were liver dysfunction (53.3%),dyslipidemia (52.0%),obstructive sleep apnea (45.3%),type 2 diabetes mellitus (38.7%),and arterial hypertension (37.3%),which were improved by 75.0%,58.3%,83.3%,75.0% and 58.3% three years after surgery. The mean %EWL at 1,2,and 3 years after surgery was 81.6±34.7,80.9±30.2 and 79.7±30.8,respectively. The proportions of patients achieving successful weight loss were 81.7% (n=49),81.0% (n=34),and 79.3% (n=23) at 1,2,and 3 years (%EWL>50%). Early severe complications (Clavien-Dindo classification>2) occurred in 2.6% of patients,and the most common late complications was gastroesophageal reflux disease,which could be relieved by acid suppressants.Conclusion LSG is effective and safe in treating obesity and its co-morbidities.

Effect of Neoadjuvant Chemotherapy Treatment on Prognosis of Patients with Advanced Gastric Cancer: a Retrospective Study.

OBJECTIVE: To evaluate the prognostic effects of neoadjuvant chemotherapy (NAC) in patients with local advanced gastric cancer. METHODS: We retrospectively analyzed prognosis in 191 patients with advanced gastric cancer, of whom 71 were treated with NAC and 120 received surgery only between February 2007 and July 2013. Postoperative complication rate was recorded. Survival by clinicopathological features, pathological T and N stages, and histopathological tumor regression was retrospectively compared between the two groups. RESULTS: According to Response Evaluation Criteria in Solid Tumors, none of the 71 patients in the NAC followed by surgery group showed complete response, 36 showed partial response, 25 had stable disease, and 10 had progressive disease. The chemotherapy response rate was 50.7%; the disease control rate was 85.9%. Grade 3/4 adverse events were seen in less than 20% patients, with acceptable toxicities. No difference was found in the overall postoperative complication rates between the two groups (7 versus 22 cases, P=0.18). Median survival time was significantly different, at 54 months in the NAC combined with surgery group and 25 months in the surgery-only group (P=0.025). CONCLUSION: In patients with operable gastric adenocarcinomas, NAC can significantly improve overall survival without increasing surgical complications.

[Surgical Diagnosis and Treatment of Primary Hyperthyroidism Complicated with Occult Thyroid Carcinoma].

OBJECTIVE: To evaluate the surgical diagnosis and treatment of primary hyperthyroidism complicated with occult thyroid carcinoma. METHOD: Data of 51 cases of primary hyperthyroidism complicated with occult thyroid carcinoma admitted during January 2004 to November 2014 were analyzed retrospectively. RESULTS: The incidence of occult thyroid carcinoma was 5.03% in hyperthyroidism,and 47 cases (92.16%) were female. The preoperative diagnosis of all these 51 cases was primary hyperthyroidism and 11 cases were diagnosed thyroid carcinoma at the same time;25 cases were diagnosed thyroid carcinoma by frozen section and the remaining 26 cases were diagnosed by postoperative pathology. Finally,26 cases underwent subtotal thyroidectomy,4 cases underwent total thyroidectomy, and 21 cases underwent total thyroidectomy with lymphadenectomy. The tumor size ranged from 0.1 to 1.0 cm [mean:(0.63 ± 0.35) cm]. The lesions were less than or equal to 0.5 cm in 28 cases (54.9%). The follow-up lasted from 1 to 121 months [mean:(28.6 ± 22.7)months] in 43 patients,and all of them survived. CONCLUSIONS: Primary hyperthyroidism complicated with occult thyroid carcinoma is commonly found in female patients. Preoperative diagnosis is difficult. Ultrasound is the major examining method. Frozen section can increase the detection rate. The postoperative prognosis of hyperthyroidism complicated with occult thyroid carcinoma is satisfactory.

[Effect of n-3 polyunsaturated fatty acids on gut microbiota and endotoxin levels in portal vein of rats fed with high-fat diet].

OBJECTIVE: To investigate the effect of n-3 polyunsaturated fatty acids (n-3PUFAs) on gut microbiota and endotoxin levels in portal vein of rats fed with a high-fat diet (HFD). METHODS: Thirty-six male Sprague-Dawley rats were randomly divided into four groups and fed with normal control diet (CD), HFD, CD supplemented with n-3PUFAs, and HFD supplemented with n-3PUFAs, respectively. Fresh fecal samples were collected to analyze the gut microbiota 10 weeks after feeding. DNA was exacted from the fresh fecal samples. Quantitative PCR was used to detect the composition of the gut microbiota. The endotoxin levels were detected through modified azo chromogenic substrate limulus amebocyte lysate assay. RESULTS: The differences in body weight before breeding in each group were not statistically significant among these four groups (P=0.613). The increase in the body weight was significantly larger in the HFD group than in the CD group (P=0.0002), CD+n-3PUFAs group (P=0.0001), and HFD+n-3PUFAs group (P=0.022). There were significantly more firmicutes (P=0.002) and enterobacteriales (P=0.022) and significantly less bacteroidetes (P=0.026) and bifidobactera (P=0.034) in the gut of rats from HFD group than those from the CD group. There were significantly more bacteroidetes in the fecal samples of the rats from the CD+n-3PUFAs group compared to those from the CD group (P=0.043). There were significantly more firmicutes (P=0.044)and enterobacteriales (P=0.012) and less bacteroidetes (P=0.042) in the fecal samples of the rats from HFD group compared to those from the HFD+n-3PUFAs group. The endotoxin in plasma form portal vein of rats in HFD group were significantly higher than in CD group (P=0.007) and HFD+n-3PUFAs group (P=0.042) but showed no significant difference between CD+n-3PUFAs and CD group (P=0.210). CONCLUSIONS: HFD can increase body weight and change gut microbiota. Supplementation of n-3PUFAs can partially counteract such gut dysbiosis, lower endotoxin level in portal vein blood, and improve the body weight.

[MicroRNA and gastric cancer].

Gastric cancer is caused by the interaction of genetic and environmental factors. MicroRNA (miRNA) is involved in many cellular processes including proliferation, differentiation, and apoptosis and plays an important role in pathogenesis of gastric cancer, as demonstrated in many recent studies from perspectives including miRNA profiling, reciprocal modulation between epigenetic and miRNA, and Helicobacter pylori infection. MiRNA is highly stabe in blood, and therefore non-invasive diagnosis of gastric cancer using circulating miRNA may be promising.

[Effects of eukaryotic translation initiation factor 5A2 down-regulation by small interfering RNA on aggressiveness of MKN28 human].

OBJECTIVE: To investigate the effects of eukaryotic translation initiation factor 5A2 (EIF5A2) down-regulation by small interfering RNA (siRNA) on aggressiveness of human gastric cancer cell and its potential mechanisms. METHODS: The expressions of EIF5A2 in human gastric cancer cell lines (MKN28 and HGC27) and immortalized gastric mucosal epithelial cells (GES-1) were measured by real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blotting. EIF5A2 gene in MKN28 cells was silenced by RNA interference and the inhibitory effect was evaluated by both qRT-PCR and Western blotting. Cell proliferation was assessed by CCK-8 assay. Cell migration and invasion were assessed by Transwell assay. The possible downstream targets of EIF5A2, such as CyclinD1, CyclinD3, matrix metallopeptidase-9 (MMP-9), E-cadherin, vimintin, C-myc, and metastasis-associated protein 1 (MTA1) expression levels, were examined by Western blotting. RESULTS: High expressions of EIF5A2 were found in MKN28 cells and human gastric adenocarcinoma tissues. Both EIF5A2 mRNA and protein expression in MKN28 cells were significantly down-regulated by siRNA#1 and siRNA#2, especially siRNA#1. Knockdown of EIF5A2 caused an apparent suppression of MKN28 cell proliferation (all P<0.01), migration (P<0.001), and invasion (P<0.001). After the knockdown of EIF5A2 in MKN28 cells, E-cadherin levels were upregulated, whereas vimentin, Cyclin D1, Cyclin D3, C-myc and MTA1 levels were downregulated. CONCLUSION: Knockdown of EIF5A2 may inhibit MKN28 cell proliferation by downregulating the CyclinD1 and CyclinD3 and suppressing the cell migration and invasion by inhibiting MTA1, C-myc and epithelial-mesenchymal transition.

[Iodine nutrition and thyroid diseases].

Iodine, an essential component of the hormones produced by the thyroid gland, is widely but unevenly distributed in the earth's environment. Great difference exists in the iodine nutritional status of populations residing in different region. Both iodine deficiency and iodine excess can injure the thyroid gland. Iodine deficiency tigers endemic goiter, cretinism, and hyperthyroidism, while iodine excess can result in high iodine goiter, chronic lymphocytic thyroiditis, iodine-induced hyperthyroidism, and hypothyroidism; also, iodine deficiency or excess may affect the histological type of thyroid cancer. In 1996, China began to implement the universal salt iodization policy, which has basically eliminated the iodine deficiency disorders nationwide; however, it also caused the changes in the spectra of other thyroid diseases including iodine-induced hyperthyroidism, autoimmune thyroid disease, and papillary thyroid carcinoma. Individualized iodine nutritional status assessment for the populations, particularly those with thyroid diseases, will be beneficial.

[Surgical therapy of thyroid cancer].

The prevalence of thyroid cancer has shown an upward trend in China in recent years. Advances in thyroid ultrasound and fine needle puncture cytology have improved the accuracy of the preoperative diagnosis of thyroid cancer. Also,the application of endoscopy-assisted techniques and intraoperative nerve monitoring technology and the further understanding of thyroid lymph node metastasis have made the thyroid surgeries safer and less invasive. This article summarizes the recent advances in the surgical therapy of thyroid cancer.

[Research advances in the gut microbiota and inflammation in obesity].

Human gut microbiota plays a key role in the development of obesity. Intestinal flora can regulate energy absorption and nutrition metabolism, increasing the energy harvesting from diet. Alteration of gut flora produces excessive lipopolysaccharide, which, when absorbed into the blood, can induce inflammatory reactions and promote the high-fat diet-associated obesity and metabolic syndrome. Intestinal flora increase visceral fat deposition by lowering the expression of Fiaf in intestinal mucosa. Different immune status also affects the intestinal flora.The gut microbiota is hypothesized to be an environmental factor that contributes to obesity; by interacting with factors such as host and diet, it adjusts the energy metabolism. Antibiotics or probiotics may alter the composition of intestinal microflora and improve the metabolic syndrome, and thus provides new treatment options.

[Retrospective analysis of clinical data of patients received thyroid surgery in Peking Union Medical College Hospital from 1986 to 2012].

OBJECTIVE: To study the changes in the constituent ratio of patients received surgical therapy for their thyroid diseases in Peking Union Medical College Hospital from 1986 to 2012. METHODS: The clinical data of patients received surgical therapy with pathologically confirmed findings from 1986 to 2012 were collected, and a corresponding database was established. The constituent ratios of thyroid diseases and thyroid malignant tumor among different population groups in different years were analyzed. RESULTS: The number of patients with thyroid diseases admitted to our hospital had significantly increased in the past 27 years, particularly those with nodular goiter or thyroid cancer. The composition ratios of thyroid cancer and nodular goiter increased significantly, and among malignancies the papillary thyroid carcinoma increased obviously. The detection rate of papillary thyroid micro-carcinoma had continuously increased since 2008. CONCLUSION: Thyroid diseases and malignant tumor pathological types had dramatically changed in hospitalized patients in our hospital in the past 27 years.

[Effect of enteral nutrition via jejunostomy catheter on quality of life in gastric cancer patients who have undergone gastrectomy].

OBJECTIVE: To study the effect of enteral nutrition via jejunostomy catheter on the quality of life in gastric cancer patients who have undergone gastrectomy. METHODS: We retrospectively analyzed clinical data of 104 consecutive patients who had undergone curative resection for gastric cancer in Peking Union Medical College Hospital in 2011.All data were obtained from a prospectively maintained database of gastric cancer.The quality of life was compared between jejunostomy tube group(n=49)and tube-free group(n=55). RESULTS: The two groups were matched in gender,age,tumor size,tumor location,histological type,pTNM stage,type of surgery,body mass index(BMI),quality of life scales,and cycles of postoperative adjuvant chemotherapy(all P>0.05).Also,the global health status(P=0.154),physical function score(P=0.321),role function score(P=0.492),and fatigue symptom score(P=0.845)were not significantly different between these two groups one month after surgery.Three and 6 months after the surgery,patients in the jejunostomy tube group had significantly higher overall health status scores( P<0.001,P=0.038),physical function scores(P=0.004,P=0.005),and role function scores(P=0.002,P=0.038)and significantly lower fatigue symptom scores(P=0.020,P=0.043)when compared to patients from tube-free group. CONCLUSION: Enteral nutrition via jejunostomy catheter can improve the quality of life of gastric cancer patients who have undergone gastrectomy.

[Research advances in molecular pathogenesis of thyroid cancer].

Thyroid cancer is the one of the most common endocrine tumors. The biological behaviors and prognoses of the thyroid cancer of different histological types remarkably differ. The highly invasive thyroid cancer responds poorly to traditional therapies. Recent research advances in the molecular mechanisms of the pathogenesis of thyroid cancer have revealed the roles of many genetic and epigenetic variations such as gene mutation, abnormal gene amplification, and abnormal gene methylation in the development of thyroid cancer, which provides new insights in the molecular diagnosis, prognosis, and target therapy of the thyroid cancer.

[Expression of doublecortin-like kinase 1 in human gastric cancer and its correlation with prognosis].

OBJECTIVE: To investigate the expression of doublecortin-like kinase 1(DCLK1)in gastric cancer and its prognostic significance. METHODS: The expression of DCLK1 was examined by immunohistochemical staining of paraffin-embedded tumor specimens from 122 patients who underwent curative gastrectomy for gastric cancer at Peking Union Medical College Hospital between July 2002 and December 2006. Survival curves were described by the Kaplan-Meier method and compared by the Log-rank test. Univariate and multivariate analysis was performed with the Cox proportional hazard model. RESULTS: The expression of DCLK1 in tumor cells was significantly upregulated in 51 of 122 patients. High expression of DCLK1 in tumor cells was strongly correlated with pN stage(P=0.029)and lymphovascular invasion(P=0.029). Kaplan-Meier analysis revealed that patients with DCLK1 high expression had a significantly lower 5-year overall survival(OS)rate than that of patients with DCLK1 low expression(39. 0% vs. 65. 8%, P=0.001), as well as a significantly lower 5-year disease-free survival(DFS)rate(37. 0% vs. 64. 5%, P=0.001). Univariate and multivariate analyses showed that DCLK1 expression(both P=0.036)was an independent factor for predicting OS and DFS rate. CONCLUSIONS: High expression of DCLK1 in gastric cancer cells is associated with pN stage and lymphovascular invasion. It may be a predictor for poor survival in patients undergoing surgery for gastric cancer.

The predictive effect of cadherin-17 on lymph node micrometastasis in pN0 gastric cancer.

BACKGROUND: Previous studies identified cadherin-17 (CDH17) as one of the most upregulated genes in node-positive gastric cancer. However, the prognostic significance of CDH17 in pN0 gastric cancer and its association with lymph node micrometastasis (LNMM) have not been investigated. METHODS: Clinicopathologic features of 191 patients with node-negative gastric cancer were studied retrospectively. All dissected lymph nodes were immunostained by cytokeratin to detect micrometastasis. CDH17 and lymphatic invasion (LVI) in primary carcinoma were evaluated by immunostaining of monoclonal CDH17 and D2-40 antibody. Correlation of CDH17 with clinicopathologic characteristics was subsequently assessed. Risk factors of LNMM were analyzed by univariate and multivariate logistic regression. Cox's proportional hazard model was applied to investigate independent prognostic factors of pN0 gastric cancer. Overall survival rates of patients with positive and negative CDH17 were compared, stratifying by pT stage, Lauren grade, and LNMM status. RESULTS: CDH17 was observed in 126 patients (66.0%). Positive expression of CDH17 was significantly associated with the age, tumor size, pT, Lauren grade, LVI, and LNMM, and identified as one of the independent risk factors of LNMM. Negative predictors of pN0 gastric cancer included pT, Lauren grade, LNMM, and CDH17. Furthermore, in tumors of pT2-3, intestinal histotype, and negative-LNMM, the survival rate of patients with CDH17 was significantly lower than that of patients without CDH17. CONCLUSIONS: CDH17 was positively associated with larger tumor size, deeper invasion, diffuse/mixed histotype, LVI, and LNMM, predicting a poor prognosis in pN0 gastric cancer. Additionally, CDH17 may also serve as a potential indicator of LNMM.