Symptomatic cholelithiasis patients have an increased risk of pancreatic cancer: A population-based study.

BACKGROUND AND AIM: Pancreatic cancer is a fatal disease; currently, the risk factor survey is not suitable for sporadic pancreatic cancer, which has neither family history nor the genetic analysis data. The aim of the present study was to evaluate the roles of cholelithiasis and cholelithiasis treatments on pancreatic cancer risk. METHODS: Symptomatic adult patients with an index admission of cholelithiasis were selected from one million random samples obtained between January 2005 and December 2009. The control group was matched with a 1:1 ratio for sex, age, chronic pancreatitis, and pancreatic cystic disease. Subsequent pancreatic cancer, which we defined as pancreatic cancer that occurred ≥ 6 months later, and total pancreatic cancer events were calculated in the cholelithiasis and control groups. The cholelithiasis group was further divided into endoscopic sphincterotomy/endoscopic papillary balloon dilatation, cholecystectomy, endoscopic sphincterotomy/endoscopic papillary balloon dilatation and cholecystectomy, and no-intervention groups for evaluation. RESULTS: The cholelithiasis group and the matched control group included 8265 adults. The cholelithiasis group contained 86 cases of diagnosed pancreatic cancer, and the control group contained 8 cases (P < 0.001). The incidence rate ratio (IRR) of subsequent pancreatic cancer was significantly higher in the cholelithiasis group than in the control group (IRR: 5.28, P < 0.001). The IRR of subsequent pancreatic cancer was higher in the no-intervention group comparing with cholecystectomy group (IRR = 3.21, P = 0.039) but was similar in other management subgroups. CONCLUSION: Symptomatic cholelithiasis is a risk factor for pancreatic cancer; the risk is similar regardless of the intervention chosen for cholelithiasis.

Cholecystectomy reduces subsequent cholangiocarcinoma risk in choledocholithiasis patients undergoing endoscopic intervention.

BACKGROUND: Cholangiocarcinoma is a disease with a high mortality rate. Our previous study revealed that cholelithiasis patients who undergo endoscopic sphincterotomy (ES)/endoscopic papillary balloon dilatation are at a higher risk for subsequent cholangiocarcinoma than cholelithiasis patients who undergo cholecystectomy. AIM: To clarify the relationship between recurrent biliary events and subsequent cholangiocarcinoma risk in choledocholithiasis patients. METHODS: From one million random cases in the Taiwan National Health Insurance Research Database 2004-2011, we selected symptomatic choledocholithiasis patients older than 18 years who were admitted from January 2005 to December 2009 (study group). Cases for a control group were defined as individuals who had never been diagnosed with cholelithiasis, matched by sex and age in a 1:3 ratio. The study group was further divided into ES/endoscopic papillary balloon dilatation, both ES/endoscopic papillary balloon dilatation and cholecystectomy, and no intervention groups. RESULTS: We included 2096 choledocholithiasis patients without previous intervention or cholangiocarcinoma. A total of 12 (2.35%), 11 (0.74%), and 1 (1.00%) subsequent cholangiocarcinoma cases were diagnosed among 511 ES/endoscopic papillary balloon dilatation patients, 1485 patients with no intervention, and 100 ES/endoscopic papillary balloon dilatation and cholecystectomy patients, respectively. The incidence rates of recurrent biliary event were 527.79/1000 person-years and 286.69/1000 person-years in the subsequent cholangiocarcinoma and no cholangiocarcinoma group, showing a high correlation between subsequent cholangiocarcinoma risk and recurrent biliary events. CONCLUSION: Choledocholithiasis patients who undergo further cholecystectomy after ES/endoscopic papillary balloon dilatation have decreased subsequent cholangiocarcinoma risk due to reduced recurrent biliary events.

Favorable gallbladder cancer mortality-to-incidence ratios of countries with good ranking of world's health system and high expenditures on health.

BACKGROUND: The mortality-to-incidence ratio (MIR) is a marker that reflects the clinical outcome of cancer treatment. MIR as a prognostic marker is more accessible when compared with long-term follow-up survival surveys. Theoretically, countries with good health care systems would have favorable outcomes for cancer; however, no report has yet demonstrated an association between gallbladder cancer MIR and the World's Health System ranking. METHODS: We used linear regression to analyze the correlation of MIRs with the World Health Organization (WHO) rankings and total expenditures on health/gross domestic product (e/GDP) in 57 countries selected according to the data quality. RESULTS: The results showed high crude rates of incidence/mortality but low MIR in more developed regions. Among continents, Europe had the highest crude rates of incidence/mortality, whereas the highest age-standardized rates (ASR) of incidence/mortality were in Asia. The MIR was lowest in North America and highest in Africa (0.40 and 1.00, respectively). Furthermore, favorable MIRs were correlated with good WHO rankings and high e/GDP (p = 0.01 and p = 0.030, respectively). CONCLUSIONS: The MIR variation for gallbladder cancer is therefore associated with the ranking of the health system and the expenditure on health.

Enterotype-based Analysis of Gut Microbiota along the Conventional Adenoma-Carcinoma Colorectal Cancer Pathway.

The dysbiosis of human gut microbiota is strongly associated with the development of colorectal cancer (CRC). The dysbiotic features of the transition from advanced polyp to early-stage CRC are largely unknown. We performed a 16S rRNA gene sequencing and enterotype-based gut microbiota analysis study. In addition to Bacteroides- and Prevotella-dominated enterotypes, we identified an Escherichia-dominated enterotype. We found that the dysbiotic features of CRC were dissimilar in overall samples and especially Escherichia-dominated enterotype. Besides a higher abundance of Fusobacterium, Enterococcus, and Aeromonas in all CRC faecal microbiota, we found that the most notable characteristic of CRC faecal microbiota was a decreased abundance of potential beneficial butyrate-producing bacteria. Notably, Oscillospira was depleted in the transition from advanced adenoma to stage 0 CRC, whereas Haemophilus was depleted in the transition from stage 0 to early-stage CRC. We further identified 7 different CAGs by analysing bacterial clusters. The abundance of microbiota in cluster 3 significantly increased in the CRC group, whereas that of cluster 5 decreased. The abundance of both cluster 5 and cluster 7 decreased in the Escherichia-dominated enterotype of the CRC group. We present the first enterotype-based faecal microbiota analysis. The gut microbiota of colorectal neoplasms can be influenced by its enterotype.

Pattern formation of skin cancers: Effects of cancer proliferation and hydrodynamic interactions.

We study pattern formation of skin cancers by means of numerical simulation of a binary system consisting of cancer and healthy cells. We extend the conventional model H for macrophase separations by considering a logistic growth of cancer cells and also a mechanical friction between dermis and epidermis. Importantly, our model exhibits a microphase separation due to the proliferation of cancer cells. By numerically solving the time evolution equations of the cancer composition and its velocity, we show that the phase separation kinetics strongly depends on the cell proliferation rate as well as on the strength of hydrodynamic interactions. A steady-state diagram of cancer patterns is established in terms of these two dynamical parameters and some of the patterns correspond to clinically observed cancer patterns. Furthermore, we examine in detail the time evolution of the average composition of cancer cells and the characteristic length of the microstructures. Our results demonstrate that different sequence of cancer patterns can be obtained by changing the proliferation rate and/or hydrodynamic interactions.

Risk of cholangiocarcinoma in patients undergoing therapeutic endoscopic retrograde cholangiopancreatography or cholecystectomy: A population based study.

BACKGROUND: Cholangiocarcinoma is a highly lethal disease that had been underestimated in the past two decades. Many risk factors are well documented for in cholangiocarcinoma, but the impacts of advanced biliary interventions, like endoscopic sphincterotomy (ES), endoscopic papillary balloon dilatation (EPBD), and cholecystectomy, are inconsistent in the previous literature. AIM: To clarify the risks of cholangiocarcinoma after ES/EPBD, cholecystectomy or no intervention for cholelithiasis using the National Health Insurance Research Database (NHIRD). METHODS: From data of NHIRD 2004-2011 in Taiwan, we selected 7938 cholelithiasis cases as well as 23814 control group cases (matched by sex and age in a 1:3 ratio). We compared the previous risk factors of cholangiocarcinoma and cholangiocarcinoma rate in the cholelithiasis and control groups. The incidences of total and subsequent cholangiocarcinoma were calculated in ES/EPBD patients, cholecystectomy patients, cholelithiasis patients without intervention, and groups from the normal population. RESULTS: In total, 537 cases underwent ES/EPBD, 1743 cases underwent cholecystectomy, and 5658 cholelithiasis cases had no intervention. Eleven (2.05%), 37 (0.65%), and 7 (0.40%) subsequent cholangiocarcinoma cases were diagnosed in the ES/EPBD, no intervention, and cholecystectomy groups, respectively, and the odds ratio for subsequent cholangiocarcinoma was 3.13 in the ES/EPBD group and 0.61 in the cholecystectomy group when compared with the no intervention group. CONCLUSION: In conclusion, symptomatic cholelithiasis patients who undergo cholecystectomy can reduce the incidence of subsequent cholangiocarcinoma, while cholelithiasis patients who undergo ES/EPBD are at a great risk of subsequent cholangiocarcinoma according to our findings.

Health disparities are associated with gastric cancer mortality-to-incidence ratios in 57 countries.

AIM: To evaluate the association between mortality-to-incidence ratios (MIRs) and health disparities. METHODS: In this study, we used the GLOBOCAN 2012 database to obtain the cancer incidence and mortality data for 57 countries, and combined this information with the World Health Organization (WHO) rankings and total expenditures on health/gross domestic product (e/GDP). The associations between variables and MIRs were analyzed by linear regression analyses and the 57 countries were selected according to their data quality. RESULTS: The more developed regions showed high gastric cancer incidence and mortality crude rates, but lower MIR values than the less developed regions (0.64 vs 0.80, respectively). Among six continents, Oceania had the lowest (0.60) and Africa had the highest (0.91) MIR. A good WHO ranking and a high e/GDP were significantly associated with low MIRs (P = 0.001 and P = 0.001, respectively). CONCLUSION: The MIR variation for gastric cancer would predict regional health disparities.

Favorable liver cancer mortality-to-incidence ratios of countries with high health expenditure.

OBJECTIVE: Health expenditure is a marker associated with an advanced healthcare system, which contributes toward the good prognosis of patients. Mortality-to-incidence ratios (MIRs) are one of the predictors that reflect the prognosis of cancer patients. There remains some uncertainty on the correlation of MIRs of liver cancer with the health expenditure of countries. METHODS: We therefore analyzed the correlation of MIRs from the GLOBOCAN 2012 database with the WHO rankings and the total expenditures on health/gross domestic product from WHO by linear regression analyses. A total of 29 countries were selected in this study according to the data quality and the incidence number. RESULTS: The results showed high rates of incidence/mortality and MIRs in less developed regions (0.92 vs. 0.96 for more vs. less developed regions). Among the continents, Asia has the highest incidence/mortality in case number, crude rate, and age-standardized rate. In terms of the MIR, Northern America has the lowest MIR and Latin America and the Caribbean have the highest MIRs (0.82 and 1.04, respectively). Finally, favorable MIRs are associated significantly with good WHO ranking and high expenditures on gross domestic product (P=0.048 and 0.025, respectively). CONCLUSION: The MIR variation for liver cancer is thus found to be associated with the health expenditure and WHO ranking.

Musashi-1 promotes a cancer stem cell lineage and chemoresistance in colorectal cancer cells.

Colorectal cancers (CRCs) are a critical health issue worldwide. Cancer stem cell (CSC) lineages are associated with tumour transformation, progression, and malignant transformation. However, how lineages are transformed and how chemoresistance is acquired by CRCs remain largely unknown. In this report, we demonstrated that the RNA-binding protein Musashi-1 enhanced the development of CD44+ colorectal CSCs and triggered the formation of anti-apoptotic stress granules (SGs). Our results indicated that CD44+ CSC lineage-specific induction of tumour malignancies was controlled by Musashi-1. In addition, Musashi-1 formed SGs when CRC cell lines were treated with 5-fluorouracil. The C-terminal domain of Musashi-1 was critical for recruitment of Musashi-1 into SGs. Intracellular Musashi-1 SGs enhanced the chemoresistance of CRCs. Analysis of clinical CRC samples indicated that Musashi-1 expression was prominent in CRC stage IIA and IIB. In summary, we demonstrated that Musashi-1, a stemness gene, is a critical modulator that promotes the development of CD44+ colorectal CSCs and also enhances CRC chemoresistance via formation of SGs. Our findings elucidated a novel mechanism of CRC chemoresistance through increased anti-apoptotic effects via Musashi-1-associated SGs.

Hydrodynamics of stratified epithelium: Steady state and linearized dynamics.

A theoretical model for stratified epithelium is presented. The viscoelastic properties of the tissue are assumed to be dependent on the spatial distribution of proliferative and differentiated cells. Based on this assumption, a hydrodynamic description of tissue dynamics at the long-wavelength, long-time limit is developed, and the analysis reveals important insights into the dynamics of an epithelium close to its steady state. When the proliferative cells occupy a thin region close to the basal membrane, the relaxation rate towards the steady state is enhanced by cell division and cell apoptosis. On the other hand, when the region where proliferative cells reside becomes sufficiently thick, a flow induced by cell apoptosis close to the apical surface enhances small perturbations. This destabilizing mechanism is general for continuous self-renewal multilayered tissues; it could be related to the origin of certain tissue morphology, tumor growth, and the development pattern.

Trajectories of Listeria-type motility in two dimensions.

Force generated by actin polymerization is essential in cell motility and the locomotion of organelles or bacteria such as Listeria monocytogenes. Both in vivo and in vitro experiments on actin-based motility have observed geometrical trajectories including straight lines, circles, S-shaped curves, and translating figure eights. This paper reports a phenomenological model of an actin-propelled disk in two dimensions that generates geometrical trajectories. Our model shows that when the evolutions of actin density and force per filament on the disk are strongly coupled to the disk self-rotation, it is possible for a straight trajectory to lose its stability. When the instability is due to a pitchfork bifurcation, the resulting trajectory is a circle; a straight trajectory can also lose stability through a Hopf bifurcation, and the resulting trajectory is an S-shaped curve. We also show that a half-coated disk, which mimics the distribution of functionalized proteins in Listeria, also undergoes similar symmetry-breaking bifurcations when the straight trajectory loses stability. For both a fully coated disk and a half-coated disk, when the trajectory is an S-shaped curve, the angular frequency of the disk self-rotation is different from that of the disk trajectory. However, for circular trajectories, these angular frequencies are different for a fully coated disk but the same for a half-coated disk.

Dynamics of biomembranes with active multiple-state inclusions.

Nonequilibrium dynamics of biomembranes with active multiple-state inclusions is considered. The inclusions represent protein molecules which perform cyclic internal conformational motions driven by the energy brought with adenosine triphosphate (ATP) ligands. As protein conformations cyclically change, this induces hydrodynamical flows and also directly affects the local curvature of a membrane. On the other hand, variations in the local curvature of the membrane modify the transition rates between conformational states in a protein, leading to a feedback in the considered system. Moreover, active inclusions can move diffusively through the membrane so that their surface concentration varies. The kinetic description of this system is constructed and the stability of the uniform stationary state is analytically investigated. We show that, as the rate of supply of chemical energy is increased above a certain threshold, this uniform state becomes unstable and stationary or traveling waves spontaneously develop in the system. Such waves are accompanied by periodic spatial variations of the membrane curvature and the inclusion density. For typical parameter values, their characteristic wavelengths are of the order of hundreds of nanometers. For traveling waves, the characteristic frequency is of the order of a thousand Hz or less. The predicted instabilities are possible only if at least three internal inclusion states are present.

Stepped changes of monovalent ligand-binding force during ligand-induced clustering of integrin alphaIIB beta3.

Recent evidence demonstrated that conformational changes of the integrin during receptor activation affected its binding to extracellular matrix; however, experimental assessment of ligand-receptor binding following the initial molecular interaction has rarely been carried out at a single-molecule resolution. In the present study, laser tweezers were used to measure the binding force exerted by a live Chinese hamster ovary cell that expressed integrin alphaIIb beta3 (CHO alphaIIb beta3), to the bead carrier coated with the snake venom rhodostomin that served as an activated ligand for integrin alphaIIb beta3. A progressive increase of total binding force over time was noticed when the bead interacted with the CHO alphaIIb beta3 cell; such an increase was due mainly to the recruitment of more integrin molecules to the bead-cell interface. When the binding strength exerted by a single ligand-receptor pair was derived from the "polyvalent" measurements, surprisingly, a stepped decrease of the "monovalent binding force" was noted (from 4.15 to 2.54 piconewtons (pN)); such decrease appeared to occur during the ligand-induced integrin clustering process. On the other hand, the mutant rhodostomin defective in clustering integrins exhibited only one (1.81 pN) unit binding strength.