Abstract In United States Hispanics have disparities in the presentation and outcome of colorectal cancer (CRC) largely attributed to their late presentation and lower socioeconomic status. Impact of ...treatment, especially in the metastatic setting, in the observed outcome is an unexplored area. To explore the role of treatment in the outcome of metastatic CRC we performed a retrospective analysis to assess the contribution of demographics, tumor characteristics, and health-care setting on survival differences. We conducted a retrospective study of patients who were treated with metastatic CRC at Los Angeles County Hospital - University of Southern California (LAC-USC, a public hospital) and Norris Comprehensive Cancer Center (NCCC, private hospital) between 2002-2012. Both these institutions are staffed by the same providers and therefore treatment algorithms and access to drugs were similar. We identified metastatic CRC patients who received chemotherapy from administrative records. Demographics, tumor, and treatment related factors were collected. The primary endpoint was time to progression (TTP: time from the first day of chemotherapy to the date of progression). Overall Survival (OS) was measured from the first day of chemotherapy to death or last follow-up. Descriptive statistics were used to describe the population and chi-square, Wilcoxon, and log-rank tests were used for comparison between the groups. 242 patients, 44% Hispanic, 26% Non-Hispanic Whites (NHW), 21% Asian and 9% Black were included. Median TTP was 9.2 months (95% CI: 7.6-11.6) in Hispanics, and 20.7 months (95% CI: 9.6-27.5; P<0.05) in NHWs. Median OS in Hispanics was 16.3 months (95% CI: 13.3-18.5), and in Non-Hispanic Whites was 33.5 months (95% CI: 22.1-63.6; P<0.001). Hispanics who were treated at LAC-USC had longer TTP in comparison to Hispanics at NCCC (p= 0.04). Hispanics with metastatic CRC have shorter TTP and OS on first line therapy when adjusted for health-care setting, demographics, disease characteristics, and treatment.
Mesenchymal stromal cells (MSCs) are promising candidates for cell-based therapies, mainly due to their unique biological properties such as multipotency, self-renewal and trophic/immunomodulatory ...effects. However, clinical use has proven complex due to limitations such as high variability of MSCs preparations and high number of cells required for therapies. These challenges could be circumvented with cell immortalization through genetic manipulation, and although many studies show that such approaches are safe, little is known about changes in other biological properties and functions of MSCs. In this study, we evaluated the impact of MSCs immortalization with the TERT gene on the purinergic system, which has emerged as a key modulator in a wide variety of pathophysiological conditions. After cell immortalization, MSCs-TERT displayed similar immunophenotypic profile and differentiation potential to primary MSCs. However, analysis of gene and protein expression exposed important alterations in the purinergic signaling of in vitro cultured MSCs-TERT. Immortalized cells upregulated the CD39/NTPDase1 enzyme and downregulated CD73/NT5E and adenosine deaminase (ADA), which had a direct impact on their nucleotide/nucleoside metabolism profile. Despite these alterations, adenosine did not accumulate in the extracellular space, due to increased uptake. MSCs-TERT cells presented an impaired in vitro immunosuppressive potential, as observed in an assay of co-culture with lymphocytes. Therefore, our data suggest that MSCs-TERT have altered expression of key enzymes of the extracellular nucleotides/nucleoside control, which altered key characteristics of these cells and can potentially change their therapeutic effects in tissue engineering in regenerative medicine.
Human butyrylcholinesterase (HuBuChE), purified from outdated human plasma, is being evaluated for efficacy against nerve agents in guinea pigs and cynomolgus monkeys. Previous studies in rodents and ...nonhuman primates demonstrated that pretreatment of animals with enzymes that can scavenge nerve agents could provide significant protection against behavioral and lethal effects of nerve agent intoxication. In preparation for evaluation of efficacy of HuBuChE prior to initiating an investigational new drug (IND) application, the pharmacokinetics of HuBuChE were evaluated in guinea pigs and in cynomolgus monkeys. HuBuChE was injected intramuscularly (i.m.) at two doses, and blood samples were taken to follow the time-course of HuBuChE in blood for up to 168
h after administration. In guinea pigs, the two doses of HuBuChE, 19.9 and 32.5
mg/kg, produced similar times of maximal blood concentration (
T
max of 26.0 and 26.8
h, respectively) and similar elimination half-times (
t
1/2 of 64.6 and 75.5
h, respectively). Enzyme levels were still 10-fold over baseline at 72
h. Based on these data, guinea pigs were administered 150
mg/kg of enzyme i.m. and challenged at
T
max. Soman or VX doses were approximately 1.5, 2.0 and 2.0
×
LD
50 administered subcutaneously (s.c.) in sequence at 90–120
min apart. None of the animals displayed signs of organophosphorus (OP) anticholinesterase intoxication at any of the challenge levels, and all survived for the 14-day duration of the experiment. Similar experiments were carried out with cynomolgus monkeys to determine the pharmacokinetics of HuBuChE and its efficacy against soman. The complete survival of nearly all animals tested to date, coupled with the maximal blood concentration and half-life elimination profile obtained for HuBuChE after i.m. injection, provides strong support for the continued development of HuBuChE as a product to protect against nerve agents.
Estrogen has been shown not only to reduce the incidence of colorectal cancer but also gastric cancer (GC). Polymorphisms in estrogen receptor β gene, ESR2, correlate with colorectal cancer survival. ...To better understand the role of ESR2 in GC, genomic DNA extracted from 169 Japanese patients and 172 patients from Los Angeles County (LAC) was analyzed for association of overall survival (OS) with three ESR2 polymorphisms, which are of biological significance using multivariable Cox proportional hazard regression. ESR2 rs1271572 (C>A) and rs3020443 (T>G) had univariate and multivariable associations with OS in the Japanese cohort, whereas the C allele of ESR2 rs2978381 (T>C) predicted favorable OS in the Japanese cohort but worse OS in the LAC cohort. The interaction term of the ESR2 rs2978381 and cohort group reached statistical significance. Our study provides evidence that genetic variations in ESR2 gene are significantly associated with survival in patients with locally advanced GC.
Colorectal brain metastases (BM) are rare (1-2%) and a late-stage disease manifestation. Molecular mechanisms for BM development are not well understood. We tested whether variants within genes ...involved in overcoming the blood-brain barrier (BBB) are associated with BM susceptibility and survival in patients with BM. Germline single-nucleotide polymorphisms (SNPs, n=17) in seven genes (CXCR4, MMP9, ST6GALNAC5, ITGAV, ITGB1, ITGB3, KLF4) were analyzed from germline DNA in patients with resected BM (n=70) or no clinical evidence of BM after at least 24 months from diagnosis (control group, n=45). SNPs were evaluated for association with BM susceptibility and overall survival (OS) from BM diagnosis. ST6GALNAC5 rs17368584 and ITGB3 rs3809865 were significantly associated with BM susceptibility. In multivariable analysis adjusted for patient characteristics, KLF4 rs2236599, ITGAV rs10171481, ST6GALNAC5 rs1883778, CXCR4 rs2680880 and ITGB3 rs5918 were significant for OS. This study shows for the first time that variants within genes involved in breaching the BBB are associated with BM susceptibility and survival. These findings warrant further validation to develop better screening guidelines and to identify novel therapy targets for patients with BM.
Aim
Traffic between the plasma membrane and the endomembrane compartments is an essential feature of eukaryotic cells. The secretory pathway sends cargoes from biosynthetic compartments to the plasma ...membrane. This is counterbalanced by a retrograde endocytic route and is essential for cell homoeostasis. Cells need to adapt rapidly to environmental challenges such as the reduction of pO2 which, however, has not been analysed in relation to membrane trafficking in detail. Therefore, we determined changes in the plasma membrane trafficking in normoxia, hypoxia, and after reoxygenation.
Methods
Membrane trafficking was analysed by using the bulk membrane endocytosis marker FM 1‐43, the newly developed membrane probe mCLING, wheat germ agglutinin as well as fluorescently labelled cholera toxin subunit B. Additionally, the uptake of specific membrane proteins was determined. In parallel, a non‐biased SILAC screen was performed to analyse the abundance of membrane proteins in normoxia and hypoxia.
Results
Membrane trafficking was increased in hypoxia and quickly reversed upon reoxygenation. This effect was independent of the hypoxia‐inducible factor (HIF) system. Using SILAC technology, we identified that the actin‐bundling protein T‐plastin is recruited to the plasma membrane in hypoxia. By the use of T‐plastin knockdown cells, we could show that T‐plastin mediates the hypoxia‐induced membrane trafficking, which was associated with an increased actin density in the cells as determined by electron microscopy.
Conclusion
Membrane trafficking is highly dynamic upon hypoxia. This phenotype is quickly reversible upon reoxygenation, which suggests that this mechanism participates in the cellular adaptation to hypoxia.
Single-Balloon Enteroscopy Lenz, Philipp; Domagk, Dirk
Gastrointestinal endoscopy clinics of North America,
01/2017, Letnik:
27, Številka:
1
Journal Article
Recenzirano
Single-balloon enteroscopy is among 3 device-assisted enteroscopy systems on the market. Compared with double-balloon enteroscopy, no significant difference in diagnostic yield was found. ...Additionally, no significant difference was found in oral and anal insertion depth, adverse events, or procedure times. Some studies observed lower complete enteroscopy rates, which have evidently no diagnostic impact. With a learning curve of around 30 procedures, the single-balloon endoscope is a safe endoscopic tool, which seems equally suitable for diagnostic and therapeutic interventions. Carbon dioxide should be used for single-balloon endoscopy procedures, especially in patients with a history of surgical abdominal interventions.
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