Background Water exchange provides salvage cleansing and improves adenoma detection, but drawbacks include prolonged procedure time. Cap-assisted colonoscopy decreases cecal intubation time but is ...limited by impaired views when feces lodge in the cap. Objective To investigate the impact of combined water-exchange and cap-assisted colonoscopy (WCC) on detection of adenomas and proximal colon serrated polyps. Design Retrospective, single-center, single-colonoscopist, consecutive group observational study. Setting Veterans Affairs outpatient endoscopy suite. Patients Outpatients undergoing screening or surveillance colonoscopy. Intervention WCC data collected from 100 consecutive patients were compared to a control group of 101 consecutive patients examined with conventional air insufflation colonoscopy during the prior 4-month period. Main Outcome Measurements Adenoma detection rate (ADR), adenomas detected per colonoscopy, proximal colon serrated polyp detection rate, and proximal colon serrated polyps per colonoscopy rate. Results Compared with controls, the WCC group had a higher polyp detection rate (93.0% vs 84.2%; P = .07), ADR (75.0% vs 59.4%; P = .02), proximal colon ADR (61.0% vs 47.5%; P = .07), proximal colon serrated polyp detection rate (24.0% vs 9.9%; P = .009), number of adenomas per colonoscopy (2.70 vs 1.50; P = .002), and mean number of proximal colon serrated polyps per colonoscopy (0.38 vs 0.12; P = .004). Limitations Retrospective study; single, unblinded endoscopist. Conclusion ADR and adenomas per colonoscopy are both sensitive indicators of colonoscopy quality. WCC merges two simple methods to improve the performance of screening and surveillance colonoscopy. The data suggest that larger, prospective studies are necessary to determine if there are differences between water-exchange combined with cap-assisted maneuvers and the individual components used alone in lesion detection in screening and surveillance colonoscopy.
COPD is associated with cardiovascular disease (CVD), and coronary artery calcification (CAC) provides additional prognostic information. With increasing use of nongated CT scans in clinical ...practice, this study hypothesized that the visual Weston CAC score would perform as well as the Agatston score in predicting prevalent and incident coronary artery disease (CAD) and CVD in COPD.
CAC was measured by using Agatston and Weston scores on baseline CT scans in 1,875 current and former smokers enrolled in the Genetic Epidemiology of COPD (COPDGene) study. Baseline cardiovascular disease and incident cardiac events on longitudinal follow-up were recorded. Accuracy of the CAC scores was measured by using receiver-operating characteristic analysis, and Cox proportional hazards analyses were used to estimate the risk of incident cardiac events.
CAD was reported by 133 (7.1%) subjects at baseline. A total of 413 (22.0%) and 241 (12.9%) patients had significant CAC according to the Weston (≥ 7) and Agatston (≥ 400) scores, respectively; the two methods were significantly correlated (r = 0.84; P < .001). Over 5 years of follow-up, 127 patients (6.8%) developed incident CVD. For predicting prevalent CAD, c-indices for the Weston and Agatston scores were 0.78 and 0.74 and for predicting incident CVD, they were 0.62 and 0.61. After adjustment for age, race, sex, smoking pack-years, FEV1, percent emphysema, and CT scanner type, a Weston score ≥ 7 was associated with time to first acute coronary event (hazard ratio, 2.16 95% CI, 1.32 to 3.53; P = .002), but a Agatston score ≥ 400 was not (hazard ratio, 1.75 95% CI, 0.99-3.09; P = .053).
A simple visual score for CAC performed well in predicting incident CAD in smokers with and without COPD.
ClinicalTrials.gov; No.: NCT00608764; URL: www.clinicaltrials.gov.
MAPK signaling is required for retinoic acid (RA)-triggered G0 cell cycle arrest and cell differentiation, but the mechanism is not well defined. In this study, RA is found to cause MAPK activation ...with sustained association of RAF to MEK or ERK, leading to a MAPK-dependent accumulation of p21Waf1/Cip1 and binding to CDK2 blocking G1/S transition. BLR1, a chemokine receptor, was found to function as a critical component of RA-triggered MAPK signaling. Unlike wild-type parental cells, RA-treated BLR1 knock-out cells failed to show RAF and consequential MEK and ERK phosphorylation, failed to accumulate CDK inhibitors that control G1/S transition, and failed to differentiate and arrest in response to RA, whereas ectopically overexpressing BLR1 enhanced MAPK signaling and caused accelerated RA-induced differentiation and arrest. Ectopic overexpression of RAF enhanced BLR1 expression in response to RA, whereas inhibition of RAF or MEK by inhibitors or knockdown of RAF by short interfering RNA diminished RA-induced BLR1 expression and attenuated differentiation and growth arrest. Ectopic expression of the RAF CR3, the catalytically active domain, in the BLR1 knock-out restored RA-induced MAPK activation and the ability to differentiate and arrest, indicating that RAF effects MAPK signaling by BLR1 to propel differentiation/arrest. Taken together, RA induces cell differentiation and growth arrest through activation of a novel MAPK pathway with BLR1 as a critical component in a positive feedback mechanism that may contribute to the prolonged MAPK signaling propelling RA-induced cell cycle arrest and differentiation.
Background and Aim
Endoscopy featured water‐aided colonoscopy (WAC) as novel in the Innovation Forum in 2011. Gastrointestinal Endoscopy published a modified Delphi consensus review (MDCR) that ...supports WAC for clinical practice in 2021. We tested the hypothesis that experience was an important predictor of WAC use, either as water immersion (WI), water exchange (WE), or a combination of WI and WE.
Methods
A questionnaire was sent by email to the MDCR authors with an in‐depth knowledge of WAC. They responded and also invited colleagues and trainees without in‐depth knowledge to respond. Logistic regression analysis was used with the reasons for WAC use treated as the primary outcome. Reports related to WAC post MDCR were identified.
Results
Of 100 respondents, > 80% indicated willingness to adopt and modify practice to accommodate WAC. Higher adenoma detection rate (ADR) incentivized WE use. Procedure time slots ≤ 30 and > 30 min significantly predicted WI and WE use, respectively. Co‐authors of the MDCR were significantly more likely to perform WAC (odds ratio OR = 7.5, P = 0.037). Unfamiliarity with (OR = 0.11, P = 0.02) and absence of good experience (OR = 0.019, P = 0.002) were associated with colonoscopists less likely to perform WAC. Reports related to WAC post MDCR revealed overall and right colon WE outcomes continued to improve. Network meta‐analyses showed that WE was superior to Cap and Endocuff. On‐demand sedation with WE shortened nursing recovery time.
Conclusions
An important predictor of WAC use was experience. Superior outcomes continued to be reported with WE.
Water naturally comprises some fraction of virtually all petroleum reservoirs worldwide, yet its existence introduces complexity to asphaltene precipitation and deposition mechanisms. This global ...problem not only impacts upstream conventional and unconventional energy production but also influences downstream chemical refining, the construction industry, and the transportation sector. A transparent packed-bed microreactor (μPBR) with inline analytics was designed to merge two fields of science, oilfield chemistry and microchemical systems, to investigate the role of water on the molecular-to-the-microscale deposition of asphaltenes in quartz porous media. Porosity loss and permeability impairment of the porous media for water mass fractions of <0.001 to 34.5 wt % were investigated. Interestingly, a switch in the mechanism of water (from 0.030 to 3.18 wt %) on the accumulation was discovered. Analyses of porosity–permeability relationships revealed competition between adsorption and desorption followed by pore throat plugging via mechanical entrapment for all mass fractions of water studied. Soluble water molecules were also found to decrease the asphaltene nanoparticle collision efficiency within quartz porous media where trace amounts existed (i.e., in the range of <0.001 to 0.030 wt % water), whereas higher mass fractions (>0.030 wt %) created the possibility of emulsion water blocking with more particles (relatively speaking) depositing on pore throat surfaces, precipitating by heterogeneous nucleation at asphaltene–water interfaces and/or experiencing catalyzed nanoaggregation at interfaces. In general, the water fraction was found to control the number of closed pore throats that interconnect the quartz porous media. Transparent packed-bed microreactors that bridge molecular-to-microscale understanding of asphaltene–water interactions are promising as tools for the advancement of asphaltene science and risk management during hydrocarbon production.
Nicotinamide adenine dinucleotide (NAD) is increasingly recognized as an important signaling molecule that affects numerous biological pathways. Thus, enzymes that metabolize NAD can have important ...biological functions. One NAD-metabolizing enzyme in mammals is CD38, a type II transmembrane protein that converts NAD primarily to adenosine diphosphate ribose (ADPR) and a small amount of cyclic adenosine diphosphate ribose (cADPR). Localization of CD38 was originally thought to be only on the plasma membrane, but later reports showed either significant or solely, intracellular CD38. With the efficient NAD-hydrolysis activity, the intracellular CD38 may lead to depletion of cellular NAD, thus producing harmful effects. Therefore, the intracellular localization of CD38 needs to be carefully validated. Here, we report the synthesis and application of a cell permeable, fluorescent small molecule (SR101–F-araNMN) that can covalently label enzymatically active CD38 with minimal perturbation of live cells. Using this fluorescent probe, we revealed that CD38 is predominately on the plasma membrane of Raji and retinoic acid (RA)-treated HL-60 cells. Additionally, the probe revealed no CD38 expression in K562 cells, which was previously reported to have solely intracellular CD38. The finding that very little intracellular CD38 exists in these cell lines suggests that the major enzymatic function of CD38 is to hydrolyze extracellular rather than intracellular NAD. The fluorescent activity-based probes that we developed allow the localization of CD38 in different cells to be determined, thus enabling a better understanding of the physiological function.
Directed differentiation of embryonic stem cells indicates that mesodermal lineages in the mammalian heart (cardiac, endothelial, and smooth muscle cells) develop from a common, multipotent ...cardiovascular precursor. To isolate and characterize the lineage potential of a resident pool of cardiovascular progenitor cells (CPcs), we developed BAC transgenic mice in which enhanced green fluorescent protein (EGFP) is placed under control of the c-kit locus (c-kitBAC-EGFP mice). Discrete c-kit-EGFP⁺ cells were observed at different stages of differentiation in embryonic hearts, increasing in number to a maximum at about postnatal day (PN) 2; thereafter, EGFP⁺ cells declined and were rarely observed in the adult heart. EGFP⁺ cells purified from PN 0-5 hearts were nestin⁺ and expanded in culture; 67% of cells were fluorescent after 9 days. Purified cells differentiated into endothelial, cardiac, and smooth muscle cells, and differentiation could be directed by specific growth factors. CPc-derived cardiac myocytes displayed rhythmic beating and action potentials characteristic of multiple cardiac cell types, similar to ES cell-derived cardiomyocytes. Single-cell dilution studies confirmed the potential of individual CPcs to form all 3 cardiovascular lineages. In adult hearts, cryoablation resulted in c-kit-EGFP⁺ expression, peaking 7 days postcryolesion. Expression occurred in endothelial and smooth muscle cells in the revascularizing infarct, and in terminally differentiated cardiomyocytes in the border zone surrounding the infarct. Thus, c-kit expression marks CPc in the neonatal heart that are capable of directed differentiation in vitro; however, c-kit expression in cardiomyocytes in the adult heart after injury does not identify cardiac myogenesis.
Abstract
Background and study aims
Adverse events are uncommon with cold snaring, but cold techniques are generally reserved for lesions ≤ 9 mm out of concern for incomplete resection or inability ...to mechanically resect larger lesions. In a non-distended, water-filled lumen, colorectal lesions are not stretched, enabling capture and en bloc resection of large lesions. We assessed the effectiveness and safety of underwater cold snare resection (UCSR) without submucosal injection (SI) of ≥ 10 mm non-pedunculated, non-bulky (≤ 5 mm elevation) lesions with small, thin wire snares.
Patients and methods
Retrospective analysis of an observational cohort of lesions removed by UCSR during colonoscopy. A single endoscopist performed procedures using a small thin wire (9-mm diameter) cold or (10-mm diameter) hybrid snare.
Results
Fifty-three lesions (mean 15.8 mm SD 6.9; range 10–35 mm) were removed by UCSR from 44 patients. Compared to a historical cohort, significantly more lesions were resected en bloc by UCSR (84.9 % 45/53;
P
= 0.04) compared to conventional endoscopic mucosal resection (EMR) (64.0 % 32/50). Results were driven by high en bloc resection rates for 10– to 19-mm lesions (97.3 % 36/37;
P
= 0.01). Multiple logistic regression analysis adjusted for potential confounders showed en bloc resection was significantly associated with UCSR compared to conventional EMR (OR 3.47,
P
= 0.027). Omission of SI and forgoing prophylactic clipping of post-resection sites did not result in adverse outcomes.
Conclusions
UCSR of ≥ 10 mm non-pedunculated, non-bulky colorectal lesions is feasible with high en bloc resection rates without adverse outcomes. Omission of SI and prophylactic clipping decreased resource utilization with economic benefits. UCSR deserves further evaluation in a prospective comparative study.
Retinoic acid (RA) causes HL-60 human myeloblastic leukemia cell myeloid differentiation that is dependent on MAPK signaling. The process is propelled by c-Cbl, which binds the CD38 receptor as part ...of a signaling complex generating MAPK signaling. Here we report that the capability of c-Cbl to do this is lost in the G306E tyrosine kinase-binding domain mutant. Unlike wild-type (WT) c-Cbl, the G306E mutant c-Cbl fails to propel RA-induced differentiation, and disrupts the normal association with CD38. The G306E mutant does, like WT c-Cbl, co-immunoprecipitate with Vav, Slp-76, and p38. But unlike WT c-Cbl, does not cause MAPK signaling. In contrast, the C381A Ring finger domain mutant functions like WT c-Cbl. It binds CD38 and is part of the same apparent c-Cbl/Slp-76/Vav/p38 signaling complex. The C381A mutant causes MAPK signaling and propels RA-induced differentiation. In addition to HL-60 cells and their WT or mutant c-Cbl stable transfectants, the c-Cbl/Vav/Slp-76 complex is also found in NB4 cells where c-Cbl was previously also found to bind CD38. The data are consistent with a model in which the G306E mutant c-Cbl forms a signaling complex that includes Slp-76, Vav, and p38; but does not drive MAPK signaling because it fails to bind the CD38 receptor. Without the G306E mutation the c-Cbl unites CD38 with the signaling complex and delivers a MAPK signal that drives RA-induced differentiation. The results demonstrate the importance of the Gly306 residue in the ability of c-Cbl to propel RA-induced differentiation.
6-Formylindolo(3,2-b)carbazole (FICZ) is a photoproduct of tryptophan and an endogenous high affinity ligand for aryl hydrocarbon receptor (AhR). It was previously reported that, in patient-derived ...HL-60 myeloblastic leukemia cells, retinoic acid (RA)-induced differentiation is driven by a signalsome containing c-Cbl and AhR. FICZ enhances RA-induced differentiation, assessed by expression of the membrane differentiation markers CD38 and CD11b, cell cycle arrest and the functional differentiation marker, inducible oxidative metabolism. Moreover, FICZ augments the expression of a number of the members of the RA-induced signalsome, such as c-Cbl, Vav1, Slp76, PI3K, and the Src family kinases Fgr and Lyn. Pursuing the molecular signaling responsible for RA-induced differentiation, we characterized, using FRET and clustering analysis, associations of key molecules thought to drive differentiation. Here we report that, assayed by FRET, AhR interacts with c-Cbl upon FICZ plus RA-induced differentiation, whereas AhR constitutively interacts with Cbl-b. Moreover, correlation analysis based on the flow cytometric assessment of differentiation markers and western blot detection of signaling factors reveal that Cbl-b, p-p38α and pT390-GSK3β, are not correlated with other known RA-induced signaling components or with a phenotypic outcome. We note that FICZ plus RA elicited signaling responses that were not typical of RA alone, but may represent alternative differentiation-driving pathways. In clusters of signaling molecules seminal to cell differentiation, FICZ co-administered with RA augments type and intensity of the dynamic changes induced by RA. Our data suggest relevance for FICZ in differentiation-induction therapy. The mechanism of action includes modulation of a SFK and MAPK centered signalsome and c-Cbl-AhR association.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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