ライフサイエンスコーパス: CRC

1 CRC has high mortality when detected at advanced stages,

2 CRCs exhibiting elevated microsatellite alterations at s

3 In total, > 79.000 CRC patients per year fulfil genetic criteria for high s

4 Fas-associated factor 1 gene (FAF1) in DLD-1 CRC cells using CRISPR/Cas9 gene editing; some cells wer

5 astases (LNMs), and liver metastases from 10 CRC patients.

6 t targeted sequencing of 205 genes for 2,105 CRC cases with survival data.

7 association studies (GWASs) including 55,105 CRC-affected case subjects and 65,079 control subjects o

8 fic biomarker discovery with a cohort of 134 CRCs, and with a newly developed high-efficiency CNA pro

9 ed colorectal tumor and nontumor samples (30 CRC; 32 AAs) from patients in Spain.

10 2 colorectal specimens from 2010 to 2012 (46 CRCs, 74 advanced adenomas and 32 normal colon tissues).

11 results from fecal immunochemical tests in a CRC screening program.

12 ere, we identify and functionally validate a CRC 'trio' constituted by three transcription factors (T

13 d the cost-effectiveness of the risk-adapted CRC screening program will be assessed by decision analy

14 and the cost-effectiveness of a risk-adapted CRC screening strategy for individuals under 50 years of

15 loping CRC, are diagnosed with less advanced CRC, and are at increased risk of dying from CRC, althou

16 , cucumbers, pumpkins and zucchini), against CRC.

17 have the poorest clinical outcomes among all CRC patients.

18 B1status in CRC stage III and IV (35% of all CRC) was not different from stage I and II (50% vs. 36%,

19 urotransmitter-dependent communication among CRC cells.

20 both recurrence (HR 1.58, CI 1.21-2.06) and CRC-specific death (HR 1.59, CI 1.19-2.12).

21 , advanced adenoma (range, 20.0%-33.6%), and CRC (range, 0%-7.1%) were similar.

22 In our study, advanced adenoma and CRC were associated with activation of beta-catenin in p

23 riants in MMR genes with risk of adenoma and CRC, and somatic mutations in APC and CTNNB1 in colorect

24 a3 were elevated in patients with UC, CD and CRC patients compared to healthy controls (all p < 0.000

25 th the gastrointestinal disorders UC, CD and CRC, in comparison to healthy controls.

26 ng-term risks of colorectal cancer (CRC) and CRC-related death following adenoma removal are uncertai

27 effect of rs7198799 on ZFP90 expression and CRC cellular malignant phenotype.

28 asm 6 mm or greater, advanced neoplasia, and CRC for mt-sDNA were 54.2%, 22.7%, and 1.9% respectively

29 peting risks incidence of CRC recurrence and CRC-specific death.

30 -catenin in the intestinal crypt, augmenting CRC tumorigenesis in an adenomatous polyposis coli (APC(

31 gains can be made by deploying the available CRC screening modalities in ways that optimize outcomes

32 plasia was highest among those with baseline CRC (43.7%; 95% CI 13.0%-74.4%), followed by those with

33 e that metabolic subphenotypes exist between CRCs due to intertumoral molecular and genomic variation

34 ded incidence of sporadic colorectal cancer (CRC) (~91:100,000), whereas rural African (RA) people ha

35 The long-term risks of colorectal cancer (CRC) and CRC-related death following adenoma removal are

36 syndrome (LS)-associated colorectal cancer (CRC) and endometrial cancer (EC), but they have not been

37 among male patients with colorectal cancer (CRC) and the role of open surgery in the association.

38 dard treatment option for colorectal cancer (CRC) but its rapid metabolism and systemic instability (

39 significant proportion of colorectal cancer (CRC) cases have familial aggregation but little is known

40 9 RNP into 293T cells and colorectal cancer (CRC) cells, thus displaying high genome-editing activity

41 tide resolution in intact colorectal cancer (CRC) cells.

42 146 patients in a Chinese colorectal cancer (CRC) cohort, among which 70 had metastatic CRC (mCRC).

43 ents with stage II or III colorectal cancer (CRC) exhibit various clinical outcomes after radical tre

44 e (CMS) classification of colorectal cancer (CRC) has been established, which may ultimately help to

45 tely 35% of patients with colorectal cancer (CRC) have a family history of the disease attributed to

46 ents affected by advanced colorectal cancer (CRC) have still a poor prognosis.

47 e decreasing incidence of colorectal cancer (CRC) in older populations, the incidence has nearly doub

48 detection and therapy of colorectal cancer (CRC) in recent years, CRC has remained a major challenge

49 Colorectal cancer (CRC) incidence and mortality are increasing among person

50 Colorectal cancer (CRC) incidence is increasing among young adults below sc

51 copy surveillance reduces colorectal cancer (CRC) incidence or mortality is weak.

52 vailable to patients with colorectal cancer (CRC) is increasing, with a parallel rise in the use of b

53 Colorectal cancer (CRC) is the second deadliest cancer in the US due to its

54 Colorectal cancer (CRC) is the second most common malignant disease and the

55 esponse is inefficient in colorectal cancer (CRC) liver metastasis following existing therapies due t

56 ens, and is implicated in colorectal cancer (CRC) pathogenesis.

57 mutations in the blood of colorectal cancer (CRC) patients are emerging as biomarkers of acquired res

58 e and overall survival of colorectal cancer (CRC) patients negatively correlates with stromal PKCzeta

59 ly identified a subset of colorectal cancer (CRC) patients who are heterozygous for a wild-type and a

60 is a treatment option for colorectal cancer (CRC) patients with inoperable, chemorefractory hepatic m

61 bacterium associated with colorectal cancer (CRC) proliferation, chemoresistance, inflammation, metas

62 (CDCP1) is predictive of colorectal cancer (CRC) recurrence and poor patient survival.

63 ntestinal homeostasis and colorectal cancer (CRC) remain controversial.

64 Accurate colorectal cancer (CRC) risk prediction models are critical for identifying

65 elines recommend starting colorectal cancer (CRC) screening before age 50 years for African Americans

66 have a lower incidence of colorectal cancer (CRC) than men, however, they have a higher incidence of

67 ne (MIR34A) expression in colorectal cancer (CRC) tissues compared with non-cancer one and to prelimi

68 Colorectal cancer (CRC) tumors can be partitioned into four biologically di

69 tients with stage I - III colorectal cancer (CRC) using convolutional neural network (CNN) to elucida

70 has been associated with colorectal cancer (CRC), but causal alterations preceding CRC have not been

71 eic and genetic models of colorectal cancer (CRC), which can be attributed to defective Th1 and CD8+

72 incidence of early-onset colorectal cancer (CRC), which occurs in individuals <50 years of age, has

73 mmonly used to screen for colorectal cancer (CRC).

74 with an increased risk of colorectal cancer (CRC).

75 l solid tumors, including colorectal cancer (CRC).

76 have an increased risk of colorectal cancer (CRC).

77 metabolites) and risk of colorectal cancer (CRC).

78 enced by sex hormones and colorectal cancer (CRC).

79 e FOXA1 function in human colorectal cancer (CRC).

80 d protein levels in human colorectal cancer (CRC).

81 with an increased risk of colorectal cancer (CRC).

82 sensitivity (>= 2.12) for colorectal cancer (CRC).

83 e and reduced survival in colorectal cancer (CRC).

84 affect the development of colorectal cancer (CRC).

85 human cancers, including colorectal cancers (CRC), oncogenic KRAS has been extremely challenging to t

86 e frequently observed in colorectal cancers (CRC).

87 31,587 colectomies, 5608 colorectal cancers (CRCs) 6608 cholecystectomies, and 41,055 patient deaths.

88 (hi) population in human colorectal cancers (CRCs) and two CD73(-) murine tumor models, including a m

89 The majority of colorectal cancers (CRCs) initiate following APC mutations, resulting in Wnt

90 EBV in patient-derived colorectal carcinoma (CRC) cells typifying all molecular subtypes of CRC.

91 out half of the human colorectal carcinomas (CRC) and in other cancers.

92 ory of CRC carry genetic variants that cause CRC with high or moderate penetrance, but these account

93 Core regulatory circuitry (CRC)-dependent transcriptional network is critical for d

94 s core transcriptional regulatory circuitry (CRC).

95 implications of the findings, we classified CRC patients of independent data into two groups based o

96 OTCH3 as a putative target for advanced CMS4 CRC patients.

97 ary factors contributing to post-colonoscopy CRC.

98 tailed mechanistic insights into the complex CRC-associated microbiota would potentially reveal avenu

99 l use of colonoscopy to effectively decrease CRC incidence and mortality.

100 ad primary prevention strategies to decrease CRC risk, screening is the most powerful public health t

101 -secreted activin A induced ligand-dependent CRC epithelial cell migration and epithelial to mesenchy

102 c inhibition of MYC activity in SMS-depleted CRC cells dramatically induces Bim expression and apopto

103 Most of the patient-derived CRC cells expressing slow NAT2 also show sensitivity to

104 d decreased proliferation of patient-derived CRC organoids.

105 fied, the full molecular mechanisms deriving CRC tumorigenesis are not fully understood.

106 Patients with desmoplastic CRC have a significantly worse prognosis and do not bene

107 strategy for chemoresistant and desmoplastic CRCs.

108 at baseline 0-107 years), 162,226 developed CRC, and 559,375 developed diabetes.

109 of CRC have an increased risk of developing CRC before age 50, there are recommendations to start sc

110 with UC are at increased risk of developing CRC, are diagnosed with less advanced CRC, and are at in

111 dividuals at low and high risk of developing CRC, as they can then be offered targeted screening and

112 -PK test as a non-invasive assay to diagnose CRC and adenomatous polyps.

113 associated with an increased risk of distal CRC.

114 Downstream, CRC TFs coordinately regulate gene expression networks i

115 her which specific taxa or metabolites drive CRC biology and to fully characterize the underlying mec

116 Early CRC staging classified nodal involvement by level of inv

117 -term survival in an aggressive experimental CRC liver metastasis model.

118 mmarize current knowledge of common familial CRC, provide an update on syndromes associated with CRC

119 s of age with potentially increased familial CRC risk.

120 of genetic variants associated with familial CRC.

121 percentage has a fair diagnostic ability for CRC with an AUC of 0.63 (95%CI = 0.55-0.71).

122 azard ratios (HRs) for incident CRC, and for CRC mortality, taking tumour stage into account.

123 consolidate the strategy and methodology for CRC discovery.

124 These cell lines offer a model for CRC metastatic progression; SW480 derived from primary a

125 identified several potential predictors for CRC in a BCSP population.

126 ects of a risk-adapted screening program for CRC in individuals between 25 and 50 years of age with p

127 red to sigmoidoscopy, the detection rate for CRC was similar in the first FIT round (0.25% vs 0.27%;

128 P < .001); corresponding detection rates for CRC were 0.23% and 0.31%, respectively (P = .43).Conclus

129 ultivariable analysis, the hazard ratios for CRC incidence after high-quality versus low-quality colo

130 pes), and review current recommendations for CRC screening and surveillance.

131 sed risk; these factors also affect risk for CRC onset after age 50.

132 ic biomarkers and therapeutic strategies for CRC.

133 d develop advanced adenomas, a surrogate for CRC.

134 serve as the basis for new therapeutics for CRC and other PRMT5/YBX1/NF-kappaB-associated cancers.

135 the intestinal microbiome might be used for CRC screening and modified for chemoprevention and treat

136 In the UC cohort, 639 patients died from CRC (0.55 per 1000 person-years), compared with 4451 ref

137 CRC, and are at increased risk of dying from CRC, although these excess risks have declined substanti

138 The assay was proven in plasma from CRC patients and healthy donors, and full discrimination

139 Functionally, CRC factors contribute significantly to cell proliferati

140 tains distal chromosomal fragments harboring CRC-driven enhancers.

141 4, 2.12; Pheterogeneity <= 0.001), CIMP-high CRC (OR per 5 kg/m2: 1.57; 95% CI: 1.30, 1.89; Pheteroge

142 score the importance of assessing histologic CRC subtypes independently.

143 However, whether and how CRC contributes to transcription regulation in Ewing sar

144 tic factor in microsatellite stable stage II CRC.

145 on included 1169 newly diagnosed stage I-III CRC patients from 2 prospective cohorts.

146 red by ALN status in patients with stage III CRC beyond that provided by TNM N status.

147 n For Stage III CRC, if combined with imaging or pathologic evidence, th

148 In CRC patients, NOTCH3 expression correlates positively wi

149 Clinically, high CAF abundancy in CRC tissues correlates strongly with elevated CD73 activ

150 e DNA viruses included into this analysis in CRC development.

151 data, we show that FOXA1 inhibits anoikis in CRC cells.

152 ical role of eosinophils in tumor control in CRC and introduce the GM-CSF-IRF5 axis as a critical dri

153 The positive nuclear CTNNB1status in CRC stage III and IV (35% of all CRC) was not different

154 mplex reoriented toward the local Wnt cue in CRC cells with full-length APC, but not if APC was trunc

155 and 324 miRNAs significantly deregulated in CRC and AA tissues, respectively, 7 and 5 of these miRNA

156 In men, no meaningful differences in CRC risk were observed for the investigated molecular fe

157 ively rewired PPIN nodes occur frequently in CRC and are prognostic of poor patient outcomes.

158 phasizing the role of APC as a gatekeeper in CRC, this study also demonstrates that combined partial

159 strategies to address current limitations in CRC screening.

160 as additional genes significantly mutated in CRC.

161 cription factors is a frequent occurrence in CRC, and the accompanying drastic changes in gene expres

162 herapeutics to improve treatment outcomes in CRC patients.

163 ations for tumor progression and outcomes in CRC patients.

164 we show that AMPKalpha1 is overexpressed in CRC patient specimens and the high expression is correla

165 The primary outcome was participation in CRC screening within 18 weeks after enrollment into the

166 t immune and oncogenic signaling pathways in CRC.

167 ght on the complicated metastatic pattern in CRC and has great clinical implications.

168 hitecture induced an epithelial phenotype in CRC cells while disordered ECM drove a mesenchymal pheno

169 Allele (A) was highly prevalent in CRC tissues represented 0.56 (P < 0.001).

170 ng the role of this cell surface receptor in CRC have not been defined.

171 py yielded profound and stable reductions in CRC incidence and mortality throughout the entire follow

172 est that TMPRSS13 plays an important role in CRC cell survival and in promoting resistance to drug-in

173 tenin pathway, which plays critical roles in CRC pathogenesis.

174 se findings uncover a key survival signal in CRC through convergent repression of Bim expression by d

175 A quantum step in CRC prevention might come with the development of new sc

176 PRSS13 protein on the cancer cell surface in CRC patient samples; in contrast, the majority of normal

177 ly, transgenic overexpression of TMPRSS13 in CRC cell lines increased tolerance to apoptosis-inducing

178 , this study confirms MIR34A upregulation in CRC tissues, and its rs2666433 (A/G) variant showed asso

179 Therefore, a common architecture in CRCs is a simple cell hierarchy based on the differentia

180 t baseline in 1995-1996, and 10,200 incident CRC cases occurred over 16 y and 6,464,527 person-years

181 to compute hazard ratios (HRs) for incident CRC, and for CRC mortality, taking tumour stage into acc

182 rom 1986 through 2012 with risk for incident CRC.

183 that treatment of mice with PGE(2) increased CRC cells invasive activity and ability to form liver an

184 ncogenic CD44 isoforms (CD44v) and increased CRC cell growth that was rescued by concurrent knockdown

185 , which may ultimately help to individualize CRC therapy.

186 well established in microsatellite instable CRC.

187 patients and 77 male patients) with stage IV CRC who underwent molecular profiling and pretreatment c

188 croenvironment, potentially factors in local CRC pathogenesis.

189 quality examination resulted in 2-fold lower CRC incidence (SIR, 0.16 [CI, 0.13 to 0.20]) and mortali

190 e metabolic and immune pathways that mediate CRC development.

191 The main microbial and metabolic CRC-associated markers were not significantly altered in

192 (CRC) cohort, among which 70 had metastatic CRC (mCRC).

193 patients with BRAF(V600E)-mutated metastatic CRC previously treated with one or two regimens were ran

194 ET/CT imaging of 10 patients with metastatic CRC to assess metastasis avidity.

195 Methods: CRC patients treated in the HEPAR II and SIM studies wer

196 -sDNA vs CT colonography for all except 6-mm CRC at CT colonography).

197 Although alternative methods for modeling CRC have been developed, animal models of CRC remain hel

198 -) murine tumor models, including a modified CRC.

199 nd more strongly associated with risk of MSI CRC (OR per 5 kg/m2: 1.69; 95% CI: 1.34, 2.12; Pheteroge

200 For the association of BMI with MSI CRC, we observed effect modification by sex (Pinteractio

201 catenin-mediated transcription in APC mutant CRC cells.

202 ing the differential responses of APC-mutant CRCs to chemotherapy are not well understood.

203 1.89; Pheterogeneity <= 0.001), BRAF-mutated CRC (OR per 5 kg/m2: 1.56; 95% CI: 1.22, 1.99; Pheteroge

204 fy potential vulnerabilities in KRAS-mutated CRC, we characterize the impact of oncogenic KRAS on the

205 o identify patients with advanced neoplasms (CRCs or AAs) based on their miRNA profiles, using findin

206 nce, but these account for only 5% to 10% of CRC cases.

207 nformation for risk-adapted starting ages of CRC screening for patients with diabetes, who are at hig

208 cle arrest and caspase-mediated-apoptosis of CRC cells.

209 results in an irreversible growth arrest of CRC.

210 fidence interval (CI) for the association of CRC diagnosed more than 1 year after colonoscopy, with p

211 In addition, we found an association of CRC-risk allele C of rs7198799 with elevated transcript

212 ng pro-metastatic cytokine in the context of CRC.

213 Determination of CRC risk based on family cancer history and results of g

214 ption factors involved in the development of CRC will provide new insights into the pathological mech

215 s in FAF1 that associate with development of CRC.

216 Approximately 1 in 10 new diagnoses of CRC are now made in individuals 50 years or younger.

217 model called CRCNet for optical diagnosis of CRC by training on 464,105 images from 12,179 patients a

218 IPO11 knockout decreased colony formation of CRC cell lines and decreased proliferation of patient-de

219 l cancer registry; veterans who were free of CRC at their baseline colonoscopy through 3 years of fol

220 igration and anchorage-independent growth of CRC cells.

221 for those with additional family history of CRC (12-21 years earlier depending on sex and benchmark

222 All participants with a family history of CRC are invited to a shared decision making process to d

223 Some families with a history of CRC carry genetic variants that cause CRC with high or m

224 ce that individuals with a family history of CRC have an increased risk of developing CRC before age

225 s assess a participant's familial history of CRC using a short questionnaire.

226 of patients from families with a history of CRC, we identified variants in FAF1 that associate with

227 tcomes were the competing risks incidence of CRC recurrence and CRC-specific death.

228 90-BMP4 pathway underlying the initiation of CRC.

229 Here, we found that bacterial invasion of CRC cells and cocultured immune cells induced a differen

230 Knowledge of CRC in cancer is fundamental to understanding cancer-spe

231 tic patients attained the screening level of CRC risk earlier than the general Swedish population.

232 ng CRC have been developed, animal models of CRC remain helpful when analyzing molecular aspects of p

233 contribute to development and progression of CRC with multicomponent, adaptive interventions, at mult

234 a group (7563 patients) had a higher risk of CRC (hazard ratio [HR] 2.61; 95% confidence interval [CI

235 d not have a significant increase in risk of CRC (HR 1.29; 95% CI 0.89-1.88) or related death (HR 0.6

236 as were associated with an increased risk of CRC and related death, supporting early colonoscopy surv

237 for the associations between BMI and risk of CRC by major molecular pathological features: microsatel

238 rmine a group of patients with a low risk of CRC detection that requires no further evaluation.

239 e associated with a reduced relative risk of CRC in men and women.

240 rogeneity = 0.01), compared with the risk of CRC in subjects with the molecular feature counterpart.

241 e need the information regarding the risk of CRC in those patients not referred to colonoscopy, a FAS

242 e show that SpAn predicts the 5-year risk of CRC recurrence with a mean AUROC of 88.5% (SE of 0.1%),

243 without a colonoscopy, the absolute risk of CRC varied according to the polygenic risk score and the

244 In patients with SPs, risk of CRC was not increased until 3 years or more after the fi

245 Also, in women, the risk of CRC with the serrated pathway features was more strongly

246 ongly increased with higher BMI than risk of CRC with the traditional pathway features (OR per 5 kg/m

247 ealth care setting, we examined the risks of CRC and related death by baseline colonoscopy adenoma fi

248 abetes reach the 10-year cumulative risks of CRC in 50-year-old men and women (most common age of fir

249 atients with PSC-IBD have increased risks of CRC, hepatopancreatobiliary cancers, and death compared

250 mains revealing a spatially-mediated role of CRC consensus molecular subtype features with the potent

251 and standardized mortality ratios (SMRs) of CRC after high- and low-quality single negative screenin

252 et 30 genes that are implied in all steps of CRC tumorigenesis.

253 ction of BCL9 in a poor-prognosis subtype of CRC tumors characterized by expression of stromal and ne

254 C) cells typifying all molecular subtypes of CRC.

255 In addition, the susceptibility of CRC cells to JCV and BKV was examined using a long-term

256 e as a curative therapy for the treatment of CRC liver metastasis.

257 t PGE(2) might be developed for treatment of CRC.

258 therapeutically exploitable vulnerability of CRC tumors.

259 tM2-PK measurement test for the diagnosis of CRCs and adenomatous polyps in plasma and stool samples

260 l reconstitution and biologic exploration of CRCs across various human malignancies, and consolidate

261 Official CRC screening starts at age 50.

262 but risk factors associated with early-onset CRC (EOCRC) have not been widely studied.

263 betes, who are at higher risk of early-onset CRC than the general population.

264 , 95% confidence interval (CI) 0.84-1.26] or CRC-specific death (HR 1.14, CI 0.91-1.43).

265 n in feces can identify patients with AAs or CRC more accurately than fecal hemoglobin concentration

266 al neoplasia (aCRN, high-grade dysplasia, or CRC) in patients with IBD.

267 Mutations in TP53 are associated with poorer CRC-specific survival, which is most pronounced in cases

268 ncer (CRC), but causal alterations preceding CRC have not been elucidated.

269 se with inflammatory bowel disease, previous CRC, previous multiple large polyps, or hereditary cance

270 f generalization of the signature to similar CRC data sets is predicted to be high.

271 me contribute to the development of sporadic CRC or result from it.

272 mucosal tissues from patients with sporadic CRC colonized with vs without CoPEC by quantitative reve

273 of 5-year OS in patients with advanced-stage CRC.Keywords: Abdomen/GI, CT, Comparative Studies, Large

274 This is a large study on LNM in T1 CRC, including validation, showing that LVI and perineur

275 additional surgery after locally resected T1 CRC is dependent on the risk of LNM.

276 ntegration could be provided after long term CRC cell cultivation in presence of viral particles.

277 The CRC protein triadin (T95) is localized in the sarcoplasm

278 of 1,730 peritoneal dialysis patients in the CRC for ESRD prospective cohort from 2008 to 2014 were e

279 MIR34A expression in the CRC specimens was significantly upregulated (median = 21

280 llection of components characteristic of the CRC iTME.

281 gic and molecular factors that contribute to CRC development in different populations.

282 al cytokine secretion that may contribute to CRC metastasis.

283 nt of colonic adenomas and may contribute to CRC prevention.

284 ctivation of APC significantly contribute to CRC tumorigenesis.

285 re the association of one related variant to CRC risk.

286 of delivering high payload of 5-FU to treat CRC.

287 etter estimate the total number of treatable CRC patients, we here determined whether tumor cells ret

288 est strategy is for offering population-wide CRC screening.

289 9; Pheterogeneity = 0.04), and KRAS-wildtype CRC (OR per 5 kg/m2: 1.35; 95% CI: 1.17, 1.54; Pheteroge

290 7 (95% CI: 0.885-1.009, p < 0.0001) and with CRC from healthy controls was 0.890 (95% CI: 0.809-0.972

291 ovide an update on syndromes associated with CRC (including the nonpolyposis and polyposis types), an

292 entially synergistic drivers associated with CRC metastasis.

293 tween diabetes and variables associated with CRC risk and ADR.

294 666433 (A/G) variant showed association with CRC and a high somatic mutation rate in cancer tissues.

295 dentify markers with strong association with CRC, and to investigate the correlation between markers.

296 polyp >=10 mm), and 2.6% were diagnosed with CRC.

297 athogenic variants (PVs) among patients with CRC and EC.

298 PREMM(5) effectively identify patients with CRC and/or EC with LS, although MSI/IHC has better speci

299 In all, 107 patients with CRC, 113 IBD patients with colonic lesions, and 96 parti

300 of colorectal cancer (CRC) in recent years, CRC has remained a major challenge in clinical practice.