The control of mRNA degradation is an important component of the regulation of gene expression since the steady-state concentration of mRNA is determined both by the rates of synthesis and of decay. ...Two general pathways of mRNA decay have been described in eukaryotes. Both pathways share the exonucleolytic removal of the poly(A) tail (deadenylation) as the first step. In one pathway, deadenylation is followed by the hydrolysis of the cap and processive degradation of the mRNA body by a 5′ exonuclease. In the second pathway, the mRNA body is degraded by a complex of 3′ exonucleases before the remaining cap structure is hydrolyzed. This review discusses the proteins involved in the catalysis and control of both decay pathways.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, GIS, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
23.
Radiation-related damage to dentition Kielbassa, Andrej M; Hinkelbein, Wolfgang; Hellwig, Elmar ...
The lancet oncology,
04/2006, Letnik:
7, Številka:
4
Journal Article
Recenzirano
Because of typical tissue reactions to ionising radiation, radiotherapy in the head and neck region usually results in complex oral complications affecting the salivary glands, oral mucosa, bone, ...masticatory musculature, and dentition. When the oral cavity and salivary glands are exposed to high doses of radiation, clinical consequences including hyposalivation, mucositis, taste loss, trismus, and osteoradionecrosis should be regarded as the most common side-effects. Mucositis and taste loss are reversible consequences, usually subsiding early post-irradiation, whereas hyposalivation is commonly irreversible. Additionally, the risk of rampant tooth decay with its sudden onset and osteonecrosis is a lifelong threat. Thus, early, active participation of the dental profession in the development of preventive and therapeutic strategies, and in the education and rehabilitation of patients is paramount in consideration of quality-of-life issues during and after radiotherapy. This Review focuses on the multifactorial causes of so-called radiation caries and presents possible treatment strategies to avoid loss of dentition.
We describe the assay of the human cytochrome P450 2D6 in a set of 30 genotyped liver samples using the 'absolute quantification' (AQUA) technique. We found approximately 30 fmol CYP2D6 per μg of ...microsomal protein, with the values spanning from 0 to nearly 80 fmol/μg. This is greater by a factor of 5-10 from the compared to the currently accepted value, which was around 5 fmol/μg. Our results thus suggest that the amount of cytochrome P450 (CYP) enzymes in liver have to be reassessed. We used quantitative Western blotting, calibration standards and activity assays, to validate the results. Our results show, that using the AQUA technique a true assay of CYP2D6 in human liver was possible.
Objective
Several single-nucleotide polymorphisms have been identified to be disadvantageous or protective in regard to disease severity in patients with non-alcoholic fatty liver disease (NAFLD). ...However, it is unclear, whether including genetic risk factor(s) either alone or combined into risk stratification algorithms for NAFLD actually provides incremental benefit over clinical risk factors.
Design
Patients with biopsy-proven NAFLD were genotyped for the
PNPLA3
-
rs738409
(minor allele:G),
TM6SF2
-
rs58542926
(minor allele:T) and
HSD17B13
-
rs72613567
(minor allele:TA) variants. The NAFLD activity score (NAS) and fibrosis stage (F0–F4) were used to grade and stage all liver biopsy samples. Patients from seven centers throughout Central Europe were considered for the study.
Results
703 patients were included: NAS ≥ 5:173(24.6%); Fibrosis: F3–4:81(11.5%).
PNPLA3
G/G genotype was associated with a NAS ≥ 5(aOR 2.23,
p
= 0.007) and advanced fibrosis (aOR-3.48,
p
< 0.001).
TM6SF2
T/- was associated with advanced fibrosis (aOR 1.99,
p
= 0.023).
HSD17B13
TA/- was associated with a lower probability of NAS ≥ 5(TA/T: aOR 0.65,
p
= 0.041, TA/TA: aOR 0.40,
p
= 0.033). Regarding the predictive capability for NAS ≥ 5, well-known risk factors (age, sex, BMI, diabetes, and ALT; baseline model) had an AUC of 0.758, Addition of
PNPLA3
(AUC 0.766),
HSB17B13
(AUC 0.766), and their combination(AUC 0.775), but not of
TM6SF2
(AUC 0.762), resulted in a higher diagnostic accuracy of the model. Addition of genetic markers for the prediction of advanced fibrosis (baseline model: age, sex, BMI, diabetes: AUC 0.777) resulted in a higher AUC if
PNPLA3
(AUC 0.789), and TM6SF2(AUC 0.786) but not if
HSD17B13
(0.777) were added.
Conclusion
In biopsy-proven NAFLD,
PNPLA3
G/-,
TM6SF2
T/- and
HSD17B13
TA/- carriage are associated with severity of NAFLD. Incorporating these genetic risk factors into risk stratification models might improve their predictive accuracy for severity of NAFLD and/or advanced fibrosis on liver biopsy.
The gastrin-releasing peptide receptor (GRPR) is overexpressed in breast cancer. The present study evaluates GRPR imaging as a novel imaging modality in breast cancer by employing positron emission ...tomography (PET) and the GRPR antagonist (68)Ga-RM2.
Fifteen female patients with biopsy confirmed primary breast carcinoma (3 bilateral tumors; median clinical stage IIB) underwent (68)Ga-RM2-PET/CT for pretreatment staging. In vivo tumor uptake of (68)Ga-RM2 was correlated with estrogen (ER) and progesterone (PR) receptor expression, HER2/neu status and MIB-1 proliferation index in breast core biopsy specimens.
13/18 tumors demonstrated strongly increased (68)Ga-RM2 uptake compared to normal breast tissue (defined as PET-positive). All PET-positive primary tumors were ER- and PR-positive (13/13) in contrast to only 1/5 PET-negative tumors. Mean SUVMAX of ER-positive tumors was 10.6±6.0 compared to 2.3±1.0 in ER-negative tumors (p=0.016). In a multivariate analysis including ER, PR, HER2/neu and MIB-1, only ER expression predicted (68)Ga-RM2 uptake (model: r(2) =0.55, p=0.025). Normal breast tissue showed inter- and intraindividually variable, moderate GRPR binding (SUVMAX 2.3±1.0), while physiological uptake of other organs was considerably less except pancreas. Of note, (68)Ga-RM2-PET/CT detected internal mammary lymph nodes with high (68)Ga-RM2 uptake (n=8), a contralateral axillary lymph node metastasis (verified by biopsy) and bone metastases (n=1; not detected by bone scan and CT).
Our study demonstrates that (68)Ga-RM2-PET/CT is a promising imaging method in ER-positive breast cancer. In vivo GRPR binding assessed by (68)Ga-RM2-PET/CT correlated with ER expression in primary tumors of untreated patients.
Social withdrawal after laryngectomy Danker, Helge; Wollbrück, Dorit; Singer, Susanne ...
European archives of oto-rhino-laryngology,
04/2010, Letnik:
267, Številka:
4
Journal Article
Recenzirano
This investigation focuses on the psychosocial concomitants of a laryngectomy. Semistructured interviews were conducted with 218 laryngectomized patients. Standardised questionnaires were used to ...assess patients’ social activity (FPAL, EORTC QLQ-C30), intelligibility of speech (PLTT, FPAL), mental well-being (HADS), and perceived stigmatisation (FPAL). More than 40% of the patients withdrew from conversation. Only one-third of all patients regularly took part in social activities. About 87% perceived stigmatisation because of their changed voice and more than 50% felt embarrassed because of their tracheostoma. Almost one-third of the patients had increased anxiety and depression scores. Moderate objective speech intelligibility was found, though patients were not particularly satisfied with their voice. Social activity emerged to be independent from age, gender, treatment variables, and stage of disease. Multivariate analysis resulted in two independent factors representing two patterns of social withdrawal. On the one hand, there was withdrawal from conversation accompanied by increased depression and poor speech intelligibility. On the other hand, there were reduced social activities accompanied by increased anxiety and perceived stigmatisation.
As hearing rehabilitation research evolves to include both retrospective and momentary assessment outcome measures, it is important to understand how in-the-moment contextual factors influence ...subjective ratings. We aimed to determine, over a 4-week period of participants responding to ecological momentary assessments (EMAs) in their own environments, whether: (1) participants will complete surveys in speech-in-noise listening situations; (2) ratings of speech in noise change in a predictable manner as the acoustic conditions change; and (3) EMAs provide patient insights beyond those provided from retrospective ratings.
Fourteen adults aged 26 to 86 years with at least 6 months of hearing aid experience were recruited for an 8-week crossover field trial (4 weeks wearing hearing aids with no EMA; 4 weeks wearing hearing aids with EMA). Participants were fitted with hearing aids and provided with a streamer and a smartphone with an app that analyzed the acoustic signal from the hearing aids and alerted the participant to respond to a survey when predetermined acoustic conditions were detected. Participants were prompted to complete brief surveys up to 9 times/day that contained establishing questions, quality ratings, and items assessing perceived benefit, residual activity limitation, and satisfaction. Participants also completed retrospective questionnaires at intake and after each 4-week field trial.
Participants completed an average of 4.4 surveys per day. The quality ratings changed as the acoustics changed: Ratings of intelligibility were lower for 10 dB signal-to-noise ratio (SNR) than 20 dB SNR (p = 0.006); ratings of noisiness were higher for 10 dB SNR than 20 dB SNR (p = 0.001) and higher for 65 dB SPL than 50 dB SPL (p < 0.001); ratings of effort were higher for 65 dB SPL than 50 dB SPL (p = 0.004); ratings of loudness were higher for 65 dB SPL than 50 dB SPL (p = 0.001). Descriptive analysis of satisfaction, benefit, and residual activity limitation responses showed that the momentary surveys provided more detail about individual variability across acoustic conditions than the retrospective questions.
Participants completed more than 99% of the triggered surveys, demonstrating high compliance. Because the quality ratings generally changed in the hypothesized direction, it is concluded that the participants provided valid responses. The greater variability in responses with EMA than retrospective questionnaires demonstrates its potential utility as a clinical tool for exploring hearing aid outcomes in real-world environments.
Compensated advanced chronic liver disease (cACLD) identifies patients at risk for clinically significant portal hypertension (CSPH), and thus, for liver-related complications. The limited ...availability of liver stiffness measurements (LSM) impedes the identification of patients at risk for cACLD/CSPH outside of specialized clinics. We aimed to develop a blood-based algorithm to identify cACLD by fibrosis-4 (FIB-4) and CSPH by von Willebrand factor/platelet count ratio (VITRO).
Patients with (suspected) compensated chronic liver disease undergoing FIB-4+LSM were included in the LSM/FIB-4 cohorts from Vienna and Salzburg. The HVPG/VITRO cohorts included patients undergoing HVPG-measurement + VITRO from Vienna and Bern.LSM/FIB-4-derivation-cohort: We included 6143 patients, of whom 211 (3.4%) developed hepatic decompensation. In all, 1724 (28.1%) had LSM ≥ 10 kPa, which corresponded to FIB-4 ≥ 1.75. Importantly, both LSM (AUROC:0.897 95% CI:0.865-0.929) and FIB-4 (AUROC:0.914 95% CI:0.885-0.944) were similarly accurate in predicting hepatic decompensation within 3 years. FIB-4 ≥ 1.75 identified patients at risk for first hepatic decompensation (5 y-cumulative incidence:7.6%), while in those <1.75, the risk was negligible (0.3%).HVPG/VITRO-derivation cohort: 247 patients of whom 202 had cACLD/FIB-4 ≥ 1.75 were included. VITRO exhibited an excellent diagnostic performance for CSPH (AUROC:0.889 95% CI:0.844-0.934), similar to LSM (AUROC:0.856 95% CI:0.801-0.910, p = 0.351) and the ANTICIPATE model (AUROC:0.910 95% CI:0.869-0.952, p = 0.498). VITRO < 1.0/ ≥ 2.5 ruled-out (sensitivity:100.0%)/ruled-in (specificity:92.4%) CSPH. The diagnostic performance was comparable to the Baveno-VII criteria.LSM/FIB-4-derivation cohort findings were externally validated in n = 1560 patients, while HVPG/VITRO-derivation-cohort findings were internally (n = 133) and externally (n = 55) validated.
Simple, broadly available laboratory tests (FIB-4/VITRO) facilitate cACLD detection and CSPH risk stratification in patients with (suspected) liver disease. This blood-based approach is applicable outside of specialized clinics and may promote early intervention.
PDF
