The purpose of this study was to evaluate associations between germline epidermal growth factor receptor (EGFR) variants involved in transcriptional regulation and overall survival in white patients ...with non‐small‐cell lung cancer (NSCLC) treated with the EGFR tyrosine kinase inhibitor, gefitinib. Of 175 consecutive patients treated with oral gefitinib (250 mg/day), 170 (median age: 67 years; 72% men) were evaluable for genotyping and survival. Fifty‐five patients (33%) had stable disease and 17 (10%) had an objective response. The most common of four haplotypes was G‐C (EGFR*1) at the EGFR −216G>T and −191C>A loci (frequency, 0.45). After adjusting for performance status, previous platinum‐containing chemotherapy and occurrence of skin rash or diarrhea during the first treatment cycle in patients with performance status 0 or 1 (N=139), the absence of EGFR*1 was associated with significantly better survival (hazard ratio: 0.54; 95% confidence interval: 0.32–0.91; P=0.015). The results may help identify patients with NSCLC who can benefit from gefitinib treatment.
Clinical Pharmacology & Therapeutics (2008) 83, 3, 477–484.doi:10.1038/sj.clpt.6100320
p63 is a transcription factor with a "master" role in the asymmetric cell division of stratified epithelia. The transcriptional strategy is exerted by activating and repressing a wide range of genes. ...Our understanding of the pathways and networks controlled by p63 is starting to emerge, thanks to profiling arrays and ChIP on chip experiments. We discuss recent advancements in the identification of bona fide targets, which suggests that several independent, as well as interconnected pathways are controlled by p63. Not surprisingly, the list includes genes previously shown to play a key role in differentiation processes, as well as targets involved in cell-cycle control, signalling and transcription.
Background
Tendon resident cells (TCs) are a mixed population made of terminally differentiated tenocytes and tendon stem/progenitor cells (TSPCs). Since the enrichment of progenitors proportion ...could enhance the effectiveness of treatments based on these cell populations, the interest on the effect of culture conditions on the TSPCs is growing.
In this study the clonal selection and the culture in presence or absence of basic fibroblast growth factor (bFGF) were used to assess their influences on the stemness properties and phenotype specific features of tendon cells.
Methods
Cells cultured with the different methods were analyzed in terms of clonogenic and differentiation abilities, stem and tendon specific genes expression and immunophenotype at passage 2 and passage 4.
Results
The clonal selection allowed to isolate cells with a higher multi-differentiation potential, but at the same time a lower proliferation rate in comparison to the whole population. Moreover, the clones express a higher amounts of stemness marker
OCT4
and tendon specific transcription factor Scleraxis (
SCX
) mRNA, but a lower level of decorin (
DCN
). On the other hand, the number of cells obtained by clonal selection was extremely low and most of the clones were unable to reach a high number of passages in cultures.
The presence of bFGF influences TCs morphology, enhance their proliferation rate and reduce their clonogenic ability. Interestingly, the expression of CD54, a known mesenchymal stem cell marker, is reduced in presence of bFGF at early passages. Nevertheless, bFGF does not affect the chondrogenic and osteogenic potential of TCs and the expression of tendon specific markers, while it was able to downregulate the
OCT4
expression.
Conclusion
This study showed that clonal selection enhance progenitors content in TCs populations, but the extremely low number of cells produced with this method could represent an insurmountable obstacle to its application in clinical approaches. We observed that the addition of bFGF to the culture medium promotes the maintenance of a higher number of differentiated cells, reducing the proportion of progenitors within the whole population. Overall our findings demonstrated the importance of the use of specific culture protocols to obtain tendon cells for possible clinical applications.
The transcription factor p63, member of the p53 family, is crucial for epithelial development. An RNAi screening identified the apoptotic gene Procaspase-8 as a target activated by p63. The caspase-8 ...inhibitor FLIP is also under p63 control. We analysed and detailed the direct transactivation through the use of RNAi, reporter assays, ChIPs, western blots, confocal studies in HaCat, as well as in primary human keratinocytes. The direct DeltaNp63 regulation of these targets was confirmed in vivo using transgenic DeltaNp63 mice under the K5 promoter, as compared with p63 knockout mice, and in vitro in normal human primary keratinocytes following UV irradiation. Lowering the steady state of p63 protein levels changes the relative ratio of FLIP isoforms, causing the activation of the expressed, inactive Procaspase-8, into the active isoform thus triggering the proapoptotic cascade. Therefore, p63 fine-tunes the Procaspase-8-FLIP pro- and antiapoptotic pathway in keratinocytes.
In the context of tendon degenerative disorders, the need for innovative conservative treatments that can improve the intrinsic healing potential of tendon tissue is progressively increasing. In this ...study, the role of pulsed electromagnetic fields (PEMFs) in improving the tendon healing process was evaluated in a rat model of collagenase-induced Achilles tendinopathy.
A total of 68 Sprague Dawley rats received a single injection of type I collagenase in Achilles tendons to induce the tendinopathy and then were daily exposed to PEMFs (1.5 mT and 75 Hz) for up to 14 days - starting 1, 7, or 15 days after the injection - to identify the best treatment option with respect to the phase of the disease. Then, 7 and 14 days of PEMF exposure were compared to identify the most effective protocol.
The daily exposure to PEMFs generally provided an improvement in the fibre organization, a decrease in cell density, vascularity, and fat deposition, and a restoration of the physiological cell morphology compared to untreated tendons. These improvements were more evident when the tendons were exposed to PEMFs during the mid-acute phase of the pathology (7 days after induction) rather than during the early (1 day after induction) or the late acute phase (15 days after induction). Moreover, the exposure to PEMFs for 14 days during the mid-acute phase was more effective than for 7 days.
PEMFs exerted a positive role in the tendon healing process, thus representing a promising conservative treatment for tendinopathy, although further investigations regarding the clinical evaluation are needed.Cite this article:
2020;9(9):613-622.
Background
Prevalence and incidence of atrial fibrillation (AF) are high in hemodialysis (HD) patients. Intra-atrial conduction velocity slowing plays an important role in AF onset. The aim of our ...study was to measure P wave duration (Pwd), expression of intra-atrial conduction velocity, in HD patients with and without a history of AF.
Methods
The study was performed in 47 end stage renal disease (ESRD) patients, subdivided into four groups: 19 patients within the first 6 months from starting HD therapy (HD1); the same patients studied 18 ± 3 months later (HD2); patients with no history of AF and long dialytic age (HD3,
n
= 13); and patients with sinus rhythm but history of AF (HDAF,
n
= 15); and 18 healthy controls. In all patients P wave high resolution recording and electrolyte plasma values were obtained before and after a HD session, and atrial diameter was assessed by echocardiography.
Results
Patients with the shortest dialysis vintage showed the shortest Pwd 131.2 ± 11.0 (HD1) vs. 139.8 ± 11.7 (HD2), 142.1 ± 7.2 (HD3), 152.3 ± 15.0 (HDAF) ms;
p
< 0.05, while Pwd was prolonged in patients with AF history when compared to all other groups (
p
< 0.03). At multivariate analysis atrial dimension was independently related to Pwd (
R
= 0.40,
p
< 0.02). HD session induced a significant increase of Pwd (141 ± 14.0–152 ± 17.0 ms,
p
< 0.001), that was correlated to modifications of K
+
concentration (
R
= 0.8,
p
< 0.0001).
Conclusions
HD therapy prolongs Pwd. HD patients with a history of AF have prolonged Pwd compared to patients without, suggesting that increased Pwd is a marker of AF risk in patients with ESRD. HD session acutely increases Pwd, creating conditions favoring AF onset.
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