Fibroblast growth factor receptors (FGFRs) are aberrantly activated through single-nucleotide variants, gene fusions and copy number amplifications in 5–10% of all human cancers, although this frequency increases to 10–30% in urothelial carcinoma and intrahepatic cholangiocarcinoma. We begin this review by highlighting the diversity of FGFR genomic alterations identified in human cancers and the current challenges associated with the development of clinical-grade molecular diagnostic tests to accurately detect these alterations in the tissue and blood of patients. The past decade has seen significant advancements in the development of FGFR-targeted therapies, which include selective, non-selective and covalent small-molecule inhibitors, as well as monoclonal antibodies against the receptors. We describe the expanding landscape of anti-FGFR therapies that are being assessed in early phase and randomised controlled clinical trials, such as erdafitinib and pemigatinib, which are approved by the Food and Drug Administration for the treatment of FGFR3-mutated urothelial carcinoma and FGFR2-fusion cholangiocarcinoma, respectively. However, despite initial sensitivity to FGFR inhibition, acquired drug resistance leading to cancer progression develops in most patients. This phenomenon underscores the need to clearly delineate tumour-intrinsic and tumour-extrinsic mechanisms of resistance to facilitate the development of second-generation FGFR inhibitors and novel treatment strategies beyond progression on targeted therapy.Subject terms: Cancer, Cancer相似文献
Objectives Compare the effect of high doses of inhaled corticosteroids on bone loss in subjects with moderate to severe asthma or mild asthma, and examine the influence of dietary intake on bone metabolism. Design A survey on the effects of corticotherapy and nutrition on bone density was conducted in 74 subjects currently being treated for asthma in the asthma clinic of Hospital Laval (Sainte-Foy, Quebec, Canada). Fifty-eight subjects completed the study (attrition RATE=15%).
Main outcome measures In all subjects expiratory volumes were determined and urinary analysis was conducted for hydroxyproline, calcium, phosphorus, and cortisol levels. Osteocalcin, calcium, phosphorus, cortisol, alkaline phosphatase, and γ-glutamyltransferase levels were measured in blood samples. Bone density of the lumbar spine was determined by means of dual-energy x-ray absorptiometry. Nutrition evaluation was based on a 3-day food diary analyzed using progiciel Nutri 91. The nutritional parameters examined were calcium; phosphorus; magnesium; zinc; vitamins A, C, and D; protein; total fiber; oxalates; energy; caffeine; and alcohol in relation to bone density.
Subjects Thirty-one patients with moderate to severe asthma who had been taking more than 1,000 μg beclomethasone per day or the equivalent for more than 2 years and 27 patients with mild asthma who were taking less than 500 μg beclomethasone per day or the equivalent.
Statistical analyses performed Four factor analysis of variance with hierarchized interactions of four levels, Duncan's test, Pearson correlation coefficients.
Results Blood levels of osteocalcin and protein intake were lower in patients with moderate to severe asthma than in those with mild asthma (P<.05). Significant correlations (P<.02) were observed between bone density and calcium intake (r=.40), phosphorus intake (r=.35), protein intake (r=.30), and serum alkaline phosphatase level (r=−.30). Bone density was not significantly different between the two groups of patients with asthma.
Applications A follow-up of patients with asthma who are taking inhaled corticosteroids is needed to assess bone density, osteocalcin levels, and dietary intakes of calcium. Verify if osteocalcin level decreases over time in patients with moderate to severe asthma, monitor possible modifications in bone density, and verify if the correlation between dietary calcium and bone density is maintained. J Am Diet Assoc. 1997;97:1401–1406. 相似文献
The aim of the study was to subclassify the soma-dendritic α2-autoreceptors in the locus coeruleus (LC) of the rat by means of antagonists. To this end, the frequency of spontaneous action
potentials was recorded extracellularly from single LC neurones in brain slices. The neurones fired spontaneously at an average
rate of 1 Hz. The selective α2-adrenoceptor agonist 5-bromo-6-(2-imidazolin-2-ylamino)-quinoxaline (UK 14,304) and noradrenaline decreased the action potential
discharge with IC50 values of 5 and 510 nM, respectively. The concentration-inhibition curves of UK 14,304 and noradrenaline were shifted to the
right by phentolamine (0.15 μM) and rauwolscine (0.15 μM) but not by prazosin (1 μM). Apparent Kd values of phentolamine were 17 nM (against UK 14,304) and 20 nM (against noradrenaline). Apparent Kd values of rauwolscine were 47 nM (against UK 14,304) and 70 nM (against noradrenaline). (+)-Oxaprotiline (1 μM) suppressed
the firing of the neurones within 10 to 33 min. In the continued presence of oxaprotiline, phentolamine and rauwolscine restored
firing with EC50 values of 120 and 250 nM, respectively. Prazosin (1 μM) again was ineffective. All three antagonist affinity estimates –
against UK 14,304, exogenous noradrenaline and endogenous noradrenaline (that accumulates in the extracellular space in the
presence of oxaprotiline) – yield an affinity order phentolamine > rauwolscine >> prazosin, prazosin being ineffective even
at a concentration of 1 μM. These findings identify the soma-dendritic α2-autoreceptors of the LC as the rat variant of the α2A/D-adrenoceptor, i.e. α2D. Not only presynaptic but also soma-dendritic α2-autoreceptors may at least predominantly be α2A/D throughout the nervous system.
Received: 3 March 1997 / Accepted: 21 April 1997 相似文献