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Biomedical subjects

X Chen

Publications and source records attributed to X Chen.

At least 55 records · Page 3Linked to original sources
PubMed2006

Tranilast attenuates connective tissue growth factor-induced extracellular matrix accumulation in renal cells.

Tranilast (N-[3,4-dimethoxycinnamoyl]anthranilic acid) is a synthetic compound that we have recently reported to inhibit transforming growth factor-beta1 (TGF-beta1)-induced tubulointerstitial fibrosis in the kidney. Connective tissue growth factor (CTGF) is recognized as a potent downstream mediator of TGF-beta1. Both proximal tubule cells (PTCs) and cortical fibroblasts (CFs) are considered to be responsible for the production of tubulointerstitial extracellular matrix (ECM). These studies were undertaken to assess the profibrotic effects of CTGF in an in vitro model of the human PTCs and CFs, and to determine whether tranilast is effective in limiting the in vitro matrix responses induced by CTGF. Primary cultures of PTCs and CFs were exposed to CTGF (20 ng/ml)+/-tranilast (100 microM). Cell hypertrophy and the secretion of the ECM proteins fibronectin and collagen IV were determined. The effects of tranilast on TGF-beta1-induced CTGF mRNA expression and on phosphorylation of Smad2 were determined. CTGF significantly induced cell hypertrophy, increased fibronectin, and collagen IV secretion in PTCs and CFs. In all cases, the CTGF-induced increase in ECM protein was inhibited in the presence of tranilast. Tranilast reduced CTGF mRNA and phosphorylation of Smad2, which were induced by TGF-beta1 in PTCs and CFs. These results suggest that tranilast is a potential effective antifibrotic compound in the kidney, exerting its effects via inhibition of TGF-beta1-induced CTGF expression and downstream activation of the Smad2 pathway in both PTCs and CFs.

Anti-Allergic Agents↗
PubMed2006

Operational strategies for thermophilic anaerobic digestion of organic fraction of municipal solid waste in continuously stirred tank reactors.

Three operational strategies to reduce inhibition due to ammonia during thermophilic anaerobic digestion of source-sorted organic fraction of municipal solid waste (SS-OFMSW) rich in proteins were investigated. Feed was prepared by diluting SS-OFMSW (ratio of 1:4) with tap water or reactor process water with or without stripping ammonia. Three continuously stirred tank reactors were operated at 55 degrees C with 11.4 gVS d(-1) loading rate and 15 d retention time. Total ammonia nitrogen (TAN) level in the reactor fed with recirculated water alone was spiked to 3.5 and 5.5 g-N l(-1) through ammonium bicarbonate additions. Dilution of SS-OFMSW with fresh water showed a stable performance with volatile fatty acids of < 1g l(-1) and methane yield of 0.40 m3 kg(-1) volatile solids (VS). Use of recirculated process water after stripping ammonia showed even better performance with a methane yield of 0.43 m3 kg(-1) VS. Recirculation of process water alone on the other hand, resulted in process inhibition at both TAN levels of 3.5 and 5.5 g-N l(-1). However, after a short period, the process recovered and adapted to the tested TAN levels. Thus, use of recirculated process water after stripping ammonia would not only evade potential inhibition due to ammonia but could avoid the use of fresh water for dilution of high solids protein-rich SS-OFMSW.

Ammonia↗
PubMed2006

Role of Th1-stimulating cytokines in bacillus Calmette-Guérin (BCG)-induced macrophage cytotoxicity against mouse bladder cancer MBT-2 cells.

Previously, we have demonstrated that macrophages exhibited cytotoxicity toward mouse bladder cancer MBT-2 cells upon bacille Calmette-Guérin (BCG) stimulation. In this study, we have investigated the role of Th1-stimulating cytokines in BCG-induced macrophage cytotoxicity. Thioglycollate-elicited peritoneal exudate cells (PECs) were used as a conventional source for macrophages and the induction of PEC effector functions (cytolytic activity and cytokine production) by BCG was evaluated in vitro. The BCG-activated PECs showed potent cytotoxicity and killed MBT-2 cells in a dose-dependent manner. Depletion of T cells, natural killer (NK) cells, or both, in PEC preparations exhibited a marginal or small reduction of MBT-2 cell killing, suggesting that macrophages played a primary role in PEC cytotoxicity. Transwell assays indicated that the maximal PEC cytotoxicity required both direct cell-cell contact and soluble factors such as interferon (IFN)-gamma and tumour necrosis factor (TNF)-alpha. Neutralizing endogenous cytokines interleukin (IL)-12, IL-18, IFN-gamma or TNF-alpha reduced PEC cytotoxicity by 38%, 22%, 15% and 94%, respectively. Supplementation of BCG with recombinant (r)IL-2, rIL-12 or rIL-18 increased PEC cytotoxicity by approximately twofold. Compared with control BCG for PEC stimulation, rBCGs expressing IL-2 or IL-18 showed enhanced MBT-2 cell killing by PECs. Increased cytokine production (IFN-gamma, TNF-alpha and IL-6) was also observed in rBCG-stimulated PEC cultures. Taken together, these results suggest that Th1-stimulating cytokines play an important role in BCG-induced macrophage cytotoxicity and that combination of BCG with selected Th1-stimulating cytokines, either supplemented or expressed by BCG, may enhance the effect of BCG in the treatment of bladder cancer patients.

Animals↗
PubMed2006

Podocalyxin-like protein 1 expression in primary hepatic tumours and tumour-like lesions.

AIMS: The differential diagnosis of benign hepatic lesions and well-differentiated hepatocellular carcinomas can be a challenge, especially in small biopsy specimens. Recently, novel proteins expressed by the neovasculature in hepatocellular carcinoma (HCC) have been identified. The aim of this study was to compare the expression of podocalyxin-like protein 1 (PODXL1), a CD34-related sialomucin, in HCC and benign liver tumours or tumour-like lesions. METHODS AND RESULTS: Vascular marker expression was examined using tissue microarrays as well as standard paraffin sections from formalin fixed paraffin-embedded liver tissue samples. Expression of PODXL1 was compared with anti-CD34, CD31 and von Willebrand factor VIII staining by immunohistochemistry. PODXL1 is expressed in tumour-associated microvasculature endothelial cells in HCC, as well as in capillarized sinusoidal endothelium of focal nodular hyperplasia (FNH) and hepatic adenoma. Expression in cirrhotic nodules correlates with CD34 and highlights endothelium in the inflow area. In dysplastic nodules CD34 and PODXL1 are not or only focally expressed. CONCLUSIONS: Expression patterns of CD34 and PODXL1 are almost identical in primary hepatic tumours and tumour-like lesions. The presence of CD34+ and PODXL1+ sinusoidal endothelial cells aids in the diagnosis of HCC. Sinusoidal expression of PODXL1 is also seen in a less diffuse pattern in FNH and adenoma.

Antigens, CD34↗
PubMed2006

Response of interleukin-1beta in the magnocellular system to salt-loading.

Drinking 2% NaCl decreases interleukin (IL)-1beta in the neural lobe and enhances IL-1 Type 1 receptor expression in magnocellular neurones and pituicytes. To quantify cytokine depletion from the neural lobe during progressive salt loading and determine whether the changes are reversible and correspond with stores of vasopressin (VP) or oxytocin (OT), rats were given water on day 0 and then 2% NaCl to drink for 2, 5, 8 or 5 days followed by 5 days of water (rehydration). Control rats drinking only water were pair-fed amounts eaten by 5-day salt-loaded animals. Animals were decapitated on day 8, the neural lobe frozen and plasma hormones analysed by radioimmunoassay (OT, VP) or enzyme-linked immunosorbent assay (IL-1beta). IL-1beta, VP and OT in homogenates of the neural lobe were quantified by immunocapillary electrophoresis with laser-induced fluorescence detection. Differences were determined by ANOVA, Tukey's t-test, Dunnett's procedure, Fisher's least significant difference and linear regression analysis. In response to salt-loading, rats lost body weight similar to pair-fed controls, drank progressively more 2% NaCl and excreted greater urine volumes. Plasma VP increased at days 2 and 8 of salt-loading, whereas osmolality, OT and cytokine were enhanced after 8 days with IL-1beta remaining elevated after rehydration. In the neural lobe, all three peptides decreased progressively with increasing duration of salt-loading (IL-1beta, r2 = 0.98; OT, r2 = 0.94; VP, r2 = 0.93), beginning on day 2 (IL-1beta; VP) or 5 (OT), with only VP replenished by rehydration. IL-1beta declined more closely (P < 0.0001; ANOVA interaction analysis) with OT (r2 = 0.96) than VP (r2 = 0.86), indicative of corelease from the neural lobe during chronic dehydration. Local effects of IL-1beta on magnocellular terminals, pituicytes and microglia in the neural lobe with activation of forebrain osmoregulatory structures by circulating cytokine may sustain neurosecretion of OT and VP during prolonged salt-loading.

Analysis of Variance↗
PubMed2006

Association of intercellular adhesion molecule 1 polymorphisms with retinopathy in Chinese patients with Type 2 diabetes.

AIMS: To investigate the relationship of the K469E and G241R polymorphisms of the intercellular adhesion molecule 1 (ICAM-1) gene with diabetic retinopathy in Chinese patients with Type 2 diabetes mellitus. PATIENTS AND METHODS: One hundred and seventy-two Chinese patients with Type 2 diabetes and 80 normal control subjects were recruited. Patients with diabetes were placed into two groups: the diabetic retinopathy (DR) group and the non-diabetic retinopathy (NDR) group. The DR group was subdivided into those with proliferative retinopathy (PDR) and non-proliferative retinopathy (NPDR). Genomic DNA was prepared using the hydroxybenzene-chloroform extraction method. Genotypes and alleles were detected by polymerase chain reaction-heteroduplex-single-strand conformation polymorphism (PCR-HA-SSCP) analysis combined with gene sequencing. RESULTS: The patients with retinopathy had an increased frequency of the K469K genotype compared with both the patients without retinopathy and the control subjects (61.4 vs. 40.0 and 35.0%, respectively; chi(2) = 8.280 and 13.952, respectively; P < 0.05). The frequency of the K allele in the DR group was higher than in the NDR group and control subjects (75.4 vs. 58.8 and 61.3%, respectively; chi(2) = 9.693 and 11.219, respectively; P < 0.05). Genotype and allele frequencies were similar in the NDR group and control subjects, and in the PDR and NPDR groups. CONCLUSION: The ICAM-1 gene K469E polymorphism is associated with diabetic retinopathy in Chinese patients with Type 2 diabetes. Patients with the K469K genotype were more likely to have diabetic retinopathy than patients with the K469E or E469E genotype.

Adult↗
PubMed2006

Effect of ganciclovir on the hydrolytic degradation of poly(lactide-co-glycolide) microspheres.

Ganciclovir (GCV)-loaded poly(lactide-co-glycolide) (PLGA) microspheres, 125 +/- 11 mum in diameter, are produced using the emulsification/solvent evaporation technique. The release rate of the drug is studied for 20 weeks in a phosphate-buffered solution of pH 7 at 37 degrees C. The release of the drug shows a triphasic release pattern, i.e., an initial burst, a diffusive phase, and a second burst. The initial burst occurs within the first 2 days of immersion. After the burst, the release is by diffusion for up to 13 weeks, followed by another burst release, which signals the onset of bulk degradation of the PLGA polymer. The presence of GCV molecules decreases the hydrolytic rate of PLGA degradation. Gel permeation chromatography (GPC), differential scanning calorimetry (DSC), field emission scanning electron microscopy (FESEM), and ultraviolet (UV) spectroscopy are used to assess the hydrolytic degradation and drug release rate of the microspheres.

Absorbable Implants↗
PubMed2006

Novel IRF6 mutations in Chinese patients with Van der Woude syndrome.

Van der Woude syndrome (VWS) (OMIM 119300) is a dominantly inherited, developmental disorder that is characterized by pits and/or sinuses of the lower lip and a cleft lip and/or cleft palate. Mutations in the interferon regulatory factor 6 gene (IRF6) have been recently identified in patients with VWS, with more than 60 mutations reported. However, the VWS phenotype, IRF6 mutation genotypes, and their interrelationships in Chinese VWS patients have not been studied. Here, we report 11 Chinese families with variable clinical phenotypes of VWS and identified mutations in all patients. Of the 11 mutations, 8 appeared to be novel: CC5.6GT, T342A, 566delA, C748T, C756A, C989A, C1209G, and 1316delT. Seven mutations caused a change or loss of the IRF6 domain. The marked phenotypic variation may be caused by the action of certain modifier genes on IRF6 function.

Adult↗
PubMed2006

Internet resources related to drug action and human response: a review.

It has been demonstrated that numerous proteins interact with drugs or their metabolites. Knowledge of these proteins is necessary to understand the mechanisms of drug action and human response. Progress in modern genetics, molecular biology, biochemistry and pharmacology is generating a comprehensive mechanistic understanding of drug-target interaction on the molecular level. This is valuable for researchers and pharmaceutical companies in their efforts to improve the efficacy of existing drugs and to discover new ones. Most recently, the integration of a systems biology approach into drug discovery processes calls for more holistic knowledge and easily accessible resources of the proteins that are important in drug action and human response. We have reviewed many publicly accessible internet resources of these proteins, according to their roles in drug action and human response, such as therapeutic effect, adverse reaction, absorption, distribution, metabolism and excretion.

Adverse Drug Reaction Reporting Systems↗
PubMed2005

Nonspherical colloidal crystals fabricated by the thermal pressing of colloidal crystal chips.

Nonspherical colloids and their ordered arrays may be more attractive in applications such as photonic crystals than their spherical counterparts because of their lower symmetries, although such structures are difficult to achieve. In this letter, we describe the fabrication and characterization of colloidal crystals constructed from nonspherical polyhedrons. We fabricated such nonspherical colloidal crystals by pressing spherical polymer colloidal crystal chips at a temperature slightly lower than the glass-transition temperature (T(g)) of these polymer colloids. During this process, the polymer microspheres were distinctively transformed into polyhedrons according to their crystal structures, whereas the long-range order of the 3D lattice was essentially preserved. Because a working temperature lower than T(g) effectively prevented the colloidal crystals from fusing into films, the spherical colloidal crystals were transformed greatly under pressure, which lead to obvious change in the optical properties of colloidal crystals. Besides their special symmetry and optical properties, these nonspherical colloidal crystals can be used as templates for 2D or 3D structures of special symmetry, such as 2D nano-networks. We anticipate that this fabrication technique for nonspherical colloidal crystals can also be extended to nonspherical porous materials.

Journal Article↗
PubMed2005

Sonomyography: monitoring morphological changes of forearm muscles in actions with the feasibility for the control of powered prosthesis.

Electromyography (EMG) has been widely used for the assessment of musculoskeletal functions and the control of electrical prostheses, which make use of the EMG signal generated by the contraction of the residual muscles. In spite of the successful applications of EMG in different fields, it has some inherent limitations, such as the difficulty to differentiate the actions of neighboring muscles and to collect signals from deep muscles using the surface EMG. The majority of current EMG controlled prostheses can only provide sequential on-off controls using signals from two groups of muscles, so the users are required to put many conscious efforts in monitoring the speed and range of motion of the terminal devices being controlled. Recently, many alternative signals based on the detection of dimensional changes of muscles or tendons during actions have been reported. The objective of this study was to investigate the potential of the dimensional change of muscles detected using sonography for musculoskeletal assessment and control. A portable B-mode ultrasound scanner was used to collect the dynamic ultrasound images of the forearm muscles of six normally limbed young adults and three amputee subjects. A motion analysis system was used to collect the movement of the wrist angle during the experiments for the normal subjects. It was demonstrated that the morphological changes of forearm muscles during actions can be successfully detected by ultrasound and linearly correlated (R(2)=0.876+/-0.042, mean+/-S.D.) with the wrist angle. We named these sonographically detected signals about the architectural change of the muscle as sonomyography (SMG). The mean ratio between the wrist angle and the percentage deformation of the forearm muscle was 7.2+/-3.7 degrees /% for the normal subjects. The intraclass correlation coefficient (ICC) of this ratio among the three repeated tests was 0.868. The SMG signals from the residual forearms were also successfully detected when the three amputee subjects contracted their residual muscles. The results demonstrated that SMG had potentials for the musculoskeletal control and assessment.

Amputees↗
PubMed2005

Chinese medicinal herbs for acute bronchitis.

BACKGROUND: Acute bronchitis is one of the most common diagnoses made by primary-care physicians. It is traditionally treated with antibiotics, (although the evidence for their effectiveness is weak and modest at best), and other even less effective treatments. Chinese medicinal herbs have been also used as treatment. OBJECTIVES: This review aims to summarise the existing evidence on the comparative effectiveness and safety of Chinese medicinal herbs for treating uncomplicated acute bronchitis. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 1, 2005), which includes the Cochrane Acute Respiratory Infections Group's specialised register; The Chinese Cochrane Centre's Controlled Trials Register (up to December 2004); MEDLINE (1966 to March Week 1, 2005); EMBASE (1988 to December 2004); and the Chinese Biomedical Database (CBM) (1980 to December 2004). SELECTION CRITERIA: Randomised controlled trials comparing Chinese medicinal herbs with placebo, antibiotics or other Western medicines for the treatment of uncomplicated acute bronchitis. DATA COLLECTION AND ANALYSIS: At least two authors extracted data and assessed trial quality. MAIN RESULTS: Four trials reported the time to improvement of cough, fever, and rales associated with bronchitis and showed that patients treated with Chinese herbs had a shorter duration of signs and symptoms. Two trials reported the proportion of patients with improved signs and symptoms at follow up and showed that Chinese herbs were beneficial in terms of relief of signs and symptoms. Thirteen trials analysed the data on physician global assessment of improvement at follow up. Nine of thirteen trials showed that Chinese herbs were superior to routine treatment and the other four trials showed a similar effect to routine treatment. In general, Chinese herbs appeared beneficial. Only one trial reported on adverse effects during treatment. AUTHORS' CONCLUSIONS: There is insufficient quality data to recommend the routine use of Chinese herbs for acute bronchitis. The benefit found in this systematic review could be due to publication bias and study-design limitations of the individual studies. In addition, the safety of Chinese herbs is unknown due to the lack of toxicological evidence on these Chinese herbs, though adverse events are rarely reported. Chinese herbs should be used carefully.

Acute Disease↗
PubMed2005

Preparation and electrochemical hydrogen storage of boron nitride nanotubes.

Boron nitride (BN) nanotubes were synthesized through chemical vapor deposition over a wafer made by a LaNi5/B mixture and nickel powder at 1473 K. Scanning electron microscopy, transmission electron microscopy, energy-dispersive spectroscopy, X-ray diffraction, and X-ray photoelectron spectroscopy were performed to characterize the microstructure and composition of BN nanotubes. It was found that the obtained BN nanotubes were straight with a diameter of 30-50 nm and a length of up to several microns. We first verify that the BN nanotubes can storage hydrogen by means of an electrochemical method, though its capacity is low at present. The hydrogen desorption of nonelectrochemical recombination in cyclic voltammograms, which is considered as the slow reaction at BN nanotubes, suggests the possible existence of strong chemisorption of hydrogen, and it may lead to the lower discharge capacity of BN nanotubes. It is tentatively concluded that the improvement of the electrocatalytic activity by surface modification with metal or alloy would enhance the electrochemical hydrogen storage capacity of BN nanotubes.

Journal Article↗
PubMed2005

PPARgamma agonists exert antifibrotic effects in renal tubular cells exposed to high glucose.

Peroxisome proliferator-activated receptor-gamma (PPARgamma) are ligand-activated transcription factors that regulate cell growth, inflammation, lipid metabolism, and insulin sensitivity. We recently demonstrated that PPARgamma agonists limit high glucose-induced inflammation in a model of proximal tubular cells (PTC; Panchapakesan U, Pollock CA, and Chen XM. Am J Physiol Renal Physiol 287: F528-F534, 2004). However, the role of PPARgamma in the excess extracellular matrix production is largely unknown. We evaluated the effect of 24- to 48-h 8 microM l-805645 or 10 microM pioglitazone on 25 mM D-glucose-induced markers of fibrosis in HK-2 cells. High D-glucose induced nuclear binding of activator protein-1 (AP-1) to 140.8 +/- 10.9% (P < 0.05), which was attenuated with L-805645 and pioglitazone to 82.3 +/- 14.4 (P < 0.01 vs. high D-glucose) and 99.3 +/- 12.2% (P < 0.05 vs. high D-glucose), respectively. High D-glucose increased total production of transforming growth factor (TGF)-beta(1) 139.6 +/- 6.5% (P < 0.05), which was reversed with L-805645 and pioglitazone to 68.73 +/- 5.7 (P < 0.01 vs. high D-glucose) and 112 +/- 13.6% (P < 0.05 vs. high D-glucose). L-805645 and pioglitazone reduced high d-glucose-induced fibronectin from 156.0 +/- 24.9 (P < 0.05) to 81.9 +/- 16.0 and 57.4 +/- 12.7%, respectively (both P < 0.01 vs. high D-glucose). Collagen IV was not induced by high d-glucose. L-805645 and pioglitazone suppressed collagen IV to 68.0 +/- 14.5 (P < 0.05) and 46.5 +/- 11.6% (P < 0.01) vs. high D-glucose, respectively. High D-glucose increased the nuclear binding of NF-kappaB to 167 +/- 22.4% (P < 0.05), which was not modified with PPARgamma agonists. In conclusion, PPARgamma agonists exert antifibrotic effects in human PTC in high glucose by attenuating the increase in AP-1, TGF-beta(1), and the downstream production of the extracellular matrix protein fibronectin.

Cell Culture Techniques↗
PubMed2005

Effects of pleiotrophin (PTN) over-expression on mouse long bone development, fracture healing and bone repair.

Pleiotrophin (PTN) was found to have potent effects on regulation of osteoblast recruitment, proliferation and differentiation. The present study examined the long-term effects of targeted PTN over-expression on bone development and repair in a transgenic mouse model. Femurs and tibiae from the PTN transgenic mice and the wild type mice at age 1, 2, 4, 6, 12 and 24 months were collected, and examined by radiography, peripheral quantitative computed tomography (pQCT), histology and mechanical testing. Age-matched PTN and the control mice received a standardized femoral fracture, followed by regular x-rays and sacrificed at day 16 post-fracture for histology examination. A cortical hole was drilled on the tibiae of age-matched PTN and wild type mice, collagen sponge with either saline, 100 ng of rhBMP-2 or rhPTN was implanted in the holes, and animals were sacrificed 10 days later, subject to pQCT and histology examinations. During early stages of bone development, the PTN mice had advanced bone growth in length and maturation, but the difference diminished in later life. The fracture healing was impaired in the PTN mice, and there was delayed callus formation and remodelling. The cortical holes treated with BMP-2 in the PTN mice had significantly less trabecular bone formation. The current study confirmed that the targeted PTN over-expression in mouse bone has moderate enhancing effects on early bone development; but the bones become brittle in later life. Fracture healing was impaired in the adult PTN mice and this may be due to inhibitory effects of PTN over-expression on BMP-2 mediated bone induction.

Animals↗
PubMed2005

Intersubgenomic heterosis in seed yield potential observed in a new type of Brassica napus introgressed with partial Brassica rapa genome.

This paper reports the observation on the intersubgenomic heterosis for seed yield among hybrids between natural Brassica napus (A(n)A(n)C(n)C(n)) and a new type of B. napus with introgressions of genomic components of Brassica rapa (A(r)A(r)). This B. napus was selected from the progeny of B. napus x B. rapa and (B. napus x B. rapa) x B. rapa based on extensive phenotypic and cytological observation. Among the 129 studied partial intersubgenomic hybrids, which were obtained by randomly crossing 13 lines of the new type of B. napus in F(3) or BC(1)F(3) to 27 cultivars of B. napus from different regions as tester lines, about 90% of combinations exceeded the yield of their respective tester lines, whereas about 75% and 25% of combinations surpassed two elite Chinese cultivars, respectively. This strong heterosis was further confirmed by reevaluating 2 out of the 129 combinations in a successive year and by surveying hybrids between 20 lines of the new type of B. napus in BC(1)F(5) and its parental B. napus in two locations. Some DNA segments from B. rapa were identified with significant effects on seed yield and yield components of the new type of B. napus in BC(1)F(5) and intersubgenomic hybrids in positive or negative direction. It seems that the genomic components introgressed from B. rapa contributed to improvement of seed yield of rapeseed.

Analysis of Variance↗
PubMed2005

Low frequency of CHEK2 1100delC allele in Australian multiple-case breast cancer families: functional analysis in heterozygous individuals.

A protein-truncating variant of CHEK2, 1100delC, is associated with a moderate increase in breast cancer risk. We have determined the prevalence of this allele in index cases from 300 Australian multiple-case breast cancer families, 95% of which had been found to be negative for mutations in BRCA1 and BRCA2. Only two (0.6%) index cases heterozygous for the CHEK2 mutation were identified. All available relatives in these two families were genotyped, but there was no evidence of co-segregation between the CHEK2 variant and breast cancer. Lymphoblastoid cell lines established from a heterozygous carrier contained approximately 20% of the CHEK2 1100delC mRNA relative to wild-type CHEK2 transcript. However, no truncated CHK2 protein was detectable. Analyses of expression and phosphorylation of wild-type CHK2 suggest that the variant is likely to act by haploinsufficiency. Analysis of CDC25A degradation, a downstream target of CHK2, suggests that some compensation occurs to allow normal degradation of CDC25A. Such compensation of the 1100delC defect in CHEK2 might explain the rather low breast cancer risk associated with the CHEK2 variant, compared to that associated with truncating mutations in BRCA1 or BRCA2.

Adult↗