Beneficial Effects of Saw Palmetto Fruit Extract on Urinary Symptoms in Japanese Female Subjects by a Multicenter, Randomized, Double-Blind, Placebo-Controlled Study.

Saw palmetto berry extract (SPE) is the most commonly consumed supplement by men with benign prostatic hyperplasia (BPH). The oral administration of SPE was previously shown to significantly attenuate urodynamic symptoms in the hyperactive bladders of female rats by increasing bladder capacity and prolonging the micturition interval. The amelioration of urodynamic symptoms by SPE may be partly attributed to its binding to muscarinic receptors in the urinary bladder and its inhibition of vanilloid receptors on afferent nerves. Therefore, SPE may be pharmacologically effective at mitigating lower urinary tract symptoms (LUTS) in women. The efficacy and safety of a 12-week treatment with SPE in adult women with urinary symptoms were examined herein. The daytime frequency score in the core lower urinary symptom score (CLSS) questionnaire was significantly lower in women with LUTS treated with SPE for 12 weeks than in the placebo group. A subgroup analysis revealed that SPE alleviated the symptoms of daytime frequency (CLSS Q1) and nocturia (CLSS Q2) in a subset of subjects with a CLSS Q5 score of 1 or higher. The daytime frequency of urination in overactive bladder symptom score (OABSS) Q1 was also significantly improved by the SPE treatment. In conclusion, the present study is the first to demonstrate the potential of SPE to mitigate LUTS in adult women.

Detection of bazedoxifene, a selective estrogen receptor modulator, in human urine by liquid chromatography-tandem mass spectrometry.

Bazedoxifene, a selective estrogen receptor modulator, has been explicitly included in the prohibited list issued by the World Anti-Doping Agency (WADA) since January 2020. A high-resolution liquid chromatography-tandem mass spectrometric detection method was developed to identify bazedoxifene and its metabolites in human urine and to quantify bazedoxifene (free plus glucuronide) for doping control purposes. Bazedoxifene acetate (20 mg) was orally administered to seven male volunteers, and the urine samples collected were analyzed using the developed method. The linearity ranged from 0.5 to 200 ng/ml, and the limit of detection was <0.2 ng/ml. The interday precision (2.2% to 3.6%) and the interday accuracy (-10.0% to 1.9%) were adequate. Bazedoxifene, bazedoxifene-N-oxide, and bazedoxifene glucoconjugates were identified in the urine samples. The profiles of the urinary excretion indicated the presence of small amounts of free bazedoxifene and bazedoxifene-N-oxide, whereas bazedoxifene glucuronide was the predominant metabolite. The cumulative excretion amount of bazedoxifene (free form plus glucuronide conjugate) within 78 h after the administration was 0.7% to 1.3% of the total dose. In all subjects, bazedoxifene (free plus glucuronide) could be detected in urine up to 78 h after administration.

Efficacy and safety of intravesical instillation of KRP-116D (50% dimethyl sulfoxide solution) for interstitial cystitis/bladder pain syndrome in Japanese patients: A multicenter, randomized, double-blind, placebo-controlled, clinical study.

OBJECTIVE: To evaluate the efficacy and safety of intravesical KRP-116D, 50% dimethyl sulfoxide solution compared with placebo, in interstitial cystitis/bladder pain syndrome patients. METHODS: Japanese interstitial cystitis/bladder pain syndrome patients with an O'Leary-Sant Interstitial Cystitis Symptom Index score of ≥9, who exhibited the bladder-centric phenotype of interstitial cystitis/bladder pain syndrome diagnosed by cystoscopy and bladder-derived pain, were enrolled. Patients were allocated to receive either KRP-116D (n = 49) or placebo (n = 47). The study drug was intravesically administered every 2 weeks for 12 weeks. RESULTS: For the primary endpoint, the change in the mean O'Leary-Sant Interstitial Cystitis Symptom Index score from baseline to week 12 was -5.2 in the KRP-116D group and -3.4 in the placebo group. The estimated difference between the KRP-116D and placebo groups was -1.8 (95% confidence interval -3.3, -0.3; P = 0.0188). Statistically significant improvements for KRP-116D were also observed in the secondary endpoints including O'Leary-Sant Interstitial Cystitis Problem Index score, micturition episodes/24 h, voided volume/micturition, maximum voided volume/micturition, numerical rating scale score for bladder pain, and global response assessment score. The adverse drug reactions were mild to moderate, and manageable. CONCLUSIONS: This first randomized, double-blind, placebo-controlled trial shows that KRP-116D improves symptoms, voiding parameters, and global response assessment, compared with placebo, and has a well-tolerated safety profile in interstitial cystitis/bladder pain syndrome patients with the bladder-centric phenotype.

A randomized controlled study of the efficacy of tadalafil monotherapy versus combination of tadalafil and mirabegron for the treatment of persistent overactive bladder symptoms in men presenting with lower urinary tract symptoms (CONTACT Study).

AIM: To evaluate efficacy and safety of combination of tadalafil + mirabegron for overactive bladder/benign prostatic hyperplasia (OAB/BPH). METHODS: Male patients with lower urinary tract symptoms (50 to 89 years), with remaining OAB symptoms even after administering tadalafil for more than 8 weeks were randomly assigned to either tadalafil monotherapy group (5 mg/day) or tadalafil/mirabegron combination therapy group (5 mg/50 mg/day). The primary endpoint was change from baseline in total OAB symptom score (OABSS) at week 12. The secondary endpoints were changes in International Prostate Symptom Score (IPSS), NIH-chronic prostatitis symptom index (NIH-CPSI), and micturition chart parameters at weeks 4 and 12. RESULTS: A total of 176 patients were randomized to either monotherapy (87 patients) or combination therapy (89 patients). The baseline characteristics of patients in the two groups were similar. The total OABSS (95% confidence interval) of combination therapy was significantly decreased by 1.78 (1.05-2.50) points compared with that of monotherapy (P < .001). Changes from baseline in OABSS nighttime voiding score, urgency score, urgency incontinence score, IPSS storage subscores, NIH-CPSI total score, and numbers of voids, nighttime-voids, and urgency episodes/day in micturition chart were significantly reduced in combination therapy (all P < .001). Patient-reported outcome was significantly more satisfactory in combination therapy than in monotherapy (P < .001). One moderate adverse event (pain in hip joint) with hardly presumed causal relationship with therapy and seven mild adverse events were noted in monotherapy and combination therapy group, respectively. CONCLUSIONS: The effect of tadalafil/mirabegron combination therapy on relieving OAB symptoms appeared to be greater than that of tadalafil monotherapy and can be safely used.

Clinical Effects of Formulated Food of Peucedanum japonicum Extract and Saw Palmetto Extract in Male Patients with Lower Urinary Tract Symptoms.

OBJECTIVES: To evaluate changes over time in subjective symptom scores and urination parameters before and after oral administration of formulated food containing a combination of Peucedanum japonicum (P. japonicum) extract and saw palmetto extract (SPE) in male patients with lower urinary tract symptoms (LUTS). METHODS: This study was conducted in an open label manner on male patients with untreated LUTS. The urination state of patients was evaluated before and after administration of food formulated with P. japonicum extract and SPE for 4 weeks, based on urodynamic parameters and subjective symptom scores (International Prostate Symptom Score [IPSS and IPSS-QOL], Overactive Bladder Symptom Score [OABSS], Overactive Bladder Questionnaire [OAB-q], and International Index of Erectile Function [IIEF]). RESULTS: After the administration of food formulated with these extracts, the following results were obtained: (i) Subjective findings: The IPSS-QOL score improved significantly; both parameters related to nocturia, i.e., frequency of nighttime urination and OABSS-2, improved significantly; other ratings for subjective symptoms slightly improved. (ii) Objective findings: Residual urine volume decreased significantly, and blood prostate specific antigen (PSA) and urinary 8-OHdG levels decreased slightly after the treatment. (iii) Other findings: Blood pressure decreased slightly. No adverse drug reactions were reported. (iv) Patient impressions: 75% of patients gave a rating of "Good" or higher, with 15 out of 20 patients wanting to continue treatment after the end of 4-week administration period. CONCLUSIONS: Food formulated with P. japonicum extract and SPE may be useful to decrease frequency of nighttime urination and residual urine volume in male patients with LUTS.

Spironolactone reduces cardiovascular and cerebrovascular morbidity and mortality in hemodialysis patients.

OBJECTIVES: This study sought to assess whether spironolactone treatment reduces the high incidence of cardiovascular and cerebrovascular (CCV) morbidity and mortality in hemodialysis (HD) patients. BACKGROUND: Aldosterone receptor blockers reduce cardiac-related events, but the efficacy of the agents in HD patients is unclear. METHODS: A 3-year randomized trial involving 5 clinics was performed. Of the 309 oligoanuric HD patients enrolled in the study, 157 patients were randomly assigned to receive 25 mg/day of spironolactone without any restriction on dietary potassium intake (treatment group), and 152 patients were assigned to a control group. The primary outcome was a composite of death from CCV events or hospitalization for CCV events, and the secondary outcome was death from all causes. RESULTS: During the 3-year follow-up, the primary outcome occurred in 5.7% of patients in the treatment group and in 12.5% of patients in the control group. Hazard ratios (HRs) for the primary outcome for treatment were 0.404 (95% confidence interval [CI]: 0.202 to 0.809; p = 0.017) and 0.379 (95% CI: 0.173 to 0.832; p = 0.016) before and after adjustment, respectively. The secondary outcome was significantly reduced in the treatment group compared with the control group (6.4% vs. 19.7%; HRs: 0.355 [95% CI: 0.191 to 0.662; p = 0.002] and 0.335 [95% CI: 0.162 to 0.693; p = 0.003] before and after adjustment, respectively). Gynecomastia or breast pain was reported in 16 patients (10.2%) in the treatment group. Serious hyperkalemia led to treatment discontinuation in 3 patients (1.9%). CONCLUSIONS: Aldosterone receptor blockade using spironolactone may substantially reduce the risk of both CCV morbidity and death among HD patients; however, larger-scale studies are recommended to further confirm its efficacy. (Effects of Spironolactone on Cardio- and Cerebrovascular Morbidity and Mortality in Hemodialysis Patients; NCT01687699).

Association between dopamine beta hydroxylase rs5320 polymorphism and smoking behaviour in elderly Japanese.

The dopaminergic brain pathway is involved in many addictive behaviours, hence represents a good candidate in the study of smoking behaviour and nicotine addiction. Dopamine beta hydroxylase (DBH) is an enzyme that catalyses the conversion of dopamine into noradrenaline. This study, the first of its kind, was done to investigate the role of DBH rs5320 polymorphism in smoking behaviour of elderly Japanese. This was done by collecting blood samples from 2521 subjects with various smoking habits to genotype the DBH rs5320 polymorphism. Participants also had to fill out a questionnaire containing questions regarding their lifestyles. Some of the questions were from the Fagerström Test for Nicotine Dependence (FTND) and the Tobacco Dependence Screener (TDS). It was found that male ever-smokers with AA genotype smoked less cigarettes per day than those with GG and AG genotypes. FTND scores were also lowest in male ever-smokers with AA genotype and in female ever-smokers with AG genotype. There was no correlation detected between the TDS scores and any of the genotypes. This study shows that DBH rs5320 polymorphism influences nicotine dependence.

Genetic susceptibility to lung cancer.

Lung cancer is a highly environmental disease, but cancer researchers have long been interested in investigating genetic susceptibility to lung cancer. This paper is a historical review and provides updated perspectives on lung cancer susceptibility research. The recent introduction of easier genotyping methods and the availability of an almost complete human genome database facilitated the association study to thousands of cases and controls for millions of genetic markers. Discoveries in the field of behavior genetics, that is, the genetic aspects of smoking behavior and nicotine addiction, unexpectedly indicated that polymorphisms in the human central nervous system play an important role in eventually leading to lung cancer. These findings were achieved by using comprehensive approaches, such as a genome, transcriptome, or proteome approach, and the studies were often conducted without a hypothesis. Another-omics approach, the "adductome" or "exposome" approach to how life style information can be integrated into the framework of genetic association studies, has recently emerged. These new paradigms will influence the area of lung cancer risk evaluation in genome cohort studies.

Metachronous multiple adenocarcinomas of the pancreas.

We report a rare case of metachronous multiple adenocarcinoma of the pancreas. A 59-year-old Japanese man visited our institute for a routine workup as a hepatitis C virus carrier, resulting in detection of a 3-cm tumor in the pancreatic body by screening echogram. Results from several imaging modalities were consistent with pancreatic carcinoma. Distal pancreatectomy along with dissection of partial gastrectomy, transverse colectomy, and lymph node dissection were performed in November 2003. Histological examination confirmed a pancreatic ductal adenocarcinoma with a clear surgical margin and negative lymph node metastases. Gemcitabine was administered for 5 years, then suspended because no recurrent signs were found. The patient returned to our hospital in March 2009, with obstructive jaundice along with a 2-cm tumor in the head of the remnant pancreas. The condition of the patient was carefully investigated and extra-pancreatic metastatic lesions were not found; a pancreaticoduodenectomy was then carried out. Histological examination revealed a diagnosis of pancreatic adenocarcinoma arising from the remnant pancreas gland.

Association between neuropeptide Y receptor 2 polymorphism and the smoking behavior of elderly Japanese.

Molecular heterogeneity of neuropeptide Y (NPY) and its three receptors (1, 2 and 5) has recently been discovered. NPY2R polymorphisms have been shown to be related to cocaine and alcohol dependence in European Americans. To test our hypothesis that these polymorphisms influence the smoking behavior of Japanese population, we investigated the prevalence of the rs4425326 and rs6857715 polymorphisms, which have been suggested to be related to alcohol dependence in European Americans, in 2517 Japanese elderly subjects for whom information on smoking behaviors was available. The prevalence of current smokers was greater among Japanese men having the rs4425326 C allele than ex-smokers. Among the ever-smokers, the Fagerström Test for Nicotine Dependence scores were higher in men having the rs4425326 homozygous T allelotype, and the numbers of cigarettes smoked per day were also significantly higher in the male smokers having the TT genotype. No correlations between the Tobacco Dependence Screener scores and any genotypes were detected. These results suggest that rs4425326 polymorphism may be related to smoking behavior in the Japanese elderly population. This study for the first time suggests NPY2R genotype as a possible genetic factor in nicotine dependence.

Secreted form of EphA7 in lung cancer.

EPHA7 is a member of the EPHA family of receptor kinases, among which several members are known to be involved in human lung carcinogenesis. We report here a novel spliced variant, the so-called secreted form of EPHA7, recently reported in malignant lymphoma, in human lung cancer cell lines and primary lung cancer. In contrast to the EPHA7 down-regulation in colorectal cancer by promoter hypermethylation, EPHA7 is expressed at a substantial level in most human lung cancers and the secreted form of EPHA7 mRNA was found in a fraction of primary lung cancer tissues, lung cancer cell lines, and immortalized bronchogenic epithelial cell lines. Interestingly, the secreted form of EPHA7 message was predominantly detected in non-adeno type lung carcinoma. The mechanistic role of the secreted form of EPHA7 in human lung carcinogenesis is not clear, but the presence of this form could distinctly exclude adenocarcinoma of the lung from the other categories, i.e., squamous cell carcinoma, small cell carcinoma and large cell carcinoma, which have strong association with smoking. This is the first study to detect the secreted form of EPHA7 in human epithelial tissues. EPHA7 warrants further investigation to determine its possible involvement in smoking related lung carcinogenesis.

EML4-ALK fusion transcripts in immunohistochemically ALK-positive non-small cell lung carcinomas.

EML4-ALK fusion transcripts have been found in a subset of non-small cell lung carcinomas (NSCLCs); however, their protein expression status has not yet been fully elucidated. In this study we investigated ALK protein expression in 302 NSCLCs and 291 gastric carcinomas by means of immunohistochemical analysis. Twelve (4.0%) NSCLCs, but none of the gastric carcinomas, were found to be positive for ALK. The ALK signal was detected in the cytoplasm of cancer cells. Subsequent RNA analysis of 10 RNA-available, immunohistochemically ALK-positive tumors revealed that three tumors had EML4-ALK variant 1, three tumors had variant 2, three tumors had variants 3a and 3b, and one tumor had a novel variant in which exon 14 of EML4 is connected to the nucleotide at position 53 of exon 20 of ALK by a 2-bp insertion. These results suggest that immunohistochemical ALK detection is a useful way to screen NSCLCs for tumors containing ALK fusions.

Altered expression of the human base excision repair gene NTH1 in gastric cancer.

A base excision repair enzyme, NTH1, has activity that is capable of removing oxidized pyrimidines, such as thymine glycol (Tg), from DNA. To clarify whether the NTH1 gene is involved in gastric carcinogenesis, we first examined the NTH1 expression level in eight gastric cancer cell lines, and the results showed that NTH1 expression was downregulated in all of them, including cell line AGS. Next, a comparison of excisional repair activity against Tg by empty vector-transfected AGS clones and FLAG-NTH1-expressing AGS clones showed that a low NTH1 expression level led to low capacity to repair the damaged base in the gastric epithelial cells. Reduced messenger RNA expression of NTH1 was also detected in 36% (18/50) of primary gastric cancers. Moreover, immunohistochemical analysis revealed that NTH1 was predominantly localized in the cytoplasm in 24% (12/50) of the primary gastric cancers in contrast to the nuclear localization in non-cancerous tissue, suggesting impaired excisional repair ability for nuclear DNA. No associations between clinicopathological factors and NTH1 expression level or localization pattern were detected in the gastric cancers. Next, we found two novel genetic polymorphisms, i.e. c.-163C>G and c.-241_-221del, in the NTH1 promoter region, and a luciferase assay showed that both were associated with reduced promoter activity. However, there were no associations between the polymorphisms and risk of gastric cancer in a gastric cancer case-control study. These findings suggested that downregulation of NTH1 expression and abnormal localization of NTH1 may be involved in the pathogenesis of a subset of gastric cancers.

Characterization of adenocarcinoma of the lung in a familial adenomatous polyposis patient.

The incidence of several extracolonic tumors, such as duodenal carcinoma, is higher in familial adenomatous polyposis (FAP) patients than in the general population, but there is little information about lung carcinoma in FAP. A 43-year-old woman presented with a lung tumor 17 years after total colectomy for FAP. Pathohistological analysis of the lung tumor demonstrated mixed adenocarcinoma consisting of a papillary adenocarcinoma component and a bronchioloalveolar carcinoma component. Sequencing analysis indicated a germline APC mutation from TCA to TGA (stop) at codon 1110, but no pathogenic germline MYH mutations. The other APC allele in the lung carcinoma was not inactivated by somatic mutations, promoter methylation, or chromosomal deletion. No somatic mutations in any of the coding regions of the p53 gene or in the mutation hot spot regions of the K-ras or EGFR genes were detected in the carcinoma. Amplification, however, of three chromosome regions, 5p, 8q, and 12q14-12q21, was identified in the carcinoma on genome-wide high-resolution single-nucleotide polymorphism (SNP) microarray. The present results suggest that the chromosomal copy number alterations detected on SNP microarray were involved in the carcinogenesis of the adenocarcinoma of the lung in the present FAP patient.

Inverse relationship between the length of the EGFR CA repeat polymorphism in lung carcinoma and protein expression of EGFR in the carcinoma.

BACKGROUND AND OBJECTIVES: There is a CA dinucleotide repeat polymorphism in the first intron of the epidermal growth factor receptor (EGFR) gene. Our aim was to examine the relationship between the CA repeat length in lung carcinoma and EGFR mutation, EGFR gene copy number, and EGFR protein expression level in the carcinoma. METHODS: We examined 168 lung carcinomas for the length of the CA repeat polymorphism by PCR-polyacrylamide gel electrophoresis analysis, for EGFR mutations by sequencing analysis, for EGFR gene copy number by fluorescence in situ hybridization analysis, and for EGFR protein expression by immunohistochemical analysis. RESULTS: When the carcinomas were divided into two groups according to the length of their CA repeat polymorphism, the EGFR protein expression level was found to be significantly higher in the shorter allele group than in the longer allele group (P = 0.0116), but its length was not associated with EGFR somatic mutations, high EGFR gene copy numbers, or clinicopathological factors, such as histological type or stage. CONCLUSIONS: The results suggested that the length of the EGFR CA repeat polymorphism in lung carcinoma is inversely related with level of EGFR protein expression in the carcinoma.

Fluorescence-labeled methylation-sensitive amplified fragment length polymorphism (FL-MS-AFLP) analysis for quantitative determination of DNA methylation and demethylation status.

The PCR-based DNA fingerprinting method called the methylation-sensitive amplified fragment length polymorphism (MS-AFLP) analysis is used for genome-wide scanning of methylation status. In this study, we developed a method of fluorescence-labeled MS-AFLP (FL-MS-AFLP) analysis by applying a fluorescence-labeled primer and fluorescence-detecting electrophoresis apparatus to the existing method of MS-AFLP analysis. The FL-MS-AFLP analysis enables quantitative evaluation of more than 350 random CpG loci per run. It was shown to allow evaluation of the differences in methylation level of blood DNA of gastric cancer patients and evaluation of hypermethylation and hypomethylation in DNA from gastric cancer tissue in comparison with adjacent non-cancerous tissue.

EML4-ALK fusion transcripts, but no NPM-, TPM3-, CLTC-, ATIC-, or TFG-ALK fusion transcripts, in non-small cell lung carcinomas.

EML4-ALK gene fusions have recently been discovered in a subset of human lung carcinomas, and fusions of the ALK tyrosine kinase gene with the NPM, TPM3, CLTC, ATIC, and TFG genes have been found in hematological malignancies. To elucidate the role of fusions between ALK and other genes in pulmonary carcinogenesis, we examined 77 non-small cell lung carcinomas (NSCLCs) for EML4-, NPM-, TPM3-, CLTC-, ATIC-, and TFG-ALK fusion transcripts by RT-PCR and subsequent sequencing analysis. Although no expression of NPM-, TPM3-, CLTC-, ATIC-, or TFG-ALK fusion transcripts were detected in any of the cases, expression of EML4-ALK fusion transcripts was detected in two (2.6%) of the 77 NSCLCs. In one of the two NSCLCs there was fusion between exon 13 of EML4 and exon 20 of ALK, i.e., variant 1, and in the other there was fusion between exon 20 of EML4 and exon 20 of ALK, i.e., variant 2. Both patients had a history of smoking, and histologically the carcinomas were adenocarcinoma. No somatic mutations were detected in the mutation cluster regions of the EGFR, K-RAS, and PIK3CA genes in these two carcinomas, however, a Pro177Ser mutation of the p53 gene was detected in the carcinoma that contained the variant 1 EML4-ALK fusion transcripts. In situ PCR of a paraffin block section showed that the carcinoma with expression of the variant 1 actually contained an EML4-ALK fusion gene. These results suggested that the EML4-ALK fusion gene product is involved in the carcinogenesis of a subset of NSCLCs.

Novel mutations of the GLA gene in Japanese patients with Fabry disease and their functional characterization by active site specific chaperone.

Fabry disease is an X-linked recessive inborn metabolic disorder caused by a deficiency of the lysosomal enzyme alpha-galactosidase A (EC 3.2.1.22). The causative mutations are diverse, include both large rearrangements and single-base substitutions, and are dispersed throughout the 7 exons of the alpha-galactosidase A gene (GLA). Mutation hotspots for Fabry disease do not exist. We examined 62 Fabry patients in Japan and found 24 GLA mutations, including 11 novel ones. A potential treatment reported for Fabry disease is active site specific chaperone (ASSC) therapy using 1-deoxygalactonojirimycin (DGJ), an inhibitor of alpha-galactosidase A, at subinhibitory concentrations. We transfected COS-7 cells with the 24 mutant GLAs and analyzed the alpha-galactosidase A activities. We then treated the transfected COS-7 cells with DGJ and analyzed its effect on the mutant enzyme activities. The activity of 11 missense mutants increased significantly with DGJ. Although ASSC therapy is useful only for misfolding mutants and therefore not applicable to all cases, it may be useful for treating many Japanese patients with Fabry disease.

PIK3CA mutation and amplification in human lung cancer.

To explore the significance of phosphatidylinositol-3-kinase, catalytic, alpha (PIK3CA) in the carcinogenesis in human lung, mutations and copy number changes were investigated in 148 Japanese patients with primary cancer of the lung. For biological validation, the effects of exogenously expressed wild-type and mutated PIK3CA were studied in an immortalized human airway epithelial cell line. Mutations in PIK3CA were found in five (3.6%) of the 139 available patients, and copy number gains were found in 21 (18.3%) of 115 patients, respectively. Overall, mutations or copy number gains were detected in 24 of the 106 patients (22.6%) for whom results in both analyses were available. The prevalence of copy number gains was higher in men, smokers, and in patients with squamous cell carcinoma than in the opposite categories. The copy number changes showed a trend toward higher prevalence in the earlier stages (P = 0.038). Interestingly, the presence of mutations and of copy number alterations were mutually exclusive in the present patients, implying that both entail equivalent oncogenic potential. Over-expressed wild-type PIK3CA and its two common mutants, K545E and H1047R, significantly enhanced the anchorage-independent growth activity and migration activity of immortalized airway epithelium 16HBE14o- cells, but the effects of the K545E and H1047R mutants were more remarkable than those of the wild-type. The present demonstrates an important role of PIK3CA in human lung carcinogenesis.