ANXA2 (annexin A2) is crucial to ATG7-mediated autophagy, leading to tumor aggressiveness in triple-negative breast cancer cells.

Triple-negative breast cancer (TNBC) is associated with a poor prognosis and metastatic growth. TNBC cells frequently undergo macroautophagy/autophagy, contributing to tumor progression and chemotherapeutic resistance. ANXA2 (annexin A2), a potential therapeutic target for TNBC, has been reported to stimulate autophagy. In this study, we investigated the role of ANXA2 in autophagic processes in TNBC cells. TNBC patients exhibited high levels of ANXA2, which correlated with poor outcomes. ANXA2 increased LC3B-II levels following bafilomycin A1 treatment and enhanced autophagic flux in TNBC cells. Notably, ANXA2 upregulated the phosphorylation of HSF1 (heat shock transcription factor 1), resulting in the transcriptional activation of ATG7 (autophagy related 7). The mechanistic target of rapamycin kinase complex 2 (MTORC2) played an important role in ANXA2-mediated ATG7 transcription by HSF1. MTORC2 did not affect the mRNA level of ANXA2, but it was involved in the protein stability of ANXA2. HSPA (heat shock protein family A (Hsp70)) was a potential interacting protein with ANXA2, which may protect ANXA2 from lysosomal proteolysis. ANXA2 knockdown significantly increased sensitivity to doxorubicin, the first-line chemotherapeutic regimen for TNBC treatment, suggesting that the inhibition of autophagy by ANXA2 knockdown may overcome doxorubicin resistance. In a TNBC xenograft mouse model, we demonstrated that ANXA2 knockdown combined with doxorubicin administration significantly inhibited tumor growth compared to doxorubicin treatment alone, offering a promising avenue to enhance the effectiveness of chemotherapy. In summary, our study elucidated the molecular mechanism by which ANXA2 modulates autophagy, suggesting a potential therapeutic approach for TNBC treatment.Abbreviation: ATG: autophagy related; ChIP: chromatin-immunoprecipitation; HBSS: Hanks' balanced salt solution; HSF1: heat shock transcription factor 1; MTOR: mechanistic target of rapamycin kinase; TNBC: triple-negative breast cancer; TFEB: transcription factor EB; TFE3: transcription factor binding to IGHM enhancer 3.

Plexiform Angiomyxoid Myofibroblastic Tumor of the Stomach: a Rare Case.

Plexiform angiomyxoid myofibroblastic tumor (PAMT) of the stomach is a very rare mesenchymal tumor of the gastrointestinal tract. We report a case of asymptomatic gastric PAMT that was pathologically confirmed after surgical resection. The tumor had a multinodular plexiform growth pattern, bland-looking spindle cells, and an Alcian blue-positive myxoid stromal matrix rich in small blood vessels. Immunohistochemistry analysis revealed that the tumor cells of the PAMT were positive for smooth muscle actin (SMA) and negative for c-kit, CD34, S-100 protein, epithelial membrane antigen (EMA), and desmin. PAMT should be differentiated from other submucosal tumors of the stomach by immunohistochemical findings. Considering the benign features of this tumor, observation without resection may be an option for the treatment of PAMT if the tumor is asymptomatic.

Meaning-Making Coping Among Cancer Patients in Sweden and South Korea: A Comparative Perspective.

The present study compared meaning-making coping among cancer patients in Sweden and South Korea, with a focus on the sociocultural context. Semi-structured interviews were conducted with 51 Swedes and 33 Koreans. The results showed significant differences between the two countries as well as similarities in existential, spiritual, and religious coping. For example, Swedes primarily used meaning-making coping as a means of meditation or relaxation, whereas Koreans relied on coping with prayer and using healthy foods as a means to survive. The present study confirms the significance of investigating cultural context when we explore the use of meaning-making coping among people who have experienced cancer.

Validation study associating glutaminase promoter variations with hepatic encephalopathy in East Asian populations.

BACKGROUND AND AIM: In a recent study, microsatellite variations (GCA tandem repeats) in the promoter region of the (kidney-type) glutaminase gene were associated with the development of hepatic encephalopathy (HE) in Spanish patients with cirrhosis. The objective of this study was to validate the relation between microsatellite variations in the glutaminase promoter region and the development of overt HE in Korean patients with liver cirrhosis. METHODS: We performed a prospective cohort study of 154 cirrhotic patients who underwent a glutaminase microsatellite study without previous overt HE history at baseline. The primary end point was the first episode of overt HE. The microsatellite length was categorized into three groups based on its repeated number, with a cutoff value of 14; 65 (42.2%), 70 (45.5%), and 19 (12.3%) patients had the short-short, short-long, and long-long alleles, respectively. RESULTS: Over a median 3.5 years of follow-up (range = 0.1-4.4), overt HE developed in 28 patients (18.2%). The 3-year cumulative incidence of overt HE was 18.4%. Multivariate Cox model indicated that past hepatocellular carcinoma history, alcoholic etiology for cirrhosis, higher Model for End-Stage Liver Disease scores and their deterioration, and serum ammonium levels were independently associated with HE development. However, microsatellite length was not associated with the development of overt HE. CONCLUSIONS: In Korean patients with cirrhosis, microsatellite variations in the glutaminase promoter region were not associated with development of overt HE. Thus, additional studies are needed to identify other genetic factors related to glutaminase activity in Asians with overt HE.

A Risk-prediction Model Based on Lymph-node Metastasis for Incorporation Into a Treatment Algorithm for Signet Ring Cell-type Intramucosal Gastric Cancer.

OBJECTIVE: The aim of the study was to develop a reliable and easy-to-use risk-scoring system (RSS) to predict lymph-node metastasis (LNM) and determine the feasibility of endoscopic submucosal dissection for mucosa-confined signet ring cell carcinomas (SRCs). BACKGROUND: Fewer LNM and better survival rates have been reported for early gastric SRCs compared with other undifferentiated early gastric cancers (EGCs). METHODS: Data from 1544 patients with mucosa-confined SRCs were reviewed. Stepwise logistic regression analysis determined the independent predictors of LNM. Risk scores were based on the final predictive factors for LNM, and performance was internally validated using a split-sample approach. External validation was also performed in an independent dataset (n = 208) to assess the discriminatory power of the RSS. RESULTS: The overall LNM incidence was 3.8% (57/1544). Three risk factors (tumor size ≥1.7 cm, tumors of elevated type, and lymphatic-vascular involvement) were significantly associated with LNM. These factors were incorporated into the RSS, and were assigned scores ranging from 0 to 4. The area under the receiver-operating characteristic curve for predicting LNM after internal and external validation was 0.68 (95% confidence interval, 0.0793-0.2865) and 0.686 (95% confidence interval, 0.618-0.748), respectively. A score of 2 points was the optimal cut-off value for LNM prediction, and the overall diagnostic accuracy was 96%. LNM were found in 2.9% and 23.8% of the low and high-risk groups of the RSS, respectively. CONCLUSIONS: A RSS may help to predict LNM and evaluate endoscopic submucosal dissection feasibility in patients with intramucosal SRC.

Exploring Existential Coping Resources: The Perspective of Koreans with Cancer.

The present study aimed to explore the use of meaning-making coping (existential, spiritual, and religious coping) among cancer patients in Korea and to investigate the impact of culture on their choice of coping methods. Thirty-three participants with various kinds of cancer were interviewed. Four different kinds of coping resources emerged from analyses of the interview transcripts: (1) belief in the healing power of nature; (2) mind-body connection; (3) relying on transcendent power; and (4) finding oneself in relationships with others. The findings of this study suggest the importance of investigating cultural context when exploring the use of the meaning-making coping strategies in different countries.

Long-Term Outcome of Endoscopic Resection vs. Surgery for Early Gastric Cancer: A Non-inferiority-Matched Cohort Study.

OBJECTIVES: Few studies have compared the long-term outcomes of endoscopic resection and surgery. The aim of this study was to compare the long-term outcomes of endoscopic resection with those of surgery for early gastric cancer (EGC). METHODS: We reviewed prospectively collected data of patients who had undergone endoscopic resection (1,290 patients) or surgery (1,273 patients) for EGC. To reduce the effect of selection bias, we performed a propensity score-matching analysis between the two groups. The primary outcome was overall survival (OS). The secondary outcomes were disease-specific survival, disease-free survival (DFS), recurrence-free survival (RFS), occurrence of metachronous gastric cancer, treatment-related complications, length of hospital stay, and 30-day outcomes. The study was designed as a non-inferiority study and tested in an intention-to-treat analysis. RESULTS: In a propensity-matched analysis of 611 pairs, the 10-year OS proportion was 96.7% in the endoscopic resection group and 94.9% in the surgery group (P=0.120) (risk difference -1.8%, 95% confidence interval (CI) -4.04-0.44, Pnon-inferiority=0.014), which met the non-inferiority criterion. In contrast, the 10-year RFS proportion was 93.5% in the endoscopic resection group and 98.2% in the surgery group (P<0.001) (risk difference 4.7%, 95% CI 2.50-6.97, Pnon-inferiority=0.820), which did not meet the non-inferiority criterion, mainly because of metachronous recurrence in the endoscopic resection group. The rate of early complications was higher in the endoscopic resection group than in the surgery group (9.0 vs. 6.6%, P=0.024), whereas the rate of late complications was higher in the surgery group than in the endoscopic resection group (0.5 vs. 2.9%, P<0.001). In the multiple Cox regression analysis, patient's age, the comorbidity index, the performance index, sex, tumor morphology, and depth of invasion were predictors of OS in patients with EGC. CONCLUSIONS: Endoscopic resection might not be inferior to surgery with respect to OS in patients with EGC lesions that meet the absolute or expanded criteria. However, DFS, RFS, and metachronous RFS might be lower after endoscopic resection than after surgery.

Efficacy and safety of endoscopic submucosal dissection for early gastric cancer in patients with comorbid diseases.

BACKGROUND/AIMS: Endoscopic submucosal dissection (ESD), a new and potentially curative method for treating gastrointestinal neoplasms, may have longer procedure time and the risk of complications when compared to conventional endoscopic mucosal resection. This study evaluated the efficacy and safety of ESD in patients with comorbid diseases. METHODS: The outcomes of 337 patients who underwent ESD for early gastric cancer at Samsung Medical Center from April 2003 to December 2006 were analyzed retrospectively. The Charlson comorbidity scale was used to divide the patients into low-risk (no risk factor) and high-risk (at least one risk factor) groups. The outcomes and complications were compared between the high- and low-risk groups. RESULTS: The low- and high-risk groups comprised 240 and 97 patients with mean ages of 61.1 and 64.7 years, respectively (p=0.002). Tumor location, tumor size, depth of invasion, procedure duration, and rates of en bloc resection, complete resection, complication, and recurrence did not differ significantly between the two groups (p>0.05). CONCLUSIONS: ESD may be a safe and effective treatment for early gastric cancer in patients with comorbid diseases.

Endoscopists' view on superficial spreading type of early gastric cancer--endoscopic resection or surgery?

OBJECTIVE: The superficial spreading type of early gastric cancer (EGC) possesses unique features different from other types of EGC. We aimed to elucidate the clinicopathological features of superficial spreading type of EGC. MATERIAL AND METHODS: We analyzed 1455 EGC lesions from 1398 patients who had undergone surgical treatment at Samsung Medical Center from 2000 to 2002. Then the clinicopathological features of 224 superficial-spreading EGC lesions (15.4%) was compared to that of 1231 lesions of a common type of EGC. RESULTS: In the superficial spreading type of EGC, the incidence of undifferentiated type and submucosal invasion were higher than those of common type of EGC (55.4 vs 38.0%, p < .01 and 58.5 vs 37.8%, p < .01, respectively). Lymph node metastasis and lymphovascular invasion were more frequent in superficial spreading type than in common type of EGC (19.2 vs 7.6%, p < .01 and 15.2 vs 7.4%, p < .01, respectively). There was no difference in recurrence rate or 5-year survival rate between the two groups. CONCLUSION: Considering higher risk of submucosal invasion and lymph node metastasis in superficial spreading type, a careful consideration should be done before the application of endoscopic resection to the superficial spreading type of EGC.

Ketohexokinase-dependent metabolism of fructose induces proinflammatory mediators in proximal tubular cells.

Increased consumption of fructose may play an important role in the epidemic of metabolic syndrome and may presage the development of diabetes, cardiovascular disease, and chronic kidney disease. Once in the cell, fructose is phosphorylated by ketohexokinase (KHK), leading to consumption of ATP, formation of AMP, and generation of uric acid through xanthine oxidoreductase (XOR). This study aimed to examine the direct effects of fructose in human kidney proximal tubular cells (HK-2) and whether they are mediated by the fructose metabolism via KHK. At a similar concentration to that observed in peripheral blood after a meal, fructose induced production of monocyte chemotactic protein 1 (MCP-1) and reactive oxygen species in HK-2 cells. Knockdown of KHK by stable transfection with small hairpin RNA demonstrated that these processes were KHK dependent. Several antioxidants, including specific inhibitors of NADPH oxidase and XOR, prevented MCP-1 secretion. We detected XOR mRNA in HK-2 cells and confirmed its activity by identifying uric acid by mass spectrometry. Fructose increased intracellular uric acid, and uric acid induced production of MCP-1 as well. In summary, postprandial concentrations of fructose stimulate redox- and urate-dependent inflammatory mediators in proximal tubular cells.

Simultaneous determination of uric acid metabolites allantoin, 6-aminouracil, and triuret in human urine using liquid chromatography-mass spectrometry.

Uric acid (UA) can be directly converted to allantoin enzymatically by uricase in most mammals except humans or by reaction with superoxide. UA can react directly with nitric oxide to generate 6-aminouracil and with peroxynitrite to yield triuret; both of these metabolites have been identified in biological samples. We now report a validated high-performance liquid chromatography and tandem mass spectrometry method for the determination of these urinary UA metabolites. Urine samples were diluted 10-fold, filtered and directly injected onto HPLC for LC-MS/MS analysis. The urinary metabolites of UA were separated using gradient HPLC. Identification and quantification of UA urinary metabolites was performed with electrospray in positive ion mode by selected-reaction monitoring (SRM). Correlation coefficients were 0.991-0.999 from the calibration curve. The intra- and inter-day precision (R.S.D., %) of the metabolites ranged from 0.5% to 13.4% and 2.5-12.2%, respectively. In normal individuals (n=21), urinary allantoin, 6-aminouracil and triuret, were 15.30 (+/-8.96), 0.22 (+/-0.12), and 0.12 (+/-0.10) microg/mg of urinary creatinine (mean (+/-S.D.)), respectively. The new method was used to show that smoking, which can induce oxidative stress, is associated with elevated triuret levels in urine. Thus, the method may be helpful in identifying pathways of oxidative stress in biological samples.

Decreased expression of Bax-interacting factor-1 (Bif-1) in invasive urinary bladder and gallbladder cancers.

AIMS: Mounting evidence indicates that deregulation of apoptosis is involved in the mechanisms of cancer development. Bax-interacting factor-1 (Bif-1) interacts with both Bax and Bak that are crucial for the intrinsic apoptosis signalling. Functionally, loss of Bif-1 expression has been proven to enhance tumorigenesis. The aim of this study was to explore whether loss of Bif-1 expression occurs in urinary bladder (UB) and gallbladder (GB) cancer tissues. METHODS: We analysed Bif-1 protein expression in 41 transitional cell carcinomas of UB and 26 GB adenocarcinomas by immunohistochemistry. RESULTS: In both UB and GB, normal mucosal epithelial cells strongly expressed Bif-1 protein. In the UB cancers, Bif-1 expression was strongly positive in 25 cases (61.0%), but the remaining 16 cases showed no (14.6%) or markedly decreased (24.4%) Bif-1 immunostaining compared with the normal mucosal epithelial cells. Similarly, in the GB cancers, Bif-1 immunostaining was strong in 17 cases (65.4%), while the remaining nine cases showed no (15.4%) or markedly decreased (19.2%) Bif-1 immunostaining compared with the normal mucosal epithelial cells. CONCLUSION: The decreased expression of Bif-1 in large fractions of both UB and GB cancers (39.0% and 34.6%, respectively) compared with their normal mucosal cells suggested that loss of Bif-1 expression might play a role in tumorigenesis in both UB and GB cancers, possibly by inhibiting apoptosis mediated by Bif-1.

Inactivation of nitric oxide by uric acid.

The 1980 identification of nitric oxide (NO) as an endothelial cell-derived relaxing factor resulted in an unprecedented biomedical research of NO and established NO as one of the most important cardiovascular, nervous and immune system regulatory molecule. A reduction in endothelial cell NO levels leading to "endothelial dysfunction" has been identified as a key pathogenic event preceding the development of hypertension, metabolic syndrome, and cardiovascular disease. The reduction in endothelial NO in cardiovascular disease has been attributed to the action of oxidants that either directly react with NO or uncouple its substrate enzyme. In this report, we demonstrate that uric acid (UA), the most abundant antioxidant in plasma, reacts directly with NO in a rapid irreversible reaction resulting in the formation of 6-aminouracil and depletion of NO. We further show that this reaction occurs preferentially with NO even in the presence of oxidants peroxynitrite and hydrogen peroxide and that the reaction is at least partially blocked by glutathione. This study shows a potential mechanism by which UA may deplete NO and cause endothelial dysfunction, particularly under conditions of oxidative stress in which UA is elevated and intracellular glutathione is depleted.

SLC11A1 polymorphisms are associated with the risk of chronic obstructive pulmonary disease in a Korean population.

The solute carrier family 11 member 1 (SLC11A1) protein plays important roles in macrophage activation and displays pleiotropic effects on various macrophage functions, including the regulation of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and oxidative burst. Considering the important roles of macrophage in the pathogenesis of chronic obstructive pulmonary disease (COPD), we hypothesized that the SLC11A1 gene may act as a low-penetrance susceptibility gene for COPD. To test this hypothesis, we first examined the frequencies of 12 candidate polymorphisms in the SLC11A1 gene in 27 healthy Korean individuals, and then genotyped 3 haplotype-tagging polymorphisms [IVS4 + 14G > C (rs3731865), D543 N (rs17235409), and (*)86A > G (rs1059823)] in 83 COPD patients and 203 healthy controls. Individuals with at least one variant allele of the D543 N and (*)86A > G polymorphisms were at a significantly increased risk for COPD compared with carriers with each homozygous wild-type allele [adjusted odds ratio (OR) = 2.23, 95% confidence interval (CI) = 1.24-4.02, P = 0.007; and adjusted OR = 1.92, 95% CI = 1.10-3.35, P = 0.022, respectively]. Consistent with the findings of the genotyping analysis, the 122 haplotype carrying both the 543 N and (*)86G alleles was associated with a significantly increased risk for COPD compared with the 111 haplotype with the 542D and (*)86A alleles (adjusted OR = 2.05, 95% CI = 1.19-3.51, P = 0.009 and Bonferroni corrected P = 0.027). These findings suggest that the SLC11A1 polymorphisms could be used as markers for genetic susceptibility to COPD. However, further studies with large numbers of subjects are needed to confirm our findings.

Polymorphisms in the survivin gene and the risk of lung cancer.

BACKGROUND: Survivin is an apoptosis inhibitor and plays an important role in the development and progression of cancer. Polymorphisms in the survivin gene may influence survivin production or activity, thereby modulating susceptibility to lung cancer. To test this hypothesis, we investigated the association between survivin polymorphisms and the risk of lung cancer in a Korean population. METHODS: We first screened for polymorphisms in the survivin gene by direct sequencing of genomic DNA samples from 27 healthy Koreans. We selected identified SNPs based on their frequency, linkage disequilibrium status and haplotype tagging status, and then genotyped the selected SNPs in 582 lung cancer patients and 582 healthy controls who were frequency matched for age and gender. RESULTS: We identified 8 single nucleotide polymorphisms (SNPs): 6 known SNPs [-644T>C, -625G>C, -31C>G, 9194A>G (K129E), 9386T>C and 9809T>C] and 2 novel SNPs (9974C>T and 10347G>A). Among the SNPs studied, only the -31C>G genotype distribution was significantly different between the cases and controls (P=0.04). Individuals with at least one -31G allele were at a significantly decreased risk of lung cancer compared to those individuals with the -31CC genotype [adjusted odds ratio (OR)=0.74, 95% confidence interval (CI)=0.57-0.96, P=0.02]. When the lung cancer cases were categorized by tumor histology, the -31G allele was associated with a significantly decreased risk of adenocarcinoma (adjusted OR=0.59, 95% CI=0.41-0.84, P=0.003). Consistent with the results of the genotyping analysis, the -625G/-31G/9194A/9809T haplotype carrying the -31G allele was associated with a significantly decreased risk of adenocarcinoma (adjusted OR=0.56, 95% CI=0.40-0.77, P=0.0004). The promoter assay revealed the -31G allele to have a significantly lower promoter activity than the -31C allele. CONCLUSION: These results suggest that the survivin -31C>G polymorphism influences survivin expression, thus contributing to the genetic susceptibility to lung cancer.

Identification of polymorphisms in the Caspase-3 gene and their association with lung cancer risk.

Caspase-3 (CASP-3) is a primary effector CASP that executes programmed cell death, and it plays an important role in the development and progression of cancer. Polymorphisms in the CASP-3 gene may influence CASP-3 production and/or activity, thereby modulating the susceptibility to lung cancer. To test this hypothesis, we first screened for polymorphisms in the CASP-3 gene by direct sequencing of genomic DNA samples from 27 healthy Koreans, and then evaluated their associations with lung cancer in a case-control study that consisted of 582 lung cancer patients and 582 healthy controls. Individuals with at least one variant allele of the -928A > G, 77G > A, and 17532A > C polymorphisms were at a significantly decreased risk for lung cancer in comparison to the carriers with each homozygous wild-type allele [adjusted odds ratio (OR) = 0.79, 95% confidence interval (CI) = 0.62-1.00, P = 0.05; adjusted OR = 0.78, 95% CI = 0.61-0.99, P = 0.04; and adjusted OR = 0.74, 95% CI = 0.58-0.95, P = 0.02, respectively]. Consistent with the results of genotyping analysis, the GAGC haplotype carrying the variant allele at all of the -928A > G, 77G > A, and 17532A > C loci was associated with a significantly decreased risk of lung cancer compared to the AGGA haplotype carrying no variant alleles at the three loci (adjusted OR = 0.66, 95% CI = 0.51-0.86, P = 0.002 and Bonferroni corrected P = 0.008). These results suggest that the CASP-3 polymorphisms and their haplotypes contribute to the genetic susceptibility to lung cancer.

Polymorphisms in the epidermal growth factor receptor gene and the risk of primary lung cancer: a case-control study.

BACKGROUND: Polymorphisms in Epidermal Growth Factor Receptor (EGFR) gene may influence EGFR production and/or activity, thereby modulating susceptibility to lung cancer. To test this hypothesis, we investigated the association between polymorphisms in the EGFR gene and the risk of lung cancer in a Korean population. METHODS: We first examined the frequencies of 39 candidate polymorphisms in the EGFR gene in 27 healthy Korean individuals. After then, we genotyped five polymorphisms (127378C>T, 142285G>A, 162093G>A, 181946C>T and 187114T>C) that have variant allele frequencies greater than 10%, in 582 lung cancer patients and in 582 healthy controls. RESULTS: Of the 5 polymorphisms, the 181946C>T genotype distribution was significantly different between the cases and controls (P = 0.04). Compared with the 181946 CC + CT genotype, the 181946 TT genotype was associated with a significantly decreased risk of lung cancer (adjusted OR = 0.63, 95% CI = 0.45-0.88, P = 0.007). When the analyses were stratified by smoking status, the protective effect of the TT genotype was statistically significant in ever-smokers (adjusted OR = 0.59, 95% CI = 0.41-0.86, P = 0.007), but not in never-smokers (adjusted OR = 0.89, 95% CI = 0.45-1.75, P = 0.73; P = 0.08, test for homogeneity). Consistent with the results of the genotyping analysis, the CGGCT haplotype with the 181946C allele was associated with a significantly increased risk of lung cancer compared to the CGGTT haplotype carrying the 181946T allele (adjusted OR = 1.50, 95% CI = 1.09-2.07, P = 0.012 and Bonferroni corrected P-value = 0.048). CONCLUSION: These results suggest that the EGFR polymorphisms, particularly the 181945C>T polymorphism, could be used as markers for the genetic susceptibility to lung cancer.

Lead, at low levels, accelerates arteriolopathy and tubulointerstitial injury in chronic kidney disease.

Chronic lead exposure has been epidemiologically linked with hypertension and renal disease. Clinical studies suggest that low lead levels may contribute to renal progression. However, experimental studies have not examined whether low levels of lead accelerate progression in experimental chronic renal disease. Sprague-Dawley rats were administered lead (L; 150 ppm in drinking water, n = 16) for 4 wk, followed by remnant kidney (RK) surgery with continuation of lead for an additional 12 wk; control rats (n = 9) were treated similarly but did not receive lead. Lead treatment was well tolerated and resulted in modest elevations in whole blood lead levels (26.4 +/- 4.5 vs. 1 +/- 0 mug/dl, week 16, P < 0.001). Lead treatment was associated with higher systolic blood pressure (P < 0.05) and worse renal function (creatinine clearance 1.4 +/- 0.4 vs. 1.8 +/- 0.5 ml/min, RK+L vs. RK, P < 0.05), and with a tendency for greater proteinuria (6.6 +/- 6.1 vs. 3.6 +/- 1.5 mg protein/mg creatinine, RK+L vs. RK, P = 0.08). While glomerulosclerosis tended to be worse in lead-treated rats (37.6 +/- 11 vs. 28.8 +/- 2.3%, RK+L vs. RK, P = 0.06), the most striking finding was the development of worse arteriolar disease (P < 0.05), peritubular capillary loss (P < 0.05), tubulointerstitial damage, and macrophage infiltration (P < 0.05) in association with significantly increased renal expression of monocyte chemoattractant protein-1 mRNA. In conclusion, lead accelerates chronic renal disease, primarily by raising blood pressure and accelerating microvascular and tubulointerstitial injury.

EGFR, ERBB2, and KRAS mutations in Korean non-small cell lung cancer patients.

The epidermal growth factor receptor (EGFR), and its family members play an important role in the development and progression of lung cancers. It has been reported that somatic mutations in the tyrosine kinase domain of the EGFR or ERBB2 genes occur in a subset of patients with lung cancer. We searched for mutations of the EGFR, ERBB2, and KRAS genes in surgically resected non-small cell lung cancers (NSCLCs) to determine the prevalence of these mutations in Korean lung cancer patients. In addition, we examined the relationship between the mutations and clinicopathologic features of lung cancers. Mutations of the EGFR, ERBB2, and KRAS genes were determined by polymerase chain reaction-based direct sequencing in 115 surgically resected non-small cell lung cancers. EGFR mutations were present in 20 patients (17.4%). The EGFR mutations were found only in adenocarcinomas (20 of 55 adenocarcinomas, 36.4%). The ERBB2 mutation was found in 1 adenocarcinoma of the 115 NSCLCs (0.9% overall; 1.8% of the 55 adenocarcinomas). KRAS mutations were found in 6 (5.2%) of the 115 NSCLCs (2 of 60 squamous cell carcinomas, or 3.3%, and 4 of 55 adenocarcinomas, or 7.3%). EGFR mutations in adenocarcinomas were more frequent in women (P = 0.02) and in never-smokers (P = 0.004). EGFR mutations in adenocarcinomas were not associated with pathologic stage in never-smokers, but were more frequent in pathologic stage II-IV than in stage I in ever-smokers (P = 0.01). Of the 55 adenocarcinomas, 25 (45.5%) had mutations of one or another of the three genes; EGFR mutations were never found in adenocarcinomas together with ERBB2 or KRAS mutations. These findings suggest that the EGFR mutation is frequent in Korean lung cancer patients, and that the ERBB2 mutation is rare. Further studies are needed to investigate the role of EGFR mutations in the carcinogenesis of adenocarcinoma among smokers.