Tumor Location Is an Independent Prognostic Factor in Completely Resected Pathological Stage I Non-Small Cell Lung Cancer: A Multicenter Retrospective Study.

Previous studies suggested that the location of the primary tumor in non-small cell lung cancer (NSCLC) is associated with clinical features and prognosis, but results are conflicting. The purpose of this study was to explore tumor location as an independent risk factor of survival for patients with completely resected pathological stage I NSCLC. This was a multicenter retrospective study conducted in Taiwan. Included patients were diagnosed with stage I NSCLC and had undergone primary tumor resection. Variables including tumor location, pathological stage, histological differentiation, and International Association for the Study of Lung Cancer (IASLC) grade were evaluated for predictive ability for disease-free survival (DFS) and overall survival (OS). A total of 208 patients were included, with 123 (59.1%) patients having a primary tumor in the upper and middle lobes. The median duration of follow-up for survivors was 60.5 months. Compared to patients with IASLC Grade 3 disease, patients with Grade 1 disease had significantly longer DFS. Tumor location and IASLC grade were independent predictors for OS in multivariate analysis. Specifically, patients with NSCLC in the lower lobe and patients who are histologically classified as IASLC Grade 3 may have poorer prognosis and require greater attention to improve outcomes.

Role of Peritoneal Equilibration Test in Assessing Folate Transport During Peritoneal Dialysis.

OBJECTIVES: Low plasma folate levels have been reported in patients undergoing hemodialysis and peritoneal dialysis (PD) in clinical studies. However, folate transport has never been mentioned as a factor contributing to low plasma folate levels in patients undergoing PD. The peritoneal equilibrium test (PET) assesses the plasma creatinine level and glucose transport abilities. This study aimed to evaluate the association between plasma folate levels and folate transport during PD based on PET grades. METHODS: This study recruited 50 patients who underwent PD for ≥3 months and were categorized according to PET grades. Data regarding plasma folate levels and dialysate folate were collected. The primary outcomes were the relationship between the PET grade and plasma folate level and between the PET grade and dialysate-to-plasma folate concentration ratio (D/P folate). Furthermore, the difference in the plasma folate level and D/P folate between men and women was assessed. RESULTS: The plasma folate level and the D/P folate significantly differed among the 4 PET groups (both P < .001). PET grade was significantly negatively correlated with plasma folate levels (r = -0.56, P < .001) and positively correlated with D/P folate (r = 0.686, P < .001). In subgroup analysis, neither the plasma folate level nor the D/P folate significantly differed between men and women. CONCLUSIONS: Our study provides clinical evidence that the PET grade is associated with the plasma folate level and D/P folate, regardless of sex. Larger cohort studies are warranted to assess the importance of folate supplementation during PD based on PET grades.

Comparison of Clinical Outcomes Among Different Fixed-Dose Combinations of Long-Acting Muscarinic Antagonists and Long-Acting ß2-Agonists in Patients With COPD.

BACKGROUND: Researchers have yet to obtain conclusive evidence differentiating among fixed-dose combinations (FDCs) of long-acting muscarinic antagonists (LAMAs) and long-acting ß2-agonists (LABAs) for COPD in terms of real-world clinical outcomes. RESEARCH QUESTION: What are the differences between available LAMA/LABA FDCs in the risk of acute exacerbation (AE) and cardiovascular events? STUDY DESIGN AND METHODS: This retrospective cohort study based on a national insurance claims database included patients with COPD ≥ 40 years of age who were newly prescribed glycopyrronium (GLY)/indacaterol (IND), umeclidinium (UMEC)/vilanterol (VI), or tiotropium (TIO)/olodaterol (OLO) FDC between January 1, 2015, and June 30, 2019. Propensity score matching and Cox regression models were used to compare outcomes of AE and cardiovascular events associated with LAMA/LABA FDC treatment. RESULTS: Among the 44,498 patients identified and included, 15,586 received GLY/IND, 20,460 received UMEC/VI, and 8,452 received TIO/OLO. Baseline characteristics were well balanced after 1:1 matching of UMEC/VI and GLY/IND, 2:1 matching of UMEC/VI and TIO/OLO, and 2:1 matching of GLY/IND and TIO/OLO. Risk of severe AE was lower among patients treated with UMEC/VI or GLY/IND than among those who received TIO/OLO (UMEC/VI vs TIO/OLO: 17.85 vs 29.32 per 100 person-years; hazard ratio, 0.76; 95% CI, 0.68-0.84; GLY/IND vs TIO/OLO: 15.54 vs 25.53 per 100 person-years; hazard ratio, 0.77; 95% CI, 0.67-0.88). In addition, GLY/IND users tended to have a lower risk of cardiovascular events than TIO/OLO users, but the difference dissipated when restricting follow up to a shorter duration. INTERPRETATION: Our results revealed that the risk of severe AE was lower among patients with COPD receiving UMEC/VI or GLY/IND than among those receiving TIO/OLO, whereas the incidence of cardiovascular events was similar across groups but was slightly lower in GLY/IND users when compared with TIO/OLO users. Further research will be required to confirm these findings.

The Effects of High-Intensity Power Training versus Traditional Resistance Training on Exercise Performance.

Background: High-intensity interval training (HIIT) features short, repeated bursts of relatively vigorous exercise with intermittent periods of rest or low-intensity exercise. High-intensity power training (HIPT), in combination with HIIT and traditional resistance training (TRT), is characterized as multijoint high-intensity resistance exercises with low interset rest periods. HIPT requires people to finish the exercise as fast as possible, which increases acute physiological demands. The aim of the study was to investigate the differences between eight-week HIPT or TRT on exercise performance. Methods: Twenty-four college students were recruited and randomly assigned to either the HIPT or TRT group in a counterbalanced order. The power of upper and lower limbs (50% 1RM bench press and vertical jump) and anaerobic power were tested before and after the training (weeks 0 and 9). The results were analyzed by two-way analysis of variance (ANOVA) or Friedman's test with a significance level of α = 0.05 to compare the effects of the intervention on exercise performance. Results: There were significant differences in the explosive force of the upper and lower limbs between the pretest and post-test in both the HIPT and TRT groups (p < 0.05). However, only the HIPT group showed a significant difference in the mean power on the Wingate anaerobic test between the pretest and post-test (p < 0.05). Conclusions: Both HIPT and TRT can improve upper and lower limb explosive force. HIPT is an efficient training protocol, which took less time and produced a better improvement in mean anaerobic power.

Cestocidal activities of bioactive garlic compounds against Hymenolepis nana.

Hymenolepis nana, a parasitic tapeworm distributed worldwide, is very prevalent in countries with poor sanitary conditions. Garlic is widely used as a seasoning and medicinal plant all over the world, and its derivatives have proven anti-microbial and anti-inflammatory effects. Our study explored the cestocidal and therapeutic effects of allicin derivatives against H. nana in vitro and in vivo. Worms taken from a host were cultured in vitro, and the effects of allyl sulfide (DAS), allyl disulfide (DADS) and dimethyl sulfoxide (DMSO) treatments were observed. Male BALB/c mice were then fed eggs to produce infection, given drugs for ten days and dissected. The results of this study showed that DADS in garlic exhibited good cestocidal effects in vitro and in vivo. DADS and DATS reduced motility, induced mortality and damaged body segments of worms in vitro. In vivo, the number of worms in the low-dose and high-dose DADS groups was significantly less than the infected control group. DADS effected cytokine changes in BALB/c mice after infection. IFN-γ increased, IL-2, 4, 6 and 13 decreased, and IL-5, 10 and IL-12 p70 did not change significantly. As a medicinal plant, garlic has many active ingredients that can developed as anti-microbial or parasite-related drugs.

Correction: Weng et al. New International Association for the Study of Lung Cancer (IASLC) Pathology Committee Grading System for the Prognostic Outcome of Advanced Lung Adenocarcinoma. Cancers 2020, 12, 3426.

The authors would like to make a correction to their published paper [...].

Combination of Mesenchymal Stem Cell-Delivered Oncolytic Virus with Prodrug Activation Increases Efficacy and Safety of Colorectal Cancer Therapy.

Although oncolytic viruses are currently being evaluated for cancer treatment in clinical trials, systemic administration is hindered by many factors that prevent them from reaching the tumor cells. When administered systemically, mesenchymal stem cells (MSCs) target tumors, and therefore constitute good cell carriers for oncolytic viruses. MSCs were primed with trichostatin A under hypoxia, which upregulated the expression of CXCR4, a chemokine receptor involved in tumor tropism, and coxsackievirus and adenovirus receptor that plays an important role in adenoviral infection. After priming, MSCs were loaded with conditionally replicative adenovirus that exhibits limited proliferation in cells with a functional p53 pathway and encodes Escherichia coli nitroreductase (NTR) enzymes (CRAdNTR) for targeting tumor cells. Primed MSCs increased tumor tropism and susceptibility to adenoviral infection, and successfully protected CRAdNTR from neutralization by anti-adenovirus antibodies both in vitro and in vivo, and specifically targeted p53-deficient colorectal tumors when infused intravenously. Analyses of deproteinized tissues by UPLC-MS/QTOF revealed that these MSCs converted the co-administered prodrug CB1954 into cytotoxic metabolites, such as 4-hydroxylamine and 2-amine, inducing oncolysis and tumor growth inhibition without being toxic for the host vital organs. This study shows that the combination of oncolytic viruses delivered by MSCs with the activation of prodrugs is a new cancer treatment strategy that provides a new approach for the development of oncolytic viral therapy for various cancers.

Co-Expression of Coxsackievirus/Adenovirus Receptors and Desmoglein 2 in Lung Adenocarcinoma: A Comprehensive Analysis of Bioinformatics and Tissue Microarrays.

INTRODUCTION: Coxsackievirus/adenovirus receptors (CARs) and desmoglein-2 (DSG2) are similar molecules to adenovirus-based vectors in the cell membrane. They have been found to be associated with lung epithelial cell tumorigenesis and can be useful markers in predicting survival outcome in lung adenocarcinoma (LUAD). METHODS: A gene ontology enrichment analysis disclosed that DSG2 was highly correlated with CAR. Survival analysis was then performed on 262 samples from the Cancer Genome Atlas, forming "Stage 1A" or "Stage 1B". We therefore analyzed a tissue microarray (TMA) comprised of 108 lung samples and an immunohistochemical assay. Computer counting software was used to calculate the H-score of the immune intensity. Cox regression and Kaplan-Meier analyses were used to determine the prognostic value. RESULTS: CAR and DSG2 genes are highly co-expressed in early stage LUAD and associated with significantly poorer survival (p = 0.0046). TMA also showed that CAR/DSG2 expressions were altered in lung cancer tissue. CAR in the TMA was correlated with proliferation, apoptosis, and epithelial-mesenchymal transition (EMT), while DSG2 was associated with proliferation only. The Kaplan-Meier survival analysis revealed that CAR, DSG2, or a co-expression of CAR/DSG2 was associated with poorer overall survival. CONCLUSIONS: The co-expression of CAR/DSG2 predicted a worse overall survival in LUAD. CAR combined with DSG2 expression can predict prognosis.

New International Association for the Study of Lung Cancer (IASLC) Pathology Committee Grading System for the Prognostic Outcome of Advanced Lung Adenocarcinoma.

The impact of the new International Association for the Study of Lung Cancer pathology committee grading system for advanced lung adenocarcinoma (LADC) on survival is unclear, especially in Asian populations. In this study, we reviewed the prognostic outcomes of patients with late-stage disease according to the new grading system. We reviewed 136 LADC cases who underwent a small biopsy from 2007 to 2018. Tumors were classified according to the new grading system for LADC. Baseline characteristics (age, sex, smoking status, body mass index, and driver gene mutations) were analyzed. Kaplan-Meier and Cox regression analyses were used to determine correlations with the new grading system and prognosis. Patients with poorly differentiated adenocarcinoma were significantly correlated with a poor progression-free survival (PFS) (p = 0.013) but not overall survival (OS) (p = 0.154). Subgroup analysis showed that wild-type EGFR patients with poorly differentiated adenocarcinoma treated with chemotherapy had significantly worse PFS (p = 0.011). There was no significant difference in survival among the patients with epidermal growth factor receptor mutations who were treated with tyrosine kinase inhibitors. Patients aged >70 years and those with a BMI ≤ 25 kg/m2 and wild-type patients had significantly worse OS in both univariate (HR = 1.822, p = 0.006; HR = 2.250, p = 0.004; HR = 1.537, p = 0.046, respectively) and multivariate analyses (HR = 1.984, p = 0.002; HR = 2.383, p = 0.002; HR = 1.632, p = 0.028, respectively). Despite therapy, patients with poorly differentiated tumors still fared worse than those with better differentiated tumors. No differences were found among the EGFR mutations treated with TKI. Our findings highlight that the therapeutic regimen should be adjusted for EGFR Wild-type patients with poorly differentiated adenocarcinoma treated with chemotherapy to provide better outcomes.

Nucleolar control by a non-apoptotic p53-caspases-deubiquitinylase axis promotes resistance to bacterial infection.

The nucleolus is best known for its cellular role in regulating ribosome production and growth. More recently, an unanticipated role for the nucleolus in innate immunity has recently emerged whereby downregulation of fibrillarin and nucleolar contraction confers pathogen resistance across taxa. The mechanism of this downregulation, however, remains obscure. Here we report that rather than fibrillarin itself being the proximal factor in this pathway, the key player is a fibrillarin-stabilizing deubiquitinylase USP-33. This was discovered by a candidate-gene search of Caenorhabditis elegans in which CED-3 caspase was revealed to execute targeted cleavage of USP-33, thus destabilizing fibrillarin. We also showed that cep-1 and ced-3 mutant worms altered nucleolar size and decreased antimicrobial peptide gene, spp-1, expression rendering susceptibility to bacterial infection. These phenotypes were reversed by usp-33 knockdown, thus linking the CEP-1-CED-3-USP-33 pathway with nucleolar control and resistance to bacterial infection in worms. Parallel experiments with the human analogs of caspases and USP36 revealed similar roles in coordinating these two processes. In summary, our work outlined a conserved cascade that connects cell death signaling to nucleolar control and innate immune response.

Anthelmintic activities of aporphine from Nelumbo nucifera Gaertn. cv. Rosa-plena against Hymenolepis nana.

Nelumbo nucifera Gaertn. cv. Rosa-plena (Nelumbonaceae), commonly known as lotus, is a perennial aquatic plant grown and consumed throughout Asia. All parts of N. nucifera have been used for various medicinal purposes in oriental medicine. From the leaves of Nelumbo nucifera Gaertn. cv. Rosa-plena (an aquatic plant), liriodenine (1), lysicamine (2), (-)-anonaine (3), (-)-asimilobine (4), (-)-caaverine (5), (-)-N-methylasimilobine (6), (-)-nuciferine (7), (-)-nornuciferine (8), (-)-roemerine (9), 7-hydroxydehydronuciferine (10) and cepharadione B (11) were isolated and identification and anthelmintic activities of aporphine was evaluated against Anisakis simplex and Hymenolepis nana. This study found that the above constituents killed H. nana or reduced their spontaneous movements (oscillation/peristalsis). However, the above constituents at various concentrations demonstrated no larvicidal effect or ability to halt spontaneous parasite movement for 72 h against A. simplex, respectively. In addition, according to an assay of cestocidal activity against H. nana and nematocidal activity against A. simplex, we found that the above compounds showed greater lethal efficacy on H. nana than against A. simplex. Further investigation showed that these above constituents have effects against peroxyl radicals under cestocidal effect. Together, these findings suggest that these constituents of Nelumbo nucifera Gaertn. cv. Rosa-plena might be used as anthelmintic agents against H. nana.

Dietary intake of vitamin B(6) and risk of breast cancer in Taiwanese women.

BACKGROUND: B vitamins, including vitamin B(6), are coenzymes that are important for DNA integrity and stability. Deficiencies in B vitamins may promote tumor carcinogenesis. METHODS: We examined the association of dietary vitamin B(6) intake with overall breast cancer risk and breast cancers stratified by hormone receptor status. This case-control study included 391 breast cancer cases and 782 control subjects enrolled at the Tri-Service General Hospital in Taipei, Taiwan. Energy-adjusted intake of vitamin B(6) was derived from a food frequency questionnaire. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression. RESULTS: As compared with women in the lowest tertile, the multivariate-adjusted ORs for breast cancer among women in the second and highest tertiles of vitamin B(6) intake were 0.78 (95% CI, 0.64-2.52) and 0.64 (0.26-0.92), respectively. In addition, higher vitamin B(6) intake was associated with a significantly lower risk of developing ER-negative breast tumors. CONCLUSIONS: Our findings suggest that higher intake of vitamin B(6) is associated with a reduction in breast cancer risk, particularly ER-negative tumors.

Vitamin D decreases risk of breast cancer in premenopausal women of normal weight in subtropical taiwan.

BACKGROUND: Evidence for an association between vitamin D status and breast cancer is now more convincing, but is uncertain in subtropical areas like Taiwan. This hospital-based case-control study examined the relationship of breast cancer with vitamin D intake and sunlight exposure. METHODS: A total of 200 incident breast cancer cases in a Taipei hospital were matched with 200 controls by date of interview and menopausal status. Information on risk factors for breast cancer was collected in face-to-face interviews and assessed with reference to vitamin D intake (foods and nutrients) and sunlight exposure. Vitamin D intake was divided into quartiles, and threshold effect was evaluated by comparing Q2-Q4 with Q1. RESULTS: After controlling for age, education, parity, hormone replacement therapy, body mass index (BMI), energy intake, menopausal status, and daily sunlight exposure, the risk of breast cancer in participants with a dietary vitamin D intake greater than 5 µg per day was significantly lower (odds ratio [OR], 0.48; 95% confidence interval [CI], 0.24-0.97) than that of participants with an intake less than 2 µg per day. In analysis stratified by menopausal status and BMI, both dietary vitamin D and total vitamin D intakes were associated with a protective effect among premenopausal women. There was a significant linear trend for breast cancer risk and dietary vitamin D intake in premenopausal women (P = 0.02). In participants with a BMI lower than 24 kg/m(2) (ie, normal weight), dietary vitamin D intake was inversely related to breast cancer risk (P for trend = 0.002), and a threshold effect was apparent (Q2-Q4 vs Q1: OR, 0.46; 95% CI, 0.23-0.90). CONCLUSIONS: Vitamin D had a protective effect against breast cancer in premenopausal women of normal weight in subtropical Taiwan, especially an intake greater than 5 µg per day.

Joint effect of peroxisome proliferator-activated receptor γ genetic polymorphisms and estrogen-related risk factors on breast cancer risk: results from a case-control study in Taiwan.

Peroxisome proliferator-activated receptor γ (PPARγ) has been linked with possible antineoplastic effects in colorectal carcinogenesis. However, data for the possible link between PPARγ and breast cancer risk are sparse. We assessed the association of three polymorphisms in PPARγ (rs10865710 [C-681T], rs1805192 [Pro12Ala], and rs3856806 [C1431T]) with the risk of breast cancer in an ethnic Chinese female population in Taiwan. In addition, interactions with estrogen exposures were also explored. Genotypes for the PPARγ polymorphisms were determined on 291 incident breast cancer cases and 589 matched controls by fluorogenic 5'-nuclease assay. The at-risk haplotypes were defined according to the three polymorphisms in the following order: C-681T, Pro12Ala, and C1431T, which include CCT, GGT, and GGC. In addition, a critical period of estrogen exposure was estimated by the interval between age at menarche and age at first full-term pregnancy. Overall, there was no evidence of a significant impact of individual polymorphisms of PPARγ on breast cancer risk. However, the haplotype analysis revealed that women harboring at-risk haplotypes showed a significant 67% increase in breast cancer risk [adjusted odds ratio (OR) 1.67; 95% confidence interval (CI) 1.11-2.52]. Furthermore, there was a significant joint effect of estrogen exposure-related factors and at-risk haplotypes of PPARγ on breast cancer risk (adjusted OR 4.04; 95% CI 1.89-8.65), particularly in premenopausal women. The present study implicates a role for PPARγ in breast cancer risk. Mechanistic studies to fully elucidate the mechanisms underlying PPARγ's effects should be pursued in future investigations.

Atg1-mediated myosin II activation regulates autophagosome formation during starvation-induced autophagy.

Autophagy is a membrane-mediated degradation process of macromolecule recycling. Although the formation of double-membrane degradation vesicles (autophagosomes) is known to have a central role in autophagy, the mechanism underlying this process remains elusive. The serine/threonine kinase Atg1 has a key role in the induction of autophagy. In this study, we show that overexpression of Drosophila Atg1 promotes the phosphorylation-dependent activation of the actin-associated motor protein myosin II. A novel myosin light chain kinase (MLCK)-like protein, Spaghetti-squash activator (Sqa), was identified as a link between Atg1 and actomyosin activation. Sqa interacts with Atg1 through its kinase domain and is a substrate of Atg1. Significantly, myosin II inhibition or depletion of Sqa compromised the formation of autophagosomes under starvation conditions. In mammalian cells, we found that the Sqa mammalian homologue zipper-interacting protein kinase (ZIPK) and myosin II had a critical role in the regulation of starvation-induced autophagy and mammalian Atg9 (mAtg9) trafficking when cells were deprived of nutrients. Our findings provide evidence of a link between Atg1 and the control of Atg9-mediated autophagosome formation through the myosin II motor protein.

Increased matriptase zymogen activation in inflammatory skin disorders.

Matriptase, a type 2 transmembrane serine protease, and its inhibitor hepatocyte growth factor activator inhibitor (HAI)-1 are required for normal epidermal barrier function, and matriptase activity is tightly regulated during this process. We therefore hypothesized that this protease system might be deregulated in skin disease. To test this, we examined the level and activation state of matriptase in examples of 23 human skin disorders. We first examined matriptase and HAI-1 protein distribution in normal epidermis. Matriptase was detected at high levels at cell-cell junctions in the basal layer and spinous layers but was present at minimal levels in the granular layer. HAI-1 was distributed in a similar pattern, except that high-level expression was retained in the granular layer. This pattern of expression was retained in most skin disorders. We next examined the distribution of activated matriptase. Although activated matriptase is not detected in normal epidermis, a dramatic increase is seen in keratinocytes at the site of inflammation in 16 different skin diseases. To gain further evidence that activation is associated with inflammatory stimuli, we challenged HaCaT cells with acidic pH or H(2)O(2) and observed matriptase activation. These findings suggest that inflammation-associated reactive oxygen species and tissue acidity may enhance matriptase activation in some skin diseases.

Adipocytokine resistin and breast cancer risk.

Adipocytokine resistin is a member of the newly discovered family of cysteine-rich protein. Recent data suggest that macrophages are a major source of human resistin. Given the obesity-breast cancer link and convergence of adipocyte and macrophage function, resistin may provide unique insight into links between obesity, inflammation, and breast cancer risk in humans. We conducted a hospital-based case-control study to evaluate whether plasma resistin levels were associated with breast cancer risk in women. We also examined the modification effect of estrogen exposures on the resistin-breast cancer link. Questionnaire information, anthropometric measures, and blood samples were taken before treatment from 380 incident cases with breast cancer and 760 controls admitted for health examination at the Tri-Service General Hospital, Taipei between 2004 and 2008. Plasma levels of resistin were measured by enzyme immunoassay. Cumulative exposure to estrogens were estimated according to the age at menarche and age at enrollment for premenopausal women and age at menarche and age at menopause for postmenopausal women. Cases with breast cancer had significantly elevated resistin concentrations as compared with control subjects. Compared with those in the lowest quartile, the adjusted odds ratios of breast cancer for women in the second, third, and highest quartiles were 1.48 [95% confidence interval (CI) = 0.65-3.38], 1.76 (95% CI = 1.00-4.73), and 2.08 (95% CI = 1.04-3.85), respectively. Furthermore, the biological gradient of breast cancer risk by plasma resistin levels remained after adjustment for measures of adiposity. The dose-dependent relationship of resistin levels with breast cancer risk was notably pronounced among women with excess exposure to estrogens. Adipocytokine resistin may have an adiposity-independent role in breast carcinogenesis. Mechanistic studies to fully elucidate the mechanisms underlying resistin's effects should be pursued in future investigations.

Relationships between critical period of estrogen exposure and circulating levels of insulin-like growth factor-I (IGF-I) in breast cancer: evidence from a case-control study.

Epidemiological observations suggest that insulin-like growth factor-I (IGF-I), a potent mitogenic and anti-apoptotic peptide, plays a role in the etiology of breast cancer. Estrogen, which is crucial in breast carcinogenesis, both regulates and is influenced by IGF-I family. A case-control study was conducted to assess the role of IGF-I as a biomarker for breast cancer and to evaluate the potential joint effect of circulating IGF-I and critical period of estrogen exposure, as estimated by the interval between age at menarche and age at first full-term pregnancy on the risk of breast cancer. Questionnaire information and blood samples were taken before treatment from 297 incident cases with breast cancer and 593 controls admitted for health examination at the Tri-Service General Hospital, Taipei between 2004 and 2006. Plasma levels of IGF-I and IGFBP-3 were measured by immunoradiometric assay. Conditional logistic regression was used to calculate odds ratios (ORs) and their 95% confidence intervals (CIs). Our case-control data indicate that breast cancer risk related to IGF-I differs according to menopausal status. High circulating levels of IGF-I increased risk of pre- but not postmenopausal breast cancer (top vs. bottom tertile, adjusted OR, 1.86; 95% CI, 1.01-3.44). Furthermore, elevated IGF-I concentrations in conjunction with prolonged interval of critical period of estrogen exposure were associated with significantly increased risk of breast cancer, particularly among estrogen-positive cases (adjusted OR, 2.42, 95% CI, 1.33-4.38). These results suggest that the joint effect of IGF-I and estrogens may provide novel methods of breast cancer risk reduction among women.

Androgen receptor gene CAG repeats, estrogen exposure status, and breast cancer susceptibility.

The length of a polymorphic CAG repeat in exon 1 of the androgen receptor (AR) is inversely correlated with AR transactivation activity. As heightened androgenic stimulation may oppose breast cell proliferation, which is mediated by AR, we examined whether AR-CAG repeat lengths are related to breast cancer susceptibility. A nested case-control study of 88 newly diagnosed cases of breast cancer between 1992 and 2000 and 334 matched controls was carried out in Taiwanese women. Risk factors were obtained through a standardized questionnaire interview and blood samples were collected and used to determine the number of AR-CAG repeats. Women with one or more long AR (CAG)n repeat alleles (>22 repeats) were not at significantly increased risk of breast cancer [odds ratio (OR), 1.52; 95% confidence interval (CI), 0.80-2.90]. Of particular interest was a significantly increased risk associated with the long-allele AR genotype that was present mostly among women with a short duration (<10 years) of early estrogen exposure, as indicated by the interval between age at menarche and age at first full-term pregnancy, as compared with short AR allele genotypes (OR, 2.70; 95% CI, 1.00-7.31), although no such significant association in women with a long duration of early estrogen exposure (OR, 0.70; 95% CI, 0.25-1.59) was detected. These data suggest that longer AR (CAG)n repeat alleles may confer an increased risk of breast cancer among particular subsets of individuals, although these findings need replication in other populations.