Recommendations and guidelines for the diagnosis and management of Coronavirus Disease-19 (COVID-19) associated bacterial and fungal infections in Taiwan.

Coronavirus disease-19 (COVID-19) is an emerging infectious disease caused by SARS-CoV-2 that has rapidly evolved into a pandemic to cause over 600 million infections and more than 6.6 million deaths up to Nov 25, 2022. COVID-19 carries a high mortality rate in severe cases. Co-infections and secondary infections with other micro-organisms, such as bacterial and fungus, further increases the mortality and complicates the diagnosis and management of COVID-19. The current guideline provides guidance to physicians for the management and treatment of patients with COVID-19 associated bacterial and fungal infections, including COVID-19 associated bacterial infections (CABI), pulmonary aspergillosis (CAPA), candidiasis (CAC) and mucormycosis (CAM). Recommendations were drafted by the 7th Guidelines Recommendations for Evidence-based Antimicrobial agents use Taiwan (GREAT) working group after review of the current evidence, using the grading of recommendations assessment, development, and evaluation (GRADE) methodology. A nationwide expert panel reviewed the recommendations in March 2022, and the guideline was endorsed by the Infectious Diseases Society of Taiwan (IDST). This guideline includes the epidemiology, diagnostic methods and treatment recommendations for COVID-19 associated infections. The aim of this guideline is to provide guidance to physicians who are involved in the medical care for patients with COVID-19 during the ongoing COVID-19 pandemic.

COVID-19 associated mold infections: Review of COVID-19 associated pulmonary aspergillosis and mucormycosis.

COVID-19-associated mold infection (CAMI) is defined as development of mold infections in COVID-19 patients. Co-pathogenesis of viral and fungal infections include the disruption of tissue barrier following SARS CoV-2 infection with the damage in the alveolar space, respiratory epithelium and endothelium injury and overwhelming inflammation and immune dysregulation during severe COVID-19. Other predisposing risk factors permissive to fungal infections during COVID-19 include the administration of immune modulators such as corticosteroids and IL-6 antagonist. COVID-19-associated pulmonary aspergillosis (CAPA) and COVID-19-associated mucormycosis (CAM) is increasingly reported during the COVID-19 pandemic. CAPA usually developed within the first month of COVID infection, and CAM frequently arose 10-15 days post diagnosis of COVID-19. Diagnosis is challenging and often indistinguishable during the cytokine storm in COVID-19, and several diagnostic criteria have been proposed. Development of CAPA and CAM is associated with a high mortality despiteappropriate anti-mold therapy. Both isavuconazole and amphotericin B can be used for treatment of CAPA and CAM; voriconazole is the primary agent for CAPA and posaconazole is an alternative for CAM. Aggressive surgery is recommended for CAM to improve patient survival. A high index of suspicion and timely and appropriate treatment is crucial to improve patient outcome.

Recommendations and guidelines for the treatment of infections due to multidrug resistant organisms.

Antimicrobial drug resistance is one of the major threats to global health. It has made common infections increasingly difficult or impossible to treat, and leads to higher medical costs, prolonged hospital stays and increased mortality. Infection rates due to multidrug-resistant organisms (MDRO) are increasing globally. Active agents against MDRO are limited despite an increased in the availability of novel antibiotics in recent years. This guideline aims to assist clinicians in the management of infections due to MDRO. The 2019 Guidelines Recommendations for Evidence-based Antimicrobial agents use in Taiwan (GREAT) working group, comprising of infectious disease specialists from 14 medical centers in Taiwan, reviewed current evidences and drafted recommendations for the treatment of infections due to MDRO. A nationwide expert panel reviewed the recommendations during a consensus meeting in Aug 2020, and the guideline was endorsed by the Infectious Diseases Society of Taiwan (IDST). This guideline includes recommendations for selecting antimicrobial therapy for infections caused by carbapenem-resistant Acinetobacter baumannii, carbapenem-resistant Pseudomonas aeruginosa, carbapenem-resistant Enterobacterales, and vancomycin-resistant Enterococcus. The guideline takes into consideration the local epidemiology, and includes antimicrobial agents that may not yet be available in Taiwan. It is intended to serve as a clinical guide and not to supersede the clinical judgment of physicians in the management of individual patients.

The association of cellulitis incidence and meteorological factors in Taiwan.

Cellulitis is a common infection of the skin and soft tissue. Susceptibility to cellulitis is related to microorganism virulence, the host immunity status and environmental factors. This retrospective study from 2001 to 2013 investigated relationships between the monthly incidence rate of cellulitis and meteorological factors using data from the Taiwanese Health Insurance Dataset and the Taiwanese Central Weather Bureau. Meteorological data included temperature, hours of sunshine, relative humidity, total rainfall and total number of rainy days. In otal, 195 841 patients were diagnosed with cellulitis and the incidence rate was strongly correlated with temperature (γS = 0.84, P < 0.001), total sunshine hours (γS = 0.65, P < 0.001) and total rainfall (γS = 0.53, P < 0.001). The incidence rate of cellulitis increased by 3.47/100 000 cases for every 1° elevation in environmental temperature. Our results may assist clinicians in educating the public of the increased risk of cellulitis during warm seasons and possible predisposing environmental factors for infection.

Prophylactic supplement with melatonin successfully suppresses the pathogenesis of periodontitis through normalizing RANKL/OPG ratio and depressing the TLR4/MyD88 signaling pathway.

Periodontitis (PD) is an inflammatory disease characterized by gingival inflammation and resorption of alveolar bone. Impaired receptor activator of nuclear factor-kappa B ligand/osteoprotegerin (RANKL/OPG) signaling caused by enhanced production of pro-inflammatory cytokines plays an essential role in the pathogenesis of PD. Considering melatonin possesses significant anti-inflammatory property, this study aimed to determine whether prophylactic treatment with melatonin would effectively normalize RANKL/OPG signaling, depress toll-like receptor 4/myeloid differentiation factor 88 (TLR4/MyD88)-mediated pro-inflammatory cytokine activation, and successfully suppress the pathogenesis of PD. PD was induced in adult rats by placing the ligature at molar subgingival regions. Fourteen days before PD induction, 10, 50, or 100 mg/kg of melatonin was intraperitoneally injected for consecutive 28 days. Biochemical and enzyme-linked immunosorbent assay were used to detect TLR4/MyD88 activity, RANKL, OPG, interleukin 1ß, interleukin 6, and tumor necrosis factor-α levels, respectively. The extent of bone loss, bone mineral intensity, and calcium intensity was further evaluated by scanning electron microscopy, micro-computed tomography, and energy-dispersive X-ray spectroscopy. Results indicated that high RANKL/OPG ratio, TLR4/MyD88 activity, and pro-inflammatory cytokine levels were detected following PD. Impaired biochemical findings paralleled well with severe bone loss and reduced calcium intensity. However, in rats pretreated with melatonin, all above parameters were successfully returned to nearly normal levels with maximal change observed in rats receiving 100 mg/kg. As prophylactic treatment with melatonin effectively normalizes RANKL/OPG signaling by depressing TLR4/MyD88-mediated pro-inflammatory cytokine production, dietary supplement with melatonin may serve as an advanced strategy to strengthen oral health to counteract PD-induced destructive damage.

Association of eNOS and Cav-1 gene polymorphisms with susceptibility risk of large artery atherosclerotic stroke.

Endothelial nitric oxide synthase (eNOS) is localized in caveole and has important effects on caveolar coordination through its interaction with caveolin-1 (Cav-1), which supports normal functioning of vascular endothelial cells. However, the relationship between genotypic polymorphisms of e-NOS and Cav-1 genes and ischemic stroke (IS) remains lesser reported. This hospital-based case-control study aimed to determine the genetic polymorphisms of the eNOS (Glu298Asp) and Cav-1 (G14713A and T29107A) genes in association with susceptibility risk in patients who had suffered from a large artery atherosclerotic (LAA) stroke. Genotyping determination for these variant alleles was performed using the TaqMan assay. The distributions of observed allelic and genotypic frequencies for the polymorphisms were in Hardy-Weinberg equilibrium in healthy controls. The risk for an LAA stroke in the Asp298 variant was 1.72 (95% CI = 1.09-2.75) versus Glu298 of the eNOS. In the GA/AA (rs3807987) variant, it was 1.79 (95% CI = 1.16-2.74) versus GG and in TA/AA (rs7804372) was 1.61 (95% CI = 1.06-2.43) versus TT of the Cav-1, respectively. A tendency toward an increased LAA stroke risk was significant in carriers with the eNOS Glu298Asp variant in conjunction with the G14713 A and T29107A polymorphisms of the Cav-1 (aOR = 2.03, P-trend = 0.002). A synergistic effect between eNOS and Cav-1 polymorphisms on IS risk elevation was significantly influenced by alcohol drinking, heavy cigarette smoking (P-trend<0.01), and hypercholesterolemia (P-trend < 0.001). In conclusion, genotypic polymorphisms of the eNOS Glu298Asp and Cav-1 14713A/29107A polymorphisms are associated with the elevated risk of LAA stroke among Han Chinese in Taiwan.

The effects of climate factors on scabies. A 14-year population-based study in Taiwan.

Scabies is a common infectious disease and can cause severe outbreaks if not controlled quickly. Besides personal contact history, environmental factors are also important. This study analyzed the effects of environmental climate factors on the incidence of scabies in Taiwan. We conducted a 14-year nationwide population-based study: a total of 14,883 patients with scabies infestation were enrolled. Monthly climate data were collected from Taiwan's Central Weather Bureau, including data on temperature, relative humidity, total rainfall, total rain days, and total sunshine hours. The linear relationships between these climate factors and scabies infestations or other risk factors were examined by Pearson's correlation analysis. Overall, the incidence of scabies was negatively correlated with temperature (γ = -0.152, p < 0.001), while being positively correlated with humidity (γ = 0.192, p < 0.001). This useful information may provide evidence for lowering humidity at nursing facilities, hospitals, and military camps with scabies infestations, which may help to reduce its spread and prevent outbreaks.

A novel estrogen receptor-microRNA 190a-PAR-1-pathway regulates breast cancer progression, a finding initially suggested by genome-wide analysis of loci associated with lymph-node metastasis.

To identify microRNAs that are important in regulating breast cancer progression, the present study used data for the 199 961 single-nucleotide polymorphisms (SNPs) in 837 breast cancer patients genotyped in a recent genome-wide association study to identify loci associated with lymph node metastasis (LNM). SNPs tagging the 15q22.2 locus showed a significant association with LNM and miR-190a was found to be the only microRNA in this region. The role of miR-190a in LNM was supported by the findings that increased miR-190a expression inhibited cell migration and invasiveness and that the target of miR-190a was protease-activated-receptor 1 (PAR-1), which is a metastasis promoting protein in several cancers. In addition, the promoter region of miR-190a was defined and found to contain half of an estrogen response element, suggesting that miR-190a is regulated by estrogen receptor (ER) signaling. This was confirmed by the findings that miR-190a expression was activated by 17ß-estradiol and that ERα bound directly to this promoter. The importance of this ERα-miR190a-PAR-1 link in breast tumorigenesis is suggested by the findings of (i) an association between genetic polymorphism of the miR-190a-containing region and LNM that is modified by SNPs of PAR-1 and is particularly significant in ERα-positive patients and (ii) a combined effect of ERα and miR-190a expression on tumor grade/cancer stage. More importantly, the level of miR-190a expression in primary breast carcinomas correlated with overall survival. These findings suggest a novel pathway in which ERα signaling regulates miR-190a expression, causing inhibition of PAR-1 expression, correlated with inhibition of cancer metastasis.

Hollow three-dimensional endothelialized microvessel networks based on femtosecond laser ablation.

In this study, a novel method for the fabrication of hollow three-dimensional (3D) poly(lactic-co-glycolic acid) (PLGA) microvessel scaffolds is proposed. In this novel fabrication method, a salt ingot, which was used as a temporary frame to define the shape of the desired scaffold, was fabricated by extrusion molding. The salt ingot was immersed in a PLGA solution and the PGLA enveloped the ingot entirely. The femtosecond laser ablation technique was used for ablating the desired pattern on the PLGA layer and then the salt ingot was completely dissolved in distilled deionized water. A hollow 3D PLGA scaffold was obtained using this process on which bovine endothelial cells (BECs) were then cultured. Scanning electron microscopy (SEM) and fluorescent images of the cell seeding demonstrate that the BECs adhered and grew well on both the side-wall of the branches and the surroundings of each branch.

Prognostic significance of cyclin D1, ß-catenin, and MTA1 in patients with invasive ductal carcinoma of the breast.

BACKGROUND: To investigate markers for predicting breast cancer progression, we performed a candidate gene-based study that assessed expression change of three genes, cyclin D1, ß-catenin, and metastasis-associated protein-1 (MTA1), involving in aggressive phenotypes of cancerous cells, namely hyperproliferation, epithelial-mesenchymal transition, and global transcriptional regulation. METHODS: Specimens were from 150 enrolled female patients, with invasive ductal carcinoma, followed up for more than 10 years. mRNA expression of cyclin D1, ß-catenin, and MTA1 in cancerous and noncancerous cells microdissected from the primary tumor site was determined by quantitative real-time PCR. The relationship between mRNA expression levels of the genes and clinicopathologic features was assessed by statistical analysis. Disease-free and overall survival (DFS and OS) were analyzed by Kaplan-Meier analysis with log-rank test and a multivariate Cox regression model. RESULTS: Cyclin D1 was shown to be overexpressed in late-stage breast cancer (stage III/IV). Breast cancer with lymph node metastasis (LNM) showed significantly higher frequency of overexpressed cyclin D1, ß-catenin, and MTA1 (P < 0.05). Patients carrying greater numbers of overexpressed genes had joint effects on increased risk in tumors of advanced stages (P ( trend ) = 0.03) and LNM (P ( trend ) < 0.01). In the LNM-negative group, patients whose tumors with greater number of cyclin D1, ß-catenin, and MTA1 overexpressions were associated with poorer clinical outcomes, with hazard ratio of 14.79 for OS (P = 0.015) and 7.54 for DFS (P = 0.015) using multivariate Cox regression analysis during the 10-year follow-up. CONCLUSIONS: Higher expression of cyclin D1, ß-catenin, and MTA1 mRNAs in breast cancers may prove effective in predicting unfavorable outcomes of breast cancer.

Evaluation of a vancomycin dosing nomogram in achieving high target trough concentrations in Taiwanese patients.

BACKGROUND: The use of a vancomycin dosing nomogram is an alternative and more cost-effective method to conventional dosing; it reliably allows the achievement of trough vancomycin serum concentrations of 5-15 mg/l, with a successful clinical response. Recent guidelines have further recommended that the trough concentration be maintained at 15-20mg/l for complicated infections. However, to date no published nomogram has been constructed to achieve the optimal trough of 15-20mg/l in an Asian population. This study aimed to develop two vancomycin nomograms for the achievement of trough concentrations of 5-15 mg/l and 15-20mg/l in the Taiwanese population, and to ensure the clinical efficacy and safety of such nomograms. METHODS: The estimated concentrations and the real concentrations in our patient population were compared between six pharmacokinetic models to see which was the most precise. As the Ambrose method was the best at predicting the trough, this was used to create two nomograms, one for a target trough at 5-15 mg/l and the other for a target trough at 15-20mg/l. We then evaluated the nomograms by analyzing the number of patients with the target vancomycin trough concentration, clinical and microbiological outcomes, and safety. RESULTS: More patients who had dosing according to the nomogram had a vancomycin trough concentration within the desired target range than patients who had conventional dosing (65.1% vs. 32.1%, p = 0.001). These patients also had a higher rate of 'cure' as the clinical response (35.7% vs. 27.1%) and 'eradication' as the microbiological response (46.4% vs. 29.2%), and a lower rate of nephrotoxicity (14.3% vs. 22.9%). For the patients with a complicated infection, more had a trough between 15 and 20mg/l when vancomycin was dosed with the nomogram than when dosed conventionally (41.2% vs. 12.1%, p = 0.019). CONCLUSIONS: We found that when dosing vancomycin with these nomograms, patients tended to have vancomycin trough concentrations within the target range and also to have a better outcome with regard to clinical efficacy and the safety profile.

Fabrication of pillared PLGA microvessel scaffold using femtosecond laser ablation.

One of the persistent challenges confronting tissue engineering is the lack of intrinsic microvessels for the transportation of nutrients and metabolites. An artificial microvascular system could be a feasible solution to this problem. In this study, the femtosecond laser ablation technique was implemented for the fabrication of pillared microvessel scaffolds of polylactic-co-glycolic acid (PLGA). This novel scaffold facilitates implementation of the conventional cell seeding process. The progress of cell growth can be observed in vitro by optical microscopy. The problems of becoming milky or completely opaque with the conventional PLGA scaffold after cell seeding can be resolved. In this study, PLGA microvessel scaffolds consisting of 47 µm × 80 µm pillared branches were produced. Results of cell culturing of bovine endothelial cells demonstrate that the cells adhere well and grow to surround each branch of the proposed pillared microvessel networks.

MicroRNA-30a inhibits cell migration and invasion by downregulating vimentin expression and is a potential prognostic marker in breast cancer.

Tumor recurrence and metastasis result in an unfavorable prognosis for cancer patients. Recent studies have suggested that specific microRNAs (miRNAs) may play important roles in the development of cancer cells. However, prognostic markers and the outcome prediction of the miRNA signature in breast cancer patients have not been comprehensively assessed. The aim of this study was to identify miRNA biomarkers relating to clinicopathological features and outcome of breast cancer. A miRNA microarray analysis was performed on breast tumors of different lymph node metastasis status and with different progression signatures, indicated by overexpression of cyclin D1 and ß-catenin genes, to identify miRNAs showing a significant difference in expression. The functional interaction between the candidate miRNA, miR-30a, and the target gene, Vim, which codes for vimentin, a protein involved in epithelial-mesenchymal transition, was examined using the luciferase reporter assay, western blotting, and migration and invasion assays. The association between the decreased miR-30a levels and breast cancer progression was examined in a survival analysis. miR-30a negatively regulated vimentin expression by binding to the 3'-untranslated region of Vim. Overexpression of miR-30a suppressed the migration and invasiveness phenotypes of breast cancer cell lines. Moreover, reduced tumor expression of miR-30a in breast cancer patients was associated with an unfavorable outcome, including late tumor stage, lymph node metastasis, and worse progression (mortality and recurrence) (p < 0.05). In conclusion, these findings suggest a role for miR-30a in inhibiting breast tumor invasiveness and metastasis. The finding that miR-30a downmodulates vimentin expression might provide a therapeutic target for the treatment of breast cancer.

Polymorphisms of DNA repair pathway genes and cigarette smoking in relation to susceptibility to large artery atherosclerotic stroke among ethnic Chinese in Taiwan.

AIM: Cigarette-smoking induced oxidative DNA damage to endothelial cells has been reported to play an etiological role in atherosclerosis development. Individual vulnerability to oxidative stress through smoking exposure and the ability to repair DNA damage, which plays a critical role in modifying the risk susceptibility of large artery atherosclerotic (LAA) stroke, is hypothesized. Thus, we examined the effect of genetic polymorphisms of DNA repair pathway genes and cigarette smoking in relation to risk susceptibility of LAA stroke. METHODS: We enrolled 116 LAA stroke patients and 315 healthy controls from the Armed Forces Taoyuan General Hospital, Taoyuan, Taiwan. Genotyping of polymorphisms of the OGG1 (Ser326Cys), XRCC1 (Arg399Gln), ERCC2 (Lys751Gln), and ERCC5 (Asp1104His) genes was performed and used to evaluate LAA stroke susceptibility. RESULTS: Of those non-synonymous polymorphisms, the ERCC2 Lys751Gln variant was found to be associated with LAA stroke risk (OR: 1.69, 95%CI: 1.02-2.86), and this association was more pronounced in smokers, manifesting a 2.73-fold increased risk of LAA stroke (p=0.027). A joint effect on risk elevation of LAA stroke was seen in those patients with OGG1 and ERCC2 polymorphisms (OR: 2.75, 95%CI: 1.26-6.00). Moreover, among smokers carrying the OGG1 Ser326Cys polymorphism, there was a tendency toward an increased risk of LAA stroke in those patients who had a greater number of high-risk genotypes of XRCC1, ERCC2, and ERCC5 polymorphisms (p(trend)=0.010). CONCLUSION: The susceptible polymorphisms of DNA repair pathway genes may have a modifying effect on the elevated risk of LAA stroke in smokers among ethnic Chinese in Taiwan.

Mortality predictors of Pneumocystis jirovecii pneumonia in human immunodeficiency virus-infected patients at presentation: Experience in a tertiary care hospital of northern Taiwan.

BACKGROUND: Pneumocystis jirovecii pneumonia (PJP) remains the leading cause of opportunistic infections and deaths among human immunodeficiency virus (HIV)-infected patients. We would like to identify the predictors of mortality of these patients at initial presentation, and assist clinicians to aware the patients in risk of mortality earlier. METHODS: From 1997 to 2009, adults with HIV infection and a discharge diagnosis of PJP at Mackay Memorial Hospital were included in this retrospective study. Patients' demographic data and laboratory data were analyzed by reviewing the medical records. RESULTS: Eighty-five patients were included in this study. The overall mortality rate was 37.7%. Univariate analysis revealed several host factors significantly related to mortality, including age, systolic blood pressure, diastolic blood pressure, partial pressure of oxygen in arterial blood (PaO(2)), percentage of lymphocyte, percentage of CD4 lymphocyte, CD4 counts, serum total protein, serum albumin, and blood urea nitrogen. Multivariate analysis identified three independent predictors associated with mortality, i.e. systolic blood pressure ≤110 mmHg [adjusted odds ratio (AOR) 3.88; 95% confidence interval (CI) 1.17-12.83; p = 0.03], PaO(2) at room air ≤60 mmHg (AOR 4.97; 95% CI 1.34-18.23; p = 0.01), and lymphocytes ≤10% (AOR 8.19; 95% CI 1.48-45.36; p = 0.02). With these predictors, we can stratify patients into three groups with increasing risks for mortality, ≤one predictor (mortality rate 14%), any two predictors (47%), and three predictors (75%). CONCLUSIONS: HIV-infected patients with PJP can be clinically stratified by three prognostic variables identified by multivariate analysis. Early recognition of patients in higher risk can assist clinicians to prevent rapid deterioration and seek for better outcomes.

Association of MTHFR, MTR, and MTRR polymorphisms with Parkinson's disease among ethnic Chinese in Taiwan.

BACKGROUND: Influence of folate/homocysteine conversion is considered to be important in the pathogenesis of Parkinson's disease (PD). However, association of the folate metabolic pathway gene polymorphisms with PD susceptibility remains unclear. METHODS: To test this possibility in PD, we conducted a hospital-based case-control study constituting 211 patients and 218 age- and sex-matched controls of ethnic Chinese in Taiwan. Genotyping assay was performed to screen for polymorphisms of the methylenetetrahydrofolate reductase (MTHFR C677T), methyltetrahydrofolate-homocysteine methyltransferase (MTR A2756G), and 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR A1049G and C1783T) genes and assess the association between these genotype polymorphisms and PD risk using logistic regression analysis. RESULTS: Of these four non-synonymous polymorphisms, the MTRR 1049GG variant was significantly associated with PD susceptibility (OR=3.17, 95%CI=1.08-9.35). Furthermore, we stratified our patients based on the MTHFR 677TT genotype in different strata, a significant association between the joint effect of polymorphisms and PD risk was observed in those patients whose genotypes were MTRR A1049G/MTR A2756G or MTRR C1783T/MTR A2756G (P<0.05). CONCLUSION: Our findings provide support for the synergistic effects of polymorphisms in the folate metabolic pathway genes in PD susceptibility; the increased PD risk would be more significant in carriers with the polymorphisms of MTHFR, MTR, and MTRR genes.

Genotype polymorphisms of GGCX, NQO1, and VKORC1 genes associated with risk susceptibility in patients with large-artery atherosclerotic stroke.

BACKGROUND: Gamma-glutamyl carboxylation, a reaction essential for the biosynthesis of vitamin K-dependent coagulation factors, requires the participation of the gamma-glutamyl carboxylase (GGCX), vitamin K epoxide reductase (VKORC1), and NAD(P)H:quinone oxidoreductase (NQO1). We evaluated the role of these genotype polymorphisms in patients with large-artery atherosclerotic stroke. METHODS: In this hospital-based case-control study, 117 patients who were categorized as having large-artery atherosclerotic stroke and 115 age- and gender-matched controls were recruited. Genotyping determination for the GGCX1 (Gln325Arg), NQO1 (Pro187Ser), and VKORC1 (rs9923231) polymorphisms was performed. The associations of genotype with ischemic stroke (IS) risk were examined. RESULTS: A higher genotypic frequency of NQO1 C609T was found in the controls than in the patients, manifesting a 0.47-fold risk reduction in IS (95% CI=0.25-0.87). A tendency toward a reduced IS risk was statistically significant in those subjects who carried a greater number of the NQO1, GGCX, and VKORC1 polymorphisms (aOR=0.58, P(trend)=0.005). The synergistic effect of multiple genes on risk reduction was more significant in a subset of patients who were not alcoholics and who were non-smokers (P<0.05). CONCLUSIONS: Compartmentation of coagulation factor metabolism may account for the preferential role of NQO1, GGCX, and VKORC1 polymorphisms to lower the risk for large-artery atherosclerotic stroke.

Synergistic effects of polymorphisms in DNA repair genes and endogenous estrogen exposure on female breast cancer risk.

BACKGROUND: Endogenous estrogen is suggested to initiate cell proliferation and cause oxidative DNA damage during breast tumorigenesis. Cells eliminate DNA damage by means of repair enzymes. Genotypic variants of DNA damage repair genes, participating in base excision repair (BER) and nucleotide excision repair (NER) pathways, may act as modifiers that affect the association between estrogen exposure and breast cancer. METHODS: In a hospital-based case-control study of female breast cancer, DNA samples were obtained from 401 cases and 533 enrolled healthy controls, all of whom were Chinese women in Taiwan. Genotyping of polymorphisms of XRCC1 (Arg194Trp and Arg399Gln), OGG1 (Ser326Cys and Arg229Gln), ERCC2 Lys751Gln, ERCC4 Ser662Pro, and ERCC5 His1104Asp was performed and used to evaluate breast cancer susceptibility. RESULTS: Of the nonsynonymous polymorphisms, the ERCC5 1104Asp variant was significantly associated with breast cancer (odds ratio = 1.42; 95% confidence interval = 1.08-1.97), and this association was more pronounced in women with lengthy estrogen exposure. A trend toward an increased risk of developing breast cancer was observed in women who carried greater numbers of combined high-risk genotypes of BER and NER genes (P(trend) = .038). The synergistic effect of multiple genes on the increase of risk was significant in women with a longer period of estrogen exposure (>26 years), greater age at first full-term pregnancy (>26 years), a longer menarche-to-first full-term pregnancy interval (>11 years), and higher body mass index (>22) (all P<.05). CONCLUSIONS: This study demonstrates that genotype polymorphisms related to DNA damage repair confer greater susceptibility to endogenous estrogen in the development of breast cancer in women.

The clinical implications of MMP-11 and CK-20 expression in human breast cancer.

BACKGROUND: Tumor invasiveness and metastasis in cancer progression is manifested by epigenetic abnormality. However, it remains unknown whether transcription regulation of matrix metalloproteinase-11(MMP-11) and cytoskeleton-20 (CK-20) genes for the homoeostasis of epithelial/connective interface that can enhance cell dissemination and invasion may act as alternative mutators to tumor clinicopathology. METHODS: Paired cancerous and tumor-adjacent normal tissues from 72 breast cancer patients were assayed for the expression of MMP-11 and CK-20 by using real-time RT-PCR. The expression profiles were evaluated for the association with clinicopathological factors. RESULTS: Breast tumor tissues displayed higher expression levels of MMP-11 and CK-20 than those of the adjacent non-cancerous tissues. Overexpression of either MMP-11 or CK-20 correlated with patients having poorly differentiated tumors (P(MMP-11)=0.01 and P(CK-20)=0.05) and lymph node metastasis (LNM) (P(MMP-11)=0.004 and P(CK-20)=0.001). A synergistic effect between MMP-11 and CK-20 on risk elevation was significant in patients with advanced tumor stage (OR=2.03, 95%CI=1.10-3.77) and LNM (OR=2.83, 95%CI=1.20-4.71). Additionally, patients lacking progesterone receptor exhibited high expression of MMP-11 and CK-20. CONCLUSION: We demonstrate that MMP-11 and CK-20 are probable prognostic markers whose expression reflects the stages of tumor differentiation and LNM of breast cancer.

Polymorphism of cytosolic serine hydroxymethyltransferase, estrogen and breast cancer risk among Chinese women in Taiwan.

Cytosolic serine hydroxymethyltransferase (cSHMT) is key to intersection of folate-metabolic pathway, participating in the pyrimidine synthesis for DNA repair. Based on the hypothesis that variants of the cSHMT C1420T together with methionine synthase (MS A2756G) and 5,10-methylenetetrahydrofolate reductase (MTHFR C677T and A1298C) are associated with breast cancer, we performed a multigenic case-control study of the effects to breast cancer risk of four polymorphisms of folate-metabolizing genes against duration of estrogen exposure. Support of our hypothesis came from the following observations: (i) Allelic frequency of cSHMT C1420T was higher in the controls than in the cases, manifesting a 0.56-fold risk reduction in breast cancer (95%CI = 0.39-0.80); and this association was more significant in those women are susceptible to time of estrogen exposure. (ii) A joint effect of the cSHMT and MS polymorphisms significantly reduced susceptibility to breast cancer (aOR = 0.55; 95%CI = 0.34-0.88). (iii) There was a trend toward a reduced risk of breast cancer in women carrying a greater number of putative low-risk genotypes (Ptrend = 0.048). (iv) This synergistic effects on risk reduction was significantly interacted with length of estrogen exposure, exhibiting a longer time of estrogen exposure (> or =30 years), menarche-to-FFTP interval (>11 years), age at the first full-term pregnancy (< or =25 years), and body mass index (< or =24). In conclusion, our study provides support to account for the preferential role of cSHMT polymorphism to lower risk of female breast cancer, and such reduced risk would be more significant in carriers with the polymorphisms of MS and MTHFR genes.