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Background: Toll-like receptors (TLRs) regulate the balance between the innate and adaptive immune responses. Missense single nucleotide polymorphisms (SNPs) in TLRs might be functional and thus influence the risks of chronic infection and cancer development. Here, we investigated the association of two missense SNPs, rs3775291 (c.1234G>A) in the TLR3 gene and rs4833095 (c.743T>C) in the TLR1 gene, with relapse-free survival (RFS) in a cohort of prospectively observed breast cancer patients. Methods: In this prospective observational study, rs3775291 in TLR3 and rs4833095 in TLR1 were genotyped in 715 patients with primary breast cancer in a Chinese population. Results: Univariate analysis revealed that the patients with the AA genotype of rs3775291 had a shorter RFS compared with those carrying the G allele in the recessive model (P<0.01), but this finding was not observed with the dominant model (P = 0.31). The results remained significant after adjusting for the clinical parameters in the recessive model (HR = 3.53, 95% confidence interval [CI]: 1.98–6.31, P<0.01). Further survival analysis indicated that this SNP was significant in the luminal-B, triple-negative breast cancer (TNBC), and human epidermal growth factor receptor 2-positive (HER2+) patients using the recessive model but that it was not significant in the luminal-A patients. The SNP rs4833095 showed a non-significant tendency toward an increased RFS rate in the patients with the TT genotype. Conclusion: Our results suggest that the SNP rs3775291 in TLR3 may influence patient outcome. Further studies with larger sample sizes should be conducted to validate our findings. [ABSTRACT FROM AUTHOR]

Purpose: Obesity is associated with poorer outcomes in patients with hormone receptor-positive breast cancers, but this association is not well established for women with triple-negative breast cancers (TNBC). Here, we investigated the prognostic effects of body mass index (BMI) on clinical outcomes in patients with TNBC. Methods: We identified 1106 patients with TNBC who met the inclusion criteria and were treated between January 2002 and June 2012. Clinical and biological features were collected to evaluate the relation between BMI and breast cancer-specific survival (BCSS) and overall survival (OS) after controlling for other clinically significant variables. Results: Of 1106 patients, 656 (59.3%) were normal weight (BMI ≤24) and 450 patients (40.7%) were overweight(BMI>24). Median follow-up time was 44.8 months. Breast cancer specific death was observed in 140 patients. After adjusting for clinicopathologic risk factors, overweight was associated with OS (hazard ratio [HR]: 1.46, 95% confidence interval [CI]: 1.04-2.06, P =0.028) but not BCSS (HR: 1.34, 95% CI: 0.90–2.01, P =0.15)in all the patients with TNBC. When stratified with menopausal status, overweight was associated with BCSS and OS (HR: 2.27, 95% CI: 1.11-4.63, P = 0.024 and HR: 2.16, 95% CI: 1.21-3.87, P = 0.010, respectively) in premenopausal women. BMI was not associated with BCSS or OS in postmenopausal women. Conclusions: Overweight is an independent prognostic factor of OS in all women with TNBC, and menopause status may be a mitigating factor. Among premenopausal women, overweight women are at a greater risk of poor prognosis than normal weight women. If validated, these findings should be considered in developing preventive programs. [ABSTRACT FROM AUTHOR]

Purpose: The study was to estimate the likelihood of axillary downstaging and to identify the factors predicting a pathologically node negative status after neoadjuvant chemotherapy (NAC) with or without trastuzumab in HER2-positive breast cancer. Methods: Patients with HER2-positive, stage IIa-IIIc breast cancer were enrolled. Axillary status was evaluated by palpation and fine needle aspiration (FNA) before NAC. All patients received 4–6 cycles of PCrb (paclitaxel 80 mg/m2 and carboplatin AUC = 2 d1, 8, and 15 of a 28-day cycle, or paclitaxel 175 mg/m2 and carboplatin AUC = 6 every-3-week) and were non-randomly administered trastuzumab (2 mg/kg weekly or 6 mg/kg every-3-week) or not. After NAC, each patient underwent standard axillary lymph node dissection and breast-conserving surgery or mastectomy. And some patients received sentinel lymph node biopsy (SLNB) before axillary dissection. Results: Between November-2007 and June-2013, 255 patients were enrolled. Of them, 157 were confirmed as axillary node positive by FNA (group-A) and 98 as axillary node negative either by FNA or impalpable (group-B). After axillary dissection, the overall pathologically node negative rates (pNNR) were 52.9% in group-A and 69.4% in group-B. The ER-poor/HER2-positive subtype acquired the highest pNNR (79.6% in group-A and 87.9% in group-B, respectively) and the lowest rate of residual with ≥4 nodes involvement (1.9% and 3%, respectively) after PCrb plus trastuzumab. In multivariate analysis, trastuzumab added and ER-poor status were independent factors in predicting a higher pNNR in HER2-positive breast cancer. Forty-six tested patients showed that the ER-poor/HER2-positive subtype acquired a considerable high pNNR and axillary status with SLNB was well macthed with the axillary dissection. Conclusions: ER-poor/HER2-positive subtype of breast cancer is a potential candidate for undergoing sentinel lymph node biopsy instead of regional node dissection for accurate axillary evaluation after effective downstaging by neoadjuvant chemo-trastuzumab therapy. [ABSTRACT FROM AUTHOR]

Background: Reduced overall survival has been observed in patients with left-sided versus right-sided breast cancer due to cardiac toxicity after radiotherapy. However, the effect of laterality and primary tumor site on breast cancer-specific mortality (BCSM) remains unclear. Patients and Methods: We analyzed data from 305,443 women ages 20- to 79-years-old diagnosed with breast cancer between 1990 and 2009. The data were obtained from the population-based Surveillance, Epidemiology, and End Results (SEER) program of the U.S. National Cancer Institute. The survival outcomes with regard to laterality and primary tumor site were compared using univariate and multivariate (Cox proportional hazards regression model) methods. Results: In the multivariate analysis, BCSM was affected by the primary tumor site (P<0.0001) but not laterality (P = 0.331). The combined effect was piecewise: using the left upper-outer quadrant as the reference, the BCSM hazard ratio (HR) was not significant in the right upper quadrant (P = 0.755) and the right central portion (P = 0.329). The BCSM HR was slightly increased in the left central portion as well as the left and right lower-outer quadrants (HRs from 1.136 to 1.145; P<0.0001). The BCSM HR was significantly increased in the upper-inner and lower-inner quadrants (HRs from 1.242 to 1.372; P<0.0001) on both sides. Laterality only impacted BCSM in patients with breast cancer located in the central portion (HR, 1.100; P = 0.013, using the right side as the reference). Conclusion: Patients with tumors in the upper-outer quadrant of both sides and the right central portion have a better prognosis than patients with tumors at other locations. Laterality is not regarded as a prognostic factor in breast cancer. [ABSTRACT FROM AUTHOR]

Background: Tumor size is one of the most important factors in making clinical and pathological assessment of breast cancer. In the present study, we aimed to determine whether the preoperative measurement of tumor size, by imaging modalities, deviate from the postoperative pathological measurement in breast cancer. Patients and Methods: 1296 patients diagnosed with invasive ductal breast carcinoma (IDC) during 2007 and 2009 were involved. Pre- and postoperative measurements of tumor size were compared using paired t-test and Chi-square test. Results: The mean maximum diameters of tumors by imaging modalities and pathology were 27.9 mm and 22.4 mm, respectively. There was a statistically significant difference of 5.5 mm (95% CI: 4.7–6.2, p<0.001) between them. The discordance between pre- and post-surgical measurements of tumor size had significant effect on choosing surgery type, causing less application of breast conserving therapy (p<0.0001). Conclusion: Compared to pathological size, preoperative measurement by imaging modalities tends to overestimate tumor size. These differences could have implications in the treatment of patients with breast cancer. [ABSTRACT FROM AUTHOR]

Background: Postmastectomy breast reconstruction is widely used in breast cancer patients for its aesthetic effect. Although several studies have casted suspicion upon the oncological safety of immediate breast reconstruction after mastectomy, the potential impact of different reconstruction methods on patient survival remains unclear. Patients and Methods: We identified 35,126 female patients diagnosed with breast cancer from January 1, 1998 to December 31, 2002 in the Surveillance, Epidemiology, and End Results database. Breast cancer-specific survival (BCSS) and overall survival (OS) were compared among patients who underwent mastectomy with or without immediate breast reconstruction (autologous reconstruction or implant reconstruction) using Cox proportional hazard regression models. Results: In multivariate analysis unadjusted for family income, patients undergoing immediate postmastectomy reconstruction exhibited improved BCSS [pooled reconstruction (any types of reconstruction): hazard ratio (HR)  =  0.87, 95% confidence interval (CI) 0.80–0.95, P = 0.001] and OS (pooled reconstruction: HR = 0.70, 95% CI 0.65–0.75, P<0.001) compared to patients who underwent mastectomy alone. However, after stratifying by family income, patients receiving reconstruction showed limited advantage in BCSS and OS compared with those undergoing mastectomy alone. When comparing between the two reconstruction methods, no significant differences were observed in either BCSS (implant versus autologous reconstruction: HR = 1.11, 95%CI 0.90–1.35, P = 0.330) or OS (implant versus autologous reconstruction: HR = 1.07, 95% 0.90–1.28, P = 0.424). Conclusions: Compared to mastectomy alone, immediate postmastectomy reconstruction had limited advantage in survival after adjusting for confounding factor of family income. Our findings, if validated in other large databases, may help to illustrate the actual effect of immediate postmastectomy reconstruction on patient survival. [ABSTRACT FROM AUTHOR]

The inhibitory effect of two chemokine decoy receptors (CDRs), DARC and D6, on breast cancer metastasis is mainly due to their ability to sequester pro-malignant chemokines. We hypothesized that genetic variants in the DARC and CCBP2 (encoding D6) genes may be associated with breast cancer progression. In the present study, we evaluated the genetic contributions of DARC and CCBP2 to metastatic potential, indicated by lymph node metastasis (LNM). Ten single-nucleotide polymorphisms (SNPs) (potentially functional SNPs and block-based tagging SNPs) in DARC and CCBP2 were genotyped in 785 breast cancer patients who had negative lymph nodes and 678 patients with positive lymph nodes. Two non-synonymous SNPs, rs12075 (G42D) in DARC and rs2228468 (S373Y) in CCBP2, were observed to be associated with LNM in univariate analysis and remained significant after adjustment for conventional clinical risk factors, with odds ratios (ORs) of 0.54 (95% confidence interval [CI], 0.37 to 0.79) and 0.78 (95% CI, 0.62 to 0.98), respectively. Additional functional experiments revealed that both of these significant SNPs could affect metastasis of breast cancer in xenograft models by differentially altering the chemokine sequestration ability of their corresponding proteins. Furthermore, heterozygous GD genotype of G42D on human erythrocytes had a significantly stronger chemokine sequestration ability than homozygous GG of G42D ex vivo. Our data suggest that the genetic variants in the CDR genes are probably associated with the varied metastatic potential of breast cancer. The underlying mechanism, though it needs to be further investigated, may be that CDR variants could affect the chemokine sequestration ability of CDR proteins. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the association between polymorphism rs1061170 (T1277C, Y402H) in age-related macular degeneration (AMD) susceptibility gene Complement Factor H (CFH) and treatment response of neovascular AMD. Methods: We performed a literature-based meta-analysis including 10 published association studies involving 1,510 patients. Treatments included anti-VEGF (bevacizumab and ranibizumab) or photodynamic therapy. Summary odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using fixed- and random-effects models. Q-statistic test was used to assess heterogeneity. Results:Polymorphism rs1061170 showed a significant summary OR of 1.68 (95% CI, 1.09 to 2.60; P = 0.020; CC versus TT; random-effects) for treatment response of neovascular AMD with heterogeneity of 0.09. In subgroup analysis, rs1061170 was more likely to be a predictor of response to anti-VEGF therapy (P = 0.011). However, heterozygous TC genotype was not associated with altered treatment response (OR = 1.18, 95% CI, 0.95 to 1.47; P = 0.145; fixed-effects). Influence analysis indicated the robustness of our findings. Conclusions: rs1061170 might be associated with treatment response of neovascular AMD, especially for the anti- VEGF agents. It might be the first meta-analytically confirmed genetic marker predictive for AMD treatment response though a further validation in larger studies is needed. [ABSTRACT FROM AUTHOR]

Background: To evaluate the relationship between body mass index (BMI) and response to neoadjuvant chemotherapy (NCT) for breast cancer among Chinese women. Patients and Methods: A total of 307 eligible patients were assigned to receive four cycles of paclitaxel and carboplatin before standard surgery for breast cancer from 2007 to 2011 at Shanghai Cancer Hospital. The patients were categorized as obese, overweight, normal weight, or underweight based on BMI according to World Health Organization (WHO) criteria. Pathological complete response (pCR) was defined as no invasive cancer in the breast or axillary tissue. A logistic regression and the Chi-squared test were used for detecting the predictors of pCR and determining the relationship between BMI category and pCR rate in the subgroup analysis with respect to other variables. Results: Categorical BMI, estrogen receptor (ER), and progesterone receptor (PR) status were independent predictors of pCR according to the multivariate analysis. Patients with BMI$25 were less likely to achieve a pCR to NCT compared with patients with BMI<25 (Odds ratio: 0.454, p = 0.033, multivariate analysis). In the subgroup analysis, the predictive value of BMI for pCR to NCT was significantly shown in post-menopausal patients (p = 0.004) and hormonal receptor status-negative patients (p = 0.038). The incidence of treatment-induced toxicity was similar among the different BMI categories. Conclusion: Higher BMI was associated with worse pCR to NCT. Further approaches to investigating the mechanism of this influence of BMI on treatment response and a more appropriate schedule for calculating NCT dose for high-BMI-patients should be considered. [ABSTRACT FROM AUTHOR]

Background: A few polymorphisms are located in the mature microRNA sequences. Such polymorphisms could directly affect the binding of microRNA to hundreds of target mRNAs. It remains unknown whether rs4919510:C>G located in the mature miR-608 alters breast cancer susceptibility. Methods: The association of rs4919510:C>G with risk and pathologic features of breast cancer were investigated in two independent case-control studies, the first set including 1,138 sporadic breast cancer patients (including 927 invasive ductal carcinoma patients, 777 of them with known subtypes: 496 luminal-like, 133 HER2-positive, and 148 triple-negative) and 1,434 community-based controls, and the second set including 294 familial/early-onset breast cancer patients and 500 hospital-based cancer-free controls. Odds ratios (ORs) were estimated by logistic regression. Predicted targets of miR-608 and complementary sequences containing rs4919510:C.G were surveyed to reveal potential pathological mechanism. Results: In the first set, although rs4919510:C>G was unrelated to breast cancer in general patients, variant genotypes (CG/ GG) were specifically associated with increased risk of HER2-positive subtype (Adjusted OR = 1.97, 95% CI, 1.34-2.90 in the recessive model). Variant G-allele was the risk allele with OR of 1.62 (95% CI, 1.2322.15). Patients carrying GG-genotype also had larger HER2-positive tumors (P for Kruskal-Wallis test = 0.006). The relationship between rs4919510:C>G and risk of HER2-positive subgroup was validated in the second set (Bonferroni corrected P = 0.06). The adjusted combined OR (total 164 HER2-positive cases) in the recessive model was 1.97 (95% CI, 1.43-2.72) for GG genotype (corrected P = 1.1×10-4). Bioinformatic analysis indicated that, HSF1, which is required for HER2-induced tumorigenesis, might be a target of miR-608. The minimum free-energy of ancestral-miR-608 (C-allele) binding to HSF1 is 235.9 kcal/mol, while that of variant-form (Gallele) is 231.5 kcal/mol, indicating a lower affinity of variant-miR-608 to HSF1 mRNA. Conclusion: rs4919510:C>G in mature miR-608 may influence HER2-positive breast cancer risk and tumor proliferation. [ABSTRACT FROM AUTHOR]

Previous studies have shown that let-7 can repress the post-transcriptional translation of LIN28, and LIN28 in turn could block the maturation of let-7, forming a double-negative feedback loop. In this study, we investigated the effect of germline genetic variants on regulation of the homeostasis of the let-7/LIN28 loop and breast cancer risk. We initially demonstrated that the T/C variants of rs3811463, a single nucleotide polymorphism (SNP) located near the let-7 binding site in LIN28, could lead to differential regulation of LIN28 by let-7. Specifically, the C allele of rs3811463 weakened let-7-induced repression of LIN28 mRNA, resulting in increased production of LIN28 protein, which could in turn down-regulate the level of mature let-7. This effect was then validated at the tissue level in that the normal breast tissue of individuals with the rs3811463-TC genotype expressed significantly lower levels of let-7 and higher levels of LIN28 protein than those individuals with the rs3811463-TT genotype. Because previous in vitro and ex vivo experiments have consistently suggested that LIN28 could promote cellular transformation, we then systematically evaluated the relationship between rs3811463 as well as other common LIN28 SNPs and the risk of breast cancer in a stepwise manner. The first hospital-based association study (n = 2,300) demonstrated that two SNPs were significantly associated with breast cancer risk, one of which was rs3811463, while the other was rs6697410. The C allele of the rs3811463 SNP corresponded to an increased risk of breast cancer with an odds ratio (OR) of 1.25 (P = 0.0091), which was successfully replicated in a second independent study (n = 1,156) with community-based controls. The combined P-value of the two studies was 8.0610-5. Taken together, our study demonstrates that host genetic variants could disturb the regulation of the let-7/LIN28 double-negative feedback loop and alter breast cancer risk. [ABSTRACT FROM AUTHOR]

Purpose: Previous studies have suggested that postmenopausal women with breast cancer who present with wild-type CYP2D6 may actually have similar or superior recurrence-free survival outcomes when given tamoxifen in place of aromatase inhibitors (AIs). The present study established a CYP2D6 multiple-genotype-based model to determine the optimal endocrine therapy for patients harboring wild-type CYP2D6. Methods: We created a Markov model to determine whether tamoxifen or AIs maximized 5-year disease-free survival (DFS) for extensive metabolizer (EM) patients using annual hazard ratio (HR) data from the BIG 1-98 trial. We then replicated the model by evaluating 9-year event-free survival (EFS) using HR data from the ATAC trial. In addition, we employed two-way sensitivity analyses to explore the impact of HR of decreased-metabolizer (DM) and its frequency on survival by studying a range of estimates. Results: The 5-year DFS of tamoxifen-treated EM patients was 83.3%, which is similar to that of genotypically unselected patients who received an AI (83.7%). In the validation study, we further demonstrated that the 9-year EFS of tamoxifentreated EM patients was 81.4%, which is higher than that of genotypically unselected patients receiving tamoxifen (78.4%) and similar to that of patients receiving an AI (83.2%). Two-way sensitivity analyses demonstrated the robustness of the results. Conclusions: Our modeling analyses indicate that, among EM patients, the DFS/EFS outcome of patients receiving tamoxifen is similar to that of patients receiving an AI. Further prospective clinical trials are needed to evaluate the value of the CYP2D6 genotype in the selection of endocrine therapy. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the relationship between age and axillary lymph node (LN) involvement in Chinese breast cancer patients, and to replicate a recently identified piecewise relationship between age and LN involvement. Methods: A dataset, consisting of 3,715 patients (with complete information on study variables) with operable breast cancer consecutively surgically treated between 1996 and 2006, was derived from the database of Shanghai Cancer Hospital. Univariate and multivariate logistic regression were employed to analyze the relationship between age and LN. We subsequently performed a similar analysis on another dataset including 1,832 consecutive patients treated between 2007 and 2008 to replicate our findings in the first dataset. Results: A U-shaped relationship (previously observed in two European populations) between age and LN status failed to be replicated in our dataset of Chinese patients. Instead, we observed a linear rather than piecewise relationship. After multivariate adjustment, the linear relationship was still present. Moreover, the interaction between age and LN involvement was not modified by tumor size. The odds of LN involvement decreased by 1.5% for each year increase in age (OR 0.985, 95% CI 0.979-0.991, P,0.001). Breast cancer subtypes were also associated with LN status. Proportions of basallike and ERBB2+ subtypes decreased with increasing age. The observations in the first dataset were successfully replicated in a second independent dataset. Conclusion: We confirmed a straightforward but not piecewise relationship between age and LN status in Chinese patients. The different pattern between Chinese and European elderly patients should be considered when making clinical decisions. [ABSTRACT FROM AUTHOR]

Typhoid-conjugate vaccines (TCVs) provide an opportunity to reduce the burden of typhoid fever, caused by Salmonella Typhi, in endemic areas. As policymakers design vaccination strategies, accurate and high-resolution data on disease burden is crucial. However, traditional blood culture-based surveillance is resource-extensive, prohibiting its large-scale and sustainable implementation. Salmonella Typhi is a water-borne pathogen, and here, we tested the potential of Typhi-specific bacteriophage surveillance in surface water bodies as a low-cost tool to identify where Salmonella Typhi circulates in the environment. In 2021, water samples were collected and tested for the presence of Salmonella Typhi bacteriophages at two sites in Bangladesh: urban capital city, Dhaka, and a rural district, Mirzapur. Salmonella Typhi-specific bacteriophages were detected in 66 of 211 (31%) environmental samples in Dhaka, in comparison to 3 of 92 (3%) environmental samples from Mirzapur. In the same year, 4,620 blood cultures at the two largest pediatric hospitals of Dhaka yielded 215 (5%) culture-confirmed typhoid cases, and 3,788 blood cultures in the largest hospital of Mirzapur yielded 2 (0.05%) cases. 75% (52/69) of positive phage samples were collected from sewage. All isolated phages were tested against a panel of isolates from different Salmonella Typhi genotypes circulating in Bangladesh and were found to exhibit a diverse killing spectrum, indicating that diverse bacteriophages were isolated. These results suggest an association between the presence of Typhi-specific phages in the environment and the burden of typhoid fever, and the potential of utilizing environmental phage surveillance as a low-cost tool to assist policy decisions on typhoid control., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Hooda et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Environmental surveillance, using detection of Salmonella Typhi DNA, has emerged as a potentially useful tool to identify typhoid-endemic settings; however, it is relatively costly and requires molecular diagnostic capacity. We sought to determine whether S. Typhi bacteriophages are abundant in water sources in a typhoid-endemic setting, using low-cost assays., Methodology: We collected drinking and surface water samples from urban, peri-urban and rural areas in 4 regions of Nepal. We performed a double agar overlay with S. Typhi to assess the presence of bacteriophages. We isolated and tested phages against multiple strains to assess their host range. We performed whole genome sequencing of isolated phages, and generated phylogenies using conserved genes., Findings: S. Typhi-specific bacteriophages were detected in 54.9% (198/361) of river and 6.3% (1/16) drinking water samples from the Kathmandu Valley and Kavrepalanchok. Water samples collected within or downstream of population-dense areas were more likely to be positive (72.6%, 193/266) than those collected upstream from population centers (5.3%, 5/95) (p=0.005). In urban Biratnagar and rural Dolakha, where typhoid incidence is low, only 6.7% (1/15, Biratnagar) and 0% (0/16, Dolakha) river water samples contained phages. All S. Typhi phages were unable to infect other Salmonella and non-Salmonella strains, nor a Vi-knockout S. Typhi strain. Representative strains from S. Typhi lineages were variably susceptible to the isolated phages. Phylogenetic analysis showed that S. Typhi phages belonged to the class Caudoviricetes and clustered in three distinct groups., Conclusions: S. Typhi bacteriophages were highly abundant in surface waters of typhoid-endemic communities but rarely detected in low typhoid burden communities. Bacteriophages recovered were specific for S. Typhi and required Vi polysaccharide for infection. Screening small volumes of water with simple, low-cost (~$2) plaque assays enables detection of S. Typhi phages and should be further evaluated as a scalable tool for typhoid environmental surveillance., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Shrestha et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The global spread of carbapenem-resistant Acinetobacter baumannii (A. baumannii) strains has restricted the therapeutic options available to treat infections due to this pathogen. Understanding the prevalence of such infections and the underlying genetic mechanisms of resistance may help in the implementation of adequate measures to control and prevent acquisition of nosocomial infections, especially in an intensive care unit setting. This study describes the molecular characteristics and risk factors associated with OXA-23-producing A. baumannii infections. A case-control study was undertaken from September/2013 to April/2015. Acquisition of OXA-23-producing A. baumannii was found to be associated with the use of nasogastric tubes, haemodialysis, and the use of cephalosporins. These isolates were only susceptible to amikacin, gentamicin, tigecycline, and colistin, and contained the ISAba1 insertion sequence upstream ofblaOXA-23 and blaOXA-51 genes. Twenty-six OXA-23-producing A. baumannii strains belonged to the ST79 (CC79) clonal group,and patients infected or colonised by these isolates had a higher mortality rate (34.6%). In conclusion, this study showed a dissemination of OXA-23-producing A. baumannii strains that was associated with several healthcare-related risk factors and high mortality rates among intensive care unit patients., Competing Interests: A.C.G. has recently received research funding and/or consultation fees from Bayer, MSD, and Pfizer. This does not alter our adherence to PLOS ONE policies on sharing data and materials. The other authors have nothing to declare.

The inhibitory effect of two chemokine decoy receptors (CDRs), DARC and D6, on breast cancer metastasis is mainly due to their ability to sequester pro-malignant chemokines. We hypothesized that genetic variants in the DARC and CCBP2 (encoding D6) genes may be associated with breast cancer progression. In the present study, we evaluated the genetic contributions of DARC and CCBP2 to metastatic potential, indicated by lymph node metastasis (LNM). Ten single-nucleotide polymorphisms (SNPs) (potentially functional SNPs and block-based tagging SNPs) in DARC and CCBP2 were genotyped in 785 breast cancer patients who had negative lymph nodes and 678 patients with positive lymph nodes. Two non-synonymous SNPs, rs12075 (G42D) in DARC and rs2228468 (S373Y) in CCBP2, were observed to be associated with LNM in univariate analysis and remained significant after adjustment for conventional clinical risk factors, with odds ratios (ORs) of 0.54 (95% confidence interval [CI], 0.37 to 0.79) and 0.78 (95% CI, 0.62 to 0.98), respectively. Additional functional experiments revealed that both of these significant SNPs could affect metastasis of breast cancer in xenograft models by differentially altering the chemokine sequestration ability of their corresponding proteins. Furthermore, heterozygous GD genotype of G42D on human erythrocytes had a significantly stronger chemokine sequestration ability than homozygous GG of G42D ex vivo. Our data suggest that the genetic variants in the CDR genes are probably associated with the varied metastatic potential of breast cancer. The underlying mechanism, though it needs to be further investigated, may be that CDR variants could affect the chemokine sequestration ability of CDR proteins.

Purpose: To investigate the association between polymorphism rs1061170 (T1277C, Y402H) in age-related macular degeneration (AMD) susceptibility gene Complement Factor H (CFH) and treatment response of neovascular AMD., Methods: We performed a literature-based meta-analysis including 10 published association studies involving 1,510 patients. Treatments included anti-VEGF (bevacizumab and ranibizumab) or photodynamic therapy. Summary odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using fixed- and random-effects models. Q-statistic test was used to assess heterogeneity., Results: Polymorphism rs1061170 showed a significant summary OR of 1.68 (95% CI, 1.09 to 2.60; P = 0.020; CC versus TT; random-effects) for treatment response of neovascular AMD with heterogeneity of 0.09. In subgroup analysis, rs1061170 was more likely to be a predictor of response to anti-VEGF therapy (P = 0.011). However, heterozygous TC genotype was not associated with altered treatment response (OR = 1.18, 95% CI, 0.95 to 1.47; P = 0.145; fixed-effects). Influence analysis indicated the robustness of our findings., Conclusions: rs1061170 might be associated with treatment response of neovascular AMD, especially for the anti-VEGF agents. It might be the first meta-analytically confirmed genetic marker predictive for AMD treatment response though a further validation in larger studies is needed.

Background: To evaluate the relationship between body mass index (BMI) and response to neoadjuvant chemotherapy (NCT) for breast cancer among Chinese women., Patients and Methods: A total of 307 eligible patients were assigned to receive four cycles of paclitaxel and carboplatin before standard surgery for breast cancer from 2007 to 2011 at Shanghai Cancer Hospital. The patients were categorized as obese, overweight, normal weight, or underweight based on BMI according to World Health Organization (WHO) criteria. Pathological complete response (pCR) was defined as no invasive cancer in the breast or axillary tissue. A logistic regression and the Chi-squared test were used for detecting the predictors of pCR and determining the relationship between BMI category and pCR rate in the subgroup analysis with respect to other variables., Results: Categorical BMI, estrogen receptor (ER), and progesterone receptor (PR) status were independent predictors of pCR according to the multivariate analysis. Patients with BMI≥25 were less likely to achieve a pCR to NCT compared with patients with BMI<25 (Odds ratio: 0.454, p = 0.033, multivariate analysis). In the subgroup analysis, the predictive value of BMI for pCR to NCT was significantly shown in post-menopausal patients (p = 0.004) and hormonal receptor status-negative patients (p = 0.038). The incidence of treatment-induced toxicity was similar among the different BMI categories., Conclusion: Higher BMI was associated with worse pCR to NCT. Further approaches to investigating the mechanism of this influence of BMI on treatment response and a more appropriate schedule for calculating NCT dose for high-BMI-patients should be considered.

Background: A few polymorphisms are located in the mature microRNA sequences. Such polymorphisms could directly affect the binding of microRNA to hundreds of target mRNAs. It remains unknown whether rs4919510:C>G located in the mature miR-608 alters breast cancer susceptibility., Methods: The association of rs4919510:C>G with risk and pathologic features of breast cancer were investigated in two independent case-control studies, the first set including 1,138 sporadic breast cancer patients (including 927 invasive ductal carcinoma patients, 777 of them with known subtypes: 496 luminal-like, 133 HER2-positive, and 148 triple-negative) and 1,434 community-based controls, and the second set including 294 familial/early-onset breast cancer patients and 500 hospital-based cancer-free controls. Odds ratios (ORs) were estimated by logistic regression. Predicted targets of miR-608 and complementary sequences containing rs4919510:C>G were surveyed to reveal potential pathological mechanism., Results: In the first set, although rs4919510:C>G was unrelated to breast cancer in general patients, variant genotypes (CG/GG) were specifically associated with increased risk of HER2-positive subtype (Adjusted OR = 1.97, 95% CI, 1.34-2.90 in the recessive model). Variant G-allele was the risk allele with OR of 1.62 (95% CI, 1.23-2.15). Patients carrying GG-genotype also had larger HER2-positive tumors (P for Kruskal-Wallis test = 0.006). The relationship between rs4919510:C>G and risk of HER2-positive subgroup was validated in the second set (Bonferroni corrected P = 0.06). The adjusted combined OR (total 164 HER2-positive cases) in the recessive model was 1.97 (95% CI, 1.43-2.72) for GG genotype (corrected P = 1.1 × 10(-4)). Bioinformatic analysis indicated that, HSF1, which is required for HER2-induced tumorigenesis, might be a target of miR-608. The minimum free-energy of ancestral-miR-608 (C-allele) binding to HSF1 is -35.9 kcal/mol, while that of variant-form (G-allele) is -31.5 kcal/mol, indicating a lower affinity of variant-miR-608 to HSF1 mRNA., Conclusion: rs4919510:C>G in mature miR-608 may influence HER2-positive breast cancer risk and tumor proliferation.

Previous studies have shown that let-7 can repress the post-transcriptional translation of LIN28, and LIN28 in turn could block the maturation of let-7, forming a double-negative feedback loop. In this study, we investigated the effect of germline genetic variants on regulation of the homeostasis of the let-7/LIN28 loop and breast cancer risk. We initially demonstrated that the T/C variants of rs3811463, a single nucleotide polymorphism (SNP) located near the let-7 binding site in LIN28, could lead to differential regulation of LIN28 by let-7. Specifically, the C allele of rs3811463 weakened let-7-induced repression of LIN28 mRNA, resulting in increased production of LIN28 protein, which could in turn down-regulate the level of mature let-7. This effect was then validated at the tissue level in that the normal breast tissue of individuals with the rs3811463-TC genotype expressed significantly lower levels of let-7 and higher levels of LIN28 protein than those individuals with the rs3811463-TT genotype. Because previous in vitro and ex vivo experiments have consistently suggested that LIN28 could promote cellular transformation, we then systematically evaluated the relationship between rs3811463 as well as other common LIN28 SNPs and the risk of breast cancer in a stepwise manner. The first hospital-based association study (n = 2,300) demonstrated that two SNPs were significantly associated with breast cancer risk, one of which was rs3811463, while the other was rs6697410. The C allele of the rs3811463 SNP corresponded to an increased risk of breast cancer with an odds ratio (OR) of 1.25 (P = 0.0091), which was successfully replicated in a second independent study (n = 1,156) with community-based controls. The combined P-value of the two studies was 8.0 × 10⁻⁵. Taken together, our study demonstrates that host genetic variants could disturb the regulation of the let-7/LIN28 double-negative feedback loop and alter breast cancer risk., Competing Interests: The authors have declared that no competing interests exist.

Purpose: Previous studies have suggested that postmenopausal women with breast cancer who present with wild-type CYP2D6 may actually have similar or superior recurrence-free survival outcomes when given tamoxifen in place of aromatase inhibitors (AIs). The present study established a CYP2D6 multiple-genotype-based model to determine the optimal endocrine therapy for patients harboring wild-type CYP2D6., Methods: We created a Markov model to determine whether tamoxifen or AIs maximized 5-year disease-free survival (DFS) for extensive metabolizer (EM) patients using annual hazard ratio (HR) data from the BIG 1-98 trial. We then replicated the model by evaluating 9-year event-free survival (EFS) using HR data from the ATAC trial. In addition, we employed two-way sensitivity analyses to explore the impact of HR of decreased-metabolizer (DM) and its frequency on survival by studying a range of estimates., Results: The 5-year DFS of tamoxifen-treated EM patients was 83.3%, which is similar to that of genotypically unselected patients who received an AI (83.7%). In the validation study, we further demonstrated that the 9-year EFS of tamoxifen-treated EM patients was 81.4%, which is higher than that of genotypically unselected patients receiving tamoxifen (78.4%) and similar to that of patients receiving an AI (83.2%). Two-way sensitivity analyses demonstrated the robustness of the results., Conclusions: Our modeling analyses indicate that, among EM patients, the DFS/EFS outcome of patients receiving tamoxifen is similar to that of patients receiving an AI. Further prospective clinical trials are needed to evaluate the value of the CYP2D6 genotype in the selection of endocrine therapy.

Purpose: To investigate the relationship between age and axillary lymph node (LN) involvement in Chinese breast cancer patients, and to replicate a recently identified piecewise relationship between age and LN involvement., Methods: A dataset, consisting of 3,715 patients (with complete information on study variables) with operable breast cancer consecutively surgically treated between 1996 and 2006, was derived from the database of Shanghai Cancer Hospital. Univariate and multivariate logistic regression were employed to analyze the relationship between age and LN. We subsequently performed a similar analysis on another dataset including 1,832 consecutive patients treated between 2007 and 2008 to replicate our findings in the first dataset., Results: A U-shaped relationship (previously observed in two European populations) between age and LN status failed to be replicated in our dataset of Chinese patients. Instead, we observed a linear rather than piecewise relationship. After multivariate adjustment, the linear relationship was still present. Moreover, the interaction between age and LN involvement was not modified by tumor size. The odds of LN involvement decreased by 1.5% for each year increase in age (OR 0.985, 95% CI 0.979-0.991, P<0.001). Breast cancer subtypes were also associated with LN status. Proportions of basal-like and ERBB2+ subtypes decreased with increasing age. The observations in the first dataset were successfully replicated in a second independent dataset., Conclusion: We confirmed a straightforward but not piecewise relationship between age and LN status in Chinese patients. The different pattern between Chinese and European elderly patients should be considered when making clinical decisions.