| 1. |
- Accoti, Anastasia, et al.
(författare)
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Discovery of Novel Entomopathogenic Fungi for Mosquito-Borne Disease Control
- 2021
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Ingår i: Frontiers in Fungal Biology. - : Frontiers Media S.A.. - 2673-6128. ; 2
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Tidskriftsartikel (refereegranskat)abstract
- The increased application of chemical control programs has led to the emergence and spread of insecticide resistance in mosquitoes. Novel environmentally safe control strategies are currently needed for the control of disease vectors. The use of entomopathogenic fungi could be a suitable alternative to chemical insecticides. Currently, Beauveria spp. and Metarhizium spp. are the most widely used entomopathogenic fungi for mosquito control, but increasing the arsenal with additional fungi is necessary to mitigate the emergence of resistance. Entomopathogenic fungi are distributed in a wide range of habitats. We have performed a comprehensive screen for candidate mosquitocidal fungi from diverse outdoor environments in Maryland and Puerto Rico. An initial screening of 22 fungi involving exposure of adult Anopheles gambiae to 2-weeks-old fungal cultures identified five potent pathogenic fungi, one of which is unidentified and the remaining four belonging to the three genera Galactomyces sp., Isaria sp. and Mucor sp. These fungi were then screened against Aedes aegypti, revealing Isaria sp. as a potent mosquito killer. The entomopathogenic effects were confirmed through spore-dipping assays. We also probed further into the killing mechanisms of these fungi and investigated whether the mosquitocidal activities were the result of potential toxic fungus-produced metabolites. Preliminary assays involving the exposure of mosquitoes to sterile filtered fungal liquid cultures showed that Galactomyces sp., Isaria sp. and the unidentified isolate 1 were the strongest producers of factors showing lethality against An. gambiae. We have identified five fungi that was pathogenic for An. gambiae and one for Ae. aegypti, among these fungi, four of them (two strains of Galactomyces sp., Mucor sp., and the unidentified isolate 1) have never previously been described as lethal to insects. Further characterization of these entomopathogenic fungi and their metabolites needs to be done to confirm their potential use in biologic control against mosquitoes.
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| 2. |
- Daelman, Bo, et al.
(författare)
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Frailty and cognitive function in middle-aged and older adults with congenital heart disease
- 2024
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Ingår i: Journal of the American College of Cardiology. - : Elsevier. - 0735-1097 .- 1558-3597. ; 83:12, s. 1149-1159
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Tidskriftsartikel (refereegranskat)abstract
- Background: Life expectancy of patients with congenital heart disease (CHD) has increased rapidly, resulting in a growing and aging population. Recent studies have shown that older people with CHD have higher morbidity, health care use, and mortality. To maintain longevity and quality of life, understanding their evolving medical and psychosocial challenges is essential.Objectives: The authors describe the frailty and cognitive profile of middle-aged and older adults with CHD to identify predictor variables and to explore the relationship with hospital admissions and outpatient visits.Methods: Using a cross-sectional, multicentric design, we included 814 patients aged ≥40 years from 11 countries. Frailty phenotype was determined using the Fried method. Cognitive function was assessed by the Montreal Cognitive Assessment.Results: In this sample, 52.3% of patients were assessed as robust, 41.9% as prefrail, and 5.8% as frail; 38.8% had cognitive dysfunction. Multinomial regression showed that frailty was associated with older age, female sex, higher physiologic class, and comorbidities. Counterintuitively, patients with mild heart defects were more likely than those with complex lesions to be prefrail. Patients from middle-income countries displayed more prefrailty than those from higher-income countries. Logistic regression demonstrated that cognitive dysfunction was related to older age, comorbidities, and lower country-level income.Conclusions: Approximately one-half of included patients were (pre-)frail, and more than one-third experienced cognitive impairment. Frailty and cognitive dysfunction were identified in patients with mild CHD, indicating that these concerns extend beyond severe CHD. Assessing frailty and cognition routinely could offer valuable insights into this aging population.
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| 3. |
- De Bus, Liesbet, et al.
(författare)
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Antimicrobial de-escalation in the critically ill patient and assessment of clinical cure : the DIANA study
- 2020
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Ingår i: Intensive Care Medicine. - : Springer Science and Business Media LLC. - 0342-4642 .- 1432-1238. ; 46:7, s. 1404-1417
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: The DIANA study aimed to evaluate how often antimicrobial de-escalation (ADE) of empirical treatment is performed in the intensive care unit (ICU) and to estimate the effect of ADE on clinical cure on day 7 following treatment initiation.METHODS: Adult ICU patients receiving empirical antimicrobial therapy for bacterial infection were studied in a prospective observational study from October 2016 until May 2018. ADE was defined as (1) discontinuation of an antimicrobial in case of empirical combination therapy or (2) replacement of an antimicrobial with the intention to narrow the antimicrobial spectrum, within the first 3 days of therapy. Inverse probability (IP) weighting was used to account for time-varying confounding when estimating the effect of ADE on clinical cure.RESULTS: Overall, 1495 patients from 152 ICUs in 28 countries were studied. Combination therapy was prescribed in 50%, and carbapenems were prescribed in 26% of patients. Empirical therapy underwent ADE, no change and change other than ADE within the first 3 days in 16%, 63% and 22%, respectively. Unadjusted mortality at day 28 was 15.8% in the ADE cohort and 19.4% in patients with no change [p = 0.27; RR 0.83 (95% CI 0.60-1.14)]. The IP-weighted relative risk estimate for clinical cure comparing ADE with no-ADE patients (no change or change other than ADE) was 1.37 (95% CI 1.14-1.64).CONCLUSION: ADE was infrequently applied in critically ill-infected patients. The observational effect estimate on clinical cure suggested no deleterious impact of ADE compared to no-ADE. However, residual confounding is likely.
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| 4. |
- Haiman, Christopher A., et al.
(författare)
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A common variant at the TERT-CLPTM1L locus is associated with estrogen receptor-negative breast cancer
- 2011
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 43:12, s. 61-1210
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Tidskriftsartikel (refereegranskat)abstract
- Estrogen receptor (ER)-negative breast cancer shows a higher incidence in women of African ancestry compared to women of European ancestry. In search of common risk alleles for ER-negative breast cancer, we combined genome-wide association study (GWAS) data from women of African ancestry (1,004 ER-negative cases and 2,745 controls) and European ancestry (1,718 ER-negative cases and 3,670 controls), with replication testing conducted in an additional 2,292 ER-negative cases and 16,901 controls of European ancestry. We identified a common risk variant for ER-negative breast cancer at the TERT-CLPTM1L locus on chromosome 5p15 (rs10069690: per-allele odds ratio (OR) = 1.18 per allele, P = 1.0 x 10(-10)). The variant was also significantly associated with triple-negative (ER-negative, progesterone receptor (PR)-negative and human epidermal growth factor-2 (HER2)-negative) breast cancer (OR = 1.25, P = 1.1 x 10(-9)), particularly in younger women (<50 years of age) (OR = 1.48, P = 1.9 x 10(-9)). Our results identify a genetic locus associated with estrogen receptor negative breast cancer subtypes in multiple populations.
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| 5. |
- Nene, Vishvanath, et al.
(författare)
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Genome sequence of Aedes aegypti, a major arbovirus vector.
- 2007
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Ingår i: Science (New York, N.Y.). - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 316:5832, s. 1718-23
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Tidskriftsartikel (refereegranskat)abstract
- We present a draft sequence of the genome of Aedes aegypti, the primary vector for yellow fever and dengue fever, which at approximately 1376 million base pairs is about 5 times the size of the genome of the malaria vector Anopheles gambiae. Nearly 50% of the Ae. aegypti genome consists of transposable elements. These contribute to a factor of approximately 4 to 6 increase in average gene length and in sizes of intergenic regions relative to An. gambiae and Drosophila melanogaster. Nonetheless, chromosomal synteny is generally maintained among all three insects, although conservation of orthologous gene order is higher (by a factor of approximately 2) between the mosquito species than between either of them and the fruit fly. An increase in genes encoding odorant binding, cytochrome P450, and cuticle domains relative to An. gambiae suggests that members of these protein families underpin some of the biological differences between the two mosquito species.
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| 6. |
- Purrington, Kristen S., et al.
(författare)
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Genome-wide association study identifies 25 known breast cancer susceptibility loci as risk factors for triple-negative breast cancer
- 2014
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Ingår i: Carcinogenesis. - : Oxford University Press (OUP). - 0143-3334 .- 1460-2180. ; 35:5, s. 1012-1019
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Tidskriftsartikel (refereegranskat)abstract
- In a genome-wide scan, we show that 30 variants in 25 genomic regions are associated with risk of TN breast cancer. Women carrying many of the risk variants may have 4-fold increased risk relative to women with few variants.Triple-negative (TN) breast cancer is an aggressive subtype of breast cancer associated with a unique set of epidemiologic and genetic risk factors. We conducted a two-stage genome-wide association study of TN breast cancer (stage 1: 1529 TN cases, 3399 controls; stage 2: 2148 cases, 1309 controls) to identify loci that influence TN breast cancer risk. Variants in the 19p13.1 and PTHLH loci showed genome-wide significant associations (P < 5 x 10(-) (8)) in stage 1 and 2 combined. Results also suggested a substantial enrichment of significantly associated variants among the single nucleotide polymorphisms (SNPs) analyzed in stage 2. Variants from 25 of 74 known breast cancer susceptibility loci were also associated with risk of TN breast cancer (P < 0.05). Associations with TN breast cancer were confirmed for 10 loci (LGR6, MDM4, CASP8, 2q35, 2p24.1, TERT-rs10069690, ESR1, TOX3, 19p13.1, RALY), and we identified associations with TN breast cancer for 15 additional breast cancer loci (P < 0.05: PEX14, 2q24.1, 2q31.1, ADAM29, EBF1, TCF7L2, 11q13.1, 11q24.3, 12p13.1, PTHLH, NTN4, 12q24, BRCA2, RAD51L1-rs2588809, MKL1). Further, two SNPs independent of previously reported signals in ESR1 [rs12525163 odds ratio (OR) = 1.15, P = 4.9 x 10(-) (4)] and 19p13.1 (rs1864112 OR = 0.84, P = 1.8 x 10(-) (9)) were associated with TN breast cancer. A polygenic risk score (PRS) for TN breast cancer based on known breast cancer risk variants showed a 4-fold difference in risk between the highest and lowest PRS quintiles (OR = 4.03, 95% confidence interval 3.46-4.70, P = 4.8 x 10(-) (69)). This translates to an absolute risk for TN breast cancer ranging from 0.8% to 3.4%, suggesting that genetic variation may be used for TN breast cancer risk prediction.
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| 7. |
- S. Engdahl, Cecilia, et al.
(författare)
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Discovery of novel natural products for mosquito control
- 2022
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Ingår i: Parasites & Vectors. - : BioMed Central (BMC). - 1756-3305. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- Vector control plays a key role in reducing the public health burden of mosquito-borne diseases. Today’s vector control strategies largely rely on synthetic insecticides that can have a negative environmental impact when applied outdoors and often become inefficient because of the mosquitoes’ ability to develop resistance. An alternative and promising approach to circumvent these challenges involves the implementation of insecticides derived from nature (biopesticides) for vector control. Biopesticides can constitute naturally occurring organisms or substances derived from them that have lifespan-shortening effects on disease vectors such as mosquitoes. Here we present the discovery and evaluation of natural product-based biological control agents that can potentially be developed into biopesticides for mosquito control. We screened a natural product collection comprising 390 compounds and initially identified 26 molecules with potential ability to kill the larval stages of the yellow fever mosquito Aedes aegypti, which is responsible for transmitting viruses such as dengue, Zika, chikungunya and yellow fever. Natural products identified as hits in the screen were further evaluated for their suitability for biopesticide development. We show that a selection of the natural product top hits, bactobolin, maytansine and ossamycin, also killed the larval stages of the malaria-transmitting mosquito Anopheles gambiae as well as the adult form of both species. We have further explored the usefulness of crude extracts and preparations from two of the best candidates’ sources (organisms of origin) for mosquitocidal activity, that is extracts from the two bacteria Burkholderia thailandensis and Streptomyces hygroscopicus var. ossamyceticus.
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| 8. |
- Springer Engdahl, Cecilia, et al.
(författare)
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Chromobacterium biopesticide exposure does not select for resistance in Aedes mosquitoes
- 2023
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Ingår i: mBio. - 2161-2129 .- 2150-7511. ; 14:2
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Tidskriftsartikel (refereegranskat)abstract
- Developing effective tools to control mosquito populations is essential for reducing the incidence of diseases like malaria and dengue. Biopesticides of microbial origin are a rich, underexplored source of mosquitocidal compounds. We previously developed a biopesticide from the bacterium Chromobacterium sp. Panama that rapidly kills vector mosquito larvae, including Aedes aegypti and Anopheles gambiae. Here, we demonstrate that two independent Ae. aegypti colonies exposed to a sublethal dose of that biopesticide over consecutive generations persistently exhibited high mortality and developmental delays, indicating that resistance did not develop during the study period. Critically, the descendants of biopesticide-exposed mosquitoes experienced decreased longevity and did not display increased susceptibility to dengue virus or decreased susceptibility to common chemical insecticides. Through RNA sequencing, we observed no link between biopesticide exposure and the increased activity of xenobiotic metabolism and detoxification genes typically associated with insecticide resistance. These findings indicate that the Chromobacterium biopesticide is an exciting, emerging mosquito control tool.IMPORTANCE: Vector control is an essential part of mitigating diseases caused by pathogens that mosquitoes spread. Modern vector control is highly reliant on using synthetic insecticides to eliminate mosquito populations before they can cause disease. However, many of these populations have become resistant to commonly used insecticides. There is a strong need to explore alternative vector control strategies that aim to mitigate disease burden. Biopesticides, insecticides of biological origin, can have unique mosquitocidal activities, meaning they can effectively kill mosquitoes that are already resistant to other insecticides. We previously developed a highly effective mosquito biopesticide from the bacterium Chromobacterium sp. Csp_P. Here, we investigate whether exposure to a sublethal dose of this Csp_P biopesticide over 9 to 10 generations causes resistance to arise in Aedes aegypti mosquitoes. We find no evidence of resistance at the physiological or molecular levels, confirming that the Csp_P biopesticide is a highly promising new tool for controlling mosquito populations.
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| 9. |
- Stevens, Kristen N., et al.
(författare)
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Common Breast Cancer Susceptibility Loci Are Associated with Triple-Negative Breast Cancer
- 2011
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Ingår i: Cancer Research. - 1538-7445. ; 71:19, s. 6240-6249
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Tidskriftsartikel (refereegranskat)abstract
- Triple-negative breast cancers are an aggressive subtype of breast cancer with poor survival, but there remains little known about the etiologic factors that promote its initiation and development. Commonly inherited breast cancer risk factors identified through genome-wide association studies display heterogeneity of effect among breast cancer subtypes as defined by the status of estrogen and progesterone receptors. In the Triple Negative Breast Cancer Consortium (TNBCC), 22 common breast cancer susceptibility variants were investigated in 2,980 Caucasian women with triple-negative breast cancer and 4,978 healthy controls. We identified six single-nucleotide polymorphisms, including rs2046210 (ESR1), rs12662670 (ESR1), rs3803662 (TOX3), rs999737 (RAD51L1), rs8170 (19p13.1), and rs8100241 (19p13.1), significantly associated with the risk of triple-negative breast cancer. Together, our results provide convincing evidence of genetic susceptibility for triple-negative breast cancer. Cancer Res; 71(19); 6240-9. (C)2011 AACR.
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