320 results on '"da Silva EM"'
Search Results
2. The Impact of Different Surface Treatments on Topography and Bond Strength of Resin Cement to Lithium Disilicate Glass Ceramic
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Noronha Filho, JD, primary, Delforge, GE, additional, Xing, Y, additional, da Cruz Silva Trugilho Duarte, M, additional, Medeiros, IS, additional, Rabello, TB, additional, Poskus, LT, additional, and da Silva, EM, additional
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- 2023
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3. Bond Strength Stability of Self-adhesive Resin Cement to Etched Vitrified Yttria-stabilized Tetragonal Zirconia Polycrystal Ceramic After Thermomechanical Cycling
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Maroun, EV, primary, Guimarães, JGA, primary, de Miranda, WG, primary, Netto, LRC, primary, Elias, AB, primary, and da Silva, EM, primary
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- 2019
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4. 229 Genetic heterogeneity of ovarian sex cord-stromal tumors
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Kim, SH, primary, Da Cruz Paula, A, additional, da Silva, EM, additional, Stylianou, A, additional, Abu-Rustum, NR, additional, Soslow, RA, additional, Reis-Filho, J, additional, and Weigelt, B, additional
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- 2019
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5. Cryptosporidium spp. and Giardia sp. in aquatic mammals in northern and northeastern Brazil
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Borges, JCG, primary, Lima, DS, additional, da Silva, EM, additional, Moreira, ALO, additional, Marmontel, M, additional, Carvalho, VL, additional, Amaral, RS, additional, Lazzarini, SM, additional, and Alves, LC, additional
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- 2017
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6. Effect of Toothbrushing-mouthrinse-cycling on Surface Roughness and Topography of Nanofilled, Microfilled, and Microhybrid Resin Composites
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da Silva, EM, primary, de Sá Rodrigues, CUF, primary, Dias, DA, primary, da Silva, S, primary, Amaral, CM, primary, and Guimarães, JGA, primary
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- 2014
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7. Widening the digital divide: A study on the possible impact of the convergence Bill of 2003 on the South African cybereconomy
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Da Silva, EM, primary and Kruger, CJ, additional
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- 2014
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8. Impact of the application of neurolinguistic programming to mothers of children enrolled in a day care center of a shantytown
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Palma D, de Miranda Ct, de Nóbrega Fj, da Silva Em, de Paula Cs, and Denise Martin
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Gerontology ,Pediatrics ,medicine.medical_specialty ,Day care center ,Mothers ,lcsh:Medicine ,Context (language use) ,Language Development ,Bayley Scales of Infant Development ,Home environment ,law.invention ,Randomized controlled trial ,law ,Poverty Areas ,Intervention (counseling) ,medicine ,Humans ,Child development ,Psychomotor learning ,Mother’s mental health ,business.industry ,lcsh:R ,Infant ,Child Day Care Centers ,General Medicine ,Mental health ,Mothers mental health ,Mental Health ,Child, Preschool ,Female ,business ,Neurolinguistic Programming ,Psychomotor Performance - Abstract
CONTEXT: Of the members of a family, the mother is without doubt the most important one, which provides justification for including an evaluation of her mental health as one of the variables to be considered as determining factors in each child’s level of development. OBJECTIVE: To assess the impact of the application of Neurolinguistic Programming (NLP) on child development, home environment and maternal mental health. DESIGN: Randomised controlled trial. SETTING: The study included children enrolled in the municipal day care center of a shantytown in the City of São Paulo. PARTICIPANTS: 45 pairs of mothers and respective children between 18 and 36 months of age. MAIN MEASUREMENTS: Children’s development (Bayley scales); home environment variation (HOME); and maternal mental health (SRQ). Comparison between before and after the intervention was made in terms of children’s psychomotor development, home environment and maternal mental health. INTERVENTION: Application of the NLP technique to the experimental group and comparison with a control group. 1 - Experimental (EG), consisting of 23 children submitted to intervention by NLP; and 2 - Control (CG), with 22 children with no intervention. Length of intervention: 15 sessions of NLP. RESULTS: 37 children remained in the study (EG = 10, CG = 27). Variations in mental development (OR 1.21, IC 95% 0.0 to 23.08) in their home environment (Wilcoxon): p = 0.96 (before) and p = 0.09 (after); in maternal mental health: p = 0.26, 2 df. CONCLUSIONS: There was a trend that indicated positive effects on the home environment from the intervention. CONTEXTO: Entre os componentes do grupo familiar, sem dúvida a mãe é o mais importante, justificando-se por isso uma avaliação de sua saúde mental enquanto uma das variáveis a ser considerada dentre os fatores que determinam o nível de desenvolvimento da criança.OBJETIVO: Avaliar o impacto no desenvolvimento infantil, ambiente familiar e saúde mental materna da aplicação da Programação Neurolingüística (PNL) nos pais, em creche de favela de São Paulo. TIPO DE ESTUDO: ensaio clínico randomizado. LOCAL: Creche municipal em favela de São Paulo. AMOSTRA: 45 mães e suas crianças de 18 a 36 meses. VARIÁVEIS ESTUDADAS: desenvolvimento psicomotor infantil, ambiente familiar e saúde mental materna. Desenvolvimento infantil: Escalas Bayley, ambiente familiar: HOME, saúde mental materna: SRQ. INTERVENÇÃO: PNL: 15 sessões. Experimental (GE); 23 crianças, intervenção pelo PNL e controle (GC); 22 crianças sem intervenção. RESULTADOS: 37 crianças remanescentes (GE = 10, GC = 27): Variações no desenvolvimento mental (OR = 1,21 - IC 95% 0,0 - 23,08); no ambiente familiar (Wilcoxon): antes p = 0,96; após p = 0,09; na saúde mental materna: p = 0,26, 2 g.l. CONCLUSÕES : Existe tendência mostrando efeito positivo da intervenção no ambiente familiar.
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- 1999
9. Reproduction of Cubaris murina (Crustacea: Isopoda) under laboratory conditions and its use in ecotoxicity tests
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Niemeyer, JC., primary, Santos, VC., additional, Araújo, PB., additional, and da Silva, EM., additional
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- 2009
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10. Brazilian health technology assessment bulletin: editorial process, dissemination strategies, critical appraisal, and initial impact.
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Silva MT, de Almeida RT, Gava CM, Galvao TF, da Silva EM, Santos VC, Ronchini MA, de Mesquita AM, Elias FT, d'Oliveira AL, and Atallah AN
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- 2012
11. Use of NSAIDs in triathletes: prevalence, level of awareness and reasons for use.
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Gorski T, Cadore EL, Pinto SS, da Silva EM, Correa CS, Beltrami FG, and Kruel LF
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Objective To determine the level of awareness regarding nonsteroidal anti-inflammatory drugs (NSAIDs) and the prevalence and reasons for their consumption among athletes competing at the 2008 Brazil Ironman Triathlon (3.8 km swim, 180 km cycle and 42.2 km run). Design Survey study. Setting 2008 Brazil Ironman Triathlon, Florianópolis, Brazil, May 2008. Participants 327 Of the 1250 athletes competing at the 2008 Brazil Ironman Triathlon were enrolled in the study. Main Outcome Measures Athletes answered a questionnaire about NSAID effects, side effects and consumption at the bike checkout or awards lunch. Results 196 (59.9%) Athletes reported using NSAIDs in the previous 3 months; of these, 25.5% (n=50), 17.9% (n=35) and 47.4% (n=93) consumed NSAIDs the day before, immediately before and during the race, respectively. Among NSAID users, 48.5% (n=95) consumed them without medical prescription. The main reason given for NSAID consumption in the previous 3 months was the treatment of injuries, while the main reason given for consuming NSAIDs during the race was pain prevention. Despite anti-inflammatory and analgesic effects, most athletes were unaware of the effects of NSAIDs, and the only adverse effects known by most athletes were the gastrointestinal complications. Conclusions This study found a high prevalence of NSAID consumption, limited awareness of the effects and side effects of them and a high rate of nonprescribed use. It is suggested that long-distance triathlon events include in their programmes educational devices such as talks or folders about NSAID use, effects and side effects. [ABSTRACT FROM AUTHOR]
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- 2011
12. Cytotoxicity of current adhesive systems: in vitro testing on cell culture of L929 and balb/c 3T3 fibroblasts.
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Poskus LT, Lima RSM, Lima IR, Guimarães JGA, da Silva EM, and Granjeiro JMG
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Purpose: The aim of this study was to evaluate the cytotoxicity of three current adhesives: Prime&Bond NT (PBNT), Single Bond (SB) and XENO III (XENO). Methods: After embedding and curing circles of filter paper with the tested adhesives, the filters were placed in contact with the solidified agar surface over L929 monolayer cells plated in 6-well cell culture plate and incubated for 24 h. The inhibition zone around the filter papers was measured in mm. MTT assay was performed using fibroblasts Balb/c 3T3 cell lines in multiwell culture plates. All assays were done in triplicate. Results: All materials were cytotoxic (Kruskal-Wallis, P<0.05) in a similar level to latex (P>0.05). For intra-groups analysis, SB presented the lowest cytotoxicity (P<0.01), while there was no statistical difference between PBNT and XENO (P>0.05). MTT assay confirmed the cytotoxicity of the tested adhesives. Conclusion: Considering the limits of this work, all adhesives tested were as cytotoxic as latex. [ABSTRACT FROM AUTHOR]
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- 2009
13. Physiological adaptations to strength and circuit training in postmenopausal women with bone loss.
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Brentano MA, Cadore EL, Da Silva EM, Ambrosini AB, Coertjens M, Petkowicz R, Viero I, and Kruel LFM
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Strength training (ST; high intensity/low volume/long rest) has been used in several populations, including children, young adults, and older adults. However, there is no information about circuit weight training (CWT; low intensity/high volume/short rest) in apparently healthy postmenopausal women. The purpose of the present study was to analyze the effects of high-intensity ST and circuit training on isometric strength (IS), upper limb dynamic strength (ULS) and lower limb dynamic strength (LLS), muscle activation of quadriceps (EMG quad), maximal oxygen uptake (VO2 max), time to exhaustion (TE), and bone mineral density (BMD). Twenty-eight postmenopausal women were divided into 3 groups: 1) ST group (STG, n = 9, 45-80% 1 repetition maximum (1RM), 2-4 sets, 20-6 reps), 2) circuit training group (CTG, n = 10, 45-60% 1RM, 2-3 sets, 20-10 reps), and 3) a control group (CON, n = 9, no exercise). Significance level was defined as p
- Published
- 2008
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14. Hormonal responses to resistance exercise in long-term trained and untrained middle-aged men.
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Cadore EL, Lhullier FLR, Brentano MA, da Silva EM, Ambrosini MB, Spinelli R, Silva RF, and Kruel LFM
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This cross-sectional study compared hormonal responses to resistance exercise between trained and untrained men to investigate the adaptations of the endocrine system to long-term strength training in middle-aged men. Twenty-one middle-aged men were recruited for this study and matched into a strength-trained group (SG) (n = 10) and an untrained group (UG) (n = 11). In the SG, the individuals had practiced strength training for hypertrophy for at least 3 years. Upper- and lower-body muscle strength was measured with a 1 repetition maximum (1RM) test. Blood samples were collected at rest and after multiple sets of a superset strength training protocol (SSTP), with an intensity of 75% of 1RM values. With these blood samples, the levels of total testosterone (TT), free testosterone (FT), dehydroepiandrosterone (DHEA), cortisol, and sex hormone-binding globulin (SHBG) were determined. In addition, the TT-to-cortisol ratio and TT-to-SHBG ratio were calculated. There was no difference at rest between groups in hormonal values for TT, FT, DHEA, cortisol, the TT-to-SHBG ratio, and the TT-to-cortisol ratio. There were increases after SSTP in the levels of TT, FT, DHEA, and cortisol and the TT-to-SHBG ratio in the UG, but only FT increased in the SG. The SG demonstrated lower values in the TT-to-SHBG ratio after the training session. These results suggest the presence of alterations in anabolic and catabolic hormonal responses to resistance exercise in long-term trained middle-aged men, with the trained subjects demonstrating lower responsiveness in the hormone values. Long-term trained men seem to require a higher volume of training, at least similar to their daily workout, to stimulate greater hormone responses. [ABSTRACT FROM AUTHOR]
- Published
- 2008
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15. Analysis of muscle activation during different leg press exercises at submaximum effort levels.
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da Silva EM, Brentano MA, Cadore EL, De Almeida APV, and Kruel LFM
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Many studies have analyzed muscle activity during different strength exercises. Although the leg press (LP) is one of the most common exercises performed, there is little evidence of lower limb muscle activity patterns during this exercise and its variations. Thus, this study aimed to verify how mechanical changes and loads affect lower limb muscle activity during the performance of different LP exercises. Fourteen women performed 3 LP exercises: 45 degrees LP (LP45), LP high (LPH), and LP low (LPL) at 40% and 80% of the 1 repetition maximum. The electromyographic activity of the rectus femoris, vastus lateralis, biceps femoris, gastrocnemius, and gluteus maximus was recorded. Results suggested that mechanical changes affect lower limb muscle activity and that it is related to the load used. At moderate effort levels, the rectus femoris and gastrocnemius were more active during the LP45 and LPL than during the LPH. At a high effort level, the rectus femoris and vastus lateralis (quadriceps) were more active during the LPL than the LPH. Again, the rectus femoris and gastrocnemius were more active during the LP45 and LPL than the LPH. On the other hand, gluteus maximus activity was greater during the LPH than the LPL. This study found that coordination patterns of muscle activity are different when performing LP variations at high or moderate effort levels because of mechanical changes and different loads lifted during the different LP exercises. These results suggest that if the goal is to induce greater rectus femoris and vastus lateralis (quadriceps) activation, the LPL should be performed. On the other hand, if the goal is to induce gluteus maximus activity, the LPH should be performed. [ABSTRACT FROM AUTHOR]
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- 2008
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16. Tailoring an HIV-prevention intervention for cocaine injectors and crack users in Porto Alegre, Brazil.
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Leukefeld CG, Pechansky F, Martin SS, Surratt HL, Inciardi JA, Kessler FHP, Orsi MM, Von Diemen L, and Da Silva EM
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Brazil has the second largest number of reported AIDS cases in the world. Porto Alegre, like most other large urban centres in Brazil, has been greatly impacted by an AIDS epidemic driven by high rates of drug use and risky sexual behaviours. While epidemiologic surveillance of HIV/AIDS and treatment initiatives for HIV-infected individuals are well developed in Brazil, comparatively little attention has focused on developing interventions directed toward high-risk populations. Intervention programmes, particularly those tailored for chronic drug users, are lacking. This pilot project successfully adapted and tailored a cognitive behavioural HIV intervention developed in the US to the cultural setting in Porto Alegre. The project established feasibility and acceptability of the approach for targeting risky drug and sexual behaviours among a group of male Brazilian drug users. A sample of 120 male cocaine users was recruited from a public health clinic serving the target population in the city of Porto Alegre. The average age of the participants was 29; they averaged less than 8 years of formal education; and less than half (41%) were married. Lifetime self-reported drug use was high with 93% reporting cocaine use, 87% reporting crack use, and 100% reporting marijuana use. 43% of the sample reported ever injecting drugs. Reports of risky sexual behaviours were similarly elevated. Almost half (45%) tested positive for HIV. Preliminary evidence suggests that intervention acceptability was high among participants. Given the reported high risk sexual and drug use behaviours among these men, HIV interventions must be evaluated and expanded to include this population as well as their sexual partners. [ABSTRACT FROM AUTHOR]
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- 2005
17. Long-term breast cancer response to CDK4/6 inhibition defined by TP53-mediated geroconversion.
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Kudo R, Safonov A, Jones C, Moiso E, Dry JR, Shao H, Nag S, da Silva EM, Yildirim SY, Li Q, O'Connell E, Patel P, Will M, Fushimi A, Benitez M, Bradic M, Fan L, Nakshatri H, Sudhan DR, Denz CR, Reis-Filho JS, Goel S, Koff A, Weigelt B, Khan QJ, Razavi P, and Chandarlapaty S
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- 2024
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18. Comparative Anatomical, Histochemical, and Phytochemical Characterization of Species of the Genus Cucumis L.
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da Silva EM, Magalhães CDS, and Randau KP
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Cucumis anguria L. and Cucumis dipsaceus Ehrenb. ex Spach belong to the Cucurbitaceae family and are popularly known as "maxixe." In folk medicine, they are used to treat pneumonia, hyperglycemia, wounds, and malaria. This study aims to characterize the anatomy, histochemistry, and phytochemistry of C. anguria and C. dipsaceus. Conventional methods in plant anatomy and microscopy were used to prepare and analyze semi-permanent slides containing cross-sections of the stem, petiole, leaves, and paradermal sections of the leaf blade. For the histochemical analysis, different reagents were used according to the target metabolite. Phytochemical tests of methanolic extracts of leaves were performed by thin-layer chromatography. The microscopic analysis allowed obtaining the differentiation of plant cells, the presence of tector and glandular trichomes, in addition to showing anatomical traits such as stem shape, petiole shape, and organization of the mesophyll. Histochemistry showed the presence of alkaloids, starch, phenolic compounds, lipophilic compounds, lignin, and tannins. Phytochemical prospection identified monoterpenes, sesquiterpenes, triterpenes, steroids, alkaloids, and reducing sugars. The obtained results provide important information for quality control and species differentiation since there are few studies in the literature on these species., (© 2024 Wiley Periodicals LLC.)
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- 2024
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19. Proposals of indigenous peoples and local communities from Brazil for multilateral benefit-sharing from digital sequence information.
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de Souza de Lima A, Julião CG, da Silva EM, Dias AF, de Jesus JM, da Silva MT, Almada ED, de Andrade JP, Bensusan N, Zank S, and Soldati GT
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- 2024
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20. A Genomics-Driven Artificial Intelligence-Based Model Classifies Breast Invasive Lobular Carcinoma and Discovers CDH1 Inactivating Mechanisms.
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Pareja F, Dopeso H, Wang YK, Gazzo AM, Brown DN, Banerjee M, Selenica P, Bernhard JH, Derakhshan F, da Silva EM, Colon-Cartagena L, Basili T, Marra A, Sue J, Ye Q, Da Cruz Paula A, Yeni Yildirim S, Pei X, Safonov A, Green H, Gill KY, Zhu Y, Lee MCH, Godrich RA, Casson A, Weigelt B, Riaz N, Wen HY, Brogi E, Mandelker DL, Hanna MG, Kunz JD, Rothrock B, Chandarlapaty S, Kanan C, Oakley J, Klimstra DS, Fuchs TJ, and Reis-Filho JS
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- Humans, Female, Algorithms, Carcinoma, Lobular genetics, Carcinoma, Lobular pathology, Cadherins genetics, Breast Neoplasms genetics, Breast Neoplasms pathology, Antigens, CD genetics, Artificial Intelligence, Genomics methods, Mutation
- Abstract
Artificial intelligence (AI) systems can improve cancer diagnosis, yet their development often relies on subjective histologic features as ground truth for training. Herein, we developed an AI model applied to histologic whole-slide images using CDH1 biallelic mutations, pathognomonic for invasive lobular carcinoma (ILC) in breast neoplasms, as ground truth. The model accurately predicted CDH1 biallelic mutations (accuracy = 0.95) and diagnosed ILC (accuracy = 0.96). A total of 74% of samples classified by the AI model as having CDH1 biallelic mutations but lacking these alterations displayed alternative CDH1 inactivating mechanisms, including a deleterious CDH1 fusion gene and noncoding CDH1 genetic alterations. Analysis of internal and external validation cohorts demonstrated 0.95 and 0.89 accuracy for ILC diagnosis, respectively. The latent features of the AI model correlated with human-explainable histopathologic features. Taken together, this study reports the construction of an AI algorithm trained using a genetic rather than histologic ground truth that can robustly classify ILCs and uncover CDH1 inactivating mechanisms, providing the basis for orthogonal ground truth utilization for development of diagnostic AI models applied to whole-slide image. Significance: Genetic alterations linked to strong genotypic-phenotypic correlations can be utilized to develop AI systems applied to pathology that facilitate cancer diagnosis and biologic discoveries., (©2024 American Association for Cancer Research.)
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- 2024
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21. Postural balance, mobility, and handgrip strength one year after hospitalization due to COVID-19.
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de Godoy CG, Schmitt ACB, Ochiai GS, Gouveia E Silva EC, de Oliveira DB, da Silva EM, de Carvalho CRF, Junior CT, D'Andre A Greve JM, Hill K, and Pompeu JE
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- Humans, Male, Female, Prospective Studies, Middle Aged, SARS-CoV-2, Aged, Mobility Limitation, Adult, Activities of Daily Living, COVID-19 physiopathology, Postural Balance physiology, Hand Strength physiology, Hospitalization statistics & numerical data
- Abstract
Background: Symptoms such as impairment of postural balance, mobility and muscle strength can last up to 12 months post COVID-19 hospitalization, need to be better understood, as they can have repercussions in activities of daily living., Research Question: What happens to postural balance, mobility, and handgrip strength of COVID-19 patients after hospitalization?, Methods: A prospective cohort study was conducted with patients of both sexes, aged ≥18, admitted to hospital diagnosed with COVID-19. Outcomes were assessed at 1, 4, 6, and 12 months post-discharge, including: postural balance - Brief-Balance Evaluation Systems Test, mobility - Timed "Up & Go" Test, and handgrip strength - dynamometry. Prevalence values of impaired postural balance and mobility and lower-than-expected handgrip strength were calculated by point estimate and 95 % confidence interval. Shapiro-Wilk test showed that our data did not have a normal distribution, so the Friedman Test and the test of proportions were used for the statistical analysis., Results: Performance on postural balance was improved after four months of hospital discharge, but the improvement in mobility and handgrip strength only occurred after six months. After six months of discharge, the proportion of individuals with impairments began to decrease. A higher prevalence of impairments in postural balance and mobility occurred at one month post-discharge, which reduced over time. However, the values of impairments for postural balance and mobility were still high after 12 months of follow-up., Significance: There was a high prevalence of postural balance and mobility impairment 1 month after discharge, which was still high 12 months after discharge. The prevalence of lower-than-expected handgrip strength demonstrated limited change over time. Results highlight the need for assessment of postural balance, mobility and hand grip strength in post COVID-19 related hospitalization protocols, and long-term physical therapy interventions to address these impairments when identified to improve long term outcomes., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)
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- 2024
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22. Hematological and biochemical profiles, infection and habitat quality in an urban rat population.
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Carvalho-Pereira T, Pedra GG, de Oliveira DS, Souza FN, Zeppelini CG, Santos LRN, Couto RD, Bahiense TC, da Silva EM, Begon M, Reis MG, Ko AI, Childs JE, and Costa F
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Host condition is key in understanding disease dynamics. In an urban population of Rattus norvegicus, we aimed to assess whether infection of Leptospira interrogans and helminths was associated with patterns of host hematological and hormone-biochemical stress-related conditions. Rat kidney imprints and urine were used to identify and quantify L. interrogans, and feces samples for helminth eggs and corticosterone metabolites. Blood samples were taken for complete blood counts and specific biochemicals in rats' sera. Principal Component Analyses were performed to check whether rats would be grouped according to health profiles. We obtained hematological and hormone-biochemical data from 95 and 61 rats, respectively. Hematological PCA revealed distinct rat groups: typical (T), eosinophil deficient (Eos-D), eosinophil- and monocyte- deficient (EM-D) and monocyte deficient with high immature neutrophils (Mon-D). No association between L. interrogans or helminths and rat health profiles was observed, except with Trichiuridae, which mean intensity was significantly higher when all deficient groups were pooled together compared to the T-group. The poorest condition group was found in areas with fewer rat burrows than the T-group, indicating EM-D had a reduced ability to occupy "good" quality habitats. In natural populations, hematological profiles may reflect host's overall condition, instead of responses to specific infections., Competing Interests: Author Disclosure Statement No competing financial interests exist.
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- 2024
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23. Brazil nut-enriched diet modulates bone mineral density and body composition in an experimental model of chronic kidney disease.
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Da Cruz BO, Almeida PP, Silva-Costa N, Brito ML, Degani VAN, da Silva EM, Magliano DC, Mebarek S, Brizuela L, Cardozo LFMF, and Stockler-Pinto MB
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- Animals, Male, Rats, Absorptiometry, Photon, Calcium blood, Nuts, Bone Density, Rats, Wistar, Body Composition, Renal Insufficiency, Chronic diet therapy, Renal Insufficiency, Chronic physiopathology, Disease Models, Animal, Diet methods, Bertholletia, Femur physiopathology
- Abstract
Objective: This study investigates the effects of a Brazil nut-enriched diet on body composition and bone parameters in CKD animal model., Methods: Male Wistar rats were assigned to the following groups: Sham (n=8), Nx (n=6), nephrectomized rats, and NxBN (n=6), nephrectomized rats and an enricheddiet with 5% Brazil nut. Body composition parameters were obtained by dual-energy X- ray absorptiometry (DXA). Bioclin kits determined plasmatic calcium. The femurs werecollected to determine absolute mass and length, bone mineral density, and biomechanical tests., Results: The NxBN group exhibited a higher total body bone mineral density (BMD) value than the Nx group (0.177±0.004g/cm
2 vs 0,169±0.003g/cm2 ; p=0.0397). No significant differences were observed regarding absolute mass, length, BMD, and biomechanical parameters in the femurs of the groups. Moreover, no significant differences were found in plasmatic calcium levels among the groups., Conclusions: Brazil-nut enriched diet modulated BMD in CKD experimental model, and further studies are demanded to understand the pathways involved in this finding., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)- Published
- 2024
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24. Chromothripsis-mediated small cell lung carcinoma.
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Rekhtman N, Tischfield SE, Febres-Aldana CA, Lee JJ, Chang JC, Herzberg BO, Selenica P, Woo HJ, Vanderbilt CM, Yang SR, Xu F, Bowman AS, da Silva EM, Noronha AM, Mandelker DL, Mehine M, Mukherjee S, Blanco-Heredia J, Orgera JJ, Nanjangud GJ, Baine MK, Aly RG, Sauter JL, Travis WD, Savari O, Moreira AL, Falcon CJ, Bodd FM, Wilson CE, Sienty JV, Manoj P, Sridhar H, Wang L, Choudhury NJ, Offin M, Yu HA, Quintanal-Villalonga A, Berger MF, Ladanyi M, Donoghue MTA, Reis-Filho JS, and Rudin CM
- Abstract
Small cell lung carcinoma (SCLC) is a highly aggressive malignancy that is typically associated with tobacco exposure and inactivation of RB1 and TP53 genes. Here we performed detailed clinicopathologic, genomic and transcriptomic profiling of an atypical subset of SCLC that lacked RB1 and TP53 co-inactivation and arose in never/light smokers. We found that most cases were associated with chromothripsis - massive, localized chromosome shattering - recurrently involving chromosomes 11 or 12, and resulting in extrachromosomal (ecDNA) amplification of CCND1 or co-amplification of CCND2/CDK4/MDM2, respectively. Uniquely, these clinically aggressive tumors exhibited genomic and pathologic links to pulmonary carcinoids, suggesting a previously uncharacterized mode of SCLC pathogenesis via transformation from lower-grade neuroendocrine tumors or their progenitors. Conversely, SCLC in never-smokers harboring inactivated RB1 and TP53 exhibited hallmarks of adenocarcinoma-to-SCLC derivation, supporting two distinct pathways of plasticity-mediated pathogenesis of SCLC in never-smokers.
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- 2024
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25. Marginal integrity and physicomechanical properties of a thermoviscous and regular bulk-fill resin composites.
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Soares BM, Barbosa MP, de Almeida RV, Jardim RN, and da Silva EM
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- Hardness, Microscopy, Confocal, In Vitro Techniques, Dental Restoration, Permanent methods, Dental Stress Analysis, Composite Resins chemistry, Materials Testing, Polymerization, Dental Marginal Adaptation, Surface Properties, Elastic Modulus, Flexural Strength
- Abstract
Objectives: To evaluate the marginal integrity (MI%) and to characterize specific properties of a thermoviscous bulk-fill resin composite, two regular bulk-fill resin composites, and a non-bulk-fill resin composite., Materials and Methods: VisCalor bulk (VBF), Filtek One Bulk Fill (OBF), and Aura Bulk Fill (ABF) were evaluated. Filtek Z250 XT (ZXT) was used as non-bulk-fill control. MI% was evaluated in standardized cylindrical cavities restored with the composites by using a 3D laser confocal microscope. The following properties were characterized: volumetric polymerization shrinkage (VS%), polymerization shrinkage stress (Pss), degree of conversion (DC%), microhardness (KHN), flexural strength (FS), and elastic modulus (EM). Data were analyzed by one-way and two-way ANOVA, and Tukey HSD post-hoc test (α = 0.05)., Results: VBF presented the highest MI% and the lowest VS% and Pss (p < 0.05). DC% ranged from 59.4% (OBF) to 71.0% (ZXT). ZXT and VBF presented similar and highest KHN than OBF and ABF (p < 0.05). ABF presented the lowest FS (p < 0.05). EM ranged from 5.5 GPa to 7.7 GPa, with the values of ZXT and VBF being similar and statistically higher than those of OBF and ABF (p < 0.05)., Conclusions: Thermoviscous technology employed by VisCalor bulk was able to improve its mechanical behavior comparatively to regular bulk-fill resin composites and to contribute to a better marginal integrity in restorations built up in cylindrical cavities with similar geometry to a class I cavity as well. Although presenting overall better physicomechanical properties, Z250 XT presented the worst MI%., Clinical Relevance: The marginal integrity, which is pivotal for the success of resin composite restorations, could be improved using VisCalor bulk-fill. The worst MI% presented by Z250 XT reinforces that non-bulk-fill resin composites shall not be bulk-inserted in the cavity to be restored., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
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- 2024
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26. FOXK2 amplification promotes breast cancer development and chemoresistance.
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Yu Y, Cao WM, Cheng F, Shi Z, Han L, Yi J, da Silva EM, Dopeso H, Chen H, Yang J, Wang X, Zhang C, and Zhang H
- Subjects
- Animals, Female, Humans, Mice, 3-Phosphoinositide-Dependent Protein Kinases metabolism, 3-Phosphoinositide-Dependent Protein Kinases genetics, Antineoplastic Agents pharmacology, Cell Movement drug effects, Cyclin-Dependent Kinase 2 genetics, Cyclin-Dependent Kinase 2 metabolism, Estrogen Receptor alpha genetics, Estrogen Receptor alpha metabolism, Gene Amplification, Gene Expression Regulation, Neoplastic drug effects, MCF-7 Cells, Mice, Nude, Pyruvate Dehydrogenase Acetyl-Transferring Kinase genetics, Pyruvate Dehydrogenase Acetyl-Transferring Kinase metabolism, Thiazoles pharmacology, Xenograft Model Antitumor Assays, Breast Neoplasms genetics, Breast Neoplasms pathology, Breast Neoplasms drug therapy, Breast Neoplasms metabolism, Cell Proliferation drug effects, Drug Resistance, Neoplasm genetics, Forkhead Transcription Factors genetics, Forkhead Transcription Factors metabolism
- Abstract
Oncogene activation through DNA amplification or overexpression is a crucial driver of cancer initiation and progression. The FOXK2 gene, located on chromosome 17q25, encodes a transcription factor with a forkhead DNA-binding domain. Analysis of genomic datasets reveals that FOXK2 is frequently amplified and overexpressed in breast cancer, correlating with poor patient survival. Knockdown of FOXK2 significantly inhibited breast cancer cell proliferation, migration, anchorage-independent growth, and delayed tumor growth in a xenograft mouse model. Additionally, inhibiting FOXK2 sensitized breast cancer cells to chemotherapy. Co-overexpression of FOXK2 and mutant PI3KCA transformed non-tumorigenic MCF-10A cells, suggesting a role for FOXK2 in PI3KCA-driven tumorigenesis. CCNE2, PDK1, and ESR1 were identified as transcriptional targets of FOXK2 in MCF-7 cells. Small-molecule inhibitors of CCNE2/CDK2 (dinaciclib) and PDK1 (dichloroacetate) exhibited synergistic anti-tumor effects with PI3KCA inhibitor (alpelisib) in vitro. Inhibition of FOXK2 by dinaciclib synergistically enhanced the anti-tumor effects of alpelisib in a xenograft mouse model. Collectively, these findings highlight the oncogenic function of FOXK2 and suggest that FOXK2 and its downstream genes represent potential therapeutic targets in breast cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)
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- 2024
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27. Spatial molecular profiling of mixed invasive ductal and lobular breast cancers reveals heterogeneity in intrinsic molecular subtypes, oncogenic signatures, and mutations.
- Author
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Shah OS, Nasrazadani A, Foldi J, Atkinson JM, Kleer CG, McAuliffe PF, Johnston TJ, Stallaert W, da Silva EM, Selenica P, Dopeso H, Pareja F, Mandelker D, Weigelt B, Reis-Filho JS, Bhargava R, Lucas PC, Lee AV, and Oesterreich S
- Subjects
- Humans, Female, Cadherins genetics, Cadherins metabolism, Gene Expression Regulation, Neoplastic, Biomarkers, Tumor genetics, Biomarkers, Tumor metabolism, Triple Negative Breast Neoplasms genetics, Triple Negative Breast Neoplasms pathology, Triple Negative Breast Neoplasms metabolism, Transcriptome, Gene Expression Profiling methods, Carcinoma, Lobular genetics, Carcinoma, Lobular pathology, Carcinoma, Lobular metabolism, Carcinoma, Ductal, Breast genetics, Carcinoma, Ductal, Breast pathology, Carcinoma, Ductal, Breast metabolism, Mutation, Breast Neoplasms genetics, Breast Neoplasms pathology, Breast Neoplasms metabolism, Breast Neoplasms classification
- Abstract
Mixed invasive ductal and lobular carcinoma (MDLC) is a rare histologic subtype of breast cancer displaying both E-cadherin positive ductal and E-cadherin negative lobular morphologies within the same tumor, posing challenges with regard to anticipated clinical management. It remains unclear whether these distinct morphologies also have distinct biology and risk of recurrence. Our spatially resolved transcriptomic, genomic, and single-cell profiling revealed clinically significant differences between ductal and lobular tumor regions including distinct intrinsic subtype heterogeneity - e.g., MDLC with triple-negative breast cancer (TNBC) or basal ductal and estrogen receptor positive (ER+) luminal lobular regions, distinct enrichment of cell cycle arrest/senescence and oncogenic (ER and MYC ) signatures, genetic and epigenetic CDH1 inactivation in lobular but not ductal regions, and single-cell ductal and lobular subpopulations with unique oncogenic signatures further highlighting intraregional heterogeneity. Altogether, we demonstrated that the intratumoral morphological/histological heterogeneity within MDLC is underpinned by intrinsic subtype and oncogenic heterogeneity which may result in prognostic uncertainty and therapeutic dilemma., Competing Interests: Competing interests statement:The authors declare no competing interest.
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- 2024
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28. Volatile fatty acid and methane production from vinasse and microalgae using two-stage anaerobic co-digestion.
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Pinheiro AAD, da Silva EM, de Oliveira DCP, Magnus BS, Motteran F, Florencio L, and Leite WRM
- Abstract
The effects of adding vinasse (VIN) as a co-substrate on the stability and production of volatile fatty acids (VFA) and methane (CH
4 ) during the anaerobic digestion (AD) of microalgal biomass (MB) were evaluated. The AD system consisted of an acidogenic reactor (AR) followed by a methanogenic reactor (MR). The experiment was divided into phase I-start-up and AD of VIN; phase II-MB+VIN co-digestion (50:50 based on chemical oxygen demand (COD)); and phase III-co-digestion of pretreated MB and VIN (PTMB+VIN, 50:50). In phase I, the total amount of VFA in the AR increased from 240 to 2126 mg/L. In the MR, the conversion of VFA into CH4 yielded an average of 71 ± 37 NmL CH4 /g CODin . In phase II, the initial CH4 production was 246 ± 31 mL CH4 /g CODin but it decreased to 63 mL CH4 /g CODin due to the accumulation of longer chain acids. More stable conditions were achieved after two hydraulic retention cycles and the average CH4 yield in this phase was 183 mL CH4 /g CODin . In phase III, when using PTMB, 197 ± 72 NmL CH4 /g CODin were obtained, i.e., a 2.7- and 1.1-fold increases compared to phases I and II, respectively. The predominance of acetate producers and syntrophic organisms suggests acetoclastic methanogenesis, confirmed by the occurrence of Methanosaeta (10.5%)., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)- Published
- 2024
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29. Spatial molecular profiling of mixed invasive ductal-lobular breast cancers reveals heterogeneity in intrinsic molecular subtypes, oncogenic signatures, and mutations.
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Shah OS, Nasrazadani A, Foldi J, Atkinson JM, Kleer CG, McAuliffe PF, Johnston TJ, Stallaert W, da Silva EM, Selenica P, Dopeso H, Pareja F, Mandelker D, Weigelt B, Reis-Filho JS, Bhargava R, Lucas PC, Lee AV, and Oesterreich S
- Abstract
Mixed invasive ductal and lobular carcinoma (MDLC) is a rare histologic subtype of breast cancer displaying both E-cadherin positive ductal and E-cadherin negative lobular morphologies within the same tumor, posing challenges with regard to anticipated clinical management. It remains unclear whether these distinct morphologies also have distinct biology and risk of recurrence. Our spatially-resolved transcriptomic, genomic, and single-cell profiling revealed clinically significant differences between ductal and lobular tumor regions including distinct intrinsic subtype heterogeneity (e.g., MDLC with TNBC/basal ductal and ER+/luminal lobular regions), distinct enrichment of senescence/dormancy and oncogenic (ER and MYC) signatures, genetic and epigenetic CDH1 inactivation in lobular, but not ductal regions, and single-cell ductal and lobular sub-populations with unique oncogenic signatures further highlighting intra-regional heterogeneity. Altogether, we demonstrated that the intra-tumoral morphological/histological heterogeneity within MDLC is underpinned by intrinsic subtype and oncogenic heterogeneity which may result in prognostic uncertainty and therapeutic dilemma., Significance: MDLC displays both ductal and lobular tumor regions. Our multi-omic profiling approach revealed that these morphologically distinct tumor regions harbor distinct intrinsic subtypes and oncogenic features that may cause prognostic uncertainty and therapeutic dilemma. Thus histopathological/molecular profiling of individual tumor regions may guide clinical decision making and benefit patients with MDLC, particularly in the advanced setting where there is increased reliance on next generation sequencing.
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- 2024
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30. Adenoid cystic carcinoma of the Bartholin's gland is underpinned by MYB- and MYBL1- rearrangements.
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Feinberg J, Da Cruz Paula A, da Silva EM, Pareja F, Patel J, Zhu Y, Selenica P, Leitao MM Jr, Abu-Rustum NR, Reis-Filho JS, Joehlin-Price A, and Weigelt B
- Subjects
- Humans, Female, Middle Aged, Adult, Aged, Proto-Oncogene Proteins, Carcinoma, Adenoid Cystic genetics, Carcinoma, Adenoid Cystic pathology, Carcinoma, Adenoid Cystic metabolism, Vulvar Neoplasms genetics, Vulvar Neoplasms pathology, Vulvar Neoplasms metabolism, Bartholin's Glands pathology, Bartholin's Glands metabolism, Oncogene Proteins, Fusion genetics, Trans-Activators genetics, Proto-Oncogene Proteins c-myb genetics, Proto-Oncogene Proteins c-myb metabolism, Gene Rearrangement
- Abstract
Objective: Adenoid cystic carcinoma (AdCC) of the Bartholin's gland (AdCC-BG) is a very rare gynecologic vulvar malignancy. AdCC-BGs are slow-growing but locally aggressive and are associated with high recurrence rates. Here we sought to characterize the molecular underpinning of AdCC-BGs., Methods: AdCC-BGs (n = 6) were subjected to a combination of RNA-sequencing, targeted DNA-sequencing, reverse-transcription PCR, fluorescence in situ hybridization (FISH) and MYB immunohistochemistry (IHC). Clinicopathologic variables, somatic mutations, copy number alterations and chimeric transcripts were assessed., Results: All six AdCC-BGs were biphasic, composed of ductal and myoepithelial cells. Akin to salivary gland and breast AdCCs, three AdCC-BGs had the MYB::NFIB fusion gene with varying breakpoints, all of which were associated with MYB overexpression by IHC. Two AdCC-BGs were underpinned by MYBL1 fusion genes with different gene partners, including MYBL1::RAD51B and MYBL1::EWSR1 gene fusions, and showed MYB protein expression. Although the final AdCC-BG studied had MYB protein overexpression, no gene fusion was identified. AdCC-BGs harbored few additional somatic genetic alterations, and only few mutations in cancer-related genes were identified, including GNAQ, GNAS, KDM6A, AKT1 and BCL2, none of which were recurrent. Two AdCC-BGs, both with a MYB::NFIB fusion gene, developed metastatic disease., Conclusions: AdCC-BGs constitute a convergent phenotype, whereby activation of MYB or MYBL1 can be driven by the MYB::NFIB fusion gene or MYBL1 rearrangements. Our observations further support the notion that AdCCs, irrespective of organ site, constitute a genotypic-phenotypic correlation. Assessment of MYB or MYBL1 rearrangements may be used as an ancillary marker for the diagnosis of AdCC-BGs., Competing Interests: Declaration of competing interest B. Weigelt reports research funding from REPARE Therapeutics, outside the submitted work. F. Pareja is a member of the scientific advisory board of MultiplexDx Inc. J.S. Reis-Filho reported receiving personal/consultancy fees from Goldman Sachs, Bain Capital, REPARE Therapeutics, Saga Diagnostics and Paige.AI, membership of the scientific advisory boards of VolitionRx, REPARE Therapeutics and Paige.AI, membership of the Board of Directors of Grupo Oncoclinicas, and ad hoc membership of the scientific advisory boards of AstraZeneca, Merck, Daiichi Sankyo, Roche Tissue Diagnostics and Personalis, outside the submitted work. M. Leitao reports personal fees from Medtronic, Intuitive Surgical, J&J/Ethicon, and Immunogen. N.R. Abu-Rustum reports research funding paid to the institution from GRAIL; Memorial Sloan Kettering Cancer Center also has equity in GRAIL. The remaining authors have no competing interests to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)
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- 2024
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31. APOBEC3 mutagenesis drives therapy resistance in breast cancer.
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Gupta A, Gazzo A, Selenica P, Safonov A, Pareja F, da Silva EM, Brown DN, Zhu Y, Patel J, Blanco-Heredia J, Stefanovska B, Carpenter MA, Pei X, Frosina D, Jungbluth AA, Ladanyi M, Curigliano G, Weigelt B, Riaz N, Powell SN, Razavi P, Harris RS, Reis-Filho JS, Marra A, and Chandarlapaty S
- Abstract
Acquired genetic alterations commonly drive resistance to endocrine and targeted therapies in metastatic breast cancer
1-7 , however the underlying processes engendering these diverse alterations are largely uncharacterized. To identify the mutational processes operant in breast cancer and their impact on clinical outcomes, we utilized a well-annotated cohort of 3,880 patient samples with paired tumor-normal sequencing data. The mutational signatures associated with apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3) enzymes were highly prevalent and enriched in post-treatment compared to treatment-naïve hormone receptor-positive (HR+) cancers. APOBEC3 mutational signatures were independently associated with shorter progression-free survival on antiestrogen plus CDK4/6 inhibitor combination therapy in patients with HR+ metastatic breast cancer. Whole genome sequencing (WGS) of breast cancer models and selected paired primary-metastatic samples demonstrated that active APOBEC3 mutagenesis promoted resistance to both endocrine and targeted therapies through characteristic alterations such as RB1 loss-of-function mutations. Evidence of APOBEC3 activity in pre-treatment samples illustrated a pervasive role for this mutational process in breast cancer evolution. The study reveals APOBEC3 mutagenesis to be a frequent mediator of therapy resistance in breast cancer and highlights its potential as a biomarker and target for overcoming resistance.- Published
- 2024
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32. Anaerobic co-digestion of microalgal biomass, sugarcane vinasse, and residual glycerol from biodiesel using simplex-centroid mixture design: methane potential, synergic effect, and microbial diversity.
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da Silva EM, de Araújo SC, Veras STS, Pinheiro AAD, Motteran F, Kato MT, Florencio L, and Leite WRM
- Abstract
Microalgal biomass (MB) is a promising feedstock for bioenergy production. Nonetheless, the cell recalcitrance and the low C/N ratio limit the methane yield during anaerobic digestion. As an alternative to overcome these challenges, MB co-digestion with different feedstocks has been proposed. Thus, this study evaluated the anaerobic co-digestion (AcoD) of MB cultivated in wastewater with sugarcane vinasse (VIN) and residual glycerol from biodiesel production (GLY). Batch tests were conducted using augmented simplex-centroid mixture design to investigate the impact of AcoD on methane production (SMP), synergistic effects, and the influence on microbial community. When compared to MB digestion, 150 NmL CH
4 .g-1 VS, binary and ternary AcoD achieved SMP increases from 120 to 337%. The combination of 16.7:16.7:66.7 (MB:VIN:GLY) showed the highest SMP for a ternary mixture (631 NmL CH4 .g-1 VS). Optimal synergies ranged from 1.3 to 1.4 and were primarily found for the MB:GLY AcoD. Acetoclastic Methanosaeta genus was predominant, regardless the combination between substrates. Despite the largest SMP obtained from the MB:GLY AcoD, other ternary mixtures were also highly synergetic and therefore had strong potential as a strategic renewable energy source., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)- Published
- 2024
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33. Molecular profiling of primary endometrioid endometrial cancer and matched lung metastases: CTNNB1 mutation as a potential driver.
- Author
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Gordhandas S, Da Cruz Paula A, Kertowidjojo EC, Pareja F, Dessources K, da Silva EM, Derakhshan F, Mueller JJ, Abu-Rustum NR, Chui MH, and Weigelt B
- Abstract
•Both primary endometrial cancers (ECs) and matched lung metastases shared a common ancestor with independent evolution at each site.•The two endometrioid ECs studied acquired additional mutations during the distant metastatic process.•Subclonal CTNNB1 hotspot mutations in the two primary ECs studied became clonal in the distant metastases., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [B. Weigelt reports research funding from Repare Therapeutics and employment of an immediate family member at AstraZeneca, outside the submitted work. F. Pareja is a member of the scientific advisory board of MultiplexDx, and a member of the diagnostic advisory board and speaker for AstraZeneca. N.R. Abu-Rustum reports research funding from GRAIL paid to Memorial Sloan Kettering Cancer Center.]., (© 2024 The Authors.)
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- 2024
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34. Influence of Specimen Dimension, Water Immersion Protocol, and Surface Roughness on Water Sorption and Solubility of Resin-Based Restorative Materials.
- Author
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da Silva EM, Amaral CM, Jardim RN, Barbosa MP, and Rabello TB
- Abstract
The evaluation of water sorption and solubility is pivotal for the development of new resin-based restorative materials with the potential for clinical application. The purpose of the present study was to evaluate the influence of the specimen dimension, water immersion protocol, and surface roughness on the water sorption and solubility of three resin-based restorative materials. Disk-shaped specimens of 15 mm × 1 mm, 10 mm × 1 mm, and 6 mm × 1 mm were produced with a composite resin (Z100), a resin cement (RelyX ARC), and an adhesive system (Single Bond 2-SB2). The specimens were immersed in distilled water according to four protocols: ISO (all the specimens for each group were vertically immersed in 50 mL); IV-10 (the specimens were individually and vertically immersed in 10 mL); IH-10 (the specimens were individually and horizontally immersed in 10 mL); and IH-2 (the specimens were individually and horizontally immersed in 2 mL). The surface roughness (Sa and Sp) was evaluated using an atomic force microscope, and the degree of conversion was determined using FT-IR spectrometry. The specimen dimension and water immersion protocol had no effect on water sorption and solubility. For the three resin-based restorative materials, Sp was higher than Sa. The degree of conversion was not influenced by the specimen dimension. The variations in the specimen dimension and water immersion protocol compared to those determined by ISO 4049 did not prevent the comparison between the values of water sorption and solubility obtained for a given resin-based restorative material.
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- 2024
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35. Cisplatin Toxicity Causes Neutrophil-Mediated Inflammation in Zebrafish Larvae.
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Padovani BN, Morales Fénero C, Paredes LC, Amaral MAD, Domínguez-Amorocho O, Cipelli M, Gomes JMM, da Silva EM, Silva LM, Vieira RS, Pereira MT, Cruz MC, and Câmara NOS
- Subjects
- Animals, Zebrafish, Neutrophils metabolism, Larva, Inflammation chemically induced, Inflammation metabolism, Cytokines metabolism, Mammals, Cisplatin toxicity, Cisplatin metabolism, Acute Kidney Injury metabolism
- Abstract
Cisplatin is an antineoplastic agent used to treat various tumors. In mammals, it can cause nephrotoxicity, tissue damage, and inflammation. The release of inflammatory mediators leads to the recruitment and infiltration of immune cells, particularly neutrophils, at the site of inflammation. Cisplatin is often used as an inducer of acute kidney injury (AKI) in experimental models, including zebrafish ( Danio rerio ), due to its accumulation in kidney cells. Current protocols in larval zebrafish focus on studying its effect as an AKI inducer but ignore other systematic outcomes. In this study, cisplatin was added directly to the embryonic medium to assess its toxicity and impact on systemic inflammation using locomotor activity analysis, qPCR, microscopy, and flow cytometry. Our data showed that larvae exposed to cisplatin at 7 days post-fertilization (dpf) displayed dose-dependent mortality and morphological changes, leading to a decrease in locomotion speed at 9 dpf. The expression of pro-inflammatory cytokines such as interleukin (il)-12 , il6 , and il8 increased after 48 h of cisplatin exposure. Furthermore, while a decrease in the number of neutrophils was observed in the glomerular region of the pronephros, there was an increase in neutrophils throughout the entire animal after 48 h of cisplatin exposure. We demonstrate that cisplatin can have systemic effects in zebrafish larvae, including morphological and locomotory defects, increased inflammatory cytokines, and migration of neutrophils from the hematopoietic niche to other parts of the body. Therefore, this protocol can be used to induce systemic inflammation in zebrafish larvae for studying new therapies or mechanisms of action involving neutrophils.
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- 2024
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36. Genomic and epigenomic basis of breast invasive lobular carcinomas lacking CDH1 genetic alterations.
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Dopeso H, Gazzo AM, Derakhshan F, Brown DN, Selenica P, Jalali S, Da Cruz Paula A, Marra A, da Silva EM, Basili T, Gusain L, Colon-Cartagena L, Bhaloo SI, Green H, Vanderbilt C, Oesterreich S, Grabenstetter A, Kuba MG, Ross D, Giri D, Wen HY, Zhang H, Brogi E, Weigelt B, Pareja F, and Reis-Filho JS
- Abstract
CDH1 (E-cadherin) bi-allelic inactivation is the hallmark alteration of breast invasive lobular carcinoma (ILC), resulting in its discohesive phenotype. A subset of ILCs, however, lack CDH1 genetic/epigenetic inactivation, and their genetic underpinning is unknown. Through clinical targeted sequencing data reanalysis of 364 primary ILCs, we identified 25 ILCs lacking CDH1 bi-allelic genetic alterations. CDH1 promoter methylation was frequent (63%) in these cases. Targeted sequencing reanalysis revealed 3 ILCs harboring AXIN2 deleterious fusions (n = 2) or loss-of-function mutation (n = 1). Whole-genome sequencing of 3 cases lacking bi-allelic CDH1 genetic/epigenetic inactivation confirmed the AXIN2 mutation and no other cell-cell adhesion genetic alterations but revealed a new CTNND1 (p120) deleterious fusion. AXIN2 knock-out in MCF7 cells resulted in lobular-like features, including increased cellular migration and resistance to anoikis. Taken together, ILCs lacking CDH1 genetic/epigenetic alterations are driven by inactivating alterations in other cell adhesion genes (CTNND1 or AXIN2), endorsing a convergent phenotype in ILC., (© 2024. The Author(s).)
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- 2024
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37. Nonlobular Invasive Breast Carcinomas with Biallelic Pathogenic CDH1 Somatic Alterations: A Histologic, Immunophenotypic, and Genomic Characterization.
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Derakhshan F, Da Cruz Paula A, Selenica P, da Silva EM, Grabenstetter A, Jalali S, Gazzo AM, Dopeso H, Marra A, Brown DN, Ross DS, Mandelker D, Razavi P, Chandarlapaty S, Wen HY, Brogi E, Zhang H, Weigelt B, Pareja F, and Reis-Filho JS
- Subjects
- Humans, Female, Cadherins genetics, Genomics, Antigens, CD genetics, Carcinoma, Lobular pathology, Breast Neoplasms pathology, Carcinoma, Ductal, Breast pathology
- Abstract
CDH1 encodes for E-cadherin, and its loss of function is the hallmark of invasive lobular carcinoma (ILC). Albeit vanishingly rare, biallelic CDH1 alterations may be found in nonlobular breast carcinomas (NL-BCs). We sought to determine the clinicopathologic characteristics and repertoire of genetic alterations of NL-BCs harboring CDH1 biallelic genetic alterations. Analysis of 5842 breast cancers (BCs) subjected to clinical tumor-normal sequencing with an FDA-cleared multigene panel was conducted to identify BCs with biallelic CDH1 pathogenic/likely pathogenic somatic mutations lacking lobular features. The genomic profiles of NL-BCs with CDH1 biallelic genetic alterations were compared with those of ILCs and invasive ductal carcinomas (IDCs), matched by clinicopathologic characteristics. Of the 896 CDH1-altered BCs, 889 samples were excluded based on the diagnosis of invasive mixed ductal/lobular carcinoma or ILC or the detection of monoallelic CDH1 alterations. Only 7 of the 5842 (0.11%) BCs harbored biallelic CDH1 alterations and lacked lobular features. Of these, 4/7 (57%) cases were ER-positive/HER2-negative, 1/7 (14%) was ER-positive/HER2-positive, and 2/7 (29%) were ER-negative/HER2-negative. In total, 5/7 (71%) were of Nottingham grade 2, and 2/7 (29%) were of grade 3. The NL-BCs with CDH1 biallelic genetic alterations included a mucinous carcinoma (n = 1), IDCs with focal nested growth (n = 2), IDC with solid papillary (n = 1) or apocrine (n = 2) features, and an IDC of no special type (NST; n = 1). E-cadherin expression, as detected by immunohistochemistry, was absent (3/5) or aberrant (discontinuous membranous/cytoplasmic/granular; 2/5). However, NL-BCs with CDH1 biallelic genetic alterations displayed recurrent genetic alterations, including TP53, PIK3CA (57%, 4/7; each), FGFR1, and NCOR1 (28%, 2/7, each) alterations. Compared with CDH1 wild-type IDC-NSTs, NL-BCs less frequently harbored GATA3 mutations (0% vs 47%, P = .03), but no significant differences were detected when compared with matched ILCs. Therefore, NL-BCs with CDH1 biallelic genetic alterations are vanishingly rare, predominantly comprise IDCs with special histologic features, and have genomic features akin to luminal B ER-positive BCs., (Copyright © 2023 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)
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- 2024
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38. Decreased HER2 expression in endometrial cancer following anti-HER2 therapy.
- Author
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Chui MH, Brown DN, Da Cruz Paula A, da Silva EM, Momeni-Boroujeni A, Reis-Filho JS, Zhang Y, Makker V, Ellenson LH, and Weigelt B
- Subjects
- Female, Humans, In Situ Hybridization, Fluorescence, Neoplasm Recurrence, Local genetics, Trastuzumab therapeutic use, Gene Amplification, Receptor, ErbB-2 genetics, Receptor, ErbB-2 metabolism, Endometrial Neoplasms drug therapy, Endometrial Neoplasms genetics, Endometrial Neoplasms pathology
- Abstract
Trastuzumab has demonstrated clinical efficacy in the treatment of HER2-positive serous endometrial cancer (EC), which led to its incorporation into standard-of-care management of this aggressive disease. Acquired resistance remains an important challenge, however, and its underlying mechanisms in EC are unknown. To define the molecular changes that occur in response to anti-HER2 therapy in EC, targeted next-generation sequencing (NGS), HER2 immunohistochemistry (IHC), and fluorescence in situ hybridization (FISH) were performed on pre- and post-treatment tumour samples from 14 patients with EC treated with trastuzumab or trastuzumab emtansine. Recurrent tumours after anti-HER2 therapy acquired additional genetic alterations compared with matched pre-treatment ECs and frequently showed decreased HER2 protein expression by IHC (7/14, 50%). Complete/near-complete absence of HER2 protein expression (score 0/1+) observed post-treatment (4/14, 29%) was associated with retained HER2 gene amplification (n = 3) or copy number neutral status (n = 1). Whole-exome sequencing performed on primary and recurrent tumours from the latter case, which exhibited genetic heterogeneity of HER2 amplification in the primary tumour, revealed selection of an early HER2-non-amplified clone following therapy. Our findings demonstrate that loss of target expression, by selection of HER2-non-amplified clones or, more commonly, by downregulation of expression, may constitute a mechanism of resistance to anti-HER2 therapy in HER2-positive EC. © 2023 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd., (© 2023 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)
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- 2024
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39. Evaluation of glomerular sirtuin-1 and claudin-1 in the pathophysiology of nondiabetic focal segmental glomerulosclerosis.
- Author
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Lopes-Gonçalves G, Costa-Pessoa JM, Pimenta R, Tostes AF, da Silva EM, Ledesma FL, Malheiros DMAC, Zatz R, Thieme K, Câmara NOS, and Oliveira-Souza M
- Subjects
- Humans, Mice, Animals, Claudin-1 genetics, Claudin-1 metabolism, Sirtuin 1 genetics, Sirtuin 1 metabolism, Kidney Glomerulus pathology, Doxorubicin pharmacology, Glomerulosclerosis, Focal Segmental pathology, Podocytes metabolism, Kidney Diseases pathology
- Abstract
Focal segmental glomerulosclerosis (FSGS) is the leading cause of nephrotic syndrome, which is characterized by podocyte injury. Given that the pathophysiology of nondiabetic glomerulosclerosis is poorly understood and targeted therapies to prevent glomerular disease are lacking, we decided to investigate the tight junction protein claudin-1 and the histone deacetylase sirtuin-1 (SIRT1), which are known to be involved in podocyte injury. For this purpose, we first examined SIRT1, claudin-1 and podocin expression in kidney biopsies from patients diagnosed with nondiabetic FSGS and found that upregulation of glomerular claudin-1 accompanies a significant reduction in glomerular SIRT1 and podocin levels. From this, we investigated whether a small molecule activator of SIRT1, SRT1720, could delay the onset of FSGS in an animal model of adriamycin (ADR)-induced nephropathy; 14 days of treatment with SRT1720 attenuated glomerulosclerosis progression and albuminuria, prevented transcription factor Wilms tumor 1 (WT1) downregulation and increased glomerular claudin-1 in the ADR + SRT1720 group. Thus, we evaluated the effect of ADR and/or SRT1720 in cultured mouse podocytes. The results showed that ADR [1 µM] triggered an increase in claudin-1 expression after 30 min, and this effect was attenuated by pretreatment of podocytes with SRT1720 [5 µM]. ADR [1 µM] also led to changes in the localization of SIRT1 and claudin-1 in these cells, which could be associated with podocyte injury. Although the use of specific agonists such as SRT1720 presents some benefits in glomerular function, their underlying mechanisms still need to be further explored for therapeutic use. Taken together, our data indicate that SIRT1 and claudin-1 are relevant for the pathophysiology of nondiabetic FSGS., (© 2023. The Author(s).)
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- 2023
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40. Dentine biomodification by sulphonamides pre-treatment: bond strength, proteolytic inhibition, and antimicrobial activity.
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Portela MB, Barboza CM, da Silva EM, de Moraes DC, Simão RA, de Souza CR, Cardoso VDS, Ferreira-Pereira A, Vermelho AB, and Supuran CT
- Subjects
- Humans, Spectroscopy, Fourier Transform Infrared, Sulfonamides pharmacology, Collagen, Dentin chemistry, Anti-Infective Agents pharmacology
- Abstract
We evaluated the effects of dentine biomodification after pre-treatment with two sulphonamide carbonic anhydrase inhibitors (CAIs) of the N-[4-sulphamoylphenethylcarbamoyl]benzenesulphonamide type, investigating matrix metalloproteases activity, resin-dentine micro tensile bond strength, dentine surface wettability, and antimicrobial activities. Ninety-five sound-extracted human molars were selected for the study. Inhibitory effects were evaluated by gelatinase and collagenase activity tests and collagen degradation FT-IR spectroscopic analysis. Pre-treatment with the two CAIs kept the micro tensile values after 12 months of storage (32.23 ± 5.95) and cariogenic challenge (34.13 ± 2.71) similar to the initial, pre-treatment values (33.56 ± 4.34). A decreased Streptococcus mutans biofilm formation on dentine surfaces and antibacterial activity against planktonic bacteria were observed after CAI treatment. Dentine pre-treatment with sulphonamide CAIs maintained adhesion strength stability, allowed better dentine wettability, maintained matrix collagen, and showed anti- S. mutans activity.
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- 2023
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41. In vitro evaluation of human intravenous immunoglobulin in combination with antimicrobials and human serum against multidrug-resistant isolates of Acinetobacter baumannii.
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de Lima FCG, de Araújo AR, do Nascimento AV, Bezerra Cavalcanti CL, Oliveira Júnior JB, Sandes JM, da Silva EM, de Freitas CF, Veras DL, Alves LC, and Brayner FA
- Subjects
- Humans, Anti-Bacterial Agents pharmacology, Anti-Bacterial Agents therapeutic use, Immunoglobulins, Intravenous pharmacology, Immunoglobulins, Intravenous therapeutic use, Meropenem pharmacology, Meropenem therapeutic use, Colistin pharmacology, Amikacin pharmacology, Amikacin therapeutic use, Microbial Sensitivity Tests, Drug Resistance, Multiple, Bacterial, Drug Synergism, Acinetobacter baumannii, Acinetobacter Infections drug therapy, Acinetobacter Infections microbiology, Anti-Infective Agents pharmacology
- Abstract
The high incidence of multidrug-resistant (MDR) Acinetobacter baumannii has been a challenge for health worldwide, due to the reduction of therapeutic options, making the use of antimicrobial combinations necessary for the treatment, such as meropenem, amikacin, and colistin. Antibodies against bacterial species, mainly immunoglobulins G (IgG), are produced for acting as effector mechanisms (neutralization, opsonization, phagocytosis, and complement system activation). Some studies have demonstrated promising results of IgG in combination with antimicrobial preparations against bacterial infections, in which the direct action of IgG has restored the immune system balance. Serious problem caused by the increase of MDR A. baumannii isolates results in a constant search for therapeutic alternatives to defeat these infections. However, this study aims to verify in vitro the phagocytosis rate of the A. baumannii-infected human monocytes, as well as to analyze possible morphological changes induced by intravenous immunoglobulin G (IVIG) with human serum in association with antimicrobials. The phagocytosis rate and bacterial cell binding capacity of IVIG were determined for two A. baumannii isolates submitted to 4 mg/mL of human IVIG alone and in combination with different sub-minimum inhibitory concentrations (sub-MICs) of meropenem, amikacin, and colistin and processed for indirect immunofluorescence. Subsequently, these isolates were resubmitted and coupled with human serum and processed for scanning electron microscopy. There was no statistical difference for phagocytosis rates in the isolates tested. Bacterial isolates showed alterations in cell morphology when exposed to IVIG/human serum alone and in combination with antimicrobials such as alteration in shape, wrinkling, membrane depression, and especially cell rupture with extravasation of cytoplasmic material. The isolates visually differed in the IVIG binding to the bacterial cell, with higher fluorescence intensity, which corresponds to the highest IVIG binding, in the isolate more sensitive to meropenem, amikacin, and colistin. No differences between treatments were observed in the IVIG binding to the bacterial cell. The combined action of IVIG with meropenem, amikacin, and colistin against A. baumannii MDR isolates induced several bacterial cell damages. And when associated with human serum, a massive destruction of cells can be observed. These results may suggest the analysis of the use of IgG preparations for the treatment of A. baumannii MDR infections., (© 2023. The Author(s) under exclusive licence to Sociedade Brasileira de Microbiologia.)
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- 2023
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42. Teleworking as a work modality: reflections from institutional analysis.
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Chaves BR, Colares FLDS, da Silva EM, Dóbies DV, and Spagnol CA
- Abstract
This opinion article addresses teleworking, which has gained momentum in Brazil due to the COVID-19 pandemic. The discussions arose from a course in the Professional Master's Degree in Health Services Management at a nursing school in the state of Minas Gerais, Brazil. The authors raised teleworking-related questions, which are not only affecting their lives, but also the lives of workers in general, causing problems socially, economically, and related to workers' health. The reflections were drawn up using some concepts from institutional analysis. This article aimed to analyze teleworking as an analyzer of work in the context of the COVID-19 pandemic. As teleworking rapidly took off, the benefits were envisioned, but the potential detriments of this type of work were not considered. As a result, many professionals working from home began to work in unsuitable conditions, lacking the necessary infrastructure and support to perform their activities, such as ergonomic furniture, equipment, materials, internet access, technical assistance, training, and support. However, teleworking should not be overlooked, as many workers have identified with this type of work and many organizations have benefited from it becoming institutionalized. However, we cannot remain "numb," waiting for some miraculous reversion to pre-pandemic conditions, in order to organize the new type of "normal" in the world of work in a less alienated way., Competing Interests: Conflicts of interest: None
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- 2023
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43. Genomic Profiling Reveals Germline Predisposition and Homologous Recombination Deficiency in Pancreatic Acinar Cell Carcinoma.
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Mandelker D, Marra A, Zheng-Lin B, Selenica P, Blanco-Heredia J, Zhu Y, Gazzo A, Wong D, Yelskaya Z, Rai V, Somar J, Ostafi S, Mehta N, Yang C, Li Y, Brown DN, da Silva EM, Pei X, Linkov I, Terraf P, Misyura M, Ceyhan-Birsoy O, Ladanyi M, Berger M, Pareja F, Stadler Z, Offit K, Riaz N, Park W, Chou J, Capanu M, Koehler M, Rosen E, O'Reilly EM, and Reis-Filho JS
- Subjects
- Male, Humans, BRCA2 Protein genetics, BRCA1 Protein genetics, Germ-Line Mutation, Genetic Predisposition to Disease, Homologous Recombination, Genomics, Pancreatic Neoplasms, Carcinoma, Acinar Cell genetics, Pancreatic Neoplasms genetics
- Abstract
Purpose: To determine the genetic predisposition underlying pancreatic acinar cell carcinoma (PACC) and characterize its genomic features., Methods: Both somatic and germline analyses were performed using an Food and Drug Administration-authorized matched tumor/normal sequencing assay on a clinical cohort of 28,780 patients with cancer, 49 of whom were diagnosed with PACC. For a subset of PACCs, whole-genome sequencing (WGS; n = 12) and RNA sequencing (n = 6) were performed., Results: Eighteen of 49 (36.7%) PACCs harbored germline pathogenic variants in homologous recombination (HR) and DNA damage response (DDR) genes, including BRCA1 (n = 1), BRCA2 (n = 12), PALB2 (n = 2), ATM (n = 2), and CHEK2 (n = 1). Thirty-one PACCs displayed pure, and 18 PACCs harbored mixed acinar cell histology. Fifteen of 31 (48%) pure PACCs harbored a germline pathogenic variant affecting HR-/DDR-related genes. BRCA2 germline pathogenic variants (11 of 31, 35%) were significantly more frequent in pure PACCs than in pancreatic adenocarcinoma (86 of 2,739, 3.1%; P < .001), high-grade serous ovarian carcinoma (67 of 1,318, 5.1%; P < .001), prostate cancer (116 of 3,401, 3.4%; P < .001), and breast cancer (79 of 3,196, 2.5%; P < .001). Genomic features of HR deficiency (HRD) were detected in 7 of 12 PACCs undergoing WGS, including 100% (n = 6) of PACCs with germline HR-related pathogenic mutations and 1 of 6 PACCs lacking known pathogenic alterations in HR-related genes. Exploratory analyses revealed that in PACCs, the repertoire of somatic driver genetic alterations and the load of neoantigens with high binding affinity varied according to the presence of germline pathogenic alterations affecting HR-/DDR-related genes and/or HRD., Conclusion: In a large pan-cancer cohort, PACC was identified as the cancer type with the highest prevalence of both BRCA2 germline pathogenic variants and genomic features of HRD, suggesting that PACC should be considered as part of the spectrum of BRCA -related malignancies.
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- 2023
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44. Endometrial/Endometrioid Stromal Tumors With Extensive Whorling and CTNNB1 Translocation : A Report of 3 Cases.
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Boyraz B, da Cruz Paula A, Deveraux KA, Tran I, da Silva EM, Young RH, Snuderl M, Weigelt B, and Oliva E
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- Female, Humans, beta Catenin genetics, In Situ Hybridization, Fluorescence, Mitosis, Biomarkers, Tumor genetics, Biomarkers, Tumor analysis, Endometrial Stromal Tumors pathology, Endometrial Neoplasms genetics, Endometrial Neoplasms surgery, Endometrial Neoplasms metabolism, Sarcoma, Endometrial Stromal genetics, Sarcoma, Endometrial Stromal surgery, Sarcoma, Endometrial Stromal pathology
- Abstract
Endometrial/endometrioid stromal tumors are rare and morphologically heterogenous, and their diagnosis may be challenging. We identified 3 endometrial/endometrioid stromal tumors with identical and previously undescribed histologic features and herein report their morphologic, immunohistochemical, and molecular profiles. Patients were 53, 62, and 79 years. Tumors were well-circumscribed, tan-yellow solid masses measuring 10.0, 11.0, and 18.7 cm, and were intramyometrial (n=2) or in the broad ligament (n=1). All showed small, tight whorls of epithelioid to slightly spindled tumor cells with minimal cytoplasm and negligible mitoses, multifocally associated with hyalinization and myxoid change set in a loose fibroblastic background with small, delicate vessels. This morphology was seen throughout in 1 tumor and in ∼20% and 70% of the 2 others with the remaining areas showing sex cord-like differentiation. Tumor cells expressed CD10 (3/3, 1 focal), calretinin (3/3 diffuse), WT1 (3/3 diffuse), estrogen receptor (1/1, diffuse). RNA-sequencing was successful in 1 tumor and revealed a GREB1-CTNNB1 in-frame fusion. All 3 tumors harbored a CTNNB1 translocation by fluorescence in situ hybridization correlating with nuclear β-catenin expression. Whole-genome DNA methylation analysis classified all 3 tumors within the low-grade endometrial stromal sarcoma reference class with flat copy number profiles. One patient (79-y-old) died of unrelated causes 2 months after surgery and the other 2 were alive without disease after 13 and 75 months. We have described a rare subset of endometrial/endometrioid stromal tumors with extensive whorling and a CTNNB1 translocation, expanding the morphologic and molecular spectrum of these neoplasms., Competing Interests: Conflicts of Interest and Source of Funding: B.W. reports research funding from Repare Therapeutics, outside the scope of this study. For the remaining authors none were declared., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)
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- 2023
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45. Clinicopathologic and genomic features of lobular like invasive mammary carcinoma: is it a distinct entity?
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Yu J, da Silva EM, La HS, Clark BZ, Fine JL, Carter GJ, Villatoro TM, Soong TR, Lee AV, Oesterreich S, Basili T, Blanco-Heredia J, Selenica P, Ye Q, Da Cruz Paula A, Dopeso H, Gazzo A, Marra A, Pareja F, Reis-Filho JS, and Bhargava R
- Abstract
This study describes "lobular-like invasive mammary carcinomas" (LLIMCas), a group of low- to intermediate-grade invasive mammary carcinomas with discohesive, diffusely infiltrative cells showing retained circumferential membranous immunoreactivity for both E-cadherin and p120. We analyzed the clinical-pathologic features of 166 LLIMCas compared to 104 classical invasive lobular carcinomas (ILCs) and 100 grade 1 and 2 invasive ductal carcinomas (IDCs). Tumor size and pT stage of LLIMCas were intermediate between IDCs and ILCs, and yet often underestimated on imaging and showed frequent positive margins on the first resection. Despite histomorphologic similarities to classical ILC, the discohesion in LLIMCa was independent of E-cadherin/p120 immunophenotypic alteration. An exploratory, hypothesis-generating analysis of the genomic features of 14 randomly selected LLIMCas and classical ILCs (7 from each category) was performed utilizing an FDA-authorized targeted capture sequencing assay (MSK-IMPACT). None of the seven LLIMCas harbored CDH1 loss-of-function mutations, and none of the CDH1 alterations detected in two of the LLIMCas was pathogenic. In contrast, all seven ILCs harbored CDH1 loss-of-function mutations coupled with the loss of heterozygosity of the CDH1 wild-type allele. Four of the six evaluable LLIMCas were positive for CDH1 promoter methylation, which may partially explain the single-cell infiltrative morphology seen in LLIMCa. Further studies are warranted to better define the molecular basis of the discohesive cellular morphology in LLIMCa. Until more data becomes available, identifying LLIMCas and distinguishing them from typical IDCs and ILCs would be justified. In patients with LLIMCas, preoperative MRI should be entertained to guide surgical management., (© 2023. The Author(s).)
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- 2023
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46. FOXK2 amplification and overexpression promotes breast cancer development and chemoresistance.
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Yu Y, Cao WM, Cheng F, Shi Z, Han L, Yi JL, da Silva EM, Dopeso H, Chen H, Yang J, Wang X, Zhang C, and Zhang H
- Abstract
Activation of oncogenes through DNA amplification/overexpression plays an important role in cancer initiation and progression. Chromosome 17 has many cancer-associated genetic anomalies. This cytogenetic anomaly is strongly associated with poor prognosis of breast cancer. FOXK2 gene is located on 17q25 and encodes a transcriptional factor with a forkhead DNA binding domain. By integrative analysis of public genomic datasets of breast cancers, we found that FOXK2 is frequently amplified and overexpressed in breast cancers. FOXK2 overexpression in breast cancer patients is associated with poor overall survival. FOXK2 knockdown significantly inhibits cell proliferation, invasion and metastasis, and anchorage-independent growth, as well as causes G0/G1 cell cycle arrest in breast cancer cells. Moreover, inhibition of FOXK2 expression sensitizes breast cancer cells to frontline anti-tumor chemotherapies. More importantly, co-overexpression of FOXK2 and PI3KCA with oncogenic mutations (E545K or H1047R) induces cellular transformation in non-tumorigenic MCF10A cells, suggesting that FOXK2 is an oncogene in breast cancer and is involved in PI3KCA-driven tumorigenesis. Our study identified CCNE2 , PDK1 , and Estrogen receptor alpha ( ESR1 ) as direct transcriptional targets of FOXK2 in MCF-7 cells. Blocking CCNE2- and PDK1-mediated signaling by using small molecule inhibitors has synergistic anti-tumor effects in breast cancer cells. Furthermore, FOXK2 inhibition by gene knockdown or inhibitors for its transcriptional targets (CCNE2 and PDK1) in combination with PI3KCA inhibitor, Alpelisib, showed synergistic anti-tumor effects on breast cancer cells with PI3KCA oncogenic mutations. In summary, we provide compelling evidence that FOXK2 plays an oncogenic role in breast tumorigenesis and targeting FOXK2-mediated pathways may be a potential therapeutic strategy in breast cancer., Competing Interests: Conflict of interest statement: These authors declare no conflict of interests.
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- 2023
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47. Tumor-neutrophil crosstalk promotes in vitro and in vivo glioblastoma progression.
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Rubenich DS, de Souza PO, Omizzollo N, Aubin MR, Basso PJ, Silva LM, da Silva EM, Teixeira FC, Gentil GFS, Domagalski JL, Cunha MT, Gadelha KA, Diel LF, Gelsleichter NE, Rubenich AS, Lenz GS, de Abreu AM, Kroeff GM, Paz AH, Visioli F, Lamers ML, Wink MR, Worm PV, Araújo AB, Sévigny J, Câmara NOS, Ludwig N, and Braganhol E
- Subjects
- Animals, Mice, Mice, Nude, Signal Transduction, Immunity, Tumor Microenvironment, Neutrophils, Glioblastoma
- Abstract
Introduction: The tumor microenvironment (TME) of glioblastoma (GB) is characterized by an increased infiltration of immunosuppressive cells that attenuate the antitumor immune response. The participation of neutrophils in tumor progression is still controversial and a dual role in the TME has been proposed. In this study, we show that neutrophils are reprogrammed by the tumor to ultimately promote GB progression., Methods: Using in vitro and in vivo assays, we demonstrate the existence of bidirectional GB and neutrophil communication, directly promoting an immunosuppressive TME., Results and Discussion: Neutrophils have shown to play an important role in tumor malignancy especially in advanced 3D tumor model and Balb/c nude mice experiments, implying a time- and neutrophil concentration-dependent modulation. Studying the tumor energetic metabolism indicated a mitochondria mismatch shaping the TME secretome. The given data suggests a cytokine milieu in patients with GB that favors the recruitment of neutrophils, sustaining an anti-inflammatory profile which is associated with poor prognosis. Besides, glioma-neutrophil crosstalk has sustained a tumor prolonged activation via NETs formation, indicating the role of NFκB signaling in tumor progression. Moreover, clinical samples have indicated that neutrophil-lymphocyte ratio (NLR), IL-1β, and IL-10 are associated with poor outcomes in patients with GB., Conclusion: These results are relevant for understanding how tumor progression occurs and how immune cells can help in this process., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Rubenich, de Souza, Omizzollo, Aubin, Basso, Silva, da Silva, Teixeira, Gentil, Domagalski, Cunha, Gadelha, Diel, Gelsleichter, Rubenich, Lenz, de Abreu, Kroeff, Paz, Visioli, Lamers, Wink, Worm, Araújo, Sévigny, Câmara, Ludwig and Braganhol.)
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- 2023
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48. Effects of Passovia ovata Mistletoe on Pro-Inflammatory Markers In Vitro and In Vivo.
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Magalhães IFB, Figueirêdo ALM, da Silva EM, de Miranda AAB, da Rocha CQ, da Silva Calabrese K, Almeida-Souza F, and Abreu-Silva AL
- Abstract
New agents that can suppress inflammatory responses are being sought, since chronic inflammation is associated with several pathologies. This work aims to elucidate phytochemicals from the hydroethanolic extract of mistletoe Passovia ovata (POH) and its anti-inflammatory potential. POH is submitted to HPLC-UV, qualitative analysis of chemical constituents, and flavonoid quantification. Cytotoxicity is evaluated in RAW 264.7 macrophages by MTT. LPS-stimulated RAW 264.7 cells are treated with POH and, after 48 h, the nitrite and cytokine levels are quantified. BALB/c mice are treated by gavage with POH and stimulated with λ-carrageenan to induce paw oedema or peritonitis. POH yield is 25% with anthraquinones, tannins, anthocyanins, anthocyanidins, flavonols, catechins and flavanones present and flavonoid content of 4.44 ± 0.157 mg QE/g dry weight. POH exhibits low cytotoxicity and significantly reduced ( p < 0.01) nitrite, IL-1β, IL-6, and TNF-α quantification at 500 μg/mL. POH at 500 mg/kg prevents paw edema increase and also reduces inflammatory infiltrate and mast cells in the footpad. In the peritonitis model, POH does not influence cytokines levels or cell counts. Overall, POH demonstrates a high concentration of flavonoids and prominent effects in the reduction in pro-inflammatory markers in vitro and in the inhibition of paw oedema.
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- 2023
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49. Functional impact on adults and older people after hospitalization by Covid-19.
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Ochiai GS, de Godoy CG, Silva ÉCGE, de Oliveira DB, da Silva EM, Viana BOC, da Silva JM, de Souza ROB, Dos Santos MD, de Campos CM, Schmitt ACB, de Carvalho CRF, Fu C, Tanaka C, Toufen C Jr, de Carvalho CRR, and Pompeu JE
- Subjects
- Humans, Adult, Aged, Activities of Daily Living, Cross-Sectional Studies, SARS-CoV-2, Hospitalization, Frailty, Sarcopenia, COVID-19
- Abstract
Background and Objectives: Hospitalization by Covid-19 can cause persistent functional consequences after hospital discharge due to direct and indirect effects of SARS-COV-2 in several organs and systems of the body added to post-intensive care syndrome and prolonged bed rest. These impacts can lead to dependency in activities of daily living, mainly in older people due to aging process and functional decline. This study aimed to compare the effects of hospitalization by Covid-19 on functional capacity of adults and older people and to identify its associated factors., Methods: Cross-sectional observational study of 159 survivors of hospitalization by Covid-19 after 1 month from discharge at Hospital das Clínicas of the University of São Paulo, divided into groups: adults (aged < 60 years) and older people (aged ≥ 60 years). Those who did not accept to participate, without availability or without ability to understand the questionnaires were excluded. Functional capacity was assessed by the Barthel Index and patients were classified according to their scores. Data analysis was performed in JASP Statistics program and the sample was compared between the age groups. Wilcoxon test was applied to compare before and after periods, Mann-Whitney test was used for between groups comparison. We adopted alpha = 0.05., Results: The total Barthel Index median score was lower 1 month after hospital discharge than in the pre-Covid-19 period. Older people had worse functional status than adults before and also showed greater impairment after hospital discharge. Both groups showed lower Barthel Index classification than before, and older people presented more functional dependence than adults in both periods. Age, sarcopenia and frailty were associated factors., Discussion: Hospitalization by Covid-19 impacts functional capacity after 1 month from discharge, especially in older people. Age, sarcopenia and frailty are associated factors. These results suggest need for care and rehabilitation of Covid-19 survivors., (© 2022 John Wiley & Sons Ltd.)
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- 2023
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50. Evolution of roughness and optical properties of resin composites submitted to whitening toothpastes-cigarette smoking cycling.
- Author
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da Silva EM, Maia JND, Amaral CM, Noronha-Filho JD, Jardim RN, Poskus LT, and Guimarães JGA
- Subjects
- Toothbrushing, Surface Properties, Composite Resins, Analysis of Variance, Color, Toothpastes, Cigarette Smoking
- Abstract
Purpose: To evaluate the effect of cycling whitening toothpaste with cigarette smoking (WTCS) on the evolution of roughness, color, translucency, and gloss of microfilled, microhybrid, and nanofilled resin composites., Methods: 15 specimens of Durafill - DVS, Empress Direct - ED, and Z350 - FZ were divided into three groups according to the toothpastes:: conventional, control group, (Colgate - C) and Whitening (Colgate Luminous White - CW and Oral B 3D White - OW) and roughness, color, translucency, and gloss were evaluated before and after the specimens were submitted to WTCS for 8 weeks. Data were analyzed by two-way ANOVA, 3-way repeated measures ANOVA, and Tukey HSD post hoc test (α= 0.05)., Results: Only ED and FZ brushed with CW and FZ brushed with C presented an increase in roughness after WTCS. The three composites suffered a significant color alteration after WTCS. Excepting DVS brushed with CW, all the other groups presented a significant reduction in translucency after WTCS. DVS was the only resin composite that maintained its gloss stability after WTCS. Whitening toothpastes behaved similarly to conventional (control) toothpaste regarding the evolution of roughness and optical stability of the three resin composites., Clinical Significance: Whitening toothpastes were not capable of maintaining the color stability of the three resin composites after 8 weeks of toothpastes-cigarette smoking cycling., Competing Interests: The authors declared no conflict of interest., (Copyright©American Journal of Dentistry.)
- Published
- 2023
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