RESUMO
Ro60 ribonucleoproteins (RNPs), composed of the ring-shaped Ro 60-kDa (Ro60) protein and noncoding RNAs called Y RNAs, are present in all three domains of life. Ro60 was first described as an autoantigen in patients with rheumatic disease, and Ro60 orthologs have been identified in 3% to 5% of bacterial genomes, spanning the majority of phyla. Their functions have been characterized primarily in Deinococcus radiodurans, the first sequenced bacterium with a recognizable ortholog. In D. radiodurans, the Ro60 ortholog enhances the ability of 3'-to-5' exoribonucleases to degrade structured RNA during several forms of environmental stress. Y RNAs are regulators that inhibit or allow the interactions of Ro60 with other proteins and RNAs. Studies of Ro60 RNPs in other bacteria hint at additional functions, since the most conserved Y RNA contains a domain that is a close tRNA mimic and Ro60 RNPs are often encoded adjacent to components of RNA repair systems.
Assuntos
Proteínas de Bactérias/genética , Regulação Bacteriana da Expressão Gênica , RNA Bacteriano/genética , RNA não Traduzido/genética , Ribonucleoproteínas/genética , Ribonucleoproteínas/metabolismo , Bactérias/química , Bactérias/genética , Bactérias/metabolismo , Proteínas de Bactérias/metabolismo , Exorribonucleases/genética , Exorribonucleases/metabolismo , Conformação de Ácido Nucleico , Estabilidade de RNA , Ribonucleoproteínas/classificaçãoRESUMO
Antarctic terrestrial biodiversity faces multiple threats, from invasive species to climate change. Yet no large-scale assessments of threat management strategies exist. Applying a structured participatory approach, we demonstrate that existing conservation efforts are insufficient in a changing world, estimating that 65% (at best 37%, at worst 97%) of native terrestrial taxa and land-associated seabirds are likely to decline by 2100 under current trajectories. Emperor penguins are identified as the most vulnerable taxon, followed by other seabirds and dry soil nematodes. We find that implementing 10 key threat management strategies in parallel, at an estimated present-day equivalent annual cost of US$23 million, could benefit up to 84% of Antarctic taxa. Climate change is identified as the most pervasive threat to Antarctic biodiversity and influencing global policy to effectively limit climate change is the most beneficial conservation strategy. However, minimising impacts of human activities and improved planning and management of new infrastructure projects are cost-effective and will help to minimise regional threats. Simultaneous global and regional efforts are critical to secure Antarctic biodiversity for future generations.
Assuntos
Conservação dos Recursos Naturais , Spheniscidae , Animais , Humanos , Regiões Antárticas , Biodiversidade , Espécies Introduzidas , Mudança Climática , EcossistemaRESUMO
PURPOSE: Few breast cancer risk assessment models account for the risk profiles of different tumor subtypes. This study evaluated whether a subtype-specific approach improves discrimination. METHODS: Among 3389 women who had a screening mammogram and were later diagnosed with invasive breast cancer we performed multinomial logistic regression with tumor subtype as the outcome and known breast cancer risk factors as predictors. Tumor subtypes were defined by expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) based on immunohistochemistry. Discrimination was assessed with the area under the receiver operating curve (AUC). Absolute risk of each subtype was estimated by proportioning Gail absolute risk estimates by the predicted probabilities for each subtype. We then compared risk factor distributions for women in the highest deciles of risk for each subtype. RESULTS: There were 3,073 ER/PR+ HER2 - , 340 ER/PR +HER2 + , 126 ER/PR-ER2+, and 300 triple-negative breast cancers (TNBC). Discrimination differed by subtype; ER/PR-HER2+ (AUC: 0.64, 95% CI 0.59, 0.69) and TNBC (AUC: 0.64, 95% CI 0.61, 0.68) had better discrimination than ER/PR+HER2+ (AUC: 0.61, 95% CI 0.58, 0.64). Compared to other subtypes, patients at high absolute risk of TNBC were younger, mostly Black, had no family history of breast cancer, and higher BMI. Those at high absolute risk of HER2+ cancers were younger and had lower BMI. CONCLUSION: Our study provides proof of concept that stratifying risk prediction for breast cancer subtypes may enable identification of patients with unique profiles conferring increased risk for tumor subtypes.
Assuntos
Biomarcadores Tumorais , Neoplasias da Mama , Receptor ErbB-2 , Receptores de Estrogênio , Receptores de Progesterona , Humanos , Feminino , Medição de Risco/métodos , Medição de Risco/estatística & dados numéricos , Pessoa de Meia-Idade , Neoplasias da Mama/patologia , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/genética , Receptor ErbB-2/metabolismo , Receptores de Progesterona/metabolismo , Receptores de Estrogênio/metabolismo , Idoso , Adulto , Fatores de Risco , Curva ROC , Estudos de Viabilidade , Imuno-Histoquímica , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/epidemiologia , Neoplasias de Mama Triplo Negativas/metabolismo , MamografiaRESUMO
BACKGROUND: Currently, racial disparities exist in access to genetic testing. Recent developments have helped narrow the gap in accessibility. The purpose of this study was to determine whether racial disparities in genetic consultation attendance and completion of genetic testing persist, and, if so, factors that contribute to under-utilization of these resources. METHODS: A single-institution retrospective review of breast patients referred for genetic counseling between 2017 and 2019 was performed. Univariate and multivariate logistic regression evaluated factors associated with genetic counseling attendance and genetic testing. RESULTS: A total of 596 patients were referred for genetic counseling: 433 (72.7%) white; 138 (23.2%) black; and 25 (4.2%) other or unknown. In multivariate analysis, black patients, patients without breast cancer family history, and patients without a current cancer diagnosis, classified as high risk, were significantly less likely to attend their genetics appointment (p = 0.010, p = 0.007, p = 0.005, respectively). Age, insurance type, distance from facility, and need for chemotherapy did not significantly impact consult completion rate. Of the patients who completed a genetic consult, 84.4% (n = 248) had genetic testing and 17.7% (n = 44) had a pathogenic variant. For patients who attended counseling, there were no significant factors that were predictive with receipt of genetic testing. CONCLUSIONS: In this study, there was a significant association between race and attending genetic counseling. Once counseled, most patients went on to receive genetic testing, and racial disparities in testing disappeared, emphasizing the value of providing additional education about the importance and purpose of genetic testing.
Assuntos
Neoplasias da Mama , Aconselhamento Genético , Testes Genéticos , Disparidades em Assistência à Saúde , Adulto , Idoso , Feminino , Humanos , Pessoa de Meia-Idade , Negro ou Afro-Americano , Neoplasias da Mama/genética , Neoplasias da Mama/diagnóstico , Seguimentos , Aconselhamento Genético/estatística & dados numéricos , Predisposição Genética para Doença , Testes Genéticos/estatística & dados numéricos , Acessibilidade aos Serviços de Saúde/estatística & dados numéricos , Prognóstico , Encaminhamento e Consulta/estatística & dados numéricos , Estudos Retrospectivos , População Branca/estatística & dados numéricos , População Branca/genética , BrancosRESUMO
The small ice-free areas of Antarctica are essential locations for both biodiversity and scientific research but are subject to considerable and expanding human impacts, resulting primarily from station-based research and support activities, and local tourism. Awareness by operators of the need to conserve natural values in and around station and visitor site footprints exists, but the cumulative nature of impacts often results in reactive rather than proactive management. With human activity spread across many isolated pockets of ice-free ground, the pathway to the greatest reduction of human impacts within this natural reserve is through better management of these areas, which are impacted the most. Using a case study of Australia's Casey Station, we found significant natural values persist within the immediate proximity (<10 m) of long-term station infrastructure, but encroachment by physical disturbance results in ongoing pressures. Active planning to better conserve such values would provide a direct opportunity to enhance protection of Antarctica's environment. Here we introduce an approach to systematic conservation planning, tailored to Antarctic research stations, to help managers improve the conservation of values surrounding their activity locations. Use of this approach provides a potential mechanism to balance the need for scientific access to the continent with international obligations to protect its environment. It may also facilitate the development of subordinate conservation tools, including management plans and natural capital accounting. By proactively minimising and containing their station footprints, national programs can also independently demonstrate their commitment to protecting Antarctica's environment.
Assuntos
Biodiversidade , Conservação dos Recursos Naturais , Humanos , Regiões Antárticas , Atividades Humanas , Efeitos AntropogênicosRESUMO
PURPOSE: Latin American reports on genetic cancer risk assessments are scarce. In Chile, current breast cancer (BC) guidelines do not define strategies for germline genetic testing. Our study sought to quantify the disparities in access to genetic testing in Chilean BC patients, according to international standards and their clinical characteristics to explore improvement strategies. METHODS: Retrospective analysis of invasive BC databases including patients treated in a Public Hospital (PH) and in an Academic Private Center (AC) in Santiago, Chile between 2012 and 2021. RESULTS: Of 5438 BC patients, 3955 had enough data for National Comprehensive Cancer Network (NCCN) categorization. From these, 1911 (48.3%) fulfilled NCCN criteria for germline testing, of whom, 300 were tested for germline mutations and 268 with multigene panels. A total of 65 pathogenic variants were found in this subset. As expected, BRCA1/2 mutations were the most frequent (17.7%). Access to genetic testing was higher in AC versus PH (19.6% vs. 10.3%, p = 0.0001). Other variables associated with germline genetic testing were BC diagnosis after 2018, being 45 years old or younger at diagnosis, BC family history (FH), FH of ovarian cancer, non-metastatic disease, and triple-negative subtype. CONCLUSION: In our cohort, 15% of BC patients who met NCCN criteria for germline testing were effectively tested. This percentage was even lower at the PH. Current recommendations encourage universal genetic testing for BC patients; however, our findings suggest that Chile is far from reaching such a goal and national guidelines in this regard are urgently needed. To our knowledge, this is the first study of its kind in Chile and Latin America.
Assuntos
Neoplasias da Mama , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Proteína BRCA1/genética , Chile/epidemiologia , Estudos Retrospectivos , Predisposição Genética para Doença , Proteína BRCA2/genética , Testes Genéticos , Mutação em Linhagem GerminativaRESUMO
BACKGROUND: Gastric adenocarcinoma (GAC) is the fifth most common cancer in the world, and the presence of germline pathogenic variants has been linked with approximately 5% of gastric cancer diagnoses. Multiple GAC susceptibility genes have been identified, but information regarding the risk associated with pathogenic variants in these genes remains obscure. We conducted a systematic review of existing studies reporting the penetrance of GAC susceptibility genes. METHODS: A structured search query was devised to identify GAC-related papers indexed in MEDLINE/PubMed. A semi-automated natural language processing algorithm was applied to identify penetrance papers for inclusion. Original studies reporting the penetrance of GAC were included and the full-text articles were independently reviewed. Summary statistics, effect estimates, and precision parameters from these studies were compiled into a table using a predetermined format to ensure consistency. RESULTS: Forty-five studies were identified reporting the penetrance of GAC among patients harboring mutations in 13 different genes: APC, ATM, BRCA1, BRCA2, CDH1, CHEK2, MLH1, MSH2, MSH6, PMS2, MUTYH-Monoallelic, NBN, and STK11. CONCLUSION: Our systematic review highlights the importance of testing for germline pathogenic variants in patients before the development of GAC. Management of patients who harbor a pathogenic mutation is multifactorial, and clinicians should consider cancer risk for each applicable gene-cancer association throughout the screening and management process. The scarcity of studies we found investigating the risk of GAC among patients with pathogenic variants in GAC susceptibility genes highlights the need for more investigations that focus on producing robust risk estimates for gene-cancer associations.
Assuntos
Adenocarcinoma , Neoplasias Gástricas , Humanos , Penetrância , Neoplasias Gástricas/genética , Predisposição Genética para Doença , Mutação , Mutação em Linhagem Germinativa , Adenocarcinoma/genéticaRESUMO
Immune-mediated hypersensitivities such as autoimmunity, allergy, and allogeneic graft rejection are treated with therapeutics that suppress the immune system, and the lack of specificity is associated with significant side effects. The delivery of disease-relevant antigens (Ags) by carrier systems such as poly(lactide-co-glycolide) nanoparticles (PLG-Ag) and carbodiimide (ECDI)-fixed splenocytes (SP-Ag) has demonstrated Ag-specific tolerance induction in model systems of these diseases. Despite therapeutic outcomes by both platforms, tolerance is conferred with different efficacy. This investigation evaluated Ag loading and total particle dose of PLG-Ag on Ag presentation in a coculture system of dendritic cells (DCs) and Ag-restricted T cells, with SP-Ag employed as a control. CD25 expression was observed in nearly all T cells even at low concentrations of PLG-Ag, indicating efficient presentation of Ag by dendritic cells. However, the secretion of IL-2, Th1, and Th2 cytokines (IFNγ and IL-4, respectively) varied depending on PLG-Ag concentration and Ag loading. Concentration escalation of soluble Ag resulted in an increase in IL-2 and IFNγ and a decrease in IL-4. Treatment with PLG-Ag followed a similar trend but with lower levels of IL-2 and IFNγ secreted. Transcriptional Activity CEll ARrays (TRACER) were employed to measure the real-time transcription factor (TF) activity in Ag-presenting DCs. The kinetics and magnitude of TF activity was dependent on the Ag delivery method, concentration, and Ag loading. Ag positively regulated IRF1 activity and, as carriers, NPs and ECDI-treated SP negatively regulated this signaling. The effect of Ag loading and dose on tolerance induction were corroborated in vivo using the delayed-type hypersensitivity (DTH) and experimental autoimmune encephalomyelitis (EAE) mouse models where a threshold of 8 µg/mg Ag loading and 0.5 mg PLG-Ag dose were required for tolerance. Together, the effect of Ag loading and dosing on in vitro and in vivo immune regulation provide useful insights for translating Ag-carrier systems for the clinical treatment of immune disorders.
Assuntos
Encefalomielite Autoimune Experimental , Nanopartículas , Animais , Camundongos , Linfócitos T , Interleucina-2 , Interleucina-4/uso terapêutico , Antígenos , Encefalomielite Autoimune Experimental/tratamento farmacológicoRESUMO
Antarctica has been subject to widespread, long-term and on-going human activity since the establishment of permanent research stations became common in the 1950s. Equipment may become intentionally or inadvertently lost in Antarctic marine and terrestrial environments as a result of scientific research and associated support activities, but this has been poorly quantified to date. Here we report the quantity and nature of equipment lost by the UK's national operator in Antarctica, the British Antarctic Survey (BAS). Over the 15-year study period (2005-2019), 125 incidents of loss were reported, with c. 23 tonnes of equipment lost of which 18% by mass was considered hazardous. The geographical distribution of lost equipment was widespread across the BAS operational footprint. However, impacts are considered low compared to those associated with research station infrastructure establishment and operation. To reduce environmental impact overall, we recommend that, where possible, better use is made of existing research station capacity to facilitate field research, thereby reducing the need for construction of new infrastructure and the generation of associated impacts. Furthermore, to facilitate reporting on the state of the Antarctic environment, we recommend that national Antarctic programmes reinvigorate efforts to comply with Antarctic Treaty System requirements to actively record the locations of past activities and make available details of lost equipment. In a wider context, analogous reporting is also encouraged in other pristine areas subject to new research activities, including in other remote Earth environments and on extra-terrestrial bodies.
Assuntos
Meio Ambiente , Atividades Humanas , Humanos , Regiões AntárticasRESUMO
PURPOSE: Several male breast cancer (MBC) susceptibility genes have been identified, but the MBC risk for individuals with a pathogenic variant in each of these genes (i.e., penetrance) remains unclear. We conducted a systematic review of studies reporting the penetrance of MBC susceptibility genes to better summarize current estimates of penetrance. METHODS: A search query was developed to identify MBC-related papers indexed in PubMed/MEDLINE. A validated natural language processing method was applied to identify papers reporting penetrance estimates. These penetrance studies' bibliographies were reviewed to ensure comprehensiveness. We accessed the potential ascertainment bias for each enrolled study. RESULTS: Fifteen penetrance studies were identified from 12,182 abstracts, covering five purported MBC susceptibility genes: ATM, BRCA1, BRCA2, CHEK2, and PALB2. Cohort (n = 6, 40%) and case-control (n = 5, 33%) studies were the two most common study designs, followed by family-based (n = 3, 20%), and a kin-cohort study (n = 1, 7%). Seven of the 15 studies (47%) adjusted for ascertainment adequately and therefore the MBC risks reported by these seven studies can be considered applicable to the general population. Based on these seven studies, we found pathogenic variants in ATM, BRCA2, CHEK2 c.1100delC, and PALB2 show an increased risk for MBC. The association between BRCA1 and MBC was not statistically significant. CONCLUSION: This work supports the conclusion that pathogenic variants in ATM, BRCA2, CHEK2 c.1100delC, and PALB2 increase the risk of MBC, whereas pathogenic variants in BRCA1 may not be associated with increased MBC risk.
Assuntos
Neoplasias da Mama Masculina , Predisposição Genética para Doença , Penetrância , Proteínas Mutadas de Ataxia Telangiectasia/genética , Neoplasias da Mama Masculina/epidemiologia , Neoplasias da Mama Masculina/genética , Quinase do Ponto de Checagem 2/genética , Estudos de Coortes , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética , Genes BRCA2 , Humanos , MasculinoRESUMO
BACKGROUND: Nipple-sparing mastectomy (NSM) is an oncologically safe alternative to skin-sparing mastectomy (SSM). This study evaluated whether NSM patients were more satisfied than SSM patients in short- and long-term follow-up. METHODS: Women who underwent NSM or SSM between 2009 and 2019 completed a postoperative BREAST-Q survey at least 1 year after surgery and patient characteristics were compared. Patient satisfaction at 1-5 years and 6-10 years after NSM and SSM were analyzed. RESULTS: Overall, 431 patients were included; 247 had NSM and 184 had SSM 1-10 years prior to BREAST-Q survey completion. SSM patients were older, had higher body mass index (BMI), larger breast weight, and more hypertension than NSM patients, but oncologic treatments were similar between groups. BREAST-Q Psychosocial Well-Being and Sexual Well-Being scores were significantly higher in NSM patients compared with SSM patients in the 1-5 years cohort; however, scores attenuated in the 6-10 years cohort. Satisfaction with breasts was nearly significantly higher in NSM patients compared with SSM patients in the 1-5 years cohort (p = 0.056), but no different in the 6-10 years cohort. Receipt of adjuvant chemotherapy, receipt of postmastectomy radiation therapy, and BMI ≥30 were independent risk factors for dissatisfaction with breasts. CONCLUSIONS: Women who are not candidates for NSM should be reassured that long-term qualify of life is not significantly different between SSM and NSM. Dissatisfaction with reconstructed breasts is linked with other factors (besides the nipple), which patients should be made aware of at the time of surgical decision making.
Assuntos
Neoplasias da Mama , Mamoplastia , Mastectomia Subcutânea , Neoplasias da Mama/cirurgia , Feminino , Humanos , Mastectomia , Mamilos/cirurgia , Satisfação do Paciente , Estudos RetrospectivosRESUMO
BACKGROUND: Fewer than 1% of all breast cancers occur in men. As a result, a distinct lack of data exists regarding the management and outcomes in this cohort. METHODS: Any male patient with pathologically confirmed breast cancer diagnosed between August 2000 and October 2017 at either Massachusetts General Hospital or Brigham and Women's Hospital/Dana-Farber Cancer Institute and their affiliate satellite locations were included. Primary chart review was used to assess clinical and pathologic characteristics. Patient and treatment variables were reported via descriptive statistics. Local-regional failure (LRF), overall survival (OS), breast cancer-specific survival (BCSS), and disease-free survival (DFS) were estimated using the Kaplan-Meier method. RESULTS: 100 patients were included in this study. Median follow-up was 112 months (range 1-220 months). Approximately 1/3 of patients experienced at least a 3-month delay to presentation. 83 patients ultimately underwent mastectomy as definitive surgical treatment. 46 patients received adjuvant radiation therapy, and 37 patients received chemotherapy. Of 82 hormone receptor-positive patients with invasive cancer, 94% (n = 77) received endocrine therapy. Of the fifty-eight patients who underwent genetic testing, 15 (26%) tested positive. The 5-year OS, BCSS, DFS, and LRF rates were 91.5%, 96.2%, 86%, and 4.8%, respectively. Delay to presentation was not associated with worse survival. CONCLUSIONS: Male breast cancer remains a rare diagnosis. Despite this, the majority of patients in this study received standard of care therapy and experienced excellent oncologic outcomes. Penetration for genetic testing improved over time.
Assuntos
Neoplasias da Mama Masculina , Neoplasias da Mama , Mama , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/terapia , Neoplasias da Mama Masculina/diagnóstico , Neoplasias da Mama Masculina/terapia , Quimioterapia Adjuvante , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Massachusetts , Mastectomia , Estudos RetrospectivosRESUMO
PURPOSE: Safe breast cancer lumpectomies require microscopically clear margins. Real-time margin assessment options are limited, and 20-40% of lumpectomies have positive margins requiring re-excision. The LUM Imaging System previously showed excellent sensitivity and specificity for tumor detection during lumpectomy surgery. We explored its impact on surgical workflow and performance across patient and tumor types. METHODS: We performed IRB-approved, prospective, non-randomized studies in breast cancer lumpectomy procedures. The LUM Imaging System uses LUM015, a protease-activated fluorescent imaging agent that identifies residual tumor in the surgical cavity walls. Fluorescent cavity images were collected in real-time and analyzed using system software. RESULTS: Cavity and specimen images were obtained in 55 patients injected with LUM015 at 0.5 or 1.0 mg/kg and in 5 patients who did not receive LUM015. All tumor types were distinguished from normal tissue, with mean tumor:normal (T:N) signal ratios of 3.81-5.69. T:N ratios were 4.45 in non-dense and 4.00 in dense breasts (p = 0.59) and 3.52 in premenopausal and 4.59 in postmenopausal women (p = 0.19). Histopathology and tumor receptor testing were not affected by LUM015. Falsely positive readings were more likely when tumor was present < 2 mm from the adjacent specimen margin. LUM015 signal was stable in vivo at least 6.5 h post injection, and ex vivo at least 4 h post excision. CONCLUSIONS: Intraoperative use of the LUM Imaging System detected all breast cancer subtypes with robust performance independent of menopausal status and breast density. There was no significant impact on histopathology or receptor evaluation.
Assuntos
Neoplasias da Mama , Mastectomia Segmentar , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/cirurgia , Feminino , Humanos , Neoplasia Residual , Peptídeo Hidrolases , Estudos Prospectivos , ReoperaçãoRESUMO
BACKGROUND: The prevalence of non-medullary thyroid cancer (NMTC) is increasing worldwide. Although most NMTCs grow slowly, conventional therapies are less effective in advanced tumors. Approximately 5-15% of NMTCs have a significant germline genetic component. Awareness of the NMTC susceptibility genes may lead to earlier diagnosis and better cancer prevention. OBJECTIVE: The aim of this study was to provide the current panorama of susceptibility genes associated with NMTC and the spectrum of diseases associated with these genes. METHODS: Twenty-five candidate genes were identified by searching for relevant studies in PubMed. Each candidate gene was carefully checked using six authoritative genetic resources: ClinGen, National Comprehensive Cancer Network guidelines, Online Mendelian Inheritance in Man, Genetics Home Reference, GeneCards, and Gene-NCBI, and a validated natural language processing (NLP)-based literature review protocol was used to further assess gene-disease associations where there was ambiguity. RESULTS: Among 25 candidate genes, 10 (APC, DICER1, FOXE1, HABP2, NKX2-1, PRKAR1A, PTEN, SDHB, SDHD, and SRGAP1) were verified among the six genetic resources. Two additional genes, CHEK2 and SEC23B, were verified using the NLP protocol. Seventy-nine diseases were found to be associated with these 12 NMTC susceptibility genes. The following diseases were associated with more than one NMTC susceptibility gene: colorectal cancer, breast cancer, gastric cancer, kidney cancer, gastrointestinal stromal tumor, paraganglioma, pheochromocytoma, and benign skin conditions. CONCLUSION: Twelve genes predisposing to NMTC and their associated disease spectra were identified and verified. Clinicians should be aware that patients with certain pathogenic variants may require more aggressive surveillance beyond their thyroid cancer risk.
Assuntos
Predisposição Genética para Doença , Câncer Papilífero da Tireoide , Neoplasias da Glândula Tireoide , Mutação em Linhagem Germinativa , Humanos , Câncer Papilífero da Tireoide/genética , Neoplasias da Glândula Tireoide/genéticaRESUMO
BACKGROUND: Nipple-sparing mastectomy (NSM) is now routinely offered to BRCA mutation carriers for risk reduction. We assessed the rates of ipsilateral cancer events after prophylactic and therapeutic NSM in BRCA1 and BRCA2 mutation carriers. METHODS: BRCA1 and BRCA2 mutation carriers undergoing NSM from October 2007 to June 2019 were identified in a single-institution prospective database, with variants of unknown significance being excluded. Patient, tumor, and outcomes data were collected. Follow-up analysis was by cumulative breast-years (total years of follow-up of each breast) and woman-years (total years of follow-up of each woman). RESULTS: Overall, 307 BRCA1 and BRCA2 mutation carriers (160 BRCA1, mean age 41.4 years [range 21-65]; and 147 BRCA2, mean age 43.8 years [range 23-65]) underwent 607 NSMs, with a median follow-up of 42 months (range 1-143). 388 bilateral prophylactic NSMs had 744 cumulative woman-years of follow-up, with no new cancers seen (< 0.0013 new cancers per woman-years); 251 BRCA1 prophylactic NSMs had 1034 cumulative breast-years of follow-up, with no new ipsilateral cancers seen (< 0.0010 per breast-year); 66 BRCA1 therapeutic NSMs had 328 cumulative breast-years of follow-up, with one ipsilateral cancer recurrence not directly involving the nipple or areola (0.0030 per breast-year); 237 BRCA2 prophylactic NSMs had 926 cumulative breast-years of follow-up, with no new ipsilateral cancers seen (< 0.0011 per breast-year); and 53 BRCA2 therapeutic NSMs had 239 cumulative breast-years of follow-up, with two ipsilateral recurrent cancers, neither of which directly involved the nipple or areola (0.0084 per breast-year). CONCLUSIONS: The risk of new ipsilateral breast cancers is extremely low after NSM in BRCA1 and BRCA2 mutation carriers. NSM is an effective risk-reducing strategy for BRCA gene mutations.
Assuntos
Neoplasias da Mama , Mastectomia Profilática , Adulto , Idoso , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/genética , Neoplasias da Mama/prevenção & controle , Neoplasias da Mama/cirurgia , Feminino , Humanos , Mastectomia , Pessoa de Meia-Idade , Mutação , Recidiva Local de Neoplasia , Mamilos/cirurgia , Adulto JovemRESUMO
The early life gut microbiota plays a crucial role in regulating and maintaining the intestinal barrier, with disturbances in these communities linked to dysregulated renewal and replenishment of intestinal epithelial cells. Here we sought to determine pathological cell shedding outcomes throughout the postnatal developmental period, and which host and microbial factors mediate these responses. Surprisingly, neonatal mice (Day 14 and 21) were highly refractory to induction of cell shedding after intraperitoneal administration of liposaccharide (LPS), with Day 29 mice showing strong pathological responses, more similar to those observed in adult mice. These differential responses were not linked to defects in the cellular mechanisms and pathways known to regulate cell shedding responses. When we profiled microbiota and metabolites, we observed significant alterations. Neonatal mice had high relative abundances of Streptococcus, Escherichia, and Enterococcus and increased primary bile acids. In contrast, older mice were dominated by Candidatus Arthromitus, Alistipes, and Lachnoclostridium, and had increased concentrations of SCFAs and methyamines. Antibiotic treatment of neonates restored LPS-induced small intestinal cell shedding, whereas adult fecal microbiota transplant alone had no effect. Our findings further support the importance of the early life window for microbiota-epithelial interactions in the presence of inflammatory stimuli and highlights areas for further investigation.
Assuntos
Animais Recém-Nascidos/microbiologia , Microbioma Gastrointestinal/fisiologia , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Animais , Animais Recém-Nascidos/metabolismo , Antibacterianos/administração & dosagem , Ácidos e Sais Biliares/metabolismo , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Transplante de Microbiota Fecal , Feminino , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/genética , Interações entre Hospedeiro e Microrganismos/efeitos dos fármacos , Interações entre Hospedeiro e Microrganismos/fisiologia , Inflamação/metabolismo , Inflamação/microbiologia , Inflamação/patologia , Mucosa Intestinal/metabolismo , Intestino Delgado/metabolismo , Intestino Delgado/microbiologia , Intestino Delgado/patologia , Lipopolissacarídeos/administração & dosagem , Camundongos , Camundongos Endogâmicos C57BL , Transdução de SinaisRESUMO
Artificial intelligence (AI) technologies can play a key role in preventing, detecting, and monitoring epidemics. In this paper, we provide an overview of the recently published literature on the COVID-19 pandemic in four strategic areas: (1) triage, diagnosis, and risk prediction; (2) drug repurposing and development; (3) pharmacogenomics and vaccines; and (4) mining of the medical literature. We highlight how AI-powered health care can enable public health systems to efficiently handle future outbreaks and improve patient outcomes.
Assuntos
Inteligência Artificial , COVID-19/terapia , Medicina de Precisão/métodos , Humanos , Pandemias , Pesquisa , SARS-CoV-2/isolamento & purificaçãoRESUMO
Antarctica currently has few non-native species, compared to other regions of the planet, due to the continent's isolation, extreme climatic conditions and the lack of habitat. However, human activity, particularly the activities of national government operators and tourism, increasingly contributes to the risk of non-native species transfer and establishment. Trichocera (Saltitrichocera) maculipennis Meigen, 1888 (Diptera, Trichoceridae) is a non-native fly originating from the Northern Hemisphere that was unintentionally introduced to King George Island in the maritime Antarctic South Shetland Islands around 15 years ago, since when it has been reported within or in the vicinity of several research stations. It is not explicitly confirmed that T. maculipennis has established in the natural environment, but life-history characteristics make this likely, thereby making potential eradication or control a challenge. Antarctic Treaty Parties active in the region are developing a coordinated and expanding international response to monitor and control T. maculipennis within and around stations in the affected area. However, there remains no overarching non-native invasive species management plan for the island or the wider maritime Antarctic region (which shares similar environmental conditions and habitats to those of King George Island). Here we present some options towards the development of such a plan. We recommend the development of (1) clear mechanisms for the timely coordination of response activities by multiple Parties operating in the vicinity of the introduction location and (2) policy guidance on acceptable levels of environmental impacts resulting from eradication attempts in the natural environment, including the use of pesticides.
Assuntos
Biodiversidade , Dípteros , Animais , Regiões Antárticas , Humanos , Cooperação Internacional , IlhasRESUMO
BACKGROUND: The objective of the current study was to provide insight into the effect of coronavirus disease 2019 (COVID-19) on breast cancer screening, breast surgery, and genetics consultations. METHODS: User data from a risk assessment company were collected from February 2 to April 11, 2020. The use of risk assessment was used as a proxy for the use of 3 breast cancer services, namely, breast imaging, breast surgery, and genetics consultation. Changes in the use of these services during the study period were analyzed. RESULTS: All 3 services experienced significant declines after the COVID-19 outbreak. The decline in breast surgery began during the week of March 8, followed by breast imaging and genetics consultation (both of which began during the week of March 15). Breast imaging experienced the most significant reduction, with an average weekly decline of 61.7% and a maximum decline of 94.6%. Breast surgery demonstrated an average weekly decline of 20.5%. When surgical consultation was stratified as breast cancer versus no breast cancer, the decrease among in non-breast cancer patients was more significant than that of patients with breast cancer (a decline of 66.8% vs 11.5% from the pre-COVID average weekly volume for non-breast cancer patients and patients with breast cancer, respectively). During the week of April 5, use of genetics consultations dropped to 39.9% of the average weekly volumes before COVID-19. CONCLUSIONS: COVID-19 has had a significant impact on the number of patients undergoing breast cancer prevention, screening, diagnosis, and treatment.
Assuntos
Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/genética , Neoplasias da Mama/cirurgia , COVID-19 , Mastectomia/estatística & dados numéricos , Neoplasias da Mama/prevenção & controle , Feminino , Aconselhamento Genético/estatística & dados numéricos , Humanos , Mamografia/estatística & dados numéricos , Medição de Risco , Estados Unidos/epidemiologiaRESUMO
PURPOSE: The goal of breast cancer surgery is to remove all of the cancer with a minimum of normal tissue, but absence of full 3-dimensional information on the specimen makes this difficult to achieve. METHOD: Micro-CT is a high resolution, X-ray, 3D imaging method, widely used in industry but rarely in medicine. RESULTS: We imaged and analyzed 173 partial mastectomies (129 ductal carcinomas, 14 lobular carcinomas, 28 DCIS). Imaging was simple and rapid. The size and shape of the cancers seen on Micro-CT closely matched the size and shape of the cancers seen at specimen dissection. Micro-CT images of multicentric/multifocal cancers revealed multiple non-contiguous masses. Micro-CT revealed cancer touching the specimen edge for 93% of the 114 cases judged margin positive by the pathologist, and 28 of the cases not seen as margin positive on pathological analysis; cancer occupied 1.55% of surface area when both the pathologist and Micro-CT suggested cancer at the edge, but only 0.45% of surface area for the "Micro-CT-Only-Positive Cases". Thus, Micro-CT detects cancers that touch a very small region of the specimen surface, which is likely to be missed on sectioning. CONCLUSIONS: Micro-CT provides full 3D images of breast cancer specimens, allowing one to identify, in minutes rather than hours, while the patient is in OR, margin-positive cancers together with information on where the cancer touches the edge, in a fashion more accurate than possible from the histology slides alone.