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1.
Artigo em Inglês | MEDLINE | ID: mdl-38634663

RESUMO

BACKGROUND: There is anecdotal evidence of Fetal Pillow® use, but no formal local information on clinician practices and perspectives. AIMS: To assess obstetrician use of the Fetal Pillow®, knowledge of relevant research, and interest in a proposed randomised controlled trial in Aotearoa New Zealand. MATERIALS AND METHODS: Anonymous cross-sectional survey of practising obstetricians and obstetric trainees in Aotearoa New Zealand distributed by the Royal Australian and New Zealand College of Obstetricians and Gynaecologists. RESULTS: Of 136 respondents (69% specialists and 31% trainees), 130 had heard of the Fetal Pillow® device, and 108 had used it at least once (43% more than ten times). The device was available in 17/21 units represented. The 108 users of the device reported this was most commonly on collegial advice (63%) or after personal experience of a difficult delivery (33%) and most (80%) believed it reduced maternal morbidity. Only around one-third of the 130 respondents who had heard of the device agreed there was adequate research demonstrating its efficacy for maternal (36%) and neonatal (30%) morbidity. The majority reported they would change practice in response to a randomised trial, although they were more likely to start use (81% of current non-users) than stop (53% of users). Most (70%) respondents agreed they would encourage patients to participate in a randomised trial. CONCLUSIONS: The Fetal Pillow® is available in most maternity units in Aotearoa New Zealand. The majority of obstetric clinicians believe it reduces maternal morbidity, while acknowledging the lack of scientific evidence. Most would support a randomised trial.

2.
BJOG ; 2024 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-38287196

RESUMO

OBJECTIVE: To investigate associations of the Fetal Pillow® with maternal and neonatal morbidity. DESIGN: Retrospective cohort. SETTING: Two tertiary maternity units, New Zealand. POPULATION OR SAMPLE: Full dilatation singleton, term, cephalic caesarean section, with three comparisons: at Unit A (1) before versus after introduction of the Fetal Pillow® (1 Jaunary 2016-31 October 2021); (2) with versus without the Fetal Pillow® after introduction (27 July 2017-31 October 2021); and (3) between Unit A and Unit B during the same time period (1 January 2019-31 October 2021). The Fetal Pillow® is unavailable at Unit B. METHODS: Cases were ascertained and clinical data were extracted from electronic clinical databases and records. Outcome data were adjusted and presented as adjusted odds ratios (aOR) with 95% CI. MAIN OUTCOME MEASURES: Primary outcome "any" uterine incision extension; secondary outcomes included major extension (into adjacent structures), and a composite neonatal outcome. RESULTS: In all, 1703 caesareans were included; 375 with the device and 1328 without. Uterine incision extension rates were: at Unit A before versus after introduction: 26.8% versus 24.8% (aOR 0.88, 95% CI 0.65-1.19); at Unit A with the Fetal Pillow® versus without: 26.1% versus 23.8% (aOR 1.14, 95% CI 0.83-1.57); and at Unit A versus Unit B: 24.2% versus 29.2% (aOR 0.73, 95% CI 0.54-0.99). No differences were found in major extensions, or neonatal composite outcome. CONCLUSIONS: Despite the relatively large size of this study, it could not rule out either a positive or a negative association between use of the Fetal Pillow® and uterine extensions, major uterine incision extensions, and neonatal morbidity. Randomised controlled trial evidence is required to assess efficacy.

3.
Cancers (Basel) ; 15(14)2023 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-37509364

RESUMO

PTK6, a non-receptor tyrosine kinase, modulates the pathogenesis of breast and prostate cancers and is recognized as a biomarker of breast cancer prognosis. There are over 30 known substrates of PTK6, including signal transducers, transcription factors, and RNA-binding proteins. Many of these substrates are known drivers of other cancer types, such as colorectal cancer. Colon and rectal tumors also express higher levels of PTK6 than the normal intestine suggesting a potential role in tumorigenesis. However, the importance of PTK6 in colorectal cancer remains unclear. PTK6 inhibitors such as XMU-MP-2 and Tilfrinib have demonstrated potency and selectivity in breast cancer cells when used in combination with chemotherapy, indicating the potential for PTK6 targeted therapy in cancer. However, most of these inhibitors are yet to be tested in other cancer types. Here, we discuss the current understanding of the function of PTK6 in normal intestinal cells compared with colorectal cancer cells. We review existing PTK6 targeting therapeutics and explore the possibility of PTK6 inhibitory therapy for colorectal cancer.

4.
Int J Mol Sci ; 24(13)2023 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-37445934

RESUMO

The process of human embryonic mammary development gives rise to the structures in which mammary cells share a developmental lineage with skin epithelial cells such as keratinocytes. As some breast carcinomas have previously been shown to express high levels of involucrin, a marker of keratinocyte differentiation, we hypothesised that some breast tumours may de-differentiate to a keratinocyte-derived 'evolutionary history'. To confirm our hypothesis, we investigated the frequency of involucrin expression along with that of Brk, a tyrosine kinase expressed in up to 86% of breast carcinomas whose normal expression patterns are restricted to differentiating epithelial cells, most notably those in the skin (keratinocytes) and the gastrointestinal tract. We found that involucrin, a keratinocyte differentiation marker, was expressed in a high proportion (78%) of breast carcinoma samples and cell lines. Interestingly, tumour samples found to express high levels of involucrin were also shown to express Brk. 1,25-dihydroxyvitamin D3, a known differentiation agent and potential anti-cancer agent, decreased proliferation in the breast cancer cell lines that expressed both involucrin and Brk, whereas the Brk/involucrin negative cell lines tested were less susceptible. In addition, responses to 1,25-dihydroxyvitamin D3 were not correlated with vitamin D receptor expression. These data contribute to the growing body of evidence suggesting that cellular responses to 1,25-dihydroxyvitamin D3 are potentially independent of vitamin D receptor status and provide an insight into potential markers, such as Brk and/or involucrin that could predict therapeutic responses to 1,25-dihydroxyvitamin D3.


Assuntos
Neoplasias da Mama , Receptores de Calcitriol , Humanos , Feminino , Neoplasias da Mama/metabolismo , Colecalciferol , Calcitriol , Proteínas de Neoplasias/metabolismo , Proteínas Tirosina Quinases
5.
Cogn Emot ; 37(6): 1090-1104, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37376760

RESUMO

Emotion plays a significant role in our reasoning even without awareness, perhaps especially for individuals who have difficulties tolerating strong, negative emotions. Opportunity for reflection may help such individuals decide when emotions should influence reasoning. Two studies attempted to clarify the relationships among reasoning, emotions, and emotion tolerance (measured with the Affect Intolerance Scale). The first examined the effect of affect intolerance on a reasoning task. Participants were asked to determine whether conclusions logically followed from both emotional and neutral if-then statements. Emotion had a small effect on performance on the reasoning task, unmoderated by affect intolerance. The second study examined whether reflection on emotional responses impacts performance on the same reasoning task. Participants asked to reflect on their emotions performed more poorly on the reasoning task than participants asked to reflect on the task's cognitive aspects. People who endorse greater affect tolerance performed better in the cognitive reflection condition than the emotional reflection condition. People with less tolerance performed the same in both conditions. Overall, these studies support previous findings that emotion can negatively impact performance on reasoning tasks but suggest a more complex relationship for affect intolerance.


Assuntos
Emoções , Resolução de Problemas , Humanos , Emoções/fisiologia
6.
Int J Mol Sci ; 23(16)2022 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-36012147

RESUMO

ACBD3 overexpression has previously been found to correlate with worse prognosis for breast cancer patients and, as an incredibly diverse protein in both function and cellular localisation, ACBD3 may have a larger role in breast cancer than previously thought. This study further investigated ACBD3's role in breast cancer. Bioinformatic databases were queried to characterise ACBD3 expression and mutation in breast cancer and to investigate how overexpression affects breast cancer patient outcomes. Immunohistochemistry was carried out to examine ACBD3 location within cells and tissue structures. ACBD3 was more highly expressed in breast cancer than in any other cancer or matched normal tissue, and expression over the median level resulted in reduced relapse-free, overall, and distant metastasis-free survival for breast cancer patients as a whole, with some differences observed between subtypes. IHC analysis found that ACBD3 levels varied based on hormone receptor status, indicating that ACBD3 could be a candidate biomarker for poor patient prognosis in breast cancer and may possibly be a biomarker for ER signal reprogramming of precancerous breast tissue.


Assuntos
Neoplasias da Mama , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Biomarcadores Tumorais/genética , Neoplasias da Mama/metabolismo , Biologia Computacional , Feminino , Humanos , Proteínas de Membrana/metabolismo , Recidiva Local de Neoplasia
7.
Genes (Basel) ; 13(3)2022 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-35327957

RESUMO

Breast tumour kinase (Brk/PTK6) is overexpressed in up to 86% of breast cancers and is associated with poorer patient outcomes. It is considered a potential therapeutic target in breast cancer, even though the full spectrum of its kinase activity is not known. This study investigated the role of the kinase domain in promoting tumour growth and its potential in sensitising triple negative breast cancer cells to standard of care chemotherapy. Triple negative human xenograft models revealed that both kinase-inactive and wild-type Brk promoted xenograft growth. Suppression of Brk activity in cells subsequently co-treated with the chemotherapy agents doxorubicin or paclitaxel resulted in an increased cell sensitivity to these agents. In triple negative breast cancer cell lines, the inhibition of Brk kinase activity augmented the effects of doxorubicin or paclitaxel. High expression of the alternatively spliced isoform, ALT-PTK6, resulted in improved patient outcomes. Our study is the first to show a role for kinase-inactive Brk in human breast tumour xenograft growth; therefore, it is unlikely that kinase inhibition of Brk, in isolation, would halt tumour growth in vivo. Breast cancer cell responses to chemotherapy in vitro were kinase-dependent, indicating that treatment with kinase inhibitors could be a fruitful avenue for combinatorial treatment. Of particular prognostic value is the ratio of ALT-PTK6:Brk expression in predicating patient outcomes.


Assuntos
Neoplasias de Mama Triplo Negativas , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Xenoenxertos , Humanos , Proteínas de Neoplasias , Paclitaxel/farmacologia , Proteínas Tirosina Quinases , Neoplasias de Mama Triplo Negativas/tratamento farmacológico
8.
BMC Pharmacol Toxicol ; 22(1): 49, 2021 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-34530934

RESUMO

BACKGROUND: Preconditioning of the heart ameliorates doxorubicin (Dox)-induced cardiotoxicity. We tested whether pretreating cardiomyocytes by mitochondrial-targeted antioxidants, mitoquinone (MitoQ) or SKQ1, would provide better protection against Dox than co-treatment. METHODS: We investigated the dose-response relationship of MitoQ, SKQ1, and vitamin C on Dox-induced damage on H9c2 cardiomyoblasts when drugs were given concurrently with Dox (e.g., co-treatment) or 24 h prior to Dox (e.g., pretreatment). Moreover, their effects on intracellular and mitochondrial oxidative stress were evaluated by 2,7-dichlorofluorescin diacetate and MitoSOX, respectively. RESULTS: Dox (0.5-50 µM, n = 6) dose-dependently reduced cell viability. By contrast, co-treatment of MitoQ (0.05-10 µM, n = 6) and SKQ1 (0.05-10 µM, n = 6), but not vitamin C (1-2000 µM, n = 3), significantly improved cell viability only at intermediate doses (0.5-1 µM). MitoQ (1 µM) and SKQ1 (1 µM) significantly increased cell viability to 1.79 ± 0.12 and 1.59 ± 0.08 relative to Dox alone, respectively (both p < 0.05). Interestingly, when given as pretreatment, only higher doses of MitoQ (2.5 µM, n = 9) and SKQ1 (5 µM, n = 7) showed maximal protection and improved cell viability to 2.19 ± 0.13 and 1.65 ± 0.07 relative to Dox alone, respectively (both p < 0.01), which was better than that of co-treatment. Moreover, the protective effects were attributed to the significant reduction in Dox-induced intracellular and mitochondrial oxidative stress. CONCLUSION: The data suggest that MitoQ and SKQ1, but not vitamin C, mitigated DOX-induced damage. Moreover, MitoQ pretreatment showed significantly higher cardioprotection than its co-treatment and SKQ1, which may be due to its better antioxidant effects.


Assuntos
Antibióticos Antineoplásicos/toxicidade , Antioxidantes/administração & dosagem , Cardiotônicos/administração & dosagem , Doxorrubicina/toxicidade , Mitocôndrias/efeitos dos fármacos , Compostos Organofosforados/administração & dosagem , Plastoquinona/análogos & derivados , Ubiquinona/análogos & derivados , Animais , Ácido Ascórbico/administração & dosagem , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Esquema de Medicação , Interações Medicamentosas , Mitocôndrias/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Plastoquinona/administração & dosagem , Ratos , Superóxidos/metabolismo , Ubiquinona/administração & dosagem
9.
New Phytol ; 229(4): 2120-2134, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33124043

RESUMO

Phytochemicals are used often in vitro and in vivo in cancer research. The plant hormones jasmonates (JAs) control the synthesis of specialized metabolites through complex regulatory networks. JAs possess selective cytotoxicity in mixed populations of cancer and normal cells. Here, direct incubation of leaf explants from the non-medicinal plant Arabidopsis thaliana with human breast cancer cells, selectively suppresses cancer cell growth. High-throughput LC-MS identified Arabidopsis metabolites. Protein and transcript levels of cell cycle regulators were examined in breast cancer cells. A synergistic effect by methyljasmonate (MeJA) and by compounds upregulated in the metabolome of MeJA-treated Arabidopsis leaves, on the breast cancer cell cycle, is associated with Cell Division Cycle 6 (CDC6), Cyclin-dependent kinase 2 (CDK2), Cyclins D1 and D3, indicating that key cell cycle components mediate cell viability reduction. Bioactives such as indoles, quinolines and cis-(+)-12-oxophytodienoic acid, in synergy, could act as anticancer compounds. Our work suggests a universal role for MeJA-treatment of Arabidopsis in altering the DNA replication regulator CDC6, supporting conservation, across kingdoms, of cell cycle regulation, through the crosstalk between the mechanistic target of rapamycin, mTOR and JAs. This study has important implications for the identification of metabolites with anti-cancer bioactivities in plants with no known medicinal pedigree and it will have applications in developing disease treatments.


Assuntos
Proteínas de Arabidopsis , Arabidopsis , Neoplasias , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , Ciclopentanos/farmacologia , Humanos , Oxilipinas/farmacologia , Reguladores de Crescimento de Plantas/farmacologia , Serina-Treonina Quinases TOR
10.
Nanoscale ; 13(1): 85-99, 2021 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-33211048

RESUMO

The evolving threat of antibiotic resistance development in pathogenic bacteria necessitates the continued cultivation of new technologies and agents to mitigate associated negative health impacts globally. It is no surprise that infection prevention and control are cited by the Centers for Disease Control and Prevention (CDC) as two routes for combating this dangerous trend. One technology that has gained great research interest is antimicrobial photodynamic inactivation of bacteria, or APDI. This technique permits controllable activation of antimicrobial effects by combining specific light excitation with the photodynamic properties of a photosensitizer; when activated, the photosensitizer generates reactive oxygen species (ROS) from molecular oxygen via either a type I (electron transfer) or type II (energy transfer) pathway. These species subsequently inflict oxidative damage on nearby bacteria, resulting in suppressed growth and cell death. To date, small molecule photosensitizers have been developed, yet the scalability of these as widespread sterilization agents is limited due to complex and costly synthetic procedures. Herein we report the use of brominated carbon nanodots (BrCND) as new photosensitizers for APDI. These combustion byproducts are easily and inexpensively collected; incorporation of bromine into the nanodot permits photosensitization effects that are not inherent to the carbon nanodot structure alone-a consequence of triplet character gained by the heavy atom effect. BrCND demonstrate both type I and type II photosensitization under UV-A irradiation, and furthermore are shown to have significant antimicrobial effects against both Gram-negative Escherichia coli and Gram-positive Staphylococcus aureus and Listeria monocytogenes as well. A mechanism of "dark" toxicity is additionally reported; the pH-triggered release of reactive nitrogen species is detected from a carbon nanodot structure for the first time. The results described present the BrCND structure as a competitive new antimicrobial agent for controllable sterilization of bacteria.


Assuntos
Anti-Infecciosos , Fotoquimioterapia , Antibacterianos/farmacologia , Anti-Infecciosos/farmacologia , Bactérias , Carbono , Fármacos Fotossensibilizantes/farmacologia
11.
Health Educ Behav ; 46(6): 1012-1023, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31789076

RESUMO

The purpose of the study was to examine the characteristics of Internet memes created and disseminated by proponents and opponents of vaccinations. A quantitative content analysis was performed on 234 pro- and antivaccine memes culled from the vaccination fan pages with the greatest number of followers on Facebook. Coding variables included whether the meme was pro- or antivaccine, percentage of factually incorrect claims, mention of the out-group, persuasive appeals (emotion, fear, and rationality), degree of sarcasm, and number of reactions and shares. The most prevalent themes concerned vaccine-preventable diseases, vaccine injury/safety/autism, and conspiracy theories. Independent t tests indicated that provaccination memes were more likely to use sarcasm whereas antivaccination memes were more likely to contain emotion and fear appeals and inaccurate claims. The percentage veracity of the claims in each meme was fact-checked using authoritative scientific sources. A path analysis applying structural equation modeling revealed that memes containing characteristics that were antivaccine (vs. provaccine), appealed to emotion, and appealed to rationality significantly contributed to greater likelihood of social media reactions and shares. Additional analysis determined that both pro- and antivaccination memes tended to contain more gist than verbatim information, and both groups did not significantly differ on this gist-to-verbatim variable. Findings offer insights to understand the persuasion tactics that provaccine and antivaccine groups apply in memes to persuade others via social media. Understanding these techniques will enable the development of health communication strategies to combat false and damaging vaccine information disseminated on the Internet.


Assuntos
Medo , Internet , Vacinação/efeitos adversos , Vacinação/psicologia , Defesa do Consumidor , Humanos , Comunicação Persuasiva , Opinião Pública
12.
PLoS One ; 13(7): e0201070, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30044836

RESUMO

Sample preparation is a leading bottleneck in rapid detection of pathogenic bacteria. Here, we use Lyse-It® for bacterial cellular lysis, genomic DNA fragmentation, and protein release and degradation for both Listeria monocytogenes and Vibrio cholerae. The concept of Lyse-It® employs a conventional microwave and Lyse-It® slides for intensely focused microwave irradiation onto the sample. High microwave power and a <60 second irradiation time allow for rapid cellular lysis and subsequent intracellular component release. The pathogenic bacteria are identified by quantitative polymerase chain reaction (qPCR), which subsequently demonstrates the viability of DNA for amplification post microwave-induced lysis. Intracellular component release, degradation, and detection of L. monocytogenes and V. cholerae has been performed and shown in this paper. These results demonstrate a rapid, low-cost, and efficient way for bacterial sample preparation on both food and water-borne Gram-positive and -negative organisms alike.


Assuntos
Técnicas Bacteriológicas , Listeria monocytogenes , Vibrio cholerae , Animais , DNA Bacteriano , Listeria monocytogenes/genética , Listeria monocytogenes/isolamento & purificação , Micro-Ondas , Reação em Cadeia da Polimerase , Ovinos , Temperatura , Vibrio cholerae/genética , Vibrio cholerae/isolamento & purificação
13.
Carcinogenesis ; 39(3): 407-417, 2018 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-29126163

RESUMO

To date, microarray analyses have led to the discovery of numerous individual 'molecular signatures' associated with specific cancers. However, there are serious limitations for the adoption of these multi-gene signatures in the clinical environment for diagnostic or prognostic testing as studies with more power need to be carried out. This may involve larger richer cohorts and more advanced analyses. In this study, we conduct analyses-based on gene regulatory network-to reveal distinct and common biomarkers across cancer types. Using microarray data of triple-negative and medullary breast, ovarian and lung cancers applied to a combination of glasso and Bayesian networks (BNs), we derived a unique network-containing genes that are uniquely involved: small proline-rich protein 1A (SPRR1A), follistatin like 1 (FSTL1), collagen type XII alpha 1 (COL12A1) and RAD51 associated protein 1 (RAD51AP1). RAD51AP1 and FSTL1 are significantly overexpressed in ovarian cancer patients but only RAD51AP1 is upregulated in lung cancer patients compared with healthy controls. The upregulation of RAD51AP1 was mirrored in the bloods of both ovarian and lung cancer patients, and Kaplan-Meier (KM) plots predicted poorer overall survival (OS) in patients with high expression of RAD51AP1. Suppression of RAD51AP1 by RNA interference reduced cell proliferation in vitro in ovarian (SKOV3) and lung (A549) cancer cells. This effect appears to be modulated by a decrease in the expression of mTOR-related genes and pro-metastatic candidate genes. Our data describe how an initial in silico approach can generate novel biomarkers that could potentially support current clinical practice and improve long-term outcomes.


Assuntos
Adenocarcinoma/genética , Biomarcadores Tumorais/genética , Cistadenocarcinoma Seroso/genética , Proteínas de Ligação a DNA/genética , Neoplasias Pulmonares/genética , Neoplasias Ovarianas/genética , Adenocarcinoma/mortalidade , Adenocarcinoma de Pulmão , Biomarcadores Tumorais/análise , Carcinoma Medular/genética , Carcinoma Medular/mortalidade , Cistadenocarcinoma Seroso/mortalidade , Feminino , Redes Reguladoras de Genes , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/mortalidade , Masculino , Neoplasias Ovarianas/mortalidade , Prognóstico , Proteínas de Ligação a RNA , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/mortalidade
14.
Can J Public Health ; 108(4): e348-e354, 2017 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-29120304

RESUMO

OBJECTIVES: To examine school- and student-level correlates of physical activity. METHODS: Cross-sectional Year 2 data collected from 45 298 grade 9-12 students attending 89 secondary schools in the COMPASS study were examined using multi-level modelling to predict the likelihood of students a) achieving 60 minutes of moderate to vigorous physical activity (MVPA) daily; and b) achieving the Canadian Society for Exercise Physiology (CSEP) activity guideline for youth (60 minutes/MVPA daily, vigorous physical activity at least three days in a week, and resistance training at least three days in a week). RESULTS: The prevalence of students achieving 60 minutes of MVPA daily and meeting the CSEP guideline was 49.3% and 31.0% respectively. Modest between-school variability was identified (1.1% for 60 minutes MVPA and 0.8% for CSEP guideline). School-level characteristics significantly associated with the outcome measures included location, school size, quality of facilities, and accessibility of facilities. Significant student-level correlates included sex, grade, weekly income, binge drinking, fruit and vegetable consumption, and body mass index. CONCLUSIONS: Most youth in this large study reported inadequate physical activity levels. Students were more likely to achieve 60 minutes of MVPA if they attended a larger school or a school in an urban location, whereas students were less likely to meet the CSEP guideline if they attended a school in a small urban location. However, student-level factors, such as binge drinking and inadequate fruit and vegetable consumption, were more strongly associated with the outcomes examined.


Assuntos
Exercício Físico , Fidelidade a Diretrizes/estatística & dados numéricos , Guias como Assunto , Instituições Acadêmicas/estatística & dados numéricos , Estudantes/estatística & dados numéricos , Adolescente , Canadá , Estudos Transversais , Feminino , Humanos , Masculino
15.
Oncotarget ; 8(37): 61890-61900, 2017 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-28977912

RESUMO

Narrowing the search for the critical hTERT repressor sequence(s) has identified three regions on chromosome 3p (3p12-p21.1, 3p21.2 and 3p21.3-p22). However, the precise location and identity of the sequence(s) responsible for hTERT transcriptional repression remains elusive. In order to identify critical hTERT repressor sequences located within human chromosome 3p12-p22, we investigated hTERT transcriptional activity within 21NT microcell hybrid clones containing chromosome 3 fragments. Mapping of chromosome 3 structure in a single hTERT-repressed 21NT-#3fragment hybrid clone, revealed a 490kb region of deletion localised to 3p21.3 and encompassing the histone H3, lysine 36 (H3K36) trimethyltransferase enzyme SETD2; a putative tumour suppressor gene in breast cancer. Three additional genes, BAP1, PARP-3 and PBRM1, were also selected for further investigation based on their location within the 3p21.1-p21.3 region, together with their documented role in the epigenetic regulation of target gene expression or hTERT regulation. All four genes (SETD2, BAP1, PARP-3 and PBRM1) were found to be expressed at low levels in 21NT. Gene copy number variation (CNV) analysis of SETD2, BAP1, PARP-3 and PBRM1 within a panel of nine breast cancer cell lines demonstrated single copy number loss of all candidate genes within five (56%) cell lines (including 21NT cells). Stable, forced overexpression of BAP1, but not PARP2, SETD2 or PBRM1, within 21NT cells was associated with a significant reduction in hTERT expression levels relative to wild-type controls. We propose that at least two sequences exist on human chromosome 3p, that function to regulate hTERT transcription within human breast cancer cells.

16.
Am J Cancer Res ; 7(3): 383-404, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28400999

RESUMO

The mTOR pathway was discovered in the late 1970s after the compound and natural inhibitor of mTOR, rapamycin was isolated from the bacterium Streptomyces hygroscopicus. mTOR is serine/threonine kinase belonging to the phosphoinositide 3-kinase related kinase (PIKK) family. It forms two distinct complexes; mTORC1 and mTORC2. mTORC1 has a key role in regulating protein synthesis and autophagy whilst mTORC2 is involved in regulating kinases of the AGC family. mTOR signaling is often over active in multiple cancer types including breast cancer. This can involve mutations in mTOR itself but more commonly, in breast cancer, this is related to an increase in activity of ErbB family receptors or alterations and mutations of PI3K signaling. Rapamycin and its analogues (rapalogues) bind to the intercellular receptor FKBP12, and then predominantly inhibit mTORC1 signaling via an allosteric mechanism. Research has shown that inhibition of mTOR is a useful strategy in tackling cancers, with it acting to slow tumor growth and limit the spread of a cancer. Rapalogues have now made their way into the clinic with the rapalogue everolimus (RAD-001/Afinitor) approved for use in conjunction with exemestane, in post-menopausal breast cancer patients with advanced disease who are HER-2 negative (normal expression), hormone receptor positive and whose prior treatment with non-steroidal aromatase inhibitors has failed. Testing across multiple trials has proven that everolimus and other rapalogues are a viable way of treating certain types of cancer. However, rapalogues have shown some drawbacks both in research and clinically, with their use often activating feedback pathways that counter their usefulness. As such, new types of inhibitors are being explored that work via different mechanisms, including inhibitors that are ATP competitive with mTOR and which act to perturb signaling from both mTOR complexes.

17.
Biomacromolecules ; 17(8): 2710-8, 2016 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-27409712

RESUMO

In view of the growing worldwide rise in microbial resistance, there is considerable interest in designing new antimicrobial copolymers. The aim of the current study was to investigate the relationship between antimicrobial activity and copolymer composition/architecture to gain a better understanding of their mechanism of action. Specifically, the antibacterial activity of several copolymers based on 2-(methacryloyloxy)ethyl phosphorylcholine [MPC] and 2-hydroxypropyl methacrylate (HPMA) toward Staphylococcus aureus was examined. Both block and graft copolymers were synthesized using either atom transfer radical polymerization or reversible addition-fragmentation chain transfer polymerization and characterized via (1)H NMR, gel permeation chromatography, rheology, and surface tensiometry. Antimicrobial activity was assessed using a range of well-known assays, including direct contact, live/dead staining, and the release of lactate dehydrogenase (LDH), while transmission electron microscopy was used to study the morphology of the bacteria before and after the addition of various copolymers. As expected, PMPC homopolymer was biocompatible but possessed no discernible antimicrobial activity. PMPC-based graft copolymers comprising PHPMA side chains (i.e. PMPC-g-PHPMA) significantly reduced both bacterial growth and viability. In contrast, a PMPC-PHPMA diblock copolymer comprising a PMPC stabilizer block and a hydrophobic core-forming PHPMA block did not exhibit any antimicrobial activity, although it did form a biocompatible worm gel. Surface tensiometry studies and LDH release assays suggest that the PMPC-g-PHPMA graft copolymer exhibits surfactant-like activity. Thus, the observed antimicrobial activity is likely to be the result of the weakly hydrophobic PHPMA chains penetrating (and hence rupturing) the bacterial membrane.


Assuntos
Anti-Infecciosos/farmacologia , Materiais Biocompatíveis/química , Géis/farmacologia , Polímeros/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Anti-Infecciosos/química , Géis/química , Polimerização , Polímeros/química , Reologia , Propriedades de Superfície
18.
Front Microbiol ; 7: 806, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27303388

RESUMO

Anthrax outbreaks in livestock have social, economic and health implications, altering farmer's livelihoods, impacting trade and posing a zoonotic risk. Our study investigated the survival of Bacillus thuringiensis and B. anthracis spores sporulated at 15, 20, or 37°C, over 33 days of composting. Spores (∼7.5 log10 CFU g(-1)) were mixed with manure and composted in laboratory scale composters. After 15 days, the compost was mixed and returned to the composter for a second cycle. Temperatures peaked at 71°C on day 2 and remained ≥55°C for an average of 7 days in the first cycle, but did not exceed 55°C in the second. For B. thuringiensis, spores generated at 15 and 21°C exhibited reduced (P < 0.05) viability of 2.7 and 2.6 log10 CFU g(-1) respectively, as compared to a 0.6 log10 CFU g(-1) reduction for those generated at 37°C. For B. anthracis, sporulation temperature did not impact spore survival as there was a 2.5, 2.2, and 2.8 log10 CFU g(-1) reduction after composting for spores generated at 15, 21, and 37°C, respectively. For both species, spore viability declined more rapidly (P < 0.05) in the first as compared to the second composting cycle. Our findings suggest that the duration of thermophilic exposure (≥55°C) is the main factor influencing survival of B. anthracis spores in compost. As sporulation temperature did not influence survival of B. anthracis, composting may lower the viability of spores associated with carcasses infected with B. anthracis over a range of sporulation temperatures.

19.
Proteomics ; 16(11-12): 1718-25, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27226230

RESUMO

MALDI-MS Imaging is a novel label-free technique that can be used to visualize the changes in multiple mass responses following treatment. Following treatment with proinflammatory cytokine interleukin-22 (IL-22), the epidermal differentiation of Labskin, a living skin equivalent (LSE), successfully modeled psoriasis in vitro. Masson's trichrome staining enabled visualization and quantification of epidermal differentiation between the untreated and IL-22 treated psoriatic LSEs. Matrix-assisted laser desorption ionization mass spectrometry imaging was used to observe the spatial location of the psoriatic therapy drug acetretin following 48 h treatments within both psoriatic and normal LSEs. After 24 h, the drug was primarily located in the epidermal regions of both the psoriatic and nonpsoriatic LSE models whereas after 48 h it was detectible in the dermis.


Assuntos
Epiderme/ultraestrutura , Psoríase/genética , Pele/efeitos dos fármacos , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Animais , Diferenciação Celular/efeitos dos fármacos , Modelos Animais de Doenças , Epiderme/efeitos dos fármacos , Humanos , Imageamento Tridimensional/métodos , Interleucinas/administração & dosagem , Camundongos , Psoríase/patologia , Pele/metabolismo , Pele/fisiopatologia , Engenharia Tecidual/métodos , Interleucina 22
20.
Prev Med ; 74: 74-80, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25732538

RESUMO

OBJECTIVES: To examine the prevalence of different communication- and media-based sedentary behaviors and examine how they are associated with modifiable risk behaviors and key demographic correlates among a large sample of youth. METHODS: Data from 23,031 grade 9 to grade 12 students in Year 1 (2012-2013) of the COMPASS study (Canada) were used to examine the prevalence of sedentary behaviors by gender and by grade. The between-school variance in sedentary behaviors was calculated and models were developed to examine how modifiable risk factors and demographic correlates were associated with sedentary behaviors. RESULTS: Youth averaged 494 (± 313) min/day of sedentary behavior and 96.7% of the sample exceeded the sedentary behavior guidelines of no more than 2h per day. Significant between-school random variation in the sedentary behaviors was identified. Substance use, weight status, ethnicity, and gender were the main predictors of the sedentary behaviors examined. CONCLUSIONS: The vast majority of youth in the COMPASS sample are considered highly sedentary. The evidence clearly suggests we need to develop more effective methods of intervening, that school-based programming is warranted, and that gender-specific programming may be required.


Assuntos
Meios de Comunicação/estatística & dados numéricos , Comportamentos Relacionados com a Saúde , Recreação , Assunção de Riscos , Comportamento Sedentário , Adolescente , Distribuição por Idade , Canadá/epidemiologia , Telefone Celular/estatística & dados numéricos , Telefone Celular/tendências , Estudos de Coortes , Meios de Comunicação/tendências , Dieta , Feminino , Guias como Assunto , Humanos , Internet/estatística & dados numéricos , Internet/tendências , Masculino , Atividade Motora , Obesidade/epidemiologia , Obesidade/etiologia , Prevalência , Distribuição por Sexo , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Transtornos Relacionados ao Uso de Substâncias/etiologia , Inquéritos e Questionários , Televisão/estatística & dados numéricos , Televisão/tendências , Fatores de Tempo , Jogos de Vídeo/estatística & dados numéricos , Jogos de Vídeo/tendências
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