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1.
Artigo em Inglês | MEDLINE | ID: mdl-33619020

RESUMO

Background Combined oral contraceptive use is associated with a decreased risk of invasive epithelial ovarian cancer (ovarian cancer). There is suggestive evidence of an inverse association between progestin-only contraceptive use and ovarian cancer risk, but studies have been underpowered. Methods The current study used primary data from 7,977 women with ovarian cancer and 11,820 control women in seven case-control studies from the Ovarian Cancer Association Consortium to evaluate the association between use of depot-medroxyprogesterone acetate (DMPA), an injectable progestin-only contraceptive, and ovarian cancer risk. Logistic models were fit to determine the association between ever use of DMPA and ovarian cancer risk overall and by histotype. A systematic review of the association between DMPA use and ovarian cancer risk was conducted. Results Ever use of DMPA was associated with a 35% decreased risk overall (OR=0.65, 95% CI 0.50-0.85). There was a statistically significant trend of decreasing risk with increasing duration of use (p-trend<0.001). The systematic review yielded six studies, four of which showed an inverse association and two showed increased risk. Conclusions DMPA use appears to be associated with a decreased risk of ovarian cancer in a duration-dependent manner based on the preponderance of evidence. Further study of the mechanism through which DMPA use is associated with ovarian cancer is warranted. Impact The results of this study are of particular interest given the rise in popularity of progestin-releasing intrauterine devices which have a substantially lower progestin dose than that in DMPA, but may have a stronger local effect.

2.
J Natl Compr Canc Netw ; 19(2): 191-226, 2021 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-33545690

RESUMO

Epithelial ovarian cancer is the leading cause of death from gynecologic cancer in the United States and is the country's fifth most common cause of cancer mortality in women. A major challenge in treating ovarian cancer is that most patients have advanced disease at initial diagnosis. These NCCN Guidelines discuss cancers originating in the ovary, fallopian tube, or peritoneum, as these are all managed in a similar manner. Most of the recommendations are based on data from patients with the most common subtypes─high-grade serous and grade 2/3 endometrioid. The NCCN Guidelines also include recommendations specifically for patients with less common ovarian cancers, which in the guidelines include the following: carcinosarcoma, clear cell carcinoma, mucinous carcinoma, low-grade serous, grade 1 endometrioid, borderline epithelial, malignant sex cord-stromal, and malignant germ cell tumors. This manuscript focuses on certain aspects of primary treatment, including primary surgery, adjuvant therapy, and maintenance therapy options (including PARP inhibitors) after completion of first-line chemotherapy.

3.
Nature ; 585(7824): 277-282, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32879489

RESUMO

Abnormal epigenetic patterns correlate with effector T cell malfunction in tumours1-4, but the cause of this link is unknown. Here we show that tumour cells disrupt methionine metabolism in CD8+ T cells, thereby lowering intracellular levels of methionine and the methyl donor S-adenosylmethionine (SAM) and resulting in loss of dimethylation at lysine 79 of histone H3 (H3K79me2). Loss of H3K79me2 led to low expression of STAT5 and impaired T cell immunity. Mechanistically, tumour cells avidly consumed methionine and outcompeted T cells for methionine by expressing high levels of the methionine transporter SLC43A2. Genetic and biochemical inhibition of tumour SLC43A2 restored H3K79me2 in T cells, thereby boosting spontaneous and checkpoint-induced tumour immunity. Moreover, methionine supplementation improved the expression of H3K79me2 and STAT5 in T cells, and this was accompanied by increased T cell immunity in tumour-bearing mice and patients with colon cancer. Clinically, tumour SLC43A2 correlated negatively with T cell histone methylation and functional gene signatures. Our results identify a mechanistic connection between methionine metabolism, histone patterns, and T cell immunity in the tumour microenvironment. Thus, cancer methionine consumption is an immune evasion mechanism, and targeting cancer methionine signalling may provide an immunotherapeutic approach.


Assuntos
Sistema L de Transporte de Aminoácidos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Histonas/metabolismo , Metionina/metabolismo , Metilação , Neoplasias/metabolismo , Sistema L de Transporte de Aminoácidos/deficiência , Animais , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Epigênese Genética , Feminino , Histonas/química , Humanos , Camundongos , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/patologia , Receptores de Antígenos de Linfócitos T/metabolismo , Fator de Transcrição STAT5/metabolismo
4.
Artigo em Inglês | MEDLINE | ID: mdl-32949433

RESUMO

AIM: To explore the experiences of Victorian foster and kinship carers in accessing health services for children in their care and to quantify the frequency of potential barriers to health care. METHODS: On-line survey co-designed with the Foster Care Association of Victoria measuring carer-reported health service engagement by a child/young person in their care, ease of service access, time to receiving Medicare number and out-of-pocket health-related costs. A total of 239 foster and 51 kinship carers were recruited through email and social media by carer support agencies. RESULTS: In total, 90% of children/young people had engaged with a general practitioner. Most had engaged with dental (75%), paediatric (72%), optometry (61%) and audiology (54%) services. Mental health services were most likely to be needed but not yet received. Neither carer education nor socio-economic status was associated with likelihood of service engagement. Carers reported that it was hardest to get appointments with mental health and paediatric services. Twenty-seven percent had waited to see a health service because of delays in carers receiving their Medicare number. Sixty percent of carers had paid out-of-pocket for health services; 78% of these had not been reimbursed. CONCLUSION: Victorian foster and kinship carers report high health service use for children and young people in their care. Mental health services were the hardest to access with the largest gap between identified need and service use. Timely access to Medicare numbers and financial support are barriers to access that could be addressed. The development of integrated paediatric health care and clinicians co-located with child protection could also assist.

5.
JCI Insight ; 5(18)2020 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-32780724

RESUMO

Tumor-associated macrophages (TAMs) affect cancer progression and therapy. Ovarian carcinoma often metastasizes to the peritoneal cavity. Here, we found 2 peritoneal macrophage subsets in mice bearing ID8 ovarian cancer based on T cell immunoglobulin and mucin domain containing 4 (Tim-4) expression. Tim-4+ TAMs were embryonically originated and locally sustained while Tim-4- TAMs were replenished from circulating monocytes. Tim-4+ TAMs, but not Tim-4- TAMs, promoted tumor growth in vivo. Relative to Tim-4- TAMs, Tim-4+ TAMs manifested high oxidative phosphorylation and adapted mitophagy to alleviate oxidative stress. High levels of arginase-1 in Tim-4+ TAMs contributed to potent mitophagy activities via weakened mTORC1 activation due to low arginine resultant from arginase-1-mediated metabolism. Furthermore, genetic deficiency of autophagy element FAK family-interacting protein of 200 kDa resulted in Tim-4+ TAM loss via ROS-mediated apoptosis and elevated T cell immunity and ID8 tumor inhibition in vivo. Moreover, human ovarian cancer-associated macrophages positive for complement receptor of the immunoglobulin superfamily (CRIg) were transcriptionally, metabolically, and functionally similar to murine Tim-4+ TAMs. Thus, targeting CRIg+ (Tim-4+) TAMs may potentially treat patients with ovarian cancer with peritoneal metastasis.

6.
Gynecol Oncol ; 159(2): 509-514, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32847676

RESUMO

OBJECTIVE: Aromatase inhibitors (AI) are frequently prescribed in gynecologic oncology. We sought to define the frequency and duration of AI use, characterize AI side effects and determine the reasons for discontinuation in these patients. METHODS: Uterine and ovarian cancer patients with AI use for gynecologic cancer therapy were identified retrospectively. Data were abstracted from the electronic medical record, including cancer type, stage, prior cancer treatments, body mass index, concurrent medications, prevalence of AI side effects before and during AI therapy, length of AI treatment and reason for AI discontinuation. RESULTS: 146 women received AI therapy, with 68 for ovarian cancer (46.6%) and 78 for uterine cancer (53.4%). The majority (71.9%) had advanced stage disease at diagnosis. 54.1% noted AI-associated side effects within the first three visits after starting AI therapy. The most common side effects were arthralgias (29.5%), hot flashes (25.3%), new/worsening fatigue (16.4%), muscle or joint stiffness (8.2%) and myalgias (6.8%). The mean duration of therapy was 14.7 months. Gabapentin or selective serotonin reuptake inhibitor (SSRI) use was associated with decreased musculoskeletal side effects (gabapentin: p < .001, OR 0.88, 95% CI 0.83-0.94; SSRI: p < .001, OR 0.82, 95% CI 0.77-0.89). The most common reason for AI discontinuation was disease progression (87.9%), with 5.0% discontinuing due to side effects and 7.1% for other reasons. CONCLUSION: AI therapy for gynecologic cancers is frequently associated with musculoskeletal side effects, but rarely leads to treatment discontinuation. Thus, AI side effects should be assessed in gynecologic cancer patients to allow potential mitigation of symptoms through adjunct therapies.

7.
Gynecol Oncol ; 158(3): 702-709, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32641237

RESUMO

PURPOSE: Prior studies of menopausal hormone therapy (MHT) and ovarian cancer survival have been limited by lack of hormone regimen detail and insufficient sample sizes. To address these limitations, a comprehensive analysis of 6419 post-menopausal women with pathologically confirmed ovarian carcinoma was conducted to examine the association between MHT use prior to diagnosis and survival. METHODS: Data from 15 studies in the Ovarian Cancer Association Consortium were included. MHT use was examined by type (estrogen-only (ET) or estrogen+progestin (EPT)), duration, and recency of use relative to diagnosis. Cox proportional hazards models were used to estimate the association between hormone therapy use and survival. Logistic regression and mediation analysis was used to explore the relationship between MHT use and residual disease following debulking surgery. RESULTS: Use of ET or EPT for at least five years prior to diagnosis was associated with better ovarian cancer survival (hazard ratio, 0.80; 95% CI, 0.74 to 0.87). Among women with advanced stage, high-grade serous carcinoma, those who used MHT were less likely to have any macroscopic residual disease at the time of primary debulking surgery (p for trend <0.01 for duration of MHT use). Residual disease mediated some (17%) of the relationship between MHT and survival. CONCLUSIONS: Pre-diagnosis MHT use for 5+ years was a favorable prognostic factor for women with ovarian cancer. This large study is consistent with prior smaller studies, and further work is needed to understand the underlying mechanism.

8.
Cancers (Basel) ; 12(8)2020 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-32726910

RESUMO

Within the ovarian cancer tumor microenvironment, cancer stem-like cells (CSC) interact with carcinoma associated mesenchymal stem/stromal cells (CA-MSC) through multiple secreted cytokines and growth factors. These paracrine interactions have been revealed to cause enrichment of CSC and their chemoprotection; however, it is still not known if platelet-derived growth factor (PDGF) signaling is involved in facilitating these responses. In order to probe this undiscovered bidirectional communication, we created a model of ovarian malignant ascites in the three-dimensional (3D) hanging drop heterospheroid array, with CSC and CA-MSC. We hypothesized that PDGF secretion by CA-MSC increases self-renewal, migration, epithelial to mesenchymal transition (EMT) and chemoresistance in ovarian CSC. Our results indicate that PDGF signaling in the CSC-MSC heterospheroids significantly increased stemness, metastatic potential and chemoresistance of CSC. Knockdown of PDGFB in MSC resulted in abrogation of these phenotypes in the heterospheroids. Our studies also reveal a cross-talk between PDGF and Hedgehog signaling in ovarian cancer. Overall, our data suggest that when the stromal signaling via PDGF to ovarian CSC is blocked in addition to chemotherapy pressure, the tumor cells are significantly more sensitive to chemotherapy. Our results emphasize the importance of disrupting the signals from the microenvironment to the tumor cells, in order to improve response rates. These findings may lead to the development of combination therapies targeting stromal signaling (such as PDGF and Hedgehog) that can abrogate the tumorigenic, metastatic and platinum resistant phenotypes of ovarian CSC through additional investigations.

9.
BMC Public Health ; 20(1): 993, 2020 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-32580720

RESUMO

BACKGROUND: Universal child health services (UCHS) provide an important pragmatic platform for the delivery of universal and targeted interventions to support families and optimize child health outcomes. We aimed to identify brief, evidence-based interventions for common health and developmental problems that could be potentially implemented in UCHS. METHODS: A restricted evidence assessment (REA) of electronic databases and grey literature was undertaken covering January 2006 to August 2019. Studies were eligible if (i) outcomes related to one or more of four areas: child social and emotional wellbeing (SEWB), infant sleep, home learning environment or parent mental health, (ii) a comparison group was used, (iii) universal or targeted intervention were delivered in non-tertiary settings, (iv) interventions did not last more than 4 sessions, and (v) children were aged between 2 weeks postpartum and 5 years at baseline. RESULTS: Seventeen studies met the eligibility criteria. Of these, three interventions could possibly be implemented at scale within UCHS platforms: (1) a universal child behavioural intervention which did not affect its primary outcome of infant sleep but improved parental mental health, (2) a universal screening programme which improved maternal mental health, and (3) a targeted child behavioural intervention which improved parent-reported infant sleep problems and parental mental health. Key lessons learnt include: (1) Interventions should impart the maximal amount of information within an initial session with future sessions reinforcing key messages, (2) Interventions should see the family as a holistic unit by considering the needs of parents with an emphasis on identification, triage and referral, and (3) Brief interventions may be more acceptable for stigmatized topics, but still entail considerable barriers that deter the most vulnerable. CONCLUSIONS: Delivery and evaluation of brief evidence-based interventions from a UCHS could lead to improved maternal and child health outcomes through a more responsive and equitable service. We recommend three interventions that meet our criteria of "best bet" interventions.


Assuntos
Serviços de Saúde da Criança/organização & administração , Serviços de Saúde da Criança/estatística & dados numéricos , Medicina Baseada em Evidências/organização & administração , Medicina Baseada em Evidências/estatística & dados numéricos , Cobertura Universal do Seguro de Saúde/organização & administração , Cobertura Universal do Seguro de Saúde/estatística & dados numéricos , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino
10.
JCI Insight ; 5(11)2020 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-32369446

RESUMO

BACKGROUNDEpidemiologic studies suggest that metformin has antitumor effects. Laboratory studies indicate metformin impacts cancer stem-like cells (CSCs). As part of a phase II trial, we evaluated the impact of metformin on CSC number and on carcinoma-associated mesenchymal stem cells (CA-MSCs) and clinical outcomes in nondiabetic patients with advanced-stage epithelial ovarian cancer (EOC).METHODSThirty-eight patients with stage IIC (n = 1)/III (n = 25)/IV (n = 12) EOC were treated with either (a) neoadjuvant metformin, debulking surgery, and adjuvant chemotherapy plus metformin or (b) neoadjuvant chemotherapy and metformin, interval debulking surgery, and adjuvant chemotherapy plus metformin. Metformin-treated tumors, compared with historical controls, were evaluated for CSC number and chemotherapy response. Primary endpoints were (a) a 2-fold or greater reduction in aldehyde dehydrogenase-positive (ALDH+) CD133+ CSCs and (b) a relapse-free survival at 18 months of more than 50%.RESULTSMetformin was well tolerated. Median progression-free survival was 18.0 months (95% CI 14.0-21.6) with relapse-free survival at 18 months of 59.3% (95% CI 38.6-70.5). Median overall survival was 57.9 months (95% CI 28.0-not estimable). Tumors treated with metformin had a 2.4-fold decrease in ALDH+CD133+ CSCs and increased sensitivity to cisplatin ex vivo. Furthermore, metformin altered the methylation signature in CA-MSCs, which prevented CA-MSC-driven chemoresistance in vitro.CONCLUSIONTranslational studies confirm an impact of metformin on EOC CSCs and suggest epigenetic change in the tumor stroma may drive the platinum sensitivity ex vivo. Consistent with this, metformin therapy was associated with better-than-expected overall survival, supporting the use of metformin in phase III studies.TRIAL REGISTRATIONClinicalTrials.gov NCT01579812.

11.
Gynecol Oncol ; 157(2): 487-493, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32033800

RESUMO

OBJECTIVE: To design and implement a standardized postoperative voiding management protocol that accurately identifies patients with urinary retention and reduces unnecessary re-catheterization. METHODS: A postoperative voiding management protocol was designed and implemented in patients undergoing major, inpatient, non-radical abdominal surgery with a gynecologic oncologist. No patients had epidural catheters. The implemented quality improvement (QI) protocol included: 1) Foley removal at six hours postoperatively; 2) universal bladder scan after the first void; and 3) limiting re-catheterization to patients with bladder scan volumes >150 ml. A total of 96 patients post-protocol implementation were compared to 52 patients pre-protocol. Along with baseline demographic data and timing of catheter removal, we recorded the presence or absence of urinary retention and/or unnecessary re-catheterization and postoperative urinary tract infection rates. Fisher's exact test and student's t-tests were performed for comparisons. RESULTS: The overall rate of postoperative urinary retention was 21.6% (32/148). The new voiding management protocol reduced the rate of unnecessary re-catheterization by 90% (13.5% vs 2.1%, p = 0.01), without overlooking true urinary retention (23.1% vs 20.8%, p = 0.83). Additionally, there was a significant increase in hospital-defined early discharge prior to 11:00 AM (4.0% vs 22.0%, p = 0.022). There was no difference in the postoperative urinary tract infection rate between the groups (p = 1.00). Risk factors associated with urinary retention included older age (p < 0.01), use of medications with anticholinergic properties (p < 0.01), and preexisting urinary dysfunction (p < 0.01). CONCLUSIONS: Implementation of this new voiding management protocol reduced unnecessary re-catheterization, captured and treated true urinary retention, and facilitated early hospital discharge.


Assuntos
Neoplasias dos Genitais Femininos/cirurgia , Retenção Urinária/terapia , Fatores Etários , Estudos de Coortes , Feminino , Procedimentos Cirúrgicos em Ginecologia/efeitos adversos , Procedimentos Cirúrgicos em Ginecologia/métodos , Humanos , Pessoa de Meia-Idade , Complicações Pós-Operatórias/diagnóstico por imagem , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/terapia , Melhoria de Qualidade , Estudos Retrospectivos , Bexiga Urinária/diagnóstico por imagem , Cateterismo Urinário/métodos , Retenção Urinária/diagnóstico por imagem , Retenção Urinária/etiologia
12.
Theor Appl Genet ; 133(3): 967-980, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31950199

RESUMO

KEY MESSAGE: Novel major gene resistance against Potato virus Y in diploid populations of Solanum tuberosum Groups Phureja and Tuberosum was biologically and genetically characterised. Named Ry(o)phu, it mapped to chromosome 9. A new source of genetic resistance derived from Solanum tuberosum Group Phureja against Potato virus Y (PVY) was identified and genetically characterised in three diploid biparental potato populations. Segregation data for two populations (05H1 and 08H1) suggested the presence of a single dominant gene for resistance to PVY which, following DaRT analysis of the 08H1 cross, was mapped to chromosome 9. More detailed genetic analysis of resistance utilised a well-characterised SNP-linkage map for the 06H1 population, together with newly generated marker data. In these plants, which have both S. tuberosum Group Phureja and S. tuberosum Group Tuberosum in their pedigree, the resistance was shown to map to chromosome 9 at a locus not previously associated with PVY resistance, although there is evidence for at least one other genetic factor controlling PVY infection. The resistance factor location on chromosome 9 (named as Ry(o)phu) suggests a potential role of NB-LRR genes in this resistance. Phenotypic analysis using a GUS-tagged virus revealed that a small amount of PVY replication occurred in occasional groups of epidermal cells in inoculated leaves of resistant plants, without inducing any visible hypersensitive response. However, the virus did not enter the vascular system and systemic spread was completely prevented.


Assuntos
Resistência à Doença/genética , Interações Hospedeiro-Patógeno/genética , Doenças das Plantas/genética , Potyvirus/patogenicidade , Solanum tuberosum/genética , Mapeamento Cromossômico , Cromossomos de Plantas , Genes de Plantas , Marcadores Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Doenças das Plantas/virologia , Folhas de Planta/genética , Folhas de Planta/metabolismo , Folhas de Planta/virologia , Ploidias , Polimorfismo de Nucleotídeo Único , Potyvirus/genética , Potyvirus/metabolismo , Locos de Características Quantitativas , Solanum tuberosum/metabolismo , Solanum tuberosum/virologia
13.
J Natl Compr Canc Netw ; 17(8): 896-909, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31390583

RESUMO

Epithelial ovarian cancer is the leading cause of death from gynecologic cancer in the United States, with less than half of patients living >5 years from diagnosis. A major challenge in treating ovarian cancer is that most patients have advanced disease at initial diagnosis. The best outcomes are observed in patients whose primary treatment includes complete resection of all visible disease plus combination platinum-based chemotherapy. Research efforts are focused on primary neoadjuvant treatments that may improve resectability, as well as systemic therapies providing improved long-term survival. These NCCN Guidelines Insights focus on recent updates to neoadjuvant chemotherapy recommendations, including the addition of hyperthermic intraperitoneal chemotherapy, and the role of PARP inhibitors and bevacizumab as maintenance therapy options in select patients who have completed primary chemotherapy.


Assuntos
Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/terapia , Terapia Combinada/efeitos adversos , Terapia Combinada/métodos , Gerenciamento Clínico , Feminino , Humanos , Terapia Neoadjuvante , Resultado do Tratamento
14.
Gynecol Oncol ; 154(2): 283-289, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31196575

RESUMO

OBJECTIVES: To investigate the impact of the increased use of neoadjuvant chemotherapy on the complexity of cytoreductive surgeries for ovarian cancer. METHODS: Using the National Cancer Database, we performed a retrospective cohort study of women diagnosed between 2004 and 2015 with stage III or IV epithelial ovarian cancer who underwent either primary cytoreductive surgery (PDS) followed by adjuvant chemotherapy, neoadjuvant chemotherapy (NACT) followed by interval debulking surgery. Cases were assigned a surgical complexity category as 1) Inadequate, 2) Low, 3) Moderate and, 4) High complexity. The primary outcome was the trend in surgical complexity over time. Secondary outcomes included temporal trends in treatment modality, perioperative mortality, and survival. RESULTS: At total of 52,582 (76.3%) underwent PDS and 16,307 (23.7%) underwent NACT. The utilization of NACT increased from 7.7% in 2004 to 27.8% in 2015 (p-trend < 0.001). Patients undergoing moderate complexity surgeries increased from 28.9% to 33.5% and high complexity surgeries from 26.3% to 30% (p-trend < 0.001, for both). Trends in increasing surgical complexity were seen in both NACT and PDS cohorts. This increase in surgical complexity was seen most profoundly at the high-volume centers. Overall 30-day mortality decreased from 3.4% in 2004 to 1.4% in 2015; and 90-day mortality decreased from 7.6% to 4%. During the same time, 5-year survival increased from 39.7% to 49%. CONCLUSIONS: Increase in the utilization of NACT is associated with decreased 30- and 90-day mortality and increase in five-year survival. Moreover, the overall complexity of ovarian cancer surgery has increased in both PDS and NACT cohorts.


Assuntos
Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/cirurgia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Epitelial do Ovário/mortalidade , Quimioterapia Adjuvante/mortalidade , Quimioterapia Adjuvante/estatística & dados numéricos , Procedimentos Cirúrgicos de Citorredução/mortalidade , Procedimentos Cirúrgicos de Citorredução/estatística & dados numéricos , Bases de Dados Factuais , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Ovarianas/mortalidade , Estudos Retrospectivos , Análise de Sobrevida
15.
JAMA Netw Open ; 2(5): e194270, 2019 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-31125099

RESUMO

Importance: A growing body of literature suggests that having a strong sense of purpose in life leads to improvements in both physical and mental health and enhances overall quality of life. There are interventions available to influence life purpose; thus, understanding the association of life purpose with mortality is critical. Objective: To evaluate whether an association exists between life purpose and all-cause or cause-specific mortality among older adults in the United States. Design, Setting, and Participants: The Health and Retirement Study (HRS) is a national cohort study of US adults older than 50 years. Adults between the ages of 51 to 61 were enrolled in the HRS, and their spouses or partners were enrolled regardless of age. Initially, individuals born between 1931 and 1941 were enrolled starting in 1992, but subsequent cohort enrichment was carried out. The present prospective cohort study sample was drawn from 8419 HRS participants who were older than 50 years and who had filled out a psychological questionnaire during the HRS 2006 interview period. Of these, 1142 nonresponders with incomplete life purpose data, 163 respondents with missing sample weights, 81 participants lost to follow-up, 1 participant with an incorrect survival time, and 47 participants with missing information on covariates were excluded. The final sample for analysis was 6985 individuals. Data analyses were conducted between June 5, 2018, and April 22, 2019. Exposures: Purpose in life was assessed for the 2006 interview period with a 7-item questionnaire from the modified Ryff and Keyes Scales of Psychological Well-being evaluation using a Likert scale ranging from 1 to 6, with higher scores indicating greater purpose in life; for all-cause and cause-specific mortality analyses, 5 categories of life purpose scores were used (1.00-2.99, 3.00-3.99, 4.00-4.99, 5.00-5.99, and 6.00). Main Outcomes and Measures: All-cause and cause-specific mortality were assessed between 2006 and 2010. Weighted Cox proportional hazards models were used to evaluate life purpose and mortality. Results: Of 6985 individuals included in the analysis, 4016 (57.5%) were women, the mean (SD) age of all participants was 68.6 (9.8) years, and the mean (SD) survival time for decedents was 31.21 (15.42) months (range, 1.00-71.00 months). Life purpose was significantly associated with all-cause mortality in the HRS (hazard ratio, 2.43; 95% CI, 1.57-3.75, comparing those in the lowest life purpose category with those in the highest life purpose category). Some significant cause-specific mortality associations with life purpose were also observed (heart, circulatory, and blood conditions: hazard ratio, 2.66; 95% CI, 1.62-4.38). Conclusions and Relevance: This study's results indicated that stronger purpose in life was associated with decreased mortality. Purposeful living may have health benefits. Future research should focus on evaluating the association of life purpose interventions with health outcomes, including mortality. In addition, understanding potential biological mechanisms through which life purpose may influence health outcomes would be valuable.


Assuntos
Atitude Frente a Morte , Causas de Morte , Acontecimentos que Mudam a Vida , Qualidade de Vida/psicologia , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Prospectivos , Fatores de Risco
16.
J Paediatr Child Health ; 55(12): 1470-1475, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30968526

RESUMO

AIM: To describe the health needs identified in children attending a comprehensive health assessment at a tertiary hospital, multidisciplinary clinic for children following entry to out-of-home care and timeliness of referral and assessment compared with national recommendations. METHODS: This was a retrospective audit of all the children who attended the Pathway to Good Health clinic at The Royal Children's Hospital, Melbourne from May 2013 until 31 August 2016. RESULTS: A total of 119 children aged 0-12 years attended the clinic during the audit period. Of these children, 17% (including more than 30% of 0-2-year-olds) were not up-to-date with immunisations, and 87% had physical health concerns that were addressed on the day or needed further management. Over 50% had mental health concerns identified (76% of 7-12-year-olds). In children aged 3-6 years, 64% had behavioural problems and 77% had developmental problems identified. Only a third of the children was referred to the Pathway to Good Health clinic within the national standard of 30 days post-entry to care, and 24% of children attended within 3 months of entry to care. CONCLUSION: Children in out-of-home care within Victoria have high rates of physical, mental and developmental health concerns, consistent with previous studies. Timeliness of attendance at the clinic was low compared with national recommendations, even within a programme designed to facilitate timely health checks. This is the second and largest Australian study exploring timeliness of health checks. Further research would establish whether these results are more systemic.

17.
BMJ Paediatr Open ; 3(1): e000400, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30815588

RESUMO

Introduction: Children entering out-of-home care have high rates of health needs across all domains of health. To identify these needs early and optimise long-term outcomes, routine health assessment on entry to care is recommended by child health experts and included in policy in many jurisdictions. If effective, this ought to lead to high rates of health service use as needs are addressed. Victoria (Australia) has no state-wide approach to deliver routine health assessments and no data to describe the timing and use of health service visits for children in out-of-home care. This retrospective cohort data linkage study aims to describe the extent and timeliness of health service use by Victorian children (aged 0-12 years) who entered out-of-home care for the first time between 1 April 2010 and 31 December 2015, in the first 12 months of care. Methods and analysis: The sample will be identified in the Victorian Child Protection database. Child and placement variables will be extracted. Linked health databases will provide additional data: six state databases that collate data about hospital admissions, emergency department presentations and attendances at dental, mental and community health services and public hospital outpatients. The federal Medicare Benefits Schedule claims dataset will provide information on visits to general practitioners, specialist physicians (including paediatricians), optometrists, audiologists and dentists. The number, type and timing of visits to different health services will be determined and benchmarked to national standards. Multivariable logistic regression will examine the effects of child and system variables on the odds of timely health visits, and proportional-hazards regression will explore the effects on time to first health visits. Ethics and dissemination: Ethical and data custodian approval has been obtained for this study. Dissemination will include presentation of findings to policy and service stakeholders in addition to scientific papers.

18.
Oncogene ; 38(9): 1576-1584, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30305729

RESUMO

Ovarian carcinoma-associated mesenchymal stem cells (CA-MSC) produce not only high levels of interleukin-6 (IL6) but also the related cytokine leukemia inhibitory factor (LIF). IL6-mediated activation of STAT3 is implicated as a critical therapeutic target for cancer therapy. Less is known about the role of LIF, which can similarly activate STAT3, in ovarian cancer. We therefore sought to evaluate the tumorigenic effects of CA-MSC paracrine LIF signaling and the redundancy of IL6 and LIF in activating ovarian cancer STAT3 mediated cancer growth. As expected, we found that both IL6 and LIF induce STAT3 phosphorylation in tumor cells. In addition, both IL6 and LIF increased the percentage of ALDH+ ovarian cancer stem-like cells (CSC). Supporting redundancy of function by the two cytokines, CA-MSC induced STAT3 phosphorylation and increased cancer cell "stemness". This effect was not inhibited by LIF or IL6 blocking antibodies alone, but was prevented by dual IL6/LIF blockade or JAK2 inhibition. Similarly, small hairpin RNA (shRNA)-mediated reduction of IL6 or LIF in CA-MSC partially decreased but could not completely abrograte the ability of CA-MSC to induce STAT3 phosphorylation and stemness. Importantly, the in vivo pro-tumorigenic effect of CA-MSC is abrogated by dual blockade with the JAK2 inhibitor ruxolitinib to a much greater extent than treatment with anti-IL6 or anti-LIF antibody alone. Ruxolitinib treatment also improves survival in the immunocompetent ovarian cancer mouse model system with ID8 tumor cells plus MSC. Ruxolitinib-treated tumors in both the immunocompromised and immunocompetent animal models demonstrate decreased phospho-STAT3, indicating on-target activity. In conclusion, CA-MSC activate ovarian cancer cell STAT3 signaling via IL6 and LIF and increase tumor cell stemness. This functional redundancy suggests that therapeutic targeting of a single cytokine may be less effective than strategies such as dual inhibitor therapy or targeting shared downstream factors of the JAK/STAT pathway.


Assuntos
Interleucina-6/genética , Fator Inibidor de Leucemia/genética , Neoplasias Ovarianas/genética , Fator de Transcrição STAT3/genética , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Janus Quinase 2/antagonistas & inibidores , Camundongos , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Fosforilação , Ligação Proteica , Pirazóis/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
19.
J Exp Bot ; 70(3): 835-843, 2019 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-30395257

RESUMO

Potato tuber bud dormancy break followed by premature sprouting is a major commercial problem which results in quality losses and decreased tuber marketability. An approach to controlling premature tuber sprouting is to develop potato cultivars with a longer dormancy period and/or reduced rate of sprout growth. Our recent studies using a potato diploid population have identified several quantitative trait loci (QTLs) that are associated with tuber sprout growth. In the current study, we aim to characterize a candidate gene associated with one of the largest effect QTLs for rapid tuber sprout growth on potato chromosome 3. Underlying this QTL is a gene encoding a TERMINAL FLOWER 1/CENTRORADIALIS homologue (PGSC0003DMG400014322). Here, we use a transgenic approach to manipulate the expression level of the CEN family member in a potato tetraploid genotype (cv. Désirée). We demonstrate a clear effect of manipulation of StCEN expression, with decreased expression levels associated with an increased rate of sprout growth, and overexpressing lines showing a lower rate of sprout growth than controls. Associated with different levels of StCEN expression were different levels of abscisic acid and cytokinins, implying a role in controlling the levels of plant growth regulators in the apical meristem.


Assuntos
Genes de Plantas , Proteínas de Plantas/genética , Tubérculos/crescimento & desenvolvimento , Solanum tuberosum/genética , Família Multigênica , Proteínas de Plantas/metabolismo , Tubérculos/genética , Locos de Características Quantitativas , Solanum tuberosum/crescimento & desenvolvimento
20.
Neoplasia ; 20(12): 1209-1218, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30412857

RESUMO

DNA damage repair alterations play a critical role in ovarian cancer tumorigenesis. Mechanistic drivers of the DNA damage response consequently present opportunities for therapeutic targeting. The chromatin-binding DEK oncoprotein functions in DNA double-strand break repair. We therefore sought to determine the role of DEK in epithelial ovarian cancer. DEK is overexpressed in both primary epithelial ovarian cancers and ovarian cancer cell lines. To assess the impact of DEK expression levels on cell growth, small interfering RNA and short hairpin RNA approaches were utilized. Decreasing DEK expression in ovarian cancer cell lines slows cell growth and induces apoptosis and DNA damage. The biologic effects of DEK depletion are enhanced with concurrent chemotherapy treatment. The in vitro effects of DEK knockdown are reproduced in vivo, as DEK depletion in a mouse xenograft model results in slower tumor growth and smaller tumors compared to tumors expressing DEK. These findings provide a compelling rationale to target the DEK oncoprotein and its pathways as a therapeutic strategy for treating epithelial ovarian cancer.


Assuntos
Proteínas Cromossômicas não Histona/metabolismo , Proteínas Oncogênicas/metabolismo , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , Animais , Apoptose/genética , Biomarcadores Tumorais , Linhagem Celular Tumoral , Proteínas Cromossômicas não Histona/genética , Quebras de DNA de Cadeia Dupla , Modelos Animais de Doenças , Feminino , Expressão Gênica , Humanos , Imuno-Histoquímica , Camundongos , Proteínas Oncogênicas/genética , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/mortalidade , Proteínas de Ligação a Poli-ADP-Ribose/genética , Ensaios Antitumorais Modelo de Xenoenxerto
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