118 research outputs found
Inhibition of the JAK2/STAT3 pathway in ovarian cancer results in the loss of cancer stem cell-like characteristics and a reduced tumor burden
Background Current treatment of ovarian cancer patients with chemotherapy leaves behind a residual tumor which results in recurrent ovarian cancer within a short time frame. We have previously demonstrated that a single short-term treatment of ovarian cancer cells with chemotherapy in vitro resulted in a cancer stem cell (CSC)-like enriched residual population which generated significantly greater tumor burden compared to the tumor burden generated by control untreated cells. In this report we looked at the mechanisms of the enrichment of CSC-like residual cells in response to paclitaxel treatment. Methods The mechanism of survival of paclitaxel-treated residual cells at a growth inhibitory concentration of 50% (GI50) was determined on isolated tumor cells from the ascites of recurrent ovarian cancer patients and HEY ovarian cancer cell line by in vitro assays and in a mouse xenograft model. Results Treatment of isolated tumor cells from the ascites of ovarian cancer patients and HEY ovarian cancer cell line with paclitaxel resulted in a CSC-like residual population which coincided with the activation of Janus activated kinase 2 (JAK2) and signal transducer and activation of transcription 3 (STAT3) pathway in paclitaxel surviving cells. Both paclitaxel-induced JAK2/STAT3 activation and CSC-like characteristics were inhibited by a low dose JAK2-specific small molecule inhibitor CYT387 (1 μM) in vitro. Subsequent, in vivo transplantation of paclitaxel and CYT387-treated HEY cells in mice resulted in a significantly reduced tumor burden compared to that seen with paclitaxel only-treated transplanted cells. In vitro analysis of tumor xenografts at protein and mRNA levels demonstrated a loss of CSC-like markers and CA125 expression in paclitaxel and CYT387-treated cell-derived xenografts, compared to paclitaxel only-treated cell-derived xenografts. These results were consistent with significantly reduced activation of JAK2 and STAT3 in paclitaxel and CYT387-treated cell-derived xenografts compared to paclitaxel only-treated cell derived xenografts. Conclusions This proof of principle study demonstrates that inhibition of the JAK2/STAT3 pathway by the addition of CYT387 suppresses the ‘stemness’ profile in chemotherapy-treated residual cells in vitro, which is replicated in vivo, leading to a reduced tumor burden. These findings have important implications for ovarian cancer patients who are treated with taxane and/or platinum-based therapies. Keywords: Ovarian carcinoma, Cancer stem cell, Metastasis, Ascites, Chemoresistance, Recurrence, JAK2/STAT3 pathwa
Conidiation Color Mutants of Aspergillus fumigatus Are Highly Pathogenic to the Heterologous Insect Host Galleria mellonella
The greater wax moth Galleria mellonella has been widely used as
a heterologous host for a number of fungal pathogens including Candida
albicans and Cryptococcus neoformans. A positive
correlation in pathogenicity of these yeasts in this insect model and animal
models has been observed. However, very few studies have evaluated the
possibility of applying this heterologous insect model to investigate virulence
traits of the filamentous fungal pathogen Aspergillus
fumigatus, the leading cause of invasive aspergillosis. Here, we have
examined the impact of mutations in genes involved in melanin biosynthesis on
the pathogenicity of A. fumigatus in the G.
mellonella model. Melanization in A. fumigatus confers
bluish-grey color to conidia and is a known virulence factor in mammal models.
Surprisingly, conidial color mutants in B5233 background that have deletions in
the defined six-gene cluster required for DHN-melanin biosynthesis caused
enhanced insect mortality compared to the parent strain. To further examine and
confirm the relationship between melanization defects and enhanced virulence in
the wax moth model, we performed random insertional mutagenesis in the Af293
genetic background to isolate mutants producing altered conidia colors. Strains
producing conidia of previously identified colors and of novel colors were
isolated. Interestingly, these color mutants displayed a higher level of
pathogenicity in the insect model compared to the wild type. Although some of
the more virulent color mutants showed increased resistance to hydrogen
peroxide, overall phenotypic characterizations including secondary metabolite
production, metalloproteinase activity, and germination rate did not reveal a
general mechanism accountable for the enhanced virulence of these color mutants
observed in the insect model. Our observations indicate instead, that
exacerbated immune response of the wax moth induced by increased exposure of
PAMPs (pathogen-associated molecular patterns) may cause self-damage that
results in increased mortality of larvae infected with the color mutants. The
current study underscores the limitations of using this insect model for
inferring the pathogenic potential of A. fumigatus strains in
mammals, but also points to the importance of understanding the innate immunity
of the insect host in providing insights into the pathogenicity level of
different fungal strains in this model. Additionally, our observations that
melanization defective color mutants demonstrate increased virulence in the
insect wax moth, suggest the potential of using melanization defective mutants
of native insect fungal pathogens in the biological control of insect
populations
Mapping geographical inequalities in childhood diarrhoeal morbidity and mortality in low-income and middle-income countries, 2000–17: analysis for the Global Burden of Disease Study 2017
© 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license Background: Across low-income and middle-income countries (LMICs), one in ten deaths in children younger than 5 years is attributable to diarrhoea. The substantial between-country variation in both diarrhoea incidence and mortality is attributable to interventions that protect children, prevent infection, and treat disease. Identifying subnational regions with the highest burden and mapping associated risk factors can aid in reducing preventable childhood diarrhoea. Methods: We used Bayesian model-based geostatistics and a geolocated dataset comprising 15 072 746 children younger than 5 years from 466 surveys in 94 LMICs, in combination with findings of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017, to estimate posterior distributions of diarrhoea prevalence, incidence, and mortality from 2000 to 2017. From these data, we estimated the burden of diarrhoea at varying subnational levels (termed units) by spatially aggregating draws, and we investigated the drivers of subnational patterns by creating aggregated risk factor estimates. Findings: The greatest declines in diarrhoeal mortality were seen in south and southeast Asia and South America, where 54·0% (95% uncertainty interval [UI] 38·1–65·8), 17·4% (7·7–28·4), and 59·5% (34·2–86·9) of units, respectively, recorded decreases in deaths from diarrhoea greater than 10%. Although children in much of Africa remain at high risk of death due to diarrhoea, regions with the most deaths were outside Africa, with the highest mortality units located in Pakistan. Indonesia showed the greatest within-country geographical inequality; some regions had mortality rates nearly four times the average country rate. Reductions in mortality were correlated to improvements in water, sanitation, and hygiene (WASH) or reductions in child growth failure (CGF). Similarly, most high-risk areas had poor WASH, high CGF, or low oral rehydration therapy coverage. Interpretation: By co-analysing geospatial trends in diarrhoeal burden and its key risk factors, we could assess candidate drivers of subnational death reduction. Further, by doing a counterfactual analysis of the remaining disease burden using key risk factors, we identified potential intervention strategies for vulnerable populations. In view of the demands for limited resources in LMICs, accurately quantifying the burden of diarrhoea and its drivers is important for precision public health. Funding: Bill & Melinda Gates Foundation
Targeting cancer metabolism: a therapeutic window opens
Genetic events in cancer activate signalling pathways that alter cell metabolism. Clinical evidence has linked cell metabolism with cancer outcomes. Together, these observations have raised interest in targeting metabolic enzymes for cancer therapy, but they have also raised concerns that these therapies would have unacceptable effects on normal cells. However, some of the first cancer therapies that were developed target the specific metabolic needs of cancer cells and remain effective agents in the clinic today. Research into how changes in cell metabolism promote tumour growth has accelerated in recent years. This has refocused efforts to target metabolic dependencies of cancer cells as a selective anticancer strategy.Burroughs Wellcome FundSmith Family FoundationStarr Cancer ConsortiumDamon Runyon Cancer Research FoundationNational Institutes of Health (U.S.
Past, present, and future of global health financing : a review of development assistance, government, out-of-pocket, and other private spending on health for 195 countries, 1995-2050
Background Comprehensive and comparable estimates of health spending in each country are a key input for health policy and planning, and are necessary to support the achievement of national and international health goals. Previous studies have tracked past and projected future health spending until 2040 and shown that, with economic development, countries tend to spend more on health per capita, with a decreasing share of spending from development assistance and out-of-pocket sources. We aimed to characterise the past, present, and predicted future of global health spending, with an emphasis on equity in spending across countries. Methods We estimated domestic health spending for 195 countries and territories from 1995 to 2016, split into three categories-government, out-of-pocket, and prepaid private health spending-and estimated development assistance for health (DAH) from 1990 to 2018. We estimated future scenarios of health spending using an ensemble of linear mixed-effects models with time series specifications to project domestic health spending from 2017 through 2050 and DAH from 2019 through 2050. Data were extracted from a broad set of sources tracking health spending and revenue, and were standardised and converted to inflation-adjusted 2018 US dollars. Incomplete or low-quality data were modelled and uncertainty was estimated, leading to a complete data series of total, government, prepaid private, and out-of-pocket health spending, and DAH. Estimates are reported in 2018 US dollars, 2018 purchasing-power parity-adjusted dollars, and as a percentage of gross domestic product. We used demographic decomposition methods to assess a set of factors associated with changes in government health spending between 1995 and 2016 and to examine evidence to support the theory of the health financing transition. We projected two alternative future scenarios based on higher government health spending to assess the potential ability of governments to generate more resources for health. Findings Between 1995 and 2016, health spending grew at a rate of 4.00% (95% uncertainty interval 3.89-4.12) annually, although it grew slower in per capita terms (2.72% [2.61-2.84]) and increased by less than 8.0 trillion (7.8-8.1) in 2016 (comprising 8.6% [8.4-8.7] of the global economy and 5252 (5184-5319) in high-income countries, 81 (74-89) in lower-middle-income countries, and 9.5 billion, 24.3% of total DAH), although spending on other infectious diseases (excluding tuberculosis and malaria) grew fastest from 2010 to 2018 (6.27% per year). The leading sources of DAH were the USA and private philanthropy (excluding corporate donations and the Bill & Melinda Gates Foundation). For the first time, we included estimates of China's contribution to DAH ( 15.0 trillion (14.0-16.0) by 2050 (reaching 9.4% [7.6-11.3] of the global economy and $ 21.3 trillion [19.8-23.1] in purchasing-power parity-adjusted dollars), but at a lower growth rate of 1.84% (1.68-2.02) annually, and with continuing disparities in spending between countries. In 2050, we estimate that 0.6% (0.6-0.7) of health spending will occur in currently low-income countries, despite these countries comprising an estimated 15.7% of the global population by 2050. The ratio between per capita health spending in high-income and low-income countries was 130.2 (122.9-136.9) in 2016 and is projected to remain at similar levels in 2050 (125.9 [113.7-138.1]). The decomposition analysis identified governments' increased prioritisation of the health sector and economic development as the strongest factors associated with increases in government health spending globally. Future government health spending scenarios suggest that, with greater prioritisation of the health sector and increased government spending, health spending per capita could more than double, with greater impacts in countries that currently have the lowest levels of government health spending. Interpretation Financing for global health has increased steadily over the past two decades and is projected to continue increasing in the future, although at a slower pace of growth and with persistent disparities in per-capita health spending between countries. Out-of-pocket spending is projected to remain substantial outside of high-income countries. Many low-income countries are expected to remain dependent on development assistance, although with greater government spending, larger investments in health are feasible. In the absence of sustained new investments in health, increasing efficiency in health spending is essential to meet global health targets.Peer reviewe
Past, present, and future of global health financing: a review of development assistance, government, out-of-pocket, and other private spending on health for 195 countries, 1995–2050
Background: Comprehensive and comparable estimates of health spending in each country are a key input for health
policy and planning, and are necessary to support the achievement of national and international health goals. Previous
studies have tracked past and projected future health spending until 2040 and shown that, with economic development,
countries tend to spend more on health per capita, with a decreasing share of spending from development assistance
and out-of-pocket sources. We aimed to characterise the past, present, and predicted future of global health spending,
with an emphasis on equity in spending across countries.
Methods: We estimated domestic health spending for 195 countries and territories from 1995 to 2016, split into three
categories—government, out-of-pocket, and prepaid private health spending—and estimated development assistance
for health (DAH) from 1990 to 2018. We estimated future scenarios of health spending using an ensemble of linear
mixed-effects models with time series specifications to project domestic health spending from 2017 through 2050
and DAH from 2019 through 2050. Data were extracted from a broad set of sources tracking health spending and
revenue, and were standardised and converted to inflation-adjusted 2018 US dollars. Incomplete or low-quality data
were modelled and uncertainty was estimated, leading to a complete data series of total, government, prepaid private,
and out-of-pocket health spending, and DAH. Estimates are reported in 2018 US dollars, 2018 purchasing-power
parity-adjusted dollars, and as a percentage of gross domestic product. We used demographic decomposition
methods to assess a set of factors associated with changes in government health spending between 1995 and 2016
and to examine evidence to support the theory of the health financing transition. We projected two alternative future
scenarios based on higher government health spending to assess the potential ability of governments to generate
more resources for health.
Findings: Between 1995 and 2016, health spending grew at a rate of 4·00% (95% uncertainty interval 3·89–4·12)
annually, although it grew slower in per capita terms (2·72% [2·61–2·84]) and increased by less than 8·0 trillion (7·8–8·1) in 2016 (comprising 8·6% [8·4–8·7] of the global economy and 5252 (5184–5319) in high-income
countries, 81 (74–89) in lower-middle-income countries, and
9·5 billion, 24·3% of total DAH), although spending on other infectious diseases
(excluding tuberculosis and malaria) grew fastest from 2010 to 2018 (6·27% per year). The leading sources of DAH
were the USA and private philanthropy (excluding corporate donations and the Bill & Melinda Gates Foundation).
For the first time, we included estimates of China’s contribution to DAH (15·0 trillion (14·0–16·0) by 2050 (reaching 9·4% [7·6–11·3] of the global
economy and $21·3 trillion [19·8–23·1] in purchasing-power parity-adjusted dollars), but at a lower growth rate of
1·84% (1·68–2·02) annually, and with continuing disparities in spending between countries. In 2050, we estimate
that 0·6% (0·6–0·7) of health spending will occur in currently low-income countries, despite these countries
comprising an estimated 15·7% of the global population by 2050. The ratio between per capita health spending in
high-income and low-income countries was 130·2 (122·9–136·9) in 2016 and is projected to remain at similar levels
in 2050 (125·9 [113·7–138·1]). The decomposition analysis identified governments’ increased prioritisation of the
health sector and economic development as the strongest factors associated with increases in government health
spending globally. Future government health spending scenarios suggest that, with greater prioritisation of the
health sector and increased government spending, health spending per capita could more than double, with greater
impacts in countries that currently have the lowest levels of government health spending
Interpretation: Financing for global health has increased steadily over the past two decades and is projected to continue
increasing in the future, although at a slower pace of growth and with persistent disparities in per-capita health
spending between countries. Out-of-pocket spending is projected to remain substantial outside of high-income
countries. Many low-income countries are expected to remain dependent on development assistance, although with
greater government spending, larger investments in health are feasible. In the absence of sustained new investments
in health, increasing efficiency in health spending is essential to meet global health targets.
Funding: Bill & Melinda Gates Foundatio
Global, regional, and national burden of neurological disorders during 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015
Background
Comparable data on the global and country-specific burden of neurological disorders and their trends are crucial for health-care planning and resource allocation. The Global Burden of Diseases, Injuries, and Risk Factors (GBD) Study provides such information but does not routinely aggregate results that are of interest to clinicians specialising in neurological conditions. In this systematic analysis, we quantified the global disease burden due to neurological disorders in 2015 and its relationship with country development level.
Methods
We estimated global and country-specific prevalence, mortality, disability-adjusted life-years (DALYs), years of life lost (YLLs), and years lived with disability (YLDs) for various neurological disorders that in the GBD classification have been previously spread across multiple disease groupings. The more inclusive grouping of neurological disorders included stroke, meningitis, encephalitis, tetanus, Alzheimer's disease and other dementias, Parkinson's disease, epilepsy, multiple sclerosis, motor neuron disease, migraine, tension-type headache, medication overuse headache, brain and nervous system cancers, and a residual category of other neurological disorders. We also analysed results based on the Socio-demographic Index (SDI), a compound measure of income per capita, education, and fertility, to identify patterns associated with development and how countries fare against expected outcomes relative to their level of development.
Findings
Neurological disorders ranked as the leading cause group of DALYs in 2015 (250·7 [95% uncertainty interval (UI) 229·1 to 274·7] million, comprising 10·2% of global DALYs) and the second-leading cause group of deaths (9·4 [9·1 to 9·7] million], comprising 16·8% of global deaths). The most prevalent neurological disorders were tension-type headache (1505·9 [UI 1337·3 to 1681·6 million cases]), migraine (958·8 [872·1 to 1055·6] million), medication overuse headache (58·5 [50·8 to 67·4 million]), and Alzheimer's disease and other dementias (46·0 [40·2 to 52·7 million]). Between 1990 and 2015, the number of deaths from neurological disorders increased by 36·7%, and the number of DALYs by 7·4%. These increases occurred despite decreases in age-standardised rates of death and DALYs of 26·1% and 29·7%, respectively; stroke and communicable neurological disorders were responsible for most of these decreases. Communicable neurological disorders were the largest cause of DALYs in countries with low SDI. Stroke rates were highest at middle levels of SDI and lowest at the highest SDI. Most of the changes in DALY rates of neurological disorders with development were driven by changes in YLLs.
Interpretation
Neurological disorders are an important cause of disability and death worldwide. Globally, the burden of neurological disorders has increased substantially over the past 25 years because of expanding population numbers and ageing, despite substantial decreases in mortality rates from stroke and communicable neurological disorders. The number of patients who will need care by clinicians with expertise in neurological conditions will continue to grow in coming decades. Policy makers and health-care providers should be aware of these trends to provide adequate services
Health sector spending and spending on HIV/AIDS, tuberculosis, and malaria, and development assistance for health: progress towards Sustainable Development Goal 3
Background: Sustainable Development Goal (SDG) 3 aims to “ensure healthy lives and promote well-being for all at all
ages”. While a substantial effort has been made to quantify progress towards SDG3, less research has focused on
tracking spending towards this goal. We used spending estimates to measure progress in financing the priority areas
of SDG3, examine the association between outcomes and financing, and identify where resource gains are most
needed to achieve the SDG3 indicators for which data are available.
Methods: We estimated domestic health spending, disaggregated by source (government, out-of-pocket, and prepaid
private) from 1995 to 2017 for 195 countries and territories. For disease-specific health spending, we estimated
spending for HIV/AIDS and tuberculosis for 135 low-income and middle-income countries, and malaria in
106 malaria-endemic countries, from 2000 to 2017. We also estimated development assistance for health (DAH) from
1990 to 2019, by source, disbursing development agency, recipient, and health focus area, including DAH for
pandemic preparedness. Finally, we estimated future health spending for 195 countries and territories from 2018 until
2030. We report all spending estimates in inflation-adjusted 2019 US7·9 trillion (95% uncertainty interval 7·8–8·0) in 2017 and is expected to increase to 20·2 billion
(17·0–25·0) and on tuberculosis it was 5·1 billion (4·9–5·4). Development assistance for health was 374 million of DAH was provided
for pandemic preparedness, less than 1% of DAH. Although spending has increased across HIV/AIDS, tuberculosis,
and malaria since 2015, spending has not increased in all countries, and outcomes in terms of prevalence, incidence,
and per-capita spending have been mixed. The proportion of health spending from pooled sources is expected to
increase from 81·6% (81·6–81·7) in 2015 to 83·1% (82·8–83·3) in 2030.
Interpretation: Health spending on SDG3 priority areas has increased, but not in all countries, and progress towards
meeting the SDG3 targets has been mixed and has varied by country and by target. The evidence on the scale-up of
spending and improvements in health outcomes suggest a nuanced relationship, such that increases in spending do
not always results in improvements in outcomes. Although countries will probably need more resources to achieve
SDG3, other constraints in the broader health system such as inefficient allocation of resources across interventions
and populations, weak governance systems, human resource shortages, and drug shortages, will also need to be
addressed.
Funding: The Bill & Melinda Gates Foundatio
Emerging concepts in biomarker discovery; The US-Japan workshop on immunological molecular markers in oncology
Supported by the Office of International Affairs, National Cancer Institute (NCI), the "US-Japan Workshop on Immunological Biomarkers in Oncology" was held in March 2009. The workshop was related to a task force launched by the International Society for the Biological Therapy of Cancer (iSBTc) and the United States Food and Drug Administration (FDA) to identify strategies for biomarker discovery and validation in the field of biotherapy. The effort will culminate on October 28th 2009 in the "iSBTc-FDA-NCI Workshop on Prognostic and Predictive Immunologic Biomarkers in Cancer", which will be held in Washington DC in association with the Annual Meeting. The purposes of the US-Japan workshop were a) to discuss novel approaches to enhance the discovery of predictive and/or prognostic markers in cancer immunotherapy; b) to define the state of the science in biomarker discovery and validation. The participation of Japanese and US scientists provided the opportunity to identify shared or discordant themes across the distinct immune genetic background and the diverse prevalence of disease between the two Nations
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