The paper proposes an additive cascade model of volatility components defined over different time periods. This volatility cascade leads to a simple AR-type model in the realized volatility with the ...feature of considering different volatility components realized over different time horizons and thus termed Heterogeneous Autoregressive model of Realized Volatility (HAR-RV). In spite of the simplicity of its structure and the absence of true long-memory properties, simulation results show that the HAR-RV model successfully achieves the purpose of reproducing the main empirical features of financial returns (long memory, fat tails, and self-similarity) in a very tractable and parsimonious way. Moreover, empirical results show remarkably good forecasting performance.
Poly(ADP-ribose) polymerase (PARP) inhibitors represent a promising strategy toward the treatment of triple-negative breast cancer (TNBC), which is often associated to genomic instability and/or BRCA ...mutations. However, clinical outcome is controversial and no benefits have been demonstrated in wild type BRCA cancers, possibly due to poor drug bioavailability and low nuclear delivery. In the attempt to overcome these limitations, we have developed H-Ferritin nanoformulated olaparib (HOla) and assessed its anticancer efficacy on both BRCA-mutated and non-mutated TNBC cells. We exploited the natural tumor targeting of H-Ferritin, which is mediated by the transferrin receptor-1 (TfR1), and its physiological tropism toward cell nucleus. TNBC cell lines over-expressing TfR-1 were successfully recognized by H-Ferritin, displaying a fast internalization into the cells. HOla induced remarkable cytotoxic effect in cancer cells, exhibiting 1000-fold higher anticancer activity compared to free olaparib (Ola). Accordingly, HOla treatment enhanced PARP-1 cleavage, DNA double strand breaks and Ola delivery into the nuclear compartment. Our findings suggest that H-Ferritin nanoformulation strongly enhances cytotoxic efficacy of Ola as a stand-alone therapy in both BRCA-mutated and wild type TNBC cells, by promoting targeted nuclear delivery.
Breast cancer (BC) is the most common malignancy in women and the second leading cause of cancer-related death; chemoresistance is still a clinical challenge mainly because of the different molecular ...features of this kind of tumour. Doxorubicin (Doxo) is widely used despite its adverse effects and the common onset of resistance. Chaperone-Mediated Autophagy (CMA) has been identified as an important mechanism through which chemotherapeutics can exert their cytotoxic effects and, in this context, LAMP-2A, the key player of CMA, can be a useful biomarker.
A cohort of patients and breast cancer cells have been screened for Doxo effect and CMA activation by analysing the LAMP-2A level. Molecular silencing has been used to clarify CMA role in BC responsiveness to treatments. Low Doxo doses were combined with other drugs (TMZ or PX-478, a HIF-1α inhibitor) to evaluate their cytotoxic ability and their role in modulating CMA.
In this paper, we showed that CMA is an important mechanism mediating the responsiveness of breast cancer cell to different treatments (Doxo and TMZ, as suggested by triple negative cells that are TMZ-resistant and fails to activate CMA). The LAMP-2A expression level was specific for different cell lines and patient-derived tumour subtypes, and was also useful in discriminating patients for their survival rates. Moreover, molecular silencing or pharmacological blockage of HIF-1α activity reverted BC resistance to TMZ. The combination of low-dose Doxo with TMZ or PX-478 showed that the drug associations have synergistic behaviours.
Here, we demonstrated that CMA activity exerts a fundamental role in the responsiveness to different treatments, and LAMP-2A can be proposed as a reliable prognostic biomarker in breast cancer. In this context, HIF-1α, a potential target of CMA, can also be assessed as a valuable therapeutic target in BC in view of identifying new, more efficient and less toxic therapeutic drug combinations. Moreover, the possibility to combine Doxo with other drugs acting on different but coherent molecular targets could help overcome resistance and open the way to a decrease in the dose of the single drugs.
Scientifically assess impacts of sustainable investments Vörösmarty, C J; Osuna, V Rodríguez; Koehler, D A ...
Science (American Association for the Advancement of Science),
02/2018, Letnik:
359, Številka:
6375
Journal Article
Recenzirano
Metrics can inform investors wary of “green washing”
The practice of selecting and managing financial assets based on their social and environmental performance is undergoing rapid growth and ...fundamental change. Investors are increasingly pressed by asset owners to prove how one company's practices are materially more or less sustainable than those of another. Yet, the basic information that companies declare is hardly standardized and is difficult to verify, with unreliable assertions (
1
) that are widely criticized as “green washing.” Metrics are mainly restricted to documenting changes to internal business practices but offer limited guidance on whether a company's actions, products, and services promote human well-being or preserve environmental integrity in the external, real-world domain, fueling reluctance on the part of otherwise enthusiastic investors (
2
,
3
). It is here where science can play an important role. Our consortium of an asset owner, an asset manager, and two research universities is designing a next generation of traceable indicators to quantify external context and impact of investments and place these into a decision-making framework useful to investors. Tests of these science-based sustainability metrics are under way on a $2.1 billion portfolio of public equities invested on behalf of a large European pension fund.
We describe a novel method to achieve a universal, massive, and fully automated analysis of cell motility behaviours, starting from time-lapse microscopy images. The approach was inspired by the ...recent successes in application of machine learning for style recognition in paintings and artistic style transfer. The originality of the method relies i) on the generation of atlas from the collection of single-cell trajectories in order to visually encode the multiple descriptors of cell motility, and ii) on the application of pre-trained Deep Learning Convolutional Neural Network architecture in order to extract relevant features to be used for classification tasks from this visual atlas. Validation tests were conducted on two different cell motility scenarios: 1) a 3D biomimetic gels of immune cells, co-cultured with breast cancer cells in organ-on-chip devices, upon treatment with an immunotherapy drug; 2) Petri dishes of clustered prostate cancer cells, upon treatment with a chemotherapy drug. For each scenario, single-cell trajectories are very accurately classified according to the presence or not of the drugs. This original approach demonstrates the existence of universal features in cell motility (a so called "motility style") which are identified by the DL approach in the rationale of discovering the unknown message in cell trajectories.
Introduction The public health consequences of the legalization of marijuana, whether for medical or recreational purposes, are little understood. Despite this, numerous states are considering ...medical or recreational legalization. In the context of abrupt changes in marijuana policy in 2009 in Colorado, the authors sought to investigate corresponding changes in marijuana-related public health indicators. Methods This observational, ecologic study used an interrupted time-series analysis to identify changes in public health indicators potentially related to broad policy changes that occurred in 2009. This was records-based research from the state of Colorado and Denver metropolitan area. Data were collected to examine frequency and trends of marijuana-related outcomes in hospital discharges and poison center calls between time periods before and after 2009 and adjusted for population. Analyses were conducted in 2014. Results Hospital discharges coded as marijuana-dependent increased 1% per month (95% CI=0.8, 1.1, p <0.001) from 2007 to 2013. A change in trend was detected in poison center calls mentioning marijuana ( p <0.01). After 2009, poison center calls increased 0.8% per month (95% CI=0.2, 1.4, p <0.01). Poison center calls also increased 56% (95% CI=49%, 63%, p <0.001) in the period following the policy change. Further, there was one hospital discharge coded as dependent for every 3,159 (95% CI=2465, 3853, p <0.001) medical marijuana registrant applications. Conclusions The abrupt nature of these changes suggests public health effects related to broad policy changes associated with marijuana. This report may be used to assist in policy decisions regarding the short-term public health effects of marijuana legalization.
Introduction
Gene-environment interactions increase psychosis risk (Gayer-Anderson
et al
. Soc Psychiatry Psychiatr Epidemiol 2020; 55(5):645-657). However, identifying the genetic variants involved ...and how they interact with environmental risk factors underlying psychosis remains challenging.
Objectives
To investigate whether there are gene-environment interactions in the relationships of childhood trauma, lifetime cannabis use, and single nucleotide variants (SNVs) of dopamine D2 receptor (D2R:
DRD2
), N-methyl-d-aspartate receptor (NMDAR:
GRIN1
,
GRIN2A
and
GRIN2B
) and cannabinoid receptor type 1 (CB1R:
CNR1
) with psychosis.
Methods
In a population-based case-control study nested in an incident study (STREAM, Brazil) (Del-Ben
et al
. Br J of Psychiatry 2019; 215(6):726-729), part of the EU-GEI consortium (Gayer-Anderson
et al
. Soc Psychiatry Psychiatr Epidemiol 2020; 55(5):645-657), 143 first-episode psychosis patients and 286 community-based controls of both sexes aged between 16 and 64 years were included over a period of 3 years. Twenty-three SNVs of D2R (rs1799978, rs7131056, rs6275), NMDAR (
GRIN1
: rs4880213, rs11146020;
GRIN2A
: rs1420040, rs11866328;
GRIN2B
: rs890, rs2098469, rs7298664), and CB1R genes (
CNR1
: rs806380, rs806379, rs1049353, rs6454674, rs1535255, rs2023239, rs12720071, rs6928499, rs806374, rs7766029, rs806378, rs10485170, rs9450898), were genotyped from peripheral blood DNA using a custom Illumina HumanCoreExome-24 BeadChip. Environmental adversities were evaluated using the Cannabis Experience Questionnaire (Di Forti et al. The Lancet Psychiatry 2009; 6(5):427–436) and the Childhood Trauma Questionnaire (Grassi-Oliveira et al. Rev Saude Publica 2006; 40(2):249-55). Associations between SNVs and environmental risk factors were performed using the nonparametric multifactor dimensionality reduction software (version 3.0.2).
Results
Single locus analysis showed no association among the 23 SNVs with psychosis; however, gene-environment analysis was significant for the polymorphic loci rs12720071 and rs7766029 in
CNR1.
The best association models were the two-factor representing by the combination of
CNR1
rs12720071 with lifetime cannabis use (p<0.001), and
CNR1
rs12720071 with childhood trauma (p<0.05), both suggesting an increased risk of psychosis. Additionally, when considering the interaction of both environmental factors in the same model, we found
CNR1
rs7766029 to be associated with psychosis (p<0.001).
Conclusions
Our study supports the hypothesis of gene-environment interactions for psychosis involving the T allele carriers of
CNR1
SNVs (rs12720071 and rs7766029), childhood trauma and lifetime cannabis use in psychosis.
Disclosure of Interest
None Declared
In many states, budget constraints are prompting earlier release of prison inmates. Prior studies have demonstrated elevated mortality rates in the post-release period but little is known about the ...health experiences of former inmates in the transition from prison to the community. The objective of this study was to understand the health-seeking experiences, perceptions of risk, and medical and mental health needs of former prisoners in the first two months after release from prison. Participants consisted of 29 former inmates within the first two months after their release from prison to the Denver, Colorado area. Using qualitative methods, trained interviewers conducted individual, in-person, semi-structured interviews exploring participants' experiences with health, mental health, and health care since release. Interview transcripts were coded and analyzed utilizing a team-based approach to inductive analysis. We found that health-related behavior occurred in the context of a complex life experience, with logistical problems exacerbated by emotional distress. Major themes included 1) transitional challenges; 2) cognitive responses including perceptions about personal risk, knowledge and priorities; 3) emotional responses including pronounced stress, fear, anxiety, disappointment; and 4) health behaviors. Former inmates reported multiple challenges, poor transitional preparation preceding release, and inadequate or absent continuity of mental and physical health care in the context of significant emotional distress and anxiety. Improved release planning, coordination between the medical, mental health and criminal justice systems may reduce the risk of poor health outcomes for this population.
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