Glioblastoma (GBM) is the deadliest form of brain cancer, with a median survival of less than 2 years despite surgical resection, radiation, and chemotherapy. GBM's rapid progression, resistance to ...therapy, and inexorable recurrence have been attributed to several factors, including its rapid growth rate, its molecular heterogeneity, its propensity to infiltrate vital brain structures, the regenerative capacity of treatment-resistant cancer stem cells, and challenges in achieving high concentrations of chemotherapeutic agents in the central nervous system. Escape from immunosurveillance is increasingly recognized as a landmark event in cancer biology. Translation of this framework to clinical oncology has positioned immunotherapy as a pillar of cancer treatment. Amid the bourgeoning successes of cancer immunotherapy, GBM has emerged as a model of resistance to immunotherapy. Here we review the mechanisms of immunotherapy resistance in GBM and discuss how insights into GBM-immune system interactions might inform the next generation of immunotherapeutics for GBM and other resistant pathologies.
We introduce a method for learning pairwise interactions in a linear regression or logistic regression model in a manner that satisfies strong hierarchy: whenever an interaction is estimated to be ...nonzero, both its associated main effects are also included in the model. We motivate our approach by modeling pairwise interactions for categorical variables with arbitrary numbers of levels, and then show how we can accommodate continuous variables as well. Our approach allows us to dispense with explicitly applying constraints on the main effects and interactions for identifiability, which results in interpretable interaction models. We compare our method with existing approaches on both simulated and real data, including a genome-wide association study, all using our R package glinternet.
Summary Checkpoint blockade immunotherapy has received mainstream attention as a result of striking and durable clinical responses in some patients with metastatic disease and a reasonable response ...rate in many tumour types. The activity of checkpoint blockade immunotherapy is not restricted to melanoma or lung cancer, and additional indications are expected in the future, with responses already reported in renal cancer, bladder cancer, and Hodgkin's lymphoma among many others. Additionally, the interactions between radiation and the immune system have been investigated, with several studies describing the synergistic effects on local and distant tumour control when radiation therapy is combined with immunotherapy. Clinical enthusiasm for this approach is strengthened by the many ongoing trials combining immunotherapy with definitive and palliative radiation. Herein, we discuss the biological and mechanistic rationale behind combining radiation with checkpoint blockade immunotherapy, with a focus on the preclinical data supporting this potentially synergistic combination. We explore potential hypotheses and important considerations for clinical trial designs. Finally, we reintroduce the notion of radiosensitising immunotherapy, akin to radiosensitising chemotherapy, as a potential definitive therapeutic modality.
Predicted climate change-induced increases in heat waves and hypoxic events will have profound effects on fishes, yet the capacity of parents to alter offspring phenotype via non-genetic inheritance ...and buffer against these combined stressors is not clear. This study tested how prolonged adult zebrafish exposure to combined diel cycles of thermal stress and hypoxia affect offspring early survival and development, parental investment of cortisol and heat shock proteins (HSPs), larval offspring stress responses, and both parental and offspring heat and hypoxia tolerance. Parental exposure to the combined stressor did not affect fecundity, but increased mortality, produced smaller embryos and delayed hatching. The combined treatment also reduced maternal deposition of cortisol and increased embryo hsf1, hsp70a, HSP70, hsp90aa and HSP90 levels. In larvae, basal cortisol levels did not differ between treatments, but acute exposure to combined heat stress and hypoxia increased cortisol levels in control larvae with no effect on larvae from exposed parents. In contrast, whereas larval basal hsf1, hsp70a and hsp90aa levels differed between parental treatments, the combined acute stressor elicited similar transcriptional responses across treatments. Moreover, the combined acute stressor only induced a marked increase in HSP47 levels in the larvae derived from exposed parents. Finally, combined hypoxia and elevated temperatures increased both thermal and hypoxia tolerance in adults and conferred an increase in offspring thermal but not hypoxia tolerance. These results demonstrate that intergenerational acclimation to combined thermal stress and hypoxia elicit complex carryover effects on stress responsiveness and offspring tolerance with potential consequences for resilience.
Problem definition
: We develop a framework for studying the impact of voluntary ecolabels and mandatory environmental regulation on
green product development among competing firms.
...Academic/practical relevance
: We contribute to the academic literature on environmental
quality competition by explicitly accounting for the credibility of environmental claims made by firms, and by exploring the implications for society of two mechanisms
used to remedy credibility-related consumer discounting of firms’ self-declared environmental qualities. We draw parallels between our findings and instances of
environmental labeling and regulation from industry to highlight the practical implications of our study.
Methodology
: We use a
game-theoretic framework to analyze a consumer-driven model of green product development.
Results
: Credibility asymmetry drives product
differentiation between two competing firms. The less credible firm always adopts external certification, while the more credible firm does so only if its
credibility is sufficiently low. Credibility may also determine whether or not the government should intervene. In the absence of an external certifier, the regulator
should intervene by imposing a mandatory environmental standard that is decreasing in stringency as the credibility of the more credible firm increases. In the
presence of a certifier, the regulator should intervene if neither firm is sufficiently credible, or if consumers do not value environmental stewardship highly.
Managerial implications
:
We identify how and when government should (and should not) intervene to stimulate green product development when competing firms can use self-labels or external
certifications to communicate their environmental performance to consumers. We also determine the optimal strategies for the competing firms and external certifiers.
The maternal match hypothesis predicts that maternal exposure to a stressor may help prepare offspring to cope with the same disturbance in later life. Although there is support for this hypothesis, ...the signals involved in non-genetic inheritance are unclear. In this study, we tested how adult zebrafish exposure to diel cycles of thermal stress (27-36°C), hypoxia (20-85% dissolved oxygen) or the combined treatment affects maternal and embryonic levels of cortisol and heat shock proteins (HSPs). While parental exposure to the thermal, hypoxic or combined treatment for 2 weeks did not affect whole-body cortisol levels, the combined exposure increased ovarian cortisol levels by 4-fold and reduced embryonic cortisol content by 60%. The combined treatment also elicited 3- and 19-fold increases in embryo transcripts involved in cortisol breakdown (11bhsd2) and export (abcb4), respectively. The thermal stress and combined exposure also elicited marked increases in ovary and embryo hsp70a (20- to 45-fold) and HSP70 (3- to 7-fold), and smaller increases in ovary and embryo hsp90aa and hsp47 (2- to 4-fold) and in embryo HSP90 and HSP47 (2- to 6-fold). In contrast, except for increases in ovary hsp90aa (2-fold) and embryo HSP90 (3-fold), the hypoxia treatment had little effect on HSP expression and transfer. Overall, while the embryonic deposition of HSPs largely paralleled the ovarian cellular stress response, the inverse relationship between ovary and embryo cortisol levels suggests the existence of barriers against cortisol deposition in response to environmental stressors. We conclude that the endocrine and cellular stress responses make stressor-specific and distinct contributions to non-genetic inheritance.
The ongoing COVID-19 pandemic is disproportionately affecting patients with comorbidities. Therefore, thorough comorbidities assessment can help establish risk stratification of patients with ...COVID-19, upon hospital admission. Charlson Comorbidity Index (CCI) is a validated, simple, and readily applicable method of estimating the risk of death from comorbid disease and has been widely used as a predictor of long-term prognosis and survival.
We performed a systematic review and meta-analysis of CCI score and a composite of poor outcomes through several databases.
Compared to a CCI score of 0, a CCI score of 1–2 and CCI score of ≥3 was prognostically associated with mortality and associated with a composite of poor outcomes. Per point increase of CCI score also increased mortality risk by 16%. Moreover, a higher mean CCI score also significantly associated with mortality and disease severity.
CCI score should be utilized for risk stratifications of hospitalized COVID-19 patients.
•The ongoing COVID-19 pandemic is disproportionately affecting patients with comorbidities.•Charlson Comorbidity Index (CCI) has been widely used as a predictor of long-term prognosis and survival.•Higher and per point increase of CCI Score is associated with poor outcomes.•CCI score should be utilized for risk stratifications of hospitalized COVID-19 patients.
Key to the mass adoption of electric vehicles (EVs) is the establishment of successful business models based on sound understanding of consumer behavior in adopting this new technology. In this ...paper, we study the impact of two major barriers to mass adoption of EVs: (i) range anxiety, the concern that the driving range of EVs may be insufficient to meet the driving needs, and (ii) resale anxiety, the concern that used values of EVs may deteriorate quickly. Using a stylized model calibrated to a data set based on the San Francisco Bay Area, we show that although both types of consumer anxieties typically harm the firm’s profit, they often improve consumer surplus. In addition, we show that a business model that requires consumers to lease the EV batteries (rather than purchase them) may lead to a greater level of adoption and emission savings when the level of resale anxiety is high. Further, a business model that offers EV range improvement through enhanced charging infrastructure typically yields greater adoption and consumer surplus, but lowers the firm’s profit, compared with one that offers enlarged batteries. Overall, we find that the combinations of battery owning/leasing with enhanced charging service, referred to as the (O, E) and (L, E) models in our paper, typically yield the best balance among the objectives of EV adoption, emission savings, profitability, and consumer surplus, when the degree of resale anxiety is low and high, respectively.
Atrial fibrillation (AF), with its significant associated morbidity and mortality contributes to significant healthcare utilisation and expenditure. Given its progressively rising incidence, ...strategies to limit AF development and progression are urgently needed. Lifestyle modification is a potentially potent but underutilised weapon against the AF epidemic. The purpose of this article is to review the role of lifestyle factors as risk factors for AF, outline potential mechanisms of pathogenesis and examine the available evidence for lifestyle intervention in primary and secondary AF prevention. It will also highlight the need for investment by physicians, researchers, health services and governments in order to facilitate delivery of the comprehensive, multidisciplinary AF care that is required to manage this complex and multifactorial disease.
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•Lifestyle modification is key to reducing AF incidence, burden and progression.•Targets include weight loss, exercise, alcohol abstinence and smoking cessation.•Collaboration at every level of healthcare is needed to improve AF care delivery.
Glioblastoma is the most common primary brain tumour in adults. Prognosis is poor: even with the current gold-standard first-line treatment—maximal safe resection and combination of radiotherapy with ...temozolomide chemotherapy—the median overall survival time is only approximately 15-17 months, because the tumour recurs in virtually all patients, and no commonly accepted standard treatment for recurrent disease exists. Several targeted agents have failed to improve patient outcomes in glioblastoma. Immunotherapy with immune checkpoint inhibitors such as ipilimumab, nivolumab, and pembrolizumab has provided relevant clinical improvements in other advanced tumours for which conventional therapies have had limited success, making immunotherapy an appealing strategy in glioblastoma. This Review summarizes current knowledge on immune checkpoint modulators and evaluates their potential role in glioblastoma on the basis of preclinical studies and emerging clinical data. Furthermore, we discuss challenges that need to be considered in the clinical development of drugs that target immune checkpoint pathways in glioblastoma, such as specific properties of the immune system in the CNS, issues with radiological response assessment, and potential interactions with established and emerging treatment strategies.
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