The future of immune checkpoint therapy Sharma, Padmanee; Allison, James P.
Science (American Association for the Advancement of Science),
04/2015, Letnik:
348, Številka:
6230
Journal Article
Recenzirano
Immune checkpoint therapy, which targets regulatory pathways in T cells to enhance antitumor immune responses, has led to important clinical advances and provided a new weapon against cancer. This ...therapy has elicited durable clinical responses and, in a fraction of patients, long-term remissions where patients exhibit no clinical signs of cancer for many years. The way forward for this class of novel agents lies in our ability to understand human immune responses in the tumor microenvironment. This will provide valuable information regarding the dynamic nature of the immune response and regulation of additional pathways that will need to be targeted through combination therapies to provide survival benefit for greater numbers of patients.
Research in two fronts has enabled the development of therapies that provide significant benefit to cancer patients. One area stems from a detailed knowledge of mutations that activate or inactivate ...signaling pathways that drive cancer development. This work triggered the development of targeted therapies that lead to clinical responses in the majority of patients bearing the targeted mutation, although responses are often of limited duration. In the second front are the advances in molecular immunology that unveiled the complexity of the mechanisms regulating cellular immune responses. These developments led to the successful targeting of immune checkpoints to unleash anti-tumor T cell responses, resulting in durable long-lasting responses but only in a fraction of patients. In this Review, we discuss the evolution of research in these two areas and propose that intercrossing them and increasing funding to guide research of combination of agents represent a path forward for the development of curative therapies for the majority of cancer patients.
Pam Sharma and Jim Allison present a comprehensive Review of the basic and clinical research that has established immunotherapy as one of the chief breakthroughs in medicine in the last decade, and they discuss what the next steps will be in order to develop curative therapies for the majority of patients with cancer.
The extracellular matrix is perturbed in tumors. The tumor matrix promotes the growth, survival, and invasion of the cancer and modifies fibroblast and immune cell behavior to drive metastasis and ...impair treatment. Here, we discuss how the tumor matrix regulates metastasis by fostering tumor cell invasion into the stroma and migration toward the vasculature. We describe the role of the tumor matrix in cancer cell intravasation and vascular dissemination. We examine the impact of the matrix on disseminated tumor cell extravasation and on tumor dormancy and metastatic outgrowth. Finally, we discuss the clinical outcome of therapeutics that normalize tumor-matrix interactions.
The extracellular matrix is perturbed in tumors. Kai et al. present a Review discussing the tumor extracellular matrix and its effect on tumor cell invasion into the stroma and vascular dissemination.
Immune checkpoint blockade is able to induce durable responses across multiple types of cancer, which has enabled the oncology community to begin to envision potentially curative therapeutic ...approaches. However, the remarkable responses to immunotherapies are currently limited to a minority of patients and indications, highlighting the need for more effective and novel approaches. Indeed, an extraordinary amount of preclinical and clinical investigation is exploring the therapeutic potential of negative and positive costimulatory molecules. Insights into the underlying biological mechanisms and functions of these molecules have, however, lagged significantly behind. Such understanding will be essential for the rational design of next-generation immunotherapies. Here, we review the current state of our understanding of T-cell costimulatory mechanisms and checkpoint blockade, primarily of CTLA4 and PD-1, and highlight conceptual gaps in knowledge.
This review provides an overview of immune checkpoint blockade therapy from a basic biology and immunologic perspective for the cancer research community.
How does racial diversity impact institutional outcomes and (in)equality? Discussions about diversity usually focus on how individuals’ identities shape their behavior, but diversity is a group-level ...characteristic. Scholars must, therefore, consider the relationship between group composition and the individual decisions that shape institutional outcomes. Using felony data from a large U.S. court system, I explore the relationship between racial diversity among the judges comprising a court and individual judges’ decisions. I find that as the percent of Black judges in a courthouse increases white judges are less likely to render incarceration sentences in cases with Black defendants. Increases in racial diversity decrease the Black–white gap in the probability of incarceration by up to 7 percentage points. However, I find no relationship between judge’s racial identities and disparities in their decisions. This study highlights the importance of conceptualizing diversity as a group characteristic and the relationship between institutional context and outcomes.
Wearable health-monitoring systems should be comfortable, non-stigmatizing, and able to achieve high data quality. Smart textiles with electronic elements integrated directly into fabrics offer a way ...to embed sensors into clothing seamlessly to serve these purposes. In this work, we demonstrate the feasibility of electrocardiogram (ECG) monitoring with sewn textile electrodes instead of traditional gel electrodes in a 3-lead, chest-mounted configuration. The textile electrodes are sewn with silver-coated thread in an overlapping zig zag pattern into an inextensible fabric. Sensor validation included ECG monitoring and comfort surveys with human subjects, stretch testing, and wash cycling. The electrodes were tested with the BIOPAC MP160 ECG data acquisition module. Sensors were placed on 8 subjects (5 males and 3 females) with double-sided tape. To detect differences in R peak detectability between traditional and sewn sensors, effect size was set at 10% of a sample mean for heart rate (HR) and R-R interval. Paired student's t-tests were run between adhesive and sewn electrode data for R-R interval and average HR, and a Wilcoxon signed-rank test was run for comfort. No statistically significant difference was found between the traditional and textile electrodes (R-R interval: t = 1.43,
> 0.1; HR: t = - 0.70,
> 0.5; comfort: V = 15,
> 0.5).
Toward a Shared Vision for Cancer Genomic Data Grossman, Robert L; Heath, Allison P; Ferretti, Vincent ...
The New England journal of medicine,
09/2016, Letnik:
375, Številka:
12
Journal Article
Recenzirano
Odprti dostop
The Genomic Data Commons will initially house raw genomic data and diagnostic, histologic, and clinical outcome data from National Cancer Institute–funded projects. A harmonization process will align ...sequencing data to the genome and identify mutations and alterations.
For the past 2 years, the National Cancer Institute (NCI), the University of Chicago, the Ontario Institute for Cancer Research, and Leidos Biomedical Research have been developing an information system called the NCI Genomic Data Commons (GDC) (see figure). The GDC will initially contain raw genomic data as well as diagnostic, histologic, and clinical outcome data from NCI-funded projects such as the Cancer Genome Atlas (TCGA) and the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) program. Unlike previous versions of these data sets, the genomic data will be “harmonized” using uniform analytic pipelines to align the raw sequencing data . . .
Bias and Judging Harris, Allison P; Sen, Maya
Annual review of political science,
05/2019, Letnik:
22, Številka:
1
Journal Article
Recenzirano
Odprti dostop
How do we know whether judges of different backgrounds are biased? We review the substantial political science literature on judicial decision making, paying close attention to how judges' ...demographics and ideology can influence or structure their decision making. As the research demonstrates, characteristics such as race, ethnicity, and gender can sometimes predict judicial decision making in limited kinds of cases; however, the literature also suggests that these characteristics are far less important in shaping or predicting outcomes than is ideology (or partisanship), which in turn correlates closely with gender, race, and ethnicity. This leads us to conclude that assuming judges of different backgrounds are biased because they rule differently is questionable. Given that the application of the law rarely provides one objectively correct answer, it is no surprise that judges' decisions vary according to their personal backgrounds and, more importantly, according to their ideology.
We investigated changes in traffic-related air pollutant concentrations in an urban area during the COVID-19 pandemic. The study was conducted in a mixed commercial-residential neighborhood in ...Somerville (MA, USA), where traffic is the dominant source of air pollution. Measurements were made between March 27 and May 14, 2020, coinciding with a dramatic reduction in traffic (71% drop in car and 46% drop in truck traffic) due to business shutdowns and a statewide stay-at-home advisory. Indicators of fresh vehicular emissions (ultrafine particle number concentration PNC and black carbon BC) were measured with a mobile monitoring platform on an interstate highway and major and minor roadways. Our results show that depending on road class, median PNC and BC contributions from traffic were 60–68% and 22–46% lower, respectively, during the lockdown compared to pre-pandemic conditions, and corresponding reductions in total on-road concentrations were 45-69% and 22-56%, respectively. A higher BC: PNC concentration ratio was observed during the lockdown period likely indicative of the higher fraction of diesel vehicles in the fleet during the lockdown. Overall, the scale of reductions in ultrafine particle and BC concentrations was commensurate with the reductions in traffic. This natural experiment allowed us to quantify the direct impacts of reductions in traffic emissions on neighborhood-scale air quality, which are not captured by the regional regulatory-monitoring network. These results underscore the importance of measurements of appropriate proxies for traffic emissions at relevant spatial scales. Our results are useful for exposure analysis as well as city and regional planners evaluating mitigation strategies for traffic-related air pollution.
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•Traffic reduced dramatically during COVID-19 lockdown (71% fewer cars and 46% fewer trucks).•Neighborhood-scale air quality improved during lockdown compared to pre-pandemic conditions.•Median total on-road PNC and BC concentrations were 45–69% and 22–56% lower, respectively.•BC:PNC ratio and fraction of diesel vehicles in the on-road fleet was higher during lockdown.•BC and PNC reductions, unlike PM2.5, were commensurate with traffic reductions.
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