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"Perry, Curtis"
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Singapore : unlikely power
\"The life of Singapore as an independent nation since 1965 has coincided with explosive growth, both of world trade and world wealth. Trade, heavily seaborne, now contributes more than half of global GNP. Largely by exploiting changing uses of the ocean, Singapore has grown remarkably rich. Constant and continuing comment in the media concerning Singapore's dramatic economic and organizational achievement has yet to find its way into a book, and this one is the first to put the story of Singapore into a global maritime context, describing and analyzing how, despite many life-threatening crises, Singapore, by using the sea, survived and prospered far beyond even its own expectations. Putting priority upon economic development and maintaining the social and economic stability that Singapore's authoritarian government has thought necessary to achieve this growth has provoked heated controversy both among Singaporeans and outside observers. Although opposition is too weak to challenge the government successfully, the struggle to define an acceptable balance between freedom and control continues. This question takes on a universal concern, intensified in our age of terrorism with its new challenges to order and stability. To what extent does authority stifle creativity?\"--Provided by publisher.
Book
Prostaglandin E2 and programmed cell death 1 signaling coordinately impair CTL function and survival during chronic viral infection
Susan Kaech and colleagues report that in chronic viral infection, prostaglandin E2 and PD-1 signaling suppressed the function and survival of cytotoxic T cells.
More than 10% of the world's population is chronically infected with HIV, hepatitis C virus (HCV) or hepatitis B virus (HBV), all of which can cause severe disease and death. These viruses persist in part because continuous antigenic stimulation causes the deterioration of virus-specific cytotoxic T lymphocyte (CTL) function and survival. Additionally, antiviral CTLs autonomously suppress their responses to limit immunopathology by upregulating inhibitory receptors such as programmed cell death 1 (PD-1). Identification and blockade of the pathways that induce CTL dysfunction may facilitate the clearance of chronic viral infections. We found that the prostaglandin E2 (PGE
2
) receptors EP2 and EP4 were upregulated on virus-specific CTLs during chronic lymphocytic choriomeningitis virus (LCMV) infection and suppressed CTL survival and function. We show that the combined blockade of PGE
2
and PD-1 signaling was therapeutic in terms of improving viral control and augmenting the numbers of functional virus-specific CTLs. Thus, PGE
2
inhibition is both an independent candidate therapeutic target and a promising adjunct therapy to PD-1 blockade for the treatment of HIV and other chronic viral infections.
Journal Article
Online survey of university students’ perception, awareness and adherence to COVID-19 prevention measures
Background
Determining factors correlated with protective measures against COVID-19 is important to improve public health response. This study describes student opinions related to university COVID-19 preventive measures.
Methods
In fall 2020, 643 US university students completed an online survey on perception, awareness, and adherence to COVID-19 preventive measures. Outcomes included protocol effectiveness (self or others), protocol adherence (self or others), consequences of protocol violation, knowledge of violations, and level of concern for COVID-19. Multiple linear regression models determined correlates of outcome variables. Covariates included gender, race, residence, area of study, class, and knowledge of someone with a positive COVID-19 test.
Results
Overall, students agreed with protective measures (equivalent to higher scores). In adjusted linear models, females (versus males) had significantly higher scores for protocol effectiveness (self) (
p
< 0.001), consequences of protocol violation (
p
= 0.005), and concern about COVID-19 (
p
< 0.001). Asian/Pacific Islander (versus white) had significantly higher scores for protocol effectiveness (self) (
p
< 0.001), consequences of protocol violation (
p
= 0.008), and concern about COVID-19 (
p
= 0.001). Graduate students (versus freshman) had higher scores for protocol effectiveness (self) (
p
< 0.001), protocol adherence (self) (p = 0.004) and concern about COVID-19 (
p
< 0.001). In contrast, participants who had a positive COVID-19 test had significantly lower scores for protocol effectiveness (self) (
p
= 0.02), protocol adherence (self) (
p
= 0.004), and consequences of protocol violation (
p
= 0.008).
Conclusion
Overall, females, Asian/Pacific Islanders, and graduate students were more likely to agree with or adhere to COVID-19 prevention guidelines but those who tested positive for COVID-19 were less likely to do so. These results may inform future prevention efforts.
Journal Article
Clinical Predictors of Survival in Patients With BRAFV600-Mutated Metastatic Melanoma Treated With Combined BRAF and MEK Inhibitors After Immune Checkpoint Inhibitors
Prospective and between trial comparisons indicate that first-line treatment with immune checkpoint inhibitors improves survival outcomes compared to first-line therapy with combined BRAF and MEK inhibitors in metastatic melanoma containing BRAFV600E/K mutations. Long-term outcomes for BRAF/MEK inhibition after progression on immunotherapy have not been reported. Moreover, clinical variables associated with outcome from treatment with combined BRAF/MEK inhibition were previously identified in the first-line setting but have not been investigated when targeted therapies are administered after progression on immune therapy. We performed a retrospective single institution analysis of 40 metastatic melanoma patients receiving combined BRAF/MEK inhibitors after progression on an anti-PD-1 or ipilimumab plus nivolumab to assess response rate by RECIST 1.1, progression-free and overall survival (PFS and OS). Pretreatment clinical variables were analyzed for association with OS. Ipilimumab/nivolumab was the first-line immunotherapy regimen in 39 patients (97.5%), and BRAFV600E/K mutations were present in 33 (83%) and 7 (17%) patients, respectively. The median OS from start of BRAF/MEK inhibitors was 20.3 months (1.73-106.4+, 95% CI of median 13.3-30.7). Clinical characteristics associated with worse survival prior to starting BRAF/MEK inhibitors included age > 60 years (median OS 14 vs. 28 months; HR 2.5; 95% CI 0.91-6.87, P = .023), ECOG-PS > 2 (median OS 7 vs. 33 months; HR 2.89; 95% CI 0.78-10.76, P = .018), and presence of bone metastases (median OS 9 vs. 52 months; HR 3.17; 95% CI 1.33-7.54, P = .002). These associations with shorter survival maintained their significance on multivariate analysis. If confirmed in larger cohorts, the identified prognostic variables can be used for stratification of patients in future randomized trials.
Long-term clinical outcomes for patients receiving BRAF/MEKi after progression on immune therapy have not been fully described, and clinical predictors of long-term response and survival are not known. This article reports an analysis of patients receiving BRAF/MEKi after progression on one or more lines of immune checkpoint inhibitor therapy to assess response and clinical variables associated with survival.
Journal Article
Causal identification of single-cell experimental perturbation effects with CINEMA-OT
Recent advancements in single-cell technologies allow characterization of experimental perturbations at single-cell resolution. While methods have been developed to analyze such experiments, the application of a strict causal framework has not yet been explored for the inference of treatment effects at the single-cell level. Here we present a causal-inference-based approach to single-cell perturbation analysis, termed CINEMA-OT (causal independent effect module attribution + optimal transport). CINEMA-OT separates confounding sources of variation from perturbation effects to obtain an optimal transport matching that reflects counterfactual cell pairs. These cell pairs represent causal perturbation responses permitting a number of novel analyses, such as individual treatment-effect analysis, response clustering, attribution analysis, and synergy analysis. We benchmark CINEMA-OT on an array of treatment-effect estimation tasks for several simulated and real datasets and show that it outperforms other single-cell perturbation analysis methods. Finally, we perform CINEMA-OT analysis of two newly generated datasets: (1) rhinovirus and cigarette-smoke-exposed airway organoids, and (2) combinatorial cytokine stimulation of immune cells. In these experiments, CINEMA-OT reveals potential mechanisms by which cigarette-smoke exposure dulls the airway antiviral response, as well as the logic that governs chemokine secretion and peripheral immune cell recruitment.
CINEMA-OT is a framework that enables accurate causal inference of the effects of perturbation experiments at the single-cell level.
Journal Article
CCR7 expression alters memory CD8 T-cell homeostasis by regulating occupancy in IL-7– and IL-15–dependent niches
C-C receptor 7 (CCR7) is important to allow T cells and dendritic cells to migrate toward CCL19- and CCL21-producing cells in the T-cell zone of the spleen and lymph nodes. The role of this chemokine receptor in regulating the homeostasis of effector and memory T cells during acute viral infection is poorly defined, however. In this study, we show that CCR7 expression alters memory CD8 T-cell homeostasis following lymphocytic choriomeningitis virus infection. Greater numbers of CCR7-deficient memory T cells were formed and maintained compared with CCR7-sufficient memory T cells, especially in the lung and bone marrow. The CCR7-deficient memory T cells also displayed enhanced rates of homeostatic turnover, which may stem from increased exposure to IL-15 as a consequence of reduced exposure to IL-7, because removal of IL-15, but not of IL-7, normalized the numbers of CCR7-sufficient and CCR7-deficient memory CD8 T cells. This result suggests that IL-15 is the predominant cytokine supporting augmentation of the CCR7−/− memory CD8 T-cell pool. Taken together, these data suggest that CCR7 biases memory CD8 T cells toward IL-7–dependent niches over IL-15–dependent niches, which provides insight into the homeostatic regulation of different memory T-cell subsets.
Journal Article
Interactions among tumor subtype, PPARγ expression, and adipose proliferation shape outcomes in breast cancer
Breast cancer progression is influenced by tumor subtype, metabolic environment, and patient factors, including menopausal status and BMI. In this study, we utilized publicly available data to investigate the prognostic relevance of PPARγ gene's expression across different subgroups. We also examined adipose tissue proliferation in patients with various tumor subtypes and phenotypic cohorts. We analyzed RNA‐seq data from primary breast cancer patients in the TCGA‐BRCA cohort, stratifying patients by PPARγ expression, menopausal status, and tumor receptor subtype. Kaplan–Meier analyses revealed that high PPARγ expression was associated with improved overall survival, particularly in premenopausal patients. Complementing this, we analyzed PET‐CT scans from breast cancer patients in the ACRIN‐6888 trial, focusing on standardized uptake value (SUV) metrics of a cell cycle tracer, 3′‐deoxy‐3′‐[18F]‐fluorothymidine (18F‐FLT) in visceral and subcutaneous adipose tissue. Postmenopausal patients had lower visceral adipose tissue SUVmean, and patients with ER+ or non‐TNBC tumors showed lower SUVpeak and SUVmax of both adipose tissue types, indicating metabolic/proliferative reprogramming of adipose tissue based on tumor subtype. We hypothesize that PPARγ expression and adipose proliferation differentially affect survival across subtypes and menopausal status, providing deeper insight into PPARγ as a therapeutic target in breast cancer and the potential implications for precision medicine treatments.
Journal Article
B cell depletion or absence does not impede anti-tumor activity of PD-1 inhibitors
Background
PD-1 inhibitors are approved for multiple malignancies and function by stimulating T cells. However, the role of B cells in the anti-tumor activity of these drugs is unknown, as is their activity in patients who have received B cell depleting drugs or with immunoglobulin deficiencies.
Methods
We studied B cell content in 40 melanomas from patients treated with pembrolizumab or nivolumab and assessed the association with response to therapy. Murine MC38 colon cancer and YUMMER1.7 melanoma models were used to determine whether concomitant anti-CD20 antibody injections diminish the anti-tumor effects of anti-PD-1. Results were validated in
mu
MT mice, which lack B cells.
Results
B cells were sparse in most melanomas and B cell content was not associated with response to anti-PD-1 or overall survival. Employing MC38 and YUMMER1.7 models, we demonstrated that anti-CD20 antibodies reduce tumor-infiltrating B cells yet had no effect on tumor growth, response to PD-1 inhibition, or survival. In
mu
MT mice, T-cell dependent tumor rejection and anti-PD-1 responses were no different than in wildtype C57BL/6 J mice.
Conclusions
The degree of tumor infiltrating B cell content is not associated with response to anti-PD-1 inhibitors in melanoma. PD-1 inhibitors cause tumor shrinkage in murine cancer models even when B cells are absent or are depleted. PD-1 inhibitors are likely to be active in patients with impaired B cell function, such as patients undergoing B cell depletion with drugs including rituximab for conditions such as B cell malignancies or autoimmune disorders.
Journal Article
IL-7 plays a critical role for the homeostasis of allergen-specific memory CD4 T cells in the lung and airways
Memory T cells respond rapidly to repeated antigen exposure and can maintain their population for extended periods through self-renewal. These characteristics of memory T cells have mainly been studied during viral infections, whereas their existence and functions in allergic diseases have been studied incompletely. Since allergic patients can suffer repeated relapses caused by intermittent allergen exposure, we hypothesized that allergen- specific memory Th2 cells are present and the factors necessary for the maintenance of these cells are provided by the lung and airways. Using a murine model of airway inflammation, we found that allergen-specific CD4 T cells survived longer than 70 days in the lung and airways in an IL-7 dependent fashion. These T cells showing homeostatic proliferation were largely found in the mediastinal lymph node (mLN), rather than the airways; however, cells residing in the lung and airways developed recall responses successfully. We also found that CD4 T cells exhibited differential phenotypes in the mLN and in the lung. Altogether, we believe that allergen-specific memory T cells reside and function in the lung and airways, while their numbers are replenished through homeostatic turnover in the mLNs. Furthermore, we determined that IL-7 signaling is important for the homeostasis of these cells.
Journal Article