Archetypes of checkpoint-responsive immunity.
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ABSTRACT:
SUBMITTER: Im K
PROVIDER: S-EPMC8724347 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundNowadays, numerous health-related mobile apps implement gamification in an attempt to draw on the motivational potential of video games and thereby increase user engagement or foster certain health behaviors. However, research on effective gamification is still in its infancy and researchers increasingly recognize methodological shortcomings of existing studies. What we actually know about the phenomenon today stems from fragmented pieces of knowledge, and a variety of different perspectives. Existing research primarily draws on conceptual knowledge that is gained from research prototypes, and isolated from industry best practices. We still lack knowledge on how gamification has been successfully designed and implemented within the industry and whether certain gamification approaches have shown to be particularly suitable for certain health behaviors.ObjectiveWe address this lack of knowledge concerning best practices in the design and implementation of gamification for health-related mobile apps by identifying archetypes of gamification approaches that have emerged in pertinent health-related mobile apps and analyzing to what extent those gamification approaches are influenced by the underlying desired health-related outcomes.MethodsA 3-step research approach is employed. As a first step, a database of 143 pertinent gamified health-related mobile apps from the Apple App Store and Google Play Store is set up. Second, the gamification approach of each app within the database is classified based on an established taxonomy for gamification in health-related apps. Finally, a 2-step cluster analysis is conducted in order to identify archetypes of the most dominant gamification approaches in pertinent gamified health-related mobile apps.ResultsEight archetypes of gamification emerged from the analysis of health-related mobile apps: (1) competition and collaboration, (2) pursuing self-set goals without rewards, (3) episodical compliance tracking, (4) inherent gamification for external goals, (5) internal rewards for self-set goals, (6) continuous assistance through positive reinforcement, (7) positive and negative reinforcement without rewards, and (8) progressive gamification for health professionals. The results indicate a close relationship between the identified archetypes and the actual health behavior that is being targeted.ConclusionsBy unveiling salient best practices and discussing their relationship to targeted health behaviors, this study contributes to a more profound understanding of gamification in mobile health. The results can serve as a foundation for future research that advances the knowledge on how gamification may positively influence health behavior change and guide practitioners in the design and development of highly motivating and effective health-related mobile health apps.
| S-EPMC7605978 | biostudies-literature
Project description:Group 2 innate lymphoid cells (ILC2s) and CD4+ type 2 helper T cells (TH2 cells) are defined by their similar effector cytokines, which together mediate the features of allergic immunity. We found that tissue ILC2s and TH2 cells differentiated independently but shared overlapping effector function programs that were mediated by exposure to the tissue-derived cytokines interleukin 25 (IL-25), IL-33 and thymic stromal lymphopoietin (TSLP). Loss of these three tissue signals did not affect lymph node priming, but abrogated the terminal differentiation of effector TH2 cells and adaptive lung inflammation in a T cell-intrinsic manner. Our findings suggest a mechanism by which diverse perturbations can activate type 2 immunity and reveal a shared local-tissue-elicited checkpoint that can be exploited to control both innate and adaptive allergic inflammation.
| S-EPMC5275767 | biostudies-literature
Project description:Alcoholic liver disease (ALD) is an escalating global problem accounting for more than 3 million deaths annually. Bacterial infections are diagnosed in 25-47% of hospitalized patients with cirrhosis and represent the most important trigger for acute decompensation, multi-organ failure, septic shock and death. Current guidelines recommend intensive antibiotic therapy, but this has led to the emergence of multi-drug resistant bacteria, which are associated with increased morbidity and mortality rates. As such, there is a pressing need to explore new paradigms for anti-infective therapy and host-directed immunomodulatory therapies are a promising approach. Paradoxically, cirrhotic patients are characterised by heightened immune activity and exacerbated inflammatory processes but are unable to contend with bacterial infection, demonstrating that whilst immune effector cells are primed, their antibacterial effector functions are switched-off, reflecting a skewed homeostatic balance between anti-pathogen immunity and host-induced immunopathology. Preservation of this equilibrium physiologically is maintained by multiple immune-regulatory checkpoints and these feedback receptors serve as pivotal regulators of the host immunity. Checkpoint receptor blockade is proving to be effective at rescuing deranged/exhausted immunity in pre-clinical studies for chronic viral infection and sepsis. This approach has also obtained FDA approval for restoring anti-tumor immunity, with improved response rates and good safety profiles. To date, no clinical studies have investigated checkpoint blockade in ALD, highlighting an area for development of host-targeted immunotherapeutic strategies in ALD, for which there are no current specific treatment options. This review aims at framing current knowledge on immune checkpoints and the possibility of their therapeutic utility in ALD-associated immune dysfunctions.
| S-EPMC5999155 | biostudies-literature
Project description:PurposePrevious studies on neighborhoods and breast cancer survival examined neighborhood variables as unidimensional measures (e.g. walkability or deprivation) individually and thus cannot inform how the multitude of highly correlated neighborhood domains interact to impact breast cancer survival. Neighborhood archetypes were developed that consider interactions among a broad range of neighborhood social and built environment attributes and examine their associations with breast cancer survival.MethodsArchetypes were measured using latent class analysis (LCA) fit to California census tract-level data. Thirty-nine social and built environment attributes relevant to eight neighborhood domains (socioeconomic status (SES), urbanicity, demographics, housing, land use, commuting and traffic, residential mobility, and food environment) were included. The archetypes were linked to cancer registry data on breast cancer cases (diagnosed 1996-2005 with follow-up through Dec 31, 2017) to evaluate their associations with overall and breast cancer-specific survival using Cox proportional hazards models. Analyses were stratified by race/ethnicity.ResultsCalifornia neighborhoods were best described by nine archetypal patterns that were differentially associated with overall and breast cancer-specific survival. The lowest risk of overall death was observed in the upper middle class suburb (reference) and high status neighborhoods, while the highest was observed among inner city residents with a 39% greater risk of death (95% CI = 1.35 to 1.44). Results were similar for breast cancer-specific survival. Stratified analyses indicated that differences in survival by neighborhood archetypes varied according to individuals' race/ethnicity.ConclusionsBy describing neighborhood archetypes that differentiate survival following breast cancer diagnosis, the study provides direction for policy and clinical practice addressing contextually-rooted social determinants of health including SES, unhealthy food environments, and greenspace.
| S-EPMC8133764 | biostudies-literature
Project description:Kinetochores are specialized multi-protein complexes that play a crucial role in maintaining genome stability. They bridge attachments between chromosomes and microtubules during mitosis and they activate the spindle assembly checkpoint (SAC) to arrest division until all chromosomes are attached. Kinetochores are able to efficiently integrate these two processes because they can rapidly respond to changes in microtubule occupancy by switching localized SAC signalling ON or OFF. We show that this responsiveness arises because the SAC primes kinetochore phosphatases to induce negative feedback and silence its own signal. Active SAC signalling recruits PP2A-B56 to kinetochores where it antagonizes Aurora B to promote PP1 recruitment. PP1 in turn silences the SAC and delocalizes PP2A-B56. Preventing or bypassing key regulatory steps demonstrates that this spatiotemporal control of phosphatase feedback underlies rapid signal switching at the kinetochore by: allowing the SAC to quickly transition to the ON state in the absence of antagonizing phosphatase activity; and ensuring phosphatases are then primed to rapidly switch the SAC signal OFF when kinetochore kinase activities are diminished by force-producing microtubule attachments.
| S-EPMC6485516 | biostudies-literature
Project description:Emerging evidence suggests a role for radiation in eliciting antitumour immunity. We aimed to investigate the role of macrophages in modulating the immune response to radiation. Irradiation to murine tumours generated from colorectal (MC38) and pancreatic (KPC) cell lines induced Colony Stimulating Factor 1 (CSF-1). Coincident with the elevation in CSF-1, macrophages increased in tumours, peaking five days following irradiation. These tumour-associated macrophages (TAMs) were skewed toward an immunosuppressive phenotpye. Macrophage depletion via anti-CSF (aCSF) reduced macrophage numbers, yet only achieved tumour growth delay when combined with radiation. The tumour growth delay from aCSF after radiation was abrogated by depletion of CD8 T cells. There was enhanced recognition of tumour cell antigens by T cells isolated from irradiated tumours, consistent with increased antigen priming. The addition of anti-PD-L1 (aPD-L1) resulted in improved tumour suppression and even regression in some tumours. In summary, we show that adaptive immunity induced by radiation is limited by the recruitment of highly immunosuppressive macrophages. Macrophage depletion partly reduced immunosuppression, but additional treatment with anti-PD-L1 was required to achieve tumour regression.
| S-SCDT-88789_2_1540197428_jats | biostudies-other
Project description:Immunotherapeutics represent highly promising agents with the potential to improve patient outcomes in a variety of cancer types. Unfortunately, single-agent immunotherapy has achieved limited clinical benefit to date in patients suffering from pancreatic ductal adenocarcinoma (PDAC). This may be due to the presence of a uniquely immunosuppressive tumor microenvironment (TME) present in PDACs, which creates a barrier to effective immune surveillance. Critical obstacles to immunotherapy in PDAC tumors include the dense desmoplastic stroma that acts as a barrier to T-cell infiltration and the high numbers of tumor-associated immunosuppressive cells. We have identified hyperactivated focal adhesion kinase (FAK) activity in neoplastic PDAC cells as a significant regulator of the fibrotic and immunosuppressive TME. We found that FAK activity was elevated in human PDAC tissues and correlates with high levels of fibrosis and poor CD8+ cytotoxic T-cell infiltration. Single-agent FAK inhibition (VS-4718) dramatically limited tumor progression, resulting in a doubling of survival in the p48-Cre/LSL-KrasG12D/p53Flox/+ (KPC) mouse model of human PDAC. This alteration in tumor progression was associated with dramatically reduced tumor fibrosis, decreased numbers of tumor-infiltrating immature myeloid cells and immunosuppressive macrophages. We postulated that these desirable effects of FAK inhibition on the TME might render PDAC tumors more sensitive to immunotherapy. Accordingly, we found that VS-4718 rendered the previously unresponsive KPC mouse model responsive to anti-PD1 and anti-CTLA4 antagonists leading to a nearly tripling of survival times. These data suggest that FAK inhibition increases immune surveillance by overcoming the fibrotic and immunosuppressive PDAC TME thus rendering tumors more responsive to immunotherapy. We treated KP orthotopic tumor-bearing mice with vehicle and FAK inhibitor (FAKi) for 14 days, then extracted total RNA from tumor tissues.
2015-11-21 | E-GEOD-75233 | biostudies-arrayexpress
Project description:Despite expression of immunogenic polypeptides, tumors escape immune surveillance by engaging T cell checkpoint regulators and expanding Tregs, among other mechanisms. What orchestrates these controls is unknown. We report that free C3d, a fragment of the third component of complement, inside tumor cells - or associated with irradiated tumor cells and unattached to antigen - recruits, accelerates, and amplifies antitumor T cell responses, allowing immunity to reverse or even to prevent tumor growth. C3d enhances antitumor immunity independently of B cells, NK cells, or antibodies, but it does so by increasing tumor infiltrating CD8+ lymphocytes, by depleting Tregs, and by suppressing expression of programmed cell death protein 1 (PD-1) by T cells. These properties of C3d appear specific for the tumor and dependent on complement receptor 2, and they incur no obvious systemic toxicity. The heretofore unrecognized properties of free C3d suggest that protein might determine the effectiveness of immune surveillance and that increasing availability of the protein might prove advantageous in the treatment or prevention of cancer and premalignant conditions.
| S-EPMC5414554 | biostudies-literature
Project description:The efficacy of cancer immunotherapy depends on the fine interplay between tumoral immune checkpoints and host immune system. However, the up-to-date clinical performance of checkpoint blockers in cancer therapy revealed that higher-level regulation should be further investigated for better therapeutic outcomes. It is becoming increasingly evident that the expression of immune checkpoints is largely associated to the immunotherapeutic response and consequent prognosis. Deubiquitinating enzymes (DUBs) with their role of cleaving ubiquitin from proteins and other molecules, thus reversing ubiquitination-mediated protein degradation, modulate multiple cellular processes, including, but not limited to, transcriptional regulation, cell cycle progression, tissue development, and antiviral response. Accumulating evidence indicates that DUBs also have the critical influence on anticancer immunity, simply by stabilizing pivotal checkpoints or key regulators of T-cell functions. Therefore, this review summarizes the current knowledge about DUBs, highlights the secondary checkpoint-like role of DUBs in cancer immunity, in particular their direct effects on the stability control of pivotal checkpoints and key regulators of T-cell functions, and suggests the therapeutic potential of DUBs-based strategy in targeted immunotherapy for cancer.
| S-EPMC7426525 | biostudies-literature
Project description:Single-agent immunotherapy has achieved limited clinical benefit to date in patients with pancreatic ductal adenocarcinoma (PDAC). This may be a result of the presence of a uniquely immunosuppressive tumor microenvironment (TME). Critical obstacles to immunotherapy in PDAC tumors include a high number of tumor-associated immunosuppressive cells and a uniquely desmoplastic stroma that functions as a barrier to T cell infiltration. We identified hyperactivated focal adhesion kinase (FAK) activity in neoplastic PDAC cells as an important regulator of the fibrotic and immunosuppressive TME. We found that FAK activity was elevated in human PDAC tissues and correlated with high levels of fibrosis and poor CD8(+) cytotoxic T cell infiltration. Single-agent FAK inhibition using the selective FAK inhibitor VS-4718 substantially limited tumor progression, resulting in a doubling of survival in the p48-Cre;LSL-Kras(G12D);Trp53(flox/+) (KPC) mouse model of human PDAC. This delay in tumor progression was associated with markedly reduced tumor fibrosis and decreased numbers of tumor-infiltrating immunosuppressive cells. We also found that FAK inhibition rendered the previously unresponsive KPC mouse model responsive to T cell immunotherapy and PD-1 antagonists. These data suggest that FAK inhibition increases immune surveillance by overcoming the fibrotic and immunosuppressive PDAC TME and renders tumors responsive to immunotherapy.
| S-EPMC4935930 | biostudies-literature