Cellular senescence has emerged as a potent tumor suppressor mechanism in numerous human neoplasias. Senescent cells secrete a distinct set of factors, collectively termed the senescence-associated ...secretory phenotype (SASP), which has been postulated to carry both pro- and antitumorigenic properties depending on tissue context. However, the in vivo effect of the SASP is poorly understood due to the difficulty of studying the SASP independently of other senescence-associated phenotypes. Here, we report that disruption of the interleukin-1 (IL-1) pathway completely uncouples the SASP from other senescence-associated phenotypes such as cell cycle exit. Transcriptome profiling of IL-1 receptor (IL-1R)-depleted senescent cells indicates that IL-1 controls the late arm of the senescence secretome, which consists of proinflammatory cytokines induced by NF-κB. Our data suggest that both IL-1α and IL-1β signal through IL-1R to upregulate the SASP in a cooperative manner. Finally, we show that IL-1α inactivation impairs tumor progression and immune cell infiltration without affecting cell cycle arrest in a mouse model of pancreatic cancer, highlighting the protumorigenic property of the IL-1-dependent SASP in this context. These findings provide novel insight into the therapeutic potential of targeting the IL-1 pathway in inflammatory cancers.
Cumulative evidence has demonstrated the presence of cancer stem cells (CSC) in breast cancer and its putative role in cancer progression. Nonetheless, the clinical significance of CSC in breast ...cancer remains elusive. The underlying reasons could be due to the heterogeneity of breast cancer subtypes as well as different markers used to define breast CSC. In this study, three widely used markers (aldehyde dehydrogenase (ALDH)1+ and CD24−CD44+) were used to define two populations of CSC in a large cohort of breast cancers. The expressions of these markers were correlated with different clinicopathological features and the molecular subtypes. ALDH1+ breast cancers were associated with basal-like and HER2-overexpressing subtypes and the characteristics histologic features were related to these two subtypes. On the other hand, CD24−CD44+ breast cancers were associated positively with the presence of extensive in situ component, the absence of lymph node involvement, and basal markers, but negatively with HER2. CD24−CD44+ breast cancers were also positively associated with luminal B cancers. As the expression of CSC markers varied among different molecular subtypes and different clinicopathological features, it appeared that each CSC population could have distinct clinical values in different subgroups of breast cancers. For improved prognostication with CSC, combining the analysis of CSC markers would be required. Within the luminal cancers, CSC appeared to identify cancers with poor outcome. The presence of CSC populations was associated with ER−PR+ cancers and tumors expressing basal markers. Basal marker expression can complement with CSC for improved indicator for poor prognosis in luminal breast cancers. For the first time, the possible contribution of CSC to these aggressive luminal cancers was demonstrated. The association of basal features and CSC in luminal cancers also raised the possibility that luminal cancer cells may acquire basal phenotype and CSC properties together during their progression.
Recent work indicates that there are distinct response habituation mechanisms that can be recruited by different stimulation rates and that can underlie different components (e.g., the duration or ...speed) of a single behavioral response. These findings raise the question: why is “the simplest form of learning” so complicated mechanistically? Beyond evolutionary selection for robustness of plasticity in learning to ignore, it is proposed in this article that multiple mechanisms of habituation have evolved to streamline shifts in ongoing behavioral strategy. Then, speculations are offered regarding the implications of this reconceptualization of habituation for approaching the analysis of mechanisms of more complex forms of learning and memory.
Multiple independent mechanisms of response habituation learning have recently been identified. In this article, it is proposed that these mechanisms serve to adaptively shift behavioral strategy. Then, speculations are offered regarding the importance of this reconceptualization of habituation for understanding neuropsychiatric disorders and more complex forms of learning and memory.
Irritable bowel syndrome (IBS) is a complex, functional gastrointestinal disorder characterized by chronic abdominal pain or discomfort and altered bowel habits. Despite the global prevalence and ...disease burden of IBS, its underlying pathophysiology remains unclear. Inflammation may play a pathogenic role in IBS. Studies have highlighted the persistence of mucosal inflammation at the microscopic and molecular level in IBS, with increased recruitment of enteroendocrine cells. Substantial overlaps between IBS and inflammatory bowel disease have also been reported. This review thus aimed to discuss the body of evidence pertaining to the presence of mucosal inflammation in IBS, its putative role in the disease process of IBS, and its clinical relevance. Increased mast cell density and activity in the gut may correlate with symptoms of visceral hypersensitivity. As evidenced by patients who develop postinfectious IBS, infective gastroenteritis could cause systemic inflammation and altered microbiome diversity, which in turn perpetuates a cycle of chronic, low-grade, subclinical inflammation. Apart from mucosal inflammation, neuroinflammation is probably involved in the pathophysiology of IBS via the "gut-brain" axis, resulting in altered neuroendocrine pathways and glucocorticoid receptor genes. This gives rise to an overall proinflammatory phenotype and dysregulated hypothalamic-pituitary-adrenal axis and serotonergic (5-HT) functioning, which could, at least in part, account for the symptoms of IBS. Although a definite and reproducible pattern of immune response has yet to be recognized, further research into anti-inflammatories may be of clinical value.
How do leaders use external events or pressures as political levers to facilitate domestic reforms? In this article, we build a theory of aspirational politics to address this question. We show that ...aspirations to improve a country's international status can help leaders justify the implementation of their preferred domestic policies. For instance, the aspiration of wanting to join prestigious international organizations or agreements creates focal narratives that reformers can use to highlight the need to catch up and rhetorically constrain domestic actors who oppose reforms. We illustrate this mechanism through the Chinese leaders' counterintuitively positive statements towards the Trans-Pacific Partnership (TPP) from 2013 to 2016. By framing the TPP as an aspiration through which China can enhance its international status, Chinese leaders were able to justify domestic economic reforms. Unlike conventional explanations, this was done without the onset of crises or actually signing the TPP. We substantiate this claim using evidence from computer-assisted text analysis of Chinese news coverage of the TPP from 2008-2018 (N = 10189) and process-tracing of the establishment of the Shanghai Free Trade Zone.
This study evaluated in vivo, an intraoral device against the gold standard esophageal device for gastroesophageal reflux disease (GERD) monitoring. Subjects scheduled for a catheter-based esophageal ...pH/impedance testing at a gastroenterology clinic were recruited. They were screened using the GerdQ questionnaire, demographics and dental conditions recorded. A prototype intraoral device, consisting of a Bravo™ capsule embedded in an Essix-style retainer fabricated for each subject, monitored intraoral pH. Concurrently, subjects underwent 24-h esophageal pH-impedance monitoring. A self-administered survey elicited the comfort and acceptance of both devices. The study recruited ten adult subjects (23 to 60-years-old) with a median GerdQ score of 9.5 corresponding to a 79% likelihood of GERD. Subjects with severe dental erosion had significantly (p < 0.05) higher acid exposure time and more non-meal reflux events. No adverse events were associated with the intraoral device while one was recorded for the esophageal device. The intraoral device was significantly more comfortable to place, more comfortable to wear, and interfered less with daily routine compared to the esophageal device. Accuracy of the intraoral device ranged between 86.15% and 37.82%. Being more tolerable than traditional esophageal pH monitoring, intraoral pH monitoring may be a useful adjunct for the diagnosis and management of GERD.
China’s attempt to build geopolitical influence through economic instruments has become a critical facet of US-China competition. How can rising powers convince follower states to join alternative ...(geoeconomic) initiatives created and/or led by the rising powers, in the shadow of potential rebuke from the hegemon? This article theorizes how rising powers can use strategic narratives to ameliorate the follower states’ concerns of antagonizing the hegemon for aligning with alternative initiatives. We argue that rising powers can control the narrative through “two-front narration”: simultaneously telling the hegemon that they seek limited changes, while telling follower states that they do not have to worry about crossfire because the rising powers-hegemon relations are non-zero-sum. By sending the right messages to different audiences to induce motivated reasoning, rising powers can manufacture the appearance of consensus among multiple audiences to help follower states hedge, while blunting the formation of containment coalitions. We adopt a mixed-methods approach to substantiate our theory: (1) text analysis of China’s messaging about the Trans-Pacific Partnership (TPP) from 2008 to 2016; (2) case study of the rhetorical action-reactions between China, the United States, and the follower states on the relationship between the TPP and the Regional Comprehensive Economic Partnership; and (3) parallel case study of the rhetorical action-reactions between China, the United States, and the follower states on the relationship between the Asian Infrastructure Investment Bank and multilateral development banks such as the World Bank. Our analysis has implications for theories of strategic narratives in international politics and debates about geoeconomic competition/hedging in Asia.
: Autism spectrum disorder (ASD) is a complex developmental condition typically characterized by deficits in social and communicative behaviors as well as repetitive patterns of behaviors. Despite ...its prevalence (affecting 0.1% to 1.8% of the global population), the pathogenesis of ASD remains incompletely understood. Patients with ASD are reported to have more frequent gastrointestinal (GI) complaints. There is some anecdotal evidence that probiotics are able to alleviate GI symptoms as well as improve behavioral issues in children with ASD. However, systematic reviews of the effect of prebiotics/probiotics on ASD and its associated symptoms are lacking.
: Using the keywords (prebiotics OR probiotics OR microbiota OR gut) AND (autism OR social OR ASD), a systematic literature search was conducted on PubMed, EMBASE, Medline, Clinicaltrials.gov and Google Scholar databases. The inclusion criteria were original clinical trials, published in English between the period 1st January 1988 and 1st February 2019.
: A total of eight clinical trials were systematically reviewed. Two clinical trials examined the use of prebiotic and/or diet exclusion while six involved the use of probiotic supplementation in children with ASD. Most of these were prospective, open-label studies. Prebiotics only improved certain GI symptoms; however, when combined with an exclusion diet (gluten and casein free) showed a significant reduction in anti-sociability scores. As for probiotics, there is limited evidence to support the role of probiotics in alleviating the GI or behavioral symptoms in children with ASD. The two available double-blind, randomized, placebo-controlled trials found no significant difference in GI symptoms and behavior.
: Despite promising preclinical findings, prebiotics and probiotics have demonstrated an overall limited efficacy in the management of GI or behavioral symptoms in children with ASD. In addition, there was no standardized probiotics regimen, with multiple different strains and concentrations of probiotics, and variable duration of treatments.
Several observational studies from locations around the globe have documented a positive correlation between air pollution and the severity of COVID-19 disease. Observational studies cannot identify ...the causal link between air quality and the severity of COVID-19 outcomes, and these studies face three key identification challenges: 1) air pollution is not randomly distributed across geographies; 2) air-quality monitoring networks are sparse spatially; and 3) defensive behaviors to mediate exposure to air pollution and COVID-19 are not equally available to all, leading to large measurement error bias when using rate-based COVID-19 outcome measures (e.g., incidence rate or mortality rate). Using a quasi-experimental design, we explore whether traffic-related air pollutants cause people with COVID-19 to suffer more extreme health outcomes in New York City (NYC). When we address the previously overlooked challenges to identification, we do not detect causal impacts of increased chronic concentrations of traffic-related air pollutants on COVID-19 death or hospitalization counts in NYC census tracts.
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