Socio-Economic and Clinical Factors as Predictors of Disease Evolution and Acute Events in COPD Patients

BACKGROUND: Socio-economic, cultural and environmental factors are becoming increasingly important determinants of chronic obstructive pulmonary disease (COPD). We conducted a study to investigate socio-demographic, lifestyle and clinical factors, and to assess their role as predictors of acute events (mortality or hospitalization for respiratory causes) in a group of COPD patients. METHODS: Subjects were recruited among outpatients who were undertaking respiratory function tests at the Pneumology Unit of the Sant'Orsola-Malpighi Hospital, Bologna. Patients were classified according to the GOLD Guidelines. RESULTS: 229 patients with COPD were included in the study, 44 with Mild, 68 Moderate, 52 Severe and 65 Very Severe COPD (GOLD stage). Significant differences among COPD stage, in terms of smoking status and fragility index, were detected. COPD stage significantly affected the values of all clinical tests (spirometry and ABG analysis). Kaplan-Meier estimates showed a significant difference between survival curves by COPD stage with lower event-free probability in very severe COPD stage. Significant risk factors for acute events were: underweight (HR = 4.08; 95% CI 1.01-16.54), having two or more comorbidities (HR = 4.71; 95% CI 2.52-8.83), belonging to moderate (HR = 3.50; 95% CI 1.01-12.18) or very severe COPD stage (HR = 8.23; 95% CI 2.35-28.85). CONCLUSIONS: Our findings indicate that fragility is associated with COPD stage and that comorbidities and the low body mass index are predictors of mortality or hospitalization. Besides spirometric analyses, FeNO measure and comorbidities, body mass index could also be considered in the management and monitoring of COPD patients

Radiation-Induced c-Jun Activation Depends on MEK1-ERK1/2 Signaling Pathway in Microglial Cells

Radiation-induced normal brain injury is associated with acute and/or chronic inflammatory responses, and has been a major concern in radiotherapy. Recent studies suggest that microglial activation is a potential contributor to chronic inflammatory responses following irradiation; however, the molecular mechanism underlying the response of microglia to radiation is poorly understood. c-Jun, a component of AP-1 transcription factors, potentially regulates neural cell death and neuroinflammation. We observed a rapid increase in phosphorylation of N-terminal c-Jun (on serine 63 and 73) and MAPK kinases ERK1/2, but not JNKs, in irradiated murine microglial BV2 cells. Radiation-induced c-Jun phosphorylation is dependent on the canonical MEK-ERK signaling pathway and required for both ERK1 and ERK2 function. ERK1/2 directly interact with c-Jun in vitro and in cells; meanwhile, the JNK binding domain on c-Jun is not required for its interaction with ERK kinases. Radiation-induced reactive oxygen species (ROS) potentially contribute to c-Jun phosphorylation through activating the ERK pathway. Radiation stimulates c-Jun transcriptional activity and upregulates c-Jun-regulated proinflammatory genes, such as tumor necrosis factor-α, interleukin-1β, and cyclooxygenase-2. Pharmacologic blockade of the ERK signaling pathway interferes with c-Jun activity and inhibits radiation-stimulated expression of c-Jun target genes. Overall, our study reveals that the MEK-ERK1/2 signaling pathway, but not the JNK pathway, contributes to the c-Jun-dependent microglial inflammatory response following irradiation

Sensing and Integration of Erk and PI3K Signals by Myc

The transcription factor Myc plays a central role in regulating cell-fate decisions, including proliferation, growth, and apoptosis. To maintain a normal cell physiology, it is critical that the control of Myc dynamics is precisely orchestrated. Recent studies suggest that such control of Myc can be achieved at the post-translational level via protein stability modulation. Myc is regulated by two Ras effector pathways: the extracellular signal-regulated kinase (Erk) and phosphatidylinositol 3-kinase (PI3K) pathways. To gain quantitative insight into Myc dynamics, we have developed a mathematical model to analyze post-translational regulation of Myc via sequential phosphorylation by Erk and PI3K. Our results suggest that Myc integrates Erk and PI3K signals to result in various cellular responses by differential stability control of Myc protein isoforms. Such signal integration confers a flexible dynamic range for the system output, governed by stability change. In addition, signal integration may require saturation of the input signals, leading to sensitive signal integration to the temporal features of the input signals, insensitive response to their amplitudes, and resistance to input fluctuations. We further propose that these characteristics of the protein stability control module in Myc may be commonly utilized in various cell types and classes of proteins

Emerging roles of ATF2 and the dynamic AP1 network in cancer

Cooperation among transcription factors is central for their ability to execute specific transcriptional programmes. The AP1 complex exemplifies a network of transcription factors that function in unison under normal circumstances and during the course of tumour development and progression. This Perspective summarizes our current understanding of the changes in members of the AP1 complex and the role of ATF2 as part of this complex in tumorigenesis.Fil: Lopez Bergami, Pablo Roberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina; ArgentinaFil: Lau, Eric . Burnham Institute for Medical Research; Estados UnidosFil: Ronai, Zeev . Burnham Institute for Medical Research; Estados Unido

Socio-Economic and Clinical Factors as Predictors of Disease Evolution and Acute Events in COPD Patients

BACKGROUND: Socio-economic, cultural and environmental factors are becoming increasingly important determinants of chronic obstructive pulmonary disease (COPD). We conducted a study to investigate socio-demographic, lifestyle and clinical factors, and to assess their role as predictors of acute events (mortality or hospitalization for respiratory causes) in a group of COPD patients. METHODS: Subjects were recruited among outpatients who were undertaking respiratory function tests at the Pneumology Unit of the Sant'Orsola-Malpighi Hospital, Bologna. Patients were classified according to the GOLD Guidelines. RESULTS: 229 patients with COPD were included in the study, 44 with Mild, 68 Moderate, 52 Severe and 65 Very Severe COPD (GOLD stage). Significant differences among COPD stage, in terms of smoking status and fragility index, were detected. COPD stage significantly affected the values of all clinical tests (spirometry and ABG analysis). Kaplan-Meier estimates showed a significant difference between survival curves by COPD stage with lower event-free probability in very severe COPD stage. Significant risk factors for acute events were: underweight (HR = 4.08; 95% CI 1.01-16.54), having two or more comorbidities (HR = 4.71; 95% CI 2.52-8.83), belonging to moderate (HR = 3.50; 95% CI 1.01-12.18) or very severe COPD stage (HR = 8.23; 95% CI 2.35-28.85). CONCLUSIONS: Our findings indicate that fragility is associated with COPD stage and that comorbidities and the low body mass index are predictors of mortality or hospitalization. Besides spirometric analyses, FeNO measure and comorbidities, body mass index could also be considered in the management and monitoring of COPD patients

Inactive footsteps. Monitoring behavioral risk factors in the post-pandemic era: weight gain, inactivity and active mobility in Emilia-Romagna

Background Restrictive measures due the COVID-19 pandemic and their psychological impact changed human behavior. The aim of the study was to describe the trend in weight gain and sedentary lifestyle among adults (18-69 years) before and after the pandemic outbreak in the Emilia-Romagna region. Methods We analysed data from the Italian-behavioral-risk-factor-surveillance-system (PASSI) from 2008-2021 on excessive weight, sedentary lifestyle prior and after the pandemic outbreak, stratifying the population by sex, age, educational and socio-economic characteristics. Furthermore, preliminary data on active mobility from 2018-2021 was analysed. Results Data from 42122 interviews were collected between 2008- 2021 (3085 in 2019, 927 in 2020, 1834 in 2021). Prevalence of overweight showed an increasing trend in the pandemic period (28,7%, IC 95% [27,1-30,4] in 2019 vs 30,9% [27,8-34,3] in 2020 vs 31,2% [29,0-33,5] in 2021), which broke the declining trend observed over the last decade, with a higher variation among ages 35 to 49. People with lower economic status showed high levels both in 2020 and 2021. Prevalence of obesity showed a slight reduction in 2020, which returned to pre-pandemic values in 2021 (12,2% [11,0-13,5] in 2019 vs 9,7% [7,8-11,9] in 2020 vs 11,3% [9,8-12,9] in 2021). No differences were observed when stratifying by age and sex. As for sedentary lifestyle, there was a foreseeable increase in 2020 with a sudden decrease in 2021 (16,3% [15,0-17,7%] in 2019 vs 16,8% [14,4-19,5] in 2020 vs 14,8% [13,1-16,7] in 2021) which is in line with the decreasing trend observed in over the last decade. In 2020, women and people with a lower economic status were affected the most. Finally, data on active mobility showed a decrease in 2020 both for cycling (19,1% [17,7-20,6] in 2019 vs 15,4% [12,9- 18,3] in 2020) and walking (45,7% [43,9-47,6] in 2019 vs 42,3% [39,1-46,1] in 2020) to go to work in. In 2021 the trend increases towards pre-pandemic levels for cycling (18,1% [16,2-20,1]) but not for walking (37,4% [35,1-39,8]) which continues decreasing. Conclusions The pandemic outbreak had a negative effect on behavioral risk factors specifically regarding excessive weight gain, sedentary lifestyles, the latter having a higher impact on women and people with lower economic status. Data on sedentary lifestyle and active mobility in 2020 is compatible with national lockdown and smart working. As for the 2021 gap between cycling and walking, among other reasons, it may be justified by the quota related to public transportations and the grown fear of using it. Targeted public health interventions are needed to encourage active lifestyles

Ras activity regulates cyclin E degradation by the Fbw7 pathway

The Skp1–Cullin1 F-box protein–Fbw7 ubiquitin ligase regulates phosphorylation-dependent cyclin E degradation, and disruption of this pathway is associated with genetic instability and tumorigenesis. Fbw7 is a human tumor suppressor that is targeted for mutation in primary cancers. However, mechanisms other than mutation of Fbw7 may also disrupt cyclin E proteolysis in cancers. We show that oncogenic Ha-Ras activity regulates cyclin E degradation by the Fbw7 pathway. Activated Ras impairs Fbw7-driven cyclin E degradation, and, conversely, inhibition of normal Ras activity decreases cyclin E abundance. Moreover, activation of the mitogen-activated protein kinase pathway is the essential Ras function that inhibits cyclin E turnover, and activated Ha-Ras expression inhibits both the binding of cyclin E to Fbw7 and cyclin E ubiquitination. Last, we found that oncogenic Ras activity potentiates cyclin E-induced genetic instability but only when cyclin E is susceptible to degradation by Fbw7. Thus, we conclude that Ras activity regulates Fbw7-mediated cyclin E proteolysis and suggest that impaired cyclin E proteolysis is a mechanism through which Ras mutations promote tumorigenesis