Conditional Agreements For Innovative Therapies In Italy: The Case Of Pirfenidone

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Uniting against a common enemy: Perceived outgroup threat elicits ingroup cohesion in chimpanzees

チンパンジーは外集団の脅威に対して仲間の結束を高めることを解明 --戦争と協力の共進化の可能性--. 京都大学プレスリリース. 2021-02-25.Outgroup threat has been identified as an important driver of ingroup cohesion in humans, but the evolutionary origin of such a relationship is unclear. Chimpanzees (Pan troglodytes) in the wild are notably aggressive towards outgroup members but coordinate complex behaviors with many individuals in group hunting and border patrols. One hypothesis claims that these behaviors evolve alongside one another, where outgroup threat selects for ingroup cohesion and group coordination. To test this hypothesis, 5 groups of chimpanzees (N = 29 individuals) were observed after hearing either pant-hoots of unfamiliar wild chimpanzees or control crow vocalizations both in their typical daily environment and in a context of induced feeding competition. We observed a behavioral pattern that was consistent both with increased stress and vigilance (self-directed behaviors increased, play decreased, rest decreased) and increased ingroup cohesion (interindividual proximity decreased, aggression over food decreased, and play during feeding competition increased). These results support the hypothesis that outgroup threat elicits ingroup tolerance in chimpanzees. This suggests that in chimpanzees, like humans, competition between groups fosters group cohesion

Resonances, Unstable Systems and Irreversibility: Matter Meets Mind

The fundamental time-reversal invariance of dynamical systems can be broken in various ways. One way is based on the presence of resonances and their interactions giving rise to unstable dynamical systems, leading to well-defined time arrows. Associated with these time arrows are semigroups bearing time orientations. Usually, when time symmetry is broken, two time-oriented semigroups result, one directed toward the future and one directed toward the past. If time-reversed states and evolutions are excluded due to resonances, then the status of these states and their associated backwards-in-time oriented semigroups is open to question. One possible role for these latter states and semigroups is as an abstract representation of mental systems as opposed to material systems. The beginnings of this interpretation will be sketched.Comment: 9 pages. Presented at the CFIF Workshop on TimeAsymmetric Quantum Theory: The Theory of Resonances, 23-26 July 2003, Instituto Superior Tecnico, Lisbon, Portugal; and at the Quantum Structures Association Meeting, 7-22 July 2004, University of Denver. Accepted for publication in the Internation Journal of Theoretical Physic

Defining the molecular role of gp91phox in the immune manifestation of acute allergic asthma using a preclinical murine model

<p>Abstract</p> <p>Objective</p> <p>The phenomena manifested during inflammation require interplay between circulating effector cells, local resident cells, soluble mediators and genetic host factors to establish, develop and maintain itself. Of the molecues involed in the initiation and perpetuation of acute allergic inflammation in asthma, the involvement of effector cells in redox reactions for producing O₂^-(superoxide anion) through the mediation of NADPH oxidase is a critical step. Prior data suggest that reactive oxygen species (ROS) produced by NADPH oxidase homologues in non-phagocytic cells play an important role in the regulation of signal transduction, while macrophages use a membrane-associated NADPH oxidase to generate an array of oxidizing intermediates which inactivate MMPs on or near them.</p> <p>Materials and Methods and Treatment</p> <p>To clarify the role of gp91phox subunit of NADPH oxidase in the development and progression of an acute allergic asthma phenotype, we induced allergen dependent inflammation in a gp91<it>^phox</it>-/- single knockout and a gp91phox-/-MMP-12-/- double knockout mouse models.</p> <p>Results</p> <p>In the knockout mice, both inflammation and airway hyperreactivity were more extensive than in wildtype mice post-OVA. Although OVA-specific IgE in plasma were comparable in wildtype and knockout mice, enhanced inflammatory cell recruitment from circulation and cytokine release in lung and BALf, accompanied by higher airway resistance as well as Penh in response to methacholine, indicate a regulatory role for NADPH oxidase in development of allergic asthma. While T cell mediated functions like Th2 cytokine secretion, and proliferation to OVA were upregulated synchronous with the overall robustness of the asthma phenotype, macrophage upregulation in functions such as proliferation, and mixed lymphocyte reaction indicate a regulatory role for gp91phox and an overall non-involvement or synergistic involvement of MMP12 in the response pathway (comparing data from gp91phox-/- and gp91phox-/-MMP-12-/- mice).</p

Non-symplectic symmetries and bi-Hamiltonian structures of the rational Harmonic Oscillator

The existence of bi-Hamiltonian structures for the rational Harmonic Oscillator (non-central harmonic oscillator with rational ratio of frequencies) is analyzed by making use of the geometric theory of symmetries. We prove that these additional structures are a consequence of the existence of dynamical symmetries of non-symplectic (non-canonical) type. The associated recursion operators are also obtained.Comment: 10 pages, submitted to J. Phys. A:Math. Ge

DNA methylation of enhancer elements in myeloid neoplasms: think outside the promoters?

Gene regulation through DNA methylation is a well described phenomenon that has a prominent role in physiological and pathological cell-states. This epigenetic modification is usually grouped in regions denominated CpG islands, which frequently co-localize with gene promoters, silencing the transcription of those genes. Recent genome-wide DNA methylation studies have challenged this paradigm, demonstrating that DNA methylation of regulatory regions outside promoters is able to influence cell-type specific gene expression programs under physiologic or pathologic conditions. Coupling genome-wide DNA methylation assays with histone mark annotation has allowed for the identification of specific epigenomic changes that affect enhancer regulatory regions, revealing an additional layer of complexity to the epigenetic regulation of gene expression. In this review, we summarize the novel evidence for the molecular and biological regulation of DNA methylation in enhancer regions and the dynamism of these changes contributing to the fine-tuning of gene expression. We also analyze the contribution of enhancer DNA methylation on the expression of relevant genes in acute myeloid leukemia and chronic myeloproliferative neoplasms. The characterization of the aberrant enhancer DNA methylation provides not only a novel pathogenic mechanism for different tumors but also highlights novel potential therapeutic targets for myeloid derived neoplasms

NADPH Oxidase has a Regulatory Role in Acute Allergic Asthma

Objective: For the establishment of inflammation, a constant interplay between different effector cells from circulation, local resident cells, soluble mediators and genetic host factors is required. Molecular mechanisms, initiating and perpetuating inflammation, in particular, the involvement of effector cells in redox reactions for producing O2- (superoxide anion) through the mediation of NADPH oxidase is a critical step. Prior data suggest that reactive oxygen species (ROS) produced by NADPH oxidase homologues in non-phagocytic cells play an important role in the regulation of signal transduction, while macrophages use a membrane-associated NADPH oxidase to generate an array of oxidizing intermediates which inactivate MMPs on or near them. Materials, Methods and Treatment: To clarify the role of NADPH oxidase in T cell-initiated, macrophage-associated allergic asthma, we induced allergen dependent inflammation in a gp91phox-/- mouse. Results: Both inflammation and airway hyperreactivity were more extensive than in wildtype mice post-OVA. Although OVA-specific IgE in plasma were comparable in wildtype and knockout mice, enhanced inflammatory cell recruitment from circulation and cytokine release in lung and BALf, accompanied by higher airway resistance as well as Penh in response to methacholine, indicates a regulatory role for NADPH oxidase in development of allergic asthma. While T cell-mediated functions like Th2 cytokine secretion, and proliferation to OVA were up-regulated synchronous with the overall robustness of the asthma phenotype, macrophage up-regulation in functions such as proliferation, mixed lymphocyte reaction, and MCP-1 directed chemotaxis, but downregulation of respiratory burst response indicates a forking in their signaling pathways. gp91phox-/- MMP12 double knockout (DKO) mice show a similar phenotype as the gp91phox-/- showing the non-involvement or synergistic involvement of MMP12 in the response pathway. In mixed lymphocyte reaction using the Increased B7.1 but reduced B7.2 and MHC class II expression indicating alteration of co-stimulatory molecule expression critical for T cell activation on both gp91phox-/- and DKO mice may explain the mechanism by which gp91phox may regulate Th2 pathway in allergic asthma

SITC 2018 workshop report: Immuno-Oncology Biomarkers: State of the Art.

Identification of biomarkers in cancer immunotherapy that predict therapeutic response and/or limit adverse events are a critical need in the field. To address recent progress and hurdles around cancer biomarker development and utilization, the Society for Immunotherapy of Cancer (SITC) convened a workshop, Immuno-Oncology Biomarkers: State of the Art, on May 16-17, 2018. Topics discussed included challenges in handling biospecimens, identification and validation of new biomarkers, data sharing, and collaborating across disciplines to advance biomarker development. Panel discussions followed session presentations to help foster participant conversation and discuss future projects and collaborations. The results of the Workshop include the development of new initiatives for the SITC Biomarkers Committee

Combating Cancer Through Public Health Practice in the United States: An In-Depth Look at the National Comprehensive Cancer Control Program

Cancer is the second leading cause of the death in the United States (U.S.). The National Comprehensive Cancer Control Program (NCCCP) is a national, public health practice program funded by the U.S. Centers for Disease Control and Prevention. The NCCCP has been planning and implementing interventions to reduce the burden of cancer since 1998. Interventions are implemented across three areas primary prevention, early detection, and survivorship using health systems and environmental changes to promote sustainable cancer control. The aim of this chapter is to provide a summary of the NCCCP, and highlight specific examples of interventions and successes to aid cancer planning in other countries. Cancer plan analyses show that all NCCCP participant cancer plans address reducing tobacco use for cancer prevention and 98% contain activities to increase colorectal cancer screening. The vast majority implement activities to improve the quality of life following a cancer diagnosis (94%). Relatively fewer cancer plans contain activities to reduce radon exposure (42%), promote human papilloma virus vaccination (62%), and incorporate the use of genomics in cancer control (56%). The examples of NCCCP activities demonstrate success in controlling cancer and other non-communicable diseases through public health practice

Survival prediction of high-risk outborn neonates with congenital diaphragmatic hernia from capillary blood gases

BACKGROUND: The extent of lung hypoplasia in neonates with congenital diaphragmatic hernia (CDH) can be assessed from gas exchange. We examined the role of preductal capillary blood gases in prognosticating outcome in patients with CDH. ----- METHODS: We retrospectively reviewed demographic data, disease characteristics, and preductal capillary blood gases on admission and within 24 h following admission for 44 high-risk outborn neonates. All neonates were intubated after delivery due to acute respiratory distress, and were emergently transferred via ground ambulance to our unit between 1/2000 and 12/2014. The main outcome measure was survival to hospital discharge and explanatory variables of interest were preductal capillary blood gases obtained on admission and during the first 24 h following admission. ----- RESULTS: Higher ratio of preductal partial pressure of oxygen to fraction of inspired oxygen (PcO2/FIO2) on admission predicted survival (AUC = 0.69, P = 0.04). However, some neonates substantially improve PcO2/FIO2 following initiation of treatment. Among neonates who survived at least 24 h, the highest preductal PcO2/FIO2 achieved in the initial 24 h was the strongest predictor of survival (AUC = 0.87, P = 0.002). Nonsurvivors had a mean admission preductal PcCO2 higher than survivors (91 ± 31 vs. 70 ± 25 mmHg, P = 0.02), and their PcCO2 remained high during the first 24 h of treatment. ----- CONCLUSION: The inability to achieve adequate gas exchange within 24 h of initiation of intensive care treatment is an ominous sign in high-risk outborn neonates with CDH. We suggest that improvement of oxygenation during the first 24 h, along with other relevant clinical signs, should be used when making decisions regarding treatment options in these critically ill neonates