Ariel - Volume 4 Number 1

Editors David A. Jacoby Eugenia Miller Tom Williams Associate Editors Paul Bialas Terry Burt Michael Leo Gail Tenikat Editor Emeritus and Business Manager Richard J. Bonnano Movie Editor Robert Breckenridg

Ariel - Volume 5 Number 5

Editors Mark Dembert J. D. Kanofsky Entertainment Robert Breckenridge Joe Conti Gary Kaskey Photographer Scot Kastner Overseas Editor Mike Sinason Circulation Jay Amsterdam Humorist Jim McCann Staff Ken Jaffe Bob Sklaroff Janet Welsh Dave Jacoby Phil Nimoityn Frank Chervane

Ariel - Volume 4 Number 7

Editors David Jacoby Eugenia Miller Tom Williams Associate Editors Paul Bialas Terry Burt Michael Leo Gail Tenikat Editor Emeritus and Business Manager Richard J. Bonnano Movie Editor Robert Breckenridge Staff Richard Blutstein Mary F. Buechler J.D. Kanofsky David Mayer Rocket Webe

Macrophage TNF-α mediates parathion-induced airway hyperreactivity in guinea pigs.

Organophosphorus pesticides (OPs) are implicated in human asthma. We previously demonstrated that, at concentrations that do not inhibit acetylcholinesterase activity, the OP parathion causes airway hyperreactivity in guinea pigs as a result of functional loss of inhibitory M2 muscarinic receptors on parasympathetic nerves. Because macrophages are associated with asthma, we investigated whether macrophages mediate parathion-induced M2 receptor dysfunction and airway hyperreactivity. Airway physiology was measured in guinea pigs 24 h after a subcutaneous injection of parathion. Pretreatment with liposome-encapsulated clodronate induced alveolar macrophage apoptosis and prevented parathion-induced airway hyperreactivity in response to electrical stimulation of the vagus nerves. As determined by qPCR, TNF-α and IL-1β mRNA levels were increased in alveolar macrophages isolated from parathion-treated guinea pigs. Parathion treatment of alveolar macrophages ex vivo did not significantly increase IL-1β and TNF-α mRNA but did significantly increase TNF-α protein release. Consistent with these data, pretreatment with the TNF-α inhibitor etanercept but not the IL-1β receptor inhibitor anakinra prevented parathion-induced airway hyperreactivity and protected M2 receptor function. These data suggest a novel mechanism of OP-induced airway hyperreactivity in which low-level parathion activates macrophages to release TNF-α-causing M2 receptor dysfunction and airway hyperreactivity. These observations have important implications regarding therapeutic approaches for treating respiratory disease associated with OP exposures

Persistent molecular disease in adult patients with AML evaluated with whole-exome and targeted error-corrected DNA sequencing

PURPOSE: Persistent molecular disease (PMD) after induction chemotherapy predicts relapse in AML. In this study, we used whole-exome sequencing (WES) and targeted error-corrected sequencing to assess the frequency and mutational patterns of PMD in 30 patients with AML. MATERIALS AND METHODS: The study cohort included 30 patients with adult AML younger than 65 years who were uniformly treated with standard induction chemotherapy. Tumor/normal WES was performed for all patients at presentation. PMD analysis was evaluated in bone marrow samples obtained during clinicopathologic remission using repeat WES and analysis of patient-specific mutations and error-corrected sequencing of 40 recurrently mutated AML genes (MyeloSeq). RESULTS: WES for patient-specific mutations detected PMD in 63% of patients (19/30) using a minimum variant allele fraction (VAF) of 2.5%. In comparison, MyeloSeq identified persistent mutations above 0.1% VAF in 77% of patients (23/30). PMD was usually present at relatively high levels (\u3e2.5% VAFs), such that WES and MyeloSeq agreed for 73% of patients despite differences in detection limits. Mutations in CONCLUSION: PMD and clonal hematopoiesis are both common in patients with AML in first remission. These findings demonstrate the importance of baseline testing for accurate interpretation of mutation-based tumor monitoring assays for patients with AML and highlight the need for clinical trials to determine whether these complex mutation patterns correlate with clinical outcomes in AML

A systematic review of higher-risk myelodysplastic syndromes clinical trials to determine the benchmark of azacitidine and explore alternative endpoints for overall survival

The hypomethylating agent azacitidine can prolong overall survival (OS) in patients with higher risk-myelodysplastic syndromes (HR-MDS) compared to conventional regimens. However, outcomes differ largely between studies, making it challenging to determine the contribution of novel therapies added to azacitidine. Further, a discrepancy is seen between complete (CR) or partial (PR) response rates and OS improvement with azacitidine, making it challenging to rely on earlier endpoints than OS. We conducted a systematic literature search and study-level systematic review of 237 clinical studies to better understand outcomes for HR-MDS patients treated with azacitidine. Pooled marrow CR was 9% (N = 2654; 95% CI: 6-13 %), CR rate was 17 % (N = 6943; 95% CI: 15-20 %), and median OS (mOS) was 18.6 months (N = 2820; 95% CI: 15.3-21.9). A weak correlation to mOS was detected with CR rate (207 patient cohorts, Pearson\u27s r = 0.315; P \u3c 0.0005), and a much stronger correlation with median progression-free survival (mPFS) (r=0.88, P = 3 × 1

Behind the stiff upper lip: war narratives of older men with dementia.

The concept of the stiff upper lip stands as a cultural metaphor for the repression and figurative ¿biting back¿ of traumatic experience, particularly in military contexts. For men born in the first half of the 20th century, maintaining a stiff upper lip involved the ability to exert high levels of cognitive control over the subjective, visceral and emotional domains of experience. In the most common forms of dementia, which affect at least one in five men now in their 80s and 90s, this cognitive control is increasingly lost. One result is that, with the onset of dementia, men who have in the intervening years maintained a relative silence about their wartime experiences begin to disclose detailed memories of such events, in some cases for the first time. This article draws on narrative biographical data from three men with late-onset dementia who make extensive reference to their experience of war. The narratives of Sid, Leonard and Nelson are used to explore aspects of collective memory of the two World Wars, and the socially constructed masculinities imposed on men who grew up and came of age during those decades. The findings show that in spite of their difficulties with short term memory, people with dementia can contribute rich data to cultural studies research. Some aspects of the narratives discussed here may also be considered to work along the line of the counter-hegemonic, offering insights into lived experiences of war that have been elided in popular culture in the post-War years

Molecular gas in the inner 0.7kpc-radius ring of M31

The study of the gas kinematic in the central 1.5kpc x 1.5kpc region of M31 has revealed several surprises. The starting point of this investigation was the detection at the IRAM-30m telescope of molecular gas with very large line splittings up to 260km/s within the beam (40 pc). In this region, which is known for its low gas content, we also detect an ionised gas outflow in the circumnuclear region (within 75pc from the centre) extending to the whole area in X-ray. Relying on atomic, ionised, and molecular gas, we account for most observables with a scenario that assumes that a few hundreds Myr ago, M31 underwent a frontal collision with M32, which triggered some star-formation activity in the centre, and this collision explains the special configuration of M31 with two rings observed at 0.7kpc and 10kpc. The inner disc (whose rotation is detected in HI and ionised gas ([NII])) has thus been tilted (inclination: 43deg, PA: 70deg) with respect to the main disc (inclination: 77deg, PA: 35deg). One of the CO velocity components is compatible with this inner disc, while the second one comes from a tilted ring-like material with 40deg inclination and PA=-35deg. The relic star formation estimated by previous works to have occurred more than 100Myr ago could have been triggered by the collision and could be linked to the outflow detected in the ionised gas. Last, we demonstrate that the amplitude of the line splittings detected in CO centred on the systemic velocity with a relatively high spatial resolution (40pc) cannot be accounted for by a possible weak bar that is roughly aligned along the minor axis. Although M31 has a triaxial bulge, there are no bar indicators in the gas component (photometry, no strong skewness of the isovelocities, etc.).Comment: 20 pages, 20 figures, Astronomy and Astrophysics, accepte