Pathogens with persistent environmental stages can have devastating effects on wildlife communities. White-nose syndrome (WNS), caused by the fungus Pseudogymnoascus destructans, has caused ...widespread declines in bat populations of North America. In 2009, during the early stages of the WNS investigation and before molecular techniques had been developed to readily detect P. destructans in environmental samples, we initiated this study to assess whether P. destructans can persist in the hibernaculum environment in the absence of its conclusive bat host and cause infections in naive bats. We transferred little brown bats (Myotis lucifugus) from an unaffected winter colony in northwest Wisconsin to two P. destructans contaminated hibernacula in Vermont where native bats had been excluded. Infection with P. destructans was apparent on some bats within 8 weeks following the introduction of unexposed bats to these environments, and mortality from WNS was confirmed by histopathology at both sites 14 weeks following introduction. These results indicate that environmental exposure to P. destructans is sufficient to cause the infection and mortality associated with WNS in naive bats, which increases the probability of winter colony extirpation and complicates conservation efforts.
White-nose syndrome (WNS) has caused recent catastrophic declines among multiple species of bats in eastern North America. The disease's name derives from a visually apparent white growth of the ...newly discovered fungus Geomyces destructans on the skin (including the muzzle) of hibernating bats. Colonization of skin by this fungus is associated with characteristic cutaneous lesions that are the only consistent pathological finding related to WNS. However, the role of G. destructans in WNS remains controversial because evidence to implicate the fungus as the primary cause of this disease is lacking. The debate is fuelled, in part, by the assumption that fungal infections in mammals are most commonly associated with immune system dysfunction. Additionally, the recent discovery that G. destructans commonly colonizes the skin of bats of Europe, where no unusual bat mortality events have been reported, has generated further speculation that the fungus is an opportunistic pathogen and that other unidentified factors are the primary cause of WNS. Here we demonstrate that exposure of healthy little brown bats (Myotis lucifugus) to pure cultures of G. destructans causes WNS. Live G. destructans was subsequently cultured from diseased bats, successfully fulfilling established criteria for the determination of G. destructans as a primary pathogen. We also confirmed that WNS can be transmitted from infected bats to healthy bats through direct contact. Our results provide the first direct evidence that G. destructans is the causal agent of WNS and that the recent emergence of WNS in North America may represent translocation of the fungus to a region with a naive population of animals. Demonstration of causality is an instrumental step in elucidating the pathogenesis and epidemiology of WNS and in guiding management actions to preserve bat populations against the novel threat posed by this devastating infectious disease.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Atovaquone, a US Food and Drug Administration–approved antiparasitic drug previously shown to reduce interleukin-6/STAT3 signaling in myeloma cells, is well tolerated, and plasma concentrations of 40 ...to 80 µM have been achieved with pediatric and adult dosing. We conducted preclinical testing of atovaquone with acute myeloid leukemia (AML) cell lines and pediatric patient samples. Atovaquone induced apoptosis with an EC50 <30 µM for most AML lines and primary pediatric AML specimens. In NSG mice xenografted with luciferase-expressing THP-1 cells and in those receiving a patient-derived xenograft, atovaquone-treated mice demonstrated decreased disease burden and prolonged survival. To gain a better understanding of the mechanism of atovaquone, we performed an integrated analysis of gene expression changes occurring in cancer cell lines after atovaquone exposure. Atovaquone promoted phosphorylation of eIF2α, a key component of the integrated stress response and master regulator of protein translation. Increased levels of phosphorylated eIF2α led to greater abundance of the transcription factor ATF4 and its target genes, including proapoptotic CHOP and CHAC1. Furthermore, atovaquone upregulated REDD1, an ATF4 target gene and negative regulator of the mechanistic target of rapamycin (mTOR), and caused REDD1-mediated inhibition of mTOR activity with similar efficacy as rapamycin. Additionally, atovaquone suppressed the oxygen consumption rate of AML cells, which has specific implications for chemotherapy-resistant AML blasts that rely on oxidative phosphorylation for survival. Our results provide insight into the complex biological effects of atovaquone, highlighting its potential as an anticancer therapy with novel and diverse mechanisms of action, and support further clinical evaluation of atovaquone for pediatric and adult AML.
•Atovaquone induces AML blast apoptosis and prolongs survival in AML xenografts.•Atovaquone induces proapoptotic signaling and inhibits the mTOR pathway through upregulation of ATF4 and also suppresses OXPHOS.
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Background: Although in recent clinical trials the 5-year event-free survival rates for pediatric Acute Myeloid Leukemia (AML) range between 49% and 64%, relapse still occurs in up to one-third of ...cases. Long-term outcomes of children with relapsed or refractory disease remain poor, with overall survival under 40%. Novel drugs directed toward distinct pathways and new molecular targets are required to continue improving outcomes for this aggressive hematological disease.
Use of the BCL-2 inhibitor, venetoclax, has improved overall and event-free survival in adult patients with newly diagnosed, intensive-chemotherapy ineligible AML, however, its effects in pediatric AML patients remain unclear. We reviewed our multi-institutional experience with venetoclax in this population.
Methods: We performed a retrospective review of patients ages 0 to 23 y/o with AML and treated with at least one cycle of venetoclax at either MD Anderson Cancer Center or Texas Children's Hospital prior to May 2021. Flow cytometry was used to assess morphology and response to therapy. Adverse events (AEs) associated with venetoclax were graded according to the Common Terminology Criteria for Adverse Events version 5.0. Descriptive statistics were used to report efficacy and toxicity data.
Results: 46 patients with AML who received venetoclax-containing regimens were identified. There was a similar proportion of males and females (52% and 48%) and most were Caucasian (48%). The median age was 21 years (range, 1-23) with eight patients (17%) <12 years of age. The most common AML subtype was M2 (30%; n=14) and the most common genetic mutations were FLT3-ITD (15%; n=7) and KMT2A (26%; n=12). Eight (17%) patients received venetoclax within front-line therapy and 38 (83%) as part of therapy for relapsed or refractory disease. Patients received a median of 2 therapies (range, 0-7) before venetoclax, with ten patients (22%) receiving at least four lines of prior therapy and twenty (43%) at least one prior allogeneic transplant. Venetoclax was combined with a hypomethylating agent in 28 (61%) patients. Dosing varied significantly ranging from 34-479 mg/m2 with 20% (n=9) requiring dose reduction due to concomitant use of azole antifungals. The most common grade 3/4 AE's observed included febrile neutropenia (41%; n=19), neutropenia (35%; n=16), anemia (20%; n=9), and thrombocytopenia (33%; n=15). No patients discontinued treatment because of AEs. The overall response rate in the 38 patients evaluated for disease at the end of cycle 1 was 53% (n=20). Complete remission (CR) or complete remission with incomplete blood count recovery (CRi) was achieved in 42% (n=16) of patients. Among those with CR/CRi, 9 (56%) were MRD negative. Of those sixteen, 4 (25%) had received venetoclax as front-line therapy. In total, seventeen patients (37%) were able to successfully transition to hematopoietic stem cell transplant. The median follow-up time was 8.5 months. Median progression-free survival (PFS) was 5.5 months (range, 0.13-36.61) and overall survival (OS) was 10 months (range, 0.13-36.61). Patients who received venetoclax as part of front-line therapy had a median PFS of 16.8 months (range, 0.72-17.5) and OS of 16.8 months (range, 0.72-28.75) with 4 (50%) patients still in ongoing remission.
Conclusion: Our findings suggest that in pediatric and early young adults, venetoclax is well-tolerated with a variety of cytotoxic agents and has a safety profile similar to that in adults. Patients should be monitored closely for prolonged myelosuppression and febrile neutropenia. As dosing varied significantly in our cohort, more studies are needed to establish an optimal dose in the pediatric population. Longer follow-up is expected to provide more insight on the improvement venetoclax may have on overall and progression-free survival.
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Kadia: Sanofi-Aventis: Consultancy; Dalichi Sankyo: Consultancy; Genentech: Consultancy, Other: Grant/research support; Genfleet: Other; AstraZeneca: Other; Astellas: Other; Pulmotech: Other; Cure: Speakers Bureau; Cellonkos: Other; Jazz: Consultancy; Pfizer: Consultancy, Other; Ascentage: Other; Novartis: Consultancy; Liberum: Consultancy; BMS: Other: Grant/research support; Amgen: Other: Grant/research support; Aglos: Consultancy; AbbVie: Consultancy, Other: Grant/research support. Konopleva: Cellectis: Other: grant support; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support; KisoJi: Research Funding; Calithera: Other: grant support, Research Funding; Rafael Pharmaceuticals: Other: grant support, Research Funding; Ascentage: Other: grant support, Research Funding; Sanofi: Other: grant support, Research Funding; Forty Seven: Other: grant support, Research Funding; Ablynx: Other: grant support, Research Funding; Agios: Other: grant support, Research Funding; AstraZeneca: Other: grant support, Research Funding; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights; Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights; Stemline Therapeutics: Research Funding; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding. DiNardo: Takeda: Honoraria; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; ImmuneOnc: Honoraria, Research Funding; AbbVie: Consultancy, Research Funding; Forma: Honoraria, Research Funding; Agios/Servier: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria; Foghorn: Honoraria, Research Funding; Celgene, a Bristol Myers Squibb company: Honoraria, Research Funding. Daver: Bristol Myers Squibb: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Sevier: Consultancy, Research Funding; Novartis: Consultancy; Astellas: Consultancy, Research Funding; Glycomimetics: Research Funding; Novimmune: Research Funding; Hanmi: Research Funding; Genentech: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; FATE Therapeutics: Research Funding; ImmunoGen: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Trovagene: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Dava Oncology (Arog): Consultancy; Celgene: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; Kite Pharmaceuticals: Consultancy; SOBI: Consultancy; STAR Therapeutics: Consultancy; Karyopharm: Research Funding; Newave: Research Funding. Short: AstraZeneca: Consultancy; Jazz Pharmaceuticals: Consultancy; NGMBio: Consultancy; Novartis: Honoraria; Astellas: Research Funding; Takeda Oncology: Consultancy, Research Funding; Amgen: Consultancy, Honoraria. Issa: Kura Oncology: Consultancy, Research Funding; Syndax Pharmaceuticals: Research Funding; Novartis: Consultancy, Research Funding. Ravandi: Amgen: Honoraria, Research Funding; Xencor: Honoraria, Research Funding; Taiho: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Novartis: Honoraria; AstraZeneca: Honoraria; AbbVie: Honoraria, Research Funding; Prelude: Research Funding; Astex: Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Syros Pharmaceuticals: Consultancy, Honoraria, Research Funding. Kantarjian: Ascentage: Research Funding; Astra Zeneca: Honoraria; Pfizer: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; KAHR Medical Ltd: Honoraria; Ipsen Pharmaceuticals: Honoraria; NOVA Research: Honoraria; Novartis: Honoraria, Research Funding; Immunogen: Research Funding; Astellas Health: Honoraria; BMS: Research Funding; Aptitude Health: Honoraria; Jazz: Research Funding; AbbVie: Honoraria, Research Funding; Precision Biosciences: Honoraria; Amgen: Honoraria, Research Funding; Taiho Pharmaceutical Canada: Honoraria.
Introduction: Lineage switch (LS) refers to the transformation of acute leukemia from one cell lineage to another (e.g., lymphoid (ALL) to myeloid (AML)). This rare phenomenon, distinct from ...treatment induced malignancy (i.e., t-AML) and mixed phenotype acute leukemia (MPAL), is increasingly being observed following cell surface antigen targeting. Given challenges in the diagnosis and treatment of LS, Project EVOLVE was developed to globally identify cases of LS following immunotherapy.
Methods: A protocol and data collection form for this IRB exempt study was widely disseminated to capture deidentified LS case information across multiple centers and cancer consortia. This included collection of data from published reports of LS, with authors contacted to obtain additional information.
For this analysis, LS was defined by the emergence of cell-surface markers warranting reclassification of the original leukemia as a different lineage derivation based on the immunophenotype, including cases of AML emerging alongside the original ALL. “Confirmed” LS cases included those where retention of original cytogenetic or molecular aberrations and/or the clonal immunoglobulin rearrangement patterns were verified to confirm the clonal relationship. “Suspected” LS cases included those where samples to confirm clonality marker retention could not be obtained, but the clinical presentation was consistent with LS. The term “transition” was applied when immunophenotypic shifts were transient. Cases with new cytogenetic abnormalities unrelated to the original diagnosis and compatible with t-AML were excluded. Statistical analysis was primarily descriptive. Data cut-off was July 26, 2023.
Results: A total of 58 cases were identified, including 19 cases referenced in prior publications. Of the 58, 11 cases were excluded from this initial analysis, including: 4 cases of t-AML, 2 cases of T-ALL to AML, and 5 “transition” cases. Collectively, 47 cases of LS (43 “confirmed”; 4 “suspected”), spanning across 3 continents and 8 countries, were analyzed. (Fig. 1A)
Cases included transition from B-ALL to AML in 36 (76.6%) and to MPAL/biphenotypic/ambiguous lineage in 11 (23.4%). Two likely had MPAL at diagnosis and a third with chronic myeloid leukemia. The median age at initial diagnosis was 8.4 years (range, 1 day-76.5 years); median age at LS presentation was 11.0 years (range 0.4-77.3 years). Twenty-three (48.9%) were male and 19 (40.4%) had prior stem cell transplant (SCT). Baseline cytogenetics showed KMT2A rearrangement in 27 (57.4%). Baseline myeloid antigen co-expression was seen in 22 of 23 patients with submitted data, but variation in degree of expression across patients and antigens was substantial.
The most proximal immunotherapy prior to development of LS was CAR T-cells in 23 (48.9%) and blinatumomab in 24 (51.1%). The median time from the most proximal immunotherapy to development of LS was 1.6 months (range, 7 days-36.5 months). In 7 (29.2%) patients receiving blinatumomab, LS developed during the infusion. LS presented as isolated marrow relapse in 27 (57.4%), isolated CNS in 2 (4.3%), isolated non-CNS extramedullary disease in 3 (6.4%), combined relapse in 14 (29.8%) and unreported in 1.
First line treatment for LS was chemotherapy induction in 31 (66.0%), palliative care/no therapy in 8 (17.0%), and alternative therapies in the remaining 8 (17.0%). In 35 (74.5%) patients, remission induction was the goal of first line therapy. Fifteen (31.9%) achieved a complete remission (CR) of whom 2 were treated with palliative intent.
Across all patients, 8 (17.0%) are alive in remission, the longest being 4.7 years from LS diagnosis; 2 (4.3%) are alive with active LS and 37 (78.7%) died from LS, their original disease, or complications of treatment of LS (Fig 1B). For those alive in CR (n=8), 7 (87.5%) proceeded to a consolidative SCT for treatment of LS and 1 patient, an octogenarian remains in remission after AML directed therapy.
Conclusions: LS is emerging as an important mechanism of immune escape following immunotherapy. Project EVOLVE provides the largest dataset of patients with LS to date. This systematic, international effort reveals substantial complexity and variability in diagnosing and managing LS. Unfortunately, outcomes following LS are grim, underscoring the critical need to identify risk factors of and optimal therapies for this leukemia transformation.
Thesis (M.S.)--University of Wisconsin--Madison, 2005.
Typescript. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.
Injury Research Li, Guohua; Baker, Susan P
2012, 2012-01-06
eBook
Injury is recognized as a major public health issue worldwide. In most countries, injury is the leading cause of death and disability for children and young adults age 1 to 39 years. Each year in the ...United States, injury claims about 170,000 lives and results in over 30 million emergency room visits and 2.5 million hospitalizations. Injury is medically defined as organ/tissue damages inflicted upon oneself or by an external agent either accidentally or deliberately. Injury encompasses the undesirable consequences of a wide array of events, such as motor vehicle crashes, poisoning, burns, falls, and drowning, medical error, adverse effects of drugs, suicide and homicide. The past two decades have witnessed a remarkable growth in injury research, both in scope and in depth. To address the tremendous health burden of injury morbidity and mortality at the global level, the World Health Organization in 2000 created the Department of Injury and Violence Prevention, which has produced several influential reports on violence, traffic injury, and childhood injury. The biennial World Conference on Injury Control and Safety Promotion attracts a large international audience and has been successfully convened nine times in different countries. In the United States, the National Center for Injury Prevention and Control became an independent program of the federal Centers for Disease Prevention and Control in 1997. Since then, each state health department has created an office in charge of injury prevention activities and over a dozen universities have established injury control research centers. This volume will fill an important gap in the scientific literature by providing a comprehensive and up-to-date reference resource to researchers, practitioners, and students working on different aspects of the injury problem and in different practice settings and academic fields.
Fast mutual exclusion for uniprocessors Bershad, Brian N.; Redell, David D.; Ellis, John R.
ASPLOS-V proceedings,
09/1992, Letnik:
27, Številka:
9
Journal Article
Odprti dostop
In this paper we describe restartable atomic sequences, an
optimistic
mechanism for implementing simple atomic operations (such as
Test-And-Set
) on a uniprocessor. A thread that is suspended within ...a restartable atomic sequence is resumed by the operating system at the beginning of the sequence, rather than at the point of suspension. This guarantees that the thread eventually executes the sequence
atomically
. A restartable atomic sequence has significantly less overhead than other software-based synchronization mechanisms, such as kernel emulation or software reservation. Consequently, it is an attractive alternative for use on uniprocessors that do no support atomic operations. Even on processors that do support atomic operations in hardware, restartable atomic sequences can have lower overhead.
We describe different implementations of restartable atomic sequences for the Mach 3.0 and Taos operating systems. These systems' thread management packages rely on atomic operations to implement higher-level mutual exclusion facilities. We show that improving the performance of low-level atomic operations, and therefore mutual exclusion mechanisms, improves application performance.
Fast mutual exclusion for uniprocessors Bershad, Brian N.; Redell, David D.; Ellis, John R.
ASPLOS-V proceedings,
10/1992, Letnik:
27, Številka:
9
Conference Proceeding, Journal Article
Odprti dostop
In this paper we describe restartable atomic sequences, an optimistic mechanism for implementing simple atomic operations (such as Test-And-Set) on a uniprocessor. A thread that is suspended within a ...restartable atomic sequence is resumed by the operating system at the beginning of the sequence, rather than at the point of suspension. This guarantees that the thread eventually executes the sequence atomically. A restartable atomic sequence has significantly less overhead than other software-based synchronization mechanisms, such as kernel emulation or software reservation. Consequently, it is an attractive alternative for use on uniprocessors that do no support atomic operations. Even on processors that do support atomic operations in hardware, restartable atomic sequences can have lower overhead.
We describe different implementations of restartable atomic sequences for the Mach 3.0 and Taos operating systems. These systems' thread management packages rely on atomic operations to implement higher-level mutual exclusion facilities. We show that improving the performance of low-level atomic operations, and therefore mutual exclusion mechanisms, improves application performance.
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