Limited information is available on the safety of a rechallenge with an immune checkpoint inhibitor (ICI) after an immune-related adverse event (irAE).
To identify the recurrence rate of the same ...irAE that prompted discontinuation of ICI therapy after an ICI rechallenge in patients with cancer and to identify the clinical features associated with such recurrences.
This observational, cross-sectional, pharmacovigilance cohort study examined individual case safety reports from the World Health Organization database VigiBase, which contains case reports from more than 130 countries. Case reports were extracted from database inception (1967) to September 1, 2019. All consecutive ICI cases with at least 1 associated irAE were included.
The primary outcome was the rate of recurrence of the initial irAE after an ICI rechallenge. Secondary outcomes included the factors associated with the recurrence after a rechallenge among informative rechallenges, the recurrence rate according to the ICI regimen (anti-programmed cell death 1 or anti-programmed cell death ligand 1 monotherapy, anti-cytotoxic T-lymphocyte antigen-4 monotherapy, or combination therapy), and the rate of occurrence of a different irAE after a rechallenge.
A total of 24 079 irAE cases associated with at least 1 ICI were identified. Among the irAEs, 452 of 6123 irAEs associated with ICI rechallenges (7.4%) were informative rechallenges. One hundred thirty recurrences (28.8%; 95% CI, 24.8-33.1) of the initial irAE were observed. In a rechallenge, colitis (reporting odds ratio OR, 1.77; 95% CI, 1.14-2.75; P = .01), hepatitis (reporting OR, 3.38; 95% CI, 1.31-8.74; P = .01), and pneumonitis (reporting OR, 2.26; 95% CI, 1.18-4.32; P = .01) were associated with a higher recurrence rate, whereas adrenal events were associated with a lower recurrence rate (reporting OR, 0.33; 95% CI, 0.13-0.86; P = .03) compared with other irAEs.
This cohort study found a 28.8% recurrence rate of the same irAE associated with the discontinuation of ICI therapy after a rechallenge with the same ICI. Resuming ICI therapy could be considered for select patients, with appropriate monitoring and use of standard treatment algorithms to identify and treat toxic effects.
Processing of external information by mammalian cells often involves seemingly redundant isoforms of signaling molecules and transcription factors. Understanding the functional relevance of ...coexpressed isoforms that respond to the same signal and control a shared set of genes is still limited. Here we show, using imaging of individual living mammalian cells, that the closely related transcription factors NFAT1 and NFAT4 possess distinct nuclear localization dynamics in response to cell stimulation. NFAT4 shows a fast response, with rapid stochastic bursts of nuclear localization. Burst frequency grows with signal level, while response amplitude is fixed. In contrast, NFAT1 has a slow, continuous response, and its amplitude increases with signal level. These diverse dynamical features observed for single cells are translated into different impulse response strategies at the cell population level. We suggest that dynamic response diversity of seemingly redundant genes can provide cells with enhanced capabilities of temporal information processing.
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► Two isoforms of the NFAT proteins possess distinct and diverse dynamic responses ► NFAT4 shows fast, stochastic, and frequency-modulated bursts of nuclear localization ► NFAT1 shows a slow, continuous, and amplitude-modulated nuclear localization ► Dynamic diversity can endow cells with enhanced signal processing capabilities
Signal-transduction cascades are usually studied on cell averages, masking variability between individual cells. To address this, we studied in individual cells the dynamic response of ERK2, a ...well-characterized MAPK signaling protein, which enters the nucleus upon stimulation. Using fluorescent tagging at the endogenous chromosomal locus, we found that cells show wide basal variation in ERK2 nuclear levels. Upon EGF stimulation, cells show (1) a fold-change response, where peak nuclear accumulation of ERK2 is proportional to basal level in each cell; and (2) exact adaptation in nuclear levels of ERK2, returning to original basal level of each cell. The timing of ERK2 dynamics is more precise between cells than its amplitude. We further found that in some cells ERK2 exhibits a second pulse of nuclear entry, smaller than the first. The present study suggests that this signaling system compensates for natural biological noise: despite large variation in nuclear basal levels, ERK2's fold dynamics is similar between cells.
Abstract
The representation of turbulent mixing within the lower troposphere is needed to accurately portray the vertical thermodynamic and kinematic profiles of the atmosphere in mesoscale model ...forecasts. For mesoscale models, turbulence is mostly a subgrid-scale process, but its presence in the planetary boundary layer (PBL) can directly modulate a simulation’s depiction of mass fields relevant for forecast problems. The primary goal of this work is to review the various parameterization schemes that the Weather Research and Forecasting Model employs in its depiction of turbulent mixing (PBL schemes) in general, and is followed by an application to a severe weather environment. Each scheme represents mixing on a local and/or nonlocal basis. Local schemes only consider immediately adjacent vertical levels in the model, whereas nonlocal schemes can consider a deeper layer covering multiple levels in representing the effects of vertical mixing through the PBL. As an application, a pair of cold season severe weather events that occurred in the southeastern United States are examined. Such cases highlight the ambiguities of classically defined PBL schemes in a cold season severe weather environment, though characteristics of the PBL schemes are apparent in this case. Low-level lapse rates and storm-relative helicity are typically steeper and slightly smaller for nonlocal than local schemes, respectively. Nonlocal mixing is necessary to more accurately forecast the lower-tropospheric lapse rates within the warm sector of these events. While all schemes yield overestimations of mixed-layer convective available potential energy (MLCAPE), nonlocal schemes more strongly overestimate MLCAPE than do local schemes.
In this book, Ariel Cohen makes the novel proposal that an implicit quantifier isn't simply an empty category, but is generated by well-defined reinterpretation mechanisms. He demonstrates how this ...theory naturally accounts for puzzling properties of implicit quantification.
The considerable progress made in the field of cancer treatment has led to a dramatic improvement in the prognosis of patients with cancer. However, toxicities resulting from these treatments ...represent a cost that can be harmful to short- and long-term outcomes. Adverse events affecting the cardiovascular system are one of the greatest challenges in the overall management of patients with cancer, as they can compromise the success of the optimal treatment against the tumor. Such adverse events are associated not only with older chemotherapy drugs such as anthracyclines but also with many targeted therapies and immunotherapies. Recognizing this concern, several American and European governing societies in oncology and cardiology have published guidelines on the cardiovascular monitoring of patients receiving potentially cardiotoxic cancer therapies, as well as on the management of cardiovascular toxicities. However, the low level of evidence supporting these guidelines has led to numerous discrepancies, leaving clinicians without a consensus strategy to apply. A cardio-oncology expert panel from the French Working Group of Cardio-Oncology has undertaken an ambitious effort to analyze and harmonize the most recent American and European guidelines to propose roadmaps and decision algorithms that would be easy for clinicians to use in their daily practice. In this statement, the experts addressed the cardiovascular monitoring strategies for the cancer drugs associated with the highest risk of cardiovascular toxicities, as well as the management of such toxicities.
Immune checkpoint inhibitors (ICIs) represent a major advance in the treatment of cancer. Although clinical trials reported a low incidence of immune-related cardiovascular adverse events, the number ...of published life-threatening cases of cardiotoxicity is increasing. In this descriptive observational analysis, we aimed to describe the clinical manifestations, management, and outcomes of patients who developed ICI-related cardiotoxicity.
Abstract
Aims
While pulmonary embolism (PE) appears to be a major issue in COVID-19, data remain sparse. We aimed to describe the risk factors and baseline characteristics of patients with PE in a ...cohort of COVID-19 patients.
Methods and results
In a retrospective multicentre observational study, we included consecutive patients hospitalized for COVID-19. Patients without computed tomography pulmonary angiography (CTPA)-proven PE diagnosis and those who were directly admitted to an intensive care unit (ICU) were excluded. Among 1240 patients (58.1% men, mean age 64 ± 17 years), 103 (8.3%) patients had PE confirmed by CTPA. The ICU transfer and mechanical ventilation were significantly higher in the PE group (for both P < 0.001). In an univariable analysis, traditional venous thrombo-embolic risk factors were not associated with PE (P > 0.05), while patients under therapeutic dose anticoagulation before hospitalization or prophylactic dose anticoagulation introduced during hospitalization had lower PE occurrence odds ratio (OR) 0.40, 95% confidence interval (CI) 0.14–0.91, P = 0.04; and OR 0.11, 95% CI 0.06–0.18, P < 0.001, respectively. In a multivariable analysis, the following variables, also statistically significant in univariable analysis, were associated with PE: male gender (OR 1.03, 95% CI 1.003–1.069, P = 0.04), anticoagulation with a prophylactic dose (OR 0.83, 95% CI 0.79–0.85, P < 0.001) or a therapeutic dose (OR 0.87, 95% CI 0.82–0.92, P < 0.001), C-reactive protein (OR 1.03, 95% CI 1.01–1.04, P = 0.001), and time from symptom onset to hospitalization (OR 1.02, 95% CI 1.006–1.038, P = 0.002).
Conclusion
PE risk factors in the COVID-19 context do not include traditional thrombo-embolic risk factors but rather independent clinical and biological findings at admission, including a major contribution to inflammation.
Graphical Abstract
Graphical Abstract
Proteome Half-Life Dynamics in Living Human Cells Eden, Eran; Geva-Zatorsky, Naama; Issaeva, Irina ...
Science (American Association for the Advancement of Science),
02/2011, Letnik:
331, Številka:
6018
Journal Article
Recenzirano
Cells remove proteins by two processes: degradation and dilution due to cell growth. The balance between these basic processes is poorly understood. We addressed this by developing an accurate and ...noninvasive method for measuring protein half-lives, called "bleach-chase," that is applicable to fluorescently tagged proteins. Assaying 100 proteins in living human cancer cells showed half-lives that ranged between 45 minutes and 22.5 hours. A variety of stresses that stop cell division showed the same general effect: Long-lived proteins became longer-lived, whereas short-lived proteins remained largely unaffected. This effect is due to the relative strengths of degradation and dilution and suggests a mechanism for differential killing of rapidly growing cells by growth-arresting drugs. This approach opens a way to understand proteome half-life dynamics in living cells.
The square of disposition Cohen, Ariel
Glossa (London),
08/2018, Letnik:
3, Številka:
1
Journal Article
Recenzirano
Odprti dostop
I propose a classification of dispositions according to two parameters: (i) whether their argument is a causer, and (ii) whether they are (almost) always realized or only sometimes realized. This ...results in a four way distinction, which I represent as the Square of Disposition. Each cell of this square corresponds to a different type of disposition; I show that each such type is expressed by a distinct linguistic expression. This correspondence between philosophy-based and linguistics-based distinctions shows the potential usefulness of linguistic considerations in philosophical debates.
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