Hyperthermia, the mild elevation of temperature to 40-43°C, can induce cancer cell death and enhance the effects of radiotherapy and chemotherapy. However, achievement of its full potential as a ...clinically relevant treatment modality has been restricted by its inability to effectively and preferentially heat malignant cells. The limited spatial resolution may be circumvented by the intravenous administration of cancer-targeting magnetic nanoparticles that accumulate in the tumor, followed by the application of an alternating magnetic field to raise the temperature of the nanoparticles located in the tumor tissue. This targeted approach enables preferential heating of malignant cancer cells whilst sparing the surrounding normal tissue, potentially improving the effectiveness and safety of hyperthermia. Despite promising results in preclinical studies, there are numerous challenges that must be addressed before this technique can progress to the clinic. This review discusses these challenges and highlights the current understanding of targeted magnetic hyperthermia.
The COVID-19 pandemic progresses unabated in many regions of the world. An effective antiviral against SARS-CoV-2 that could be administered orally for use following high-risk exposure would be of ...substantial benefit in controlling the COVID-19 pandemic. Herein, we show that MK-4482, an orally administered nucleoside analog, inhibits SARS-CoV-2 replication in the Syrian hamster model. The inhibitory effect of MK-4482 on SARS-CoV-2 replication is observed in animals when the drug is administered either beginning 12 h before or 12 h following infection in a high-risk exposure model. These data support the potential utility of MK-4482 to control SARS-CoV-2 infection in humans following high-risk exposure as well as for treatment of COVID-19 patients.
We detected delayed and reduced antibody and T-cell responses after BNT162b2 vaccination in 71 elderly persons (median age 81 years) compared with 123 healthcare workers (median age 34 years) in ...Germany. These data emphasize that nonpharmaceutical interventions for coronavirus disease remain crucial and that additional immunizations for the elderly might become necessary.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Review of how neutrophils contribute to antibody‐dependent allergic and inflammatory reactions.
Neutrophils are notorious for their efficacy in microbial killing. Various mechanisms, such as ...phagocytosis, production of ROS, cytokines/chemokines and lipid mediators, degranulation of antimicrobials and enzymes, as well as NETosis contribute to this capacity. However, every incidence of neutrophil activation bears a risk to cause damage to the host. Several distinct steps, i.e., adhesion to endothelial cells, transmigration, chemotaxis, cytokine stimulation, and TLR signaling, are thought to control the extent of neutrophil activation. In the absence of a microbial stimulus, other pathways can induce neutrophil activation, among which FcR‐induced activation when neutrophils encounter ICs. In these situations (inflammation, autoimmunity, allergy), neutrophils may act as primary or secondary effectors of immune reactions. In the presence of circulating ICs, neutrophils can indeed get stimulated directly in the bloodstream and trigger an immune response. Upon deposition of antibody complexes inside of tissues, neutrophils are first recruited and primed before being highly activated to amplify the ongoing inflammation. This review focuses on the engagement, activation, and responses of neutrophils to antibody ICs, inside of tissues or in the vasculature.
The World Health Organization (WHO) classification and grading system attempts to predict the clinical course of meningiomas based on morphological parameters. However, because of high interobserver ...variation of some criteria, more reliable prognostic markers are required. Here, we assessed the TERT promoter for mutations in the hotspot regions C228T and C250T in meningioma samples from 252 patients. Mutations were detected in 16 samples (6.4% across the cohort, 1.7%, 5.7%, and 20.0% of WHO grade I, II, and III cases, respectively). Data were analyzed by t test, Fisher's exact test, log-rank test, and Cox proportional hazard model. All statistical tests were two-sided. Within a mean follow-up time in surviving patients of 68.1 months, TERT promoter mutations were statistically significantly associated with shorter time to progression (P < .001). Median time to progression among mutant cases was 10.1 months compared with 179.0 months among wild-type cases. Our results indicate that the inclusion of molecular data (ie, analysis of TERT promoter status) into a histologically and genetically integrated classification and grading system for meningiomas increases prognostic power. Consequently, we propose to incorporate the assessment of TERT promoter status in upcoming grading schemes for meningioma.
Public neoantigens (NeoAgs) represent an elite class of shared cancer-specific epitopes derived from recurrently mutated driver genes. Here we describe a high-throughput platform combining ...single-cell transcriptomic and T cell receptor (TCR) sequencing to establish whether mutant PIK3CA, among the most frequently genomically altered driver oncogenes, generates an immunogenic public NeoAg. Using this strategy, we developed a panel of TCRs that recognize an endogenously processed neopeptide encompassing a common PIK3CA hotspot mutation restricted by the prevalent human leukocyte antigen (HLA)-A*03:01 allele. Mechanistically, immunogenicity to this public NeoAg arises from enhanced neopeptide/HLA complex stability caused by a preferred HLA anchor substitution. Structural studies indicated that the HLA-bound neopeptide presents a comparatively 'featureless' surface dominated by the peptide's backbone. To bind this epitope with high specificity and affinity, we discovered that a lead TCR clinical candidate engages the neopeptide through an extended interface facilitated by an unusually long CDR3β loop. In patients with diverse malignancies, we observed NeoAg clonal conservation and spontaneous immunogenicity to the neoepitope. Finally, adoptive transfer of TCR-engineered T cells led to tumor regression in vivo in mice bearing PIK3CA-mutant tumors but not wild-type PIK3CA tumors. Together, these findings establish the immunogenicity and therapeutic potential of a mutant PIK3CA-derived public NeoAg.
Background Anaphylaxis can proceed through distinct IgE- or IgG-dependent pathways, which have been investigated in various mouse models. We developed a novel mouse strain in which the human ...low-affinity IgG receptor locus, comprising both activating (hFcγRIIA, hFcγRIIIA, and hFcγRIIIB) and inhibitory (hFcγRIIB) hFcγR genes, has been inserted into the equivalent murine locus, corresponding to a locus swap. Objective We sought to determine the capabilities of hFcγRs to induce systemic anaphylaxis and identify the cell types and mediators involved. Methods hFcγR expression on mouse and human cells was compared to validate the model. Passive systemic anaphylaxis was induced by injection of heat-aggregated human intravenous immunoglobulin and active systemic anaphylaxis after immunization and challenge. Anaphylaxis severity was evaluated based on hypothermia and mortality. The contribution of receptors, mediators, or cell types was assessed based on receptor blockade or depletion. Results The human-to-mouse low-affinity FcγR locus swap engendered hFcγRIIA/IIB/IIIA/IIIB expression in mice comparable with that seen in human subjects. Knock-in mice were susceptible to passive and active anaphylaxis, accompanied by downregulation of both activating and inhibitory hFcγR expression on specific myeloid cells. The contribution of hFcγRIIA was predominant. Depletion of neutrophils protected against hypothermia and mortality. Basophils contributed to a lesser extent. Anaphylaxis was inhibited by platelet-activating factor receptor or histamine receptor 1 blockade. Conclusion Low-affinity FcγR locus-switched mice represent an unprecedented model of cognate hFcγR expression. Importantly, IgG-related anaphylaxis proceeds within a native context of activating and inhibitory hFcγRs, indicating that, despite robust hFcγRIIB expression, activating signals can dominate to initiate a severe anaphylactic reaction.
For the first time in 2023, countries will assess their collective progress with respect to reaching the climate policy aims of the United Nations Framework Convention on Climate Change’s (UNFCCC) ...Paris Agreement.1 Much of the attention of this so-called global stocktake will be focused on mitigation efforts to reduce greenhouse gas emissions at the national level. According to the Paris Agreement, this stocktake will take place every five years, and should be done in a “comprehensive and facilitative manner, considering mitigation, adaptation and the means of implementation and support, and in the light of equity and the best available science.” Using event attribution to assess impacts At present, the impacts of climate change mostly manifest through the changing likelihood and intensity of extreme weather events (e.g., heat waves, floods, droughts) or slow-onset events like sea level rise or changes in seasonality, e.g., the lack of frost (Pfleiderer et al. 2019). ...to assess loss and damage, plan adaptation and feed into the global stocktake, we need to use currently available science.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In August 2017 Bangladesh faced one of its worst river flooding events in
recent history. This paper presents, for the first time, an attribution of this
precipitation-induced flooding to ...anthropogenic climate change from a
combined meteorological and hydrological perspective. Experiments were
conducted with three observational datasets and two climate models to
estimate changes in the extreme 10-day precipitation event frequency over the
Brahmaputra basin up to the present and, additionally, an outlook to 2 ∘C warming since pre-industrial times.
The precipitation fields were then used as meteorological input for four
different hydrological models to estimate the corresponding changes in river
discharge, allowing for comparison between approaches and for the robustness
of the attribution results to be assessed. In all three observational precipitation datasets the climate change trends
for extreme precipitation similar to that observed in August 2017 are not
significant, however in two out of three series, the sign of this
insignificant trend is positive. One climate model ensemble shows a
significant positive influence of anthropogenic climate change, whereas the
other large ensemble model simulates a cancellation between the increase due
to greenhouse gases (GHGs) and a decrease due to sulfate aerosols. Considering
discharge rather than precipitation, the hydrological models show that
attribution of the change in discharge towards higher values is somewhat less
uncertain than in precipitation, but the 95 % confidence intervals still
encompass no change in risk. Extending the analysis to the future, all models
project an increase in probability of extreme events at 2 ∘C global
heating since pre-industrial times, becoming more than 1.7 times more likely
for high 10-day precipitation and being more likely by a factor of about 1.5 for
discharge. Our best estimate on the trend in flooding events similar to the
Brahmaputra event of August 2017 is derived by synthesizing the observational
and model results: we find the change in risk to be greater than 1 and of
a similar order of magnitude (between 1 and 2) for both the meteorological and
hydrological approach. This study shows that, for precipitation-induced
flooding events, investigating changes in precipitation is useful, either as
an alternative when hydrological models are not available or as an
additional measure to confirm qualitative conclusions. Besides this, it highlights
the importance of using multiple models in attribution studies, particularly
where the climate change signal is not strong relative to natural variability
or is confounded by other factors such as aerosols.
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