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ACS Applied Bio Materials Jul 2024The increasing prevalence of multidrug-resistant (MDR) pathogens has promoted the development of innovative approaches, such as drug repurposing, synergy, and efficient...
The increasing prevalence of multidrug-resistant (MDR) pathogens has promoted the development of innovative approaches, such as drug repurposing, synergy, and efficient delivery, in complement to traditional antibiotics. In this study, we present an approach based on biocompatible nanocarriers containing antimicrobial cations and known antibiotics. The matrices were prepared by coordinating Ga or In to formulations of chitosan/tripolyphosphate or catechol-functionalized chitosan with or without encapsulated antibiotics, yielding particles of 100-200 nm in hydrodynamic diameter. MDR clinical isolates of were found to be effectively inhibited by the nanocarriers under nutrient-limiting conditions. Fractional inhibitory concentration (FIC) indices revealed that cation- and antibiotic-encapsulated nanomatrices were effective against both Gram-negative and Gram-positive pathogens. Metallophores, such as deferoxamine (DFO), were probed to facilitate the sequestration and transport of the antimicrobial cations Ga or In. Although the antimicrobial activities were less significant with DFO, the eradication of biofilm-associated bacteria showed promising trends against and . Interestingly, indium-containing compounds showed enhanced activity on biofilm formation and eradication, neutralizing under Fe-limiting conditions. In particular, In-cross-linked catechol-modified chitosan matrices were able to inhibit pathogenic growth together with DFO. The nanocarriers showed low cytotoxicity toward A549 cells and improvable CC values with NIH/3T3 cells.
PubMed: 38963757
DOI: 10.1021/acsabm.4c00619 -
Biopreservation and Biobanking Jul 2024
PubMed: 38963755
DOI: 10.1089/bio.2024.0022 -
Current Opinion in Allergy and Clinical... Jul 2024Cancer immunotherapy is one of the most emerging and rapidly growing fields.Ocular side effects associated with these therapies are common and can be present in up to...
PURPOSE OF REVIEW
Cancer immunotherapy is one of the most emerging and rapidly growing fields.Ocular side effects associated with these therapies are common and can be present in up to 70% of patients.The cornea may be involved in different pathogenic mechanisms triggered by different immunotherapeutic agents, and corneal disease varies from mild symptoms to severe corneal ulceration and melting with visual loss.We aimed to review the incidence, mechanism, and management of ocular surface side effects in cancer patients receiving immunotherapy.
RECENT FINDINGS
With the recent use of immunotherapeutic agents in cancer patients, in particular immune checkpoint inhibitors (ICIs) and epidermal growth factor receptor (EGFR) inhibitors, ocular surface and corneal involvement are common side effects.These patients can be at risk of sight threatening complications that warrant prompt diagnosis and careful monitoring and management.
SUMMARY
Immunotherapy- related corneal complications in cancer patients are associated with a decreased quality of life. Prompt recognition and an interdisciplinary approach between ophthalmologists and oncologists are crucial to handle immune related ocular adverse events in these patients, in order to maintain ocular surface integrity and avoid a vision threatening complication.
PubMed: 38963724
DOI: 10.1097/ACI.0000000000001007 -
European Thyroid Journal Jul 2024Impaired sensitivity to thyroid hormones encompasses disorders with defective transport of hormones into cells, reduced hormone metabolism and resistance to hormone...
Impaired sensitivity to thyroid hormones encompasses disorders with defective transport of hormones into cells, reduced hormone metabolism and resistance to hormone action. Mediated by heritable single gene defects, these rare conditions exhibit different patterns of discordant thyroid function associated with multisystem phenotypes. In this context, challenges include ruling out other causes of biochemical discordance, making a diagnosis using clinical features together with identification of pathogenic variants in causal genes and managing these rare disorders with a limited evidence base. For each condition, the present guidelines aim to inform clinical practice by summarising key clinical features and useful investigations, criteria for molecular genetic diagnosis and pathways for management and therapy. Specific, key recommendations were developed by combining the best research evidence available with the knowledge and clinical experience of panel members, to achieve a consensus.
PubMed: 38963712
DOI: 10.1530/ETJ-24-0125 -
The Journal of Clinical Investigation Jul 2024Antibiotic-Refractory Lyme Arthritis (ARLA) involves a complex interplay of T cell responses targeting Borrelia burgdorferi antigens succeeding towards autoantigens by...
BACKGROUND
Antibiotic-Refractory Lyme Arthritis (ARLA) involves a complex interplay of T cell responses targeting Borrelia burgdorferi antigens succeeding towards autoantigens by epitope spreading. However, the precise molecular mechanisms driving the pathogenic T cell response in ARLA remain unclear. Our aim was to elucidate the molecular program of disease-specific Th cells.
METHODS
Using flow cytometry, high-throughput T cell receptor (TCR) sequencing and scRNA-seq of CD4+ Th cells isolated from the joints of European ARLA patients, we aimed at inferring antigen specificity through unbiased analysis of TCR repertoire patterns, identifying surrogate markers for disease-specific TCRs and connecting TCR specificity to transcriptional patterns.
RESULTS
PD-1hiHLA-DR+CD4+ effector T cells were clonally expanded within the inflamed joints and persisted throughout disease course. Among these cells, we identified a distinct TCRβ motif restricted to HLA-DRB1*11 or *13 alleles. These alleles, being underrepresented in North American ARLA patients, were unexpectedly prevalent in our European cohort. The identified TCRβ motif served as surrogate marker for a convergent TCR response specific to ARLA, distinguishing it from other rheumatic diseases. In the scRNA-seq dataset, the TCRβ motif particularly mapped to peripheral T helper (TPH) cells displaying signs of sustained proliferation, continuous TCR signaling, and expressing CXCL13 and IFN-γ.
CONCLUSION
By inferring disease-specific TCRs from synovial T cells we identified a convergent TCR response in the joints of ARLA patients that continuously fueled the expansion of TPH cells expressing a pathogenic cytokine effector program. The identified TCRs will aid in uncovering the major antigen targets of the maladaptive immune response.
FUNDING
Supported by the German Research Foundation (DFG) MO 2160/4-1; the Federal Ministry of Education and Research (BMBF; Advanced Clinician Scientist-Program INTERACT; 01EO2108) embedded in the Interdisciplinary Center for Clinical Research (IZKF) of the University Hospital Würzburg; the German Center for Infection Research (DZIF; Clinical Leave Program; TI07.001_007) and the Interdisciplinary Center for Clinical Research (IZKF) Würzburg (Clinician Scientist Program, Z-2/CSP-30).
PubMed: 38963700
DOI: 10.1172/JCI179391 -
American Journal of Biological... Jul 2024Here we investigate infectious diseases that potentially contribute to osteological lesions in individuals from the early medieval necropolis of La Olmeda (6th-11th c....
OBJECTIVE
Here we investigate infectious diseases that potentially contribute to osteological lesions in individuals from the early medieval necropolis of La Olmeda (6th-11th c. CE) in North Iberia.
MATERIALS AND METHODS
We studied a minimum number of 268 individuals (33 adult females; 38 adult males, 77 unknown/indeterminate sex; and 120 non-adults), including articulated and commingled remains. Individuals with differential diagnoses suggesting chronic systemic infectious diseases were sampled and bioinformatically screened for ancient pathogen DNA.
RESULTS
Five non-adults (and no adults) presented skeletal evidence of chronic systemic infectious disease (1.87% of the population; 4.67% of non-adults). The preferred diagnoses for these individuals included tuberculosis, brucellosis, and malaria. Ancient DNA fragments assigned to the malaria-causing pathogen, Plasmodium spp., were identified in three of the five individuals. Observed pathology includes lesions generally consistent with malaria; however, additional lesions in two of the individuals may represent hitherto unknown variation in the skeletal manifestation of this disease or co-infection with tuberculosis or brucellosis. Additionally, spondylolysis was observed in one individual with skeletal lesions suggestive of infectious disease.
CONCLUSIONS
This study sheds light on the pathological landscape in Iberia during a time of great social, demographic, and environmental change. Genetic evidence challenges the hypothesis that malaria was absent from early medieval Iberia and demonstrates the value of combining osteological and archaeogenetic methods. Additionally, all of the preferred infectious diagnoses for the individuals included in this study (malaria, tuberculosis, and brucellosis) could have contributed to the febrile cases described in historical sources from this time.
PubMed: 38963678
DOI: 10.1002/ajpa.24994 -
Molecular and Cellular Biochemistry Jul 2024Gastrointestinal (GI) cancers are a major global health burden, representing 20% of all cancer diagnoses and 22.5% of global cancer-related deaths. Their aggressive... (Review)
Review
Gastrointestinal (GI) cancers are a major global health burden, representing 20% of all cancer diagnoses and 22.5% of global cancer-related deaths. Their aggressive nature and resistance to treatment pose a significant challenge, with late-stage survival rates below 15% at five years. Therefore, there is an urgent need to delve deeper into the mechanisms of gastrointestinal cancer progression and optimize treatment strategies. Increasing evidence highlights the active involvement of abnormal arachidonic acid (AA) metabolism in various cancers. AA is a fatty acid mainly metabolized into diverse bioactive compounds by three enzymes: cyclooxygenase, lipoxygenase, and cytochrome P450 enzymes. Abnormal AA metabolism and altered levels of its metabolites may play a pivotal role in the development of GI cancers. However, the underlying mechanisms remain unclear. This review highlights a unique perspective by focusing on the abnormal metabolism of AA and its involvement in GI cancers. We summarize the latest advancements in understanding AA metabolism in GI cancers, outlining changes in AA levels and their potential role in liver, colorectal, pancreatic, esophageal, gastric, and gallbladder cancers. Moreover, we also explore the potential of targeting abnormal AA metabolism for future therapies, considering the current need to explore AA metabolism in GI cancers and outlining promising avenues for further research. Ultimately, such investigations aim to improve treatment options for patients with GI cancers and pave the way for better cancer management in this area.
PubMed: 38963615
DOI: 10.1007/s11010-024-05057-2 -
Infection Jul 2024Listeria monocytogenes causes severe bacterial infections with the highest mortality rate among foodborne pathogens in Europe. Combination treatment with ampicillin and...
PURPOSE
Listeria monocytogenes causes severe bacterial infections with the highest mortality rate among foodborne pathogens in Europe. Combination treatment with ampicillin and gentamicin is recommended for invasive manifestations. However, evidence to support this treatment approach remains limited due to a lack of randomised controlled trials. To explore this critical issue further, we conducted this retrospective, single-center study.
METHODS
We identified all patients hospitalized with invasive listeriosis at the University Medical Center Hamburg-Eppendorf between 2009 and 2020 and analyzed the effect of gentamicin combination treatment versus monotherapy on 90-day mortality.
RESULTS
In total, 36 patients with invasive listeriosis were included, of which 21 patients received gentamicin combination treatment and 15 received monotherapy. The mean age-adjusted Charlson Comorbidity Index (aaCCI) value was lower in the gentamicin combination treatment group (5.4 vs. 7.4). Neurolisteriosis was more common in the gentamicin group (81% vs. 20%). The 90-day mortality was with significantly lower in the gentamicin combination treatment group (10%) compared to the monotherapy group (60%). Multivariable cox regression analysis, adjusted for a propensity score computed based on neurolisteriosis, aaCCI and sex, revealed a significantly reduced hazard ratio of 0.07 (95% CI: 0.01-0.53, p = 0.01) for 90-day mortality for the gentamicin combination treatment.
CONCLUSION
This retrospective study highlights the benefit of gentamicin combination treatment in reducing the 90-day mortality rate among patients with invasive listeriosis. The high prevalence of monotherapy in this study cohort raises concerns about the adequacy of antibiotic therapy in clinical practice.
PubMed: 38963609
DOI: 10.1007/s15010-024-02330-w -
Biomolecular NMR Assignments Jul 2024Synucleinopathies are neurodegenerative diseases characterized by the accumulation of α-synuclein protein aggregates in the neurons and glial cells. Both ex vivo and in...
Synucleinopathies are neurodegenerative diseases characterized by the accumulation of α-synuclein protein aggregates in the neurons and glial cells. Both ex vivo and in vitro α-synuclein fibrils tend to show polymorphism. Polymorphism results in structure variations among fibrils originating from a single polypeptide/protein. The polymorphs usually have different biophysical, biochemical and pathogenic properties. The various pathologies of a single disease might be associated with distinct polymorphs. Similarly, in the case of different synucleinopathies, each condition might be associated with a different polymorph. Fibril formation is a nucleation-dependent process involving the formation of transient and heterogeneous intermediates from monomers. Polymorphs are believed to arise from heterogeneous oligomer populations because of distinct selection mechanisms in different conditions. To test this hypothesis, we isolated and incubated different intermediates during in vitro fibrillization of α-synuclein to form different polymorphs. Here, we report C and N chemical shifts and the secondary structure of fibrils prepared from the helical intermediate using solid-state nuclear magnetic spectroscopy.
PubMed: 38963588
DOI: 10.1007/s12104-024-10188-0 -
Journal of Mathematical Biology Jul 2024The Ebola virus disease (EVD) has been endemic since 1976, and the case fatality rate is extremely high. EVD is spread by infected animals, symptomatic individuals, dead...
The Ebola virus disease (EVD) has been endemic since 1976, and the case fatality rate is extremely high. EVD is spread by infected animals, symptomatic individuals, dead bodies, and contaminated environment. In this paper, we formulate an EVD model with four transmission modes and a time delay describing the incubation period. Through dynamical analysis, we verify the importance of blocking the infection source of infected animals. We get the basic reproduction number without considering the infection source of infected animals. And, it is proven that the model has a globally attractive disease-free equilibrium when the basic reproduction number is less than unity; the disease eventually becomes endemic when the basic reproduction number is greater than unity. Taking the EVD epidemic in Sierra Leone in 2014-2016 as an example, we complete the data fitting by combining the effect of the media to obtain the unknown parameters, the basic reproduction number and its time-varying reproduction number. It is shown by parameter sensitivity analysis that the contact rate and the removal rate of infected group have the greatest influence on the prevalence of the disease. And, the disease-controlling thresholds of these two parameters are obtained. In addition, according to the existing vaccination strategy, only the inoculation ratio in high-risk areas is greater than 0.4, the effective reproduction number can be less than unity. And, the earlier the vaccination time, the greater the inoculation ratio, and the faster the disease can be controlled.
Topics: Hemorrhagic Fever, Ebola; Basic Reproduction Number; Humans; Animals; Mathematical Concepts; Models, Biological; Sierra Leone; Ebolavirus; Epidemics; Computer Simulation; Epidemiological Models; Disease Outbreaks
PubMed: 38963509
DOI: 10.1007/s00285-024-02122-8