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PloS One 2024Art v4.01 is a well-known profilin protein belonging to the pan-allergens group and is commonly involved in triggering allergic asthma, polyallergy, and...
Art v4.01 is a well-known profilin protein belonging to the pan-allergens group and is commonly involved in triggering allergic asthma, polyallergy, and cross-sensitization. It is also referred to as Wormwood due to its origin. Crude wormwood extracts are applied for allergen-specific immunotherapy (AIT). Whether the recombinant Art v4.01 (rArt v4.01) can produce in vivo immunological tolerance by subcutaneous immunotherapy (SCIT) remains elusive. In this study, to investigate the in vivo immunological response of rArt v4.01, Th2, Th1, Treg, Th17 type-related cytokines and phenotypes of immune cells were tested, facilitating the exploration of the underlying mechanisms. The expression and purification of Art v4.01 were carried out using recombinant techniques. Allergic asthma female BALB/c mice were induced by subcutaneous sensitization of wormwood pollen extract and intranasal challenges. SCIT without adjuvant was performed using the rArt v4.01 and wormwood pollen extract for 2 weeks. Following exposure to challenges, the levels of immunoglobulin E (IgE), cytokines, and inflammatory cells were assessed through enzyme-linked immunosorbent assay (ELISA) and histological examination of sera, bronchoalveolar lavage fluid (BALF), and lung tissue. These parameters were subsequently compared between treatment groups receiving rArt v4.01 and wormwood pollen extract. The rArt v4.01 protein was expressed, which had a high purity (>90%) and an allergenic potency. Compared with the pollen extract, rArt v4.01 was superior in terms of reducing the number of white blood cells (WBCs), total nucleated cells (TNCs), and monocytes (MNs) in BALF and the degree of lung inflammation (1.77±0.99 vs. 2.31±0.80, P > 0.05). Compared with the model group, only rArt v4.01 reduced serum IgE level (1.19±0.25 vs. 1.61±0.17 μg/ml, P = 0.062), as well as the levels of Th2 type-related cytokines (interleukin-4 (IL-4) (107.18±16.17 vs. 132.47±20.85 pg/ml, P < 0.05) and IL-2 (19.52±1.19 vs. 24.02±2.14 pg/ml, P < 0.05)). The study suggested that rArt v4.01 was superior to pollen extract in reducing the number of inflammatory cells in BALF, pneumonitis, levels of pro-inflammatory cytokines, and serum IgE level. These findings confirmed that Art v4.01 could be a potential candidate protein for allergen-specific immunotherapy.
Topics: Animals; Female; Asthma; Mice; Mice, Inbred BALB C; Disease Models, Animal; Immune Tolerance; Recombinant Proteins; Cytokines; Immunoglobulin E; Pollen; Desensitization, Immunologic; Allergens; Profilins; Bronchoalveolar Lavage Fluid; Injections, Subcutaneous
PubMed: 38941291
DOI: 10.1371/journal.pone.0280418 -
ELife Jun 2024Genetic diversity is a hallmark of RNA viruses and the basis for their evolutionary success. Taking advantage of the uniquely large genomic database of SARS-CoV-2, we...
Genetic diversity is a hallmark of RNA viruses and the basis for their evolutionary success. Taking advantage of the uniquely large genomic database of SARS-CoV-2, we examine the impact of mutations across the spectrum of viable amino acid sequences on the biophysical phenotypes of the highly expressed and multifunctional nucleocapsid protein. We find variation in the physicochemical parameters of its extended intrinsically disordered regions (IDRs) sufficient to allow local plasticity, but also observe functional constraints that similarly occur in related coronaviruses. In biophysical experiments with several N-protein species carrying mutations associated with major variants, we find that point mutations in the IDRs can have nonlocal impact and modulate thermodynamic stability, secondary structure, protein oligomeric state, particle formation, and liquid-liquid phase separation. In the Omicron variant, distant mutations in different IDRs have compensatory effects in shifting a delicate balance of interactions controlling protein assembly properties, and include the creation of a new protein-protein interaction interface in the N-terminal IDR through the defining P13L mutation. A picture emerges where genetic diversity is accompanied by significant variation in biophysical characteristics of functional N-protein species, in particular in the IDRs.
Topics: SARS-CoV-2; Coronavirus Nucleocapsid Proteins; Mutation; COVID-19; Humans; Intrinsically Disordered Proteins; Phosphoproteins; Nucleocapsid Proteins; Thermodynamics; Protein Stability
PubMed: 38941236
DOI: 10.7554/eLife.94836 -
Cell Reports Jun 2024Our skin provides a protective barrier that shields us from our environment. Barrier function is typically associated with the interfollicular epidermis; however,...
Our skin provides a protective barrier that shields us from our environment. Barrier function is typically associated with the interfollicular epidermis; however, whether hair follicles influence this process remains unclear. Here, we utilize a potent genetic tool to probe barrier function by conditionally ablating a quintessential epidermal barrier gene, Abca12, which is mutated in the most severe skin barrier disease, harlequin ichthyosis. With this tool, we deduced 4 ways by which hair follicles modulate skin barrier function. First, the upper hair follicle (uHF) forms a functioning barrier. Second, barrier disruption in the uHF elicits non-cell-autonomous responses in the epidermis. Third, deleting Abca12 in the uHF impairs desquamation and blocks sebum release. Finally, barrier perturbation causes uHF cells to move into the epidermis. Neutralizing IL-17a, whose expression is enriched in the uHF, partially alleviated some disease phenotypes. Altogether, our findings implicate hair follicles as multi-faceted regulators of skin barrier function.
PubMed: 38941190
DOI: 10.1016/j.celrep.2024.114347 -
Cell Reports Jun 2024TDP-43 protein is dysregulated in several neurodegenerative diseases, which often have a multifactorial nature and may have extrinsic stressors as a "second hit." TDP-43...
TDP-43 protein is dysregulated in several neurodegenerative diseases, which often have a multifactorial nature and may have extrinsic stressors as a "second hit." TDP-43 undergoes reversible nuclear condensation in stressed cells including neurons. Here, we demonstrate that stress-inducible nuclear TDP-43 condensates are RNA-depleted, non-liquid assemblies distinct from the known nuclear bodies. Their formation requires TDP-43 oligomerization and ATP and is inhibited by RNA. Using a confocal nanoscanning assay, we find that amyotrophic lateral sclerosis (ALS)-linked mutations alter stress-induced TDP-43 condensation by changing its affinity to liquid-like ribonucleoprotein assemblies. Stress-induced nuclear condensation transiently inactivates TDP-43, leading to loss of interaction with its protein binding partners and loss of function in splicing. Splicing changes are especially prominent and persisting for STMN2 RNA, and STMN2 protein becomes rapidly depleted early during stress. Our results point to early pathological changes to TDP-43 in the nucleus and support therapeutic modulation of stress response in ALS.
PubMed: 38941189
DOI: 10.1016/j.celrep.2024.114421 -
Oncology and Therapy Jun 2024Breast cancer presents diverse molecular subtypes affecting treatment strategies. Human epidermal growth factor receptor 2 (HER2)-low, hormone receptor-positive (HR+)...
BACKGROUND
Breast cancer presents diverse molecular subtypes affecting treatment strategies. Human epidermal growth factor receptor 2 (HER2)-low, hormone receptor-positive (HR+) breast cancer poses a challenge due to limited targeted therapies. Current neoadjuvant treatment primarily utilizes chemotherapy, with conflicting results regarding efficacy in patients with HER2-low breast cancer. Trastuzumab deruxtecan (T-DXd) shows promise in HER2-low metastatic disease, and preliminary evidence suggests synergy with endocrine therapy.
OBJECTIVE
This editorial explores the hypothesis that neoadjuvant T-DXd with or without endocrine therapy offers efficacy in the clinical management of HR+/HER2-low breast cancer.
METHODS
We propose a phase II study with two treatment arms: T-DXd + letrozole and T-DXd alone. The primary endpoint is the radiological complete response rate. Secondary endpoints include pathological complete response rate, safety, event-free survival, and overall survival. Exploratory analyses will compare the arms to identify potential for optimizing treatment efficacy and minimizing side effects.
CONCLUSIONS
This study design allows for initial assessment of T-DXd with or without endocrine therapy in the treatment of HER2-low breast cancer. The findings may pave the way for personalized treatment strategies and inform future research, potentially leading to a chemotherapy-sparing approach.
PubMed: 38941050
DOI: 10.1007/s40487-024-00286-3 -
Alternative Therapies in Health and... Jun 2024Root canal therapy is a widely adopted clinical approach for managing endodontic diseases. However, patients undergoing multiple root canal treatments face an increased...
BACKGROUND
Root canal therapy is a widely adopted clinical approach for managing endodontic diseases. However, patients undergoing multiple root canal treatments face an increased risk of reinfection, complicating treatment outcomes.
OBJECTIVE
This study aims to evaluate the effects of both multiple and one-time root canal therapy on the immune and inflammatory responses in endodontic patients.
DESIGN
A randomized controlled study was conducted.
SETTING
The research was carried out at the 8th People's Hospital of Shanghai.
PARTICIPANTS
A total of 100 endodontic patients admitted to the Stomatology Department of the hospital from January 2021 to December 2022 were randomly allocated to either the study group or the control group, with each group consisting of 50 cases.
INTERVENTIONS
The control group received multiple root canal therapy, while the study group underwent one-time root canal treatment.
PRIMARY OUTCOME MEASURES
(1) Clinical treatment effectiveness, (2) pain intensity, (3) levels of inflammatory factors, (4) oral immune factor levels, (5) oral health-related quality of life, and (6) occurrence of adverse reactions were assessed.
RESULTS
The study group demonstrated a significantly higher total effective rate compared to the control group (P < .05). Post-treatment, the study group exhibited lower pain scores, reduced levels of inflammatory factors, improved oral health-related quality of life, and fewer adverse reactions compared to the control group (P < .05). Additionally, the study group showed elevated levels of lysozyme, human β-defensin 2, and secretory Immunoglobulin A compared to the control group (P < .05).
CONCLUSIONS
One-time root canal therapy in endodontic patients yields superior outcomes, effectively reducing adverse reactions and inflammatory factor levels, enhancing chewing function, alleviating pain, and demonstrating clinical utility. This study underscores the importance and efficacy of adopting a one-time root canal treatment approach in endodontic practice.
PubMed: 38940800
DOI: No ID Found -
Alternative Therapies in Health and... Jun 2024Expectoration and wheezing are prevalent symptoms of respiratory diseases. Acupoint application and back tapping have shown effectiveness in alleviating cough, wheezing,...
BACKGROUND
Expectoration and wheezing are prevalent symptoms of respiratory diseases. Acupoint application and back tapping have shown effectiveness in alleviating cough, wheezing, and associated symptoms.
OBJECTIVE
This study aimed to investigate the influence of combining acupoint application with back tapping in patients experiencing expectoration and wheezing.
DESIGN
A retrospective study design was employed.
SETTING
The study was conducted at Lujiang County Hospital of Traditional Chinese Medicine.
PARTICIPANTS
A total of 96 patients presenting with expectoration and wheezing between January 2019 and June 2021 were randomly allocated into an observation group (n=48) and a control group (n=48).
INTERVENTIONS
The control group received an acupoint application using white mustard seed. In contrast, the observation group received additional back-tapping along meridians.
PRIMARY OUTCOME MEASURES
(1) Clinical efficacy; (2) traditional Chinese medicine (TCM) syndrome scores; (3) levels of inflammatory factors; (4) blood gas analysis indexes; (5) pulmonary function indexes; and (6) quality of life was assessed.
RESULTS
Following treatment, the observation group exhibited superior clinical efficacy (P < .05), reduced traditional Chinese medicine syndrome scores for cough, expectoration, and wheezing (P < .05), more pronounced improvements in inflammatory factor levels (P < .05), blood gas analysis indexes (P < .05), pulmonary function indexes (P < .05), and higher quality of life (P < .05) compared to the control group.
CONCLUSIONS
Combining acupoint application with back tapping effectively alleviated symptoms and inflammatory responses, improved blood gas and pulmonary function, and enhanced the quality of life in patients experiencing expectoration and wheezing.
PubMed: 38940795
DOI: No ID Found -
Alternative Therapies in Health and... Jun 2024To investigate the effects of holistic nursing on the quality of life overall, inflammation, and lung function in older persons experiencing acute episodes of chronic...
OBJECTIVE
To investigate the effects of holistic nursing on the quality of life overall, inflammation, and lung function in older persons experiencing acute episodes of chronic obstructive pulmonary disease (COPD).
METHODS
Considering that good nursing care improves cardiorespiratory fitness, increases treatment adherence and improves prognosis in patients with chronic obstructive pulmonary disease (COPD), From June 2019 through May 2020, 96 patients with newly diagnosed acute COPD will be recruited to take part in the trial. In total, 48 people were split into the study group and the control group at random. When compared to the control group, the research group received more comprehensive care. Procalcitonin (PCT), C-reactive protein (CRP), and interleukin-6 (IL-6) blood levels were compared before and after care, as were forced expiratory volume in one second (FEV1), forced vital capacity (FVC), FEV1/FEV1, and quality of life.
RESULTS
None of the demographic characteristics, including mean age, BMI, illness duration, gender, or comorbidities, differed significantly (P > .05) between the two groups. After care, serum PCT, CRP, and IL-6 levels decreased in both groups compared to pre-nursing values (P < .05); however, after care, serum PCT, CRP, and IL-6 levels were significantly lower in the study group compared to the control group. Both groups' FEV1, FVC, and FVC improved significantly (P < .05) after care compared to their baseline conditions; Statistics show that after care, the study group had significantly better FEV1, FVC, and FVC than the control group. The overall success rate of the study group was statistically significantly higher than that of the control group (P < .05). After Care, both groups' scores for illness impact, disease symptoms, and mobility restriction were much lower than they were before to care, and the difference was statistically significant (P < .05); After Care, people in the study group significantly improved on measures of mobility impairment, sickness symptoms, and disease effect compared to those in the control group. There was a statistically significant difference (P < .05) between the two groups. Patients in the study group reported significantly higher levels of satisfaction with their nursing care than patients in the control group (P < .05).
CONCLUSION
Elderly patients with acute COPD can benefit greatly from holistic nursing care in terms of reduced inflammation, enhanced lung function, and enhanced quality of life.
PubMed: 38940789
DOI: No ID Found -
Microbiology Spectrum Jun 2024Traditionally, successful vaccines rely on specific adaptive immunity by activating lymphocytes with an attenuated pathogen, or pathogen subunit, to elicit heightened...
UNLABELLED
Traditionally, successful vaccines rely on specific adaptive immunity by activating lymphocytes with an attenuated pathogen, or pathogen subunit, to elicit heightened responses upon subsequent exposures. However, recent work with and other pathogens has identified a role for "trained" monocytes in protection through memory-like but non-specific immunity. Here, we used an co-culture approach to study the potential role of trained macrophages, including lung alveolar macrophages, in immune responses to the Live Vaccine Strain (LVS) of is an intracellular bacterium that replicates within mammalian macrophages and causes respiratory as well as systemic disease. We vaccinated mice with LVS and then obtained lung alveolar macrophages, or derived macrophages from bone marrow. LVS infected and replicated comparably in both types of macrophages, whether naïve or from LVS-vaccinated mice. LVS-infected macrophages were then co-cultured with either naïve splenocytes, splenocytes from mice vaccinated intradermally, or splenocytes from mice vaccinated intravenously. For the first time, we show that immune (but not naïve) splenocytes controlled bacterial replication within alveolar macrophages, similar to previous results using bone marrow-derived macrophage. However, no differences in control of intramacrophage bacterial replication were found between co-cultures with naïve macrophages or macrophages from LVS-vaccinated mice; furthermore, nitric oxide levels and interferon-gamma production in supernatants were largely comparable across all conditions. Thus, in the context of co-cultures, the data do not support development of trained macrophages in bone marrow or lungs of mice vaccinated with LVS intradermally or intravenously.
IMPORTANCE
The discovery of non-specific "trained immunity" in monocytes has generated substantial excitement. However, to date, training has been studied with relatively few microbes (e.g., Bacille Calmette-Guérin, a live attenuated intracellular bacterium used as a vaccine) and microbial substances (e.g., LPS), and it remains unclear whether training during infection is common. We previously demonstrated that vaccination of mice with Live Vaccine Strain (LVS), another live attenuated intracellular bacterium, protected against challenge with the unrelated bacterium . The present study therefore tested whether LVS vaccination engenders trained macrophages that contributed to this protection. To do so, we used a previous co-culture approach with murine bone marrow-derived macrophages to expand and study lung alveolar macrophages. We demonstrated that alveolar macrophages can be productively infected and employed to characterize interactions with LVS-immune lymphocytes. However, we find no evidence that either bone marrow-derived or alveolar macrophages are trained by LVS vaccination.
PubMed: 38940590
DOI: 10.1128/spectrum.00028-24 -
The Oncologist Jun 2024There is little evidence on the safety, efficacy, and survival benefit of restarting immune checkpoint inhibitors (ICI) in patients with cancer after discontinuation due...
BACKGROUNDS
There is little evidence on the safety, efficacy, and survival benefit of restarting immune checkpoint inhibitors (ICI) in patients with cancer after discontinuation due to immune-related adverse events (irAEs) or progressive disease (PD). Here, we performed a meta-analysis to elucidate the possible benefits of ICI rechallenge in patients with cancer.
METHODS
Systematic searches were conducted using PubMed, Embase, and Cochrane Library databases. The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and incidence of irAEs were the outcomes of interest.
RESULTS
Thirty-six studies involving 2026 patients were analyzed. ICI rechallenge was associated with a lower incidence of all-grade (OR, 0.05; 95%CI, 0.02-0.13, P < .05) and high-grade irAEs (OR, 0.37; 95%CI, 0.21-0.64, P < .05) when compared with initial ICI treatment. Though no significant difference was observed between rechallenge and initial treatment regarding ORR (OR, 0.69; 95%CI, 0.39-1.20, P = .29) and DCR (OR, 0.85; 95%CI, 0.51-1.40, P = 0.52), patients receiving rechallenge had improved PFS (HR, 0.56; 95%CI, 0.43-0.73, P < .05) and OS (HR, 0.55; 95%CI, 0.43-0.72, P < .05) than those who discontinued ICI therapy permanently. Subgroup analysis revealed that for patients who stopped initial ICI treatment because of irAEs, rechallenge showed similar safety and efficacy with initial treatment, while for patients who discontinued ICI treatment due to PD, rechallenge caused a significant increase in the incidence of high-grade irAEs (OR, 4.97; 95%CI, 1.98-12.5, P < .05) and a decrease in ORR (OR, 0.48; 95%CI, 0.24-0.95, P < .05).
CONCLUSION
ICI rechallenge is generally an active and feasible strategy that is associated with relative safety, similar efficacy, and improved survival outcomes. Rechallenge should be considered individually with circumspection, and randomized controlled trials are required to confirm these findings.
PubMed: 38940446
DOI: 10.1093/oncolo/oyae134