bluuebunny/crossref_metadata_2025 huggingface dataset:
Sex-biased immunogenicity of a mucosal subunit vaccine against SARS-CoV-2 in mice
Authors: Li Jianping , Hsu Kevin S. , Howe Savannah E. , Hoang Tanya , Xia Zheng , Berzofsky Jay A. , Sui Yongjun
Published: May 2024

Introduction

Current vaccines against COVID-19 administered via parenteral route have limited ability to induce mucosal immunity. There is a need for an effective mucosal vaccine to combat SARS-CoV-2 virus replication in the respiratory mucosa. Moreover, sex differences are known to affect systemic antibody responses against vaccines. However, their role in mucosal cellular responses against a vaccine remains unclear and is underappreciated.

Methods

We evaluated the mucosal immunogenicity of a booster vaccine regimen that is recombinant protein-based and administered intranasally in mice to explore sex differences in mucosal humoral and cellular responses.

Results

Our results showed that vaccinated mice elicited strong systemic antibody (Ab), nasal, and bronchiole alveolar lavage (BAL) IgA responses, and local T cell immune responses in the lung in a sex-biased manner irrespective of mouse genetic background. Monocytes, alveolar macrophages, and CD103+ resident dendritic cells (DCs) in the lungs are correlated with robust mucosal Ab and T cell responses induced by the mucosal vaccine.

Discussion

Our findings provide novel insights into optimizing next-generation booster vaccines against SARS-CoV-2 by inducing spike-specific lung T cell responses, as well as optimizing mucosal immunity for other respiratory infections, and a rationale for considering sex differences in future vaccine research and vaccination practice.
Immunotherapy in the context of sepsis-induced immunological dysregulation
Authors: Wu Yiqi , Wang Lu , Li Yun , Cao Yuan , Wang Min , Deng Zihui , Kang Hongjun
Published: May 2024

Sepsis is a clinical syndrome caused by uncontrollable immune dysregulation triggered by pathogen infection, characterized by high incidence, mortality rates, and disease burden. Current treatments primarily focus on symptomatic relief, lacking specific therapeutic interventions. The core mechanism of sepsis is believed to be an imbalance in the host’s immune response, characterized by early excessive inflammation followed by late immune suppression, triggered by pathogen invasion. This suggests that we can develop immunotherapeutic treatment strategies by targeting and modulating the components and immunological functions of the host’s innate and adaptive immune systems. Therefore, this paper reviews the mechanisms of immune dysregulation in sepsis and, based on this foundation, discusses the current state of immunotherapy applications in sepsis animal models and clinical trials.
Lactate and lactylation in macrophage metabolic reprogramming: current progress and outstanding issues
Authors: Xu Bangjun , Liu Yi , Li Ning , Geng Qing
Published: May 2024

It is commonly known that different macrophage phenotypes play specific roles in different pathophysiological processes. In recent years, many studies have linked the phenotypes of macrophages to their characteristics in different metabolic pathways, suggesting that macrophages can perform different functions through metabolic reprogramming. It is now gradually recognized that lactate, previously overlooked as a byproduct of glycolytic metabolism, acts as a signaling molecule in regulating multiple biological processes, including immunological responses and metabolism. Recently, lactate has been found to mediate epigenetic changes in macrophages through a newfound lactylation modification, thereby regulating their phenotypic transformation. This novel finding highlights the significant role of lactate metabolism in macrophage function. In this review, we summarize the features of relevant metabolic reprogramming in macrophages and the role of lactate metabolism therein. We also review the progress of research on the regulation of macrophage metabolic reprogramming by lactylation through epigenetic mechanisms.
Sex differences in immune protection in mice conferred by heterologous vaccines for pneumonic plague
Authors: Davies Michael L. , Biryukov Sergei S. , Rill Nathaniel O. , Klimko Christopher P. , Hunter Melissa , Dankmeyer Jennifer L. , Miller Jeremy A. , Shoe Jennifer L. , Mlynek Kevin D. , Talyansky Yuli , Toothman Ronald G. , Qiu Ju , Bozue Joel A. , Cote Christopher K.
Published: May 2024

Background

Yersinia pestis is the etiological agent of plague, which can manifest as bubonic, septicemic, and/or pneumonic disease. Plague is a severe and rapidly progressing illness that can only be successfully treated with antibiotics initiated early after infection. There are no FDA-approved vaccines for plague, and some vaccine candidates may be less effective against pneumonic plague than bubonic plague. Y. pestis is not known to impact males and females differently in mechanisms of pathogenesis or severity of infection. However, one previous study reported sex-biased vaccine effectiveness after intranasal Y. pestis challenge. As part of developing a safe and effective vaccine, it is essential that potential sex differences are characterized.

Methods

In this study we evaluated novel vaccines in male and female BALB/c mice using a heterologous prime-boost approach and monitored survival, bacterial load in organs, and immunological correlates. Our vaccine strategy consisted of two subcutaneous immunizations, followed by challenge with aerosolized virulent nonencapsulated Y. pestis. Mice were immunized with a combination of live Y. pestis pgm- pPst-Δcaf1, live Y. pestis pgm- pPst-Δcaf1/ΔyopD, or recombinant F1-V (rF1-V) combined with adjuvants.

Results

The most effective vaccine regimen was initial priming with rF1-V, followed by boost with either of the live attenuated strains. However, this and other strategies were more protective in female mice. Males had higher bacterial burden and differing patterns of cytokine expression and serum antibody titers. Male mice did not demonstrate synergy between vaccination and antibiotic treatment as repeatedly observed in female mice.

Conclusions

This study provides new knowledge about heterologous vaccine strategies, sex differences in plague-vaccine efficacy, and the immunological factors that differ between male and female mice.
COVID-19 PBMCs are doubly harmful, through LDN-mediated lung epithelial damage and monocytic impaired responsiveness to live Pseudomonas aeruginosa exposure
Authors: Gaudin Clémence , Born-Bony Maëlys , Villeret Bérengère , Jaillet Madeleine , Faille Dorothée , Timsit Jean-François , Tran-Dinh Alexy , Montravers Philippe , Crestani Bruno , Garcia-Verdugo Ignacio , Sallenave Jean-Michel
Published: May 2024

Introduction

Although many studies have underscored the importance of T cells, phenotypically and functionally, fewer have studied the functions of myeloid cells in COVID disease. In particular, the potential role of myeloid cells such as monocytes and low-density neutrophils (LDNs) in innate responses and particular in the defense against secondary bacterial infections has been much less documented.

Methods

Here, we compared, in a longitudinal study, healthy subjects, idiopathic fibrosis patients, COVID patients who were either hospitalized/moderate (M-) or admitted to ICU (COV-ICU) and patients in ICU hospitalized for other reasons (non-COV-ICU).

Results

We show that COVID patients have an increased proportion of low-density neutrophils (LDNs), which produce high levels of proteases (particularly, NE, MMP-8 and MMP-9) (unlike non-COV-ICU patients), which are partly responsible for causing type II alveolar cell damage in co-culture experiments. In addition, we showed that M- and ICU-COVID monocytes had reduced responsiveness towards further live Pseudomonas aeruginosa (PAO1 strain) infection, an important pathogen colonizing COVID patients in ICU, as assessed by an impaired secretion of myeloid cytokines (IL-1, TNF, IL-8,…). By contrast, lymphoid cytokines (in particular type 2/type 3) levels remained high, both basally and post PAO1 infection, as reflected by the unimpaired capacity of T cells to proliferate, when stimulated with anti-CD3/CD28 beads.

Discussion

Overall, our results demonstrate that COVID circulatory T cells have a biased type 2/3 phenotype, unconducive to proper anti-viral responses and that myeloid cells have a dual deleterious phenotype, through their LDN-mediated damaging effect on alveolar cells and their impaired responsiveness (monocyte-mediated) towards bacterial pathogens such as P. aeruginosa.
Cynaroside ameliorates methotrexate-induced enteritis in rats through inhibiting NLRP3 inflammasome activation
Authors: Lang Wuying , Wen Xin , Zhang Shuangqi , Liang Xuhua , Chen Lin , Zhang Dezhu , Zhou Ruina , Ali Ihsan , Hu Xuansheng , Zhang Haihua , Cheng Min
Published: May 2024

Introduction

Cynaroside exhibits various biological properties, including anti-inflammatory, antiviral, antitumor, and cardioprotective effects. However, its involvement in methotrexate (MTX)-induced intestinal inflammation remains inadequately understood. Thus, we investigated the impact of cynaroside on MTX-induced intestinal inflammation and its potential mechanisms.

Methods

To assess the protective potential of cynaroside against intestinal inflammation, Sprague-Dawley rats were subjected to a regimen of 7 mg/kg MTX for 3 days, followed by treatment with cynaroside at varying doses (10, 20, or 40 mg/kg). Histopathological evaluations were conducted alongside measurements of inflammatory mediators to elucidate the involvement of the NLRP3 inflammasome in alleviating intestinal inflammation.

Results

Administration of 7 mg/kg MTX resulted in decreased daily food intake, increased weight loss, and elevated disease activity index in rats. Conversely, treatment with cynaroside at 20 or 40 mg/kg ameliorated the reductions in body weight and daily food intake and suppressed the MTX-induced elevation in the disease activity index. Notably, cynaroside administration at 20 or 40 mg/kg attenuated inflammatory cell infiltration, augmented goblet cell numbers and lowered serum levels of tumor necrosis factor-α, interleukin (IL)-1β, and IL-18, as well as the CD68-positive cell rate in the intestines of MTX-induced rats. Furthermore, cynaroside downregulated the expression levels of NLRP3, cleaved caspase 1, and cleaved IL-1β in MTX-induced rats.

Discussion

Collectively, our findings indicated that cymaroside alleviates intestinal inflammatory injury by inhibiting the activation of NLRP3 inflammasome in MTX-induced rats.
Efferocytosis in dendritic cells: an overlooked immunoregulatory process
Authors: Ma Yanyan , Jiang Tangxing , Zhu Xun , Xu Yizhou , Wan Ke , Zhang Tingxuan , Xie Miaorong
Published: May 2024

Efferocytosis, the process of engulfing and removing apoptotic cells, plays an essential role in preserving tissue health and averting undue inflammation. While macrophages are primarily known for this task, dendritic cells (DCs) also play a significant role. This review delves into the unique contributions of various DC subsets to efferocytosis, highlighting the distinctions in how DCs and macrophages recognize and handle apoptotic cells. It further explores how efferocytosis influences DC maturation, thereby affecting immune tolerance. This underscores the pivotal role of DCs in orchestrating immune responses and sustaining immune equilibrium, providing new insights into their function in immune regulation.
Glacial activity and paleoclimatic evolution records in the Cosmonaut Sea since the last glacial maximum
Authors: Chen Dong , Ge Qian , Lei Ziyan , Zhou Bingfu , Han Xibin
Published: May 2024

This research explored the origin and paleoenvironmental significance of sediments from the Cosmonaut Sea, Antarctica, focusing on the period since the Last Glacial Maximum (LGM, 26,000 cal a BP). Sediment samples from core ANT37-C5/6-07 were subjected to AMS14C dating, clay-mineral assemblage analysis, grain size evaluation, and geochemical testing. Results indicated illite as the dominant clay mineral (average 46%), followed by kaolinite (22%) and smectite (21%), with chlorite (11%) being the least abundant. Comparison with previous studies suggested that these sediments are largely derived from weathered material from Prydz Bay and Enderby Land coastal regions. The study of mineral ratios, geochemical elements, and sediment grain size, alongside δ18O values from the East Antarctica EDML ice core, revealed that the ice sheet in the study area retreated around 18600 cal a BP, melted more markedly during 16800-15000 cal a BP, tended to expand during 14800-13500 cal a BP, and then the ice sheet remained in a state of retreat until it expanded again around 5000 cal a BP. It is largely synchronous with the phased changes in the Antarctic climate since the LGM (26ka) of the Cosmonaut Sea. Notably, the sediment record aligns with major paleoclimatic events, including Heinrich Stadial 1 and the Younger Dryas in the northern hemisphere and the Antarctic cold reversal, reflecting a climatic ‘seesaw’ effect. These findings suggest that the sedimentary record in the Cosmonaut Sea is a sensitive indicator of climatic conditions, highlighting a history of glacial movements and revealing East Antarctica’s climatic fluctuations. Additionally, the research indicates that the regional ice sheet is more sensitive to climatic changes than previously believed, underscoring its instability.
Are microplastics efficient remediation tools for removing the statin Lipitor? A laboratory experiment with meiobenthic nematodes
Authors: Aldraiwish Bayan M. , Alaqeel Maha M. , Al-Hoshani Nawal , Özdemir Sadin , Pacioglu Octavian , Necula Marian , Milea Eduard C. , Hedfi Amor , Rudayni Hassan A. , Boufahja Fehmi
Published: May 2024

Introduction

The current experiment investigated the multifaceted effects induced by microplastics and the statin Lipitor on marine benthic nematodes.

Methods

The nematodes were exposed to a single polystyrene and polyvinyl chlorides (both at 1 mg.kg-1 Dry Weight) and two Lipitor concentrations (0.1 and 1 mg.l-1), as well as to a mixture of both types of pollutants, for 30 days.

Results

The results highlighted a significant decrease in the abundance, individual biomass, and diversity of nematodes directly with the addition of polyvinyl chlorides and/or Lipitor. These treatments induced a greater mortality rate among microvores and diatom feeders compared to other feeding types of nematodes.

Discussion

The nematofauna underwent a strong restructuring phase following exposure to microplastics and Lipitor when added alone, leading to the disappearance of sensitive species and their replacement by more tolerant taxa. The toxicity of Lipitor is attenuated by the physical bonding with polystyrene when added to a mixture and has no negative effect on marine nematode species.
Profiling sediment bacterial communities and the response to pattern-driven variations of total nitrogen and phosphorus in long-term polyculture ponds
Authors: Zhang Yan , Li Tiejun , Li Guangzhi , Yuan Tao , Zhang Yao , Jin Lei
Published: May 2024

Sediment bacterial communities are decisive drivers of nutrient cycling processes in aquaculture ecosystems and are readily affected by surrounding environmental factors. However, the knowledge of sediment nutrient accumulations and bacterial community structure is limited in the emerging polyculture systems. Herein, we investigated the profiles of sediment properties and bacterial communities in six typical polyculture ponds and primarily explored the influence of total nitrogen and phosphorus on the bacterial species and diversity. In almost all sediment samples, Proteobacteria, Chloroflexi, and Bacteroides were the dominant species at the phylum level, and the five most abundant bacterial genera were Sulfurovum, Woeseia, Ilumatobacter, Robiginitalea, and Cyanobium_PCC-6307. A clear different bacterial community was observed with the most dominant bacterial phylum Firmicutes and the lowest bacterial diversity in TZ1 pond sediment; meanwhile, the TZ1 pond also showed the highest TN and TP concentrations. Notably, sediments from WZ1 and WZ2 ponds in low-latitude regions exhibited higher bacterial richness and diversity. Based on Pearson’s correlation analysis, bacterial α-diversity indices showed significant negative correlation with sediment TP content, and TN content contributed the most to the abundance of sediment dominant bacterial genus, indicating that the bacterial community is highly associated with sediment nutrient concentrations. Moreover, co-occurrence network analysis further revealed some keystone taxa that exhibited high correlations with other bacterial species, especially the high-abundance genus Robiginitalea bridging a large number of connections. Compared to traditional mono-mariculture pattern, our study provided direct evidence of lower nutrient loadings and different bacterial communities in the polyculture ponds. This could assist polyculture practitioners in developing effective strategies for detailed nutritional management.
Environmental factors modulate the distribution of elasmobranchs in southern Mozambique
Authors: Murie Calum J. G. , Oliver Simon P. , Gavard Livia , Lebrato Mario , Brown James , Lawrence Andrew
Published: May 2024

Investigating the spatiotemporal ecology of elasmobranchs is an important precursor to their effective management. Understanding long-term patterns in the movement and habitat use of threatened species can improve management plans so that they yield increased conservation benefits. We investigated the spatiotemporal and environmental drivers that underpin the abundance and distribution of elasmobranchs around reef habitats in southern Mozambique to highlight reefs that are important (“hotspots”) to the regional elasmobranch community. Visual belt transects (n = 738), supported by video recordings, were completed on 16 reef sites off the coast of southern Mozambique from 2018 to 2022. Nine elasmobranch species were encountered annually (Carcharhinus amblyrhynchos, Triaenodon obesus, Stegostoma tigrinum, Neotrygon caeruleopunctata, Pateobatis jenkinsii, Taeniurops meyeni, Mobula kuhlii, Mobula alfredi, Mobula birostris) and 11 individual environmental and spatiotemporal parameters (horizontal water visibility, tidal range and state, moon illumination, temperature on the reef, cloud cover, time of day, day of the year, transect distance from shore, transect depth, and the region that the transect occurred in) were measured. All species, (bar P. jenkinsii) were significantly more abundant around certain reefs in the sampled region. Total counts for most species were highest in the austral summer however two species’ (M. birostris and S. tigrinum) were most abundant in the winter months. The tidal state, tidal range, and moon illumination correlated significantly with the numbers of each of the nine elasmobranch species. Non-Metric Multidimensional Scaling (NMDS) indicated that species’ responses to the measured parameters grouped taxonomically. Environmental influences resulted in strong seasonal patterns of reef use by large-bodied and pelagic elasmobranch species (e.g. manta rays). The measured environmental parameters also resulted in daily, monthly, and seasonal patterns of abundance of reef-resident stingray and shark species. Banning extraction of elasmobranch species around the reefs where they aggregate and reflecting species distributions within fisheries regulations may significantly benefit the regional elasmobranch community.
Enhancing comfort of resident physicians treating adults with intellectual and developmental disabilities by facilitating meaningful interactions
Authors: Sanders Jessica Solomon , Williams Kathryn , Thompson Darcy , Shapiro Hannah F.
Published: May 2024

Background

Many physicians feel uncomfortable caring for patients with intellectual and developmental disabilities (IDD). While some residency training programs include lecture content on IDD, few provide structured experiences with individuals with IDD. One strategy for improving comfort is “contact theory:” increasing interactions with “dissimilar” people can lead to decreased negative attitudes toward that population.

Objective

Evaluate the impact of an interactive session on resident physicians’ comfort with adults with IDD.

Methods

Small groups of resident physicians and artists with IDD collaborated on art projects during the noon conference. A prospective pre-post-intervention survey, including the validated Interaction with Disabled Persons Scale (IDP), evaluated residents’ comfort with patients with IDD before and after the session.

Results

53 residents completed both pre- and post-conference surveys. Mean IDP scores decreased from 78.7 (10.9) to 75.8 (9.5; p < 0.01), indicating decreasing discomfort. The mean level of comfort interacting with individuals with IDD increased from uncomfortable 3.6 (1.2), before the intervention, to comfortable 4.4 (1.2) after the intervention (p = <0.01). The mean level of comfort treating individuals with IDD increased from uncomfortable 3.5 (1.1) to comfortable 4.1 (1.3) after the intervention (p < 0.01).

Discussion

Providing resident physicians with real-life connections with people with IDD was associated with increased comfort. If statistically significant improvements occurred after one session, future studies should evaluate if additional experiences with people with IDD could have more substantial, lasting impacts on future doctors’ comfort with and willingness to care for patients with IDD.
Case report: Prone positioning in the improvement of severe post-operative hypoxia following aortic dissection
Authors: Wang Yun , Cheng Xuping , Jiang Xuandong , Chen Lijun
Published: May 2024

Postoperative hypoxemia after aortic dissection surgery presents a considerable clinical challenge, and acute respiratory distress syndrome (ARDS) is a common etiology. Prone positioning treatment has emerged as a potential intervention for improving respiratory function in this context. We report the case of a 27-year-old male who developed severe hypoxemia complicated by pulmonary embolism after aortic dissection surgery. He was diagnosed with postoperative hypoxemia combined with pulmonary embolism following aortic dissection. His respiratory status continued to deteriorate despite receiving standard postoperative care, thereby necessitating an alternative approach. Implementation of prone positioning treatment led to a substantial amelioration in his oxygenation and overall respiratory health, with a consistent hemodynamic state observed throughout the treatment. This technique resulted in significant relief in symptoms and improvement in respiratory parameters, facilitating successful extubation and, ultimately, discharge. This case underlines the possible efficacy of prone positioning therapy in managing severe hypoxia complicated by pulmonary embolism following aortic dissection surgery, warranting more thorough research to explore the potential of this treatment modality.
Genus_Ruminococcus and order_Burkholderiales affect osteoporosis by regulating the microbiota-gut-bone axis
Authors: Li Ning , Wang Haiyang , Pei Huan , Wu Yueying , Li Lei , Ren Yu , Wang Si , Ma Yuan , Luo Miao , Yuan Jiali , Li Lvyu , Qin Dongdong
Published: May 2024

Background

This study aimed to clarify the relationship between the gut microbiota and osteoporosis combining Mendelian randomization (MR) analysis with animal experiments.

Methods

We conducted an analysis on the relationship between differential bacteria and osteoporosis using open-access genome-wide association study (GWAS) data on gut microbe and osteoporosis obtained from public databases. The analysis was performed using two-sample MR analysis, and the causal relationship was examined through inverse variance weighting (IVW), MR Egger, weighted median, and weighted mode methods. Bilateral oophorectomy was employed to replicate the mouse osteoporosis model, which was assessed by micro computed tomography (CT), pathological tests, and bone transformation indexes. Additionally, 16S rDNA sequencing was conducted on fecal samples, while SIgA and indexes of IL-6, IL-1β, and TNF-α inflammatory factors were examined in colon samples. Through immunofluorescence and histopathology, expression levels of tight junction proteins, such as claudin-1, ZO-1, and occludin, were assessed, and conduct correlation analysis on differential bacteria and related environmental factors were performed.

Results

A positive correlation was observed between g_Ruminococcus1 and the risk of osteoporosis, while O_Burkholderiales showed a negative correlation with the risk of osteoporosis. Furthermore, there was no evidence of heterogeneity or pleiotropy. The successful replication of the mouse osteoporosis model was assessed, and it was found that the abundance of the O_Burkholderiales was significantly reduced, while the abundance of g_Ruminococcus was significantly increased in the ovariectomized (OVX)-mice. The intestinal SIgA level of OVX mice decreased, the expression level of inflammatory factors increased, barrier damage occurred, and the content of LPS in the colon and serum significantly increased. The abundance level of O_Burkholderiales is strongly positively correlated with bone formation factors, gut barrier indicators, bone density, bone volume fraction, and trabecular bone quantity, whereas it was strongly negatively correlated with bone resorption factors and intestinal inflammatory factors, The abundance level of g_Ruminococcus shows a strong negative correlation with bone formation factors, gut barrier indicators, and bone volume fraction, and a strong positive correlation with bone resorption factors and intestinal inflammatory factors.

Conclusion

O_Burkholderiales and g_Ruminococcus may regulate the development of osteoporosis through the microbiota-gut-bone axis.
Variation of carbon, nitrogen and phosphorus content in fungi reflects their ecology and phylogeny
Authors: Pánek Matěj , Vlková Tereza , Michalová Tereza , Borovička Jan , Tedersoo Leho , Adamczyk Bartosz , Baldrian Petr , Lopéz-Mondéjar Rubén
Published: May 2024

Fungi are an integral part of the nitrogen and phosphorus cycling in trophic networks, as they participate in biomass decomposition and facilitate plant nutrition through root symbioses. Nutrient content varies considerably between the main fungal habitats, such as soil, plant litter or decomposing dead wood, but there are also large differences within habitats. While some soils are heavily loaded with N, others are limited by N or P. One way in which nutrient availability can be reflected in fungi is their content in biomass. In this study, we determined the C, N, and P content (in dry mass) of fruiting bodies of 214 fungal species to inspect how phylogeny and membership in ecological guilds (soil saprotrophs, wood saprotrophs, and ectomycorrhizal fungi) affect the nutrient content of fungal biomass. The C content of fruiting bodies (415 ± 25 mg g–1) showed little variation (324–494 mg g–1), while the range of N (46 ± 20 mg g–1) and P (5.5 ± 3.0 mg g–1) contents was within one order of magnitude (8–103 mg g–1 and 1.0–18.9 mg g–1, respectively). Importantly, the N and P contents were significantly higher in the biomass of soil saprotrophic fungi compared to wood saprotrophic and ectomycorrhizal fungi. While the average C/N ratio in fungal biomass was 11.2, values exceeding 40 were recorded for some fungi living on dead wood, typically characterized by low N content. The N and P content of fungal mycelium also showed a significant phylogenetic signal, with differences in nutrient content being relatively low within species and genera of fungi. A strong correlation was found between N and P content in fungal biomass, while the correlation of N content and the N-containing fungal cell wall biopolymer—chitin showed only weak significance. The content of macronutrients in fungal biomass is influenced by the fungal life style and nutrient availability and is also limited by phylogeny.
Identification of TonB-dependent siderophore receptor inhibitors against Flavobacterium columnare using a structure-based high-throughput virtual screening method
Authors: Li Minghao , Chen Baipeng , Xu Ming , Li Fulong , Geng Yi , Chen Defang , Ouyang Ping , Huang Xiaoli , Deng Yongqiang
Published: May 2024

TonB-dependent siderophore receptors play a critical transport role for Flavobacterium columnare virulence formation and growth, and have become valuable targets for the development of novel antimicrobial agents. Traditional Chinese medicine has demonstrated notable efficacy in the treatment of fish diseases and includes potential antibacterial agents. Herein, we performed molecular docking-based virtual screening to discover novel TonB-dependent siderophore receptor inhibitors from traditional Chinese medicine and provide information for developing novel antibacterial agents. Firstly, we efficiently obtained 11 potential inhibitors with desirable drug-like characteristics from thousands of compounds in the TCM library based on virtual screening and property prediction. The antibacterial activity of Enoxolone, along with its interaction characteristics, were determined via an MIC assay and molecular dynamic simulation. Transcriptional profiling, along with validation experiments, subsequently revealed that an insufficient uptake of iron ions by bacteria upon binding to the TonB-dependent siderophore receptors is the antibacterial mechanism of Enoxolone. Finally, Enoxolone's acceptable toxicity was illustrated through immersion experiments. In summary, we have used virtual screening techniques for the first time in the development of antimicrobial agents in aquaculture. Through this process, we have identified Enoxolone as a promising compound targeting the TonB-dependent siderophore receptor of F. columnare. In addition, our findings will provide new ideas for the advancement of innovative antimicrobial medications in aquaculture.
Amelioration of experimental autoimmune encephalomyelitis by gemfibrozil in mice via PPARβ/δ: implications for multiple sclerosis
Authors: Mondal Susanta , Sheinin Monica , Rangasamy Suresh B. , Pahan Kalipada
Published: May 2024

It is important to describe effective and non-toxic therapies for multiple sclerosis (MS), an autoimmune demyelinating disease. Experimental autoimmune encephalomyelitis (EAE) is an immune-mediated inflammatory disease that serves as a model for MS. Earlier we and others have shown that, gemfibrozil, a lipid-lowering drug, exhibits therapeutic efficacy in EAE. However, the underlying mechanism was poorly understood. Although gemfibrozil is a known ligand of peroxisome proliferator-activated receptor α (PPARα), here, we established that oral administration of gemfibrozil preserved the integrity of blood–brain barrier (BBB) and blood–spinal cord barrier (BSB), decreased the infiltration of mononuclear cells into the CNS and inhibited the disease process of EAE in both wild type and PPARα–/– mice. On the other hand, oral gemfibrozil was found ineffective in maintaining the integrity of BBB/BSB, suppressing inflammatory infiltration and reducing the disease process of EAE in mice lacking PPARβ (formerly PPARδ), indicating an important role of PPARβ/δ, but not PPARα, in gemfibrozil-mediated preservation of BBB/BSB and protection of EAE. Regulatory T cells (Tregs) play a critical role in the disease process of EAE/MS and we also demonstrated that oral gemfibrozil protected Tregs in WT and PPARα–/– EAE mice, but not PPARβ–/– EAE mice. Taken together, our findings suggest that gemfibrozil, a known ligand of PPARα, preserves the integrity of BBB/BSB, enriches Tregs, and inhibits the disease process of EAE via PPARβ, but not PPARα.
Clarifying the association between Parkinson’s disease and vitiligo: a population-based large-scale study
Authors: Kridin Khalaf , Ofir Lior , Weinstein Orly , Badarny Samih
Published: May 2024

Objective

Our knowledge about the association between vitiligo and Parkinson’s disease (PD) is sparse. We sought to investigate the bidirectional epidemiological association between vitiligo and PD.

Methods

A population-based study was conducted using Clalit Health Services (CHS) database (2002–2019) using both a cohort study and a case–control study design. Adjusted hazard ratio (HR) and odds ratio (OR) were calculated by multivariate Cox and logistic regressions, respectively.

Results

Overall, 20,851 vitiligo patients and 102,475 controls were included. The incidence of new-onset PD was 2.9 (95% CI, 2.1–4.1) and 4.3 (95% CI, 3.8–4.9) cases per 10,000 person-years among patients with vitiligo and controls, respectively. Patients with vitiligo had a significantly decreased risk of developing new-onset PD [adjusted HR, 0.62; 95% confidence interval (CI), 0.43–0.89, p = 0.009]. On the other hand, the likelihood of having vitiligo after a preexisting diagnosis of PD was not statistically different (adjusted OR, 0.80; 95% CI, 0.61–1.06; p = 0.117). Relative to the remaining patients with vitiligo, those with vitiligo and comorbid PD experienced an elevated risk of all-cause mortality (adjusted HR, 2.63; 95% CI, 1.82–3.80; p < 0.001) and higher prevalence of cardiometabolic comorbidities.

Conclusion

Vitiligo is associated with a lower risk of developing PD. The presence of comorbid PD predisposes patients with vitiligo to elevated mortality and cardiometabolic outcomes.
Biological functions and therapeutic potential of SRY related high mobility group box 5 in human cancer
Authors: Xue Juan-di , Xiang Wan-fang , Cai Ming-qin , Lv Xiao-yun
Published: May 2024

Cancer is a heavy human burden worldwide, with high morbidity and mortality. Identification of novel cancer diagnostic and prognostic biomarkers is important for developing cancer treatment strategies and reducing mortality. Transcription factors, including SRY associated high mobility group box (SOX) proteins, are thought to be involved in the regulation of specific biological processes. There is growing evidence that SOX transcription factors play an important role in cancer progression, including tumorigenesis, changes in the tumor microenvironment, and metastasis. SOX5 is a member of SOX Group D of Sox family. SOX5 is expressed in various tissues of human body and participates in various physiological and pathological processes and various cellular processes. However, the abnormal expression of SOX5 is associated with cancer of various systems, and the abnormal expression of SOX5 acts as a tumor promoter to promote cancer cell viability, proliferation, invasion, migration and EMT through multiple mechanisms. In addition, the expression pattern of SOX5 is closely related to cancer type, stage and adverse clinical outcome. Therefore, SOX5 is considered as a potential biomarker for cancer diagnosis and prognosis. In this review, the expression of SOX5 in various human cancers, the mechanism of action and potential clinical significance of SOX5 in tumor, and the therapeutic significance of Sox5 targeting in cancer were reviewed. In order to provide a new theoretical basis for cancer clinical molecular diagnosis, molecular targeted therapy and scientific research.
Application of multimodal standardized analgesia under the concept of enhanced recovery after surgery in laparoscopic radical colorectal cancer surgery
Authors: Cao Lu , Zhang Le , Chen Baoyu , Yan Likun , Shi Xianpeng , Tian Lifei
Published: May 2024

Aims

To observe the efficacy and safety of multimodal standardized analgesia in patients undergoing laparoscopic radical colorectal cancer surgery.

Methods

A prospective, double-blind, randomized study of patients who were admitted to our hospital between December 2020 and March 2022 with a diagnosis of colorectal cancer and who intended to undergo elective laparoscopic radical colorectal cancer surgery was conducted. The participants were randomly divided into two intervention groups, namely, a multimodal standardized analgesia group and a routine analgesia group. In both groups, the visual analogue scale (VAS) pain scores while resting at 6 h, 24 h, 48 h and 72 h and during movement at 24 h, 48 h and 72 h; the number of patient controlled intravenous analgesia (PCIA) pump button presses and postoperative recovery indicators within 3 days after surgery; the interleukin-6 (IL-6) and C-reactive protein (CRP) levels on the 1st and 4th days after surgery; and the incidence of postoperative adverse reactions and complications were recorded.

Results

Compared with the control group, the multimodal standardized analgesia group had significantly lower VAS pain scores at different time points while resting and during movement (P<0.05), significantly fewer PCIA pump button presses during the first 3 postoperative days (P<0.05), and significantly lower IL-6 and CRP levels on the 1st postoperative day (P<0.05). There was no statistically significant difference in the time to out-of-bed activity, the time to first flatus, the IL-6 and CRP levels on the 4th postoperative day or the incidence of postoperative adverse reactions and complications between the two groups (P >0.05).

Conclusion

For patients undergoing laparoscopic radical colorectal cancer surgery, multimodal standardized analgesia with ropivacaine combined with parecoxib sodium and a PCIA pump had a better analgesic effect, as it effectively inhibited early postoperative inflammatory reactions and promoted postoperative recovery and did not increase the incidence of adverse reactions and complications. Therefore, it is worthy of widespread clinical practice.
Case report: A rare DLST mutation in patient with metastatic pheochromocytoma: clinical implications and management challenges
Authors: Li Chang , Han Liang , Song Yuming , Liu Rui
Published: May 2024

Background

Pheochromocytoma is one of the most hereditary human tumors with at least 20 susceptible genes undergoing germline and somatic mutations, and other mutations less than 1% -2%. In recent years, other rare mutations have gradually been discovered to be possibly related to the pathogenesis and metastasis of pheochromocytoma. Most patients with pheochromocytoma experience common symptoms like headaches, palpitations, and sweating, while some may have less common symptoms. The diversity of symptoms, genetic mutations, and limited treatment options make management challenging.

Case presentation

A 53-year-old woman was hospitalized after experiencing episodic epigastric pain for one month. A mass was found in her right adrenal gland and she underwent robot-assisted laparoscopic surgery, revealing a pheochromocytoma. At the 16-month follow-up, multiple metastatic lesions consistent with metastatic pheochromocytoma were found. A germline mutation in the dihydrolipoamide succinyltransferase (DLST) gene (c.330 + 14A>G) was detected, and despite trying chemotherapy and adjuvant therapy, the patient had a limited response with an overall survival of 27 months.

Conclusions

DLST mutation is one of the rare pheochromocytoma-related mutated genes, and genetic sequencing is crucial for effective clinical management.
A hybrid protocol CLAG-M, a possible player for the first-line therapy of patients with mixed phenotype acute leukemia. A Polish Adult Leukemia Group experience
Authors: Karasek Magdalena , Armatys Anna , Skarupski Marek , Bołkun Łukasz , Budziszewska Katarzyna , Drozd-Sokołowska Joanna , Zarzycka Ewa , Mensah-Glanowska Patrycja , Gajewska Małgorzata , Hałka Janusz , Kopacz Agnieszka , Prejzer Witold , Chyrko Olga , Wróbel Tomasz , Wierzbowska Agnieszka , Sobas Marta
Published: May 2024

Introduction

Mixed-phenotype acute leukemia (MPAL) is a rare disease with poor prognosis. So far, no standard approach has been established as the “know-how” of MPAL is based only on retrospective analyses performed on small groups of patients.

Materials and methods

In this study, a retrospective analysis of the outcomes of adult MPAL patients included in the PALG registry between 2005 and 2024 who received the CLAG-M hybrid protocol as induction or salvage therapy was performed.

Results

Sixteen of 98 MPAL patients received CLAG-M: eight as first-line and eight as salvage therapy. In the first line, two patients achieved partial response (PR), and six achieved complete remission (CR), of whom four successfully underwent allogeneic hematopoietic stem cell transplantation (alloHSCT). Two patients who did not undergo alloHSCT promptly relapsed. Within the whole group, the overall response rate (ORR) was 75% (n = 12/16). With the median follow-up of 13 months, six out of eight patients remain in CR, however, two of them died due to acute graft versus host disease. Out of eight patients who received CLAG-M in the second line, four patients (50%) obtained CR. AlloHSCT was conducted in seven cases, six of which were in CR. Only two patients remained in CR at the time of the last follow-up. Tolerance to treatment was good. The median times for severe neutropenia and thrombocytopenia were 22 days (range, 16–24) and 17 days (range, 12–24), respectively. Overall, grade 3-4 infections were observed in 12 cases, and all infections presented successful outcomes.

Conclusions

CLAG-M is an effective first-line salvage regimen for MPAL with an acceptable safety profile. Early achievement of CR with prompt alloHSCT allows for satisfactory disease control.
Interleukin-41: a novel serum marker for the diagnosis of alpha-fetoprotein-negative hepatocellular carcinoma
Authors: Li Yazhao , Wang Haoyu , Ren Danfeng , Li Jingyu , Mu Zihan , Li Chaoyi , He Yongchao , Zhang Jiayi , Fan Rui , Yin Jiayuan , Su Jiaojiao , He Yinli , Yao Bowen
Published: May 2024

Background

For the lack of effective serum markers for hepatocellular carcinoma(HCC) diagnosis, it is difficult to detect liver cancer and identify its recurrence early.

Methods

Databases were used to analyze the genes potentially associated with alpha-fetoprotein(AFP). ELISA assay was used to detect the serum IL-41 in HCC, liver metastases, hepatitis, and healthy people. Immunohistochemical staining was used to analyze the relative quantification of IL-41 in HCC and paracancer tissues. Various survival curves were plotted according to clinical pathological data and helped us draw the ROC curve of IL-41 diagnosis of HCC.

Results

The serum expression of IL-41 was highest in AFP negative HCC patients and significantly higher than that in AFP positive HCC and metastatic cancer patients. There was a significant negative correlation between elevated serum IL-41 and AFP(<1500ng/ml). The clinicopathological features suggested that the serum IL-41 level was significantly correlated with capsule invasion, low differentiation and AFP. High serum expression of IL-41 suggests poorer survival and earlier recurrence after resection, and IL-41 upregulated in patients with early recurrence and death. The expression of IL-41 was higher in HCC tissues of patients with multiple tumors or microvascular invasion. The ROC curve showed that serum IL-41 had a sensitivity of 90.17 for HCC and a sensitivity of 96.63 for AFP-negative HCC, while the specificity was higher than 61%.

Conclusion

IL-41 in serum and tissue suggests poor prognosis and postoperative recurrence in HCC patients and could be a new serum diagnostic marker for AFP negative patients.
Nomograms for metastasis of non-sentinel lymph nodes or more than three lymph nodes in patients with one or two positive sentinel lymph nodes
Authors: Wang Xue-Er , Bi Zhao , Zhang Jin , Wang Yong-Sheng
Published: May 2024

Purpose

The purpose of this study was to provide advice for the indication of regional nodal irradiation (RNI) in patients with one to two positive sentinel lymph nodes (SLNs) without axillary lymph node dissection (ALND).

Methods

We conducted a retrospective study in Shandong Cancer Hospital, Fudan University Shanghai Cancer Center, and West China Hospital. Logistic analysis was performed in order to explore the influencing factors of positive non-SLNs (NSLNs) and >3 positive nodes among patients with one to two SLNs+. Then, nomograms were constructed.

Results

Between May 2010 and 2020, among the 2,845 patients with one to two SLNs+ undergoing ALND (1,992 patients in the training set and 853 patients in the validation set), there were 34.3% harbored NSLNs+ and 15.6% harbored >3 positive nodes. Multivariate analysis showed that cN stage, the number of positive/negative SLN, pathological tumor stage, lympho-vascular invasion (LVI), multicenter, and molecular subtypes were significantly associated with NSLN metastasis. Similarly, multivariate analysis also showed that cN stage, the number of positive/negative SLNs, pathological tumor stage, and LVI could be independent predictors of >3 positive nodes. Then, nomograms for NSLN metastasis and >3 positive nodes were constructed using these parameters, respectively.

Conclusions

The nomograms will be useful in estimating positive NSLNs and >3 positive nodes, and they might provide advice for the optimization of RNI.
Organoids as a new approach for improving pediatric cancer research
Authors: Lampis Silvia , Galardi Angela , Di Paolo Virginia , Di Giannatale Angela
Published: May 2024

A key challenge in cancer research is the meticulous development of models that faithfully emulates the intricacies of the patient scenario, with emphasis on preserving intra-tumoral heterogeneity and the dynamic milieu of the tumor microenvironment (TME). Organoids emerge as promising tool in new drug development, drug screening and precision medicine. Despite advances in the diagnoses and treatment of pediatric cancers, certain tumor subtypes persist in yielding unfavorable prognoses. Moreover, the prognosis for a significant portion of children experiencing disease relapse is dismal. To improve pediatric outcome many groups are focusing on the development of precision medicine approach. In this review, we summarize the current knowledge about using organoid system as model in preclinical and clinical solid-pediatric cancer. Since organoids retain the pivotal characteristics of primary parent tumors, they exert great potential in discovering novel tumor biomarkers, exploring drug-resistance mechanism and predicting tumor responses to chemotherapy, targeted therapy and immunotherapies. We also examine both the potential opportunities and existing challenges inherent organoids, hoping to point out the direction for future organoid development.