Node Cells Research Articles

Antibiotic prophylaxis dysregulates dental implant placement surgery-induced osteoimmune wound healing and attenuates the alveolar bone-implant interface in mice.

Antimicrobial-induced shifts in commensal oral microbiota can dysregulate helper T-cell oral immunity to affect osteoclast-osteoblast actions in alveolar bone. Antibiotic prophylaxis is commonly performed with dental implant placement surgery to prevent post-surgical complications. However, antibiotic prophylaxis effects on osteoimmune processes supporting dental implant osseointegration are unknown. The aim of the study was to discern the impact of antibiotic prophylaxis on dental implant placement surgery-induced osteoimmune wound healing and osseointegration. We performed SHAM or dental implant placement surgery in mice. Groups were administered prophylactic antibiotics (amoxicillin or clindamycin) or vehicle. Gingival bacteriome was assessed via 16S sequencing. Helper T-cell oral immunity was evaluated by flow cytometry. Osteoclasts and osteoblasts were assessed via histomorphometry. Implant osseointegration was evaluated by micro-computed tomography. Dental implant placement surgery up-regulated TH 1, TH 2 and TREG cells in cervical lymph nodes (CLNs), which infers helper T-cell oral immunity contributes to dental implant placement osseous wound healing. Prophylactic antibiotics with dental implant placement surgery caused a bacterial dysbiosis, suppressed TH 1, TH 2 and TREG cells in CLNs, reduced osteoclasts and osteoblasts lining peri-implant alveolar bone, and attenuated the alveolar bone-implant interface. Antibiotic prophylaxis dysregulates dental implant placement surgery-induced osteoimmune wound healing and attenuates the alveolar bone-implant interface in mice.

Abstract P416: Differences In Immune Cell Composition And Response Between Spontaneously Hypertensive Bph/2 Mice And Normotensive Bpn/3 Mice

There is considerable evidence for a role for the immune system in different animal models of hypertension. However, whether there are differences in the immune systems of Bph/2 spontaneously hypertensive mice and Bpn/3 normotensive mice is not known. To address this, we characterized the immune composition and response of male Bph/2 and Bpn/3 mice. Bph/2 mice had significantly lower body weight compared to Bpn/3 mice (Bpn: 32.0 ± 0.5 g; Bph: 23.0 ± 0.5 g) with a proportionately lower spleen weight (Bpn: 70.1 ± 9.8 mg; Bph: 48.6 ± 2.1 mg). As expected, Bph/2 mice had higher blood pressure than Bpn/3 mice. Bph/2 mice also had a higher percentage of CD4 T cells in brachial lymph nodes compared to Bpn/3 mice (Bpn: 48.0 ± 0.57, Bph: 58.6 ± 1.94) and a lower percentage of CD8 T cells (Bpn: 46.4 ± 1.07, Bph: 38.9 ± 1.84), causing an increased CD4:CD8 T cell ratio in Bph/2 mice (Bpn: 1.04 ± 0.03, Bph: 1.53 ± 0.12). This trend was also observed in inguinal lymph nodes, but not in spleens or mesenteric lymph nodes. There were also differences in the response of anti-CD3/anti-CD28-activated splenocytes. Specifically, IFNγ secretion was markedly lower in splenic T cells from Bph/2 mice compared to those from Bpn/3 mice 24 h after activation (Bpn: 4902 ± 1532 pg/ml, Bph/2: 921 ± 462 pg/ml). Similarly, IL-2 (Bpn: 3960 ± 1070 pg/ml; Bph: 1121 ± 247 pg/ml), IL-6 (Bpn: 297 ± 94 pg/ml, Bph: 64 ± 15 pg/ml) and TNFα (Bpn: 170 ± 33 pg/ml; Bph: 59 ± 15 pg/ml) induction was also lower in T cells from Bph/2 mice. Interestingly, we also found that Bpn/3 mice do not express the NK cell marker, NK1.1. Taken together, the data suggest significant differences in immune composition and response between Bph/2 and Bpn/3 mice and indicate a need to further evaluate the role of the immune system in the development of hypertension in this model.

Pre-existing CD4 T cell help boosts antibody responses but has limited impact on germinal center, antigen-specific B cell frequencies after influenza infection.

The influenza virus is a persistent burden on global health, with seasonal vaccines providing incomplete protection. CD4+ T cells help shape B cell and antibody responses; however, the selectivity of help and the effect on various antigen-specific B cell populations have not been fully elucidated. Here, we studied the specificity, selectivity, and influence of nucleoprotein (NP) CD4+ T cells on the magnitude and quality of hemagglutinin (HA) and NP-specific B cells and antibody responses. We identified immunodominant peptides and showed that peptide immunization was sufficient to induce CD4+ cells with Th1 and Tfh phenotypes. Surprisingly, while preexisting CD4+ T cells enhanced the influx of total germinal center (GC) B cells in the mediastinal lymph node after infection, this was not reflected by an increase in the frequency of antigen-specific cells within the GC. Furthermore, we demonstrated that NP-specific help was able to accelerate the kinetics and magnitude of the Ab response for NP but not for HA. Overall, our results showed that pre-existing CD4+ T cells provide strong cognate help during immunization or infection to enhance Ab production but not antigen-specific GC or memory B cells.

Lentinan-functionalized graphene oxide hydrogel as a sustained antigen delivery system for vaccines

Hydrogel has been proven to have the ability to deliver antigens continuously to achieve slow vaccine delivery, which makes it a promising candidate for an adjuvant delivery platform. Meanwhile, graphene oxide (GO) has garnered significant attention due to its good biosafety, excellent surface area and easy modification. However, GO exists as weak colloidal particles and poses challenges in self-assembling into a hydrogel structure. Here, we propose an innovative strategy involving self-assembling lentinan-functionalized graphene oxide hydrogel ((LNT-GO Gel) by simply mixing lentinan (LNT)-functionalized GO with polyethylene imide (PEI), which can simultaneously encapsulate antigens, achieve long-lasting release of antigens and generate excellent adjuvant activity. The results indicated that the LNT-GO Gel can control the release of OVA at the injection site and confer targeted delivering capacity to lymph nodes. And the date demonstrates that LNT-GO Gel displays favorable safety and biodegradability in vivo. Moreover, LNT-GO Gel can enhance the activation and maturation of dendritic cells (DCs) in lymph node, induce stronger OVA-specific antibody response, and promote spleen T lymphocyte differentiation, which underscores that LNT-GO Gel has ability to generate stronger antigen-specific humoral and cellular immune responses. Collectively, these results demonstrate the adjuvant potential of the lentinan-functionalized graphene oxide hydrogel (LNT-GO Gel) for subunit vaccine.

Oligodendrocyte progenitor cells differentiation induction with MAPK/ERK inhibitor fails to support repair processes in the chronically demyelinated CNS.

Remyelination failure is considered a major obstacle in treating chronic-progressive multiple sclerosis (MS). Studies have shown blockage in the differentiation of resident oligodendrocyte progenitor cells (OPC) into myelin-forming cells, suggesting that pushing OPC into a differentiation program might be sufficient to overcome remyelination failure. Others stressed the need for a permissive environment to allow proper activation, migration, and differentiation of OPC. PD0325901, a MAPK/ERK inhibitor, was previously shown to induce OPC differentiation, non-specific immunosuppression, and a significant therapeutic effect in acute demyelinating MS models. We examined PD0325901 effects in the chronically inflamed central nervous system. Treatment with PD0325901 induced OPC differentiation into mature oligodendrocytes with high morphological complexity. However, treatment of Biozzi mice with chronic-progressive experimental autoimmune encephalomyelitis with PD0325901 showed no clinical improvement in comparison to the control group, no reduction in demyelination, nor induction of OPC migration into foci of demyelination. PD0325901 induced a direct general immunosuppressive effect on various cell populations, leading to a diminished phagocytic capability of microglia and less activation of lymph-node cells. It also significantly impaired the immune-modulatory functions of OPC. Our findings suggest OPC regenerative function depends on a permissive environment, which may include pro-regenerative inflammatory elements. Furthermore, they indicate that maintaining a delicate balance between the pro-myelinating and immune functions of OPC is of importance. Thus, the highly complex mission of creating a pro-regenerative environment depends upon an appropriate immune response controlled in time, place, and intensity. We suggest the need to employ a multi-systematic therapeutic approach, which cannot be achieved through a single molecule-based therapy.

Lipid-Polymer Hybrid Nanoparticles with Both PD-L1 Knockdown and Mild Photothermal Effect for Tumor Photothermal Immunotherapy.

In developing countries, the incidence of colorectal cancer (CRC) is on the rise. The combination of programmed cell death ligand-1 (PD-L1) siRNA (siPD-L1) and mild photothermal therapy (PTT) is a promising strategy for CRC treatment. In this study, dopamine-modified polyethylenimine (PEI) was prepared to fabricate an IR780 and siPD-L1 codelivery lipid-polymer hybrid nanoparticle (lip@PSD-siP) for the photothermal immunotherapy of CRC. The modification of dopamine can significantly reduce the cytotoxicity of PEI. lip@PSD-siP can be effectively taken up by CT26 cells and successfully escaped from lysosomes after entering the cells for 4 h. After CT26 cells were transfected with lip@PSD-siP, the PD-L1 positive cell rate decreased by 82.4%, and its PD-L1 knockdown effect was significantly stronger than the positive control Lipo3000-siP. In vivo studies showed that lip@PSD-siP-mediated mild PTT and efficient PD-L1 knockdown exhibited primary and distal tumor inhibition, metastasis delay, and rechallenged tumor inhibition. The treatment with lip@PSD-siP significantly promoted the maturation of dendritic cells in lymph nodes. The amount of T cell infiltration in the tumor tissues increased significantly, and the frequency of CD8+ T cells and CD4+ T cells was significantly higher than that of other groups. The percentage of immunosuppressive regulatory cells (Tregs) in the tumor tissue on the treatment side decreased by 88% compared to the PBS group, and the proportion of CD8+CD69+ T cells in the distal tumor tissue was 2.8 times that of the PBS group. The memory T cells of mice in the long-term antitumor model were analyzed. The results showed that after treatment with lip@PSD-siP, the frequency of effector memory T cells (Tem cells) significantly increased, suggesting the formation of immune memory.

Impaired tissue homing by the Ikzf3N159S variant is mediated by interfering with Ikaros function.

AIOLOS, encoded by IKZF3, is a member of the IKZF family of proteins that plays an important role in regulating late B-cell differentiation. Human individuals heterozygous for the AIOLOS p.N160S variant displayed impaired humoral immune responses as well as impaired B and T cell development. We have previously reported that a mouse strain harboring an Ikzf3N159S allele that corresponds to human IKZF3N160S recapitulated immune-deficient phenotypes, such as impaired B cell development and loss of CD23 expression. In this study, we investigated the effect of the Ikzf3N159S variant and found that B1a cell development was impaired in Ikzf3N159S/N159S mice. In addition, CD62L expression was severely decreased in both B and T lymphocytes by the Ikzf3N159S mutation, in a dose-dependent manner. Mixed bone marrow chimera experiments have revealed that most immunodeficient phenotypes, including low CD62L expression, occur in intrinsic cells. Interestingly, while Ikzf3N159S/N159S lymphocytes were still present in the spleen, they were completely outcompeted by control cells in the lymph nodes, suggesting that the capacity for homing or retention in the lymph nodes was lost due to the Ikzf3N159S mutation. The homing assay confirmed severely decreased homing abilities to lymph nodes of Ikzf3N159S/N159S B and T lymphocytes but selective enrichment of CD62L expressing Ikzf3N159S/N159S lymphocytes in lymph nodes. This finding suggests that impaired CD62L expression is the major reason for the impaired homing capacity caused by the Ikzf3N159S mutation. Interestingly, an excess amount of Ikaros, but not Aiolos, restored CD62L expression in Ikzf3N159S/N159S B cells. Together with the loss of CD62L expression due to Ikaros deficiency, the AiolosN159S mutant protein likely interferes with Ikaros function through heterodimerization, at least in activating the Sell gene encoding CD62L expression. Thus, our results revealed that AiolosN159S causes some immunodeficient phenotypes via the pathogenesis referred to as the heterodimeric interference as observed for AiolosG158R variant.

Unraveling the Role of EV-Derived miR-150-5p in Prostate Cancer Metastasis and Its Association with High-Grade Gleason Scores: Implications for Diagnosis.

Metastasis remains the leading cause of mortality in prostate cancer patients. The presence of tumor cells in lymph nodes is an established prognostic indicator for several cancer types, such as melanoma, breast, oral, pancreatic, and cervical cancers. Emerging evidence highlights the role of microRNAs enclosed within extracellular vesicles as facilitators of molecular communication between tumors and metastatic sites in the lymph nodes. This study aims to investigate the potential diagnostic utility of EV-derived microRNAs in liquid biopsies for prostate cancer. By employing microarrays on paraffin-embedded samples, we characterized the microRNA expression profiles in metastatic lymph nodes, non-metastatic lymph nodes, and primary tumor tissues of prostate cancer. Differential expression of microRNAs was observed in metastatic lymph nodes compared to prostate tumors and non-metastatic lymph node tissues. Three microRNAs (miR-140-3p, miR-150-5p, and miR-23b-3p) were identified as differentially expressed between tissue and plasma samples. Furthermore, we evaluated the expression of these microRNAs in exosomes derived from prostate cancer cells and plasma samples. Intriguingly, high Gleason score samples exhibited the lowest expression of miR-150-5p compared to control samples. Pathway analysis suggested a potential regulatory role for miR-150-5p in the Wnt pathway and bone metastasis. Our findings suggest EV-derived miR-150-5p as a promising diagnostic marker for identifying patients with high-grade Gleason scores and detecting metastasis at an early stage.

An Approach to Nodal T- and NK-Cell Lymphomas—A Systemic Review

AbstractT-cell lymphomas are rare neoplasms that have complex pathology. The multiparameter approach has been recommended by World Health Organization (WHO) for the classification of T-cell lymphomas taking into account morphology, immunophenotype, genetics, and clinical features. This also includes division established on the possible cell-of-origin (COO) from T regulatory or T-follicular helper (TFH) cells. The recent WHO-HAEM5 has classified entities as precursor T-lymphoblastic neoplasms, mature T-cell neoplasms, Epstein-Barr virus (EBV)-related T- and NK/T-cell lymphomas, and tumor-like lesions with T-cells predominance. Distinct entities have been recognized within the anaplastic large cell lymphoma (ALCL) family founded on the status of anaplastic lymphoma kinase (ALK) gene rearrangement: ALK-positive and molecularly heterogeneous ALK-negative. The family of lymphomas arising from TFH cells consists of three distinct nodal TFH cell lymphoma entities: angioimmunoblastic-type, follicular-type, and not otherwise specified. These three entities show significant clinical and immunophenotypic overlap. The cases that do not qualify for ALCL or nodal TFH cell lymphomas are labelled as peripheral T-cell lymphomas-not otherwise specified after ruling out nodal EBV-positive T- and NK- cell lymphoma. The new category termed tumor-like lesions with T cell predominance has a high chance to be misdiagnosed as lymphoma. This category includes entities such as Kikuchi-Fujimoto disease, indolent T-lymphoblastic proliferation, and autoimmune lymphoproliferative syndrome. For pathologists, diagnosing nodal T-cell lymphomas may be thought-provoking due to their broad histopathologic spectrum that mimics reactive as well as other neoplastic processes. This review provides a comprehensive diagnostic criterion of the most commonly encountered nodal T-cell and NK cell lymphomas in day-to-day training and an algorithmic approach.

Chronic oral exposure to low-concentration fumonisin B2 significantly exacerbates the inflammatory responses of allergies in mice via inhibition of IL-10 release by regulatory T cells in gut-associated lymphoid tissue.

Contamination with fumonisins produced by Fusarium spp. is rapidly growing in both developing and developed countries. The purpose of this study was to determine whether oral exposure to fumonisin contributed to the development of allergic diseases. We initially examined the immunotoxic potential of short-term, oral administration of fumonisin B1 (FB1, 1mg/kg) and fumonisin B2 (FB2, 1mg/kg), both naturally occurring fumonisins, using a BALB/c mouse model of allergic contact dermatitis and Dermatophagoides farina-induced asthma. Using an NC/nga mouse model of atopic dermatitis (AD), we evaluated the adverse effects of subchronic oral exposure to low concentrations of FB2 (2 or 200μg/kg). Finally, we explored the influence of FB2 on regulatory T cell proliferation and function in mesenteric lymph nodes after 1-week oral exposure to FB2 in BALB/c mice. Oral exposure to FB2 markedly exacerbated the symptoms of allergy, including skin thickness, histological evaluation, immunocyte proliferation, and proinflammatory cytokine production, although no change was observed following exposure to FB1. Furthermore, oral exposure to low concentrations of FB2 considerably exacerbated the AD scores, skin thickness, transepidermal water loss, histological features, and proinflammatory cytokine production. The aggravated allergic symptoms induced by oral exposure to FB2 could be attributed to the direct inhibition of IL-10 production by regulatory T cells in mesenteric lymph nodes. Our findings indicate that the recommended maximum fumonisin level should be reconsidered based on the potential for allergy development.

Impact of Primary Tumor Variables on Predicting Nodal Metastasis in Lower Extremity Marjolin's Ulcer: A Retrospective Cohort Study.

Background Marjolin's ulcer or scar carcinoma is a rare disease arising from the conversion of chronic scar into malignancy. Studies show Marjolin's ulcer squamous cell carcinoma has more chances of lymph nodal metastasis and is more aggressive with a worse survival rate. To date, no established guidelines exist for managing regional lymph nodes in cases of Marjolin's ulcer with clinically N0 nodes. Observation vs elective node dissection remains an option. In developing countries, long-term follow-up is not consistently leading to the risk of patients being kept on observation for regional nodes; presenting late with inoperable regional nodes is possible. This study aims to identify clinicopathological factors of lower extremity Marjolin's ulcer, which are associated with a high risk of inguinal lymph node metastasis. Identifying such risk factors may help provide a rationale for performing elective nodal dissection instead of observation in high-risk cases. Material and methods All clinically N0 lower extremity Marjolin's ulcer cases, more than 3 cm in size, treated at King George's Medical University, India, during the last five years, have been included in this study. Demographic, clinical, and pathological data of eligible patients were retrieved from institutional records. Various clinical and pathological factors were studied and correlated with lymph node positivity, and the strength of the correlation was tested using statistical methods. Factors correlated strongly with inguinal lymph node positivity were identified as high-risk factors. Results A total of 66 patients with lower extremity Marjolin's ulcer had no preoperative pathologically confirmed inguinal lymph nodes documented by ultrasonography and fine needle aspiration cytology. All patients underwent surgery for primary, followed by elective, inguinal lymph nodal dissection. The majority were males (n=51/66; 71%), and the most common age group was 30-50 years (n=40/66; 60%). The leg was the most common site (n=31/66; 47%). The least common site was below the ankle (n=14/66; 22%). Maximum dimension ranged from 3 cm to >15 cm, with the majority between 6 and 10 cm (n=40/66; 56%). Extension beyond the scar site was present in 24% (n=15/66) of patients. Most of the lesions in this study were well differentiated, 85% (n=56/66), and moderately differentiated, 15% (n=10/66), and none of the lesions was poorly differentiated. Perineural invasion, lymphovascular invasion, tumor necrosis, and extension below subcutaneous tissue were present in 82%, 14%, 28%, and 26%, respectively. Of 66 patients, 21.2% (n=14/66) had pathological nodal disease after elective nodal dissection. Perineural invasion (p<0.0001), depth of lesion (p<0.0001), and tumor necrosis (p=0.0002) had a statistically significant correlation with node metastasis. On ROC curve analysis, 7.5 cm was the cut-off size, above which chances of nodal metastasis increased significantly. Conclusions Marjolin's ulcer patients with no preoperative positive nodes may be segregated into high-risk and low-risk groups as per their risk of harboring cancer cells in regional lymph nodes. Those having one or more of the following risk factors should be classified as high risk: dimension more than 7.5 cm, presence of perineural invasion, tumor necrosis, and deep tumors extending below subcutaneous tissue. We recommend that such patients undergo prophylactic regional lymph node dissection instead of observation during primary surgery.

Cytological Quantification of Nodal Mast Cells in Dogs Affected by Non-Neoplastic Condition and Mast Cell Tumor Using Different Sample Preparation Techniques: An Explorative Study.

Cytological evaluation of lymph nodes (LN) in canine cutaneous mast cell tumors (MCT) has a key role in MCT staging. However, cytological discrimination between metastatic and reactive LNs is debated and diagnostic criteria inconsistent. The aim of this study was to retrospectively quantify nodal mast cells (MCs) in non-oncological (NOD) and MCT-bearing dogs (MCTBD), using different sample preparation techniques, to evaluate the significance of the MCT number. Cytological specimens from NOD-LNs (10 fine-needle aspirates-FNAs) and MCTBD-LNs (10 FNAs, 10 scrapings, 10 touch imprints) were evaluated. MCTBD-LNs were grouped in: non-metastatic, possibly-metastatic, and metastatic based on current literature criteria. MCs were counted in 4, 8, and 20 high-power-fields, and over 500, 1000, and 2000 total cells. MCs were significantly more numerous in MCTBD-LNs than in NOD-LNs and in "metastatic" samples than in "non-metastatic". There was no significant difference between "metastatic" and "possibly metastatic" samples. Sample preparation techniques did not influence these results. A negative correlation between MCs number and sample cellularity was observed. Results were confirmed regardless of the counting method applied. MCs counting per se cannot distinguish possibly metastatic and metastatic cytological samples. Sample preparation technique and the counting method applied seem to have no influence on cytological quantification of nodal MCs in MCTBDs.

Sirtuin 2 up-regulation suppresses the anti-tumour activity of exhausted natural killer cells in mesenteric lymph nodes in murine colorectal carcinoma.

Natural killer (NK) cells inhibit colorectal carcinoma (CRC) initiation and progression through their tumoricidal activity. However, cumulative evidence suggests that NK cells become functionally exhausted in patients with CRC. To deepen the understanding of the mechanisms underlying CRC-associated NK cell exhaustion, we explored the expression and effect of Sirtuin 2 (Sirt2) in mesenteric lymph node (mLN) NK cells in a murine colitis-associated CRC model. Sirt2 was remarkably up-regulated in mLN NK cells after CRC induction. Particularly, Sirt2 was increased in mLN NK cells expressing high T cell immunoglobulin and mucin domain-3 (TIM3), high lymphocyte activation protein-3 (LAG3), high programmed death-1 (PD-1), high T cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT), high NK group 2 member A (NKG2A), but low tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), low interferon-gamma and low granzyme B. In addition, Sirt2 was also increased in NK cells after induction of exhaustion in vitro. Lentivirus-mediated Sirt2 silencing did not affect the acute activation and cytotoxicity of non-exhausted NK cells. However, Sirt2 silencing partially restored the expression of interferon-gamma, granzyme B and CD107a in exhausted NK cells. Meanwhile, Sirt2 silencing down-regulated TIM3, LAG3, TIGIT and NKG2A while up-regulated TRAIL on exhausted NK cells. Consequently, Sirt2 silencing restored the cytotoxicity of exhausted NK cells. Moreover, Sirt2 silencing partially ameliorates the defects in glycolysis and mitochondrial respiration of exhausted NK cells, as evidenced by increases in glycolytic capacity, glycolytic reserve, basal respiration, maximal respiration and spare respiration capacity. Accordingly, Sirt2 negatively regulates the tumoricidal activity of exhausted NK cells in CRC.

Universal Fe/Mn Nanoadjuvant with T1/T2 MRI Self-Navigation and Gas Generation for Ideal Vaccines with Precise Tracking.

Because of the distinguished properties between nanovaccine and traditional vaccine, the precise guidelines for nanovaccines with an optimal vaccination strategy to induce ideal immunities are greatly desired for combating major diseases, including cancer and infections. Herein, we designed and synthesized a self-navigating nanoadjuvant composed of Fe-doped manganese carbonate and its nanovaccine via a facile method. First, the degradation of the nanoadjuvant under acidic milieu of immune cells in lymph nodes would generate T1 and T2 MR imaging (MRI) signals to reflect the transformation dynamics of the nanovaccine and inform us when the next vaccination needed. Under this guideline, nanovaccines with a precise vaccination strategy triggered robust antigen-specific immune responses and immunological memory to effectively prevent ovalbumin (OVA)-expressing melanoma relapse by activating dendritic cells via a stimulator of interferon genes (STING) signaling pathway and inducing antigen cross-presentation by shaping lysosome integrity with CO2 generation and upregulating transporter associated antigen processing 1 (TAP-1) transporter. This study provides a universal nanoadjuvant with imaging self-guidance, immunopotentiating, and cross-priming activities for developing precise vaccines with an optimal immunization strategy to combat major diseases.

Insight into the nodal cells transcriptome of the streptophyte green alga Chara braunii S276.

Charophyceae are the most complex streptophyte algae, possessing tissue-like structures, rhizoids and a cellulose-pectin-based cell wall akin to embryophytes. Together with the Zygnematophyceae and the Coleochaetophycae, the Charophyceae form a grade in which the Zygnematophyceae share a last common ancestor with land plants. The availability of genomic data, its short life cycle, and the ease of non-sterile cultivation in the laboratory have made the species Chara braunii an emerging model system for streptophyte terrestrialization and early land plant evolution. In this study, tissue containing nodal cells was prepared under the stereomicroscope, and an RNA-seq dataset was generated and compared to transcriptome data from whole plantlets. In both samples, transcript coverage was high for genes encoding ribosomal proteins and a homolog of the putative PAX3- and PAX7-binding protein 1. Gene ontology was used to classify the putative functions of the differently expressed genes. In the nodal cell sample, main upregulated molecular functions were related to protein, nucleic acid, ATP- and DNA binding. Looking at specific genes, several signaling-related genes and genes encoding sugar-metabolizing enzymes were found to be expressed at a higher level in the nodal cell sample, while photosynthesis-and chloroplast-related genes were expressed at a comparatively lower level. We detected the transcription of 21 different genes encoding DUF4360-containing cysteine-rich proteins. The data contribute to the growing understanding of Charophyceae developmental biology by providing a first insight into the transcriptome composition of Chara nodal cells.

Efficacy of Heshouwu () on gut mircobiota in mice with autoimmune encephalomyelitis.

To learn the mechanisms between gut microbiome and the autoimmunity benefits on Traditional Chinese Medicine (TCM) in central nervous system (CNS), we investigated the neuro-protection effects and gut mircobiota changes of Heshouwu () on experimental autoimmune encepha-lomyelitis (EAE), an animal model of multiple sclerosis (MS). Mice were randomly divided into four groups: EAE mice (control phosphate-buffered saline group), 50 mg·kg·d Heshouwu ()-treated EAE mice, 100 mg·kg·d Heshouwu ()-treated EAE mice, and 200 mg·kg·d Heshouwu ()-treated EAE mice. The spinal cords were stained with hematoxylin and eosin (HE) and luxol fast blue for evaluating inflammatory infiltration and demyelination. The percentages of granulocyte macrophage-colony stimulating factor (GM-CSF)+CD4+, interleukin 17 (IL-17)+CD4+, Foxp3 CD4+, and interferon-γ (IFN-γ)+CD4+ T cells in the inguinal lymph nodes (LNs) and brain were determined by flow cytometry analysis. 16S rRNA gene sequencing was employed to analyze the changes in gut microbiota. We found that Heshouwu () alleviated the disease severity and neuropathology of EAE as evaluated by clinical and histopathologyical scores. Heshouwu () increased the diversity and abundance of the gut microbiota, and decreased / ratio (F/B ratio). Heshouwu () also decreased the concentrations of IL-10, and IL-21 and increase the levels of GM-CSF, IL-17A, IL-17F and IL-22 in serum of EAE mice. Moreover, Heshouwu () modulated the T cell responses by inhibiting Th17 cells and restoring Treg cells in the small intestine lymphoid tissues and inguinal lymph nodes. Microbiota-depleted mice receiving Heshouwu ()-treated fecal microbiota trans-plantation had lower disease severity, neuropathology scores and alleviation of Th17/Treg imbalance compared to ad libitum group. Our findings suggested that the vital neuro-protection role of Heshouwu () (TCM) in immunomodulation effects partly by regulations of gut microbiome.

Lymph node metastasis in oral squamous cell carcinoma: Where we are and where we are going

AbstractBackgroundOral cancer is a common malignant tumour in the head and neck region, with over 90% of cases being oral squamous cell carcinoma (OSCC). Lymph node metastasis (LNM) is a significant adverse prognostic factor in OSCC; however, the mechanism of LNM in OSCC remains unclear, while the strategies for managing cervical lymph nodes (CLNs) in OSCC continue to evolve. At present, neck dissection is necessary for the vast majority of OSCC patients, but complications of surgery can significantly impair patients’ postoperative quality of life. A recent clinical trial discovery indicates that immunotherapy can activate anti‐tumour T cells in nearby lymph nodes, leading to vibrant discussions among clinicians about the importance of preserving lymph nodes during surgical treatment.AimThis review aims to provide an overview of where we are: the current knowledge of OSCC LNM patterns and management strategies, and where we are going: prospects for clinical and basic research on the issue of OSCC LNM in the era of cancer immunotherapy.ResultWe summarize the general patterns and management strategies of OSCC LNM. The process of LNM in OSCC encompasses four stages: Preparation, Unleash, Migration, and Planting (‘PUMP’ principle). We propose adopting the ‘PRECISE’ model, an overall workflow that includes seven elements—prevention, radiology, preoperative evaluation, chemotherapy, immunotherapy, surgery, and postoperative evaluation—for neck management in OSCC, promoting personalized precision medicine augmented by neoadjuvant therapy. We further discussed recent advances in clinical and basic research on OSCC LNM and provided an outlook on future research directions.ConclusionOver the past two centuries, our understanding and management strategies of LNM in OSCC have evolved, seeking more precise and personalized approaches to reduce patient burden and enhance survival and quality of life. Further research should explore lymph nodes’ role in cancer immunotherapy and OSCC interactions, leading to better, less invasive treatments and improved outcomes.

A biologic-device combination product delivering tumor-derived antigens elicits immunogenic cell death-associated immune responses against glioblastoma

BackgroundIGV-001 is a personalized, autologous cancer cell-based immunotherapy conceived to deliver a tumor-derived antigenic payload in the context of immunostimulatory signals to patients with glioblastoma (GBM). IGV-001 consists of patient-derived...

Serum levels of type I interferon (IFN-I) is associated with the severity of COVID-19.

Introduction. Caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, coronavirus disease 2019 (COVID-19) has threatened global public health. Immune damage mechanisms are essential guidelines for clinical treatment and immune prevention.Hypothesis. The dysregulated type I interferon (IFN-I) responses, lymphocytopenia and hypercytokinemia during SARS-CoV-2 infection have been reported. However, whether there is a correlation between levels of IFN-I and the severity of COVID-19 has not been reported yet.Aim. To investigate the source of IFN-I and detect the exact roles of them in the pathogenesis of COVID-19.Methodology. Here ELISA was used to detect serum IFN-I (IFN-α and IFN-β) for 137 cases with laboratory-confirmed COVID-19 admitted into one hospital in Wuhan from December 2019 to March 2020, and the relationships between IFN-α/β concentrations and patients' clinical parameters were conducted by statistical analysis.Results. Both IFN-α and IFN-β concentrations dramatically increased in COVID-19 patients, especially in old patients (>80 years) and severe cases. Statistical analysis demonstrated that serum IFN-α/β concentrations were negatively correlated with the counts of total CD3+T, CD4+ and CD8+T cells, especially in critically ill cases. Moreover, serum IFN-α levels were positively correlated to IL-6 and TNF-α. Finally, immunofluorescent double staining showed that IFN-α and IFN-β are major secretions from macrophages and dendritic cells (DCs) in lymph nodes from COVID-19 autopsies.Conclusion. These results demonstrate that macrophages and DCs are the main origination of IFN-I, and serum levels of IFN-I are positively associated with lymphopenia and cytokine storm, suggesting that IFN-α/β deteriorated the severity of COVID-19. Anti-interferon or IFN-I signalling block drugs are needed to treat ICU patients.

LFA-1/ICAM-1 Adhesion Pathway Mediates the Homeostatic Migration of Lymphocytes from Peripheral Tissues into Lymph Nodes through Lymphatic Vessels.

Lymphocyte function-associated antigen-1 (LFA-1) and its endothelial ligand intercellular adhesion molecule-1 (ICAM-1) are important for the migration of lymphocytes from blood vessels into lymph nodes. However, it is largely unknown whether these molecules mediate the homeostatic migration of lymphocytes from peripheral tissues into lymph nodes through lymphatic vessels. In this study, we find that, in naive mice, ICAM-1 is expressed on the sinus endothelia of lymph nodes, but not on the lymphatic vessels of peripheral tissues. In in vivo lymphocyte migration assays, memory CD4+ T cells migrated to lymph nodes from peripheral tissues much more efficiently than from blood vessels, as compared to naive CD4+ T cells. Moreover, ICAM-1 deficiency in host mice significantly inhibited the migration of adoptively transferred wild-type donor lymphocytes from peripheral tissues, but not from blood vessels, into lymph nodes. The migration of LFA-1-deficient donor lymphocytes from peripheral tissues into the lymph nodes of wild-type host mice was also significantly reduced as compared to wild-type donor lymphocytes. Furthermore, the number of memory T cells in lymph nodes was significantly reduced in the absence of ICAM-1 or LFA-1. Thus, our study extends the functions of the LFA-1/ICAM-1 adhesion pathway, indicating its novel role in controlling the homeostatic migration of lymphocytes from peripheral tissues into lymph nodes and maintaining memory T cellularity in lymph nodes.