Prevotella intermedia boosts OSCC progression through ISG15 upregulation: a new target for intervention.

PURPOSE: Periodontitis-associated bacteria, such as Porphyromonas gingivalis and Fusobacterium nucleatum, are closely linked to the risk of oral squamous cell carcinoma (OSCC). Emerging studies have indicated that another common periodontal pathogen, Prevotella intermedia (P. intermedia), is enriched in OSCC and could affect the occurrence and progression of OSCC. Our aim is to determine the effects of P. intermedia on the progression of OSCC and the role of antibiotics in reversing these effects. METHODS: In this study, a murine xenograft model of OSCC was established, and the mice were injected intratumorally with PBS (control group), P. intermedia (P.i group), or P. intermedia combined with an antibiotic cocktail administration (P.i + ABX group), respectively. The effects of P. intermedia and ABX administration on xenograft tumor growth, invasion, angiogenesis, and metastasis were investigated by tumor volume measurement and histopathological examination. Enzyme-linked immunosorbent assay (ELISA) was used to investigate the changes in serum cytokine levels. Immunohistochemistry (IHC) was adopted to analyze the alterations in the levels of inflammatory cytokines and infiltrated immune cells in OSCC tissues of xenograft tumors. Transcriptome sequencing and analysis were conducted to determine differential expression genes among various groups. RESULTS: Compared with the control treatment, P. intermedia treatment significantly promoted tumor growth, invasion, angiogenesis, and metastasis, markedly affected the levels of inflammatory cytokines, and markedly altered M2 macrophages and regulatory T cells (Tregs) infiltration in the tumor microenvironment. However, ABX administration clearly abolished these effects of P. intermedia. Transcriptome and immunohistochemical analyses revealed that P. intermedia infection increased the expression of interferon-stimulated gene 15 (ISG15). Correlation analysis indicated that the expression level of ISG15 was positively correlated with the Ki67 expression level, microvessel density, serum concentrations and tissue expression levels of inflammatory cytokines, and quantities of infiltrated M2 macrophages and Tregs. However, it is negatively correlated with the quantities of infiltrated CD4+ and CD8+ T cells. CONCLUSION: In conclusion, intratumoral P. intermedia infection aggravated OSCC progression, which may be achieved through upregulation of ISG15. This study sheds new light on the possible pathogenic mechanism of intratumoral P. intermedia in OSCC progression, which could be a prospective target for OSCC prevention and treatment.

Heat-killed Prevotella intermedia promotes the progression of oral squamous cell carcinoma by inhibiting the expression of tumor suppressors and affecting the tumor microenvironment.

BACKGROUND: Oral microbial dysbiosis contributes to the development of oral squamous cell carcinoma (OSCC). Our previous study showed that Prevotella intermedia (P. intermedia) were enriched in the oral mucosal surface, plaque, and saliva of patients with OSCC. Intratumoral microbiome could reshape the immune system and influence the development of various tumors. However, the invasion status of human OSCC tissues by P. intermedia and the pathway through which intratumoral P. intermedia potentiates tumor progression remain unexplored. METHODS: P. intermedia in human OSCC or normal tissues was detected by FISH. A mouse OSCC cell line SCC7 was adopted to investigate the effects of heat-killed P. intermedia treatment on cell proliferation, invasion, and cytokine release by using CCK-8 assay, transwell invasion assay and ELISA. Moreover, we established a mouse transplanted tumor model by using SCC7 cells, injected heat-killed P. intermedia into tumor tissues, and investigated the effects of heat-killed P. intermedia on tumor growth, invasion, cytokine levels, immune cell infiltrations, and expression levels by using gross observation, H&E staining, ELISA, immunohistochemistry, mRNA sequencing, and transcriptomic analysis. RESULTS: Our results indicated that P. intermedia were abundant in OSCC and surrounding muscle tissues. Heat-killed P. intermedia promoted SCC7 cell proliferation, invasion and proinflammatory cytokine secretions, accelerated transplanted tumor growth in mice, exacerbate muscle and perineural invasion of OSCC, elevated the serum levels of IL-17A, IL-6, TNF-α, IFN-γ, and PD-L1, induced Treg cells M2 type macrophages in mouse transplanted tumors. The data of transcriptomic analysis revealed that heat-killed P. intermedia increased the expression levels of inflammatory cytokines and chemokines while reduced the expression levels of some tumor suppressor genes in mouse transplanted tumors. Additionally, IL-17 signaling pathway was upregulated whereas GABAergic system was downregulated by heat-killed P. intermedia treatment. CONCLUSIONS: Taken together, our results suggest that P. intermedia could inhibit the expression of tumor suppressors, alter the tumor microenvironment, and promote the progression of OSCC.

A novel HDAC6 inhibitor interferes microtubule dynamics and spindle assembly checkpoint and sensitizes cisplatin-induced apoptosis in castration-resistant prostate cancer.

BACKGROUND: Metastatic castration-resistant prostate cancer (CRPC), the most refractory prostate cancer, inevitably progresses and becomes unresponsive to hormone therapy, revealing a pressing unmet need for this disease. Novel agents targeting HDAC6 and microtubule dynamics can be a potential anti-CRPC strategy. METHODS: Cell proliferation was examined in CRPC PC-3 and DU-145 cells using sulforhodamine B assay and anchorage-dependent colony formation assay. Flow cytometric analysis of propidium iodide staining was used to determine cell-cycle progression. Cell-based tubulin polymerization assay and confocal immunofluorescence microscopic examination determine microtubule assembly/disassembly status. Protein expressions were determined using Western blot analysis. RESULTS: A total of 82 novel derivatives targeting HDAC6 were designed and synthesized, and Compound 25202 stood out, showing the highest efficacy in blocking HDAC6 (IC50, 3.5 nM in enzyme assay; IC50, 1.0 µM in antiproliferative assay in CRPC cells), superior to tubastatin A (IC50, 5.4 µM in antiproliferative assay). The selectivity and superiority of 25202 were validated by examining the acetylation of both α-tubulin and histone H3, detecting cell apoptosis and HDACs enzyme activity assessment. Notably, 25202 but not tubastatin A significantly decreased HDAC6 protein expression. 25202 prolonged mitotic arrest through the detection of cyclin B1 upregulation, Cdk1 activation, mitotic phosphoprotein levels, and Bcl-2 phosphorylation. Compound 25202 did not mimic docetaxel in inducing tubulin polymerization but disrupted microtubule organization. Compound 25202 also increased the phosphorylation of CDC20, BUB1, and BUBR1, indicating the activation of the spindle assembly checkpoint (SAC). Moreover, 25202 profoundly sensitized cisplatin-induced cell death through impairment of cisplatin-evoked DNA damage response and DNA repair in both ATR-Chk1 and ATM-Chk2 pathways. CONCLUSION: The data suggest that 25202 is a novel selective and potent HDAC6 inhibitor. Compound 25202 blocks HDAC6 activity and interferes microtubule dynamics, leading to SAC activation and mitotic arrest prolongation that eventually cause apoptosis of CRPC cells. Furthermore, 25202 sensitizes cisplatin-induced cell apoptosis through impeding DNA damage repair pathways.

[Research Progress on the Application Strategies of Plerixafor in the Peripheral Blood Stem Cell Mobilization for Autologous Transplantation--Review].

Plerixafor, an analog of C-X-C motif chemokine receptor 4 (CXCR4), which allows the release of stem cells from the bone marrow into peripheral blood (PB) by disrupting the interaction of CXCR4 with stromal cell-derived factor-1 (SDF-1), is effective in mobilization for peripheral blood stem cells (PBSC). Due to its market approval has not been long and its high price in China, the clinical application of plerixafor is still very limited. The clinicians are actively seeking the optimal use of plerixafor to improve the success rate of PBSC collection and reduce the cost. This article reviews the latest research progress related to plerixafor application, in order to summarize the optimal use of plerixafor in autologous hematopoietic stem cell transplantation (auto-HSCT).

[Research Progress of Post-Transplant Cyclophosphamide Combined with Antithymocyte Globulin in Preventing GVHD after Hematopoietic Stem Cell Transplantation --Review].

Graft-versus-host disease (GVHD) is one of the major complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT), which seriously affects the prognosis of patients. At present, a new regimen of post-transplantation cyclophosphamide (PTCy) combined with antithymocyte globulin (ATG) has been used to prevent GVHD, indicating that PTCy combined with ATG may have a good effect on the prevention of GVHD in different types of transplantation. However, the mechanism of this regimen, its effect on immune reconstitution and viral reactivation still needs to be further studied. Therefore, this article briefly reviews the research progress of PTCy combined with ATG in preventing GVHD after HSCT.

Vacciniumchaozhouense (Ericaceae), a new species from East Guangdong, China.

Vacciniumchaozhouense (Ericaceae), a new species from East Guangdong Province, China is described and illustrated. This new species is morphologically similar to V.wrightii by having flowers with persistent and leaf-like bracts, long pedicels, and white spherical-urceolate corollas, but is distinguished by having glandular trichomes on the abaxial surface of the leaf blade, shorter pedicels, sparsely pilose corolla ridges, and anther thecae longer than the tubules. A key to the new species and morphologically similar species is also provided.

Synergistic suppressive effects on triple-negative breast cancer by the combination of JTC-801 and sodium oxamate.

Triple-negative breast cancer (TNBC) poses a significant clinical challenge due to the limited targeted therapies available at present. Cancer cells preferentially use glycolysis as their primary source of energy, characterized by increased glucose uptake and lactate production. JTC-801, a nociception/orphanin FQ opioid peptide (NOP) receptor antagonist, was reported to suppress the opioid receptor-like1 (ORL1) receptor/phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/nuclear factor (NF)-κB-mediated carbonic anhydrase 9 (CA9) signaling pathway. Sodium oxamate is an inhibitor of gluconeogenesis and a glycolysis inhibitor, as a competitive lactate dehydrogenase A (LDHA) inhibitor, which also produces tumor suppression due to loss of LDHA activity. However, the roles of opioid analgesic drugs (e.g., JTC-801) and glycolysis inhibitors (e.g., sodium oxamate) in TNBC have not fully been explored. Meanwhile, concurrent treatment with JTC-801 and sodium oxamate may cause synergistic anticancer effects in a TNBC model. In the present study, the combination of JTC-801 and sodium oxamate triggered cell death in the TNBC MDA MB-231 cell line. RNA-sequencing data revealed potential genes in the crosstalk between JTC-801 and sodium oxamate including ALDOC, DDIT4, DHTKD1, EIF6, ENO1, ENO3, FOXK1, FOXK2, HIF1A, MYC, PFKM, PFKP, PPARA, etc. The combination of JTC-801 and sodium oxamate provides a novel potential therapeutic strategy for TNBC patients via downregulating cell cycle- and amino acid metabolism-related pathways such as "Cell cycle-the metaphase checkpoint", "(L)-tryptophan pathways and transport", and "Glutamic acid pathway". Collectively, the present study demonstrated that the synergistic effect of co-treatment with JTC-801 and sodium oxamate significantly suppressed tumor growth and played a crucial role in tumor development, and in turn may serve as potential synergistic drugs for TNBC.

Attenuation of NLRP3 Inflammasome by Cigarette Smoke is Correlated with Decreased Defense Response of Oral Epithelial Cells to Candida albicans.

BACKGROUND: It is well recognized that both smoke and Candida infection are crucial risk factors for oral mucosal diseases. The nucleotide-binding domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome and its downstream effectors, interleukin (IL)-1ß and IL-18, are pivotal to the host defense against Candida and other pathogens. METHODS: The present study was designed to explore the effects of cigarette smoke and C. albicans on the NLRP3 inflammasome and its downstream signal pathway via in vitro cell model. Oral epithelial cells (Leuk-1 cells) were exposed to cigarette smoke extract (CSE) for 3 days and/or challenged with C. albicans. RESULTS: Microscopically, Leuk-1 cells exerted a defense response to C. albicans by markedly limiting the formation of germ tubes and microcolonies. CSE clearly eliminated the defense response of Leuk-1 cells. Functionally, CSE repressed NLRP3 inflammasome, and IL-1ß and IL-18 activation induced by C. albicans in Leuk-1 cells. CONCLUSION: Our results suggested that in oral epithelial cells, the NLRP3 inflammasome might be one of the target pathways by which CSE attenuates innate immunity and leads to oral disorders.

Mechanistic study of dual-function inhibitors targeting topoisomerase II and Rad51-mediated DNA repair pathway against castration-resistant prostate cancer.

BACKGROUND: Castration-resistant prostate cancer (CRPC) is refractory to hormone treatment and the therapeutic options are continuously advancing. This study aims to discover the anti-CRPC effects and underlying mechanisms of small-molecule compounds targeting topoisomerase (TOP) II and cellular components of DNA damage repair. METHODS: Cell proliferation was determined in CRPC PC-3 and DU-145 cells using anchorage-dependent colony formation, sulforhodamine B assay and flow cytometric analysis of CFSE staining. Flow cytometric analyses of propidium iodide staining and JC-1 staining were used to examine the population of cell-cycle phases and mitochondrial membrane potential, respectively. Nuclear extraction was performed to detect the nuclear localization of cellular components in DNA repair pathways. Protein expressions were determined using Western blot analysis. RESULTS: A series of azathioxanthone-based derivatives were synthesized and examined for bioactivities in which WC-A13, WC-A14, WC-A15, and WC-A16 displayed potent anti-CRPC activities in both PC-3 and DU-145 cell models. These WC-A compounds selectively downregulated both TOP IIα and TOP IIß but not TOP I protein expression. WC-A13, WC-A14, and WC-A15 were more potent than WC-A16 on TOP II inhibition, mitochondrial dysfunction, and induction of caspase cascades indicating the key role of amine-containing side chain of the compounds in determining anti-CRPC activities. Furthermore, WC-A compounds induced an increase of γH2AX and activated ATR-Chk1 and ATM-Chk2 signaling pathways. P21 protein expression was also upregulated by WC-A compounds in which WC-A16 showed the least activity. Notably, WC-A compounds exhibited different regulation on Rad51, a major protein in homologous recombination of DNA in double-stranded break repair. WC-A13, WC-A14, and WC-A15 inhibited, whereas WC-A16 induced, the nuclear translocation of Rad51. CONCLUSION: The data suggest that WC-A compounds exhibit anti-CRPC effects through the inhibition of TOP II activities, leading to mitochondrial stress-involved caspase activation and apoptosis. Moreover, WC-A13, WC-A14, and WC-A15 but not WC-A16 display inhibitory activities of Rad51-mediated DNA repair pathway which may increase apoptotic effect of CRPC cells.

A novel combination therapy of arginine deiminase and an arginase inhibitor targeting arginine metabolism in the tumor and immune microenvironment.

Tumor progression is dependent on tumor cells and their microenvironment. It is important to identify therapies that inhibit cancer cells and activate immune cells. Arginine modulation plays a dual role in cancer therapy. Arginase inhibition induced an anti-tumor effect via T-cell activation through an increase in arginine in the tumor environment. In contrast, arginine depletion by arginine deiminase pegylated with 20,000-molecular-weight polyethylene glycol (ADI-PEG 20) induced an anti-tumor response in argininosuccinate synthase 1 (ASS1)-deficient tumor cells. ADI-PEG 20 did not cause toxicity to normal immune cells, which can recycle the ADI-degraded product citrulline back to arginine. To target tumor cells and their neighboring immune cells, we hypothesized that the combination of an arginase inhibitor (L-Norvaline) and ADI-PEG 20 may trigger a stronger anticancer response. In this study, we found that L-Norvaline inhibits tumor growth in vivo. Pathway analysis based on RNA-seq data indicated that the differentially expressed genes (DEGs) were significantly enriched in some immune-related pathways. Significantly, L-Norvaline did not inhibit tumor growth in immunodeficient mice. In addition, combination treatment with L-Norvaline and ADI-PEG 20 induced a more robust anti-tumor response against B16F10 melanoma. Furthermore, single-cell RNA-seq data demonstrated that the combination therapy increased tumor-infiltrating CD8+ T cells and CCR7+ dendritic cells. The increase in infiltrated dendritic cells may enhance the anti-tumor response of CD8+ cytotoxic T cells, indicating a potential mechanism for the observed anti-tumor effect of the combination treatment. In addition, populations of immunosuppressive-like immune cells, such as S100a8+ S100a9+ monocytes and Retnla+ Retnlg+ TAMs, in tumors were dramatically decreased. Importantly, mechanistic analysis indicated that the processes of the cell cycle, ribonucleoprotein complex biogenesis, and ribosome biogenesis were upregulated after combination treatment. This study implied the possibility of L-Norvaline as a modulator of the immune response in cancer and provided a new potential therapy combined with ADI-PEG 20.

Oral squamous cell carcinoma-derived EVs promote tumor progression by regulating inflammatory cytokines and the IL-17A-induced signaling pathway.

BACKGROUND: Inflammatory cytokines in the tumor microenvironment (TME) contribute to tumor growth, proliferation, and invasion, and tumor-derived extracellular vesicles (EVs) act as critical "messengers" of communication in the tumor microenvironment. The effects of EVs derived from oral squamous cell carcinoma (OSCC) cells on tumor progression and the inflammatory microenvironment are still unclear. Our study aims to investigate the role of OSCC-derived EVs in tumor progression, the imbalanced TME, and immunosuppression and their effect on the IL-17A-induced signaling pathway. METHODS: EVs were isolated from the supernatant of a mouse OSCC cell line, SCC7. The effects of SCC7-EVs and the EV release-specific inhibitor GW4869 on the proliferation and migration of SCC7 cells were investigated in vitro by using CCK-8 and scratch wound healing assays. RT-qPCR and ELISA were performed to examine the alterations in cytokine levels. Then, a mouse xenograft model of OSCC was established by submucosal injection of SCC7 cells with or without SCC7-EV and GW4869 treatment. The effects of GW4869 and SCC7-EVs on xenograft tumor proliferation and invasion were investigated by tumor volume determination and histopathological examination. ELISA was used to investigate the changes in serum cytokine levels. Immunohistochemistry was adopted to analyze the alterations in the levels of inflammatory cytokines, immune factors, and crucial molecules in the IL-17A signaling pathway. RESULTS: SCC7-derived EVs increased the supernatant and serum levels of IL-17A, IL-10, IL-1ß, and PD-L1, while GW4869 decreased those of TNF-α and IFN-γ. SCC7-EV treatment significantly increased xenograft tumor growth and invasion in mice but resulted in little liquefactive necrosis in tumors. However, GW4869 treatment significantly inhibited xenograft tumor growth but resulted in more liquefactive necrosis. SCC7-derived EVs decreased the expression level of PTPN2, suppressing the immune responses of CD8 + T cells in vivo. Moreover, SCC7-EV treatment significantly enhanced the tumor expression levels of crucial molecules in the IL-17A pathway, including IL-17A, TRAF6 and c-FOS, whereas GW4869 treatment significantly reduced those levels in tumor tissues. CONCLUSION: Our results indicated that OSCC-derived EVs can promote tumor progression by altering the TME, causing an inflammatory cytokine imbalance, inducing immunosuppression, and contributing to overactivation of the IL-17A-induced signaling pathway. Our study might provide novel insights into the role of OSCC-derived EVs in tumor biological behavior and immune dysregulation.

Modification of Phosphorylation Sites in the Yeast Lysine Methyltransferase Set5 Exerts Influences on the Mitogen-Activated Protein Kinase Hog1 under Prolonged Acetic Acid Stress.

Responses to acetic acid toxicity in the budding yeast Saccharomyces cerevisiae have widespread implications in the biorefinery of lignocellulosic biomass and food preservation. Our previous studies revealed that Set5, the yeast lysine methyltransferase and histone H4 methyltransferase, was involved in acetic acid stress tolerance. However, it is still mysterious how Set5 functions and interacts with the known stress signaling network. Here, we revealed that elevated phosphorylation of Set5 during acetic acid stress is accompanied by enhanced expression of the mitogen-activated protein kinase (MAPK) Hog1. Further experiments uncovered that the phosphomimetic mutation of Set5 endowed yeast cells with improved growth and fermentation performance and altered transcription of specific stress-responsive genes. Intriguingly, Set5 was found to bind the coding region of HOG1 and regulate its transcription, along with increased expression and phosphorylation of Hog1. A protein-protein interaction between Set5 and Hog1 was also revealed. In addition, modification of Set5 phosphosites was shown to regulate reactive oxygen species (ROS) accumulation, which is known to affect yeast acetic acid stress tolerance. The findings in this study imply that Set5 may function together with the central kinase Hog1 to coordinate cell growth and metabolism in response to stress. IMPORTANCE Hog1 is the yeast homolog of p38 MAPK in mammals that is conserved across eukaryotes, and it plays crucial roles in stress tolerance, fungal pathogenesis, and disease treatments. Here, we provide evidence that modification of Set5 phosphorylation sites regulates the expression and phosphorylation of Hog1, which expands current knowledge on upstream regulation of the Hog1 stress signaling network. Set5 and its homologous proteins are present in humans and various eukaryotes. The newly identified effects of Set5 phosphorylation site modifications in this study benefit an in-depth understanding of eukaryotic stress signaling, as well as the treatment of human diseases.

[Clinical Value of Translocator Protein Gene in Evaluating the Efficacy of FLT3-ITD/DNMT3A R882 Double-Mutated Acute Myeloid Leukemia].

OBJECTIVE: To observe the clinical significance of translocator proteins (TSPO) gene in the treatment of FLT3-ITD/DNMT3A R882 double-mutated acute myeloid leukemia (AML). METHODS: Seventy-six patients with AML hospitalized in the Department of Hematology of the Affiliated People's Hospital of Ningbo University from June 2018 to June 2020 were selected, including 34 patients with FLT3-ITD mutation, 27 patients with DNMT3A R882 mutation, 15 patients with FLT3-ITD/DNMT3A R882 double mutation, as well as 19 patients with immune thrombocytopenia (ITP) hospitalized during the same period as control group. RNA was routinely extracted from 3 ml bone marrow retained during bone puncture, and TSPO gene expression was detected by transcriptome sequencing (using 2-deltadeltaCt calculation). RESULTS: The expression of TSPO gene in FLT3-ITD group and DNMT3A R882 group at first diagnosis was 2.02±1.04 and 1.85±0.76, respectively, which were both higher than 1.00±0.06 in control group, but the differences were not statistically significant (P=0.671, P=0.821). The expression of TSPO gene in the FLT3-ITD/DNMT3A R882 group was 3.98±1.07, wich was significantly higher than that in the FLT3-ITD group and DNMT3A R882 group, the differences were statistically significant (P=0.032, P=0.021). The expression of TSPO gene in patients who achieved complete response after chemotherapy in the FLT3-ITD/DNMT3A R882 group was 1.19±0.87, which was significantly lower than that at first diagnosis, and the difference was statistically significant (P=0.011). CONCLUSION: TSPO gene may be used as an indicator of efficacy in FLT3-ITD /DNMT3A R882 double-mutated AML.

Repurposing nitric oxide donating drugs in cancer therapy through immune modulation.

BACKGROUND: Nitric oxide-releasing drugs are used for cardiovascular diseases; however, their effects on the tumor immune microenvironment are less clear. Therefore, this study explored the impact of nitric oxide donors on tumor progression in immune-competent mice. METHODS: The effects of three different nitric oxide-releasing compounds (SNAP, SNP, and ISMN) on tumor growth were studied in tumor-bearing mouse models. Three mouse tumor models were used: B16F1 melanoma and LL2 lung carcinoma in C57BL/6 mice, CT26 colon cancer in BALB/c mice, and LL2 lung carcinoma in NOD/SCID mice. After nitric oxide treatment, splenic cytokines and lymphocytes were analyzed by cytokine array and flow cytometry, and tumor-infiltrating lymphocytes in the TME were analyzed using flow cytometry and single-cell RNA sequencing. RESULTS: Low doses of three exogenous nitric oxide donors inhibited tumor growth in two immunocompetent mouse models but not in NOD/SCID immunodeficient mice. Low-dose nitric oxide donors increase the levels of splenic cytokines IFN-γ and TNF-α but decrease the levels of cytokines IL-6 and IL-10, suggesting an alteration in Th2 cells. Nitric oxide donors increased the number of CD8+ T cells with activation gene signatures, as indicated by single-cell RNA sequencing. Flow cytometry analysis confirmed an increase in infiltrating CD8+ T cells and dendritic cells. The antitumor effect of nitric oxide donors was abolished by depletion of CD8+ T cells, indicating the requirement for CD8+ T cells. Tumor inhibition correlated with a decrease in a subtype of protumor macrophages and an increase in a subset of Arg1-positive macrophages expressing antitumor gene signatures. The increase in this subset of macrophages was confirmed by flow cytometry analysis. Finally, the combination of low-dose nitric oxide donor and cisplatin induced an additive cancer therapeutic effect in two immunocompetent animal models. The enhanced therapeutic effect was accompanied by an increase in the cells expressing the gene signature of NK cell. CONCLUSIONS: Low concentrations of exogenous nitric oxide donors inhibit tumor growth in vivo by regulating T cells and macrophages. CD8+ T cells are essential for antitumor effects. In addition, low-dose nitric oxide donors may be combined with chemotherapeutic drugs in cancer therapy in the future.

Identification of a novel porcine Teschovirus 2 strain as causative agent of encephalomyelitis in suckling piglets with high mortality in China.

BACKGROUND: Porcine Teschovirus (PTV), also named Teschovirus A, is prevalent in pig populations, mainly causing neurological symptoms, diarrhea, pneumonia, and reproductive failure, however the morbidity and mortality are usually low in pig farms. CASE PRESENTATION: In this study, we reported a PTV outbreak investigation in one large-scale pig farm in China with severe symptoms including diarrhea, lethargy, locomotor ataxia, nystagmus, paralysis of the hind limbs, and coma in piglets. More importantly, the mortality reached 38% in suckling pigs, which is remarkably high in PTV history. A novel PTV strain, named HeNZ1, was isolated from cerebral samples of one suckling pig and the genome sequence was obtained by NGS sequencing. Phylogenetic and evolutionary divergence analyses revealed that HeNZ1 belongs to PTV genotype 2. Surprisingly, the VP1 coding region of HeNZ1 shares the highest sequence similarity with European PTV-2 strains, instead of China domestic PTV-2 strains, implying it may not derive from China local PTV-2 strains. Multiple sequence alignment and B cell epitope prediction of PTV VP1 and VP2 protein revealed 10 B cell epitopes, 5 mutant clusters and 36 unique mutation sites, of which 19 unique mutation sites are located in B cell epitopes and exposed on the surface of VP1 or VP2, implying significant antigenic drift potential of HeNZ1. CONCLUSION: These results indicate that HeNZ1 is a highly virulent PTV-2 strain, which capable of causing severe neurological symptoms and high mortality in piglets. Bioinformatic analysis suggest that HeNZ1 is genetically and antigenically different from other Chinese PTV-2 strains. Overall, current case expanded our understanding of PTV-2 clinical spectrum and revealed the emergence of a highly virulent PTV-2 strain with substantial genetic diversity and antigenic drift potential in VP1 and VP2.

Safety of sugammadex for reversal of neuromuscular block: A postmarketing study based on the World Health Organization pharmacovigilance database.

AIM: Residual neuromuscular blockade is a common complication after general anaesthesia. Sugammadex can reverse the action of aminosteroid neuromuscular blockers. This study aimed to explore sugammadex safety issues in the real world and determine the spectrum of adverse reactions. METHODS: All sugammadex-related adverse events reported in VigiBase between 2010 and 2019 were classified by group queries according to the Medical Dictionary for Regulatory Activities. A disproportionality analysis of data was performed using the information component (IC); positive IC values were deemed significant. RESULTS: Overall, 16 219 410 adverse events were reported and 2032 were associated with sugammadex. The frequent reactions were recurrence of neuromuscular blockade (n = 54, IC 6.74, IC025 6.33), laryngospasm (n = 53, IC 6.05, IC025 5.64), bronchospasm (n = 119, IC 5.63, IC025 5.36) and bradycardia (n = 169, IC 5.13, IC025 4.90). Fatal cases were more likely among patients with cardiac disorders, especially those over 65 years. In addition, the common adverse drug reactions (ADRs) differed between different age groups (P < .01). ADRs were higher in the 0-17 years age group than in other age groups. The onset time of common ADRs was typically within 1 day and 68.9% occurred within half an hour after sugammadex administration. CONCLUSIONS: Anaesthesiologists should carefully monitor the anaesthesia recovery period to correct the ADRs caused by sugammadex and recommend monitoring neuromuscular function throughout the anaesthesia process. Sugammadex should be used carefully in patients with cardiovascular diseases, and electrocardiography and hemodynamic changes should be monitored after medication.

The Promotional Effect of GW4869 on C. albicans Invasion and Cellular Damage in a Murine Model of Oral Candidiasis.

Candida albicans (C. albicans) is one of the most common fungi in the human body; it is an opportunistic pathogen and can cause candidiasis. Extracellular vesicles (EVs) derived from the host cells have a potentially protective effect against pathogens and can be developed as vaccine formulations. GW4869 can inhibit the production and release of EVs. Previous studies have indicated that GW4869 can alter the immune and inflammatory responses of the host. However, the effect of GW4869 on Candida infection and the anti-Candida response of the host has not been investigated. We evaluated the effect of GW4869 on C. albicans invasion, biofilm formation, and cellular damage in a murine model of oral candidiasis. In this study, C. albicans-infected mice were injected with or without GW4869. The results proven by macroscopic, microscopic, and ultramicroscopic methods showed that GW4869 treatment exacerbated the oral candidiasis of mice, promoted C. albicans invasion and biofilm formation, and aggravated oral mucosal inflammation and cellular ultrastructural damage. The results are beneficial in the further exploration of the immune mechanism of C. albicans infection.

A metagenome-wide association study of the gut microbiota in recurrent aphthous ulcer and regulation by thalidomide.

Recurrent aphthous ulcer (RAU), one of the most common diseases in humans, has an unknown etiology and is difficult to treat. Thalidomide is an important immunomodulatory and antitumor drug and its effects on the gut microbiota still remain unclear. We conducted a metagenomic sequencing study of fecal samples from a cohort of individuals with RAU, performed biochemical assays of cytokines, immunoglobulins and antimicrobial peptides in serum and saliva, and investigated the regulation effects of thalidomide administration and withdrawal. Meanwhile we constructed the corresponding prediction models. Our metagenome-wide association results indicated that gut dysbacteriosis, microbial dysfunction and immune imbalance occurred in RAU patients. Thalidomide regulated gut dysbacteriosis in a species-specific manner and had different sustainable effects on various probiotics and pathogens. A previously unknown association between gut microbiota alterations and RAU was found, and the specific roles of thalidomide in modulating the gut microbiota and immunity were determined, suggesting that RAU may be affected by targeting gut dysbacteriosis and modifying immune imbalance. In-depth insights into sophisticated networks consisting of the gut microbiota and host cells may lead to the development of emerging treatments, including prebiotics, probiotics, synbiotics, and postbiotics.

Effects of the COVID-19 pandemic on elderly patients with head and neck squamous cell carcinoma.

Background: The 2019 novel coronavirus disease (COVID-19) strongly affects health care activities in countries around the world. The diagnosis and treatment of cancer have also been involved, and elderly head and neck squamous carcinoma is one of them. This study aimed to assess the impact of COVID-19 on elderly patients with head and neck squamous cell carcinoma (HNSCC) in our center. Methods: This retrospective study analyzed the clinical characteristics of 400 HNSCC patients over 65 years of age, calculated their treatment interruption rates, and compared the time of delayed diagnosis. Results: The rate of elderly patients with HNSCC with a delayed diagnosis was higher in the "during COVID-19 pandemic" group (DCOV19 group) than in the "during COVID-19 pandemic" group (BCOV19 group), and the difference was statistically significant (p=0.0017). There was a substantial difference in the rate of treatment interruption between the two groups (p=0.002). Conclusions: This is the first study to explore the effect of the COVID-19 pandemic on visits and treatment interruptions in elderly patients with HNSCC. The current impact of the COVID-19 pandemic on HNSCC treatment has resulted in reductions and delays in diagnosing cancer and providing treatment.

Optical-feedback cavity ring-down spectroscopy for NO2 extinction coefficient measurement using a continuous wave laser diode.

Optical-feedback (OF) cavity ring-down spectroscopy consisting of a linear cavity is developed by employing a continuous wave laser diode (LD) with multi-longitudinal modes. Due to the OF effect caused by the cavity output laser back into the LD, the laser frequency is locked, and the intracavity laser intensity is enhanced. We use different concentrations of NO2 gases to test the apparatus, and the results show good agreement with theoretical values. Owing to the compactness of the laser source and high detection accuracy, the device can be used for detection of low-concentration absorbent gases in the environmental monitoring field.