Predicting the impact of the COVID-19 pandemic on globalization.

The COVID-19 pandemic has significantly influenced the global economy, international travel, global supply chains, and how people interact, and subsequently affect globalization in coming years. In order to understand the impact of COVID-19 on globalization and provide potential guidance to policymakers, the present study predicted the globalization level of the world average and 14 specific countries in scenarios with and without COVID-19 based on a new Composite Indicator method which contains 15 indicators. Our results revealed that the world average globalization level is expected to decrease from 2017 to 2025 under the scenario without COVID-19 by -5.99%, while the decrease of globalization under the COVID-19 scenario is predicted to reach -4.76% in 2025. This finding implies that the impact of COVID-19 on globalization will not be as severe as expected in 2025. Nevertheless, the downward trend of globalization without COVID-19 is due to the decline of the Environmental indicators, whereas the decline under the COVID-19 scenario is attributed to Economic aspects (almost -50%). The impact of COVID-19 on globalization varies across individual countries. Among the countries investigated, COVID-19 had a positive impact on the globalization of Japan, Australia, the United States, the Russian Federation, Brazil, India and Togo. In contrast, the globalization in the United Kingdom, Switzerland, Qatar, Egypt, China and Gabon are expected to decrease. The variation of impact induced by COVID-19 on those countries is attributed to the weighting of economic, environmental and political aspects of globalization is different across these countries. Our results can help governments take suitable measures to balance economic, environmental and political policies, which may better support their decision-making.

The m6A demethylase ALKBH5 promotes tumor progression by inhibiting RIG-I expression and interferon alpha production through the IKKε/TBK1/IRF3 pathway in head and neck squamous cell carcinoma.

BACKGROUND: N6-methyladenosine (m6A) RNA modification plays a critical role in various physiological and pathological conditions. However, the role of m6A modification in head and neck squamous cell carcinoma (HNSCC) remains elusive. METHODS: In this study, the expression of m6A demethylases was detected by HNSCC tissue microarray. m6A-RNA immunoprecipitation (MeRIP) sequencing and RNA sequencing were used to identify downstream targets of ALKBH5. Comprehensive identification of RNA-binding proteins by mass spectrometry (ChIRP-MS) was used to explore the m6A "readers". Tumor-infiltrating lymphocytes were analyzed in SCC7-bearing xenografts in C3H mice. RESULTS: Here, we demonstrate the downregulation of m6A status and upregulation of two demethylases in HNSCC. Silencing the m6A demethylase alkB homolog 5, RNA demethylase (ALKBH5) suppresses tumor progression in vitro and in vivo. m6A-RNA immunoprecipitation sequencing reveals that ALKBH5 downregulates the m6A modification of DDX58 mRNA. Moreover, RIG-I, encoded by the DDX58 mRNA, reverses the protumorigenic characteristics of ALKBH5. ChIRP-MS demonstrates that HNRNPC binds to the m6A sites of DDX58 mRNA to promote its maturation. ALKBH5 overexpression inhibits RIG-I-mediated IFNα secretion through the IKKε/TBK1/IRF3 pathway. The number of tumor-infiltrating lymphocytes in C3H immunocompetent mice is reduced by ALKBH5 overexpression and restored by IFNα administration. Upregulation of AKLBH5 negatively correlates with RIG-I and IFNα expression in HNSCC patients. CONCLUSIONS: These findings unveil a novel mechanism of immune microenvironment regulation mediated by m6A modification through the ALKBH5/RIG-I/IFNα axis, providing a rationale for therapeutically targeting epitranscriptomic modulators in HNSCC.

RNA 5-Methylcytosine Regulator NSUN3 promotes tumor progression through regulating immune infiltration in head and neck squamous cell carcinoma.

OBJECTIVE: This study aimed to determine whether the RNA, 5-methylcytosine (m5C), is involved in the progression of head and neck squamous cell carcinoma (HNSCC). MATERIALS AND METHODS: We used least absolute shrinkage and selection operator to establish a prognostic score (PS) model based on the m5C regulator expression. Immune scores were calculated using the estimation of stromal and immune cells in malignant tumor tissues using expression data. The biological functions of the m5C regulator, NOP2/Sun RNA methyltransferase 3 (NSUN3), were thoroughly investigated in vitro and in vivo. RESULTS: The PS model acted as efficient prognostic factors in HNSCC. The expression of NSUN3, with the maximum weight, was found to be upregulated and indicated a poor prognosis. Meanwhile, NSUN3 knockdown inhibited the tumor proliferation and growth both in vitro and in vivo. High PS status was negatively correlated with CD8+ T, γδ+ T, and M1 macrophage percentages. NSUN3 knockdown increased the infiltration of M1 macrophages but decreased the percentage of M2 macrophages. CONCLUSIONS: The PS index is a novel and promising biomarker for predicting the prognosis and immune infiltration microenvironment in HNSCC. Moreover, NSUN3 plays a key role in this process and may serve as a potential therapeutic target for HNSCC.

A novel IFNα-induced long noncoding RNA negatively regulates immunosuppression by interrupting H3K27 acetylation in head and neck squamous cell carcinoma.

BACKGROUND: Interferon alpha (IFNα) is a well-established regulator of immunosuppression in head and neck squamous cell carcinoma (HNSCC), while the role of long noncoding RNAs (lncRNAs) in immunosuppression remains largely unknown. METHODS: Differentially expressed lncRNAs were screened under IFNα stimulation using lncRNA sequencing. The role and mechanism of lncRNA in immunosuppression were investigated in HNSCC in vitro and in vivo. RESULTS: We identified a novel IFNα-induced upregulated lncRNA, lncMX1-215, in HNSCC. LncMX1-215 was primarily located in the cell nucleus. Ectopic expression of lncMX1-215 markedly inhibited expression of the IFNα-induced, immunosuppression-related molecules programmed cell death 1 ligand 1 (PD-L1) and galectin-9, and vice versa. Subsequently, histone deacetylase (HDAC) inhibitors promoted the expression of PD-L1 and galectin-9. Binding sites for H3K27 acetylation were found on PD-L1 and galectin-9 promoters. Mechanistically, we found that lncMX1-215 directly interacted with GCN5, a known H3K27 acetylase, to interrupt its binding to H3K27 acetylation. Clinically, negative correlations between lncMX1-215 and PD-L1 and galectin-9 expression were observed. Finally, overexpression of lncMX1-215 suppressed HNSCC proliferation and metastasis capacity in vitro and in vivo. CONCLUSIONS: Our results suggest that lncMX1-215 negatively regulates immunosuppression by interrupting GCN5/H3K27ac binding in HNSCC, thus providing novel insights into immune checkpoint blockade treatment.

p53-targeted lincRNA-p21 acts as a tumor suppressor by inhibiting JAK2/STAT3 signaling pathways in head and neck squamous cell carcinoma.

BACKGROUND: Long intergenic noncoding RNA p21 (lincRNA-p21) is considered a target of wild-type p53, but little is known about its regulation by mutant p53 and its functions during the progression of head and neck squamous cell carcinoma (HNSCC). METHODS: RNAscope was used to detect the expression and distribution of lincRNA-p21. Chromatin immunoprecipitation and electrophoretic mobility shift assays were performed to analyze the transcriptional regulation of lincRNA-p21 in HNSCC cells. The biological functions of lincRNA-p21 were investigated in vitro and in vivo. RNA immunoprecipitation and pull-down assays were used to detect the direct binding of lincRNA-p21. RESULTS: Lower lincRNA-p21 expression was observed in HNSCC tissues and indicated worse prognosis. Both wild and mutant type p53 transcriptionally regulated lincRNA-p21, but nuclear transcription factor Y subunit alpha (NF-YA) was essential for mutant p53 in the regulation of lincRNA-p21. Ectopic expression of lincRNA-p21 significantly inhibited cell proliferation capacity in vitro and in vivo and vice versa. Moreover, the overexpression of lincRNA-p21 induced G1 arrest and apoptosis. Knockdown NF-YA expression reversed tumor suppressor activation of lincRNA-p21 in mutant p53 cells, not wild-type p53 cells. A negative correlation was observed between lincRNA-p21 and the phosphorylation of signal transducer and activator of transcription 3 (p-STAT3) in HNSCC tissues. High lincRNA-p21 expression inhibited Janus kinase 2 (JAK2)/STAT3 signal activation and vice versa. Further, we observed direct binding to STAT3 by lincRNA-p21 in HNSCC cells, which suppressed STAT3-induced oncogenic potential. CONCLUSIONS: Our results revealed the transcriptional regulation of lincRNA-p21 by the mutant p53/NF-YA complex in HNSCC. LincRNA-p21 acted as a tumor suppressor in HNSCC progression, which was attributed to direct binding to STAT3 and blocking of JAK2/STAT3 signaling.

Interferon-alpha promotes immunosuppression through IFNAR1/STAT1 signalling in head and neck squamous cell carcinoma.

BACKGROUND: An immunosuppressive microenvironment is critical for cancer initiation and progression. Whether interferon alpha (IFNα) can suppress immune and cancer cells and its involved mechanism still remain largely elusive. METHODS: We examine the expression of interferon alpha/beta receptor-1 (IFNAR1), CD8, CD56 and programmed death ligand 1 (PDL1) in head and neck squamous cell carcinomas (HNSCC). The effect of IFNα on PDL1 and programmed cell death protein 1 (PD1) expression in tumour cells and immune cells was detected in vitro and in vivo. RESULTS: Overexpression of IFNAR1, MX1 and signal transducer and activator of transcription 1 (Stat1) indicated the endogenous IFNα activation in tumour microenvironment, which correlated with immunosuppression status in HNSCC patients. Moreover, IFNα transcriptionally activated the expression of PDL1 through p-Stat1 (Tyr701) and promoted PD1 expression in immune cells through IFNAR1. The inhibition of IFNα signalling enhanced the cytotoxic activity of nature killer cells. At lastastly, we confirmed the upregulation of PDL1 and PD1 in response to IFNα treatment in both xenograft tumour models and patient-derived xenograft models. CONCLUSIONS: Our findings demonstrate that IFNα-induced PDL1 and PD1 expression is a new mechanism of immunosuppression in HNSCC, suggesting that blocking IFNα signalling may enhance the efficacy of immune checkpoint blockade.

The Bio-Safety Concerns of Three Domestic Temporary Hair Dye Molecules: Fuchsin Basic, Victoria Blue B and Basic Red 2.

Hair-coloring products include permanent, semi-permanent and temporary dyes that vary by chemical formulation and are distinguished mainly by how long they last. Domestic temporary hair dyes, such as fuchsin basic, basic red 2 and Victoria blue B, are especially popular because of their cheapness and facile applications. Despite numerous studies on the relationship between permanent hair dyes and disease, there are few studies addressing whether these domestic temporary hair dyes are associated with an increased cancer risk. Herein, to ascertain the bio-safety of these temporary hair dyes, we comparatively studied their percutaneous absorption, hemolytic effect and cytotoxic effects in this paper. Furthermore, to better understand the risk of these dyes after penetrating the skin, experimental and theoretical studies were carried out examining the interactions between the dyes and serum albumins as well as calf thymus (CT)-DNA. The results showed that these domestic temporary hair dyes are cytotoxic with regard to human red blood cells and NIH/3T3 cell lines, due to intense interactions with bovine serum albumin (BSA)/DNA. We conclude that the temporary hair dyes may have risk to human health, and those who use them should be aware of their potential toxic effects.

Interferon-alpha enhances the antitumour activity of EGFR-targeted therapies by upregulating RIG-I in head and neck squamous cell carcinoma.

BACKGROUND: The epidermal growth factor receptor (EGFR)-targeted therapies have been tested in the clinic as treatments for head and neck squamous cell carcinoma (HNSCC). Owing to intrinsic or acquired resistance, EGFR-targeted therapies often lead to a low response rate and treatment failure. Interferon-alpha (IFNα) is a chemosensitising agent and multi-functional cytokine with a tumour inhibitory effect. However, the synergic effect of IFNα and EGFR-targeted therapies (erlotinib and nimotuzumab) and their mechanisms in HNSCC remain unclear. METHODS: The interactions between IFNα, erlotinib, and nimotuzumab were evaluated in vitro in HNSCC cells. The synergistic effect of IFNα (20 000 IU per day, s.c.), erlotinib (50 mg kg-1 per day, i.g.) and nimotuzumab (10 mg kg-1 per day, i.p.) was further confirmed in vivo using HNSCC xenografts in nude mice. The upregulation of retinoic-acid inducible gene I (RIG-I) induced by IFNα and EGFR-targeted therapies and its mechanism were detected in vitro and in vivo. RESULTS: IFNα enhances the antitumour effects of erlotinib and nimotuzumab on HNSCC cells both in vitro and in vivo. Importantly, both IFNα and EGFR-targeted therapies promote the expression of RIG-I by activating signal transducers and activators of transcription 1 (STAT1) in HNSCC cells. RIG-I knockdown reduced the sensitivity of HN4 and HN30 cells to IFNα, erlotinib, and nimotuzumab. Moreover, IFNα transcriptionally induced RIG-I expression in HNSCC cells through STAT1. CONCLUSIONS: IFNα enhances the effect of EGFR-targeted therapies by upregulating RIG-I, and its expression may represent a predictor of the effectiveness of a combination treatment including IFNα in HNSCC.

Core/Shell Structured Fe3O4@TiO2-DNM Nanospheres as Multifunctional Anticancer Platform: Chemotherapy and Photodynamic Therapy Research.

The dose-dependent toxicity and low specificity against cancerous cells have restricted the clinical use of daunomycin (DNM). Titanium dioxide (TiO2) has been wildly used as an inorganic photodynamic therapy (PDT) agent and drug carrier. To facilitate the targeted drug delivery and combined therapy, in the present study, TiO2-coated Fe3O4 nanoparticles (Fe3O4@TiO2 NPs) were employed to load DNM and the drug-loaded Fe3O4@TiO2-DNM Nps exhibited smart pH-controlled releasing and satisfactory cytotoxicity as well as photocytotocity. The combination of prussian blue staining and fluorescence methods evidenced the effortless cell internalization of the fabricated Fe3O4@TiO2-DNM Nps for the cancer cells. The cell cycle status experiments indicated that the as-prepared nanospheres arrested the S and G2/M periods of the cancer cell proliferation in the dark, and further induced the apoptosis under the irradiation of ultraviolet light. The cell apoptotic results revealed that the apoptosis induced by the Fe3O4@TiO2-DNM Nps was in the early stage. The constructed Fe3O4@TiO2-DNM NPs have been endowed with multifunctions that allow them to selectively deliver combinatorial therapeutic payload and exhibit integrated therapeutic effectiveness to tumors.

One-Stage Treatment of Giant Condylar Osteoma: Alloplastic Total Temporomandibular Joint Replacement Aided by Digital Templates.

OBJECTIVES: To introduce the surgical techniques and evaluate the effect of alloplastic total temporomandibular joint (TMJ) replacement aided by digital templates in giant condylar osteoma. METHODS: Three patients with giant condylar osteoma were enrolled in this study. The maximal mouth opening was 1.9 cm on average. All the patients were underwent the computed tomography scan (slice thickness 1 mm) and the data were imported to Proplan 1.3 software for 3-dimensional bony segmentation and reconstruction. Osteotomy line and digital template according the 3-dimensional measurement were designed. All the joints were replaced with Biomet standard prosthesis under general anesthesia. RESULTS: All the operations were successfully performed. The follow-up period was from 6 to 18 months (average, 12 months). Pain relief of the joint and mouth-opening improvement were significant in 3 patients. No infection or loosening the prostheses was occurred. The occlusal relationship kept stable in all patients. CONCLUSIONS: Total TMJ replacement with standard prosthesis is a good strategy for TMJ reconstruction after giant condylar osteoma excision. The joint pain and the mouth-opening limitation resulted from giant condylar osteoma were markedly improved. Long-term effect remains to be evaluated based on a long-term follow-up.

XL413, a cell division cycle 7 kinase inhibitor enhanced the anti-fibrotic effect of pirfenidone on TGF-ß1-stimulated C3H10T1/2 cells via Smad2/4.

Pirfenidone is an orally bioavailable synthetic compound with therapeutic potential for idiopathic pulmonary fibrosis. It is thought to act through antioxidant and anti-fibrotic pathways. Pirfenidone inhibits proliferation and/or myofibroblast differentiation of a wide range of cell types, however, little studies have analyzed the effect of pirfenidone on the mesenchymal stem cells, which play an important role on the origin of myofibroblasts. We recently found that pirfenidone had anti-proliferative activity via G1 phase arrest and cell division cycle 7 (Cdc7) kinase expression decrease in transforming growth factor-ß1 (TGF-ß1)-stimulated murine mesenchymal stem C3H10T1/2 cells. Pirfenidone also had inhibiting effect on the migration and α-SMA expression. Moreover, in this study we showed for the first time that Cdc7 inhibitor XL413 enhanced the anti-fibrotic activity of pirfenidone via depressed the expression of Smad2/4 proteins, and also prevented the nuclear accumulation and translocation of Smad2 protein. In conclusion, we demonstrated that pirfenidone inhibited proliferation, migration and differentiation of TGF-ß1-stimulated C3H10T1/2 cells, which could be enhanced by Cdc7 inhibitor XL413, via Smad2/4. Combination with pirfenidone and XL413 might provide a potential candidate for the treatment of TGF-ß1 associated fibrosis. It needs in vivo studies to further validate its therapeutic function and safety in the future.

Preservation of Facial Nerve With Adjuvant Radiotherapy for Recurrent Mammary Analogue Secretory Carcinoma of Parotid Gland.

Mammary analogue secretory carcinoma of salivary glands harbors the recurrent ETV6-NTRK3 gene fusion because of the translocation t (12; 15) (p13; q25) and resembles breast secretory carcinoma. This tumor composed of papillary, cystic, solid, and cribriform patterns. Immunohistochemically, the tumors are positive for mammaglobin, CK7, CK8, STAT5a, vimentin, and S100. In this report, the authors presented a patient of recurrent parotid gland mammary analogue secretory carcinoma in a 22-year-old woman. The patient received extended parotidectomy with partial adhesive masseter surgery. The facial nerve was preserved during the surgery and adjuvant radiotherapy was performed postoperation. The patient did not suffer local recurrence and facial paralysis in the 18 months follow-up period.

Synthesis, G-quadruplexes DNA binding, and photocytotoxicity of novel cationic expanded porphyrins.

Intensive reports allowed the conclusion that molecules with extended aromatic surfaces always do good jobs in the DNA interactions. Inspired by the previous successful researches, herein, we designed a series of cationic porphyrins with expanded planar substituents, and evaluated their binding behaviors to G-quadruplex DNA using the combination of surface-enhanced raman, circular dichroism, absorption spectroscopy and fluorescence resonance energy transfer melting assays. Asymmetrical tetracationic porphyrin with one phenyl-4-N-methyl-4-pyridyl group and three N-methyl-4-pyridyl groups exhibit the best G4-DNA binding affinities among all the designed compounds, suggesting that the bulk of the substituents should be matched to the width of the grooves they putatively lie in. Theoretical calculations applying the density functional theory have been carried out and explain the binding properties of these porphyrins reasonably. Meanwhile, these porphyrins were proved to be potential photochemotherapeutic agents since they have photocytotoxic activities against both myeloma cell (Ag8.653) and gliomas cell (U251) lines.

Management of the primary intraosseous synovial sarcoma of the jaws: be careful of the surgical margin.

PURPOSE: Synovial sarcoma (SS) is extremely rare in the jaws, and only 8 cases have been reported worldwide. The specific aims of this study were to report 15 cases of primary intraosseous SS (PISS) and analyze the histologic features and outcome-related prognostic factors. MATERIALS AND METHODS: Data from patients diagnosed with PISS from 2004 to 2013 were collected in this retrospective study. Patient characteristics (primary location, histologic subtype, tumor size, and surgical margin) were defined as predictor variables. Local recurrence and tumor-related death were outcome variables. The association of tumor-related outcomes with patient characteristics was analyzed using Kaplan-Meier and Cox regression statistics. Other clinical and pathologic characteristics were summarized as a third category of variables for further analysis. RESULTS: This study examined 15 cases (women, n = 10; men, n = 5) with a mean age at diagnosis of 35 years. There was no imbalance in the distribution of primary SS locations (maxilla, n = 7; mandible, n = 8). Six patients (40%) developed local recurrence and 4 patients (26.7%) had a tumor-related death. The 5-year local recurrence-free survival (LRFS) and overall survival rates were 57% and 69.1%, respectively. The strong statistical association of surgical margin with 5-year LRFS rate was shown by univariate (P = .01) and multivariate (hazard ratio = 7.598; P = .028) analyses. CONCLUSIONS: PISS is extremely rare in the jaw. Immunohistochemical analysis played an important role in the diagnosis of PISS. The surgical margin showed a strong association with local recurrence. Thus, ideal surgical margins should be achieved during surgery to obtain better local control.

A prospective study of medial sural artery perforator flap with computed tomographic angiography-aided design in tongue reconstruction.

PURPOSE: To investigate the application of the medial sural artery perforator flap in hemiglossectomy reconstruction and evaluate the value of preoperative computed tomographic angiography (CTA) for perforator location. PATIENTS AND METHODS: Nine patients received medial sural artery perforator flaps for tongue reconstruction from August 2013 to January 2014. Of the 9 patients, 5 were male and 4 were female, with a mean age of 51 years (range 22 to 67). The number, location, and course of the perforators were measured on the CTA preoperatively. RESULTS: Of the 9 medial sural artery perforator flaps, 8 survived and 1 had developed necrosis. Thirteen perforators had been visualized by CTA, and 10 of these were used in the operation. No significant difference was found between the CTA location and the intraoperative findings in the perforators' distribution. The mean diameter of the medial sural artery was 1.0 ± 0.3 mm and of the concomitant vein was 2.0 ± 0.7 mm. The mean pedicle length was 9.7 ± 1.0 cm, with 5.1 ± 1.7 cm of the main trunk and 4.6 ± 2.1 cm of the perforator. The average number of muscular vessel branches was 23.9 ± 6.9, with 12.2 ± 5.1 from the main trunk and 10.1 ± 4.4 from the perforators; 1 (10%) perforator was septocutaneous and 9 (90%) were myocutaneous. CONCLUSIONS: The medial sural artery perforator flap is appropriate for medium-size tongue defect reconstruction, with a long pedicle of matching caliber, adequate tissue volume, and minimal donor site morbidity. CTA is a valuable and necessary method for preoperative assessment of the perforator's location.

APIP regulated by YAP propels methionine cycle and metastasis in head and neck squamous cell carcinoma.

The Yes-associated protein (YAP) plays a vital role in tumor progression and metabolic regulation. However, the involvement of YAP in metabolic reprogramming of head and neck squamous cell carcinoma remains unclear. Using RNA sequencing and ultra-high-performance liquid chromatography-tandem mass spectrometry, we observed that YAP increased the levels of the main metabolites and enzymes involved in methionine metabolism. APIP, an enzyme involved in the methionine salvage pathway, was transcriptionally activated by YAP. Further experiments showed that APIP promotes HNSCC cells migration and invasion in vitro and tumor metastasis in adjacent lymph nodes and distant organs in vivo. APIP also increases the levels of metabolites in the methionine cycle. We further found that methionine reversed the inhibition of HNSCC migration and invasion by APIP knockdown. In vivo experiments demonstrated that methionine addition promoted tumor metastasis. Mechanistically, the methionine cycle phosphorylated and inactivated GSK3ß, then induced the epithelial mesenchymal transition pathway. Increased APIP expression was detected in patients with HNSCC, especially in tumors with lymph node metastasis. Metabolites of methionine cycle were also elevated in HNSCC patients. Our findings revealed that APIP, a novel target of YAP, promotes the methionine cycle and HNSCC metastasis through GSK3ß phosphorylation.

A case study: Lecanicillium infection detected in the human body.

Lecanicillium dimorphum and Lecanicillium psalliotae are fungi that exist naturally in plants or insects, and are generally considered non-pathogenic to humans. However, in this case, we cultured Lecanicillium from the synovial fluid of a patient, and identified it through genome sequencing and sequence alignment as Lecanicillium dimorphum or Lecanicillium psalliotae. Due to the conservation of sequences, we can only identify the genus and not the species. There are very few reports on the human infection and pathogenicity of these two fungi, and this case also cannot completely prove that the pathogenic agent is this fungus. But this case also holds clinical significance, as the discovery of Lecanicillium in a human sample can alert the clinician to the presence of an uncommon mold with unclear clinical significance.

H3K9 lactylation in malignant cells facilitates CD8+ T cell dysfunction and poor immunotherapy response.

Histone lysine lactylation (Kla) is a post-translational modification, and its role in tumor immune escape remains unclear. Here, we find that increased histone lactylation is associated with poor response to immunotherapy in head and neck squamous cell carcinoma (HNSCC). H3K9la is identified as a specific modification site in HNSCC. Using cleavage under targets and tagmentation analyses, interleukin-11 (IL-11) is identified as a downstream regulatory gene of H3K9la. IL-11 transcriptionally activates immune checkpoint genes through JAK2/STAT3 signaling in CD8+ T cells. Additionally, IL-11 overexpression promotes tumor progression and CD8+ T cell dysfunction in vivo. Moreover, IL11 knockdown reverses lactate-induced CD8+ T cell exhaustion, and cholesterol-modified siIL11 restores CD8+ T cell killing activity and enhances immunotherapy efficacy. Clinically, H3K9la positively correlates with IL-11 expression and unfavorable immunotherapy responses in patients. This study reveals the crucial role of histone lactylation in immune escape, providing insights into immunotherapy strategies for HNSCC.

Metabolic landscape of head and neck squamous cell carcinoma informs a novel kynurenine/Siglec-15 axis in immune escape.

BACKGROUND: Metabolic reprograming and immune escape are two hallmarks of cancer. However, how metabolic disorders drive immune escape in head and neck squamous cell carcinoma (HNSCC) remains unclear. Therefore, the aim of the present study was to investigate the metabolic landscape of HNSCC and its mechanism of driving immune escape. METHODS: Analysis of paired tumor tissues and adjacent normal tissues from 69 HNSCC patients was performed using liquid/gas chromatography-mass spectrometry and RNA-sequencing. The tumor-promoting function of kynurenine (Kyn) was explored in vitro and in vivo. The downstream target of Kyn was investigated in CD8+ T cells. The regulation of CD8+ T cells was investigated after Siglec-15 overexpression in vivo. An engineering nanoparticle was established to deliver Siglec-15 small interfering RNA (siS15), and its association with immunotherapy response were investigated. The association between Siglec-15 and CD8+ programmed cell death 1 (PD-1)+ T cells was analyzed in a HNSCC patient cohort. RESULTS: A total of 178 metabolites showed significant dysregulation in HNSCC, including carbohydrates, lipids and lipid-like molecules, and amino acids. Among these, amino acid metabolism was the most significantly altered, especially Kyn, which promoted tumor proliferation and metastasis. In addition, most immune checkpoint molecules were upregulated in Kyn-high patients based on RNA-sequencing. Furthermore, tumor-derived Kyn was transferred into CD8+ T cells and induced T cell functional exhaustion, and blocking Kyn transporters restored its killing activity. Accroding to the results, mechanistically, Kyn transcriptionally regulated the expression of Siglec-15 via aryl hydrocarbon receptor (AhR), and overexpression of Siglec-15 promoted immune escape by suppressing T cell infiltration and activation. Targeting AhR in vivo reduced Kyn-mediated Siglec-15 expression and promoted intratumoral CD8+ T cell infiltration and killing capacity. Finally, a NH2-modified mesoporous silica nanoparticle was designed to deliver siS15, which restored CD8+ T cell function status and enhanced anti-PD-1 efficacy in tumor-bearing immunocompetent mice. Clinically, Siglec-15 was positively correlated with AhR expression and CD8+PD-1+ T cell infiltration in HNSCC tissues. CONCLUSIONS: The findings describe the metabolic landscape of HNSCC comprehensively and reveal that the Kyn/Siglec-15 axis may be a novel potential immunometabolism mechanism, providing a promising therapeutic strategy for cancers.

Longitudinal reactions of maxillary sinus in patients treated with multiple zygomatic implants: A modified radiographic evaluation with clinical follow-up.

OBJECTIVES: To investigate the effects of zygomatic implant placement on the maxillary sinus using radiographic and clinical indicators. METHODS: Patients with an atrophic maxilla who underwent zygomatic implant placement were included. The thickness and morphology of the Schneiderian membrane (SM), infundibular obstruction, and posterior bone wall of the maxillary sinus were analyzed. The generalized estimating equation and chi-square tests were performed to compare the measurements. RESULTS: Fifty patients with 100 maxillary sinuses were included. In total, 148 zygomatic implants and 105 regular implants were placed in the maxilla. Overall, the mean pre- and postoperative SM thickness was 2.79 ± 3.26 mm and 3.97 ± 5.45 mm, respectively (p = 0.063). In sinuses with two zygomatic implants, the SM thickness increased significantly from 2.12 ± 2.14 mm preoperatively to 4.07 ± 6.14 mm postoperatively (p = 0.026). The number of sinuses with type IV morphology (fully radiopaque) increased from zero preoperatively to six (13%) postoperatively. Sinuses with a single zygomatic implant showed no difference in the pre- and postoperative SM thickness. Postoperatively, six sinuses had infundibulum obstructions. Postoperative osteitis of the bilateral sinuses was found in two patients. CONCLUSIONS: We have proposed a new imaging evaluation method and system for evaluating the maxillary sinus response. Preoperative infundibulum obstruction combined with mucosal thickening and double zygomatic implant placement are more likely to induce postoperative maxillary sinus mucositis and osteitis.