Weak Cation-Solvent Interactions in Ether-Based Electrolytes Stabilizing Potassium-ion Batteries.

Conventional ether-based electrolytes exhibited a low polarization voltage in potassium-ion batteries, yet suffered from ion-solvent co-intercalation phenomena in a graphite anode, inferior potassium-metal performance, and limited oxidation stability. Here, we reveal that weakening the cation-solvent interactions could suppress the co-intercalation behaviour, enhance the potassium-metal performance, and improve the oxidation stability. Consequently, the graphite anode exhibits K+ intercalation behaviour (K||graphite cell operates 200 cycles with 86.6 % capacity retention), the potassium metal shows highly stable plating/stripping (K||Cu cell delivers 550 cycles with average Coulombic efficiency of 98.9 %) and dendrite-free (symmetric K||K cell operates over 1400 hours) properties, and the electrolyte exhibits high oxidation stability up to 4.4 V. The ion-solvent interaction tuning strategy provides a promising method to develop high-performance electrolytes and beyond.

Aberrant activation of RPB1 is critical for cell overgrowth in acute myeloid leukemia.

Acute myeloid leukemia (AML) is a group of highly aggressive malignancies with a 5-year overall survival of less than 40%. Cell overgrowth with defective apoptosis is a hallmark of AML, but little is known about how it occurs. Here, we show that aberrant activation of the largest subunit of RNA polymerase II (RPB1) encoded by POLR2A gene is critically involved in this hallmark. We retrospectively analyzed the expression profiles of POLR2A and RPB1 in a panel of AML cell lines, primary AML patients and peripheral blood samples. Meanwhile, correlation analysis was used to explore the correlation between the expression of RPB1 with tumor burden and overall survival time in untreated AML samples. RNA-Seq approach was performed to identify the differentially expressed genes between RPB1 silencing AML cells with control cells after knocking out RPB1. Furthermore, orthotopic AML models were established with RPB1 silencing and control cells to investigate the effects of RPB1 protein level on leukemia cell growth. In most AML patients, RPB1 was aberrantly activated and closely associated with poor prognosis, but not in normal hematopoietic cells. Global transcriptomic analysis revealed that POLR2A knockout strongly impaired growth of AML cells by selectively depleting a substantial set of AML-related oncogenic and anti-apoptosis genes such as MYC, RUNX2, MEIS1, CDC25A and BCL-2. Silencing RPB1 by genetic technology led to a potent regression of human refractory AML in mouse models. These findings reveal that dysregulated RPB1 is a central oncogenic hub that drives overgrowth by hijacking an array of oncogenic and anti-apoptosis factors. Targeting RPB1 is a potential therapeutic for treating AML.

MicroRNAs, TGF-ß signaling, and the inflammatory microenvironment in cancer.

Inflammatory cells and mediators form a major part of the tumor microenvironment and play important roles in the regulation of cancer initiation, tumor cell proliferation, and metastasis. MicroRNAs (miRNAs) play important roles in several physiological and pathological processes, including the regulation of the inflammatory microenvironment in cancer. Transforming growth factor-ß (TGF-ß) is an inflammation-related cytokine that functions in both tumor suppression and promotion; however, its underlying molecular mechanisms remain unclear. Recent evidence indicates an association between miRNAs and TGF-ß signaling, providing new insight into the nature of the inflammatory microenvironment in cancer. The present review is an overview of the interaction between miRNAs and inflammatory cytokines, with emphasis on the cross talk between TGF-ß signaling and miRNAs and their influence on cancer cell behavior. The emerging roles of miRNAs in cancer-related inflammation and the potential to target miRNA signaling pathways for cancer therapy are also discussed.

Ribonucleotide reductase large subunit M1 plays a different role in the invasion and metastasis of papillary thyroid carcinoma and undifferentiated thyroid carcinoma.

Ribonucleotide reductase (RR) has been reported to be associated with several types of cancer while the expression and role of RR in thyroid carcinoma (TC) has not been investigated. Here, we first examined the expression level of three RR subunit proteins (RRM1, RRM2, and RRM2B) in papillary thyroid carcinoma (PTC) and undifferentiated thyroid carcinoma (UTC) patient samples by immunohistochemistry. The results showed that RRM1 was higher expressed in 95.2 % cancer tissues compared with their adjacent normal tissues in 146 PTC samples. The expression level of RRM1 was positively correlated with T stage, lymph node metastasis (LNM), extrathyroidal invasion (ETI), and TNM stage in PTC patients. However, in 12 UTC samples, RRM1 expression was negatively expressed in six cases. To further determine the biological role of RRM1 in TC, ectopic expression or siRNA-mediated knockdown of RRM1 were carried out in the high-differentiated thyroid carcinoma cell line TPC-1 and the poor-differentiated thyroid carcinoma cell line SW579, respectively. In TPC-1 and SW579 cells, overexpression and siRNA knockdown of RRM1 demonstrated that RRM1 promoted DNA synthesis and proliferation in both cell lines as shown by EdU incorporation and cell viability assays. However, RRM1 enhanced cell migration and invasion in TPC-1 cells but inhibited that in SW579 cells as shown by wound healing and transwell assays. Moreover, we also found that RRM1 promoted PTEN expression and reduced Akt phosphorylation in a RR-activity-independent manner in the low-differentiated TC cells but not in the high-differentiated TC cells. In contrast, RRM2 expression was higher expressed in both PTC and UTC patient samples, consisting with its oncogenic role in other cancers. Therefore, we suggest that RRM1 promotes thyroid carcinoma proliferation as a component of RR but may play a different role in the invasion and metastasis of differently differentiated thyroid carcinomas through a non-RR pathway, which could be meaningful to precision treatment of thyroid carcinoma with RR inhibitors.

EBV-positive inflammatory follicular dendritic cell sarcoma of the colon with clonal immunoglobulin gene rearrangement: A case report and literature review.

Introduction: Epstein-Barr virus-positive (EBV+) inflammatory follicular dendritic cell (FDC) sarcoma is a rare neoplasm characterized by spindle-shaped follicular dendritic cells, marked lymphoplasmacytic infiltration, and a consistent link to EBV. While it typically affects the liver and spleen, it is exceptionally rare in the digestive tract. We present a special case of EBV + inflammatory FDC sarcoma arising in the colon with clonal immunoglobulin (IG) gene rearrangement. Case presentation: A 70-year-old man presented with a one-month history of abdominal distension. Colonoscopy revealed a pedunculated polyp in the ascending colon, which was subsequently removed via endoscopic polypectomy. Histological examination of the colonic polyp demonstrated a pronounced lymphoplasmacytic infiltrate with scattered EBV + neoplastic cells, as evidenced by EBV-encoded small RNA in situ hybridization (EBER ISH). The neoplastic cells were positive for FDC-specific markers, including CD21, CD35, and CD23. Additionally, the tumor exhibited clonal rearrangement of the immunoglobulin heavy chain (IGH) gene. The diagnosis was confirmed as EBV + inflammatory follicular dendritic cell sarcoma. Conclusions: We described an exceptional case of EBV + inflammatory FDC sarcoma presenting as a colonic polyp, featuring a clonal IGH gene rearrangement not previously documented in this colonic tumor type. Heightened awareness of this rare neoplasm within the gastrointestinal tract is essential for both accurate diagnosis and effective patient management.

Restructuring Electrolyte Solvation by a Partially and Weakly Solvating Cosolvent toward High-Performance Potassium-Ion Batteries.

Ether-based electrolytes are among the most important electrolytes for potassium-ion batteries (PIBs) due to their low polarization voltage and notable compatibility with potassium metal. However, their development is hindered by the strong binding between K+ and ether solvents, leading to [K+-solvent] cointercalation on graphite anodes. Herein, we propose a partially and weakly solvating electrolyte (PWSE) wherein the local solvation environment of the conventional 1,2-dimethoxyethane (DME)-based electrolyte is efficiently reconfigured by a partially and weakly solvating diethoxy methane (DEM) cosolvent. For the PWSE in particular, DEM partially participates in the solvation shell and weakens the chelation between K+ and DME, facilitating desolvation and suppressing cointercalation behavior. Notably, the solvation structure of the DME-based electrolyte is transformed into a more cation-anion-cluster-dominated structure, consequently promoting thin and stable solid-electrolyte interphase (SEI) generation. Benefiting from optimized solvation and SEI generation, the PWSE enables a graphite electrode with reversible K+ (de)intercalation (for over 1000 cycles) and K with reversible plating/stripping (the K||Cu cell with an average Coulombic efficiency of 98.72% over 400 cycles) and dendrite-free properties (the K||K cell operates over 1800 h). We demonstrate that rational PWSE design provides an approach to tailoring electrolytes toward stable PIBs.

Characterization of the structure, anti-inflammatory activity and molecular docking of a neutral polysaccharide separated from American ginseng berries.

AIM: American ginseng berries, grown in the aerial parts and harvested in August, are a potentially valuable material. The aim of the study was to analyze the specific polysaccharides in American ginseng berries, and to demonstrate the anti-inflammation effect through in vitro and in vivo experiments and molecular docking. METHODS: After deproteinization and dialysis, the extracted crude polysaccharide was separated and purified. The structure of the specific isolated polysaccharide was investigated by Fourier Transform infrared spectroscopy (FT-IR), GC-MS and nuclear magnetic resonance (NMR), and anti-inflammatory activity was evaluated using in vitro and in vivo models (Raw 264.7 cells and zebrafish). Molecular docking was used to analyze the binding capacity and interaction with cyclooxygenase-2 (COX-2). RESULTS: A novel neutral polysaccharide fraction (AGBP-A) was isolated from American ginseng berries. The structural analysis demonstrated that AGBP-A had a weight-average molecular weight (Mw) of 122,988 Da with a dispersity index (Mw/Mn) value of 1.59 and was composed of arabinose and galactose with a core structure containing →6)-Gal-(1→ residues as the backbone and a branching substitution at the C3 position. The side-chains comprised of α-L-Ara-(1→, α-L-Ara-(1→, →5)-α-L-Ara-(1→, ß-D-Gal-(1→. The results showed that it significantly decreased pro-inflammatory cytokines in the cell model. In a zebrafish model, AGBP-A reduced the massive recruitment of neutrophils to the caudal lateral line neuromast, suggesting the relief of inflammation. Molecular docking was used to analyze the combined capacity and interaction with COX-2. CONCLUSION: Our study indicated the potential efficacy of AGBP-A as a safe and valid natural anti-inflammatory component.

Gut Microbiota and Aging: Traditional Chinese Medicine and Modern Medicine.

The changing composition of gut microbiota, much like aging, accompanies people throughout their lives, and the inextricable relationship between both has recently attracted extensive attention as well. Modern medical research has revealed that a series of changes in gut microbiota are involved in the aging process of organisms, which may be because gut microbiota modulates aging-related changes related to innate immunity and cognitive function. At present, there is no definite and effective method to delay aging. However, Nobel laureate Tu Youyou's research on artemisinin has inspired researchers to study the importance of Traditional Chinese Medicine (TCM). TCM, as an ancient alternative medicine, has unique advantages in preventive health care and in treating diseases as it already has formed an independent understanding of the aging system. TCM practitioners believe that the mechanism of aging is mainly deficiency, and pathological states such as blood stasis, qi stagnation and phlegm coagulation can exacerbate the process of aging, which involves a series of organs, including the brain, kidney, heart, liver and spleen. Our current understanding of aging has led us to realise that TCM can indeed make some beneficial changes, such as the improvement of cognitive impairment. However, due to the multi-component and multi-target nature of TCM, the exploration of its mechanism of action has become extremely complex. While analysing the relationship between gut microbiota and aging, this review explores the similarities and differences in treatment methods and mechanisms between TCM and Modern Medicine, in order to explore a new approach that combines TCM and Modern Medicine to regulate gut microbiota, improve immunity and delay aging.

Structural characterization and anti-inflammatory activity of neutral polysaccharides from American ginseng.

American ginseng, a precious classic herbal medicine, is used extensively in China for life prolongation purpose. This study aimed to elucidate the structure and anti-inflammatory activity of a neutral polysaccharide isolated from American ginseng (AGP-A). Nuclear magnetic resonance in conjunction with gas chromatography-mass spectrometry were used to analyze AGP-A's structure, whereas Raw264.7 cell and zebrafish models were employed to assess its anti-inflammatory activity. According to the results, AGP-A has a molecular weight of 5561 Da and is primarily consisted of glucose. Additionally, linear α-(1 â†’ 4)-glucans with α-D-Glcp-(1 â†’ 6)-α-Glcp-(1→ residues linked to the backbone at C-6 formed the backbone of AGP-A. Furthermore, AGP-A significantly decreased pro-inflammatory cytokines (IL-1ß, IL-6 and TNF-α) in Raw264.7 cell model. AGP-A in zebrafish model significantly lower the massive recruitment of neutrophils to the neuromast of the caudal lateral line. Inflammation may be relieved by the AGP-A component in American ginseng based on these results. In conclusion, our study shows the structural characterization, remarkable anti-inflammatory properties of AGP-A and its potential curative efficacy as a safe, valid natural anti-inflammatory medicine.

Case report: Successful treatment of a patient with relapsed/refractory primary central nervous system lymphoma with thiotepa-based induction, autologous stem cell transplantation and maintenance.

Despite significant improvements in prognosis, a subset of patients with primary central nervous system lymphoma (PCNSL) remains at high risk for relapse. The treatment of relapsed and refractory (R/R) PCNSL remains a major clinical challenge. Herein, we present a 24-year-old patient with PCNSL who relapsed 4 years after initial diagnosis and subsequently became refractory to high-dose methotrexate (HD-MTX), temozolomide, whole brain radiation therapy (WBRT), ibrutinib, and lenalidomide. She received thiotepa with anti-programmed cell death protein 1 (PD-1) antibody and achieved partial remission and then underwent autologous stem cell transplantation (ASCT) with thiotepa-based conditioning. Post-transplant maintenance with thiotepa and anti-PD-1 at 3-month intervals resulted in a durable complete response (CR) in this case of R/R PCNSL. Our report highlights the important role of thiotepa in the treatment of patients with R/R PCNSL.

The impact of radiation induced lymphopenia in the prognosis of head and neck cancer: A systematic review and meta-analysis.

OBJECTIVES: Radiotherapy is a key part of head and neck cancer (HNC) treatment. Radiation induced lymphopenia (RIL) is a severe complication of radiotherapy. The aim of this study was to evaluate the prognostic role of RIL in HNC patients. METHOD: We conducted a PRISMA guideline based systematic review and meta-analysis. The studies were identified on the PubMed, Embase and Cochrane Library from 2007 to October 2021. The quality of each study was assessed by Newcastle-Ottawa Quality Assessment Form for Cohort Studies (NOS). RESULTS: There were 8 studies with 2,733 samples finally included in current study. The meta-analysis showed that the odds ratio of developing grade 3-4 RIL was 13.49 (95%CI = 7.03-25.89, I2 = 94%). The incidence rate of grade 3-4 RIL ranged from 73%-88%. Multivariate meta-analysis found that the RIL significantly decreased the overall survival (HR = 2.94, 95%CI = 1.83-4.74, I2 = 0%) and distant metastasis free survival of HNC (HR = 3.79, 95%CI = 2.06-6.97, I2 = 0%). After sensitivity analysis and excluding a potential study that caused heterogeneity, the new pooled multivariate meta-analysis showed RIL was a risk factor to the progression free survival of HNC patients (HR = 3.16, 95%CI = 1.77-5.63, I2 = 0%). CONCLUSION: This is the first meta-analysis which showed severe RIL decreased the overall survival and promoted the progression of HNC patients. Future large-scale prospective studies are required to evaluate the association between severe RIL and the prognosis of HNC.

SLPI suppresses hepatocellular carcinoma progression via endoplasmic reticulum stress induced apoptosis.

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. Secretory leukocyte protease inhibitor (SLPI) has been reported to function as a regulatory factor in several cancers. However, its biological functions and underlying mechanisms in HCC remain to be uncovered. Here, we aimed to explore the effect of SLPI in HCC. In our study, we found that the mRNA and protein expression levels of SLPI were significantly down-regulated in HCC tissues and hepatoma cell lines and low level of SLPI predicted worse survival in our HCC cohorts. In term of function, silencing of SLPI markedly promoted whereas overexpression SLPI suppressed proliferation, migration and invasion capabilities of HCC cells in vitro, and ectopic expression of SLPI inhibited the tumorigenicity of HCC cells in vivo. Mechanistic studies demonstrated that SLPI played a protective role in HCC progression via activating endoplasmic reticulum stress (ER stress)-mediated apoptosis of hepatoma cells, which could be regulated by MAPK signaling pathways. In summary, our findings highlight that SLPI could serve as a potential prognostic biomarker and putative tumor suppressor by enhancing ER stress-induced apoptosis in HCC cells mediated by MAPK signaling pathways, which provides new insights into promising therapeutic targets for HCC treatment.

The immune landscape of human thymic epithelial tumors.

Human thymic epithelial tumors (TET) are common malignancies in the anterior mediastinum with limited biological understanding. Here we show, by single cell analysis of the immune landscape, that the developmental pattern of intra-tumoral T-cells identify three types within TETs. We characterize the developmental alterations and TCR repertoires of tumor-infiltrating T cells in the context of the distinguishing epithelial tumor cell types. We demonstrate that a subset of tumor cells, featuring medullary thymic epithelial cell (TEC) phenotype and marked by KRT14/GNB3 expression, accumulate in type 1 TETs, while T-cell positive selection is inhibited. Type 2 TETs are dominated by CCL25+ cortical TEC-like cells that appear to promote T-cell positive selection. Interestingly, the CHI3L1+ medullary TEC-like cells that are the characteristic feature of type 3 TETs don't seem to support T-cell development, however, they may induce a tissue-resident CD8+ T cell response. In summary, our work suggests that the molecular subtype of epithelial tumour cells in TETs determine their tumour immune microenvironment, thus GNB3 and CHI3L1 might predict the immunological behavior and hence prognosis of these tumours.

N4BP3 promotes breast cancer metastasis via NEDD4-mediated E-cadherin ubiquitination and degradation.

The molecular mechanisms driving metastatic progression in breast cancer patients remain poorly understood. Here, we identified N4BP3 as a new regulator in promoting breast cancer metastasis. N4BP3 is enriched in breast tumor tissue and negatively correlates with clinical outcomes in breast cancer patients. The results show that N4BP3 plays a crucial role in regulating breast cancer cell invasion in vitro, and N4BP3 depletion suppresses metastases formation in vivo. N4BP3 alters the expression of epithelial-mesenchymal transition markers and specifically targets E-cadherin in breast cancer cells. Intriguingly, we identified a novel E3 ligase NEDD4 for E-cadherin, and further revealed that N4BP3 promotes breast cancer metastasis via NEDD4-mediated E-cadherin ubiquitination and degradation. Together, this study uncovers an unprecedented role for N4BP3 in breast cancer metastasis and elucidates the underlying molecular mechanisms.

Aberrantly Activated APOBEC3B Is Associated With Mutant p53-Driven Refractory/Relapsed Diffuse Large B-Cell Lymphoma.

Tumor protein 53 (TP53) mutation predicts an unfavorable prognosis in diffuse large B-cell lymphoma (DLBCL), but the molecular basis for this association remains unclear. In several malignancies, the cytidine deaminase apolipoprotein B mRNA editing enzyme catalytic subunit 3B (APOBEC3B) has been reported to be associated with the TP53 G/C-to-A/T mutation. Here, we show that the frequency of this mutation was significantly higher in relapsed/refractory (R/R) than in non-R/R DLBCL, which was positively associated with the APOBEC3B expression level. APOBEC3B overexpression induced the TP53 G/C-to-A/T mutation in vitro, resulting in a phenotype similar to that of DLBCL specimens. Additionally, APOBEC3B-induced p53 mutants promoted the growth of DLBCL cells and enhanced drug resistance. These results suggest that APOBEC3B is a critical factor in mutant p53-driven R/R DLBCL and is therefore a potential therapeutic target.

Identification of Tumor Microenvironment-Related Prognostic Genes in Sarcoma.

AIM: Immune cells that infiltrate the tumor microenvironment (TME) are associated with cancer prognosis. The aim of the current study was to identify TME related gene signatures related to the prognosis of sarcoma (SARC) by using the data from The Cancer Genome Atlas (TCGA). METHODS: Immune and stromal scores were calculated by estimation of stromal and immune cells in malignant tumor tissues using expression data algorithms. The least absolute shrinkage and selection operator (lasso) based cox model was then used to select hub survival genes. A risk score model and nomogram were used to predict the overall survival of patients with SARC. RESULTS: We selected 255 patients with SARC for our analysis. The Kaplan-Meier method found that higher immune (p = 0.0018) or stromal scores (p = 0.0022) were associated with better prognosis of SARC. The estimated levels of CD4+ (p = 0.0012) and CD8+ T cells (p = 0.017) via the tumor immune estimation resource were higher in patients with SARC with better overall survival. We identified 393 upregulated genes and 108 downregulated genes (p < 0.05, fold change >4) intersecting between the immune and stromal scores based on differentially expressed gene (DEG) analysis. The univariate Cox analysis of each intersecting DEG and subsequent lasso-based Cox model identified 11 hub survival genes (MYOC, NNAT, MEDAG, TNFSF14, MYH11, NRXN1, P2RY13, CXCR3, IGLV3-25, IGHV1-46, and IGLV2-8). Then, a hub survival gene-based risk score gene signature was constructed; higher risk scores predicted worse SARC prognosis (p < 0.0001). A nomogram including the risk scores, immune/stromal scores and clinical factors showed a good prediction value for SARC overall survival (C-index = 0.716). Finally, connectivity mapping analysis identified that the histone deacetylase inhibitors trichostatin A and vorinostat might have the potential to reverse the harmful TME for patients with SARC. CONCLUSION: The current study provided new indications for the association between the TME and SARC. Lists of TME related survival genes and potential therapeutic drugs were identified for SARC.

Expression and prognostic value of E2F3 transcription factor in non-small cell lung cancer.

E2F transcription factor 3 (E2F3) plays a vital role in the development of various types of cancer. To verify whether E2F3 is a suitable biomarker for the prognosis of lung cancer, bioinformatics analysis was performed to determine the differential expression level of E2F3 in lung cancer and the surrounding non-tumor tissues, and the results were confirmed in a NSCLC cell line and a tissue microarray (TMA). The relevance of E2F3 in non-small cell lung cancer (NSCLC) was investigated in 19 studies from the Oncomine database and confirmed in The Cancer Genome Atlas database. In the lung cancer cell line A549, the inhibition of E2F3 mRNA expression level led to decreased tumor cell viability and cell migration, which was determined by a Cell Counting Kit-8 and wound healing assays, respectively. Immunohistochemistry analyses of E2F3, Bcl-2, Bax and caspase-3 were performed in the NSCLC TMA (n=50). The assessment of TMA detected the increase of E2F3 protein expression level in the tumor tissues, as compared with that in the non-tumor tissues, which was also correlated with the increase in expression of Bcl-2 in tumors. Analysis of the clinical data from patients with NSCLC revealed that the overexpression of E2F3 was associated with early lymphatic spreading, and poor patient survival time. The OncomiR website was used to predict the E2F3 upstream microRNAs and determine their prognostic value in patients with NSCLC. The results from the present study revealed that E2F3 was overexpressed at both the transcriptional and translational levels in NSCLC tissues, as compared with that in non-tumor tissues. The overexpression of E2F3 was associated with the upregulation of the anti-apoptotic factor, Bcl-2, which may contribute to uncontrolled tumor growth. Thus, E2F3 was shown to have important oncogenic properties in the development of NSCLC, and it may become a potential biomarker for patients with NSCLC.

Combination of Radiosensitivity Gene Signature and PD-L1 Status Predicts Clinical Outcome of Patients With Locally Advanced Head and Neck Squamous Cell Carcinoma: A Study Based on The Cancer Genome Atlas Dataset.

Aim: The aim of our study was to investigate the potential predictive value of the combination of radiosensitivity gene signature and PD-L1 expression for the prognosis of locally advanced head and neck squamous cell carcinoma (HNSCC). Methods: The cohort was selected from The Cancer Genome Atlas (TCGA) and classified into the radiosensitive (RS) group and radioresistant (RR) group by a radiosensitivity-related gene signature. The cohort was also grouped as PD-L1-high or PD-L1-low based on PD-L1 mRNA expression. The least absolute shrinkage and selection operator (lasso)-based Cox model was used to select hub survival genes. An independent validation cohort was obtained from the Gene Expression Omnibus (GEO) database. Results: We selected 288 locally advanced HNSCC patients from TCGA. The Kaplan-Meier method found that the RR and PD-L1-high group had a worse survival than others (p = 0.033). The differentially expressed gene (DEG) analysis identified 553 upregulated genes and 486 downregulated genes (p < 0.05, fold change >2) between the RR and PD-L1-high group and others. The univariate Cox analysis of each DEG and subsequent lasso-based Cox model revealed five hub survival genes (POU4F1, IL34, HLF, CBS, and RNF165). A further hub survival gene-based risk score model was constructed, which was validated by an external cohort. We observed that a higher risk score predicted a worse prognosis (p = 0.0013). The area under the receiver operating characteristic curve (AUC) plots showed that this risk score model had good prediction value (1-year AUC = 0.684, 2-year AUC = 0.702, and 3-year AUC = 0.688). Five different deconvolution methods all showed that the B cells were lower in the RR and PD-L1-high group (p < 0.05). Finally, connectivity mapping analysis showed that the histone deacetylase (HDAC) inhibitor trichostatin A might have the potential to reverse the phenotype of RR and PD-L1-high in locally advanced HNSCC (p < 0.05, false discovery rate <0.1). Conclusion: The combination of 31-gene signature and the PD-L1 mRNA expression had a potential predictive value for the prognosis of locally advanced HNSCC who had RT. The B cells were lower in the RR and PD-L1-high group. The identified risk gene signature of locally advanced HNSCC and the potential therapeutic drug trichostatin A for the RR and PD-L1-high group are worth being further studied in a prospective homogenous cohort.

Case Report: Tumor Microenvironment Characteristics in a Patient With HER2 Mutant Lung Squamous Cell Carcinoma Harboring High PD-L1 Expression Who Presented Hyperprogressive Disease.

BACKGROUND: High PD-L1 expression in non-small cell lung cancer (NSCLC) is evident to predict elevated immunotherapy efficacy, to which NSCLC with onco-driver gene mutations is probed with poor responsiveness. Thus, it is of great interest to investigate how effective immune monotherapy is in the presence of concurrent high PD-L1 expression and driving gene mutation. PATIENTS AND METHODS: We present a case of squamous lung cancer with high PD-L1 expression and HER2 exon 20 insertion (20Ins) who presented hyperprogressive disease (HPD) after being treated with PD-1 inhibitor. RESULTS: A 71-year-old female was diagnosed with advanced squamous lung cancer with 98% tumor proportion score of PD-1 and 20ins. She benefited from first-line docetaxel cisplatin followed by 2 months second-line afatinib. Third-line pembrolizumab monotherapy was then given. Unfortunately, she rapidly progressed with dramatically enlarged primary site as well as mediastinal lymph nodes and pleural effusion only 2 weeks later, presenting severe dyspnea and dysphagia. Re-biopsy was conducted, and we found that compared with the baseline, CD8+ T cells were largely recruited only in tumor stroma but not in tumor parenchyma. Tumor-associated macrophages were notably increased in both tumor stroma and parenchyma. Concomitantly, CD56dim NK cells in tumor parenchyma were decreased. CONCLUSIONS: Application of immune monotherapy in patients with positive driver genes demands extreme caution, even harboring high PD-L1 expression. Abnormality of tumor microenvironment might be critically involved in immune checkpoint inhibitor-induced HPD. Further study in greater depth is required.