C-Reactive Protein Induces Immunosuppression by Activating FcγR2B in Pulmonary Macrophages to Promote Lung Metastasis.

C-reactive protein (CRP) is a liver-derived acute phase reactant that is a clinical marker of inflammation associated with poor cancer prognosis. Elevated CRP levels are observed in many types of cancer and are associated with significantly increased risk of metastasis, suggesting that CRP could have pro-metastatic actions. Here, we reported that CRP promotes lung metastasis by dampening the anti-cancer capacity of pulmonary macrophages in breast cancer and melanoma. Deletion of CRP in mice inhibited lung metastasis of breast cancer and melanoma cells without significantly impacting tumor growth compared to wildtype mice. In addition, the lungs of CRP deficient mice were enriched for activated pulmonary macrophages, which could be reduced to the level of wildtype mice by systemic administration of human CRP. Mechanistically, CRP blocked the activation of pulmonary macrophages induced by commensal bacteria in a FcγR2B-dependent manner, thereby impairing macrophage-mediated immune surveillance to promote the formation of a pre-metastatic niche in the lungs of tumor-bearing mice. Accordingly, treatment with specific CRP inhibitors activated pulmonary macrophages and attenuated lung metastasis in vivo. These findings highlight the importance of CRP in lung metastasis, which may represent an effective therapeutic target for patients with advanced solid cancers in clinics.

Enhanced Weighted Mobility Induced High Thermoelectric Performance in Argyrodite Ag8SnSe6.

The argyrodite family has emerged as a promising thermoelectric candidate due to its highly diffusive Ag ions and inherent low thermal conductivity. To address issues that commonly arise with hot pressing (HP) sintering, this study proposes to use the zone melting (ZM) method to synthesize high-density polycrystalline bulk Ag8SnSe6 samples. The thermoelectric properties of samples synthesized by the ZM and HP methods were thoroughly evaluated over a temperature range of 300 to 700 K. Due to the weaker scattering of electrons, the ZM-synthesized samples exhibited an ∼60% increase in weighted mobility, compared to those produced by the HP method. Despite the slight increase in thermal conductivity, the specimen synthesized by the ZM method achieves a higher peak zT value of 1.05 at 700 K. The average zT value also improves to 0.71 across the temperature range of 300 to 700 K. This work demonstrates the effectiveness of the ZM method in enhancing the thermoelectric performance of Ag8SnSe6, with great potential applicability to other argyrodite compounds.

The role of cornulin (CRNN) in the progression of cutaneous squamous cell carcinoma involving AKT activation in SCL-1.

Cutaneous squamous cell carcinoma (cSCC) is the second most common non-melanoma skin cancer that has been on the rise in recent times, particularly among older individuals. Cornulin (CRNN) is increasingly recognized as an oncogene involved in developing various types of tumors. However, the precise contribution to cSCC remains unclear. Our study observed a significant increase in CRNN expression in cSCC samples compared to healthy skin. CRNN expression in the SCL-1 cell line derived from cSCC was reduced, leading to a halt in cell growth during the transition from the G1 phase to the S phase. This reduction inhibits cell division, promotes cell death, and decreases cell invasion and migration. CRNN overexpression has been found to enhance cell growth and prevent cells from undergoing natural cell death, and the cancer-promoting effects of CRNN are linked to AKT activation. Using a mouse xenograft model, we demonstrated that the inhibition of CRNN led to a decline in cSCC tumor growth in a living organism, providing evidence of CRNN's involvement in cSCC occurrence and development. This study establishes a foundation for evaluating the effectiveness of CRNN in treating cSCC, enabling further investigation in this area.

Cancer-associated fibroblasts promote the progression and chemoresistance of HCC by inducing IGF-1.

Crosstalk between cancer-associated fibroblasts (CAFs) and tumour cells plays a critical role in multiple cancers, including hepatocellular carcinoma (HCC). CAFs contribute to tumorigenesis by secreting growth factors, modifying the extracellular matrix, supporting angiogenesis, and suppressing antitumor immune responses. However, effect and mechanism of CAF-mediated promotion of hepatocellular carcinoma cells are still unclear. In study, we demonstrated CAFs promoted the proliferation and inhibited the apoptosis of HCC cells by secreting interleukin-6 (IL-6), which induced autocrine insulin-like growth factor-1 (IGF-1) in HCC. IGF-1 promoted the progression and chemoresistance of HCC. IGF-1 receptor (IGF-1R) inhibitor NT157 abrogated the effect of CAF-derived IL-6 and autocrine IGF-1 on HCC. Mechanistic studies revealed that NT157 decreased IL-6-induced IGF-1 expression by inhibiting STAT3 phosphorylation and led to IRS-1 degradation, which mediated the proliferation of tumour by activating AKT signalling in ERK-dependent manner. Inhibition of IGF-1R also enhanced the therapeutic effect of sorafenib on HCC, especially chemoresistant tumours. STATEMENT OF SIGNIFICANCE: Our study showed IL-6-IGF-1 axis played crucial roles in the crosstalk between HCC and CAFs, providing NT157 inhibited of STAT3 and IGF-1R as a new targeted therapy in combination with sorafenib.

Targeting the Dendritic Cell-Secreted Immunoregulatory Cytokine CCL22 Alleviates Radioresistance.

PURPOSE: Radiation-mediated immune suppression limits efficacy and is a barrier in cancer therapy. Radiation induces negative regulators of tumor immunity including regulatory T cells (Treg). Mechanisms underlying Treg infiltration after radiotherapy (RT) are poorly defined. Given that conventional dendritic cells (cDC) maintain Treg, we sought to identify and target cDC signaling to block Treg infiltration after radiation. EXPERIMENTAL DESIGN: Transcriptomics and high dimensional flow cytometry revealed changes in murine tumor cDC that not only mediate Treg infiltration after RT but also associate with worse survival in human cancer datasets. Antibodies perturbing a cDC-CCL22-Treg axis were tested in syngeneic murine tumors. A prototype interferon-anti-epidermal growth factor receptor fusion protein (αEGFR-IFNα) was examined to block Treg infiltration and promote a CD8+ T cell response after RT. RESULTS: Radiation expands a population of mature cDC1 enriched in immunoregulatory markers that mediates Treg infiltration via the Treg-recruiting chemokine CCL22. Blocking CCL22 or Treg depletion both enhanced RT efficacy. αEGFR-IFNα blocked cDC1 CCL22 production while simultaneously inducing an antitumor CD8+ T cell response to enhance RT efficacy in multiple EGFR-expressing murine tumor models, including following systemic administration. CONCLUSIONS: We identify a previously unappreciated cDC mechanism mediating Treg tumor infiltration after RT. Our findings suggest blocking the cDC1-CCL22-Treg axis augments RT efficacy. αEGFR-IFNα added to RT provided robust antitumor responses better than systemic free interferon administration and may overcome clinical limitations to interferon therapy. Our findings highlight the complex behavior of cDC after RT and provide novel therapeutic strategies for overcoming RT-driven immunosuppression to improve RT efficacy. See related commentary by Kalinski et al., p. 4260.

Radiation-induced upregulation of FGL1 promotes esophageal squamous cell carcinoma metastasis via IMPDH1.

BACKGROUND: While radiation therapy remains pivotal in esophageal squamous cell carcinoma (ESCC) treatment, the perplexing phenomenon of post-radiation metastasis presents a formidable clinical challenge. This study investigates the role of fibrinogen-like protein 1 (FGL1) in driving ESCC metastasis following radiation exposure. METHODS: FGL1 expression in post-radiation ESCC cells was meticulously examined using qRT-PCR, western blotting, and immunofluorescence. The impact of FGL1 on ESCC cell invasion and migration was assessed through Transwell and wound healing assays. In vivo, the metastatic potential of ESCC in response to FGL1 was scrutinized using nude mice models. Comprehensive RNA sequencing and functional experiments elucidated the intricate mechanism associated with FGL1. RESULTS: Radiation induced upregulation of FGL1 in ESCC cells through FOXO4, intensifying ESCC cell invasion and migration. Targeted knockdown of FGL1 effectively alleviated these characteristics both in vitro and in vivo. FGL1 depletion concurrently suppressed IMPDH1 expression. Rescue experiments underscored that IMPDH1 knockdown robustly reversed the pro-invasive effects induced by FGL1 in ESCC cells. ESCC tissues exhibited heightened IMPDH1 mRNA levels, demonstrating a correlation with patient survival. CONCLUSIONS: Radiation-induced upregulation of FGL1 propels ESCC metastasis through IMPDH1, proposing a potential therapeutic target to mitigate post-radiotherapy metastasis in ESCC patients.

Marital Self-Disclosure Intervention for the Fear of Cancer Recurrence in Chinese Patients With Gastric Cancer: Protocol for a Quasiexperimental Study.

BACKGROUND: Patients with gastric cancer experience different degrees of fear of cancer recurrence. The fear of cancer recurrence can cause and worsen many physical and psychological problems. We considered the "intimacy and relationship processes in couples' psychosocial adaptation" model. OBJECTIVE: The study aims to examine the effectiveness of a marital self-disclosure intervention for improving the level of fear of cancer recurrence and the dyadic coping ability among gastric cancer survivors and their spouses. METHODS: This is a quasiexperimental study with a nonequivalent (pretest-posttest) control group design. The study will be conducted at 2 tertiary hospitals in Taizhou City, Jiangsu Province, China. A total of 42 patients with gastric cancer undergoing chemotherapy and their spouses will be recruited from each hospital. Participants from Jingjiang People's Hospital will be assigned to an experimental group, while participants from Taizhou People's Hospital will be assigned to a control group. The participants in the experimental group will be involved in 4 phases of the marital self-disclosure (different topics, face-to-face) intervention. Patients will be evaluated at baseline after a diagnosis of gastric cancer and reassessed 2 to 4 months after baseline. The primary outcome is the score of the Fear of Progression Questionnaire-Short Form (FoP-Q-SF) for patients. The secondary outcomes are the scores of the FoP-Q-SF for partners and the Dyadic Coping Inventory. RESULTS: Research activities began in October 2022. Participant enrollment and data collection began in February 2023 and are expected to be completed in 12 months. The primary results of this study are anticipated to be announced in June 2024. CONCLUSIONS: This study aims to assess a marital self-disclosure intervention for improving the fear of cancer recurrence in Chinese patients with gastric cancer and their spouses. The study is likely to yield desirable positive outcomes as marital self-disclosure is formulated based on evidence and inputs obtained through stakeholder interviews and expert consultation. The study process will be carried out by nurses who have received psychological training, and the quality of the intervention will be strictly controlled. TRIAL REGISTRATION: ClinicalTrials.gov NCT05606549; https://clinicaltrials.gov/study/NCT05606549. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/55102.

Radiotherapy Enhances Metastasis Through Immune Suppression by Inducing PD-L1 and MDSC in Distal Sites.

PURPOSE: Radiotherapy (RT) is a widely employed anticancer treatment. Emerging evidence suggests that RT can elicit both tumor-inhibiting and tumor-promoting immune effects. The purpose of this study is to investigate immune suppressive factors of radiotherapy. EXPERIMENTAL DESIGN: We used a heterologous two-tumor model in which adaptive concomitant immunity was eliminated. RESULTS: Through analysis of PD-L1 expression and myeloid-derived suppressor cells (MDSC) frequencies using patient peripheral blood mononuclear cells and murine two-tumor and metastasis models, we report that local irradiation can induce a systemic increase in MDSC, as well as PD-L1 expression on dendritic cells and myeloid cells, and thereby increase the potential for metastatic dissemination in distal, nonirradiated tissue. In a mouse model using two distinct tumors, we found that PD-L1 induction by ionizing radiation was dependent on elevated chemokine CXCL10 signaling. Inhibiting PD-L1 or MDSC can potentially abrogate RT-induced metastasis and improve clinical outcomes for patients receiving RT. CONCLUSIONS: Blockade of PD-L1/CXCL10 axis or MDSC infiltration during irradiation can enhance abscopal tumor control and reduce metastasis.

Enhancing the therapeutic efficacy of NK cells in the treatment of ovarian cancer (Review).

Ovarian cancer is a prevalent gynecological malignancy associated with a high mortality rate and a low 5­year survival rate. Typically, >70% of patients present with an advanced stage of the disease, resulting in a high number of ovarian cancer­associated deaths worldwide. Over the past decade, adoptive cellular immunotherapy has been investigated in clinical trials, and the results have led to the increased use in cancer treatment. Natural killer (NK) cells are cytotoxic lymphoid cells that recognize and lyse transformed cells, thereby impeding tumor growth. Thus, NK cells exhibit potential as a form of immunotherapy in the treatment of cancer. However, some patients with ovarian cancer treated with NK cells have experienced unsatisfactory outcomes. Therefore, further optimization of NK cells is required to increase the number of patients achieving long­term remission. In the present review article, studies focusing on improving NK cell function were systematically summarized, and innovative strategies that augment the anticancer properties of NK cells were proposed.

Polymyxin B-targeted liposomal photosensitizer cures MDR A. baumannii burn infections and accelerates wound healing via M1/M2 macrophage polarization.

Multidrug-resistant (MDR) Acinetobacter baumannii infections pose a significant challenge in burn wound management, necessitating the development of innovative therapeutic strategies. In this work, we introduced a novel polymyxin B (PMB)-targeted liposomal photosensitizer, HMME@Lipo-PMB, for precise and potent antimicrobial photodynamic therapy (aPDT) against burn infections induced by MDR A. baumanni. HMME@Lipo-PMB-mediated aPDT exhibited enhanced antibacterial efficacy by specifically targeting and disrupting bacterial cell membranes, and generating increased intracellular ROS. Remarkably, even at low concentrations, this targeted approach significantly reduced bacterial viability in vitro and completely eradicated burn infections induced by MDR A. baumannii in vivo. Additionally, HMME@Lipo-PMB-mediated aPDT facilitated burn infection wound healing by modulating M1/M2 macrophage polarization. It also effectively promoted acute inflammation in the early stage, while attenuated chronic inflammation in the later stage of wound healing. This dynamic modulation promoted the formation of granulation tissue, angiogenesis, and collagen regeneration. These findings demonstrate the tremendous potential of HMME@Lipo-PMB-mediated aPDT as a promising alternative for the treatment of burn infections caused by MDR A. baumannii.

Parkin-mediated ubiquitination inhibits BAK apoptotic activity by blocking its canonical hydrophobic groove.

BAK permeabilizes the mitochondrial outer membrane, causing apoptosis. This apoptotic activity of BAK is stimulated by binding prodeath activators within its canonical hydrophobic groove. Parkin, an E3 ubiquitin (Ub) ligase, can ubiquitinate BAK, which inhibits BAK apoptotic activity. However, the molecular mechanism underlying the inhibition of ubiquitination remains structurally uncharacterized. Here, we utilize truncated and soluble BAK to construct a mimetic of K113-ubiquitinated BAK (disulfide-linked UbG76C ~ BAKK113C) and further present its NMR-derived structure model. The classical L8-I44-H68-V70 hydrophobic patch of the conjugated Ub subunit binds within the canonical hydrophobic groove of BAK. This Ub occludes the binding of prodeath BID activators in the groove and impairs BID-triggered BAK activation and membrane permeabilization. Reduced interaction between Ub and BAK subunits allows BID to activate K113-ubiquitinated BAK. These mechanistic insights suggest a nonsignaling function of Ub in that it directly antagonizes stimuli targeting Ub-modified proteins rather than by recruiting downstream partners for cellular messaging.

π Bridge Engineering-Boosted Dual Enhancement of Type-I Photodynamic and Photothermal Performance for Mitochondria-Targeting Multimodal Phototheranostics of Tumor.

Designing mitochondria-targeting phototheranostic agents (PTAs), which can simultaneously possess exceptional and balanced type-I photodynamic therapy (PDT) and photothermal therapy (PTT) performance, still remains challenging. Herein, benzene, furan, and thiophene were utilized as π bridges to develop multifunctional PTAs. STB with thiophene as a π bridge, in particular, benefiting from stronger donor-accepter (D-A) interactions, reduced the singlet-triplet energy gap (ΔES1-T1), allowed more free intramolecular rotation, and exhibited outstanding near-infrared (NIR) emission, effective type-I reactive oxygen species (ROS) generation, and relatively high photothermal conversion efficiency (PCE) of 51.9%. In vitro and in vivo experiments demonstrated that positive-charged STB not only can actively target the mitochondria of tumor cells but also displayed strong antitumor effects and excellent in vivo imaging ability. This work subtly established a win-win strategy by π bridge engineering, breaking the barrier of making a balance between ROS generation and photothermal conversion, boosting a dual enhancement of PDT and PTT performance, and stimulating the development of multimodal imaging-guided precise cancer phototherapy.

Recent advances in shikonin for the treatment of immune-related diseases: Anti-inflammatory and immunomodulatory mechanisms.

Shikonin, the primary active compound found in the rhizome of the traditional Chinese medicinal herb known as "ZiCao", exhibits a diverse range of pharmacological effects. This drug has a wide range of uses, including as an anti-inflammatory, antioxidant, and anti-cancer agent. It is also effective in promoting wound healing and treating autoimmune diseases such as multiple sclerosis, diabetes, asthma, systemic lupus erythematosus, inflammatory bowel disease, psoriasis, and rheumatoid arthritis. Although shikonin has a wide range of applications, its mechanisms are still not fully understood. This review article provides a comprehensive overview of the recent advancements in the use of shikonin for the treatment of immune-related diseases. The article also delves into the anti-inflammatory and immunoregulatory mechanisms of shikonin and offers insights into the inflammation and immunopathogenesis of related diseases. Overall, this article serves as a valuable resource for researchers and clinicians working in this field. These findings not only provide significant new information on the effects and mechanisms of shikonin but also establish a foundation for the development of clinical applications in treating autoimmune diseases.

UHRF1 plays an oncogenic role in small cell lung cancer.

Small cell lung cancer (SCLC) is a malignant tumor characterized by aggressiveness and dismal prognosis. The specific role of ubiquitin-like PHD and RING finger domain (UHRF1), a frequently overexpressed cancer-promoting gene in various tumors, is poorly understood in SCLC. Herein, we explored the potential carcinogenic role of UHRF1 in SCLC. First, public databases were used to analyze the expression of UHRF1 in SCLC, and tissue specimens in our center were examined to confirm the results while clinical outcomes were collected to analyze its relationship with UHRF1. Then, UHRF1 knockdown and overexpression cell lines were established to evaluate the carcinogenic function of UHRF1 in vitro and in vivo. The mechanism of the biological consequences was determined by co-inmunoprecipitation. Moreover, we also analyzed the influence of UHRF1 on cisplatin (DDP) sensitivity of SCLC. The expression of UHRF1 was significantly higher in SCLC tissues than in normal tissues, and high levels of UHRF1 suggested a poor prognosis for SCLC. Mechanistically, UHRF1 promoted SCLC growth through yes-associated protein 1 (YAP1). Specifically, UHRF1 bound to YAP1 and inhibited YAP1 ubiquitin degradation, thus stabilizing the YAP1 protein in SCLC cells. UHRF1 downregulation enhanced DDP sensitivity in SCLC cells and was correlated with a favorable prognosis in patients with SCLC treated with platinum-based chemotherapy. UHRF1 plays an oncogenic role in SCLC by modulating YAP1. Therefore, UHRF1 could be used as a biomarker to predict the prognosis of SCLC patients and serve as a potential therapeutic target for SCLC patients.

Anti-cancer effects of ginsenoside CK on acute myeloid leukemia in vitro and in vivo.

Objectives: Acute myeloid leukemia (AML) is a malignant disease characterized by clonal proliferation of myeloid cells, and its treatment continues to be a challenge due to high morbidity and mortality. Ginsenoside compound K, a major active metabolite of the protopanaxadiol-type ginsenosides, exhibits biological activities in various cancer cells and animal models. Here, we investigated the role of CK in anticancer potential in AML both in vitro and in vivo. Materials and methods: To investigate the inhibitory effects of CK in AML cells, in vitro experiments, including cell viability assays, colony forming assays, and cell cycle and apoptosis assays were performed. AML animal experiment was established and quantitative analysis of lung tumor growth nodules and spleen weight and H&E staining were carried out to further determine the effects of CK on AML. In addition, the potential key genes induced and influenced by CK during treatment was identification by RNA-seq and qRT-PCR. Results: CK suppressed AML cell activity and induced apoptosis and G1 cell cycle arrest based on the experiment results. Moreover, significantly down-regulated expression genes of BCL2, KIT, DNMT3A, MYC and CSF-1 and up-regulated expression gene of TET2 in CK treatment AML cells were discovered. Conclusion: Our results demonstrated that CK could be used as an anti-AML drug with significant therapeutic efficacy and good biosafety.

The Role of Myeloid-Derived Suppressor Cells in the Treatment of Pancreatic Cancer.

Pancreatic cancer has the highest mortality rate of all major cancers, with a 5-year survival rate of about 10%. Early warning signs and symptoms of pancreatic cancer are vague or nonexistent, and most patients are diagnosed in Stage IV, when surgery is not an option for about 80%-85% of patients. For patients with inoperable pancreatic cancer, current conventional treatment modalities such as chemotherapy and radiotherapy (RT) have suboptimal efficacy. Tumor progression is closely associated with the tumor microenvironment, which includes peripheral blood vessels, bone marrow-derived inflammatory cells, fibroblasts, immune cells, signaling molecules, and extracellular matrix. Tumor cells affect the microenvironment by releasing extracellular signaling molecules, inducing peripheral immune tolerance, and promoting tumor angiogenesis. In turn, the immune cells of the tumor affect the survival and proliferation of cancer cells. Myeloid-derived suppressor cells are key cellular components in the tumor microenvironment and exert immunosuppressive functions by producing cytokines, recognizing other immune cells, and promoting tumor growth and metastasis. Myeloid-derived suppressor cells are the main regulator of the tumor immune response and a key target for tumor treatments. Since the combination of RT and immunotherapy is the main strategy for the treatment of pancreatic cancer, it is very important to understand the immune mechanisms which lead to MDSCs generation and the failure of current therapies in order to develop new target-based therapies. This review summarizes the research advances on the role of Myeloid-derived suppressor cells in the progression of pancreatic cancer and its treatment application in recent years.

Magnetic hyperthermia induces effective and genuine immunogenic tumor cell death with respect to exogenous heating.

Immunogenic cell death (ICD) can improve the therapeutic effects of cancer immunotherapy by initiating adaptive immune responses. Unlike the exogenous hyperthermia modality in clinics, magnetic hyperthermia (MH) is characterized by an iron oxide nano-agent acting as a heating source and the effects induced by heating acting at the intracellular region. However, the immunological effects of endogenous heating generated during MH and exogenous heating, and the difference in damage-associated molecular pattern (DAMP) emissions correlating with the ICD are unclear; whether MH elicits genuine ICD remains unknown. Herein, we have identified 10 distinct DAMP correlates of ICD induced by intracellular MH, and found that only heat shock proteins 70/90 were expressed after water bath heating (exogenous hyperthermia) in human triple-negative breast cancer (TNBC) MDA-MB-231 cells, murine TNBC 4T1 cells, and surgically resected specimens of ductal breast cancer from patients. In vivo vaccination assays were performed in immunocompetent BALB/c mice. The results demonstrated that MH with endogenous heating could stimulate the genuine ICD on 4T1 cells and achieved optimal therapeutic effects on 4T1 tumors, whereas exogenous heating under the same conditions failed to elicit these effects. These findings with regard to the MH induced genuine ICD with high efficiency are critical for the development of safe and effective therapeutics to amplify the therapeutic responses of cancer immunotherapy.

Reshaping the systemic tumor immune environment (STIE) and tumor immune microenvironment (TIME) to enhance immunotherapy efficacy in solid tumors.

The development of combination immunotherapy based on the mediation of regulatory mechanisms of the tumor immune microenvironment (TIME) is promising. However, a deep understanding of tumor immunology must involve the systemic tumor immune environment (STIE) which was merely illustrated previously. Here, we aim to review recent advances in single-cell transcriptomics and spatial transcriptomics for the studies of STIE, TIME, and their interactions, which may reveal heterogeneity in immunotherapy responses as well as the dynamic changes essential for the treatment effect. We review the evidence from preclinical and clinical studies related to TIME, STIE, and their significance on overall survival, through different immunomodulatory pathways, such as metabolic and neuro-immunological pathways. We also evaluate the significance of the STIE, TIME, and their interactions as well as changes after local radiotherapy and systemic immunotherapy or combined immunotherapy. We focus our review on the evidence of lung cancer, hepatocellular carcinoma, and nasopharyngeal carcinoma, aiming to reshape STIE and TIME to enhance immunotherapy efficacy.

Combination of Electrochemistry and Mass Spectrometry to Study Nitric Oxide Metabolism and Its Modulation by Compound K in Breast Cancer Cells.

The levels of l-arginine and asymmetric dimethylarginine (ADMA) and the amount of the nitric oxide (NO) production have recently been linked to breast cancer and pharmaceutical effect evaluation. Herein, a method combining electrochemistry and high-resolution mass spectrometry (HRMS) was established and used to study NO metabolism and its modulation by ginsenoside compound K (CK) in breast cancer cells. Platinum nanoparticles-decorated fluorine tin oxide was employed as an electrochemical sensor for in situ detection of NO release, while HRMS was used for the analysis of the NO-related metabolites. Through the combination of the electrochemical and HRMS results, decreases in arginine and NO and increases in ADMA and ornithine were observed after modulation by CK, and two highly correlated metabolic pathways including arginine and proline metabolism and vascular smooth muscle contraction were found. This method offers a new strategy for fast evaluation of pharmaceutical efficacy based on NO metabolism.

Characteristics of the immunogenicity and tumor immune microenvironment in HER2-amplified lung adenocarcinoma.

Objective: Besides breast and gastric cancer, HER2 amplification/mutation are also found in lung adenocarcinoma (LUAD). However, the correlation between HER2 variations and the phenotype of immunogenicity and tumor immune microenvironment (TIME) in LUAD compared with breast and gastric cancer has yet to be fully elucidated. Methods: We integrated public databases (discovery set) and internal data (validated set) of 288 patients representing three distinct HER2-altered tumors. Genomic data were used to identify somatic mutations, copy number variations, and calculate tumor mutational burden (TMB) and microsatellite instability score. RNA sequencing was conducted to estimate immune gene signatures and contents of tumor-infiltrating immune cell populations. Finally, IHC was used to determine PD-L1 expression and the tumoral-infiltration of immune cells in 50 HER2-variant tumor specimens with no prior therapeutic regimens. Results: Compared with HER2-amplified breast and gastric cancers, patients with HER2-amplified LUAD showed higher immunogenicity, mainly manifested in immune checkpoints expression and tissue/blood TMB. Additionally, HER2-amplified LUAD exhibited an inflamed TIME with remarkably increased genes encoding HLAs, T-cell activity and immune cell-type, and accompanied with tumor-infiltrating lymphocytes. In LUAD, patients with HER2 amplification possessed higher tissue TMB than HER2 mutation, whereas no difference was observed in PD-L1 expression. HER2 amplification (primary) was associated with significantly higher PD-L1 expression and TMB than acquired HER2 amplification after resistance to EGFR-TKIs. Conclusion: Patients with HER2-amplified LUAD have better immunogenicity and/or an inflamed TIME among HER2-aberrant tumors. Our study may provide clues for establishing the benefits and uses of ICIs for patients with this disease.