Iodine-131 intervention in hyperthyroidism with hepatic insufficiency: Metabolomic evaluation.

Hyperthyroidism, often accompanied by hepatic insufficiency (HI), poses significant clinical challenges, highlighting the necessity for identifying optimal treatment strategies and early diagnostic biomarkers to improve patient outcomes. This study aimed to determine the optimal iodine-131 (131I) intervention dose for alleviating hyperthyroidism with HI and to identify serum metabolic biomarkers for early diagnosis using UPLC-Q/TOF-MS technology. A mouse model for early 131I intervention was established to monitor changes in physiological response, body weight, fur condition, thyroid, and liver function. Metabolite identification was achieved through UPLC-Q/TOF-MS and further analyzed via MetaboAnalyst. Six biomarkers were identified and subjected to ROC analysis. Early intervention with 80 µCi 131I per gram of thyroid tissue effectively controlled hyperthyroidism and improved liver function. Metabolomics analysis uncovered 63 differentially abundant metabolites, six of which (L-kynurenine, Taurochenodesoxycholic acid, Glycocholic acid, Phytosphingosine, Tryptamine, and Betaine) were identified as early warning biomarkers. Post-intervention, these biomarkers progressively returned to normal levels. This study demonstrates the efficacy of UPLC-Q/TOF-MS in identifying metabolic biomarkers for early diagnosis of hyperthyroidism with HI and highlights the therapeutic potential of early 131I intervention in normalizing these biomarkers.

Exploration of immune cell heterogeneity by single-cell RNA sequencing and identification of secretory leukocyte protease inhibitor as an oncogene in pancreatic cancer.

Clinical outcomes remain unsatisfactory in patients with pancreatic cancer (PAC). In this study, through single-cell sequencing, we identified eight cell subpopulations in the tumor microenvironment (TME). Redimensional clustering of epithelial cells, myeloid cells, and cancer-associated fibroblasts (CAFs) revealed heterogeneity in the TME of PAC. Intercellular communication analysis showed strong direct interactions between matrix CAFs, inflammatory CAFs, and epithelial cells. Additionally, we found that the SPP1-associated pathway was activated in monocytes, whereas the vascular endothelial growth factor-associated pathway was activated in epithelial cells. These results improve the understanding of the TME of pancreatic cancer and provide a foundation for further studies on intratumoral heterogeneity. In addition, differentially expressed gene secretory leukocyte protease inhibitor (SLPI) was identified in pancreatic cancer, and functional experiments showed that SLPI had a strong impact on cell viability and apoptosis, which offers a potential therapy target for pancreatic cancer.

Macrophage-derived exosomal microRNAs promote metastasis in pancreatic ductal adenocarcinoma.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a highly invasive disease that can metastasize to distant organs such as the lung and liver. However, the exact mechanisms underlying PDAC metastasis remain unclear. Tumor-associated macrophages (TAMs) have been shown to play a critical role in cancer initiation, progression, outgrowth, and metastasis, likely through their interaction with cancer cells via extracellular vesicles known as exosomes. However, the precise mechanisms of this interaction are not fully understood. METHODS: In this study, we obtained TAMs from PDAC patients and isolated exosomes from their culture medium. We characterized these exosomes and analyzed their miRNA expression profiles using Multiplex miRNA assays with FirePlex particle technology. Additionally, we conducted in vitro co-culture experiments between PDAC cells and conditioned media or exosomes from TAMs to investigate the crosstalk between these cells via exosomes. Furthermore, we evaluated the in vivo lung metastasis of PDAC cells treated with TAM-derived exosomes in athymic nude mice. RESULTS: TAMs from PDAC patients promoted the invasiveness and migratory potential of PDAC cells, partially through the effects of TAM-derived exosomes. Specifically, we identified two microRNAs, miR-202-5p and miR-142-5p, which were transferred from TAM-derived exosomes to PDAC cells, resulting in the suppression of phosphatase and tensin homolog deleted on chromosome ten (PTEN) and promoting their invasiveness and migratory potential. We also found that distal metastasis was increased in PDAC cells treated with TAM-derived exosomes, partially through miR-202-5p and miR-142-5p. CONCLUSIONS: Exosomal transfer of miR-202-5p and miR-142-5p plays a significant role in conferring invasiveness and migratory potential to PDAC cells. Targeting exosome communication may represent a promising new therapeutic strategy for reducing cancer metastasis of PDACs.

[Efficacy and Prognostic Factors of Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation for Patients with Acute Myeloid Leukemia].

OBJECTIVE: To retrospectively analyze the efficacy and complications of our institution's modified nonmyeloablative allogeneic hematopoietic stem cell transplantation (NST) in treating intermediate-risk acute myeloid leukemia (AML) - first complete remission (CR1) and prognostic factors. METHODS: Clinical data of 50 intermediate-risk AML-CR1 patients who underwent matched related NST at the Fifth Medical Center of Chinese People's Liberation Army General Hospital from August 2004 to April 2021 were collected, the hematopoietic recovery, donor engraftment and complications were observed, and overall survival (OS) rate, leukemia-free survival (LFS) rate, treatment-related mortality (TRM), and cumulative relapse rate were calculated. Statistical analysis of factors affecting prognosis was also preformed. RESULTS: The median times for neutrophil and platelet recovery after transplantation were 10 (6-16) and 13 (6-33) days, respectively. One month after transplantation, 22 patients (44%) achieved full donor chimerism (FDC), and 22 patients (44%) achieved mixed chimerism (MC), among whom 18 cases gradually transited to FDC during 1-11 months, 4 cases maintained MC status. The overall incidence of acute graft-versus-host disease (aGVHD) was 36%, with a rate of 18% for grade II-IV aGVHD and a median onset time of 45 (20-70) days after transplantation. The overall incidence of chronic GVHD (cGVHD) was 34%, with 20% and 14% of patients having limited or extensive cGVHD, respectively. The incidence rates of infections, interstitial pneumonia, and hemorrhagic cystitis were 30%, 10%, and 16%, respectively. The 5-year OS rate, LFS rate, TRM, and cumulative relapse rate were 68%, 64%, 16%, and 20%, respectively. The increase of the number of CD34+ cells infused had shortened the recovery time for neutrophils and platelets (r =0.563, r =0.350). The number of CD34+ cells infused significantly influenced the occurrence of extensive cGVHD (OR =1.36, 95%CI : 1.06-1.84, P =0.024). CONCLUSION: Modified NST is effective in treating intermediate-risk AML-CR1 patients, however, further expansion of sample size is needed to study prognostic factors.

A risk score model based on lipid metabolism-related genes could predict response to immunotherapy and prognosis of lung adenocarcinoma: a multi-dataset study and cytological validation.

BACKGROUND: Lipid metabolism is a key factor in tumorigenesis and drug resistance, and models related to lipid metabolism have shown potential to predict survival and curative effects of adjuvant therapy in various cancers. However, the relationship between lipid metabolism and prognosis and treatment response of lung adenocarcinoma (LUAD) are still unclear. METHODS: We enrolled seven bulk RNA-sequence datasets (GSE37745, GSE19188, GSE30219, GSE31547, GSE41271, GSE42127, and GSE72094) from the GEO database and one single-cell RNA-sequencing dataset (GSE117570) from the TISCH2 database. Non-negative matrix factorization (NMF) was utilized to construct the risk score model based on lipid score calculated by GSVA algorithm. Phs000452.v3, PMID: 26359337, PMID: 32472114, PRJEB23709 datasets were used to test the response to immunotherapy. Drug sensitivity analysis was assessed according to the GDSC database, and immunotherapy response was evaluated using the Wilcoxon test. Cellular function assays including clone formation, EDU assays and flow cytometry were implemented to explore the phenotype alteration caused by the knockdown of PTDSS1, which is one of key gene in risk score model. RESULTS: We analyzed both bulk and single-cell RNA sequencing data to establish and validate a risk score model based on 18 lipid metabolism-related genes with significant impact on prognosis. After divided the patients into two groups according to risk score, we identified differences in lipid-related metabolic processes and a detailed portrait of the immune landscapes of high- and low-risk groups. Moreover, we investigated the potentials of our risk score in predicting response to immunotherapy and drug sensitivity. In addition, we silenced PTDSS1 in LUAD cell lines, and found that the proliferation of the cells was weakened, and the apoptosis of the cells was increased. CONCLUSION: Our study highlights the crucial roles of lipid metabolism in LUAD and provides a reliable risk score model, which can aid in predicting prognosis and response to immunotherapy. Furthermore, we investigated the roles of PTDSS1 in LUAD carcinogenesis, which showed that PTDSS1 regulated proliferation and apoptosis of LUAD cells.

Targeting and cytotoxicity of chimeric antigen receptor T cells grafted with PD1 extramembrane domain.

BACKGROUND: Immunosuppression induced by programmed cell death protein 1 (PD1) presents a significant constraint on the effectiveness of chimeric antigen receptor (CAR)-T therapy. The potential of combining PD1/PDL1 (Programmed cell death 1 ligand 1) axis blockade with CAR-T cell therapy is promising. However, developing a highly efficient and minimally toxic approach requires further exploration. Our attempt to devise a novel CAR structure capable of recognizing both tumor antigens and PDL1 encountered challenges since direct targeting of PDL1 resulted in systemic adverse effects. METHODS: In this research, we innovatively engineered novel CARs by grafting the PD1 domain into a conventional second-generation (2G) CAR specifically targeting CD19. These CARs exist in two distinct forms: one with PD1 extramembrane domain (EMD) directly linked to a transmembrane domain (TMD), referred to as PE CAR, and the other with PD1 EMD connected to a TMD via a CD8 hinge domain (HD), known as PE8HT CAR. To evaluate their efficacy, we conducted comprehensive assessments of their cytotoxicity, cytokine release, and potential off-target effects both in vitro and in vivo using tumor models that overexpress CD19/PDL1. RESULTS: The findings of our study indicate that PE CAR demonstrates enhanced cytotoxicity and reduced cytokine release specifically towards CD19 + PDL1 + tumor cells, without off-target effects to CD19-PDL1 + tumor cells, in contrast to 2G CAR-T cells. Additionally, PE CAR showed ameliorative differentiation, exhaustion, and apoptosis phenotypes as assessed by flow cytometry, RNA-sequencing, and metabolic parameter analysis, after encountering CD19 + PDL1 + tumor cells. CONCLUSION: Our results revealed that CAR grafted with PD1 exhibits enhanced antitumor activity with lower cytokine release and no PD1-related off-target toxicity in tumor models that overexpress CD19 and PDL1. These findings suggest that our CAR design holds the potential for effectively addressing the PD1 signal.

[Analysis on Cellular Immune Function Recovery after HLA Mismatched Allogeneic Hematopoietic Stem Cell Micro-Transp- lantation in Elderly AML Patients].

OBJECTIVE: To investigate the recovery of cellular immunity in elderly patients with acute myeloid leukemia (AML) after micro-transplantation (MST) and the changes of cellular immunity during relapse, as well as their clinical significance. METHODS: A total of 41 elderly AML patients who received MST treatment in a single center and 25 healthy elderly people were included. Immune function among different age groups in normal population was compared. Furthermore, immune fuction was compared between elderly AML patients of different age groups who achieved continuous complete remission (CR) after MST treatment and normal controls, between high risk group and medium-low risk group, as well as among before diagnosis, after CR, and relapse. Peripheral blood of patients and normal controls was collected, and the percentage of lymphocyte subsets was detected by multi-color flow cytometry. RESULTS: Thirty-five patients achieved CR after MST treatment while six patients did not. After MST treatment, CD3+ T cells, CD8+T cells and activated T cells in all age groups were higher than normal. Significant recovery of CD3+ and CD8+T cells was observed in both high risk and medium-low risk groups, and the overall recovery of immune cells in medium-low risk group was better. It was also observed that B lymphocytes and NK cells could not return to normal levels within 1 year after MST treatment. The proportion of CD3+ T cells, CD4+ T cells, and CD4/CD8 ratio were significantly decreased during relapse compared with continuous CR after MST (P<0.05). CONCLUSION: MST treatment can promote the recovery of CD3+T cells, CD8+T cells and other killer cells, so as to improve the cellular immune function of elderly patients, which provides a new immune cell therapy for elderly AML.

Mismatched donor cell infusion-related syndrome following microtransplant in patients with acute myeloid leukemia.

BACKGROUND: Immunotherapies such as adoptive immune cell infusion and immune-modulating agents are widely used for cancer treatment, and the concomitant symptoms, including cytokine release syndrome (CRS) or immune-related adverse events (irAEs), are frequently reported. However, clinical manifestations induced by mismatched donor granulocyte colony-stimulating factor mobilized peripheral blood mononuclear cell (GPBMC) infusion in patients receiving microtransplant (MST) have not yet been well depicted. METHODS: We analyzed 88 cycles of mismatched GPBMC infusion in patients with acute myeloid leukemia receiving MST and 54 cycles of chemotherapy without GPBMC infusion as a comparison. Clinical symptoms and their correlation with clinical features, laboratory findings, and clinical response were explored. RESULTS: Fever (58.0% [51/88]) and chills (43.2% [38/88]) were the significant early-onset symptoms after GPBMC infusion. Patients possessing less human leukocyte antigen-matching loci with the donor or those with unrelated donors experienced more chills (3 [2-5] loci vs. 5 [3-5] loci, P  = 0.043 and 66.7% [12/18] vs. 37.1% [26/70], P  = 0.024). On the other hand, those with decreased CD4 + /CD8 + T-cell ratio developed more fever (0.8 [0.7-1.2] vs. 1.4 [1.1-2.2], P  = 0.007). Multivariable analysis demonstrated that younger patients experienced more fever (odds ratio [OR] = 0.963, 95% confidence interval [CI]: 0.932-0.995, P  = 0.022), while patients with younger donors experienced more chills (OR = 0.915, 95% CI: 0.859-0.975, P  = 0.006). Elevated ultra-sensitive C-reactive protein levels in the absence of cytokine storm were observed following GPBMC infusion, which indicated mild and transient inflammatory response. Although no predictive value of infusion-related syndrome to leukemia burden change was found, the proportion of host pre-treatment activated T cells was positively correlated with leukemia control. CONCLUSIONS: Mismatched GPBMC infusion in MST induced unique infusion-related symptoms and laboratory changes, which were associated with donor- or recipient-derived risk factors, with less safety and tolerance concerns than reported CRS or irAEs.

Mechanisms of Thymic Repair of In Vitro-Induced Precursor T Cells as a Haploidentical Hematopoietic Stem Cell Transplantation Regimen.

Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is currently an effective treatment for malignant hematologic disease, but the immune deficiency and severe infection triggered by slow immune reconstitution are the main causes of high mortality and transplant failure. One of these outstanding problems is thymus damage, which is associated with graft-versus-host disease (GVHD), and preconditioning including irradiation and chemotherapy. Therefore, rapid repair of damaged thymus and rapid proliferation of thymus-derived donor T cells post-transplantation are key to solving the problem. This study was designed to accelerate the recovery of thymus-derived T cells post-transplantation. Wild-type mice with normal immunity were used as recipients in a haplo-HSCT mouse model to mimic clinical haplo-HSCT. A modified cell culture system using Notch ligand Delta4 and IL-7 was established that is capable of inducing and amplifying the differentiation and proliferation of hematopoietic stem cells into precursor T (preT) cells in vitro. The haplo-HSCT protocol included preT and G-CSF-mobilized donor splenic mononuclear cell (MNC) coinfusion in one group and MNC infusion alone in a second group. Thymic GVHD, thymic repair, and thymus-derived T cell development were compared in the 2 groups by polychromatic immunofluorescence tracking, flow cytometry, and detection of T cell receptor Vß. The thymus homing and T cell regeneration of allogenic preT cells were observed. The functions of preT cells in accelerating immune reconstitution, restoring thymic architecture, weakening graft-versus-host (GVH) effects, and enhancing immunotolerance post-transplantation were demonstrated. Further studies revealed that allogeneic preT cells induced by a culture system containing IL-7 and Delta4 highly express ccr9 and RANKL. Interestingly, RANK expression was promoted after preT cell thymus homing. These results suggest that the RANK/RANKL pathway may play an important role in thymus homing. Our results provide a potential therapeutic option to optimize haplo-HSCT, and also open up a new field of T cell therapy for artificial induction of allogeneic preT cells in vitro to repair the damaged thymus from irradiation and chemotherapy and to compensate for the recovery of immune function in patients with immune deficiency of various etiologies.

Effect of nanoparticles on gouty arthritis: a systematic review and meta-analysis.

OBJECTIVE: The purpose of this study was to explore the effects of nanoparticles on gouty arthritis, and to provide evidence for the preclinical application of nanoparticles in gouty arthritis and ideas for nanomedicine improvement for nanoparticle researchers. METHODS: Five databases including the Cochrane Library, PubMed, Scopus, Web of Science, and Embase were searched for eligible studies until April 2022. The quality of the selected studies was assessed by SYRCLE's risk of bias (RoB) tool, and the random-effects model was used to calculate the overall effect sizes of weighted mean differences (WMD). RESULTS: Ten studies met the inclusion criteria. Results showed that nanoparticles were effective in reducing uric acid levels (WMD: -4.91; 95% confidence interval (CI): - 5.41 to - 4.41; p < 0.001), but were not better than allopurinol (WMD: -0.20; 95% CI: - 0.42 to 0.02; p = 0.099). It was worth noting that the nanoparticles were safer than allopurinol. Subgroup analyses indicated that nanoparticle encapsulated substance, animal species, nanoparticle dosage, animal quantity, and animal gender were all sources of heterogeneity. CONCLUSION: The nanoparticles are safe medications for gouty arthritis which can effectively reduce uric acid levels in rodents. Although the results are still uncertain, it is expected to have certain clinical application value. The nanoparticles may be the preclinical medications for gouty arthritis in the future.

Hyper-CVAD-Based Stem Cell Microtransplant as Post-Remission Therapy in Acute Lymphoblastic Leukemia.

Post-remission strategies for patients with acute lymphoblastic leukemia (ALL) are limited to the multiagent chemotherapy and allogeneic stem cell transplant (allo-SCT), and cellular therapies are seldom involved. Although chemotherapy combined with mismatched granulocyte colony-stimulating factor mobilized peripheral blood mononuclear cell infusion (microtransplant, MST) has been studied in patients with acute myeloid leukemia, its efficacy in ALL is still undetermined. We enrolled 48 patients receiving hyper-CVAD-based MST between July 1, 2009, and January 31, 2018. No acute or chronic graft-versus-host disease occurred in patients receiving MST. Four-year overall survival (OS) and leukemia-free survival (LFS) were 62% and 35%, respectively, and the 4-year relapse rate was 65%. No patient experienced non-relapse mortality. Subgroup analysis showed that OS rates were comparable between groups with different age, risk stratification, minimal residual disease status prior to MST and immunophenotype. Adult patients tended to achieve better 4-year LFS (62% vs. 26%, P = .058) and lower hematologic relapse rate (38% vs. 74%, P = .058) compared with adolescent and young adult patients. Donor chimerism/microchimerism was detectable ranging from 0.002% to 42.78% in 78% (42/54) available samples within 14 days after each infusion and at 3 months or one year after the last cell infusion. Multivariate analyses demonstrated that white blood cells <30 × 109/L at diagnosis and sufficient hyper-CVAD cycles were prognostic factors for better 4-year OS and LFS, while the B-cell phenotype and higher number of infused CD34+ cells in the first cycle were predictors for favorable 4-year LFS. The hyper-CVAD-based MST was a feasible strategy for treating ALL patients with mild toxicity.

Investigation of the potential role of TGR5 in pancreatic cancer by a comprehensive molecular experiments and the liquid chromatography mass spectrometry (LC-MS) based metabolomics.

BACKGROUND: Takeda G protein receptor 5 (TGR5) is widely recognized as a potential drug target for the treatment of metabolic diseases. TGR5 is not only a metabolic regulator, but also has a potential role that participating in developing and progressing of gastrointestinal cancer. We aimed to investigate the potential role of TGR5 in pancreatic cancer by utilizing molecular experiments and the liquid chromatography mass spectrometry (LC-MS) based metabolomics. METHODS: Herein, we assessed pancreatic cancer proliferation, migration and invasion in response to TGR5 antagonist SBI-115 in vitro experiments. Cell death was examined by using TUNEL assay on agarose-embedded sections. Then we investigated the effects of TGR5 on PANC-1 and BXPC3 cells via transmission electron microscopy (TEM). Moreover, LC-MS-based metabolomics was performed to explore the potential underlying mechanisms of TGR5 in pancreatic cancer. The correlations between TGR5 and the metabolism-related genes were further analysed by GEPIA 2 database. RESULTS: We found the proliferation capacities were decreased significantly in PANC-1 and BXPC3 cells after the treatment of SBI-115 for 48 h. The results of TUNEL assay showed that antagonism of TGR5 by SBI-115 had a remarkable effect on inducing cell death. Analysis of TEM demonstrated that SBI-115 treatment could impair the morphology of mitochondria in most PANC-1 and BXPC3 cells. The LC-MS-based analyses revealed that antagonism of TGR5 could alter the metabolic profiles of PANC-1 cells in vitro. Moreover, TGR5 was associated with some metabolism-related genes in pancreatic cancer. CONCLUSION: Our data suggests that antagonism of TGR5 may suppress cell proliferation and induce apoptosis in pancreatic cancer cells. TGR5 may affect the metabolism of pancreatic cancer, and TGR5 would be an attractive target for pancreatic cancer treatment.

Second near-infrared photothermal-amplified immunotherapy using photoactivatable composite nanostimulators.

BACKGROUND: The construction of a nanoimmune controlled-release system that spatiotemporally recognizes tumor lesions and stimulates the immune system response step by step is one of the most potent cancer treatment strategies for improving the sensitivity of immunotherapy response. RESULTS: Here, a composite nanostimulator (CNS) was constructed for the release of second near-infrared (NIR-II) photothermal-mediated immune agents, thereby achieving spatiotemporally controllable photothermal-synergized immunotherapy. CNS nanoparticles comprise thermosensitive liposomes as an outer shell and are internally loaded with a NIR-II photothermal agent, copper sulfide (CuS), toll-like receptor-9 (TLR-9) agonist, cytosine-phospho-guanine oligodeoxynucleotides, and programmed death-ligand 1 (PD-L1) inhibitors (JQ1). Following NIR-II photoirradiation, CuS enabled the rapid elevation of localized temperature, achieving tumor ablation and induction of immunogenic cell death (ICD) as well as disruption of the lipid shell, enabling the precise release of two immune-therapeutical drugs in the tumor region. Combining ICD, TLR-9 stimulation, and inhibited expression of PD-L1 allows the subsequent enhancement of dendritic cell maturation and increases infiltration of cytotoxic T lymphocytes, facilitating regional antitumor immune responses. CONCLUSION: CNS nanoparticle-mediated photothermal-synergized immunotherapy efficiently suppressed the growth of primary and distant tumors in two mouse models and prevented pulmonary metastasis. This study thus provides a novel sight into photo-controllably safe and efficient immunotherapy.

The increased expression and aberrant methylation of SHC1 in non-small cell lung cancer: Integrative analysis of clinical and bioinformatics databases.

Despite the previous evidence showing that SHC adaptor protein 1 (SHC1) could encode three distinct isoforms (p46SHC, p52SHC and p66SHC) that function in different activities such as regulating life span and Ras activation, the precise underlying role of SHC1 in lung cancer also remains obscure. In this study, we firstly found that SHC1 expression was up-regulated both in lung adenocarcinoma (LUAD) and in lung squamous cell carcinoma (LUSC) tissues. Furthermore, compared to patients with lower SHC1 expression, LUAD patients with higher expression of SHC1 had poorer overall survival (OS). Moreover, higher expression of SHC1 was also associated with worse OS in patients with stages 1 and 2 but not stage 3 lung cancer. Significantly, the analysis showed that SHC1 methylation level was associated with OS in lung cancer patients. It seemed that the methylation level at specific probes within SHC1 showed negative correlations with SHC1 expression both in LUAD and in LUSC tissues. The LUAD and LUSC patients with hypermethylated SHC1 at cg12473916 and cg19356022 probes had a longer OS. Therefore, it is reasonable to conclude that SHC1 has a potential clinical significance in LUAD and LUSC patients.

Expression of CAMK1 and its association with clinicopathologic characteristics in pancreatic cancer.

Calcium/calmodulin-dependent protein kinase (CAMKs) can control a wide range of cancer-related functions in multiple tumour types. Herein, we explore the expressions and clinical significances of calcium/calmodulin-dependent protein kinase 1 (CAMK1) in pancreatic cancer (PC). The expression of CAMK1 in PC was analysed by Gene Expression Profiling Interactive Analysis 2 (GEPIA 2) database and the Oncomine database. For further validation, the protein level of CAMK1 in PC tissues was also detected in the Human Protein Atlas (HPA) database and the tissue microarray (TMA)-based immunohistochemistry (IHC). GEPIA 2 and Kaplan-Meier Plotter (KM Plotter) databases were used to explore the prognostic significances of CAMK1 in overall survival (OS) and disease-free survival (DFS) of PC at mRNA level. The relationship between CAMK1 expression and the clinicopathological characteristics of PC was further explored. Additionally, the Search Tool for the Retrieval of Interacting Genes (STRING) database was used to analyse protein-protein interactions (PPI). We found CAMK1 was highly expressed in PC both in bioinformatics analyses and TMA-IHC results. The prognostic analyses from the public databases also showed consistent results with follow-up data. The PPI network suggested that CALM1, CALM3, CREB1, CALM2, SYN1, NOS3, ATF1, GAPDH, PPM1F and FBXL12 were important significant genes associated with CAMK1. Our finding revealed CAMK1 has prognostic value in PC patients, suggesting that CAMK1 may has a distinct role in PC patients and can be used as a candidate marker for investigating clinical prognosis of PC.

GBE1 Is an Independent Prognostic Marker and Associated With CD163+ Tumor-Associated Macrophage Infiltration in Lung Adenocarcinoma.

Glycogen branching enzyme (GBE1) is a critical gene that participates in regulating glycogen metabolism. However, the correlations between GBE1 expression and the prognosis and tumor-associated macrophages in lung adenocarcinoma (LUAD) also remain unclear. Herein, we firstly analyzed the expression level of GBE1 in LUAD tissues and adjacent lung tissues via The Cancer Genome Atlas (TCGA) database. The effect of GBE1 on prognosis was estimated by utilizing TCGA database and the PrognoScan database. The relationships between the clinical characteristics and GBE1 expression were evaluated via TCGA database. We then investigated the relationships between GBE1 and infiltration of immune cells in LUAD by utilizing the CIBERSORT algorithm and Tumor Immune Estimation Resource (TIMER) database. In addition, we used a tissue microarray (TMA) containing 92 LUAD tissues and 88 adjacent lung tissues with immunohistochemistry staining to verify the association between GBE1 expression and clinical characteristics, as well as the immune cell infiltrations. We found the expression level of GBE1 was significantly higher in LUAD tissues. High expression of GBE1 was associated with poorer overall survival (OS) in LUAD. In addition, high expression of GBE1 was correlated with advanced T classification, N classification, M classification, TNM stage, and lower grade. Moreover, GBE1 was positively correlated with infiltrating levels of CD163+ tumor-associated macrophages in LUAD. In conclusion, the expression of GBE1 is associated with the prognosis and CD163+ tumor-associated macrophage infiltration in LUAD, suggesting that it has potential to be prognostic and immunological biomarkers in LUAD.

Secretion of human soluble programmed cell death protein 1 by chimeric antigen receptor-modified T cells enhances anti-tumor efficacy.

BACKGROUND AIMS: Chimeric antigen receptor (CAR) T cells have achieved favorable responses in patients with hematologic malignancies, but the outcome has been far from satisfactory in the treatment of tumors with high expression of immunosuppressive molecules. To overcome this limitation, we modified CAR T cells to secrete types of human soluble programmed cell death protein 1 (PD-1) called sPD-1 CAR T cells. METHODS: To compare the effector function between second (conventional second-generation CAR targeting CD19) and sPD-1 CAR T cells, we measured cytotoxicity, cytokine secretion and activation markers incubated with or without tumor cells expressing CD19 and/or programmed cell death ligand 1 (PD-L1). Furthermore, the anti-tumor efficacy of second and sPD-1 CAR T cells was determined using an NSG mouse model bearing NALM-6-PD-L1. Finally, the underlying mechanism was investigated by metabolic parameters and RNA sequencing analysis of different CAR T cells. RESULTS: Compared with second CAR T cells, sPD-1 CAR T cells enhanced killing efficiency toward CD19+PD-L1+ tumor cells in vitro. Furthermore, sPD-1 CAR T cells reduced the tumor burden and prolonged overall survival of the NSG (NOD-SCID-IL2rg) mice bearing NALM-6-PD-L1. To explore the effect of soluble PD-1 on CAR T cells, we found that sPD-1 CAR T cells exhibited higher levels of activation and ameliorative profiles of differentiation, exhaustion, glycolysis and apoptosis. CONCLUSIONS: With constitutive soluble PD-1 secretion, sPD-1 CAR T cells have tended to eradicate tumors with a high expression of PD-L1 more effectively than second CAR T cells. This may be due to soluble PD-1 enhancing apoptosis resistance, aerobic metabolism and a more "stem" differentiation of CAR T cells. Overall, our study presents a feasible strategy to increase the efficacy of CAR T cells.

Thermal ablation versus hepatic resection for the treatment of liver metastases from gastrointestinal stromal tumors: a retrospective study.

Objective: The study aimed to compare effectiveness and safety of thermal ablation and hepatic resection in patients with liver metastases of gastrointestinal stromal tumors (GISTs).Method: A total of 55 patients (27 in the ablation group and 28 in the surgery group) with liver metastases were included. Overall survival (OS) and progression-free survival (PFS) were assessed with Kaplan-Meier's survival estimate curves. Univariate and multivariate regression analyses were carried out to identify potential prognostic factors.Results: The median OS was 102.0 months in the ablation group and 117.0 months in the surgery group (p = .875). The 1-, 3- and 5-year OS rates were 100%, 88.9% and 74.1% in the ablation group and 92.8%, 82.1% and 78.6% in the surgery group, respectively. The 1-, 3- and 5-year PFS rates were 48.1%, 25.9% and 18.5% in the ablation group and 67.8%, 64.3% and 64.3% in the surgery group, respectively. Multivariate analysis showed that preoperative tyrosine kinase inhibitor (TKI) treatment (progressive disease, PD) (HR, 13.985; 95% CI, 1.791-109.187; p = .012) was the only significant independent prognostic factor for OS. Tumor number (HR, 1.318; 95% CI, 1.021-1.702; p = .034) was identified as an independent predictor for PFS in multivariate analysis. There were fewer postoperative complications (18.5% vs. 78.6%, p = .001) and shorter lengths of hospital stay (8.0 vs. 16.5 days, p = .001) in the ablation group.Conclusion: Compared with resection, thermal ablation offered comparable OS for liver metastases of GISTs. Furthermore, thermal ablation had the advantages of fewer complications and shorter lengths of hospital stay.

Perioperative Nursing of Patients with Pancreatic Cancer Treated with a Nanoknife.

To summarize the experience of 40 patients with pancreatic adenocarcinoma treated with irreversible electroporation ablation (IRE), their experiences with surgical nurses, and to explore the best nursing methods before and during IRE ablation. Preoperative visits were conducted to assess the condition of patients, and psychological counseling was subsequently given to them. All material and medication required for the operation were prepared in advance, and placed in appropriate locations. All 40 patients were treated successfully. The mean time of IRE ablation was 63.33±12.26 (range, 37-87) minutes, and mean blood loss was 2.09±0.49 (range: 1.0-2.8) mL. There were no ablation-related deaths. Skillful mastery of nanoknife usage and troubleshooting methods, intensive observation of patients' vital signs during ablation, and active cooperation with surgeons can ensure successful ablation and can reduce the influence of improper nursing during ablation on patients' prognosis.

LncRNA MYCNOS facilitates proliferation and invasion in hepatocellular carcinoma by regulating miR-340.

Hepatocellular carcinoma (HCC) remains one of the most common and aggressive human cancers worldwide. Accumulating evidences indicate that non-coding RNAs are critical regulators implicated in various physiological processes including HCC development. Long non-coding RNA (lncRNA) MYCN opposite-strand (MYCNOS) was reported to be up-regulated in several human cancers, yet its role in HCC progression is still elusive. In the present study, MYCNOS was up-regulated in both HCC tissues and cell lines, and elevated MYCNOS expression was correlated to shorter survival time of HCC patients. We knocked down MYCNOS expression using short hairpin RNAs specifically targeting MYCNOS. MYCNOS knockdown significantly inhibited proliferation in HCC cells in vitro accompanied by exacerbated cell apoptosis; it also suppressed tumor growth in mouse model in vivo. Besides, the migration and invasion of HCC cells were remarkably inhibited after MYCNOS knockdown. In addition, MYCNOS acted as a negative regulator of miR-340 in HCC cells, and all effects of MYCNOS knockdown were abrogated by further miR-340 inhibition. We also discovered that oncogene phosphatidylinositol-3, 4, 5-trisphosphate-dependent Rac exchange factor 2 (PREX2) was a downstream target of miR-340, and PREX2 expression was positively correlated to that of MYCNOS in HCC tissues. In conclusion, our findings demonstrated that MYCNOS knockdown inhibited HCC progression through regulating miR-340.