Tenascin C activates the toll­like receptor 4/NF­κB signaling pathway to promote the development of polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a globally prevalent gynecological disorder among women of childbearing age. The present study aimed to investigate the role of tenascin C (TNC) in PCOS and its potential mechanisms. Fasting blood glucose and serum insulin, the homeostasis model assessment of insulin resistance and the serum hormone levels were determined in PCOS rats. In addition, H&E staining was used for assessing pathology. In addition, the effects of TNC on oxidative stress and inflammation response in PCOS rat and cell models was assessed. Furthermore, the roles of TNC on KGN cell proliferation and apoptosis were determined employing EdU assay and flow cytometry. TLR4/NF­κB pathway­related proteins were measured using western blotting, immunofluorescence and immunohistochemistry. It was found that the mRNA and protein expression was upregulated in PCOS rats and in KGN cells induced by dihydrotestosterone (DHT). Knockdown of TNC relieved the pathological characteristics and the endocrine abnormalities of PCOS rats. Knockdown of TNC inhibited ovarian cell apoptosis, oxidative stress and inflammation in PCOS rats. Knockdown of TNC reversed the DHT­induced reduction in cell proliferation and increase in apoptosis in KGN cells. Furthermore, knockdown of TNC alleviated oxidative stress and inflammatory responses induced by DHT in KGN cells. Additionally, knockdown of TNC inhibited the toll­like receptor 4 (TLR4)/NF­κB signaling pathway in PCOS rats and DHT­treated KGN cells. In conclusion, knockdown of TNC could ameliorate PCOS in both rats and a cell model by inhibiting cell apoptosis, oxidative stress and inflammation via the suppression of the TLR4/NF­κB signaling pathway.

Development and validation of ELISA method for quantification of Q-1802 in serum and its application to pharmacokinetic study in ICR Mouse.

Q-1802 is a humanized bispecific antibody targeting programmed death-ligand 1 (PD-L1) and Claudin 18.2 (CLDN18.2). It can bind to CLDN18.2 and mediate antibody-dependent cell-mediated cytotoxicity against tumor cells. The Fc segment of the antibody recognizing PD-L1 blocks PD-1 signaling and activates innate immunity and adaptive immunity. In this study, we report the development, validation, and application of sensitive and high-throughput enzyme-linked immunosorbent assays (ELISA) to measure the concentrations of Q-1802 in ICR mouse serum. The assay is sensitive, with a lower limit of quantification of 50 ng/mL, has a broad dynamic range of 50-3200 ng/mL, and exhibits excellent precision and accuracy. These assays were successfully applied to in vitro serum stability and pharmacokinetic (PK) studies. In conclusion, we have developed and validated a highly sensitive and selective method for measuring Q-1802 in ICR mouse serum. The development and validation steps of assays met the required criteria for validation, which suggested that these can be applied to quantify Q-1802, as well as in PK studies.

Chemical tools to define and manipulate interferon-inducible Ubl protease USP18.

Ubiquitin-specific protease 18 (USP18) is a multifunctional cysteine protease primarily responsible for deconjugating interferon-inducible ubiquitin-like (Ubl) modifier ISG15 from protein substrates. Here, we report the design and synthesis of activity-based probes (ABPs) capable of selectively detecting USP18 activity over other ISG15 cross-reactive deubiquitinases (DUBs) by incorporating unnatural amino acids into the C-terminal tail of ISG15. Combining with a ubiquitin-based DUB ABP, the selective USP18 ABP is employed in a chemoproteomic screening platform to identify and assess inhibitors of DUBs including USP18. We further demonstrate that USP18 ABPs can be utilized to profile differential activities of USP18 in lung cancer cell lines, providing a strategy that will help define the activity-related landscape of USP18 in different disease states and unravel important (de)ISGylation-dependent biological processes.

Portulaca oleracea L. polysaccharide inhibits ovarian cancer via inducing ACSL4-dependent ferroptosis.

The antitumor effect of Portulaca oleracea L. polysaccharide (POL) has been demonstrated, but whether it curbs the development of ovarian cancer has not been reported. Here, we treated ovarian cancer cells with different concentrations of POL, detected cell activity by CCK-8 assay, and apoptosis rate by flow cytometry. The results showed that SKOV3 and Hey cell survival decreased with increasing POL concentration in a dose-dependent manner. POL significantly inhibited ovarian cancer cell migration and increased cell death compared with the control group. Ferroptosis inhibitors, but not apoptosis, necrosis, and autophagy inhibitors, reversed POL-induced cell death. Further studies revealed that POL promoted the accumulation of lipid reactive oxygen species (ROS), Fe2+, malondialdehyde (MDA), and decreased glutathione (GSH) production. Moreover, POL significantly increased the mortality of ovarian cancer cells. In vivo studies confirmed that POL reduced the volume and weight of tumors and increased the levels of Fe2+ and MDA in mice in vivo. Western blot assay revealed that POL increased the expression of ACSL4 in ovarian cancer cells as well as in tumors in mice in vivo. More importantly, the POL-mediated increase in lipid ROS, Fe2+, MDA, and decrease in GSH were significantly reversed after knocking down ACSL4 in ovarian cancer cells. Thus, POL can effectively inhibit ovarian cancer development, which may be achieved by increasing ACSL4-mediated ferroptosis. These results suggest that POL has the potential to be a potential drug for targeted treatment of ovarian cancer.

Prox1 Suppresses Proliferation and Drug Resistance of Retinoblastoma Cells via Targeting Notch1.

OBJECTIVE: Retinoblastoma (RB) is a prevalent type of eye cancer in youngsters. Prospero homeobox 1 (Prox1) is a homeobox transcriptional repressor and downstream target of the proneural gene that is relevant in lymphatic, hepatocyte, pancreatic, heart, lens, retinal, and cancer cells. The goal of this study was to investigate the role of Prox1 in RB cell proliferation and drug resistance, as well as to explore the underlying Notch1 mechanism. METHODS: Human RB cell lines (SO-RB50 and Y79) and a primary human retinal microvascular endothelial cell line (ACBRI-181) were used in this study. The expression of Prox1 and Notch1 mRNA and protein in RB cells was detected using quantitative real time-polymerase chain reaction (RT-qPCR) and Western blotting. Cell proliferation was assessed after Prox1 overexpression using the Cell Counting Kit-8 and the MTS assay. Drug-resistant cell lines (SO-RB50/vincristine) were generated and treated with Prox1 to investigate the role of Prox1 in drug resistance. We employed pcDNA-Notch1 to overexpress Notch1 to confirm the role of Notch1 in the protective function of Prox1. Finally, a xenograft model was constructed to assess the effect of Prox1 on RB in vivo. RESULTS: Prox1 was significantly downregulated in RB cells. Overexpression of Prox1 effectively decreased RB cell growth while increasing the sensitivity of drug-resistant cells to vincristine. Notch1 was involved in Prox1's regulatory effects. Notch1 was identified as a target gene of Prox1, which was found to be upregulated in RB cells and repressed by increased Prox1 expression. When pcDNA-Notch1 was transfected, the effect of Prox1 overexpression on RB was removed. Furthermore, by downregulating Notch1, Prox1 overexpression slowed tumor development and increased vincristine sensitivity in vivo. CONCLUSION: These data show that Prox1 decreased RB cell proliferation and drug resistance by targeting Notch1, implying that Prox1 could be a potential therapeutic target for RB.

Diagnosis, testing, treatment, and outcomes among patients with advanced non-small cell lung cancer in the United States.

INTRODUCTION: Characteristics of patients in clinical trials may differ from those of real-world patients. Our objective was to describe biomarker testing and outcomes among patients with advanced non-small cell lung cancer (aNSCLC) in a real-world setting. METHODS: This retrospective cohort study included patients ≥18 years old, diagnosed with stage IIIB/C or IV NSCLC, and in the TEMPUS oncology dataset from January 1, 2012, to December 31, 2020. Patient characteristics associated with biomarker testing were evaluated in patients with positive biomarkers using univariate logistic regression models. Cox proportional hazard models were used to estimate median survival. RESULTS: Of 9540 patients included, 41.7% had biomarker testing, and 2158 had a positive biomarker result. Men (vs women; odds ratio [OR], 0.82; 95% CI: 0.74-0.91), Black patients (vs White; OR, 0.83; 95% CI: 0.72-0.97), patients with squamous (OR, 0.22; 95% CI: 0.19-0.25) or unknown histology (OR, 0.53; 95% CI: 0.45-0.61) (vs non-squamous histology), and patients with an Eastern Cooperative Oncology Group performance status (ECOG PS) of 2+ (OR, 0.69; 95% CI: 0.57-0.84) or missing (OR, 0.56; 95% CI: 0.48-0.66) (vs ECOG PS of 0) were less likely to undergo biomarker testing. Patients with positive biomarkers who received NCCN-recommended treatment options (55.7%) had significantly longer median overall survival (OS) (hazard ratio [HR], 0.84; 95% CI: 0.75-0.95) and real-world progression-free survival (rwPFS) (HR, 0.68; 95% CI: 0.62-0.75). CONCLUSION: More than 50% of patients were untested for biomarkers. Patients who were less likely to be tested included men, Black patients, current smokers, patients with squamous aNSCLC, and patients with an ECOG PS of 2+. Patients with positive biomarkers who received NCCN-recommended treatment options had significantly longer OS and PFS.

Identification of the Shared Gene Signatures of HCK, NOG, RNF125 and Biological Mechanism in Pediatric Acute Lymphoblastic Leukaemia and Pediatric Sepsis.

The shared mechanisms between pediatric acute lymphoblastic leukaemia (ALL) and pediatric sepsis are currently unclear. This study was aimed to explore the shared key genes of pediatric ALL and pediatric sepsis. The datasets involved were downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) between disease and control samples in GSE13904 and GSE79533 were intersected. The least absolute shrinkage and selection operator (LASSO) and the boruta analyses were performed in GSE13904 and GSE79533 separately based on shared DEGs, and shared key genes were obtained by taking the intersection of sepsis-related key genes and ALL-related key genes. Three shared key genes (HCK, NOG, RNF125) were obtained, that have a good diagnostic value for both sepsis and ALL. The correlation between shared key genes and differentially expressed immune cells was higher in GSE13904 and conversely, the correlation of which was lower in GSE79533. Suggesting that the sharing key genes had a different impact on the immune environment in pediatric ALL and pediatric sepsis. We make the case that this study provides a new perspective to study the relationship between pediatric ALL and pediatric sepsis.

Lycorine eliminates B-cell acute lymphoblastic leukemia cells by targeting PSAT1 through the serine/glycine metabolic pathway.

B-cell acute lymphoblastic leukemia (B-ALL) has been confirmed as the most common malignant hematologic neoplasm among children. A novel antitumor mechanism of lycorine was elucidated in this study. As revealed by the result of this study, lycorine significantly inhibited the growth and proliferation of REH and NALM-6 and induced their apoptosis. The result of the RNA-seq analysis suggested that lycorine targeted PSAT1 of serine/glycine metabolism in B-ALL cells. As indicated by the result of the GSEA analysis, the genes enriched in the amino acid metabolic pathways were down-regulated by lycorine. As revealed by the results of ectopic expression, shRNA knockdown assays, and further liquid-phase tandem mass spectrometry (LC-MS) analysis, lycorine reduced serine/glycine metabolites by down-regulating PSAT1, further disrupting carbon metabolism and eliminating B-ALL cells. Furthermore, lycorine showed a synergistic effect with cytarabine in ALL treatments. Lastly, lycorine significantly down-regulated leukemia progression in the cell line-derived xenograft (CDX) model. In brief, this study has suggested for the first time that lycorine is a promising anti-ALL drug, and a novel amino acid metabolism-associated property of lycorine was identified.

Harnessing Nuclear Energy to Gold Nanoparticles for the Concurrent Chemoradiotherapy of Glioblastoma.

Nuclear fission reactions can release massive amounts of energy accompanied by neutrons and γ photons, which create a mixed radiation field and enable a series of reactions in nuclear reactors. This study demonstrates a one-pot/one-step approach to synthesizing radioactive gold nanoparticles (RGNP) without using radioactive precursors and reducing agents. Trivalent gold ions are reduced into gold nanoparticles (8.6-146 nm), and a particular portion of 197Au atoms is simultaneously converted to 198Au atoms, rendering the nanoparticles radioactive. We suggest that harnessing nuclear energy to gold nanoparticles is feasible in the interests of advancing nanotechnology for cancer therapy. A combination of RGNP applied through convection-enhanced delivery (CED) and temozolomide (TMZ) through oral administration demonstrates the synergistic effect in treating glioblastoma-bearing mice. The mean survival for RGNP/TMZ treatment was 68.9 ± 9.7 days compared to that for standalone RGNP (38.4 ± 2.2 days) or TMZ (42.8 ± 2.5 days) therapies. Based on the verification of bioluminescence images, positron emission tomography, and immunohistochemistry inspection, the combination treatment can inhibit the proliferation of glioblastoma, highlighting the niche of concurrent chemoradiotherapy (CCRT) attributed to RGNP and TMZ.

Self-driven immune checkpoint blockade and spatiotemporal-sensitive immune response monitoring in acute myeloid leukemia using an all-in-one turn-on bionanoprobe.

Immune checkpoint (ICP) blockade (ICB) is one of the most promising immunotherapies for acute myeloid leukemia (AML). However, owing to their heterogeneity, AML cells may cause uncoordinated metabolic fluxes and heterogeneous immune responses, inducing the release of a spatiotemporally sensitive immune response marker. Timely and in situ detection of immune responses in ICB therapy is important for therapeutic strategy adjustment. Herein, we constructed an all-in-one nanoprobe for self-driving ICB and simultaneously detecting an immune response in the same AML cell in vivo, thus enabling accurate evaluation of heterogenetic immune responses in living AML mice without additional drug treatment or probe processes. The nature-inspire polydopamine (PDA) nanoparticles loaded with an ICP blocker were targeted to the leukocyte immunoglobulin like receptor B4 (a new ICP) of AML cells to induce the release of immune response marker granzyme B (GrB). The PDA nanoparticles were additionally paired with carbon-derived graphene quantum dots (GQDs) to construct a full-organic 'turn-on' bionanoprobe that can transfer fluorescence resonance energy for GrB detection. This multifunctional nanoprobe was validated for triggering ICB therapy and monitoring the changes of GrB levels in real-time both in vitro and in vivo. The organic nanoprobe showed excellent permeability and retention in tumor cells and high biocompatibility in vivo. This bionanoprobe orderly interacted with the upstream ICP molecules and downstream signal molecule GrB, thereby achieving in situ immune response signals within the therapeutic efficacy evaluation window.

The Mechanics of Tumor Cells Dictate Malignancy via Cytoskeleton-Mediated APC/Wnt/ß-Catenin Signaling.

Tumor cells progressively remodel cytoskeletal structures and reduce cellular stiffness during tumor progression, implicating the correlation between cell mechanics and malignancy. However, the roles of tumor cell cytoskeleton and the mechanics in tumor progression remain incompletely understood. We report that softening/stiffening tumor cells by targeting actomyosin promotes/suppresses self-renewal in vitro and tumorigenic potential in vivo. Weakening/strengthening actin cytoskeleton impairs/reinforces the interaction between adenomatous polyposis coli (APC) and ß-catenin, which facilitates ß-catenin nuclear/cytoplasmic localization. Nuclear ß-catenin binds to the promoter of Oct4, which enhances its transcription that is crucial in sustaining self-renewal and malignancy. These results demonstrate that the mechanics of tumor cells dictate self-renewal through cytoskeleton-APC-Wnt/ß-catenin-Oct4 signaling, which are correlated with tumor differentiation and patient survival. This study unveils an uncovered regulatory role of cell mechanics in self-renewal and malignancy, and identifies tumor cell mechanics as a hallmark not only for cancer diagnosis but also for mechanotargeting.

Revised Thyroid Imaging Reporting and Data System (TIRADS): imitating the American College of Radiology TIRADS, a single-center retrospective study.

Background: The incidence of thyroid lumps is more and more high in population, and most biopsies of thyroid nodules are benign. To develop a practical risk stratification system based on five ultrasound features to stratify the malignancy risk of thyroid neoplasms. Methods: This retrospective investigation enrolled 999 consecutive patients with 1,236 thyroid nodules who underwent ultrasound screening. Fine-needle aspiration and/or surgery was performed, and pathology results were obtained at the Seventh Affiliated Hospital of Sun Yat-sen University in Shenzhen, China, which is a tertiary referral center, from May 2018 to February 2022. Each thyroid nodule's score was calculated based on five ultrasound features: composition, echogenicity, shape, margin, and echogenic foci. Additionally, each nodule's malignancy rate was calculated. The chi-square test was used to test whether the malignancy rate was different among the three subcategories (scores of 4-6, 7-8, and 9 or more) of thyroid nodules. We proposed the revised Thyroid Imaging Reporting and Data System (R-TIRADS), and its sensitivity and specificity were compared to the two existing systems [the American College of Radiology TIRADS (ACR TIRADS) and the Korean Society of Thyroid Radiology TIRADS (K-TIRADS)]. Results: The final dataset consisted of 425 nodules from 370 patients. The malignancy rates of three subcategories [malignancy rate: 28.8% (scores from 4-6), 64.7% (scores from 7-8), and 84.2% (scores of 9 or more)] were significantly different (P<0.01). The unnecessary biopsy rates of the three systems (ACR TIRADS, R-TIRADS, and K-TIRADS) were 28.7%, 25.2%, and 14.8%, respectively. The R-TIRADS presented better diagnostic performance than the ACR TIRADS or K-TIRADS [area under the curve: 0.79 (95% CI: 0.74-0.83) vs. 0.69 (95% CI: 0.64-0.75), P=0.046; 0.79 (95% CI: 0.74-0.83) vs. 0.66 (95% CI: 0.60-0.71), P=0.041, respectively]. The R-TIRADS had the highest sensitivity [0.746 (95% CI: 0.689-0.803)], followed by the K-TIRADS [0.399 (95% CI: 0.335-0.463), P=0.000] and ACR TIRADS [0.377 (95% CI: 0.314-0.441), P=0.000]. Conclusions: The R-TIRADS enables radiologists to diagnose thyroid nodules efficiently, and the number of unnecessary fine-needle aspirations can be considerably reduced.

SCARNA10 regulates p53 acetylation-dependent transcriptional activity.

The tumor suppressor p53 is involved in variety of cell progresses including cell cycle arrest, apoptosis, DNA repair, senescence, cell metabolism and ferroptosis. Here, we identified lncRNA SCARNA10 (Small Cajal Body-Specific RNA 10) as a novel cellular factor that interacts with the DNA binding domain (DBD) of p53. Upon binding the DBD of p53 and CREB-binding protein (CBP), SCARNA10 promotes the acetylation of p53, and activates p53-mediated transcriptional activation. Overexpress or knockdown SCARNA10 leads to up (or down)-regulation of p53-mediated transcriptional activation, whereas not affecting p53 protein levels. Moreover, SCARNA10 directly activates transcription by increasing the acetylation of p53 C-terminal domain (CTD) without affecting p53 phosphorylation at Ser15. These results indicate that SCARNA10 is a novel factor which regulates p53 acetylation-dependent transcriptional activity and tumor suppression.

Smart Design of Nanostructures for Boosting Tumor Immunogenicity in Cancer Immunotherapy.

Although tumor immunotherapy has emerged as a promising therapeutic method for oncology, it encounters several limitations, especially concerning low response rates and potential off-targets that elicit side effects. Furthermore, tumor immunogenicity is the critical factor that predicts the success rate of immunotherapy, which can be boosted by the application of nanotechnology. Herein, we introduce the current approach of cancer immunotherapy and its challenges and the general methods to enhance tumor immunogenicity. Importantly, this review highlights the integration of anticancer chemo/immuno-based drugs with multifunctional nanomedicines that possess imaging modality to determine tumor location and can respond to stimuli, such as light, pH, magnetic field, or metabolic changes, to trigger chemotherapy, phototherapy, radiotherapy, or catalytic therapy to upregulate tumor immunogenicity. This promotion rouses immunological memory, such as enhanced immunogenic cell death, promoted maturation of dendritic cells, and activation of tumor-specific T cells against cancer. Finally, we express the related challenges and personal perspectives of bioengineered nanomaterials for future cancer immunotherapy.

Mitochondrial energy metabolism is downregulated in repeated implantation failure patients related to alteration of PGC-1α acetylation level.

Herein we aimed at exploring mitochondrial energy metabolism status in patients with repeated implantation failure (RIF) and whether key regulatory factor PGC-1α of energy metabolism is involved in the decidualization of endometrial stromal cells. Mitochondrial oxidative phosphorylation level and ATP synthesis were compared in primary endometrial stromal cells from RIF and control group. At the same time, as one of key transcription regulators of mitochondrial energy metabolism, the expression level and acetylation level of PGC-1α were compared with two groups. Then, we downregulated the acetylation levels of PGC-1α, and the expression of decidual markers (PRL and IGFBP1) was observed further. Mitochondrial energy metabolism, showing by mitochondrial oxidative phosphorylation level and ATP synthesis, was decreased in the endometrial stromal cells of the RIF group (RIF-hEnSCs). Meanwhile, PGC-1α acetylation levels were significantly higher in RIF-hEnSCs. When we reduced the acetylation levels of PGC-1α in RIF-hEnSCs, the basal O2 consumption rate and maximal respiration were increased, and also the PRL and IGFBP1. Overall, our data indicated that the endometrial stromal cells of the RIF patients had low level of mitochondrial energy metabolism. Reducing acetylation level of key energy metabolism regulator PGC-1α can increase the decidualization level of RIF-hEnSCs. These findings may inspire new ideas about the treatment of RIF.

ACT001 Relieves NMOSD Symptoms by Reducing Astrocyte Damage with an Autoimmune Antibody.

Neuromyelitis optica spectrum disorder (NMOSD) is a central nervous system inflammatory demyelinating disease, the pathogenesis of which involves autoantibodies targeting the extracellular epitopes of aquaporin-4 on astrocytes. We neutralized the AQP4-IgG from NMOSD patient sera using synthesized AQP4 extracellular epitope peptides and found that the severe cytotoxicity produced by aquaporin-4 immunoglobin (AQP4-IgG) could be blocked by AQP4 extracellular mimotope peptides of Loop A and Loop C in astrocyte protection and animal models. ACT001, a natural compound derivative, has shown anti-tumor activity in various cancers. In our study, the central nervous system anti-inflammatory effect of ACT001 was investigated. The results demonstrated the superior astrocyte protection activity of ACT001 at 10 µM. Furthermore, ACT001 decreases the behavioral score in the mouse NMOSD model, which was not inferior to Methylprednisolone Sodium Succinate, the first-line therapy of NMOSD in clinical practice. In summary, our study showed that astrocytes are protected by specific peptides, or small molecular drugs, which is a new strategy for the treatment of NMOSD. It is possible for ACT001 to be a promising therapy for NMOSD.

Single-Cell RNA-Seq Analysis Reveals Macrophages Are Involved in the Pathogenesis of Human Sporadic Acute Type A Aortic Dissection.

Macrophages play an important role in the progression of sporadic acute type A aortic dissection (ATAAD). The aim of this study was to characterize the cellular heterogeneity of macrophages in ATAAD tissues by scRNA-seq. Ascending aortic wall tissue from six ATAAD patients and three heart transplant donors was assessed by scRNA-seq and then analyzed and validated by various bioinformatic algorithms and histopathology experiments. The results revealed that the proportion of macrophages in ATAAD tissues (24.51%) was significantly higher than that in normal tissues (13.69%). Among the six macrophage subclusters, pro-inflammatory macrophages accounted for 14.96% of macrophages in the AD group and 0.18% in the normal group. Chemokine- and inflammation-related genes (CCL2, CCL20, S100A8, and S100A9) were expressed more intensively in macrophages in ATAAD tissue than in those in normal tissue. Additionally, intercellular communication analysis and transcription factor analysis indicated the activation of inflammation and degradation of the extracellular matrix in ATAAD tissue. Finally, immunohistochemistry, immunofluorescence, and Western blot experiments confirmed the overexpression of macrophage marker genes (CD68 and CD163) and matrix metalloproteinases (MMP9 and MMP2) in ATAAD tissue. Collectively, our study provides a preliminary evaluation of the role of macrophages in ATAAD, and the results could aid in the development of therapeutic options in the future.

Gastric cancer clinical characteristics and their altered trends in South China: An epidemiological study with 2,800 cases spanning 26 years.

Background: Gastric cancer (GC) is a serious threat to human health. The clinical GC characteristics in China may be impacted by changes in people's lifestyles and the promotion of early GC (EGC) screening. The present study aims to evaluate the recent trends of GC characteristics in South China and search for hazardous factors limiting the survival time of GC patients. Methods: Data on GC patients that were hospitalized in the Department of Digestive Center, the First Affiliated Hospital, Sun Yat-sen University, from 1994 to 2019 were collected and divided into two categories according to the time when the EGC screening began in China: the PRE group (previous 13 years, 1994-2006) and the PAS group (past 13 years, 2007-2019). Results: We found that, although the 5-year survival rate increased in the PAS group compared with the PRE group (P < 0.0001), patients with age ≥60 years or Borrmann type IV still had a worse prognosis. In the PAS group, the larger percentages of elderly patients and patients with Borrmann type IV in the lymphatic metastases (N1) group (41.0% vs. 51.1%, P = 0.0014) and stage IV subgroup (20.7% vs. 32.2%, P = 0.016), respectively, when compared with the PRE group, may have contributed to the poor outcome of GC. By comparing the odds ratio (OR) of 5-year overall survival (OS) in the two 13-year periods, female sex and T2 turned into risk factors because of a greater proportion of Borrmann type IV or elderly patients in the PAS group (OR = 0.983, 95% CI = 0.723-1.336 vs. OR = 1.277, 95% CI = 1.028-1.586 and OR = 1.545, 95% CI = 0.499-4.775 vs. OR = 2.227, 95% CI = 1.124-4.271, respectively). Conclusions: Despite the GC epidemiology changes, the overall prognosis of GC patients has improved in South China. However, old age and Borrmann type IV are still the major restrictions affecting the survival of GC patients, a situation which calls for additional attention.

BSA-templated synthesis of Ir/Gd bimetallic oxide nanotheranostics for MR/CT imaging-guided photothermal and photodynamic synergistic therapy.

Precision medicine urges the development of theranostics which can efficiently integrate precise diagnosis and effective therapy. In this study, a facile synthesis of Ir/Gd bimetallic oxide nanotheranostics (termed BSA@Gd2O3/IrO2 NPs) with good biocompatibility was demonstrated using a biomineralization method where bovine serum albumin (BSA) served as a versatile template. BSA@Gd2O3/IrO2 NPs exhibited high longitudinal relaxivity (5.2 mM-1 s-1) and X-ray absorption capability (14.5 Hu mM-1), illustrating them to be a good contrast agent for magnetic resonance (MR) and computed tomography (CT) dual-modal imaging. Moreover, BSA@Gd2O3/IrO2 NPs can act as not only a photothermal conversion agent with ultrahigh efficiency (66.7%) as well as a good photosensitizer, but also an effective catalase to decompose endogenous H2O2 to produce O2, thus relieving hypoxia and enhancing the phototherapeutic effect. Both in vitro and in vivo experiments demonstrated the high effectiveness of BSA@Gd2O3/IrO2 NPs in MR/CT dual-modal imaging and photothermal and photodynamic synergistic tumor treatments. This work sheds new light on the development of versatile nanotheranostic systems using mild and robust biomineralization methods.

The heat shock protein DNAJB2 as a novel biomarker for essential thrombocythemia diagnosis associated with immune infiltration.

BACKGROUND AND OBJECTIVE: Essential thrombocythemia (ET) is a rare myeloproliferative malignancy which may lead to severe thrombohemorrhagic complications. The diagnosis of ET is primarily based on bone marrow morphology and exclusion of other possibilities of myeloproliferative neoplastic diseases; the lack of gene biomarkers fails to provide a prompt diagnosis of ET. Therefore, this study was designed to identify biomarkers for early ET diagnosis, especially that associated with immune cell infiltration, by using the Gene Expression Omnibus (GEO) database and machine-learning algorithms. METHODS: Two publicly available gene expression profiles (GSE9827 and GSE123732) from the GEO database were used to identify the differentially expressed genes (DEGs) between bone marrow samples of ET patients and healthy individuals, and functional enrichment analyses were conducted. The least absolute shrinkage and selection operator (LASSO) regression model and Support Vector Machine-Recursive Feature Elimination (SVM-RFE) machine-learning algorithm were performed to select the candidate gene biomarker. The expression level and diagnostic effectiveness of the identified gene biomarker were further validated using GSE567 and GSE2006 datasets. The involvement of infiltrating immune cells and their correlations with the gene biomarker were examined using cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT) algorithm. RESULTS: There were 105 DEGs identified between ET and healthy control samples. Disease Ontology (DO) analysis showed that the diseases enriched by those DEGs were mainly human cancers, neurological diseases and inflammation while Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis demonstrated that pathways related to immune responses were primarily involved. The heat shock protein, DNAJB2, was identified as the potential biomarker for ET diagnosis with high effectiveness, with the area under the receiver operating characteristic (ROC) curve (AUC) equals to 0.905 in the validation cohort. The expression level of DNAJB2 in ET samples was indeed significantly higher than that in healthy control ones. The immune cell infiltration analysis showed that DNAJB2 was positively correlated with CD8+ T cells in ET with the proportion significantly higher than that in normal controls. CONCLUSION: The present study identified DNAJB2 as a novel diagnostic biomarker for ET with high effectiveness based on ET and normal samples from the GEO database, which provides new insights into predicting ET with accuracy and promptness in clinical practice.