The αPD-L1 antibody-based immune checkpoint blockade therapy is still limited by the poor clinical response rate as it is mainly utilized to block surface PD-L1 on tumor cells while ignoring abundant PD-L1 exosomes secreted in the environment, causing tumor immune evasion. Here, we proposed an exosome biogenesis inhibition strategy to suppress tumor exosomes secretion from the source, reducing the inhibitory effect on T cells and enhancing chemo-immunotherapy efficacy. We developed sulfafurazole homodimers (SAS) with disulfide linkages, effectively releasing the drug in response to glutathione (GSH) and inhibiting 4T1 tumor-derived exosomes secretion. Subsequently, gemcitabine (Gem) was encapsulated to induce immunogenic cell death (ICD). Consequently, Gem@SAS inhibited the secretion of tumor exosomes by more than 70%, increased proliferation and granzyme B secretion ability of T cells by more than 2 times, and showed superior efficacy in breast cancer treatment as well as lung metastasis of breast cancer.

Chemotherapy-induced peripheral neurotoxicity (CIPN) is a severe dose-limiting adverse event of chemotherapy. Presently, the mechanism underlying the induction of CIPN remains unclear, and no effective treatment is available. In this study, through metabolomics analyses, we found that nab-paclitaxel therapy markedly increased serum serotonin [5-hydroxtryptamine (5-HT)] levels in both cancer patients and mice compared to the respective controls. Furthermore, nab-paclitaxel-treated enterochromaffin (EC) cells showed increased 5-HT synthesis, and serotonin-treated Schwann cells showed damage, as indicated by the activation of CREB3L3/MMP3/FAS signaling. Venlafaxine, an inhibitor of serotonin and norepinephrine reuptake, was found to protect against nerve injury by suppressing the activation of CREB3L3/MMP3/FAS signaling in Schwann cells. Remarkably, venlafaxine was found to significantly alleviate nab-paclitaxel-induced CIPN in patients without affecting the clinical efficacy of chemotherapy. In summary, our study reveals that EC cell-derived 5-HT plays a critical role in nab-paclitaxel-related neurotoxic lesions, and venlafaxine co-administration represents a novel approach to treating chronic cumulative neurotoxicity commonly reported in nab-paclitaxel-based chemotherapy.
Paclitaxel/toxicity* ; Animals ; Albumins/adverse effects* ; Serotonin/metabolism* ; Mice ; Humans ; Male ; Female ; Venlafaxine Hydrochloride/therapeutic use* ; Neurotoxicity Syndromes/metabolism* ; Middle Aged ; Schwann Cells/metabolism* ; Peripheral Nervous System Diseases/drug therapy* ; Antineoplastic Agents

Objective:To investigate the clinicopathological, immunohistochemical, and molecular genetic characteristics of microsecretory adenocarcinoma (MSA) of the salivary gland, and to improve the understanding of this rare tumor.Methods:Cases originally diagnosed as MSA at the Department of Oral Pathology, the Ninth People′s Hospital of Shanghai Jiao Tong University School of Medicine were retrospectively collected. The cases of polymorphous adenocarcinoma and adenocarcinoma, not otherwise specified from January 2000 to January 2020 were reviewed to identify potential misdiagnosed MSA cases. Clinicopathological analysis and follow-up of all confirmed MSA cases were performed, and relevant literature was reviewed.Results:A total of 4 MSA cases were identified, including 2 screened from the polymorphous adenocarcinoma cohort. Of the 4 MSA patients, 3 were male and 1 was female, with an average age of 53 years (range, 37-67 years). Three cases occurred in the palate, and one in the buccal region. The clinical manifestation was usually a slow-growing painless mass. Tumors were generally small, with a maximum diameter ranging from 0.7 to 1.8 cm (average, 1.2 cm). Microscopically, the tumor was unencapsulated and showed an infiltrative growth pattern. The tumor cells appeared small in size and showed bland, cubic and flattened cytological features, forming microcystic lumens and glandular tubes. Significant basophilic secretions were seen in the lumens. Between the tumor nests there was fibro-myxoid stroma. Immunohistochemistry showed diffusely or partially positive staining for cytokeratin 7, S-100, SOX-10, p63 and vimentin and negative staining for p40, mammaglobin, and calponin. The proliferation index of Ki-67 was relatively low (1%-3%). Four MSA cases all harbored SS18 gene rearrangement as shown by fluorescence in situ hybridization (FISH), including 2 cases with MEF2C::SS18 fusion gene through RNA-targeted next generation sequencing. All 4 patients underwent surgical resection without any adjuvant treatments. Three patients were followed up for a period of 2 to 203 months. No tumor recurrence, metastasis, or disease-related death was found.Conclusions:Salivary gland MSA is a novel and rare low-grade carcinoma with unique and consistent histological morphology, immunophenotype, and molecular changes. Immunohistochemical staining and SS18 break apart FISH are useful for the diagnosis of the tumor with atypical morphology and high-grade transformation.

Objective:To identify early diagnostic biomarkers for preeclampsia by analyzing the placental and peripheral circulatory transcriptomic data of patients.Methods:Clinical information and microarray expression profiles of preeclampsia patients were sourced from high-throughput gene expression databases. Multi-omics approaches, including differential gene expression analysis, enrichment analysis, and weighted gene co-expression network analysis (WGCNA), were utilized to identify candidate diagnostic markers and explore potential mechanisms of preeclampsia. Subsequently, a combination of machine learning techniques, including random forest, support vector machine, and least absolute shrinkage and selection operator (LASSO), were employed for further screening of these candidates. Finally, the selected diagnostic markers were validated using a peripheral circulation dataset.Results:Differential gene expression analysis revealed 71 upregulated and 21 downregulated genes in preeclampsia. WGCNA linked the onset of preeclampsia with blue and teal modules. Enrichment analysis of candidate biomarkers suggested changes in cell cycle, cellular senescence, and immune-related pathways as primary drivers of preeclampsia. Further refinement through machine learning identified significant upregulation of COL17A1 and DIO2 genes in the peripheral blood of patients, demonstrating robust diagnostic potential. Conclusions:COL17A1 and DIO2 genes can be used as peripheral circulating diagnostic markers for the early diagnosis of eclampsia.

  Objective  To establish a prediction model for non-curative resection in patients with early gastric cancer (EGC) who underwent endoscopic submucosal dissection (ESD), and to evaluate its predictive value.  Methods  Clinical data of EGC patients in the Second Hospital & Clinical Medical School, Lanzhou University from January 2014 to July 2023 were retrospectively collected. According to the postoperative pathological results of ESD, the patients were divided into curative resection group and non-curative resection group. Multifactorial Logistic regression analysis was used to screen the risk factors for non-curative resection after ESD surgery and establish a prediction model, and the model was evaluated using receiver operating characteristic(ROC) curves, calibration curves and clinical decision curve analysis.  Results  A total of 479 EGC patients who underwent ESD were included, with 60 cases in the non-curative resection group and 419 cases in the curative resection group. The results of multifactorial Logistic regression analysis showed that the lesion diameter > 2 cm (OR=3.017, 95% CI: 1.483-6.136, P=0.002), flat lesion morphology (OR=2.712, 95% CI: 0.774-9.497, P=0.043), undifferentiated/mixed histologic type (OR= 4.199, 95% CI: 1.621-10.872, P=0.003), and submucosal infiltration (OR=30.329, 95% CI: 13.059-70.436, P < 0.001) were independent risk factors for non-curative resection after ESD in EGC patients. The area under the curve of ROC validated within the column-line graph prediction model constructed accordingly was 0.867 (95% CI: 0.811-0.923), the calibration curve showed that the model had good calibration, and decision curve analysis showed the model had a good clinical usefulness.  Conclusions  The prediction model constructed based on lesion diameter, lesion morphology, histologic type, and depth of mucosal infiltration has good differentiation, calibration, and clinical utility. This model is expected to assist in the early clinical screening of the population at high risk for noncurative resection after ESD in patients with EGC, and to provide a basis for the development of optimal clinical decisions.

Systemic lupus erythematosus (SLE) shows a significant gender difference. In addition to X chromosome inactivation (XCI) abnormalities, which may lead to the gender difference in SLE, studies have found that estrogen plays a key role in regulating Th17/Treg immune balance in SLE. Estrogen indirectly affects the quantity and function of Th17 and Treg cells by acting on B cells. In this process, the mutual influence and the interaction between B and T cells promote the development of SLE. Recent studies have reported gender differences in intestinal microbiota, which may lead to sex-dependent genetic susceptibility and epigenetic changes in autoimmune diseases represented by SLE. The interaction between estrogen and intestinal microbiota in SLE affects the immune balance of Th17/Treg cells. This paper mainly reviews the way estrogen works, and the mechanisms by which estrogen regulates Th17/Treg immune balance and the interaction between B and T cells in SLE, hoping to provide new targets for new therapeutic strategies such as selective estrogen receptor modulators.

Cyclic GMP-AMP synthase (cGAS)-stimulator of interferon gene (STING) pathway, as an important part of the innate immune system, is the main pathway for cytoplasmic DNA recognition and cGAS can be triggered by a variety of cytoplasmic dsDNA. This pathway has become an important bridge connecting autoimmunity, aseptic inflammatory response and cell aging. In recent years, cGAS-STING pathway has attracted increasing attention in autoimmune diseases. In rheumatoid arthritis (RA), neutrophil extracellular traps (NETs) induce typeⅠ interferon response and accelerate the production of anti-citrullinated peptide antibody (ACPA) through the cGAS-STING pathway. In addition, the cGAS-STING pathway also participates in synovitis, bone destruction and RA progression by promoting the proliferation and activation of fibroblast-like synovitis cells and the polarization of M1 macrophages. Inhibition of the cGAS-STING pathway or its downstream signaling pathway can reduce synovial inflammation in RA, suggesting that cGAS-STING pathway may be a potential therapeutic target for RA.

This paper introduces the concept of natural language processing, summarizes the status quo and advantages of the application of natural language processing based on electronic health records in symptom management of cancer patients, points out the existing shortcomings, and puts forward corresponding suggestions, aiming to provide reference for further improving the quality of nursing services for cancer patients in China and promoting the informatization and digitization of hospice care.

Objective:To investigate the relationship between long non-coding RNA (lncRNA) DHRS4-AS1 and disease-free survival in osteosarcoma patients and the mechanisms of its effect on proliferation and migration of osteosarcoma cells in vitro.Methods:The data of DHRS4-AS1 transcriptome levels and survival status of osteosarcoma patients in GEPIA database were collected since the database was established, and the patients were divided into high DHRS4-AS1 expression group and low DHRS4-AS1 expression group based on the median DHRS4-AS1 transcriptome level, with 59 cases in each group, and the Kaplan-Meier method was used to analyze the disease-free survival of the two groups. Real-time fluorescence quantitative polymerase chain reaction (qRT-PCR) was used to detect the expression of DHRS4-AS1 in osteosarcoma cell lines MG-63, HOS, 143B, U-2OS, Saos2 and normal osteoblast cell line hFOB1.19, and the osteosarcoma cell line with the lowest DHRS4-AS1 expression level was selected for subsequent experiments. The plasmid carrying DHRS4-AS1 sequence and the plasmid carrying negative control sequence were transfected into the selected osteosarcoma cells as DHRS4-AS1 group and control group. CCK-8 method was used to detect the proliferation of each group of cells, and the absorbance value was used as the cell proliferation ability; cell scratch assay was used to detect the migration of each group of cells. The bioinformatics website starBase V2.0 was used to predict the target genes of DHRS4-AS1, and the dual luciferase reporter gene assay was used to verify the targeting relationship between DHRS4-AS1 and the target genes. The expression levels of target genes and downstream genes of osteosarcoma cells in control group and DHRS4-AS1 group were detected by qRT-PCR and Western blotting.Results:Survival analysis showed that the disease-free survival of osteosarcoma patients in the high DHRS4-AS1 expression group in GEPIA database was superior to that of the low DHRS4-AS1 expression group ( P < 0.001). Compared with normal osteoblastic hFOB1.19 cells, the expression level of DHRS4-AS1 was low in all osteosarcoma cells (all P < 0.01), with the lowest expression level of DHRS4-AS1 in U-2OS cells ( P < 0.001). Cell proliferation ability was reduced in U-2OS cells of the DHRS4-AS1 group after 1, 2, 3 and 4 d of culture compared with the control group (all P < 0.05). The migration rate of U-2OS cells in the DHRS4-AS1 group was lower than that in the control group [(31±6)% vs. (63±4)%, t = 4.38, P = 0.005]. starBase V2.0 website predicted that DHRS4-AS1 complementarily bound to miRNA-411-3p (miR-411-3p); dual luciferase reporter gene assay showed that miR-411-3p overexpression reduced the luciferase activity of the wild-type DHRS4-AS1 reporter gene ( P < 0.001), but had no effect on the luciferase activity of the mutant DHRS4-AS1 reporter gene ( P > 0.05). qRT-PCR showed that the relative expression of miR-411-3p in U-2OS cells of the DHRS4-AS1 group was low (0.22±0.06 vs. 1.06±0.23, t = 3.55, P = 0.012) and the relative expression of metastasis suppressor MTSS1 mRNA was high (5.58±1.03 vs. 1.06±0.22, t = 4.28, P = 0.005) compared with the control group; Western blotting showed that MTSS1 expression was elevated, and the expression levels of cell proliferation phenotype proteins CDK3 and cyclin C and cell migration phenotype proteins ZEB2 and KLF8 were low. Conclusions:Osteosarcoma patients with high expression of lncRNA DHRS4-AS1 have better disease-free survival, and its expression is low in osteosarcoma cell lines. DHRS4-AS1 may promote MTSS1 gene expression and inhibit cell proliferation and migration by targeting and down-regulating miR-411-3p expression in osteosarcoma cells.

Objective:To analyze the clinicopathological characteristics of IgG4-related sialadenitis (IgG4-RS).Methods:A total of 40 cases diagnosed with IgG4-RS were collected from the Department of Oral Pathology, Shanghai Ninth People′s Hospital, Shanghai Jiao Tong University School of Medicine from January 2019 to December 2022. Among them, there were 26 males and 14 females. The age range was 29-77 years old [(59.4±11.8) years old], with 23 patients being older than 60 years. The lesion site, imaging manifestations, histopathological features, serological test and treatment information of patients were collected. The expression of IgG4 and IgG proteins was detected by immunohistochemistry.Results:Submandibular region swelling was the most common initial symptom of IgG4-RS (38/40, 95.0%). All the patients having serum IgG4 levels> 1.35 g/L. Serum IgG4 levels were significantly increased in patients aged>60 years ( Z=-2.45, P=0.014) and those involving multiple glands ( Z=-2.04, P=0.042). Thirty six cases received major salivary gland biopsy, and all the cases showed dense lymphocyte and plasma cell infiltration. Lymphoid follicle, storiform fibrosis and obliterative phlebitis were seen in 88.9% (32/36), 63.9% (23/36), 30.6% (11/36) of the cases, respectively. Twenty one cases received labial salivary gland biopsy, 66.7% (14/21) showed lymphocyte and plasma cell infiltration, 19.0% (4/21) had lymphoid follicle structures, and 33.3% (7/21) showed no obvious histological abnormalities. No signs of fibrosis or obliterative phlebitis were observed in all labial salivary gland biopsies. And 95.0% (38/40) of cases had IgG4 positive plasma cell>10/HPF, 82.5% (33/40) of cases had IgG4/IgG positive plasma cell ratio>40%. All the patients had a decrease in serum IgG4 levels after glucocorticoid treatment, but only 21.4% (6/28) of cases had reduced to normal levels (≤1.35 g/L), and there were still significant fluctuations in serum IgG4 levels thereafter. Conclusions:IgG4-RS has a predilection for middle-aged and elderly male patients, and serum IgG4 levels are significantly related to the patient′s age and whether multiple glands are involved. Labial salivary gland biopsy cannot replace submandibular gland for histopathological evaluation. It is a common phenomenon that serum IgG4 levels cannot restored to normal levels after glucocorticoid treatment. This study provides certain assistance for clinical and pathological diagnosis of IgG4-RS. This study is beneficial for further understanding IgG4-RS and improving the clinical and pathological diagnosis of the disease.