Inetetamab combined with tegafur as second-line treatment for human epidermal growth factor receptor-2-positive gastric cancer: A case report.

BACKGROUND: Human epidermal growth factor receptor-2 (HER-2) plays a vital role in tumor cell proliferation and metastasis. However, the prognosis of HER2-positive gastric cancer is poor. Inetetamab, a novel anti-HER2 targeting drug independently developed in China, exhibits more potent antibody-dependent cell-mediated cytotoxicity than trastuzumab, which is administered as the first-line treatment for HER2-positive gastric cancer in combination with chemotherapy. In this case, the efficacy and safety of inetetamab combined with tegafur was investigated as a second-line treatment for HER2-positive gastric cancer. CASE SUMMARY: A 52-year-old male patient with HER2-positive gastric cancer presented with abdominal distension, poor appetite, and fatigue two years after receiving six cycles of oxaliplatin combined with tegafur as first-line treatment after surgery, followed by tegafur monotherapy for six months. The patient was diagnosed with postoperative recurrence of gastric adenocarcinoma. He received 17 cycles of a combination of inetetamab, an innovative domestically developed anti-HER2 monoclonal antibody, and tegafur chemotherapy as the second-line treatment (inetetamab 200 mg on day 1, every 3 wk combined with tegafur twice daily on days 1-14, every 3 wk). Evaluation of the efficacy of the second-line treatment revealed that the patient achieved a stable condition and progression-free survival of 17 months. He tolerated the treatment well without exhibiting any grade 3-4 adverse events. CONCLUSION: Inetetamab combined with chemotherapy for the treatment of metastatic HER2-positive gastric cancer demonstrates significant survival benefits and acceptable safety.

Integrative scATAC-seq and scRNA-seq analyses map thymic iNKT cell development and identify Cbfß for its commitment.

Unlike conventional αßT cells, invariant natural killer T (iNKT) cells complete their terminal differentiation to functional iNKT1/2/17 cells in the thymus. However, underlying molecular programs that guide iNKT subset differentiation remain unclear. Here, we profiled the transcriptomes of over 17,000 iNKT cells and the chromatin accessibility states of over 39,000 iNKT cells across four thymic iNKT developmental stages using single-cell RNA sequencing (scRNA-seq) and single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq) to define their developmental trajectories. Our study discovered novel features for iNKT precursors and different iNKT subsets and indicated that iNKT2 and iNKT17 lineage commitment may occur as early as stage 0 (ST0) by two distinct programs, while iNKT1 commitments may occur post ST0. Both iNKT1 and iNKT2 cells exhibit extensive phenotypic and functional heterogeneity, while iNKT17 cells are relatively homogenous. Furthermore, we identified that a novel transcription factor, Cbfß, was highly expressed in iNKT progenitor commitment checkpoint, which showed a similar expression trajectory with other known transcription factors for iNKT cells development, Zbtb16 and Egr2, and could direct iNKT cells fate and drive their effector phenotype differentiation. Conditional deletion of Cbfß blocked early iNKT cell development and led to severe impairment of iNKT1/2/17 cell differentiation. Overall, our findings uncovered distinct iNKT developmental programs as well as their cellular heterogeneity, and identified a novel transcription factor Cbfß as a key regulator for early iNKT cell commitment.

scRNA-Seq and imaging mass cytometry analyses unveil iNKT cells-mediated anti-tumor immunity in pancreatic cancer liver metastasis.

Invariant natural killer T (iNKT) cells are innate-like T cells that are abundant in liver sinusoids and play a critical role in tumor immunity. However, the role of iNKT cells in pancreatic cancer liver metastasis (PCLM) has not been fully explored. In this study, we employed a hemi-spleen pancreatic tumor cell injection mouse model of PCLM, a model that closely mimics clinical conditions in humans, to explore the role of iNKT cells in PCLM. Activation of iNKT cells with α-galactosylceramide (αGC) markedly increased immune cell infiltration and suppressed PCLM progression. Via single cell RNA sequencing (scRNA-seq) we profiled over 30,000 immune cells from normal liver and PCLM with or without αGC treatment and were able to characterize the global changes of the immune cells in the tumor microenvironment upon αGC treatment, identifying a total of 12 subpopulations. Upon treatment with αGC, scRNA-Seq and flow cytometry analyses revealed increased cytotoxic activity of iNKT/NK cells and skewing CD4 T cells towards a cytotoxic Th1 profile and CD8 T cells towards a cytotoxic profile, characterized by higher proliferation and reduced exhaustion marker PD1 expression. Moreover, αGC treatment excluded tumor associated macrophages. Lastly, imaging mass cytometry analysis uncovered the reduced epithelial to mesenchymal transition related markers and increased active CD4 and CD8 T cells in PCLM with αGC treatment. Overall, our findings uncover the protective function of activated iNKT cells in pancreatic cancer liver metastasis through increased NK and T cell immunity and decreased tumor associated macrophages.

Hippocampal gene expression patterns in Sevoflurane anesthesia associated neurocognitive disorders: A bioinformatic analysis.

Background: Several studies indicate general anesthetics can produce lasting effects on cognitive function. The commonly utilized anesthetic agent Sevoflurane has been implicated in neurodegenerative processes. The present study aimed to identify molecular underpinnings of Sevoflurane anesthesia linked neurocognitive changes by leveraging publically available datasets for bioinformatics analysis. Methods: A Sevoflurane anesthesia related gene expression dataset was obtained. Sevoflurane related genes were obtained from the CTD database. Neurocognitive disorders (NCD) related genes were downloaded from DisGeNET and CTD. Intersecting differentially expressed genes between Sevoflurane and NCD were identified as cross-talk genes. A protein-protein interaction (PPI) network was constructed. Hub genes were selected using LASSO regression. Single sample gene set enrichment analysis; functional network analysis, pathway correlations, composite network analysis and drug sensitivity analysis were performed. Results: Fourteen intersecting cross-talk genes potentially were identified. These were mainly involved in biological processes including peptidyl-serine phosphorylation, cellular response to starvation, and response to gamma radiation, regulation of p53 signaling pathway, AGE-RAGE signaling pathway and FoxO signaling. Egr1 showed a central role in the PPI network. Cdkn1a, Egr1, Gadd45a, Slc2a1, and Slc3a2 were identified as important or hub cross-talk genes. Among the interacting pathways, Interleukin-10 signaling and NF-kappa B signaling enriched among Sevoflurane-related DEGs were highly correlated with HIF-1 signaling enriched in NCD-related genes. Composite network analysis showed Egr1 interacted with AGE-RAGE signaling and Apelin signaling pathways, Cdkn1a, and Gadd45a. Cdkn1a was implicated in in FoxO signaling, PI3K-Akt signaling, ErbB signaling, and Oxytocin signaling pathways, and Gadd45a. Gadd45a was involved in NF-kappa B signaling and FoxO signaling pathways. Drug sensitivity analysis showed Egr1 was highly sensitive to GENIPIN. Conclusion: A suite of bioinformatics analysis revealed several key candidate hippocampal genes and associated functional signaling pathways that could underlie Sevoflurane associated neurodegenerative processes.

Surface translocation of ACE2 and TMPRSS2 upon TLR4/7/8 activation is required for SARS-CoV-2 infection in circulating monocytes.

Infection of human peripheral blood cells by SARS-CoV-2 has been debated because immune cells lack mRNA expression of both angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease type 2 (TMPRSS2). Herein we demonstrate that resting primary monocytes harbor abundant cytoplasmic ACE2 and TMPRSS2 protein and that circulating exosomes contain significant ACE2 protein. Upon ex vivo TLR4/7/8 stimulation, cytoplasmic ACE2 was quickly translocated to the monocyte cell surface independently of ACE2 transcription, while TMPRSS2 surface translocation occurred in conjunction with elevated mRNA expression. The rapid translocation of ACE2 to the monocyte cell surface was blocked by the endosomal trafficking inhibitor endosidin 2, suggesting that endosomal ACE2 could be derived from circulating ACE2-containing exosomes. TLR-stimulated monocytes concurrently expressing ACE2 and TMPRSS2 on the cell surface were efficiently infected by SARS-CoV-2, which was significantly mitigated by remdesivir, TMPRSS2 inhibitor camostat, and anti-ACE2 antibody. Mass cytometry showed that ACE2 surface translocation in peripheral myeloid cells from patients with severe COVID-19 correlated with its hyperactivation and PD-L1 expression. Collectively, TLR4/7/8-induced ACE2 translocation with TMPRSS2 expression makes circulating monocytes permissive to SARS-CoV-2 infection.

MiR-579 Inhibits Lung Adenocarcinoma Cell Proliferation and Metastasis via Binding to CRABP2.

Background: Lung cancer is the cancer with the highest morbidity and mortality. Lung adenocarcinoma (LUAD) is a subtype of lung cancer. The aim of this study is to explore the functions of miR-579 and CRABP2 in lung adenocarcinoma. Methods: Cell counting kit-8 (CCK-8) and colony formation assays were applied to calculate cell proliferative abilities. Transwell assay was utilized to measure cell invasive ability. Results: MiR-579 is low expressed in LUAD tissues and cell lines. MiR-579 inhibits cell viability and invasion of lung adenocarcinoma. Knockdown of CRABP2 inhibits cell proliferation and invasion of Calu-3 cells. MiR-579 suppresses cell proliferation and invasion by regulating CRABP2 in Calu-3 cells. Conclusion: Our study reveals that miR-579 acts as a tumor suppressor in LUAD and miR-579 can target and regulate the expression of CRABP2 to mediate cell proliferation and invasion. This study indicates that miR-579 has a potential to be a candidate biomarker for the treatment of LUAD.

MicroRNA-155 Regulates MAIT1 and MAIT17 Cell Differentiation.

Mucosal-associated invariant T (MAIT) cells are innate-like T cells that develop in the thymus through three maturation stages to acquire effector function and differentiate into MAIT1 (T-bet+) and MAIT17 (RORγt+) subsets. Upon activation, MAIT cells release IFN-γ and IL-17, which modulate a broad spectrum of diseases. Recent studies indicate defective MAIT cell development in microRNA deficient mice, however, few individual miRNAs have been identified to regulate MAIT cells. MicroRNA-155 (miR-155) is a key regulator of numerous cellular processes that affect some immune cell development, but its role in MAIT cell development remains unclear. To address whether miR-155 is required for MAIT cell development, we performed gain-of-function and loss-of-function studies. We first generated a CD4Cre.miR-155 knock-in mouse model, in which miR-155 is over-expressed in the T cell lineage. We found that overexpression of miR-155 significantly reduced numbers and frequencies of MAIT cells in all immune organs and lungs and blocked thymic MAIT cell maturation through downregulating PLZF expression. Strikingly, upregulated miR-155 promoted MAIT1 differentiation and blocked MAIT17 differentiation, and timely inducible expression of miR-155 functionally inhibited peripheral MAIT cells secreting IL-17. miR-155 overexpression also increased CD4-CD8+ subset and decreased CD4-CD8- subset of MAIT cells. We further analyzed MAIT cells in conventional miR-155 knockout mice and found that lack of miR-155 also promoted MAIT1 differentiation and blocked MAIT17 differentiation but without alteration of their overall frequency, maturation and function. Overall, our results indicate that adequate miR-155 expression is required for normal MAIT1 and MAIT17 cell development and function.

Histone deacetylase 3 controls lung alveolar macrophage development and homeostasis.

Alveolar macrophages (AMs) derived from embryonic precursors seed the lung before birth and self-maintain locally throughout adulthood, but are regenerated by bone marrow (BM) under stress conditions. However, the regulation of AM development and maintenance remains poorly understood. Here, we show that histone deacetylase 3 (HDAC3) is a key epigenetic factor required for AM embryonic development, postnatal homeostasis, maturation, and regeneration from BM. Loss of HDAC3 in early embryonic development affects AM development starting at E14.5, while loss of HDAC3 after birth affects AM homeostasis and maturation. Single-cell RNA sequencing analyses reveal four distinct AM sub-clusters and a dysregulated cluster-specific pathway in the HDAC3-deficient AMs. Moreover, HDAC3-deficient AMs exhibit severe mitochondrial oxidative dysfunction and deteriorative cell death. Mechanistically, HDAC3 directly binds to Pparg enhancers, and HDAC3 deficiency impairs Pparg expression and its signaling pathway. Our findings identify HDAC3 as a key epigenetic regulator of lung AM development and homeostasis.