ABSTRACT
Acute graft-versus-host disease (aGVHD) is primarily driven by allogeneic donor T cells associated with an altered composition of the host gut microbiome and its metabolites. The severity of aGVHD after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is not solely determined by the host and donor characteristics; however, the underlying mechanisms remain unclear. Using single-cell RNA sequencing, we decoded the immune cell atlas of 12 patients who underwent allo-HSCT: six with aGVHD and six with non-aGVHD. We performed a fecal microbiota (16SrRNA sequencing) analysis to investigate the fecal bacterial composition of 82 patients: 30 with aGVHD and 52 with non-aGVHD. Fecal samples from these patients were analyzed for bile acid metabolism. Through multi-omic analysis, we identified a feedback loop involving "immune cell-gut microbes-bile acid metabolites" contributing to heightened immune responses in patients with aGVHD. The dysbiosis of the gut microbiota and disruption of bile acid metabolism contributed to an exaggerated interleukin-1 mediated immune response. Our findings suggest that resistin and defensins are crucial in mitigating against aGVHD. Therefore, a comprehensive multi-omic atlas incorporating immune cells, gut microbes, and bile acid metabolites was developed in this study and used to propose novel, non-immunosuppressive approaches to prevent aGVHD.
Subject(s)
Bile Acids and Salts , Feces , Gastrointestinal Microbiome , Graft vs Host Disease , Bile Acids and Salts/metabolism , Humans , Graft vs Host Disease/immunology , Graft vs Host Disease/microbiology , Gastrointestinal Microbiome/immunology , Female , Male , Feces/microbiology , Middle Aged , Acute Disease , Adult , Feedback, Physiological , Immunity , Metabolomics , Hematopoietic Stem Cell Transplantation , MultiomicsABSTRACT
Flowers and fruits are the reproductive organs in plants and play essential roles in natural beauty and the human diet. CLAVATA (CLV) signaling has been well characterized as regulating floral organ development by modulating shoot apical meristem (SAM) size; however, the signaling molecules downstream of the CLV pathway remain largely unknown in crops. Here, we found that functional disruption of CsCLV3 peptide and its receptor CsCLV1 both resulted in flowers with extra organs and stumpy fruits in cucumber. A heterotrimeric G protein α-subunit (CsGPA1) was shown to interact with CsCLV1. Csgpa1 mutant plants derived from gene editing displayed significantly increased floral organ numbers and shorter and wider fruits, a phenotype resembling that of Csclv mutants in cucumber. Moreover, the SAM size was enlarged and the longitudinal cell size of fruit was decreased in Csgpa1 mutants. The expression of the classical stem cell regulator WUSCHEL (WUS) was elevated in the SAM, while the expression of the fruit length stimulator CRABS CLAW (CRC) was reduced in the fruit of Csgpa1 mutants. Therefore, the Gα-subunit CsGPA1 protein interacts with CsCLV1 to inhibit floral organ numbers but promote fruit elongation, via repressing CsWUS expression and activating CsCRC transcription in cucumber. Our findings identified a new player in the CLV signaling pathway during flower and fruit development in dicots, increasing the number of target genes for precise manipulation of fruit shape during crop breeding.
ABSTRACT
Abdominal aortic aneurysm (AAA) is a potentially life-threatening vascular disease primarily in the male elderly population, but there is a lack of approved medical therapies to prevent the progression and rupture of AAA. Activating Transcription Factor 4 (ATF4) has been established to be involved in cardiovascular diseases, such as heart failure and calcific aortic valve disease. However, the role of ATF4 in the pathogenesis of AAA remains unclear. We found that ATF4 expression was significantly increased in patients with AAA and mouse models of AAA and was mainly confined to macrophages in arteries. ATF4 knockdown significantly attenuated aneurysm formation in experimental mouse model of AAA, while ATF4 overexpression promoted the development of AAA. RNA sequencing suggested that ATF4 was strongly related to the biological function of acute inflammatory response. Macrophages-specific ATF4 knockout significantly reduced the incidence and development of AAA, and decreased M1 polarization of macrophages in mice. Sphingomyelin phosphodiesterase 3 (SMPD3), a regulator of inflammatory responses in monocytes/macrophages, has been identified as a target gene of ATF4 through RNA sequencing, ChIP sequencing, and standard ChIP analyses. ATF4 induces M1 polarization of macrophages through the activation of SMPD3, thereby promoting inflammatory responses. Together, these results suggest that ATF4 mediated macrophage M1 polarization by regulating the expression of target genes SMPD3, leading to an increased inflammatory response, which further promotes the formation and development of AAA. These findings suggest ATF4 may be a new therapeutic target for AAA.
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INTRODUCTION: At the 65th American Society of Hematology (ASH) 2023 Annual Meeting, the latest advancements in CD20×CD3 BsAbs for B-cell lymphoma (BCL) were highlighted, particularly in relapsed/refractory (R/R) follicular lymphoma (FL) and R/R diffuse large B-cell lymphoma (DLBCL). AREAS COVERED: This summary highlights some of the major studies on CD20×CD3 BsAbs for BCL. EXPERT OPINION/COMMENTARY: CD20×CD3 is the most widely studied BsAb, with promising results in patients with R/R DLBCL and R/R FL ≥ two prior lines of systemic therapy. Trials with the first line of B-cell lymphoma also revealed promising results. Hopefully, BsAb monotherapy or BsAb-containing regimens may become the standard therapy in patients with FL and DLBCL.
Subject(s)
Antibodies, Bispecific , Antigens, CD20 , CD3 Complex , Immunotherapy , Lymphoma, Large B-Cell, Diffuse , Adult , Humans , Antibodies, Bispecific/therapeutic use , Antigens, CD20/immunology , Antineoplastic Agents, Immunological/therapeutic use , CD3 Complex/immunology , Lymphoma, B-Cell/immunology , Lymphoma, B-Cell/drug therapy , Lymphoma, B-Cell/therapy , Lymphoma, Follicular/immunology , Lymphoma, Follicular/drug therapy , Lymphoma, Follicular/therapy , Lymphoma, Large B-Cell, Diffuse/immunology , Lymphoma, Large B-Cell, Diffuse/drug therapy , Lymphoma, Large B-Cell, Diffuse/therapy , Congresses as TopicABSTRACT
Lateral branches are important components of shoot architecture and directly affect crop yield and production cost. Although sporadic studies have implicated abscisic acid (ABA) biosynthesis in axillary bud outgrowth, the function of ABA catabolism and its upstream regulators in shoot branching remain elusive. Here, we showed that the MADS-box transcription factor AGAMOUS-LIKE 16 (CsAGL16) is a positive regulator of axillary bud outgrowth in cucumber (Cucumis sativus). Functional disruption of CsAGL16 led to reduced bud outgrowth, whereas overexpression of CsAGL16 resulted in enhanced branching. CsAGL16 directly binds to the promoter of the ABA 8'-hydroxylase gene CsCYP707A4 and promotes its expression. Loss of CsCYP707A4 function inhibited axillary bud outgrowth and increased ABA levels. Elevated expression of CsCYP707A4 or treatment with an ABA biosynthesis inhibitor largely rescued the Csagl16 mutant phenotype. Moreover, cucumber General Regulatory Factor 1 (CsGRF1) interacts with CsAGL16 and antagonizes CsAGL16-mediated CsCYP707A4 activation. Disruption of CsGRF1 resulted in elongated branches and decreased ABA levels in the axillary buds. The Csagl16 Csgrf1 double mutant exhibited a branching phenotype resembling that of the Csagl16 single mutant. Therefore, our data suggest that the CsAGL16-CsGRF1 module regulates axillary bud outgrowth via CsCYP707A4-mediated ABA catabolism in cucumber. Our findings provide a strategy to manipulate ABA levels in axillary buds during crop breeding to produce desirable branching phenotypes.
Subject(s)
Abscisic Acid , Cucumis sativus , Gene Expression Regulation, Plant , Plant Proteins , Cucumis sativus/growth & development , Cucumis sativus/genetics , Cucumis sativus/metabolism , Abscisic Acid/metabolism , Plant Proteins/metabolism , Plant Proteins/genetics , Transcription Factors/metabolism , Transcription Factors/genetics , Plant Shoots/growth & development , Plant Shoots/metabolism , Plant Shoots/genetics , Plant Growth Regulators/metabolism , Promoter Regions, Genetic/genetics , Plants, Genetically Modified , Cytochrome P-450 Enzyme SystemABSTRACT
Introduction Bispecific antibodies (BsAbs) represent a novel and potentially effective approach in cancer immunotherapy. These antibodies feature two unique binding domains, enabling them to simultaneously attach to two antigens or two epitopes of a single antigen. Recently, a variety of BsAbs targeting distinct B-cell antigens and myeloid lineage-specific surface markers-such as CD19xCD3, CD38xCD3, and CD123xCD3-have demonstrated promising results in heavily pretreated relapsed/refractory acute lymphoblastic leukemia (R/R ALL) and relapsed/refractory acute myeloid leukemia (R/R AML) patients. Areas covered New trail results were reported by different research groups at the 65th annual meeting of the American Society of Hematology (ASH). We provide a summary of the latest progress in BsAbs for immunotherapy in adult acute leukemia. Expert opinion B-ALL is the most favored leukemia for treatment with BsAbs, unlike T-ALL and AML, which are limited in constructs and results. The clinical application of blinatumomab in the first-line setting, combined with other therapies, has clearly benefited these B-ALL patients, especially older adults, due to its lower toxicity. In the B-ALL relapsed/refractory setting, new combinations with blinatumomab are under investigation, such as PD-1 or CTLA-4 inhibitors. We believe that with more clinical trial results, it is possible that blinatumomab will be used in new clinical indications soon. No novel BsAbs developed for B-ALL have yielded better results.
Subject(s)
Antibodies, Bispecific , Immunotherapy , Leukemia, Myeloid, Acute , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Antibodies, Bispecific/therapeutic use , Antibodies, Bispecific/immunology , Humans , Leukemia, Myeloid, Acute/immunology , Leukemia, Myeloid, Acute/therapy , Leukemia, Myeloid, Acute/drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/immunology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Adult , AnimalsABSTRACT
BACKGROUND: Identifying precise biomarkers of immunotherapy response for non-small cell lung carcinoma (NSCLC) before treatment is challenging. This study aimed to construct and investigate the potential performance of a sub-regional radiomics model (SRRM) as a novel tumor biomarker in predicting the response of patients with NSCLC treated with immune checkpoint inhibitors, and test whether its predictive performance is superior to that of conventional radiomics, tumor mutational burden (TMB) score and programmed death ligand-1 (PD-L1) expression. METHODS: We categorized 264 patients from retrospective databases of two centers into training (n = 159) and validation (n = 105) cohorts. Radiomic features were extracted from three sub-regions of the tumor region of interest using the K-means method. We extracted 1,896 features from each sub-region, resulting in 5688 features per sample. The least absolute shrinkage and selection operator regression method was used to select sub-regional radiomic features. The SRRM was constructed and validated using the support vector machine algorithm. We used next-generation sequencing to classify patients from the two cohorts into high TMB (≥ 10 muts/Mb) and low TMB (< 10 muts/Mb) groups; immunohistochemistry was performed to assess PD-L1 expression in formalin-fixed, paraffin-embedded tumor sections, with high expression defined as ≥ 50% of tumor cells being positive. Associations between the SRRM and progression-free survival (PFS) and variant genes were assessed. RESULTS: Eleven sub-regional radiomic features were employed to develop the SRRM. The areas under the receiver operating characteristic curve (AUCs) of the proposed SRRM were 0.90 (95% confidence interval [CI] 0.84-0.96) and 0.86 (95% CI 0.76-0.95) in the training and validation cohorts, respectively. The SRRM (low vs. high; cutoff value = 0.936) was significantly associated with PFS in the training (hazard ratio [HR] = 0.35 [0.24-0.50], P < 0.001) and validation (HR = 0.42 [0.26-0.67], P = 0.001) cohorts. A significant correlation between the SRRM and three variant genes (H3C4, PAX5, and EGFR) was observed. In the validation cohort, the SRRM demonstrated a higher AUC (0.86, P < 0.001) than that for PD-L1 expression (0.66, P = 0.034) and TMB score (0.54, P = 0.552). CONCLUSIONS: The SRRM had better predictive performance and was superior to conventional radiomics, PD-L1 expression, and TMB score. The SRRM effectively stratified the progression-free survival (PFS) risk among patients with NSCLC receiving immunotherapy.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Carcinoma, Non-Small-Cell Lung/diagnostic imaging , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/therapy , B7-H1 Antigen/genetics , Radiomics , Retrospective Studies , Immunotherapy , Biomarkers, Tumor , Lung Neoplasms/diagnostic imaging , Lung Neoplasms/genetics , Lung Neoplasms/therapyABSTRACT
Plant defence against pathogens generally occurs at the expense of growth and yield. Uncoupling the inverse relationship between growth and defence is of great importance for crop breeding, while the underlying genes and regulatory mechanisms remain largely elusive. The exocytosis complex was shown to play an important role in the trafficking of receptor kinases (RKs) to the plasma membrane (PM). Here, we found a Cucumis sativus exocytosis subunit Exo70B (CsExo70B) regulates the abundance of both development and defence RKs at the PM to promote fruit elongation and disease resistance in cucumber. Knockout of CsExo70B resulted in shorter fruit and susceptibility to pathogens. Mechanistically, CsExo70B associates with the developmental RK CsERECTA, which promotes fruit longitudinal growth in cucumber, and contributes to its accumulation at the PM. On the other side, CsExo70B confers to the spectrum resistance to pathogens in cucumber via a similar regulatory module of defence RKs. Moreover, CsExo70B overexpression lines showed an increased fruit yield as well as disease resistance. Collectively, our work reveals a regulatory mechanism that CsExo70B promotes both fruit elongation and disease resistance by maintaining appropriate RK levels at the PM and thus provides a possible strategy for superior cucumber breeding with high yield and robust pathogen resistance.
Subject(s)
Cucumis sativus , Cucumis sativus/genetics , Fruit/metabolism , Disease Resistance/genetics , Plant Breeding , Cell MembraneABSTRACT
Pancreatic cancer (PCa) is one of the most fatal human malignancies. The enhanced infiltration of stromal tissue into the PCa tumor microenvironment limits the identification of key tumor-specific transcription factors and epigenomic abnormalities in malignant epithelial cells. Integrated transcriptome and epigenetic multiomics analyses of the paired PCa organoids indicate that the basic helix-loop-helix transcription factor 40 (BHLHE40) is significantly upregulated in tumor samples. Increased chromatin accessibility at the promoter region and enhanced mTOR pathway activity contribute to the elevated expression of BHLHE40. Integrated analysis of chromatin immunoprecipitation-seq, RNA-seq, and high-throughput chromosome conformation capture data, together with chromosome conformation capture assays, indicate that BHLHE40 not only regulates sterol regulatory element-binding factor 1 (SREBF1) transcription as a classic transcription factor but also links the enhancer and promoter regions of SREBF1. It is found that the BHLHE40-SREBF1-stearoyl-CoA desaturase axis protects PCa cells from ferroptosis, resulting in the reduced accumulation of lipid peroxidation. Moreover, fatostatin, an SREBF1 inhibitor, significantly suppresses the growth of PCa tumors with high expressions of BHLHE40. This study highlights the important roles of BHLHE40-mediated lipid peroxidation in inducing ferroptosis in PCa cells and provides a novel mechanism underlying SREBF1 overexpression in PCa.
Subject(s)
Ferroptosis , Pancreatic Neoplasms , Humans , Homeodomain Proteins/genetics , Ferroptosis/genetics , Transcription Factors/genetics , Basic Helix-Loop-Helix Transcription Factors/genetics , Basic Helix-Loop-Helix Transcription Factors/metabolism , Pancreatic Neoplasms/genetics , Tumor Microenvironment , Sterol Regulatory Element Binding Protein 1/genetics , Sterol Regulatory Element Binding Protein 1/metabolismABSTRACT
Background: The circulation and the genomic evolution of influenza A(H3N2) viruses during the 2021/2022 and 2022/2023 seasons were studied and associated with infection outcomes. Methods: Remnant influenza A-positive samples following standard-of-care testing from patients across the Johns Hopkins Health System (JHHS) were used for the study. Samples were randomly selected for whole viral genome sequencing. The sequence-based pEpitope model was used to estimate the predicted vaccine efficacy (pVE) for circulating H3N2 viruses. Clinical data were collected and associated with viral genomic data. Results: A total of 121 683 respiratory specimens were tested for influenza at JHHS between 1 September 2021 and 31 December 2022. Among them, 6071 (4.99%) tested positive for influenza A. Of these, 805 samples were randomly selected for sequencing, with hemagglutinin (HA) segments characterized for 610 samples. Among the characterized samples, 581 were H3N2 (95.2%). Phylogenetic analysis of HA segments revealed the exclusive circulation of H3N2 viruses with HA segments of the 3C.2a1b.2a.2 clade. Analysis of a total of 445 complete H3N2 genomes revealed reassortments; 200 of 227 of the 2022/2023 season genomes (88.1%) were found to have reassorted with clade 3C.2a1b.1a. The pVE was estimated to be -42.53% for the 2021/2022 season and 30.27% for the 2022/2023 season. No differences in clinical presentations or admissions were observed between the 2 seasons. Conclusions: The increased numbers of cases and genomic diversity of influenza A(H3N2) during the 2022/2023 season were not associated with a change in disease severity compared to the previous influenza season.
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BACKGROUND: Gene status has become the focus of prognosis prediction. Furthermore, deep learning has frequently been implemented in medical imaging to diagnose, prognosticate, and evaluate treatment responses in patients with cancer. However, few deep learning survival (DLS) models based on mutational genes that are directly associated with patient prognosis in terms of progression-free survival (PFS) or overall survival (OS) have been reported. Additionally, DLS models have not been applied to determine IO-related prognosis based on mutational genes. Herein, we developed a deep learning method to predict the prognosis of patients with lung cancer treated with or without immunotherapy (IO). METHODS: Samples from 6542 patients from different centers were subjected to genome sequencing. A DLS model based on multi-panels of somatic mutations was trained and validated to predict OS in patients treated without IO and PFS in patients treated with IO. RESULTS: In patients treated without IO, the DLS model (low vs. high DLS) was trained using the training MSK-MET cohort (HR = 0.241 [0.213-0.273], P < 0.001) and tested in the inter-validation MSK-MET cohort (HR = 0.175 [0.148-0.206], P < 0.001). The DLS model was then validated with the OncoSG, MSK-CSC, and TCGA-LUAD cohorts (HR = 0.420 [0.272-0.649], P < 0.001; HR = 0.550 [0.424-0.714], P < 0.001; HR = 0.215 [0.159-0.291], P < 0.001, respectively). Subsequently, it was fine-tuned and retrained in patients treated with IO. The DLS model (low vs. high DLS) could predict PFS and OS in the MIND, MSKCC, and POPLAR/OAK cohorts (P < 0.001, respectively). Compared with tumor-node-metastasis staging, the COX model, tumor mutational burden, and programmed death-ligand 1 expression, the DLS model had the highest C-index in patients treated with or without IO. CONCLUSIONS: The DLS model based on mutational genes can robustly predict the prognosis of patients with lung cancer treated with or without IO.
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BACKGROUND: LIPH, a membrane-associated phosphatidic acid-selective phospholipase A1a, can produce LPA (Lysophosphatidic acid) from PA (Phosphatidic acid) on the outer leaflet of the plasma membrane. It is well known that LIPH dysfunction contributes to lipid metabolism disorder. Previous study shows that LIPH was found to be a potential gene related to poor prognosis with pancreatic ductal adenocarcinoma (PDAC). However, the biological functions of LIPH in PDAC remain unclear. METHODS: Cell viability assays were used to evaluate whether LIPH affected cell proliferation. RNA sequencing and immunoprecipitation showed that LIPH participates in tumor glycolysis by stimulating LPA/LPAR axis and maintaining aldolase A (ALDOA) stability in the cytosol. Subcutaneous, orthotopic xenograft models and patient-derived xenograft PDAC model were used to evaluate a newly developed Gemcitabine-based therapy. RESULTS: LIPH was significantly upregulated in PDAC and was related to later pathological stage and poor prognosis. LIPH downregulation in PDAC cells inhibited colony formation and proliferation. Mechanistically, LIPH triggered PI3K/AKT/HIF1A signaling via LPA/LPAR axis. LIPH also promoted glycolysis and de novo synthesis of glycerolipids by maintaining ALDOA stability in the cytosol. Xenograft models show that PDAC with high LIPH expression levels was sensitive to gemcitabine/ki16425/aldometanib therapy without causing discernible side effects. CONCLUSION: LIPH directly bridges PDAC cells and tumor microenvironment to facilitate aberrant aerobic glycolysis via activating LPA/LPAR axis and maintaining ALDOA stability, which provides an actionable gemcitabine-based combination therapy with limited side effects.
Subject(s)
Carcinoma, Pancreatic Ductal , Pancreatic Neoplasms , Humans , Fructose-Bisphosphate Aldolase/genetics , Fructose-Bisphosphate Aldolase/metabolism , Fructose-Bisphosphate Aldolase/pharmacology , Phosphatidylinositol 3-Kinases/metabolism , Cell Line, Tumor , Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/pathology , Pancreatic Neoplasms/pathology , Gemcitabine , Cell Proliferation , Glycolysis , Phenotype , Gene Expression Regulation, Neoplastic , Tumor MicroenvironmentABSTRACT
According to recent research, bispecific antibodies (BsAbs) are a promising new immunotherapy method. Various BsAb forms are constantly being developed. In the year 2022 alone, four BsAbs (tebentafusp, faricimab, mosunetuzumab, and teclistamab) were approved for clinical applications. BsAbs including odronextamab, talquetamab, linvoseltamab, and elranatamab are being actively evaluated in different clinical studies. Preliminary results show promising response rates in relapsed/refractory follicular lymphoma (RRFL), relapsed/refractory diffuse large B-cell lymphoma (RRDLBCL), and relapsed/refractory multiple myeloma (RRMM), especially in heavily pretreated patients, including those who have progressed after proteasome inhibitors, immunomodulatory drugs, anti-CD38 antibodies, and CAR-T therapies. We summarized data published at the 28th European Hematology Association (EHA) annual meeting, which was held in Frankfurt between 8 June 2023 and 11 June 2023 on BsAbs monotherapy or combination therapy for RRFL, RRDLBCL, and RRMM.
Subject(s)
Antibodies, Bispecific , Antineoplastic Agents , Hematologic Neoplasms , Hematology , Lymphoma, Large B-Cell, Diffuse , Lymphoma, Non-Hodgkin , Multiple Myeloma , Humans , Antibodies, Bispecific/therapeutic use , Hematologic Neoplasms/drug therapy , Lymphoma, Non-Hodgkin/drug therapy , Antineoplastic Agents/therapeutic use , Multiple Myeloma/pathology , Lymphoma, Large B-Cell, Diffuse/drug therapyABSTRACT
Risk stratification for normal karyotype acute myeloid leukemia (NK-AML) remains unsatisfactory, which is reflected by the high incidence of leukemia relapse. This study aimed to evaluate the role of gene mutations and clinical characterization in predicting the relapse of patients with NK-AML. A prognostic system for NK-AML was constructed. A panel of gene mutations was explored using next-generation sequencing. A nomogram algorithm was used to build a genomic mutation signature (GMS) nomogram (GMSN) model that combines GMS, measurable residual disease, and clinical factors to predict relapse in 347 patients with NK-AML from four centers. Patients in the GMS-high group had a higher 5-year incidence of relapse than those in the GMS-low group (p < 0.001). The 5-year incidence of relapse was also higher in patients in the GMSN-high group than in those in the GMSN-intermediate and -low groups (p < 0.001). The 5-year disease-free survival and overall survival rates were lower in patients in the GMSN-high group than in those in the GMSN-intermediate and -low groups (p < 0.001) as confirmed by training and validation cohorts. This study illustrates the potential of GMSN as a predictor of NK-AML relapse.
Subject(s)
Leukemia, Myeloid, Acute , Nucleophosmin , Humans , Mutation , Prognosis , Chronic Disease , Leukemia, Myeloid, Acute/genetics , Recurrence , KaryotypeABSTRACT
Neuropathy is a feature more frequently observed in pancreatic ductal adenocarcinoma (PDAC) than other tumors. Schwann cells, the most prevalent cell type in peripheral nerves, migrate toward tumor cells and associate with poor prognosis in PDAC. To unveil the effects of Schwann cells on the neuro-stroma niche, here we perform single-cell RNA-sequencing and microarray-based spatial transcriptome analysis of PDAC tissues. Results suggest that Schwann cells may drive tumor cells and cancer-associated fibroblasts (CAFs) to more malignant subtypes: basal-like and inflammatory CAFs (iCAFs), respectively. Moreover, in vitro and in vivo assays demonstrate that Schwann cells enhance the proliferation and migration of PDAC cells via Midkine signaling and promote the switch of CAFs to iCAFs via interleukin-1α. Culture of tumor cells and CAFs with Schwann cells conditioned medium accelerates PDAC progression. Thus, we reveal that Schwann cells induce malignant subtypes of tumor cells and CAFs in the PDAC milieu.
Subject(s)
Cancer-Associated Fibroblasts , Carcinoma, Pancreatic Ductal , Pancreatic Neoplasms , Humans , Cancer-Associated Fibroblasts/metabolism , Pancreatic Neoplasms/pathology , Carcinoma, Pancreatic Ductal/pathology , Schwann Cells/metabolism , Tumor Microenvironment/genetics , Cell Line, Tumor , Fibroblasts/metabolism , Pancreatic NeoplasmsABSTRACT
The rapidity with which SARS-CoV-2 XBB variants rose to predominance has been alarming. We used a large cohort of patients diagnosed with Omicron infections between September 2022 and mid-February 2023 to evaluate the likelihood of admission or need for supplemental oxygen in patients infected with XBB variants. Our data showed no significant association between XBB or XBB.1.5 infections and admissions. Older age groups, lack of vaccination, immunosuppression and underlying heart, kidney, and lung disease showed significant associations with hospitalization.
Subject(s)
COVID-19 , Humans , Aged , SARS-CoV-2/genetics , Cluster Analysis , HospitalizationABSTRACT
BACKGROUND: Checkpoint-based immunotherapy has failed to elicit responses in the majority of patients with pancreatic cancer. In our study, we aimed to identify the role of a novel immune checkpoint molecule V-set Ig domain-containing 4 (VSIG4) in pancreatic ductal adenocarcinoma (PDAC). METHODS: Online datasets and tissue microarray (TMA) were utilized to analyze the expression level of VSIG4 and its correlation with clinical parameters in PDAC. CCK8, transwell assay and wound healing assay were applied to explore the function of VSIG4 in vitro. Subcutaneous, orthotopic xenograft and liver metastasis model was established to explore the function of VSIG4 in vivo. TMA analysis and chemotaxis assay were conducted to uncover the effect of VSIG4 on immune infiltration. Histone acetyltransferase (HAT) inhibitors and si-RNA were applied to investigate factors that regulate the expression of VSIG4. RESULTS: Both mRNA and protein levels of VSIG4 were higher in PDAC than normal pancreas in TCGA, GEO, HPA datasets and our TMA. VSIG4 showed positive correlations with tumor size, T classification and liver metastasis. Patients with higher VSIG4 expression were related to poorer prognosis. VSIG4 knockdown impaired the proliferation and migration ability of pancreatic cancer cells both in vitro and in vivo. Bioinformatics study showed positive correlation between VSIG4 and infiltration of neutrophil and tumor-associated macrophages (TAMs) in PDAC, and it inhibited the secretion of cytokines. According to our TMA panel, high expression of VSIG4 was correlated with fewer infiltration of CD8+ T cells. Chemotaxis assay also showed knockdown of VSIG4 increased the recruitment of total T cells and CD8+ T cells. HAT inhibitors and knockdown of STAT1 led to decreased expression of VSIG4. CONCLUSIONS: Our data indicate that VSIG4 contributes to cell proliferation, migration and resistance to immune attack, thus identified as a promising target for PDAC treatment with good prognostic value.
Subject(s)
Carcinoma, Pancreatic Ductal , Liver Neoplasms , Pancreatic Neoplasms , Humans , Immune Checkpoint Proteins , CD8-Positive T-Lymphocytes/metabolism , Carcinoma, Pancreatic Ductal/pathology , Pancreatic Neoplasms/pathology , Prognosis , Immunoglobulin Domains , Liver Neoplasms/pathology , Pancreatic NeoplasmsABSTRACT
BACKGROUND: An increase in influenza like illness in children and adolescents at the Johns Hopkins Health system during summer 2022 was associated with increased positivity for enterovirus/ rhinovirus. We sought to characterize the epidemiology and viral evolution of enterovirus D68 (EV-D68). METHODS: A cohort of remnant respiratory samples tested at the Johns Hopkins Microbiology Laboratory was screened for EV-D68. EV-D68 positives were characterized by whole genome sequencing and viral loads were assessed by droplet digital PCR (ddPCR). Genomic changes and viral loads were analyzed along with patients' clinical presentations. RESULTS: Of 566 screened samples, 126 were EV-D68 (22.3%). The median age of EV-D68 infected patients was four years, a total of 52 required supplemental oxygen (41.3%), and 35 (27.8%) were admitted. Lung disease was the most frequent comorbidity that was associated with hospitalization. A total of 75 complete and 32 partial genomes were characterized that made a new cluster within the B3 subclade that was closest to US genomes from 2018. Amino acid changes within the BC and DE loops were identified from 31 genomes (29%) which correlated with an increase in average viral load in respiratory specimens and the need for supplemental oxygen. CONCLUSIONS: EV-D68 outbreaks continue to cause influenza like illness that could be overwhelming for the health system due to a significant demand for high flow oxygen. Viral evolution and an increase in the susceptible population are likely driving the trends of the increased EV-D68 infections.
Subject(s)
Enterovirus D, Human , Enterovirus Infections , Influenza, Human , Respiratory Tract Infections , Virus Diseases , Child , Adolescent , Humans , Infant , Child, Preschool , Enterovirus D, Human/genetics , Influenza, Human/epidemiology , Virus Diseases/epidemiology , Enterovirus Infections/epidemiology , Disease Outbreaks , PhylogenyABSTRACT
Pollen tube guidance within female tissues of flowering plants can be divided into preovular guidance, ovular guidance and a connecting stage called pollen tube emergence. As yet, no female factor has been identified to positively regulate this transition process. In this study, we show that an ovary-expressed bHLH transcription factor Cucumis sativus ALCATRAZ (CsALC) functions in pollen tube emergence in cucumber. CsALC knockout mutants showed diminished pollen tube emergence, extremely reduced entry into ovules, and a 95% reduction in female fertility. Further examination showed two rapid alkalinization factors CsRALF4 and CsRALF19 were less expressed in Csalc ovaries compared to WT. Besides the loss of male fertility derived from precocious pollen tube rupture as in Arabidopsis, Csralf4 Csralf19 double mutants exhibited a 60% decrease in female fertility due to reduced pollen tube distribution and decreased ovule targeting efficiency. In brief, CsALC regulates female fertility and promotes CsRALF4/19 expression in the ovary during pollen tube guidance in cucumber.
Subject(s)
Arabidopsis Proteins , Arabidopsis , Cucumis sativus , Cucumis sativus/genetics , Ovary/metabolism , Pollen Tube/genetics , Pollen Tube/metabolism , Arabidopsis/metabolism , Arabidopsis Proteins/metabolism , Ovule/metabolismABSTRACT
PURPOSE: It remains controversial whether busulfan-based versus total body irradiation (TBI)-based regimens have comparable outcomes in patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic stem-cell transplantation (allo-HSCT). We investigated the efficacy and toxicity of busulfan plus cyclophosphamide (BuCy) and TBI plus cyclophosphamide (TBI-Cy) conditioning in allo-HSCT for adult standard-risk B-cell-ALL in first complete remission (CR1). PATIENTS AND METHODS: We performed an open-label, randomized phase III trial at 13 hospitals in China. Eligible patients (age 14-65 years) had standard-risk ALL in CR1. Patients were randomly assigned (1:1) to BuCy (0.8 mg/kg four times per day on days -7 to -4 and cyclophosphamide 60 mg/kg once daily on days -3 to -2) or TBI-Cy (4.5 Gy TBI on days -5 to -4 and cyclophosphamide 60 mg/kg once daily on days -3 to -2). The primary end point was 2-year overall survival. Analysis was per protocol. This trial is registered with ClinicalTrials.gov (identifier: NCT02670252) and is complete. RESULTS: Between January 2016 and February 2020, 275 patients were assigned to receive BuCy (273 assessed) and 275 to TBI-Cy (272 assessed). The 2-year overall survival was 76.6% (95% CI, 71.7 to 81.8) and 79.4% (74.7 to 84.4; P = .457; difference 2.9%; 95% CI, -4.1 to 9.8; P = .022), indicating noninferiority of BuCy. The 2-year relapse was 20.2% (95% CI, 15.6 to 25.1) and 18.4% (14.0 to 23.2; P = .616), and the nonrelapse mortality was 11.0% (95% CI, 7.6 to 15.0) and 11.0% (7.7 to 15.1; P = .988) in the BuCy and TBI-Cy groups, respectively. There were no differences in regimen-related toxicity, graft-versus-host disease, or late effects between the two groups. CONCLUSION: The BuCy regimen has noninferior efficiency and safety as TBI-Cy (4.5 Gy × 2) for patients with adult standard-risk B cell-ALL in CR1 undergoing HLA-matched allo-HSCT.