Both partial inactivation as well as activation of NF-κB signaling lead to hypertension and chronic kidney disease.

BACKGROUND AND HYPOTHESIS: Activation of NF-κB-signalling is key in the pathogenesis of chronic kidney diseases (CKD). However, a certain level of NF-κB activity is necessary to enable tissue repair. METHODS: To investigate the relationship between activated and inactivated NF-κB signaling on the pathogenesis of CKD using mouse models of NF-κB partial inactivation (mutating cysteine at position 59 of the sixth exon on the NF-κB gene into alanine) and activation (mutating cysteine at position 59 of the sixth exon on the NF-κB gene into serine). RESULTS: The density of CD3, CD8, CD68 positive cells, as well as the expression of IL-6, TRAF-1, and NAF-1 in the kidney tissues of NF-κBC59A mice were reduced, whereas an opposing pattern was observed in the NF-κBC59S mice. Blood pressure, kidney fibrosis (analyzed by PAS-, Masson trichrome-, and Sirius-Red-staining as well as α-SMA immunofluorescence), serum creatinine and urinary albumin-to-creatinine-ratio are markedly increased in NF-κB activated and inactivated mice compared to controls. Transmission electron microscopy indicated that the glomerular basement membrane was thicker in both NF-κBC59A and NF-κBC59S mice compared to wild-type mice. CONCLUSIONS: Using mice models with partially activated and inactivated NF-κB pathways suggests that there is an apparently U-shaped relationship between blood pressure, kidney function as well as morphology and the activation of the NF-κB pathway. A certain optimal activity of the NF-κB pathway seems to be important to maintain optimal kidney function and morphology.

Advances in bulk and single-cell multi-omics approaches for systems biology and precision medicine.

Multi-omics allows the systematic understanding of the information flow across different omics layers, while single omics can mainly reflect one aspect of the biological system. The advancement of bulk and single-cell sequencing technologies and related computational methods for multi-omics largely facilitated the development of system biology and precision medicine. Single-cell approaches have the advantage of dissecting cellular dynamics and heterogeneity, whereas traditional bulk technologies are limited to individual/population-level investigation. In this review, we first summarize the technologies for producing bulk and single-cell multi-omics data. Then, we survey the computational approaches for integrative analysis of bulk and single-cell multimodal data, respectively. Moreover, the databases and data storage for multi-omics, as well as the tools for visualizing multimodal data are summarized. We also outline the integration between bulk and single-cell data, and discuss the applications of multi-omics in precision medicine. Finally, we present the challenges and perspectives for multi-omics development.

GRNdb: decoding the gene regulatory networks in diverse human and mouse conditions.

Gene regulatory networks (GRNs) formed by transcription factors (TFs) and their downstream target genes play essential roles in gene expression regulation. Moreover, GRNs can be dynamic changing across different conditions, which are crucial for understanding the underlying mechanisms of disease pathogenesis. However, no existing database provides comprehensive GRN information for various human and mouse normal tissues and diseases at the single-cell level. Based on the known TF-target relationships and the large-scale single-cell RNA-seq data collected from public databases as well as the bulk data of The Cancer Genome Atlas and the Genotype-Tissue Expression project, we systematically predicted the GRNs of 184 different physiological and pathological conditions of human and mouse involving >633 000 cells and >27 700 bulk samples. We further developed GRNdb, a freely accessible and user-friendly database (http://www.grndb.com/) for searching, comparing, browsing, visualizing, and downloading the predicted information of 77 746 GRNs, 19 687 841 TF-target pairs, and related binding motifs at single-cell/bulk resolution. GRNdb also allows users to explore the gene expression profile, correlations, and the associations between expression levels and the patient survival of diverse cancers. Overall, GRNdb provides a valuable and timely resource to the scientific community to elucidate the functions and mechanisms of gene expression regulation in various conditions.

Systematic profiling of ACE2 expression in diverse physiological and pathological conditions for COVID-19/SARS-CoV-2.

Recent retrospective studies of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19) revealed that the patients with common comorbidities of cancers and chronic diseases face significantly poorer clinical outcomes than those without. Since the expression profile of ACE2, a crucial cell entry receptor for SARS-CoV-2, could indicate the susceptibility to SARS-CoV-2 infection, here we systematically dissected ACE2 expression using large-scale multi-omics data from 30 organs/tissues, 33 cancer types and some common chronic diseases involving >28 000 samples. It was found that sex and age could be correlated with the susceptibility of SARS-CoV-2 infection for certain tissues. Strikingly, ACE2 was up-regulated in cervical squamous cell carcinoma and endocervical adenocarcinoma, colon adenocarcinoma, oesophageal carcinoma, kidney renal papillary cell carcinoma, lung adenocarcinoma and uterine corpus endometrial carcinoma compared to controls. Furthermore, the patients with common chronic diseases regarding angiocardiopathy, type 2 diabetes, liver, pneumonia and hypertension were also with higher ACE2 expression compared to related controls, which were validated using independent data sets. Collectively, our study may reveal a novel important mechanism that the patients with certain cancers and chronic diseases may express higher ACE2 expression compared to the individuals without diseases, which could lead to their higher susceptibility to multi-organ injury of SARS-CoV-2 infection.

Thiostrepton induces oxidative stress, mitochondrial dysfunction and ferroptosis in HaCaT cells.

TST has been mainly studied for its anti-tumor proliferation and antimicrobial effects, but not widely used in dermatological diseases. The mechanism of cellular damage by TST in response to H2O2-mediated oxidative stress was investigated in human skin immortalized keratinocytes (HaCaT) as an in vitro model. The findings reveal that TST treatment leads to increased oxidative stress in the cells by reducing levels of superoxide dismutase (SOD), glutathione (GSH), and catalase (CAT). This effect is further supported by an upsurge in the expression of malondialdehyde (MDA, a pivotal marker of lipid peroxidation). Additionally, dysregulation of FoxM1 at both gene and protein levels corroborates its involvement TST associated effects. Analysis of ferroptosis-related genes confirms dysregulation following TST treatment in HaCaT cells. Furthermore, TST treatment exhibits effects on mitochondrial morphology and function, affirming its induction of apoptosis in the cells through heightened oxidative stress due to mitochondrial damage and dysregulation of mitochondrial membrane potential.

Atractylenolide-I Alleviates Hyperglycemia-Induced Heart Developmental Malformations through Direct and Indirect Modulation of the STAT3 Pathway.

BACKGROUND: Gestational diabetes could elevate the risk of congenital heart defects (CHD) in infants, and effective preventive and therapeutic medications are currently lacking. Atractylenolide-I (AT-I) is the active ingredient of Atractylodes Macrocephala Koidz (known as Baizhu in China), which is a traditional pregnancy-supporting Chinese herb. PURPOSE: In this study, we investigated the protective effect of AT-I on the development of CHD in embryos exposed to high glucose (HG). STUDY DESIGN AND METHODS: First, systematic review search results revealed associations between gestational diabetes mellitus (GDM) and cardiovascular malformations. Subsequently, a second systematic review indicated that heart malformations were consistently associated with oxidative stress and cell apoptosis. We assessed the cytotoxic impacts of Atractylenolide compounds (AT-I, AT-II, and AT-III) on H9c2 cells and chick embryos, determining an optimal concentration of AT-I for further investigation. Second, immunofluorescence, western blot, Polymerase Chain Reaction (PCR), and flow cytometry were utilized to delve into the mechanisms through which AT-I mitigates oxidative stress and apoptosis in cardiac cells. Molecular docking was employed to investigate whether AT-I exerts cardioprotective effects via the STAT3 pathway. Then, we developed a streptozotocin-induced diabetes mellitus (PGDM) mouse model to evaluate AT-I's protective efficacy in mammals. Finally, we explored how AT-I protects hyperglycemia-induced abnormal fetal heart development through microbiota analysis and untargeted metabolomics analysis. RESULTS: The study showed the protective effect of AT-I on embryonic development using a chick embryo model which rescued the increase in the reactive oxygen species (ROS) and decrease in cell survival induced by HG. We also provided evidence suggesting that AT-I might directly interact with STAT3, inhibiting its phosphorylation. Further, in the PGDM mouse model, we observed that AT-I not only partially alleviated PGDM-related blood glucose issues and complications but also mitigated hyperglycemia-induced abnormal fetal heart development in pregnant mice. This effect is hypothesized to be mediated through alterations in gut microbiota composition. We proposed that dysregulation in microbiota metabolism could influence the downstream STAT3 signaling pathway via EGFR, consequently impacting cardiac development and formation. CONCLUSIONS: This study marks the first documented instance of AT-I's effectiveness in reducing the risk of early cardiac developmental anomalies in fetuses affected by gestational diabetes. AT-I achieves this by inhibiting the STAT3 pathway activated by ROS during gestational diabetes, significantly reducing the risk of fetal cardiac abnormalities. Notably, AT-I also indirectly safeguards normal fetal cardiac development by influencing the maternal gut microbiota and suppressing the EGFR/STAT3 pathway.

Corrigendum: HER-2 positive primary neuroendocrine neoplasms of the breast with signet ring feature: A case report and review of literature.

[This corrects the article DOI: 10.3389/fonc.2022.1029007.].

Preclinical and Basic Research Strategies for Overcoming Resistance to Targeted Therapies in HER2-Positive Breast Cancer.

The amplification of epidermal growth factor receptor 2 (HER2) is associated with a poor prognosis and HER2 gene is overexpressed in approximately 15-30% of breast cancers. In HER2-positive breast cancer patients, HER2-targeted therapies improved clinical outcomes and survival rates. However, drug resistance to anti-HER2 drugs is almost unavoidable, leaving some patients with an unmet need for better prognoses. Therefore, exploring strategies to delay or revert drug resistance is urgent. In recent years, new targets and regimens have emerged continuously. This review discusses the fundamental mechanisms of drug resistance in the targeted therapies of HER2-positive breast cancer and summarizes recent research progress in this field, including preclinical and basic research studies.

Neoadjuvant adebrelimab in locally advanced resectable esophageal squamous cell carcinoma: a phase 1b trial.

Overall survival (OS) benefits of neoadjuvant immunotherapy remain elusive in locally advanced esophageal squamous cell carcinomas (ESCC). Here, we reported the results of a phase 1b trial of neoadjuvant PD-L1 blockade with adebrelimab in resectable ESCC. Patients received two neoadjuvant doses of adebrelimab followed by surgery. The primary endpoints were safety and feasibility; secondary endpoints included pathologic complete response (pCR) and OS. Our data showed the primary endpoints of safety and feasibility had been met. Common treatment-related adverse events were anorexia (32%) and fatigue (16%), without grade 3 or more adverse events. Of the 30 patients enrolled in the trial, 25 underwent successful resection without surgery delay and 24% had major pathologic responses including a pCR rate of 8%. The 2-year OS was 92%. Responsive patients had an immune-enriched tumor microenvironment phenotype, whereas nonresponsive patients had greater infiltration of cancer-associated fibroblasts at baseline. Clonotypic dynamics of pre-existing intratumoral T cells was a hallmark of responsive patients. These findings provide a rational for neoadjuvant anti-PD-L1 monotherapy as a therapeutic strategy for patients with resectable ESCC. ClinicalTrials.gov identifier: NCT04215471 .

Homologous recombination deficiency status predicts response to platinum-based chemotherapy in Chinese patients with high-grade serous ovarian carcinoma.

BACKGROUND: Homologous Recombination Deficiency (HRD) is a predictive biomarker for ovarian cancer treated with PARP inhibitors or for breast cancer treated with first-line platinum-based chemotherapy. However, limited research is documented on platinum-based treatment prediction with HRD as a biomarker in ovarian cancer patients, especially in the Chinese population. METHODS: We investigated the association between HRD status and the response of platinum-based chemotherapy in 240 Chinese HGSOC patients. RESULTS: The Pt-sensitive patients showed higher HRD scores than Pt-resistant ones, but this was not significant(median: 42.6 vs. 31.6, p = 0.086). (Pt)-sensitive rate was higher in HRD + BRCAm tumors and in HRD + BRCAwt tumors (HRD + BRCAm: 97%, p = 0.004 and HRD + BRCAwt: 90%, p = 0.04) compared with 74% in the HRD-BRCAwt tumors. We also found Pt-sensitive patients tend to be enriched in patients with BRCA mutations or non-BRCA HRR pathway gene mutations (BRCA: 93.6% vs 75.4%, p < 0.001; non-BRCA HRR: 88.6% vs 75.4%, p = 0.062). Patients with HRD status positive had significantly improved PFS compared with those with HRD status negative (median PFS: 30.5 months vs. 16.8 months, Log-rank p = 0.001). Even for BRCAwt patients, positive HRD was also associated with better PFS than the HRD-negative group (median: 27.5 months vs 16.8 months, Log-rank p = 0.010). Further, we found patients with pathogenic mutations located in the DNA-binding domain (DBD) of BRCA1 had improved FPS, compared to those with mutations in other domains. (p = 0.03). CONCLUSIONS: The HRD status can be identified as an independent significance in Chinese HGSOC patients treated with first-line platinum-based chemotherapy.

HER-2-positive primary neuroendocrine neoplasms of the breast with signet ring feature: A case report and review of literature.

Background: Primary neuroendocrine neoplasm of the breast (BNEN) is an uncommon breast neoplasm, and in most cases, it presents as hormone receptors positive and HER-2 negative. Moreover, in neuroendocrine neoplasms (NENs), the signet ring feature is a rare morphological subtype, and only a few cases have been reported. Here, we report the case of a primary breast neuroendocrine neoplasm with an unusual signet ring cell appearance in this paper. The documentation of this case, combined with a review of the literature, may add to existing knowledge about the outcome and management of this rare tumor. Methods: In the present review, we describe a unique case of HER-2-positive primary BNEN with a signet ring feature that has not been reported in English. Additionally, we performed a literature search of the PubMed and Web of Science databases and calculated statistics for clinical data and follow-up. Results: Our literature search, excluding non-English literature, identified 15 articles with data from 24 cases, including ours. The mean age was 51.25 years (range, 30-79 years), and there were 13 male patients (54%) and 11 female patients (46%). Of the 24 cases, some cases (11/24) were associated with lymph node metastases, a few cases (6/24) had distant metastasis, and the vast majority of cases (23/24) occurred in the digestive system. Primary hepatic signet ring cell neuroendocrine tumor showed slow progression and good prognosis. Lymph node involvement was identified in one of eight (12.5%) documented cases, and one of eight (12.5%) reported cases presented with distant metastatic disease. However, the prognosis of neuroendocrine tumors with signet ring cells in the pancreas and stomach was poor. Lymph node involvement was identified in 9 of 15 (60%) documented cases, and 5 of 15 (33.3%) reported cases presented with distant metastatic disease. Conclusion: NENs with a signet ring feature is uncommon, and this is the first case report of its occurrence in the breast. Current knowledge is limited to anecdotal experience based on case reports and small case series. We provide a literature review to summarize knowledge about this rare entity.

Deficits in Sense of Body Ownership, Sensory Processing, and Temporal Perception in Schizophrenia Patients With/Without Auditory Verbal Hallucinations.

It has been claimed that individuals with schizophrenia have difficulty in self-recognition and, consequently, are unable to identify the sources of their sensory perceptions or thoughts, resulting in delusions, hallucinations, and unusual experiences of body ownership. The deficits also contribute to the enhanced rubber hand illusion (RHI; a body perception illusion, induced by synchronous visual and tactile stimulation). Evidence based on RHI paradigms is emerging that auditory information can make an impact on the sense of body ownership, which relies on the process of multisensory inputs and integration. Hence, we assumed that auditory verbal hallucinations (AVHs), as an abnormal auditory perception, could be linked with body ownership, and the RHI paradigm could be conducted in patients with AVHs to explore the underlying mechanisms. In this study, we investigated the performance of patients with/without AVHs in the RHI. We administered the RHI paradigm to 80 patients with schizophrenia (47 with AVHs and 33 without AVHs) and 36 healthy controls. We conducted the experiment under two conditions (synchronous and asynchronous) and evaluated the RHI effects by both objective and subjective measures. Both patient groups experienced the RHI more quickly and strongly than HCs. The RHI effects of patients with AVHs were significantly smaller than those of patients without AVHs. Another important finding was that patients with AVHs did not show a reduction in RHI under asynchronous conditions. These results emphasize the disturbances of the sense of body ownership in schizophrenia patients with/without AVHs and the associations with AVHs. Furthermore, it is suggested that patients with AVHs may have multisensory processing dysfunctions and internal timing deficits.

Exploring Additional Valuable Information From Single-Cell RNA-Seq Data.

Single-cell RNA-seq (scRNA-seq) technologies are broadly applied to dissect the cellular heterogeneity and expression dynamics, providing unprecedented insights into single-cell biology. Most of the scRNA-seq studies mainly focused on the dissection of cell types/states, developmental trajectory, gene regulatory network, and alternative splicing. However, besides these routine analyses, many other valuable scRNA-seq investigations can be conducted. Here, we first review cell-to-cell communication exploration, RNA velocity inference, identification of large-scale copy number variations and single nucleotide changes, and chromatin accessibility prediction based on single-cell transcriptomics data. Next, we discuss the identification of novel genes/transcripts through transcriptome reconstruction approaches, as well as the profiling of long non-coding RNAs and circular RNAs. Additionally, we survey the integration of single-cell and bulk RNA-seq datasets for deconvoluting the cell composition of large-scale bulk samples and linking single-cell signatures to patient outcomes. These additional analyses could largely facilitate corresponding basic science and clinical applications.