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BioRxiv : the Preprint Server For... Jun 2024Cellular mechanical properties influence cellular functions across pathological and physiological systems. The observation of these mechanical properties is limited in...
Cellular mechanical properties influence cellular functions across pathological and physiological systems. The observation of these mechanical properties is limited in part by methods with a low throughput of acquisition or with low accessibility. To overcome these limitations, we have designed, developed, validated, and optimized a microfluidic cellular deformation system (MCDS) capable of mechanotyping suspended cells on a population level at a high throughput rate of ∼300 cells pers second. The MCDS provides researchers with a viable method for efficiently quantifying cellular mechanical properties towards defining prognostic implications of mechanical changes in pathology or screening drugs to modulate cytoskeletal integrity.
PubMed: 38948841
DOI: 10.1101/2024.06.17.599307 -
BioRxiv : the Preprint Server For... Jun 2024Solid carcinomas are often highly heterogenous cancers, arising from multiple epithelial cells of origin. Yet, how the cell of origin influences the response of the...
Solid carcinomas are often highly heterogenous cancers, arising from multiple epithelial cells of origin. Yet, how the cell of origin influences the response of the tumor microenvironment is poorly understood. Lung adenocarcinoma (LUAD) arises in the distal alveolar epithelium which is populated primarily by alveolar epithelial type I (AT1) and type II (AT2) cells. It has been previously reported that AT1 cells can give rise to a histologically-defined LUAD that is distinct in pathology and transcriptomic identity from that arising from AT2 cells . To determine how cells of origin influence the tumor immune microenvironment (TIME) landscape, we comprehensively characterized transcriptomic, molecular, and cellular states within the TIME of AT1 and AT2-derived LUAD using KRAS oncogenic driver mouse models. Myeloid cells within the AT1-derived LUAD TIME were increased, specifically, immunoreactive monocytes and tumor associated macrophages (TAMs). In contrast, the AT2 LUAD TIME was enriched for Arginase-1 myeloid derived suppressor cells (MDSC) and TAMs expressing profiles suggestive of immunosuppressive function. Validation of immune infiltration was performed using flow cytometry, and intercellular interaction analysis between the cells of origin and major myeloid cell populations indicated that cell-type specific markers SFTPD in AT2 cells and CAV1 in AT1 cells mediated unique interactions with myeloid cells of the differential immunosuppressive states within each cell of origin mouse model. Taken together, AT1-derived LUAD presents with an anti-tumor, immunoreactive TIME, while the TIME of AT2-derived LUAD has hallmarks of immunosuppression. This study suggests that LUAD cell of origin influences the composition and suppression status of the TIME landscape and may hold critical implications for patient response to immunotherapy.
PubMed: 38948812
DOI: 10.1101/2024.06.19.599651 -
BioRxiv : the Preprint Server For... Jun 2024SARS-CoV-2 is a highly transmissible virus that causes COVID-19 disease. Mechanisms of viral pathogenesis include excessive inflammation and viral-induced cell death,...
SARS-CoV-2 is a highly transmissible virus that causes COVID-19 disease. Mechanisms of viral pathogenesis include excessive inflammation and viral-induced cell death, resulting in tissue damage. We identified the host E3-ubiquitin ligase TRIM7 as an inhibitor of apoptosis and SARS-CoV-2 replication via ubiquitination of the viral membrane (M) protein. mice exhibited increased pathology and virus titers associated with epithelial apoptosis and dysregulated immune responses. Mechanistically, TRIM7 ubiquitinates M on K14, which protects cells from cell death. Longitudinal SARS-CoV-2 sequence analysis from infected patients revealed that mutations on M-K14 appeared in circulating variants during the pandemic. The relevance of these mutations was tested in a mouse model. A recombinant M- K14/K15R virus showed reduced viral replication, consistent with the role of K15 in virus assembly, and increased levels of apoptosis associated with the loss of ubiquitination on K14. TRIM7 antiviral activity requires caspase-6 inhibition, linking apoptosis with viral replication and pathology.
PubMed: 38948778
DOI: 10.1101/2024.06.17.599107 -
Frontiers in Pharmacology 2024Pancreatoblastoma (PB), a neoplasm derived from pancreatic follicular cells, primarily affects the pediatric population. Although infrequent in adults, it is associated...
Pancreatoblastoma (PB), a neoplasm derived from pancreatic follicular cells, primarily affects the pediatric population. Although infrequent in adults, it is associated with a considerably worse prognosis. Approximately one-third of patients are diagnosed with metastatic disease, with liver metastases being the most prevalent. Diagnosis relies on histopathological alterations including squamous vesicles, positive staining for CK8/CK18/CK19, and nuclear displacement of β-catenin. Additionally, liver metastases demonstrate substantial enhancement during the arterial phase of a contrast-enhanced computed tomography (CT) scan. Surgical resection serves as the principal therapeutic approach for addressing primary lesions and liver metastatic PB. In instances where surgical intervention is not viable, patients may derive benefits from systemic therapy and radiotherapy. This particular case report presents the clinical details of a 27-year-old female patient diagnosed with PB, who subsequently developed multiple liver metastases following a pancreaticoduodenectomy. Genomic examinations revealed the presence of ERBB2 amplification, RAD54L deletion, low TMB-L, and MSS in the patient. Despite the patient undergoing chemotherapy and Her-2 targeted therapy in conjunction with immunotherapy, no reduction in lesion size was observed until the administration of surufatinib. Subsequently, a notable outcome ensued, where the metastatic lesions were effectively excised via surgical intervention. Surufatinib has demonstrated a progression-free survival (PFS) of no less than 14 months, and the patient's survival has endured for a duration of 33 months. This indicates the potential efficacy of surufatinib as a viable therapeutic alternative for adult patients afflicted with PB.
PubMed: 38948477
DOI: 10.3389/fphar.2024.1361628 -
Frontiers in Pharmacology 2024Genomic profiling has revolutionized therapeutic interventions and the clinical management of liver cancer. However, pathogenetic mechanisms, molecular determinants of...
Genomic profiling has revolutionized therapeutic interventions and the clinical management of liver cancer. However, pathogenetic mechanisms, molecular determinants of recurrence, and predictive biomarkers for first-line treatment (anti-PD-(L)1 plus bevacizumab) in liver cancer remain incompletely understood. Targeted next-generation sequencing (tNGS) (a 603-cancer-gene panel) was applied for the genomic profiling of 232 hepatocellular carcinoma (HCC) and 22 intrahepatic cholangiocarcinoma (ICC) patients, among which 47 unresectable/metastatic HCC patients underwent anti-PD-1 plus bevacizumab therapy. Genomic alterations were estimated for their association with vascular invasion (VI), location of onset, recurrence, overall survival (OS), recurrence-free survival (RFS), and anti-PD-1 plus bevacizumab therapy response. The genomic landscape exhibited that the most commonly altered genes in HCC were , , , , , and , while , , , , , and were frequently altered in ICC; notably, (18.18% vs. 1.29%) and (13.64% vs. 1.29%) alterations were significantly more prevalent in ICC. Comparison analysis demonstrated the distinct clinicopathological/genomic characterizations between Chinese and Western HCC cohorts. Genomic profiling of HCC underlying VI showed that , , , , and were frequently altered in the VI group compared to patients without VIs. Compared to the right hepatic lobes of HCC patients, the left hepatic lobe of HCC patients had superior OS (median OS: 36.77 months vs. unreached, < 0.05). By further comparison, Notch signaling pathway-related alterations were significantly prevalent among the right hepatic lobes of HCC patients. Of note, multivariate Cox regression analysis showed that altered , , , , and , as independent prognostic factors, were significantly correlated with the OS of HCC patients. Furthermore, altered was abundantly enriched in the HCC-recurrent group, and impressively, it was independent of clinicopathological features in predicting RFS (median RFS of altered type vs. wild-type: 5.57 months vs. 22.47 months, < 0.01). Regarding those treated HCC patients, TMB value, altered , and cell cycle-related alterations were identified to be positively associated with the objective response rate (ORR), but alterations were negatively correlated with ORR. In addition, altered and cell cycle signaling were significantly associated with reduced and increased time to progression-free survival (PFS), respectively. Comprehensive genomic profiling deciphered distinct molecular characterizations underlying VI, location of onset, recurrence, and survival time in liver cancer. The identification of novel genetic predictors of response to anti-PD-1 plus bevacizumab in HCC facilitated the development of an evidence-based approach to therapy.
PubMed: 38948469
DOI: 10.3389/fphar.2024.1416295 -
Frontiers in Pharmacology 2024Inflammatory bowel disease (IBD) is a chronic condition that can be managed with treatment, but it is challenging to get IBD cured. Resveratrol, a non-flavonoid...
Inflammatory bowel disease (IBD) is a chronic condition that can be managed with treatment, but it is challenging to get IBD cured. Resveratrol, a non-flavonoid polyphenolic organic compound derived from various plants, has a potential effect on IBD. The current research was set out to investigate the therapeutic effects of resveratrol on animal models of IBD. A comprehensive search of PubMed, Embase, Web of Science, and Chinese databases was performed. The literature search process was completed independently by two people and reviewed by a third person. The risk of bias in the included literature was assessed using the Collaborative Approach to Meta Analysis and Review of Animal Data from Experimental Stroke (CAMARADES) 10-point quality checklist. The meta-analysis utilized Review Manager 5.4 software to evaluate the efficacy of resveratrol, with histopathological index as the primary outcome measure. Subgroup analysis was conducted based on this indicator. Additionally, meta-analyses were carried out on different outcomes reported in the literature, including final disease activity index, final body weight change, colon length, splenic index, and inflammatory factors. After conducting a thorough literature search and selection process, a total of 28 studies were ultimately included in the analysis. It was found that over half of the selected studies had more than five items with low risk of bias in the bias risk assessment. Relevant datas from included literature indicated that the histopathological index of the resveratrol group was significantly lower than that of the control group (WMD = -2.58 [-3.29, -1.87]). Subgroup analysis revealed that higher doses of resveratrol (>80 mg/kg) had a better efficacy (WMD = -3.47 [-4.97, -1.98]). Furthermore, The data summary and quantitative analysis results of SI and colon length also showed that resveratrol was effective in alleviating intestinal mucosal pathological injury of IBD. In terms of biochemical indicators, the summary analysis revealed that resveratrol affected interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-10 (IL-10), tumor necrosis factor-α (TNF-α), transforming growth factor-β (TGF-β), interferon-γ (IFN-γ), malondialdehyde (MDA), myeloperoxidase (MPO), superoxide dismutase (SOD), and prostaglandin E2 (PGE2) significantly. These effects may be attributed to the mechanism of resveratrol in regulating immune response and inhibiting oxidative stress. This review suggests that resveratrol demonstrated a notable therapeutic impact in preclinical models of IBD, particularly at doses exceeding 80 mg/kg. This efficacy is attributed to the protective mechanisms targeting the intestinal mucosa involved in the pathogenesis of IBD through various pathways. As a result, resveratrol holds promising prospects for potential clinical use in the future.
PubMed: 38948464
DOI: 10.3389/fphar.2024.1411566 -
Frontiers in Genetics 2024The Euchromatic Histone Methyl Transferase Protein 2 (EHMT2), also known as G9a, deposits transcriptionally repressive chromatin marks that play pivotal roles in the...
The Euchromatic Histone Methyl Transferase Protein 2 (EHMT2), also known as G9a, deposits transcriptionally repressive chromatin marks that play pivotal roles in the maturation and homeostasis of multiple organs. Recently, we have shown that inactivation in the mouse pancreas alters growth and immune gene expression networks, antagonizing Kras-mediated pancreatic cancer initiation and promotion. Here, we elucidate the essential role of Ehmt2 in maintaining a transcriptional landscape that protects organs from inflammation. Comparative RNA-seq studies between normal postnatal and young adult pancreatic tissue from conditional knockout animals ( ) targeted to the exocrine pancreatic epithelial cells ( and ), reveal alterations in gene expression networks in the whole organ related to injury-inflammation-repair, suggesting an increased predisposition to damage. Thus, we induced an inflammation repair response in the pancreas and used a data science-based approach to integrate RNA-seq-derived pathways and networks, deconvolution digital cytology, and spatial transcriptomics. We also analyzed the tissue response to damage at the morphological, biochemical, and molecular pathology levels. The pancreas displays an enhanced injury-inflammation-repair response, offering insights into fundamental molecular and cellular mechanisms involved in this process. More importantly, these data show that conditional inactivation in exocrine cells reprograms the local environment to recruit mesenchymal and immunological cells needed to mount an increased inflammatory response. Mechanistically, this response is an enhanced injury-inflammation-repair reaction with a small contribution of specific Ehmt2-regulated transcripts. Thus, this new knowledge extends the mechanisms underlying the role of the Ehmt2-mediated pathway in suppressing pancreatic cancer initiation and modulating inflammatory pancreatic diseases.
PubMed: 38948355
DOI: 10.3389/fgene.2024.1412767 -
Pleura and Peritoneum Jun 2024There are few data on Pressurized IntraPeritoneal Aerosol Chemotherapy with cisplatin and doxorubicin (PIPAC C/D) in women with primary unresectable or recurrent...
OBJECTIVES
There are few data on Pressurized IntraPeritoneal Aerosol Chemotherapy with cisplatin and doxorubicin (PIPAC C/D) in women with primary unresectable or recurrent platinum-resistant peritoneal metastasis (PM) from ovarian cancer (OC). We evaluated survival, histological and cytological response, Quality of Life (QoL) and toxicity after PIPAC C/D in these patients.
METHODS
Retrospective analysis of patients from the prospective PIPAC-OPC1 and -OPC2 studies. The histological response was evaluated by the Peritoneal Regression Grading Score (PRGS). QoL questionnaires were collected at baseline and after third PIPAC or 60 days. Adverse events were collected until 30 days after the last PIPAC. Demographic and survival data were analysed based on intention to treat. Response, QoL and toxicity were analysed per protocol (≥1 PIPAC).
RESULTS
Twenty-nine patients were included. Five patients (17 %) were non-accessible at PIPAC 1. One patient was excluded due to liver metastases at PIPAC 1. Thus, 23 patients had 76 PIPACs (median 2, range 1-12). Median overall survival was 8.2 months (95 % CI 4.4-10.3) from PIPAC 1. Biopsy data were available for 22 patients, and seven (32 %) patients had a major/complete histological response (PRGS≤2) at PIPAC 3. No cytological conversions were registered. Symptoms and function scores worsened, while emotional scores improved. Three patients had severe adverse reactions (two ileus, one pulmonary embolism); no life-threatening reactions or treatment-related mortality was observed.
CONCLUSIONS
PIPAC C/D was feasible and induced histological regression in a substantial proportion of patients with platinum-resistant PM from OC. Larger studies are needed to evaluate impact on survival.
PubMed: 38948328
DOI: 10.1515/pp-2023-0049 -
Pleura and Peritoneum Jun 2024Malignant pleural effusion (MPE) is a common and debilitating condition seen in advanced cancer disease, and life-expectancy is short. Symptoms include pain and severe... (Review)
Review
BACKGROUND
Malignant pleural effusion (MPE) is a common and debilitating condition seen in advanced cancer disease, and life-expectancy is short. Symptoms include pain and severe shortness of breath. Current first-line treatment options include pleural drainage using catheters as well as pleurodesis. However, these treatment modalities are often inefficient and patients need repeated procedures. Pressurized IntraThoracic Aerosol Chemotherapy (PITAC) is a minimally invasive procedure, where antineoplastic agents are nebulized under pressure into the pleural space.
CONTENT
We present the preliminary safety, feasibility, and response assessment data for PITAC based on a comprehensive literature review.
SUMMARY
Five retrospective studies reported data on 38 PITACs in 21 patients. Data were heterogeneous and incomplete on several important aspects such as procedure, safety, local effect and long-term outcomes. PITAC seems technically feasible with a low risk of complications and may provide some reduction in MPE in selected cases.
OUTLOOK
PITAC seems feasible, but prospective phase I and II studies are needed to define safety, indications, and efficacy.
PubMed: 38948327
DOI: 10.1515/pp-2023-0048 -
Pleura and Peritoneum Jun 2024Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) is an experimental treatment option in peritoneal metastasis from pancreatic cancer (PM-PC). Aims were to...
OBJECTIVES
Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) is an experimental treatment option in peritoneal metastasis from pancreatic cancer (PM-PC). Aims were to examine mRNA profile of fibrosis due to response after systemic chemotherapy and PIPAC (Regression) compared to treatment-naïve PM-PC and chronic cholecystitis-related peritoneal fibrosis (Controls).
METHODS
Peritoneal biopsies (PBs) from PM-PC patients who had undergone systemic chemotherapy and PIPAC were evaluated with Peritoneal Regression Grading Score (PRGS). We extracted RNA from PBs with Regression (PRGS 1, n=11), treatment-naïve PM-PC (n=10), and Controls (n=10). Profiling of 800 mRNAs was performed (NanoString nCounter, PanCancer Immuno-Oncology 360 (IO-360) and 30 additional stroma-related mRNAs).
RESULTS
Regression vs. PM-PC identified six up-regulated and 197 down-regulated mRNAs (FDR≤0.05), linked to TNF-α signaling via NF-kB, G2M checkpoint, epithelial-mesenchymal transition, estrogen response, and coagulation. Regression vs. Controls identified 43 significantly up-regulated mRNAs, linked to interferon-α response, and down-regulation of 99 mRNAs, linked to TNF-α signaling via NF-kB, inflammatory response, epithelial-mesenchymal transition, KRAS signaling, and hypoxia (FDR≤0.05).
CONCLUSIONS
In regressive fibrosis of PM-PC after systemic chemotherapy and PIPAC (Regression), downregulation of mRNAs related to key tumor biological pathways was identified. Regression also showed transcriptional differences from unspecific, benign fibrosis (Controls). Future studies should explore whether mRNA profiling of PBs with PM from PC or other primaries holds prognostic or predictive value.
PubMed: 38948326
DOI: 10.1515/pp-2024-0001