Partial response of hepatocellular carcinoma to lenalidomide following progression in response to lenvatinib: A case report.

Hepatocellular carcinoma (HCC) is one of the most aggressive types of cancer. Although it has a high mortality rate, there is currently no effective treatment for HCC. Lenvatinib has traditionally been used as the first-line treatment for advanced HCC (aHCC); however, resistance to this therapy is common. It can be difficult to select effective second-line drugs to overcome lenvatinib resistance when treating aHCC. For patients with aHCC, poor treatment efficacy can result in patients missing the optimal treatment window and can lead to an irreversible situation. Lenalidomide has begun to be used to treat HCC; however, to the best of our knowledge, its efficacy in patients with lenvatinib-resistant HCC remains to be reported on in the literature. The present case report, to the best of our knowledge, describes the first case in the literature of a patient with lenvatinib-resistant aHCC who achieved a partial response after the treatment regimen was switched to lenalidomide. The present case report provides a promising novel route for the treatment of lenvatinib-resistant HCC.

Inhibition Effect of Pancreatic Exocrine Insufficiency on Immune Checkpoint Inhibitor Treatment in Pancreatic Cancer: A Retrospective Study.

Introduction: Chemotherapy combined with immune checkpoint inhibitors (ChIM) is used to treat advanced pancreatic ductal adenocarcinoma (PDAC). However, the efficacy of ChIM is similar to that of chemotherapy alone. Methods: To assess potential factors affecting the effectiveness of ChIM, we analyzed the clinical data of 359 patients with PDAC who visited the hospital during June 2017 to December 2022. Results: Surgical resection, diabetes, and ChIM were risk factors for pancreatic exocrine insufficiency (PEI). The adjusted odds ratio of ChIM was 2.63 (95% confidence interval (CI) 1.492-4.626) (P = 0.001). The incidence of PEI in the ChIM group (76.9%) was significantly higher than that of the chemotherapy group (60.2%) (P = 0.004). Survival analysis showed that ChIM did not improve the survival rate of patients with PDAC (hazard ratio (HR) 0.92, 0.707-1.197) (P = 0.534) in comparison with that of the chemotherapy group. However, in patients without PEI, those receiving ChIM showed a higher 1-year overall survival (OS) rate of 70.8% (two-sided, P = 0.045) and a median OS of 22.0 months (95% CI 11.5-32.5). Moreover, pancreatic enzyme replacement therapy significantly improved the OS of patients with PDAC (HR = 0.73, 95% CI = 0.561-0.956) (P = 0.022). Conclusion: Immune checkpoint inhibitors (ICIs) increased the incidence of PEI in patients with PDAC. The OS was not different between patients receiving chemotherapy and ChIM due to irregular PERT treatment. The finding show that pancreatic enzyme replacement therapy may improve the response rate of patients with PDAC to ICIs.

A pan-cancer analysis of potassium channel tetramerization domain containing 12 in human cancer.

Abnormal expression of the potassium channel tetramerization domain containing 12 (KCTD12) is closely related to the occurrence and development of various tumors, but a pan-cancer analysis of KCTD12 has not yet been conducted. We explored the association between KCTD12 and more than 30 human malignancies using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. First, the mRNA and protein levels of KCTD12 were examined and their correlations with tumor stage and survival were explored. Second, we analyzed the infiltration of CD8+ and CD4+ T cells and cancer-associated fibroblasts in tumors and explored the correlation between KCTD12 expression and tumor cell stemness, genomic heterogeneity, and diagnostic specificity. Finally, we explored the molecular mechanisms associated with KCTD12 using KEGG/GO analysis. The results showed that KCTD12 mRNA and protein expression levels decreased in most tumors was significantly associated with the prognosis of tumor patients, and the phosphorylation level of KCTD12 decreased in several tumors, such as S200 and T196, pancreatic adenocarcinoma (PAAD), lung adenocarcinoma (LUAD), and breast invasive cancer (BRCA). The expression of KCTD12 was positively correlated with the degree of cancer-associated fibroblasts infiltration in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), head and neck squamous cell carcinoma (HNSC), PAAD, and stomach adenocarcinoma (STAD). The relationship between KCTD12 expression and CD8+ and CD4+ T cell infiltration was also clarified. KCTD12 showed high diagnostic sensitivity for various types of tumors and may be involved in tumor cell biology by affecting tumor cell stemness, tumor burden, and other characteristics. Finally, we analyzed the molecular functions of KCTD12 and possible KEGG/GO signaling pathways. In this study, we developed a biological marker for diagnosis, prognosis, and immune infiltration of the pan-cancers.

Cancer Stem Cells are Actually Stem Cells with Disordered Differentiation: the Monophyletic Origin of Cancer.

Cancer stem cells (CSCs) play an important role in cancer development. Based on advancements in CSC research, we propose a monophyletic model of cancer. This model is based on the idea that CSCs are stem cells with disordered differentiation whose original purpose was to repair damaged tissues. Inflammatory responses and damage repair signals are crucial for the creation and maintenance of CSCs. Normal quiescent stem cells are activated by environmental stimulation, such as an inflammatory response, and undergo cell division and differentiation. In the initial stage of cancer development, stem cell differentiation leads to heteromorphism due to the accumulation of gene mutations, resulting in the development of metaplasia or precancerosis. In the second stage, accumulated mutations induce poor differentiation and lead to cancer development. The monophyletic model illustrates the evolution, biological behavior, and hallmarks of CSCs, proposes a concise understanding of the origin of cancer, and may encourage a novel therapeutic approach.

Immortalization-upregulated protein promotes pancreatic cancer progression by regulating NPM1/FHL1-mediated cell-cycle-checkpoint protein activity.

Immortalization-upregulated protein (IMUP) plays a vital role in cell proliferation and tumor progression. However, its role in pancreatic ductal adenocarcinoma (PDAC) remains unclear. Here, we select IMUP as an alternative gene based on GeneChip analysis of clinical PDAC tissues and transcriptome data from The Cancer Genome Atlas. IMUP expression is upregulated in PDAC tumor tissues. Moreover, high IMUP expression correlates with poor prognosis, while IMUP depletion inhibits PDAC cell proliferation and colony formation capacity in vitro, and decreases xenograft tumor growth in vivo. IMUP downregulation leads to cell-cycle arrest in the S phase. IMUP knockdown increases the expression of four-and-a-half LIM domain protein 1 (FHL1), which regulates the phosphorylation of cell division cycle 25A (CDC25A) by cycle checkpoint kinase 1 (CHK1) and promotes cytoplasmic distribution of CDC25A by interaction with 14-3-3ξ. Furthermore, FHL1 knockdown restores the effects induced by IMUP depletion. Liquid chromatography tandem mass spectrometry and immunoprecipitation analysis further show that IMUP interacts directly with nucleophosmin (NPM1) and enhances its stability. DNA methylation sequencing shows that FHL1 promoter methylation decreases when IMUP is downregulated. Overexpression of NPM1 can increase the methylation level of FHL1, thereby decreasing its expression. Our study provides a novel perspective on IMUP/NPM1/FHL1-mediated cell-cycle arrest by regulating CDC25A phosphorylation in PDAC. These findings may provide a new therapeutic target for PDAC.

Identifying cancer cell-secreted proteins that activate cancer-associated fibroblasts as prognostic factors for patients with pancreatic cancer.

The study aimed to investigate the mechanism by which cancer-associated fibroblasts (CAFs) are activated by cancer cells and construct a risk model to predict the prognosis of patients with pancreatic cancer (PC) after surgery. Pancreatic stellate cells were isolated from human pancreatic tissue and co-cultured with cancer cells to verify their crosstalk. Liquid chromatography-tandem mass spectrometry was used to detect proteins secreted by cancer cells. The online tools Gene Expression Profiling Interactive Analysis, UALCAN, and the Human Protein Atlas were used to analyse gene expression in PC. Expression data from the cancer genome atlas and the clinical samples were used to develop a training receiver operating characteristic (ROC) model and an external validation ROC model, respectively. We identified that cancer cells promote the activation of inflammatory CAFs (iCAF) through secretory proteins, which promote PC metastasis. Six candidate proteins secreted by cancer cells were identified which promote iCAF formation. These proteins were highly expressed in tumours and were associated with a poor prognosis in patients with PC. Moreover, a 6-gene model was constructed to predict death risk in patients at 1, 2 and 3 years after surgery. The training areas under the ROC curves (AUC) of 1-, 2- and 3-year death risks were 0.780, 0.792 and 0. 825, respectively. The externally validated AUC of death at 3 years post-surgery was 0.728. In conclusion, cancer cell-secreted proteins play a vital role in iCAF formation, and the 6-gene model may be a potential marker for predicting whether PC patients will benefit from surgery.

LINC01419 Promotes the Proliferation of Hepatoma Cells by Recruiting XRCC5 and Regulating Its Phosphorylation to Repair DNA Damage.

Background: Hepatocellular carcinoma (HCC) is one of the most common and fatal malignancies in human beings. Studies have shown that long non-coding RNAs (lncRNAs) play key parts in the occurrence and development of HCC. Although many lncRNAs have been studied in the HCC specifically for DNA damage repair, the role of LINC01419 in cellular DNA damage repair has not yet been studied. Objective: This study is aimed at exploring the biological role of LINC01419 and its potential mechanism in HCC. Methods: qRT-PCR was used to detect the expression level of LINC01419 in HCC tissues and cells, the proteins which were involved were detected by Western blot. Effect of LINC01419 knockdown on cell cycle, apoptosis, DNA damage, cell proliferation, wound healing, colony formation, and migration of HCC cells was studied in vitro. Results: The analysis showed that LINC01419 was overexpressed in HCC tissues and cells. Silencing of LINC01419 expression significantly inhibited the proliferation and migration ability of the HCC cells and resulted in cell cycle arrest at G0/G1 phase. Furthermore, the knockdown of LINC01419 increased the DNA damage, and to some extent, promoted sensitivity of HCC cells to doxorubicin. In addition, we performed RIP analysis which showed XRCC5 as a potential protein related to DNA damage repair in hepatoma cells. Conclusion: In conclusion, the LINC01419 acts as an oncogene in HCC and regulates DNA damage repair through XRCC5 in HCC cells.

Sensitivity analysis of factors influencing pollutant removal from shallow groundwater by the PRB method based on numerical simulation.

Permeable reactive barrier (PRB) is one of the most promising in situ treatment methods for shallow groundwater pollution. However, optimal design of PRB is very difficult due to a lack of comprehensive understanding of various complex influencing factors of PRB remediation. In this study, eight of the main factors of PRB, including hydraulic gradient I, permeability coefficient KPRB of PRB material, PRB length L, PRB width W, PRB distance from pollution source Dist., the ratio of the maximum adsorption capacity to Langmuir constant of PRB material Qmax/KL, the discharge rate of pollution source DR, and recharge concentration RC were investigated, to carry out the sensitivity analysis of PRB removal efficiency. The simulation experiments for Morris analysis were designed, and pollutant removal efficiency was numerically simulated by coupling MODFLOW and MT3DMS under two scenarios of high and low permeability and dispersivity. For a typical low permeability with low dispersity medium, the sensitivity ranking of factors from high to low is DR, RC, I, W, L, Dist., Qmax/KL, and KPRB, and for a typical high permeability with a high dispersity medium, the sensitivity ranking of factors from high to low is I, W, DR, Qmax/KL, L, RC, Dist., and KPRB. When considering multiple factors in PRB design, the greater the KPRB, L, W, Qmax/KL is, the higher the removal efficiency is; the greater the RC, I is, the lower the removal efficiency is. The rest factors remain ambiguous enhancement to removal efficiency.

miR-199a-5p inhibits the proliferation of hepatocellular carcinoma cells by regulating CDC25A to induce cell cycle arrest.

BACKGROUND: Hepatocellular carcinoma (HCC) has been verified as a really common cancer worldwide. Several studies have suggested that the suppression of malignancy growth can be traced to miR-199a-5p. Even though CDC25A could activate the tumorigenesis of various cancer by modulating cell cycle, the modulation of the miR-199a-5p/CDC25A axis is still not clear in HCC. Our aim is to identify the modulation of the miR-199a-5p/CDC25A axis in HCC. METHODS: The expression of CDC25A and miR-199a-5p in HCC cells and tissues was assessed using qRT-PCR. After using western blot assay to confirm the protein level, luciferase reporter and RNA pull-down assays were performed to explore the relation between CDC25A and miR-199a-5p. Functional assays such as CCK8 assay, BrdU proliferation assay and flow cytometry analysis identified the cell progression. RESULTS: Experimental findings indicated the downregulation of miR-199a-5p in HCC samples. It was also found that miR-199a-5p overexpression declined the development of the cells with HCC and that it could bind to CDC25A to suppress the progression of HCC. CONCLUSION: Research suggested that miR-199a-5p could restrain the proliferation ability of HCC cells by regulating CDC25A, thus inducing cell-cycle arrest.

Retrospective analysis of the effect of current clinical medications and clinicopathological factors on viral shedding in COVID-19 patients.

The aim of the present study was to identify the risk factors associated with prolonged shedding in patients with coronavirus disease 2019 (COVID-19), and to evaluate the effects of current clinical and clinicopathological factors on viral shedding in patients. A total of 186 COVID-19 inpatients were enrolled in this multicentre retrospective analysis. Detailed clinical data of each patient were collected, and the factors that affected the duration of viral shedding were retrospectively analysed. The median duration of viral shedding in the 186 COVID-19 patients was 13 days. The median duration of viral shedding was 12 days in non-severe patients, and 17 days in severe patients, and there was a significant difference between the two groups (P<0.001). Multi-factor regression analysis suggested that the onset-hospitalization interval [odds ratio (OR), 1.27; 95% confidence interval (CI), 1.15-1.41; P<0.001] and comorbidity with a chronic disease (OR, 2.43; 95% CI, 1.14-5.17; P=0.021) were independent risk factors for prolonged viral shedding, whereas lopinavir/ritonavir (LPV/r) was an independent protective factor (OR, 0.28; 95% CI, 0.11-0.75; P=0.011). Spearman's rank correlation analysis showed that the onset-drug interval was positively correlated with the duration of viral shedding (r=0.446; P<0.0001). Umifenovir, and low and short courses of glucocorticoids were not associated with prolonged viral shedding. The prolonged viral shedding was the initial causative factor of persistent aggravation of the patient's conditions. The interval between presentation of symptoms and hospitalization as well as complications with a comorbid chronic disease were independent risk factors for prolonged viral shedding. LPV/r shortened the duration of viral shedding, and the smaller the interval between presentation and LPV/r onset was, the faster viral shedding occurred.

Research Advances on DNA Methylation in Idiopathic Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic complex lung disease with no specific treatment and poor prognosis, characterized by the pulmonary progressive fibrosis and dysfunctions that lead to respiratory failure. Several factors may impact the progress of IPF, including age, cigarette smoking, and dusts, of which genetic and epigenetic factors mainly contribute to lung tissue fibrosis. DNA methylation is one of epigenetic processes that occur in many diseases and regulate chromosomal and extrachromosomal DNA functions in response to environmental exposures. The methylation plays pivotal roles in regulation of gene expression to facilitate the formation of fibroblastic foci and lung fibrosis. This chapter will describe alterations and effects of the DNA methylation on gene expression, the potential application of DNA methylation as a biomarker, and significance as therapeutic targets. Those understanding will provide us new insight into the treatment and prognosis of IPF.

Application of Single-Cell RNA Sequencing in Pancreatic Cancer and the Endocrine Pancreas.

The pancreas is a complex organ composed of an endocrine (pancreatic islets) and an exocrine portion. This mixed cell population has resulted in an implacable barrier to exploring the detailed mechanism and function of each cell type in previous investigative approaches. In recent years, single-cell RNA sequencing (scRNA-seq) technologies have provided in-depth analysis of cell heterogeneity in the pancreas and in pancreatic cancer. It is especially effective in cell-type-specific molecule identification and detection of interactions between cancer cells and the stromal microenvironment. To date, numerous reports have described the application of scRNA-seq in studies of pancreatic islets and pancreatic cancer. The aim of this paper is to review recent advances of pancreatic transcriptomics and pancreatic cancer using scRNA-seq strategies.

Long noncoding RNA EPIC1 interacts with YAP1 to regulate the cell cycle and promote the growth of pancreatic cancer cells.

Pancreatic cancer (PC) is a fatal disease; most patients are asymptomatic before the disease enters the advanced stage, but molecular mechanisms of early PC that can be exploited for diagnosis are not clear. Long noncoding RNAs (lncRNAs) play key roles in the progression of PC. In this study, we found that the expression of the lncRNA EPIC1 (Lnc-EPIC1) is high in PC and closely related to tumor size, TNM staging and lymph node metastasis status. Silencing Lnc-EPIC1 by siRNA targeting could significantly inhibit the cell growth and colony formation ability of PC cells and induced G1/S cell cycle arrest and apoptosis in PC cells. Lnc-EPIC1-specific siRNAs could downregulate the expression of cyclins and CDKs, such as CDC20, CDK4 and Cyclin A1. Knocking out YAP1 with the CRISPR/Cas-9 gene editing method recapitulated the effects of the Lnc-EPIC1-specific siRNAs on cell growth, colony formation ability and apoptosis in PC cells. In addition, the Lnc-EPIC1-specific siRNAs did not further inhibit cell growth or promote apoptosis in YAP1-knockout (YAP1-KO) cells. RNA immunoprecipitation (RIP) results showed that there was a direct interaction between Lnc-EPIC1 and YAP1. An Lnc-EPIC1-overexpressing lentiviral vector promoted the growth of PC cells. The results show that Lnc-EPIC1 interacts with YAP1 to promote the progression of PC.

Emergence of Bias During the Synthesis and Amplification of cDNA for scRNA-seq.

The advent of single-cell omics technology has promoted our understanding of the genomic, epigenomic, and transcriptomic heterogeneity in individual cells. Compared to traditional sequencing studies using bulk cells, single-cell transcriptome technology is naturally more dynamic for in depth analysis of genomic variation resulting from cell division and is useful in unraveling the regulatory mechanisms of gene networks in many diseases. However, there are still some limitations of current single-cell RNA sequencing (scRNA-seq) protocols. Biases that arise during the RNA reverse transcription and cDNA pre-amplification steps are the most common problems and play pivotal roles in limiting the quantitative accuracy of scRNA-seq. In this review, we will describe how these biases emerge and impact scRNA-seq protocols. Moreover, we will introduce several current and convenient modified scRNA-seq methods that allow for bias to be decreased and estimated.

Effects of matrix metalloproteinase inhibitor doxycycline and CD147 antagonist peptide-9 on gallbladder carcinoma cell lines.

Gallbladder carcinoma is the most common and aggressive malignancy of the biliary tree and highly expresses CD147, which is closely related to disease prognosis in a variety of human cancers. Doxycycline exhibited anti-tumor properties in many cancer cells. CD147 antagonist peptide-9 is a polypeptide and can specifically bind to CD147. The effect of these two drugs on gallbladder cancer cells has not been studied. The aim of this study is to investigate the effect of doxycycline and antagonist peptide-9 on gallbladder carcinoma cells and the possible mechanism of inhibition on cancer cell of doxycycline. To investigate the effects of doxycycline and antagonist peptide-9 on gallbladder carcinoma cells (GBC-SD and SGC-996), cell proliferation, CD147 expression, and early-stage apoptosis rate were measured after treated with doxycycline. Matrix metalloproteinase-2 and matrix metalloproteinase-9 activities were measured after treated with different concentrations of doxycycline, antagonist peptide-9, and their combination. The results demonstrated that doxycycline inhibited cell proliferation, reduced CD147 expression level, and induced an early-stage apoptosis response in GBC-SD and SGC-996 cells. The matrix metalloproteinase-2 and matrix metalloproteinase-9 activities were inhibited by antagonist peptide-9 and doxycycline, and the inhibitory effects were enhanced by combined drugs in gallbladder carcinoma cell lines. Taken together, doxycycline showed inhibitory effects on gallbladder carcinoma cell lines and reduced the expression of CD147, and this may be the mechanism by which doxycycline inhibits cancer cells. This study provides new information and tries to implement the design of adjuvant therapy method for gallbladder carcinoma.