Circ_0001946 Promotes the Development of Acute Myeloid Leukemia by Upregulating PDL1

Objective: Circ_0001946 has been identified as an oncogenic factor, and the aim of this study was to explore the detailed roles and putative targets of circ_0001946 in acute myeloid leukemia (AML). Materials and Methods: Levels of circ_0001946 were examined in AML tissues and cells. Furthermore, the regulatory functions of circ_0001946 in AML were explored. The expression of circ_0001946 was evaluated in AML samples and a matched para-carcinoma control, as well as in AML cell lines and a human bone marrow stromal cell line using reverse transcription-quantitative polymerase chain reaction. Cell proliferation was examined using a CCK-8 kit, and migration/invasion was measured by transwell assay. Furthermore, interactions between associated molecules were assessed using RNA pulldown, and the mRNA stability of the relevant gene was examined by mRNA stability assay. Results: Our data indicated that circ_0001946 was upregulated in AML specimens/cells. Additionally, overexpression of circ_0001946 promoted the proliferation, migration, and invasion of AML cells and, vice versa, these biological processes were suppressed by knockdown of circ_0001946. Furthermore, PDL1 is a potential downstream molecule of circ_0001946 in AML and its stability was improved by circ_0001946. The expression of PDL1 was increased in AML specimens and positively correlated with circ_0001946 expression. Moreover, biological behavioral alterations in AML cells induced by oe-circ_0001946 were abrogated by sh-PDL1 and the effects of sh-circ_0001946 were enhanced by treatment with sh-PDL1. Conclusion: Taken together, these data suggest that levels of circ_0001946 are elevated in AML and that circ_0001946 could promote the growth of AML cells. Furthermore, PDL1 is a novel downstream molecule of circ_0001946 in AML. Circ_0001946/PDL1 signaling may play crucial roles in tumor progression in AML and could be a novel candidate for targeted treatments for AML patients.

Ultrasound-guided perineal laser ablation versus prostatic arterial embolization for benign prostatic hyperplasia: two similar short-term efficacies.

BACKGROUND: There are many ways to treat prostatic hyperplasia; these are currently more inclined to minimally invasive treatment. We mainly compared the differences between two treatment methods， ultrasound-guided transperineal laser ablation (US-TPLA) and prostatic artery embolization (PAE). PURPOSE: To evaluate the efficacy and safety of US-TPLA and PAE in the treatment of benign prostatic hyperplasia (BPH). MATERIAL AND METHODS: The clinical information for 40 patients with BPH admitted to our hospital between June 2018 and January 2021 were retrospectively analyzed. The changes in International Prostate Symptom Score (IPSS), quality of life (QoL), maximum urinary flow rate (Qmax), postvoid residual (PVR), prostate volume (PV), and the incidence of complications were compared between groups. RESULTS: The IPSS (P < 0.001; P < 0.001), QoL (P < 0.001; P < 0.001), Qmax (P < 0.001; P < 0.001), PVR (P < 0.001; P < 0.001), and PV (P < 0.001; P < 0.001) at three and six months after US-TPLA and PAE improved with respect to those before surgery. There was no significant difference in IPSS (P = 0.235; P = 0.151), QoL (P = 0.527; P = 0.294), Qmax (P = 0.776; P = 0.420), PVR (P = 0.745; P = 0.607), and PV (P = 0.527; P = 0.573) between the groups at three and six months after surgery. No serious complications occurred in either group. CONCLUSION: US-TPLA and PAE seem to have a similar short-term efficacy. The efficacy of the two procedures is comparable, and neither is associated with serious complications. US-TPLA and PAE are both effective complementary measures for the treatment of BPH.

Multifactorial Analysis of Clinical Prognosis of Liver Metastasis and Vascular Intervention Combined with Ablation in Colorectal Cancer.

Colorectal cancer is one of the leading causes of deaths in China. The initial stages of colorectal cancer can be treated by surgery, radiation, and chemotherapy. However, in the advanced stages, it warrants an application of multimodality treatment. With advances in the medical field, there are applications of new modality of treatment that could possibly provide the appropriate treatment for the advanced stage tumours. The first site of metastasis after colorectal cancer is the liver and the conventional treatment to cure the metastatic lesion involves the administration of chemotherapy. With further advancement, chemotherapy has been directly administered at the thorough transarterial chemoembolization (TACE) which is a vascular intervention. With further advancement, the nonvascular intervention, such as radiofrequency ablations (RFAs), has been administered to the patients. A large amount of data support the use of vascular intervention (TACE) with ablation for hepatic carcinoma; there is no sufficient literature to support the application of the modality in the metastatic liver lesion. In this prospective observational study, we have enrolled 80 patients with metastatic liver lesion from the adenocarcinoma of colon or rectum, treated the patients with a combination of the TACE and ablation therapy, and followed up the patients for a period of 3 years. A multivariate analysis of the various factors that influence the prognosis and outcome has been studied and it has been concluded that the combination therapy is medically beneficial for individuals with aggressive liver lesions, improving overall as well as progression-free life span.

Synergistic effects of Rapamycin and Fluorouracil to treat a gastric tumor in a PTEN conditional deletion mouse model.

The tumor suppressor gene phosphatase and tensin homolog (PTEN) in PI3K/Akt/mTOR pathway is essential in inhibiting tumor growth and metastasis. However, whether the mutation of PTEN gene could induce tumorigenesis and impact the treatment of gastric cancer is still unclear. The purpose of the study was to investigate the combined treatment of gastric tumorigenesis using Rapamycin and Fluorouracil (5-Fu) through interfering with the Akt/mTOR pathway in a mouse model with PTEN conditional deletion. Three groups of mice were exposed for 5 days to Rapamycin and 5-Fu separately and together. The gene expression of the Akt/mTOR pathway, the protein expression of caspase-3 and p-Akt, p-S6K and p-4EBP1, and the pathological changes in stomachs were analyzed. Our study demonstrates that the conditional PTEN deletion in the cells of glandular stomach induces hyperplastic gastric tumors in mice. The combined Rapamycin administration with 5-Fu resulted in better outcomes than their separate administration for the treatment of gastric cancer by inhibiting the mTOR signal pathway. Our study indicates that Rapamycin has a synergistic interaction with chemotherapeutic 5-Fu, and demonstrates a potential therapeutic combination treatment on glandular stomach tumor with PTEN functional absence or aberrantly activated Akt/mTOR pathway. It provides important insights into the inhibition of the Akt/mTOR pathway in gastric cancer clinical therapy.

Effect of infection after liver cancer interventional therapy on T lymphocyte subsets and Toll-like receptors in peripheral blood mononuclear cells and its mechanism.

BACKGROUND: The T lymphocyte subset levels are an indicator used to evaluate the immune status of the body. In recent years, many studies have investigated the correlation between T lymphocyte subset levels and postoperative infection. OBJECTIVES: To investigate the incidence of infection after liver cancer interventional therapy and its influence on T lymphocyte subset levels and toll-like receptors (TLRs). MATERIAL AND METHODS: A total of 325 patients with primary liver cancer receiving interventional therapy were divided into an infection group (n = 37) and a non-infection group (n = 288). The infection site and the distribution of pathogenic bacteria in the infection group were observed. The serum T lymphocyte subset level and TLR2 and TLR4 levels in peripheral blood mononuclear cells were compared. The clinical value of the postoperative TLR2 and TLR4 levels in evaluating infection was analyzed using receiver operating characteristic (ROC) curves. RESULTS: Among 51 strains of pathogens isolated from the infected patients, strains of Escherichia coli (27.45%) and Pseudomonas aeruginosa (19.61%) were the most commonly observed. After surgery, the levels of CD3+, CD4+ and CD4+/CD8+ decreased, while the level of CD8+ increased in both groups; the levels of TLR2 and TLR4 decreased in the non-infection group, while the levels of TLR2 and TLR4 increased in the infection group (all p < 0.05). Furthermore, the decreases and increases were more significant in the infection group than in the non-infection group (all p < 0.001). The area under the curve of postoperative TLR2 and TLR4 levels in evaluating infection were greater than 0.700 (p < 0.001). CONCLUSIONS: Gram-negative bacteria account for the majority of infections in patients after liver cancer interventional therapy, and the main infection sites are the lung and abdomen. The infected patients show changes in T lymphocyte level and decreased immune function. The TLR2 and TLR4 can be used as auxiliary indicators to evaluate infection after surgery.

MicroRNA-183 promotes migration and invasion of CD133(+)/CD326(+) lung adenocarcinoma initiating cells via PTPN4 inhibition.

Non-small cell lung cancer (NSCLC) is the most common cancer worldwide and is a leading cause of lung cancer mortality due to early stage metastases. Cancer stem-like cells (CSLCs) or tumor-initiating cells (TICs) are rare subpopulation cells that are responsible for maintaining tumor growth and invasion leading to recurrence and metastasis. Previous studies revealed that miR-183 can mediate the invasiveness and growth of NSCLC. However, the exact role of miR-183 in regulating the biological behavior of CSLCs in NSCLC remains unclear. In the present study, we explored the regulation of protein tyrosine phosphatase non-receptor type 4 (PTPN4) by miR-183 in vitro using luciferase reporter assays, and we further analyzed the effects of miR-183 on the invasiveness of CSLCs in vitro and in vivo using transwell and bioluminescence assays. Following our finding that miR-183 binds to PTPN4 messenger RNA (mRNA) to prevent its translation through the 3'-untranslated region (UTR), we found that overexpression of miR-183 in CSLCs decreased PTPN4 protein levels while inhibition of miR-183 increased PTPN4 protein levels. The suppression of PTPN4 levels in CSLCs by miR-183 paralleled with a significant promotion in their motility in vitro and in vivo, while anti-sense miR-183 increased PTPN4 levels in CSLCs, which paralleled with a significant decrease in their invasiveness. Furthermore, correlation analysis between miR-183 and PTPN4 in clinical samples demonstrated a statistically significant inverse correlation between PTPN4 mRNA levels and miR-183. In brief, our data indicate that miR-183 plays a pro-invasive role by inverse regulation of PTPN4, and this axis may be a new therapeutic target for suppressing the metastatic capability of CSLCs in NSCLC.

Demonstrating approaches to chemically modify the surface of Ag nanoparticles in order to influence their cytotoxicity and biodistribution after single dose acute intravenous administration.

With the advance in material science and the need to diversify market applications, silver nanoparticles (AgNPs) are modified by different surface coatings. However, how these surface modifications influence the effects of AgNPs on human health is still largely unknown. We have evaluated the uptake, toxicity and pharmacokinetics of AgNPs coated with citrate, polyethylene glycol, polyvinyl pyrolidone and branched polyethyleneimine (Citrate AgNPs, PEG AgNPs, PVP AgNPs and BPEI AgNPs, respectively). Our results demonstrated that the toxicity of AgNPs depends on the intracellular localization that was highly dependent on the surface charge. BPEI AgNPs (ζ potential = +46.5 mV) induced the highest cytotoxicity and DNA fragmentation in Hepa1c1c7. In addition, it showed the highest damage to the nucleus of liver cells in the exposed mice, which is associated with a high accumulation in liver tissues. The PEG AgNPs (ζ potential = -16.2 mV) showed the cytotoxicity, a long blood circulation, as well as bioaccumulation in spleen (34.33 µg/g), which suggest better biocompatibility compared to the other chemically modified AgNPs. Moreover, the adsorption ability with bovine serum albumin revealed that the PEG surface of AgNPs has an optimal biological inertia and can effectively resist opsonization or non-specific binding to protein in mice. The overall results indicated that the biodistribution of AgNPs was significantly dependent on surface chemistry: BPEI AgNPs > Citrate AgNPs = PVP AgNPs > PEG AgNPs. This toxicological data could be useful in supporting the development of safe AgNPs for consumer products and drug delivery applications.

Monitoring microRNAs using a molecular beacon in CD133+/ CD338+ human lung adenocarcinoma-initiating A549 cells.

Lung cancer is the most common causes of cancer-related deaths worldwide, and a lack of effective methods for early diagnosis has greatly impacted the prognosis and survival rates of the affected patients. Tumor-initiating cells (TICs) are considered to be largely responsible for tumor genesis, resistance to tumor therapy, metastasis, and recurrence. In addition to representing a good potential treatment target, TICs can provide clues for the early diagnosis of cancer. MicroRNA (miRNA) alterations are known to be involved in the initiation and progression of human cancer, and the detection of related miRNAs in TICs is an important strategy for lung cancer early diagnosis. As Hsa-miR-155 (miR-155) can be used as a diagnostic marker for non-small cell lung cancer (NSCLC), a smart molecular beacon of miR-155 was designed to image the expression of miR-155 in NSCLC cases. TICs expressing CD133 and CD338 were obtained from A549 cells by applying an immune magnetic bead isolation system, and miR-155 was detected using laser-scanning confocal microscopy. We found that intracellular miR- 155 could be successfully detected using smart miR-155 molecular beacons. Expression was higher in TICs than in A549 cells, indicating that miR-155 may play an important role in regulating bio-behavior of TICs. As a non-invasive approach, molecular beacons could be implemented with molecular imaging to diagnose lung cancer at early stages.

Identification of a cancer stem-like population in the Lewis lung cancer cell line.

OBJECTIVE: Although various human cancer stem cells (CSCs) have been defined, their applications are restricted to immunocompromised models. Developing a novel CSC model which could be used in immunocompetent or transgenic mice is essential for further understanding of the biomolecular characteristics of tumor stem cells. Therefore, in this study, we analyzed murine lung cancer cells for the presence of CSCs. METHODS: Side population (SP) cells were isolated by fluorescence activated cell sorting, followed by serum-free medium (SFM) culture, using Lewis lung carcinoma cell (LLC) line. The self-renewal, differentiated progeny, chemosensitivity, and tumorigenic properties in SP and non-SP cells were investigated through in vitro culture and in vivo serial transplantation. Differential expression profiles of stem cell markers were examined by RT-PCR. RESULTS: The SP cell fraction comprised 1.1% of the total LLC population. SP cells were available to grow in SFM, and had significantly enhanced capacity for cell proliferation and colony formation. They were also more resistant to cisplatin in comparison to non-SP cells, and displayed increased tumorigenic ability. Moreover, SP cells showed higher mRNA expression of Oct-4, ABCG2, and CD44. CONCLUSION: We identified SP cells from a murine lung carcinoma, which possess well-known characteristics of CSCs. Our study established a useful model that should allow investigation of the biological features and pharmacosensitivity of lung CSCs, both in vitro and in syngeneic immunocompetent or transgenic/knockout mice.

Aberrant microRNAs expression in CD133⁺/CD326⁺ human lung adenocarcinoma initiating cells from A549.

Increasing evidence demonstrates that miRNAs are involved in the dysregulation of tumor initiating cells (TICs) in various tumors. Due to a lack of definitive markers, cell sorting is not an ideal separation method for lung adenocarcinoma initiating cells. In this study, we combined paclitaxel with serum-free medium cultivation (inverse-induction) to enrich TICs from A549 cells, marked by CD133/CD326, defined features of stemness. We next investigated aberrant microRNAs in this subpopulation compared to normal cells with miRNA microarray and found that 50 miRNAs exhibited a greater than 2-fold change in expression. As further validation, 10 miRNAs were chosen to perform quantitative RT-PCR on the A549 cell line and primary samples. The results suggest that aberrant expression of miRNAs such as miR-29ab, miR-183, miR-17-5p and miR-127-3P may play an important role in regulating the bio-behavior of TICs.