CAFs-derived Exosomal miR-889-3p Might Repress M1 Macrophage Polarization to Boost ESCC Development by Regulating STAT1.

Cancer-associated fibroblasts (CAFs) represent one of the major components of the tumor stroma, which might create an immunosuppressive tumor microenvironment by inducing and functionally polarizing protumoral macrophages. Previous studies indicated that exosomes derived from CAFs might transmit regulating signals and boost esophageal squamous cell carcinoma (ESCC) development. This study is designed to explore the role and mechanism of CAFs-derived exosomal microRNA-889-3p (miR-889-3p) in ESCC progression. Macrophage polarization was detected using flow cytometry. miR-889-3p, Tumor necrosis factor alpha (TNF-α), and inducible nitric oxide synthase (iNOS) levels were detected by real-time quantitative polymerase chain reaction (RT-qPCR). Cell proliferation, cycle progression, migration, and invasion were assessed using Cell Counting Kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EdU), scratch assay, and Transwell assays. α-SMA, FAP, CD63, CD81, and signal transducer and activator of transcription 1 (STAT1) protein levels were detected using western blot. Exosomes were characterized using an electron microscope and nanoparticle tracking analysis (NTA). Binding between miR-889-3p and STAT1 was predicted by Starbase, and verified by a dual-luciferase reporter and RNA pull-down. The effect of CAFs-derived exosomal miR-889-3p on ESCC tumor growth in vivo was detected using mice xenograft assay. miR-889-3p level was decreased in LPS-induced M0 macrophages. CAF-derived exosomal miR-889-3p knockdown suppressed ESCC proliferation, migration, and invasion. CAFs might transfer miR-889-3p to M0 macrophages via exosomes. STAT1 was a target of miR-889-3p. Besides, in vivo studies confirmed that CAFs-derived exosomal miR-889-3p can accelerate ESCC tumor growth by regulating STAT1. CAFs-derived exosomal miR-889-3p facilitates esophageal squamous cell carcinoma cell proliferation, migration, and invasion by inhibiting M1 macrophage polarization through down-regulation of STAT1, providing a promising therapeutic target for ESCC.

METTL3 mediates m6A modification of hsa_circ_0072380 to regulate the progression of gestational diabetes mellitus.

BACKGROUND: m6A modification plays a vital role in gestational diabetes mellitus (GDM) progression. However, the role of METTL3 and differential m6A-modified circRNAs in GDMremainsto be investigated. METHODS: Placental tissue samples from GDM patients and normal controls (NC) were collected to measure changes in m6A modification levels. MeRIP-seq on placental tissue was performed to detect differential m6A-modified circRNAs.High glucose (HG)-treated JEG3 cells were used to establish the GDM cell model. Differentially expressed circRNAs levels in GDM and NC groups were measured by qRT-PCR. We knocked down METTL3 to study its function. Additionally, we conducted functional recovery experiments. Dot blot assay was utilized to assess changes in m6A levels. MeRIP-qPCR was performed to evaluate the effect of knocking down METTL3 on m6A modification of hsa_circ_0072380 in JEG3 cells. RESULTS: Compared with the NC group, the GDM group exhibited increased levels of m6A modification and METTL3 expression. Differences in m6A modification of circRNAs exist between the GDM and NC groups. Hsa_circ_0000994, hsa_circ_0058733, and hsa_circ_0072380 were significantly down-regulated in the GDM group while hsa_circ_0036376, hsa_circ_0000471, and hsa_circ_0001173 showed no significant differences between two groups. HG treatment promoted METTL3 expression and m6A level of JEG3 cells, and inhibited cell proliferation, migration, and invasion abilities. Knocking down METTL3 reversed these effects. After HG treatment, hsa_circ_0072380 was significantly down-regulated. Knocking down METTL3 led to up-regulation of hsa_circ_0072380, while knocking down hsa_circ_0072380 restored the function of SiMETTL3. Additionally, knocking down METTL3 significantly reduced the m6A modification of hsa_circ_0072380. CONCLUSION: METTL3 mediated m6A modification of hsa_circ_0072380 to regulate GDM progression.

Risk Factors and Prediction Models for Postoperative Pathologically Malignant TI-RADS 3 Thyroid Nodules.

Objective: Our goal was to detect the risk factors for malignant TI-RADS 3 nodule and to construct a predictive model. Patients and Methods: All 199 patients with TI-RADS 3 nodule underwent first-time thyroid surgery from January 2018 to September 2021. Univariate analysis identified potential risk covariates and then incorporated these covariates into multivariate logistic regression to determine the risk factors for malignant TI-RADS 3 nodule and construct a predictive model. Results: Binary logistic regression analysis showed that age [odds ratio (OR): 0.926, 95% CI: 0.865-0.992; P = .029), low level of parathyroid hormone (OR: 0.940, 95% CI: 0.890-0.993; P = .027), and preoperative ultrasound features of TI-RADS 3 nodule, such as echogenicity (OR: 8.496, 95% CI: 1.377-52.406; P = .021), echogenic foci (OR: 8.611, 95% CI: 1.484-49.957; P = .016), and maximum tumor diameter (OR: 0.188, 95% CI: 0.040-0.888; P = .035) were independent risk factors for malignant TI-RADS 3 nodule. Based on these independent risk factors, a logistic regression model was established. The area under curve of the prediction model for TI-RADS 3 thyroid cancer was 0.921 (95% CI: 0.856-0.986, P < 0.001). The maximum Youden index was 0.698. The cut-off value, sensitivity, and specificity were 0.074, 84.6%, and 85.2%, respectively. Conclusion: Young age, iso/hypo/very hypo echo, echogenic foci, nodule diameter <30 mm, and low level of PTH are independent risk factors for TI-RADS 3 thyroid carcinomas. This prediction model has a high sensitivity and specificity. A prediction model value of more than 0.074 implies that the TI-RADS 3 nodule has undergone a malignant transformation, and fine needle aspiration is recommended in these cases.

Prediction of ROS1 and TRKA/B/C occupancy in plasma and cerebrospinal fluid for entrectinib alone and in DDIs using physiologically based pharmacokinetic (PBPK) modeling approach.

PURPOSE: Entrectinib (ENT) is a potent c-ros oncogene 1(ROS1) and neurotrophic tyrosine receptor kinase (NTRKA/B/C) inhibitor. To determine the optimum dosage of ENT using ROS1 and NTRKA/B/C occupancy in plasma and cerebrospinal fluid (CSF) in drug-drug interactions (DDIs), physiologically-based pharmacokinetic (PBPK) models for healthy subjects and cancer population were developed for ENT and M5 (active metabolite). METHODS: The PBPK models were built using the modeling parameters of ENT and M5 that were mainly derived from the published paper on the ENT PBPK model, and then validated by the observed pharmacokinetics (PK) in plasma and CSF from healthy subjects and patients. RESULTS: The PBPK model showed that AUC, Cmax, and Ctrough ratios between predictions and observations are within the range of 0.5-2.0, except that the M5 AUC ratio is slightly above 2.0 (2.34). Based on the efficacy (> 75% occupancy for ROS1 and NTRKA/B/C) and safety (AUC < 160 µM·h and Cmax < 8.9 µM), the appropriate dosing regimens were identified. The appropriate dosage is 600 mg once daily (OD) when administered alone, reduced to 200 mg and 400 mg OD with itraconazole and fluconazole, respectively. ENT is not recommended for co-administration with rifampicin or efavirenz, but is permitted with fluvoxamine or dexamethasone. CONCLUSION: The PBPK models can serve as a powerful approach to predict ENT concentration as well as ROS1 and NTRKA/B/C occupancy in plasma and CSF.

CircHSPB6 Promotes Tumor-Associated Macrophages M2 Polarization and Infiltration to Accelerate Cell Malignant Properties in Lung Adenocarcinoma by CCL2.

Circular RNAs (circRNAs) are reported to be involved in the tumorigenesis of lung adenocarcinoma (LUAD). Here, this study focused on studying the function and mechanism of circHSPB6 in LUAD progression. Levels of genes and proteins were tested using qRT-PCR and western blotting analyses. The 5-ethynyl-2'-deoxyuridine (EdU), colony formation, flow cytometry, and transwell assays were adopted for in vitro assays. In vivo assay was conducted using mouse xenograft models. The binding between let-7a-2-3p and circHSPB6 or CCL2 was validated using RIP and dual-luciferase reporter assays. The M2 polarization of tumor-associated macrophages (TAMs) was analyzed by flow cytometry. LUAD tissues and cells showed high circHSPB6 expression, knockdown of circHSPB6-suppressed LUAD cell proliferation, migration, invasion, and induced cell apoptosis in vitro, as well as hindered tumor growth in vivo. Mechanistically, circHSPB6/let-7a-2-3p/CCL2 forms a feedback loop. CircHSPB6 could regulate CCL2 expression via sponging let-7a-2-3p. Further rescue assays showed that the effects of circHSPB6 silencing on LUAD cells were reversed by let-7a-2-3p inhibition or CCL2 overexpression. Moreover, circHSPB6 promoted the M2 polarization and infiltration of TAMs by CCL2. Functionally, circHSPB6 knockdown in A549 and H1299 cells inhibited TAM M2 polarization and then suppressed cell proliferation, migration, invasion, and emergency medical technicians (EMT) progression, while these effects were reversed by CCL2 up-regulation CircHSPB6 induced TAM M2 polarization to promote LUAD cell proliferation, migration, invasion, and EMT progression through let-7a-2-3p/CCL2 axis.

Clinical role of CYP1B1 gene polymorphism in prediction of postoperative chemotherapy efficacy in NSCLC based on individualized health model.

Non-small cell lung cancer (NSCLC) is one of the most common cancers worldwide, and chemotherapy is one of its main treatment methods. However, there are significant differences in patients' reactions to chemotherapy, leading to unsatisfactory treatment outcomes. Therefore, identifying relevant factors that affect the efficacy of chemotherapy can help doctors better develop personalized treatment plans, improve the treatment effectiveness, and quality of life of patients. This article aims to understand the specific clinical role of CYP1B1 gene in NSCLC. Therefore, based on the individualized health model of CYP1B1 gene polymorphism, this article analyzes the prediction of postoperative chemotherapy efficacy for NSCLC. Through a study on the control variables of postoperative recovery of stage III NSCLC in a hospital, according to the findings of this study, 14 of the 32 patients in the EGFR mutation-positive group relapsed. In the EGFR-negative group, 13 of the 36 patients relapsed. It can be considered that CYP1B1 gene polymorphism has a good curative effect in postoperative chemotherapy of NSCLC, and it can effectively control the recurrence rate of cancer.

Systematic evaluation of clinical efficacy of CYP1B1 gene polymorphism in EGFR mutant non-small cell lung cancer observed by medical image.

Lung cancer is the cancer with the highest mortality rate and the highest incidence in the world at this stage. Among them, non-small lung cancer is the most common type of lung cancer, and most small cancers have disappeared, which is the optimal time for surgery at the time of diagnosis. To explore and systematically evaluate the clinical efficacy of CYP1B1 gene polymorphism in the treatment of epidermal growth factor receptor (EGFR) Mutant non-small cell lung cancer, this article proposes the principles of lung cancer screening based on CYP1B1 gene polymorphism and polarization imaging and explores the diagnosis and treatment of non-EGFR mutant lung cancer. Based on a large number of medical image data, imageomics can directly reflect the correlation between tumor molecular phenotype and image characteristics by deeply mining some imaging features of the image, which has important value in the early diagnosis of disease, the formulation of personalized treatment plan, and efficacy evaluation and prognosis prediction. A total of 141 NSCLC patients with sensitive EGFR mutation were included in this study, including 101 patients with EGFR single-gene mutation and 40 patients with EGFR multigene mutation coexisting mutation. Both groups of patients were female, aged ≥60 years, no smoking history, no family history of leukemia, adenocarcinoma, lung cancer, stage IV, lymph node metastasis, living, far from metastasis, and ECOG score of 0-2. This study examined the relative number of gene expression and PFS in EGFR multigene co-existing mutations. When the number of mixed genes is 1, 2, and higher, the PFS is 9 months, 8 months, and 6 months, respectively. The PFS time of this group of patients gradually shortened. Therefore, this study examined the benefit of polygenic mutation in estimation by comparing the clinical characteristics of patients with EGFR single-gene mutation and polygenic mutation, to provide measurement of EGFR-TKI and to provide suggestions for future drug selection.

Potent Uncompetitive Inhibitors of Nicotinamide N-Methyltransferase (NNMT) as In Vivo Chemical Probes.

NNMT uses SAM as a cofactor to catalyze the methylation of nicotinamide, producing 1-methylnicotinamide. Recent studies have shown that NNMT upregulation in cancer-associated fibroblasts (CAFs) is required to maintain the CAF phenotype in high-grade serous carcinoma. These observations suggest that NNMT should be evaluated as a therapeutic target, especially in cancer. Although several small-molecule inhibitors of NNMT have been identified, there remains a need for highly potent and selective inhibitors with excellent in vivo activity and ADME properties that can be used as reliable chemical probes. We have identified azaindoline carboxamide 38 as a selective and potent NNMT inhibitor with favorable PK/PD and safety profiles as well as excellent oral bioavailability and pharmaceutical properties. Our mechanistic studies indicate that 38 binds uncompetitively with SAM but competitively with nicotinamide consistent with its binding in the nicotinamide binding site and likely forming a positive interaction with SAM.

Medical Data Analysis of CYP1B1 Gene Polymorphism and Clinical Prognosis of Minimally Invasive Surgery for Lung Cancer.

To address the issue of genetic mutations in medical records, clinical studies on minimally invasive surgery for breast cancer have been proposed. The CYP1B1 gene is mainly a single-nucleotide mutation, which affects the enzymatic reaction related to carcinogens and causes the susceptibility differences of different individuals. First, the survival rate and other factors influencing the estimation of 120 leukemia patients were examined with the help of various medical records by establishing an organization for auxiliary diagnosis of lung cancer based on expertise. Secondly, through the treatment of 120 leukemia patients after minor surgery, the average life expectancy of 120 patients was 19 months, the one-year survival rate was 74.61%, and the two-year survival rate was 32.70%. Currently, there are more than 160 cases of CYP1B1 discovered. In recent years, people have gradually entered into in-depth research on the correlation between genes and lung cancer, which is of great significance to the treatment and research of lung cancer. An analysis showed patients' age, stage, whether they would work, whether radiation therapy and antibiotics were offered, and so on. s has a direct impact on patient survival, and many tests have shown that the patient's age, stage, whether it will work, and whether fire radiation and drug therapy are provided are important interventions for patients with anemia. Finally, in patients with leukemia, especially during the restricted period, combined treatment with a physician, radiologist, and surgeon should be initiated as soon as possible. For a wide range of disease, depending on the use of chemotherapy, local metastasis with antibiotics can improve the disease. After success, it is more beneficial to choose second-line treatment.

Association of the Microbiota and Pancreatic Cancer: Opportunities and Limitations.

The human body is thoroughly colonized by a wide variety of microorganisms, termed microbiota. Pancreatic cancer, one of the most aggressive forms of cancer, is no exception. The microbiota of pancreatic cancer largely influences and even dominates the occurrence, development and outcome of pancreatic cancer in many ways. Studies have shown that microbiota could change the malignant phenotype and prognosis of pancreatic cancer by stimulating persistent inflammation, regulating the antitumor immune system, changing the tumor microenvironment and affecting cellular metabolism. This is why the association of the microbiota with pancreatic cancer is an emerging area of research that warrants further exploration. Herein, we investigated the potential microbial markers of pancreatic cancer, related research models, the mechanism of action of microbiota in pancreatic cancer, and pancreatic cancer-microbiota-related treatment.

The role of circular RNA circ_0008285 in gestational diabetes mellitus by regulating the biological functions of trophoblasts

BACKGROUND: Circular RNAs (circRNAs) has emerged as vital regulator involved in various diseases. In this study, we identified and investigated the potential circRNAs involved in gestational diabetes mellitus (GDM). METHODS: High-throughput sequencing was used to collect the plasma circRNAs expression profiles of GDM patients. Quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) was used to measure the expressions of circ_0008285 and circ_0001173 in the plasma specimens. The Pearson's correlation test was employed to assess the correlation between 2 circRNAs expression and the clinicopathologic data. Two circRNAs expression was verified in high glucose (HG)-induced HTR-8/SVneo cells. MTS, transwell assay was used to evaluate the effects of circ_0008285 expression on HG-induced HTR-8/SVneo cells. The network of circ_0008285 was constructed using cytocape. RESULTS: In GDM patients, the expression of circ_0008285 was significantly upregulated, while that of circ_0001173 was decreased. Circ_0008285 was significantly correlated with the total cholesterol and LDL-C levels. Circ_0001173 was significantly correlated with glycated hemoglobin. HG promoted the proliferation, invasion, and migration in HTR-8/SVneo cells, while the knockdown of circ_0008285 exerted reverse effects. In addition, network construction exhibited that circ_0008285 had 45 miRNA binding sites, which correlated with 444 mRNA. CONCLUSIONS: circ_0008285 plays an important role and provides a clue for the usage of therapeutic targets in the development of GDM.

Glucagon-Like Peptide-2 Receptor is Involved in Spatial Cognitive Dysfunction in Rats After Chronic Cerebral Hypoperfusion.

Chronic cerebral hypoperfusion (CCH) affects the aging population and especially patients with neurodegenerative diseases, such as Alzheimer's disease or Parkinson's disease. CCH is closely related to the cognitive dysfunction in these diseases. Glucagon-like peptide-2 receptor (GLP2R) mRNA and protein are highly expressed in the gut and in hippocampal neurons. This receptor is involved in the regulation of food intake and the control of energy balance and glucose homeostasis. The present study employed behavioral techniques, electrophysiology, western blotting, immunohistochemistry, quantitative real time polymerase chain reaction (qRT-PCR), and Golgi staining to investigate whether the expression of GLP2R changes after CCH and whether GLP2R is involved in cognitive impairment caused by CCH. Our findings show that CCH significantly decreased hippocampal GLP2R mRNA and protein levels. GLP2R upregulation could prevent CCH-induced cognitive impairment. It also improved the CCH-induced impairment of long-term potentiation and long-term depression. Additionally, GLP2R modulated after CCH the AKT-mTOR-p70S6K pathway in the hippocampus. Moreover, an upregulation of the GLP2R increased the neurogenesis in the dentate gyrus, neuronal activity, and density of dendritic spines and mushroom spines in hippocampal neurons. Our findings reveal the involvement of GLP2R via a modulation of the AKT-mTOR-p70S6K pathway in the mechanisms underlying CCH-induced impairments of spatial learning and memory. We suggest that the GLP2R and the AKT-mTOR-p70S6K pathway in the hippocampus are promising targets to treat cognition deficits in CCH.

Resveratrol counteracts bone loss via mitofilin-mediated osteogenic improvement of mesenchymal stem cells in senescence-accelerated mice.

Rational: Senescence of mesenchymal stem cells (MSCs) and the related functional decline of osteogenesis have emerged as the critical pathogenesis of osteoporosis in aging. Resveratrol (RESV), a small molecular compound that safely mimics the effects of dietary restriction, has been well documented to extend lifespan in lower organisms and improve health in aging rodents. However, whether RESV promotes function of senescent stem cells in alleviating age-related phenotypes remains largely unknown. Here, we intend to investigate whether RESV counteracts senescence-associated bone loss via osteogenic improvement of MSCs and the underlying mechanism. Methods: MSCs derived from bone marrow (BMMSCs) and the bone-specific, senescence-accelerated, osteoblastogenesis/osteogenesis-defective mice (the SAMP6 strain) were used as experimental models. In vivo application of RESV was performed at 100 mg/kg intraperitoneally once every other day for 2 months, and in vitro application of RESV was performed at 10 µM. Bone mass, bone formation rates and osteogenic differentiation of BMMSCs were primarily evaluated. Metabolic statuses of BMMSCs and the mitochondrial activity, transcription and morphology were also examined. Mitofilin expression was assessed at both mRNA and protein levels, and short hairpin RNA (shRNA)-based gene knockdown was applied for mechanistic experiments. Results: Chronic intermittent application of RESV enhances bone formation and counteracts accelerated bone loss, with RESV improving osteogenic differentiation of senescent BMMSCs. Furthermore, in rescuing osteogenic decline under BMMSC senescence, RESV restores cellular metabolism through mitochondrial functional recovery via facilitating mitochondrial autonomous gene transcription. Molecularly, in alleviating senescence-associated mitochondrial disorders of BMMSCs, particularly the mitochondrial morphological alterations, RESV upregulates Mitofilin, also known as inner membrane protein of mitochondria (Immt) or Mic60, which is the core component of the mitochondrial contact site and cristae organizing system (MICOS). Moreover, Mitofilin is revealed to be indispensable for mitochondrial homeostasis and osteogenesis of BMMSCs, and that insufficiency of Mitofilin leads to BMMSC senescence and bone loss. More importantly, Mitofilin mediates resveratrol-induced mitochondrial and osteogenic improvements of BMMSCs in senescence. Conclusion: Our findings uncover osteogenic functional improvements of senescent MSCs as critical impacts in anti-osteoporotic practice of RESV, and unravel Mitofilin as a novel mechanism mediating RESV promotion on mitochondrial function in stem cell senescence.

Cinchonine activates endoplasmic reticulum stress-induced apoptosis in human liver cancer cells.

Cinchonine is a natural compound present in Cinchona bark. It exerts multidrug resistance reversal activity and synergistic apoptotic effect with paclitaxel in uterine sarcoma cells. Whether cinchonine is effective against human liver cancer, however, remains elusive. A total of five liver cancer cell lines including Bel-7402, MHCC97H, HepG2, Hep3B and SMCC7721 were used. The anti-proliferative effects of cinchonine on these liver cancer cell lines were assessed by MTT assay. The apoptotic effects of cinchonine on liver cancer cell lines were assessed by flow cytometry with Annexin V/propidium iodide assay. Caspase-3 activation, poly (ADP-Ribose) polymerase (PARP) cleavage as well as the endoplasmic-reticulum (ER) stress response was detected by western blotting. Balb/c-nude mice bearing HepG2 xenograft tumors were used to evaluate the in vivo antitumor effect of cinchonine. It was demonstrated that cinchonine inhibited cell proliferation and promoteed apoptosis in liver cancer cells in a dose-dependent manner. Cinchonine promoted caspase-3 activation and PARP1 cleavage in liver cancer cells. Furthermore, cinchonine activated the ER stress response by upregulating GRP78 and promoting PERK and Eukaryotic Translation Initiation Factor 2 α phosphorylation. The Balb/c-nude mice experiment revealed that cinchonine suppressed HepG2 xenograft tumor growth in mice. The findings indicated that cinchonine promoted ER stress-induced apoptosis in liver cancer cells and suggested that cinchonine may have a potential beneficial effect for liver cancer treatment.

Luteolin Could Improve Cognitive Dysfunction by Inhibiting Neuroinflammation.

Neuroinflammation and oxidative stress play an important role in cognition deficit following chronic cerebral hypoperfusion (CCH). Luteolin, a natural flavonoid found in many plants, is known for a variety of pharmacological activities, such as its anti-inflammatory, anti-allergy, urate, anti-tumor, antibacterial, and antiviral effects. To assess whether luteolin could prevent CCH-induced cognitive dysfunction, through its anti-inflammatory and anti-oxidative-stress effects, we used enzyme-linked immunosorbent assays, enzyme activity assays, behavioral methods, immunohistochemistry, and electrophysiology to detect neuroinflammation and oxidative stress, cognition alterations, and long-term potential (LTP), in a bilateral common carotid arteries ligation (2VO) rat model. We demonstrated that CCH increased tumor necrosis factor α (TNF-α), interleukin 1ß (IL-1ß), interleukin 6 (IL-6), and malondialdehyde (MDA), and decreased superoxide dismutase (SOD) and glutathione peroxidase (GPx) levels. Further, it caused microglia over-activation and astrogliosis, learning and short-term memory dysfunction, and an LTP deficit. Luteolin treatment reversed CCH-induced changes. Specifically, luteolin prevented the increase of TNF-α and IL-1ß, IL-6, and MDA, improved the activity of SOD and GPx, inhibited microglia over-activation and astrogliosis (particularly in the hippocampus and cortex), and ameliorated learning and short-term memory dysfunction, and LTP deficit. Thus, our study suggested that luteolin could be a preferable anti-inflammatory agent to protect cognitive function and synaptic plasticity following CCH. Luteolin could also be putative therapeutic candidate for other inflammation-related brain diseases.

Targeting MRP4 expression by anti-androgen treatment reverses MRP4-mediated docetaxel resistance in castration-resistant prostate cancer.

It has been demonstrated that docetaxel (DTX) may improve the overall survival of patients with castration-resistant prostate cancer (CRPC). However, its effectiveness is limited with time, and tumor escape is eventually inevitable. DTX resistance is the main reason for the failure of chemotherapy for CRPC. In the present study, the expression status of multidrug resistance protein 4 (MRP4) in DTX-resistant prostate cancer cells was investigated, and it was explored whether anti-androgen treatment may inhibit MRP4 expression and overcome DTX resistance. DTX-resistant C4-2/D cells were established by exposing DTX-sensitive C4-2/S cells to gradually increasing concentrations of DTX. MRP4 gene expression and the effect of androgen signaling on its expression were assessed by reverse transcription-polymerase chain reaction and western blotting. Intracellular and extracellular concentrations of DTX were detected by high-performance liquid chromatography. Anti-androgen treatment effects on DTX sensitivity were determined by a clonogenic test and an MTT cytotoxicity assay. MRP4 was overexpressed in C4-2/D cells, while its expression was barely detectable in C4-2/S cells. MRP4 expression levels were elevated in C4-2/D cells by dihydrotestosterone, whereas they were blocked by anti-androgen bicalutamide (BKL) treatment. Intracellular and extracellular DTX concentrations in C4-2/D cells were associated with MRP4 levels. The downregulation of MRP4 by BKL increased the intracellular concentration of DTX in C4-2/D cells and re-sensitized C4-2/D cells to DTX. These results indicated that overexpression of MRP4 mediates acquired DTX resistance, and suggest that targeting MRP4 expression by anti-androgen treatment may reverse DTX-resistant prostate cancer cells to DTX chemotherapy.

CYP1B1 G199T Polymorphism Affects Prognosis of NSCLC Patients with the Potential to Be an Indicator and Target for Precise Drug Intervention.

CYP1B1 gene single nucleotide polymorphisms G119T, C432G, and A453G were tested among 164 NSCLC patients treated by Video-Assisted Thoracoscopic Surgery. After a follow-up period of 5 years, it was found that CYP1B1 G119T mutant genotypes were related to a higher risk of tumor recurrence and death after surgical resection. However, C432G and A453G genotypes had no influence on long-term prognosis of the study cohort. Thus, G199T alleles are supposed to be an auxiliary predictor for prognosis of NSCLC patients and a potential target for precise drug intervention, as well as a candidate for further anticancer drug research.

Human colorectal cancer-specific CCAT1-L lncRNA regulates long-range chromatin interactions at the MYC locus.

The human 8q24 gene desert contains multiple enhancers that form tissue-specific long-range chromatin loops with the MYC oncogene, but how chromatin looping at the MYC locus is regulated remains poorly understood. Here we demonstrate that a long noncoding RNA (lncRNA), CCAT1-L, is transcribed specifically in human colorectal cancers from a locus 515 kb upstream of MYC. This lncRNA plays a role in MYC transcriptional regulation and promotes long-range chromatin looping. Importantly, the CCAT1-L locus is located within a strong super-enhancer and is spatially close to MYC. Knockdown of CCAT1-L reduced long-range interactions between the MYC promoter and its enhancers. In addition, CCAT1-L interacts with CTCF and modulates chromatin conformation at these loop regions. These results reveal an important role of a previously unannotated lncRNA in gene regulation at the MYC locus.

Multiple logistic regression analysis of risk factors associated with denture plaque and staining in Chinese removable denture wearers over 40 years old in Xi'an--a cross-sectional study.

BACKGROUND: Removable dentures are subject to plaque and/or staining problems. Denture hygiene habits and risk factors differ among countries and regions. The aims of this study were to assess hygiene habits and denture plaque and staining risk factors in Chinese removable denture wearers aged >40 years in Xi'an through multiple logistic regression analysis (MLRA). METHODS: Questionnaires were administered to 222 patients whose removable dentures were examined clinically to assess wear status and levels of plaque and staining. Univariate analyses were performed to identify potential risk factors for denture plaque/staining. MLRA was performed to identify significant risk factors. RESULTS: Brushing (77.93%) was the most prevalent cleaning method in the present study. Only 16.4% of patients regularly used commercial cleansers. Most (81.08%) patients removed their dentures overnight. MLRA indicated that potential risk factors for denture plaque were the duration of denture use (reference, ≤0.5 years; 2.1-5 years: OR = 4.155, P = 0.001; >5 years: OR = 7.238, P<0.001) and cleaning method (reference, chemical cleanser; running water: OR = 7.081, P = 0.010; brushing: OR = 3.567, P = 0.005). Potential risk factors for denture staining were female gender (OR = 0.377, P = 0.013), smoking (OR = 5.471, P = 0.031), tea consumption (OR = 3.957, P = 0.002), denture scratching (OR = 4.557, P = 0.036), duration of denture use (reference, ≤0.5 years; 2.1-5 years: OR = 7.899, P = 0.001; >5 years: OR = 27.226, P<0.001), and cleaning method (reference, chemical cleanser; running water: OR = 29.184, P<0.001; brushing: OR = 4.236, P = 0.007). CONCLUSION: Denture hygiene habits need further improvement. An understanding of the risk factors for denture plaque and staining may provide the basis for preventive efforts.