ABSTRACT
The major limitation of cancer treatment is multidrug resistance (MDR), which leads to the inactivation of chemotherapeutic drugs and greater than 90% mortality. To solve this ordeal, we applied ligand-based drug design and bioiosteric replacement strategy from an indazole to a pyrazole ring to discover compounds 27 and 43 with good potential for reversing drug resistance in combination with paclitaxel, and their reversal fold values were 53.2 and 51.0 at 5 µM, respectively, against an MDR cancer cell line (KBvin). Based on the PK profile results, we selected compound 43 with a longer half-life for mechanistic and animal experiments. Combination treatment with compound 43 and paclitaxel-induced apoptosis and enhanced subG1 by decreasing mitochondrial membrane potential in KBvin cells. In addition, 43 also inhibited P-gp function by interfering with ATPase activity. Meanwhile, cotreatment with compound 43 and paclitaxel significantly suppressed tumor growth (TGI = 55.5%) at a dose of 200 mg/kg (PO) in a xenograft model and showed no obvious liver or kidney toxicity by H&E staining. Overall, compound 43 may serve as a safe and effective oral resistance reversal chemotherapeutic agent.
Subject(s)
Antineoplastic Agents , Apoptosis , Drug Resistance, Multiple , Drug Resistance, Neoplasm , Paclitaxel , Humans , Drug Resistance, Neoplasm/drug effects , Drug Resistance, Multiple/drug effects , Animals , Paclitaxel/pharmacology , Paclitaxel/therapeutic use , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Apoptosis/drug effects , Cell Line, Tumor , Administration, Oral , Mice , Xenograft Model Antitumor Assays , Drug Discovery , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists & inhibitors , Membrane Potential, Mitochondrial/drug effects , Mice, NudeABSTRACT
Temozolomide (TMZ) is the first line chemotherapy for glioblastoma (GBM) treatment, but the P-glycoprotein (P-gp) expressed in blood-brain barrier (BBB) will pump out TMZ from the brain leading to decreased TMZ concentration. Tariquidar (TQD), a selective and potent P-gp inhibitor, may be suitable for combination therapy to increase concentration of TMZ in brain. Hydroxyapatite (HAP) is a biodegradable material with sustained release characteristics, and stearic acid surface-modified HAP (SA-HAP) can increase hydrophobicity to facilitate TQD loading. TQD-loaded stearic acid surface-modified HAP (SA-HAP-TQD) was prepared with optimal size and high TQD loading efficiency, and in vitro release and cellular uptake of SA-HAP-TQD showed that SA-HAP-TQD were taken up into lysosome and continuously released TQD from macrophages. In vivo studies have found that over 70% of SA-HAP was degraded and 80% of TQD was released from SA-HAP-TQD 28 days after administration. SA-HAP-TQD could increase brain penetration of TMZ, but it would not enhance adverse effects of TMZ in healthy mice. SA-HAP-TQD and TMZ combination had longer median survival than TMZ single therapy in GL261 orthotopic model. These results suggest that SA-HAP-TQD has sustained release characteristics and are potential for improving antitumor effect with TMZ treatment.
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Exogenous insulin therapy is the mainstay treatment for Type-1 diabetes (T1D) caused by insulin deficiency. A fine-tuned insulin supply system is important to maintain the glucose homeostasis. In this study, we present a designed cell system that produces insulin under an AND gate control, which is triggered only in the presence of both high glucose and blue light illumination. The glucose-sensitive GIP promoter induces the expression of GI-Gal4 protein, which forms a complex with LOV-VP16 in the presence of blue light. The GI-Gal4:LOV-VP16 complex then promotes the expression of UAS-promoter-driven insulin. We transfected these components into HEK293T cells, and demonstrated the insulin was secreted under the AND gate control. Furthermore, we showed the capacity of the engineered cells to improve the blood glucose homeostasis through implantation subcutaneously into Type-1 diabetes mice.
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Background: Non-structural protein 1 (NS1), one of the viral proteins of influenza A viruses (IAVs), plays a crucial role in evading host antiviral immune response. It is known that the IAV NS1 protein regulates the antiviral genes response mainly through several different molecular mechanisms in cytoplasm. Current evidence suggests that NS1 represses the transcription of IFNB1 gene by inhibiting the recruitment of Pol II to its exons and promoters in infected cells. However, IAV NS1 whether can utilize a common mechanism to antagonize antiviral response by interacting with cellular DNA and immune-related transcription factors in the nucleus, is not yet clear. Methods: Chromatin immunoprecipitation and sequencing (ChIP-seq) was used to determine genome-wide transcriptional DNA-binding sites for NS1 and NF-κB in viral infection. Next, we used ChIP-reChIP, luciferase reporter assay and secreted embryonic alkaline phosphatase (SEAP) assay to provide information on the dynamic binding of NS1 and NF-κB to chromatin. RNA sequencing (RNA-seq) transcriptomic analyses were used to explore the critical role of NS1 and NF-κB in IAV infection as well as the detailed processes governing host antiviral response. Results: Herein, NS1 was found to co-localize with NF-κB using ChIP-seq. ChIP-reChIP and luciferase reporter assay confirmed the co-localization of NS1 and NF-κB at type III IFN genes, such as IFNL1, IFNL2, and IFNL3. We discovered that NS1 disturbed binding manners of NF-κB to inhibit IFNL1 expression. NS1 hijacked NF-κB from a typical IFNL1 promoter to the exon-intron region of IFNL1 and decreased the enrichment of RNA polymerase II and H3K27ac, a chromatin accessibility marker, in the promoter region of IFNL1 during IAV infection, consequently reducing IFNL1 gene expression. NS1 deletion enhanced the enrichment of RNA polymerase II at the IFNL1 promoter and promoted its expression. Conclusion: Overall, NS1 hijacked NF-κB to prevent its interaction with the IFNL1 promoter and restricted the open chromatin architecture of the promoter, thereby abating antiviral gene expression.
Subject(s)
Antiviral Agents , Influenza A virus , Alkaline Phosphatase/metabolism , Antiviral Agents/pharmacology , Chromatin/metabolism , Immunity , Influenza A virus/genetics , NF-kappa B/metabolism , RNA Polymerase II/genetics , RNA Polymerase II/metabolismABSTRACT
N7-methylguanosine (m7G) modification on internal RNA positions plays a vital role in several biological processes. Recent research shows m7G modification is associated with multiple cancers. However, in hepatocellular carcinoma (HCC), its implications remain to be determined. In this place, we need to interrogate the mRNA patterns for 29 key regulators of m7G RNA modification and assess their prognostic value in HCC. Initial, the details from The Cancer Genome Atlas (TCGA) database concerning transcribed gene data and clinical information of HCC patients were inspected systematically. Second, according to the mRNA profiles of 29 m7G RNA methylation regulators, two clusters (named 1 and 2, respectively) were identified by consensus clustering. Furthermore, robust risk signature for seven m7G RNA modification regulators was constructed. Last, we used the Gene Expression Omnibus (GEO) dataset to validate the prognostic associations of the seven-gene risk signature. We figured out that 24/29 key regulators of m7G RNA modification varied remarkably in their grades of expression between the HCC and the adjacent tumor control tissues. Cluster one compared with cluster two had a substandard prognosis and was also positively correlated with T classification (T), pathological stage, and vital status (fustat) significantly. Consensus clustering results suggested the expression pattern of m7G RNA modification regulators was correlated with the malignancy of HCC strongly. In addition, cluster one was extensively enriched in metabolic-related pathways. Seven optimal genes (METTL1, WDR4, NSUN2, EIF4E, EIF4E2, NCBP1, and NCBP2) were selected to establish the risk model for HCC. Indicating by further analyses and validation, the prognostic model has fine anticipating command and this probability signature might be a self supporting presage factor for HCC. Finally, a new prognostic nomogram based on age, gender, pathological stage, histological grade, and prospects were established to forecast the prognosis of HCC patients accurately. In essence, we detected association of HCC severity and expression levels of m7G RNA modification regulators, and developed a risk score model for predicting prognosis of HCC patients' progression.
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Oncocytic adrenal cortical neoplasms are rare cases and are divided into oncocytoma, oncocytic neoplasms of uncertain malignant potential and oncocytic adrenal cortical carcinomas, based on the Lin-Weiss-Bisceglia (LWB) histological system adopted in the current World Health Organization (WHO). We reported a 42-year-old female diagnosed with an oncocytic neoplasm of uncertain malignant potential initially, which turned out to be a carcinoma owing to distant metastasis to the scalp and lung. To our knowledge, this is the first published case of oncocytic adrenal cortical carcinoma with scalp metastasis. This case also highlights the limitation of the current diagnostic algorithm and emphasizes the importance of two parameters (PHH3 and Ki-67) for determining the malignant potential of oncocytic adrenal cortical neoplasms.
Subject(s)
Adenoma, Oxyphilic , Adrenal Cortex Neoplasms , Adrenocortical Carcinoma , Adenoma, Oxyphilic/diagnosis , Adrenal Cortex Neoplasms/diagnosis , Adrenal Cortex Neoplasms/pathology , Adrenocortical Carcinoma/diagnosis , Adrenocortical Carcinoma/pathology , Adult , Female , HumansABSTRACT
Joint analysis of multiple protein expressions and tissue morphology patterns is important for disease diagnosis, treatment planning, and drug development, requiring cross-staining alignment of multiple immunohistochemical and histopathological slides. However, cross-staining alignment of enormous gigapixel whole slide images (WSIs) at single cell precision is difficult. Apart from gigantic data dimensions of WSIs, there are large variations on the cell appearance and tissue morphology across different staining together with morphological deformations caused by slide preparation. The goal of this study is to build an image registration framework for cross-staining alignment of gigapixel WSIs of histopathological and immunohistochemical microscopic slides and assess its clinical applicability. To the authors' best knowledge, this is the first study to perform real time fully automatic cross staining alignment of WSIs with 40× and 20× objective magnification. The proposed WSI registration framework consists of a rapid global image registration module, a real time interactive field of view (FOV) localization model and a real time propagated multi-level image registration module. In this study, the proposed method is evaluated on two kinds of cancer datasets from two hospitals using different digital scanners, including a dual staining breast cancer data set with 43 hematoxylin and eosin (H&E) WSIs and 43 immunohistochemical (IHC) CK(AE1/AE3) WSIs, and a triple staining prostate cancer data set containing 30 H&E WSIs, 30 IHC CK18 WSIs, and 30 IHC HMCK WSIs. In evaluation, the registration performance is measured by not only registration accuracy but also computational time. The results show that the proposed method achieves high accuracy of 0.833 ± 0.0674 for the triple-staining prostate cancer data set and 0.931 ± 0.0455 for the dual-staining breast cancer data set, respectively, and takes only 4.34 s per WSI registration on average. In addition, for 30.23% data, the proposed method takes less than 1 s for WSI registration. In comparison with the benchmark methods, the proposed method demonstrates superior performance in registration accuracy and computational time, which has great potentials for assisting medical doctors to identify cancerous tissues and determine the cancer stage in clinical practice.
Subject(s)
Breast Neoplasms , Prostatic Neoplasms , Breast Neoplasms/diagnostic imaging , Eosine Yellowish-(YS) , Hematoxylin , Humans , Male , Prostatic Neoplasms/diagnostic imaging , Prostatic Neoplasms/pathology , Staining and LabelingABSTRACT
Objective: This study is aimed to determine the potential prognostic significance of nutritional risk index (NRI) in patients with stage III gastric cancer. Methods: A total of 202 patients with stage III gastric cancer were enrolled in this study. NRI was an index based on ideal body weight, present body weight, and serum albumin levels. All patients were divided into two groups by receiver operating characteristic curve: low NRI group (NRI<99) and high NRI group (NRI≥99). The relationship between NRI and clinicopathologic characteristics was evaluated by Chi-square test. The clinical survival outcome was analyzed by Kaplan-Meier method and compared using log-rank test. The univariate and multivariate analyses were used to detect the potential prognostic factors. A nomogram for individualized assessment of disease-free survival (DFS) and overall survival (OS). The calibration curve was used to evaluate the performance of the nomogram for predicted and the actual probability of survival time. The decision curve analysis was performed to assess the clinical utility of the nomogram by quantifying the net benefits at different threshold probabilities. Results: The results indicated that NRI had prognostic significance by optimal cutoff value of 99. With regard to clinicopathologic characteristics, NRI showed significant relationship with age, weight, body mass index, total protein, albumin, albumin/globulin, prealbumin, glucose, white blood cell, neutrophils, lymphocyte, hemoglobin, red blood cell, hematocrit, total lymph nodes, and human epidermal growth factor receptor 2 (P<0.05). Through the univariate and multivariate analyses, NRI, total lymph nodes, and tumor size were identified as the independent factor to predict the DFS and OS. The nomogram was used to predict the 1-, 3-, and 5-year survival probabilities, and the calibration curve showed that the prediction line matched the reference line well for 1-, 3-, and 5-year DFS and OS. Furthermore, the decision curve analysis also showed that the nomogram model yielded the best net benefit across the range of threshold probability for 1-, 3-, 5-year DFS and OS. Conclusions: NRI is described as the potential prognostic factor for patients with stage III gastric cancer and is used to predict the survival and prognosis.
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Bladder cancer progression and metastasis have become major threats in clinical practice, increasing mortality and therapeutic refractoriness; recently, epigenetic dysregulation of epithelial-to-mesenchymal transition (EMT)-related signaling pathways has been explored. However, research in the fields of long noncoding RNA (lncRNA) and competing endogenous RNA (ceRNA) regulation in bladder cancer progression is just beginning. This study was designed to determine potential EMT-related ceRNA regulation in bladder cancer progression and elucidate the underlying mechanisms that provoke aggressiveness. After screening the intersection of bioinformatic pipelines, LINC02470 was identified as the most upregulated lncRNA during bladder cancer initiation and progression. Both in vitro and in vivo biological effects indicated that LINC02470 promotes bladder cancer cell viability, migration, invasion, and tumorigenicity. On a molecular level, miR-143-3p directly targets and reduces both LINC02470 and SMAD3 RNA expression. Therefore, the LINC02470-miR-143-3p-SMAD3 ceRNA axis rescues SMAD3 translation upon LINC02470 sponging miR-143-3p, and SMAD3 consequently activates the TGF-ß-induced EMT process. In conclusion, this is the first study to demonstrate that LINC02470 plays a pivotally regulatory role in the promotion of TGF-ß-induced EMT through the miR-143-3p/SMAD3 axis, thereby aggravating bladder cancer progression. Our study warrants further investigation of LINC02470 as an indicatively prognostic marker of bladder cancer.
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COVID-19 is mainly associated with respiratory distress syndrome, but a subset of patients often present gastrointestinal (GI) symptoms. Imbalances of gut microbiota have been previously linked to respiratory virus infection. Understanding how the gut-lung axis affects the progression of COVID-19 can provide a novel framework for therapies and management. In this study, we examined the gut microbiota of patients with COVID-19 (n = 47) and compared it to healthy controls (n = 19). Using shotgun metagenomic sequencing, we have identified four microorganisms unique in COVID-19 patients, namely Streptococcus thermophilus, Bacteroides oleiciplenus, Fusobacterium ulcerans, and Prevotella bivia. The abundances of Bacteroides stercoris, B. vulgatus, B. massiliensis, Bifidobacterium longum, Streptococcus thermophilus, Lachnospiraceae bacterium 5163FAA, Prevotella bivia, Erysipelotrichaceae bacterium 6145, and Erysipelotrichaceae bacterium 2244A were enriched in COVID-19 patients, whereas the abundances of Clostridium nexile, Streptococcus salivarius, Coprococcus catus, Eubacterium hallii, Enterobacter aerogenes, and Adlercreutzia equolifaciens were decreased (p < 0.05). The relative abundance of butyrate-producing Roseburia inulinivorans is evidently depleted in COVID-19 patients, while the relative abundances of Paraprevotella sp. and the probiotic Streptococcus thermophilus were increased. We further identified 30 KEGG orthology (KO) modules overrepresented, with 7 increasing and 23 decreasing modules. Notably, 15 optimal microbial markers were identified using the random forest model to have strong diagnostic potential in distinguishing COVID-19. Based on Spearman's correlation, eight species were associated with eight clinical indices. Moreover, the increased abundance of Bacteroidetes and decreased abundance of Firmicutes were also found across clinical types of COVID-19. Our findings suggest that the alterations of gut microbiota in patients with COVID-19 may influence disease severity. Our COVID-19 classifier, which was cross-regionally verified, provides a proof of concept that a set of microbial species markers can distinguish the presence of COVID-19.
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Gemcitabine (GCB) resistance is a major issue in bladder cancer chemoresistance, but its underlying mechanism has not been determined. Epithelial-mesenchymal transition (EMT) has been shown to be comprehensively involved in GCB resistance in several other cancer types, but the direct connection between EMT and GCB remains unclear. This study was designed to elucidate the mechanism of EMT-related GCB resistance in bladder cancer and identify a potential phytochemical to modulate drug sensitivity. The biological effects of ellagic acid (EA) or its combined effects with GCB were compared in GCB-resistant cells and the GCB-sensitive line in terms of cell viability, apoptosis, motility, and in vivo tumorigenicity. The molecular regulation of EMT-related GCB resistance was evaluated at both the mRNA and protein expression levels. Our results indicated that TGF-ß/Smad induced the overactivation of EMT in GCB-resistant cells and reduced the expression of GCB influx transporters (hCNT1 and hENT1). Moreover, ellagic acid (EA) inhibited the TGF-ß signaling pathway both in vitro and in vivo by reducing Smad2, Smad3, and Smad4 expression and thereby resensitized GCB sensitivity. In conclusion, our results demonstrate that TGF-ß/Smad-induced EMT contributes to GCB resistance in bladder cancer by reducing GCB influx and also elucidate the novel mechanisms of EA-mediated inhibition of TGF-ß/Smad-induced EMT to overcome GCB resistance. Our study warrants further investigation of EA as an effective therapeutic adjuvant agent for overcoming GCB resistance in bladder cancer.
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BACKGROUND: To realize the association between stratified expression levels of ER and PgR and long-term prognosis of breast cancer patients who received adjuvant hormone therapy, this study aimed to propose better prognostic cut-off levels for estrogen receptor (ER) and progesterone receptor (PgR). METHODS: Patients who received adjuvant hormone therapy after surgical intervention were selected. The ER and PgR status and their effects on breast cancer-specific survival (BCSS) and disease-free survival (DFS) over 5 and 10 years were evaluated. Next, subgroups were generated based on ER and PgR expression percentage and Allred scores. Survival curves were constructed using the Kaplan-Meier method. RESULTS: ER and PgR expression were significantly associated with better prognosis in 5 years, whereas only PgR expression was significantly associated during the 10-year follow-up. The optimal cut-off values for better 5-year BCSS were ER > 50%; ER Allred score > 7; PgR ≥ 1%; or PgR Allred score ≥ 3; the corresponding values for DFS were ER > 40%; ER Allred score > 6; PgR > 10%; or PgR Allred score ≥ 3. In the long-term follow-up, PgR of > 50% or Allred score of > 5 carriers revealed a better prognosis of both BCSS and DFS. CONCLUSION: Patients with a PgR expression > 50% or an Allred score > 5 exhibited better 10-year BCSS and DFS.
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The aim of the study is to investigate the ability of phytochemicals to overcome the multiple drug resistance (MDR) of bladder cancer. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to evaluate the cytotoxic sensitivity of T24-GCB cells, a GCB resistant cell line, to different phytochemicals, including capsaicin, quercetin, curcumin, and resveratrol, and their combination with gemcitabine. Western blot analysis was used to detect the expression of membranous ABCC2 and metabolic proteins, DCK, TK1, and TK2 in tumor cells. Animal models were used to confirm the treatment efficacy of phytochemicals in combination with gemcitabine to bladder cancer. The observed/expected ratio of cytotoxicity analysis revealed that capsaicin has synergistic effect with gemcitabine to T24-GCB cells in a dose-dependent pattern. Quercetin, curcumin, and resveratrol have additive effect with gemcitabine to T24-GCB cells. Capsaicin and quercetin alone and combination with gemcitabine decreased the expression of ABCC2 and DCK and TKs, in T24-GCB cells. On the contrary, resveratrol and curcumin alone and combination with gemcitabine increased the expression of ABCC2 but decreased cytoplasmic kinases simultaneously. In xenografted subcutaneous tumor model on nude mice, combination treatment of capsaicin and gemcitabine demonstrated the highest tumor suppression effect when compared to capsaicin or gemcitabine treatment alone. The MDR of bladder cancer is closely related to membranous ABCC2, cytoplasmic DCK, and TKs expression. Capsaicin owns the strongest synergistic cytotoxic effect of gemcitabine to T24-GCB cells. This combination regimen may provide as an adjunctive treatment for overcoming MDR in bladder cancer.
Subject(s)
Drug Resistance, Neoplasm , Phytochemicals/therapeutic use , Urinary Bladder Neoplasms/drug therapy , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Cell Death/drug effects , Cell Line, Tumor , Cell Survival/drug effects , Deoxycytidine/analogs & derivatives , Deoxycytidine/pharmacology , Drug Resistance, Multiple/drug effects , Drug Resistance, Neoplasm/drug effects , Female , Humans , Mice, Inbred BALB C , Mice, Nude , Multidrug Resistance-Associated Protein 2 , Phytochemicals/pharmacology , Urinary Bladder Neoplasms/pathology , Xenograft Model Antitumor Assays , GemcitabineABSTRACT
Exosomes are essential for several tumor progression-related processes, including the epithelial-mesenchymal transition (EMT). Long non-coding RNAs (lncRNAs) comprise a major group of exosomal components and regulate the neoplastic development of several cancer types; however, the progressive role of exosomal lncRNAs in bladder cancer have rarely been addressed. In this study, we identified two potential aggressiveness-promoting exosomal lncRNAs, LINC00960 and LINC02470. Exosomes derived from high-grade bladder cancer cells enhanced the viability, migration, invasion and clonogenicity of recipient low-grade bladder cancer cells and activated major EMT-upstream signaling pathways, including ß-catenin signaling, Notch signaling, and Smad2/3 signaling pathways. Nevertheless, LINC00960 and LINC02470 were expressed at significantly higher levels in T24 and J82 cells and their secreted exosomes than in TSGH-8301 cells. Moreover, exosomes derived from LINC00960 knockdown or LINC02470 knockdown T24 cells significantly attenuated the ability of exosomes to promote cell aggressiveness and activate EMT-related signaling pathways in recipient TSGH-8301 cells. Our findings indicate that exosome-derived LINC00960 and LINC02470 from high-grade bladder cancer cells promote the malignant behaviors of recipient low-grade bladder cancer cells and induce EMT by upregulating ß-catenin signaling, Notch signaling, and Smad2/3 signaling. Both lncRNAs may serve as potential liquid biomarkers for the prognostic surveillance of bladder cancer progression.
Subject(s)
Epithelial-Mesenchymal Transition/genetics , Exosomes/metabolism , RNA, Long Noncoding/metabolism , Urinary Bladder Neoplasms/genetics , Urinary Bladder Neoplasms/pathology , Cell Communication/drug effects , Cell Line, Tumor , Cell Movement/drug effects , Cell Survival/drug effects , Culture Media, Conditioned/pharmacology , Gene Expression Regulation, Neoplastic , Humans , Models, Biological , Neoplasm Grading , Neoplasm Invasiveness , RNA, Long Noncoding/genetics , Reproducibility of Results , Urinary Bladder Neoplasms/ultrastructureABSTRACT
Gemcitabine (GCB), which functions via the inhibition of DNA synthesis, is commonly used in the treatment of bladder cancer; however, its response rate is not satisfactory due to the development of drug resistance. The potential for phytochemicals to reverse drug resistance in bladder cancer tumor cells was evaluated. A human bladder cancer cell line, T24, was cultured, and GCB-resistant cells (T24-GCB) were also established. The acquired resistance of T24-GCB to GCB was measured using an MTT assay. The gene expression of ATP-binding cassette (ABC) transporter protein family members was analyzed using reverse transcription-quantitative PCR analysis, and western blotting was performed to verify ABC family protein, cytoplasmic thymidine kinase (TK) and poly (ADP-ribose) polymerase (PARP) expression on whole cell lysates. Subsequently, resveratrol and curcumin were used to evaluate their modulation potential in decreasing the drug resistance of T24-GCB cells to GCB using MTT and migration assays. T24-GCB cells have increased drug resistance ability, with an 18.75-fold higher ID50 value compared with native T24 cells (105 vs. 5.6 nM). T24-GCB cells also exhibit increased cross resistance to mitomycin C and paclitaxel. The mRNA expression of ABCC2 in T24-GCB cells increased compared with that in native T24 cells. Via western blot analysis, it was determined that the expression of ABCC2 protein was also increased in T24-GCB cells. Conversely, the expression of ABCB1, ABCG2, deoxycytidine kinase (DCK), TK1 and TK2 decreased. Following curcumin and resveratrol treatment alone or combined with GCB, additive cytotoxic enhancement was observed, and the migratory abilities of T24-GCB cells were significantly decreased. Western blot analysis revealed that ABCC2 protein expression increased, and DCK, TK1 and TK2 expression decreased following co-treatment of T24-GCB cells with GCB + curcumin or resveratrol compared with GCB alone. Of note, there was a marked increase in cleaved-PARP expression in T24-GCB cells treated with a combination of GCB + curcumin or resveratrol. Both curcumin and resveratrol could reverse the drug resistance of T24-GCB cells in an additive pattern though PARP enhancement without changes in ABCC2 and DCK, TK1 and TK2 expression.
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Elucidating whether and how long-term survival of breast cancer is mainly due to cure after early detection and effective treatment and therapy or overdiagnosis resulting from the widespread use of mammography provides a new insight into the role mammography plays in screening, surveillance, and treatment of breast cancer. Given information on detection modes, the impact of overdiagnosis due to mammography screening on long-term breast cancer survival was quantitatively assessed by applying a zero (cured or overdiagnosis)-inflated model design and analysis to a 15-year follow-up breast cancer cohort in Dalarna, Sweden. The probability for non-progressive breast cancer (the zero part) was 56.14% including the 44.34% complete cure after early detection and initial treatment and a small 11.80% overdiagnosis resulting from mammography screening program (8.94%) and high awareness (2.86%). The 15-year adjusted cumulative survival of breast cancer was dropped from 88.25% to 74.80% after correcting for the zero-inflated part of overdiagnosis. The present findings reveal that the majority of survivors among women diagnosed with breast cancer could be attributed to the cure resulting from mammography screening and accompanying effective treatment and therapy and only a small fraction of those were due to overdiagnosis.
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BACKGROUND: Androgen deprivation therapy (ADT) has been a mainstay of treatment for advanced prostate cancer (PCa), but limited studies have been performed to investigate the association between ADT and autoimmune diseases. METHODS: We conducted a population-based nationwide cohort study of 17,168 patients newly diagnosed with PCa between 1996 and 2013 using the National Health Insurance Research Database (NHIRD) of Taiwan. Cox proportional hazards models with 1:1 propensity score-matched analysis were used to investigate the association between ADT use and the risk of autoimmune diseases. The autoimmune diseases included Graves' disease, Crohn's disease, psoriasis, systemic lupus erythematosus, rheumatoid arthritis, ankylosing spondylitis, Guillain-Barre syndrome, Sjogren's syndrome, myasthenia gravis, pernicious anemia, hereditary hemolytic anemia, polyarteritis nodosa, Celiac disease, uveitis, polymyalgia rheumatica, dermatomyositis, Hashimoto's thyroiditis, hypersensitivity vasculitis, Behcet's disease, polymyositis, alopecia areata, Wegener's granulomatosis, ulcerative colitis, autoimmune hemolytic anemia, pemphigus, multiple sclerosis, systemic sclerosis, Goodpasture syndrome, giant cell arteritis, thromboangitis obliterans, arteritis obliterans, and Kawasaki disease. The duration of ADT use as a time-dependent variable was also examined for its association with autoimmune diseases. We also performed six secondary analyses. RESULTS: Of the 17,168 selected PCa patients, 14,444 patients met all the inclusion and exclusion criteria. After propensity score matching, 5590 ADT users and 5590 non-ADT users were included in the study cohort. A propensity score-matched analysis (adjusted hazard ratio (aHR), 0.619, 95% confidence interval (CI), 0.51-0.75, P < 0.001) demonstrated a significantly decreased risk of autoimmune diseases in ADT users. A significant decrease in the risk of autoimmune diseases with increasing ADT duration was also demonstrated (P < 0.001). CONCLUSIONS: We observed that ADT use in patients with PCa was associated with a decreased risk of autoimmune diseases. These novel findings provide a potential role for androgen deprivation therapy in the modification of inflammation and autoimmunity in Asian patients with prostate cancer.
Subject(s)
Androgen Antagonists/therapeutic use , Androgens/immunology , Autoimmune Diseases/epidemiology , Prostatic Neoplasms/therapy , Aged , Aged, 80 and over , Androgens/metabolism , Autoimmune Diseases/prevention & control , Databases, Factual/statistics & numerical data , Humans , Male , Middle Aged , Prostatic Neoplasms/pathology , Retrospective Studies , Risk Assessment , Taiwan/epidemiologyABSTRACT
Both periodontal disease (PD) and inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are important diseases of the alimentary tract. Microbiome and immune-mediated inflammatory processes play important roles in these diseases. An association between PD and IBD may exist. This study investigated the risk of IBD in patients with PD. This study used data from the National Health Insurance Research Database of Taiwan from 1996 to 2013. A total of 27,041 patients with PD were enrolled as a study group, and 108,149 patients without PD were selected as the control group after matching by gender, age, insured region, urbanization, and income with a 1:4 ratio. Cox proportional hazards regression was used to calculate the risk of IBD. Of the 135,190 participants enrolled in this study, 5392 (4%) with newly diagnosed IBD were identified. The overall incidence of subsequent IBD was similar in both groups (3.8% vs. 4%, adjusted hazard ratio (aHR) = 1.01, 95% confidence interval (CI): 0.94â»1.08). However, an increased risk of UC in the PD group was found after adjusting confounding factors (aHR: 1.56, 95% CI: 1.13â»2.15; p < 0.05). This study demonstrated that patients with PD had approximately one-half higher risk of subsequent UC. Further studies are warranted to elucidate the relationship between PD and UC.
Subject(s)
Chronic Disease/epidemiology , Colitis, Ulcerative/epidemiology , Colitis, Ulcerative/etiology , Periodontal Diseases/complications , Periodontal Diseases/epidemiology , Adult , Aged , Cohort Studies , Crohn Disease/epidemiology , Crohn Disease/etiology , Databases, Factual , Female , Humans , Incidence , Male , Middle Aged , Proportional Hazards Models , Risk Assessment , Risk Factors , Taiwan/epidemiology , Young AdultABSTRACT
Installation of olefins into molecules is a key transformation in organic synthesis. The recently discovered decarboxylation-assisted olefination in the biosynthesis of rhabduscin by a mononuclear non-heme iron enzyme ( P.IsnB) represents a novel approach in olefin construction. This method is commonly employed in natural product biosynthesis. Herein, we demonstrate that a ferryl intermediate is used for C-H activation at the benzylic position of the substrate. We further establish that P.IsnB reactivity can be switched from olefination to hydroxylation using electron-withdrawing groups appended on the phenyl moiety of the analogues. These experimental observations imply that a pathway involving an initial C-H activation followed by a benzylic carbocation species or by electron transfer coupled ß-scission is likely utilized to complete CâC bond formation.
Subject(s)
Alkenes/metabolism , Nonheme Iron Proteins/metabolism , Alkenes/chemistry , Biocatalysis , Decarboxylation , Molecular StructureABSTRACT
Two non-heme iron enzymes, IsnB and AmbI3, catalyze a novel decarboxylation-assisted olefination to produce indole vinyl isonitrile, an important building block for many natural products. Compared to other reactions catalyzed by this enzyme family, decarboxylation-assisted olefination represents an attractive biosynthetic route and a mechanistically unexplored pathway in constructing a CâC bond. Using mechanistic probes, transient state kinetics, reactive intermediate trapping, spectroscopic characterizations, and product analysis, we propose that both IsnB and AmbI3 initiate stereoselective olefination via a benzylic C-H bond activation by an Fe(IV)-oxo intermediate, and the reaction likely proceeds through a radical- or carbocation-induced decarboxylation to complete CâC bond installation.