The rise in cancer cases in recent years is an alarming situation worldwide. Despite the tremendous research and invention of new cancer therapies, the clinical outcomes are not always reassuring. ...Cancer cells could develop several evasive mechanisms for their survivability and render therapeutic failure. The continuous use of conventional cancer therapies leads to chemoresistance, and a higher dose of treatment results in even greater toxicities among cancer patients. Therefore, the search for an alternative treatment modality is crucial to break this viscous cycle. This paper explores the suitability of curcumin combination treatment with other cancer therapies to curb cancer growth. We provide a critical insight to the mechanisms of action of curcumin, its role in combination therapy in various cancers, along with the molecular targets involved. Curcumin combination treatments were found to enhance anticancer effects, mediated by the multitargeting of several signalling pathways by curcumin and the co-administered cancer therapies. The preclinical and clinical evidence in curcumin combination therapy is critically analysed, and the future research direction of curcumin combination therapy is discussed.
Background. Pyroptosis has a dual function in malignant tumor progression and management. The action of pyroptosis-related genes (PRGs) in pancreatic cancer (PC), however, remains uncertain. Methods. ...Differential expression analyses of 57 PRGs were conducted in the TCGA TARGET GTEx dataset. The candidate genes were determined using LASSO Cox regression and random forest analyses. A risk model was developed with the TCGA dataset and validated with the ICGC dataset. Results. Three prognosis-related PRGs (BAK1, GSDMC, and IL18) were chosen to create a risk model. High-risk patients from the TCGA and ICGC cohorts had an unfavorable overall survival (all p<0.05). The risk modelʼs accuracy and independent predictability were assessed by receiver operating characteristic curves and multivariate Cox regression analysis, respectively. High-risk patients possessed different molecular pathways, higher KRAS and TP53 mutations, increased expression of PD-L1, C1 immune subtype, and immunosuppressive microenvironment characterized by parainflammation compared to low-risk patients. KRAS and TP53 mutations participated in different inflammatory pathways and played different prognostic roles between the two risk groups. KRAS mutations in high-risk patients caused a more unfavorable prognosis than wild-type KRAS (p=0.016), whereas TP53 mutations in low-risk patients exhibited a poorer outcome than wild-type TP53 (p=0.009). Spearman correlation analyses revealed that the parainflammatory response in PC might be implicated in GSDMC-mediated pyroptosis via cytosolic DNA-sensing pathways under hypoxic conditions. Furthermore, the risk scores were significantly and positively related to the expression of HNRNPC, RBM15, YTHDF1, and YTHDF2, as well as sensitivity to gemcitabine, cisplatin, and erlotinib. Conclusions. This study created a novel pyroptosis-based risk model related to the parainflammatory immune microenvironment, which might help identify novel biomarkers, evaluate the tumor immune microenvironment, and develop management strategies for PC patients.
The number of people suffering from scrub typhus, which is not of concern, is increasing year by year, especially in Yunnan Province, China. From June 1, 2021 to August 15, 2022, a total of 505 ...mammalian samples were collected from farm, forest, and residential habitats with high incidence of scrub typhus in Yunnan, China, for nPCR (nested PCR) and qPCR (quantitative real-time PCR) detection of Orientia tsutsugamushi. A total of 4 orders of murine-like animals, Rodentia (87.52%, n = 442), Insectivora (10.29%, n = 52), Lagomorpha (1.79%, n = 9) and Scandentia (0.40%, n = 2) were trapped. Comparing the qPCR infection rates in the three habitats, it was no significant difference that the infection rate of residential habitat (44.44%) and that of the farm habitat (45.05%, P>0.05), which is much larger than that of the forest habitat (3.08%) (P<0.001). Three genotypes (Karp-like, Kato-like and TA763-like) of O. tsutsugamushi were found from Yunnan, China in this study.
Based on the basic principles of thermodynamics and fluid mechanics, the temperature and pressure model of natural gas hydrate hydraulic lifting pipeline, the hydrate decomposition mass transfer ...model and the mathematical model of pipeline multiphase flow are established. The relationship between the back pressure of the pipeline outlet, the decomposition surface and the depth of the seawater was analyzed. On this basis, the numerical simulation and experimental verification of natural gas hydrate pipeline transmission were carried out. The effects of pipe diameter, inlet velocity and solid phase parameters on the three-phase flow of natural gas hydrate pipelines were analyzed. The result shows that with the outlet pressure increasing, the position at which the hydrate begins to decompose moves up and the decomposition rate slows down. As the depth of mining increases, the rate of hydrate decomposition slows and the position at which decomposition begins to move up. In deep sea mining below 1500 m, the increase of mining depth has little effect on the decomposition rate of hydrate, and the decomposition starting position is always near 510 m in sea depth. The pipe pressure loss gradient decreases as the pipe diameter increases. After the pipe diameter is larger than 300 mm, the pressure loss gradient decreases slowly, and the pressure loss gradient drops sharply at 450 mm, and eventually stabilizes after 500 mm. When the inlet velocity of the pipe is low, the fluid flow in the pipe is unstable and reflow occurs. The pipe pressure loss gradient first decreases and then increases as the fluid flow rate increases, and there is an optimal flow rate value that minimizes the pressure loss gradient.
•In the paper, based on the basic principles of thermodynamics and fluid mechanics, the temperature and pressure model of natural gas hydrate hydraulic lifting pipeline, the hydrate decomposition mass transfer model and the mathematical model of pipeline multiphase flow are established.•The relationship between the back pressure of the pipeline outlet, the decomposition surface and the depth of the seawater was analyzed.•On this basis, the numerical simulation and experimental verification of natural gas hydrate pipeline transmission were carried out.•The effects of pipe diameter, inlet velocity and solid phase parameters on the three-phase flow of natural gas hydrate pipelines were analyzed.
Prostate cancer (PCa) is a major cause of death since ancient time documented in Egyptian Ptolemaic mummy imaging. PCa detection is critical to personalized medicine and varies considerably under an ...MRI scan. 172 patients with 2,602 morphologic images (axial 2D T2-weighted imaging) of the prostate were obtained. A deep learning with deep convolutional neural network (DCNN) and a non-deep learning with SIFT image feature and bag-of-word (BoW), a representative method for image recognition and analysis, were used to distinguish pathologically confirmed PCa patients from prostate benign conditions (BCs) patients with prostatitis or prostate benign hyperplasia (BPH). In fully automated detection of PCa patients, deep learning had a statistically higher area under the receiver operating characteristics curve (AUC) than non-deep learning (P = 0.0007 < 0.001). The AUCs were 0.84 (95% CI 0.78-0.89) for deep learning method and 0.70 (95% CI 0.63-0.77) for non-deep learning method, respectively. Our results suggest that deep learning with DCNN is superior to non-deep learning with SIFT image feature and BoW model for fully automated PCa patients differentiation from prostate BCs patients. Our deep learning method is extensible to image modalities such as MR imaging, CT and PET of other organs.
In rheumatoid arthritis (RA), macrophage is one of the major sources of inflammatory mediators. Macrophages produce inflammatory cytokines through toll‐like receptor (TLR)‐mediated signalling during ...RA. Herein, we studied macrophages from the synovial fluid of RA patients and observed a significant increase in activation of inositol‐requiring enzyme 1α (IRE1α), a primary unfolded protein response (UPR) transducer. Myeloid‐specific deletion of the IRE1α gene protected mice from inflammatory arthritis, and treatment with the IRE1α‐specific inhibitor 4U8C attenuated joint inflammation in mice. IRE1α was required for optimal production of pro‐inflammatory cytokines as evidenced by impaired TLR‐induced cytokine production in IRE1α‐null macrophages and neutrophils. Further analyses demonstrated that tumour necrosis factor (TNF) receptor‐associated factor 6 (TRAF6) plays a key role in TLR‐mediated IRE1α activation by catalysing IRE1α ubiquitination and blocking the recruitment of protein phosphatase 2A (PP2A), a phosphatase that inhibits IRE1α phosphorylation. In summary, we discovered a novel regulatory axis through TRAF6‐mediated IRE1α ubiquitination in regulating TLR‐induced IRE1α activation in pro‐inflammatory cytokine production, and demonstrated that IRE1α is a potential therapeutic target for inflammatory arthritis.
A key transducer of the unfolded protein response is required for pro‐inflammatory cytokine production in macrophages, being regulated by a novel TLR/TRAF6/ubiquitination axis that controls IRE1α phosphorylation.
Drug resistance of paclitaxel (TAX), the first-line chemotherapy drug for breast cancer, was reported to develop in 90% of patients with breast cancer, especially metastatic breast cancer. ...Investigating the mechanism of TAX resistance of breast cancer cells and developing the strategy improving its therapeutic efficiency are crucial to breast cancer cure.
We here report an elegant nanoparticle (NP)-based technique that realizes efficient breast cancer treatment of TAX. Using lentiviral vector-mediated gene knockdown, we first demonstrated that TAX therapeutic efficiency was closely correlated with metadherin (MTDH) gene expression in breast cancer cell lines. This finding was also supported by efficacy of TAX treatment in breast cancer patients from our clinical studies. Specifically, TAX treatment became more effective when MTDH expression was decreased in MCF-7 cancer cells by the blocking nuclear factor-kappa B (NF-κB) pathway. Based on these findings, we subsequently synthesized a polymeric NP that could co-deliver MTDH-small interfering RNA (MTDH-siRNA) and TAX into the breast cancer tumors in tumor-bearing mice. The NPs were composed of a cationic copolymer, which wrapped TAX in the inside and adsorbed the negatively charged siRNA on their surface with high drug-loading efficiency and good stability.
NP-based co-delivery approach can effectively knock down the MTDH gene both in vitro and in vivo, which dramatically inhibits breast tumor growth, achieving effective TAX chemotherapy treatment without overt side effects. This study provides a potential therapeutic strategy for the treatment of a wide range of solid tumors highly expressing MTDH.
This study was conducted to assess the merits and limitations of various high-pressure membranes, tight nanofiltration （NF） membranes in particular, for the removal of trace organic compounds ...（TrOCs）. The performance of a low-pressure reverse osmosis （LPRO） membrane （ESPA1）, a tight NF membrane （NF90） and two loose NF membranes （HL and NF270） was compared for the rejection of 23 different pharmaceuticals （PhACs）. Efforts were also devoted to understand the effect of adsorption on the rejection performance of each membrane. Difference in hydrogen bond formation potential （HFP） was taken into consideration. Results showed that NF90 performed similarly to ESPA1 with mean rejection higher than 95%. NF270 outperformed HL in terms of both water permeability and PhAC rejection higher than 90%. Electrostatic effects were more significant in PhAC rejection by loose NF membranes than tight NF and LPRO membranes. The adverse effect of adsorption on rejection by HL and ESPA1 was more substantial than NF270 and NF90, which could not be simply explained by the difference in membrane surface hydrophobicity, selective layer thickness or pore size. The HL membrane had a lower rejection of PhACs of higher hydrophobicity （log D〉0） and higher HFP （〉0.02）. Nevertheless, the effects of PhAC hydrophobicity and HFP on rejection by ESPA1 could not be discerned. Poor rejection of certain PhACs could generally be explained by aspects of steric hindrance, electrostatic interactions and adsorption. High-pressure membranes like NF90 and NF270 have a high promise in TrOC removal from contaminated water.
Two commercial forward osmosis (FO) membranes (HTI-ES and HTI-NW) were employed to study the rejection performance of 24 pharmaceuticals (PhACs) using NaCl as the draw solute. The PhAC permeability ...coefficient (B value) was determined for each PhAC by using both the reverse osmosis (RO) mode method and the diffusion cell method. The B values were used to predict the rejection ratios in the FO mode. The rejection ratio increased with the increase of draw solute (NaCl) concentration for each PhAC. Under a NaCl concentration of 1mol/L, all PhACs were highly rejected by >90%, except for a few including nalidixic acid, gemfibrozil, carbamazepine and sulfamethoxazole, which were rejected by 80–90% when HTI-ES membrane was used. The HTI-NW membrane could reject PhACs better than the HTI-ES membrane; however, the PhACs followed almost an identical sequence in terms of the rejection ratios. Results showed that the B values for several charged PhACs of relatively low molecular weight obtained by the diffusion cell method could be substantially larger than that determined by the RO mode method. In comparison with the experimental data, the B values obtained by the diffusion cell method were more appropriate to be used to predict the rejection ratios of the PhACs by the solution–diffusion model during FO operation. The underestimation of the B values by using the RO mode method might be primarily due to the ion exchange mechanism caused by reverse draw solute permeation during FO operation. Compared with the hydrophobicity and the charge properties, the molecular weight of PhAC was a more important factor in determining its B value. Very low B value is expected if the molecular weight is higher than 300Da. Exceptions, however, were found including clofibric acid, gemfibrozil and sulfadiazine. The solute-membrane affinity should also be taken into consideration when trying to link the B values with physicochemical properties of the PhACs.
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•Rejection ratios for 24 pharmaceuticals by two FO membranes were ranked.•The solution–diffusion model could predict the rejection ratio well.•The permeability coefficient obtained by the diffusion cell method was more appropriate for model prediction.•Permeability coefficient is primarily determined by molecular weight.
Urinary acrolein metabolite levels in severe acute alcoholic hepatitis patients Vatsalya, Vatsalya; Kong, Maiying; Gobejishvili, Leila ...
American journal of physiology. Gastrointestinal and liver physiology/American journal of physiology: Gastrointestinal and liver physiology,
01/2019, Volume:
316, Issue:
1
Journal Article
Peer reviewed
Open access
Alcohol-associated liver disease (ALD) remains a major health concern worldwide. Alcohol consumption gives rise to reactive/toxic acrolein, a pathogenic mediator of liver injury in experimental ALD. ...Elevated acrolein adducts and metabolites are detectable in blood and urine. This study evaluates the major urinary acrolein metabolite, 3-hydroxypropylmercapturic acid (HPMA), in patients with acute alcoholic hepatitis (AAH) and examines its association with disease severity and markers of hepatic inflammation and injury. Urine HPMA was significantly higher in patients with severe model for end-stage liver disease (MELD) ≥ 20 AAH compared with nonsevere AAH (MELD ≤ 19) or non-alcohol-consuming controls, suggesting that urine HPMA is a novel noninvasive biomarker in severe AAH. The association between HPMA and MELD in patients with AAH was nonlinear. In patients with nonsevere AAH, there was a positive trend, although not significant, whereas in severe AAH the association was negative, indicative of extensive injury and glutathione depletion. Consistent with the multifactorial etiology of ALD, our data identified strong combined effects of HPMA and proinflammatory cytokines on hepatocyte cell death, thereby supporting the pathogenic role of acrolein in liver injury. HPMA, together with IL-1β, showed robust associations with cytokeratin 18 caspase-cleaved fragment (CK18-M30; adjusted R
= 0.812, P = 0.016) and cytokeratin 18 full-length protein (CK18-M65; adjusted R
= 0.670, P = 0.048); similarly, HPMA, with IL-8, correlated with CK18-M30 (adjusted R
= 0.875, P = 0.007) and CK18-M65 (adjusted R
= 0.831, P = 0.013). The apoptosis index (CK18-M30:CK18-M65 ratio) strongly correlated with HPMA, together with IL-1β (adjusted R
= 0.777, P = 0.022) or tumor necrosis factor-α (TNFα; adjusted R
= 0.677, P = 0.046). In patients with severe AAH, IL-1β, IL-8, and TNFα are the predominant proinflammatory cytokines that interact with HPMA and play important mediating roles in influencing the extent/pattern of liver cell death. NEW & NOTEWORTHY This is the first study to examine the urinary acrolein metabolite 3-hydroxypropylmercapturic acid (HPMA) in alcoholic liver disease. HPMA was higher in patients with severe acute alcoholic hepatitis (AAH) compared with controls or nonsevere AAH and may be a novel selective, noninvasive biomarker for severe AAH. Consistent with the multifactorial etiology of alcohol-associated liver disease, we identified strong combined effects of HPMA and proinflammatory cytokines (IL-1β, IL-8, and TNFα) on the extent/pattern of liver cell death, thereby supporting the pathogenic role of acrolein.
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