Inhibitor Treatment
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2021 ◽  
Vol 12 ◽  
Deling Zou ◽  
Yanyu Li ◽  
Guangping Sun

Chronic heart failure (HF) frequently causes progressive decline in kidney function, known as cardiorenal syndrome-2 (CRS2). Current treatment options for CRS2 remain unacceptably limited. Trimethylamine-N-oxide (TMAO), a metabolite of gut microbiota, has recently been implicated in the pathogenesis of both HF and chronic kidney disease. Here we examined whether circulating TMAO is elevated in CRS2 and if so, whether attenuation of circulating TMAO would ameliorate the progression of CRS2. Sprague-Dawley rats underwent surgery for myocardial infarction (MI) or sham (week 0) followed by subtotal (5/6) nephrectomy (STNx) or sham at week 4 to induce CRS2 or control. At week 6, MI + STNx rats and control rats received vehicle or 1.0% 3,3-Dimethyl-1-butanol (DMB, a TMAO inhibitor) treatment for 8 weeks. Compared with control rats, MI + STNx rats exhibited elevated serum TMAO at week 6, which was increased further at week 14 but was attenuated by DMB treatment. MI + STNx rats showed cardiac dysfunction as assessed by echocardiography and renal dysfunction as evidenced by increased serum creatinine and urinary kidney injury molecule-1 and decreased creatinine clearance at week 6. The cardiac and renal dysfunction in MI + STNx rats was exacerbated at week 14 but was prevented by DMB treatment. Molecular and histological studies revealed myocyte hypertrophy and increases in interstitial myocardial fibrosis and gene expression of pro-hypertrophic and pro-fibrotic markers in both heart and kidney at week 14, which were accompanied by elevated gene expression of proinflammatory cytokines. The changes in molecular and histological parameters observed in MI + STNx rats were significantly reduced by DMB treatment. These findings suggest that rats with CRS2 have elevated circulating TMAO, which is associated with the exacerbation of cardiac and renal dysfunction. Attenuation of circulating TMAO can ameliorate cardiac and renal injury and prevents the progression of CRS2.

2021 ◽  
Xiaofeng Xu ◽  
Dian Fu ◽  
Hai Zhao ◽  
Jie Huang ◽  
Zuheng Wang ◽  

Abstract Background Urothelial bladder cancer (UBC) is one of the most lethal cancers worldwide, the 5-year survival rate remain poor with platinum-based chemotherapy regimens as the standard of cancer treatment protocol. Recent FDA approval of a programmed death ligand-1 (PD-L1) inhibitor, atezolizumab, in advanced UBC patients is changing the therapeutic landscape. Although the response to anti-PD-L1 is correlated to PD-L1 expression and tumor mutation burden, the molecule determinants of responsiveness or non-responsiveness to immune checkpoint inhibitor (ICI) is largely unknown. Result A published immunotherapy cohort with whole exome sequencing, RNAseq and clinic outcome data for 29 metastatic urothelial cancer patients was used, paralleled with The Cancer Genome Altas Bladder Cancer cohort for validation. Genomic mutational profiling, mutational signature, a panel genes in antigen presentation and interferon signaling in bladder cancer were delineated with little correlation with durable clinic benefit (DCB) or non-DCB of PD-L1 inhibitor treatment. Whereas, characterized immune-responsive or resistant associated genes showed differentially expressed between DCB group and non-DCB group. Further more, transcriptional signature and transcriptional regulators between DCB and non-DCB were identified from transcripome data. Conclusion Our exploratory analyses provided multidimension view of complexity of determinants of immune-responsiveness and suggest the influences of transcriptional reprogram in immune checkpoint blockage therapy.

2021 ◽  
Haixiang Qin ◽  
Yingqiang Lu ◽  
Lin Du ◽  
Jingyan Shi ◽  
Haoli Yin ◽  

Abstract Background: Emerging evidence suggests that LMNB1 is involved in the development of multiple cancer types. However, there is no study reporting the potential role of LMNB1 in a systematic pan-cancer manner.Methods: The gene expression level and potential oncogenic roles of LMNB1 in The Cancer Genome Atlas (TCGA) database were analyzed with Tumor Immune Estimation Resource version 2 (TIMER2.0), Gene Expression Profiling Interactive Analysis version 2 (GEPIA2), UALCAN and Sangerbox tools. Pathway enrichment analysis was carried out to explore the possible mechanism of LMNB1 on tumorigenesis and tumor progression. The therapeutic effects of LMNB1 knockdown combined with PARP inhibition on human cancers were further investigated in vitro. Results: LMNB1 upregulation is generally observed in the tumor tissues of most TCGA cancer types, and is verified in kidney renal clear cell carcinoma using clinical specimens of our institute. High level of LMNB1 expression usually predicts poor overall survival and disease free survival for patients with tumors. Mechanically, LMNB1 level is positively correlated with CD4+ Th2 cell infiltration and DNA homologous recombination repair gene expression. In vitro experiments reveal that targeting LMNB1 has a synergistic effect on prostate cancer with PARP inhibitor treatment. Conclusions: LMNB1 is a biomarker of CD4+ Th2 cell infiltration and DNA homologous recombination repair in human cancers. Blockage of LMNB1 combined with PARP inhibitor treatment could be a promising therapeutic strategy for patients with cancers.

2021 ◽  
Wan-Yu Huang ◽  
Yen-Ling Lai ◽  
Ko-Hung Liu ◽  
Shankung Lin ◽  
Hsuan-Ying Chen ◽  

Abstract BackgroundSystemic inflammation is a potent contributor to increased seizure susceptibility. However, less is known about the effects of systemic inflammation on blood-brain barrier (BBB) that affect neuron excitability. Necroptosis and inflammation are intimately associated in various neurological diseases. We hypothesized that necroptosis is involved in the mechanism underlying sepsis-associated neuronal excitability in BBB components.MethodsSystemic inflammation was induced by LPS. Seizure susceptibility of mice was measured by kainic acid intraperitoneal injection. Pharmacological inhibitors (C87 and GSK872) were used to block signaling of TNFα receptors and necroptosis. To identify the features of sepsis-associated response in the BBB and CNS, brain tissues of mice were obtained for assays of the necroptosis-related protein expression, and immunofluorescence staining for morphological changes of endothelia and glia. Microdialysis assay was also used to evaluate the changes of extracellular potassium and glutamate levels in brain.ResultsSignificant findings including induced increased seizure susceptibility and BBB endothelia necroptosis and leakage, Kir4.1 dysfunction, and microglia activation were observed in mice following LPS injection. Inhibition of TNFa receptor inhibitor C87 significantly attenuated increased kainic acid-induced seizure susceptibility and endothelia necroptosis and microglia activation, and restored kir4.1 protein expression, compared with those in controls. GSK872 (a RIP3 inhibitor) treatment, like C87, had consistent effects on these changes following LPS.ConclusionsOur results showed that TNFα-mediated necroptosis in BBB endothelia damage contributes to the development of increased seizure susceptibility in mice after systemic inflammation. Pharmacologic inhibition targeting this necroptosis pathway may provide a promising therapeutic approach to reduce sepsis-associated BBB dysfunction, astrocyte ion channel dysfunction, and subsequent neuronal excitability.

eLife ◽  
2021 ◽  
Vol 10 ◽  
E Josue Ruiz ◽  
Adan Pinto-Fernandez ◽  
Andrew P Turnbull ◽  
Linxiang Lan ◽  
Thomas M Charlton ◽  

Lung squamous cell carcinoma (LSCC) is a considerable global health burden, with an incidence of over 600,000 cases per year. Treatment options are limited, and patient 5-year survival rate is less than 5%. The ubiquitin specific protease 28 (USP28) has been implicated in tumorigenesis through its stabilization of the oncoproteins c-MYC, c-JUN and Dp63. Here, we show that genetic inactivation of Usp28 induced regression of established murine LSCC lung tumours. We developed a small molecule that inhibits USP28 activity in the low nanomole range. While displaying cross-reactivity against the closest homologue USP25, this inhibitor showed a high degree of selectivity over other deubiquitinases. USP28 inhibitor treatment resulted in a dramatic decrease in c-MYC, c-JUN and Dp63 proteins levels and consequently induced substantial regression of autochthonous murine LSCC tumors and human LSCC xenografts, thereby phenocopying the effect observed by genetic deletion. Thus, USP28 may represent a promising therapeutic target for the treatment of squamous cell lung carcinoma.

2021 ◽  
Hendro Vico ◽  
Riezal Arieffiandhany ◽  
Indra Sanjaya ◽  
Lambertus Francisco ◽  
Yasinta Dewi Setiawati ◽  

Abstract The Brani-Field is located offshore Northwest Java and currently produces hydrocarbons from a sandstone reservoir with an average watercut of 83%. Some high watercut wells are prone to scale problems and need repetitive clean outs to overcome production decline. In 2019, downhole scale inhibitor treatment was evaluated and planned for application in these wells. Scale inhibitors are able to prevent the formation of scale so the well is able to deliver higher average oil production with lower intervention cost. In Brani wells, scale deposits are formed in perforations, downhole completion equipment, and flowlines depending on the water composition, temperature, and a reduction in dissolved carbon dioxide partial pressure. These scales deposits restrict the fluid flow causing significant production loss. In extreme conditions, the production tubing was blocked completely with the scale deposits and cease the production. Normally, the scale restriction problem in Brani wells were handled by a combination of mechanical and acidizing treatment using Coiled Tubing (CT) for downhole completion and acidizing treatment for flowline restrictions. These treatment were performed periodically every 2-4 months depending on well conditions with scaling becoming more severe in higher watercut wells. From an economic standpoint, current scale treatment methods lead to very high well intervention costs due to expensive liftboat and CT unit daily rates. The economics of these conventional treatments is further deterred by low yearly average oil production. Evaluation for scale inhibitor treatment started with the candidate selection, fluids compatibility test, core re-gain permeability test, and economic evaluation. BRG-10 well was selected as first candidate due to scale problem severity and low oil production rate. This well normally delivers 140 bopd with 90% watercut, but scale build up in the tubing and flowline prevented the fluids flow and lowered the production to 30 bopd in just two months. Laboratory test results demonstrated that the core regained permeability with the main pill fluids to a relatively high, 77.96% without any fluids compatibility issues. Deployment of a scale inhibitor squeeze treatment in BRG-10 well was executed in Jan 2020 by bullheading 657 bbl inhibitor fluids into the formation. The well was then shut in for 24 hours of soaking time. The post treatment results showed a very promising result with much more stable oil production after 11 months treatment, welltest on December 2020 showed the well was still producing 130 bopd with 90% watercut. Following the successful application in BRG-10, the scale inhibitor treatment was applied in other wells, BRK-7 in June 2020 and BRG-5L in August 2020. So far, those two wells show good production performance with 93 bopd with 85% watercut for BRK-7 and 264 bopd with 76% for BRG-5L.

Lung Cancer ◽  
2021 ◽  
Yu-Ning Chien ◽  
Yi-Chun Lin ◽  
Chia-Lun Chang ◽  
Wei-Chun Lin ◽  
Szu-Yuan Wu

2021 ◽  
Vol 11 (19) ◽  
pp. 9128
Jwa-Young Kim ◽  
Dae-Won Kim ◽  
Suk Keun Lee ◽  
Je-Yong Choi ◽  
Xiangguo Che ◽  

In our previous study, 4-hexylresorcinol (4HR) increased the expression level of vascular endothelial growth factor in human umbilical vein endothelial cells (HUVECs) via the transforming growth factor-β1 (TGF-β1)-mediated pathway. Endoplasmic reticulum (ER) and mitochondrial stress is a positive regulator of cellular differentiation. As TGF-β1 is a master regulator for cellular differentiation, 4HR treatment may increase TGF-β1 expression via ER stress. In this study, HUVECs were treated using 4HR (1–100 μM) for 24 h. The 4HR treatment increased ER stress-associated markers and mitochondrial stress. Increased TGF-β1 expression by 4HR administration was alleviated by tauroursodeoxycholate (ER stress inhibitor) treatment. Combining these activities with the elevated acetylation level of histone 3 (H3) by 4HR treatment, TGF-β1 expression was increased in HUVECs. Overall, 4HR increased TGF-β1 expression through upregulation of the stress response of ER as well as H3 acetylation in HUVECs.

2021 ◽  
pp. 1-7
Weicheng Zheng ◽  
Qingfeng Xue ◽  
Xueping Sha ◽  
Yao Wang ◽  
Yuan Wang ◽  

2021 ◽  
Yan Ma ◽  
Xiao Ma ◽  
Jingting Wang ◽  
Shanshan Shan Wu ◽  
Jing Wang ◽  

Abstract Background This study aimed to investigate the predictive values of serum biomarkers including absolute eosinophil count (AEC), neutrophil–lymphocyte ratio (NLR), and platelet–lymphocyte ratio (PLR) with respect to immune-related adverse events (irAEs) during anti-PD-1/PD-L1 inhibitor treatment in patients with advanced malignant tumors.Methods We retrospectively analyzed 95 patients with advanced cancer who were treated with anti-PD-1/PD-L1 inhibitors from January 1, 2017 to May 1, 2020, in our cancer center. We then analyzed associations between irAEs and anti-PD-1/PD-L1 inhibitor responses and evaluated the predictive values of serum biomarkers with respect to risk of irAEs.Results The incidence of irAEs was 55.8%. There were no statistically significant differences between the irAEs and no-irAEs groups in objective response rate (ORR) or disease control rate (DCR). However, landmark analysis showed that the irAEs group had better survival after 120 days following the initiation of anti-PD-1/PD-L1 inhibitor treatment, compared with the no-irAEs group. The incidences of irAEs were greater in the high-AEC and low-NLR groups than in the low-AEC and high-NLR groups. Univariate logistic analysis showed that low NLR, ECOG performance status (0–1), and high AEC were risk factors for irAEs. Multivariate logistic analysis showed that high AEC and good ECOG performance status were independent predictors for irAEs.Conclusions irAEs may be associated with a survival benefit. Baseline AEC is a strong predictor of irAEs in patients undergoing treatment with anti-PD-1/PD-L1 inhibitors.

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