Identification of the central role of RNA polymerase mitochondrial for angiogenesis.

Mitochondria are central to endothelial cell activation and angiogenesis, with the RNA polymerase mitochondrial (POLRMT) serving as a key protein in regulating mitochondrial transcription and oxidative phosphorylation. In our study, we examined the impact of POLRMT on angiogenesis and found that its silencing or knockout (KO) in human umbilical vein endothelial cells (HUVECs) and other endothelial cells resulted in robust anti-angiogenic effects, impeding cell proliferation, migration, and capillary tube formation. Depletion of POLRMT led to impaired mitochondrial function, characterized by mitochondrial depolarization, oxidative stress, lipid oxidation, DNA damage, and reduced ATP production, along with significant apoptosis activation. Conversely, overexpressing POLRMT promoted angiogenic activity in the endothelial cells. In vivo experiments demonstrated that endothelial knockdown of POLRMT, by intravitreous injection of endothelial specific POLRMT shRNA adeno-associated virus, inhibited retinal angiogenesis. In addition, inhibiting POLRMT with a first-in-class inhibitor IMT1 exerted significant anti-angiogenic impact in vitro and in vivo. Significantly elevated expression of POLRMT was observed in the retinal tissues of streptozotocin-induced diabetic retinopathy (DR) mice. POLRMT endothelial knockdown inhibited pathological retinal angiogenesis and mitigated retinal ganglion cell (RGC) degeneration in DR mice. At last, POLRMT expression exhibited a substantial increase in the retinal proliferative membrane tissues of human DR patients. These findings collectively establish the indispensable role of POLRMT in angiogenesis, both in vitro and in vivo.

The requirement of the mitochondrial protein NDUFS8 for angiogenesis.

Mitochondria are important for the activation of endothelial cells and the process of angiogenesis. NDUFS8 (NADH:ubiquinone oxidoreductase core subunit S8) is a protein that plays a critical role in the function of mitochondrial Complex I. We aimed to investigate the potential involvement of NDUFS8 in angiogenesis. In human umbilical vein endothelial cells (HUVECs) and other endothelial cell types, we employed viral shRNA to silence NDUFS8 or employed the CRISPR/Cas9 method to knockout (KO) it, resulting in impaired mitochondrial functions in the endothelial cells, causing reduction in mitochondrial oxygen consumption and Complex I activity, decreased ATP production, mitochondrial depolarization, increased oxidative stress and reactive oxygen species (ROS) production, and enhanced lipid oxidation. Significantly, NDUFS8 silencing or KO hindered cell proliferation, migration, and capillary tube formation in cultured endothelial cells. In addition, there was a moderate increase in apoptosis within NDUFS8-depleted endothelial cells. Conversely, ectopic overexpression of NDUFS8 demonstrated a pro-angiogenic impact, enhancing cell proliferation, migration, and capillary tube formation in HUVECs and other endothelial cells. NDUFS8 is pivotal for Akt-mTOR cascade activation in endothelial cells. Depleting NDUFS8 inhibited Akt-mTOR activation, reversible with exogenous ATP in HUVECs. Conversely, NDUFS8 overexpression boosted Akt-mTOR activation. Furthermore, the inhibitory effects of NDUFS8 knockdown on cell proliferation, migration, and capillary tube formation were rescued by Akt re-activation via a constitutively-active Akt1. In vivo experiments using an endothelial-specific NDUFS8 shRNA adeno-associated virus (AAV), administered via intravitreous injection, revealed that endothelial knockdown of NDUFS8 inhibited retinal angiogenesis. ATP reduction, oxidative stress, and enhanced lipid oxidation were detected in mouse retinal tissues with endothelial knockdown of NDUFS8. Lastly, we observed an increase in NDUFS8 expression in retinal proliferative membrane tissues obtained from human patients with proliferative diabetic retinopathy. Our findings underscore the essential role of the mitochondrial protein NDUFS8 in regulating endothelial cell activation and angiogenesis.

Autophagy of OTUD5 destabilizes GPX4 to confer ferroptosis-dependent kidney injury.

Ferroptosis is an iron-dependent programmed cell death associated with severe kidney diseases, linked to decreased glutathione peroxidase 4 (GPX4). However, the spatial distribution of renal GPX4-mediated ferroptosis and the molecular events causing GPX4 reduction during ischemia-reperfusion (I/R) remain largely unknown. Using spatial transcriptomics, we identify that GPX4 is situated at the interface of the inner cortex and outer medulla, a hyperactive ferroptosis site post-I/R injury. We further discover OTU deubiquitinase 5 (OTUD5) as a GPX4-binding protein that confers ferroptosis resistance by stabilizing GPX4. During I/R, ferroptosis is induced by mTORC1-mediated autophagy, causing OTUD5 degradation and subsequent GPX4 decay. Functionally, OTUD5 deletion intensifies renal tubular cell ferroptosis and exacerbates acute kidney injury, while AAV-mediated OTUD5 delivery mitigates ferroptosis and promotes renal function recovery from I/R injury. Overall, this study highlights a new autophagy-dependent ferroptosis module: hypoxia/ischemia-induced OTUD5 autophagy triggers GPX4 degradation, offering a potential therapeutic avenue for I/R-related kidney diseases.

A Nickel Dissolution Process for Multilayer Electroforming to Achieve Ultrahigh Adhesion Strength.

Multilayer electroforming has a high potential to produce Ni/Ni layer structured metal walls with excellent material properties and a high thickness uniformity. However, Ni is easily oxidized in air, which fundamentally leads to a low adhesion strength between the Ni layers. Here, a novel in situ treatment is proposed for improving the adhesion performance between Ni layers. This treatment integrated the steps of electrochemical dissolution, surface protection, and electroforming. A study of the polarization behavior implied the electroformed Ni layer was dissolved efficiently in the NH2SO3H solution, beginning at a dissolution current density of 5 A·cm-2, which could remove the oxide film. A smooth substrate surface with a good surface hydrophilicity was obtained starting at 8 A·cm-2, helping to protect the activated substrate from being contaminated and oxidized. The experimental results showed that ultrahigh normal and shear adhesion strengths over 400 MPa between the Ni layers were achieved.

USP18 enhances the resistance of BRAF-mutated melanoma cells to vemurafenib by stabilizing cGAS expression to induce cell autophagy.

This study aims to discern the possible molecular mechanism of the effect of ubiquitin-specific peptidase 18 (USP18) on the resistance to BRAF inhibitor vemurafenib in BRAF V600E mutant melanoma by regulating cyclic GMP-AMP synthase (cGAS). The cancer tissues of BRAF V600E mutant melanoma patients before and after vemurafenib treatment were collected, in which the protein expression of USP18 and cGAS was determined. A BRAF V600E mutant human melanoma cell line (A2058R) resistant to vemurafenib was constructed with its viability, apoptosis, and autophagy detected following overexpression and depletion assays of USP18 and cGAS. Xenografted tumors were transplanted into nude mice for in vivo validation. Bioinformatics analysis showed that the expression of cGAS was positively correlated with USP18 in melanoma, and USP18 was highly expressed in melanoma. The expression of cGAS and USP18 was up-regulated in cancer tissues of vemurafenib-resistant patients with BRAF V600E mutant melanoma. Knockdown of cGAS inhibited the resistance to vemurafenib in A2058R cells and the protective autophagy induced by vemurafenib in vitro. USP18 could deubiquitinate cGAS to promote its protein stability. In vivo experimentations confirmed that USP18 promoted vemurafenib-induced protective autophagy by stabilizing cGAS protein, which promoted resistance to vemurafenib in BRAF V600E mutant melanoma cells. Collectively, USP18 stabilizes cGAS protein expression through deubiquitination and induces autophagy of melanoma cells, thereby promoting the resistance to vemurafenib in BRAF V600E mutant melanoma.

The mitochondrial protein TIMM44 is required for angiogenesis in vitro and in vivo.

The mitochondrial integrity and function in endothelial cells are essential for angiogenesis. TIMM44 (translocase of inner mitochondrial membrane 44) is essential for integrity and function of mitochondria. Here we explored the potential function and the possible mechanisms of TIMM44 in angiogenesis. In HUVECs, human retinal microvascular endothelial cells and hCMEC/D3 brain endothelial cells, silence of TIMM44 by targeted shRNA largely inhibited cell proliferation, migration and in vitro capillary tube formation. TIMM44 silencing disrupted mitochondrial functions in endothelial cells, causing mitochondrial protein input arrest, ATP reduction, ROS production, and mitochondrial depolarization, and leading to apoptosis activation. TIMM44 knockout, by Cas9-sgRNA strategy, also disrupted mitochondrial functions and inhibited endothelial cell proliferation, migration and in vitro capillary tube formation. Moreover, treatment with MB-10 ("MitoBloCK-10"), a TIMM44 blocker, similarly induced mitochondrial dysfunction and suppressed angiogenic activity in endothelial cells. Contrarily, ectopic overexpression of TIMM44 increased ATP contents and augmented endothelial cell proliferation, migration and in vitro capillary tube formation. In adult mouse retinas, endothelial knockdown of TIMM44, by intravitreous injection of endothelial specific TIMM44 shRNA adenovirus, inhibited retinal angiogenesis, causing vascular leakage, acellular capillary growth, and retinal ganglion cells degeneration. Significant oxidative stress was detected in TIMM44-silenced retinal tissues. Moreover, intravitreous injection of MB-10 similarly induced oxidative injury and inhibited retinal angiogenesis in vivo. Together, the mitochondrial protein TIMM44 is important for angiogenesis in vitro and in vivo, representing as a novel and promising therapeutic target of diseases with abnormal angiogenesis.

Bardoxolone methyl ameliorates osteoarthritis by inhibiting osteoclastogenesis and protecting the extracellular matrix against degradation.

Inflammation and oxidative damage are closely related to the development of osteoarthritis. Bardoxolone methyl (CDDO-Me), a semisynthetic oleanane triterpenoid, plays a strong anti-inflammatory and antioxidant role. The purpose of our research was to explore fundamental mechanisms of CDDO-Me in orthopaedics development. The results showed that CDDO-Me inhibited nuclear factor-κB ligand (RANKL)-induced osteoclast formation and extracellular matrix (ECM) degradation by activating the Nrf2/HO-1 signaling pathways and inhibiting NF-κB pathway activation and excess ROS production. In vivo, CDDO-Me significantly attenuated articular cartilage proteoglycan loss and the number of TRAP-positive osteoclasts in a destabilized medial meniscus (DMM) mouse model of OA. Taken together, these data demonstrate that CDDO-Me inhibits osteoclastogenesis and ECM degradation, underscoring its potential therapeutic value in treating OA.

ATFE-Net: Axial Transformer and Feature Enhancement-based CNN for ultrasound breast mass segmentation.

Breast mass is one of the main clinical symptoms of breast cancer. Recently, many CNN-based methods for breast mass segmentation have been proposed. However, these methods have difficulties in capturing long-range dependencies, causing poor segmentation of large-scale breast masses. In this paper, we propose an axial Transformer and feature enhancement-based CNN (ATFE-Net) for ultrasound breast mass segmentation. Specially, an axial Transformer (Axial-Trans) module and a Transformer-based feature enhancement (Trans-FE) module are proposed to capture long-range dependencies. Axial-Trans module only calculates self-attention in width and height directions of input feature maps, which reduces the complexity of self-attention significantly from O(n2) to O(n). In addition, Trans-FE module can enhance feature representation by capturing dependencies between different feature layers, since deeper feature layers have richer semantic information and shallower feature layers have more detailed information. The experimental results show that our ATFE-Net achieved better performance than several state-of-the-art methods on two publicly available breast ultrasound datasets, with Dice coefficient of 82.46% for BUSI and 86.78% for UDIAT, respectively.

Discovery of novel analogs of KHS101 as transforming acidic coiled coil containing protein 3 (TACC3) inhibitors for the treatment of glioblastoma.

Transforming acidic coiled coil containing protein 3 (TACC3) is emerging as an attractive anticancer target in recent years, however, few TACC3 small-molecular inhibitors have been reported up to now. In this study, fifteen compounds were designed and synthesized based on the lead compound KHS101 to find more potent TACC3 inhibitors. Among them, the most potent compound 7g exhibited about 10-folds more potent antiproliferative activities than KHS101 in various cancer cell lines. Two different protein-drug binding assays including DARTS, and CETSA revealed TACC3 as a biologically relevant target of compound 7g. In addition, compound 7g induced cell cycle arrest at the G2/M phase and induced cell apoptosis. Furthermore, compound 7g depolarized the MMP and induced ROS generation in a dose-dependent manner in U87 cells. More importantly, 7g reduced tumor weight by 72.7% in U87 xenograft model at a dose of 20 mg/kg/day without obvious toxicity. Altogether, compound 7g deserved further investigations as a novel, safe and efficacious TACC3 inhibitor for the treatment of GBM.

Total neoadjuvant therapy or standard chemoradiotherapy for locally advanced rectal cancer: A systematic review and meta-analysis.

Background and Aim: The effectiveness of total neoadjuvant therapy (TNT) on patients with locally advanced rectal cancer (LARC) is controversy. This study aims to compare the prognostic value of TNT with standard neoadjuvant chemoradiotherapy (CRT) for LARC. Methods: We searched databases (Embase [Ovid], Medline [Ovid], PubMed, Cochrane Library, and Web of Science) for articles published between January 1, 2000, and March 10, 2022. Studies on evaluating the effects of TNT and standard CRT on the prognosis of LARC were included. The primary outcomes were overall survival (OS) and disease-free survival (DFS). Results: 19 primary studies, involving 10 randomized controlled trials, 3 prospective studies and 6 retrospective studies, with data on 5,074 patients treated for LARC were included in the meta-analysis. Statistical analyses revealed that, compared with standard CRT, TNT significantly improved OS (hazard ratio [HR]=0.77, 95% confidence interval [CI]=0.65-0.90, I 2 = 30%, P = 0.17), DFS (HR = 0.85, 95% CI = 0.74-0.97, I² = 11%, P = 0.35), distant metastases-free survival (DMFS, HR = 0.76, 95% CI = 0.65-0.90, I² = 0%, P = 0.50), pathological complete response rate (pCR, OR = 1.89, 95% CI = 1.61-2.22, I² = 0%, P = 0.47), and R0 resection rate (OR = 1.33, 95% CI = 1.07-1.67, I² = 16%, P = 0.28), but local recurrence-free survival (LRFS, HR = 1.12, 95% CI = 0.90-1.39, I² = 4%, P = 0.37). Conclusions: Comprehensive literature research shows that TNT showed excellent short-term efficacy in terms of pCR and R0 resection rate while also improved the long-term outcomes of OS, DFS and DMFS, might become a new standard of treatment in patients with LARC. Even so, more studies and longer follow-up were still warranted.

The Level of Histone Deacetylase 4 is Associated with Aging Cartilage Degeneration and Chondrocyte Hypertrophy.

Purpose: To determine the role of histone deacetylase 4 (HDAC4)-controlled chondrocyte hypertrophy in the onset and development of age-related osteoarthritis (OA). Methods: Morphological analysis of human knee cartilages was performed to observe structural changes during cartilage degeneration. HDAC4 expression was deleted in adult aggrecan (Acan)-CreERT2; HDAC4fl/fl transgenic mice. The onset and development of age-related OA were investigated in transgenic and control mice using hematoxylin and eosin (H&E) and Safranin O staining. Furthermore, the progression of ACLT-induced OA following adenovirus-mediated HDAC4 overexpression was explored in rats. The expression levels of genes related to hypertrophy, cartilage matrix and its digestion, and chondrocyte proliferation were investigated using qPCR. Immunohistochemistry (IHC) was used to explore the mechanisms underlying HDAC4-controlled age-related changes in OA progression. Results: In human cartilage, we performed morphological analysis and IHC, the results showed that hypertrophy-related structural changes are related to HDAC4 expression. Age-related OA was detected early (OARSI scores 2.7 at 8-month-old) following HDAC4 deletion in 2-month-old mice. Furthermore, qPCR and IHC results showed changes in hypertrophy-related genes Col10a1, Runx2 and Sox9 in chondrocytes, particularly in the expression of Runt-related transcription factor 2 (Runx2, 13.29±0.99 fold). The expression of the main cartilage matrix-related genes Col2a1 and Acan decreased, that of cartilage matrix digestion-related gene MMP-13 increased, while that of chondrocyte proliferation-related genes PTHrP, Ihh and Gli1 changed. In contrast, rat cartilage's qPCR and IHC results showed opposite outcomes after HDAC4 overexpression. Conclusion: Based on the results above, we concluded that HDAC4 expression regulates the onset and development of age-related OA by controlling chondrocyte hypertrophy. These results may help in the development of early diagnosis and treatment of age-related OA.

Comparison of the prognosis of four different surgical strategies for proximal gastric cancer: a network meta-analysis.

BACKGROUND: There is controversy regarding the long-term prognosis and short-term postoperative complications of different surgical strategies for proximal gastric cancer (PGC). METHODS: We searched for articles published in Embase (Ovid), Medline (Ovid), PubMed, Cochrane Library, and Web of Science between January 1, 1990, and February 1, 2021. We screened out the literature comparing different surgical strategies. We then evaluated the long-term and short-term outcome of different surgical strategies using a network meta-analysis, which summarizes the hazard ratio, odds ratio, mean difference, and 95% confidence interval. RESULTS: There were no significant differences between different surgical strategies for 5-year overall survival (OS), anastomotic leakage, or weight loss after 1 year. Compared with total gastrectomy with Roux-en-Y reconstruction (TG-RY) and proximal gastrectomy with double tract reconstruction (PG-DTR), the proximal gastrectomy with esophagogastrostomy (PG-EG) strategy significantly increased the incidence of reflux esophagitis; and the operation time and blood loss of the PG-EG strategy were significantly less than those of the other surgical strategies. The anastomotic stenosis rates of the PG-EG and proximal gastrectomy with jejunum interstitial (PG-JI) strategies were significantly higher than those of TG-RY and PG-DTR; the hemoglobin level after 1 year for the PG-DTR strategy was significantly higher than that of the TG-RY strategy. CONCLUSION: Our comprehensive literature research found that different surgical strategies had no significant difference in the long-term survival of PGC, but the incidence of reflux esophagitis and anastomotic stenosis after PG-DTR and TG-RY was significantly reduced.

To explore the active constituents of Sedum aizoon L in the treatment of coronary heart disease based on network pharmacology and molecular docking methodology.

Background: There is a lack of effective drugs for the treatment of coronary heart disease (CHD). Sedum aizoon L (SL) has multiple effects, and there is no report on CHD in SL at present. The aim of this study is to explore the mechanisms of action of SL in the treatment of CHD based on network pharmacology and molecular docking technology. Methods: The targets and active ingredients of SL were screened using the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database, and CHD-related targets were obtained by searching GeneCards and DisGeNet databases. The intersection of LS active ingredient targets and CHD targets was used to construct a "drug-ingredient-disease-target" network using the Cytoscape software. The STRING database was used to construct a protein-protein interaction (PPI) network, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed. Key targets and core active ingredients were selected and molecular docking was performed using the AutoDock software. Results: According to the predicted results, a total of 134 corresponding target genes for LS, 12 active components, 1,704 CHD-related targets, and 52 intersecting targets were obtained. GO function and KEGG pathway analysis showed that the key targets were involved with signal transducer and activator of transcription 3 (STAT3), tumor protein p53 (TP53), and vascular endothelial growth factor A (VEGFA). The molecular docking results showed that the key targets bound to the important active ingredients in a stable conformation. The core active ingredients of LS in the treatment of CHD were determined to be ursolic acid, myricetin, and beta-sitosterol. Conclusions: SL may act on targets such as STAT3, TP53, and VEGFA through tumor necrosis factor (TNF) signaling pathway, interleukin 17A (IL-17A) signaling pathway, AGE-RAGE signaling pathway in diabetic complications, and other related pathways, thereby playing a role in preventing and treating CHD.

[Research advances in nano liquid chromatography instrumentation].

The miniaturization of liquid chromatography equipment is among the most important focus areas in chromatographic technology. It involves the miniaturization of the physical dimensions of the instrument, size of the separation material, and inner diameter of the column. The advantages of a reduced inner diameter of the column have been investigated for several decades, and can be summarized as follows. First, the sample consumption is lower, which is particularly beneficial when a limited amount of sample is available, as is the case with natural products, and in biochemistry and biomedicine. Second, the consumption of the mobile phase is reduced, making the process environmentally friendly and facilitating green chemistry. This allows the addition of more expensive solvent additives, such as chiral additives or isotopic reagents, while maintaining a low analysis cost. Moreover, the degree of band dilution in the column is lower than that with conventional liquid chromatography under the same sample injection conditions. Thus, enhanced mass sensitivity is achieved. Other benefits of a reduced inner diameter of the column include temperature control due to effective heat transfer through the columns and easier coupling to mass detectors, which is particularly advantageous for analyzing complex samples. Typically, the term “nano liquid chromatography” is associated with liquid chromatography, which employs capillary columns of inner diameters less than 100 μm and flow rates in the range of tens to hundreds of nanoliters per minute. Because of the extremely low flow rates and small column volume, the extra-column effect becomes more prominent. Thus, the requirements for every component of liquid chromatographs are augmented toward improving their performance and optimizing the extra-column band broadening of the entire system. The solvent delivery equipment should be able to pump mobile phases accurately and steadily at nanoliter-level flow rates. A gradient mode is required to achieve this, which implies that the lowest flow rate for a single pump unit should reach a few nanoliters per minute. A certain operating pressure is also necessary to employ columns with different inner diameters and particle sizes. A precise and repeatable sample injection procedure is essential for nano liquid chromatography. The injection volume and mode should be suitable for capillary columns, without inducing a significant extra-column effect. A higher-sensitivity detector should be employed, and sample dispersion should be limited. The improved tubing and connection method in nano liquid chromatography should offer stability, reliability, and ease of operation. The extra-column volume should also be restricted to suit nanoliter-level flow rates. Considering that most nano liquid chromatographic instruments have been coupled with a mass detector, this review mainly focused on nanoliter solvent delivery modules, sample injection modules, and tubing and connection modules. By searching and summarizing research articles, technical patents, and brochures of instrument manufacturers, technical routes and research progress on these modules were described in detail. The pump designs can be classified into four types. Pneumatic amplifying pumps have been used in ultra-high-pressure applications. The flow-splitting delivery system, though easy to realize, may lead to a large amount of solvent wastage. Splitless pumps, which are classified based on two main principles, are widely used. Some pumps based on other physical phenomena have been suggested; however, they lacked stability and robustness. Two types of injection modes have been utilized in nano liquid chromatography. The direct nanoliter injection mode typically takes advantage of the groove on the rotor of a switching valve. The trapping injection mode uses trap columns to enable the introduction of large sample volumes. As for the tubing and connection, a few appropriate designs can be acquired from commercial suppliers. The robustness has been improved using some patented technologies. The optimization principles and research progress on optical absorption detection are briefly introduced. Finally, commercial nano liquid chromatographic systems are compared by considering the pumps and injectors.

ß-Elemene Triggers ROS-dependent Apoptosis in Glioblastoma Cells Through Suppressing STAT3 Signaling Pathway.

Glioblastoma is one of the most aggressive primary brain tumors with few treatment strategies. ß-Elemene is a sesquiterpene known to have broad spectrum antitumor activity against various cancers. However, the signaling pathways involved in ß-elemene induced apoptosis of glioblastoma cells remains poorly understood. In this study, we reported that ß-elemene exhibited antiproliferative activity on U87 and SHG-44 cells, and induced cell death through induction of apoptosis. Incubation of these cells with ß-elemene led to the activation of caspase-3 and generation of reactive oxygen species (ROS). Western blot assay showed that ß-elemene suppressed phosphorylation of STAT3, and subsequently down-regulated the activation of p-JAK2 and p-Src. Moreover, pre-incubation of cells with ROS inhibitor N-acetyl-L-cysteine (NAC) significantly reversed ß-elemene-mediated apoptosis effect and down-regulation of JAK2/Src-STAT3 signaling pathway. Overall, our findings implied that generation of ROS and suppression of STAT3 signaling pathway is critical for the apoptotic activity of ß-elemene in glioblastoma cells.

A novel selective mitochondrial-targeted curcumin analog with remarkable cytotoxicity in glioma cells.

Naturally occurring polyphenol curcumin (4) or demethoxycurcumin (5) and their synthetic derivatives display promising anticancer activities. However, their further development is limited by low bioavailability and poor selectivity. Thus, a mitochondria-targeted compound 14 (DMC-TPP) was prepared in the present study by conjugating a triphenylphosphine moiety to the phenolic hydroxyl group of demethoxycurcumin to enhance its bioavailability and treatment efficacy. The in vitro biological experiments of DMC-TPP showed that it not only displayed higher cytotoxicity as compared with its parent compound 5, but also exhibited superior mitochondria accumulation ability. Glioma cells were more sensitive to DMC-TPP, which inhibited the proliferation of U251 cells with an IC50 of 0.42 µM. The mechanism studies showed that DMC-TPP triggers mitochondria-dependent apoptosis, caused by caspase activation, production of reactive oxygen species (ROS) and decrease of mitochondrial membrane potential (MMP). In addition, DMC-TPP efficiently inhibited cellular thioredoxin reductase, which contributed to its cytotoxicity. Significantly, DMC-TPP delayed tumor progression in a mouse xenograft model of human glioma cancer. Taken together, the potent in vitro and in vivo antitumor activity of DMC-TPP warrant further comprehensive evaluation as a novel anti-glioma agent.

Comparison of the prognosis of four different treatment strategies for acute left malignant colonic obstruction: a systematic review and network meta-analysis.

BACKGROUND: There is controversy regarding the efficacy of different treatment strategies for acute left malignant colonic obstruction. This study investigated the 5-year overall survival (OS) and disease-free survival (DFS) of several treatment strategies for acute left malignant colonic obstruction. METHODS: We searched for articles published in PubMed, Embase (Ovid), MEDLINE (Ovid), Web of Science, and Cochrane Library between January 1, 2000, and July 1, 2020. We screened out the literature comparing different treatment strategies. Evaluate the primary and secondary outcomes of different treatment strategies. The network meta-analysis summarizes the hazard ratio, odds ratio, mean difference, and its 95% confidence interval. RESULTS: The network meta-analysis involved 48 articles, including 8 (randomized controlled trials) RCTs and 40 non-RCTs. Primary outcomes: the 5-year overall survival (OS) and disease-free survival (DFS) of the CS-BTS strategy and the DS-BTS strategy were significantly better than those of the ES strategy, and the 5-year OS of the DS-BTS strategy was significantly better than that of CS-BTS. The long-term survival of TCT-BTS was not significantly different from those of CS-BTS and ES. SECONDARY OUTCOMES: compared with emergency resection (ER) strategies, colonic stent-bridge to surgery (CS-BTS) and transanal colorectal tube-bridge to surgery (TCT-BTS) strategies can significantly increase the primary anastomosis rate, CS-BTS and decompressing stoma-bridge to surgery (DS-BTS) strategies can significantly reduce mortality, and CS-BTS strategies can significantly reduce the permanent stoma rate. The hospital stay of DS-BTS is significantly longer than that of other strategies. There was no significant difference in the anastomotic leakage levels of several treatment strategies. CONCLUSION: Comprehensive literature research, we find that CS-BTS and DS-BTS strategies can bring better 5-year OS and DFS than ER. DS-BTS strategies have a better 5-year OS than CS-BTS strategies. Without considering the hospital stays, DS-BTS strategy is the best choice.

INHBA is a Prognostic Biomarker and Correlated With Immune Cell Infiltration in Cervical Cancer.

Background: Inhibin A (INHBA), a member of the TGF-ß superfamily, has been shown to be differentially expressed in various cancer types and is associated with prognosis. However, its role in cervical cancer remains unclear. Methods: We aimed to demonstrate the relationship between INHBA expression and pan-cancer using The Cancer Genome Atlas (TCGA) database. Next, we validated INHBA expression in cervical cancer using the Gene Expression Omnibus (GEO) database, including GSE7803, GSE63514, and GSE9750 datasets. Enrichment analysis of INHBA was performed using the R package "clusterProfiler." We analyzed the association between immune infiltration level and INHBA expression in cervical cancer using the single-sample gene set enrichment analysis (ssGSEA) method by the R package GSVA. We explored the association between INHBA expression and prognosis using the R package "survival". Results: Pan-cancer data analysis showed that INHBA expression was elevated in 19 tumor types, including cervical cancer. We further confirmed that INHBA expression was higher in cervical cancer samples from GEO database and cervical cancer cell lines than in normal cervical cells. Survival prognosis analysis indicated that higher INHBA expression was significantly associated with reduced Overall Survival (p = 0.001), disease Specific Survival (p = 0.006), and Progression Free Interval (p = 0.001) in cervical cancer and poorer prognosis in other tumors. GSEA and infiltration analysis showed that INHBA expression was significantly associated with tumor progression and some types of immune infiltrating cells. Conclusion: INHBA was highly expressed in cervical cancer and was significantly associated with poor prognosis. Meanwhile, it was correlated with immune cell infiltration and could be used as a promising prognostic target for cervical cancer.

Comprehensive Analysis to Identify SPP1 as a Prognostic Biomarker in Cervical Cancer.

Background: SPP1, secreted phosphoprotein 1, is a member of the small integrin-binding ligand N-linked glycoprotein (SIBLING) family. Previous studies have proven SPP1 overexpressed in a variety of cancers and can be identified as a prognostic factor, while no study has explored the function and carcinogenic mechanism of SPP1 in cervical cancer. Methods: We aimed to demonstrate the relationship between SPP1 expression and pan-cancer using The Cancer Genome Atlas (TCGA) database. Next, we validated SPP1 expression of cervical cancer in the Gene Expression Omnibus (GEO) database, including GSE7803, GSE63514, and GSE9750. The receiver operating characteristic (ROC) curve was used to evaluate the feasibility of SPP1 as a differentiating factor by the area under curve (AUC) score. Cox regression and logistic regression were performed to evaluate factors associated with prognosis. The SPP1-binding protein network was built by the STRING tool. Enrichment analysis by the R package clusterProfiler was used to explore potential function of SPP1. The single-sample GSEA (ssGSEA) method from the R package GSVA and TIMER database were used to investigate the association between the immune infiltration level and SPP1 expression in cervical cancer. Results: Pan-cancer data analysis showed that SPP1 expression was higher in most cancer types, including cervical cancer, and we got the same result in the GEO database. The ROC curve suggested that SPP1 could be a potential diagnostic biomarker (AUC = 0.877). High SPP1 expression was associated with poorer overall survival (OS) (P = 0.032). Further enrichment and immune infiltration analysis revealed that high SPP1 expression was correlated with regulating the infiltration level of neutrophil cells and some immune cell types, including macrophage and DC. Conclusion: SPP1 expression was higher in cervical cancer tissues than in normal cervical epithelial tissues. It was significantly associated with poor prognosis and immune cell infiltration. Thus, SPP1 may become a promising prognostic biomarker for cervical cancer patients.

Prognostic impact of at least 12 lymph nodes after neoadjuvant therapy in rectal cancer: A meta-analysis.

BACKGROUND: The number of dissected lymph nodes (LNs) in rectal cancer after neoadjuvant therapy has a controversial effect on the prognosis. AIM: To investigate the prognostic impact of the number of LN dissected in rectal cancer patients after neoadjuvant therapy. METHODS: We performed a systematic review and searched PubMed, Embase (Ovid), MEDLINE (Ovid), Web of Science, and Cochrane Library from January 1, 2000 until January 1, 2020. Two reviewers examined all the publications independently and extracted the relevant data. Articles were eligible for inclusion if they compared the number of LNs in rectal cancer specimens resected after neoadjuvant treatment (LNs ≥ 12 vs LNs < 12). The primary endpoints were the overall survival (OS) and disease-free survival (DFS). RESULTS: Nine articles were included in the meta-analyses. Statistical analysis revealed a statistically significant difference in OS [hazard ratio (HR) = 0.76, 95% confidence interval (CI): 0.66-0.88, I 2 = 12.2%, P = 0.336], DFS (HR = 0.76, 95%CI: 0.63-0.92, I 2 = 68.4%, P = 0.013), and distant recurrence (DR) (HR = 0.63, 95%CI: 0.48-0.93, I 2 = 30.5%, P = 0.237) between the LNs ≥ 12 and LNs < 12 groups, but local recurrence (HR = 0.67, 95%CI: 0.38-1.16, I 2 = 0%, P = 0.348) showed no statistical difference. Moreover, subgroup analysis of LN negative patients revealed a statistically significant difference in DFS (HR = 0.67, 95%CI: 0.52-0.88, I 2 = 0%, P = 0.565) between the LNs ≥ 12 and LNs < 12 groups. CONCLUSION: Although neoadjuvant therapy reduces LN production in rectal cancer, our data indicate that dissecting at least 12 LNs after neoadjuvant therapy may improve the patients' OS, DFS, and DR.