circ_PPAPDC1A promotes Osimertinib resistance by sponging the miR-30a-3p/ IGF1R pathway in non-small cell lung cancer (NSCLC).

BACKGROUND: Recent evidence has demonstrated that abnormal expression and regulation of circular RNA (circRNAs) are involved in the occurrence and development of a variety of tumors. The aim of this study was to investigate the effects of circ_PPAPDC1A in Osimertinib resistance in NSCLC. METHODS: Human circRNAs microarray analysis was conducted to identify differentially expressed (DE) circRNAs in Osimertinib-acquired resistance tissues of NSCLC. The effect of circ_PPAPDC1A on cell proliferation, invasion, migration, and apoptosis was assessed in both in vitro and in vivo. Dual-luciferase reporter assay, RT-qPCR, Western-blot, and rescue assay were employed to confirm the interaction between circ_PPAPDC1A/miR-30a-3p/IGF1R axis. RESULTS: The results revealed that circ_PPAPDC1A was significantly upregulated in Osimertinib acquired resistance tissues of NSCLC. circ_PPAPDC1A reduced the sensitivity of PC9 and HCC827 cells to Osimertinib and promoted cell proliferation, invasion, migration, while inhibiting apoptosis in Osimertinib-resistant PC9/OR and HCC829/OR cells, both in vitro and in vivo. Silencing circ_PPAPDC1A partially reversed Osimertinib resistance. Additionally, circ_PPAPDC1A acted as a competing endogenous RNA (ceRNA) by targeting miR-30a-3p, and Insulin-like Growth Factor 1 Receptor (IGF1R) was identified as a functional gene for miR-30a-3p in NSCLC. Furthermore, the results confirmed that circ_PPAPDC1A/miR-30a-3p/IGF1R axis plays a role in activating the PI3K/AKT/mTOR signaling pathway in NSCLC with Osimertinib resistance. CONCLUSIONS: Therefore, for the first time we identified that circ_PPAPDC1A was significantly upregulated and exerts an oncogenic role in NSCLC with Osimertinib resistance by sponging miR-30a-3p to active IGF1R/PI3K/AKT/mTOR pathway. circ_PPAPDC1A may serve as a novel diagnostic biomarker and therapeutic target for NSCLC patients with Osimertinib resistance.

Association between pretreatment emotional distress and immune checkpoint inhibitor response in non-small-cell lung cancer.

Emotional distress (ED), commonly characterized by symptoms of depression and/or anxiety, is prevalent in patients with cancer. Preclinical studies suggest that ED can impair antitumor immune responses, but few clinical studies have explored its relationship with response to immune checkpoint inhibitors (ICIs). Here we report results from cohort 1 of the prospective observational STRESS-LUNG study, which investigated the association between ED and clinical efficacy of first-line treatment of ICIs in patients with advanced non-small-cell lung cancer. ED was assessed by Patient Health Questionnaire-9 and Generalized Anxiety Disorder 7-item scale. The study included 227 patients with 111 (48.9%) exhibiting ED who presented depression (Patient Health Questionnaire-9 score ≥5) and/or anxiety (Generalized Anxiety Disorder 7-item score ≥5) symptoms at baseline. On the primary endpoint analysis, patients with baseline ED exhibited a significantly shorter median progression-free survival compared with those without ED (7.9 months versus 15.5 months, hazard ratio 1.73, 95% confidence interval 1.23 to 2.43, P = 0.002). On the secondary endpoint analysis, ED was associated with lower objective response rate (46.8% versus 62.1%, odds ratio 0.54, P = 0.022), reduced 2-year overall survival rate of 46.5% versus 64.9% (hazard ratio for death 1.82, 95% confidence interval 1.12 to 2.97, P = 0.016) and detriments in quality of life. The exploratory analysis indicated that the ED group showed elevated blood cortisol levels, which was associated with adverse survival outcomes. This study suggests that there is an association between ED and worse clinical outcomes in patients with advanced non-small-cell lung cancer treated with ICIs, highlighting the potential significance of addressing ED in cancer management. ClinicalTrials.gov registration: NCT05477979 .

Modulating Polyalanine Motifs of Synthetic Spidroin for Controllable Preassembly and Strong Fiber Formation.

Spider dragline (major ampullate) silk is one of the toughest known fibers in nature and exhibits an excellent combination of high tensile strength and elasticity. Increasing evidence has indicated that preassembly plays a crucial role in facilitating the proper assembly of silk fibers by bridging the mesoscale gap between spidroin molecules and the final strong fibers. However, it remains challenging to control the preassembly of spidroins and investigate its influence on fiber structural and mechanical properties. In this study, we explored to bridge this gap by modulating the polyalanine (polyA) motifs in repetitive region of spidroins to tune their preassemblies in aqueous dope solutions. Three biomimetic silk proteins with varying numbers of alanine residues in polyA motif and comparable molecular weights were designed and biosynthesized, termed as N16C-5A, N15C-8A, and N13C-12A, respectively. It was found that all three proteins could form nanofibril assemblies in the concentrated aqueous dopes, but the size and structural stability of the fibrils were distinct from each other. The silk protein N15C-8A with 8 alanine residues in polyA motif allowed for the formation of stable nanofibril assemblies with a length of approximately 200 nm, which were not prone to disassemble or aggregate as that of N16C-5A and N13C-12A. More interestingly, the stable fibril assembly of N15C-8A enabled spinning of simultaneously strong (623.3 MPa) and tough (107.1 MJ m-3) synthetic fibers with fine molecular orientation and close interface packing of fibril bundles. This work highlights that modulation of polyA motifs is a feasible way to tune the morphology and stability of the spidroin preassemblies in dope solutions, thus controlling the structural and mechanical properties of the resulting fibers.

Discovery of novel thiophene-3-carboxamide derivatives as potential VEGFR-2 inhibitors with anti-angiogenic properties.

VEGFR-2 is an attractive target for the development of anti-tumor drugs and plays a crucial role in tumor angiogenesis. This study reports a series of novel thiophene-3-carboxamide derivatives based on PAN-90806 as VEGFR-2 inhibitors, among which compound 14d exhibits excellent anti-proliferative activity against HCT116, MCF7, PC3, and A549 cell lines, and has effective VEGFR-2 inhibitory activity with an IC50 value of 191.1 nM. Additionally, CETSA results indicated that VEGFR-2 was a relevant target of compound 14d in the cell lines, and compound 14d could also inhibit VEGFR-2 protein phosphorylation in A549 cell line. Furthermore, compound 14d inhibited colony formation, cell migration, and HUVECs tube formation in a dose-dependent manner. The mechanism by which 14d induced cancer cell death involves blocking the cell cycle, increasing ROS production, inducing apoptosis, and dose-dependently reducing the levels of phosphorylated ERK and MEK. Molecular docking and molecular dynamics simulations had shown that compound 14d could stably bind to the active site of VEGFR-2. These results confirmed that compound 14d might be a promising lead compound for anti-angiogenesis.

18F-FDG PET/CT based model for predicting malignancy in pulmonary nodules: a meta-analysis.

BACKGROUND: Several studies to date have reported on the development of positron emission tomography (PET)/computed tomography (CT)-based models intended to effectively distinguish between benign and malignant pulmonary nodules (PNs). This meta-analysis was designed with the goal of clarifying the utility of these PET/CT-based conventional parameter models as diagnostic tools in the context of the differential diagnosis of PNs. METHODS: Relevant studies published through September 2023 were identified by searching the Web of Science, PubMed, and Wanfang databases, after which Stata v 12.0 was used to conduct pooled analyses of the resultant data. RESULTS: This meta-analysis included a total of 13 retrospective studies that analyzed 1,731 and 693 malignant and benign PNs, respectively. The respective pooled sensitivity, specificity, PLR, and NLR values for the PET/CT-based studies developed in these models were 88% (95%CI: 0.86-0.91), 78% (95%CI: 0.71-0.85), 4.10 (95%CI: 2.98-5.64), and 0.15 (95%CI: 0.12-0.19). Of these endpoints, the pooled analyses of model sensitivity (I2 = 69.25%), specificity (I2 = 78.44%), PLR (I2 = 71.42%), and NLR (I2 = 67.18%) were all subject to significant heterogeneity. The overall area under the curve value (AUC) value for these models was 0.91 (95%CI: 0.88-0.93). When differential diagnosis was instead performed based on PET results only, the corresponding pooled sensitivity, specificity, PLR, and NLR values were 92% (95%CI: 0.85-0.96), 51% (95%CI: 0.37-0.66), 1.89 (95%CI: 1.36-2.62), and 0.16 (95%CI: 0.07-0.35), with all four being subject to significant heterogeneity (I2 = 88.08%, 82.63%, 80.19%, and 86.38%). The AUC for these pooled analyses was 0.82 (95%CI: 0.79-0.85). CONCLUSIONS: These results suggest that PET/CT-based models may offer diagnostic performance superior to that of PET results alone when distinguishing between benign and malignant PNs.

Unraveling the impact of cancer-associated fibroblasts on hypovascular pancreatic neuroendocrine tumors.

BACKGROUND: Pancreatic neuroendocrine tumors (PNETs) with low microvessel density and fibrosis often exhibit clinical aggressiveness. Given the contribution of cancer-associated fibroblasts (CAFs) to the hypovascular fibrotic stroma in pancreatic ductal adenocarcinoma, investigating whether CAFs play a similar role in PNETs becomes imperative. In this study, we investigated the involvement of CAFs in PNETs and their effects on clinical outcomes. METHODS: We examined 79 clinical PNET specimens to evaluate the number and spatial distribution of α-smooth muscle actin (SMA)-positive cells, which are indicative of CAFs. Then, the findings were correlated with clinical outcomes. In vitro and in vivo experiments were conducted to assess the effects of CAFs (isolated from clinical specimens) on PNET metastasis and growth. Additionally, the role of the stromal-cell-derived factor 1 (SDF1)-AGR2 axis in mediating communication between CAFs and PNET cells was investigated. RESULTS: αSMA-positive and platelet-derived growth factor-α-positive CAFs were detected in the hypovascular stroma of PNET specimens. A higher abundance of α-SMA-positive CAFs within the PNET stroma was significantly associated with a higher level of clinical aggressiveness. Notably, conditioned medium from PNET cells induced an inflammatory phenotype in isolated CAFs. These CAFs promoted PNET growth and metastasis. Mechanistically, PNET cells secreted interleukin-1, which induced the secretion of SDF1 from CAFs. This cascade subsequently elevated AGR2 expression in PNETs, thereby promoting tumor growth and metastasis. The downregulation of AGR2 in PNET cells effectively suppressed the CAF-mediated promotion of PNET growth and metastasis. CONCLUSION: CAFs drive the growth and metastasis of aggressive PNETs. The CXCR4-SDF1 axis may be a target for antistromal therapy in the treatment of PNET. This study clarifies mechanisms underlying PNET aggressiveness and may guide future therapeutic interventions targeting the tumor microenvironment.

Songorine modulates macrophage polarization and metabolic reprogramming to alleviate inflammation in osteoarthritis.

Introduction: Osteoarthritis (OA) is a prevalent joint disorder characterized by multifaceted pathogenesis, with macrophage dysregulation playing a critical role in perpetuating inflammation and joint degeneration. Methods: This study focuses on Songorine, derived from Aconitum soongaricum Stapf, aiming to unravel its therapeutic mechanisms in OA. Comprehensive analyses, including PCR, Western blot, and immunofluorescence, were employed to evaluate Songorine's impact on the joint microenvironment and macrophage polarization. RNA-seq analysis was conducted to unravel its anti-inflammatory mechanisms in macrophages. Metabolic alterations were explored through extracellular acidification rate monitoring, molecular docking simulations, and PCR assays. Oxygen consumption rate measurements were used to assess mitochondrial oxidative phosphorylation, and Songorine's influence on macrophage oxidative stress was evaluated through gene expression and ROS assays. Results: Songorine effectively shifted macrophage polarization from a pro-inflammatory M1 phenotype to an anti-inflammatory M2 phenotype. Notably, Songorine induced metabolic reprogramming, inhibiting glycolysis and promoting mitochondrial oxidative phosphorylation. This metabolic shift correlated with a reduction in macrophage oxidative stress, highlighting Songorine's potential as an oxidative stress inhibitor. Discussion: In an in vivo rat model of OA, Songorine exhibited protective effects against cartilage damage and synovial inflammation, emphasizing its therapeutic potential. This comprehensive study elucidates Songorine's multifaceted impact on macrophage modulation, metabolic reprogramming, and the inflammatory microenvironment, providing a theoretical foundation for its therapeutic potential in OA.

ACC SYNTHASE4 inhibits gibberellin biosynthesis and FLOWERING LOCUS T expression during citrus flowering.

Flowering is an essential process in fruit trees. Flower number and timing have a substantial impact on the yield and maturity of fruit. Ethylene and gibberellin (GA) play vital roles in flowering, but the mechanism of coordinated regulation of flowering in woody plants by GA and ethylene is still unclear. In this study, a lemon (Citrus limon L. Burm) 1-aminocyclopropane-1-carboxylic acid synthase gene (CiACS4) was overexpressed in Nicotiana tabacum and resulted in late flowering and increased flower number. Further transformation of citrus revealed that ethylene and starch content increased, and soluble sugar content decreased in 35S:CiACS4 lemon. Inhibition of CiACS4 in lemon resulted in effects opposite to that of 35S:CiACS4 in transgenic plants. Overexpression of the CiACS4-interacting protein ETHYLENE RESPONSE FACTOR3 (CiERF3) in N. tabacum resulted in delayed flowering and more flowers. Further experiments revealed that the CiACS4-CiERF3 complex can bind the promoters of FLOWERING LOCUS T (CiFT) and GOLDEN2-LIKE (CiFE) and suppress their expression. Moreover, overexpression of CiFE in N. tabacum led to early flowering and decreased flowers, and ethylene, starch, and soluble sugar contents were opposite to those in 35S:CiACS4 transgenic plants. Interestingly, CiFE also bound the promoter of CiFT. Additionally, GA3 and 1-aminocyclopropanecarboxylic acid (ACC) treatments delayed flowering in adult citrus, and treatment with GA and ethylene inhibitors increased flower number. ACC treatment also inhibited the expression of CiFT and CiFE. This study provides a theoretical basis for the application of ethylene to regulate flower number and mitigate the impacts of extreme weather on citrus yield due to delayed flowering.

Systemic inflammation and insulin resistance-related indicator predicts poor outcome in patients with cancer cachexia.

BACKGROUND: The C-reactive protein (CRP)-triglyceride-glucose (TyG) index (CTI), which is a measure representing the level of inflammation and insulin resistance (IR), is related to poor cancer prognosis; however, the CTI has not been validated in patients with cancer cachexia. Thus, this study aimed to explore the potential clinical value of the CTI in patients with cancer cachexia. METHODS: In this study, our prospective multicenter cohort included 1411 patients with cancer cachexia (mean age 59.45 ± 11.38, 63.3% male), which was a combined analysis of multiple cancer types. We randomly selected 30% of the patients for the internal test cohort (mean age 58.90 ± 11.22% 61.4% male). Additionally, we included 307 patients with cancer cachexia in the external validation cohort (mean age 61.16 ± 11, 58.5% male). Receiver operating characteristic (ROC) and calibration curves were performed to investigate the prognostic value of CTI. The prognostic value of the CTI was also investigated performing univariate and multivariate survival analyses. RESULTS: The survival curve indicated that the CTI showed a significant prognostic value in the total, internal, and external validation cohorts. Prognostic ROC curves and calibration curves revealed that the CTI showed good consistency in predicting the survival of patients with cancer cachexia. Multivariate survival analysis showed that an elevated CTI increased the risk of death by 22% (total cohort, 95% confidence interval [CI] = 1.13-1.33), 34% (internal test cohort, 95%CI = 1.11-1.62), and 35% (external validation cohort, 95%CI = 1.14-1.59) for each increase in the standard deviation of CTI. High CTI reliably predicted shorter survival (total cohort, hazard ratio [HR] = 1.45, 95%CI = 1.22-1.71; internal test cohort, HR = 1.62, 95%CI = 1.12-2.36; external validation cohort, HR = 1.61, 95%CI = 1.15-2.26). High CTI significantly predicted shorter survival in different tumor subgroups, such as esophageal [HR = 2.11, 95%CI = 1.05-4.21] and colorectal cancer [HR = 2.29, 95%CI = 1.42-3.71]. The mediating effects analysis found that the mediating proportions of PGSGA, ECOG PS, and EORTC QLQ-C30 on the direct effects of CTI were 21.72%, 19.63%, and 11.61%, respectively We found that there was a significant positive correlation between the CTI and 90-day [HR = 2.48, 95%CI = 1.52-4.14] and 180-day mortality [HR = 1.77,95%CI = 1.24-2.55] in patients with cancer cachexia. CONCLUSION: The CTI can predict the short- and long-term survival of patients with cancer cachexia and provide a useful prognostic tool for clinical practice.

Synergistic effects of trace sulfadiazine and corrosion scales on disinfection by-product formation in bulk water of cast iron pipe.

The effects of trace sulfadiazine (SDZ) and cast-iron corrosion scales on the disinfection by-product (DBP) formation in drinking water distribution systems (DWDSs) were investigated. The results show that under the synergistic effect of trace SDZ (10 µg/L) and magnetite (Fe3O4), higher DBP concentration occurred in the bulk water with the transmission and distribution of the drinking water. Microbial metabolism-related substances, one of the important DBP precursors, increased under the SDZ/Fe3O4 condition. It was found that Fe3O4 induced a faster microbial extracellular electron transport (EET) pathway, resulting in a higher microbial regrowth activity. On the other hand, the rate of chlorine consumption was quite high, and the enhanced microbial EET based on Fe3O4 eliminated the need for microorganisms to secrete excessive extracellular polymeric substances (EPS). More importantly, EPS could be continuously secreted due to the higher microbial activity. Finally, high reactivity between EPS and chlorine disinfectant resulted in the continuous formation of DBPs, higher chlorine consumption, and lower EPS content. Therefore, more attention should be paid to the trace antibiotics polluted water sources and cast-iron corrosion scale composition in the future. This study reveals the synergistic effects of trace antibiotics and corrosion scales on the DBP formation in DWDSs, which has important theoretical significance for the DBP control of tap water.

Comprehensive molecular findings in primary malignant melanoma of the esophagus: A multicenter study.

Primary malignant melanoma of the esophagus (PMME) is an extremely rare but highly aggressive malignancy with a poor prognosis. Due to the scarcity of driver gene alterations, there is a need for more clinical data to comprehensively depict its molecular alterations. This study reviewed 26 PMME cases from three medical centers. Hybrid capture-based targeted sequencing of 295 and 1021 genes was performed in 14 and 12 cases, respectively. We found that PMME patients had a relatively low tumor mutation burden (median, 2.88 mutations per Mb) and were simultaneously accompanied by mutations in genes such as KIT (6/26, 23%), TP53 (6/26, 23%), SF3B1 (4/26, 15%), and NRAS (3/26, 12%). KIT, NRAS, and BRAF were mutually exclusive, and SF3B1 co-occurred with KIT mutation and amplification. The most common pathways affected were the mitogen-activated protein kinases and DNA damage response (DDR) pathways. Stage IV was a risk factor for both progression-free survival (hazard ratio [HR] = 5.14, 95% confidence interval [CI] = 1.32-19.91) and overall survival (OS), HR = 4.33, 95% CI = 1.22-15.30). Treatment with immune-checkpoint inhibitors (ICIs) was an independent factor for favorable OS (HR = 0.10, 95% CI = 0.01-0.91). Overall, PMME is a complex malignancy with diverse gene alterations, especially with harboring DDR alterations for potentially response from ICIs.

Distinct interactions stabilize EGFR dimers and higher-order oligomers in cell membranes.

The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase with important roles in many cellular processes as well as in cancer and other diseases. EGF binding promotes EGFR dimerization and autophosphorylation through interactions that are well understood structurally. How these dimers relate to higher-order EGFR oligomers seen in cell membranes, however, remains unclear. Here, we used single-particle tracking (SPT) and Förster resonance energy transfer imaging to examine how each domain of EGFR contributes to receptor oligomerization and the rate of receptor diffusion in the cell membrane. Although the extracellular region of EGFR is sufficient to drive receptor dimerization, we find that the EGF-induced EGFR slowdown seen by SPT requires higher-order oligomerization-mediated in part by the intracellular tyrosine kinase domain when it adopts an active conformation. Our data thus provide important insight into the interactions required for higher-order EGFR assemblies involved in EGF signaling.

Oncogenic KRAS, Mucin 4, and Activin A-Mediated Fibroblast Activation Cooperate for PanIN Initiation.

Over 90% of patients with pancreatic ductal adenocarcinoma (PDAC) have oncogenic KRAS mutations. Nevertheless, mutated KRAS alone is insufficient to initiate pancreatic intraepithelial neoplasia (PanIN), the precursor of PDAC. The identities of the other factors/events required to drive PanIN formation remain elusive. Here, optic-clear 3D histology is used to analyze entire pancreases of 2-week-old Pdx1-Cre; LSL-KrasG12D/+ (KC) mice to detect the earliest emergence of PanIN and observed that the occurrence is independent of physical location. Instead, it is found that the earliest PanINs overexpress Muc4 and associate with αSMA+ fibroblasts in both transgenic mice and human specimens. Mechanistically, KrasG12D/+ pancreatic cells upregulate Muc4 through genetic alterations to increase proliferation and fibroblast recruitments via Activin A secretion and consequently enhance cell transformation for PanIN formation. Inhibition of Activin A signaling using Follistatin (FST) diminishes early PanIN-associated fibroblast recruitment, effectively curtailing PanIN initiation and growth in KC mice. These findings emphasize the vital role of interactions between oncogenic KrasG12D/+ -driven genetic alterations and induced microenvironmental changes in PanIN initiation, suggesting potential avenues for early PDAC diagnostic and management approaches.

Prognostic value of systemic inflammation and for patients with colorectal cancer cachexia.

BACKGROUND: The development and progression of cancer cachexia are connected to systemic inflammation and physical performance. However, few relevant studies have reported the survival outcomes prediction of systemic inflammation and physical performance in patients with colorectal cancer (CRC) cachexia. This study investigated the prognostic prediction value of systemic inflammation and performance status in patients with CRC cachexia. METHODS: This multicentre cohort study prospectively collected 905 patients with CRC (58.3% males, 59.3 ± 11.5 years old). Cancer cachexia was diagnosed according to the 2011 Fearon Cachexia Diagnostic Consensus. The prognostic value of systematic inflammatory indicators was determined using the area under the curve, concordance index, and multivariate survival analysis. Performance status was evaluated with Eastern Coopertive Oncology Group performance score (ECOG-PS). Survival data were analysed using univariate and multivariate Cox regression analyses. RESULTS: The area under the curve, concordance index and survival analysis showed that C-reactive protein (CRP), lymphocyte to CRP ratio (LCR) and CRP to albumin ratio (CAR) were more stable and consistent with the survival of patients with CRC, both in non-cachexia and cachexia populations. Among patients with CRC cachexia, high inflammation [low LCR, hazard ratio (HR) 95% confidence interval (95% CI) = 3.33 (2.08-5.32); high CAR, HR (95% CI) = 2.92 (1.88-4.55); high CRP, HR (95% CI) = 3.12 (2.08-4.67)] indicated a worse prognosis, compared with non-cachexia patients [low LCR, HR (95% CI) = 2.28 (1.65-3.16); high CAR, HR (95% CI) = 2.36 (1.71-3.25); high CRP, HR (95% CI) = 2.58 (1.85-3.60)]. Similarly, among patients with CRC cachexia, high PS [ECOG-PS 2, HR (95% CI) = 1.61 (1.04-2.50); ECOG-PS 3/4, HR (95% CI) = 2.91 (1.69-5.00]) indicated a worse prognosis, compared with patients with CRC without cachexia [ECOG-PS 2, HR (95% CI) = 1.28 (0.90-1.81); ECOG-PS 3/4, HR (95% CI) = 2.41 (1.32-4.39]). Patients with CRC cachexia with an ECOG-PS score of 2 or 3-4 and a high inflammation had a shorter median survival time, compared with patients with an ECOG-PS score of 0/1 and a low inflammation. CONCLUSIONS: The systemic inflammatory markers LCR, CAR and CRP have stable prognostic values in patients with CRC. The ECOG-PS may be an independent risk factor for CRC. Combined evaluation of systemic inflammation and ECOG-PS in patients with CRC cachexia could provide a simple survival prediction.

Design, synthesis of auristatins-glucuronide conjugates targeting the ß-glucuronidase in tumor microenvironment.

Auristatins-glucuronide conjugates designed targeting the ß-Glucuronidase in tumor microenvironment were synthesized and evaluated on stabilities, the release of auristatins and the antitumor activities in this study. Conjugates 20 and 21 showed remarkable stabilities in phosphate buffer and bovine serum solution, and excellent selectivity between the in vitro antiproliferative activities against ß-glucuronidase pretreated and untreated cancer cells (IC50 = 5.7 nM âˆ¼ 9.7 nM, IC50 (-Enz) > 1 µM). Furthermore, conjugate 20 showed potent antitumor efficacy in HCT-116 xenograft mouse model without inducing side effects.

Computed tomography-determined skeletal muscle density predicts 3-year mortality in initial-dialysis patients in China.

BACKGROUND: Skeletal muscle mass and quality assessed by computed tomography (CT) images of the third lumbar vertebra (L3) level have been established as risk factors for poor clinical outcomes in several illnesses, but the relevance for dialysis patients is unclear. A few studies have suggested a correlation between CT-determined skeletal muscle mass and quality at the first lumbar vertebra (L1) level and adverse outcomes. Generally, chest CT does not reach beyond L1. We aimed to determine whether opportunistic CT scan (chest CT)-determined skeletal muscle mass and quality at L1 are associated with mortality in initial-dialysis patients. METHODS: This 3-year multicentric retrospective study included initial-dialysis patients from four centres between 2014 and 2017 in China. Unenhanced CT images of the L1 and L3 levels were obtained to assess skeletal muscle mass [by skeletal muscle index, (SMI), cm2 /m2 ] and quality [by skeletal muscle density (SMD), HU]. Skeletal muscle measures at L1 were compared with those at L3. The sex-specific optimal cutoff values of L1 SMI and L1 SMD were determined in relation to all-cause mortality. The outcomes were all-cause death and cardiac death. Cox regression models were applied to investigate the risk factors for death. RESULTS: A total of 485 patients were enrolled, of whom 257 had both L1 and L3 images. Pearson's correlation coefficient between L1 and L3 SMI was 0.84 (P < 0.001), and that between L1 and L3 SMD was 0.90 (P < 0.001). No significant association between L1 SMI and mortality was observed (P > 0.05). Low L1 SMD (n = 280, 57.73%) was diagnosed based on the optimal cutoff value (<39.56 HU for males and <33.06 HU for females). Multivariate regression analysis revealed that the low L1 SMD group had higher risks of all-cause death (hazard ratio 1.80; 95% confidence interval 1.05-3.11, P = 0.034) and cardiac death (hazard ratio 3.74; 95% confidence interval 1.43-9.79, P = 0.007). CONCLUSIONS: In initial-dialysis patients, there is high agreement between the L1 and L3 measures for SMI and SMD. Low SMD measured at L1, but not low SMI, is an independent predictor of both all-cause death and cardiac death.

Design, synthesis and anti-osteosarcoma activity study of novel pyrido[2,3-d]pyrimidine derivatives by inhibiting DKK1-Wnt/ß-catenin pathway.

Osteosarcoma is a common primary malignant bone tumor in adolescents. Wnt/ß-catenin has been proved to play a pro-oncogenic role and was overactivated in osteosarcoma. Therefore, this pathway has become an interesting therapeutic target for osteosarcoma. Herein we report the design, synthesis and biological activities of a series of novel pyrido[2,3-d]pyrimidine derivatives based on our previous work. Among these, the representative compound 2-{[1,3-dimethyl-7-(4-methylpiperazin-1-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-5-yl]amino}-N-[4-(trifluoromethoxy)phenyl]acetamide (7m) has exhibited good antiproliferative activity towards 143B and MG63 cells with good selectivity over non-cancerous HSF cells. In the assay of Ca2+ concentration, the compound 7m increased the intracellular Ca2+ concentration in 143B cells. In addition, the expression of DKK1 increased, and that of p-ß-catenin decreased by 7m treatment. Finally, the Hoechst 33,342 staining, Annexin-FITC/PI staining and mitochondrial fluorescence staining have clearly demonstrated that compound 7m induced apoptosis in 143B cells.

Exploring the Anti-Cancer Effects of Fish Bone Fermented Using Monascus purpureus: Induction of Apoptosis and Autophagy in Human Colorectal Cancer Cells.

Fish bone fermented using Monascus purpureus (FBF) has total phenols and functional amino acids that contribute to its anti-oxidant and anti-inflammatory properties. Colorectal cancer, one of the most prevalent cancers and the third largest cause of death worldwide, has become a serious threat to global health. This study investigates the anti-cancer effects of FBF (1, 2.5 or 5 mg/mL) on the cell growth and molecular mechanism of HCT-116 cells. The HCT-116 cell treatment with 2.5 or 5 mg/mL of FBF for 24 h significantly decreased cell viability (p < 0.05). The S and G2/M phases significantly increased by 88-105% and 25-43%, respectively (p < 0.05). Additionally, FBF increased the mRNA expression of caspase 8 (38-77%), protein expression of caspase 3 (34-94%), poly (ADP-ribose) polymerase (PARP) (31-34%) and induced apoptosis (236-773%) of HCT-116 cells (p < 0.05). FBF also increased microtubule-associated protein 1B light chain 3 (LC3) (38-48%) and phosphoinositide 3 kinase class III (PI3K III) (32-53%) protein expression, thereby inducing autophagy (26-52%) of HCT-116 cells (p < 0.05). These results showed that FBF could inhibit HCT-116 cell growth by inducing S and G2/M phase arrest of the cell cycle, apoptosis and autophagy. Thus, FBF has the potential to treat colorectal cancer.

Purification mechanism of microbial metabolism in kitchen-oil wastewater enhanced by cationic vacancies on γ-Al2O3.

The use of catalyst materials to mediate the enhancement of microbial degradation in wastewater is a new economic and energy saving breakthrough in water treatment technology. In this study, γ-Al2O3, which is commonly used as catalyst/carrier, is used as biological filler to treat kitchen-oil wastewater with low biodegradability, and the COD removal rate is about 50 %. It is found that the complexation of cationic vacancies on Al2O3 surface with extracellular polymeric substance (EPS) secreted by microorganisms in wastewater lead to the polarization of electron distribution on biofilm. The efficient degrading bacteria are enriched on reaction interface and obtain electrons to maintain electron dynamic balance by enhancing the transmembrane metabolism of pollutants. The aluminum vacancies on Al2O3 surface accelerate the microbial degradation of pollutants. The cationic vacancies in the structure of catalyst accelerate the acquisition of exogenous electrons by microorganisms without the addition of external energy, which provides a new idea for catalytic fillers to enhance wastewater degradation.