Nephrotoxicity of Immune Checkpoint Inhibitors: A Disproportionality Analysis from 2013 to 2020.

Nephrotoxicity occasionally occurs during treatment with immune checkpoint inhibitors (ICIs). Few related studies compare the differences between these drugs. This study aimed to systematically characterize nephrotoxicity after ICI initiation. Data were extracted from the US FDA Adverse Event Reporting System (FAERS) database. Disproportionality analysis, including information components (ICs) and reporting odds ratios (RORs), was performed to determine the potential renal toxicity of ICIs. A total of 7,204 reports of renal adverse events (AEs) were identified in the FAERS database. Renal AEs were most commonly reported for nivolumab (46.84%). Strong signals were detected in male patients combined with ICIs. In the clinical application of ICIs, attention should be paid to patients, especially male patients, with acute kidney injury, nephritis, autoimmune nephritis and other nephrotoxic AEs. The use of ICIs is likely to aggravate their condition.

Protein Corona-Triggered Catalytic Inhibition of Insufficient POSS Polymer-Caged Gold Nanoparticles for Sensitive Colorimetric Detection of Metallothioneins.

Metallothioneins (MTs) are important biomarkers for the early diagnosis of heavy metal poisoning and malignancies. Convenient and cost-effective approaches for the rapid detection of MTs are therefore highly desirable for clinical monitoring. Herein, by taking advantage of the enzyme-mimetic activity of nanoparticles and protein corona-based recognition, insufficient polyhedral oligomeric silsesquioxane (POSS) polymer-caged gold nanoparticles (denoted as PP-AuNPs) are developed for the sensitive colorimetric analysis of MTs. In the presence of MTs, the catalytic reduction of yellow 4-nitrophenol to colorless 4-aminophenol is inhibited due to masking of the exposed PP-AuNPs catalytic surface with MTs corona. MTs are quantified by the presented color contrast with a superior sensitivity up to a 1.5 nM detection limit. Most importantly, the heavy metal ion- and aptamer-free PP-AuNPs platform exhibits excellent selectivity toward MTs over various ions, neutral biomolecules, and protein species, and successful applications are demonstrated by the detection of MTs in complex biological samples.

[Interaction of folate deficiency and aberrant profile of DNA methyltransferase 1 in the progression of cervix carcinogenesis].

OBJECTIVE: To explore the interaction of folate deficiency and aberration of DNA methyltransferase 1 (DNMT1) in the progression of cervix carcinogenesis. METHODS: All clinical samples were collected from 80 patients with cervix squamous cell carcinoma (SCC), 105 patients with cervical intraepithelial neoplasm (CINI, n = 52; CINII/III, n = 53) and 53 patients with cervix inflammation (CI). The participants were diagnosed by histology at Shanxi Province Tumor Hospital and Second Hospital of Shanxi Medical University during the period of September 2009 to May 2010. Meanwhile, cervical cancer cell lines Caski and C33A were treated with different concentration of folate. Radioimmunoassay (RIA), Western blotting and real-time PCR were used to detect the levels of serum folate, the expression of DNMT1 protein and mRNA, respectively. The data were analyzed by Student t test, ANOVA, chi-square test and Spearman correlation using SPSS statistical package. The correlation strength between factors and cervical canceration was calculated by OR and 95%CI value. Interaction effect was evaluated by the application of additive effect model. RESULTS: The levels of serum folate (median inter-quartile range) were (2.66 ± 1.82), (2.83 ± 2.23), (3.17 ± 1.91) and (3.21 ± 1.74) ng/ml, the levels of DNMT1 protein (x(-) ± s) were 2.28 ± 0.55, 1.84 ± 0.37, 1.33 ± 0.38 and 0.92 ± 0.29, the Ct-ratio (Ct value of DNMT1/Ct value of ß-actin) of DNMT1 mRNA (x(-) ± s) were 1.26 ± 0.13, 1.27 ± 0.12, 1.27 ± 0.12 and 1.33 ± 0.11 in the group of SCC, CINII/III, CINIand CI, respectively. The results showed that the serum folate levels were descended, and the expression levels of DNMT1 protein (χ(2)(tend) = 50.80, P < 0.05) and mRNA (χ(2)(tend) = 17.63, P < 0.05) were increased steadily with the severity of the cervix lesions. Moreover, our results revealed that there was an additive interaction between folate deficiency and high-expression of DNMT1 protein related to the risk of CIN and SCC. And it showed that the relative excess risk of interaction (RERI), attributable proportion of interaction (API) and synergy index(S) was 0.27, 0.14 and 1.40 in CINI group, 0.47, 0.19, 1.46 in CINII/III group, 1.60, 0.31, 1.61 in SCC group, respectively. It was found that folate was able to reduce the proliferation of Caski and C33A cells (r values were 0.954 and 0.969, all P values < 0.05), with 11.4% and 13.6% of growth inhibition at the concentration of 10 µg/ml, 64.8% and 49.4% at 1000 µg/ml in Caski and C33A cells, respectively. The result showed there was an inverse correlation between the levels of folate and DNMT1 protein (r values were -0.859 and -0.914, all P values < 0.05), with 1.96 and 1.92 of expression levels at the concentration of 10 µg/ml, and 1.60 and 1.38 at 1000 µg/ml in Caski and C33A cells, respectively. At folate concentration of 1000 µg/ml, the expression of DNMT1 protein or mRNA was higher in Caski cell than in C33A cell (t values were -4.22 and 3.50, all P values < 0.05). CONCLUSION: Our finding indicated that the low levels of serum folate and high-expression of DNMT1 protein or mRNA seemed to be associated with high risk of cervical cancer and cervix precancerous lesion. Sufficient folate is able to effectively inhibit the growth of cervical cancer cells in vitro, and would counteract transcriptional and posttranscriptional aberration of DNMT1. It suggested that there might be a synergistic action between folate deficiency and aberration of DNMT1 in the progression of cervix carcinogenesis.

[Effect of bisphenol A exposure on sex hormone level in occupational women].

OBJECTIVE: To explore the effect of bisphenol A (BPA) exposure on sex hormone levels in occupational women. METHODS: 51 women workers with at least a year of BPA exposure and 104 women workers without BPA exposure were chosen to do a case; control study. The information in general population characteristics, exposure, menstruation state, etc and the venous blood samples on an empty stomach were collected for the two groups. The endocrine hormones levels of follicle stimulating hormone (FSH), prolactin (PRL) , progesterone (P), estradiol (E2), luteinizing hormone (LH) were detected by RIA analysis. RESULT: The PRL level in the BPA exposure group was significantly higher to that in the control group (t = 2.127, P = 0.047). It was found that the proportion of abnormal PRL in the exposure group was significantly higher to the control group (chi2 = 4.924, P = 0. 026). In the age class of more than 30 years, the proportion of abnormal PRL in the exposure group was significantly higher to the control group (chi2 = 5.131, P = 0.023) and the proportion of abnormal progesterone in the exposure group was significantly to the control group (chi2 = 4.665, P = 0.031)in the same age class. In the people of no taking vitamin, the proportion of abnormal PRL in the exposure group was significantly higher to the control group (chi2 = 6.541, P = 0.011). The proportion of abnormal progesterone in the group of less than 5 years exposure was significantly higher to the group of more than 5 years exposure (chi2 = 3.938, P = 0. 047). The multivariate analysis found that BPA exposure was the independent risk factor to effect serum PRL (OR = 2.623, P = 0.030) of occupational women. Effect of BPA on FSH, E2, LH level couldn't be found through this study. CONCLUSION: BPA occupational exposure of women maked PRL level set up and effected progesterone level. After adjusting for age, exposure age and other potential confounding factors, BPA exposure is an independent risk factor to arise the level of serum PRL in occupational women.

GALNT6 promotes invasion and metastasis of human lung adenocarcinoma cells through O-glycosylating chaperone protein GRP78.

Lung adenocarcinoma remains a threat to human health due to its high rate of recurrence and distant metastasis. However, the molecular mechanism underlying lung adenocarcinoma metastasis remains yet incompletely understood. Here, we show that upregulated expression of polypeptide N-acetylgalactosaminyltransferase6 (GALNT6) in lung adenocarcinoma is associated with lymph node metastasis and poor prognosis. In lung adenocarcinoma cells, GALNT6 over-expression promoted epithelial-mesenchymal transition (EMT), wound healing, and invasion which could be significantly reversed by GALNT6 silencing. GALNT6 silencing also mitigated the metastasis of lung adenocarcinoma and prolonged the survival of xenograft tumor-bearing mice. Furthermore, GALNT6 directly interacted with, and O-glycosylated chaperone protein GRP78, which promoted EMT by enhancing the MEK1/2/ERK1/2 signaling in lung cancer cells. Therefore, GALNT6 is emerging as novel positive regulator for the malignancy of human lung adenocarcinoma. Targeting GALNT6-GRP78-MEK1/2/ERK1/2 may thus represent a new avenue to develop therapeutics against lung cancer metastasis.

M2 macrophages promote NSCLC metastasis by upregulating CRYAB.

The mechanism by which tumor-associated macrophages (TAMs) affect cancer progression is not fully understood. This study developed a microfluidic-based co-culture device to mimic the tumor microenvironment to assess TAM effects on invasion and metastasis in NSCLC. The results showed lung carcinoma cells could cause macrophages to show the M2 (a TAM-like) phenotype, and these M2 macrophages promoted lung cancer cell EMT and invasion. Proteomic analysis by the iTRAQ quantitation strategy and GO ontology of the cancer cells indicated that αB-Crystallin (CRYAB) might be involved in this process. Further, we confirmed the role of CRYAB in cancer invasion and metastasis through cell and animal experiments, as well as human cancer tissue assessment. Overall, we demonstrated that M2 macrophages promote malignancy in lung cancer through the EMT by upregulating CRYAB expression and activating the ERK1/2/Fra-1/slug signaling pathway.

AKR1B10 (Aldo-keto reductase family 1 B10) promotes brain metastasis of lung cancer cells in a multi-organ microfluidic chip model.

Brain metastasis (BM) is a leading cause of mortality in patients with non-small cell lung cancer (NSCLC). However, the molecular mechanisms underlying BM of NSCLC remain largely unknown because of the lack of models to accurately investigate such a dynamic and complex process. Here we developed a multi-organ microfluidic chip as a new methodological platform to study BM. The chip consisted of two bionic organ units - an upstream "lung" and a downstream "brain" characterized by a functional "blood-brain barrier (BBB)" structure, allowing real-time visual monitoring of the entire BM process, from the growth of primary tumor to its breaking through the BBB, and finally reaching the brain parenchyma. The chip was verified by lung cancer cell lines with differing metastatic abilities and then applied for the BM research where we first demonstrated that the protein expression of Aldo-keto reductase family 1 B10 (AKR1B10) was significantly elevated in lung cancer BM. Silencing AKR1B10 in brain metastatic tumor cells suppressed their extravasation through the BBB in the in vitro Transwell model, in our ex vivo microfluidic chip, as well as the in vivo model of brain metastasis in nude mice. Moreover, AKR1B10 downregulated the expression of matrix metalloproteinase (MMP)-2 and MMP-9 via MEK/ERK signaling in metastatic lung cancers. These data suggest that our multi-organ microfluidic chip is a practical alternative to study BM pathogenesis, and AKR1B10 is a diagnostic biomarker and a prospective therapeutic target for NSCLC BM. STATEMENT OF SIGNIFICANCE: Brain metastasis (BM) of non-small cell lung cancer (NSCLC) is a complex cascade, and in particular, the process of lung cancer cells penetrating the blood-brain barrier (BBB) is very unique. However, due to the lack of reliable models that can faithfully mimic the dynamic process of BBB breaking, its molecular mechanisms have not well elucidated so far. In addition, although Aldo-keto reductase family 1 B10 (AKR1B10) has been implicated to the tumor development of liver cancer and many other cancers, little is known on its roles in the BM. Here, we established a multi-organ microfluidic bionic chip platform to recapitulate the entire BM process, and applied it to the BM pathology research, especially BBB extravasation. By using the chip and traditional models synergistically, we first demonstrated that AKR1B10 was significantly elevated in lung cancer BM, and defined the value of AKR1B10 as a diagnostic serum biomarker for lung cancer patients suffering from BM. Further, we investigated the role and mechanisms of AKR1B10 in BM that it promotes the extravasation of cancer cells through the BBB.

Discrimination and highly selective adsorption of phosphoproteins and glycoproteins with arginine-functionalized polyhedral oligomeric silsesquioxane frameworks.

The crosstalk between phosphoproteins and glycoproteins causes many difficulties in their selective isolation/enrichment from biological samples. This issue is of high significance in proteomics study, but thus far, it has not received proper attention. Herein, an arginine-functionalized polyhedral oligomeric silsesquioxane (POSS) framework, PP-x-Arg (x = 0, 1, 2, … denotes the amount of salt in preparation), was developed by combining salt-templated thermal polymerization of POSS and pyromellitic dianhydride (PMDA) with post-modification using arginine. PP-x-Arg possesses a porous nanostructure and abundant functional groups, namely, guanidine and zwitterionic groups, enabling the selective adsorption of phosphoproteins or glycoproteins via specific phosphate-guanidine affinity or hydrophilic interaction between PP-x-Arg and glycoproteins, respectively. In particular, the adsorption selectivity exhibited by PP-x-Arg can be easily regulated by adjusting the pH values of the adsorption medium. The PP-x-Arg framework was further employed for the discrimination and isolation of phosphoproteins and glycoproteins from biological samples.

Folate deficiency and aberrant expression of DNA methyltransferase 1 were associated with cervical cancerization.

DNA methyltransferase 1 (DNMT1) plays a significant role in maintaining DNA methylation. Aberrant DNA methylation is a recognized feature of human cancers and folate is directly involved in DNA methylation via one-carbon metabolism. Previous reports also have suggested that folate deficiency was associated with many cancers. The aim of the present study was to evaluate the effect of folate deficiency and aberrant expression of DNA methyltransferase 1 (DNMT1) on cervical cancerization. The expression of DNMT1 protein and mRNA and levels of serum folate were detected in 238 women with a diagnosis of normal cervix (NC，n = 53), cervical intraepithelial neoplasia (CIN I, n = 52; CIN II/III, n = 53), and squamous cell carcinoma of the cervix (SCC; n = 80). In addition, the expression of DNMT1 protein and mRNA was measured in cervical cancer cells (Caski and C33A) treated by different concentration of folate. Serum folate levels decreased and expression levels of DNMT1 protein and mRNA increased gradually with progressive severity of the cervix lesions (P<0.001). It was found that folate was able to reduce the viability of Caski or C33A cell (r=0.978, P=0.002; r=0.984, P<0.001) and regulated aberrant expression of DNMT1 protein (r=-0.859, P=0.01; r=-0.914, P<0.001) and mRNA (r=-0.297, P=0.159; r=0.433, P=0.034) in vitro. Our findings indicated that the low-level of serum folate and high-expression of DNMT1 protein or mRNA was significantly associated with cervical carcinogenesis. Folate deficiency and aberrant expression of DNA methyltransferase 1 had additive effect on cervical cancerization. Folate supplement and recovery of aberrant DNA methylation status may offer a new strategy for prevention and therapy of cancers.

Preparation of poly(vinyltetrazole) chain-grafted poly(glycidymethacrylate-co-ethylenedimethacrylate) beads by surface-initiated atom transfer radical polymerization for the use in weak cation exchange and hydrophilic interaction chromatography.

A novel stationary phase for weak cation exchange (WCX) and hydrophilic interaction chromatography (HILIC) was prepared with surface-initiated atom transfer radical polymerization (SI-ATRP). Vinyltetrazole was grafted onto the surface of the beads in water medium with the polyglycidylmethacrylate beads (P(GMA/EDMA)) previously modified with 2-bromoisobutryl bromide as the macromolecule initiators and CuCl as catalyst. The poly(vinyltetrazole)-grafted beads obtained with different atom transfer radical polymerization (ATRP) formulations were tried as chromatographic packings in ion-exchange chromatography. The results showed that the prepared columns could separate the tested proteins with high efficiency and high capacity, and the retention time of protein had a positive relationship with increasing the chain lengths of the grafted poly(vinyltetrazole) (PVT). The prepared column was also found to be able to separate nucleosides by hydrophilic interaction chromatographic mode.