Association between Urinary Lead and Female Breast Cancer: A Population-Based Cross-Sectional Study.

BACKGROUND: Previous studies have explored the relationship between serum lead levels and the risk of female breast cancer (FBC). However, it is still uncertain whether urinary lead levels are associated with FBC. This study aimed to investigate the potential association between urinary lead and FBC. METHODS: A cross-sectional case-control study was conducted using the National Health and Nutrition Examination Survey (NHANES), which is a series of cross-sectional, nationally representative surveys of the United States population consisting of 10 survey waves from 1999 to 2018. This study analyzed a total of 2795 female participants (≥20 years), consisting of 210 participants with FBC and 2585 healthy controls. Urinary lead was detected using Inductively Coupled Plasma-Mass Spectrometry, which was divided into four levels by using quartiles-defining cut points. Multivariate logistic regression was used to analyze the association between urinary lead and FBC. RESULTS: Multivariate logistic regression revealed that urinary lead was positively correlated with FBC (Odds ratio [OR], 2.16; 95% confidence interval [CI]: [1.18, 3.95], p < 0.05) in a fully adjusted model. There were significantly increased ORs of FBC in quartile 4 (Q4) and quartile 3 (Q3), compared with the lowest quartile 1 (Q1) (Q4, OR = 1.48, 95% CI [0.89, 2.48]; Q3: OR = 1.01, 95% CI [0.59, 1.73], p for trend = 0.021). No significant interaction effects were observed between urinary lead levels and FBC between the subgroups (age, race, educational status, body mass index (BMI), marital status, family income to poverty ratio, hypertension status, diabetes status, renal function status, smoking history, ever been pregnant, oral contraceptive use, occupation classification, etc.) (All interaction p-value > 0.05). CONCLUSIONS: Urinary lead is likely positively associated with FBC in the US population.

Revealing and modeling of fire products in gas-phase for epoxy/black phosphorus-based nanocomposites.

This work aims at revealing and optimizing the mechanism, to promote the design of phosphorus-based flame retardants (PFRs) for controlling the spread of fire risk caused by the continuous spread of polymers. Herein, we synthesized about 10 nm TiO2 grown in situ on the surface of BP through a simple hydrothermal procedure to introduce it into epoxy (EP/BP-TiO2). In the first place, EP/BP-TiO22.0 nanocomposite achieves a reduction of 58.96% and 50.35% in PHRR and THR, respectively. Secondly, the pyrolysis of BP from Pn to P4, P3 and P2 is revealed. As a guide, P4 is established as a characteristic product of the analytical model for evaluating the effects in the gas phase for BP-based hybrids. Finally, this work clarifies the enhancement path for BP-TiO2 is optimized for the capturing of OH· and H· radicals by P4(POx). Crucially, this study reveals and controls the mechanism of the BP-based hybrids at the molecular level, which is expected to provide a promising analytical model for broad market PFRs design to address the risks and challenges of casualties and ecology caused by composites fire.

5-Aminonaphthalene derivatives as selective nonnucleoside nuclear receptor binding SET domain-protein 2 (NSD2) inhibitors for the treatment of multiple myeloma.

Approximately 20% of multiple myeloma (MM) are caused by a chromosomal translocation t (4; 14) that leads to the overexpression of the nuclear receptor binding SET domain-protein 2 (NSD2) histone methyltransferase. NSD2 catalyzes the methylation of lysine 36 on histone H3 (H3K36me2) and is associated with transcriptionally active regions. Using high-throughput screening (HTS) with biological analyses, a series of 5-aminonaphthalene derivatives were designed and synthesized as novel NSD2 inhibitors. Among all the prepared compounds, 9c displayed a good NSD2 inhibitory activity (IC50 = 2.7 µM) and selectivity against both SET-domain-containing and non-SET-domain-containing methyltransferases. Preliminary research indicates the inhibition mechanism of compound 9c by significantly suppressed the methylation of H3K36me2. Compound 9c specifically inhibits the proliferation of the human B cell precursor leukemia cell line RS4:11 and the human myeloma cell line KMS11 by inducing cell cycle arrest and apoptosis with little cytotoxicity. It has been reported that the anti-cancer effect of compound 9c is partly achieved by completely suppressing the transcriptional activation of NSD2-targeted genes. When administered intraperitoneally at 25 mg/kg, compound 9c suppressed the tumor growth of RS4:11 xenografts in vivo and no body weight loss was detected in the tested SCID mice.

A Strategy of NIR Dual-Excitation Upconversion for Ratiometric Intracellular Detection.

Intracellular detection is highly desirable for biological research and clinical diagnosis, yet its quantitative analysis with noninvasivity, sensitivity, and accuracy remains challenging. Herein, a near-infrared (NIR) dual-excitation strategy is reported for ratiometric intracellular detection through the design of dye-sensitized upconversion probes and employment of a purpose-built NIR dual-laser confocal microscope. NIR dye IR808, a recognizer of intracellular analyte hypochlorite, is introduced as energy donor and Yb,Er-doped NaGdF4 upconversion nanoparticles are adopted as energy acceptor in the as-designed nanoprobes. The efficient analyte-dependent energy transfer and low background luminescence endow the nanoprobes with ultrahigh sensitivity. In addition, with the nonanalyte-dependent upconversion luminescence (UCL) excited by 980 nm as a self-calibrated signal, the interference from environmental fluctuation can be alleviated. Furthermore, the dual 808/980 nm excited ratiometric UCL is demonstrated for the quantification of the level of intracellular hypochlorite. Particularly, the intrinsic hypochlorite with only nanomolar concentration in live MCF-7 cells in the absence of exogenous stimuli is determined. Such an NIR dual-excitation ratiometric strategy based on dye-sensitized UCL probes can be easily extended to detect various intracellular analytes through tailoring the reactive NIR dyes, which provides a promising tool for probing biochemical processes in live cells and diagnosing diseases.

Lanthanide Metal-Organic Framework Nanoprobes for the In Vitro Detection of Cardiac Disease Markers.

Acute myocardial infarction (AMI) is one of the leading causes of death around the world. An early and accurate diagnosis of AMI is critical to reduce the mortality rate. As an important cardiac biomarker, creatine kinase (CK) has been used in the clinical diagnosis of AMI. However, it still remains a great challenge to realize highly sensitive and selective CK detection in blood specimens. Herein, we have developed an ultrasensitive platform for the detection of CK activity based on time-resolved (TR) luminescent lanthanide metal-organic framework nanoprobes (Eu-QPTCA). Benefiting from the intense emission of lanthanide ions sensitized by the organic ligands and the eliminated short-lived autofluorescence by the TR technique, these nanoprobes enabled the homogeneous detection of CK activity with a limit of detection down to 1.0 U/L, which is about 1 order of magnitude improvement relative to that of the traditional methods. In addition, the Eu-QPTCA nanoprobes showed superior selectivity and reliability toward the practical detection of CK activity in human serum, indicating the great significance of our method in the early diagnosis of AMI. We envision that the proposed bioassay strategy can be extended to the detection of other phosphorylation enzymes, paving a way for promising applications in clinical diagnostics.

Expression of miR-106 in endometrial carcinoma RL95-2 cells and effect on proliferation and invasion of cancer cells.

Expression of miR-106 in endometrial carcinoma RL95-2 cell line and its effect on proliferation and invasion of cancer cells was investigated. miR-106 expression vector was constructed and transiently transfected into in vitro cultured RL95-2 cells of human endometrial carcinoma. Cells were divided into three groups including blank control cells (MOCK group), miR-106 transfection group (miR-106 group) and negative control group (siNC group). Reverse-transcription quantitative PCR (RT-qPCR) was used to detect the expression of miR-106. Proliferation and in vitro migration of RL95-2 cells were detected by MTT and scratch assay, and cell apoptosis was detected by flow cytometry. Compared with MOCK and siNC group, cell apoptosis rate was significantly decreased but cell proliferation rate was significantly increased in miR-106 group (p<0.05). In addition, cell migration and invasion ability was significantly increased in miR-106 group (p<0.05). Overexpression of miR-106 can promote proliferation and inhibit apoptosis of endometrial cancer RL95-2 cells, and miR-106 may serve as a new target for the treatment of endometrial cancer in the future.

MYCN amplification predicts poor prognosis based on interphase fluorescence in situ hybridization analysis of bone marrow cells in bone marrow metastases of neuroblastoma.

BACKGROUND: MYCN gene amplification is related to risk stratification. Therefore it is important to identify accurately the level of the MYCN gene as early as possible in neuroblastoma (NB); however, for patients with bone marrow (BM) metastasis who need chemotherapy before surgery, timely detection of the MYCN gene is not possible due to the unavailability of primary tumors. METHODS: MYCN gene status was evaluated in 81 BM metastases of NB by interphase fluorescence in situ hybridization (FISH) analysis of BM cells. The clinicobiological characteristics and prognostic impact of MYCN amplification in NB metastatic to BM were analyzed. RESULTS: MYCN amplification was found in 16% of patients with metastases, and the results were consistent with the primary tumors detected by pathological tissue FISH. MYCN amplification was associated with age, lactate dehydrogenase (LDH) levels and prognosis (P = 0.038, P < 0.001, P = 0.026). Clinical outcome was poorer in patients with MYCN amplification than in those without amplification (3-year EFS 28.8 ± 13.1 vs. 69.7 ± 5.7%, P = 0.005; 3-year OS 41.5 ± 14.7 vs. 76.7 ± 5.5%, P = 0.005). CONCLUSIONS: MYCN amplification predicts a poor outcome in NB metastatic to BM, and interphase FISH of bone marrow cells provides a timely direct and valid method to evaluate the MYCN gene status.

The dynamic response of a flexible indium based metal-organic framework to gas sorption.

A doubly interpenetrated microporous indium based metal-organic framework was solvothermally synthesized, in which cage-like pores and one-dimensional channels coexist. Due to its flexible nature, the complex exhibits a novel dynamic response to N2, Ar and CO2 sorption. Furthermore, the material shows a high H2 uptake capacity.

Inosine triphosphate pyrophosphohydrolase (ITPA) polymorphic sequence variants in Chinese ALL children and possible association with mercaptopurine related toxicity.

Genetic polymorphisms are important factors in effects and toxicity of chemotherapeutics. This study aimed to investigate whether there was a correlation between genotype or haplotype of inosine triphosph pyrophosphohydrolase(ITPA) and toxicities during maintenance therapy with mercaptopurine (6-MP) in Chinese patients with acute lymphoblastic leukemia (ALL). 95 ALL children who hospitalized between October 2004 and September 2007,were retrospectively analyzed. 6-MP toxicity was documented according to Common Toxicity Criteria, Version 2.0. ITPA sequencing was undertaken. Correlation between genotype/haplotype and 6-MP toxicity was analyzed. The results indicated that 50 cases (52.6%) had grade III-IV of bone marrow inhibition. These children had long-term disease-free survival (DFS), without hepatic and other organs' dysfunction and secondary tumors. Three variations were observed in ITPA exon 2 (94 C → A), exon 3 (138 G → A), and exon 8 (561 G → A), the 94A carriers (CA and AA) had a lower risk of developing 6-MP toxicity when compared with carriers of the CC genotype (odds ratio [OR] 0.34, 95% confidence interval [CI] 0.12-0.98, P = 0.039). The risk of 6-MP intolerance was decreased in patients with 138 allele and 561 allele polymorphism, but with no significant difference. Patients carrying the haplotype 94A-138A-561A was tolerance compared to those with wild-type haplotype 94C-138G-561G (OR: 0.26, 95% CI 0.07-0.94 P = 0.043). In conclusion, the risk of 6-MP intolerance was decreased in patients with 138 allele and 561 allele polymorphism, but without significant difference. Patients carrying the haplotype 94A-138A-561A was tolerance compared to those with the wild-type haplotype 94C-138G-561G.

Therapeutic potential of targeting the oncogenic SHP2 phosphatase.

The Src homology 2 domain containing protein tyrosine phosphatase-2 (SHP2) is an oncogenic phosphatase associated with various kinds of leukemia and solid tumors. Thus, there is substantial interest in developing SHP2 inhibitors as potential anticancer and antileukemia agents. Using a structure-guided and fragment-based library approach, we identified a novel hydroxyindole carboxylic acid-based SHP2 inhibitor 11a-1, with an IC50 value of 200 nM and greater than 5-fold selectivity against 20 mammalian PTPs. Structural and modeling studies reveal that the hydroxyindole carboxylic acid anchors the inhibitor to the SHP2 active site, while interactions of the oxalamide linker and the phenylthiophene tail with residues in the ß5-ß6 loop contribute to 11a-1's binding potency and selectivity. Evidence suggests that 11a-1 specifically attenuates the SHP2-dependent signaling inside the cell. Moreover, 11a-1 blocks growth factor mediated Erk1/2 and Akt activation and exhibits excellent antiproliferative activity in lung cancer and breast cancer as well as leukemia cell lines.

[Ionizing radiation-regulated killing of human hepatoma cells by liposome-mediated CDglyTK gene delivery].

EGR-1 gene promoter and CDglyTK gene were used to construct the pcDNA3-EGR-CDglyTK recombinant vector, in which CDglyTK gene expression was under the control of EGR-1 gene promoter. Cationic liposome LipofectAMINE was used to transfect plasmids into human hepatoma 7402 cell line. Subsequently, the transfected cells were treated with different doses of gamma-ray. Northern blot and Western blot showed that ionizing radiation can induce CDglyTK gene expression drived by EGR-1 promoter,in a dose-dependant manner. There was no ionizing radiation-inducible effect in pcDNA3-CMV-CDglyTK control group. Ionizing radiation also markedly enhanced the sensitivity of tumor cells transfected with pcDNA3-EGR-CDglyTK to prodrugs (GCV/5-FC) in tumor cell killing. The data indicated that EGR-1 promoter was inducible by ionizing radiation, whereas the CMV promoter was not. There was a synergetic effect between GCV and 5-FC. The cytotoxic effect of the suicide gene-ionizing radiation combination was stronger than suicide gene alone or ionizing radiation alone.