Identifying therapeutic targets for breast cancer: insights from systematic Mendelian randomization analysis.

Background: Breast cancer (BC) exhibits a high incidence rate, imposing a substantial burden on healthcare systems. Novel drug targets are urgently needed for BC. Mendelian randomization (MR) has gained widespread application for identifying fresh therapeutic targets. Our endeavor was to pinpoint circulatory proteins causally linked to BC risk and proffer potential treatment targets for BC. Methods: Through amalgamating protein quantitative trait loci from 2,004 circulating proteins and comprehensive genome-wide association study data from the Breast Cancer Association Consortium, we conducted MR analyses. Employing Steiger filtering, bidirectional MR, Bayesian colocalization, phenotype scanning, and replication analyses, we further solidified MR study outcomes. Additionally, protein-protein interaction (PPI) network was harnessed to unveil latent associations between proteins and prevailing breast cancer medications. The phenome-wide MR (Phe-MR) was employed to assess potential side effects and indications for the druggable proteins of BC. Finally, we further affirmed the drugability of potential drug targets through mRNA expression analysis and molecular docking. Results: Through comprehensive analysis, we identified five potential drug targets, comprising four (TLR1, A4GALT, SNUPN, and CTSF) for BC and one (TLR1) for BC_estrogen receptor positive. None of these five potential drug targets displayed reverse causation. Bayesian colocalization suggested that these five latent drug targets shared variability with breast cancer. All drug targets were replicated within the deCODE cohort. TLR1 exhibited PPI with current breast cancer therapeutic targets. Furthermore, Phe-MR unveiled certain adverse effects solely for TLR1 and SNUPN. Conclusion: Our study uncovers five prospective drug targets for BC and its subtypes, warranting further clinical exploration.

Cloning and characterization of nitrate reductase gene in Ulva prolifera (Ulvophyceae, Chlorophyta).

Ulva spp. dominates green tides around the world, which are occurring at an accelerated rate. The competitive nitrogen assimilation efficiency in Ulva is suggested to result in ecological success against other seaweeds. However, molecular characterization of genes involved in nitrogen assimilation has not been conducted. Here, we describe the identification of the nitrate reductase (NR) gene from a green seaweed Ulva prolifera, an alga which is responsible for the world's largest green tide in the Yellow Sea. Using rapid amplification of cDNA ends and genome walking, the NR gene from U. prolifera (UpNR) was cloned, which consisted of six introns and seven exons encoding 863 amino acids. According to sequence alignment, the NR in U. prolifera was shown to possess all five essential domains and 21 key invariant residues in plant NRs. The GC content of third codon position of UpNR (82.75%) was as high as those of green microalgae, and the intron number supported a potential loss issue from green microalga to land plant. Real-time quantitative PCR results showed that UpNR transcript level was induced by nitrate and repressed by ammonium, which could not be removed by addition of extra nitrate, indicating that U. prolifera preferred ammonium to nitrate. Urea would not repress NR transcription by itself, while it weakened the induction effect of nitrate, implying it possibly inhibited nitrate uptake rather than nitrate reduction. These results suggest the use of UpNR as a gene-sensor to probe the N assimilation process in green tides caused by Ulva.

Integrative transcriptome, proteome, phosphoproteome and genetic mapping reveals new aspects in a fiberless mutant of cotton.

To investigate the molecular mechanisms of fiber initiation in cotton (Gossypium spp.), an integrated approach combining transcriptome, iTRAQ-based proteome and genetic mapping was taken to compare the ovules of the Xuzhou 142 wild type (WT) with its fuzzless-lintless (fl) mutant at -3 and 0 day post-anthesis. A total of 1,953 mRNAs, 187 proteins, and 131 phosphoproteins were differentially expressed (DE) between WT and fl, and the levels of transcripts and their encoded proteins and phosphoproteins were highly congruent. A functional analysis suggested that the abundance of proteins were mainly involved in amino sugar, nucleotide sugar and fatty acid metabolism, one carbon pool for folate metabolism and flavonoid biosynthesis. qRT-PCR, Western blotting, and enzymatic assays were performed to confirm the regulation of these transcripts and proteins. A molecular mapping located the lintless gene li3 in the fl mutant on chromosome 26 for the first time. A further in-silico physical mapping of DE genes with sequence variations between fl and WT identified one and four candidate genes in the li3 and n2 regions, respectively. Taken together, the transcript abundance, phosphorylation status of proteins at the fiber initiation stage and candidate genes have provided insights into regulatory processes underlying cotton fiber initiation.

Prediction of health status based on postoperative radiographic variables in adult scoliosis.

OBJECTIVE: To evaluate the effect of surgical treatment on health related quality of life (HRQOL) and radiographic variables in patients with adult scoliosis. METHODS: Sixty-eight patients with adult spinal deformities underwent radiographic analysis. The enrollment criteria were as follows: age older than 18 years, adult degenerative or progressive idiopathic scoliosis (Cobb angle >10°), and surgical treatment within one year before this study was undertaken. The following variables were measured: curve type, apical level, curve magnitude, coronal and sagittal balance using a C7 plumb line (C7 PL) and gravity line, lateral intervertebral olisthesis, lumbar lordosis, sacral slope and pelvic tilt. HRQOL was assessed by the Oswestry Disability Index (ODI). Both preoperative and postoperative data were collected and changes in radiographically assessed variables and ODI scores attributable to surgery calculated; correlations between these changes were then assessed. The radiographically assessed variables and ODI scores were analyzed with SigmaStat (SPSS, Chicago, IL, USA). The level of statistical significance was set at P < 0.05. RESULTS: Surgical treatment resulted in improvements in ODI scores and several radiographically assessed variables, including sagittal balance, lumbar lordosis, lateral olisthesis and coronal Cobb angle. Only sagittal balance expressed as C7 PL was correlated to both preoperative and postoperative ODI. Gravity line, an alternative measurement of spinal balance, did not provide better correlations with HRQOL than C7 PL. CONCLUSIONS: Spinal balance assessed by gravity line did not provide a better correlation with HRQOL than C7 PL. Loss of sacral slope and retroverted pelvis are commonly seen in adult scoliosis and are not significantly changed by surgical treatment, including restoration of lumbar lordosis and sagittal balance.

[Fluorescence spectroscopic study on the biointeraction of new organometallic carborane derivatives with bovine serum albumin].

The biointeractions between a series of new organometallic carborane derivatives and model protein bovine serum albumin (BSA) were investigated by means of fluorescence and synchronous spectroscopy. The observations demonstrate that the ferrocene-carborane conjugates (FcSB1, FcSB2 and FcSBCO) and the ruthenium(II)-arene carborane complexes (RuBFc and RuBCOOH) can form a steady complex with BSA and statically quench its fluorescence. The ferrocene-carborane conjugates could remarkably affect the tertiary structure of BSA and induce the microenvironment changes of Trp and Tyr residues from hydrophilic to hydrophobic environment. But the effect of the ruthenium(II)-arene carborane complexes on the tertiary structure of BSA is much less. This study would give meaningful insights into the evaluation of the promising biomedical applications of the new carborane derivatives and benefit the development of potential multifunctional metallodrugs.

Ligand-based neutral ruthenium(II) arene complex: selective anticancer action.

Two new ruthenium(II) arene complexes, 2a (C(24)H(34)B(10)FeRuS(2)) and 2b (C(15)H(26)B(10)O(2)RuS(2)), bearing a carborane unit and other different functional groups were synthesized, and their cytostatic effects on cancerous cells were evaluated. Our observations illustrate that a structural change from a ferrocene unit to a carboxyl group could lead to high selectivity toward cancer cells and facilitate the efficient inhibition of the proliferation of target cells, indicating that the tuning of the overall properties of the ruthenium(II) arene complex by appropriate ligand tagging is critical to creating a selective antineoplastic agent.

Addition of ethynylferrocene to transition-metal complexes containing a chelating 1,2-dicarba-closo-dodecaborane-1,2-dichalcogenolate ligand--in vitro cooperativity of a ruthenium compound on cellular uptake of an anticancer drug.

The addition reactions of the 16e half-sandwich complexes (p-cymene)M(S2C2B10H10) (, M=Ru; , M=Os) and Cp*Ir(E2C2B10H10) (, E=S; , E=Se) with ethynylferrocene lead selectively to the 18e complexes (p-cymene)Ru(S2C2B10H9)(H2CCFc) (Fc=ferrocenyl) (), (p-cymene)Os(S2C2B10H9)(H2CCFc) (), Cp*Ir(S2C2B10H9)(H2CCFc) () and Cp*Ir(Se2C2B10H9)(H2CCFc) (), in which the alkyne is regio- and stereoselectively inserted into one of the M-E bonds that may further lead to metal-induced B-H activation, hydrogen atom transfer from the carborane via the metal center to the inserted alkyne, and the generation of a M-B bond. In all complexes the S-eta2-(Fc)C-C and C-B(M) moieties occupy a cisoid position. The four new complexes are characterized by IR, MS, NMR spectroscopy and microanalysis, and the X-ray structural analysis of is performed. was observed to promote the uptake of anticancer drug daunorubicin in drug-resistant leukemia K562 cells.