Design And Synthesis Of Enzalutamide-Isothiocyanate Hybrid Drug As Anti-Prostate Cancer Agent

Isothiocyanate (ITC), such as sulforaphane (SFN), is an active metabolite of dietary glucosinolate from cruciferous vegetables. SFN-rich extracts have been recently tested in recurrent prostate cancer (PCa) patients and notably prolonged PSA doubling time without Grade 3 adverse events. One of the anti-PCa mechanisms of SFN is to inhibit HDAC6, which further triggering androgen receptor (AR) degradation. We have incorporated ITC to the chemical scaffold of enzalutamide (Enz) to create Enz-ITC hybrid molecules with an intention to intracellularly deliver ITC to AR-Hsp90-HDAC6 complex and therefore improving anti-PCa efficacy of both parental drugs. Two Enz-ITCs and one Enz-ITC N-acetyl cysteine (NAC) conjugate, i.e. compound 12b (C6-ITC), 12a (C4-ITC) and 13 (C6-NAC) were successfully synthesized. Our results support that Enz-ITCs inhibit AR transcriptional activity, induce AR protein down-regulation (more effective than SFN) and suppress proliferation of both androgen-sensitive and insensitive prostate cancer cells. The AR antagonist activity of Enz-ITC was confirmed by the results of MTT and ARE-luciferase assays. We’ve also synthesized amide analogue of Enz-ITC 19 with reduced AR affinity while keeps the activity of ITC for future mechanistic studies. As a relevant strategy to study AR-directed HDAC inhibition, a representative Enz-HDAC inhibitor (HDACi) hybrid, compound 1005 was synthesized. 1005 and its prodrug 29 suppressed proliferation of both androgen-sensitive and insensitive prostate cancer cells

A Prospective Randomized Study of Adjuvant Chemotherapy in Resected Stage IIIA-N2 Non-small Cell Lung Cancer

Background and objective Lung cancer is one of the leading cause of cancer-related death around the world. Surgery is the primary treatment for patients with stage I, II, or IIIA non-small cell lung cancer (NSCLC). However, longterm survival of NSCLC patients after surgery alone is largely unsatisfactory. We undertook to determine whether adjuvant vinorelbine/paclitaxel plus carboplatin prolong overall survival among patients with completely resected stage IIIA-N2 nonsmall cell lung cancer. Methods We randomly assigned patients with completely resected stage IIIA-N2 non-small cell lung cancer to vinorelbine/paclitaxel plus carboplatin or to observation. Results A total of 150 patients (1999-2003) underwent randomization to vinorelbine/paclitaxel plus carboplatin (79 patients) or observation. In both groups, the median age was 57 years, 73 percent were male, and 28 percents had squamous carcinoma. Chemotherapy caused neutropenia in 82 percents of patients (including grade 3 and 4 neutropenia in 42 percent) and there was no treatment-related death observed in this trial. After median follow-up of 39 months (range 1-110), overall survival was significantly prolonged in the chemotherapy group as compared with the observation group (33 months versus 24 months, χ2=4.363, P=0.037), as was disease-free survival (32 months versus 20 months, χ2=5.413, P=0.020). Five-year overall survival rates were 31.1 percent and 19.1 percent, respectively. Conclusion Adjuvant vinorelbine/paclitaxel plus carboplatin have an acceptable level of toxicity and prolongs disease-free and overall survival among patients with completely resected stage IIIA-N2 non-small cell lung cancer

Insight into the Spatial Arrangement of the Lysine Tyrosylquinone and Cu2+ in the Active Site of Lysyl Oxidase-like 2

Lysyl oxidase-2 (LOXL2) is a Cu2+ and lysine tyrosylquinone (LTQ)-dependent amine oxidase that catalyzes the oxidative deamination of peptidyl lysine and hydroxylysine residues to promote crosslinking of extracellular matrix proteins. LTQ is post-translationally derived from Lys653 and Tyr689, but its biogenesis mechanism remains still elusive. A 2.4 Å Zn2+-bound precursor structure lacking LTQ (PDB:5ZE3) has become available, where Lys653 and Tyr689 are 16.6 Å apart, thus a substantial conformational rearrangement is expected to take place for LTQ biogenesis. However, we have recently shown that the overall structures of the precursor (no LTQ) and the mature (LTQ-containing) LOXL2s are very similar and disulfide bonds are conserved. In this study, we aim to gain insights into the spatial arrangement of LTQ and the active site Cu2+ in the mature LOXL2 using a recombinant LOXL2 that is inhibited by 2-hydrazinopyridine (2HP). Comparative UV-vis and resonance Raman spectroscopic studies of the 2HP-inhibited LOXL2 and the corresponding model compounds and an EPR study of the latter support that 2HP-modified LTQ serves as a tridentate ligand to the active site Cu2. We propose that LTQ resides within 2.9 Å of the active site of Cu2+ in the mature LOXL2, and both LTQ and Cu2+ are solvent-exposed

Adverse drug events associated with linezolid administration: a real-world pharmacovigilance study from 2004 to 2023 using the FAERS database

Introduction: Linezolid is an oxazolidinone antibiotic that is active against drug-resistant Gram-positive bacteria and multidrug-resistant Mycobacterium tuberculosis. Real-world studies on the safety of linezolid in large populations are lacking. This study aimed to determine the adverse events associated with linezolid in real-world settings by analyzing data from the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS).Methods: We retrospectively extracted reports on adverse drug events (ADEs) from the FAERS database from the first quarter of 2004 to that of 2023. By using disproportionality analysis including reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), along with the multi-item gamma Poisson shrinker (MGPS), we evaluated whether there was a significant association between linezolid and ADE. The time to onset of ADE was further analyzed in the general population and within each age, weight, reporting population, and weight subgroups.Results: A total of 11,176 reports of linezolid as the “primary suspected” drug and 263 significant adverse events of linezolid were identified, including some common adverse events such as thrombocytopenia (n = 1,139, ROR 21.98), anaemia (n = 704, ROR 7.39), and unexpected signals that were not listed on the drug label such as rhabdomyolysis (n = 90, ROR 4.33), and electrocardiogram QT prolonged (n = 73, ROR 4.07). Linezolid-induced adverse reactions involved 27 System Organ Class (SOC). Gender differences existed in ADE signals related to linezolid. The median onset time of all ADEs was 6 days, and most ADEs (n = 3,778) occurred within the first month of linezolid use but some may continue to occur even after a year of treatment (n = 46).Conclusion: This study reports the time to onset of adverse effects in detail at the levels of SOC and specific preferred term (PT). The results of our study provide valuable insights for optimizing the use of linezolid and reducing potential side effects, expected to facilitate the safe use of linezolid in clinical settings

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Crystal structures of di-μ-chlorido-bis­({(E)-5-(ethyl­amino)-4-methyl-2-[(pyridin-2-yl)diazen­yl]phen­o­lato}copper(II)) and chlorido­bis­(1,10-phen­anthroline)copper(II) chloride tetra­hydrate

The dark-red title complex crystallized from an equimolar methanol solution of (E)-5-(ethyl­amino)-4-methyl-2-[(pyridin-2-yl)diazen­yl]phenol and CuCl2(phen) (phen = 1,10-phenanthroline) as a centrosymmetric dimer, [CuCl(C14H15N4O)]2. The Cu atoms are bridged by two Cl ligands and have a slightly distorted square-pyramidal coordination, where two N atoms from the azo and the pyridine moieties, a phenolic O and a Cl atom comprise the base and the other Cl occupies the apex position. The apical Cu—Cl bond, 2.6192 (4) Å, is longer than the basal one, 2.2985 (3) Å, due to Jahn–Teller distortion. The dimers are associated via weak inter­molecular hydrogen bonds and π–π stacking inter­actions between phenyl and pyridine rings. A monomeric by-product of the same reaction, [CuCl(phen)2]Cl·4H2O, has a trigonal–bipyramidal coordination of Cu with equatorial Cl ligand, and extensive outer-sphere disorder. In the structure of 4, the packing of cations leaves continuous channels containing disordered Cl− anions and solvent mol­ecules. The identity of the solvent (water or a water/methanol mixture) was not certain. The disordered anion/solvent regions comprise 28% of the unit-cell volume. The disorder was approximated by five partly occupied positions of the Cl− anion and ten positions of O atoms with a total occupancy of 3, giving a total of 48 electrons per asymmetric unit, in agreement with the integral electron density of 47.8 electrons in the disordered region, as was estimated using the BYPASS-type solvent-masking program [van der Sluis & Spek (1990). Acta Cryst. A46, 194–201]

The Influence of Land Disposition Derived from Land Finance on Urban Innovation in China: Mechanism Discussion and Empirical Evidence

As China’s economy advances into a new stage of high-quality development driven by scientific and technological innovation, it is of great practical importance to probe what effects land disposition, which underpinned the previous round of rapid economic growth, and may have an exertion on developing innovation. Based on a deep exploration of the potential positive and negative influences of land disposition in relation to the effects of land finance on urban innovation, we employed a dynamic spatial Durbin model, along with panel data from 266 Chinese prefecture-level cities over the period 2004–2017. The empirical results show that the development of China’s urban innovation has had significant path dependence, spatial agglomeration, and inhibiting effects on neighboring cities, and these effects are attributed to inter-governmental competition and the Matthew effect. Overall, the combined impacts of land disposition modes on urban innovation have changed, from facilitative in the early stage to inhibitory at present. In the developed cities of east China, the facilitative effect of land disposition has weakened gradually, and tends to disappear entirely, while the change in impact over time in less developed mid-western cities is consistent with the national sample. This study broadens our understanding of the role of land disposition in China’s urban innovative development and has meaningful direct implications for policymakers

Effects of smart agricultural production investment announcements on shareholder value : Evidence from China

The advent of the era of the smart economy has made agricultural production more intelligent. An increasing number of companies have launched a series of investment activities aimed at smart agricultural production (SAP). However, whether smart agricultural production investment (SAPI) impacts the stock market has yet to be confirmed. Therefore, based on the sample data of 118 listed companies in China from 2010 to 2019, this study empirically examines the impact of SAPI announcements on shareholder value, as indicated by abnormal returns of stocks. Further, we tested the moderating effect of certain characteristic factors on abnormal stock returns. The research results illustrate a significant positive connection between SAPI announcements and shareholder value. Moreover, considering the announcement content and company factors, this study investigates the impacts of different investment targets and industries on the market reaction to SAPI announcements. We find that non-agricultural companies have a more positive market reaction to SAPI than agricultural companies; the higher the liability-asset ratio, the more positive will be the stock market reaction to SAPI.Funding Agencies|Major Program of the National Social Science Foundation of China [18ZDA060]</p

Identification of an Amino Acid Metabolism-Related Gene Signature for Predicting Prognosis in Lung Adenocarcinoma

Dysregulation of amino acid metabolism (AAM) is an important factor in cancer progression. This study intended to study the prognostic value of AAM-related genes in lung adenocarcinoma (LUAD). Methods: The mRNA expression profiles of LUAD datasets from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) were applied as the training and validation sets. After identifying the differentially expressed AAM-related genes, an AAM-related gene signature (AAMRGS) was constructed and validated. Additionally, we systematically analyzed the differences in immune cell infiltration, biological pathways, immunotherapy response, and drug sensitivity between the two AAMRGS subgroups. Results: The prognosis-related signature was constructed on the grounds of key AAM-related genes. LUAD patients were divided into AAMRGS-high and -low groups. Patients in the two subgroups differed in prognosis, tumor microenvironment (TME), biological pathways, and sensitivity to chemotherapy and immunotherapy. The area under the receiver operating characteristics (ROC) and calibration curves showed good predictive ability for the nomogram. Analysis of immune cell infiltration revealed that the TME of the AAMRGS-low group was in a state of immune activation. Conclusion: We constructed an AAMRGS that could effectively predict prognosis and guide treatment strategies for patients with LUAD