Design, Synthesis, and Biological Evaluation of Novel Arylomycins against Multidrug-Resistant Gram-Negative Bacteria.

G0775, an arylomycin-type SPase I inhibitor that is being evaluated in a preclinical study, exhibited potent antibacterial activities against some Gram-negative bacteria but meanwhile suffered defects such as a narrow antibacterial spectrum and poor pharmacokinetic properties. Herein, systematic structural modifications were carried out, including optimization of the macrocyclic skeleton, warheads, and lipophilic regions. The optimization culminated in the discovery of 138f, which showed more potent activity and a broader spectrum against clinically isolated carbapenem-resistant Gram-negative bacteria, especially against Acinetobacter baumannii and Pseudomonas aeruginosa. 162, the free amine of 138f, exhibited an excellent pharmacokinetic profile in rats. In a neutropenic mouse thigh model of infection with multidrug-resistant P. aeruginosa, the potent in vivo antibacterial efficacy of 162 was confirmed and superior to that of G0775 (3.5-log decrease vs 1.1-log decrease in colony-forming unit (CFU)). These results support 162 as a potential antimicrobial agent for further research.

Predicting prognosis and immune status in sarcomas by identifying necroptosis-related lncRNAs.

BACKGROUND: Sarcomas are a type of highly heterogeneous malignant tumors originating from mesenchymal tissues. Necroptosis is intricately connected to the oncogenesis and progression of tumors. The main goal of this research is to assess the prognostic value of necroptosis-related lncRNAs (NRlncRNAs) in sarcomas and to develop a risk model based on NRlncRNAs to evaluate prognostic and immune status of the sarcomas. METHODS: We screened NRlncRNAs using the gene co-expression network, developed a prognostic risk model of sarcomas, and then verified the model. Following that, various bioinformatics analysis algorithms were employed to analyze the distinct characteristics of patients of the risk model. Furthermore, the function and regulatory mechanism of NRlncRNA SNHG6 in sarcomas were investigated through osteosarcoma cell experiments, such as qRT-PCR, Western blot, CCK-8, clone formation, and transwell assay. RESULTS: We successfully developed a NRlncRNAs-related prognostic risk model and screened 5 prognosis-related NRlncRNAs, with SNGH6 being the most significant for prognosis of patients. According to results, the significant differences exist in prognosis, clinical characteristics, and tumor immune status among patients of the risk model. The experiments of osteosarcoma cells demonstrated that NRlncRNA SNHG6 knockdown significantly attenuated the cells' proliferation, migration, and invasion. qRT-PCR and WB results showed that SNHG6 regulated AXL and AKT signaling. CONCLUSIONS: We have developed an innovative investigation on NRlncRNAs, which can serve as a reference for diagnosis, therapy, and prognosis of sarcomas. Additionally, we demonstrated that NRlncRNA SNHG6 regulated AXL and AKT signaling in osteosarcoma cells and the proliferation, migration, and invasion of tumor cells.

Craig-Hückel Hybrid Aromatic Metalla-dehydro[11]annulenes Constructed by a Formal [10+1] Cycloaddition Reaction.

Aromatic metalla-annulenes are important aromatic compounds, research into which has been mainly concentrated on metal-benzenes and their lower homologues. Reports on their superior homologs are rare, and this has greatly limited the systematic study of their properties. In this work, a series of osma-dehydro[11]annulenes with good air and thermal stability were prepared in high yields through a simple [10+1] strategy, by incorporating a metal fragment into conjugated ten-carbon chains in a one-pot reaction. They are the first monometallic aromatic metalla-[n]annulenes with the ring size larger than 6, and their Craig-Hückel hybrid aromaticity is supported by various physical and computational parameters. Besides, these complexes show versatile reactivities, not only giving further evidence for their aromaticity, but also demonstrating their physical and chemical properties can easily be regulated. This work enriches the metalla-aromatic chemistry, and provides a new avenue for the synthesis of large metalla-annulenes with different ring sizes.

Risk factors for recurrent cerebral amyloid angiopathy-related intracerebral hemorrhage.

Background: Cerebral amyloid angiopathy (CAA) is the most common cause of lobar intracerebral hemorrhage (ICH) in the elderly, and its multifocal and recurrent nature leads to high rates of disability and mortality. Therefore, this study aimed to summarize the evidence regarding the recurrence rate and risk factors for CAA-related ICH (CAA-ICH). Methods: We performed a systematic literature search of all English studies published in PubMed, Embase, Web of Science, Cochrane Library, Scopus, and CINAHL from inception to June 10, 2023. Studies reporting CAA-ICH recurrence rates and risk factors for CAA-ICH recurrence were included. We calculated pooled odds ratios (ORs) with their corresponding 95% confidence intervals (CIs) using a random/fixed-effects model based on the I2 assessment of heterogeneity between studies. Publication bias was assessed using Egger's test. Results: Thirty studies were included in the final analysis. Meta-analysis showed that the recurrence rate of CAA-ICH was 23% (95% CI: 18-28%, I2 = 96.7%). The risk factors significantly associated with CAA-ICH recurrence were: previous ICH (OR = 2.03; 95% CI: 1.50-2.75; I2 = 36.8%; N = 8), baseline ICH volume (OR = 1.01; 95% CI: 1-1.02; I2 = 0%; N = 4), subarachnoid hemorrhage (cSAH) (OR = 3.05; 95% CI: 1.86-4.99; I2 = 0%; N = 3), the presence of cortical superficial siderosis (cSS) (OR = 2.04; 95% CI: 1.46-2.83; I2 = 0%; N = 5), disseminated cSS (OR = 3.21; 95% CI: 2.25-4.58; I2 = 16.0%; N = 6), and centrum semiovale-perivascular spaces (CSO-PVS) severity (OR = 1.67; 95% CI: 1.14-2.45; I2 = 0%; N = 4). Conclusion: CAA-ICH has a high recurrence rate. cSAH, cSS (especially if disseminated), and CSO-PVS were significant markers for recurrent CAA-ICH. The onset of ICH in patients with CAA is usually repeated several times, and recurrence is partly related to the index ICH volume. Identifying clinical and neuroimaging predictors of CAA-ICH recurrence is of great significance for evaluating outcomes and improving the prognosis of patients with CAA-ICH. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=400240, identifier [CRD42023400240].

Long non-coding RNA SOX21-AS1: A potential tumor oncogene in human cancers.

Emerging data have proposed that the aberrant level of long noncoding RNAs (lncRNA) is related to the onset and progression of cancer. Among them, lncRNA SOX21-AS1 was shown to upregulate and seem to be a novel oncogene in various cancer, including ovarian cancer, lung cancer, breast cancer, pancreatic cancer, osteosarcoma, and melanoma. Available data indicated that SRY-box transcription factor 21 antisense divergent transcript 1 (SOX21-AS1) mostly acts as a competing endogenous RNA (ceRNA) to inhibit the level of its target microRNAs (miRNAs), leading to upregulation of their targets. In addition, SOX21-AS1 is engaged in various signaling pathways like transforming growth factor-ß (TGF-ß) signaling, Wnt signaling, and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling. Moreover, this lncRNA was revealed to be correlated with the clinicopathological features of affected patients. SOX21-AS1 was also proved to enhance the resistance of ovarian cancer cells to cisplatin chemotherapy. SOX21-AS1 is markedly associated with poor prognosis and low survival of patients, proposing that it may be a prognostic and diagnostic biomarker in cancer. Overexpression of SOX21-AS1 is related to various cancer-related pathways, like epithelial mesenchymal transition (EMT), invasion, migration, apoptosis, and cell cycle arrest. In this work, we aimed to discuss the biogenesis, function, and underlying molecular mechanism of SOX21-AS1 in cancer progression as well as its potential as a prognostic and diagnostic biomarker in human cancers.

Evidence for the transmission of antimicrobial resistant bacteria between humans and companion animals: A scoping review.

Objective: Transmission of antimicrobial resistant bacteria between people and household pets, such as dogs and cats, is an emerging global public health problem. This scoping review synthesized existing evidence of human-pet bacteria transmission to understand the magnitude and breadth of this issue. Methods: The search included specific and generic terms for bacteria, resistance, transmission, pets, and humans. Searches were conducted through PubMed, Scopus, Web of Science, CABI Global Health, Networked Digital Library of Theses and Dissertations, Google Scholar. All studies published in English and Mandarin that isolated bacteria from pets (cats and dogs) and humans who had contact with the pets, and reported phenotypic or genotypic antimicrobial sensitivity test results, were included in this review. In cases of bacterial species that are commonly associated with pets, such as Staphylococcus pseudintermedius and Pasteurella multocida, we also included studies that only isolated bacteria from humans. Results: After removing duplication, the search captured 9355 studies. A total of 1098 papers were screened in the full-text review, and 562 studies were identified as eligible according to our inclusion criteria. The primary reason for exclusion was the lack of sensitivity testing. The included studies were published between 1973 and 2021. The most common study location was the United States (n = 176, 31.3%), followed by the United Kingdom (n = 53, 9.4%), Japan (n = 29, 5.2%), and Canada (n = 25, 4.4%). Most of the included studies were case reports (n = 367, 63.4%), cross-sectional/prevalence studies (n = 130, 22.4%), and case series (n = 51, 8.8%). Only few longitudinal studies (n = 14, 2.4%), case-control studies (n = 12, 2.1%), and cohort studies (n = 5, 0.9%) were included in our review. Most studies focused on Pasteurella multocida (n = 221, 39.3%), Staphylococcus aureus (n = 81, 14.4%), and Staphylococcus pseudintermedius (n = 52, 8.9%). For the 295 studies that used strain typing methods to compare bacteria from humans and pets, most used DNA banding pattern-based methods (n = 133, 45.1%) and DNA sequencing-based methods (n = 118, 40.0%). Conclusion: Transmission of bacteria could occur in both directions: pets to humans (e.g., S. pseudintermedius and P. multocida) and humans to pets (e.g., S. aureus). The majority of studies provided a low level of evidence of transmission (e.g., case reports), suggesting that more rigorous longitudinal, cohort, or case-control studies are needed to fully understand the risk of human-pet resistant bacterial transmission.

Discovery of a Novel Bifunctional Steroid Analog, YXG-158, as an Androgen Receptor Degrader and CYP17A1 Inhibitor for the Treatment of Enzalutamide-Resistant Prostate Cancer.

The androgen/androgen receptor (AR) signaling pathway plays an important role in castration-resistant prostate cancer (CRPC). Bifunctional agents that simultaneously degrade AR and inhibit androgen synthesis are expected to block the androgen/AR signaling pathway more thoroughly, demonstrating the promising therapeutic potential for CRPC, even enzalutamide-resistant CRPC. Herein, a series of steroid analogs were designed, synthesized, and identified as selective AR degraders, among which YXG-158 (23-h) was the most potent antitumor compound with dual functions of AR degradation and CYP17A1 inhibition. In addition, 23-h abrogated the hERG inhibition and exhibited excellent PK profiles. In vivo, 23-h effectively inhibited the growth of hormone-sensitive organs in the Hershberger assay and exhibited robust antitumor efficacy both in enzalutamide-sensitive (LNCaP/AR) and enzalutamide-resistant (C4-2b-ENZ) xenograft models. Thus, 23-h was chosen as a preclinical candidate for the treatment of enzalutamide-resistant prostate cancer.

Synergistic Optimization of Buried Interface by Multifunctional Organic-Inorganic Complexes for Highly Efficient Planar Perovskite Solar Cells.

For the further improvement of the power conversion efficiency (PCE) and stability of perovskite solar cells (PSCs), the buried interface between the perovskite and the electron transport layer is crucial. However, it is challenging to effectively optimize this interface as it is buried beneath the perovskite film. Herein, we have designed and synthesized a series of multifunctional organic-inorganic (OI) complexes as buried interfacial material to promote electron extraction, as well as the crystal growth of the perovskite. The OI complex with BF4- group not only eliminates oxygen vacancies on the SnO2 surface but also balances energy level alignment between SnO2 and perovskite, providing a favorable environment for charge carrier extraction. Moreover, OI complex with amine (- NH2) functional group can regulate the crystallization of the perovskite film via interaction with PbI2, resulting in highly crystallized perovskite film with large grains and low defect density. Consequently, with rational molecular design, the PSCs with optimal OI complex buried interface layer which contains both BF4- and -NH2 functional groups yield a champion device efficiency of 23.69%. More importantly, the resulting unencapsulated device performs excellent ambient stability, maintaining over 90% of its initial efficiency after 2000 h storage, and excellent light stability of 91.5% remaining PCE in the maximum power point tracking measurement (under continuous 100 mW cm-2 light illumination in N2 atmosphere) after 500 h.

Screening and identification of susceptibility genes for osteosarcoma based on bioinformatics analysis.

Background: Gene play an important role in malignant tumors. However, there is still insufficient research on genetic variations in osteosarcoma (OS) patients. Therefore, we aimed to analyze the gene expression profile of OS using bioinformatics and to explore the pathogenesis of OS at the molecular level. Methods: The gene chip dataset of OS samples was downloaded from the Gene Expression Omnibus (GEO) database for screening differentially expressed genes (DEGs). The R language clusterProfiler software package was used to perform Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis for DEGs. The central node proteins of the protein interaction network were analyzed by the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database, Cytoscape, and its plug-ins cytoHubba and NetworkAnalyzer to find the key genes. Results: A total of 631 DEGs were obtained, including 362 upregulated genes and 269 downregulated genes. DEGs were mainly involved in the regulation of leukocyte chemotaxis and migration, vascular development, and other biological processes (BPs); mediation of receptor ligand activity, growth factor binding, growth factor activity, integrin binding, and other molecular functions (MFs); and were enriched in the extracellular matrix (ECM). Conclusions: DEGs in the ECM and growth factors play a key role in the development of OS. The leukocyte transendothelial migration pathway and the PI3K-AKT pathway are closely related to OS, and the related molecular mechanism is worthy of further study.

Experimental and theoretical evidences for the formation of transition metal complexes with five coplanar metal-carbon σ bonds.

The σ bond is an important concept in chemistry, and the metal-carbon (M-C) σ bond in particular is a central feature in organometallic chemistry. Synthesis of stable complexes with five coplanar M-C σ bonds is challenging. Here, we describe the synthesis of two different types of stable complexes with five coplanar M-C σ bonds, and examine the stability of such complexes which use rigid conjugated carbon chains to chelate with the metal center. Density functional theory (DFT) calculations show that the M-C σ bonds in these complexes have primarily a covalent character. Besides the σ nature, there are also a π conjugation component among the metal center and carbons, which causes delocalization. This work expanded the coplanar M-C σ bonds to five.

Systematic review of Kaixinsan in treating depression: Efficacy and pharmacological mechanisms.

Introduction: Kaixinsan (KXS) has been in use as an effective classic formulation of traditional Chinese medicine for depression. However, its active components and action mechanism against depression remain elusive. The purpose of this study was to summarize and evaluate the efficacy and potential pharmacological mechanisms of KXS in antidepressant treatment. Materials and methods: Reports on the use of KXS in the treatment of depression were systematically collected from PubMed, Web of Science, Embase, China National Knowledge Infrastructure, Chongqing VIP, and Wanfang Data from the establishment to July 2022, including those on mood disorders in neurological diseases such as Alzheimer's disease. Meta-analysis was conducted with the Review Manager 5.3 software. Online datasets, traditional Chinese medicine system pharmacological analysis platform, GeneCards, online Mendelian inheritance in man, and DisGeNET were used to investigate the depression-related genes. The gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichments were performed to construct the 'component-target-pathways' network using Metascape online analyses. Result: Ten studies were included in the analysis. Meta-analysis showed that both low-dose KXS (SMD = 19.66, Z = 7.96, and I 2 = 42%) and high-dose KXS (SMD = 23.84, Z = 8.46, and I 2 = 13%) could increase the sucrose preference in depression models. In addition, 5-hydroxytryptamine (5-HT) (SMD = 10.91, Z = 2.95, and I 2 = 50%) returned to normal level after the treatment at low dose KXS. In network pharmacology, 50 active components and 376 gene targets were screened out. AKT1, GAPDH, ALB, TNF, and TP53 were the core target proteins. GO analysis showed that KXS mainly treats depression in biological processes such as response to drugs, cellular calcium ion homeostasis, and regulation of chemical synaptic signal transmission. KEGG results show that the mechanism of action of KXS in treating depression is through neural activity ligand-receptor interaction, the calcium signaling and CAMP signaling pathways. Discussion: The study reveals the active components and potential molecular mechanism of KXS in the treatment of depression and provides evidence for future basic research.

Condensed Osmaquinolines with NIR-II Absorption Synthesized by Aryl C-H Annulation and Aromatization.

The structural design and tuning of properties of metallaaromatics are crucial in materials and energy science. Herein, we describe the rapid synthesis of tetracyclic metallaaromatics containing quinoline and pentalene motifs fused by a metal-bridged fragment. These unique compounds display remarkably broad absorption, enabling for the first time the absorption of metallaaromatics to reach the second near-infrared (NIR-II) bio-window. The formation of osmaquinoline unit involves an unconventional C(sp2 )-C(sp3 ) coupling promoted by AgBF4 to achieve [3+3] cycloaddition. The introduction of cyclic dπ -pπ conjugation and extension of the aromatic π-framework can effectively shrink the HOMO-LUMO gap, thus broadening the absorption window. The considerable photothermal conversion efficiency (PCE) in both the NIR-I and NIR-II windows, the high photothermal stability and the excellent electrochemical behavior suggest many potential applications of these condensed metallaquinolines.

Design, Synthesis, and Biological Evaluation of Androgen Receptor Degrading and Antagonizing Bifunctional Steroidal Analogs for the Treatment of Advanced Prostate Cancer.

Metastatic castration-resistant prostate cancer (mCRPC) with high mortality has seriously threatened men's health. Bifunctional agents simultaneously degrade and antagonize androgen receptor (AR), display robust AR signaling pathway blockade, and show the therapeutic prospect for mCRPC. Herein, systemic structural modifications on the C-3, C-6, and C-17 positions of galeterone led to the discovery of 67-b with the dual functions of AR antagonism and degradation. In vitro, 67-b exhibited excellent antiproliferative activity and potent AR degradation activity in different PCa cells (LNCaP and 22RV1), as well as outstanding antagonistic activity against wild-type and mutant (W741L, T877A, and F876L) ARs. In vivo, 67-b effectively inhibited the growth of hormone-sensitive organs in the Hershberger assay and exhibited tumor regression in the enzalutamide-resistant (c4-2b-ENZ) xenograft model. These results confirmed 67-b to be a promising AR degrader and antagonist for the treatment of mCRPC patients.

Anchoring Vertical Dipole to Enable Efficient Charge Extraction for High-Performance Perovskite Solar Cells.

Perovskite solar cells (PSCs) via two-step sequential method have received great attention in recent years due to their high reproducibility and low processing costs. However, the relatively high trap-state density and poor charge carrier extraction efficiency pose challenges. Herein, highly efficient and stable PSCs via a two-step sequential method are fabricated using organic-inorganic (OI) complexes as multifunctional interlayers. In addition to reduce the under-coordinated Pb2+ ions related trap states by forming interactions with the functional groups, the complexes interlayer tends to form dipole moment which can enhance the built-in electric field, thus facilitating charge carrier extraction. Consequently, with rational molecular design, the resulting devices with a vertical dipole moment that parallels with the built-in electric field yield a champion efficiency of 23.55% with negligible hysteresis. More importantly, the hydrophobicity of the (OI) complexes contributes to an excellent ambient stability of the resulting device with 91% of initial efficiency maintained after 3000 h storage.

What is the Real Origin of the Activity of Fe-N-C Electrocatalysts in the O2 Reduction Reaction? Critical Roles of Coordinating Pyrrolic N and Axially Adsorbing Species.

Fe-N-C electrocatalysts have emerged as promising substitutes for Pt-based catalysts for the oxygen reduction reaction (ORR). However, their real catalytic active site is still under debate. The underlying roles of different types of coordinating N including pyridinic and pyrrolic N in catalytic performance require thorough clarification. In addition, how to understand the pH-dependent activity of Fe-N-C catalysts is another urgent issue. Herein, we comprehensively studied 13 different N-coordinated FeNxC configurations and their corresponding ORR activity through simulations which mimic the realistic electrocatalytic environment on the basis of constant-potential implicit solvent models. We demonstrate that coordinating pyrrolic N contributes to a higher activity than pyridinic N, and pyrrolic FeN4C exhibits the highest activity in acidic media. Meanwhile, the in situ active site transformation to *O-FeN4C and *OH-FeN4C clarifies the origin of the higher activity of Fe-N-C in alkaline media. These findings can provide indispensable guidelines for rational design of better durable Fe-N-C catalysts.

Analysis on Acupoint Selection and Combination for Amyotrophic Lateral Sclerosis Treated with Acupuncture Based on Data Mining.

Objective: The aim of the study was to explore the regularity of acupoints in the treatment of amyotrophic lateral sclerosis (ALS) by means of data mining technology. Methods: Nine databases, including SinoMed, Chongqing VIP (CQVIP), China National Knowledge Infrastructure (CNKI), Wanfang Data, Cochrane Library, PubMed, MEDLINE, Web of Science, and Embase, were comprehensively searched till December 2021. The published clinical literature testing acupuncture in the treatment of ALS was eligible for inclusion. Studies were organized to establish the prescription database. Modular data mining analysis, including acupoint frequency, complex network analysis, association rule analysis, and cluster analysis were used to conduct statistical analysis. Results: Forty-two literature studies on 141 acupoints were included, involving 626 times the total application frequency. The top 5 acupoints in application frequency were Hegu (LI 4, 67%), Zusanli (ST 36, 67%), Quchi (LI 11, 52%), Sanyinjiao (SP 6, 48%), and Yanglingquan (GB 34, 45%). The most involved meridian was the large intestine meridian of hand Yangming (90 times). The generally used acupoints were mainly distributed in the lower limbs. The top 5 combinations in application frequency were Hegu-Quchi (75 times), Quchi-Zusanli (66 times), Zusanli-Sanyinjiao (54 times), Hegu-Sanyinjiao (54 times), and Quchi-Sanyinjiao (49 times). The acupoint combinations with the strongest association were Quchi, Hegu, Zusanli, Sanyinjiao, and Shousanli (LI 10). There were 7 acupoint groups according to the cluster analysis. The core prescriptions were Hegu, Zusanli, Quchi, and Jiaji (EX-B 2). Conclusions: Hegu, Zusanli, Quchi, and Jiaji could be used as the main prescriptions in treating ALS. The combination of Quchi, Hegu, Zusanli, and Sanyinjiao should be selected with priority in acupuncture therapy.

Anatomical changes in lumbosacral vertebrae and their correlation with facet joint-derived low back pain in patients with hip osteoarthritis after total hip arthroplasty: a cohort study.

Background: Little is known about the anatomical changes in lumbosacral vertebrae and their correlation with facet joint-derived low back pain in patients with hip osteoarthritis (HOA) after total hip arthroplasty. Methods: Seventy-four HOA patients with low back pain who underwent initial total hip arthroplasty were included. Their Harris Hip Score (HHS), Oswestry Disability Index (ODI), Visual Analogue Scale (VAS) and anatomical parameters were analyzed. Paired t-tests were used to compare the various index scores before and after surgery, and independent sample t-tests were used for the between-group comparisons. Results: The HHS and ODI significantly changed at 3 and 6 months postoperatively [HHS: preoperative (43.56±4.34) vs. 3 months (80.34±5.23) vs. 6 months (84.37±4.78); ODI: preoperative (36.26±5.34) vs. 3 months (26.44±3.23) vs. 6 months (19.34±3.27); P<0.001]. At the first 3 months after surgery, the VAS low back pain score decreased from 5.24±1.21 to 2.89±1.03 (P<0.001), and the VAS hip pain score decreased from 7.45±1.32 to 2.34±1.12 (P<0.001). There was also a statistically significant difference between the preoperative and 1-month postoperative anatomical indices: lumbar lordosis (LL) increased significantly after surgery [preoperative (43.46°±13.89°) vs. 1 month (48.27°±14.42°), P=0.001], while slip angle (SA) decreased significantly [preoperative (89.20°±5.03°) vs. 1 month (84.45°±4.89°), P=0.010]. Sacral slope (SS) and radial abduction angle (RAA) showed significant postoperative changes compared with preoperative assessments; after surgery, SS increased significantly [preoperative (31.33°±8.23°) vs. 1 month (37.65°±8.19°), P=0.006), while RAA decreased significantly [preoperative (42.32°±8.12°) vs. 1 month (35.45°±7.67°), P=0.021]. Moreover, the increase of LL was both significantly correlated with the decrease of the VAS low back pain (P=0.009) and the VAS hip pain score (P=0.038). Conclusions: Total hip arthroplasty was associated with the anatomical changes in lumbosacral vertebrae.

Different angular kyphosis locations have different relative positions of aorta to spine in patients with Pott's deformity.

BACKGROUND: The position of the aorta relative to the spine in kyphosis secondary to Pott's deformity is little understood. The purpose of this study was to investigate the anatomic relationship between the aorta and the spine in patients with Pott's deformity and to compare it with the normal people. METHODS: Seventy-six patients with Pott's deformity (Group TB) and seventy-two age- and sex-matched patients with a normal spine (group NC) were enrolled in this study. The relative position of aorta to the spine was evaluated from T4 to L4 on the computed tomographic angiography scans for controls and at the apex level for TB patient, and was classified into 4 kinds of degrees. RESULTS: The left pedicle-aorta angle in group TB was significantly larger than that in group NC at the T6-L3 levels. Group TB exhibited significantly smaller left pedicle-aorta distance, pedicular line-aorta distance and vertebra/rib-aorta distance than those in group NC at the T5-T10 levels, but bigger at the L1-3 levels. Patients with grade 3 and 4 aorta had more segments involved compared with those with grade 1 aorta. Patients with grade 2, 3, and 4 aorta showed larger kyphotic angles than those with grade 1. CONCLUSIONS: Patients whose morbid segments involved only thoracic vertebrae presented with an "Ω" shaped aorta in sagittal plane, and 4 different kinds of degrees of aorta relative to the vertebra/rib in axial plane. Patients whose morbid segments covered lumbar vertebrae presented with an "M" shaped aorta in sagittal plane, and the aorta shifted further from apex vertebra but was located in close proximity to the vertebral body at levels above and below the osteotomy levels in axial plane.

Discovery of Thieno[2,3-e]indazole Derivatives as Novel Oral Selective Estrogen Receptor Degraders with Highly Improved Antitumor Effect and Favorable Druggability.

Endocrine therapies in the treatment of early and metastatic estrogen receptor α positive (ERα+) breast cancer (BC) are greatly limited by de novo and acquired resistance. Selective estrogen receptor degraders (SERDs) like fulvestrant provide new strategies for endocrine therapy combinations due to unique mechanisms. Herein, we disclose our structure-based optimization of LSZ102 by replacing 6-hydroxybenzothiophene with 6H-thieno[2,3-e]indazole. Subsequent acrylic acid degron modifications led us to identify compound 40 as the preferred candidate. In general, compound 40 showed much better pharmacological profiles than the lead LSZ102, exhibiting growth inhibition of wild-type or tamoxifen-resistant MCF-7 cells, potent ERα degradation, together with superior pharmacokinetic properties, directional target tissue distribution including the brain, and robust antitumor efficacy in the mice breast cancer xenograft model. Currently, 40 is being evaluated in preclinical trials.

Electrophilic aromatic substitution reactions of compounds with Craig-Möbius aromaticity.

Electrophilic aromatic substitution (EAS) reactions are widely regarded as characteristic reactions of aromatic species, but no comparable reaction has been reported for molecules with Craig-Möbius aromaticity. Here, we demonstrate successful EAS reactions of Craig-Möbius aromatics, osmapentalenes, and fused osmapentalenes. The highly reactive nature of osmapentalene makes it susceptible to electrophilic attack by halogens, thus osmapentalene, osmafuran-fused osmapentalene, and osmabenzene-fused osmapentalene can undergo typical EAS reactions. In addition, the selective formation of a series of halogen substituted metalla-aromatics via EAS reactions has revealed an unprecedented approach to otherwise elusive compounds such as the unsaturated cyclic chlorirenium ions. Density functional theory calculations were conducted to study the electronic effect on the regioselectivity of the EAS reactions.