Deoxyshikonin: a promising lead drug grass against drug resistance or sensitivity to Helicobacter pylori in an acidic environment.

Helicobacter pylori (H. pylori) is closely associated with the diseases such as gastric sinusitis, peptic ulcers, and gastric adenocarcinoma. Its drug resistance is very severe, and new antibiotics are urgently needed. Nine comfrey compounds were screened by antimicrobial susceptibility testing, among which deoxyshikonin had the best inhibitory effect, with a minimum inhibitory concentration (MIC) of 0.5-1 µg/mL. In addition, deoxyshikonin also has a good antibacterial effect in an acidic environment, it is highly safe, and H. pylori does not readily develop drug resistance. Through in vivo experiments, it was proven that deoxyshikonin (7 mg/kg) had a beneficial therapeutic effect on acute gastritis in mice infected with the multidrug-resistant H. pylori BS001 strain. After treatment with desoxyshikonin, colonization of H. pylori in the gastric mucosa of mice was significantly reduced, gastric mucosal damage was repaired, inflammatory factors were reduced, and the treatment effect was better than that of standard triple therapy. Therefore, deoxyshikonin is a promising lead drug to solve the difficulty of drug resistance in H. pylori, and its antibacterial mechanism may be to destroy the biofilm and cause an oxidation reaction.

A network meta-analysis of efficacy and safety for first-line and second/further-line therapies in postmenopausal women with hormone receptor-positive, HER2-negative, advanced breast cancer.

BACKGROUND: Hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR + /HER2 -) advanced breast cancer is a prevalent subtype among postmenopausal women. Despite the growing number of randomized clinical trials (RCTs) exploring this topic, the efficacy and safety of first-line and second/further-line treatments remain uncertain. Accordingly, our aim was to conduct a comprehensive evaluation of the efficacy and safety of these therapies through network meta-analysis. METHODS: RCTs were identified by searching Pubmed, Embase, and major cancer conferences. The efficacy of interventions was assessed using the hazard ratios (HRs) of progression-free survival (PFS) and overall survival (OS), while safety was indicated by the incidence of any grade adverse events (AEs), grade 3-5 AEs, AEs leading to treatment discontinuation, and AEs leading to death. Both time-variant HRs fractional polynomial models and time-invariant HRs Cox-proportional hazards models were considered for handling time-to-event data. Safety indicators were analyzed using Bayesian network meta-analysis. Additionally, subgroup analyses were conducted based on patient characteristics. RESULTS: A total of 41 RCTs (first-line 17, second/further-lines 27) were included in the analysis. For first-line treatment, the addition of Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors to endocrine therapy significantly improved therapeutic efficacy in terms of both PFS and OS, demonstrating the best performance across all mechanisms. Specifically, the combination of Abemaciclib and Letrozole demonstrated the most favorable performance in terms of PFS, while Ribociclib plus Fulvestrant yielded the best outcomes in OS. Incorporating the immune checkpoint inhibitor Avelumab into the regimen with CDK4/6 inhibitors and selective estrogen receptor degraders significantly enhanced both PFS and OS in second-line or later treatments. Regarding safety, endocrine monotherapy performed well. Regarding safety, endocrine monotherapy performed well. There is mounting evidence suggesting that most CDK4/6 inhibitors may demonstrate poorer performance with respect to hematologic AEs. However, additional evidence is required to further substantiate these findings. CONCLUSIONS: CDK4/6 inhibitors, combined with endocrine therapy, are pivotal in first-line treatment due to their superior efficacy and manageable AEs. For second/further-line treatment, adding immune checkpoint inhibitors to CDK4/6 inhibitors plus endocrine therapy may produce promising results. However, to reduce the results' uncertainty, further trials comparing these novel treatments are warranted. TRIAL REGISTRATION: Registration number: PROSPERO (CRD42022377431).

Cyclometalated Half-Sandwich Ruthenium Complexes: Preparation, Structure, and Catalytic Synthesis of Phenolic Esters from Aryl Halides without Using External CO under Air.

A series of cyclometalated C,N-chelate half-sandwich ruthenium complexes based on N-heterocyclic ligands were prepared through a simple route with good yields. These air- and moisture-stable cyclometalated ruthenium complexes showed excellent catalytic efficiency in phenoxy carbonylation of aryl halides with phenyl formate derivatives as a CO source and phenol as a coupling partner under air. Ester products were obtained with high yields at room temperature and without the need for an inert atmosphere. The excellent catalytic activity, broad substrate range, and mild reaction conditions made this catalytic system potential for industrial production. In addition, DFT study has been carried out to elaborate the possible mechanism of this Ru-catalyzed reaction.

Is Breast Magnetic Resonance Imaging Superior to Sonography in Gynecomastia Evaluation and Surgery Planning.

BACKGROUND: Data on the value of magnetic resonance imaging (MRI) in the preoperative evaluation and surgery planning of gynecomastia are limited. The purpose of this study is to reveal MRI features and categories of gynecomastia and compare surgical outcomes following MRI and sonography as well as their diagnostic accuracy. METHODS: The area of the gland and the whole breast on the transverse plane via nipple of MRI were measured to calculate the ratio between them. Areola, mass and branch patterns were categorized to represent three different gynecomastia type on MRI. 183 patients were included, with 38 in MRI group and 145 in sonography group. Diagnostic accuracy was assessed by the level of agreement between preoperative imaging findings and intraoperative observations. Surgical data, patients' satisfaction and complications were compared between the two groups. RESULTS: MRI in 75 gynecomastic breasts demonstrated the average ratio of the gland to the whole breast was 10.6%±13.3%. The most common MRI categories were branch patterns (45.3%). The diagnostic concordance rate of MRI was higher than sonography (100% vs. 86.8%, p = 0.001). Among those junior surgeons, the length of surgery was reduced in MRI group (100 min vs. 115 min, p = 0.048). There was no difference in terms of patient's satisfaction and complication rate between MRI and sonography. CONCLUSION: MRI was superior to sonography in diagnostic accuracy to assess the tissue components of gynecomastia and provided informative guidance especially for junior surgeons. Surgical outcomes were comparable regardless of the use of MRI or sonography for evaluation. LEVEL OF EVIDENCE IV: IThis journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Fused Lateral Clitoral Hood and Labia Minora: New Classification Based on Anatomic Variation of the Clitoral Hood-Labia Minora Complex and Simple Surgical Management.

BACKGROUND: Existing classifications of the clitoral hood-labia minora complex (CLC) have neglected its integrity and anatomic variation, resulting in failure to optimize approaches tailored to individuals. OBJECTIVES: The aim of this study was to present a new classification system for comprehensive evaluation of variations of the CLC and to introduce a simple surgical approach for the fused type. METHODS: Anatomic variations of the CLC were classified into 3 types: isolated labia minora or lateral clitoral hood hypertrophy (Type 1); conventional combined hypertrophy (Type 2); and fused lateral clitoral hood and labia minora (Type 3). A modified procedure for the fused type was performed in 4 steps: the anterior border of labia minora was defined first, then the hypertrophic lateral clitoral hood and labia minora were each removed separately, and finally the junction region was trimmed. Satisfaction questionnaires were administered during follow-ups. RESULTS: Among all 301 patients (602 sides), Type 2 was the most common variation (285 sides, 47.3%). Type 3 variations in 67 patients (105 sides, 17.5%) were identified, and 77.6% of these patients answered the questionnaires 3 months after surgery. For patients with type 3 variations, the satisfaction rate in the 4-step excision group was 91.7%, which was significantly higher than that in the wedge excision group (56.3%) (P = 0.01). The complication rate of the 4-step excision was 2.5%. CONCLUSIONS: Preoperative evaluation based on the new classification facilitated recognition of variations of the CLC, especially of the fused type. The 4-step excision is a simple, effective, and safe approach to treat the fused variation with high satisfaction.

Unique TP53 neoantigen and the immune microenvironment in long-term survivors of Hepatocellular carcinoma.

Neoantigens are T-cell antigens derived from protein-coding mutations in tumor cells. Although neoantigens have recently been linked to anti-tumor immunity in long-term survivors of cancers such as melanoma, their prognostic and immune-modulatory role in many cancer types remain unexplored. We investigate neoantigens in hepatocellular carcinoma (HCC) through a combination of whole exome sequencing (WES), RNA sequencing (RNA-seq), computational bioinformation, and immunohistochemistry. Our analysis reveals that patients carried with TP53 neoantigen have a longer overall survival than others (p = 0.0371) and they showed higher Immune score (p = 0.0441), higher cytotoxic lymphocytes infiltration (p = 0.0428), and higher CYT score (p = 0.0388). In contrast, the prognosis is not associated with TMB and neoantigen load. Our study draws a preliminary conclusion that it is not TMB or neoantigen load but the TP53 specific neoantigen is related to overall survival of HCC patients. We suggest that the TP53 neoantigen may affect prognosis by regulating anti-tumor immunity and that the TP53 neoantigen may be harnessed as potential targets for immunotherapies of HCC.

Half-Sandwich Iridium Complexes Based on ß-Ketoamino Ligands: Preparation, Structure, and Catalytic Activity in Amide Synthesis.

A series of ß-ketoamino-based N,O-chelate half-sandwich iridium complexes with the general formula [Cp*IrClL] have been prepared in good yields. These air-insensitive iridium complexes showed desirable catalytic activity in an amide preparation under mild conditions. A number of amides with diverse substituted groups were furnished in a one-pot reaction with good-to-excellent yields through an amidation reaction of NH2OH·HCl with aldehydes in the presence of these iridium(III) precursors. The excellent catalytic activity, mild reaction conditions, and broad substrate scope gave this type of iridium catalyst potential for use in industry. All of the obtained iridium complexes were well characterized by different spectroscopy techniques. The exact molecular structure of complex 3 has been confirmed by single-crystal X-ray analysis.

Integrated analysis of serum lipid profile for predicting clinical outcomes of patients with malignant biliary tumor.

BACKGROUND: Serum lipids were reported to be the prognostic factors of various cancers, but their prognostic value in malignant biliary tumor (MBT) patients remains unclear. Thus we aim to assess and compare prognosis values of different serum lipids, and construct a novel prognostic nomogram based on serum lipids. METHODS: Patients with a confirmed diagnosis of MBT at our institute from 2003 to 2017 were retrospectively reviewed. Prognosis-related factors were identified via univariate and multivariate Cox regression analyses. Then the novel prognostic nomogram and a 3-tier staging system were constructed based on these factors and further compared to the TNM staging system. RESULTS: A total of 368 patients were included in this study. Seven optimal survival-related factors-TC/HDL >  10.08, apolipoprotein B >  0.9 g/L, lipoprotein> 72 mg/L, lymph node metastasis, radical cure, CA199 > 37 U/mL, and tumor differentiation -were included to construct the prognostic nomogram. The C-indexes in training and validation sets were 0.738 and 0.721, respectively. Besides, ROC curves, calibration plots, and decision curve analysis all suggested favorable discrimination and predictive ability. The nomogram also performed better predictive ability than the TNM system and nomogram without lipid parameters. And the staging system based on nomogram also presented better discriminative ability than TNM system (P < 0.001). CONCLUSIONS: The promising prognostic nomogram based on lipid parameters provided an intuitive method for performing survival prediction and facilitating individualized treatment and was a great complement to the TNM staging system in predicting overall survival.

Germline mutations in 40 cancer susceptibility genes among Chinese patients with high hereditary risk breast cancer.

Multigene panel testing of breast cancer predisposition genes have been extensively conducted in Europe and America, which is relatively rare in Asia however. In this study, we assessed the frequency of germline mutations in 40 cancer predisposition genes, including BRCA1 and BRCA2, among a large cohort of Chinese patients with high hereditary risk of BC. From 2015 to 2016, consecutive BC patients from 26 centers of China with high hereditary risk were recruited (n = 937). Clinical information was collected and next-generation sequencing (NGS) was performed using blood samples of participants to identify germline mutations. In total, we acquired 223 patients with putative germline mutations, including 159 in BRCA1/2, 61 in 15 other BC susceptibility genes and 3 in both BRCA1/2 and non-BRCA1/2 gene. Major mutant non-BRCA1/2 genes were TP53 (n = 18), PALB2 (n = 11), CHEK2 (n = 6), ATM (n = 6) and BARD1 (n = 5). No factors predicted pathologic mutations in non-BRCA1/2 genes when treated as a whole. TP53 mutations were associated with HER-2 positive BC and younger age at diagnosis; and CHEK2 and PALB2 mutations were enriched in patients with luminal BC. Among high hereditary risk Chinese BC patients, 23.8% contained germline mutations, including 6.8% in non-BRCA1/2 genes. TP53 and PALB2 had a relatively high mutation rate (1.9 and 1.2%). Although no factors predicted for detrimental mutations in non-BRCA1/2 genes, some clinical features were associated with mutations of several particular genes.

Stabilizing G-quadruplex DNA by methylazacalix[n]pyridine through shape-complementary interaction.

It is found that G-quadruplexes have important functions in biological systems, such as gene expression. Molecules which can stabilize the G-quadruplex structure may have potential application in regulating the expression of gene. A series of methylazacalix[n]pyridine (n=4, 6, 7, 8, 9) has been tested to stabilize the intermolecular human telomeric G-quadruplex (T12 and H12), intramolecular TBA, c-kit and bcl-2 G-quadruplex by CD denaturation experiments. The results showed that only methylazacalix[6]pyridine (MACP6) can stabilize the intermolecular G-quadruplex formed from the 12bp human telomere. Further studies evidenced that the shape-complementary binding mode was what contributed to the interaction between MACP6 and T12 G-quadruplex.

Synthesis and evaluation of substituted 3-(pyridin-2-yl)benzenesulfonamide derivatives as potent herbicidal agents.

In an attempt to obtain novel candidate compound for weed control, a series of newly substituted 3-(pyridin-2-yl)benzenesulfonamide derivatives 2 were designed and synthesized using compound II7 as a lead compound by Intermediate Derivatization Methods and their herbicidal activities were evaluated. The herbicidal activity assay in greenhouse tests showed several compounds (2g, 2i, 2j, 2k, 2l, 2m, 2n and 2o) exhibited significant herbicidal activity for controlling velvet leaf (Abutilon theophrasti medic.) and youth-and-old age (Zinnia elegans jacq.) at 37.5ga.i./ha. In particular, 2h was found to be the most potential candidate herbicide and was proved higher activity than the lead compound II7. The result of the weed controlling spectrum test showed that 2h could effectively control dayflower (Commelina tuberosa), bur beggarticks (Bidens tripartita linn.), youth-and-old age, cassia tora (Cassiaobtusifolia L.), velvet leaf, purslane (Portulaca oleracea) and false daisy (Eclipta prostrata L.). In addition, the mixture of compound 2h and propanil could produce a synergistic effect and enhance herbicidal activity. The result of the herbicidal activity assay in field test demonstrated that 2h could effectively control dayflower and nightshade (Disambiguation) with long-lasting persistence. The present work indicates that 2h may be a novel compound candidate as a potential herbicide.

Discovery of pyridine-based agrochemicals by using Intermediate Derivatization Methods.

Pyridine-based compounds have been playing a crucial role as agrochemicals or pesticides including fungicides, insecticides/acaricides and herbicides, etc. Since most of the agrochemicals listed in the Pesticide Manual were discovered through screening programs that relied on trial-and-error testing and new agrochemical discovery is not benefiting as much from the in silico new chemical compound identification/discovery techniques used in pharmaceutical research, it has become more important to find new methods to enhance the efficiency of discovering novel lead compounds in the agrochemical field to shorten the time of research phases in order to meet changing market requirements. In this review, we selected 18 representative known agrochemicals containing a pyridine moiety and extrapolate their discovery from the perspective of Intermediate Derivatization Methods in the hope that this approach will have greater appeal to researchers engaged in the discovery of agrochemicals and/or pharmaceuticals.

G4LDB: a database for discovering and studying G-quadruplex ligands.

The G-quadruplex ligands database (G4LDB, http://www.g4ldb.org) provides a unique collection of reported G-quadruplex ligands to streamline ligand/drug discovery targeting G-quadruplexes. G-quadruplexes are guanine-rich nucleic acid sequences in human telomeres and gene promoter regions. There is a growing recognition for their profound roles in a wide spectrum of diseases, such as cancer, diabetes and cardiovascular disease. Ligands that affect the structure and activity of G-quadruplexes can shed light on the search for G-quadruplex-targeting drugs. Therefore, we built the G4LDB to (i) compile a data set covering various physical properties and 3D structure of G-quadruplex ligands; (ii) provide Web-based tools for G-quadruplex ligand design; and (iii) to facilitate the discovery of novel therapeutic and diagnostic agents targeting G-quadruplexes. G4LDB currently contains >800 G-quadruplex ligands with ∼4000 activity records, which, to our knowledge, is the most extensive collection of its kind. It offers a user friendly interface that can meet a variety of data inquiries from researchers. For example, ligands can be searched for by name, molecular properties, structures, ligand activities and so on. Building on the reported data, the database also provides an online ligand design module that can predict ligand binding affinity in real time.

Mechanistic research: Selenium regulates virulence factors, reducing adhesion ability and inflammatory damage of Helicobacter pylori.

BACKGROUND: The pathogenicity of Helicobacter pylori is dependent on factors including the environment and the host. Although selenium is closely related to pathogenicity as an environmental factor, the specific correlation between them remains unclear. AIM: To investigate how selenium acts on virulence factors and reduces their toxicity. METHODS: H. pylori strains were induced by sodium selenite. The expression of cytotoxin-associated protein A (CagA) and vacuolating cytotoxin gene A (VacA) was determined by quantitative PCR and Western blotting. Transcriptomics was used to analyze CagA, CagM, CagE, Cag1, Cag3, and CagT. C57BL/6A mice were infected with the attenuated strains subjected to sodium selenite induction, and H. pylori colonization, inflammatory reactions, and the cell adhesion ability of H. pylori were assessed. RESULTS: CagA and VacA expression was upregulated at first and then downregulated in the H. pylori strains after sodium selenite treatment. Their expression was significantly and steadily downregulated after the 5th cycle (10 d). Transcriptome analysis revealed that sodium selenite altered the levels affect H. pylori virulence factors such as CagA, CagM, CagE, Cag1, Cag3, and CagT. Of these factors, CagM and CagE expression was continuously downregulated and further downregulated after 2 h of induction with sodium selenite. Moreover, CagT expression was upregulated before the 3rd cycle (6 d) and significantly downregulated after the 5th cycle. Cag1 and Cag3 expression was upregulated and downregulated, respectively, but no significant change was observed by the 5th cycle. C57BL/6A mice were infected with the attenuated strains subjected to sodium selenite induction. The extent of H. pylori colonization in the stomach increased; however, sodium selenite also induced a mild inflammatory reaction in the gastric mucosa of H. pylori-infected mice, and the cell adhesion ability of H. pylori was significantly weakened. CONCLUSION: These results demonstrate that H. pylori displayed virulence attenuation after the 10th d of sodium selenite treatment. Sodium selenite is a low toxicity compound with strong stability that can reduce the cell adhesion ability of H. pylori, thus mitigating the inflammatory damage to the gastric mucosa.

Comprehensive aesthetic corrections of gynecomastia using the reproducible safe and minimally invasive surgical strategy.

BACKGROUND: Minimally invasive access and fast recovery are trends of gynecomastia surgery. We placed great importance on liposuction and modified original pull-through technique. The purpose of this study was to present a refined surgical strategy for gynecomastia in grade I and II. METHODS: The refined strategy embraced enhanced liposuction to remove the intraglandular fat sufficiently, followed by open resection of gland using the pull-through and bottom-up technique with adjuvant liposuction in the end. Surgical data were recorded and satisfactory questionnaires with 5-point scales were administered during follow-up. RESULTS: Between January 2017 and May 2022, 165 patients underwent enhanced liposuction combined with the pull-through and bottom-up technique for gland excision. Age ranged from 12 to 56 years. The median length of surgery was 100 min. A median of 300 ml of fat was aspirated and a median of 20.8 g of gland was excised. Seventy-seven patients (46.7%) responded the questionnaires at least 6 months postoperatively, and the average overall satisfaction was 4.68 ± 0.52 points. Thirteen sides of breasts developed complications with a rate of 4.0%. CONCLUSION: Enhanced liposuction combined with pull-through and bottom-up technique proved effective to treat grade I and II gynecomastia with minimal scarring and high satisfaction. The refined strategy was simple and safe, and would obtain optimal outcomes even for inexperienced surgeons.

Controlled interconversion of macrocyclic atropisomers via defined intermediates.

Macrocyclic conformations play a crucial role in regulating their properties. Our understanding of the determinants to control macrocyclic conformation interconversion is still in its infancy. Here we present a macrocycle, octamethyl cyclo[4](1,3-(4,6)-dimethylbenzene)[4]((4,6-benzene)(1,3-dicarboxylate) (OC-4), that can exist at 298 K as two stable atropisomers with C2v and C4v symmetry denoted as C2v-OC-4 and C4v-OC-4, respectively. Heating induces the efficient stepwise conversion of C2v- to C4v-OC-4 via a Cs-symmetric intermediate (Cs-OC-4). It differs from the typical transition state-mediated processes of simple C-C single bond rotations. Hydrolysis and further esterification with a countercation dependence promote the generation of C2v- and Cs-OC-4 from C4v-OC-4. In contrast to C2v-OC-4, C4v-OC-4 can bind linear guests to form pseudo-rotaxans, or bind C60 or C70 efficiently. The present study highlights the differences in recognition behavior that can result from conformational interconversion, as well as providing insights into the basic parameters that govern coupled molecular rotations.

Interaction between intratumoral microbiota and tumor mediates the response of neoadjuvant therapy for rectal cancer.

Background: Previous observations have demonstrated that the response to neoadjuvant chemoradiotherapy (nCRT) is highly variable in patients with locally advanced rectal cancer (LARC). Recent studies focusing on the intratumoral microbiota of colorectal cancer have revealed its role in oncogenesis and tumor progression. However, limited research has focused on the influence of intratumoral microbiota on the nCRT of LARC. Methods: We explored the microbial profiles in the tumor microenvironment of LARC using RNA-seq data from a published European cohort. Microbial signatures were characterized in pathological complete response (pCR) and non-pCR groups. Multi-omics analysis was performed between intratumor microbiomes and transcriptomes. Results: Microbial α and ß diversity were significantly different in pCR and non-pCR groups. Twelve differential microbes were discovered between the pCR and non-pCR groups, six of which were related to subclusters of cancer-associated fibroblasts (CAFs) associated with extracellular matrix formation. A microbial risk score based on the relative abundance of seven differential microbes had predictive value for the nCRT response (AUC = 0.820, p < 0.001). Conclusion: Our study presents intratumoral microbes as potential independent predictive markers for the response of nCRT to LARC and demonstrates the underlying mechanism by which the interaction between intratumoral microbes and CAFs mediates the response to nCRT.

Footprints: Stamping hallmarks of lung cancer with patient-derived models, from molecular mechanisms to clinical translation.

The conventional two-dimensional (2D) tumor cell lines in Petri dishes have played an important role in revealing the molecular biological mechanism of lung cancer. However, they cannot adequately recapitulate the complex biological systems and clinical outcomes of lung cancer. The three-dimensional (3D) cell culture enables the possible 3D cell interactions and the complex 3D systems with co-culture of different cells mimicking the tumor microenvironments (TME). In this regard, patient-derived models, mainly patient-derived tumor xenograft (PDX) and patient-derived organoids discussed hereby, are with higher biological fidelity of lung cancer, and regarded as more faithful preclinical models. The significant Hallmarks of Cancer is believed to be the most comprehensive coverage of current research on tumor biological characteristics. Therefore, this review aims to present and discuss the application of different patient-derived lung cancer models from molecular mechanisms to clinical translation with regards to the dimensions of different hallmarks, and to look to the prospects of these patient-derived lung cancer models.