The involvement and application potential of exosomes in breast cancer immunotherapy.

Breast cancer has a high incidence and a heightened propensity for metastasis. The absence of precise targets for effective intervention makes it imperative to devise enhanced treatment strategies. Exosomes, characterized by a lipid bilayer and ranging in size from 30 to 150 nm, can be actively released by various cells, including those in tumors. Exosomes derived from distinct subsets of immune cells have been shown to modulate the immune microenvironment within tumors and influence breast cancer progression. In addition, tumor-derived exosomes have been shown to contribute to breast cancer development and progression and may become a new target for breast cancer immunotherapy. Tumor immunotherapy has become an option for managing tumors, and exosomes have become therapeutic vectors that can be used for various pathological conditions. Edited exosomes can be used as nanoscale drug delivery systems for breast cancer therapy, contributing to the remodeling of immunosuppressive tumor microenvironments and influencing the efficacy of immunotherapy. This review discusses the regulatory role of exosomes from different cells in breast cancer and the latest applications of exosomes as nanoscale drug delivery systems and immunotherapeutic agents in breast cancer, showing the development prospects of exosomes in the clinical treatment of breast cancer.

LC-MS/MS-Guided Molecular Networking for Targeted Discovery of Undescribed and Bioactive Ophiobolins from Bipolaris eleusines.

An integrated purification procedure through the LC-MS/MS-based molecular networking strategy combined with bioactive evaluation was first ushered for discovering bioactive ophiobolins from Bipolaris eleusines. Ophiobolins were mainly dispersed in five clusters, which were classified based on different ring systems and functional groups. Nine undescribed ophiobolins (1-6 and 9-11) and an undescribed natural product (8) along with two known analogs (7 and 12) were isolated in target. The undescribed structures were characterized by HR-ESI-MS, NMR spectra, and X-ray diffraction experiments. Compounds 3-12 exhibited strong phytotoxic effects on green foxtails by producing visible lesions, and compounds 1-10 and 12 displayed different levels of cytotoxic activities against cancer cell lines B16, Hep G2, and MCF-7, from which the possible structure-activity relationships were then suggested. The results have supported that bioactivity-guided molecular networking is an efficient strategy to expedite the discovery of undescribed bioactive natural products.

Maize intercropping enriches plant growth-promoting rhizobacteria and promotes both the growth and volatile oil concentration of Atractylodes lancea.

In the Atractylodes lancea (A. lancea)-maize intercropping system, maize can promote the growth of A. lancea, but it is unclear whether this constitutes an aboveground or belowground process. In this study, we investigated the mechanisms of the root system interaction between A. lancea and maize using three different barrier conditions: no barrier (AI), nylon barrier (AN), and plastic barrier (AP) systems. The biomass, volatile oil concentration, physicochemical properties of the soil, and rhizosphere microorganisms of the A. lancea plant were determined. The results showed that (1) the A. lancea - maize intercropping system could promote the growth of A. lancea and its accumulation of volatile oils; (2) a comparison of the CK, AI, and AP treatments revealed that it was the above-ground effect of maize specifically that promoted the accumulation of both atractylon and atractylodin within the volatile oils of A. lancea, but inhibited the accumulation of hinesol and ß-eudesmol; (3) in comparing the soil physicochemical properties of each treatment group, intercropping maize acidified the root soil of A. lancea, changed its root soil physicochemical properties, and increased the abundance of the acidic rhizosphere microbes of A. lancea at the phylum level; (4) in an analysis of rhizosphere microbial communities of A. lancea under different barrier systems, intercropping was found to promote plant growth-promoting rhizobacteria (PGPR) enrichment, including Streptomyces, Bradyrhizobium, Candidatus Solibacter, Gemmatirosa, and Pseudolabrys, and the biomass of A. lancea was significantly influenced by PGPR. In summary, we found that the rhizosphere soil of A. lancea was acidified in intercropping with maize, causing the accumulation of PGPR, which was beneficial to the growth of A. lancea.

Bioelectrical impedance spectroscopy can assist to identify the parathyroid gland during thyroid surgery.

Objective: This study aimed to explore the effectiveness of bioelectrical impedance spectroscopy in the identification of parathyroid glands during thyroid surgeries. Method: All patients who received thyroid surgeries at our department from January 2018 to February 2020 were recruited for this study. The bioelectrical impedance spectroscopy analyzer was applied to analyze on following tissues: thyroid tissues, lymph nodes, adipose tissues, and the tissues suspected to be parathyroid glands. Postoperative pathological reports were obtained as the golden standard to compare with the characteristic parameters obtained from bioelectrical impedance spectroscopy. The receiver operating characteristic curve analysis was used to assess the diagnostic value and the selection of the optimal threshold of these parameters from bioelectrical impedance spectroscopy. Results: A total of 512 patients were enrolled in the study and 1898 specimens were measured by the bioelectrical impedance spectroscopy analyzer. There were significant differences in the parameter of f c among parathyroid glands, thyroid tissues, lymph nodes, and adipose tissues (252.2 ± 45.8 vs 144.7 ± 26.1, 491.7 ± 87.4, 602.3 ± 57.3; P<0.001, P<0.001, P<0.001). The area under the receiver operating characteristic curves was 0.993 (95%CI: 0.989-0.996) for f c. When the diagnostic criterion of f c was set at 188.85 kHz~342.55 kHz, the sensitivity and specificity to identify parathyroid glands from lymph nodes and adipose tissues were both 100%. At this f c, the sensitivity and specificity to identify parathyroid glands from thyroid tissues were 91.1% and 99.0%, respectively. Conclusion: In conclusion, bioelectrical impedance spectroscopy could assist to differentiate parathyroid glands from peripheral tissues during thyroid surgeries.

Discovery and preclinical profile of LX-039, a novel indole-based oral selective estrogen receptor degrader (SERD).

We previously described the discovery of a novel indole series compounds as oral SERD for ER positive breast cancer treatment. Further SAR exploration focusing on substitutions on indole moiety of compound 12 led to the discovery of a clinical candidate LX-039. We report herein its profound anti-tumor activity, desirable ER antagonistic characteristics combined with favorable pharmacokinetic and preliminary safety properties. LX-039 is currently in clinical trial (NCT04097756).

Diverse Intercropping Patterns Enhance the Productivity and Volatile Oil Yield of Atractylodes lancea (Thunb.) DC.

Commercial cultivation of the medicinal plant Atractylodes lancea is significantly restricted by low survival rates and reduced yields. Intercropping can reasonably coordinate interspecific interactions, effectively utilize environmental resources, and increase survival and yield. We conducted a field experiment from 2014 to 2016 to analyze the advantages and effects of intercropping on A. lancea survival, growth traits, individual volatile oil content, and total volatile oil content. In addition to A. lancea monoculture (AL), five intercropping combinations were planted: Zea mays L. (ZM) + A. lancea, Tagetes erecta L. (TE) + A. lancea, Calendula officinalis L. (CO) + A. lancea, Glycine max (Linn.) Merr. (GM) + A. lancea, and Polygonum hydropiper L. (PH) + A. lancea. The survival and average rhizome weight of A. lancea was higher in the ZM, CO, and TE treatments than in the monoculture treatment, and the average plant height was higher in all intercropping treatments than in the monoculture. The volatile oil content of A. lancea from the ZM and CO treatments was significantly improved relative to that of monoculture plants. The volatile oil harvest was higher in the ZM, CO, and TE treatments than in the monoculture. We conclude that intercropping is an effective way to increase the survival and yield of A. lancea. Furthermore, intercropping with ZM, CO, and TE increases the harvest of four volatile oils from A. lancea.

Investigations of CO2 Capture from Gas Mixtures Using Porous Liquids.

Porous liquids, a new porous material with fluidity, can be applied in numerous fields, such as gas storage and/or separation. In this work, the separation of binary gas mixtures CO2/N2 and CO2/CH4 with porous liquids was examined by molecular dynamics (MD) simulations. The pure gas adsorption capacity was analyzed with different concentrations of porous liquids. The dependence of the separation effect of a gas mixture on the total pressure and temperature was investigated. Meanwhile, for both CO2/N2 and CO2/CH4 systems, the adsorption and separation effects of porous liquids with a cage:solvent ratio of 1:12 are better than those of 1:91 and 1:170. The results of the spatial distribution function and/or trajectories indicated that porous liquids prefer CO2, leading to the location of CO2 in the channels formed in porous liquids. However, N2 and CH4 are hardly adsorbed into the bulk. The diffusion of gas molecules follows the order of CO2 > N2 (for CO2/N2) and CH4 > CO2 (for CO2/CH4) in the bulk and N2 > CO2 (for CO2/N2) and CH4 > CO2 (for CO2/CH4) at the interface of porous liquids. Upon increasing the concentrations of porous liquids, the working capacities of CO2 show small decreases in CO2/N2 and CO2/CH4 systems, but the sorbent selection parameters are higher in pressure- and temperature-swing adsorption processes. The porous liquid with a cage:solvent ratio of 1:12 is more suitable for the separation of CO2/N2 and CO2/CH4 systems than ratios of 1:91 and 1:170.

A field trials-based authentication study of conventionally and organically grown Chinese yams using light stable isotopes and multi-elemental analysis combined with machine learning algorithms.

In this study, stable isotopes and multi-element signatures combined with chemometrics were used to distinguish conventional and organic Chinese yams based on field trials. Four light stable isotopes δD, δ13C, δ15N, δ18O, and 20 elements (e.g. Li, Na, Mn) were determined, then evaluated using significance analysis and correlation analysis, and modeling of various chemometrics methods. Consequently, the RandomForest model showed the best performance with AUC value of 0.972 and predictive accuracy of 97.3%, and Mn, Cr, Se, Na, δD, As, and δ15N were screened as significant variables. Moreover, many chemical components and antioxidant activity of yam samples were determined spectrophotometrically. The results indicated that organic yams had advantages in secondary metabolites such as polyphenol, flavonoid and saponin; conversely, conventional samples had more primary metabolites like protein and amino acids. Above all, this work provides a beneficial case in the authentication and quality evaluation of conventional and organic yams.

Design, syntheses and evaluations of novel indole derivatives as orally selective estrogen receptor degraders (SERD).

Most estrogen receptor positive (ER +) breast cancers depend on ER signaling pathway to develop. Clinical application of SERD fulvestrant effectively degraded ER, blocked its function and prolonged progression free survival of ER + breast cancer patients. However, current SERD suffers from limited bioavailability, therefore is given as intramuscular (IM) injection. In this paper, we report herein a novel indole series compounds with nanomolar range ER degradation potencies and oral systemic exposures. Selected compounds suppressed tumor growth in vivo in ER + MCF7 breast cancer CDX model via p.o. administration. All those data supported further optimizations of this analog to develop preclinical candidate as oral SERD for ER + breast cancer's treatment.

Discovery of 3-Quinazolin-4(3H)-on-3-yl-2,N-dimethylpropanamides as Orally Active and Selective PI3Kα Inhibitors.

Phosphoinositide 3-kinases (PI3Ks) mediate a series of events related to cell growth, proliferation, survival, and differentiation. Overexpression of PI3Ks can lead to the dysregulation of cell homeostasis and cause tumorigenesis. In this study, rationally designed compounds were investigated as PI3Kα-selective inhibitors. Our efforts culminated in the discovery of a series of quinazolin-4(3H)-one derivatives with 2-substituted-N-methylpropanamide substitutions as PI3Kα-selective inhibitors. The best compound, 10, has PI3Kα enzymatic and cellular IC50 values of 1.8 and 12.1 nM, respectively. It exhibits biochemical selectivities for PI3Kα over PI3Kß/δ/γ of 150/7.72/7.67-fold and cellular selectivities of 115/15.1/>826-fold, respectively. Compound 10 is 59% orally bioavailable with a dose-normalized AUC of 3090 nM. These effects translated into in vivo conditions, as 10 significantly time- and dose-dependently inhibited phosphorylation of Akt in BT-474 subcutaneous xenograft mice and inhibited tumor growth.

Risk Factors for and Prediction Model of Skip Metastasis to Lateral Lymph Nodes in Papillary Thyroid Carcinoma.

BACKGROUND: Cervical lymph node metastasis is a prognostic factor of papillary thyroid carcinoma (PTC). Skip metastasis (central lymph node negative and lateral lymph node positive) of PTC is not uncommon. This study aimed to retrospectively investigate the risk factors for skip metastasis in PTC and develop a prediction model for skip metastasis. METHODS: A total of 745 PTC patients underwent total thyroidectomy and central plus lateral lymph node dissection at the First Affiliated Hospital of Chongqing Medical University from January 2012 to December 2017. Clinicopathological characteristics were collected and analyzed. Univariate and multivariate analyses were performed to detect the risk factors for skip metastasis. A prediction model was established based on the results of multivariate analyses. RESULTS: The skip metastasis rate was 9.7% (72/745). Age > 55 years (OR 2.63, 95% CI 1.34-5.04, p = 0.004), tumor located in the upper portion (OR 4.15, 95% CI 2.30-7.63, p = 0.001), and unilaterality (OR 2.76, 95% CI 1.14-8.23, p = 0.040) were independent risk factors for skip metastasis. Clinically lymph node-negative (cN0) patients with tumor in the upper portion (24.6%, 43/175) had higher possibility of skip metastasis than those of clinically lateral lymph node-positive (cN1b) patients (5.9%, 10/169) (p = 0.001). The area under the receiver operating characteristic curve of prediction model was 0.734 and 0.740 in derivation group and validation group, respectively. However, skip metastasis was not associated with tumor-free survival rate of PTC patients (p = 0.274). CONCLUSION: Age > 55 years, tumor located in the upper portion, and unilaterality may increase the risk of skip metastasis. We developed the first prediction model for skip metastasis based on clinicopathological parameters in PTC patients.

Effect of iron salt type and dosing mode on Fenton-based pretreatment of rice straw for enzymatic hydrolysis.

Fenton-based processes with four different iron salts in two different dosing modes were used to pretreat rice straw (RS) samples to increase their enzymatic digestibility. The composition analysis shows that the RS sample pretreated by the dosing mode of iron salt adding into H2O2 has a much lower hemicellulose content than that pretreated by the dosing mode of H2O2 adding into iron salt, and the RS sample pretreated by the chloride salt-based Fenton process has a much lower lignin content and a slightly lower hemicellulose content than that pretreated by the sulphate salt-based Fenton process. The higher concentration of reducing sugar observed on the RS sample with lower lignin and hemicellulose contents justifies that the Fenton-based process could enhance the enzymic hydrolysis of RS by removing hemicellulose and lignin and increasing its accessibility to cellulase. FeCl3·6H2O adding into H2O2 is the most efficient Fenton-based process for RS pretreatment.

Comparison of epidemiological features, clinicopathological features, and treatments between premenopausal and postmenopausal female breast cancer patients in western China: a retrospective multicenter study of 15,389 female patients.

Premenopausal and postmenopausal breast cancers are considered different types. Thus, this study aimed to explore differences in risk factors, epidemiological features, clinicopathological features, and treatment modes of premenopausal breast cancer compared to postmenopausal patients in western China. This was a hospital-based, retrospective, multicenter epidemiological study of patients with breast cancer. Using the Western China Clinical Cooperation Group database, we obtained the records of 15,389 female breast cancers between January 2010 and April 2017. These patients were divided into premenopausal and postmenopausal groups, and their risk factors, epidemiological feature, clinicopathological features, and treatment modes were compared. Chi-square tests, t-test, and the multivariate logistic regression analysis were applied for statistical analysis. A total of 8395 patients were categorized as premenopausal, and 6994 patients were categorized as postmenopausal. Their risk factors, epidemiological features, clinicopathological features, and treatment modes were compared. Premenopausal patients with breast cancer had a greater tumor diameter at diagnosis (P = 0.008); higher rates of estrogen receptor (ER) expression (P < 0.0001), progesterone receptor (PR) expression (P < 0.0001), negative human epidermal growth factor receptor 2 (HER2) expression (P = 0.015), and negative P53 expression (P < 0.0001); and higher proportions of receiving breast-conserving surgery and breast reconstruction (P < 0.0001), chemotherapy (P < 0.0001), radiotherapy (P < 0.0001), and endocrine therapy (P < 0.0001). The ethnicity, age at menarche, marital status, number of pregnancies, and number of births were the risk factors for age at diagnosis of breast cancer before or after menopause in western China. We found that the fall in the fertility rate, early menarche age, married, and less breastfeeding might have increased the possibility of premenopausal breast cancer. Significant differences exist in the tumor size, hormone receptor state, HER2 expression, epidemiological features, and treatment modes between premenopausal and postmenopausal female breast cancer patients in western China. Its further implementation requires prospective clinical testing.

Livin participates in resistance to trastuzumab therapy for breast cancer through ERK1/2 and AKT pathways and promotes EMT-like phenotype.

Trastuzumab resistance has emerged as a major issue in anti-human epidermal growth factor receptor-2 (HER2) therapy for breast cancers. The cell lines maintain overexpression of HER2. Upon treatment with trastuzumab, R-SKBR3 and R-BT474 cell lines displayed an increased growth rate and invasiveness, accompanied by activation of the ERK1/2 and AKT signaling pathways, and also a parental EMT-like transition (epithelial-mesenchymal transition) was promoted, with increases in N-cadherin, vimentin, and fibronectin and a decrease in E-cadherin. A further investigation found that livin played a key role in the development of trastuzumab resistance. Knockdown of the expression of livin by livin-shRNA3 in R-SKBR3 and R-BT474 cells decreased ERK1/2 and AKT, resensitized the resistant cells to the therapeutic activities of trastuzumab by inducing growth arrest, inhibition of proliferation, and G1-S cell cycle checking in the presence of the antibody, and they also exhibited an EMT-like transition (epithelial-mesenchymal transition), with a decrease in N-cadherin and an increase in E-cadherin, and the cell invasiveness was inhibited in response to the downregulation of livin. Conversely, SKBR3 and BT474 cells that had been stably transfected with pcDNA3.1-livin underwent promotion of an EMT-like transition and displayed a significant decrease in E-cadherin and increases in N-cadherin, vimentin, and fibronectin, and ectopic expression of livin in HER2-overexpressing breast cancer cells conferred resistance to trastuzumab. In vivo, the administration of livin AS (antisense oligonucleotides) restored sensitivity to trastuzumab in resistant breast cancer xenografts via the ERK1/2 and AKT signaling pathways. Patients with livin-overexpressing breast cancers exhibited significantly poorer responses to trastuzumab-based therapy than those with normal livin levels. In summary, our data suggest that the upregulation of livin activates the ERK1/2 and AKT signaling pathways and promotes an EMT-like transition. This could be an important mechanism that leads to trastuzumab resistance in HER2-overexpressing breast cancer cells.

Quorum-sensing contributes to virulence, twitching motility, seed attachment and biofilm formation in the wild type strain Aac-5 of Acidovorax citrulli.

Acidovorax citrulli is a seed-borne pathogen causing bacterial fruit blotch of cucurbits including melon and watermelon. We investigated the roles of quorum sensing in the wild-type group II strain Aac-5 of A. citrulli by generating aacR and aacI knockout mutants and their complementation strains. We found that twitching motility and virulence were reduced, but biofilm formation and seed attachment were increased significantly in the two mutants as compared to the wild type strain. Deletion of aacR and aacI, however, had no effect on swimming motility and polar flagella formation of Aac-5. Furthermore, deletion of aacR resulted in reduced gene expression of hrpE, hrcN and pilT, while deletion of aacI affected only the expression of hrpE and pilT, not hrcN.

Genome Sequence of a Pseudomonas syringae pv. tabaci Strain, yuexi-1, Causing Wildfire Disease in Tobacco.

We determined the draft genome sequence of the Pseudomonas syringae pv. tabaci strain yuexi-1. It was isolated from tobacco sample of yuexi-1, Sichuan province, China, by our laboratory. The genome contains 6,232,497 bp and has a G+C content of 58.2 mol%.