Machine learning based on metabolomics unveils neutrophil extracellular trap-related metabolic signatures in non-small cell lung cancer patients undergoing chemoimmunotherapy.

BACKGROUND: Non-small cell lung cancer (NSCLC) is the primary form of lung cancer, and the combination of chemotherapy with immunotherapy offers promising treatment options for patients suffering from this disease. However, the emergence of drug resistance significantly limits the effectiveness of these therapeutic strategies. Consequently, it is imperative to devise methods for accurately detecting and evaluating the efficacy of these treatments. AIM: To identify the metabolic signatures associated with neutrophil extracellular traps (NETs) and chemoimmunotherapy efficacy in NSCLC patients. METHODS: In total, 159 NSCLC patients undergoing first-line chemoimmunotherapy were enrolled. We first investigated the characteristics influencing clinical efficacy. Circulating levels of NETs and cytokines were measured by commercial kits. Liquid chromatography tandem mass spectrometry quantified plasma metabolites, and differential metabolites were identified. Least absolute shrinkage and selection operator, support vector machine-recursive feature elimination, and random forest algorithms were employed. By using plasma metabolic profiles and machine learning algorithms, predictive metabolic signatures were established. RESULTS: First, the levels of circulating interleukin-8, neutrophil-to-lymphocyte ratio, and NETs were closely related to poor efficacy of first-line chemoimmunotherapy. Patients were classed into a low NET group or a high NET group. A total of 54 differential plasma metabolites were identified. These metabolites were primarily involved in arachidonic acid and purine metabolism. Three key metabolites were identified as crucial variables, including 8,9-epoxyeicosatrienoic acid, L-malate, and bis(monoacylglycerol)phosphate (18:1/16:0). Using metabolomic sequencing data and machine learning methods, key metabolic signatures were screened to predict NET level as well as chemoimmunotherapy efficacy. CONCLUSION: The identified metabolic signatures may effectively distinguish NET levels and predict clinical benefit from chemoimmunotherapy in NSCLC patients.

Self-Illuminating Nanoagonist Simultaneously Induces Dual Cell Death Pathways via Death Receptor Clustering for Cancer Therapy.

Inducing death receptor 5 (DR5) clustering holds particular promise in tumor-specific therapeutics because it could trigger an apoptotic cascade in cancerous cells. Herein, we present a tumor microenvironment H2O2-responsive self-illuminating nanoagonist, which could induce dual tumor cell death pathways through enhancing DR5 clustering. By conjugating DR5 ligand peptides onto the surfaces of self-illuminating nanoparticles with cross-linking capacity, this strategy not only provides scaffolds for ligands to bind receptors but also cross-links them through photo-cross-linking. This strategy allows for efficient activation of DR5 downstream signaling, initiating the extrinsic apoptosis pathway and immunogenic cell death of tumor cells, and contributes to improved tumor-specific immune responses, resulting in enhanced antitumor efficacy and minimized systemic adverse effects.

Study on blood pressure rhythm in hypertensive patients withdeficiency syndrome and a random forest model for predicting hypertension withdeficiency syndrome.

OBJECTIVE: To investigate blood pressure rhythm (BPR) in Yin deficiency syndrome of hypertension (YDSH) patients and develop a random forest model for predicting YDSH. METHODS: Our study was consistent with technical processes and specification for developing guidelines of Evidence-based Chinese medicine clinical practice (T/CACM 1032-2017). We enrolled 234 patients who had been diagnosed with primary hypertension without antihypertensive medications prior to the enrollment. All participants were divided into Yin deficiency group (YX, n = 74) and non-Yin deficiency group (NYX, n = 160). Participants were professionally grouped by three experienced chief Traditional Chinese Medicine (TCM) physicians according to four examinations (i.e., inspection, listening and smelling, inquiry and palpation). We collected data on 24 h ambulatory blood pressure monitoring (ABPM) and YDSH rating scale. We divided 24 h of a day into 12 two-hour periods [Chen-Shi (7:00-9:00), Si-Shi (9:00-11:00), Wu-Shi (11:00-13:00), Wei-Shi (13:00-15:00), Shen-Shi (15:00-17:00), You-Shi (17:00-19:00), Xu-Shi (19:00-21:00), Hai-Shi (21:00-23:00), Zi-Shi (23:00-1:00), Chou-Shi (1:00-3:00), Yin-Shi (3:00-5:00), Mao-Shi (5:00-7:00)] according to the theory of "midnight-midday ebb flow". We used random forest to build the diagnostic model of YDSH, with whether it was Yin deficiency syndrome as the outcome. RESULTS: Compared with NYX group, YX group had more female participants with older age, lower waist circumference, body mass index (BMI), diastolic blood pressure (DBP), and smoking and drinking rate (all P ＜ 0.05). The YDSH rating scores of YX group [28.5 (21.0-36.0)] were significantly higher than NYX group [13.0 (8.0-22.0)] (P < 0.001), and the typical symptoms of YX group included vexing heat in the chest, palms and soles, dizziness, dry eyes, string-like and fine pulse, soreness and weakness of lumbus and knees, palpitations, reddened cheeks, and tinnitus (all P < 0.05). The ratio of non-dipper hypertension in YX group was higher than in NYX group (56.9% vs 44.4%, P = 0.004). Compared with NYX group, 24 h DBP standard deviation (SD), nighttime DBP SD, Si-Shi DBP, Si-Shi mean arterial pressure (MAP), Hi-Shi systolic blood pressure (SBP), Hi-Shi DBP, Hi-Shi MAP, Zi-Shi SBP, Zi-Shi DBP, Zi-Shi MAP, Chou-Shi SBP SD, Chou-Shi DBP SD, Chou-Shi SBP coefficient of variation (CV) were lower in YX group (all P ＜ 0.05). Binary Logistic Regression analysis showed that the diagnosis of YDSH was positively correlated with age, heart rate, YDSH rating scores, and four TCM symptoms including vexing heat in the chest, palms and soles, string-like and fine pulse, soreness and weakness of lumbus and knees, and reddened cheeks (all P ＜ 0.05), but was negatively correlated with smoking (P﹥0.05). In addition, the diagnosis of YDSH was positively correlated with daytime SBP SD, nighttime SBP SD, nighttime SBP CV, and Hi-Shi SBP CV, but was negatively correlated with 24 h SBP CV, daytime DBP SD, nighttime DBP SD, and Hi-Shi DBP (all P ＜ 0.05). Hi-Shi SBP CV had independent and positive correlation with the diagnosis of YDSH after adjusting the variables of age, gender, course of hypertension, BMI, waist circumference, SBP, DBP, heart rate, smoking and drinking (P = 0.029). Diagnostic model of YDSH was established and verified based on the random forest. The results showed that the calculation accuracy, specificity and sensitivity were 77.3%, 77.8% and 76.9%, respectively. CONCLUSION: The BPR was significantly attenuated in YDSH patients, including lower 24 h DBP SD and nighttime DBP SD, and Hi-Shi SBP CV is independently correlated with the diagnosis of YDSH. The prediction accuracy of diagnosis model of YDSH based on the random forest was good, which could be valuable for clinicians to differentiate YDSH and non-Yin deficiency patients for more effective hypertensive treatment of TCM.

Multi-omics reveals the molecular mechanism of the combined toxic effects of PFOA and 4-HBP exposure in MCF-7 cells and the key player: mTORC1.

With the discovery of evidence that many endocrine-disrupting chemicals (EDCs) in the environment influence human health, their toxic effects and mechanisms have become a hot topic of research. However, investigations into their endocrine-disrupting toxicity under combined binary exposure, especially the molecular mechanism of combined effects, have rarely been documented. In this study, two typical EDCs, perfluorooctanoic acid (PFOA) and 4-hydroxybenzophenone (4-HBP), were selected to examine their combined effects and molecular mechanism on MCF-7 cell proliferation at environmentally relevant exposure concentrations. We have successfully established a model to evaluate the binary combined toxic effects of endocrine disruptors, presenting combined effects in a simple and direct way. Results indicated that the combined effect changed from additive to synergistic from 1.25 × 10-8 M to 4 × 10-7 M. Metabolomics analyses suggested that exposure to PFOA and 4-HBP caused significant alterations in purine metabolism, arginine, and proline metabolism and had superimposed influences on metabolism. Enhanced combined effects were observed in glycine, serine, and threonine metabolic pathways compared to exposure to PFOS and 4-HBP alone. Additionally, the differentially expressed genes (DEGs) are primarily involved in Biological Processes, especially protein targeting the endoplasmic reticulum, and significantly impact the oxidative phosphorylation and thermogenesis-related KEGG pathway. By integrating metabolome and transcriptome analyses, PFOA and 4-HBP regulate purine metabolism, the TCA cycle, and endoplasmic reticulum protein synthesis in MCF-7 cells via mTORC1, which provides genetic material, protein, and energy for cell proliferation. Furthermore, molecular docking confirmed the ability of PFOA and 4-HBP to stably bind the estrogen receptor, indicating that they have different binding pockets. Collectively, these findings will offer new insights into understanding the mechanisms by which EDCs produce combined toxicity.

Proposals for the delineation of neck clinical target volume for definitive Radiation therapy in patients with oral/ oropharyngeal squamous cell cancer based on lymph node distribution.

PURPOSE/OBJECTIVE(S): To establish the distribution pattern of cervical lymph node metastasis (LNM) and propose optimized clinical target volume (CTV) boundaries specific to oral/ oropharyngeal squamous cell cancer (OSCC/OPSCC). MATERIALS/METHODS: 531 patients with pathologically confirmed OSCC/OPSCC were enrolled from January 2013 to June 2022. Patients were stratified into two groups based on the minimal distance from the lesion's edge to the body's midline: ≤1 cm or > 1 cm. The geometric center of cervical metastatic LN was marked on a template CT. LN distribution probability maps were established. The relationships between the LN distribution and consensus guidelines were analyzed to propose modifications for CTV boundaries specific to OSCC/OPSCC. RESULTS: A total of 1962 positive LNs were enrolled. Compared with the > 1 cm group, the ≤ 1 cm group has following feature tendencies: male smokers, younger, median organs, large gross lesion, infiltrative growth pattern, contralateral LNM. The most frequently involved level of LNM was ipsilateral II, but ipsilateral Ib had the highest involvement rate in the > 1 cm OSCC group. In addition, tongue cancer had a higher incidence of LN extranodal extension (ENE), which mainly distributes in ipsilateral level II. The skip metastasis was prone to from level III to Vb (3.5 %) in LN(+)/ENE (-), and level Ib to VIa (3.7 %) in LN(+)/ENE (+). Accordingly, we proposed the following modifications: 1. only including lateral and posterior margin of submandibular gland within 5 mm; 2. retracting posterior boundary of level II to front edge of levator scapula muscle, and descending the upper boundary to transverse process of C2 vertebra only for OSCC; 3. including posterior third of thyroglossal muscle or anterior edge of sternocleidomastoid muscle; 4. sparing level Va in case of only level II involvement; 5. including upper area of the thyroid cartilage plate in case of level Ib LN(+)/ENE (+); 6. sparing level VIIa is considered. CONCLUSION: This is the first description of LN topographic spread patterns for OSCC/OPSCC. Modified CTV for prophylactic irradiation was proposed to spare the organs at risk and minimize adverse effects.

Radiofrequency radiation reshapes tumor immune microenvironment into antitumor phenotype in pulmonary metastatic melanoma by inducing active transformation of tumor-infiltrating CD8+ T and NK cells.

Immunosuppression by the tumor microenvironment is a pivotal factor contributing to tumor progression and immunotherapy resistance. Priming the tumor immune microenvironment (TIME) has emerged as a promising strategy for improving the efficacy of cancer immunotherapy. In this study we investigated the effects of noninvasive radiofrequency radiation (RFR) exposure on tumor progression and TIME phenotype, as well as the antitumor potential of PD-1 blockage in a model of pulmonary metastatic melanoma (PMM). Mouse model of PMM was established by tail vein injection of B16F10 cells. From day 3 after injection, the mice were exposed to RFR at an average specific absorption rate of 9.7 W/kg for 1 h per day for 14 days. After RFR exposure, lung tissues were harvested and RNAs were extracted for transcriptome sequencing; PMM-infiltrating immune cells were isolated for single-cell RNA-seq analysis. We showed that RFR exposure significantly impeded PMM progression accompanied by remodeled TIME of PMM via altering the proportion and transcription profile of tumor-infiltrating immune cells. RFR exposure increased the activation and cytotoxicity signatures of tumor-infiltrating CD8+ T cells, particularly in the early activation subset with upregulated genes associated with T cell cytotoxicity. The PD-1 checkpoint pathway was upregulated by RFR exposure in CD8+ T cells. RFR exposure also augmented NK cell subsets with increased cytotoxic characteristics in PMM. RFR exposure enhanced the effector function of tumor-infiltrating CD8+ T cells and NK cells, evidenced by increased expression of cytotoxic molecules. RFR-induced inhibition of PMM growth was mediated by RFR-activated CD8+ T cells and NK cells. We conclude that noninvasive RFR exposure induces antitumor remodeling of the TIME, leading to inhibition of tumor progression, which provides a promising novel strategy for TIME priming and potential combination with cancer immunotherapy.

Sialic Acid-Modified O-GlcNAc Transferase Inhibitor Liposome Presents Antitumor Effect in Hepatocellular Carcinoma.

O-linked-N-acetylglucosaminylation (O-GlcNAcylation) plays a key role in hepatocellular carcinoma (HCC) development, and the inhibition of O-GlcNAcylation has therapeutic potential. To decrease the systemic adverse events and increase targeting, we used sialic acid (SA)-decorated liposomes loaded with OSMI-1, an inhibitor of the O-GlcNAcylation, to further improve the anti-HCC effect. Fifty pairs of HCC tissue samples and the cancer genome atlas database were used to analyze the expression of O-GlcNAc transferase (OGT) and its effects on prognosis and immune cell infiltration. OSMI-1 cells were treated with SA and liposomes. Western blotting, immunofluorescence, cell proliferation assay, flow cytometry, enzyme-linked immunosorbent assay, immunohistochemistry, and tumorigenicity assays were used to investigate the antitumor effect of SA-modified OSMI-1 liposomes in vitro and in vivo. OGT was highly expressed in HCC tissues, negatively correlated with the degree of tumor infiltration of CD8+ and CD4+T cells and prognosis, and positively correlated with the degree of Treg cell infiltration. SA-modified OSMI-1 liposome (OSMI-1-SAL) was synthesized with stable hydrodynamic size distribution. Both in vitro and in vivo, OSMI-1-SAL exhibited satisfactory biosafety and rapid uptake by HCC cells. Compared to free OSMI-1, OSMI-1-SAL had a stronger capacity for suppressing the proliferation and promoting the apoptosis of HCC cells. Moreover, OSMI-1-SAL effectively inhibited tumor initiation and development in mice. OSMI-1-SAL also promoted the release of damage-associated molecular patterns, including anticalreticulin, high-mobility-group protein B1, and adenosine triphosphate, from HCC cells and further promoted the activation and proliferation of the CD8+ and CD4+T cells. In conclusion, the OSMI-1-SAL synthesized in this study can target HCC cells, inhibit tumor proliferation, induce tumor immunogenic cell death, enhance tumor immunogenicity, and promote antitumor immune responses, which has the potential for clinical application in the future.

Morphophylogenetic evidence reveals four new fungal species within Tetraplosphaeriaceae (Pleosporales, Ascomycota) from tropical and subtropical forest in China.

Tetraplosphaeriaceae (Pleosporales, Ascomycota) is a family with many saprobes recorded from various hosts, especially bamboo and grasses. During a taxonomic investigation of microfungi in tropical and subtropical forest regions of Guizhou, Hainan and Yunnan provinces, China, several plant samples were collected and examined for fungi. Four newly discovered species are described based on morphology and evolutionary relationships with their allies inferred from phylogenetic analyses derived from a combined dataset of LSU, ITS, SSU, and tub2 DNA sequence data. Detailed illustrations, descriptions and taxonomic notes are provided for each species. The four new species of Tetraplosphaeriaceae reported herein are Polyplosphaeriaguizhouensis, Polyplosphaeriahainanensis, Pseudotetraploayunnanensis, and Tetraploahainanensis. A checklist of Tetraplosphaeriaceae species with available details on their ecology is also provided.

Long-term survival with a combination of immunotherapy, anti-angiogenesis, and traditional radiotherapy in brain metastatic small cell lung cancer: a case report.

Purpose: Brain metastases (BMs) are common in Small Cell Lung Cancer (SCLC), but the prognosis is very poor. Currently, there is no standard of care on what constitutes optimal treatment, and there is no consensus regarding maintenance therapy in SCLC. Case description: We report the case of a 55-year-old man with advanced SCLC. After the initial diagnosis, he received routine chemotherapy and chest radiotherapy but developed brain metastases with 2 lesions seven months later. We used an effective combination therapy consisting of the antiangiogenic inhibitor, Anlotinib and whole-brain radiotherapy. We then administered anti-PD-L1 immunotherapy Atezolizumab in combination with Anlotinib as long-term maintenance therapy. Twelve months later, there was a progression in one of the brain metastases. The patient underwent further stereotactic radiotherapy (SRT) for the lesion. However, after four months of treatment with SRT, the lesion began to gradually grow in size. The patient underwent surgical resection of the lesion, which confirmed radioactive brain necrosis. After a full 3-year course of anti-PD-L1 therapy, the patient discontinued immunotherapy and was administered only Anlotinib as maintenance. At the time of writing up this report, the patient was alive and the overall survival reached 41 months after the onset of BM. Conclusion: This indicated a potential synergistic effect of combined immunotherapy and antiangiogenic targeted therapy with local radiotherapy in patients with BM-SCLC and can provide directions for future clinical decisions.

Eosinophil dynamics during chemo-radiotherapy correlate to clinical outcome in stage â ¡-â £a nasopharyngeal carcinoma patients: Results from a large cohort study.

BACKGROUND AND PURPOSE: We investigated the dynamics of eosinophil depletion during definitive concurrent chemo-radiotherapy (CCRT) and their association with the prognosis of stage Ⅱ-Ⅳa nasopharyngeal carcinoma (NPC) patients. MATERIALS AND METHODS: Fuzzy C-means algorithm (FCMA) assessed longitudinal trends in circulating eosinophil counts (CECs) of 1225 patients throughout the period of radical radiotherapy. The prognostic impact on patients' survival was evaluated with Kaplan-Meier analysis and Cox proportional risk model was used to determine the hazard ratio for adverse prognostic effects in grades of eosinophil depletion. The interactive effect of pre-treatment CECs and CCRT on outcomes was evaluated using HRs within the framework of Cox regression models. RESULTS: Three grades of eosinophil depletion, as defined by the interaction between dynamic types of CECs in the period of treatment and the value of CECs at the termination of treatment, significantly stratified the poor prognosis in terms of progression-free survival (PFS), overall survival (OS), and distant metastasis-free survival (DMFS) [1.57-fold (P = 0.001), 1.69-fold (P = 0.007), and 1.51-fold (P = 0.019) for G1, 2.4-fold (P < 0.001), 2.76-fold (P < 0.001), and 2.31-fold (P < 0.001) for G2, as compared with G0]. Furthermore, high levels of pre-treatment CECs acted as the strongest protective factor against severe depletion grade (G0 vs. G2, HR = 0.20, P = 0.005; G1 vs. G2, HR = 0.14, P < 0.001). However, compared with radiotherapy alone, the benefit from CCRT was attenuated in patients with high pre-treatment CECs. CONCLUSIONS: CECs reduction after treatment in patients with NPC may be helpful in the clinical setting to aid in assessing the prognosis for standard treatment of NPC.

[Comparison of clinical efficacy between closed reduction combined with semi-circular external fixator and minimally invasive percutaneous plate osteosynthesis (MIPPO) in the treatment of middle and distal tibia fractures].

OBJECTIVE: To compare the clinical efficacy between closed reduction combined with semi-circular external fixator and minimally invasive percutaneous plate osteosynthesis (MIPPO) in the treatment of middle anddistal tibia fractures. METHODS: The clinical data of sixty patients with middle and distal tibia fractures admitted between January 2019 and November 2022, were retrospectively analyzed. These patients were categorized into external fixation group (n=30) and internal fixation group (n=30). There were 18 males and 12 females in the external fixation group, with an average age of (49.29±2.35) years old. Among them, 14 patients presented with fractures on the left side, and 16 patients presented with fractures on the right side. Closed reduction, arched wire, and semi-circular external fixator were used for treatment. There were 20 males and 10 females in the internal fixation group, with an average age of (48.96±1.87) years old. Among them, 15 patients presented with fractures on the left side, and 15 patients presented with fractures on the right side. MIPPO technique was used for the treatment. Perioperative parameters, including time injury to surgery, surgical duration, incision length, intraoperative bleeding, time to active activity, and incision healing level, were compared between the two groups. Clinical outcomes were also assessed, including Johner-Wruhs scores, time to minimum pain-adapted full weight-bearing, visual analog scale (VAS), SF-36 scale, and complications. RESULTS: The external fixation group exhibited a significantly shorter incision length (1.36±0.86) cm and lower intraoperative bleeding (10.83±5.73) ml compared to the internal fixation group (12.74±3.12) cm and (86.47±8.90) ml, respectively(P<0.05). The postoperative active activity time (1.50±0.54) days and minimum pain-adapted full weight-bearing activity time(108.87±3.43) days in the external fixation group were slightly delayed than the internal fixation group(1.15±0.98) days and (105.27±3.68) days, respectively(P<0.05). Over a mean postoperative follow-up duration of (6.23±1.89) months, both groups showed improved VAS and SF-36 scale scores. There were no statistically significant differences in VAS and SF-36 scale scores 1, 3, 6 months post-operatively between the two groups(P>0.05). The intraoperative surgical time in the external fixation group (35.42±9.31) minutes was shorter than that in the internal fixation group(74.22±7.81) minutes (P<0.05). There was no intraoperative vascular or nerve injury, nor postoperative skin necrosis in the external fixation group. However, skin necrosis was observed in 6 patientsin the internal fixation group, representing a statistically significant difference (P<0.05). CONCLUSION: Both external fixation and plate internal fixation are effective methods for the treatment of middle and distal tibia fractures. External fixation exhibits the advantage of less surgical trauma and a lower incidence of complications.

A photo-activable nano-agonist for the two-signal model of T cell in vivo activation.

The two-signal model of T cell activation has helped shape our understanding of the adaptive immune response for over four decades. According to the model, activation of T cells requires a stimulus through the T cell receptor/CD3 complex (signal 1) and a costimulatory signal 2. Stimulation of activatory signals via T cell agonists has thus emerged. However, for a robust T cell activation, it necessitates not only the presence of both signal 1 and signal 2, but also a high signaling strength. Herein, we report a photo-activable nano-agonist for the two-signal model of T cell in vivo activation. A UV-crosslinkable polymer is coated onto upconversion nanoparticles with satisfactory NIR-to-UV light conversion efficiency. Then dual signal molecules, i.e., signal 1 and signal 2, are conjugated to the polymer end to yield the photo-activable T cell nano-agonist. In melanoma and breast cancer models, photo-activable nano-agonist could bind onto corresponding activatory receptors on the surface of T cells, but has limited activity without the application of NIR light (absence of photo-crosslinking of receptors and consequently a poor signaling strength). While when the NIR light is switched on locally, T cells in tumor are remarkably activated and kill tumor cells effectively. Moreover, we do not observe any detectable toxicities related to the photo-activable nano-agonist. We believe with two activatory signals being simultaneously strengthened by local photo-switched crosslinking, T cells realize a robust and selective activation in tumor and, consequently contribute to an enhanced and safe tumor immunotherapy.

Study on the Relationship Between Differentially Expressed Proteins in Breast Cancer and Lymph Node Metastasis.

INTRODUCTION: Lymph node metastasis is a cause of poor prognosis in breast cancer. Mass spectrometry-based proteomics aims to map the protein landscapes of biological samples and profile tumors more comprehensively. Here, proteomics was employed to identify differentially expressed proteins (DEPs) that were associated with lymph node metastasis. METHODS: Tandem mass tag (TMT) quantitative proteomic approaches were applied for extensive profiling of conditioned medium of MDA-MB-231 and MCF7 cell lines and serums of patients who did or did not have lymph node metastasis, and DEPs were analyzed by bioinformatics. Furthermore, potential secreted or membrane proteins MUC5AC, ITGB4, CTGF, EphA2, S100A4, PRDX2, and PRDX6 were selected for verification in 114 tissue microarray samples of breast cancer using the immunohistochemical method. The relevant data was analyzed and processed by independent sample t test, chi-square test, or Fisher's exact test using SPSS 22.0 software. RESULTS: In the conditioned medium of MDA-MB-231 cell lines, 154 proteins were upregulated, while 136 were downregulated compared to those of MCF7. In the serum of patients with breast cancer and lymph node metastasis, 17 proteins were upregulated, and 5 proteins were downregulated compared to those without lymph node metastasis. Furthermore, according to tissue verification, CTGF, EphA2, S100A4, and PRDX2 were associated with breast cancer lymph node metastasis. CONCLUSION: Our study provides a new perspective for the understanding of the role of DEPs (especially CTGF, EphA2, S100A4, and PRDX2) in the development and metastasis of breast cancer. They could become potential diagnostic and prognostic biomarkers and therapeutic targets.

Multiomics reveals new biomarkers and mechanistic insights into the combined toxicity effects of 2,2',4,4',5,5'-hexachlorobiphenyl and atrazine exposures in MCF-7 cells.

Humans are constantly exposed to complicated chemical mixtures from the environment and food rather than being exposed to a single pollutant. The underlying mechanisms of the complicated combined toxicity of endocrine disrupting chemicals (EDCs) are still mainly unexplored. In this study, two representative EDCs, 2,2',4,4',5,5'-hexachlorobiphenyl (PCB153) and atrazine (ATZ), were selected to explore their combined effects on MCF-7 cell proliferation at environmental exposure concentrations by an integrated analysis of metabolomics and transcriptomics. The results showed that 1 µM ATZ and PCB153 combined exposure significantly accelerated MCF-7 cell growth by 18.2%. More than 400 metabolites detected by UHPLC-QTOF/MS were used to observe metabolism differences induced by binary mixtures. Metabolomics analysis verified that ATZ and PCB153 exposure alone or in combination could have an additive effect on metabolism and induce significant disruption to glycolysis, purine metabolism and the TCA cycle, which provide energy demand and biosynthetic substrates for cell proliferation. Compared to PCB153 and ATZ exposure alone, a combined effect was observed in purine and pyrimidine metabolic pathways. Hexokinase 3 (HK3) and cytochrome P450 19 subfamily A1 (CYP19A1) were identified as differentially expressed genes based on transcriptomic analysis. By integrating metabolome and transcriptome analysis, the proliferation effects of ATZ and PCB153 were induced at low doses in MCF-7 cells through potential interference with the downstream transcription signaling of CYP19A1. Furthermore, molecular docking indicated that PCB153 and ATZ directly affected CYP19A1. Altogether, the regulation of pivotal metabolites and differentially expressed genes could provide helpful information to reveal the mechanism by which PCB153 and ATZ affect MCF-7 cell proliferation.

Correlation between gene mutation status and clinicopathologic features in early multiple primary lung cancer.

Objective: To understand the characteristics of genetic mutation in multiple primary lung cancer so as to guide clinical decisions in targeted therapy. Methods: We analyzed a total of 265 tumors from 111 patients who underwent surgery for multiple lung cancers. Individual tumors were subjected to histological evaluation and gene mutation analysis using ABI 7500 Fluorescence quantitative PCR. Results: In this study, we analyzed demographic and clinical parameters such as age, gender, smoking, alcohol consumption, pathological type, number of nodules, and other details of 111 patients with early multiple primary lung cancer. We also compared the clinicopathologic characteristics of different populations based on the gene mutation status of pulmonary nodules. Subsequently, we performed a clinicopathological analysis of all 265 pulmonary nodules from these patients. Results showed significant differences in clinicopathological features of pulmonary nodules in different genetic mutations. Conclusion: This study revealed the gene mutation characteristics and clinicopathological features in early multiple primary lung cancer. We found that the gene mutation status between different nodules in patients with early multiple primary lung cancer was inconsistent in most cases. Therefore, the use of targeted therapy based on the genetic sequencing of only one nodule, is unreliable. We hope this study can be helpful in guiding clinical treatment decisions.

New Guaiane-Type Sesquiterpenoids Biscogniauxiaols A-G with Anti-Fungal and Anti-Inflammatory Activities from the Endophytic Fungus Biscogniauxia Petrensis.

Seven undescribed guaiane-type sesquiterpenoids named biscogniauxiaols A-G (1-7) were isolated from the endophytic fungus Biscogniauxia petrensis on Dendrobium orchids. Their structures were determined by extensive spectroscopic analyses, electronic circular dichroism (EC) and specific rotation (SR) calculations. Compound 1 represented a new family of guaiane-type sesquiterpenoids featuring an unprecedented [5/6/6/7] tetracyclic system. A plausible biosynthetic pathway for compounds 1-7 was proposed. The anti-fungal, anti-inflammatory and multidrug resistance reversal activities of the isolates were evaluated. Compounds 1, 2 and 7 exhibited potent inhibitory activities against Candida albicans with MIC values ranging from 1.60 to 6.30 µM, and suppressed nitric oxide (NO) production with IC50 ranging from 4.60 to 20.00 µM. Additionally, all compounds (100 µg/mL) enhanced the cytotoxicity of cisplatin in cisplatin-resistant non-small cell lung cancer cells (A549/DDP). This study opened up a new source for obtaining bioactive guaiane-type sesquiterpenoids and compounds 1, 2, and 7 were promising for further optimization as multifunctional inhibitors for anti-fungal (C. albicans) and anti-inflammatory purposes.

Neogrisphenol A, a Potential Ovarian Cancer Inhibitor from a New Record Fungus Neohelicosporium griseum.

From the rice fermentation product of a new record fungus, Neohelicosporium griseum, two new polyketides, neogrisphenol A (1) and neogrisphenol B (2), one new isochroman-1-one, (S)-6-hydroxy-7-methoxy-3,5-dimethylisochroman-1-one (3), and four known compounds (4-7) were isolated. Their structures were determined using 1D- and 2D-NMR, mass spectrometry, and chemical calculations. The C-3~C-2' polymerization mode between the two α-naphthalenone derivative moieties is uncommon in compounds 1 and 2. Meanwhile, compounds 1-2 and 5 exhibited antibacterial activity against Bacillus subtilis, Clostridium perfringens, Staphylococcus aureus, and Staphylococcus aureus, with MIC values ranging between 16 and 31 µg/mL. In addition, compound 5 showed antifungal activity against Sclerotinia sclerotiorum and Phytophthora nicotianae var. nicotianae, with respective IC50 values of 88.14 ± 2.21 µg/mL and 52.36 ± 1.38 µg/mL. Compound 1 showed significant cytotoxicity against A2780, PC-3, and MBA-MD-231 cell lines with respective IC50 values of 3.20, 10.68, and 16.30 µM, and the cytotoxicity against A2780 cells was even higher than that of cisplatin (CDDP). With an IC50 value of 10.13 µM, compound 2 also exhibited cytotoxicity against A2780. The in vitro results showed that compound 1 inhibited A2780 cell proliferation, induced apoptosis, and arrested the cell cycle at the S-phase in a concentration-dependent manner.

Intraoperative dexmedetomidine use is associated with lower incidence of acute kidney injury after non-cardiac surgery.

BACKGROUND: Previous studies have shown that perioperative dexmedetomidine could reduce the incidence of postoperative AKI in cardiovascular surgery, however, its effectiveness in the non-cardiovascular surgery patient population has not been reported. The aim of this study was to investigate the effect of intraoperative dexmedetomidine on the incidence of postoperative AKI and postoperative ICU admissions in patients undergoing non-cardiovascular surgery. DESIGN AND SETTING: A single-center retrospective cohort study obtained from the database of the Center for Anesthesia and Surgery, the Third Xiangya Hospital. PATIENTS: Inpatients between 18 and 75 years of age who were admitted to our hospital for non-cardiovascular surgery from 2012 to 2019. RESULTS: Overall 2391 patients who used dexmedetomidine intraoperatively were analyzed in comparison to 4552 patients who did not use dexmedetomidine after one-to-two matching. The two cohorts had similar baseline values and demographic characteristics. The incidence of AKI was lower in patients with intraoperative dexmedetomidine use than in the nonuse group (OR 0.60, p < .001). The rate of severe renal failure needing dialysis was also lower than in the nonuse group (ß = -0.02, p < .05). After adjusting for confounding factors, the rate of AKI was still lower in the dexmedetomidine group. The rate of postoperative ICU admissions and in-hospital deaths were similar in the two groups (p > .05). CONCLUSION: For non-cardiovascular surgery patient population, intraoperative use of dexmedetomidine was associated with a lower incidence and less severity of postoperative AKI. However, there was no significant correlation with postoperative ICU occupancy or in-hospital mortality. Further prospective RCTs are needed in the future.