Multiomics-based molecular subtyping based on the commensal microbiome predicts molecular characteristics and the therapeutic response in breast cancer.

The gut microbiota has been demonstrated to be correlated with the clinical phenotypes of diseases, including cancers. However, there are few studies on clinical subtyping based on the gut microbiota, especially in breast cancer (BC) patients. Here, using machine learning methods, we analysed the gut microbiota of BC, colorectal cancer (CRC), and gastric cancer (GC) patients to identify their shared metabolic pathways and the importance of these pathways in cancer development. Based on the gut microbiota-related metabolic pathways, human gene expression profile and patient prognosis, we established a novel BC subtyping system and identified a subtype called "challenging BC". Tumours with this subtype have more genetic mutations and a more complex immune environment than those of other subtypes. A score index was proposed for in-depth analysis and showed a significant negative correlation with patient prognosis. Notably, activation of the TPK1-FOXP3-mediated Hedgehog signalling pathway and TPK1-ITGAE-mediated mTOR signalling pathway was linked to poor prognosis in "challenging BC" patients with high scores, as validated in a patient-derived xenograft (PDX) model. Furthermore, our subtyping system and score index are effective predictors of the response to current neoadjuvant therapy regimens, with the score index significantly negatively correlated with both treatment efficacy and the number of immune cells. Therefore, our findings provide valuable insights into predicting molecular characteristics and treatment responses in "challenging BC" patients.

Enantiomer-Dependent Supramolecular Immunosuppressive Modulation for Tissue Reconstruction.

Modulating the properties of biomaterials in terms of the host immune response is critical for tissue repair and regeneration. However, it is unclear how the preference for the cellular microenvironment manipulates the chiral immune responses under physiological or pathological conditions. Here, we reported that in vivo and in vitro oligopeptide immunosuppressive modulation was achieved by manipulation of macrophage polarization using chiral tetrapeptide (Ac-FFFK-OH, marked as FFFK) supramolecular polymers. The results suggested that chiral FFFK nanofibers can serve as a defense mechanism in the restoration of tissue homeostasis by upregulating macrophage M2 polarization via the Src-STAT6 axis. More importantly, transiently acting STAT6, insufficient to induce a sustained polarization program, then passes the baton to EGR2, thereby continuously maintaining the M2 polarization program. It is worth noting that the L-chirality exhibits a more potent effect in inducing macrophage M2 polarization than does the D-chirality, leading to enhanced tissue reconstruction. These findings elucidate the crucial molecular signals that mediate chirality-dependent supramolecular immunosuppression in damaged tissues while also providing an effective chiral supramolecular strategy for regulating macrophage M2 polarization and promoting tissue injury repair based on the self-assembling chiral peptide design.

Tumor-mesothelium HOXA11-PDGF BB/TGF ß1-miR-181a-5p-Egr1 feedforward amplifier circuity propels mesothelial fibrosis and peritoneal metastasis of gastric cancer.

A proportion of gastric cancer (GC) patients suffer from peritoneal metastasis (PM) in the late stage of tumor and these patients have a poor prognosis. To provide more care for GC patient with PM, a deeper exploration of the molecular characteristics of GC-PM is needed. Here we performed the in vitro and in vivo study to illustrate the effect of HOXA11 over-expressed GC cells on peritoneal mesothelial cells (HMrSV5), transcriptomics analyses of HMrSV5 cells co-cultured with HOXA11 over-expressed GC cells, counterparts or alone, cytokine array analyses of serum-free culture medium of HOXA11 over-expressed GC cells, we validated our findings through genetic manipulation of HMrSV5 cells and neutralizing antibodies targeting cytokines secreted by HOXA11 over-expressed GC cells in vitro, as well as utilized human peritoneal metastatic lesions to validate expression of potential targets. We identified that HOXA11 over-expressed GC cells strongly propelled mesothelial fibrosis in vivo and in vitro, and HOXA11 regulated paracrine and autocrine of PDGF BB and TGF ß1 in GC cells to propel mesothelial fibrosis. Meanwhile, HOXA11 over-expressed GC cells drove PDGF BB and TGF ß1 secretion to activate developmental-process related genes in HMrSV5 cells, including Egr1, which processes dependent on miR-181a-5p. Then, Egr1 could mediate peritoneal mesothelial fibrosis. Correspondingly, Egr1 over-expressed HMrSV5 cells supported migration and peritoneal dissemination of GC cells. Together our results suggest that a feedforward amplifier circuity governing GC cells and mesothelial cells in peritoneum contribute to peritoneal metastasis of GC cells.

Neratinib for HER2-positive breast cancer with an overlooked option.

Positive human epidermal growth factor receptor 2 (HER2) expression is associated with an increased risk of metastases especially those to the brain in patients with advanced breast cancer (BC). Neratinib as a tyrosine kinase inhibitor can prevent the transduction of HER1, HER2 and HER4 signaling pathways thus playing an anticancer effect. Moreover, neratinib has a certain efficacy to reverse drug resistance in patients with BC with previous HER2 monoclonal antibody or targeted drug resistance. Neratinib, as monotherapy and in combination with other therapies, has been tested in the neoadjuvant, adjuvant, and metastatic settings. Neratinib with high anticancer activity is indicated for the prolonged adjuvant treatment of HER2-positive early BC, or in combination with other drugs including trastuzumab, capecitabine, and paclitaxel for the treatment of advanced HER2-positive BC especially cancers with central nervous system (CNS) metastasis to reduce the risk of BC recurrence. This article reviewed the pharmacological profiles, efficacy, safety, tolerability, and current clinical trials pertaining to neratinib, with a particular focus on the use of neratinib in patients with metastatic breast cancer (MBC) involving the CNS. We further discussed the use of neratinib for HER2-negative and HER2-mutant breast cancers, and mechanisms of resistance to neratinib. The current evidence suggests that neratinib has promising efficacy in patients with BC which is at least non-inferior compared to previous therapeutic regimens. The most common AE was diarrhea, and the incidence, severity and duration of neratinib-related grade 3 diarrhea can be reduced with loperamide. Of note, neratinib has the potential to effectively control and prevent brain metastasis in patients with advanced BC, providing a therapeutic strategy for HER2-positive BC.

Molecular mechanism of different flower color formation of Cymbidium ensifolium.

Cymbidium ensifolium is one of the national orchids in China, which has high ornamental value with changeable flower colors. To understand the formation mechanism of different flower colors of C. ensifolium, this research conducted transcriptome and metabolome analyses on four different colored sepals of C. ensifolium. Metabolome analysis detected 204 flavonoid metabolites, including 17 polyphenols, 27 anthocyanins, 75 flavones, 34 flavonols, 25 flavonoids, 18 flavanones, and 8 isoflavones. Among them, purple-red and red sepals contain a lot of anthocyanins, including cyanidin, pelargonin, and paeoniflorin, while yellow-green and white sepals have less anthocyanins detected, and their metabolites are mainly flavonols, flavanones and flavonoids. Transcriptome sequencing analysis showed that the expression levels of the anthocyanin biosynthetic enzyme genes in red and purple-red sepals were significantly higher than those in white and yellow-green sepals of C. ensifolium. The experimental results showed that CeF3'H2, CeDFR, CeANS, CeF3H and CeUFGT1 may be the key genes involved in anthocyanin production in C. ensifolium sepals, and CeMYB104 has been proved to play an important role in the flower color formation of C. ensifolium. The results of transformation showed that the CeMYB104 is involved in the synthesis of anthocyanins and can form a purple-red color in the white perianth of Phalaenopsis. These findings provide a theoretical reference to understand the formation mechanism of flower color in C. ensifolium.

Interface Chirality: From Biological Effects to Biomedical Applications.

Chiral surface is a critical mediator that significantly impacts interaction with biological systems on regulating cell behavior. To better understand how the properties of interfacial Chirality affect cell behavior and address the limitations of chiral materials for biomedical applications, in this review, we mainly focus on the recent developments of chiral bio-interfaces for the controllable and accurate guidance of chiral biomedical phenomena. In particular, we will discuss how cells or organisms sense and respond to the chiral stimulus, as well as the chirality mediating cell fate, tissue repair, and organism immune response will be reviewed. In addition, the biological applications of chirality, such as drug delivery, antibacterial, antivirus and antitumor activities, and biological signal detection, will also be reviewed. Finally, the challenges of chiral bio-interfaces for controlling biological response and the further application of interface chirality materials for biomedical will be discussed.

Plasma Exosome Proteins ILK1 and CD14 Correlated with Organ-Specific Metastasis in Advanced Gastric Cancer Patients.

The exosome plays important roles in driving tumor metastasis, while the role of exosome proteins during organ-specific metastasis in gastric cancer has not been fully understood. To address this question, peripheral blood samples from 12 AGC patients with organ-specific metastasis, including distant lymphatic, hepatic and peritoneal metastasis, were collected to purify exosomes and to detect exosome proteins by Nano-HPLC-MS/MS. Gastric cancer cell lines were used for in vitro experiments. Peripheral blood sample and ascites sample from one patient were further analyzed by single-cell RNA sequencing. GO and KEGG enrichment analysis showed different expression proteins of hepatic metastasis were correlated with lipid metabolism. For peritoneal metastasis, actin cytoskeleton regulation and glycolysis/gluconeogenesis could be enriched. ILK1 and CD14 were correlated with hepatic and peritoneal metastasis, respectively. Overexpression of CD14 and ILK1 impacted the colony formation ability of gastric cancer and increased expression of Vimentin. CD14 derived from immune cells in malignant ascites correlated with high activation of chemokine- and cytokine-mediated signaling pathways. In summary, biological functions of plasma exosome proteins among AGC patients with different metastatic modes were distinct, in which ILK1 and CD14 were correlated with organ-specific metastasis.

Circulating neutrophils activated by cancer cells and M2 macrophages promote gastric cancer progression during PD-1 antibody-based immunotherapy.

Aims: To analyze the correlation between the neutrophil-to-lymphocyte ratio (NLR) and prognosis of advanced gastric cancer (AGC) patients treated by PD-1 antibody-based therapy and to delineate molecular characteristics of circulating neutrophils by single-cell RNA sequencing (scRNA-seq). Methods: The clinicopathological information of 45 AGC patients receiving PD-1 antibody-based regimens at the Department of Oncology, Ruijin Hospital, was reviewed. Treatment outcomes including objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were recorded. The correlation between NLR and efficacy of PD-1 antibody-based treatment was analyzed. Single-cell RNA sequencing (scRNA-seq) analysis was performed based on multisite biopsy samples from two AGC patients to explore the molecular characteristics of circulating neutrophils and their pro-tumor mechanisms. Tissue samples from 88 gastric cancer patients who underwent radial gastrectomy were collected for immunochemistry staining. Results: A high posttreatment NLR was associated with poor outcomes of AGC patients receiving PD-1 antibody-based regimens. scRNA-seq analysis showed that an increased number of circulating neutrophils were found in peripheral blood samples after treatment in which neutrophil cluster 1 (NE-1) was the major subcluster. NE-1 was featured with a neutrophil activation phenotype with the high expression of MMP9, S100A8, S100A9, PORK2, and TGF-ß1. NE-1 displayed an intermediate state in pseudotime trajectory analysis with gene function enrichment found in neutrophil activation, leukocyte chemotaxis, and negative regulation of MAP kinase activity. Cellular interaction analysis showed that the chemokine signaling pathway is the major interactional pathway of NE-1 between subclusters of malignant epithelial cells (EP-4) and M2 macrophages (M2-1 and M2-2). In turn, the MAPK signaling pathway and Jak-STAT signaling pathway of EP-4, including IL1B/IL1RAP, OSM/OSMR, and TGFB1/TGFBR2 axes, were identified as interacting pathways between EP-4 and NE-1. The high expression of OSMR in tumor cells was closely correlated with lymph node metastasis of gastric cancer. Conclusion: The posttreatment NLR could be a poor prognostic marker of AGC patients treated with immune checkpoint inhibitors (ICIs). Subclusters of circulating neutrophils activated by tumor cells and M2 macrophages could participate in gastric cancer progression through signaling interactions with tumor cells.

Principle Superiority and Clinical Extensibility of 2D and 3D Charged Nanoprobe Detection Platform Based on Electrophysiological Characteristics of Circulating Tumor Cells.

The electrical characteristic of cancer cells is neglected among tumor biomarkers. The development of nanoprobes with opposing charges for monitoring the unique electrophysiological characteristics of cancer cells. Micro-nano size adsorption binding necessitates consideration of the nanoprobe's specific surface area. On the basis of the electrophysiological characteristics of circulating tumor cells (CTCs), clinical application and performance assessment are determined. To demonstrate that cancer cells have a unique pattern of electrophysiological patterns compared to normal cells, fluorescent nanoprobes with opposing charges were developed and fabricated. Graphene oxide (GO) was used to transform three-dimensional (3D) nanoprobes into two-dimensional (2D) nanoprobes. Compare 2D and 3D electrophysiological magnetic nanoprobes (MNP) in clinical samples and evaluate the adaptability and development of CTCs detection based on cell electrophysiology. Positively charged nanoprobes rapidly bind to negatively charged cancer cells based on electrostatic interactions. Compared to MNPs(+) without GO, the GO/MNPs(+) nanoprobe is more efficient and uses less material to trap cancer cells. CTCs can be distinguished from normal cells that are fully unaffected by nanoprobes by microscopic cytomorphological inspection, enabling the tracking of the number and pathological abnormalities of CTCs in the same patient at various chemotherapy phases to determine the efficacy of treatment. The platform for recognizing CTCs on the basis of electrophysiological characteristics compensates for the absence of epithelial biomarker capture and size difference capture in clinical performance. Under the influence of electrostatic attraction, the binding surface area continues to influence the targeting of cancer cells by nanoprobes. The specific recognition and detection of nanoprobes based on cell electrophysiological patterns has enormous potential in the clinical diagnosis and therapeutic monitoring of cancer.

COVID-19 lung infection segmentation from chest CT images based on CAPA-ResUNet.

Coronavirus disease 2019 (COVID-19) epidemic has devastating effects on personal health around the world. It is significant to achieve accurate segmentation of pulmonary infection regions, which is an early indicator of disease. To solve this problem, a deep learning model, namely, the content-aware pre-activated residual UNet (CAPA-ResUNet), was proposed for segmenting COVID-19 lesions from CT slices. In this network, the pre-activated residual block was used for down-sampling to solve the problems of complex foreground and large fluctuations of distribution in datasets during training and to avoid gradient disappearance. The area loss function based on the false segmentation regions was proposed to solve the problem of fuzzy boundary of the lesion area. This model was evaluated by the public dataset (COVID-19 Lung CT Lesion Segmentation Challenge-2020) and compared its performance with those of classical models. Our method gains an advantage over other models in multiple metrics. Such as the Dice coefficient, specificity (Spe), and intersection over union (IoU), our CAPA-ResUNet obtained 0.775 points, 0.972 points, and 0.646 points, respectively. The Dice coefficient of our model was 2.51% higher than Content-aware residual UNet (CARes-UNet). The code is available at https://github.com/malu108/LungInfectionSeg.

Camrelizumab and metronomic capecitabine for patients with treatment-refractory solid tumors (McCREST trial).

This is an open-label, single-center, multi-cohort phase Ib trial, which consists of three cohorts, including cohort 1 (HER2 negative gastric or gastric esophageal junction adenocarcinoma), cohort 2 (esophageal squamous cell carcinoma and head and neck squamous cell carcinoma) and cohort 3 (hepato-biliary-pancreatic and non-stomach non-esophagi gastrointestinal carcinoma). All eligible patients will be treated by camrelizumab (200 mg, every 2 weeks) and capecitabine (500 mg, twice a day, per os). The primary end point is the safety profiles of camrelizumab plus metronomic capecitabine according to CTCAE v5.0. The secondary end points are progression free survival, overall survival, objective response rate, disease control rate and duration of response. Planned enrollment is 20 subjects for each cohort. Total duration of this trial is expected to be 2 years.

Immune checkpoint inhibitors (ICIs) such as PD-1 inhibitors have been used to treat gastrointestinal cancer patients in clinical practices. Combination with other drugs can improve the efficacy of ICIs. Metronomic chemotherapy using low dose and high frequency of cytotoxic drugs has multi-targeted anti-tumor effects and can be a potential partner of ICIs. In this study, the authors assess the safety and efficacy of a combination of a PD-1 inhibitor (camrelizumab) and an oral chemotherapy drug (capecitabine with metronomic dose) in patients with metastatic treatment-refractory solid tumors.

Cu(I)-Catalyzed Cross-Coupling Rearrangements of Terminal Alkynes with Tropylium Tetrafluoroborate: Facile Access to Barbaralyl-Substituted Allenyl Acid Esters and 7-Alkynyl Cycloheptatrienes.

Herein, we report a novel strategy for the formation of copper carbene via the cycloisomerization of the π-alkyne-Cu(I) complex from terminal alkynes and tropylium tetrafluoroborate. Mechanistic studies and DFT calculations indicate that the reaction undergoes the intramolecular cycloisomerization process from the π-alkyne-Cu(I) complex to afford the copper carbene intermediate, followed by migratory insertion with the second terminal alkyne to afford the barbaralyl-substituted allenyl acid esters. In addition, we develop a mild and highly efficient Cu(I)-catalyzed cross-coupling protocol to synthesize 7-alkynyl cycloheptatrienes that has a broad functional group tolerance and is applicable to the late-stage functionalization of natural products.

N6-Methyladenosine RNA Modification in the Tumor Immune Microenvironment: Novel Implications for Immunotherapy.

N6-methyladenosine (m6A) methylation is one of the most common modifications of RNA in eukaryotic cells, and is mainly regulated by m6A methyltransferases (writers), m6A demethylases (erasers), and m6A binding proteins (readers). Recently, accumulating evidence has shown that m6A methylation plays crucial roles in the regulation of the tumor immune microenvironment, greatly impacting the initiation, progression, and metastasis processes of various cancers. In this review we first briefly summarizes the m6A-related concepts and detection methods, and then describes in detail the associations of m6A methylation modification with various tumor immune components especially immune cells (e.g., regulatory T cells, dendritic cells, macrophages, and myeloid-derived suppressor cells) in a variety of cancers. We discuss the relationship between m6A methylation and cancer occurrence and development with the involvement of tumor immunity highlighted, suggesting novel markers and potential targets for molecular pathological diagnosis and immunotherapy of various cancers.

Preclinical Assessment of Paclitaxel- and Trastuzumab-Delivering Magnetic Nanoparticles Fe3O4 for Treatment and Imaging of HER2-Positive Breast Cancer.

Objective: The purpose of this study was to investigate the anticancer activity and the potential imaging use of the innovative combination of magnetic nanoparticles (MNPs)-Fe3O4, paclitaxel (PTX), and trastuzumab (Herceptin) in HER2-positive breast cancer. Methods: MNPs-Fe3O4 was synthesized and underwent water phase transfer and hydrophobic molecular loading, and its surface was then coupled with Herceptin mono-antibody. The morphological characteristics of MNPs-Fe3O4 were observed under transmission electron microscopy (TEM). Effects of PTX-Herceptin-MNPs-Fe3O4 on breast cancer cells were evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,4-diphenyltetrazolium bromide assay and the flow cytometric apoptosis assay. To establish a xenograft model, we injected breast cancer SK-BR-3 cells into the left thighs of nude mice. We measured the effect of PTX-Herceptin-MNPs-Fe3O4 on tumor growth by measuring tumor size and calculating inhibition rate with immunohistochemistry analysis further performed, and analyzed MNPs-Fe3O4 accumulation in tumor lesions using in vivo magnetic resonance imaging and in vivo fluorescence imaging. Results: Most MNPs were in spherical shape of about 10 nm in diameter observed under TEM. PTX-Herceptin-MNPs-Fe3O4 showed greater cytotoxic effects, and induced a higher apoptosis rate of SK-BR-3 cells than all the other groups, with corresponding changes of apoptosis-related proteins. Meanwhile, the in vivo tumor xenograft model showed that tumor inhibition rate in the PTX-Herceptin-MNPs-Fe3O4 group was higher than in the PTX-Herceptin group. Furthermore, PTX-Herceptin-MNPs-Fe3O4 enhanced the T2 imaging contrast enhancement effect on tumors in tumor-bearing mice. Conclusion: The novel PTX-Herceptin-MNPs-Fe3O4 combination may represent a promising alternative breast cancer treatment strategy and may facilitate tumor imaging.

Case Report: Severe Immune-Related Cholestatic Hepatitis and Subsequent Pneumonia After Pembrolizumab Therapy in a Geriatic Patient With Metastic Gastric Cancer.

Background: Immune checkpoint inhibitors have provided significant clinical benefits to many patients with advanced cancer; however, severe immune-related adverse events (irAEs) have occurred. Detecting and treating irAEs early could improve patient prognoses. Therefore, clinicians and patients should understand that these irAEs exist, especially those that are rare and serious. Case Presentation: In this report, an 86-year-old male patient, diagnosed with metastatic gastric cancer involving the peritoneum and retroperitoneal lymph nodes was treated with 5-cycle pembrolizumab therapy (100 mg q 2 weeks), achieving a partial response. However, the patient developed Grade 3 cholestatic hepatitis and delayed pneumonia 10 days and 2 months after the final pembrolizumab dose, respectively. After discontinuing the pembrolizumab therapy and excluding obstructive jaundice with imaging studies, the patient received steroid therapy, with a gradual symptom improvement. However, the patient developed delayed pneumonia with type 1 respiratory failure 1-month post-discharge. Several microbiologic tests were negative, and immune-associated pneumonia was suspected, but we could not exclude an opportunistic infection. The patient recovered with steroids and antibiotics and remained in partial remission 5 months after pembrolizumab withdrawal. Conclusions: Cholestatic hepatitis is a rarely reported toxicity of immune checkpoint inhibitors, which should be suspected and addressed once obstructive jaundice is ruled out. In addition, clinicians should be aware that irAEs can occur at any time in patients treated with immune checkpoint inhibitors and that a timely diagnosis should be made.

Construction of Multifunctional and Adjustable Langmuir-Blodgett Composite Films Containing Black Phosphorus with High Stability for Optically Electrical Applications.

Fabrication of composite thin-film materials based on black phosphorus (BP) will greatly broaden the applications of BP in various areas. However, it is still a challenge to prepare a BP-based composite film with good stability and controllable structure. In this work, a series of BP-based composite Langmuir-Blodgett (LB) films are prepared by the self-assembly of polyethyleneimine (PEI)-modified BP nanosheets (BPNSs) (BPNS-PEI) and dye molecules. The presence of PEI greatly improves the stability of BPNSs. As for BPNS-PEI and dye molecules, the electrostatic interactions or π-π stacking interactions ensure the formation of stable composite LB films. Due to the protonation and deprotonation of amino groups, the synthesized BPNS-PEI/dye composite films show a sensitive response to acid and alkali gases, which shows wide application prospects as a highly sensitive gas sensor. Furthermore, surface-enhanced Raman scattering (SERS) proves that the prepared LB films exhibit good reproducibility and obvious Raman enhancement effect on rhodamine 6G molecules. In addition, due to the high carrier transfer rate of the obtained composite films, they possess enhanced photocurrent generation performance than pure BPNS-PEI and pure dye films. The current work demonstrates an effective method for preparing the ordered self-assembled BP-based composite LB films with good SERS and photoelectric conversion performance.

Improve optical properties by modifying Ag nanoparticles on a razor clam SERS substrate.

Irregular substrates are inappropriate for enhancing surface enhanced Raman scattering (SERS) due to their poor performances in terms of uniformity, enhancement performance, and polarization characteristics. However, in this work, we purposely employed a natural biological razor clam material with messy and irregular structures to improve the SERS. The rough surface was achieved by magnetron sputtering Ag nanoislands on the prism layer of the razor clams, and the Ag nanoparticles were treated using the method of oil-water interface self-assembly to form relatively uniform structures. Compared to the substrate without Ag nanoparticles, the presented substrate has better reproducibility, polarization-independence, and higher SERS intensity, and the detect limitation of R6G can be decreased from 10-12 M to 10-18 M. The ultrasensitive detection of thiram gives our structures potential for high sensitivity biosensors.

Formation and In Vitro Evaluation of a Deep Eutectic Solvent Conversion Film on Biodegradable Magnesium Alloy.

The chemical conversion films from deep eutectic solvents (DESs) have recently been shown to reduce the corrosion rate of magnesium alloys, which are recognized as a kind of promising materials applied in the human body. However, the biocompatibility of the conversion films has not been investigated. This study proposes an uncommon DES system composed of lithium chloride and urea to fabricate the chemical conversion films on Mg and its alloy. The fabrication process of the conversion film is facile, which is performed by the heat treatment of the substrate in the DES at about 200 °C for 30 min. It is found that the thermal decomposition of the DES can release hydrogen, which diffuses into the Mg substrate to form MgH2-based conversion films. The DES conversion film possesses a porous structure on pure Mg, whereas it becomes dense on the alloy with some cracks. X-ray photoelectron spectroscopy shows that MgCO3 and oxides also exist in the DES conversion films, which depends on the substrate. Electrochemical corrosion test and in vitro biocompatibility tests, including hemolysis, cytotoxicity, antibacterial, and cytoskeleton staining experiments, are performed in a simulated body environment, which shows that the corrosion resistance and biocompatibility of the substrates have been improved significantly. We expect that the DES heat treatment method will be applied to the fabrication of corrosion-resistant and biocompatible surfaces for biodegradable Mg alloys.

Rationale for Lung Adenocarcinoma Prevention and Drug Development Based on Molecular Biology During Carcinogenesis.

Lung adenocarcinoma (LUAD) is the most common and aggressive subtype of lung cancer with the greatest heterogeneity and aggression. Inspite of recent years' achievements in understanding the pathogenesis of this disease, as well as the development of new therapeutic approaches, our knowledge on crucial early molecular events during its development is still rudimentary. Recent classification and grading of LUAD has postulated that LUAD does not arise spontaneously, but through a stepwise process from lung adenomatous premalignancy atypical adenomatous hyperplasia to adenocarcinoma in situ, minimally invasive adenocarcinoma, and eventually frankly invasive predominant adenocarcinoma. In this review, we discuss the molecular processes that drive the evolutionary process that results in the formation of LUAD. We also describe how to handle lung premalignancy in clinical settings based on the most recent advances in genomic biology and our own understanding of lung cancer prevention.

Modulation of LPA1 receptor-mediated neuronal apoptosis by Saikosaponin-d: A target involved in depression.

Lysophosphatidic acid (LPA) is a bioactive lipid mediator of inflammation that binds to its specific cell surface G protein coupled receptors (LPA1-6). It is reported that LPA induced cell apoptosis by targeting LPA1, while LPA1 blockade eliminated LPS-induced production of peritoneal neutrophil chemokines and cytokines. Previous studies have shown that Saikosaponin-d (SSd) mitigated depressive-like behaviors in rats exposed to chronic unpredictable mild stress (CUMS), as well as corticosterone-induced apoptosis in PC12 cells. The present study explored the role of SSd during modulating LPA1 mediated neuronal apoptosis in LPS-stimulated mice. The phenomenon that SSd alleviated LPS-induced depressive-like behaviors were observed by open field test (OPT), forced swim test (FST) and tail suspension test (TST). SSd inhibited the protein expression of LPA1 both in the CA1 and CA3 region of the hippocampus. Moreover, SSd significantly decreased the levels of RhoA, ROCK2, p-p38, p-ERK, p-p65, p-IκBα in LPS-stimulated mice as well as in LPA-stimulated SH-SY5Y cells. Additionally, SSd significantly decreased the expression of LPA1 and the degree of neuronal apoptosis in SH-SY5Y cells which were co-cultured with LPS-stimulated BV2 microglia. These results suggested that SSd improved LPS-induced depressive-like behaviors in mice and suppressed neuronal apoptosis by regulating LPA1/RhoA/ROCK2 signaling pathway.