Radiotherapy combined with anti-PD-1 and TKI for primary cardiac angiosarcoma considering the joint assessment of TLSs and PD-L1: a case report.

BACKGROUND: Primary cardiac angiosarcoma(PCA) has a low incidence rate and poor prognosis. Currently, no unified clinical treatment standards are available. CASE PRESENTATION: We report the case of a 48-year-old man presenting chest tightness, breathlessness, and dyspnea. Imaging and postoperative histopathologic studies confirmed PCA and that the tumor had invaded the entire right atrium. The patient developed progressive disease (PD) during postoperative radiotherapy. We used immunotherapy combined with targeted therapy based on the results of molecular profile and evaluation of tertiary lymphoid structures (TLSs) and programmed cell death-ligand 1 (PD-L1). After treatment, the metastatic lymph nodes of the patient were reduced to a certain extent, indicating that combination therapy was effective. CONCLUSION: To the best of our knowledge, this is the first report of radiotherapy combined with anti-PD-1 and tyrosine kinase inhibitors(TKI) for PCA. In addition, this is the first report on immunotherapy for PCA based on new evaluation methods, including TLSs, PD-L1, and genomic profile.

Salicylic acid had the potential to enhance tolerance in horticultural crops against abiotic stress.

Horticultural crops are greatly disturbed by severe abiotic stress conditions. This is considered one of the major threats to the healthy lives of the human population. Salicylic acid (SA) is famous as one of the multifunctional phytohormones that are widely found in plants. It is also an important bio-stimulator involved in the regulation of growth and the developmental stages of horticultural crops. The productivity of horticultural crops has been improved with the supplemental use of even small amounts of SA. It has good capability to reduce oxidative injuries that occur from the over-production of reactive oxygen species (ROS), potentially elevated photosynthesis, chlorophyll pigments, and stomatal regulation. Physiological and biochemical processes have revealed that SA enhances signaling molecules, enzymatic and non-enzymatic antioxidants, osmolytes, and secondary metabolites activities within the cell compartments of plants. Numerous genomic approaches have also explored that SA regulates transcriptions profiling, transcriptional apprehensions, genomic expression, and metabolism of stress-related genes. Many plant biologists have been working on SA and its functioning in plants; however, its involvement in the enhancement of tolerance against abiotic stress in horticultural crops is still unidentified and needs more attention. Therefore, the current review is focused on a detailed exploration of SA in physiological and biochemical processes in horticultural crops subjected to abiotic stress. The current information is comprehensive and aims to be more supportive of the development of higher-yielding germplasm against abiotic stress.

HNF4G stimulates the development of pancreatic cancer by promoting IGF2BP2 transcription.

OBJECTIVE: Pancreatic cancer is a devastating and lethal malignancy. Our study investigated the effective mechanism of HNF4G on pancreatic cancer cell functions through the IGF2BP2 transcription. METHODS: HNF4G and IGF2BP2 expressions in pancreatic cancer were examined. The relationship between HNF4G expression and pancreatic cancer patients' clinicopathological characteristics was evaluated. After interfering with HNF4G expression in pancreatic cancer cells, the cell proliferative, migratory, and invasive capabilities were evaluated. Also, the expression of proliferation-related gene PCNA and migration and invasion-related gene MMP2 was determined. The binding relation between HNF4G and HNF4G promoter was forecasted and testified. A tumorigenesis assay in nude mice was performed to detect the HNF4G interference's effect on the subcutaneous tumorigenic capacity of pancreatic cancer cells. RESULTS: HNF4G and IGF2BP2 expressions were up-regulated in pancreatic cancer. Specifically, interfering with HNF4G inhibited PANC-1 cell proliferative, invasive and migratory behaviors, and decreased PCNA and MMP2 expression. Mechanistically, HNF4G as a transcription factor could specifically bind to IGF2BP2 and promote its expression. Rescue assay findings showed that IGF2BP2 overexpression could reverse the inhibiting effect of HNF4G interference on pancreatic cancer cells. For the in vivo finding, interfering HNF4G expression retarded the subcutaneous tumorigenic ability of pancreatic cancer cells. CONCLUSION: We summarize that HNF4G as a transcription factor regulates IGF2BP2 expression to promote pancreatic cancer cell proliferation and migration capacities.

Regeneratively mode-locked optoelectronic oscillator.

A regeneratively mode-locked optoelectronic oscillator is proposed to realize multi-mode phase locking in optoelectronic oscillators by coupling a modulating signal generation loop. To verify the feasibility of the scheme, a numerical simulation model is established. In addition, a proof-of-concept experiment is demonstrated in a single-loop optoelectronic oscillator with a 2.2 km polarization-maintaining single-mode fiber, using an electric amplitude modulator/Mach-Zehnder modulator as an active mode-locking device. The generated microwave pulse signal has a center frequency of 10 GHz and a repetition rate of 95 kHz. We believe this scheme can provide a new approach to overcome the problem of detuning between the modulating frequency and the mode spacing during long-term operation.

Online recorded data-based finite-time composite neural trajectory tracking control for underactuated MSVs.

This paper presents an online recorded data-based composite neural finite-time control scheme for underactuated marine surface vessels (MSVs) subject to uncertain dynamics and time-varying external disturbances. The underactuation problem of the MSVs was solved by introducing the line-of-sight (LOS) method. The uncertain dynamics of MSVs are approximated by the composite neural networks (NNs). A modified prediction error signal is designed by virtue of online recorded data. The weight updating law of NN is driven by both tracking error and prediction error, introducing additional correction information to the weights of NN, thus improving the learning ability of the NN. Furthermore, disturbance observers can be devised to estimate the compound disturbances consisting of the approximation errors of NNs and external disturbances. Moreover, the smooth function is inserted into the design of the control scheme, and the finite-time composite neural trajectory tracking control of MSVs is achieved. The stability of the MSVs trajectory tracking closed-loop control system is guaranteed rigorously by the Lyapunov approach, and the tracking error will converge to the set of residuals around zero within a finite time. The simulation tests on an MSV verify the effectiveness of the proposed control scheme.

A bioinformatics framework to identify the biomarkers and potential drugs for the treatment of colorectal cancer.

Colorectal cancer (CRC), a common malignant tumor, is one of the main causes of death in cancer patients in the world. Therefore, it is critical to understand the molecular mechanism of CRC and identify its diagnostic and prognostic biomarkers. The purpose of this study is to reveal the genes involved in the development of CRC and to predict drug candidates that may help treat CRC through bioinformatics analyses. Two independent CRC gene expression datasets including The Cancer Genome Atlas (TCGA) database and GSE104836 were used in this study. Differentially expressed genes (DEGs) were analyzed separately on the two datasets, and intersected for further analyses. 249 drug candidates for CRC were identified according to the intersected DEGs and the Crowd Extracted Expression of Differential Signatures (CREEDS) database. In addition, hub genes were analyzed using Cytoscape according to the DEGs, and survival analysis results showed that one of the hub genes, TIMP1 was related to the prognosis of CRC patients. Thus, we further focused on drugs that could reverse the expression level of TIMP1. Eight potential drugs with documentary evidence and two new drugs that could reverse the expression of TIMP1 were found among the 249 drugs. In conclusion, we successfully identified potential biomarkers for CRC and achieved drug repurposing using bioinformatics methods. Further exploration is needed to understand the molecular mechanisms of these identified genes and drugs/small molecules in the occurrence, development and treatment of CRC.

Green walnut husk extracts Proliferation and Migration in Gastric Cancer.

Background: In the past few decades, natural products have become an increasingly important source of potential anti-cancer agents. The green walnut husk(GWH) extracts have been reported to inhibit multiple tumor cells and might be a promising chemopreventive agent in human neoplasia. However, it is not clear whether GWH extracts inhibit gastric cancer. Methods: Proliferation, invasion, and migration of gastric cancer cells were assessed by the CCK-8, wound-healing, and Transwell assay. The apoptotic rate was detected by flow cytometry(FCM). The expressions of Bcl-2, Bax, and Caspase-3 proteins were examined by Western blot. Moreover, the growth of gastric cancer cells was assessed using orthotopic xenograft models, and related proteins expressions were evaluated using immunohistochemistry. Finally, the Gene expression profile of gastric cancer treated with GWH extracts was evaluated by using High-throughput RNA sequencing(RNA-seq). Results: GWH extracts effectively inhibited gastric cancer cell growth in vitro and in vivo. In vivo, GWH extracts inhibited the survival of gastric cancer cells in a dose and time-dependent manner, inhibited the migration and invasion of gastric cancer cells, regulated the expressions of apoptosis-related proteins, and induced apoptosis of gastric cancer cells. In vitro, GWH extracts inhibited the growth of mouse xenografted tumors. A total of differentially expressed genes, of which 41 genes were up-regulated, and 610 genes were down-regulated, were identified by RNA-seq. GO, and KEGG analysis showed that these differentially expressed genes might be related to the mechanism of the anti-gastric cancer effect of GWH extracts. Conclusion: GWH extracts played an anti-gastric cancer effect by inducing apoptosis and inhibiting invasion. Secondly, the differential expression of many genes, multiple signal pathways, and metabolic pathways in gastric cancer play an essential role in the anti-gastric cancer effect of GWH extracts. The results suggested that GWH extracts are expected to be a low toxic drug for the treatment of gastric cancer in the future.

Stereoselective Synthesis of trans-Decalin-Based Spirocarbocycles via Photocyclization of 1,2-Diketones.

Diastereoselective synthesis of the trans-decalin-based α-hydroxyl butanone spirocarbocycles bearing all-carbon quaternary stereogenic centers has been achieved via Norrish-Yang photocyclization of trans-decalin-substituted-2,3-butanediones using daylight. Density functional theory (DFT) calculations suggest that this diastereoselective reaction is affected by both substrate conformation and intramolecular hydrogen bonds. The developed chemistry could be applied to synthesizing the derivatives of the trans-decalin-based biologically important natural products.

Characterization of the complete chloroplast genome of the Solanum tuberosum L. cv. Shepody (Solanaceae).

Potato (Solanum tuberosum L.), a species of the family Solanaceae, is the fourth most important food crop worldwide. Solanum tuberosum L. cv. Shepody is a long, smooth, white-skinned potato cultivar with medium green leaves. It has good specific gravity and boils and bakes well. To support more molecular data for breeding of S. tuberosum, the complete chloroplast (cp) genome sequence of S. tuberosum L. cv. Shepody was determined using the next-generation sequencing. In leaves, the chloroplast genome accounts for 3.88% of the total genome. The entire cp genome was determined to be 155,296 bp in length. It contained large single-copy (LSC) and small single-copy (SSC) regions of 85,737 and 18,373 bp, respectively, which were separated by a pair of 25,593 bp inverted repeat (IR) regions. The genome contained 132 total genes, including 87 protein-coding genes, 37 tRNA genes, and 8 rRNA genes. The overall GC content of the genome is 37.9%. A phylogenetic tree reconstructed by 60 chloroplast genomes reveals that S. tuberosum L. cv. Shepody was closely related to S. tuberosum L. cv. Desiree with bootstrap support values of 100%.

Characterization of the complete chloroplast genome of the Solanum tuberosum L. cv. Favorita (Solanaceae).

Potato (Solanum tuberosum L.), a species of the family Solanaceae, is the fourth most important food crop worldwide. Solanum tuberosum L. cv. Favorita is a long oval, smooth, yellowish-skinned potato variety with green and plump leaves. It has a dry matter content of 17.7% and starch content of 12.4-14.01% in the tuber. In order to support more genetic data for the taxonomy of S. tuberosum, the complete chloroplast (cp) genome sequence of S. tuberosum L. cv. Favorita was determined using next-generation sequencing. In leaves, the chloroplast genome accounts for 5.17% of the total genome. The entire cp genome was determined to be 155,296 bp in length. It contained large single-copy (LSC) and small single-copy (SSC) regions of 85,737 and 18,373 bp, respectively, which were separated by a pair of 25,593 bp inverted repeat (IR) regions. The genome contained 132 total genes, including 87 protein-coding genes, 37 tRNA genes, and eight rRNA genes. The overall GC content of the genome is 37.9%. A phylogenetic tree reconstructed by 60 chloroplast genomes reveals that S. tuberosum L. cv. Favorita is most closely related to S. tuberosum L. cv. Desiree and S. tuberosum L. cv. Atlantic.

MicroRNA-15a Carried by Mesenchymal Stem Cell-Derived Extracellular Vesicles Inhibits the Immune Evasion of Colorectal Cancer Cells by Regulating the KDM4B/HOXC4/PD-L1 Axis.

The relevance of microRNA-15a (miR-15a) to autoimmunity has been reported. Herein, we intended to probe the potential roles of miR-15a shuttled by adipose-derived mesenchymal stem cells (adMSCs)-derived extracellular vesicles (Evs) in colorectal cancer (CRC). Initially, CRC cells were treated with interferon gamma (IFN-γ) to screen out differentially expressed genes by transcriptome sequencing. Following a 24-h co-culture with 20 µM adMSCs-derived Evs, CRC cell viability, migration, invasion, and apoptosis were assessed. After the determination of histone lysine demethylase 4B (KDM4B) as our target, its regulatory miRNA was predicted by the bioinformatics websites and verified by dual-luciferase and RNA pull-down assays. Intriguingly, KDM4B downregulated homeobox C4 (HOXC4) expression, while HOXC4 bound to the promoter sequence of programmed death-ligand 1 (PD-L1). Thus, we conducted rescue experiments to study the role of KDM4B and HOXC4. Finally, we evaluated the effects of adMSCs on CRC cell growth and immune evasion through in vivo tumorigenesis experiments. AdMSCs-derived Evs overexpressing miR-15a repressed proliferation, migration, and invasion, while it promoted the apoptosis of CRC cells via downregulation of KDM4B. These in vivo findings were reproduced in vitro on CRC immune evasion. Collectively, adMSCs-derived Evs overexpressing miR-15a restricted the immune evasion of CRC via the KDM4B/HOXC4/PD-L1 axis.

Stereoselective Synthesis of Cyclohepta[b]indoles by Visible-Light-Induced [2+2]-Cycloaddition/retro-Mannich-type Reactions.

A novel method for the concise synthesis of cyclohepta[b]indoles in high yields was developed. The method involves a visible-light-induced, photocatalyzed [2+2]-cycloaddition/ retro-Mannich-type reaction of enaminones. Experimental and computational studies suggested that the reaction is a photoredox process initiated by single-electron oxidation of an enaminone moiety, which undergoes subsequent cyclobutane formation and rapidly fragmentation in a radical-cation state to form cyclohepta[b]indoles.

Silencing of FTX suppresses pancreatic cancer cell proliferation and invasion by upregulating miR-513b-5p.

BACKGROUND: Abnormal expression of long non-coding RNA (lncRNA) FTX (five prime to Xist), which is involved in X chromosome inactivation, has been reported in various tumors. However, the effect of FTX on the development of pancreatic cancer (PC) has not been elucidated. The purpose of this study was to explore the possible molecular mechanism of FTX in PC. METHODS: Quantitative real-time PCR (qRT-PCR) was used to measure the expression levels of FTX and miR-513b-5p in PC cell lines. Proliferation and apoptosis of PC cells were determined by CCK-8, Edu assay, and flow cytometry. Invasion and migration ability of PC cells were detected by Transwell assay and scratch test. Bioinformatics analysis, luciferase reporter gene assay, and RNA immunoprecipitation (RIP) assay were used to verify the direct binding between FTX and miR-513b-5p. The xenotransplantation mouse model was established to explore the effect of FTX and miR-513b-5p on the PC tumor growth in vivo. RESULTS: The expression levels of FTX were increased in PC cell lines, and silencing of FTX remarkably suppressed the invasion ability and cell viability. Besides, FTX could bind to miR-513b-5p as a competitive endogenous RNA, thus promoting the invasion and proliferation ability of PC cells. Moreover, knockdown of FTX inhibited the tumor growth and increased the expression levels of miR-513b-5p and apoptosis-related proteins in vivo. CONCLUSIONS: FTX could directly combine with miR-513b-5p as a competitive endogenous RNA, thus promoting the occurrence and development of PC in vitro and in vivo.

Long Noncoding RNA HCG18 Promotes Malignant Phenotypes of Breast Cancer Cells via the HCG18/miR-103a-3p/UBE2O/mTORC1/HIF-1α-Positive Feedback Loop.

In recent years, an increasing number of studies have reported that long noncoding RNAs (lncRNAs) play crucial roles in breast cancer (BC) progression and metastasis. Another study group of our research center reported that lncRNA HCG18 was one of the 30 upregulated lncRNAs in BC tissues compared with normal tissues in The Cancer Genome Atlas database. However, the exact biological roles of HCG18 in BC remain unclear. In this study, we demonstrated that HCG18 is significantly upregulated in BC tissues and cells and that BC patients with high HCG18 expression tend to have poor prognosis. In vitro assays indicated that HCG18 promotes BC cell proliferation and invasion and endows BC cells with cancer stemness properties. In vivo assays revealed that reducing HCG18 expression in the BC cell line MDA-MB-231 markedly decreased tumor growth and lung metastasis in xenograft mouse models. In terms of mechanism, we found that HCG18 positively regulated the expression of BC-related ubiquitin-conjugating enzyme E2O (UBE2O) by sponging miR-103a-3p, and our previous research verified that UBE2O could promote the malignant phenotypes of BC cells through the UBE2O/AMPKα2/mTORC1 axis. Furthermore, as a downstream target of the HCG18/miR-103a-3p/UBE2O/mTORC1 axis, hypoxia-inducible factor 1α transcriptionally promoted HCG18 expression and then formed a positive feedback loop in BC. Taken together, these results confirm that HCG18 plays an oncogenic role in BC and might serve as a prognostic biomarker and a potential therapeutic target for BC treatment.

Asymmetric Total Synthesis of (-)-Guignardones A and B.

The asymmetric total synthesis of (-)-guignardones A (2) and B (1) has been accomplished. The highly oxidized 6-oxabicyclo[3.2.1]octane core was constructed from d-quinic acid via substitution/desulfurization reaction with thiophenol to forge the bridged ring scaffold, and a Pummerer rearrangement and 1,4-addition/elimination sequence was employed to install the ß-carbonyl group at the congested C-1 position. A late-stage Knoevenagel condensation-6π-electrocyclization and directed hydrogenation formed (-)-guignardone B (1), which was subjected to dehydration to furnish (-)-guignardone A (2).

miR-155-5p and miR-760 mediate radiation therapy suppressed malignancy of non-small cell lung cancer cells.

MicroRNAs (miRNAs) play important roles in tumorigenesis of various cancers. Recent study suggested that miRNAs are involved in the therapeutic functions of radiation during cancer treatment. We found that radiation can decrease the migration and invasion of non-small cell lung cancer (NSCLC) cells. Mechanistically, radiation can significantly increase the expression of miR-155-5p and miR-760 in NSCLC cells. Knockdown of miR-155-5p and miR-760 can attenuate radiation suppressed proliferation of NSCLC cells. Among the various targets of miR-155-5p, radiation can decrease the expression of HIF-1α. Similarly, radiation can also suppress the expression of IL-6 via a miR-760 dependent pathway. Gain and loss of function studies confirmed that both HIF-1α and IL-6 were involved in the radiation suppressed proliferation of NSCLC cells. Collectively, our data showed that radiation can regulate the expression of miR-155-5p and miR-760 to suppress the malignancy of NSCLC cells. © 2019 BioFactors, 45(3):393-400, 2019.

Synthesis of Benzannulated [6,6]-Spiroketals by a One-Pot Carbonylative Sonogashira Coupling/Double Annulation Reaction.

A one-pot Pd-catalyzed carbonylative Sonogashira coupling in tandem with double annulation reaction to synthesize benzannulated [6,6]-spiroketals from o-iodophenols and terminal alkynols or alkynyl phenols was achieved. The protocol provides straightforward and facile access to benzannulated [6,6]-spiroketals in moderate to good yields and excellent diastereoselectivities under balloon pressure of CO at room temperature.

Identification of Metastatic Lymph Nodes in MR Imaging with Faster Region-Based Convolutional Neural Networks.

MRI is the gold standard for confirming a pelvic lymph node metastasis diagnosis. Traditionally, medical radiologists have analyzed MRI image features of regional lymph nodes to make diagnostic decisions based on their subjective experience; this diagnosis lacks objectivity and accuracy. This study trained a faster region-based convolutional neural network (Faster R-CNN) with 28,080 MRI images of lymph node metastasis, allowing the Faster R-CNN to read those images and to make diagnoses. For clinical verification, 414 cases of rectal cancer at various medical centers were collected, and Faster R-CNN-based diagnoses were compared with radiologist diagnoses using receiver operating characteristic curves (ROC). The area under the Faster R-CNN ROC was 0.912, indicating a more effective and objective diagnosis. The Faster R-CNN diagnosis time was 20 s/case, which was much shorter than the average time (600 s/case) of the radiologist diagnoses.Significance: Faster R-CNN enables accurate and efficient diagnosis of lymph node metastases. Cancer Res; 78(17); 5135-43. ©2018 AACR.

VEGFA Involves in the Use of Fluvastatin and Zoledronate Against Breast Cancer.

Our study aimed to identify key genes involved in the use of fluvastatin and zoledronate against breast cancer, as well as to investigate the roles of vascular endothelial growth factor A (VEGFA) in the malignant behaviors of breast cancer cells. The expression data GSE33552 was downloaded from Gene Expression Omnibus database, including mocked-, fluvastatin- and zoledronate-treated MDA-MB-231 cells. Differentially expressed genes (DEGs) were identified in fluvastatin- and zoledronate-treated cells using limma package, respectively. Pathway enrichment analysis and protein-protein interaction (PPI) network analysis were then performed. Then we used shRNA specifically targeting VEGFA (shVEGFA) to knock down the expression of VEGFA in MDA-MB-231 cells. Cell viability assay, scratch wound healing assay, Transwell invasion assay and flow cytometry were performed to explore the effects of VEGFA knockdown on the malignant behaviors of breast cancer cells. VEGFA was up-regulated in both fluvastatin- and zoledronate-treated breast cancer cells. Moreover, VEGFA was a hub node in PPI network. In addition, VEGFA was successfully knocked down in MDA-MB-231 cells by shVEGFA. Suppression of VEGFA promoted the migration and invasion of breast cancer MDA-MB-231 cells. Suppression of VEGFA inhibited the apoptosis of MDA-MB-231 cells. Our results indicate that up-regulation of VEGFA may prevent the progression of breast cancer after fluvastatin and zoledronate treatment via inducing cell apoptosis and inhibiting migration and invasion. VEGFA may serve as a potential prognostic indicator for clinical outcome in the management of breast cancer.

FBP1 expression is associated with basal-like breast carcinoma.

The present study aimed to investigate the value of liver fructose 1,6-bisphophatase (FBP1) and hypoxia-inducible factor-1α (HIF-1α) in the molecular subtyping of breast carcinoma. Tissue obtained from 60 surgical specimens from patients with breast carcinoma underwent immunohistochemical staining for cytokeratin 5/6, HIF-1α and FBP1. The variation in the expression levels of these markers and clinicopathological factors were compared between molecular subtypes. In addition, disease-free survival was compared between basal-like and luminal breast carcinoma, according to differing expression levels of HIF-1α and FBP1. The results revealed that HIF-1α expression was detectable in 20/60 (33.3%) of the breast carcinoma cases, and was positively associated with lymph node metastasis (P=0.007). HIF-1α-positive patients exhibited a shorter disease-free survival, compared with HIF-1α-negative patients with invasive breast cancer. The expression levels of FBP1 were positive in 33/60 tumor tissues (55%; P<0.001), and FBP1 expression was associated with nuclear grade (P=0.017) and tumor stage (P=0.012). In breast carcinoma, HIF-1α expression levels were significantly negatively correlated with FBP1 levels (r=-0.711; P<0.001). Cox regression analysis identified FBP1 and tumor size as independent prognostic factors. Therefore, the present study demonstrated that patients with basal-like breast carcinoma exhibited lower levels of FBP1 expression in tumor tissues, compared with patients with luminal type breast cancer, and that low or absent expression levels of FBP1 may be associated with reduced disease-free survival.