PD-1: A critical player and target for immune normalization.

Immune system imbalances contribute to the pathogenesis of several different diseases, and immunotherapy shows great therapeutic efficacy against tumours and infectious diseases with immune-mediated derivations. In recent years, molecules targeting the programmed cell death protein 1 (PD-1) immune checkpoint have attracted much attention, and related signalling pathways have been studied clearly. At present, several inhibitors and antibodies targeting PD-1 have been utilized as anti-tumour therapies. However, increasing evidence indicates that PD-1 blockade also has different degrees of adverse side effects, and these new explorations into the therapeutic safety of PD-1 inhibitors contribute to the emerging concept that immune normalization, rather than immune enhancement, is the ultimate goal of disease treatment. In this review, we summarize recent advancements in PD-1 research with regard to immune normalization and targeted therapy.

Nuclear cGAS suppresses DNA repair and promotes tumorigenesis.

Accurate repair of DNA double-stranded breaks by homologous recombination preserves genome integrity and inhibits tumorigenesis. Cyclic GMP-AMP synthase (cGAS) is a cytosolic DNA sensor that activates innate immunity by initiating the STING-IRF3-type I IFN signalling cascade1,2. Recognition of ruptured micronuclei by cGAS links genome instability to the innate immune response3,4, but the potential involvement of cGAS in DNA repair remains unknown. Here we demonstrate that cGAS inhibits homologous recombination in mouse and human models. DNA damage induces nuclear translocation of cGAS in a manner that is dependent on importin-α, and the phosphorylation of cGAS at tyrosine 215-mediated by B-lymphoid tyrosine kinase-facilitates the cytosolic retention of cGAS. In the nucleus, cGAS is recruited to double-stranded breaks and interacts with PARP1 via poly(ADP-ribose). The cGAS-PARP1 interaction impedes the formation of the PARP1-Timeless complex, and thereby suppresses homologous recombination. We show that knockdown of cGAS suppresses DNA damage and inhibits tumour growth both in vitro and in vivo. We conclude that nuclear cGAS suppresses homologous-recombination-mediated repair and promotes tumour growth, and that cGAS therefore represents a potential target for cancer prevention and therapy.

FOXA1/MND1/TKT axis regulates gastric cancer progression and oxaliplatin sensitivity via PI3K/AKT signaling pathway.

BACKGROUND: Drug resistance is a main factor affecting the chemotherapy efficacy of gastric cancer (GC), in which meiosis plays an important role. Therefore, it is urgent to explore the effect of meiosis related genes on chemotherapy resistance. METHODS: The expression of meiotic nuclear divisions 1 (MND1) in GC was detected by using TCGA and clinical specimens. In vitro and in vivo assays were used to investigate the effects of MND1. The molecular mechanism was determined using luciferase reporter assay, CO-IP and mass spectrometry (MS). RESULTS: Through bioinformatics, we found that MND1 was highly expressed in platinum-resistant samples. In vitro experiments showed that interference of MND1 significantly inhibited the progression of GC and increased the sensitivity to oxaliplatin. MND1 was significantly higher in 159 GC tissues in comparison with the matched adjacent normal tissues. In addition, overexpression of MND1 was associated with worse survival, advanced TNM stage, and lower pathological grade in patients with GC. Further investigation revealed that forkhead box protein A1 (FOXA1) directly binds to the promoter of MND1 to inhibit its transcription. CO-IP and MS assays showed that MND1 was coexpressed with transketolase (TKT). In addition,TKT activated the PI3K/AKT signaling axis and enhanced the glucose uptake and lactate production in GC cells. CONCLUSIONS: Our results confirm that FOXA1 inhibits the expression of MND1, which can directly bind to TKT to promote GC progression and reduce oxaliplatin sensitivity through the PI3K/AKT signaling pathway.

The role of SPI1-TYROBP-FCER1G network in oncogenesis and prognosis of osteosarcoma, and its association with immune infiltration.

Osteosarcoma is an aggressive malignant bone sarcoma worldwide. A causal gene network with specific functions underlying both the development and progression of OS was still unclear. Here we firstly identified the differentially expressed genes (DEGs) between control and OS samples, and then defined the hub genes and top clusters in the protein-protein interaction (PPI) network of these DEGs. By focusing on the hub gene TYROBP in the top 1 cluster, a conserved TYROBP co-expression network was identified. Then the effect of the network on OS overall survival was analyzed. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses and Gene Set Enrichment Analysis (GSEA) were used to explore the functions of the network. XCell platform and ssGSEA algorithm were conducted to estimate the status of immune infiltration. ChEA3 platform, GSEA enrichment analysis, and Drug Pair Seeker (DPS) were used to predict the key transcription factor and its upstream signal. We identified the downregulated SPI1-TYROBP-FCER1G network in OS, which were significantly enriched in immune-related functions. We also defined a two-gene signature (SPI1/FCER1G) that can predict poorer OS overall survival and the attenuated immune infiltration when downregulated. The SPI1-TYROBP-FCER1G network were potentially initiated by transcription factor SPI1 and would lead to the upregulated CD86, MHC-II, CCL4/CXCL10/CX3CL1 and hence increased immune infiltrations. With this study, we could better explore the mechanism of OS oncogenesis and metastasis for developing new therapies.

Controllable Heterogeneous Nucleation for Patterning High-Quality Vertical and Horizontal ZnO Microstructures toward Photodetectors.

High-quality crystalline micro- and nanostructures based on inorganic semiconductors including zinc oxide (ZnO) have attracted considerable interest in electronic and optoelectronic applications due to their outstanding properties. ZnO micro- and nanocrystals can be fabricated by the moderate and high throughput hydrothermal synthesis. Yet it is restricted by patterning large-area ZnO crystals with high-quality and programmable geometries through the hydrothermal process for the optoelectronic integration. Here, a capillary-bridge manipulation approach is demonstrated to control the dewetting process of ZnO precursor solution for patterning precursor arrays. Based on precursor arrays, vertically aligned high-quality ZnO microrod arrays with homogeneous morphology and pure crystallographic orientation are fabricated via a hydrothermal epitaxial method. Statistical results and crystallization theories guide the experimental optimization and discussion of the crystallization mechanism, dominated by the competition between homogeneous nucleation and heterogeneous nucleation. High-quality ZnO microbelt arrays are achieved through a surfactant-mediated hydrothermal method after ZnO microrod arrays are transferred to a polydimethylsiloxane substrate. Photodetectors based on ZnO microbelts exhibit a high responsivity of 2.3 × 104 A W-1 , a light on-off ratio exceeding 105 , and stable recyclability. It is anticipated that this work provides new insights into patterning inorganic high-quality micro- and nanostructures for multi-functional integrated devices.

Utility of neonatal donors in pediatric liver transplantation: A single-center experience.

BACKGROUND: The lack of age- and size-matched organs result in higher waiting list mortality in pediatric recipients than adults. Organs from deceased newborns and infants are a valuable source to increase donor pool in pediatric liver transplantation. However, the feasibility and safety of using neonatal donors have not been well evaluated. METHODS: From 2014 to 2016, 48 deceased donor pediatric liver transplantations with donor age younger than 1 year old in our center were enrolled in this study. The recipients were divided into three groups based on the donor age (<1 month, 1 month ≤ to <3 months, and 3 months ≤ to <1 year). Recipient's characteristics, perioperative data, and postoperative complications were compared. RESULTS: Two-year patient survival rates were 87.5%, 94.4%, and 95.5%, and 2-year graft survival rates were 75%, 94.4%, and 95.5%, respectively, without significant difference. The liver grafts from donors younger than 3 months were more advantageous in terms of acute rejection and virus infection, while the young grafts were related to slight higher incidence of hepatic artery thrombosis and SFSS. Those complications could be effectively prevented or treated by our perioperative care strategies. In addition, eight recipients who received neonatal livers achieved comparable outcomes with recipients with older livers. CONCLUSION: Our data revealed that the application of liver grafts from donors younger than 1 year old could achieve excellent outcome. In particular, neonatal donors could be safely used in well-selected patients.

Risk factors of hepatic artery thrombosis in pediatric deceased donor liver transplantation.

PURPOSE: Hepatic artery thrombosis (HAT) remains a life-threatening complication in liver transplantation. We aim to investigate the risk factors of HAT in deceased donor pediatric liver transplantation. METHODS: 104 recipients from 2014 to 2016 were enrolled; donor and recipient characteristics, surgical variables, graft and recipient survival rate were compared between recipients with or without HAT. Univariate and multivariate analysis were applied to identify the risk factors of HAT. RESULTS: The recipient survival rate was 87.0% and 96.3% at 1 year, and 87.0% and 96.3% at 3 years in HAT and non-HAT groups without significant difference. The graft survival rate was 73.9% and 96.3% at 1 year, and 73.9% and 95.1% at 3 years in HAT and non-HAT groups; significant difference was observed between two groups at both 1 and 3 years. Donor age less than 8.5 months, graft weight less than 190 g and GRWR less than 2.2% were identified as independent risk factors for HAT. Recipients with HAT were associated with higher incidence of post-operative biliary complications. CONCLUSIONS: Young donor age and small liver graft are risk factors for HAT in deceased donor pediatric liver transplantation.

Long Non-Coding RNA (lncRNA) Growth Arrest Specific 5 (GAS5) Suppresses Esophageal Squamous Cell Carcinoma Cell Proliferation and Migration by Inactivating Phosphatidylinositol 3-kinase (PI3K)/AKT/Mammalian Target of Rapamycin (mTOR) Signaling Pathway.

BACKGROUND lncRNA GAS5 acts as a tumor-suppressor gene in various types of malignancies, but its involvement in esophageal cancer has not been well studied. MATERIAL AND METHODS A total of 112 patients with esophageal cancer and 55 volunteers with normal physiological conditions were included in this study. Tumor tissues and adjacent healthy tissues were collected from esophageal cancer patients and blood was extracted from patients and controls. Expression of GAS5 in those tissues was detected by qRT-PCR. All patients were followed up for 5 years and diagnostic and prognostic values of serum GAS5 for esophageal cancer were investigated by ROC curve analysis and survival curve analysis, respectively. Effects of GAS5 expression on cell proliferation and migration were investigated by CCK-8 assay and Transwell cell migration assay, respectively. Effects of GAS5 overexpression on expression of PI3K/AKT/mTOR-related proteins were explored by Western blot analysis. RESULTS GAS5 expression level was lower in tumor tissues than in adjacent healthy tissues. Serum level of GAS5 was lower in cancer patients than in healthy controls, and serum level of GAS5 was decreased with increase in stage of primary tumor (T stage). GAS5 overexpression inhibited tumor cell proliferation and migration, while treatment with PI3K activator reduced the inhibitory effects. GAS5 overexpression decreased the expression level of PI3K and phosphorylation levels of Akt and mTOR in esophageal cancer cells, while PI3K activator treatment showed no significant effects on GAS5 expression. CONCLUSIONS GAS5 was downregulated in esophageal cancer patients compared to healthy controls, and GAS5 overexpression suppressed proliferation and migration of esophageal cancer cells by inactivating the PI3K/AKT/mTOR pathway.

Serum cystatin C, impaired kidney function, and geriatric depressive symptoms among older people living in a rural area: a population-based study.

BACKGROUND: The relationship between kidney function and depressive symptoms among elderly people has been rarely investigated in settings of the general population. The aim of our study was to examine the association of serum cystatin C (cysC) and impaired kidney function with geriatric depressive symptoms among older people living in a rural community in China. METHODS: This population-based cohort study included 1440 individuals (age ≥ 60 years) who were recruited for the Confucius Hometown Aging Project in 2010-2011; of the 1124 persons who were free of depressive symptoms, 669 (59.5%) were re-examined in 2014-2016. At baseline, data on demographics, lifestyle factors, health conditions, and medical history were collected through interviews, clinical examinations, and laboratory tests. We defined impaired kidney function as the cystatin C-based estimated glomerular filtration rate (eGFRcysC) < 60 ml/min/1.73 m2, and depressive symptoms as a score ≥ 5 on the 15-item Geriatric Depression Scale. Data were analyzed using multiple logistic and Cox proportional-hazards models. RESULTS: Of the 1440 participants, 316 (21.9%) were defined to have geriatric depressive symptoms at baseline. Serum cysC levels of 1.01-1.25 and > 1.25 mg/L (vs. ≤1.00 mg/L) were associated with a multiple-adjusted odds ratio (OR) of 1.41 (95% CI 1.01-1.97) and 3.20 (2.32-4.41), respectively, for having geriatric depressive symptoms (Ptrend < 0.001). Of the 669 people who were free of depressive symptoms at baseline, 157 had incident depressive symptoms at the follow-up examination. The multiple-adjusted hazard ratio (HR) for incident depressive symptoms were 2.16 (95% CI 1.43-3.27) for serum cysC > 1.25 mg/L (vs. < 1.00 mg/L). Impaired kidney function was cross-sectionally (multiple-adjusted OR = 2.95; 95% CI 2.22-3.92) and longitudinally (multiple-adjusted HR 1.54; 95% CI 1.03-2.30) associated with an increased risk of geriatric depressive symptoms. CONCLUSION: Elevated serum cysC levels and impaired kidney function are associated with an increased risk of geriatric depressive symptoms among Chinese older people living in a rural community.

Apple RING E3 ligase MdMIEL1 inhibits anthocyanin accumulation by ubiquitinating and degrading MdMYB1 protein.

MdMYB1 is an important regulator for anthocyanin accumulation in apple (Malus × domestica). Here, an apple RING E3 ligase, MdMIEL1, was screened out as a partner of MdMYB1 with a yeast two-hybrid approach. Pull-down, bimolecular fluorescence complementation and coimmunoprecipitation assays further verified the interaction between MdMIEL1 and MdMYB1 proteins. Subsequently, in vitro and in vivo experiments indicated that MdMIEL1 functioned as a ubiquitin E3 ligase to ubiquitinate MdMYB1 protein, followed by degradation through a 26S proteasome pathway. Furthermore, transgenic studies in apple calli and Arabidopsis demonstrated that MdMIEL1 negatively regulated anthocyanin accumulation by modulating the degradation of MdMYB1 protein. Taken together, our findings provide a new insight into the molecular mechanism by which MdMIEL1 negatively regulates anthocyanin biosynthesis by ubiquitinating and degrading MdMYB1 protein.

Intercalating Organic Hybrid Cadmium Antimony Sulfide Nanoparticles into Graphene Oxide Nanosheets for Electrochemical Lithium Storage.

Inorganic metal sulfides have received extensive investigation as anode materials in lithium-ion batteries (LIBs). However, applications of crystalline organic hybrid metal sulfides as anode materials in LIBs are quite rare. In addition, combining the nanoparticles of crystalline organic hybrid metal sulfides with conductive materials is expected to enhance the electrochemical lithium storage performance. Nevertheless, due to the difficulty of harvesting the nanoparticles of crystalline organic hybrid metal sulfides, this approach has never been tried to date. Herein, nanoparticles of a crystalline organic hybrid cadmium antimony sulfide (1,4-DABH2)Cd2Sb2S6 (DCAS) were prepared by a top-down method, including the procedures of solvothermal synthesis, ball milling, and ultrasonic pulverization. Thereafter, the nanoparticles of DCAS with sizes of ∼500 nm were intercalated into graphene oxide nanosheets through a freeze-drying treatment and a DCAS@GO composite was obtained. Compared with the reported Sb2S3- and CdS-based composites, the DCAS@GO composite exhibited superior electrochemical Li+ ion storage performance, including a high capacity of 1075.6 mAh g-1 at 100 mA g-1 and exceptional rate tolerances (646.8 mAh g-1 at 5000 mA g-1). In addition, DCAS@GO can provide a high capacity of 705.6 mAh g-1 after 500 cycles at 1000 mA g-1. Our research offers a viable approach for preparing the nanoparticles of crystalline organic hybrid metal sulfides and proves that intercalating organic hybrid metal sulfide nanoparticles into GO nanosheets can efficiently boost the electrochemical Li+ ion storage performance.

Stepwise analysis of thyroid diagnostic modalities with genomic imprinting detection.

BACKGROUND: The current preoperative malignancy risk evaluation for thyroid nodules involves stepwise diagnostic modalities including ultrasonography, thyroid function serology and fine-needle aspiration (FNA) cytopathology, respectively. We aimed to substantiate the stepwise contributions of each diagnostic step and additionally investigate the diagnostic significance of quantitative chromogenic imprinted gene in-situ hybridization (QCIGISH)-an adjunctive molecular test based on epigenetic imprinting alterations. METHODS: A total of 114 cytopathologically-diagnosed and histopathologically-confirmed thyroid nodules with complete ultrasonographic and serological examination records were evaluated using QCIGISH in the study. Logistic regression models for thyroid malignancy prediction were developed with the stepwise addition of each diagnostic modality and the contribution of each step evaluated in terms of discrimination performance and goodness-of-fit. RESULTS: From the baseline model using ultrasonography [area under the receiver operating characteristics curve (AUROC): 0.79; 95% confidence interval (CI): 0.71-0.86], significant improvements in thyroid malignancy discrimination were observed with the stepwise addition of thyroid function serology (AUROC: 0.82; 95% CI: 0.74-0.90; P=0.23) and FNA cytopathology (AUROC: 0.88; 95% CI: 0.81-0.94; P=0.02), respectively. The inclusion of QCIGISH as an adjunctive molecular test further advanced the preceding model's diagnostic performance (AUROC: 0.95; 95% CI: 0.91-1.00, P=0.007). CONCLUSIONS: Our study demonstrated the significant stepwise diagnostic contributions of standard clinical assessments in the malignancy risk stratification of thyroid nodules. However, the addition of molecular imprinting detection further enabled a more accurate and definitive preoperative evaluation especially for morphologically indeterminate thyroid nodules and cases with potentially discordant results among standard modalities.

Social networks and the mental health among Chinese older adults: the mediating role of loneliness and moderating role of Internet use.

Background: Although a large body of research suggests that social networks from family and friends are important factors in protecting the mental health of older adults, we know little about the mediating and moderating mechanisms behind this relationship. Using China as an example, this study aims to investigate a comprehensive model that includes social networks, loneliness, Internet use, and mental health outcomes in the older population. Methods: We analyzed data from 7,648 Chinese older people over 60 using the 2018 CLASS survey. We studied how various social networks affect their mental health. Using SPSS's PROCESS macro, we first employed descriptive statistics to examine the characteristics of the participants and calculate the correlations of core variables. Then, we assessed whether loneliness mediated this relationship and tested the moderated mediation effect of Internet use. Our findings shed light on these complex dynamics. Results: The statistics indicate a positive correlation between social networks and mental health. Furthermore, mediation models revealed that loneliness moderates the relationship between social networks and mental health. In addition, moderated mediation models revealed that Internet use played a distinct function in the family networks model compared to the friend networks model. Internet use moderates explicitly the effects of family networks on loneliness and friend networks on mental health. Conclusion: The findings emphasize the importance of differentiating the types of social networks to understand their impact on older adults well-being, encouraging policymakers, medical professionals, and families to adopt more targeted approaches when devising policy interventions and medical strategies, especially for older individuals with insufficient social support. Additionally, we urge governments to recognize the varying types of social networks among older populations and harness the protective effects of Internet technology on their well-being within a digital society.

Synthesis of bifunctional thermal response promoters for improved high-solids enzymatic hydrolysis of corncob residues.

The enzymatic hydrolysis cost of lignocellulose can be reduced by improving enzymatic hydrolysis and recycling cellulase by adding additives. A series of copolymers P(SSS-co-SPE) (PSSPs) were synthesized using sodium p-styrene sulfonate (SSS) and sulfobetaine (SPE) as monomers. PSSP exhibited upper critical solution temperature response. PSSP with high molar ratio of SSS displayed more significant improved hydrolysis performance. When 10.0 g/L PSSP5 was added to the hydrolysis system of corncob residues, and substrate enzymatic digestibility at 72 h (SED@72 h) increased by 1.4 times. PSSP with high molecular weight and moderate molar ratio of SSS, had significant temperature response, enhanced hydrolysis, and recovering cellulase properties. For high-solids hydrolysis of corncob residues, SED@48 h increased by 1.2 times with adding 4.0 g/L of PSSP3. Meanwhile, 50% of cellulase amount was saved at the room temperature. This work provides a new idea for reducing the hydrolysis cost of lignocellulose-based sugar platform technology.

Bibliometric and visual analysis of RAN methylation in cardiovascular disease.

Background: RNA methylation is associated with cardiovascular disease (CVD) occurrence and development. The purpose of this study is to visually analyze the results and research trends of global RNA methylation in CVD. Methods: Articles and reviews on RNA methylation in CVD published before 6 November 2022 were searched in the Web of Science Core Collection. Visual and statistical analysis was performed using CiteSpace 1.6.R4 advanced and VOSviewer 1.6.18. Results: There were 847 papers from 1,188 institutions and 63 countries/regions. Over approximately 30 years, there was a gradual increase in publications and citations on RNA methylation in CVD. America and China had the highest output (284 and 259 papers, respectively). Nine of the top 20 institutions that published articles were from China, among which Fudan University represented the most. The International Journal of Molecular Sciences was the journal with the most studies. Nature was the most co-cited journal. The most influential writers were Zhang and Wang from China and Mathiyalagan from the United States. After 2015, the primary keywords were cardiac development, heart, promoter methylation, RNA methylation, and N6-methyladenosine. Nuclear RNA, m6A methylation, inhibition, and myocardial infarction were the most common burst keywords from 2020 to the present. Conclusions: A bibliometric analysis reveals research hotspots and trends of RNA methylation in CVD. The regulatory mechanisms of RNA methylation related to CVD and the clinical application of their results, especially m6A methylation, are likely to be the focus of future research.

Three-dimensional chromatin architecture datasets for aging and Alzheimer's disease.

Recently, increasing studies are indicating a close association between dysregulated enhancers and neurodegenerative diseases, such as Alzheimer's disease (AD). However, their contributions were poorly defined for lacking direct links to disease genes. To bridge this gap, we presented the Hi-C datasets of 4 AD patients, 4 dementia-free aged and 3 young subjects, including 30 billion reads. As applications, we utilized them to link the AD risk SNPs and dysregulated epigenetic marks to the target genes. Combining with epigenetic data, we observed more detailed interactions among regulatory regions and found that many known AD risk genes were under long-distance promoter-enhancer interactions. For future AD and aging studies, our datasets provide a reference landscape to better interpret findings of association and epigenetic studies for AD and aging process.

Elucidating the impact of biochar with different carbon/nitrogen ratios on soil biochemical properties and rhizosphere bacterial communities of flue-cured tobacco plants.

Background and aims: In agriculture, biochar (BC) and nitrogen (N) fertilizers are commonly used for improving soil fertility and crop productivity. However, it remains unclear how different levels of BC and N fertilizer affect soil fertility and crop productivity. Methods: This study elucidates the impact of different application rates of BC (0, 600, and 1200 kg/ha) and N fertilizer (105 and 126 kg/ha) on biomass accumulation, soil microbial biomass of carbon (SMC) and nitrogen (SMN), and soil biochemical properties, including soil organic carbon (SOC), total nitrogen (TN), soil nitrate nitrogen (NO3--N), ammonium nitrogen (NH4+-N), urease (UE), acid phosphatase (ACP), catalase (CAT), and sucrase (SC) of tobacco plants. In addition, a high throughput amplicon sequencing technique was adopted to investigate the effect of different application rates of BC/N on rhizosphere bacterial communities of tobacco plants. Results: The results confirm that high dosages of BC and N fertilizer (B1200N126) significantly enhance dry matter accumulation by 31.56% and 23.97% compared with control B0N105 and B0N126 under field conditions and 23.94% and 24.52% under pot experiment, respectively. The soil biochemical properties, SMC, and SMN significantly improved under the high application rate of BC and N fertilizer (B1200N126), while it negatively influenced the soil carbon/nitrogen ratio. Analysis of rhizosphere bacteriome through amplicon sequencing of 16S rRNA revealed that the structure, diversity, and composition of rhizosphere bacterial communities dramatically changed under different BC/N ratios. Proteobacteria, Bacteroidetes, Actinobacteria, Firmicutes, and Acidobacteria were highly abundant bacterial phyla in the rhizosphere of tobacco plants under different treatments. Co-occurrence network analysis displayed fewer negative correlations among rhizosphere bacterial communities under high dosages of biochar and nitrogen (B1200N126) than other treatments, which showed less competition for resources among microbes. In addition, a redundancy analysis further proved a significant positive correlation among SMC, SMN, soil biochemical properties, and high dosage of biochar and nitrogen (B1200N126). Conclusions: Thus, we conclude that a high dosage of BC (1200 kg/ha) under a high application rate of N fertilizer (126 kg/ha) enhances the biomass accumulation of tobacco plants by improving the soil biochemical properties and activities of rhizosphere bacterial communities.

A Type I/Type III PKS Hybrid Generates Cinnamomycin A-D.

3,5-Dihydroxybenzoic acid (3,5-DHBA), biosynthesized by type III PKS and tailoring enzymes, is an unconventional starter unit for bacterial type I PKS. Genome mining of 3,5-DHBA-specific biosynthetic gene clusters could lead to discovering new type I/type III PKS hybrids. Herein, we report the discovery and characterization of atypical compounds, namely cinnamomycin A-D, exhibiting selective antiproliferative activity. The biosynthetic pathway of cinnamomycins was proposed based on genetic manipulation, enzymatic reaction, and precursor feeding.

A machine learning-based PET/CT model for automatic diagnosis of early-stage lung cancer.

Objective: The aim of this study was to develop a machine learning-based automatic analysis method for the diagnosis of early-stage lung cancer based on positron emission tomography/computed tomography (PET/CT) data. Methods: A retrospective cohort study was conducted using PET/CT data from 187 cases of non-small cell lung cancer (NSCLC) and 190 benign pulmonary nodules. Twelve PET and CT features were used to train a diagnosis model. The performance of the machine learning-based PET/CT model was tested and validated in two separate cohorts comprising 462 and 229 cases, respectively. Results: The standardized uptake value (SUV) was identified as an important biochemical factor for the early stage of lung cancer in this model. The PET/CT diagnosis model had a sensitivity and area under the curve (AUC) of 86.5% and 0.89, respectively. The testing group comprising 462 cases showed a sensitivity and AUC of 85.7% and 0.87, respectively, while the validation group comprising 229 cases showed a sensitivity and AUC of 88.4% and 0.91, respectively. Additionally, the proposed model improved the clinical discrimination ability for solid pulmonary nodules (SPNs) in the early stage significantly. Conclusion: The feature data collected from PET/CT scans can be analyzed automatically using machine learning techniques. The results of this study demonstrated that the proposed model can significantly improve the accuracy and positive predictive value (PPV) of SPNs at the early stage. Furthermore, this algorithm can be optimized into a robotic and less biased PET/CT automatic diagnosis system.

Prediction of overall survival after radical gastrectomy using nomograms created by tumor markers.

Prediction of prognosis after radical resection of gastric cancer has not been well established. Therefore, we aimed to establish a prognostic model based on a new score system of patients with gastric cancer. A total of 1235 patients who underwent curative gastrectomy at our hospital from October 2015 to April 2017 were included in this study. Univariate and multivariate analyses were used to screen for prognostic risk factors. Construction of the nomogram was based on Cox proportional hazard regression models. The construction of the new score models was analyzed by the receiver operating characteristic curve (ROC curve), calibration curve, and decision curve. Multivariate analysis showed that tumor size, T, N, carcinoembryonic antigen, CA125, and CA19-9 were independent prognostic factors. The new score model had a greater AUC (The area under the ROC curve) than other systems, and the C-index of the nomogram was highly reliable for evaluating the survival of patients with gastric cancer. Based on the tumor markers and other clinical indicators, we developed a precise model to predict the prognosis of patients with gastric cancer after radical surgery. This score system can be helpful to both surgeons and patients.