Deep learning for risk stratification of thymoma pathological subtypes based on preoperative CT images.

OBJECTIVES: This study aims to develop an innovative, deep model for thymoma risk stratification using preoperative CT images. Current algorithms predominantly focus on radiomic features or 2D deep features and require manual tumor segmentation by radiologists, limiting their practical applicability. METHODS: The deep model was trained and tested on a dataset comprising CT images from 147 patients (82 female; mean age, 54 years ± 10) who underwent surgical resection and received subsequent pathological confirmation. The eligible participants were divided into a training cohort (117 patients) and a testing cohort (30 patients) based on the CT scan time. The model consists of two stages: 3D tumor segmentation and risk stratification. The radiomic model and deep model (2D) were constructed for comparative analysis. Model performance was evaluated through dice coefficient, area under the curve (AUC), and accuracy. RESULTS: In both the training and testing cohorts, the deep model demonstrated better performance in differentiating thymoma risk, boasting AUCs of 0.998 and 0.893 respectively. This was compared to the radiomic model (AUCs of 0.773 and 0.769) and deep model (2D) (AUCs of 0.981 and 0.760). Notably, the deep model was capable of simultaneously identifying lesions, segmenting the region of interest (ROI), and differentiating the risk of thymoma on arterial phase CT images. Its diagnostic prowess outperformed that of the baseline model. CONCLUSIONS: The deep model has the potential to serve as an innovative decision-making tool, assisting on clinical prognosis evaluation and the discernment of suitable treatments for different thymoma pathological subtypes. KEY POINTS: • This study incorporated both tumor segmentation and risk stratification. • The deep model, using clinical and 3D deep features, effectively predicted thymoma risk. • The deep model improved AUCs by 16.1pt and 17.5pt compared to radiomic model and deep model (2D) respectively.

Boosting Type-I and Type-II ROS Production of Water-Soluble Porphyrin for Efficient Hypoxic Tumor Therapy.

As the most successful clinically approved photosensitizers, porphyrins have been extensively employed in the photodynamic therapy (PDT) of cancers. However, their poor water solubility, aggregation-induced self-quenching on ROS generation, and a low tolerance for a hypoxic condition usually result in unsatisfied therapeutic outcomes. Therefore, great efforts have been dedicated to improving the PDT efficacy of porphyrin-type photosensitizers in treating hypoxic tumors, including combination with additional active components or therapies, which can significantly complicate the therapeutic process. Herein, we report a novel water-soluble porphyrin with O-linked cationic side chains, which exhibits good water solubility, high photostability, and significantly enhanced ROS generation efficacy in both type-I and type-II photodynamic pathways. We have also found that the end charges of side chains can dramatically affect the ROS generation of the porphyrin. The cationic porphyrin exhibited high in vitro PDT efficacy with low IC50 values both in normoxia and hypoxia. Hence, during in vivo PDT study, the cationic porphyrin displayed highly effective tumor ablation capability. This study demonstrates the power of side-chain chemistry in tuning the photodynamic property of porphyrin, which offers a new effective strategy to enhance the anticancer performance of photosensitizers for fulfilling the increasing demands for cancer therapy in clinics.

Isosteviol derivatives as protein tyrosine Phosphatase-1B inhibitors: Synthesis, biological evaluation and molecular docking.

Protein tyrosine phosphatase (PTP1B) antagonizes insulin signaling and acts as a potential therapeutic target for insulin resistance associated with obesity and type II diabetes. In this work, a series of isosteviol derivatives 1-28 was synthesized and the inhibitory activity on PTP1B was evaluated by double antibody sandwich ELISA (DAS-ELISA) in vitro. Most isosteviol derivatives showed moderate PTP1B inhibitory activities. Among them, derivatives 10, 13, 24, 27 showed remarkable bioactivities with IC50 values ranging from 0.24 to 0.40 µM. Particularly, derivative 24 exhibited the best inhibitory activity against PTP1B (IC50 = 0.24 µM) in vitro; moreover, it showed 7-fold selectivity to PTP1B over T-cell protein tyrosine phosphatase (TCPTP) and 14-fold selectivity to PTP1B over cell division cycle 25 homolog B (CDC25B). Molecular docking studies demonstrated the hydrogen bond interaction between 24 and LYS-116 residue in PTP1B might be essential for the inhibitory activity. The results suggested that derivative 24 has great potential to be employed as drug candidate for the treatment of obesity and type II diabetes.

Design and Development of a Hair-like Sensor with Bridge-Type Flexible Amplification Mechanisms.

Compared with lever-type amplification mechanisms, bridge-type flexible amplification mechanisms have advantages in terms of amplification ratio and structural compactness. Therefore, they can effectively replace the lever-type amplification mechanism in the existing hair-like sensors and realize the development of miniature hair-like sensors with high sensitivity. With that in mind, a highly sensitive hair-like sensor based on a bridge-type amplification mechanism with distributed flexibility is presented to measure the airflow rate. First, the structural composition and operating principle of the hair-like sensor are described. Then, detailed design and analysis of the hair-like sensor are carried out, focusing on the design of the hair post structure, amplification mechanism, and resonator. Furthermore, the designed hair-like sensor is processed and prepared, and some experimental studies are conducted. The experimental results demonstrate that the developed hair-like sensor can measure the airflow rate with high sensitivity up to 8.56 Hz/(m/s)2. This provides a new concept for the structural design of hair-like sensors and expands the application of bridge-type flexible amplification mechanisms in the field of micro/nano sensors.

Progress in Isoindolone Alkaloid Derivatives from Marine Microorganism: Pharmacology, Preparation, and Mechanism.

Compound 1 (SMTP-7, also FGFC1), an isoindolone alkaloid from marine fungi Starchbotrys longispora FG216 and fungi Stachybotrys microspora IFO 30018, possessed diverse bioactivities such as thrombolysis, anti-inflammatory and anti-oxidative properties, and so on. It may be widely used for the treatment of various diseases, including cerebral infarction, stroke, ischemia/reperfusion damage, acute kidney injury, etc. Especially in cerebral infarction, compound 1 could reduce hemorrhagic transformation along with thrombolytic therapy, as the traditional therapies are accompanied with bleeding risks. In the latest studies, compound 1 selectively inhibited the growth of NSCLC cells with EGFR mutation, thus demonstrating its excellent anti-cancer activity. Herein, we summarized pharmacological activities, preparation of staplabin congeners-especially compound 1-and the mechanism of compound 1, with potential therapeutic applications.

Daphnetin, a Coumarin in Genus Stellera Chamaejasme Linn: Chemistry, Bioactivity and Therapeutic Potential.

Coumarins is a huge family of phenolic compounds containing a common structure of 2H-1-benzopyran-2-one. Nowadays, more than 1,300 natural-based coumarins have been identified in a variety of plants, bacteria and fungi, many of them exhibited promising biomedical performance. Daphnetin (7,8-dihydroxycoumarin), a typical coumarin, showed a couple of bioactivities such as anti-cancer, antibacterial, anti-inflammatory and anti-arthritis. In the treatment of diseases, it has been verified that daphnetin has outstanding therapeutic effects on diabetes, arthritis, transplant rejection, cancer and even on central nervous system diseases. In China, it is being used for clinical applications, about 93 patent publications were associated with daphnetin. Due to its wide therapeutic potentials in clinical applications, numerous research on the action mechanisms and synthetic methods of daphnetin have been performed to support the future developments. Herein, we summarized the chemical synthetic methodologies, bioactivities, therapeutic potentials and structure-activity relationships of daphnetin and its derivatives. Moreover, the state-of-the-arts in current daphnetin study and future perspective in this field were discussed. Hopefully, this review would be beneficial for the discovery of new coumarin-based biomedicine in the near future.

Synthesis and Bioactivities of Marine Pyran-Isoindolone Derivatives as Potential Antithrombotic Agents.

2,5-Bis-[8-(4,8-dimethyl-nona-3,7-dienyl)-5,7-dihydroxy-8-methyl-3-keto-1,2,7,8-teraahydro-6H-pyran[a]isoindol-2-yl]-pentanoic acid (FGFC1) is a marine pyran-isoindolone derivative isolated from a rare marine microorganism Stachybotrys longispora FG216, which showed moderate antithrombotic(fibrinolytic) activity. To further enhance its antithrombotic effect, a series of new FGFC1 derivatives (F1-F7) were synthesized via chemical modification at C-2 and C-2' phenol groups moieties and C-1″ carboxyl group. Their fibrinolytic activities in vitro were evaluated. Among the derivatives, F1-F4 and F6 showed significant fibrinolytic activities with EC50 of 59.7, 87.1, 66.6, 82.8, and 42.3 µM, respectively, via enhancement of urokinase activity. Notably, derivative F6 presented the most remarkable fibrinolytic activity (2.72-fold than that of FGFC1). Furthermore, the cytotoxicity of derivative F6 was tested as well as expression of Fas/Apo-1 and IL-1 on HeLa cells. The results showed that, compared to FGFC1, derivative F6 possessed moderate cytotoxicity and apoptotic effect on HeLa cells (statistical significance p > 0.1), making F6 a potential antithrombotic agent towards clinical application.

Syntheses and evaluation of daphnetin derivatives as novel G protein-coupled receptor inhibitors and activators.

A series of daphnetin (7,8-dihydroxycoumarin) derivatives 1-22 were synthesized including sixteen new compounds (1-5, 7-14, 18, 21 and 22) and six known compounds (6, 15-17, 19 and 20). Their pharmacological activities on G protein-coupled receptors (GPCRs) were evaluated by double antibody sandwich ELISA (DAS-ELISA) in vitro. Daphnetin derivatives with various substitution patterns/groups were obtained from inhibitors to activators on GPCRs. Derivatives 2-5, 8, 15, 16 and 18-20 possessed moderate activation potency on GPCRs. Among them, derivatives 3-5, 16 and 19 presented significant activation potency on GPCRs with EC50 values in the range of 1.18-1.91 nM. Derivatives 6, 11, 14 and 18 showed significant inhibitory potency on GPCRs with IC50 values in the range of 1.26-1.38 nM. Moreover, the structure-activity relationships (SARs) of daphnetin derivatives were discussed in detail. The new daphnetic-based GPCRs activators and inhibitors have potentials as future drug candidates for the treatment of metabolic diseases.

Novel Bioactive Polyketides Isolated from Marine Actinomycetes: An Update Review from 2013 to 2019.

Marine organism-associated actinobacteria represent a valuable resource for marine drugs due to their abundant secondary metabolites. The special environments in the ocean, for instance, high salt, high pressure, low temperature and oligotrophy, not only adapt to survival of actinomycetes but also enhance molecular diversity of actinomycete secondary metabolites production, thus making marine actinomycetes important sources of marine-based bioactive compounds, especially polyketides. Herein, we summarized the structures and pharmacological activities of polyketides from actinobacteria associated with marine organisms from 2013 to 2019; moreover, the main source species of actinomycetes were discussed as well. We expected that this review would be helpful for future in-depth research and development of marine-based bioactive polyketides.

Recent Advances on Marine Alkaloids from Sponges.

Alkaloids from marine secondary metabolites have received extensive attention from pharmacists in recent years. Miscellaneous alkaloids derived from marine sponges possessed various pharmacological activities including cytotoxicity, antimicrobial, antioxidant, and so on. Herein, we summarized 149 marine alkaloids from sponges based on their structures and bioactivities reported from 2015 to 2020 and analyzed the production environment of marine sponges with rich alkaloids. Moreover, we discussed biosynthesis routes of pyrrole and guanidine alkaloids from marine sponges Agelas and Monanchora. This article will be beneficial for future research on drugs from marine natural products.

Syntheses and bioactivities of songorine derivatives as novel G protein-coupled receptor antagonists.

Songorine isolated from Aconitum brachypodum Diels possesses prominent activity of inhibiting G protein-coupled receptors (GPCRs) in the early screening process. In this paper, a series of Songorine derivatives were synthesized and their inhibitory activities on GPCRs were also evaluated by using the Double Antibody Sandwich ELISA (DAS-ELISA) in vitro. Among them, three derivatives (3a, 4, 7) exhibited significant inhibitory activity against GPCRs with IC50 values of 0.08-0.29 nM. Moreover, the structure-activity relationships (SARs) of songorine derivatives were discussed in detail. They have great potentials as novel GPCRs antagonists in the future.

Evaluation of Marine Diindolinonepyrane in Vitro and in Vivo: Permeability Characterization in Caco-2 Cells Monolayer and Pharmacokinetic Properties in Beagle Dogs.

A marine fibrinolytic compound was studied for use in thrombolytic therapy. Firstly, the absorption and transportation characteristics of 2,5-BHPA (2,5-BHPA:2,5-Bis-[8-(4,8-dimethyl-nona-3,7-dienyl)-5,7-dihydroxy-8-methyl-3-keto-1,2,7,8-tertahydro-6H-pyran[a]isoindol-2-yl]-pentanoic acid, a novel pyran-isoindolone derivative with bioactivity isolated from a rare marine microorganism in our laboratory) in the human Caco-2 cells monolayer model were investigated. We collected 2,5-BHPA in the cells to calculate the total recovery, and its concentration was analyzed by LC/MS/MS (Liquid Chromatography/ Mass Spectrum/ Mass Spectrum). The results showed that 2,5-BHPA has low permeability and low total recoveries in the Caco-2 cells membrane. Pharmacokinetics and tissue distribution of 2,5-BHPA were investigated in beagle dogs using HPLC (High Performance Liquid Chromatography) after intravenous administration of three different doses (7.5, 5.0, 2.5 mg·kg-1). Pharmacokinetic data indicated that 2,5-BHPA fitted well to a two-compartment model. Elimination half-lives (T1/2) were 49 ± 2, 48 ± 2, and 49 ± 2 min, respectively; the peak concentrations (Cmax) were 56.48 ± 6.23, 48.63 ± 5.53, and 13.64 ± 2.76 µg·mL-1, respectively; clearance rates (CL) were 0.0062 ± 0.0004, 0.0071 ± 0.0008, and 0.0092 ±0.0006 L·min-1·kg-1, respectively; mean retention times (MRT) were 28.17 ± 1.16, 26.23 ± 0.35, and 28.66 ± 0.84 min, respectively. The low penetrability of 2,5-BHPA indicated that the intravenous route of administration is more appropriate than the oral route. Meanwhile, 2,5-BHPA showed a good pharmacokinetic profile in beagle dogs. The tissue distribution showed that 2,5-BHPA could quickly distribute into the heart, intestines, liver, stomach, spleen, lungs, testicles, urine, intestine, kidneys, brain, and feces. The concentration of 2,5-BHPA was higher in the liver and bile. Interestingly, 2,5-BHPA was detected in the brain. Taken together, the above results suggested that our work might be beneficial in the development of agents for thrombolytic treatment.

Synthesis, structure-activity relationships and biological evaluation of dehydroandrographolide and andrographolide derivatives as novel anti-hepatitis B virus agents.

Dehydroandrographolide and andrographolide, two natural diterpenoids isolated from Andrographis paniculata possessed activity against HBV DNA replication with IC50 values of 22.58 and 54.07µM and low SI values of 8.7 and 3.7 in our random assay. Consequently, 48 derivatives of dehydroandrographolide and andrographolide were synthesized and evaluated for their anti-HBV properties to yield a series of active derivatives with lower cytotoxicity, including 14 derivatives against HBsAg secretion, 19 derivatives against HBeAg secretion and 38 derivatives against HBV DNA replication. Interestingly, compound 4e could inhibit not only HBsAg and HBeAg secretions but also HBV DNA replication with SI values of 20.3, 125.0 and 104.9. Furthermore, the most active compound 2c with SI value higher than 165.1 inhibiting HBV DNA replication was revealed with the optimal logP value of 1.78 and logD values. Structure-activity relationships (SARs) of the derivatives were disclosed for guiding the future research toward the discovery of new anti-HBV drugs.

Bimetallic PtAu-Decorated SnO2 Nanospheres Exhibiting Enhanced Gas Sensitivity for Ppb-Level Acetone Detection.

Acetone is a biomarker found in the expired air of patients suffering from diabetes. Therefore, early and accurate detection of its concentration in the breath of such patients is extremely important. We prepared Tin(IV) oxide (SnO2) nanospheres via hydrothermal treatment and then decorated them with bimetallic PtAu nanoparticles (NPs) employing the approach of in situ reduction. The topology, elemental composition, as well as crystal structure of the prepared materials were studied via field emission scanning electron microscopy, transmission electron microscopy, X-ray photoelectron spectroscopy, and X-ray diffraction. The findings revealed that bimetallic PtAu-decorated SnO2 nanospheres (PtAu/SnO2) were effectively synthesized as well as PtAu NPs evenly deposited onto the surface of the SnO2 nanospheres. Pure SnO2 nanospheres and PtAu/SnO2 sensors were prepared, and their acetone gas sensitivity was explored. The findings demonstrated that in comparison to pristine SnO2 nanosphere sensors, the sensors based on PtAu/SnO2 displayed superior sensitivity to acetone of 0.166-100 ppm at 300 °C, providing a low theoretical limit of detection equal to 158 ppm. Moreover, the PtAu/SnO2 sensors showed excellent gas response (Ra/Rg = 492.3 to 100 ppm), along with fast response and recovery (14 s/13 s to 10 ppm), good linearity of correlation, excellent repeatability, long-term stability, and satisfactory selectivity at 300 °C. This improved gas sensitivity was because of the electron sensitization of the Pt NPs, the chemical sensitization of the Au NPs, as well as the synergistic effects of bimetallic PtAu. The PtAu/SnO2 sensors have considerable potential for the early diagnosis and screening of diabetes.

Suppressing ACQ of molecular photosensitizers by distorting the conjugated-plane for enhanced tumor photodynamic therapy.

Non-AIE-type molecular photosensitizers (PSs) suffer from the aggregation-caused-quenching (ACQ) effect in an aqueous medium due to the strong hydrophobic and π-π interactions of their conjugated planes, which significantly hinders the enhancement of tumor photodynamic therapy (PDT). So far, some ionic PSs have been reported with good water-solubility, though the ACQ effect can still be induced in a biological environment rich in ions, leading to unsatisfactory in vivo delivery and fluorescence imaging performance. Hence, designing molecular PSs with outstanding anti-ACQ properties in water is highly desirable, but it remains a tough challenge for non-AIE-type fluorophores. Herein, we demonstrated a strategy for the design of porphyrin-type molecular PSs with remarkable solubility and anti-ACQ properties in an aqueous medium, which was assisted by quantum chemical simulations. It was found that cationic branched side chains can induce serious plane distortion in diphenyl porphyrin (DPP), which was not observed for tetraphenyl porphyrin (TPP) with the same side chains. Moreover, the hydrophilicity of the chain spacer is also crucial to the plane distortion for attaining the desired anti-ACQ properties. Compared to ACQ porphyrin, anti-ACQ porphyrin displayed type-I ROS generation in hypoxia and much higher tumor accumulation efficacy by blood circulation, leading to highly efficient in vivo PDT for hypoxic tumors. This study demonstrates the power of sidechain chemistry in tuning the configuration and aggregation behaviors of porphyrins in water, offering a new path to boost the performance of PSs to fulfill the increasing clinical demands on cancer theranostics.

Positive regulation of the Eucommia rubber biosynthesis-related gene EuFPS1 by EuWRKY30 in Eucommia ulmoides.

Eucommia rubber is a secondary metabolite from Eucommia ulmoides that has attracted much attention because of its unique properties and enormous potential for application. However, the transcriptional mechanism regulating its biosynthesis has not yet been determined. Farnesyl pyrophosphate synthase is a key enzyme in the Eucommia rubber biosynthesis. In this study, the promoter of EuFPS1 was used as bait, EuWRKY30 was screened from the cDNA library of EuFPS1 via a yeast one-hybrid system. EuWRKY30 belongs to the WRKY IIa subfamily and contains a WRKY domain and a C2H2 zinc finger motif, and the expressed protein is located in the nucleus. EuWRKY30 and EuFPS1 exhibited similar tissue expression patterns, and yeast one-hybrid and dual-luciferase experiments confirmed that EuWRKY30 directly binds to the W-box element in the EuFPS1 promoter and activates its expression. Moreover, the overexpression of EuWRKY30 significantly upregulated the expression level of EuFPS1, further increasing the density of the rubber particles and Eucommia rubber content. The results of this study indicated that EuWRKY30 positively regulates EuFPS1, which plays a critical role in the synthesis of Eucommia rubber, provided a basis for further analysis of the underlying transcriptional regulatory mechanisms.

Synthesis of hemslecin A derivatives: a new class of hepatitis B virus inhibitors.

A series of hemslecin A derivatives were synthesized and evaluated for their anti-hepatitis B virus (HBV) activities, namely, inhibiting the secretion of hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg), and HBV DNA replication on HepG 2.2.15 cells. Most of the derivatives showed enhanced anti-HBV activities, of which compounds A1-A7, B5, C and E exhibited significant activities inhibiting HBV DNA replication with IC(50) values of 2.8-11.6 µM, comparable to that of the positive control, tenofovir. Compounds A1-A3, A5, B5, and C displayed low cytotoxicities, which resulted in high SI values of 89.7, 55.6, 77.8, >83.4, >55.8, and >150.5, respectively.

Application of Zebrafish as a Model for Anti-Cancer Activity Evaluation and Toxicity Testing of Natural Products.

Developing natural product-based anti-cancer drugs/agents is a promising way to overcome the serious side effects and toxicity of traditional chemotherapeutics for cancer treatment. However, rapid assessment of the in vivo anti-cancer activities of natural products is a challenge. Alternatively, zebrafish are useful model organisms and perform well in addressing this challenging issue. Nowadays, a growing number of studies have utilized zebrafish models to evaluate the in vivo activities of natural compounds. Herein, we reviewed the application of zebrafish models for evaluating the anti-cancer activity and toxicity of natural products over the past years, summarized its process and benefits, and provided future outlooks for the development of natural product-based anti-cancer drugs.

Formula milk brands marketing on Chinese social media Weibo - a content analysis.

Background: Parents' feeding practices in the first 2 years of life have profound effects on children's survival, health and development throughout their lives. Decisions on how to feed infants and young children should be based on the best information and evidence, not influenced by commercial interests. China is the largest and fastest-growing market for formula milk products. Social media has emerged as a distinctive marketing avenue that can reach consumers directly. Weibo is one of the most popular Chinese social media platforms. This study examined four of the most popular milk formula brands' official Weibo accounts: Biotime, Mead Johnson, YiLi-Prokido, and Friso. Question: What messages posted and what marketing practices and tactics are used by formula milk brands on Weibo. Methods: We manually downloaded all posts in the four accounts between 1 January and 31 December 2018. Based on previous studies, we developed a marketing practices coding framework and selected ten mutually exclusive categories for coding and analysing the posts. Findings: Among 2667 original posts analysed, 65% were from three dominant categories: user engagement (939/2667, 35.2%), parenting advice (516/2667, 19.3%), and celebrity endorsement (327/2667, 12.3%). Other categories included making pseudo-health or nutrition claims and portraying breastfeeding as a painful or problematic experience. Conclusion: Widespread marketing practices and tactics were found in the four examined Weibo accounts of formula milk brands. Monitoring and regulation of formula milk marketing on social media are urgently needed. Social media platforms should also be held accountable for protecting a supportive breastfeeding environment.

An Overview of Thrombin Inhibitors in the Perspective of Structureactivity Relationships.

Thrombosis is one of the most important pathogenic factors related to cardiovascular diseases. Presently, thrombin inhibitors have gradually gained prominence in clinical practice due to their unique potential, such as dabigatran. Nevertheless, the risk of bleeding is not completely eliminated, and the threats of gastrointestinal bleeding are even increased in some cases. Therefore, developing new oral thrombin inhibitors with low side effects is urgent. In this paper, we summarized recent advances in the newly synthesized and isolated thrombin inhibitors from 2000 to 2019 and their structure-activity relationships (SARs) along with structure-dependent pharmacokinetic parameters, guiding the next generation of oral thrombin inhibitors.