CMAUP database update 2024: extended functional and association information of useful plants for biomedical research.

Knowledge of the collective activities of individual plants together with the derived clinical effects and targeted disease associations is useful for plant-based biomedical research. To provide the information in complement to the established databases, we introduced a major update of CMAUP database, previously featured in NAR. This update includes (i) human transcriptomic changes overlapping with 1152 targets of 5765 individual plants, covering 74 diseases from 20 027 patient samples; (ii) clinical information for 185 individual plants in 691 clinical trials; (iii) drug development information for 4694 drug-producing plants with metabolites developed into approved or clinical trial drugs; (iv) plant and human disease associations (428 737 associations by target, 220 935 reversion of transcriptomic changes, 764 and 154121 associations by clinical trials of individual plants and plant ingredients); (v) the location of individual plants in the phylogenetic tree for navigating taxonomic neighbors, (vi) DNA barcodes of 3949 plants, (vii) predicted human oral bioavailability of plant ingredients by the established SwissADME and HobPre algorithm, (viii) 21-107% increase of CMAUP data over the previous version to cover 60 222 chemical ingredients, 7865 plants, 758 targets, 1399 diseases, 238 KEGG human pathways, 3013 gene ontologies and 1203 disease ontologies. CMAUP update version is freely accessible at https://bidd.group/CMAUP/index.html.

NPASS database update 2023: quantitative natural product activity and species source database for biomedical research.

Quantitative activity and species source data of natural products (NPs) are important for drug discovery, medicinal plant research, and microbial investigations. Activity values of NPs against specific targets are useful for discovering targeted therapeutic agents and investigating the mechanism of medicinal plants. Composition/concentration values of NPs in individual species facilitate the assessments and investigations of the therapeutic quality of herbs and phenotypes of microbes. Here, we describe an update of the NPASS natural product activity and species source database previously featured in NAR. This update includes: (i) new data of ∼95 000 records of the composition/concentration values of ∼1 490 NPs/NP clusters in ∼390 species, (ii) extended data of activity values of ∼43 200 NPs against ∼7 700 targets (∼40% and ∼32% increase, respectively), (iii) extended data of ∼31 600 species sources of ∼94 400 NPs (∼26% and ∼32% increase, respectively), (iv) new species types of ∼440 co-cultured microbes and ∼420 engineered microbes, (v) new data of ∼66 600 NPs without experimental activity values but with estimated activity profiles from the established chemical similarity tool Chemical Checker, (vi) new data of the computed drug-likeness properties and the absorption, distribution, metabolism, excretion and toxicity (ADMET) properties for all NPs. NPASS update version is freely accessible at http://bidd.group/NPASS.

Co-targeting CD47 and VEGF elicited potent anti-tumor effects in gastric cancer.

BACKGROUND: CD47, serving as an intrinsic immune checkpoint, has demonstrated efficacy as an anti-tumor target in hematologic malignancies. Nevertheless, the clinical relevance of CD47 in gastric cancer and its potential as a therapeutic target remains unclear. METHODS: The expression of CD47 in clinical gastric cancer tissues was assessed using immunohistochemistry and Western blot. Patient-derived cells were obtained from gastric cancer tissues and co-cultured with macrophages derived from human peripheral blood mononuclear cells. Flow cytometry analyses were employed to evaluate the rate of phagocytosis. Humanized patient-derived xenografts (Hu-PDXs) models were established to assess the efficacy of anti-CD47 immunotherapy or the combination of anti-CD47 and anti-VEGF therapy in treating gastric cancer. The infiltrated immune cells in the xenograft were analyzed by immunohistochemistry. RESULTS: In this study, we have substantiated the high expression of CD47 in gastric cancer tissues, establishing a strong association with unfavorable prognosis. Through the utilization of SIRPα-Fc to target CD47, we have effectively enhanced macrophage phagocytosis of PDCs in vitro and impeded the growth of Hu-PDXs. It is noteworthy that anti-CD47 immunotherapy has been observed to sustain tumor angiogenic vasculature, with a positive correlation between the expression of VEGF and CD47 in gastric cancer. Furthermore, the successful implementation of anti-angiogenic treatment has further augmented the anti-tumor efficacy of anti-CD47 therapy. In addition, the potent suppression of tumor growth, prevention of cancer recurrence after surgery, and significant prolongation of overall survival in Hu-PDX models can be achieved through the simultaneous targeting of CD47 and VEGF using the bispecific fusion protein SIRPα-VEGFR1 or by combining the two single-targeted agents. CONCLUSIONS: Our preclinical studies collectively offer substantiation that CD47 holds promise as a prospective target for gastric cancer, while also highlighting the potential of anti-angiogenic therapy to enhance tumor responsiveness to anti-CD47 immunotherapy.

TROP2-directed nanobody-drug conjugate elicited potent antitumor effect in pancreatic cancer.

BACKGROUND: Pancreatic cancer is a highly aggressive malignancy with limited treatment options and a poor prognosis. Trophoblast cell surface antigen 2 (TROP2), a cell surface antigen overexpressed in the tumors of more than half of pancreatic cancer patients, has been identified as a potential target for antibody-drug conjugates (ADCs). Almost all reported TROP2-targeted ADCs are of the IgG type and have been poorly studied in pancreatic cancer. Here, we aimed to develop a novel nanobody-drug conjugate (NDC) targeting TROP2 for the treatment of pancreatic cancer. RESULTS: In this study, we developed a novel TROP2-targeted NDC, HuNbTROP2-HSA-MMAE, for the treatment of TROP2-positive pancreatic cancer. HuNbTROP2-HSA-MMAE is characterized by the use of nanobodies against TROP2 and human serum albumin (HSA) and has a drug-antibody ratio of 1. HuNbTROP2-HSA-MMAE exhibited specific binding to TROP2 and was internalized into tumor cells with high endocytosis efficiency within 5 h, followed by intracellular translocation to lysosomes and release of MMAE to induce cell apoptosis in TROP2-positive pancreatic cancer cells through the caspase-3/9 pathway. In a xenograft model of pancreatic cancer, doses of 0.2 mg/kg and 1 mg/kg HuNbTROP2-HSA-MMAE demonstrated significant antitumor effects, and a dose of 5 mg/kg even eradicated the tumor. CONCLUSION: HuNbTROP2-HSA-MMAE has desirable affinity, internalization efficiency and antitumor activity. It holds significant promise as a potential therapeutic option for the treatment of TROP2-positive pancreatic cancer.

Innate Immunity in Cancer Biology and Therapy.

Immunotherapies including adaptive immune checkpoint inhibitors (ICIs) and chimeric antigen receptor (CAR) T cells, have developed the treatment of cancer in clinic, and most of them focus on activating T cell immunity. Although these strategies have obtained unprecedented clinical responses, only limited subsets of cancer patients could receive long-term benefits, highlighting the demand for identifying novel targets for the new era of tumor immunotherapy. Innate immunity has been demonstrated to play a determinative role in the tumor microenvironment (TME) and influence the clinical outcomes of tumor patients. A thorough comprehension of the innate immune cells that infiltrate tumors would allow for the development of new therapeutics. In this review, we outline the role and mechanism of innate immunity in TME. Moreover, we discuss innate immunity-based cancer immunotherapy in basic and clinical studies. Finally, we summarize the challenges in sufficiently motivating innate immune responses and the corresponding strategies and measures to improve anti-tumor efficacy. This review could aid the comprehension of innate immunity and inspire the creation of brand-new immunotherapies for the treatment of cancer.

Association between Serum Free Fatty Acids to HDL-Cholesterol Ratio and Nonalcoholic Fatty Liver Disease: a Cross-Sectional Study.

BACKGROUND: This cross-sectional study aimed to investigate the association between serum free fatty acids and high-density lipoprotein-cholesterol ratio (FHR) and nonalcoholic fatty liver disease (NAFLD) in a Chinese population. METHODS: A total of 760 NAFLD subjects and 379 healthy controls who took their annual health checkups were enrolled during 2019. Fasting blood samples were obtained from the population. NAFLD was diagnosed based on hepatic ultrasound examination. RESULTS: Serum FHR (*100) in NAFLD subjects was significantly higher than that in controls. We found that the serum FHR in NAFLD participants was positively correlated with BMI, DBP, WBC, HGB, ALT, AST, GGT, TG, FPG, UA, and hsCRP. Univariate and multivariate logistic regression analysis showed that FHR was independently associated with the presence of NAFLD. The area under curve (AUC) of the receiver operating characteristic (ROC) curve of FHR for NAFLD was 0.781 with the 95% confidence interval from 0.753 to 0.810. The optimal cutoff point of FHR for predicting NAFLD was 41.14 with 78.8% sensitivity and 77.3%, respectively. CONCLUSIONS: FHR was significantly associated with NAFLD and may serve as an effective indicator in NAFLD patients.

Targeting PARP and autophagy evoked synergistic lethality in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC), one of the most lethal malignancies worldwide, has limited efficient therapeutic options. Here, we first demonstrated that simultaneously targeting poly (ADP-ribose) polymerase (PARP) and autophagy could evoke striking synergistic lethality in HCC cells. Specifically, we found that the PARP inhibitor Niraparib induced cytotoxicity accompanied by significant autophagy formation and autophagic flux in HCC cells. Further experiments showed that Niraparib induced suppression of the Akt/mTOR pathway and activation of the Erk1/2 cascade, two typical signaling pathways related to autophagy. In addition, the accumulation of reactive oxygen species was triggered, which was involved in Niraparib-induced autophagy. Blocking autophagy by chloroquine (CQ) in combination with Niraparib further enhanced cytotoxicity, induced apoptosis and inhibited colony formation in HCC cells. Synergistic inhibition was also observed in Huh7 xenografts in vivo. Mechanistically, we showed that autophagy inhibition abrogated Niraparib-induced cell-cycle arrest and checkpoint activation. Cotreatment with CQ and Niraparib promoted the formation of γ-H2AX foci while inhibiting the recruitment of the homologous recombination repair protein RAD51 to double-strand break sites. Thus, the present study developed a novel promising strategy for the management of HCC in the clinic and highlighted a potential approach to expand the application of PARP inhibitors.

Serum Thyroid Hormones Levels are Significantly Associated with Nonalcoholic Fatty Liver Disease in Euthyroid Chinese Population.

BACKGROUND: Thyroid hormones play an essential role in metabolic homeostasis. Previous studies have demon-strated a close relationship between thyroid abnormalities and metabolic disorders. This retrospective cross-sectional study was to investigate whether significant differences of circulating thyroid profiles exist and to explore the potential of serum thyroid hormones in reflecting advanced fibrosis in subjects with Nonalcoholic Fatty Liver Disease (NAFLD). METHODS: Abdominal ultrasonography was performed to diagnose NAFLD. For all the participants including 522 NAFLD patients and 415 gender- and age-matched controls recruited, demographic, clinical data and thyroid functions were recorded. Fasting serum thyroid hormones including free triiodothyronine (FT3), free thyroxine (FT4), total thyroxine (TT4), total triiodothyronine (TT3), and thyroid-stimulating hormone (TSH) were evaluated. RESULTS: Serum FT3 levels in subjects with NAFLD were significantly reduced, while TSH was increased compared to that in controls. The NAFLD subjects with metabolic syndrome (MS) had significantly lower FT3 and FT4 levels and higher TSH levels than the non-MS group. Serum TSH levels were positively associated with the risk for NAFLD, while FT3 levels were inversely correlated with NAFLD. Among thyroid hormones, low serum FT4 was the only independent predictor of reflecting advanced fibrosis in NAFLD participants. CONCLUSIONS: An altered thyroid profile not only can be significantly associated with an increased incidence of NAFLD, but also had clinical predictive value for assessing significant fibrosis.

Recombinant human arginase I elicited immunosuppression in activated macrophages through inhibiting autophagy.

Arginase I has been documented to impair T cell function and attenuate cellular immunity, however, there is little evidence to reveal the effect of arginase I on macrophage function. Recently, recombinant human arginase I (rhArg) has been developed for cancer therapy and is in clinical trial for hepatocellular carcinoma, whereas the potential immunosuppression induced by rhArg limited its therapeutic efficacy. To improve the clinical outcome of rhArg, addressing the immune suppression appears to be particularly important. In this study, we found that rhArg attenuated macrophage functions, including inhibiting macrophage cell proliferation, nitric oxide (NO) and reactive oxygen species (ROS) production, cytokine secretion, MHC-II surface expression, and phagocytosis, thereby inducing immunosuppression in lipopolysaccharides (LPS)/interferon-γ (IFN-γ)-activated macrophages. Notably, we observed that rhArg downregulated autophagy in activated macrophages. Moreover, application of trehalose (an autophagy inducer) significantly restored the impaired immune function in activated macrophages, suggesting the essential role of autophagy in rhArg-induced immunosuppression. To further illustrate the effect of autophagy in immunosuppression, we then observed the effect of 3-MA (an autophagy inhibitor) on the immune function of macrophages. As expected, inhibiting autophagy by 3-MA attenuated immune functions in activated macrophages. Collectively, this study elucidated that rhArg induced immunosuppression in activated macrophages via inhibiting autophagy, providing potential strategy to ameliorate the immune suppression which is of great significance to cancer therapy and facilitating the development of rhArg as a potential therapy for malignant carcinomas.

Association between Serum Ferritin Level and Nonalcoholic Fatty Liver Disease in a Non-Obese Chinese Population: a Cross-Sectional Study.

BACKGROUND: The aim of the study is to evaluate the cross-sectional association between serum ferritin level and nonalcoholic fatty liver disease (NAFLD) in a non-obese Chinese population. METHODS: A cross-sectional study was performed among 1,020 non-obese subjects (body mass index < 25 kg/m2) who took their annual health examination at the First Affiliated Hospital, College of Medicine, Zhejiang University. Serum ferritin level and other clinical and laboratory parameters were measured in the population. Liver ultrasound examinations were performed to diagnose NAFLD. RESULTS: Of the 1,020 enrolled participants, 148 (14.51%) fulfilled the diagnostic criteria for NAFLD. Subjects with NAFLD had a higher level of serum ferritin than individuals without NAFLD in non-obese subjects. Serum ferritin level was significantly and positively correlated with parameters of MS (BMI, SBP, TG and FPG) in NAFLD group. Stepwise logistic regression analysis showed that serum ferritin level was significantly associated with the risk factor for NAFLD. After adjusting for confounders, serum ferritin level was an independent factor predicting advanced fibrosis (FIB-4 ≥ 1.3) in NAFLD participants. CONCLUSIONS: Increased serum ferritin level is significantly associated with NAFLD, and elevated serum ferritin level is an independent factor predicting advanced fibrosis for NAFLD in a non-obese Chinese population.

Disrupting CD47-SIRPα axis alone or combined with autophagy depletion for the therapy of glioblastoma.

CD47-targeting immune checkpoint inhibitors have been investigated for immunotherapy of several cancers, glioblastoma, one of the most common tumors in brain, was still a challenge for CD47-targeting therapy. Herein, we reported novel strategies for glioblastoma therapy via blocking CD47-signal regulatory protein-α (SIRPα) by SIRPα-Fc alone or in combination with autophagy inhibition. Our results showed that SIRPα-Fc increased macrophages-triggered cytotoxicity and phagocytosis of glioblastoma cells then elicited potent anti-tumor efficacy. During the treatment, SIRPα-Fc induced autophagy and autophagic flux in glioblastoma cells and Akt/mammalian target of rapamycin (mTOR) inactivation was participated in the autophagy activation. Inhibition of autophagy by pharmacological agents or small-interfering RNA increased SIRPα-Fc-triggered macrophage phagocytosis and cytotoxicity. Importantly, when compared with SIRPα-Fc treatment, blocking both CD47/SIRPα and autophagy significantly increased infiltration of macrophages and apoptosis of tumor cells, triggering potentiated anti-glioblastoma effect and extended median survival. Further experiments showed that adaptive immune response, including CD8+ T-cell subsets, was also played a crucial role in SIRPα-Fc-induced glioblastoma rejection. Our results indicated that SIRPα-Fc alone or combined with autophagy inhibitors elicited potent anti-glioblastoma effect, highlighting potential therapeutic strategies of glioblastoma via blocking CD47/SIRPα alone or in combination with autophagy inhibitor.

Dihydroquercetin ameliorated acetaminophen-induced hepatic cytotoxicity via activating JAK2/STAT3 pathway and autophagy.

Acetaminophen (APAP) overdose is currently the leading cause of acute liver disease, but therapeutic treatment strategies are commonly limited. Although dihydroquercetin (DHQ) is an attractive botanical antioxidant, its protective potential for liver disease remains elusive. The present study investigated the protective effects of DHQ against APAP-induced hepatic cytotoxicity. Primary mouse hepatocytes were treated with different concentrations of DHQ followed by APAP administration. Our data showed that DHQ relieved APAP-induced growth inhibition and lactate dehydrogenase (LDH) release in a dose-dependent manner, as well as inhibited APAP-induced necrosis and extracellular signal regulated kinase-c-Jun-N-terminal kinase (ERK-JNK) stress. In addition, reactive oxygen species (ROS) accumulation and mitochondria dysfunction were also reversed by DHQ treatment. Further study revealed that DHQ induced phosphorylation of Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) cascade and thus modulated expression of anti-apoptotic Bcl-2 family proteins. Moreover, DHQ induced autophagy which mediated its protective effects in hepatocytes. The protection was abrogated through pharmacological blockage of autophagy by chloroquine (CQ). These studies demonstrated, for the first time, that DHQ possessed hepatocellular protective effects in the context of APAP-induced cytotoxicity and subsequently revealed that the mechanisms comprised activation of JAK2/STAT3 signaling pathway and autophagy. These altogether highlighted the significant therapeutic potential of this agent during acute liver failure and other types of liver diseases.

Inhibition of autophagy potentiated the anti-tumor effects of VEGF and CD47 bispecific therapy in glioblastoma.

Glioblastoma, characterized by extensive microvascular proliferation and invasive tumor growth, is one of the most common and lethal malignancies in adults. Benefits of the conventional anti-angiogenic therapy were only observed in a subset of patients and limited by diverse relapse mechanism. Fortunately, recent advances in cancer immunotherapy have offered new hope for patients with glioblastoma. Herein, we reported a novel dual-targeting therapy for glioblastoma through simultaneous blockade of VEGF and CD47 signaling. Our results showed that VEGFR1D2-SIRPαD1, a VEGF and CD47 bispecific fusion protein, exerted potent anti-tumor effects via suppressing VEGF-induced angiogenesis and activating macrophage-mediated phagocytosis. Meanwhile, autophagy was activated by VEGFR1D2-SIRPαD1 through inactivating Akt/mTOR and Erk pathways in glioblastoma cells. Importantly, autophagy inhibitor or knockdown of autophagy-related protein 5 potentiated VEGFR1D2-SIRPαD1-induced macrophage phagocytosis and cytotoxicity against glioblastoma cells. Moreover, suppression of autophagy led to increased macrophage infiltration, angiogenesis inhibition, and tumor cell apoptosis triggered by VEGF and CD47 dual-targeting therapy, thus eliciting enhanced anti-tumor effects in glioblastoma. Our data revealed that VEGFR1D2-SIRPαD1 alone or in combination with autophagy inhibitor could effectively elicit potent anti-tumor effects, highlighting potential therapeutic strategies for glioblastoma through disrupting angiogenetic axis and CD47-SIRPα anti-phagocytic axis alone or in combination with autophagy inhibition.

Association Between Urinary Alpha1-Microglobulin Levels and Nonalcoholic Fatty Liver Disease: A Cross-Sectional Study.

BACKGROUND: We aimed to explore the association between urinary alpha1-microglobulin (A1M) levels and nonalcoholic fatty liver disease (NAFLD) in a Chinese population. STUDY: We performed a cross-sectional study among 2,215 Chinese who attended their annual health examination at First Affiliated Hospital, College of Medicine, Zhejiang University. Urinary A1M-creatinine ratio and other clinical and laboratory parameters were measured. RESULTS: A total of 20.9% of subjects fulfilled the diagnostic criteria of NAFLD. NAFLD subjects had significantly higher urinary A1M-creatinine ratios. These levels were positively associated with NAFLD prevalence. The association between A1M-creatinine ratio and NAFLD was independent of hyperglycemia status. Stepwise regression showed that urinary A1M-creatinine ratio was significantly associated with the risk for NAFLD. Urinary A1M-creatinine ratio was an independent factor predicting advanced fibrosis (FIB-4 ≥1.3) in NAFLD patients. CONCLUSIONS: Our results showed a significant association between urinary A1M-creatinine ratio and NAFLD.

Association between urine retinol-binding protein levels and nonalcoholic fatty liver disease: A cross-sectional study in Chinese population.

OBJECTIVE: The prevalence of nonalcoholic fatty liver disease (NAFLD) has been rapidly increased, becoming a public health problem worldwide. Our objective was to investigate the association between urine retinol-binding protein (RBP) and NAFLD in a Chinese population and develop a multivariate logistic regression model for NAFLD prediction. METHODS: A total of 317 NAFLD patients and 391 healthy controls were enrolled in this cross-sectional study based on inclusion and exclusion criteria, from whom fasting urine and blood were collected for further study. Urine RBP level and other parameters were measured and compared between NAFLD subjects and controls. RESULTS: Urine RBP levels (expressed by RBP/creatinine ratio) in NAFLD patients were significantly higher than controls (median 133.1 mg/g vs 110.7 mg/g; P < .001). Urine RBP/creatinine ratio was verified as an independent factor for NAFLD prediction after adjustment in multivariate logistic regression. The area under curve (AUC) of receiver operating characteristic (ROC) was 0.889 with the 95% confidence interval from 0.867 to 0.912.With a cutoff point of 0.215, the sensitivity and specificity of urine RBP/creatinine ratio in NAFLD prediction were 81.1% and 84.5%, respectively. CONCLUSION: Our results demonstrated that urine RBP/creatinine ratio was an independent risk factor for NAFLD while the predictive model for NAFLD diagnosis is noninvasive with high sensitivity and specificity.

Deprivation of asparagine triggers cytoprotective autophagy in laryngeal squamous cell carcinoma.

Laryngeal squamous cell carcinoma (LSCC), one of the most common malignancies in the head and neck, has poor prognosis and high mortality. The need of novel and effective treatment for LSCC is urgent. Asparaginase, an enzyme-depriving asparagine, has been employed for the treatment of various cancers. In this study, we reported for the first time that asparaginase could induce remarkable cytotoxicity and caspase-dependent apoptosis in human LSCC Tu212 and Tu686 cells. Meanwhile, autophagy was triggered by asparaginase in LSCC cells, which was confirmed by accumulation of autophagosomes and the conversion of light chain 3-I (LC3-I) to LC3-II. Importantly, inhibition of autophagy by chloroquine (CQ) significantly enhanced asparaginase-induced cytotoxicity, indicating that autophagy has a cytoprotective role in asparaginase-treated LSCC cells. Meanwhile, we found that mitochondrial-originated reactive oxygen species (ROS) participated in asparaginase-induced autophagy and cytotoxicity. N-acetyl-L-cysteine (NAC), a common antioxidant, was employed to scavenge ROS, and our results demonstrated that NAC could significantly block asparaginase-induced autophagy and attenuate asparaginase-induced cytotoxicity, indicating that intracellular ROS played a crucial role in asparagine deprivation therapy. Furthermore, western blot analysis showed that asparaginase-induced autophagy was mediated by inactivation of Akt/mTOR and activation of the Erk signaling pathway in Tu212 and Tu686 cells. Therefore, these results indicated the protective role of autophagy in asparaginase-treated LSCC cells and provided a new attractive therapeutic strategy for LSCC by asparaginase alone or in combination with autophagic inhibitors.

Targeting asparagine and autophagy for pulmonary adenocarcinoma therapy.

The mounting number of patients with pulmonary adenocarcinoma (ADCA) is subjected to poor prognosis and heavy mortality, which prompts us to explore new potential therapeutics for lung ADCA. Herein, we reported a novel approach for lung ADCA therapy by abolishing autophagy and asparagine. We demonstrated that deprivation of asparagine by asparaginase could induce significant cytotoxicity and apoptosis in A549 and H1975 cells. During this process, autophagy was triggered by the asparaginase treatment, characterized by the autophagic flux with three main stages including formation of autophagosomes, lysosomes fused with autophagosomes, and degradation of autophagosomes by lysosomes. Importantly, suppression of autophagy could notably enhance the cytotoxicity and accelerate the caspase 3-dependent apoptosis induced by asparaginase. Furthermore, suppression of reactive oxygen species (ROS) could attenuated both the cytotoxicity and autophagy induced by asparaginase, while inhibition of autophagy promoted the generation of ROS in A549 and H1975 cells, indicating the essential role of ROS in asparagine deprivation therapy in lung ADCA cells. Our results demonstrated that targeting cytoprotective autophagy and asparagine could potently kill the ADCA cells, which highlighted a novel approach for lung ADCA therapy in the clinics.

Synthesis and biological evaluation of novel pyrimidine-benzimidazol hybrids as potential anticancer agents.

A series of pyrimidine-benzimidazol hybrids was synthesized and evaluated for anticancer activity on four human cancer cell lines including MCF-7, MGC-803, EC-9706 and SMMC-7721. Some of the synthesized compounds exhibited moderate to potent activity against MGC-803 and MCF-7. Among them, compounds 5a-b and 6a-b showed most effective activity. Compounds 5b and 6b were more cytotoxic than 5-fluorouracil against all tested four human cancer cell lines, with IC50 values ranging from 2.03 to 10.55 µM and 1.06 to 12.89 µM, respectively. Flow cytometry analysis demonstrated that treatment of MGC-803 with 6b led to cell cycle arrest at G2/M phase accompanied by an increase in apoptotic cell death.

Revisiting Confidence Estimation: Towards Reliable Failure Prediction.

Reliable confidence estimation is a challenging yet fundamental requirement in many risk-sensitive applications. However, modern deep neural networks are often overconfident for their incorrect predictions, i.e., misclassified samples from known classes, and out-of-distribution (OOD) samples from unknown classes. In recent years, many confidence calibration and OOD detection methods have been developed. In this paper, we find a general, widely existing but actually-neglected phenomenon that most confidence estimation methods are harmful for detecting misclassification errors. We investigate this problem and reveal that popular calibration and OOD detection methods often lead to worse confidence separation between correctly classified and misclassified examples, making it difficult to decide whether to trust a prediction or not. Finally, we propose to enlarge the confidence gap by finding flat minima, which yields state-of-the-art failure prediction performance under various settings including balanced, long-tailed, and covariate-shift classification scenarios. Our study not only provides a strong baseline for reliable confidence estimation but also acts as a bridge between understanding calibration, OOD detection, and failure prediction.

Emergence of machine language: towards symbolic intelligence with neural networks.

Inspired by human language, machine language is a novel discrete representation learned from visual data only through playing the speak, guess, and draw game.