Eco-evolutionary Guided Pathomic Analysis to Predict DCIS Upstaging.

Cancers evolve in a dynamic ecosystem. Thus, characterizing cancer's ecological dynamics is crucial to understanding cancer evolution and can lead to discovering novel biomarkers to predict disease progression. Ductal carcinoma in situ (DCIS) is an early-stage breast cancer characterized by abnormal epithelial cell growth confined within the milk ducts. Although there has been extensive research on genetic and epigenetic causes of breast carcinogenesis, none of these studies have successfully identified a biomarker for the progression and/or upstaging of DCIS. In this study, we show that ecological habitat analysis of hypoxia and acidosis biomarkers can significantly improve prediction of DCIS upstaging. First, we developed a novel eco-evolutionary designed approach to define habitats in the tumor intra-ductal microenvironment based on oxygen diffusion distance in our DCIS cohort of 84 patients. Then, we identify cancer cells with metabolic phenotypes attributed to their habitat conditions, such as the expression of CA9 indicating hypoxia responding phenotype, and LAMP2b indicating a hypoxia-induced acid adaptation. Traditionally these markers have shown limited predictive capabilities for DCIS upstaging, if any. However, when analyzed from an ecological perspective, their power to differentiate between indolent and upstaged DCIS increased significantly. Second, using eco-evolutionary guided computational and digital pathology techniques, we discovered distinct spatial patterns of these biomarkers and used the distribution of such patterns to predict patient upstaging. The patterns were characterized by both cellular features and spatial features. With a 5-fold validation on the biopsy cohort, we trained a random forest classifier to achieve the area under curve(AUC) of 0.74. Our results affirm the importance of using eco-evolutionary-designed approaches in biomarkers discovery studies in the era of digital pathology by demonstrating the role of eco-evolution dynamics in predicting cancer progression.

Ferroptosis-inducing compounds synergize with docetaxel to overcome chemoresistance in docetaxel-resistant non-small cell lung cancer cells.

Development of resistance to therapy-induced cell death is a major hurdle in the effective treatment of advanced solid tumors. Erastin and RSL3 were originally found to induce synthetic lethality by induction of a novel form of cell death termed ferroptosis. Emerging evidence suggests that ferroptosis inducers enhance chemosensitivity of classic therapeutic agents by triggering ferroptotic cell death. In this study we evaluated the effects of erastin and RSL3 on the resistance of docetaxel, doxorubicin, and cisplatin, and revealed a mechanism whereby these ferroptosis inducers augment docetaxel efficacy in non-small cell lung cancer by regulating redox signaling to promote ferroptosis. Transcriptome analysis revealed that combination treatment modulated not only p53 signaling pathway but also immune responses and several signaling pathways including MAPK, NF-κB and PI3K/Akt. Considering that glutathione peroxidase 4 (GPX4) serves as the main effector to protect cells from ferroptosis, this study identified three novel non-covalent GPX4 inhibitors with the aid of pharmacophore-based virtual screening. The new ferroptosis-inducing compounds synergized with docetaxel to increase the cytotoxicity by promoting ferroptotic cell death in docetaxel-resistant A549/DTX cells. Collectively, the induction of ferroptosis contributed to docetaxel-induced cytotoxic effects and overcame drug resistance in A549/DTX cells. Ferroptosis has a great potential to become a new approach to attenuate resistance to some classic therapeutic drugs in cancer patients.

NKUT: Dataset and Benchmark for Pediatric Mandibular Wisdom Teeth Segmentation.

Germectomy is a common surgery in pediatric dentistry to prevent the potential dangers caused by impacted mandibular wisdom teeth. Segmentation of mandibular wisdom teeth is a crucial step in surgery planning. However, manually segmenting teeth and bones from 3D volumes is time-consuming and may cause delays in treatment. Deep learning based medical image segmentation methods have demonstrated the potential to reduce the burden of manual annotations, but they still require a lot of well-annotated data for training. In this paper, we initially curated a Cone Beam Computed Tomography (CBCT) dataset, NKUT, for the segmentation of pediatric mandibular wisdom teeth. This marks the first publicly available dataset in this domain. Second, we propose a semantic separation scale-specific feature fusion network named WTNet, which introduces two branches to address the teeth and bones segmentation tasks. In WTNet, We design a Input Enhancement (IE) block and a Teeth-Bones Feature Separation (TBFS) block to solve the feature confusions and semantic-blur problems in our task. Experimental results suggest that WTNet performs better on NKUT compared to previous state-of-the-art segmentation methods (such as TransUnet), with a maximum DSC lead of nearly 16%.

Intracoronary microcatheter indwelling for continuous pumping of low-dose thrombolytic drugs: A new approach to reperfusion in acute myocardial infarction.

Reperfusion therapy of acute myocardial infarction (AMI) refers to physical or chemical recanalization and restoration of blood flow to an occluded coronary artery, and current techniques for reperfusion therapy include intravenous thrombolysis, percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG). The number of patients receiving emergency CABG in the real world is decreasing due to the disadvantages of CABG and the improvement in PCI procedures. Thrombolytic therapy has some disadvantages such as low recanalization rate, high risk of reocclusion and bleeding, and short time window. On the other hand, intracoronary interventional therapy may meet the requirements of "early, complete and persistent" patency of coronary arteries at different time points. However, in the emergency PCI, although thrombus aspiration via a catheter or balloon dilation is performed, residual thrombus with heavy or low TIMI (thrombolysis in myocardial infarction) myocardial perfusion grading is still observed in some patients, suggesting disordered microcirculation. Currently, the treatment of microcirculatory disturbance in emergency PCI mainly employed injection of tirofiban, adenosine, thrombolytic agent or other drugs into the local area via a microcatheter in a short time, all of which can significantly reduce the thrombus load and improve TIMI perfusion. Herein, we report that a microcatheter was indwelled in the coronary artery for continuous pumping of low-dose thrombolytic drugs as reperfusion therapy in 12 patients with acute and subacute MI.

Association of cardio-renal biomarkers and mortality in the U.S.: a prospective cohort study.

OBJECTIVE: Diabetes poses a significant threat to human health. There is a lack of large-scale cohort studies to explore the association between mortality risk and indicators beyond blood glucose monitoring in diabetic populations. METHODS: Multivariable Cox proportional hazards regression models were performed to investigate the association of 13 blood biomarkers with mortality risk in the National Health and Nutrition Examination Survey (NHANES) and biomarker levels were log-transformed and correlated with mortality. RESULTS: During a median follow-up of 7.42 years, 1783 diabetic patients were enrolled. Compared to traditional risk factors, the addition of hs-cTnT, hs-cTnI, NT-proBNP, creatinine, cystatin C, and ß-2 microglobulin biomarkers increased the predictive ability for all-cause mortality by 56.4%, 29.5%, 38.1%, 18.8%, 35.7%, and 41.3%, respectively. However, the inclusion of blood glucose monitoring had no impact on the prediction of all-cause mortality. Compared with the 1st quartiles of creatinine and Cystatin C, the risk of diabetes mortality were higher in the highest quartiles (HR: 5.16, 95% CI: 1.87-14.22; HR: 10.06, 95% CI: 4.20-24.13). CONCLUSIONS: In the diabetic population, elevated plasma levels of hs-cTnT, hs-cTnI, NT-proBNP, creatinine, cystatin C, and ß-2 microglobulin serve as robust and straightforward predictors of long-term mortality compared to blood glucose levels and HbA1c values. Creatinine and cystatin C stand out as more precise markers for predicting diabetes mortality prior to blood glucose monitoring.

Wip1 contributes to the adaptation of HepG2 human liver cancer cells to stress hormone-induced DNA damage.

Numerous studies have shown that the release of stress hormones resulting from repeated exposure to chronic psychological stress increases DNA damage and promotes tumorigenesis. However, the mechanisms that enable cancerous cells adapt to stress hormone-induced DNA damage and survive remain unclear. The present study aimed to investigate the impact of stress hormones on the survival of liver cancer cells and the underlying mechanism. HepG2 human liver cancer cells were treated with dexamethasone (DEX), epinephrine (EPI) and norepinephrine (NE) and subjected to the testing of DNA damage, cell survival and cell apoptosis by alkaline comet assay, CCK-8 viability assay and flow cytometry, respectively. The protein expression levels of DNA damage response factors were determined by western blotting analysis. The results revealed that treatment of HepG2 cells with DEX, EPI and NE induced DNA damage without affecting cell survival or inducing apoptosis. The protein levels of wild-type p53-induced phosphatase 1 (Wip1), a type 2C family serine/threonine phosphatase, were increased, and the dephosphorylation of DNA damage response factors, including phosphorylated (p-)ataxia-telangiectasia mutated and p-checkpoint kinase 2, occurred following treatment with DEX, EPI and NE. In addition, a cycloheximide chase assay was performed to explore the protein stability under treatment with stress hormones. Compared with vehicle-treated cells, Wip1 exhibited increased protein stability in stress hormone-treated HepG2 cells. Eventually, the depletion of Wip1 using small interfering RNA verified the role of Wip1 in the modulation of stress hormone-induced DNA damage. These findings suggest that cancerous cells likely adapt to stress hormone-induced DNA damage via Wip1 upregulation. The present study provides an insight into the underlying mechanism that links chronic psychological stress with tumor growth and progression.

Kinetics of thermal degradation of raw lacquer enhanced by formaldehyde urea prepolymer.

In this study, formaldehyde-urea prepolymer (FUP) were synthesized, which were used to modify the raw lacquer (RL) and this composition named LF, while the basic properties of the RL were tested. Thermal gravimetric (TG) analysis and scanning electron microscopy (SEM) were used to analyze the degradative characteristics and the surface morphology of RL before and after modification. The result indicated that FUP can significantly improve the performance of RL. The drying time of the LF is significantly shortened, the gloss, the pencil hardness, and the impact performance are significantly enhanced at the same time. TG analysis and thermal decomposition kinetics analysis illustrated that the thermal stability and the activation energy of LF2 were stronger than that of RL. In addition, SEM analysis illustrated that the surface smoothness of RL were also improved.

Chronic stress promotes tumor immune evasion via the suppression of MHC-I expression and the upregulation of PD-L1.

Chronic stress induces cancer initiation and progression via regulation of diverse cancer risk factors including immune evasion. Our previous research demonstrated that ß-adrenergic blockade with propranolol almost completely reversed the accelerated tumor growth induced by chronic restraint stress, but the underlying mechanism of immune escape remains largely unknown. In the present study, a chronic restraint stress paradigm was applied to the H22 hepatocellular carcinoma (HCC) bearing mice to mimic the psychological stress. We observed that chronic restraint stress significantly promoted HCC growth and tumor escape from T cell surveillance. Chronic restraint stress reduced intratumor MHC-I expression and enhanced PD-L1 expression, whereas propranolol rectified the changes of MHC-I and PD-L1. Under chronic stress, the activated MAPK pathway suppressed MHC-I production by inactivating STAT1/IRF1 signaling pathway, and promoted PD-L1 translation by elevating eIF2α phosphorylation. These findings support the crucial role of ß-adrenergic signaling cascade in the tumor escape from T cell surveillance under chronic restraint stress.

Resistance and resilience of soil bacterial community to zero-valent iron disposal of lindane contamination.

Zero-valent iron (ZVI, Fe0) enables chemical reduction of environmental pollutants coupled with reactivity loss due to surface oxidation. During ZVI treatment process, however, microbial community stability in terms of resistance and resilience remains largely unclear. Here, we monitored bacterial community succession over a 4 weeks period in soil microcosms with or without 2% (w/w) Fe0 amendment. To simulate soil pollution, 100 µg g-1 chlorinated pesticide lindane (γ-hexachlorocyclohexane) was added to the microcosms as a model contaminant. In addition to microbial activity as measured by soil organic carbon mineralization, bacterial abundance, diversity and composition were determined using qPCR and high-throughput sequencing of 16 S rRNA genes. Co-occurrence analysis was performed to reveal the interaction patterns within the bacterial communities. The results indicated that ZVI caused near-complete transformation of lindane, while in the microcosms without Fe0 amendment the pesticide was recalcitrant. ZVI strongly inhibited CO2-efflux at the early stage of incubation, but the bacterial community appeared to be less sensitive to Fe0 amendment. The ratios of negative to positive correlations between network nodes suggested that Fe0 had marginal influence on community stability compared to the lindane treatments, which destabilized the bacterial community. Community succession occurred in the presence of ZVI, as exemplified by a dominancy transition from anaerobic to aerobic taxa. Yet, ZVI alleviated the stress of lindane on soil bacteria by improving community structure and increasing network complexity. Taken together, these findings demonstrate the stability of soil bacterial community under Fe0 stress, which might be conducive to functional recovery of soil microorganisms following ZVI remediation.

Thermal Degradation Kinetics of Urea-Formaldehyde Resins Modified by Almond Shells.

Almond shell-modified urea-formaldehyde resins (AUF) were prepared in this study. The optimal addition amount of almond shells was selected by formaldehyde emission and wet shear strength. The activation energy (E a) values at different conversion rates and the reaction kinetics were estimated based on the Flynn-Wall-Ozawa method. The results indicated that almond shells can significantly reduce the formaldehyde emission and increase wet shear strength and thermal stability of the urea-formaldehyde resin adhesive. The optimal addition of almond shells is 3 wt %.

Chronic restraint stress promotes the mobilization and recruitment of myeloid-derived suppressor cells through ß-adrenergic-activated CXCL5-CXCR2-Erk signaling cascades.

Myeloid-derived suppressor cells (MDSCs) play an important role in tumor immune escape. Recent studies have shown that MDSCs contribute to tumor progression under psychological stress, but the underlying mechanism of MDSCs mobilization and recruitment remains largely unknown. In the present study, a chronic restraint stress paradigm was applied to the H22 hepatocellular carcinoma (HCC) bearing mice to mimic the psychological stress. We observed that chronic restraint stress significantly promoted HCC growth, as well as the mobilization of MDSCs to spleen and tumor sites from bone marrow. Meanwhile, chronic restraint stress enhanced the expression of C-X-C motif chemokine receptor 2 (CXCR2) and pErk1/2 in bone marrow MDSCs, together with elevated chemokine (C-X-C motif) ligand 5 (CXCL5) expression in tumor tissues. In vitro, the treatments of MDSCs with epinephrine (EPI) and norepinephrine (NE) but not corticosterone (CORT)-treated H22 conditioned medium obviously inhibited T-cell proliferation, as well as enhanced CXCR2 expression and extracellular signal-regulated kinase (Erk) phosphorylation. In vivo, ß-adrenergic blockade with propranolol almost completely reversed the accelerated tumor growth induced by chronic restraint stress and inactivated CXCL5-CXCR2-Erk signaling pathway. Our findings support the crucial role of ß-adrenergic signaling cascade in the mobilization and recruitment of MDSCs under chronic restraint stress.

Improved performance of soy protein adhesive with melamine-urea-formaldehyde prepolymer.

In recent years, soy protein adhesive, as an environmentally friendly bio-based adhesive, has attracted extensive attention. In this study, in order to ameliorate the bonding quality of soy protein isolate (SPI) adhesive, the melamine-urea-formaldehyde prepolymer (MUFP) was synthesized, and different amounts of it were introduced into the SPI adhesive as a cross-linking agent. Fourier transform infrared (FT-IR) spectroscopy, gel permeation chromatography (GPC), thermogravimetric analyze (TGA), and scanning electron microscopy (SEM) were used to analysis the mechanism of modification. The results of plywood test indicated that the wet bonding strength of the adhesives was first increased and then decreased with an increase in the amount of MUFP additive. FT-IR, TGA, and SEM tests suggested that the introduction of MUFP could promote the establishment of a cross-linking structure in the cured adhesive layer to improve the bonding quality of adhesives, but presence of excessive MUFP could introduce hydrophilic groups and adversely affect water resistance.

SUMO protease SENP1 acts as a ceRNA for TGFBR2 and thus activates TGFBR2/Smad signaling responsible for LPS-induced sepsis.

This study aims to explore the roles and related mechanisms of SUMO protease SENP1 in sepsis. Here, RNA-sequencing assay showed that SENP1 was significantly increased in human umbilical vein endothelial cells (HUVECs) with LPS treatment. Gene set enrichment analysis (GSEA) of RNA-sequencing dataset revealed that a positive enrichment of inflammation signatures was observed in HUVECs with SENP1 3'UTR overexpression. Further functional annotation analysis revealed that SENP1 3'UTR overexpression was positively correlated with TGFBR2 signaling pathway. Mechanistically, TGFBR2 was identified as a ceRNA (competing endogenous RNA) target of SENP1 and the downstream effectors Smad2/3 were also overexpressed in HUVECs with SENP1 3'UTR overexpression. Injection of SENP1 siRNA following LPS treatment attenuated LPS-induced sepsis, evidenced by the downregulation of IL-2 and TNF-α secretion and prolonged the overall survival of septic mice. Consistent results were obtained in vitro. Additionally, TGFBR2 overexpression partially abrogated SENP1 siRNA-mediated inhibition on LPS-induced sepsis. Thus, these results suggest that SENP1 promotes sepsis via activating the TGFBR2 signaling.

N2-substituted O6-cyclohexylmethylguanine derivatives: potent inhibitors of cyclin-dependent kinases 1 and 2.

The adenosine 5'-triphosphate (ATP) competitive cyclin-dependent kinase inhibitor O(6)-cyclohexylmethylguanine (NU2058, 1) has been employed as the lead in a structure-based drug discovery program resulting in the discovery of the potent CDK1 and -2 inhibitor NU6102 (3, IC(50) = 9.5 nM and 5.4 nM vs CDK1/cyclinB and CDK2/cyclinA3, respectively). The SAR for this series have been explored further by the synthesis and evaluation of 45 N(2)-substituted analogues of NU2058. These studies have confirmed the requirement for the hydrogen bonding N(2)-NH group and the requirement for an aromatic N(2)-substituent to confer potency in the series. Additional potency is conferred by the presence of a group capable of donating a hydrogen bond at the 4'-position, for example, the 4'-hydroxy derivative (25, IC(50) = 94 nM and 69 nM vs CDK1/cyclinB and CDK2/cyclinA3, respectively), 4'-monomethylsulfonamide derivative (28, IC(50) = 9 nM and 7.0 nM vs CDK1/cyclinB and CDK2/cyclinA3, respectively), and 4'-carboxamide derivative (34, IC(50) = 67 nM and 64 nM vs CDK1/cyclinB and CDK2/cyclinA3, respectively). X-ray crystal structures have been obtained for key compounds and have been used to explain the observed trends in activity.