A nomogram for risk stratification of central cervical lymph node metastasis in patients with papillary thyroid carcinoma.

Background: Whether to perform prophylactic central lymph node dissection for cN0 papillary thyroid carcinoma (PTC) patients is still controversial. This retrospective study aimed to develop and validate a nomogram based on ultrasound and dual-energy computed tomography (DECT) for the risk stratification of central lymph node metastasis (CLNM) in patients with PTC. Methods: A total of 525 patients from 2017 to 2019 [Tianjin First Central Hospital (Hospital A)] were retrospectively analyzed to form the training cohort and to conduct internal validation. Another group of 204 patients in 2020 (Hospital A) formed the temporal validation cohort. A total of 107 patients in 2020 [Binzhou Medical University Hospital (Hospital B)] formed the geographic validation cohort, which was a retrospective cohort study. The area under the curve (AUC), calibration curve, and decision curve were used to evaluate the performance of the nomogram. The locally weighted regression curve was used for risk stratification. Results: Diameter, taller-than-wide, calcification, capsular invasion, and iodine concentration in the arterial and venous phases were independent risk predictors of CLNM. The AUC of the nomogram was 0.922 (95% confidence interval: 0.895-0.943) in the training cohort. Two external validation cohorts demonstrated the good performance of the nomogram in predicting CLNM, with AUCs of 0.912 and 0.861. The significantly improved net reclassification index and integrated discriminatory improvement index indicated that DECT was a powerful supplement to ultrasound for predicting CLNM. The risk stratification system divided all patients into low-risk (0-50 points), intermediate-risk (51-100 points), and high-risk groups (>100 points). Conclusions: The nomogram and risk stratification system estimated the utility of CLNM to guide individualized treatment of patients with PTC.

Interfascial planes as surgical landmarks for laparoscopic upper retroperitoneal surgery: a cadaveric and retrospectively clinical study.

Background: Radiologists currently accept the concept of "interfascial plane (IFP)" to understand retroperitoneal anatomy, replacing Meyers' classic tricompartmental theory. Despite much research on retroperitoneal anatomy, its anatomical structure, embryonic origin and developmental process still require further exploration to guide the optimization of surgical process. This study aims to explore the anatomical basis of IFP related to laparoscopic upper retroperitoneal surgery (LURS) and to compare the clinical outcomes of trans-interfascial plane procedures for LURS (TIFP-LURS) with conventional LURS (Con-LURS). Methods: The study consisted of two parts: cadaveric and clinical study. The cadaveric study involved dissecting and observing the retroperitoneal fasciae and IFP in 32 cadavers using gross anatomical and histological methods. This retrospective clinical study compared the perioperative data and complications of 229 patients who underwent TIFP-LURS and 121 patients who underwent Con-LURS for upper retroperitoneal lesions at our center. Results: The cadaveric study revealed that the retroperitoneal space was composed of multilaminar fasciae that formed potential bloodless spaces among them, that could be used as surgical landmarks and operating planes. The clinical study showed that TIFP-LURS had a significantly less estimated blood loss, lower intraoperative complication rate, lower postoperative complication rate, shorter hospital-stay and lower long-term postoperative complications rate than Con-LURS. Multivariate analysis indicated that the TIFP procedure was an independent protective factor for decreasing the risk of postoperative complications. Conclusions: The IFP are potential avascular spaces that can be used during laparoscopic surgery, and TIFP-LURS is a novel surgical approach that can improve the safety and efficacy of laparoscopic surgery for upper retroperitoneal lesions.

Sustainable carbon sequestration via olivine based ocean alkalinity enhancement in the east and South China Sea: Adhering to environmental norms for nickel and chromium.

Enhancing silicate weathering to increase oceanic alkalinity, thereby facilitating the absorption of atmospheric carbon dioxide (CO2), is considered a highly promising technique for carbon sequestration. This study aims to evaluate the feasibility and potential of olivine-based ocean alkalinity enhancement (OAE) for the removal of atmospheric CO2 and its storage in seawater as bicarbonates in the East and South China Seas (ESCS). A particular focus is placed on the potential ecological impacts arising from the release of nickel (Ni) and chromium (Cr) during the olivine weathering process. We considered two extreme scenarios: one where Ni and Cr are entirely retained in seawater, and another where they are completely deposited in sediments. These scenarios respectively represent the maximum permissible concentrations of Ni and Cr in seawater and sediments during the OAE process. Current marine environmental quality standards (EQS) were utilized as the threshold limits for Ni and Cr in both seawater and sediment, with concentrations exceeding these EQS potentially leading to significant adverse effects on marine life. When all released Ni is retained in seawater, the allowable dosage of olivine varies from 0.05 to 13.7 kg/m2 (depending on olivine particle size, temperature, and water depth); when all released Ni is captured by sediment, the permissible addition of olivine ranges from 0.21 to 2.1 kg/m2 (depending on mixing depth). Given the low solubility of Cr, it is not necessary to consider the scenario where Cr exceeds the limit in seawater. The allowable amount of Cr entirely retained in sediments ranges from 0.69 to 47.2 kg/m2.In most scenarios, the accumulation of metals in sediments preferentially exceeds the corresponding threshold value rather than remaining in seawater. Therefore, we recommend using alkalization equipment to fully dissolve olivine before discharging into the sea, enabling a larger-scale application of olivine without significant negative ecological impacts.

Safe Induction of Acute Inflammation with Enhanced Antitumor Immunity by Hydrogel-Mediated Outer Membrane Vesicle Delivery.

Acute inflammation has the potential for the recruitment of immune cells, inhibiting tumor angiogenesis, metastasis, and drug resistance thereby overcoming the tumor immunosuppressive microenvironment caused by chronic inflammation. Here, an acute inflammation inducer using bacteria outer membrane vesicles (OMVs) loaded in thermal-sensitive hydrogel (named OMVs-gel) for localized and controlled release of OMVs in tumor sites is proposed. OMVs trigger neutrophil recruitment and amplify acute inflammation inside tumor tissues. The hydrogel ensures drastic inflammation is confined within the tumor, addressing biosafety concerns that the direct administration of free OMVs may cause fatal effects. This strategy eradicated solid tumors safely and rapidly. The study further elucidates one of the possible immune mechanisms of OMVs-gel therapy, which involves the assembly of antitumor neutrophils and elastase release for selective tumor killing. Additionally, tumor vascular destruction induced by OMVs-gel results in tumor darkening, allowing for combinational photothermal therapy. The findings suggest that the use of OMVs-gel can safely induce acute inflammation and enhance antitumor immunity, representing a promising strategy to promote acute inflammation application in tumor immunotherapy.

Blockade of spinal dopamine D1/D2 receptor heteromers by levo-Corydalmine suppressed calcium signaling cascade in spinal neurons to alleviate bone cancer pain in rats.

Background: Dopamine receptors have been reported to be involved in pain, while the exact effects and mechanism in bone cancer pain have not been fully explored. Methods: Bone cancer pain model was created by implanting walker 256 mammary gland carcinoma into right tibia bone cavity. Primary cultured spinal neurons were used for in vitro evaluation. FLIPR, western-blot, immunofluorescence, and Co-IP were used to detect cell signaling pathway. Results: Our results indicated that spinal dopamine D1 receptor (D1DR) and spinal dopamine D2 receptor (D2DR) could form heteromers in TCI rats, and antagonizing spinal D1DR and D2DR reduced heteromers formation and alleviated TCI-induced bone cancer pain. Further results indicated that D1DR or D2DR antagonist induced antinociception in TCI rats could be reversed by D1DR, D2DR, and D1/D2DR heteromer agonists. And Gq, IP3, and PLC inhibitors also attenuated TCI-induced bone cancer pain. In vitro results indicated that D1DR or D2DR antagonist decreased the Ca2+ oscillations upregulated by D1DR, D2DR, and D1/D2DR heteromer agonists in activated primary cultured spinal neurons. Moreover, inhibition of D1/D2DR heteromers induced antinociception in TCI rats was partially mediated by the CaMKII and MAPKs pathway. In addition, a natural compound levo-Corydalmine (l-CDL), could inhibit D1/D2DR heteromers and attenuate bone cancer pain. Results: Inhibition of spinal D1/D2DR heteromers via l-CDL decreases excitability in spinal neurons, which might present new therapeutic strategy for bone cancer pain.

A single 8-hydroxyquinoline-appended bile acid fluorescent probe obtained by click chemistry for solvent-dependent and distinguishable sensing of zinc(II) and cadmium(II).

Construction of fluorescent probes for zinc ion (Zn2+ ) and cadmium ion (Cd2+ ) is significant for the safety of humans. However, the discriminating recognition of Zn2+ and Cd2+ by a single probe remains challenging owing to their similar properties. Herein, a novel deoxycholic acid derivative containing 8-hydroxyquinoline fluorophore has been facilely synthesized through click chemistry to form a clamp-like probe. Using its perfect bonding cavity from 1,2,3-triazole and quinoline, this molecule showed favorable solvent-dependent fluorescent responses and distinguished Zn2+ and Cd2+ in different solvents. In ethanol aqueous solution, it displayed good selectivity and ratiometric fluorescence to Zn2+ with 30 nm spectroscopic red-shifts. In acetonitrile aqueous solution, it exhibited good selectivity and ratiometric fluorescence to Cd2+ with 18 nm spectroscopic red-shifts. Moreover, the unique microstructural features of the probe in assembly were used to reflect its recognition processes. Due to its merits of low detection limit and instant response time, the probe was utilized for sensing Zn2+ and Cd2+ in water, beer and urine with high accuracy. Meanwhile, this probe served as a handy tool and was employed to obtain inexpensive test strips for the prompt and semiqualitative analysis of Zn2+ and Cd2+ with the naked eye.

The Transcriptional Repressor PerR Senses Sulfane Sulfur by Cysteine Persulfidation at the Structural Zn2+ Site in Synechococcus sp. PCC7002.

Cyanobacteria can perform both anoxygenic and oxygenic photosynthesis, a characteristic which ensured that these organisms were crucial in the evolution of the early Earth and the biosphere. Reactive oxygen species (ROS) produced in oxygenic photosynthesis and reactive sulfur species (RSS) produced in anoxygenic photosynthesis are closely related to intracellular redox equilibrium. ROS comprise superoxide anion (O2●-), hydrogen peroxide (H2O2), and hydroxyl radicals (●OH). RSS comprise H2S and sulfane sulfur (persulfide, polysulfide, and S8). Although the sensing mechanism for ROS in cyanobacteria has been explored, that of RSS has not been elucidated. Here, we studied the function of the transcriptional repressor PerR in RSS sensing in Synechococcus sp. PCC7002 (PCC7002). PerR was previously reported to sense ROS; however, our results revealed that it also participated in RSS sensing. PerR repressed the expression of prxI and downregulated the tolerance of PCC7002 to polysulfide (H2Sn). The reporter system indicated that PerR sensed H2Sn. Cys121 of the Cys4:Zn2+ site, which contains four cysteines (Cys121, Cys124, Cys160, and Cys163) bound to one zinc atom, could be modified by H2Sn to Cys121-SSH, as a result of which the zinc atom was released from the site. Moreover, Cys19 could also be modified by polysulfide to Cys19-SSH. Thus, our results reveal that PerR, a representative of the Cys4 zinc finger proteins, senses H2Sn. Our findings provide a new perspective to explore the adaptation strategy of cyanobacteria in Proterozoic and contemporary sulfurization oceans.

Chronic kidney disease promotes cerebral microhemorrhage formation.

BACKGROUND: Chronic kidney disease (CKD) is increasingly recognized as a stroke risk factor, but its exact relationship with cerebrovascular disease is not well-understood. We investigated the development of cerebral small vessel disease using in vivo and in vitro models of CKD. METHODS: CKD was produced in aged C57BL/6J mice using an adenine-induced tubulointerstitial nephritis model. We analyzed brain histology using Prussian blue staining to examine formation of cerebral microhemorrhage (CMH), the hemorrhagic component of small vessel disease and the neuropathological substrate of MRI-demonstrable cerebral microbleeds. In cell culture studies, we examined effects of serum from healthy or CKD patients and gut-derived uremic toxins on brain microvascular endothelial barrier. RESULTS: CKD was induced in aged C57BL/6J mice with significant increases in both serum creatinine and cystatin C levels (p < 0.0001) without elevation of systolic or diastolic blood pressure. CMH was significantly increased and positively correlated with serum creatinine level (Spearman r = 0.37, p < 0.01). Moreover, CKD significantly increased Iba-1-positive immunoreactivity by 51% (p < 0.001), induced a phenotypic switch from resting to activated microglia, and enhanced fibrinogen extravasation across the blood-brain barrier (BBB) by 34% (p < 0.05). On analysis stratified by sex, the increase in CMH number was more pronounced in male mice and this correlated with greater creatinine elevation in male compared with female mice. Microglial depletion with PLX3397 diet significantly decreased CMH formation in CKD mice without affecting serum creatinine levels. Incubation of CKD serum significantly reduced transendothelial electrical resistance (TEER) (p < 0.01) and increased sodium fluorescein permeability (p < 0.05) across the endothelial monolayer. Uremic toxins (i.e., indoxyl sulfate, p-cresyl sulfate, and trimethylamine-N-oxide) in combination with urea and lipopolysaccharide induced a marked drop in TEER compared with the control group (p < 0.0001). CONCLUSIONS: CKD promotes the development of CMH in aged mice independent of blood pressure but directly proportional to the degree of renal impairment. These effects of CKD are likely mediated in part by microglia and are associated with BBB impairment. The latter is likely related to gut-derived bacteria-dependent toxins classically associated with CKD. Overall, these findings demonstrate an important role of CKD in the development of cerebral small vessel disease.

The antitumor activity and pharmacokinetics research of PPD-Arg (Tos) using ultra-performance liquid chromatography-quadrupole-time-of-flight mass spectrometry.

In this study, a new compound PPD-Arg (Tos) (PAT), an arginine derivative of 20(s)-PPD, was synthesized via Fmoc-Arg (Tos)-OH and 20(s)-PPD. The pharmacokinetic properties in rats, in vitro cytotoxicity, and cell apoptosis rates of protopanaxadiol (PPD) and PAT were determined. A sensitive bioanalytical method for pharmacokinetics using ultra-performance liquid chromatography coupled with time-of-flight mass spectrometry was developed and validated. The result showed that the Tmax and t1/2 of PAT were significantly enhanced, indicating a long-lasting effect in vivo. Compared to the PPD group, the PAT group showed higher bioavailability. PAT also exhibited higher antitumor efficacy than PPD against three cancer cells, especially the strongest inhibitory activity against Huh-7, even more potent than the positive control of paclitaxel. Therefore, the apoptosis assay based on annexin V/propidium iodide-combined staining against Huh-7 further demonstrated that PAT could induce apoptosis of Huh-7 cells. Better pharmacokinetic properties and antitumor efficacy of the arginine derivative of 20(s)-PPD were important. These findings could provide references for further clinical research on amino acid derivatives of PPD as antitumor agents.

Bacterial outer membrane vesicles-based therapeutic platform eradicates triple-negative breast tumor by combinational photodynamic/chemo-/immunotherapy.

Bacterial outer membrane vesicles (OMVs) are potent immuno-stimulating agents and have the potentials to be bioengineered as platforms for antitumor nanomedicine. In this study, OMVs are demonstrated as promising antitumor therapeutics. OMVs can lead to beneficial M2-to-M1 polarization of macrophages and induce pyroptosis to enhance antitumor immunity, but the therapeutic window of OMVs is narrow for its toxicity. We propose a bioengineering strategy to enhance the tumor-targeting ability of OMVs by macrophage-mediated delivery and improve the antitumor efficacy by co-loading of photosensitizer chlorin e6 (Ce6) and chemotherapeutic drug doxorubicin (DOX) into OMVs as a therapeutic platform. We demonstrate that systemic injection of the DOX/Ce6-OMVs@M therapeutic platform, providing combinational photodynamic/chemo-/immunotherapy, eradicates triple-negative breast tumors in mice without side effects. Importantly, this strategy also effectively prevents tumor metastasis to the lung. This OMVs-based strategy with bioengineering may serve as a powerful therapeutic platform for a synergic antitumor therapy.

Discovery and Validation of Potential Serum Biomarkers with Pro-Inflammatory and DNA Damage Activities in Ulcerative Colitis: A Comprehensive Untargeted Metabolomic Study.

Ulcerative colitis is a type of non-specific inflammatory bowel disease with unclear etiology. It is considered a progressive disease with risks of bowel motility disorders, anorectal dysfunction, and even colorectal cancer. Commonly used diagnostic markers have poor specificity and cannot predict the development of ulcerative colitis. In this study, 77 serum samples (31 patients, 46 healthy controls) were analyzed using high performance liquid chromatography-quadrupole time-of-flight mass spectrometry and 31 metabolites with significant level changes were found, revealing the relationship of ulcerative colitis to disturbed glutathione metabolism and caffeine metabolism. In addition, pyroglutamic acid, a biomarker of cervical cancer and gastric cancer, was identified with elevated levels in the serum of ulcerative colitis patients. The role of pyroglutamic acid was further analyzed, and the results indicated its positive correlation with the upregulation of inflammatory factors and increased levels of phosphorylated histone H2AX (γH2AX) in IEC-6 cells, which are related to DNA damage. All these results suggest that pyroglutamic acid is not only a biomarker for distinguishing ulcerative colitis status, but that it is also a potential effective metabolite that promotes the transformation of ulcerative colitis to colorectal cancer.

Ultrasound-based radiomics XGBoost model to assess the risk of central cervical lymph node metastasis in patients with papillary thyroid carcinoma: Individual application of SHAP.

Objectives: A radiomics-based explainable eXtreme Gradient Boosting (XGBoost) model was developed to predict central cervical lymph node metastasis (CCLNM) in patients with papillary thyroid carcinoma (PTC), including positive and negative effects. Methods: A total of 587 PTC patients admitted at Binzhou Medical University Hospital from 2017 to 2021 were analyzed retrospectively. The patients were randomized into the training and test cohorts with an 8:2 ratio. Radiomics features were extracted from ultrasound images of the primary PTC lesions. The minimum redundancy maximum relevance algorithm and the least absolute shrinkage and selection operator regression were used to select CCLNM positively-related features and radiomics scores were constructed. Clinical features, ultrasound features, and radiomics score were screened out by the Boruta algorithm, and the XGBoost model was constructed from these characteristics. SHapley Additive exPlanations (SHAP) was used for individualized and visualized interpretation. SHAP addressed the cognitive opacity of machine learning models. Results: Eleven radiomics features were used to calculate the radiomics score. Five critical elements were used to build the XGBoost model: capsular invasion, radiomics score, diameter, age, and calcification. The area under the curve was 91.53% and 90.88% in the training and test cohorts, respectively. SHAP plots showed the influence of each parameter on the XGBoost model, including positive (i.e., capsular invasion, radiomics score, diameter, and calcification) and negative (i.e., age) impacts. The XGBoost model outperformed the radiologist, increasing the AUC by 44%. Conclusions: The radiomics-based XGBoost model predicted CCLNM in PTC patients. Visual interpretation using SHAP made the model an effective tool for preoperative guidance of clinical procedures, including positive and negative impacts.

Extreme gradient boosting model to assess risk of central cervical lymph node metastasis in patients with papillary thyroid carcinoma: Individual prediction using SHapley Additive exPlanations.

BACKGROUND AND OBJECTIVES: Central cervical lymph node metastasis (CLNM) is considered a risk factor for recurrence in patients with papillary thyroid carcinoma (PTC). Traditional machine learning models suffered from "black-box" problems, which could not exactly explain the interactive effects of the risk factors. We aimed to develop an eXtreme Gradient Boosting (XGBoost) model to assess CLNM, including positive and negative effects. METHODS: 1,122 patients with PTC admitted at Tianjin First Central Hospital from 2016 to 2020 were retrospectively selected. They were randomly divided into the training and test datasets with an 8:2 ratio. 108 patients with PTC admitted at Binzhou Medical University Hospital in 2020 served as the validation dataset. The XGBoost model was used to assess CLNM. The 10-fold cross-validation was utilized for model selection, and the metric used to evaluate classification performance was the average area under the curve (AUC) of 10-fold cross-validation. Interpretation and transparency of the "black-box" problem were performed. SHapley Additive exPlanations (SHAP) and local interpretable model-agnostic explanation (LIME) were used to ensure the stability and reliability of the model. RESULTS: The XGBoost model based on ultrasound and dual-energy computed tomography images of the solitary primary lesion had an excellent performance for assessing CLNM, with average AUCs of 0.918, 0.903, and 0.881 in the training, test, and validation datasets, respectively. SHAP plots showed the influence of each parameter on the XGBoost model, including positive (i.e., capsular invasion, diameter, iodine concentration in the venous phase, and calcification) and negative (i.e., sex and age) impacts. For all cases, the capsular invasion prediction weight was the highest; for individual cases, different predictors were assigned different weights. Moreover, the performance of the XGBoost model was better than classical machine-learning models. CONCLUSIONS: This study developed and validated an XGBoost model for assessing CLNM in patients with PTC. The ability to visually interpret the positive and negative effects made the XGBoost model an effective tool for guiding clinical treatment.

The Influence of Heparan Sulfate on Breast Amyloidosis and the Toxicity of the Pre-fibrils Formed by ß-casein.

Heparan sulfate (HS) as a mediator is usually involved in both inflammation and fibrosis. Besides, pre-fibrils are the intermediates of amyloid fibrils that usually cause cell death and tissue damage, like the amyloid-ß in Alzheimer's disease, α-synuclein in Parkinson disease and islet amyloid polypeptide in type II diabetes mellitus. However, the related study was involved rarely in breast. Therefore, the combing technologies including hematoxylin-eosin staining and thioflavin S staining were used to investigate the influence of HS on breast amyloidosis. To further study the toxicity of the pre-fibrils formed by ß-casein on the HC11 cells and the breast mammary gland, the combing technologies including pentamer formyl thiophene acetic acid fluorescence analysis, MTT assay, Annexin V/PI staining and hematoxylin-eosin staining were performed. The results demonstrated that HS, acted as an endogenous molecule, induced the inflammation and amyloid fibril formation at the same time, and there was a close relationship between inflammation and fibrosis of breast. In addition, the pre-fibrils formed by ß-casein were toxic because they induced the death and apoptosis of HC11 cells, as well as the inflammation of mammary gland of rats. Therefore, the early examination and identify of the pre-fibrils in the breast were worth considering to prevent the disease development, and it was interesting to explore the HS mimetics to impair the breast amyloidosis and attenuate the inflammatory response in the future.

The effect of arginine on inhibiting amyloid fibril derived from ß-casein and the binding studies with multi-spectroscopic techniques.

In general, ß-casein is a stable molecular chaperone. However, the fact that amyloid fibrils derived from ß-casein has been reported in some cases, which were usually associated with some malignant breast diseases. As an important amino acid, arginine not only exhibits the significance in casein synthesis in mammary gland, but also has great potentiality in inhibiting the amyloid fibril formation. Therefore, the influence of arginine on the amyloid fibrils formed by ß-casein and further molecular mechanism were studied firstly with multi-spectroscopic techniques in the present work. The results of Thioflavin T determination, particle size analysis, transmission electron microscope observation showed that arginine not only inhibited the aggregation of ß-casein at the growth stage, but also depolymerized the mature amyloid fibrils at the saturation stage. The further fluorescence experiment results demonstrated that the complex was formed between ß-casein and arginine. Besides, there was one binding site and 0.48 nm binding distance. The thermodynamic parameters like ΔG0, ΔS0, ΔH0 were all negative, showing their binding reaction was spontaneous, and hydrogen bond and van der Waals force were the possibly chief intermolecular forces. Furthermore, the synchronous fluorescence spectra showing that the conformation of ß-casein was affected and its tyrosine residues were gradually buried inside the protein. Our research would provide new insights into the treatments for the breast amyloidosis.

Amyloid fibril formation by casein and fatty acid composition in breast milk of mastitis patients.

Mastitis can cause changes in the nutrient composition of breast milk, which may be harmful to both newborns and lactating mothers. In this study we preliminarily evaluated amyloid fibrils formation by casein and fatty acids (FA), as well as their potential relation with each other in the breast milk of mastitis patients. Six healthy volunteers and six mastitis patients were recruited from the Maternal and Child Health Care Hospital in Changchun were enrolled. Amyloid fibril content was assessed by thioflavin T fluorescence analysis, transmission electron microscope, circular dichroism, and proton nuclear magnetic resonance. FA contents were measured by gas chromatography. Healthy breast milk contained no amyloid fibrils but inflammatory breast milk did. Several FAs (hendecanoic acid, myristolenic acid, pentadecenoic acid, eicosatrienoic acid) differed significantly between the two groups (p < .05). The concentrations of the eicosatrienoic acid and eleven carbonic acids in the inflammatory groups were lower than those in the healthy groups, but the myristolenic acid and pentadecenoic acid were the opposite trend. Early detection of amyloid fibrils should be performed in lactating mothers with mastitis. Changes in FAs may reflect the importance of abnormal metabolism in amyloid fibril formation. PRACTICAL APPLICATIONS: The work preliminarily clarified the relationship between inflammation, fibril content, and fatty acid (FA) composition in breast milk. Healthy milk contained no amyloid fibril formed by casein but the inflammatory milk did. FAs were also significantly different between the two groups. Thus, an early determination of amyloid fibrils in milk should be considered for lactating women with mastitis to avoid the further malignant development. Additionally, the changes in FAs may reflect the importance of abnormal metabolism and oxidative pathways in amyloid fibril formation in the breast. Therefore, this study provided foundations for further investigation on the association between inflammation, fibril content and FA composition in breast milk.

Hybrid Cell Membrane-Functionalized Biomimetic Nanoparticles for Targeted Therapy of Osteosarcoma.

PURPOSE: In order to prepare a biomimetic nano-carrier which has inflammatory chemotaxis, homologous targeting and reduce immune clearance, for targeted chemotherapy of osteosarcoma, we fabricated the paclitaxel-loaded poly(lactic-co-glycolic) acid (PLGA) nanoparticles coated with 143B-RAW hybrid membrane (PTX-PLGA@[143B-RAW] NPs) and evaluate its anti-cancer efficacy in vitro and vivo. METHODS: PTX-PLGA@[143B-RAW] NPs were prepared by the ultrasonic method and were characterized by size, zeta potential, polymer dispersion index (PDI), Coomassie bright blue staining, transmission electron microscopy (TEM) and high performance liquid chromatography (HPLC). Cellular uptake, cell viability assay, flow cytometry and chemotactic effect of PTX-PLGA@[143B-RAW] NPs were evaluated in vitro. Biodistribution, anti-cancer therapeutic efficacy and safety of PTX-PLGA@[143B-RAW] NPs were evaluated in 143B osteosarcoma xenograft mice. RESULTS: The hybrid membrane successfully coated onto the surface of PLGA nanoparticles. PTX-PLGA@[143B-RAW] NPs had a drug loading capacity of 4.24 ± 0.02% and showed targeting ability to osteosarcoma. PTX-PLGA@[143B-RAW] NPs showed high cellular uptake and improved anti-cancer efficacy against 143B cells. More importantly, PTX-PLGA@[143B-RAW] NPs treatment suppressed tumor growth in tumor-bearing mice with minimal damage to normal tissues. CONCLUSION: PTX-PLGA@[143B-RAW] NPs could be used for targeted drug delivery and osteosarcoma therapy.

A new prediction model for lateral cervical lymph node metastasis in patients with papillary thyroid carcinoma: Based on dual-energy CT.

PURPOSE: The current study aimed to develop and validate a prediction model to estimate the independent risk factors for lateral cervical lymph node metastasis (LLNM) in papillary thyroid carcinoma (PTC) patients based on dual-energy computed tomography (DECT). METHOD: This study retrospectively conducted 406 consecutive patients from July 2015 to June 2019 to form the derivation cohorts and performed internal validation. 101 consecutive patients from July 2019 to June 2020 were included to create the external validation cohort. Univariable and multivariable logistic regression analyses were used to evaluate independent risk factors for LLNM. A prediction model based on DECT parameters was built and presented on a nomogram. The internal and external validations were performed. RESULTS: Iodine concentration (IC) in the arterial phase (OR 2.761, 95% CI 1.028-7.415, P 0.044), IC in venous phase (OR 3.820, 95% CI 1.430-10.209, P 0.008), located in the superior pole (OR 4.181, 95% CI 2.645-6.609, P 0.000), and extrathyroidal extension (OR 4.392, 95% CI 2.142-9.004, P 0.000) were independently associated with LLNM in the derivation cohort. These four predictors were incorporated into the nomogram. The model showed good discrimination in the derivation (AUC, 0.899), internal (AUC, 0.905), and external validation (AUC, 0.912) cohorts. The decision curve revealed that more advantages would be added using the nomogram to estimate LLNM, which implied that the lateral lymph node dissection was recommended. CONCLUSIONS: DECT parameters could provide independent indicators of LLNM in PTC patients, and the nomogram based on them may be helpful in treatment decision-making.

A Comparative Analysis of Six Machine Learning Models Based on Ultrasound to Distinguish the Possibility of Central Cervical Lymph Node Metastasis in Patients With Papillary Thyroid Carcinoma.

Current approaches to predict central cervical lymph node metastasis (CLNM) in patients with papillary thyroid carcinoma (PTC) have failed to identify patients who would benefit from preventive treatment. Machine learning has offered the opportunity to improve accuracy by comparing the different algorithms. We assessed which machine learning algorithm can best improve CLNM prediction. This retrospective study used routine ultrasound data of 1,364 PTC patients. Six machine learning algorithms were compared to predict the possibility of CLNM. Predictive accuracy was assessed by sensitivity, specificity, positive predictive value, negative predictive value, and the area under the curve (AUC). The patients were randomly split into the training (70%), validation (15%), and test (15%) data sets. Random forest (RF) led to the best diagnostic model in the test cohort (AUC 0.731 ± 0.036, 95% confidence interval: 0.664-0.791). The diagnostic performance of the RF algorithm was most dependent on the following five top-rank features: extrathyroidal extension (27.597), age (17.275), T stage (15.058), shape (13.474), and multifocality (12.929). In conclusion, this study demonstrated promise for integrating machine learning methods into clinical decision-making processes, though these would need to be tested prospectively.

Nomogram to Assess the Risk of Central Cervical Lymph Node Metastasis in Patients With Clinical N0 Papillary Thyroid Carcinoma.

OBJECTIVE: To develop and validate an individualized risk prediction model for the need for central cervical lymph node dissection in patients with clinical N0 papillary thyroid carcinoma (PTC) diagnosed using ultrasound. METHODS: Upon retrospective review, derivation and internal validation cohorts comprised 1585 consecutive patients with PTC treated from January 2017 to December 2019 at hospital A. The external validation cohort consisted of 406 consecutive patients treated at hospital B from January 2016 to June 2020. Independent risk factors for central cervical lymph node metastasis (CLNM) were determined through univariable and multivariable logistic regression analysis. An individualized risk prediction model was constructed and illustrated as a nomogram, which was internally and externally validated. RESULTS: The following risk factors of CLNM were established: a solitary primary thyroid nodule's diameter, shape, calcification, and capsular abutment-to-lesion perimeter ratio. The areas under the receiver operating characteristic curves of the risk prediction model for the internal and external validation cohorts were 0.921 and 0.923, respectively. The calibration curve showed good agreement between the nomogram-estimated probability of CLNM and the actual CLNM rates in the 3 cohorts. The decision curve analysis confirmed the clinical usefulness of the nomogram. CONCLUSION: This study developed and validated a model for predicting the risk of CLNM in individual patients with clinical N0 PTC, which should be an efficient tool for guiding clinical treatment.