Dual-Region Computed Tomography Radiomics-Based Machine Learning Predicts Subcarinal Lymph Node Metastasis in Patients with Non-small Cell Lung Cancer.

BACKGROUND: Noninvasively and accurately predicting subcarinal lymph node metastasis (SLNM) for patients with non-small cell lung cancer (NSCLC) remains challenging. This study was designed to develop and validate a tumor and subcarinal lymph nodes (tumor-SLNs) dual-region computed tomography (CT) radiomics model for predicting SLNM in NSCLC. METHODS: This retrospective study included NSCLC patients who underwent lung resection and SLNs dissection between January 2017 and December 2020. The radiomic features of the tumor and SLNs were extracted from preoperative CT, respectively. Ninety machine learning (ML) models were developed based on tumor region, SLNs region, and tumor-SLNs dual-region. The model performance was assessed by the area under the curve (AUC) and validated internally by fivefold cross-validation. RESULTS: In total, 202 patients were included in this study. ML models based on dual-region radiomics showed good performance for SLNM prediction, with a median AUC of 0.794 (range, 0.686-0.880), which was superior to those of models based on tumor region (median AUC, 0.746; range, 0.630-0.811) and SLNs region (median AUC, 0.700; range, 0.610-0.842). The ML model, which is developed by using the naive Bayes algorithm and dual-region features, had the highest AUC of 0.880 (range of cross-validation, 0.825-0.937) among all ML models. The optimal logistic regression model was inferior to the optimal ML model for predicting SLNM, with an AUC of 0.727. CONCLUSIONS: The CT radiomics showed the potential for accurately predicting SLNM in NSCLC patients. The ML model with dual-region radiomic features has better performance than the logistic regression or single-region models.

Corynoxine promotes TFEB/TFE3-mediated autophagy and alleviates Aß pathology in Alzheimer's disease models.

Autophagy impairment is a key factor in Alzheimer's disease (AD) pathogenesis. TFEB (transcription factor EB) and TFE3 (transcription factor binding to IGHM enhancer 3) are nuclear transcription factors that regulate autophagy and lysosomal biogenesis. We previously showed that corynoxine (Cory), a Chinese medicine compound, protects neurons from Parkinson's disease (PD) by activating autophagy. In this study, we investigated the effect of Cory on AD models in vivo and in vitro. We found that Cory improved learning and memory function, increased neuronal autophagy and lysosomal biogenesis, and reduced pathogenic APP-CTFs levels in 5xFAD mice model. Cory activated TFEB/TFE3 by inhibiting AKT/mTOR signaling and stimulating lysosomal calcium release via transient receptor potential mucolipin 1 (TRPML1). Moreover, we demonstrated that TFEB/TFE3 knockdown abolished Cory-induced APP-CTFs degradation in N2aSwedAPP cells. Our findings suggest that Cory promotes TFEB/TFE3-mediated autophagy and alleviates Aß pathology in AD models.

Low Pi stress enhances the sensitivity of hepatocellular carcinoma to sorafenib.

Sorafenib is a tyrosine kinase inhibitor for the treatment of advanced-stage HCC; however, clinical trials of sorafenib failed to demonstrate long-term survival benefits due to drug resistance. Low Pi stress has been shown to inhibit tumor growth and the expression of multidrug resistance-associated proteins. In this study, we investigated the sensitivity of HCC to sorafenib under conditions of low Pi stress. As a result, we found that low Pi stress facilitated sorafenib-mediated suppression of migration and invasion of HepG-2 and Hepa1-6 cells by decreasing the phosphorylation or expression of AKT, Erk and MMP-9. Angiogenesis was inhibited due to decreased expression of PDGFR under low Pi stress. Low Pi stress also decreased the viability of sorafenib-resistant cells by directly regulating the expression of AKT, HIF-1a and P62. In vivo drug sensitivity analysis in the four animal models showed a similar tendency that low Pi stress enhances sorafenib sensitivity in both the normal and drug-resistant models. Altogether, low Pi stress enhances the sensitivity of hepatocellular carcinoma to sorafenib and expands the indications for sevelamer.

The application of radiomics in esophageal cancer: Predicting the response after neoadjuvant therapy.

Esophageal cancer (EC) is one of the fatal malignant neoplasms worldwide. Neoadjuvant therapy (NAT) combined with surgery has become the standard treatment for locally advanced EC. However, the treatment efficacy for patients with EC who received NAT varies from patient to patient. Currently, the evaluation of efficacy after NAT for EC lacks accurate and uniform criteria. Radiomics is a multi-parameter quantitative approach for developing medical imaging in the era of precision medicine and has provided a novel view of medical images. As a non-invasive image analysis method, radiomics is an inevitable trend in NAT efficacy prediction and prognosis classification of EC by analyzing the high-throughput imaging features of lesions extracted from medical images. In this literature review, we discuss the definition and workflow of radiomics, the advances in efficacy prediction after NAT, and the current application of radiomics for predicting efficacy after NAT.

Characterisation of a laccase isolated from Trametes hirsuta and its application in the oligomerisation of phenolic compounds.

Phenolic compounds are widely distributed in nature and industrial environment, and their detoxification or bioactive enhancement is of great value to environmental protection and industrial development. Laccases are multicopper oxidases that catalyse the oligo- or polymerisation of phenolic compounds. Identifying new laccase producers and investigating their application potential are of great importance. In this study, a white-rot fungus, Trametes hirsuta EZ1, with significantly high laccase productivity was isolated. The optimum conditions were studied for the maximum fermentation of extracellular laccase, which was achieved at 150 U/mL with a medium containing 10% strain EZ1, 7% maltodextrin, 1.5% peptone, and 0.5 mM Cu2+, and incubation at initial pH 6.0, 32 °C, and 180 rpm for nine days. Subsequently, a 70-kDa laccase was purified that showed activity over a wide range of temperature and pH, sensitivity to many metal ions and sodium dodecyl sulphate, and high tolerance to organic solvents. Purified laccase showed a significant unreported effect by catalysing catechol or ferulic acid into dimers, trimers, and tetramers or caffeic acid into dimers, trimers, tetramers, and pentamers. The oligomeric mixtures exhibited increased antioxidative capacity compared to that of each parent monomer, except for caffeic acid derivatives. Our study offers a novel strain source for laccase production and broadens its application in the enhancement of bioactive compounds.

Evaluation of the safety and efficacy of transarterial sevelamer embolization in a rabbit liver cancer model: A challenge on the size rule for vascular occlusion.

As the most efficient method to treat hepatocellular carcinoma in the immediate or advanced stage, transarterial chemoembolization (TACE) is coming into the era of microsphere (MP). Drug-eluting beads have shown their huge potential as an embolic agent and drug carrier for chemoembolization, but their sizes are strictly limited to be above 40 µm, which was considered to occlude vessels in a safe mode. microsphere smaller than 40 µm is easy to be washed out and transported to the normal liver lobe or other organs, causing severe adverse events and failed embolization. To determine whether sevelamer ultrafine particle (0.2-0.5 µm) is qualified as a safe and efficient embolic agent, we investigated the safety and therapeutic efficiency of transarterial sevelamer embolization (TASE) in the VX2 rabbit liver cancer model, aiming to challenge the "40 µm" rule on the selection criteria of the MP. In a four-arm study, blank bead (Callisphere, 100-300 µm), luminescent polystyrene microsphere (10, 100 µm), and sevelamer particle were transarterially administered to evaluate the threshold size of the MP size for intrahepatic or extrahepatic permeability. Another four-arm study was designed to clarify the safety and efficiency of preclinical transarterial sevelamer embolizationTASE tests over other techniques. Sham (saline), TASE, C-TACE, and D-TACE (n = 6) were compared in terms of serum chemistry, histopathology, and tumor necrosis ratio. In the first trials, the "40 µm" rule was detectable on the VX2 cancer model, but the regulation has no application to the new embolic agent as sevelamer ultrafine particles have not been found to leak out from the VX2 lesions, only found in the embolized vessels. Pathology proves that less viable tumor residue was found 2 weeks after the procedure, evidencing a better therapeutic outcome. No adverse events were found except for a short stress response. These results indicate that sevelamer is a safe and efficient embolic as an alternative to the current MP-based embolization therapy techniques.

Sevelamer arsenite nanoparticle as a Pi-responsive drug carrier and embolic agent for chemoembolization.

Arsenic trioxide (As2O3, ATO) has limited therapeutic benefit to treat solid tumors, whether used alone or in combination. Nanoscale drug delivery vehicles have great potential to overcome the limitation of the utility of ATO by rapid renal clearance and dose-limiting toxicity. Polymeric materials ranging from gelatin foam to synthetic polymers such as poly(vinyl alcohol) were developed for vascular embolic or chemoembolic applications. Recently, we have introduced sevelamer, an oral phosphate binder, as a new polymeric embolic for vascular interventional therapy. In this paper, sevelamer arsenite nanoparticle with a polygonal shape and a size of 50-300 nm, synthesized by anionic exchange from sevelamer chloride, was developed as a Pi-responsive bifunctional drug carrier and embolic agent for chemoembolization therapy. At the same arsenic dosage, sevelamer arsenite-induced severer tumor necrosis than ATO on the VX2 cancer model. In vitro tests evidenced that Pi deprivation by sevelamer could enhance ATO's anticancer effect. The results showed that ATO in Pi starvation reduced cell viability, induced more apoptosis, and diminished the mitochondrial membrane potential (Δψm) of cells since Pi starvation helps ATO to further down-regulate Bcl-2 expression, up-regulate Bax expression, enhance the activation of caspase-3 and increase the release of cytochrome c, and the production of excessive reactive oxygen species (ROS). Sevelamer arsenite not only plays a Pi-activated nano-drug delivery system but also integrated anticancer drug with embolic for interventional therapy. Therefore, our results presented a new administration route of ATO as well as an alternative chemoembolization therapy.

Intratumoral Pi deprivation benefits chemoembolization therapy via increased accumulation of intracellular doxorubicin.

It is a decade-long controversy that transarterial chemoembolization (TACE) has definite priority over transarterial embolization (TAE) in treating patients with hepatocellular carcinoma (HCC), since HCC cells are regularly resistant to chemotherapy by enhanced expression of proteins that confer drug resistance, and ABC transporters pump the intracellular drug out of the cell. We addressed this issue by modulating the chemo-environment. In an animal model, sevelamer, a polymeric phosphate binder, was introduced as an embolic agent to induce intratumoral inorganic phosphate (Pi) starvation, and trans-arterially co-delivered with doxorubicin (DOX). The new type of TACE was named as DOX-TASE. This Pi-starved environment enhanced DOX tumoral accumulation and retention, and DOX-TASE thereby induced more severe tumor necrosis than that induced by conventional TACE (C-TACE) and drug-eluting bead TACE (D-TACE) at the same dose. In vitro tests showed that Pi starvation increased the cellular accumulation of DOX in an irreversible manner and enhanced cytotoxicity and cell apoptosis by suppressing the expression of ABC transporters (P-glycoprotein (P-gp), BCRP, and MRP1) and the production of intracellular ATP. Our results are indicative of an alternative interventional therapy combining chemotherapy with embolization more effectively.

Impacts of Fracture Types on Success Rate of Closed Reduction and Percutaneous Pinning in Pediatric Lateral Condyle Humerus Fractures Displaced >4 mm.

BACKGROUND: Closed reduction and percutaneous pinning (CRPP) is a promising treatment for pediatric lateral condyle humerus fractures (LCHFs) displaced >4 mm. However, few studies discussed roles of fracture types on success of CRPP in LCHFs. This study aimed to analyze the impacts of types of LCHFs displaced >4 mm on the success rate of CRPP. METHODS: We retrospectively reviewed 66 consecutive pediatric LCHFs attempted CRPP at our center. Song, Milch, Jakob, and Weiss classification were used to classify LCHFs. The fracture gap ≤2 mm and step of articular surface ≤2 mm were deemed as a successful CRPP. Otherwise, open reduction and internal fixation (ORIF) would be performed. Different fracture types and preoperative displacement were analyzed for their roles on success rate of CRPP in treating LCHFs displaced >4 mm. RESULTS: Fifty patients met the inclusion criteria were finally included in this study. Results showed that Milch type II LCHFs had a higher success rate of CRPP than type I LCHFs (P=0.03, <0.05). Correlation was found between Milch types and success rate of CRPP displaced >4 mm. No difference was found between Song stage 4 and 5 LCHFs displaced >4 mm in success rate of CRPP (P=0.90, >0.05), also no difference was found in pre-operative displacement between CRPP group and ORIF group. CONCLUSIONS: Milch classification is more important than Song classification in the success rate of CRPP when treating LCHFs displaced >4 mm. Milch type II LCHFs are recommended to be treated with CRPP, while Milch type I LCHFs are recommended to be treated with ORIF. The current study confirm Song's initial report that closed reduction can be successful and should be attempted for fractures with such displacement rather than going directly to ORIF. LEVEL OF EVIDENCE: Level III.

Closed reduction and percutaneous pinning vs open reduction and internal fixation in pediatric lateral condylar humerus fractures displaced by > 4 mm: an observational cross-sectional study.

BACKGROUND: Although open reduction and internal fixation (ORIF) is recommended for lateral condylar humerus fractures (LCHFs) displaced by > 4 mm, several studies have reported the use of closed reduction and percutaneous pinning (CRPP) to treat LCHFs with significant displacement. However, little is known about the clinical differences between these two surgical techniques. This study aimed to compare the therapeutic effects of CRPP and ORIF in treating LCHFs displaced by > 4 mm. METHODS: We retrospectively reviewed pediatric LCHFs displaced by > 4 mm treated with either CRPP or ORIF at our center from June 2019 to October 2020. Song and Milch fracture classifications were used. Variables such as age at injury, sex, side injured, fracture displacement, fracture type, operating time, postoperative treatment, and complications were compared between the two techniques. RESULTS: One hundred twenty LCHFs met inclusion criteria. There were 36 Milch type I and 84 type II LCHFs, and 69 Song stage 4 and 51 stage 5 LCHFs. CRPP was performed in 45 cases and ORIF in 75 cases. No differences were found in age, sex, side injured, preoperative displacement, postoperative displacement, and length of immobilization between the CRPP and ORIF groups. There was a difference between operation time and pin duration. The CRPP group had shorter operation times and pin duration, and required no additional operations to remove internal pins. The average follow-up duration was 13.9 months. All patients achieved fracture union, and no complications such as infection, nonunion, delayed union, osteonecrosis, fishtail deformity, cubitus varus or valgus, or pain were recorded during follow-up. Bone spurs, lateral prominences, and decreased carrying angle were common complications in all groups. No obvious cubitus varus was observed. Unaesthetic scars were only observed in the ORIF groups. No differences in range of motion or elbow function was found among the different therapies. CONCLUSIONS: Both CRPP and ORIF can achieve satisfactory clinical outcomes in treating LCHFs displaced by > 4 mm. No differences were found in complications or prognoses between the two groups. However, CRPP shows some advantages over ORIF, like less invasive surgery, no obvious scarring, and no need for secondary surgery with anesthesia for pin removal.

Treatment of pediatric supracondylar humerus fractures accompanied with pink pulseless hands.

BACKGROUND: The optimal treatment for pediatric supracondylar humeral fractures accompanied with a pink pulseless hand is controversial. Some clinicians recommend close observation after closed reduction and percutaneous pinning of the fractures, while some recommend surgical exploration if the radial pulse is unpalpable. The present study aimed to analyze the benefits and outcomes of close observation for treating pediatric supracondylar humeral fractures with a pink pulseless hand. METHODS: Thirteen consecutive children presenting with a pink pulseless hand following supracondylar humeral fracture were enrolled in this study. Preoperative and postoperative color-flow Duplex ultrasound detection was used to assess brachial artery compromise in most cases. Urgent closed reduction and percutaneous pinning of the fractures were attempted first. Close observation was carried out when the hand was pink and pulseless with an absent radial pulse. RESULTS: Preoperative color-flow Duplex ultrasound showed no disruption of the brachial artery in cases detected. Compression of the artery by the proximal fragment was observed in most cases, with one case of entrapment of the artery between fragments, and thrombus considered in two cases. All cases underwent urgent surgery, after which nine experienced immediate return of the radial pulse. The remaining four without a palpable pulse were managed with close observation and no deterioration of the vascular status was observed; therefore, no surgical exploration was performed. Postoperative color-flow Duplex ultrasound revealed continuity of the artery and rich collateral circulation. Patients completed an average of 4.5 years of follow-up, during which no major complications occurred. All patients achieved excellent limb function. CONCLUSIONS: Our study demonstrates that close observation after urgent closed reduction and percutaneous pinning is a sufficient approach for the treatment of pediatric supracondylar humeral fractures accompanied with a pink pulseless hand. Surgical exploration is not necessary as long as the hand is warm and well perfused. Color-flow Duplex ultrasound is beneficial for assessing vascular compromise and determining treatment strategies.

Treatment of pediatric lateral condylar humerus fractures with closed reduction and percutaneous pinning.

BACKGROUND: Lateral condylar humerus fractures (LCHFs) are the second most common pediatric distal humerus fractures. Open reduction and internal fixation is recommended for fractures displaced by more than 2 mm. Few studies described using closed reduction and percutaneous pinning (CRPP) for treating fractures with greater displacements. This study aims to explore the feasibility of CRPP in treating displaced LCHFs. METHODS: All patients underwent attempted CRPP first. Once a satisfying reduction was obtained, as determined using fluoroscopy based on the relative anatomical position of the fragments, an intraoperative arthrogram was performed to further confirm the congruence of the articular surface of the distal humerus. Open reduction is necessary to ensure adequate reduction if the fracture gap is more than 2.0 mm on either anteroposterior view or oblique internal rotational view by fluoroscopy after CRPP. All included fractures were treated by a single pediatric surgeon. RESULTS: Forty-six patients were included, 29 boys and 17 girls, with an average age of 5.2 years. Of these, 22/28 (78%) Jakob type II fractures and 14/18 (78%) Jakob type III fractures were treated with CRPP. All cases in Song stages II and III, 19/25 (76%) cases in Song stage IV, and 14/18 (78%) cases of Song stage V were treated with CRPP. The remaining converted to open reduction with internal fixation. Overall, 36 of the 46 patients (78%) were treated with CRPP. The average pre-op displacement was 7.2 mm, and the average post-op displacement was 1.1 mm on the anteroposterior or oblique internal rotational radiograph in cases treated with CRPP. CRPP was performed in an average of 37 min. The average casting period was 4 weeks and the average time of pin removal was 6 weeks postoperatively. The average time of follow-up was 4 months. All patients achieved union, regardless of closed or open reduction. No infection, delayed union, cubitus varus or valgus, osteonecrosis of the trochlea or capitellum, or pain were recorded during follow-up. CONCLUSIONS: Closed reduction and percutaneous pinning effectively treats LCHFs with displacement more than 4 mm. More than 3/4 of Song stage V or Jakob type III patients can avoid an incision.

Bayesian approach to estimating margin of safety for total maximum daily load development.

A Bayesian-updating approach is presented to the estimation of total uncertainty-based Margin of Safety (MOS) for Total Maximum Daily Load (TMDL) calculations. Probability distributions are presented to construct the likelihood function, the prior probability distribution, and the posterior (total uncertainty) probability distribution. The Bayesian-updating approach is demonstrated through a case study for the Lower Amite River, Louisiana. The posterior probability distribution-based on the Bayesian approach updates the standard deviation of summer dissolved oxygen in the Amite River from 1.88 mg/L to 2.10 mg/L when the total uncertainty is considered. Results from the Bayesian-updating approach are compared with two conventional methods. The dissolved oxygen reserve based on a conventional margin of safety of 20% is estimated to be 45,682.26 kg/Day. The second conventional method, where we consider the standard deviation of 1.88 mg/L, produces a dissolved oxygen reserve of 40,516.09 kg/Day. The Bayesian approach yields the dissolved oxygen reserve of 38,614.43 kg/Day with the first level (µ-σ) of MOS, producing a deficit of 5606.65 kg/Day in dissolved oxygen. The dissolved oxygen reserve deficit increases to 23,895.13 kg/Day when the second level (µ-2σ) of MOS is used, which escalated to 42,383.52 kg/Day when the highest level (µ-3σ) of MOS is used. While the total uncertainty-based Bayesian approach is demonstrated for a TMDL development on the Amite River, the overall approach could be applied in any river system with similar available data.

Analysis of uncertainty propagation through model parameters and structure.

Estimation of uncertainty propagation in watershed models is challenging but useful to total maximum daily load (TMDL) calculations. This paper presents an effective approach, involving the combined application of Rosenblueth method and sensitivity analysis, to the determination of uncertainty propagation through the parameters and structure of the HSPF (Hydrologic Simulation Program-FORTRAN) model. The sensitivity analysis indicates that the temperature is a major forcing function in the DO-BOD balance and controls the overall dissolved oxygen concentration. The mean and standard deviation from the descriptive statistics of dissolved oxygen data obtained using the HSPF model are compared to those estimated using Rosenblueth's method. The difference is defined as the error propagated from water temperature through dissolved oxygen. The error propagation, while considering the second order sensitivity coefficient in Rosenblueth's method, is observed to have a mean of 0.281 mg/l and a standard deviation of 0.099 mg/l. A relative low error propagation value is attributed to low skewness of dependent and independent variables. The results provide new insights into the uncertainty propagation in the HSPF model commonly used for TMDL development.

[Comparison of EC/OC in PM2.5 between filter sampling off-line analysis and in situ on-line measurement].

Elemental carbon (EC) and organic carbon (OC) in PM2.5 were measured simultaneously at the campus of Peking University from January 2006 to April 2007 by two common used methodologies. One is quartz filter sampling followed by off-line SUNSET Lab EC/OC analyzer and the other is SUNSET in-situ on-line EC/OC analyzer. The comparison shows significant differences on OC measurements between the two methods. The results by filter sampling off-line analysis were as twice high as those by in-situ on-line method. The volatile organic carbons (VOCs) adsorbed by quartz filter led to considerable positive error of OC. The use of parallel plate organic denuder can eliminate such error but cause the evaporation of semi-volatile organic carbon on the filter which induces another negative error of OC, about 10%. The improved method of filter sampling off-line analysis using both parallel plate organic denuder and backup filter has a good agreement with in-situ online measurement.