Evaluation of polygenic risk scores to differentiate between type 1 and type 2 diabetes.

Polygenic risk scores (PRS) quantify the genetic liability to disease and are calculated using an individual's genotype profile and disease-specific genome-wide association study (GWAS) summary statistics. Type 1 (T1D) and type 2 (T2D) diabetes both are determined in part by genetic loci. Correctly differentiating between types of diabetes is crucial for accurate diagnosis and treatment. PRS have the potential to address possible misclassification of T1D and T2D. Here we evaluated PRS models for T1D and T2D in European genetic ancestry participants from the UK Biobank (UKB) and then in the Michigan Genomics Initiative (MGI). Specifically, we investigated the utility of T1D and T2D PRS to discriminate between T1D, T2D, and controls in unrelated UKB individuals of European ancestry. We derived PRS models using external non-UKB GWAS. The T1D PRS model with the best discrimination between T1D cases and controls (area under the receiver operator curve [AUC] = 0.805) also yielded the best discrimination of T1D from T2D cases in the UKB (AUC = 0.792) and separation in MGI (AUC = 0.686). In contrast, the best T2D model did not discriminate between T1D and T2D cases (AUC = 0.527). Our analysis suggests that a T1D PRS model based on independent single nucleotide polymorphisms may help differentiate between T1D, T2D, and controls in individuals of European genetic ancestry.

Automatic detection, segmentation, and classification of primary bone tumors and bone infections using an ensemble multi-task deep learning framework on multi-parametric MRIs: a multi-center study.

OBJECTIVES: To develop an ensemble multi-task deep learning (DL) framework for automatic and simultaneous detection, segmentation, and classification of primary bone tumors (PBTs) and bone infections based on multi-parametric MRI from multi-center. METHODS: This retrospective study divided 749 patients with PBTs or bone infections from two hospitals into a training set (N = 557), an internal validation set (N = 139), and an external validation set (N = 53). The ensemble framework was constructed using T1-weighted image (T1WI), T2-weighted image (T2WI), and clinical characteristics for binary (PBTs/bone infections) and three-category (benign/intermediate/malignant PBTs) classification. The detection and segmentation performances were evaluated using Intersection over Union (IoU) and Dice score. The classification performance was evaluated using the receiver operating characteristic (ROC) curve and compared with radiologist interpretations. RESULT: On the external validation set, the single T1WI-based and T2WI-based multi-task models obtained IoUs of 0.71 ± 0.25/0.65 ± 0.30 for detection and Dice scores of 0.75 ± 0.26/0.70 ± 0.33 for segmentation. The framework achieved AUCs of 0.959 (95%CI, 0.955-1.000)/0.900 (95%CI, 0.773-0.100) and accuracies of 90.6% (95%CI, 79.7-95.9%)/78.3% (95%CI, 58.1-90.3%) for the binary/three-category classification. Meanwhile, for the three-category classification, the performance of the framework was superior to that of three junior radiologists (accuracy: 65.2%, 69.6%, and 69.6%, respectively) and comparable to that of two senior radiologists (accuracy: 78.3% and 78.3%). CONCLUSION: The MRI-based ensemble multi-task framework shows promising performance in automatically and simultaneously detecting, segmenting, and classifying PBTs and bone infections, which was preferable to junior radiologists. CLINICAL RELEVANCE STATEMENT: Compared with junior radiologists, the ensemble multi-task deep learning framework effectively improves differential diagnosis for patients with primary bone tumors or bone infections. This finding may help physicians make treatment decisions and enable timely treatment of patients. KEY POINTS: • The ensemble framework fusing multi-parametric MRI and clinical characteristics effectively improves the classification ability of single-modality models. • The ensemble multi-task deep learning framework performed well in detecting, segmenting, and classifying primary bone tumors and bone infections. • The ensemble framework achieves an optimal classification performance superior to junior radiologists' interpretations, assisting the clinical differential diagnosis of primary bone tumors and bone infections.

Results of a Pilot External Quality Assessment Scheme for Genetic Testing of Newborns with Spinal Muscular Atrophy.

BACKGROUND: This study aims to evaluate the ability of laboratories to perform spinal muscular atrophy (SMA) genetic testing in newborns based on dried blood spot (DBS) samples, and to provide reference data and advance preparation for establishing the pilot external quality assessment (EQA) scheme for SMA genetic testing of newborns in China. METHODS: The pilot EQA scheme contents and evaluation principles of this project were designed by National Center for Clinical Laboratories (NCCL), National Health Commission. Two surveys were carried out in 2022, and 5 batches of blood spots were submitted to the participating laboratory each time. All participating laboratories conducted testing upon receiving samples, and test results were submitted to NCCL within the specified date. RESULTS: The return rates were 75.0% (21/28) and 95.2% (20/21) in the first and second surveys, respectively. The total return rate of the two examinations was 83.7% (41/49). Nineteen laboratories (19/21, 90.5%) had a full score passing on the first survey, while in the second survey twenty laboratories (20/20, 100%) scored full. CONCLUSIONS: This pilot EQA survey provides a preliminary understanding of the capability of SMA genetic testing for newborns across laboratories in China. A few laboratories had technical or operational problems in testing. It is, therefore, of importance to strengthen laboratory management and to improve testing capacity for the establishment of a national EQA scheme for newborn SMA genetic testing.

Establishment of Reference Range for Serum Concentration of Vitamin A and Vitamin E in Southern Sichuan Area of China.

OBJECTIVE: To establish the reference range of serum concentration of vitamin A (VA) and vitamin E (VE) in Southern Sichuan area of China. METHODS: From August 1, 2021, to May 31, 2023, 9482 blood tablets were received for the screening of VA and VE. The information was divided into four different age groups: ≤1 year old, 1< to ≤6 years, 6< to ≤17 years, and 17< to ≤59 years. In each age group, the four seasons were further subdivided into spring, summer, autumn, and winter, as well as male and female genders. The serum concentration of VA and VE was detected by liquid chromatography-tandem mass spectrometry (HPLC-MS), and the reference range was established for verification. RESULTS: The concentration of VA and VE in 9482 cases showed skewed distribution. When comparing between different age groups, the serum concentration of VA and VE was statistically significant (p < 0.05). While comparing different seasons, the serum VA levels in different seasons were significantly different (p < 0.05) except in summer and autumn. There was statistical significance in VE level in different seasons (p < 0.05). And while comparing different genders, there was no statistical significance in VA concentration levels (p > 0.05). The VE concentration levels were statistically significant (p < 0.05). The established reference range was established and verified, and the results were in accordance with the standard. CONCLUSION: The reference range of VA and VE should be set according to different ages, different seasons, and different genders.

Novel Molecular Representations Using Neumann-Cayley Orthogonal Gated Recurrent Unit.

Advances in deep neural networks (DNNs) have made a very powerful machine learning method available to researchers across many fields of study, including the biomedical and cheminformatics communities, where DNNs help to improve tasks such as protein performance, molecular design, drug discovery, etc. Many of those tasks rely on molecular descriptors for representing molecular characteristics in cheminformatics. Despite significant efforts and the introduction of numerous methods that derive molecular descriptors, the quantitative prediction of molecular properties remains challenging. One widely used method of encoding molecule features into bit strings is the molecular fingerprint. In this work, we propose using new Neumann-Cayley Gated Recurrent Units (NC-GRU) inside the Neural Nets encoder (AutoEncoder) to create neural molecular fingerprints (NC-GRU fingerprints). The NC-GRU AutoEncoder introduces orthogonal weights into widely used GRU architecture, resulting in faster, more stable training, and more reliable molecular fingerprints. Integrating novel NC-GRU fingerprints and Multi-Task DNN schematics improves the performance of various molecular-related tasks such as toxicity, partition coefficient, lipophilicity, and solvation-free energy, producing state-of-the-art results on several benchmarks.

Efficacy and safety of three endoscopic techniques for small common bile duct stones (≤ 10 mm): a multicenter, retrospective, cohort study with propensity score matching.

BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) is a major option for common bile duct (CBD) stones. Endoscopic sphincterotomy (EST), endoscopic papillary balloon dilatation (EPBD), and endoscopic sphincterotomy plus balloon dilatation (ESBD) are procedures for opening the bile duct orifice to extract CBD stones during ERCP. The optimal method for extracting small CBD stones (≤ 10 mm) has not yet been proposed. We aimed to compare the efficacy and safety of these three techniques in extracting small CBD stones. METHODS: ERCP for small stones was performed between January 2009 and November 2020 at three tertiary care centers. The incidence of post-ERCP pancreatitis (PEP) was compared among EST, EPBD, and ESBD groups. First and overall success rates of stone extraction, utilization rate of mechanical lithotripsy, and other ERCP complications such as bleeding, perforation, infection, and hyperamylasemia were compared. RESULTS: A total of 2181 patients were enrolled between January 2009 and November 2020. The proportion of young patients (≤ 45 years) in EPBD group was more than those in EST and ESBD group. Stone size in ESBD group was much larger than EST and EPBD group. After propensity score matching, the success rates of first and overall stone extraction in the three groups were high, and the rates of mechanical lithotripsy were low, with no significant difference. The PEP incidences showed no differences among the three groups. The incidence of bleeding complication in EST group was higher than that in EPBD group. No significant differences were observed in other complications between EPBD group and ESBD group. ESBD group had higher incidence of overall, infection, and hyperamylasemia complications than EST group. CONCLUSION: EPBD is equivalent to ESBD in stone removal efficiency and complication rate, but brings a lower bleeding risk than EST. Therefore, we recommend EPBD as the first choice for small CBD stones.

Engineered Peptides Enable Biomimetic Route for Collagen Intrafibrillar Mineralization.

Overcoming the short lifespan of current dental adhesives remains a significant clinical need. Adhesives rely on formation of the hybrid layer to adhere to dentin and penetrate within collagen fibrils. However, the ability of adhesives to achieve complete enclosure of demineralized collagen fibrils is recognized as currently unattainable. We developed a peptide-based approach enabling collagen intrafibrillar mineralization and tested our hypothesis on a type-I collagen-based platform. Peptide design incorporated collagen-binding and remineralization-mediating properties using the domain structure conservation approach. The structural changes from representative members of different peptide clusters were generated for each functional domain. Common signatures associated with secondary structure features and the related changes in the functional domain were investigated by attenuated total reflectance Fourier-transform infrared (ATR-FTIR) and circular dichroism (CD) spectroscopy, respectively. Assembly and remineralization properties of the peptides on the collagen platforms were studied using atomic force microscopy (AFM). Mechanical properties of the collagen fibrils remineralized by the peptide assemblies was studied using PeakForce-Quantitative Nanomechanics (PF-QNM)-AFM. The engineered peptide was demonstrated to offer a promising route for collagen intrafibrillar remineralization. This approach offers a collagen platform to develop multifunctional strategies that combine different bioactive peptides, polymerizable peptide monomers, and adhesive formulations as steps towards improving the long-term prospects of composite resins.

A "Trojan Horse" Strategy: The Preparation of Bile Acid-Modifying Irinotecan Hydrochloride Nanoliposomes for Liver-Targeted Anticancer Drug Delivery System Study.

The bile acid transport system is a natural physiological cycling process between the liver and the small intestine, occurring approximately 6-15 times during the day. There are various bile acid transporter proteins on hepatocytes that specifically recognize bile acids for transport. Therefore, in this paper, a novel liposome, cholic acid-modified irinotecan hydrochloride liposomes (named CA-CPT-11-Lip), was prepared based on the "Trojan horse" strategy. The liposomes preparation process was optimized, and some important quality indicators were investigated. The distribution of irinotecan hydrochloride in mice was then analyzed by high-performance liquid chromatography (HPLC), and the toxicity of liposomes to hepatocellular carcinoma cells (HepG-2) was evaluated in vitro. As a result, CA-CPT-11-Lip was successfully prepared. It was spherical with a particle size of 154.16 ± 4.92 nm, and the drug loading and encapsulation efficiency were 3.72 ± 0.04% and 82.04 ± 1.38%, respectively. Compared with the conventional liposomes (without cholic acid modification, named CPT-11-Lip), CA-CPT-11-Lip had a smaller particle size and higher encapsulation efficiency, and the drug accumulation in the liver was more efficient, enhancing the anti-hepatocellular carcinoma activity of irinotecan hydrochloride. The novel nanoliposome modified by cholic acid may help to expand the application of irinotecan hydrochloride in the treatment of hepatocellular carcinoma and construct the drug delivery system mode of drug liver targeting.

A Novel Drug Delivery System: Hyodeoxycholic Acid-Modified Metformin Liposomes for Type 2 Diabetes Treatment.

Metformin is a first-line drug for the clinical treatment of type 2 diabetes; however, it always leads to gastrointestinal tolerance, low bioavailability, short half-life, etc. Liposome acts as an excellent delivery system that could reduce drug side effects and promote bioavailability. Hyodeoxycholic acid, a cholesterol-like structure, can regulate glucose homeostasis and reduce the blood glucose levels. As an anti-diabetic active ingredient, hyodeoxycholic acid modifies liposomes to make it overcome the disadvantages of metformin as well as enhance the hypoglycemic effect. By adapting the thin-film dispersion method, three types of liposomes with different proportions of hyodeoxycholic acid and metformin were prepared (HDCA:ME-(0.5:1)-Lips, HDCA:ME-(1:1)-Lips, and HDCA:ME-(2:1)-Lips). Further, the liposomes were characterized, and the anti-type 2 diabetes activity of liposomes was evaluated. The results from this study indicated that three types of liposomes exhibited different characteristics-Excessive hyodeoxycholic acid decreased encapsulation efficiency and drug loading. In the in vivo experiments, liposomes could reduce the fasting blood glucose levels, improve glucose tolerance, regulate oxidative stress markers and protect liver tissue in type 2 diabetic mice. These results indicated that HDCA:ME-(1:1)-Lips was the most effective among the three types of liposomes prepared and showed better effects than metformin. Hyodeoxycholic acid can enhance the hypoglycemic effect of metformin and play a suitable role as an excipient in the liposome.

Hydrothermal treatment enhances energy recovery from pig manure digestate and improves the properties of residues.

Energy recovery from biowaste is of high significance for a sustainable society. Herein, hydrothermal treatment (HT) was applied to valorize pig manure digestate. The effects of hydrothermal operational parameters, including temperature (130-250 °C), residence time (15-90 min), and total solid (TS) concentration (10%-20%), on reducing sugar yield were investigated in this study. Among them, hydrothermal temperature was identified as the most important factor influencing reducing sugar yield, followed by the TS concentration and time. The optimal hydrothermal conditions for the pig manure digestate were 175.6 °C, 35.4 min and a TS concentration of 10% with a reduced sugar yield of 9.81 mg gTS-1. The addition of hydrolysate could enhance methane production by 21.6-50.4% from the anaerobic digestion of pig manure than that without the hydrolysate addition. After HT, the hygienic quality, including fecal coliform number and ascaris egg mortality, was improved in the residual digestate. Antibiotics such as sulfamonomethoxine, oxytetracycline, doxycycline and sulfaclodazine in the pig manure digestate were decomposed during HT and decreased environmental risk. These findings indicated that the hydrothermal process might be an effective technique to recover energy from the digestate of livestock and poultry manure and to improve the residual digestate for subsequent utilization.

FiberSim: A flexible open-source model of myofilament-level contraction.

FiberSim is a flexible open-source model of myofilament-level contraction. The code uses a spatially explicit technique, meaning that it tracks the position and status of each contractile molecule within the lattice framework. This allows the model to simulate some of the mechanical effects modulated by myosin-binding protein C, as well as the dose dependence of myotropes and the effects of varying isoform expression levels. This paper provides a short introduction to FiberSim and presents simulations of tension-pCa curves with and without regulation of thick and thin filament activation by myosin-binding protein C. A myotrope dose-dependent response as well as slack/re-stretch maneuvers to assess rates of tension recovery are also presented. The software was designed to be flexible (the user can define their own model and/or protocol) and computationally efficient (simulations can be performed on a regular laptop). We hope that other investigators will use FiberSim to explore myofilament level mechanisms and to accelerate research focusing on the contractile properties of sarcomeres.

Comparative proteomic analysis of Leptospira interrogans serogroup Icterohaemorrhagiae human vaccine strain and epidemic isolate from China.

Leptospira interrogans serogroup Icterohaemorrhagiae is the predominant pathogen causing leptospirosis in China and is still used as the vaccine strain for the current human inactivated vaccine. Unlike the clade ST17, which is distributed worldwide, ST1 is the most prevalent in serogroup Icterohaemorrhagiae in China. To further characterize leptospiral pathogens, isobaric tags for relative and absolute quantitation and parallel reaction monitoring were used to analyze differences at the proteomic level between serogroup Icterohaemorrhagiae vaccine strain 56001 (ST1) and circulating isolate 200502 (ST17) from different periods. Two hundred and eighty-one proteins were differentially expressed between the circulating isolate and vaccine strain, of which 166 were upregulated (> 1.2-fold change, P < 0.05) and 115 (< 0.8-fold change, P < 0.05) were downregulated. Function prediction revealed that nine upregulated proteins were outer membrane proteins, including several known immunogenic and/or virulence-related proteins, such as ompL1, LipL71, and LipL41. Furthermore, important expression differences in carbohydrate, amino acid, and energy metabolism and transport proteins were identified between both strains from different clusters, suggesting that these differences may reflect metabolic diversity and the potential of the pathogens to adapt to different environments. In summary, our findings provide insights into a better understanding of the component strains of the Chinese human leptospirosis vaccine at the proteomic level. Additionally, these data facilitate evaluating the mechanisms by which pathogenic Leptospira species adapt to the host environment.

Arginase 2 negatively regulates sorafenib-induced cell death by mediating ferroptosis in melanoma.

Ferroptosis, a newly defined and iron-dependent cell death, morphologically and biochemically differs from other cell deaths. Melanoma is a serious type of skin cancer, and the poor efficacy of current therapies causes a major increase in mortality. Sorafenib, a multiple kinase inhibitor, has been evaluated in clinical phase trials of melanoma patients, which shows modest efficacy. Emerging evidence has demonstrated that arginase 2 (Arg2), type 2 of arginase, is elevated in various types of cancers including melanoma. To investigate the role and underlying mechanism of Arg2 in sorafenib-induced ferroptosis in melanoma, reverse transcriptase-quantitative polymerase chain reaction, western blot analysis, adenovirus and lentivirus transduction, and in vivo tumor homograft model experiments were conducted. In this study, we show that sorafenib treatment leads to melanoma cell death and a decrease in Arg2 at both the mRNA and protein levels. Knockdown of Arg2 increases lipid peroxidation, which contributes to ferroptosis, and decreases the phosphorylation of Akt. In contrast, overexpression of Arg2 rescues sorafenib-induced ferroptosis, which is prevented by an Akt inhibitor. In addition, genetic and pharmacological suppression of Arg2 is able to ameliorate the anticancer activity of sorafenib in melanoma cells in vitro and in tumor homograft models. We also show that Arg2 suppresses ferroptosis by activating the Akt/GPX4 signaling pathway, negatively regulating sorafenib-induced cell death in melanoma cells. Our study not only uncovers a novel mechanism of ferroptosis in melanoma but also provides a new strategy for the clinical applications of sorafenib in melanoma treatment.

Three-dimensional printed customized uncemented unipolar prosthesis combined with ligament reconstruction for tumorous defect of the distal femur in children.

BACKGROUND: Hemiarthroplasty following tumor resection of the distal femur in children provides a chance to preserve the proximal tibial physis for limb elongation. Based on three-dimensional (3D) printing technology, the uncemented unipolar prosthesis with joint stability reinforced structures (JSRSs) was custom-designed for our cases. This study aimed to describe the design and assess the short-term outcomes of this refined prosthetic hemiarthroplasty. METHODS: Seven patients (four females and three males) received 3D-printed customized uncemented unipolar prosthesis for hemiarthroplasty after removal of the distal femur, from September 2019 to October 2020 at our Orthopedics department. The limb function, growth of the preserved proximal tibial physis, joint stability, and limb length discrepancy (LLD) were assessed. Complications were recorded. RESULTS: Six patients survived with no evidence of metastasis or local recurrence at the last follow-up, and one patient died of lung metastasis at 19 months postoperatively. Follow-up ranged from 19 to 32 months, with an average of 26 months. Elongation of the tibia was observed in all cases. At the last follow-up, four patients exhibited equal growth length compared with the healthy contralateral tibia. LLD ranged from 0.8 to 1.6 cm with a mean of 1.3 cm. The average knee range of motion was 95.3° of flexion and 4.5° of extension. All patients achieved satisfactory postoperative limb function with a mean MSTS score of 25.8. The results of the drawer, Lachman, and pivot shift tests were negative in all patients. During follow-up, painless joint space narrowing was observed in two patients. The screw for ligament fixation loosened in one of the seven patients at 17 months postoperatively. No subluxation of the joint, angular deformity, or breakage of the implant was detected in the remaining patients. CONCLUSIONS: 3D-printed customized uncemented unipolar prosthesis with JSRS would be a good choice for reconstructing tumorous defect in the distal femur in children.

Andrographolide: A review of its pharmacology, pharmacokinetics, toxicity and clinical trials and pharmaceutical researches.

Andrographis paniculata (Burm. f.) Wall. ex Nees, a renowned herb medicine in China, is broadly utilized in traditional Chinese medicine (TCM) for the treatment of cold and fever, sore throat, sore tongue, snake bite with its excellent functions of clearing heat and toxin, cooling blood and detumescence from times immemorial. Modern pharmacological research corroborates that andrographolide, the major ingredient in this traditional herb, is the fundamental material basis for its efficacy. As the main component of Andrographis paniculata (Burm. f.) Wall. ex Nees, andrographolide reveals numerous therapeutic actions, such as antiinflammatory, antioxidant, anticancer, antimicrobial, antihyperglycemic and so on. However, there are scarcely systematic summaries on the specific mechanism of disease treatment and pharmacokinetics. Moreover, it is also found that it possesses easily ignored security issues in clinical application, such as nephrotoxicity and reproductive toxicity. Thereby it should be kept a lookout over in clinical. Besides, the relationship between the efficacy and security issues of andrographolide should be investigated and evaluated scientifically. In this review, special emphasis is given to andrographolide, a multifunctional natural terpenoids, including its pharmacology, pharmacokinetics, toxicity and pharmaceutical researches. A brief overview of its clinical trials is also presented. This review intends to systematically and comprehensively summarize the current researches of andrographolide, which is of great significance for the development of andrographolide clinical products. Noteworthy, those un-cracked issues such as specific pharmacological mechanisms, security issues, as well as the bottleneck in clinical transformation, which detailed exploration and excavation are still not to be ignored before achieving integration into clinical practice. In addition, given that current extensive clinical data do not have sufficient rigor and documented details, more high-quality investigations in this field are needed to validate the efficacy and/or safety of many herbal products.

Autonomous-Strengthening Adhesive Provides Hydrolysis-Resistance and Enhanced Mechanical Properties in Wet Conditions.

The low-viscosity adhesive that is used to bond composite restorative materials to the tooth is readily damaged by acids, enzymes, and oral fluids. Bacteria infiltrate the resulting gaps at the composite/tooth interface, demineralize the tooth, and further erode the adhesive. This paper presents the preparation and characterization of a low-crosslink-density hydrophilic adhesive that capitalizes on sol-gel reactions and free-radical polymerization to resist hydrolysis and provide enhanced mechanical properties in wet environments. Polymerization behavior, water sorption, and leachates were investigated. Dynamic mechanical analyses (DMA) were conducted using water-saturated adhesives to mimic load transfer in wet conditions. Data from all tests were analyzed using appropriate statistical tests (α = 0.05). The degree of conversion was comparable for experimental and control adhesives at 88.3 and 84.3%, respectively. HEMA leachate was significantly lower for the experimental (2.9 wt%) compared to control (7.2 wt%). After 3 days of aqueous aging, the storage and rubbery moduli and the glass transition temperature of the experimental adhesive (57.5MPa, 12.8MPa, and 38.7 °C, respectively) were significantly higher than control (7.4MPa, 4.3 MPa, and 25.9 °C, respectively). The results indicated that the autonomic sol-gel reaction continues in the wet environment, leading to intrinsic reinforcement of the polymer network, improved hydrolytic stability, and enhanced mechanical properties.

Regio- and Stereoselective 1,2-Oxyhalogenation of Non-Conjugated Alkynes via Directed Nucleopalladation: Catalytic Access to Tetrasubstituted Alkenes.

A catalytic 1,2-oxyhalogenation method that converts non-conjugated internal alkynes into tetrasubstituted alkenes with high regio- and stereoselectivity is described. Mechanistically, the reaction involves a PdII /PdIV catalytic cycle that begins with a directed oxypalladation step. The origin of regioselectivity is the preference for formation of a six-membered palladacycle intermediate, which is facilitated by an N,N-bidentate 2-(pyridin-2-yl)isopropyl (PIP) amide directing group. Selectivity for C(alkenyl)-X versus -N (X=halide) reductive elimination from the PdIV center depends on the identity of the halide anion; bromide and iodide engage in C(alkenyl)-X formation, while intramolecular C(alkenyl)-N reductive elimination occurs with chloride to furnish a lactam product. DFT calculations shed light on the origins of this phenomenon.

Overweight with HBV infection limited the efficacy of TACE in hepatocellular carcinoma by inhibiting the upregulated HMGB1.

BACKGROUND: Transarterial chemoembolization (TACE) is an effective treatment for patients with hepatocellular carcinoma (HCC). However, the impact of hepatitis B viral (HBV) infection and body mass index (BMI) on TACE is controversial. The present study aimed to compare the influence of HBV and high BMI on TACE outcomes in advanced HCC. METHODS: Based on HBV infection history and BMI, patients were assigned to different subgroups. Blood samples were collected and analyzed by an enzyme-linked immunosorbent assay (ELISA) kit. The primary endpoint was progression-free survival (PFS) and the overall survival (OS) in the population. RESULTS: Compared to overweight combined HBV patients who received TACE, people with normal weight or no viral infection had significantly better OS and PFS. Sex, age, portal vein tumor thrombus, BCLC, ECOG, and tumor diameter are the main risk factors affecting PFS and OS. Except for the postoperative fever, no significant difference was detected in adverse reactions. Irrespective of TACE, the average expression of HMGB1 in hepatitis or obesity patients was higher than that in normal individuals and did not show upregulation after TACE. Patients without overweight or HBV infection had a low expression of serum HMGB1 that was substantially upregulated after TACE. CONCLUSIONS: In this study, overweight combined HBV infection patients had shorter PFS and OS than other HCC patients. Thus, HBV and BMI maybe two factors affecting the efficacy of TACE via upregulated HMGB1.

Controlling Bicontinuous Structures through a Solvent Segregation-Driven Gel.

The past decade has seen increased research interest in studying bicontinuous structures formed via colloidal self-assembly due to their many useful applications. A new type of colloidal gel, solvent segregation-driven gel (SeedGel), has been recently demonstrated as an effective approach to arrest bicontinuous structures with unique and intriguing properties, such as thermoreversibility, structural reproducibility, and sensitive temperature response. Here, using a model system with silica particles in the 2,6-lutidine/water binary solvent, we investigate the factors controlling the domain size of a SeedGel system by varying the particle concentration, solvent ratio, and quenching protocol. A phase diagram is identified to produce SeedGels for this model system. Our results indicate that by adjusting the sample composition, it is possible to realize bicontinuous domains with well-controlled repeating distances (periodicities). In addition, the effect of quenching rate on the domain size is systematically investigated, showing that it is a very sensitive parameter to control domain sizes. By further heating SeedGel up into the spinodal region, the structure evolution under high temperatures is also investigated and discussed. These results provide important insights into how to control bicontinuous structures in SeedGel systems.

MRI-based radiomics signature for pretreatment prediction of pathological response to neoadjuvant chemotherapy in osteosarcoma: a multicenter study.

OBJECTIVE: To develop and validate a radiomics signature based on magnetic resonance imaging (MRI) from multicenter datasets for preoperative prediction of pathologic response to neoadjuvant chemotherapy (NAC) in patients with osteosarcoma. METHODS: We retrospectively enrolled 102 patients with histologically confirmed osteosarcoma who received chemotherapy before treatment from 4 hospitals (68 in the primary cohort and 34 in the external validation cohort). Quantitative imaging features were extracted from contrast-enhanced fat-suppressed T1-weighted images (CE FS T1WI). Four classification methods, i.e., the least absolute shrinkage and selection operator logistic regression (LASSO-LR), support vector machine (SVM), Gaussian process (GP), and Naive Bayes (NB) algorithm, were compared for feature selection and radiomics signature construction. The predictive performance of the radiomics signatures was assessed with the area under receiver operating characteristics curve (AUC), calibration curve, and decision curve analysis (DCA). RESULTS: Thirteen radiomics features selected based on the LASSO-LR classifier were adopted to construct the radiomics signature, which was significantly associated with the pathologic response. The prediction model achieved the best performance between good and poor responders with an AUC of 0.882 (95% CI, 0.837-0.918) in the primary cohort. Calibration curves showed good agreement. Similarly, findings were validated in the external validation cohort with good performance (AUC, 0.842 [95% CI, 0.793-0.883]) and good calibration. DCA analysis confirmed the clinical utility of the selected radiomics signature. CONCLUSION: The constructed CE FS T1WI-radiomics signature with excellent performance could provide a potential tool to predict pathologic response to NAC in patients with osteosarcoma. KEY POINTS: • The radiomics signature based on multicenter contrast-enhanced MRI was useful to predict response to NAC. • The prediction model obtained with the LASSO-LR classifier achieved the best performance. • The baseline clinical characteristics were not associated with response to NAC.