Safety and efficacy of indocyanine green fluorescence imaging for real-time guidance of laparoscopic thermal ablation in patients with liver cancer.

PURPOSE: To evaluate the safety and efficacy of indocyanine green fluorescence imaging for real-time guidance of laparoscopic thermal ablation in patients with liver cancer. MATERIALS AND METHODS: A total of 27 patients with 40 liver lesions underwent fluorescence-assisted laparoscopic ablation between January 2020 to March 2023. The sensitivity of indocyanine green (ICG)-fluorescence imaging, technique effectiveness rate and complications of fluorescence-assisted laparoscopic thermal ablation were evaluated. RESULTS: In total, 33 out of the 40 lesions were identified by ICG-fluorescence imaging technique, with the sensitivity of 82.5%. The sensitivity of ICG-fluorescence imaging of tumor detection in liver surface of parenchyma was significantly higher than that in the deeply located hepatic parenchyma (96.8% vs 33.3%, p = 0.002). ICG-fluorescence imaging procedures detected 4 lesions that cannot be seen on intraoperative ultrasound. It provides clear demarcation lines on the hepatic surface. Technical success is achieved if the necrotic zone had at least a 5 mm ablative margin around the outer edge of the ICG-fluorescence image. Technical success of fluorescence laparoscopic radiofrequency ablation (FLRFA) and fluorescence laparoscopic microwave ablation (FLMWA) was 100% (27/27). Technical effectiveness is defined by the complete necrotic lesions of the local tumor tissue during follow-up. According to the CT/MRI one month after FLRFA or FLMWA, the technical efficacy rate was 92.5% (37/40) and local tumor progression occurred in 7.5% (3/40) of the enrolled lesions. During the follow-up period, no major complications were observed. CONCLUSION: ICG-fluorescence imaging guided laparoscopic thermal ablation was feasible, safe and effective.

Quantifying Protein Shape to Elucidate Its Influence on Solution Viscosity in High-Concentration Electrolyte Solutions.

Therapeutic proteins with a high concentration and low viscosity are highly desirable for subcutaneous and certain local injections. The shape of a protein is known to influence solution viscosity; however, the precise quantification of protein shape and its relative impact compared to other factors like charge-charge interactions remains unclear. In this study, we utilized seven model proteins of varying shapes and experimentally determined their shape factors (v) based on Einstein's viscosity theory, which correlate strongly with the ratios of the proteins' surface area to the 2/3 power of their respective volumes, based on protein crystal structures resolved experimentally or predicted by AlphaFold. This finding confirms the feasibility of computationally estimating protein shape factors from amino acid sequences alone. Furthermore, our results demonstrated that, in high-concentration electrolyte solutions, a more spherical protein shape increases the protein's critical concentration (C*), the transition concentration beyond which protein viscosity increases exponentially relative to concentration increases. In summary, our work elucidates protein shape as a key determinant of solution viscosity through quantitative analysis and comparison with other contributing factors. This provides insights into molecular engineering strategies to optimize the molecular design of therapeutic proteins, thus optimizing their viscosity.

The Emerging Landscape for Combating Resistance Associated with Energy-Based Therapies via Nanomedicine.

Cancer represents a serious disease with significant implications for public health, imposing substantial economic burden and negative societal consequences. Compared to conventional cancer treatments, such as surgery and chemotherapy, energy-based therapies (ET) based on athermal and thermal ablation provide distinct advantages, including minimally invasive procedures and rapid postoperative recovery. Nevertheless, due to the complex pathophysiology of many solid tumors, the therapeutic effectiveness of ET is often limited. Nanotechnology offers unique opportunities by enabling facile material designs, tunable physicochemical properties, and excellent biocompatibility, thereby further augmenting the outcomes of ET. Numerous nanomaterials have demonstrated the ability to overcome intrinsic therapeutic resistance associated with ET, leading to improved antitumor responses. This comprehensive review systematically summarizes the underlying mechanisms of ET-associated resistance (ETR) and highlights representative applications of nanoplatforms used to mitigate ETR. Overall, this review emphasizes the recent advances in the field and presents a detailed account of novel nanomaterial designs in combating ETR, along with efforts aimed at facilitating their clinical translation.

A Booster for Radiofrequency Ablation: Advanced Adjuvant Therapy via In Situ Nanovaccine Synergized with Anti-programmed Death Ligand 1 Immunotherapy for Systemically Constraining Hepatocellular Carcinoma.

Radiofrequency ablation (RFA) is one of the most common minimally invasive techniques for treating hepatocellular carcinoma (HCC), which could destroy tumors through hyperthermia and generate massive tumor-associated antigens (TAAs). However, residual malignant tissues or small satellite lesions are hard to eliminate, generally resulting in metastases and recurrence. Herein, an advanced in situ nanovaccine formed by layered double hydroxides carrying cGAMP (STING agonist) (LDHs-cGAMP) and adsorbed TAAs was designed to potentiate the RFA-induced antitumor immune response. As-prepared LDHs-cGAMP could effectively enter cancerous or immune cells, inducing a stronger type I interferon (IFN-I) response. After further adsorption of TAAs, nanovaccine generated sustained immune stimulation and efficiently promoted activation of dendritic cells (DCs). Notably, infiltrations of cytotoxic lymphocytes (CTLs) and activated DCs in tumor and lymph nodes were significantly enhanced after nanovaccine treatment, which distinctly inhibited primary, distant, and metastasis of liver cancer. Furthermore, such a nanovaccine strategy greatly changed the tumor immune microenvironment and promoted the response efficiency of anti-programmed death ligand 1 (αPD-L1) immunotherapy, significantly arresting the poorly immunogenic hepa1-6 liver cancer progression. These findings demonstrate the potential of nanovaccine as a booster for RFA in liver cancer therapy and provide a promising in situ cancer vaccination strategy.

Economic simulation of sports industry based on deep learning algorithm and data mining.

In recent years, the research on the domestic and international sports industry has made considerable achievements, but there are still some loopholes in the content, that is, there is still a vacancy in the comprehensive quantitative evaluation of the economic development of the sports industry, especially in the statistics of the output value of the sports industry, which lacks a comprehensive understanding of the economic development of the industry. In the state of dual demand research and application, it is still necessary to reveal the publicity and education of industrial scale, industrial structure, industrial function and industrial safety between people and industries, which is also a necessary way to develop the talent guarantee industry. In this work, we should establish an economic model related to the sports industry. It mainly applies the deep learning algorithm and data information mining technology. After allowing the extraction of information from the sports industry database, it is converted into an economic model of the sports industry. It uses scientific and efficient processing methods to analyze a large number of diverse data, in order to find the hidden laws and knowledge behind it. Therefore, this paper uses data mining technology to process and analyze the economic development data of sports industry in detail and conducts corresponding quantitative analysis according to the requirements of data development. Finally, this paper points out that the neural network in the deep learning algorithm has further training and learning on the economic data of the sports industry, which is convenient for the subsequent prediction of the economic development of the sports industry to make a greater breakthrough.

The difference effect on the prognosis between drug-coated balloon and drug eluting stent interventional therapy in patients with coronary heart disease: a retrospective comparative study / 中国医师进修杂志

Objective:To compare the effect of prognosis between drug-coated balloon (DCB) and drug eluting stent (DES) interventional therapy in patients with coronary heart disease.Methods:The clinical data of 346 coronary heart disease patients underwent interventional therapy because of small vessel lesion, in-stent restenosis and bifurcation lesion in Xuanwu Hospital, Capital Medical University from December 2018 to July 2021 were retrospectively analyzed. Among them, 179 patients were treated with DES (DES group), including small vessel lesion 81 cases, in-stent restenosis 35 cases, and bifurcation lesion 63 cases; 167 patients were treated with DCB (DCB group), including small vessel lesion 69 cases, in-stent restenosis 62 cases, and bifurcation lesion 36 cases. The major adverse cardiac and cerebrovascular event (MACCE) within 1 year after discharge was compared between two groups. Non-inferiority was analyzed, and non-inferiority margin was set to be 4%.Results:There was no statistical difference in the incidence of MACCE between DCB group and DES group: 3.59% (6/167) vs. 7.26% (13/179), P>0.05. There were no statistical differences in the incidences of MACCE in patients with small vessel lesion, in-stent restenosis and bifurcation lesion between DCB group and DES group: 1.45% (1/69) vs. 4.94% (4/81), 8.06% (5/62) vs. 14.29% (5/35) and 0 vs. 6.35% (4/63); P>0.05. Non-inferiority analysis result showed that DCB was non-inferior to DES on the prognosis in patients with coronary heart disease (95% CI - 8.41% to 1.07%). Conclusions:Non-inferiority of DCB versus DES is shown in coronary heart disease patients with small vessel lesion, in-stent restenosis and bifurcation lesion.

Research progress on pharmacological mechanism of polygona-polysaccharose / 国际中医中药杂志

Polygona-polysaccharose is an important indicator to measure the quality of Polygonati Rhizoma. The polygona-polysaccharose has the effect of lowering blood sugar, regulating blood lipid, anti-fatigue, improving learning and memory ability. The Polygonati Rhizoma, as a Chinese herbal medicine with homology of medicine and food, has a good prospect and application value in the development of food and health products.

Clinical comprehensive evaluation of Jinsang Liyan Pills/Capsules in treatment of chronic pharyngitis / 中国中药杂志

According to the Guidelines for clinical comprehensive evaluation of Chinese patent medicine(2022 version), this study comprehensively compared the clinical value of Jinsang Liyan Pills/Capsules with that of another commonly used Chinese patent medicine(drug A).(1)Effectiveness: Jinsang Liyan Pills/Capsules had antimicrobial, anti-inflammatory, and pain-relieving effects and can improve the total response rate in the treatment of chronic pharyngitis. Moreover, they took effect faster than the control group.(2)Safety: Jinsang Liyan Pills/Capsules did not cause acute toxicity and long-term toxicity, with low incidence of adverse reactions, which were mild and alleviated after drug withdrawal. Therefore, the risk of Jinsang Liyan Pills/Capsules was under control.(3)Economy: Jinsang Liyan Pills/Capsules had lower cost per course of treatment than drug A. The incremental cost-effectiveness ratio(ICER) of Jinsang Liyan Pills combined with Jinsang Qingyin Pills was-39.97 yuan compared with conventional treatment. The ICER of Jinsang Liyan Pills compared with amoxicilin was 0.01 yuan. The results meant that Jinsang Liyan Pills/Capsules had a cost-effectiveness advantage.(4)Innovation: Jinsang Liyan Pills/Capsules had reasonably formula and wide indications, meeting the clinical needs. Moreover, they had been authorized four patents of advanced manufacturing technology.(5)Suitability: the storage and administration of Jinsang Liyan Pills/Capsules were convenient, with clear instruction of medication.(6) Accessibility: Jinsang Liyan Pills/Capsules had sufficient drug reserve, caused low economic burden of patients, and presented environmental bearing capacity. Finally, Jinsang Liyan Pills/Capsules were scored 79.10 points, and drug A 67.93 points. The experts reached the consensus of grade A for Jinsang Liyan Pills/Capsules, which can be directly converted into decision making. The result of this comprehensive evaluation of Jinsang Liyan Pills/Capsules highlight the clinical advantages in the treatment of chronic pharyngitis and lay a foundation for the standardized research on the clinical basic research of the drug in the future.

Clinical comprehensive evaluation of Jinsang Sanjie Pills/Capsules in treatment of vocal nodule/polyp of vocal cord / 中国中药杂志

This study used health technology assessment methods and multi-criteria decision analysis(MCDA) model, according to the guideline for clinical comprehensive evaluation of Chinese patent medicine, we developed this assessment tool. The comprehensive evaluation score of Jinsang Sanjie Pills/Capsules is calculated based on the additive model. This score is calculated by "quantitative evaluation software v1.0 for clinical comprehensive evaluation of Chinese patent medicines" which developed by the project team. The evaluation yielded the following results.(1)Effectiveness: compared with the control group, Jinsang Sanjie Pills/Capsules can improve the total effectiveness rate of vocal nodule/polyp of vocal cord, and improve the symptoms and signs.(2)Safety: Jinsang Sanjie Pills/Capsules did not show acute toxicity and long-term toxicity. The most common adverse reaction was gastrointestinal system damage, all of the adverse reactions were either improved or cured.(3)Economy: from the perspective of the health system, evaluating the single use or combination of Jinsang Sanjie Pills/Capsules with conventional medication in the treatment of vocal nodule/polyp of vocal cord is relatively effective and cost-effective compared to conventional medication, with a stable cost-effectiveness advantage.(4) Innovation: Jinsang Sanjie Pills/Capsules are used for the treatment of slow throat paralysis(vocal nodules, polyp of vocal cord, thickening of vocal mucosa) caused by heat toxin accumulation, Qi stagnation and blood stasis, and the resulting hoarseness. Jinsang Sanjie Pills/Capsules have good innovation and targeted indications.(5) Suitability: the investigated doctors, pharmacists and patients all believed that Jinsang Sanjie Pills/Capsules have good suitability.(6)Accessibility: Jinsang Sanjie Pills/Capsules are included in the category B of the National Basic Medical Insurance, Work Injury Insurance, and Maternity Insurance Drug Catalogue(2021 edition), which have good cost-effectiveness and affordability for medical insurance and self-paid patients. Jinsang Sanjie Pills/Capsules do not contain endangered animals and plants. The supply of raw materials can meet the demand of production at present. The comprehensive evaluation score is 76.06 points. Based on all dimensions of evidence, 71.4% experts consensus on Jinsang Sanjie Pills/Capsules is class A, which can be directly converted into decision making. This study comprehensively evaluated the clinical application value of Jinsang Sanjie Pills/Capsules in the treatment of vocal nodule/polyp of vocal cord, so as to provide evidence for their rational clinical use and regulatory decision-making.

Combination of Radiofrequency Ablation With Resiquimod to Treat Hepatocellular Carcinoma Via Inflammation of Tumor Immune Microenvironment and Suppression of Angiogenesis.

Background: Radiofrequency ablation (RFA) destroys tumors through hyperthermic injury, which induces the release of immunogenic intracellular substrates and damages associated molecular patterns (DAMPs) to evoke a systemic immune response, but its therapeutic effect is limited. This study aimed to combine RFA with an immunomodulator, resiquimod (R848), to enhance the RFA-induced antitumor immunity. Methods: We performed RFA on subcutaneous tumors in immunocompetent mice and intraperitoneally injected R848 to observe the efficacy of the combination therapy. Our research investigated changes in the composition of tumor-infiltrating immune cells in primary and distant tumors by flow cytometry. Natural killer (NK) cell depletion experiment was applied to confirm the role of NK cell in the combination therapy. The expression levels of cytokines and chemokines were detected by real-time quantitative PCR. Immunohistochemical test was conducted to reveal tumor angiogenesis, tumor proliferation, and apoptosis after the different treatments. Results and Conclusion: Compared with RFA or R848 monotherapy, the combination therapy significantly slowed the tumor growth, prolonged the survival time, and shrank the tumor-draining lymph nodes of tumor-bearing mice. The flow cytometry results showed that tumor-infiltrating immune cells, total T cells, the ratio of CD8+ T and NK cells to CD45+ cells, and functional NK cells were obviously increased after the combined treatment. Distal tumor growth was also suppressed, and the profile of tumor-infiltrating immune cells was remodeled, too. In addition, the additive effect of the combination therapy disappeared after NK cell depletion. Furthermore, immunohistochemical results verified that R848 inhibited tumor angiogenesis in murine liver cancer, and the combination therapy promoted tumor cell apoptosis. In conclusion, our data suggest that RFA combined with R848 stimulated a stronger antitumor immune response and effectively inhibited liver cancer progression in a NK cell-dependent manner. Meanwhile, we confirmed that R848 inhibited tumor angiogenesis and promoted apoptosis in murine liver cancer. Overall, this is a promising therapeutic strategy to improve the efficacy of RFA in the treatment of liver cancer and provides a novel option for combined thermal ablation and immunotherapy.

Life Cycle Assessment and Multiobjective Optimization for Steam Cracking Process in Ethylene Plant.

With energy savings and emission reduction becoming national policies in recent years, the environmental impacts of industrial production are more and more critical. Most of the studies have concentrated on the environmental effects of the industrial production process. Little attention has been paid to the energy consumption and pollution emission in extracting, processing, and transporting the feedstock and other secondary materials. An integrated multiobjective optimization framework is proposed for the steam cracking process on the basis of a life cycle assessment and data-driven modeling methods. A multiobjective economic-environmental optimization model is developed on the basis of industrial and simulated data. A multiobjective optimization model combined with energy cost is also developed for comparative study. The nondominated sorting genetic algorithm-II is utilized to solve the problems, and the Pareto front is obtained. An industrial case study is carried out to indicate the effectiveness of the proposed method. The results show that the LCA-based method can better represent the environmental impacts in comparison with the standard energy cost model. Therefore, the proposed method can achieve a better tradeoff between economic benefits and environmental impacts for guiding ethylene production.

Catalytic asymmetric [3 + 2] cycloaddition of pyrazolone-derived MBH carbonate: highly stereoselective construction of the bispiro-[pyrazolone-dihydropyrrole-oxindole] skeleton.

A catalytic asymmetric construction of the bispiro[pyrazolone-dihydropyrrole-oxindole] skeleton catalyzed by chiral DMAP-derived catalyst was successfully achieved by employing recently explored pyrazolone-derived MBH carbonate in high yields with excellent stereoselectivities. The proposed transition state indicated that the intermolecular hydrogen bonds and π-π interactive forces played an essential role in stereoselective chemical transformation.

Efficacy and safety of weekly rifapentine and isoniazid for tuberculosis prevention in Chinese silicosis patients: a randomized controlled trial.

OBJECTIVE: The aim was to evaluate the efficacy, safety and completion rate of 3-month, once-weekly rifapentine and isoniazid for tuberculosis (TB) prevention among Chinese silicosis patients. METHODS: Male silicosis patients without human immunodeficiency virus infection, aged 18 years to 65 years, with or without latent TB infection, were randomized 1:1 to receive rifapentine/isoniazid under direct observation (3RPT/INH group) or were untreated (observation group). Active TB incidence was compared between the two groups with 37 months of follow-up. Safety profile and complete rates were evaluated. RESULTS: A total of 1227 adults with silicosis were screened; 513 eligible participants were enrolled and assigned to 3RPT/INH (n = 254) vs. observation (n = 259). Twenty-eight participants were diagnosed with active TB, and 9 and 19 in the 3RPT/INH group and observation groups, respectively. In the intention-to-treat analysis, the cumulative active TB rate was 3.5% (9/254) in the 3RPT/INH group and 7.3% (19/259) in the observation group (log rank p 0.055). On per protocol analysis, the cumulative active TB rates were 0.7% (1/139) and 7.3% (19/259), respectively (log rank p 0.01). Owing to an unexpected high frequency of adverse events (70.4%) and Grade 3 or 4 AEs (7.9%), the completion rate of the 3RPT/INH regimen was 54.7% (139/254). Twenty-six (10.8%) participants had flu-like systemic drug reactions; five (2.1%) experienced hepatotoxicity. DISCUSSION: Weekly rifapentine/isoniazid prophylaxis prevented active TB among Chinese people with silicosis when taken, irrespective of LTBI screening; efficacy was reduced by lack of compliance. The regimen must be used with caution because of the high rates of adverse effects. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov number: NCT02430259.

Adenosine Triphosphate-Induced Rapid Liquid-Liquid Phase Separation of a Model IgG1 mAb.

Adenosine triphosphate (ATP) is amphiphilic in nature and has the characteristics of a hydrotrope because of the charged triphosphate moiety and the large aromatic ring located on each end of its structure. Previous studies revealed that ATP can effectively maintain the solubility and prevent liquid-liquid phase separation (LLPS) of some biological proteins. In this study, we assessed the impact of ATP on the stability of a model therapeutic IgG1 antibody (MA1) to evaluate its potential application in protein formulation design. In our system, ATP promotes rapid LLPS of MA1 and we demonstrate that the ATP-MA1 static interaction drives phase separation of MA1. The attractive protein-protein interaction increased exclusively in the presence of ATP but not in the presence of other ATP analogues, such as adenosine diphosphate, adenosine monophosphate, and adenine. Through an intrinsic fluorescence quenching study, we revealed that ATP bound to MA1 electrostatically and formed static interactions; furthermore, such static ATP-MA1 interactions significantly altered the surface property of the protein and the protein-protein interactions and subsequently induced LLPS of MA1. This ATP-induced LLPS could be effectively eliminated by Mg2+, which chelated with ATP and thus negated ATP-MA1 static interaction. Our results revealed the unique molecular mechanism of ATP-induced rapid LLPS of MA1.

FDG-PET/CT Radiomics Models for The Early Prediction of Locoregional Recurrence in Head and Neck Cancer.

PURPOSE: Both CT and PET radiomics is considered as a potential prognostic biomarker in head and neck cancer. This study investigates the value of fused pre-treatment functional imaging (18F-FDG PET/CT) radiomics for modeling of local recurrence of head and neck cancers. MATERIALS AND METHODS: Firstly, 298 patients have been divided into a training set (n = 192) and verification set (n = 106). Secondly, PETs and CTs are fused based on wavelet transform. Thirdly, radiomics features are extracted from the 3D tumor area from PETCT fusion. The training set is used to select the features reduction and predict local recurrence, and the random forest prediction models combining radiomics and clinical variables are constructed. Finally, the ROC curve and KM analysis are used to evaluate the prediction efficiency of the model on the validation set. RESULTS: Two PET/CT fusion radiomics features and three clinic parameters are extracted to construct the radiomics model. AUC value in the verification set 0.70 is better than no fused sets 0.69. The accuracy of 0.66 is not the highest value (0.67). Either consistency index CI 0.70 (from 0.67 to 0.70) or the p-value 0.025 (from 0.03 to 0.025) get the best result in all four models. CONCLUSION: The radiomics model based on the fusion of PETCT is better than the model based on PET or CT alone in predicting local recurrence, the inclusion of clinical parameters may result in more accurate predictions, which has certain guiding significance for the development of personalized, precise treatment scheme.

Clinical effect of phase Ⅰ cardiac rehabilitation exercise on patients with acute myocardial infarction after percutaneous transluminal coronary intervention / 中国实用护理杂志

Objective:To explore the clinical effect of phase Ⅰ cardiac rehabilitation exercise on patients with acute myocardial infarction after percutaneous transluminal coronary intervention (PCI).Methods:Convenient sampling method was adopted, totally 84 acute myocardial infarction patients after PCI was randomized into an observation group and control group. Both groups accepted general nursing care. The observation group also accepted the phase Ⅰ cardiac rehabilitation exercise. Cardiac ultrasonic, the 6-minute walk test were used to evaluate the patients′ cardiac function and exercise tolerance, the SF-12 were used to evaluate the quality of life.Results:After repeated measurement ANOVA, before the intervention, there was no significant difference in cardiac function and quality of life between the two groups ( P>0.05); before discharge, the 6-minute walk distance of the observation group was longer than that of the control group, and the difference was significant( F value was 5.279, P=0.024). At 1 month after discharge, there were significant differences in the LVEF( F value was 8.119, P=0.006) and 6-minute walking distance( F value was 9.829, P=0.002) between the two groups ( P<0.05), analysis of the six items of SF-12 including general health( F value was 6.905, P=0.010), physical functioning( F value was 10.595, P=0.002), role physical( F value was 11.168, P=0.001), bodily pain( F value was 12.548, P=0.001), mental health( F value was 7.362, P=0.008) and vitality( F value was 13.692, P<0.001) having shown significant differences between the two groups. At 3 months after discharge, there were significant differences in the LVEF( F value was 11.156, P=0.001), 6-minute walk distance( F value was 16.554, P<0.001)and quality of life in all dimensions between the two groups ( P<0.05). Conclusion:Phase Ⅰ cardiac rehabilitation exercise can improve cardiac function and the quality of life in patients with acute myocardial infarction undergoing PCI, and enhance the exercise tolerance.

Short-term Effect of Hip Muscles Strengthening on Knee Osteoarthritis / 中国康复理论与实践

Objective:To compare the short-term effects of hip muscles strengthening and quadriceps strengthening on knee osteoarthritis (KOA), and discuss the advantages of hip muscles strengthening. Methods:From October, 2015 to May, 2016, 42 old females with KOA were divided into two groups equally. They received hip strengthening (HS group) and quadriceps strengthening (QS group) for two weeks, respectively. The pain, stiffness and physical function scores of Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) were measured. Isokinetic strength peak torque (PT) was assessed for knee extensors and flexors, and 6-minute Walk Test was also evaluated. They were followed up two months later. Results:Before exercise, there was no significant difference in all the indexes between two groups (P > 0.05). Two weeks after exercise, the knee flexor PT (t = -4.038, P = 0.001) and 6-minute walk distance (t = -2.474, P = 0.022) increased in QS group; the pain, stiffness and physical function scores of WOMAC (t > 2.487, P < 0.05), the knee extensor and flexor PT (|t| > 6.370, P < 0.001), and 6-minute walk distance (t = -2.241, P = 0.037) improved in HS group; the scores of WOMAC were lower (t > 2.087, P < 0.05) and the knee extensor PT was higher (t = -5.028, P < 0.001) in HS group than in QS group. At two-months' follow-up, the drop-out rate was significantly lower in HS group than in QS group (χ2 = 13.480, P < 0.001). Conclusion:Hip muscles strengthening is a good choice for KOA in the early stage of treatment, which could avoid the pain in quadriceps training, increase quadriceps strength and improve physical function.

Comparative Analysis of 95 Patients with Different Severity in the Early Outbreak of COVID-19 in Wuhan, China.

OBJECTIVE: To explore the clinical characteristics of patients with different severity in the early outbreak of COVID-19, hoping to provide reference for clinical diagnosis and treatment. METHODS: We retrospectively analyzed the clinical data of 95 COVID-19 patients in Wuhan Red Cross Hospital of China from January 17 to February 13, 2020. All patients were investigated with epidemiological questionnaires. Outcomes were followed up until April 1, 2020. RESULTS: There were 53 males and 42 females, aged 22-84 years (mean 57.3 years). Clinical classification included 54 cases of common type, 27 cases of severe type, and 14 cases of critical type. Six patients had been exposed to the local Huanan seafood market. There were 38 clusters of COVID-19, including 27 family clusters and 11 work unit clusters. Common symptoms included fever (86 (90.5%) of 95), cough (73 (76.8%)), and fatigue (50 (52.6%)). Laboratory findings showed that the most common abnormalities were lymphopenia (75 (78.9%)), elevated D-dimer (60 (63.2%)), and elevated C-reactive protein (56 (58.9%)) on admission. All patients had abnormal chest computed tomography, showing patchy shadows or ground-glass opacities. Severe and critical cases were older, more likely to have shortness of breath, more likely to have underlying comorbidities, and more likely to have abnormal laboratory findings than common cases. The prognosis of patients with different degrees of severity was significantly different. All common and severe patients (100%) were cured and discharged from the hospital, while 10 (71.4%) of 14 critical patients died. CONCLUSIONS: COVID-19 has fast transmission speed and high pathogenicity. We must assess the severity of the disease and take corresponding treatment measures as early as possible.

Insight Derived from Molecular Dynamics Simulation into the Selectivity Mechanism Targeting c-MYC G-Quadruplex.

Stabilizing G-quadruplex (G4) structures formed in the c-MYC oncogene promoter represents a fundamental strategy for cancer therapy. However, most G4 stabilizers lack selectivity over various G4s in the genomes. By investigating the binding characteristics of a conjugated imidazole/carbazole (IZCZ-3) molecule with the G4s of c-MYC, c-KIT, and telomere through molecular docking and molecular dynamics simulations, the present study demonstrates that though the binding affinities between IZCZ-3 and the monomeric G4s are inconsistent with the experimental data, the dimeric c-MYC and c-KIT G4s can be targeted by IZCZ-3 through forming concomitant π-π stacking interactions with the intermolecular assembly producing significant contributions to the binding affinity. In the intermolecular dimeric G4-IZCZ-3 binding complexes, IZCZ-3 prefers the c-MYC G4 that has two exposed G-tetrads per monomer over the single G-tetrad-exposed c-KIT G4 by creating more aggregation effects. Taking the aggregation effects into account, the binding affinity order of IZCZ-3 follows c-MYC G4 > c-KIT G4 > telomeric G4, agreeing well with the experimental observation. Thus, the selectivity of IZCZ-3 for c-MYC G4 probably comes from its role in stabilizing the sandwichlike intermolecular aggregates, providing a framework for the development of selective stabilizers targeting c-MYC G4.

First-order nucleation and subsequent growth promote liquid-liquid phase separation of a model IgG1 mAb.

Although protein aggregation is commonly encountered during the manufacturing and storage of bio-therapeutics, the actual aggregation mechanism remains unclear, and little has been reported about the protein aggregation kinetics from time zero under particular solution conditions. In this study, we used real-time dynamic light scattering (DLS) to continuously monitor the time-dependent evolution of the Z-average hydrodynamic radius of a model IgG1 (JM2) immediately after the JM2 solution was subjected to various low temperatures (0-4 °C). We observed that JM2 aggregated to form nuclei first, and then it subsequently grew to small liquid droplets via a two-step, first-order, reversible process without causing irreversible structural changes: a slow first step defined as the "nucleation" step, wherein nuclei formed slowly until reaching a transitional time point (tonset), and a much faster second step initiated after tonset and the nucleus size of the protein increased rapidly, which eventually caused liquid droplet formation and liquid-liquid phase separation (LLPS). The "nucleation" rate constant (Knucleation) and particle growth rate constant (Kgrowth), as well as tonset, were found to be temperature, pH and concentration dependent. The aggregation of JM2 could be universally described by these two-step first-order kinetics: under conditions where JM2 aggregated very slowly, the second step was not observed within the experimental time scale, while under conditions where JM2 aggregated very rapidly, the first step could not be recorded. We believe that these three parameters, Knucleation, Kgrowth, and tonset, can be used to quantify and compare the aggregation kinetics of JM2 under different solution and temperature conditions and, furthermore, serve as a theoretical base to account for the key characteristics of the aggregation kinetics of JM2 and other protein therapeutics under conditions of interest.