Predicting therapeutic response to neoadjuvant immunotherapy based on an integration model in resectable stage IIIA (N2) non-small cell lung cancer.

OBJECTIVE: Accurately predicting response during neoadjuvant chemoimmunotherapy for resectable non-small cell lung cancer remains clinically challenging. In this study, we investigated the effectiveness of blood-based tumor mutational burden (bTMB) and a deep learning (DL) model in predicting major pathologic response (MPR) and survival from a phase 2 trial. METHODS: Blood samples were prospectively collected from 45 patients with stage IIIA (N2) non-small cell lung cancer undergoing neoadjuvant chemoimmunotherapy. An integrated model, combining the computed tomography-based DL score, bTMB, and clinical factors, was developed to predict tumor response to neoadjuvant chemoimmunotherapy. RESULTS: At baseline, bTMB were detected in 77.8% (35 of 45) of patients. Baseline bTMB ≥11 mutations/megabase was associated with significantly greater MPR rates (77.8% vs 38.5%, P = .042), and longer disease-free survival (P = .043), but not overall survival (P = .131), compared with bTMB <11 mutations/megabase in 35 patients with bTMB available. The developed DL model achieved an area under the curve of 0.703 in all patients. Importantly, the predictive performance of the integrated model improved to an area under the curve of 0.820 when combining the DL score with bTMB and clinical factors. Baseline circulating tumor DNA (ctDNA) status was not associated with pathologic response and survival. Compared with ctDNA residual, ctDNA clearance before surgery was associated with significantly greater MPR rates (88.2% vs 11.1%, P < .001) and improved disease-free survival (P = .010). CONCLUSIONS: The integrated model shows promise as a predictor of tumor response to neoadjuvant chemoimmunotherapy. Serial ctDNA dynamics provide a reliable tool for monitoring tumor response.

Photocatalytic C-C Bond Cleavage and Fluorosulfonylation of Strained Cycloalkanols for Carbonyl-Containing Aliphatic Sulfonyl Fluorides.

In this report, we present a photocatalytic ring-opening fluorosulfonylation of strained cycloalkanols with sulfur dioxide and NFSI under mild conditions for the synthesis of carbonyl-containing aliphatic sulfonyl fluorides. The synthetic potential of the carbonyl-containing aliphatic sulfonyl fluoride products has been examined by diverse transformations, including SuFEx reactions and Baeyer-Villiger oxidation reactions. Mechanistic studies demonstrate that the reaction operates through a radical C-C bond cleavage/SO2 insertion/fluorination cascade process.

Design, Synthesis and Biological Evaluation of Glycosylated Derivatives of Silibinin as Potential Anti-Tumor Agents.

Objective: Silibinin, a natural product extracted from the seeds of the Silybum marianum, is versatile with various pharmacological effects. However, its clinical application was strongly hampered by its low bioavailability and poor water solubility. Herein, a series of glycosylated silibinin derivatives were identified as novel anti-tumor agents. Materials and Methods: The cell viability was evaluated by CCK8 assay. Furthermore, cell apoptosis and cell cycle progression were tested by flow cytometry. In addition, the pharmacokinetic assessment of compound 15 and silibinin through intravenous administration (i.v., 2 mg/kg) to ICR mice were performed. Results: The synthesized compounds showed better water solubilities than silibinin. Among them, compound 15 exhibited inhibitory activity against DU145 cells with IC50 value of 1.37 ± 0.140 µM. Moreover, it arrested cell cycle at G2/M phase and induced apoptosis in DU145 cells. Additionally, compound 15 also displayed longer half-life (T1/2 = 128.3 min) in liver microsomes than that of silibinin (T1/2 = 82.5 min) and appropriate pharmacokinetic parameters in mice. Conclusion: Overall, glycosylation of silibinin would be a valid strategy for the development of silibinin derivatives as anti-tumor agents.

Aminofluorosulfonylation of ß,γ-Unsaturated Hydrazones with Sulfur Dioxide and N-Fluorobenzenesulfonimide: Accessing Pyrazoline-Functionalized Aliphatic Sulfonyl Fluorides.

An efficient aminofluorosulfonylation strategy was developed for the synthesis of various pyrazoline-functionalized aliphatic sulfonyl fluorides using ß,γ-unsaturated hydrazones with sulfur dioxide and NFSI as the starting materials under mild conditions. The sulfonyl fluoride products could be successfully transformed into the corresponding sulfonate esters and amides via the sulfur(VI) fluoride exchange (SuFEx) click reactions. Preliminary mechanistic investigations demonstrate that the reaction operates through a radical cyclization/SO2 insertion/fluorination cascade process.

Antibiotic resistant bacteria: A bibliometric review of literature.

Antibiotic-resistant bacteria (ARB) are a serious threat to the health of people and the ecological environment. With this problem becoming more and more serious, more countries made research on the ARB, and the research number has been sharply increased particularly over the past decade. Therefore, it is quite necessary to globally retrace relevant researches on the ARB published from 2010 to 2020. This will help researchers to understand the current research situation, research trends and research hotspots in this field. This paper uses bibliometrics to examine publications in the field of ARB from 2010 to 2020 that were retrieved from the Web of Science (WOS). Our study performed a statistical analysis of the countries, institutions, journals, authors, research areas, author keywords, Essential Science Indicators (ESI) highly cited papers, and ESI hotspots papers to provide an overview of the ARB field as well as research trends, research hotspots, and future research directions in the field. The results showed that the number of related studies is increasing year by year; the USA is most published in the field of ARB; China is the most active in this field in the recent years; the Chinese Acad Sci published the most articles; Sci. Total Environ. published the greatest number of articles; CM Manaia has the most contributions; Environmental Sciences and Ecology is the most popular research area; and "antibiotic resistance," "antibiotics," and "antibiotic resistance genes" were the most frequently occurring author keywords. A citation analysis showed that aquatic environment-related antibiotic resistance is a key research area in this field, while antimicrobial nanomaterial-related research is a recent popular topic.

Drug repositioning: A bibliometric analysis.

Drug repurposing has become an effective approach to drug discovery, as it offers a new way to explore drugs. Based on the Science Citation Index Expanded (SCI-E) and Social Sciences Citation Index (SSCI) databases of the Web of Science core collection, this study presents a bibliometric analysis of drug repurposing publications from 2010 to 2020. Data were cleaned, mined, and visualized using Derwent Data Analyzer (DDA) software. An overview of the history and development trend of the number of publications, major journals, major countries, major institutions, author keywords, major contributors, and major research fields is provided. There were 2,978 publications included in the study. The findings show that the United States leads in this area of research, followed by China, the United Kingdom, and India. The Chinese Academy of Science published the most research studies, and NIH ranked first on the h-index. The Icahn School of Medicine at Mt Sinai leads in the average number of citations per study. Sci Rep, Drug Discov. Today, and Brief. Bioinform. are the three most productive journals evaluated from three separate perspectives, and pharmacology and pharmacy are unquestionably the most commonly used subject categories. Cheng, FX; Mucke, HAM; and Butte, AJ are the top 20 most prolific and influential authors. Keyword analysis shows that in recent years, most research has focused on drug discovery/drug development, COVID-19/SARS-CoV-2/coronavirus, molecular docking, virtual screening, cancer, and other research areas. The hotspots have changed in recent years, with COVID-19/SARS-CoV-2/coronavirus being the most popular topic for current drug repurposing research.

Cost-utility analysis of centrally inserted totally implanted access port (PORT) vs. peripherally inserted central catheter (PICC) in the oncology chemotherapy.

Background: Peripherally inserted central catheter (PICC) and centrally inserted totally implanted access port (PORT) are two types of intravenous infusion devices that are widely used in clinical practice. PORTs are more expensive to insert than PICCs but have fewer complications. Two cost-utility analyses of PICCs and PORTs in China have been published, but had conflicting findings. This study aimed to compare the cost-utility of PICCs and PORTs. Methods: We conducted a prospective observational trial including 404 patients with cancer and a cross-sectional study to calculate cost and complications of a PICC and PORT. Utility was measured using the EuroQol five-dimensional questionnaire (EQ-5D-5L). A cost-utility analysis was performed from a healthcare system perspective in China. Results: The average total cost of PICCs and PORTs were ¥ 4,091.7 and ¥ 4,566.8, which yielded 0.46 and 0.475 quality-adjusted life-years (QALYs) in a 6-month dwell time, respectively. The incremental cost-utility ratio (ICUR) was ¥ 31,670.9 per QALY. A one-way sensitivity analysis showed that the base-case results were robust, and the probabilistic sensitivity analysis showed that at a willingness-to-pay (WTP) threshold of ¥ 80,976 per QALY (China's per capita GDP in 2021) the probability of a PORT being cost-effective was 96%. Conclusion: PORTs were more cost-effective than PICCs for a 6 and 12-month dwell time. The total cost for a PORT was also less than that of a PICC. PORT is therefore recommended as a medium to long-term intravenous delivery device in clinical practice.

Factors associated with blood lead levels in children in Shenyang, China: a cross-sectional study.

BACKGROUND: Although blood lead levels (BLLs) in children are gradually decreasing, low-concentration lead exposure can still exert adverse effects. We studied the factors that affect BLLs in children in Shenyang, China. METHODS: We conducted a cross-sectional study by administering structured questionnaires on family demographics and food intake. The concentrations of lead in venous blood were determined by graphite furnace atomic absorption spectrometry. RESULTS: A total of 273 children aged 1-6 years were enrolled. The geometric mean (geometric standard deviation) of BLLs was 24.94 (12.70) µg/L in boys and 23.75 (11.34) µg/L in girls. The prevalence of BLLs of ≥35 µg/L was 22.7% and was mainly observed in children aged under 3 years. Often hand washing before meals was protective against BLLs ≥20 µg/L (adjusted OR: 0.427, 95%CI: 0.238-0.767, p = 0.004). Consumption of puffed grains and eggs had an adjusted OR (95%CI) for BLLs ≥20 µg/L of 1.714 (1.012-2.901) (p = 0.045) and 1.787 (1.000-3.192) (p = 0.050), respectively. CONCLUSIONS: BLLs of children in Shenyang are still higher than in developed countries. Consumption of puffed grains and eggs is associated with higher BLLs. Often hand washing before meals may be protective against high BLLs.

EPA and DHA differentially coordinate the crosstalk between host and gut microbiota and block DSS-induced colitis in mice by a reinforced colonic mucus barrier.

Background: Ulcerative colitis (UC) is a chronic inflammatory disorder of the colon with a continuously remitting and relapsing course. Its etiology is closely related to abnormal interactions between host and gut microbiota. The mucus barrier lining the gastrointestinal tract is necessary to coordinate host and gut microbiota interaction by nourishing and modulating the microbiota. Differential effects of the anti-inflammatory fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) on UC progression in mice were firstly addressed by our previous work; here, the mechanism for their respective effects were further uncovered from host-microbiome crosstalk based on mucus barrier modulation to pave the way for UC therapy. Methods: Assessment of the disease activity index and histopathology score was conducted in mice with dextran sodium sulfate (DSS)-induced colitis pre-treated with different doses of EPA and DHA. Mucin generation, glycosylation and secretion were evaluated by a combination of electron microscopy, specific mucous staining, and qPCR. Western blotting was used to analyze the underlying molecular events. Fecal short chain fatty acids were detected using gas chromatography, and the gut microbial composition was analyzed using 16S rRNA sequencing. Results: Compared with DHA, the more potent inhibitory effect of high dose EPA on DSS-induced colitis was reconfirmed, which was underlain by a reinforced mucus layer as indicated by increased mucin granule release, mucus layer stratification and markedly upregulated expression of the key modulators involved in goblet cell differentiation. In turn a remarkably enhanced mucus barrier in the EPA group functioned to modulate the gut microbiome, as demonstrated by the enriched abundance of the phylum Bacteroidetes and mucin-degrading bacterium Akkermansia muciniphila producing acetic and propionic acids. Conclusions: EPA and DHA differentially coordinate the interaction between the host and the gut microbiota and relieve mucus barrier disruption in DSS-induced colitis. EPA may develop into a promising adjunctive therapy for UC.

Colloidal assembly of polydisperse particle blends during drying.

In this work, we synthesize a polydisperse aqueous colloidal system composed of small and large zwitterionic particles, as well as medium sized standard acrylic particles. By assembling these dispersions into films by drying, we show using atomic force microscopy (AFM) how their top surfaces can be mostly covered by zwitterionic groups for a wide range of evaporation rates. We probe underneath the top film surface using Fourier-transform infrared (FTIR) spectroscopy - attenuated total reflection (ATR), observing that the content in zwitterionic particles of the film upper layer increases for faster evaporation rates. We show how polydisperse systems hold great potential to overcome the evaporation rate dependence of size segregation processes in drying colloidal blends, and we provide further insights into the assembly mechanisms involved. Polydisperse blends enhance the robustness of such processes for application in coatings and other soft products where evaporation rate can not be tuned.

Effect of Pars Plana Vitrectomy With or Without Cataract Surgery in Patients with Diabetes: A Systematic Review and Meta-Analysis.

INTRODUCTION: Pars plana vitrectomy (PPV) is considered to be an essential and effective surgical approach for the management of complications of diabetic retinopathy. Given the high rate of accelerated cataract progression after PPV, PPV combined with cataract surgery appears to be an attractive treatment option for patients with diabetes. However, this combined surgical approach remains controversial in terms of effectiveness and safety. We have therefore conducted a meta-analysis to evaluate the treatment outcome of PPV with or without cataract surgery. METHODS: A systematic search of three electronic databases (PubMed, Web of Science, and the Cochrane Library) was performed to identify relevant articles, using the key words "pars plana vitrectomy," "cataract," and "diabetic retinopathy." Main outcome measures included the final visual acuity and postoperative complications. The incidence of postoperative complications was pooled using odds ratio (OR) with 95% confidence intervals in a random effect model. RESULTS: Ultimately, one randomized controlled trial (RCT) and four high-quality retrospective studies met the inclusion criteria and were included in the meta-analysis. In four of these studies, final visual acuity did not vary significantly between patients undergoing PPV alone and those undergoing PPV combined with cataract surgery (combined surgery). Only one study reported better visual improvement in the combined treatment group. Our analysis also showed that most phakic eyes after PPV had cataract progression with varying degrees. In addition, patients receiving PPV alone had a lower risk of neovascular glaucoma (OR 0.36; P < 0.05), iris synechias to anterior capsule (OR 0.36; P < 0.05), and iris rubeosis (OR 0.26; P < 0.05) compared with those receiving combined surgery. CONCLUSION: Overall, our findings show that PPV combined with cataract surgery achieved good outcomes without a substantial increased risk to visual acuity or most complications. Given the high rates of cataract progression after PPV, combined surgery may be the more appropriate treatment for patients with diabetes and coexistent visually significant cataract.

Fabrication and evaluation of dental fillers using customized molds via 3D printing technology.

In view of the high incidence and long-term treatment of dental caries, personalized dental fillers with long therapeutic action have broad application prospects in the dental clinic. The objective of this study was to fabricate and evaluate novel dental fillers using state-of-the-art 3D printing technology. Tinidazole (TNZ), a commonly used antibacterial drug in the dental clinic, was chosen as the model compound. Models of molars with carious cavities were obtained via 3D scanning. TNZ dental fillers were indirectly produced by thermal pressing using customized 3D printed molds. In addition, bio-relevant in vitro dissolution and mechanical testing methods were developed using customized 3D printed release and compression molds, respectively. It was observed that the formability, mechanical properties, and release behavior of the TNZ dental fillers were affected by mold materials, plasticizers, and release modifiers. The developed dental fillers were capable of sustained releasing TNZ over one week. The TNZ release characteristics can be tailored based on clinical requirements by varying hydroxypropyl methylcellulose E5 (HPMC-E5) concentrations and filler dimensions. Moreover, computational simulation based on the finite element method showed that the biomechanical behavior of the TNZ dental fillers met the daily use requirement. The present study demonstrated that the state-of-the-art 3D printing technology can be used to design and fabricate personalized dental fillers with high mechanical strength and "on-demand" drug release characteristics.

Thioredoxin is implicated in the anti­apoptotic effects of grape seed proanthocyanidin extract during hyperglycemia.

Diabetic retinopathy has long been recognized as a microvascular disease, however, recent research has indicated that diabetic retinopathy may also be considered a neurodegenerative disease. The elucidation of the molecular mechanisms underlying the development of diabetic retinopathy is imperative for the development of preventive and treatment strategies for patients with diabetes. In the present study, grape seed proanthocyanidin extract (GSPE) was used to upregulate the expression of thioredoxin (Trx), in order to evaluate its potential as a novel agent for the prevention and treatment of neurodegenerative diseases, including diabetic retinopathy. Hematoxylin and eosin staining was performed to observe the morphology of retinal neurons, whereas flow cytometry and terminal deoxynucleotidyl transferase 2'­deoxyuridine, 5'­triphosphate nick­end labeling were employed to investigate cellular apoptosis. Reverse transcription­quantitative polymerase chain reaction and western blot analysis were performed to assess the mRNA and protein expression of target proteins in order to investigate the underlying molecular mechanisms. In vivo, it was found that the photoreceptor cell was damaged in diabetic mice but following GSPE treatment, the process could be inhibited. In vitro, the results of the current study demonstrated that, under hyperglycemic culture conditions, the expression of 78 kDa glucose­regulated protein, which is an endoplasmic reticulum stress marker, was upregulated. In addition, the expression of Trx was downregulated and cell apoptosis was enhanced. Notably, treatment with GSPE was revealed to inhibit the neurodegenerative process induced by hyperglycemia. However, treatment with the Trx inhibitor PX12 in combination with GSPE was demonstrated to potentiate apoptosis compared with GSPE treatment alone under hyperglycemic conditions. Furthermore, the protein expression of apoptosis signal­regulating kinase (ASK) 1 and Trx­interacting protein (Txnip) was also upregulated by hyperglycemia, whereas GSPE was revealed to counteract this upregulation. In conclusion, the results of the present study indicate that Trx may be implicated in the mechanisms underlying the protective effects of GSPE against hyperglycemia­induced cell degeneration and apoptosis. The molecular mechanisms may also involve inhibition of the activation of the Trx/ASK1/Txnip signaling pathway.

Response of Korean pine's functional traits to geography and climate.

This study analyzed the characteristics of Korean pine (Pinus koraiensis) functional trait responses to geographic and climatic factors in the eastern region of Northeast China (41°-48°N) and the linear relationships among Korean pine functional traits, to explore this species' adaptability and ecological regulation strategies under different environmental conditions. Korean pine samples were collected from eight sites located at different latitudes, and the following factors were determined for each site: geographic factors-latitude, longitude, and altitude; temperature factors-mean annual temperature (MAT), growth season mean temperature (GST), and mean temperature of the coldest month (MTCM); and moisture factors-annual precipitation (AP), growth season precipitation (GSP), and potential evapotranspiration (PET). The Korean pine functional traits examined were specific leaf area (SLA), leaf thickness (LT), leaf dry matter content (LDMC), specific root length (SRL), leaf nitrogen content (LNC), leaf phosphorus content (LPC), root nitrogen content (RNC), and root phosphorus content (RPC). The results showed that Korean pine functional traits were significantly correlated to latitude, altitude, GST, MTCM, AP, GSP, and PET. Among the Korean pine functional traits, SLA showed significant linear relationships with LT, LDMC, LNC, LPC, and RPC, and LT showed significant linear relationships with LDMC, SRL, LNC, LPC, RNC, and RPC; the linear relationships between LNC, LPC, RNC, and RPC were also significant. In conclusion, Korean pine functional trait responses to latitude resulted in its adaptation to geographic and climatic factors. The main limiting factors were precipitation and evapotranspiration, followed by altitude, latitude, GST, and MTCM. The impacts of longitude and MAT were not obvious. Changes in precipitation and temperature were most responsible for the close correlation among Korean pine functional traits, reflecting its adaption to habitat variation.

Increased expression of MMP14 correlates with the poor prognosis of Chinese patients with gastric cancer.

The role of matrix metalloproteinase 14 (MMP14) has been identified to involve tumor progression and prognosis. The purpose of this study is to investigate the role of MMP14 in tumor progression and prognosis of gastric cancer. This study indicated that MMP14 mRNA and protein were overexpressed in gastric cancer tissue (P<0.001 and P=0.037, respectively) and significantly associated with clinical stage (P=0.005), lymph node metastasis (P=0.003), and distant metastasis (P=0.017). Moreover, we found that the overexpression of MMP14 was a significant predictor of poor prognosis for gastric cancer patients (P<0.001). Furthermore, we performed a meta-analysis which included 594 cases from 3 studies and showed that MMP14 overexpression was a significantly poor prognostic factor in Chinese patients with gastric cancer and HR (95% CI) was 2.17 (1.64-2.86). In conclusion, MMP14 plays an important role on gastric cancer progression and prognosis and acts as a convictive biomarker for prognostic prediction for Chinese patients with gastric cancer.

The effect of autophagy inhibitors on drug delivery using biodegradable polymer nanoparticles in cancer treatment.

Nanoparticles of biodegradable polymers (NPs) have been widely used for drug delivery. However, there has been little research on their fate after internalized into the cells. We show in this research by using docetaxel as a model anticancer drug, which is formulated in the cholic acid conjugated nanoparticles of poly(lactic-co-glycolic acid (PLGA NPs) that the NPs induce autophagy of the cancer cells and thus may hinder the advantages of the nanomedicine. Moreover, we show both in vitro and in vivo that co-administration of autophagy inhibitors such as 3-methyladenine (3-MA) and Chloroquine (CQ) could greatly enhance the therapeutic effects of the nanoparticle formulation. The IC50 values of the drug formulated in the PLGA NPs after 24 h treatment with no autophagy inhibitor or in combination with 10 mm 3-MA or 30 µm CQ are 38.27 ± 1.23, 6.7 ± 1.05, 4.78 ± 1.75 µg/mL, which implie 5.7 or 8,0 fold efficient by the autophagy inhibition respectively. Moreover, both the volume and the weight of the shrunk tumor of the mice after 20 day treatment with the PLGA NPs formulation combined with 3-MA or CQ are found to be only about a half in comparison with the treatment with the PLGA NPs formulation alone. In this research, we reported such a new mechanism of cancer cells to have PLGA NPs captured and degraded by auto-lysosomes. The findings provide advanced knowledge for development of nanomedicine for clinical application.