OBJECTIVE: Humans are exposed to complex mixtures of environmental chemicals and other factors that can affect their health. Analysis of these mixture exposures presents several key challenges for environmental epidemiology and risk assessment, including high dimensionality, correlated exposure, and subtle individual effects. METHODS: We proposed a novel statistical approach, the generalized functional linear model (GFLM), to analyze the health effects of exposure mixtures. GFLM treats the effect of mixture exposures as a smooth function by reordering exposures based on specific mechanisms and capturing internal correlations to provide a meaningful estimation and interpretation. The robustness and efficiency was evaluated under various scenarios through extensive simulation studies. RESULTS: We applied the GFLM to two datasets from the National Health and Nutrition Examination Survey (NHANES). In the first application, we examined the effects of 37 nutrients on BMI (2011-2016 cycles). The GFLM identified a significant mixture effect, with fiber and fat emerging as the nutrients with the greatest negative and positive effects on BMI, respectively. For the second application, we investigated the association between four pre- and perfluoroalkyl substances (PFAS) and gout risk (2007-2018 cycles). Unlike traditional methods, the GFLM indicated no significant association, demonstrating its robustness to multicollinearity. CONCLUSION GFLM framework is a powerful tool for mixture exposure analysis, offering improved handling of correlated exposures and interpretable results. It demonstrates robust performance across various scenarios and real-world applications, advancing our understanding of complex environmental exposures and their health impacts on environmental epidemiology and toxicology.
Humans ; Environmental Exposure/analysis* ; Linear Models ; Nutrition Surveys ; Environmental Pollutants ; Body Mass Index

The aim of our research was to obtain Listeria bacteriophages from food and related environments,and conduc-ted the analysis of the electron microscopic morphology,host range specificity,and biological characteristics of the purified phages.The double-layer agar method and the spot test were employed for the isolation and identification of a virulent Listeria phage named LMLPA5,with the isolated strain Listeria in-nocua Lin08 as the host.Phage morphology was observed by transmission electron microscope.The biological characteris-tics of the phage were assessed by determining their host range,optimal multiplicity of infection(MOI),one-step growth curve,and physicochemical stability.Additionally,the preservation efficacy of the phage at 4 ℃,-20 ℃,and-80 ℃ was explored.The phage LMLPA5 belongs to the family Myoviridae based on morphology,exhibiting clear and transparent plaques without halo surrounded.Strains of sever-al Listeria species and different serotypes strains of Listeria monocytogenes were susceptible to lysis by LMLPA5,indica-ting its broad-spectrum activity against Listeria monocytogenes.Optimal MOIs and single-step growth curve analyses revealed optimal MOIs of 0.1 and latent period of 10 minutes for LMLPA5,with average burst size at 95.2 PFU/cell.LMLPA5 was sensitive to high temperatures,and completely inactivated after exposure to 70 ℃ for 1 h,while the phage remained stable for over 32 hours ranging from 4 ℃ to 40 ℃.Within the pH range of 4 to 10,phage titer remained stable and completely inactiva-ted until 60 minutes of ultraviolet exposure.LMLPA5 displayed insensitivity to chloroform,confirming its non-enveloped phage morphology.The phages remained stable for over 8 months when store at 4 ℃ and-80 ℃.The biological characteristics and lysis capacity of phage LMLPA5 were elucidated in this study,which provide the basis for further application.

Colorectal cancer is the third most common cancer in Korea and the third leading cause of death from cancer. Treatment outcomes for colon cancer are steadily improving due to national health screening programs with advances in diagnostic methods, surgical techniques, and therapeutic agents.. The Korea Colon Cancer Multidisciplinary (KCCM) Committee intends to provide professionals who treat colon cancer with the most up-to-date, evidence-based practice guidelines to improve outcomes and help them make decisions that reflect their patients’ values and preferences. These guidelines have been established by consensus reached by the KCCM Guideline Committee based on a systematic literature review and evidence synthesis and by considering the national health insurance system in real clinical practice settings. Each recommendation is presented with a recommendation strength and level of evidence based on the consensus of the committee.

OBJECTIVE To establish the correlation evaluation and quality evaluation method of HPLC fingerprint grade of color sorting Lonicerae Japonicae Flos, and provide technical basis for the grade standard of color sorting Lonicerae Japonicae Flos. METHODS The chromatographic column was SVEA C18(250 mm×4.6 mm, 5 μm); mobile phase was acetonitrile(A)- 0.2% formic acid aqueous solution(B); gradient elution; injection volume was 10 μL; detection wave length was 245 nm; volume flow rate was 0.5 mL·min-1; column temperature was 38 ℃. The common peak determination and similarity evaluation of HPLC chromatogram data were carried out by using the Similarity Evaluation System of Traditional Chinese Medicine Chromatographic Fingerprints(Version 2012); the color sorting grade evaluation was carried out by CA, PCA and PLS-DA. The first part of Chinese Pharmacopoeia 2020 Edition was used to measure the quality control indicators, and the data were analyzed comprehensively. RESULTS A total of 28 common peaks were identified in the fingerprints, and 7 components were identified. The similarity of 24 batches of color sorting grade samples was 0.936-0.968. CA and PCA divided 28 batches of Lonicerae Japonicae Flos samples into 4 categories, which were basically consistent with the classification of color sorting, and PLS-DA achieved a discrimination result that was very consistent with the classification of color sorting. The color sorting grade was negatively correlated with the diameter, flowering rate, damage rate, and luteolin content of Lonicerae Japonicae Flos. The color sorting grade was positively correlated with chlorogenic acid, 3,5-di-O-caffeoyl quinic acid and 4,5-di-O-caffeoyl quinic acid. There was a clear correlation between the color sorting of Lonicerae Japonicae Flos and established fingerprint overall. There were differences in the quality of Lonicerae Japonicae Flos in the color sorting grade. Based on the sensory indicators of diameter, flowering rate, and damage rate, the content, diameter, flowering rate, and damage rate of luteolin showed a trend from high to low, ranging from third grade>second grade>first grade>special grade. The content of three phenolic acids showed a trend from high to low, ranging from special grade>first grade>second grade>third grade. Among the special grade, the content of three phenolic acids was the highest. CONCLUSION Combining the content of luteolin and phenolic acids as evaluation and control indicators for color selection grade is feasible and scientific, which can achieve intelligent color sorting grade production of Lonicerae Japonicae Flos grade.

By investigating the contamination status and predicting the exposure risk of mycotoxin in Coicis Semen, we aim to provide guidance for the safety supervision of Chinese medicinal materials and the formulation(revision) of mycotoxin limit standards. The content of 14 mycotoxins in the 100 Coicis Semen samples collected from five major markets of Chinese medicinal materials in China was determined by UPLC-MS/MS. The probability evaluation model based on Monte Carlo simulation method was established after Chi-square test and One-way ANOVA of the sample contamination data. Health risk assessment was performed on the basis of margin of exposure(MOE) and margin of safety(MOS). The results showed that zearalenone(ZEN), aflatoxin B_1(AFB_1), deoxynivalenol(DON), sterigmatocystin(ST), and aflatoxin B_2(AFB_2) in the Coicis Semen samples had the detection rates of 84%, 75%, 36%, 19%, and 18%, and the mean contamination levels of 117.42, 4.78, 61.16, 6.61, and 2.13 μg·kg~(-1), respectively. According to the limit standards in the Chinese Pharmacopoeia(2020 edition), AFB_1, AFs and ZEN exceeded the standards to certain extents, with the over-standard rates of 12.0%, 9.0%, and 6.0%, respectively. The exposure risks of Coicis Semen to AFB_1, AFB2, ST, DON, and ZEN were low, while 86% of the samples were contaminated with two or more toxins, which needs more attention. It is suggested that the research on the combined toxicity of different mycotoxins should be strengthened to accelerate the cumulative exposure assessment of mixed contaminations and the formulation(revision) of toxin limit standards.
Humans ; Mycotoxins/analysis* ; Coix ; Aflatoxin B1/analysis* ; Chromatography, Liquid/methods* ; Food Contamination/analysis* ; Tandem Mass Spectrometry/methods*

The oncogenic product of BCR-ABL is an abnormal tyrosine kinase that causes chronic myeloid leukemia (CML). With further research into the pathogenesis of CML, the discovery of compounds that selectively inhibit abnormal BCR-ABL tyrosine kinases is a research focus worthy of attention. The first three generations of BCR-ABL inhibitors are orthosteric inhibitors, which competitively block the binding of ABL protein tyrosine kinase to ATP and prevent it from activating downstream signals. The fourth-generation BCR-ABL inhibitors allosterically inhibit ABL protein tyrosine kinase by binding to the myristoyl pocket, providing greater selectivity and maintaining activity against drug-resistant mutations proteins. Novel drug design strategies such as proteolytic targeting chimera (PROTAC), covalent inhibitors and dual targeting inhibitors also provide new directions for the development of BCR-ABL kinase inhibitors. This paper reviews recent research advances on BCR-ABL kinase inhibitors and discusses drug design strategies for various novel BCR-ABL inhibitors.

Objective: To perform intrauterine adhesion modeling, and to investigate the repair effect of hypoxic treated bone marrow mesenchymal stem cells (BMSC) and their derived exosomes (BMSC-exo) on endometrial injury. Methods: BMSC and their exosomes BMSC-exo extracted from rats' femur were cultured under conventional oxygen condition (21%O₂) or hypoxia condition (1%O₂). Intrauterine adhesion modeling was performed on 40 healthy female SD rats by intrauterine injection of bacterial lipopolysaccharide after curettage. On the 28th day of modeling, 40 rat models were randomly divided into five groups, and interventions were performed: (1) NC group: 0.2 ml phosphate buffered solution was injected into each uterine cavity; (2) BMSC group: 0.2 ml BMSC (1×10⁶/ml) with conventional oxygen culture was injected intrauterine; (3) L-BMSC group: 0.2 ml of hypoxic cultured BMSC (1×10⁶/ml) was injected intrauterine; (4) BMSC-exo group: 0.2 ml of BMSC-exo cultured with conventional oxygen at a concentration of 500 μg/ml was injected into the uterine cavity; (5) L-BMSC-exo group: 0.2 ml hypoxic cultured BMSC-exo (500 μg/ml) was injected intrauterine. On the 14th and 28th day of treatment, four rats in each group were sacrificed by cervical dislocation after anesthesia, and endometrial tissues were collected. Then HE and Masson staining were used to observe and calculate the number of glands and fibrosis area in the endometrium. The expressions of angiogenesis related cytokines [vascular endothelial growth factor A (VEGFA) and CD₃₁], and fibrosis-related proteins [collagen-Ⅰ, collagen-Ⅲ, smooth muscle actin α (α-SMA), and transforming growth factor β1 (TGF-β1)] in endometrial tissues were detected by western blot. Results: (1) HE and Masson staining showed that the number of endometrial glands in L-BMSC group, BMSC-exo group and L-BMSC-exo group increased and the fibrosis area decreased compared with NC group on the 14th and 28th day of treatment (all P<0.05). Noteworthily, the changes of L-BMSC-exo group were more significant than those of BMSC-exo group (all P<0.05), and the changes of BMSC-exo group were greater than those of BMSC group (all P<0.05). (2) Western blot analysis showed that, compared with NC group, the expressions of collagen-Ⅲ and TGF-β1 in BMSC group, L-BMSC group, BMSC-exo group and L-BMSC-exo group decreased on the 14th and 28th day of treatment (all P<0.05). As the treatment time went on, the expressions of fibrosis-related proteins were different. Compared with BMSC group, the expressions of collagen-Ⅲ, α-SMA and TGF-β1 in the BMSC-exo group and L-BMSC group decreased on the 28th day (all P<0.05). Moreover, the expressions of collagen-Ⅲ and TGF-β1 in L-BMSC-exo group were lower than those in BMSC-exo group on the 28th day (all P<0.05). And the expressions of collagen-Ⅰ, α-SMA and TGF-β1 in L-BMSC-exo group were lower than those in L-BMSC group on the 28th day (all P<0.05). (3) The results of western blot analysis of VEGFA and CD₃₁ showed that, the expressions of VEGFA and CD₃₁ in BMSC group, L-BMSC group, BMSC-exo group and L-BMSC-exo group increased on the 14th and 28th day of treatment compared with NC group (all P<0.05). Treatment for 28 days, the expressions of VEGFA and CD₃₁ in BMSC-exo group and CD₃₁ in L-BMSC group were higher than those in BMSC group (all P<0.05). Moreover, the expressions of VEGFA and CD₃₁ in L-BMSC-exo group were higher than those in BMSC-exo group and L-BMSC group on the 28th day (all P<0.05). Conclusions: Treatment of BMSC and their exosomes BMSC-exo with hypoxia could promote endometrial gland hyperplasia, inhibit tissue fibrosis, and further repair the damaged endometrium in rats with intrauterine adhesion. Importantly, hypoxic treatment of BMSC-exo is the most effective in intrauterine adhesion rats.
Rats ; Female ; Humans ; Animals ; Rats, Sprague-Dawley ; Transforming Growth Factor beta1/metabolism* ; Vascular Endothelial Growth Factor A ; Exosomes/metabolism* ; Uterine Diseases/therapy* ; Collagen ; Hypoxia/therapy* ; Fibrosis ; Mesenchymal Stem Cells/metabolism* ; Oxygen

In 2004, it was the first time that Wollensak and Spoerl had applied physical and chemical cross-linking methods to scleral tissue. They found that the biomechanical strength of cross-linked sclera, induced by riboflavin/ultraviolet A, glyceraldehyde and glutaraldehyde, could be improved and proposed that scleral collagen cross-linking is expected to be a new method for the treatment of pathologic myopia. In recent years, a series of explorations have been made on the effectiveness and adverse reactions of physical and chemical cross-linking in the prevention and treatment of pathologic myopia, including the establishment of various animal models and different myopia modeling methods, the improvement of cross-linking methods, the amelioration of the measurement of biomechanical strength of scleral tissue and the attention of biological parameters such as the thickness of retinal nerve fiber layer and the amplitude of electroretinogram in vivo. Genipin-crosslinking of the scleral collagen combined with posterior scleral contraction/reinforcement has been applied to clinical research. This review summarizes physical cross-linking and the genipin-crosslinking of scleral collagen to explore the effectiveness and safety of the methods in the prevention and treatment of the pathologic myopia.

Objective:To explore the risk factors for death within 1 year after hip fracture surgery in the elderly.Methods:A case control study was made on the clinical data of 551 elderly patients with hip fracture treated in Second Affiliated Hospital of Soochow University from January 2019 to December 2020, including 182 males and 369 females; aged 65-100 years [80(73,86)years]. Joint replacement, cannulated screw fixation or proximal femoral nail fixation were performed. The patients were divided into survival group ( n=494) and death group ( n=57) based on the death within 1 year after surgery recorded at postoperative telephone follow-up. The gender, age, hypertension, diabetes, cardiovascular diseases, chronic respiratory diseases, neurological diseases, chronic renal failure, anemia on admission, fracture types, American anesthesiologist Association (ASA) classification, operative methods, preoperative waiting time, duration of operation and perioperative blood transfusion were recorded in two groups. Univariate Cox regression was used to analyze the correlation between the above indexes and death within 1 year after surgery. All indexes with P<0.2 in the univariate analysis were included in multivariate Cox regression analysis to clarify the independent risk factors for death within 1 year after surgery. Results:Univariate Cox regression analysis showed that death within 1 year after surgery correlated with gender, age chronic respiratory diseases, chronic renal failure and anemia on admission (all P<0.01), but not with hypertension, diabetes, cardiovascular diseases, neurological diseases, fracture types, ASA classification, operative methods, preoperative waiting time, duration of operation or perioperative blood transfusion (all P>0.05). Multivariate Cox regression analysis showed that male ( HR=2.08, 95% CI 1.20, 3.61, P<0.01), age ≥ 80 years ( HR=2.22, 95% CI 1.15, 4.28, P<0.05), chronic respiratory diseases ( HR=2.54, 95% CI 1.19, 5.40, P<0.05), chronic renal failure ( HR=4.57, 95% CI 1.27, 16.44, P<0.05), anemia on admission ( HR=2.82, 95% CI 1.38, 5.76, P<0.01) were significantly associated with death within 1 year after surgery. Conclusion:Male age≥ 80 years, chronic respiratory disease, chronic renal failure and anemia on admission are independent risk factors for death within 1 year after hip fracture surgery in the elderly.