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Li-Li Yang,1,2,* Ping Peng,1,3,* Yun-Hong Lin,3 Ting Zhou,4 Xiao-Xue Ren,1,3 Wei-Qi Wang,1 Xing-Xing Li1,3 1Department of Dental Research, The Affiliated Stomatological Hospital of Kunming Medical University, Kunming, Yunnan, 650100, People’s Republic of China; 2Department of Periodontics, The Affiliated Stomatological Hospital of Kunming Medical University, Kunming, Yunnan, 650100, People’s Republic of China; 3Department of Prosthodontics, The Affiliated Stomatological Hospital of Kunming Medical University, Kunming, Yunnan, 650100, People’s Republic of China; 4Department of Orthodontics, The Affiliated Stomatological Hospital of Kunming Medical University, Kunming, Yunnan, 650100, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xing-Xing LiDepartment of Prosthodontics, The Affiliated Stomatological Hospital of Kunming Medical University, No. 1088 Haiyuan Road, Wuhua District, Kunming, Yunnan, 650100, People’s Republic of ChinaTel +86 13759581696Fax +86 87165330099Email lxx_drli1862@163.comObjective: This study aims to measure and analyze the lip and tooth dynamic esthetic characteristics at rest and during speech in order to provide a reference for its esthetic design and restoration among the Hani and Han populations in Yunnan Province, China.Methods: Subjects of Hani and Han ethnicity in Yunnan were selected using multistage stratified sampling and inclusive criteria. The lip and tooth dynamic esthetic characteristics of the subjects at rest and during the pinyin pronunciation of “me”, “yi”, “fu”, and “si” were recorded using digital photography and analyzed with computer software.Results: No statistical difference was detected between the Hani and Han groups in the upper central-incisor display, when pronouncing the pinyin “yi”. Furthermore, there were no statistical differences in lip dynamic esthetic parameters between the Hani and Han groups, except for the distance between the upper and lower lips when pronouncing “si”. There were three kinds of correlation between the upper central-incisor edge and lower lip: separation, contact, and overlap.Conclusion: The display of upper central incisors and the mouth width of Hani people are larger than those of Han people when at rest. When the pinyin “si” is pronounced, the display of upper central incisors and the upper–lower lip distance of Hani people is less than that of Han people due to labial muscle movement.Keywords: Hani, Han, pronunciation, lip and tooth aesthetics, digital videography

Yang Lv,1,* Qing-Yang Feng,1,* Song-Bin Lin,2,* Yi-Hao Mao,1,* Yu-Qiu Xu,1 Peng Zheng,1 Liang-Liang Yang,1 Guo-Dong He,1 Jian-Min Xu11Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, People’s Republic of China; 2Department of General Surgery, Zhongshan Hospital Xiamen Branch, Fudan University, Xiamen city, People’s Republic of China*These authors contributed equally to this workAim: Lymph node ratio (LNR) seems to be more precise than classic N stage in classifying cancer stage. Thus, we aim to construct a modified classification system based on LNR for colon cancer without distant metastasis.Methods: This study enrolled two independent cohorts of patients. The primary cohort enrolled 2,152 patients from 2008 to 2013 in Zhongshan Hospital, Fudan University. The validation cohort consisted of 77,406 patients from the Surveillance, Epidemiology, and End Results (SEER) registry from 2004 to 2014. The inclusion criteria were: pathologically confirmed colon cancer, and American Joint Committee on Cancer (AJCC) stage I/II/III. The exclusion criteria included: incomplete follow-up information, rectal cancer, and multiple primary sites. The prognostic value of LNR for overall survival was evaluated. The cutoff value of LNR was determined by the X-tile. Predictive performance of modified classification was determined by the concordance index.Results: After analysis, 0.05 and 0.50 were determined as the best threshold values of LNR. A value of 0.50 was reclassified as the mN0, mN1 and mN2 stage. A modified classification based on mN0, mN1, and mN2 was further constructed for stage I/II/III colon cancer. C-index of the modified classification was statistically more precise than AJCC classification (0.687 versus 0.605, P

BaoHui Han,1 LuLu Yang,2 Xin Wang,3 LuanDi Yao2 1Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 2Lilly Suzhou Pharmaceutical Co. Ltd, Shanghai, People’s Republic of China; 3Asia Pacific Statistical Sciences, Lilly China Drug Development and Medical Affairs Centre, Shanghai, People’s Republic of China Abstract: Pemetrexed-based chemotherapy regimens (pem regimens) are the standard first-line treatment option in patients with non-squamous non–small cell lung cancer (NSCLC). The objective of this systematic review was to assess the efficacy of pemetrexed in the context of epidermal growth factor receptor (EGFR) mutation-positive NSCLC following the failure of EGFR–tyrosine kinase inhibitor (TKI) treatment. We searched biomedical literature databases (PubMed, EMBASE, and the Cochrane library) and conference proceedings for studies evaluating the efficacy of pemetrexed monotherapy or pemetrexed combined with platinum or any other chemotherapeutic agent in EGFR–mutation-positive NSCLC after EGFR-TKI failure. We extracted data of primary outcomes of interest (progression-free survival [PFS], overall survival [OS], and overall response rate [ORR]). The weighted median PFS, OS, and ORR were then calculated. Of 83 potentially relevant studies, eight (three randomized studies and five retrospective studies) were identified (involving 1,193 patients) and included in this systematic review, with 640 patients receiving pem regimens. The weighted median PFS, median OS, and ORR for patients treated with pem regimens were 5.09 months, 15.91 months, and 30.19%, respectively. Our systematic review results showed a favorable efficacy profile of pem regimens in NSCLC patients with EGFR mutation after EGFR–TKI failure. Keywords: pemetrexed, advanced non–small cell lung cancer, epidermal growth factor receptor, tyrosine kinase inhibitor

Yi Huang,1 Qi Tao,2 Dongzhi Hou,1 Sheng Hu,1 Shuangyan Tian,1 Yanzhong Chen,3 Ruyi Gui,1 Lingling Yang,4 Yao Wang5 1College of Pharmacy, Guangdong Pharmaceutical University, 2Key Laboratory of Mineralogy and Metallogeny, Chinese Academy of Sciences, Guangdong Provincial Key Laboratory of Mineral Physics and Materials, 3Guangdong Provincial Key Laboratory of Advanced Drug Delivery Systems, Guangdong Pharmaceutical University, Guangzhou, 4State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong Academy of Medical Sciences, 5Qingdao Eye Hospital, Shandong Eye Institute, Shandong Academy of Medical Sciences, Qingdao, China Abstract: As a novel ion-exchange carrier with high surface area and excellent exchangeability, montmorillonite (Mt) was intercalated with betaxolol hydrochloride (BH) to form a nanocomposite and then encapsulated by liposomes (Mt-BH-LPs) for an ophthalmic drug-delivery system. The Mt-BH and Mt-BH-LPs were prepared by an acidification process and ethanol injection combined with ammonium sulfate gradient methods. The successful formation of Mt-BH and Mt-BH-LPs was verified by thermogravimetric analysis, X-ray diffraction, Fourier-transform infrared spectra, and transmission electron microscopy. Mt-BH-LPs possessed the favorable physical characteristics of encapsulation efficiency, drug loading, mean particle size, and ζ-potential. In vitro release studies indicated Mt-BH-LPs effectively maintained a relatively sustained slow release. Immortalized human corneal epithelial cell cytotoxicity, in vivo rabbit eye-irritation tests, and chorioallantoic membrane–trypan blue staining all revealed that Mt-BH-LPs had no obvious irritation on ocular tissues. A new in vitro tear-turnover model, including inserts containing human corneal epithelial cells, was designed to evaluate the precorneal retention time of Mt-BH-LPs. The results showed that Mt-BH-LPs maintained a certain BH concentration in tear fluid for a longer period than the BH solution. In vivo precorneal retention studies also indicated Mt-BH-LPs prolonged drug retention on the ocular surface more than the BH solution. Furthermore, pharmacodynamic studies showed that Mt-BH-LPs had a prolonged effect on decreasing intraocular optical pressure in rabbits. Our results demonstrated that Mt-BH-LPs have potential as an ophthalmic delivery system. Keywords: liposome, montmorillonite, irritation, precorneal retention time, intraocular optical pressure

X-ray microscopy is powerful in that it can probe large volumes of material at high spatial resolution with exquisite chemical, electronic and bond orientation contrast. The development of diffraction-based methods such as ptychography has, in principle, removed the resolution limit imposed by the characteristics of the X-ray optics. Here, using soft X-ray ptychography, we demonstrate the highest-resolution X-ray microscopy ever achieved by imaging 5â €..nm structures. We quantify the performance of our microscope and apply the method to the study of delithiation in a nanoplate of LiFePO 4, a material of broad interest in electrochemical energy storage. We calculate chemical component distributions using the full complex refractive index and demonstrate enhanced contrast, which elucidates a strong correlation between structural defects and chemical phase propagation. The ability to visualize the coupling of the kinetics of a phase transformation with the mechanical consequences is critical to designing materials with ultimate durability.

Ossification of the posterior longitudinal ligament (OPLL) is characterized by ectopic bone formation in spinal ligaments. Some evidence indicates that mechanical strain can lead to the development of OPLL, although the signaling mechanism is not fully understood. Connexin43 (Cx43), a gap-junction protein, has been shown to be of particular importance in bone formation. We hypothesized that Cx43 may play an important role in the signal transmission induced by mechanical strain during the development of OPLL. To explore this possibility, we cultured fibroblasts from spinal ligaments of OPLL and non-OPLL patients and preloaded mechanical stretch onto the cells via a Flexercell 4000 Tension Plus system. We evaluated expression changes in osteocalcin (OCN), alkaline phosphatase (ALP), type I collagen (COL I) and Cx43 via semi-quantitative RT-PCR and western blotting at 12 and 24 h after mechanical strain application in contrast to static conditions. We observed a significant gene up-regulation of OCN, ALP and COL I and Cx43 protein in OPLL cells after mechanical strain application, but no changes in non-OPLL cells. Notably, after RNA interference targeting Cx43 was performed in OPLL cells, we found that there were no significant changes in the expressions of OCN, ALP, COL I and Cx43 after the mechanical strain was applied for 24 h. Thus, we propose that the increase in Cx43 expression induced by mechanical strain in OPLL cells plays an important role in the progression of OPLL. [ABSTRACT FROM AUTHOR]

In addition to modern medicinal therapy, many cancer patients in Taiwan are treated regularly with herbal medicines or prescribed a traditional herbal diet. In this paper, the effect of a Taiwanese traditional herbal diet (TTHD) on pain in terminal cancer patients was investigated. A total of 2,466 patients diagnosed with a variety of cancers were included. The most common patient-reported symptoms included troublesome pain (79.2%), weakness (69.0%), anorexia (46.4%), fever (36.5%), dyspnea (31.1%), and leg edema (30.9%). The 2,466 terminal cancer patients included in the study were randomly divided into three groups. The TTHD group (n=1044; 42.3%) were given the TTHD consisting of analgesic herbs (paeony root: licorice root = 1:1) and a Taiwanese tonic vegetable soup (Lilii bulbus, Nelumbo seed, and Jujube fruit). The remaining patients were divided into a reference group, given the regular hospital diet, (n=909, 36.9%) and a control group, given the Taiwanese tonic vegetable soup without analgesic herbs, (n=513, 20.8%). All patients maintained their assigned diets for one week. A verbal numerical scale was used to assess pain. Results revealed that the patients given TTHD reported enhanced pain relief (p < 0.05) compared to the reference and control groups. We found that TTHD could alleviate the pain among ter-minal cancer patients thereby supporting the supposition that Eastern and Western medicines can be effectively co-administered to enhance terminal patient's quality of life. Further research is warranted. [ABSTRACT FROM AUTHOR]

COP9 signalosome catalytic subunit CSN5 plays a key role in tumorigenesis and tumor immunity, showing potential as an anticancer target. Currently, only a few CSN5 inhibitors have been reported, at least partially, due to the challenges in establishing assays for CSN5 deubiquitinase activity. Here, we present the establishment and validation of a simple and reliable non-catalytic activity assay platform for identifying CSN5 inhibitors utilizing a new fluorescent probe, CFP-1 , that exhibits enhanced fluorescence and fluorescence polarization features upon binding to CSN5. By using this platform, we identified 2-aminothiazole-4-carboxylic acids as new CSN5 inhibitors, which inhibited CSN5 but slightly downregulated PD-L1 in cancer cells. Furthermore, through the integration of deep learning-enabled virtual screening, we discovered that shikonins are nanomolar CSN5 inhibitors, which can upregulate PD-L1 in HCT116 cells. The binding modes of these structurally distinct inhibitors with CSN5 were explored by using microsecond-scale molecular dynamics simulations and tryptophan quenching assays.

On 9 October 2022, the Large High Altitude Air Shower Observatory (LHAASO) reported the observation of the very early TeV afterglow of the brightest-of-all-time gamma-ray burst 221009A, recording the highest photon statistics in the TeV band ever obtained from a gamma-ray burst. We use this unique observation to place stringent constraints on the energy dependence of the speed of light in vacuum, a manifestation of Lorentz invariance violation (LIV) predicted by some quantum gravity (QG) theories. Our results show that the 95% confidence level lower limits on the QG energy scales are E&#95;{QG,1}>10 times the Planck energy E&#95;{Pl} for the linear LIV effect, and E&#95;{QG,2}>6×10^{-8}E&#95;{Pl} for the quadratic LIV effect. Our limits on the quadratic LIV case improve previous best bounds by factors of 5-7.

In this Letter we try to search for signals generated by ultraheavy dark matter at the Large High Altitude Air Shower Observatory (LHAASO) data. We look for possible γ rays by dark matter annihilation or decay from 16 dwarf spheroidal galaxies in the field of view of the LHAASO. Dwarf spheroidal galaxies are among the most promising targets for indirect detection of dark matter that have low fluxes of astrophysical γ-ray background while having large amount of dark matter. By analyzing more than 700 days of observational data at LHAASO, no significant dark matter signal from 1 TeV to 1 EeV is detected. Accordingly we derive the most stringent constraints on the ultraheavy dark matter annihilation cross section up to EeV. The constraints on the lifetime of dark matter in decay mode are also derived.

Habitual daytime napping is a common behavioral and lifestyle practice in particular countries and is often considered part of a normal daily routine. However, recent evidence suggests that the health effects of habitual daytime napping are controversial. We systematically searched PubMed, Web of Science, Embase, and Cochrane Library databases from inception to March 9, 2024, to synthesize cohort studies of napping and health outcome risk. A total of 44 cohort studies with 1,864,274 subjects aged 20-86 years (mean age 56.4 years) were included. Overall, habitual napping increased the risk of several adverse health outcomes, including all-cause mortality, cardiovascular disease, metabolic disease, and cancer, and decreased the risk of cognitive impairment and sarcopenia. Individuals with a napping duration of 30 min or longer exhibited a higher risk of all-cause mortality, cardiovascular disease, and metabolic disease, whereas those with napping durations less than 30 min had no significant risks. No significant differences in napping and health risks were observed for napping frequency, percentage of nappers, sample size, sex, age, body mass index, follow-up years, or comorbidity status. These findings indicate that individuals with a long napping duration should consider shortening their daily nap duration to 30 min or less., Competing Interests: Declaration of competing interest The authors do not have any conflicts of interest to disclose., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Benzimidazoles, the representative pharmacophore of fungicides, have excellent antifungal potency, but their simple structure and single site of action have hindered their wider application in agriculture. In order to extend the structural diversity of tubulin-targeted benzimidazoles, novel benzimidazole derivatives were prepared by introducing the attractive pyrimidine pharmacophore. 2-((6-(4-(trifluoromethyl)phenoxy)pyrimidin-4-yl)thio)-1 H -benzo[ d ]imidazole ( A 25 ) exhibited optimal antifungal activity against Sclerotinia sclerotiorum ( S. s. ), affording an excellent half-maximal effective concentration (EC 50 ) of 0.158 μg/mL, which was higher than that of the reference agent carbendazim (EC 50 = 0.594 μg/mL). Pot experiments revealed that compound A 25 (200 μg/mL) had acceptable protective activity (84.7%) and curative activity (78.1%), which were comparable with that of carbendazim (protective activity: 90.8%; curative activity: 69.9%). Molecular docking displayed that multiple hydrogen bonds and π-π interactions could be formed between A 25 and β-tubulin, resulting in a stronger bonding effect than carbendazim. Fluorescence imaging revealed that the structure of intracellular microtubules can be changed significantly after A 25 treatment. Overall, these remarkable antifungal profiles of constructed novel benzimidazole derivatives could facilitate the application of novel microtubule-targeting agents.

Background: Sarcopenia, the age-related loss of muscle mass and function, brings multiple adverse outcomes including disability and death. Several sarcopenia consensuses have newly introduced the premorbid concept of possible sarcopenia and recommended early lifestyle interventions. Bidirectional transitions of premorbid states have been revealed in several chronic diseases yet not clarified in sarcopenia. This study aims to investigate the underlying transition patterns of sarcopenia states., Methods: The study utilized three waves of data from a nationally representative survey, the China Health and Retirement Longitudinal Study (CHARLS), and included community-dwelling individuals aged 60 years and older with at least two sarcopenia states assessments based on the Asian Working Group for Sarcopenia criteria 2019 (AWGS2019) between 2011 and 2015. The estimated transition intensity and probability between non-sarcopenia, possible sarcopenia, sarcopenia, and death were investigated using multi-stage Markov (MSM) models., Results: The study comprised 4395 individuals (49.2% female, median age 67 years) with a total of 10 778 records of sarcopenia state assessment, and the mean follow-up period was 3.29 years. A total of 24.5% of individuals with a current state of possible sarcopenia returned to non-sarcopenia, 60.3% remained possible sarcopenia, 6.7% progressed to sarcopenia, and 8.5% died by the next follow-up. The transition intensity of recovery to non-sarcopenia (0.252, 95% CI 0.231-0.275) was 2.8 times greater than the deterioration to sarcopenia (0.090, 95% CI 0.080-0.100) for individuals with possible sarcopenia. For individuals with possible sarcopenia, the estimated probabilities of recovering to non-sarcopenia, progressing to sarcopenia, and transitioning to death within a 1-year observation were 0.181, 0.066, and 0.035, respectively. For individuals with sarcopenia, the estimated probabilities of recovering to non-sarcopenia, recovering to possible sarcopenia, and transitioning to death within 1-year observation were 0.016, 0.125, and 0.075, respectively. In covariables analysis, age, sex, body mass index, physical function impairment, smoking, hypertension, and diabetes are important factors influencing bidirectional transitions., Conclusions: The findings highlight the bidirectional transitions of sarcopenia states among older adults and reveal a notable proportion of possible sarcopenia show potential for recovery in the natural course. Screening and intensifying interventions based on risk factors may facilitate a recovery transition., (© 2024 The Author(s). Journal of Cachexia, Sarcopenia and Muscle published by Wiley Periodicals LLC.)

Objectives: Contacts of patients with infectious tuberculosis (TB) testing positive on interferon-gamma release assay (IGRA) are followed up to exclude active disease. However, identifying factors that predispose IGRA-negative contacts to TB could improve screening and follow-up strategies in a medium TB burden country such as Singapore., Methods: We conducted a retrospective study of IGRA-negative contacts aged ≥2 years identified during contact investigation between January 2014 and December 2022. We examined the risk factors associated with developing active TB among contacts previously testing IGRA-negative, using univariate and multivariable logistic regression and odds ratios with 95% confidence intervals., Results: Of 60,377 IGRA-negative contacts, 150 developed TB disease, and half were notified within 23 months of index patient diagnosis. IGRA-negative contacts of a smear-positive index patient were more likely to develop TB. Independent risk factors for TB were age >50 years, Malay ethnicity, having diabetes or end-stage renal failure, a "family" relationship with the index patient, or exposure in a dormitory or nursing home., Conclusions: Identifying risk factors could help optimise follow-up strategies and preventive treatment in IGRA-negative individuals. The incidence rate of TB in this group was 150 per 100,000 population, substantially higher than in the community, with a median 92 weeks to develop disease. Findings suggest that follow-up should be extended to 24 months for contacts with these risk factors., Competing Interests: Declarations of competing interest The authors have no competing interests to declare., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The potato planting area of Guizhou Province ranks second in China. However, due to factors such as climatic conditions and unbalanced fertilization, soil organic matter in potato fields is consumed rapidly and has a large deficit, which affects soil biological function and soil fertility. Biochar and organic fertilizer are effective ways to supplement foreign aid organic matter to improve soil quality. However, the differences in soil fertility and microbial community structure and their relationships under the conditions of organic fertilizer or biochar combined with chemical fertilizer are not clear. In this study, three treatments of conventional fertilization （NPK）, increased application of biochar （NPKB）, and increased application of organic fertilizer （NPKO） were set up to investigate the characteristics of potato rhizosphere soil, bacterial community composition, and diversity； to analyze the effects of these factors on the soil integrated fertility index； and to explore the direct and indirect effects of IFI on soil fertility and bacterial community structure differences between treatments and their driving factors. The results showed that soil pH, available phosphorus （AP）, available potassium （AK）, total nitrogen （TN）, organic carbon （SOC）, and C/N ratio were significantly higher in the NPKB and NPKO treatments than in the NPK treatment （ P <0.05）. Soil IFI was greatest for NPKO, followed by NPKB and least for the NPK treatment. A total of 8 214 ASVs were obtained from all the soil samples, belonging to 26 phyla, 75 classes, 165 orders, 176 families, and 251 genera （excluding unidentified fungi）. Proteobacteria, Actinobacteria, and Chloroflexi were the dominant phyla, accounting for 54.85% of all ASVs. Compared to that in the NPK and NPKB treatments, the NPKO treatment had the highest bacterial diversity and number of significantly different taxa, and soil AN, AP, AK, SOC, TN, and IFI were significant correlates of bacterial diversity index （ P <0.05）. Additionally, pH, TN, and SOC were significant influencers of bacterial taxa differences （ P <0.05）, with importance ranked as TN （70.59%） &gt; SOC （49.42%） &gt; pH （27.08%）. Structural equations suggested that pH-related soil properties and bacterial community diversity were the direct pathways influencing IFI, and soil pH-related soil characteristics could also indirectly affect IFI by affecting bacterial Shannon diversity. These results indicate that soil fertility and bacterial community structure were significantly different and correlated between the biochar and organic fertilizer addition treatments and that pH and bacterial community diversity were the key factors influencing IFI, with the NPKO treatment in particular having the best effect on improving IFI. Considering the effect of soil fertilization and the functional group of bacteria, NPKO is the recommended combination for the best synergistic effect of soil fertilization, that is, N 150 kg·hm -2 +P 2 O 5 135 kg·hm -2 +K 2 O 135 kg·hm -2 +organic fertilizer 6.6 t·hm -2 .

Lonicera japonica Flos is a valuable herb in the Lonicerae family. While transcriptomic studies on L. japonica have focused on different tissues (stems, leaves, flowers) or flowering stages, few have investigated the molecular mechanisms underlying chemical composition synthesis influenced by exogenous factors, such as foliar fertilization. Moreover, most transcriptomic studies on L. Japonica have been conducted on chlorogenic acid and luteoloside, and the molecular synthesis mechanism of the overall chemical composition has not been analyzed. Methods: We conducted a single-factor, four-level foliar fertilization experiment using yeast polysaccharides. Different yeast polysaccharides concentrations were sprayed on L. japonica for six consecutive days with dynamic sampling. High-performance liquid chromatography determined the active ingredients in each group. The two groups exhibiting the most significant differences were selected for transcriptomic analysis to identify key synthetic genes responsible for L. japonica 's active ingredients. Key results: Principal component analysis conducted on samples collected on September 8 revealed significant differences in the active ingredient amounts between the 0.1 g/L yeast polysaccharides treatment group and the control group. Transcriptome sequencing analysis identified 218 significantly differentially expressed genes, including 60 upregulated and 158 downregulated genes. Twelve differential genes involved in the chemical components synthesis pathway of L. japonica under yeast polysaccharides treatment were identified: PAL1, PAL2, PAL3, 4CL1, 4CL, CHS1, CHS2, CHS, CHI1, CHI2, F3H, and SOH. Conclusions: This study contributes to the theoretical understanding of essential synthetic genes associated with L. japonica 's active ingredients. It offers data support for further gene exploration and sheds light on the molecular mechanisms underlying L. japonica quality formation. These findings hold significant implications for enhancing the content of secondary metabolites of L. japonica ., Supplementary Information: The online version contains supplementary material available at 10.1007/s12298-024-01482-1., Competing Interests: Conflict of interestThe authors declare no conflict of interest., (© Prof. H.S. Srivastava Foundation for Science and Society 2024. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Kawasaki disease, or mucocutaneous lymph node syndrome, is an acute systemic vasculitis involving small and medium-sized vessels. It can be complicated by varying degrees of cardiac damage, especially coronary artery disease. The disease mainly occurs in children aged < 5 years, with rarer cases in older children and adults. Intravenous immunoglobulin combined with aspirin is the widely accepted treatment regimen in the acute phase, but the dosage recommended by the American Heart Association guidelines is not suitable for heavier children. This article reports the successful management of an overweight 14-year-old child with Kawasaki disease., Competing Interests: CONFLICTS OF INTEREST None to report., (Copyright © 2023 National Association of Pediatric Nurse Practitioners. Published by Elsevier Inc. All rights reserved.)

Reactive oxygen species (ROS), reactive nitrogen species (RNS), and reactive sulfur species (RSS) serve as vital mediators essential for preserving intracellular redox homeostasis within the human body, thereby possessing significant implications across physiological and pathological domains. Nevertheless, deviations from normal levels of ROS, RNS, and RSS disturb redox homeostasis, leading to detrimental consequences that compromise bodily integrity. This disruption is closely linked to the onset of various human diseases, thereby posing a substantial threat to human health and survival. Small-molecule fluorescent probes exhibit considerable potential as analytical instruments for the monitoring of ROS, RNS, and RSS due to their exceptional sensitivity and selectivity, operational simplicity, non-invasiveness, localization capabilities, and ability to facilitate in situ optical signal generation for real-time dynamic analyte monitoring. Due to their distinctive transition from their spirocyclic form (non-fluorescent) to their ring-opened form (fluorescent), along with their exceptional light stability, broad wavelength range, high fluorescence quantum yield, and high extinction coefficient, rhodamine fluorophores have been extensively employed in the development of fluorescent probes. This review primarily concentrates on the investigation of fluorescent probes utilizing rhodamine dyes for ROS, RNS, and RSS detection from the perspective of different response groups since 2016. The scope of this review encompasses the design of probe structures, elucidation of response mechanisms, and exploration of biological applications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: The occurrence and development of developmental dysplasia of the hip (DDH) are related to a variety of factors, which have been reported in the literature, but the literature does not mention factors related to the severity of DDH. The purpose of this study is to analyze the related factors of the occurrence and severity of DDH in combination with the Graf ultrasonic diagnostic classification., Methods: This study was a monocentric retrospective study describing the factors associated with DDH in a large hospital of northwest China. A total of 3046 infants (6092 hips) within 6 months after birth using the Graf method were admitted to our department between 2014 and 2018. We analyzed data of DDH. After reviewing medical charts and diagnostic examination results, we assessed whether factors such as ethnicity, gender, gestational age, birth weight, diagnosis age, maternal age, mode of delivery, fetal presentation, amniotic fluid volume and birth order, had any effect on development of hip., Result: ① Analysis showed that DDH mostly occurs in female and left hip joint, related to intrauterine fetal presentation, amniotic fluid volume, gestational age, mode of delivery, prenatal weight, and diagnosis age after birth, and the occurrence of DDH is also related to maternal age (All P＜0.05). Ethnicity and first born showed have no obvious correlation with DDH incidence (p = 0.718, 0.147, respectively). ② The strongest correlation was found with amniotic fluid, followed by birth weight. ③ The severity of DDH was correlated with ethnicity, births, prenatal weight, gestational age, diagnosis age and maternal age (All P＜0.05, respectively). ④ There were significant differences in treatment methods, duration and prognosis among different types of DDH., Conclusions: The occurrence and development of DDH are related to a variety of factors. Ultrasound examination can provide an early assessment of the hip development status of infants and may play an important role in establishing an early clinical diagnosis treatment and monitoring and prognosis., Competing Interests: Declaration of competing interest No conflict of interest exits in the submission of this manuscript, and manuscript is approved by all authors for publication., (Copyright © 2023. Published by Elsevier B.V.)

Simulated body fluid (SBF) is widely utilized in preclinical research for estimating the mineralization efficacy of biomaterials. Therefore, it is of great significance to construct an efficient and stable SBF mineralization system. The conventional SBF solutions cannot maintain a stable pH value and are prone to precipitate homogeneous calcium salts at the early stages of the biomimetic process because of the release of gaseous CO 2 . In this study, a simple but efficient five times SBF buffered by 5 % CO 2 was developed and demonstrated to achieve excellent mineralized microstructure on a type of polymer-aligned nanofibrous scaffolds, which is strikingly similar to the natural human bone tissue. Scanning electron microscopy and energy-dispersive X-ray examinations indicated the growth of heterogeneous apatite with a high-calcium-to-phosphate ratio on the aligned nanofibers under 5 times SBF buffered by 5 % CO 2 . Moreover, X-ray diffraction spectroscopy and Fourier transform infrared analyses yielded peaks associated with carbonated hydroxyapatite with less prominent crystallization. In addition, the biomineralized aligned polycaprolactone nanofibers demonstrated excellent cell attachment, alignment, and proliferation characteristics in vitro. Overall, the results of this study showed that 5 × SBFs buffered by 5 % CO 2 partial pressure are attractive alternatives for the efficient biomineralization of scaffolds in bone tissue engineering, and could be used as a model for the prediction of the bone-bonding bioactivity of biomaterials., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier Ltd.)

Cerebrospinal fluid-contacting neurons (CSF-cNs) act crucial role in chemosensory and mechanosensory function in spinal cord. Recently, CSF-cNs were found to be an immature neuron and may be involved in spinal cord injury recovery. But how to culture it and explore its function in vitro are not reported in previous research. Here, we first reported culture and identification of CSF-cNs in vitro. We first established a protocol for in vitro culture of CSF-cNs from the cervical spinal cord of mice within 24 h after birth. Polycystic kidney disease 2-like 1 (PKD2L1) + cells were isolated by fluorescence-activated cell sorting and expressed the neuron marker β-tubulin III and CSF-cNs marker GABA. Intriguingly, PKD2L1 + cells formed neurosphere and expressed neural stem cell markers Nestin, Sox2 and GFAP. Thus, our research provided culture and isolation of CSF-cNs and this facilitate the investigation the CSF-cNs function in vitro., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

A Gram-stain-positive, rod-shaped bacterium, designated as HLT2-17 T , was isolated from soil sample taken from the Hailuogou glacier in Sichuan province, PR China. Strain HLT2-17 T was capable of growing at 4-25°C and in NaCl concentrations ranging from 0 to 2% (w/v). The highest level of 16S rRNA gene sequence similarity was observed with Pengzhenrongella phosphoraccumulans M0-14 T (98.3 %) and Pengzhenrongella sicca LRZ-2 T (98.2 %). The average nucleotide identity and digital DNA-DNA hybridization values between strain HLT2-17 T and its closest relatives, P. phosphoraccumulans M0-14 T and P. sicca LRZ-2 T , were 80.0-84.0 % and 23.3-27.7 %, respectively. Phylogenomic analysis indicated that strain HLT2-17 T clustered together with strains P. phosphoraccumulans M0-14 T and P. sicca LRZ-2 T . Strain HLT2-17 T contained C 16 : 0 and anteiso-C 15 : 0 as the major fatty acids, and MK-9(H 4 ) as the menaquinone. Therefore, based on a polyphasic approach, we propose that strain HLT2-17 T (=CGMCC 1.11116 T = NBRC 110443 T ) represents a novel species of the genus Pengzhenrongella and suggest the name Pengzhenrongella frigida sp. nov.

Authentication and adulteration detection of closely related herbal medicines is a thorny issue in the quality control and market standardization of traditional Chinese medicine. Taking Fritillariae Bulbus (FB) as a case study, we herein proposed a three-step strategy that integrates mass spectrometry-based metabolomics and multivariate statistical analysis to identify specific markers, thereby accurately identifying FBs and determining the adulteration level. First, an ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry-based untargeted metabolomics method was employed to profile steroid alkaloids in five sorts of FB and screen potential differential markers. Then, the reliability of the screened markers was further verified by the distribution in different FB groups acquired from ultra-high performance liquid chromatography triple quadrupole mass spectrometry-based pseudotargeted metabolomics analysis. As a result, a total of 16 compounds were screened out to be the specific markers, which were successfully applied to distinguish five FBs by using discriminant analysis model. Besides, partial least squares regression models based on specific markers allowed accurate prediction of three sets of adulterated FBs. All the models afforded good linearity and good predictive ability with regression coefficient of prediction (R 2 p ) > 0.9 and root mean square error of prediction (RMSEP) < 0.1. The reliable results of discriminant and quantitative analysis revealed that this proposed strategy could be potentially used to identify specific markers, which contributes to rapid chemical discrimination and adulteration detection of herbal medicines with close genetic relationship., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: To summarize the clinical characteristics of coronavirus disease 2019 (COVID-19) in patients with Good's syndrome. Methods: We included all cases of COVID-19 in patients with Good's syndrome in the Second Xiangya Hospital of Central South University from January 1, 2023 to August 31, 2023. In addition to our cases, we searched the published literature in Wanfang database and PubMed database using the keywords "Good's syndrome" and "COVID-19". The clinical characteristics, treatment and outcome of the patients were summarized and analyzed. Results: A total of four patients with Good's syndrome complicated by COVID-19 were identified in our hospital, all of them were male, and the days of hospitalization were 17, 23, 7, and 13 days, respectively. Databases were searched for a total of six patients with Good's syndrome complicated by COVID-19, including three females and three males, all foreign patients, with hospitalization days of 12, 22, 13, 25, 21, and 34 days respectively. All ten patients met the diagnostic criteria for severe or critical COVID-19, and three(all middle-aged males) of them died, two from sepsis and one from respiratory failure. They were. Conclusion: COVID-19 in patients with Good's syndrome are prone to develop severe or critical disease and are more likely to be infected with multiple pathogens. Timely immunoglobulin supplementation is the key to treatment.

Objective: To analyze the efficacy of high-intensity focused ultrasound (HIFU) for adenomyosis and postoperative recurrence and its influencing factors., Methods: Clinical and follow-up data of 308 patients with adenomyosis who were treated with HIFU in Haifu Center, Affiliated Hospital of Chengdu University of Traditional Chinese Medicine from September 2017 to January 2022 were retrospectively analyzed. The recurrence of adenomyosis and the efficacy of HIFU at 6 months after surgery were followed up. To explore factors influencing postoperative prognosis and recurrence, the following variables were analyzed: patients' age, course of disease, gravidity and parity, size of the uterus, duration of HIFU, duration of irradiation, treatment intensity, dysmenorrhea score, time of follow-up, combined treatment of traditional Chinese medicine (TCM), western medicine adjuvant treatment, lesion location and type, and menorrhagia., Results: Among the 308 patients, 238 (77%) were followed up from 6 to 36 months, with an average follow-up time of 15.24 ± 9.97 months. The other 70 (23%) were lost to follow-up. At 6-month after surgery, efficacy rates of dysmenorrhea and menorrhagia management were 86.7% and 89.3%, respectively. Postoperative recurrence rates were 4.8% (1-12 months), 9.0% (12-24 months), and 17.0% (24-36 months) for dysmenorrhea; and 6.3% (1-12 months), 2.4% (12-24 months), and 12.2% (24-36 months) for menorrhagia. Multivariate logistic regression analyses showed that parity (P = 0.043, OR = 1.773, 95% CI 1.018-3.087), uterine size (P = 0.019, OR = 1.004, 95% CI 1.001-1.007), combined treatment of TCM (P = 0.047, OR = 1.846, 95% CI 1.008-3.381), diffuse lesion type (P = 0.013, OR = 0.464, 95% CI 0.254-0.848) and ablation rate (P = 0.015, OR = 0.481, 95%CI 0.267-0.868) were prognostic factors (P < 0.05). Age, course of disease, gravidity, duration of HIFU, duration of irradiation, treatment intensity, preoperative dysmenorrhea score, time of follow-up, western medicine adjuvant therapy, lesion location, and preoperative menstrual volume had no effect on prognosis (P > 0.05)., Conclusion: HIFU can effectively relieve dysmenorrhea and reduce menstrual volume in patients with adenomyosis. Parity, uterine size, lesion type (diffuse), and ablation rate are risk factors for symptom recurrence after HIFU, while the combination of TCM therapy is a protective factor for relapse. We, therefore, recommend TCM in the adjuvant setting after HIFU according to patient condition., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The saponin-enriched extract from Celosiae Semen is a promising resource owing to its lipid-lowering activity. However, triterpenoid saponins are difficult to extract owing to their high molecular weight and strong water solubility. The aim of this paper was to explore an eco-friendly and effective technology of extraction and enrichment of total triterpenoid saponins to obtain high lipid-lowering fractions. Initially, Box-Behnken design experiments were employed to optimize the heat reflux extraction process on the basic of mono-factor experiments. Afterwards, the crude extract was further purified using D-101 resin, and the purification parameters were investigated based on adsorption/desorption experiments and biological activity assay. Under optimal conditions, the purity of the finally obtained total triterpenoid saponins was increased by 7.28-fold. The lipid-lowering activities of the six main triterpenoid saponins were evaluated in HepG2 cells induced by palmitic acid. The results of Oil Red O staining showed that the compounds all exhibited potential lipid-lowering activity. The structure-activity relationship analysis suggested that the oligosaccharide chain at C-28 played an essential role in their lipid-lowering activity and the substituent group at C-23 site also showed important effects. The optimal extraction and purification methods may facilitate the utilization of Celosiae Semen for the industrial production as a functional food and drug., (© 2024 John Wiley & Sons Ltd.)

Nucleic acid sensors play a critical role in recognizing and responding to pathogenic nucleic acids as danger signals. Upon activation, these sensors initiate downstream signaling cascades that lead to the production and release of pro-inflammatory cytokines, chemokines, and type I interferons. These immune mediators orchestrate diverse effector responses, including the activation of immune cells and the modulation of the tumor microenvironment. However, careful consideration must be given to balancing the activation of nucleic acid sensors to avoid unwanted autoimmune or inflammatory responses. In this review, we provide an overview of nucleic acid sensors and their role in combating cancer through the perception of various aberrant nucleic acids and activation of the immune system. We discuss the connections between different programmed cell death modes and nucleic acid sensors. Finally, we outline the development of nucleic acid sensor agonists, highlighting how their potential as therapeutic targets opens up new avenues for cancer immunotherapy., Competing Interests: Declaration of competing interest No potential conflicts of interest were disclosed., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Trillions of intestinal bacteria in the human body undergo dynamic transformations in response to physiological and pathological changes. Alterations in their composition and metabolites collectively contribute to the progression of Alzheimer's disease. The role of gut microbiota in Alzheimer's disease is diverse and complex, evidence suggests lipid metabolism may be one of the potential pathways. However, the mechanisms that gut microbiota mediate lipid metabolism in Alzheimer's disease pathology remain unclear, necessitating further investigation for clarification. This review highlights the current understanding of how gut microbiota disrupts lipid metabolism and discusses the implications of these discoveries in guiding strategies for the prevention or treatment of Alzheimer's disease based on existing data., (© 2024. The Author(s).)

Background: Metabolic reprogramming plays a key role in cancer progression and clinical outcomes; however, the patterns and primary regulators of metabolic reprogramming in colorectal cancer (CRC) are not well understood., Aim: To explore the role of nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) in promoting progression of CRC., Methods: We evaluated the expression and function of dysregulated and survival-related metabolic genes using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes. Consensus clustering was used to cluster CRC based on dysregulated metabolic genes. A prediction model was constructed based on survival-related metabolic genes. Sphere formation, migration, invasion, proliferation, apoptosis and clone formation was used to evaluate the biological function of NOX4 in CRC. mRNA sequencing was utilized to explore the alterations of gene expression NOX4 over-expression tumor cells. In vivo subcutaneous and lung metastasis mouse tumor model was used to explore the effect of NOX4 on tumor growth., Results: We comprehensively analyzed 3341 metabolic genes in CRC and identified three clusters based on dysregulated metabolic genes. Among these genes, NOX4 was highly expressed in tumor tissues and correlated with worse survival. In vitro , NOX4 overexpression induced clone formation, migration, invasion, and stemness in CRC cells. Furthermore, RNA-sequencing analysis revealed that NOX4 overexpression activated the mitogen-activated protein kinase-MEK1/2-ERK1/2 signaling pathway. Trametinib, a MEK1/2 inhibitor, abolished the NOX4-mediated tumor progression. In vivo , NOX4 overexpression promoted subcutaneous tumor growth and lung metastasis, whereas trametinib treatment can reversed the metastasis., Conclusion: Our study comprehensively analyzed metabolic gene expression and highlighted the importance of NOX4 in promoting CRC metastasis, suggesting that trametinib could be a potential therapeutic drugs of CRC clinical therapy targeting NOX4., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Ozonation of wastewater containing bromide (Br - ) forms highly toxic organic bromine. The effectiveness of ozonation in mitigating wastewater toxicity is minimal. Simultaneous application of ozone (O 3 ) (5 mg/L) and ferrate(VI) (Fe(VI)) (10 mg-Fe/L) reduced cytotoxicity and genotoxicity towards mammalian cells by 39.8% and 71.1% (pH 7.0), respectively, when the wastewater has low levels of Br - . This enhanced reduction in toxicity can be attributed to increased production of reactive iron species Fe(IV)/Fe(V) and reactive oxygen species (•OH) that possess higher oxidizing ability. When wastewater contains 2 mg/L Br - , ozonation increased cytotoxicity and genotoxicity by 168%-180% and 150%-155%, respectively, primarily due to the formation of organic bromine. However, O 3 /Fe(VI) significantly (p < 0.05) suppressed both total organic bromine (TOBr), BrO 3 - , as well as their associated toxicity. Electron donating capacity (EDC) measurement and precursor inference using Orbitrap ultra-high resolution mass spectrometry found that Fe(IV)/Fe(V) and • OH enhanced EDC removal from precursors present in wastewater, inhibiting electrophilic substitution and electrophilic addition reactions that lead to organic bromine formation. Additionally, HOBr quenched by self-decomposition-produced H 2 O 2 from Fe(VI) also inhibits TOBr formation along with its associated toxicity. The adsorption of Fe(III) flocs resulting from Fe(VI) decomposition contributes only minimally to reducing toxicity. Compared to ozonation alone, integration of Fe(VI) with O 3 offers improved safety for treating wastewater with varying concentrations of Br - ., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ye Du reports financial support was provided by National Natural Science Foundation of China. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

A type of Al-MCM-41 supported dual imidazolium ionic liquids were constructed and efficiently used as catalysts for the synthesis of 2-oxazolidinones from epoxides, amines, and CO 2 . The influence of the different catalysts and reaction parameters on the catalytic behaviours was investigated. Al-MCM-41@ILTiCl 5 was identified as the most excellent catalyst because it could efficiently promote the three-component cycloaddition of CO 2 , epoxide, and amines to form the corresponding 2-oxazolidinones in high to excellent yields (84∼96%) with excellent selectivities (98∼99.7%). In addition, the recovery and reuse performances of Al-MCM-41@ILTiCl 5 were examined. The catalyst could be recovered by simple filtration and reused six times without a change in the catalytic activity. Green reaction conditions, operational simplicity, feasibility, and sustainability of the functionalized catalyst are the main highlights of the present protocol.

Pathological cardiac hypertrophy (CH) is driven by maladaptive changes in myocardial cells in response to pressure overload or other stimuli. CH has been identified as a significant risk factor for the development of various cardiovascular diseases, ultimately resulting in heart failure. Melanoma differentiation-associated protein 5 (MDA5), encoded by interferon-induced with helicase C domain 1 (IFIH1), is a cytoplasmic sensor that primarily functions as a detector of double-stranded ribonucleic acid (dsRNA) viruses in innate immune responses; however, its role in CH pathogenesis remains unclear. Thus, the aim of this study was to examine the relationship between MDA5 and CH using cellular and animal models generated by stimulating neonatal rat cardiomyocytes with phenylephrine and by performing transverse aortic constriction on mice, respectively. MDA5 expression was upregulated in all models. MDA5 deficiency exacerbated myocardial pachynsis, fibrosis, and inflammation in vivo, whereas its overexpression hindered CH development in vitro. In terms of the underlying molecular mechanism, MDA5 inhibited CH development by promoting apoptosis signal-regulating kinase 1 (ASK1) phosphorylation, thereby suppressing c-Jun N-terminal kinase/p38 signaling pathway activation. Rescue experiments using an ASK1 activation inhibitor confirmed that ASK1 phosphorylation was essential for MDA5-mediated cell death. Thus, MDA5 protects against CH and is a potential therapeutic target., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

We present the measurements of all-particle energy spectrum and mean logarithmic mass of cosmic rays in the energy range of 0.3-30 PeV using data collected from LHAASO-KM2A between September 2021 and December 2022, which is based on a nearly composition-independent energy reconstruction method, achieving unprecedented accuracy. Our analysis reveals the position of the knee at 3.67±0.05±0.15  PeV. Below the knee, the spectral index is found to be -2.7413±0.0004±0.0050, while above the knee, it is -3.128±0.005±0.027, with the sharpness of the transition measured with a statistical error of 2%. The mean logarithmic mass of cosmic rays is almost heavier than helium in the whole measured energy range. It decreases from 1.7 at 0.3 PeV to 1.3 at 3 PeV, representing a 24% decline following a power law with an index of -0.1200±0.0003±0.0341. This is equivalent to an increase in abundance of light components. Above the knee, the mean logarithmic mass exhibits a power law trend towards heavier components, which is reversal to the behavior observed in the all-particle energy spectrum. Additionally, the knee position and the change in power-law index are approximately the same. These findings suggest that the knee observed in the all-particle spectrum corresponds to the knee of the light component, rather than the medium-heavy components.

A 34 year old female patient was scheduled to undergo surgical resection due to a "breast nodule". Preoperative examination revealed an activated partial thromboplastin time (APTT) of 66.2 seconds, coagulation factor Ⅺ activity (FⅪ: C) of 2%, and FⅪ antigen (FⅪ: Ag) of 40.3%. The patient and family members showed no abnormal bleeding symptoms. Diagnosed as hereditary coagulation factor Ⅺ deficiency. Genetic testing revealed that the F11 gene had a heterozygous nonsense mutation in exon 10, c.1107C>A (p.Tyr351stop), and a heterozygous missense mutation in exon 13, c.1562A>G (p.Tyr503Cys). The father and son were p Heterozygous carriers of Tyr351stop mutation, while the mother and daughter are p Heterozygous carriers of Tyr503Cys mutations. The in vitro expression results showed that p The Tyr351stop mutation resulted in a significant decrease in the transcription level of F11 gene, while p The Tyr503Cys mutation has no effect on the transcription level and protein expression level of F11 gene, but it leads to a significant decrease in the level of FⅪ:C in the cell culture supernatant.

Hepatocellular carcinoma is a kind of cancer with a strong invasion, a high incidence rate and mortality, and a poor prognosis. At the time of diagnosis, most patients are already in the advanced stages of a tumor and have lost the chance for radical surgical treatment. Advanced hepatocellular carcinoma treatment has a gradual transition from systemic chemotherapy to targeted therapy, immunotherapy, and combination therapy, especially immune checkpoint inhibitor-based immunotherapy combination therapy, such as combination with bevacizumab monoclonal antibodies and other drugs, or combination with TACE, HAIC, radiotherapy, ablation, and other treatment methods. Combination therapy has significant synergistic effects and thus has already become a future treatment trend for hepatocellular carcinoma. An immunotherapy-based combination therapy plan will run through the whole process of systemic therapy, which is expected to bring better survival benefits to patients with hepatocellular carcinoma. This article reviews the latest research progress in aspects of the first-line treatment of advanced hepatocellular carcinoma.