Background: Low back pain (LBP) is the leading cause of disability among the elderly, placing significant social and economic burdens on societies globally. A common cause of chronic LBP is lumbar disc degeneration. Previously, we reported that autologous or allogenic fibroblast injections could treat intervertebral disc degeneration (IVDD) in preclinical studies by maintaining disc height and stability through fibrosis. However, the pathway to successful drug development remains unclear. Methods: To develop a novel human allogenic fibroblast injection, we launched a quality-by-design (QbD) project focusing on human dermal fibroblasts (HDFs). Results: We developed a tissue separation process, HDF culture process, and HDF cryopreservation process. The tissue disinfection method used 5% povidone-iodine solution and 75% alcohol for 3–5 min each; the tissue digestion conditions used neutral protease AF followed by overnight soaking plus collagenase NB6 digestion for 2–3 h; the non-animal component medium contained high glucose dulbecco’s modified eagle medium (DMEM) + 7.5% human platelet lysate (hPL); A cell density of 14,000–18,000 cells/cm2 was used; the cell cryopreservation solution contained 75% CS10 + 10% human serum albumin (HSA) + 15% saline (NaCl). Finally, we explored its therapeutic effects by treating IVDD in rabbits. Conclusions: The model of lumbar disc degeneration in rabbits was induced by acupuncture, and HDF was injected into the intervertebral disc. The therapeutic effect of HDF was observed by imaging and histopathology at 1, 3, and 6 months after administration. HDF treatment significantly improved the water content of degenerative intervertebral discs and maintained the height and stability of intervertebral discs. Signal pathway analysis in cynomolgus monkeys suggested that the primary mechanism involves promoting disc fibrosis. Therefore, this study demonstrated the feasibility and cost-effectiveness of manufacturing FibroCellTM, a foreskin-derived human dermal fibroblast injection. FibroCellTM shows promise as a cell-based therapy for IVDD treatment.

Esophageal squamous cell carcinoma (ESCC) remains a lethal malignancy with limited therapeutic options. This study investigated the antitumor efficacy and mechanisms of decursin, a natural pyranocoumarin derivative, against ESCC. In vitro analyses demonstrated that decursin selectively inhibited ESCC cell viability (IC50: 14.62 ± 0.61–26.20 ± 2.11 μM across TE-1, KYSE-30, and KYSE-150 cell lines) without affecting normal esophageal epithelial cells (Het-1A). Decursin (10 μM) suppressed colony formation, impaired wound healing (p < 0.001 at 48 h), and reduced Transwell migration/invasion in KYSE-150 cells. Subcutaneous xenograft models revealed significant tumor growth inhibition (p < 0.01) with decursin treatment (10 mg/kg, intraperitoneal), accompanied by no systemic toxicity. Mechanistically, decursin induced G0/G1 cell cycle deceleration (p < 0.01) and apoptosis through ubiquitin–proteasome-mediated degradation of oncoproteins TP63 and SOX2. Time- and dose-dependent protein suppression was reversed by proteasome inhibitor MG-132, but unaffected by lysosomal inhibition. These findings establish decursin as a promising therapeutic agent for ESCC, functioning via proteasomal degradation of key oncogenic drivers, and provide a rationale for decursin’s further development as a targeted monotherapy or chemosensitizer in multimodal regimens.

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease, representing a growing public health burden. While previous studies indicated that lactoferrin (LF) alleviates hepatic lipid accumulation, a hallmark of NAFLD, the mechanisms involved are still elusive. Male C57BL/6 J mice were randomly divided into the control (CON), high-fat, high-cholesterol diet containing cholate (HFCCD), and HFCCD+LF groups and treated for 8 weeks' intervention. Liver and small intestine tissues were analyzed to investigate lipid metabolism and underlying mechanisms. Additionally, gut microbiota composition and short-chain fatty acid (SCFA) levels were assessed. HFCCD feeding induced hepatic steatosis, while LF intervention improved lipid metabolism by reducing fatty acid synthesis and increasing lipolysis in the liver. Mechanistically, LF downregulated the protein expression of serotonin receptor 2A (HTR2A), which is related to lipogenesis, and upregulated the protein expression of peroxisome proliferator-activated receptor α (PPARα), which is one of the pivotal lipolytic genes, and its downstream effector, carnitine palmitoyl transferase-1A (CPT-1A), in the liver. Additionally, LF increased the relative abundance of gut microbiota related to glycolipid metabolism, such as Adlercreutzia, and decreased the relative abundance of 5-HT-promoting gut microbiota, such as Clostridia. Furthermore, LF increased the levels of SCFAs, which positively correlated with the relative abundance of Adlercreutzia. Our study suggests that LF intervention alleviates HFCCD-induced NAFLD in mice, which is potentially associated with regulation of the HTR2A-PPARa-CPT-1A pathway and gut microbiota composition.

Nonalcoholic fatty liver disease (NAFLD) is commonly associated with overweight and obesity. But an increasing number of cases involve lean individuals, who tend to experience worse liver outcomes. In this study, we established mouse models of both obese and lean NAFLD by feeding mice a Western diet (WD) ad libitum and a WD with 30% caloric restriction (CR), respectively, to investigate the effects of piperine. After 12 weeks, hepatocyte lipid deposition and liver injury were similar in lean and obese NAFLD mice. Piperine treatment significantly reduced serum ALT levels and hepatic triglyceride (TG) content, alleviating hepatic steatosis in both groups. The mechanism of action involved the downregulation of fatty acid uptake, as evidenced by reduced expression of PPARγ and CD36, as well as the promotion of lipolysis through upregulation of hormone-sensitive lipase (HSL) and adipose triglyceride lipase (ATGL). Additionally, piperine enhanced hepatic mitochondrial β-oxidation in the obese NAFLD model by upregulating carnitine palmitoyltransferase 1A (CPT1A). In conclusion, feeding a WD with 30% CR successfully induced lean NAFLD in mice, and piperine effectively alleviated NAFLD in both lean and obese mice.

BackgroundUnderstanding the stepwise progression of esophageal squamous cell carcinoma (ESCC) is crucial for developing customized strategies for early detection and optimal clinical management. Herein, we aimed to unravel the transcriptional and immunologic alterations occurring during malignant transformation and identify clinically significant biomarkers of ESCC.MethodsDigital spatial profiling (DSP) was performed on 11 patients with early-stage ESCC (pT1) to explore the transcriptional alterations in epithelial, immune cell, and non-immune cell stromal compartments across regions of distinct histology, including normal tissues, low- and high-grade dysplasia, and cancerous tissues. Furthermore, single-cell spatial transcriptomics was performed using the CosMx Spatial Molecular Imaging (SMI) system on 4 additional patients with pT1 ESCC. Immunohistochemical (IHC) analysis was performed on consecutive histological sections of 20 pT1 ESCCs. Additionally, public bulk and single-cell RNA-sequencing (scRNA-seq) datasets were analyzed, and in vitro and in vivo functional studies were conducted.ResultsSpatial transcriptional reprogramming and dynamic cell signaling pathways that determined ESCC progression were delineated. Increased infiltration of macrophages from normal tissues through dysplasia to cancerous tissues occurred. Macrophage subtypes were characterized using the scRNA-seq dataset. Cell-cell communication analysis of scRNA-seq and SMI data indicated that the migration inhibitory factor (MIF)-CD74 axis may exhibit pro-tumor interactions between macrophages and epithelial cells. DSP, SMI, and IHC data demonstrated that DTX3L expression in epithelial cells and BST2 expression in stromal cells increased gradually with ESCC progression. Functional studies demonstrated that DTX3L or BST2 knockdown inhibited ESCC proliferation and migration and decreased M2 polarization of tumor-associated macrophages.ConclusionsSpatial profiling comprehensively characterized the molecular and immunological hallmarks from normal tissue to ESCC, guiding the way to a deeper understanding of the tumorigenesis and progression of this disease and contributing to the prevention of ESCC. Within this exploration, we uncovered biomarkers that exhibit a robust correlation with ESCC progression, offering potential new avenues for insightful therapeutic approaches.

Introduction: Standardization of methods for the immunohistochemical detection of CD30 expression and improvement of its reproducibility is critical for determining patient eligibility for anti-CD30 therapy. The protocol of the VENTANA CD30 assay has been well-optimized based on a pilot study. The current study aims to evaluate the staining concordance of CD30 detected by nine alternative immunohistochemical (IHC) assays in addition to the VENTANA CD30 assay. This evaluation is pivotal for exploring more equivalent detection methods to assess CD30 expression in patients with malignant lymphomas. Methods: This multi-centre retrospective study aimed to enroll 700-1,000 patients diagnosed with malignant lymphomas from 17 institutes across China. Tissue sections were stained using the VENTANA CD30 assay or at least one of the nine IHC assays utilizing different antibodies (umAB256 (zsbio); Ber-H2 (Maixin); Ber-H2 (DAKO); JCM182 (Leica) and platforms (Ventana BenchMark; DAKO; Leica). The staining results were evaluated by a panel of three independent expert hematopathologists in China based on consensus criteria. The primary objective of the study was to evaluate the concordance of semiquantitative results of CD30 staining detected by nine IHC assays and the VENTANA CD30 assay. Consistency was assessed by the intraclass correlation coefficient (ICC). To observe the effect of CD30 expression level on the concordance of different assays, cases with high-level expression (such as cHL and ALCL) and with low-level expression (with positivity <10% cells) were included in the subgroup analysis. Results: In this interim analysis, 346 patients from 12 institutes were enrolled, and 245 of whom met the inclusion criteria, after excluding those who met the exclusion and rejection criteria. With the exception of Ber-H2 (DAKO) + Ventana BenchMark assay, which showed a moderate concordance with the VENTANA CD30 assay, the concordance between the other eight CD30 IHC assays and the VENTANA CD30 assay was good or excellent, regardless whether cases with low-level expression were included. Excluding cases with high-level expression, the concordance between Ber-H2 (DAKO) + Ventana BenchMark assay and the VENTANA CD30 assay remained moderate, the same result got in Ber-H2(Maixin)+Ventana BenchMark. When excluding cases with low-level expression, the concordance of the umAB256 (zhongshanjinqiao) + Ventana BenchMark and Ber-H2 (Maixin) + Dako with the VENTANA CD30 assay turned to be moderate similarly. Conclusions: Overall, the concordance of nine CD30 IHC assays with the VENTANA CD30 assay varied from moderate to excellent, suggesting the reliability of the application of these approaches. Additional efforts are needed to optimize those assays with moderate concordance to inform treatment decisions better.

Purpose There has been a persistent claim that dairy products contain calcium-leaching proteins, although the soundness of such a claim has been challenged. A meta-analysis of randomized controlled trials (RCTs) on the effects of milk-derived protein supplementation on bone health indices in adults was performed to reconcile the controversy surrounding the potential skeletal safety concerns of proteins of dairy origin. Methods The PubMed and Web of Science databases were searched for relevant RCTs. A random-effects model was used to generate pooled effect sizes and 95% confidence intervals. Results Milk-derived protein supplementation did not significantly affect whole-body BMD ( n = 7 RCTs) and BMD at the lumbar spine ( n = 10), hip ( n = 8), femoral neck ( n = 9), trochanter ( n = 5), intertrochanter ( n = 2), and ultradistal radius ( n = 2). The concentrations of bone formation markers (bone-specific alkaline phosphatase [ n = 11], osteocalcin [ n = 6], procollagen type 1 amino-terminal propeptide [ n = 5]), bone resorption markers (N-terminal telopeptide of type 1 collagen [ n = 7], C-terminal telopeptide of type 1 collagen [ n = 7], deoxypyridinoline [ n = 4]), and parathyroid hormone ( n = 7) were not significantly affected. However, increased insulin-like growth factor-1 (IGF-1) concentrations ( n = 13) were observed. Reduced IGF-1 concentrations were observed when soy protein was used as a comparator, and increased IGF-1 concentrations were observed when carbohydrate was used. Conclusion Our findings do not support the claim that proteins of dairy origin are detrimental to bone health.

Abstract Background Biopsies obtained from primary oesophageal squamous cell carcinoma (ESCC) guide diagnosis and treatment. However, spatial intra‐tumoral heterogeneity (ITH) influences biopsy‐derived information and patient responsiveness to therapy. Here, we aimed to elucidate the spatial ITH of ESCC and matched lymph node metastasis (LNmet). Methods Primary tumour superficial (PTsup), deep (PTdeep) and LNmet subregions of patients with locally advanced resectable ESCC were evaluated using whole‐exome sequencing (WES), whole‐transcriptome sequencing and spatially resolved digital spatial profiling (DSP). To validate the findings, immunohistochemistry was conducted and a single‐cell transcriptomic dataset was analysed. Results WES revealed 15.72%, 5.02% and 32.00% unique mutations in PTsup, PTdeep and LNmet, respectively. Copy number alterations and phylogenetic trees showed spatial ITH among subregions both within and among patients. Driver mutations had a mixed intra‐tumoral clonal status among subregions. Transcriptome data showed distinct differentially expressed genes among subregions. LNmet exhibited elevated expression of immunomodulatory genes and enriched immune cells, particularly when compared with PTsup (all P < .05). DSP revealed orthogonal support of bulk transcriptome results, with differences in protein and immune cell abundance between subregions in a spatial context. The integrative analysis of multi‐omics data revealed complex heterogeneity in mRNA/protein levels and immune cell abundance within each subregion. Conclusions This study comprehensively characterised spatial ITH in ESCC, and the findings highlight the clinical significance of unbiased molecular classification based on multi‐omics data and their potential to improve the understanding and management of ESCC. The current practices for tissue sampling are insufficient for guiding precision medicine for ESCC, and routine profiling of PTdeep and/or LNmet should be systematically performed to obtain a more comprehensive understanding of ESCC and better inform treatment decisions.

Natural killer (NK) cells have been demonstrated as a promising cellular therapy as they exert potent anti-tumor immune responses. However, applications of NK cells to tumor immunotherapy, especially in the treatment of advanced hematopoietic and solid malignancies, are still limited due to the compromised survival and short persistence of the transferred NK cells in vivo . Here, we observed that fucosyltransferase (FUT) 7 and 8 were highly expressed on NK cells, and the expression of CLA was positively correlated with the accumulation of NK cells in clinical B cell lymphoma development. Via enzyme-mediated ex vivo cell-surface fucosylation, the cytolytic effect of NK cells against B cell lymphoma was significantly augmented. Fucosylation also promoted NK cell accumulation in B cell lymphoma-targeted tissues by enhancing their binding to E-selectin. Moreover, fucosylation of NK cells also facilitated stronger T cell anti-tumor immune responses. These findings suggest that ex vivo fucosylation contributes to enhancing the effector functions of NK cells and may serve as a novel strategy for tumor immunotherapy.

Whey protein (WP) and whey protein hydrolysates (WPH) may have the potency to promote weight loss, preserve muscle and improve gut microbiota composition. The present study explored the effect of WPH vs WP on weight management in obese middle-aged mice in the content of changes in fat mass, muscle mass and gut microbiota composition. The present results showed that WPH significantly reduced energy intake, attenuated weight gain and improved blood lipids and glucose. Moreover, WPH reduced ectopic fat deposition and enhanced antioxidant capacity in muscle, but did not significantly affect muscle mass. WPH failed to reverse the microbial diversity reduction caused by a high-fat diet, but increased Akkermansia and Clostridium XVIII abundances and decreased Alistipes abundance. In conclusion, WPH is expected to have good prospects in weight management in middle age.

目的 探讨肺原发性滑膜肉瘤(primary pulmonary synovial sarcoma,PPSS)的临床病理学特征和影像学表现.方法 回顾性分析苏州大学附属第一医院2011年7月～2019年5月确诊的5例PPSS临床病理学特征、影像学表现、免疫表型和SYT-SSX融合基因情况.结果 5例PPSS年龄14～63岁,中位年龄29岁.2例因发热、不同程度的胸痛及胸闷等症状就诊,3例无明显症状,体检发现.镜检:4例为梭形细胞型,肿瘤细胞为均匀一致的梭形细胞,呈片状、束状排列,无腺体结构;1例为低分化型,由胖梭形细胞组成,具有明显异型性,核分裂象易见.免疫表型:5例vimentin、BCL-2、CD99、TLE-1和EMA均阳性,2例CD56灶状阳性,CK(AE1/AE3)、CK7、TTF-1、CD34、SMA、S-100等均阴性,Ki-67增殖指数为70％ ～80％.5例行FISH和SS18-SSX免疫组化检测,其中4例SS18-SSX融合基因阳性,5例均接受手术治疗,开胸术和胸腔镜术在手术时长和患者术后入院天数上无明显差异,随访期间3例死亡,1例复发.荟萃分析显示,SYT-SSX融合基因阳性明显提高PPSS的复发率(OR=2.47,95％CI:1.54～3.96,P<0.05).结论 PPSS预后差,临床特征及影像学表现特异性差,易与其他肺部肿瘤混淆,结合病理检查、免疫表型和SYT-SSX融合基因检测有助于确诊.

This study aimed to investigate the preventive effects of lactoferrin (Lf) on chronic alcoholic liver injury (ALI) in female mice. Female C57BL/6J mice were randomly divided into four groups: control group (CON), ethanol administration group (EtOH), low-dose Lf treatment group (LLf), and high-dose Lf group (HLf). In the last three groups, chronic ALI was induced by administering 20% ethanol ad libitum for 12 weeks. Mice in the CON and EtOH groups were fed with AIN-93G diet. Meanwhile, 0.4% and 4% casein in the AIN-93G diet were replaced by Lf as the diets of LLf and HLf groups, respectively. HLf significantly reduced hepatic triglyceride content and improved pathological morphology. HLf could inhibit cytochrome P450 2E1 overexpression and promote alcohol dehydrogenase-1 expression. HLf activated protein kinase B and AMP-activated protein kinase (AMPK), as well as upregulating nuclear-factor-erythroid-2-related factor-2 expression to elevate hepatic antioxidative enzyme activities. AMPK activation also benefited hepatic lipid metabolism. Meanwhile, HLf had no obvious beneficial effects on gut microbiota. In summary, Lf could alleviate chronic ALI in female mice, which was associated with redox balance and lipid metabolism regulation.

背景与目的:肝脏血管周上皮样细胞瘤(PEComa)在临床上较为少见,且部分潜在恶性.临床上患者多为体检时偶然发现,也有少数患者出现腹部疼痛或不适、发热乏力或消瘦等症状.由于其缺乏特异性的症状和影像学表现,所以临床上较易发生误诊并影响治疗.本研究通过总结既往病例的诊疗经验并结合国内外文献复习,旨在进一步认知并掌握肝脏PEComa的诊断及治疗.方法:通过电子病历系统收集苏州大学附属第一医院普外科2014年1月-2021年10月收治的肝脏PEComa病例数据,包括术前影像学资料、实验室检查、术中资料、术后病理及免疫组化等,进行回顾性分析,根据围术期治疗情况、术后随访数据,结合国内外相关文献对该病的临床特点、影像学表现、治疗、病理结果及预后进行总结.结果:共纳入患者17例,其中6例为男性,11例为女性;年龄25～68岁,平均(45.7±13.7)岁.3例主诉右上腹不适,4例合并乙肝病毒感染,甲胎蛋白(AFP)均未见明显异常;所有患者均经过术前影像学诊断,但准确率仅为5.9％(1/17);1例行术前穿刺活检.所有患者均行手术治疗,其中7例行腹腔镜手术,10例行开放手术;8例行解剖性肝段或肝叶切除术,9例行局部切除术.手术时间50.0～250.0 min,平均(133.6±52.8)min;术中出血量 50～400 mL,平均(138.2±116.6)mL;住院期间无二次手术、无死亡病例;术后住院时间3～11d,平均(6.1±2.4)d.17例患者均为肝脏单发肿瘤,肿瘤直径1.5～9.0cm,平均(4.0±2.4)cm,经手术治疗后病理证实为肝脏PEComa,其中15例患者完成免疫组化,Melan A阳性率90.0％(9/10),黑色素瘤抗体HMB-45阳性率93.3％(14/15),平滑肌肌动蛋白SMA 阳性率 92.9％(13/14),S-100 蛋白阳性率 35.7％(5/14),CD34 阳性率 57.1％(8/14),Ki-67 指数2％～12％.所有病例Clavien-Dindo术后并发症分级均为Ⅰ级,出院后行规律随访随访时间1.0～91.0个月,平均随访时间(46.0±28.1)个月,1例已完成随访,1例失访,其余患者目前均未出现复发.结论:肝脏PEComa是一种相对罕见的肝脏间叶性肿瘤,绝大多数为良性肿瘤,恶性罕见.该病好发于中年女性,一般无特殊临床表现,术前影像学诊断准确率较低,易与其他肝脏肿瘤混淆,其确诊依赖术后病理学检查.首选治疗方案为手术切除,潜在恶性病例需行长期规律随访,总体预后良好.

An energy-restricted weight-loss approach has limitations when it used in the elderly, especially because of muscle loss. We aimed to assess the effects of whey protein (WP) or WP hydrolysate (WPH) combined with an energy-restricted diet (ERD) on weight reduction and muscle preservation in older women with overweight and obesity. A total of 60 women were randomized to the control (ERD), WP (ERD + 20 g/d WP) or WPH (ERD + 20 g/d WPH) group, using a 1:1:1 allocation ratio. After an 8-week intervention, body composition, gut microbiota, and serum metabolomics changes were compared among the three groups. The reductions in body weight (−1.11 ± 1.11 vs. −2.34 ± 1.35, p < 0.05), BMI (−0.46 ± 0.45 vs. −0.97 ± 0.54, p < 0.05), and body fat (−0.70 ± 0.92 vs. −2.45 ± 1.65, p < 0.01) were higher in the WPH group than in the control group. Body fat (%) was significantly decreased in the two protein groups. Fat-free mass did not significantly change among the three groups. Serum metabolomics showed that the tricarboxylic acid cycle pathway was upregulated in the WPH group. No significant changes in microbiota were observed among the groups. In conclusion, WP or WPH supplementation combined with an energy-restricted diet benefits older women during weight loss. WPH was more effective, possibly due to increased energy metabolism.

To investigate the effect of piperine on pancreatic β cell apoptosis, mice were fed with high-fat diet and injected with 40 mg/kg streptozotoci to establish diabetic model. The mice in the piperine group received 30 mg/kg body weight of piperine by gavage for 12 weeks. Compared with the model group, piperine intervention significantly decreased fasting blooding glucose, and increased homeostasis model assessment (HOMA)-β. Piperine also increased pancreatic superoxide dismutase and decreased malondialdehyde. Piperine significantly decreased the apoptotic rate of pancreatic β-cells, and the protein expression of Bax/Bcl-2 ratio, also up-regulated the protein expression of phosphorylated PI3K and AKT in pancreas. In addition, apoptosis was induced in mouse insulinoma 6 cells by palmitate. Piperine treatment decreased apoptosis, protein expression of Bax/Bcl-2 ratio, and cytochrome C in cells. Thus, piperine plays a beneficial role on diabetic mice by improving pancreatic β-cell dysfunction, this might be associated with regulation on PI3K/Akt-mediated anti-apoptosis signaling.

三阴性乳腺癌作为预后较差的乳腺癌亚型,高辐射抗性及分子靶点不明确是影响其放疗效果的主要原因.本研究从一条新的途径,即BCCIP/53BP1途径,研究三阴性乳腺癌高辐射抗性的机制.首先,利用高通量染色体精确分析系统检测X射线照射后53BP1缺失对BCCIP阴性小鼠乳腺癌细胞染色体畸变率的影响,并以免疫荧光染色和蛋白质印迹(Western blot)方法检测53BP1缺失对BCCIP阴性乳腺癌细胞DNA双链断裂损伤恢复效率的影响;随后,采用DR-GFP荧光报告系统和姐妹染色体互换试验检测53BP1对BCCIP阴性乳腺癌细胞同源重组修复效率的调节作用;最后,通过克隆形成试验检测X射线照射后53BP1和BCCIP的共同缺失对乳腺癌细胞存活率的调控效果.结果表明:53BP1缺失下调BCCIP阴性小鼠乳腺癌细胞X射线照射后染色体畸变率的发生;53BP1/BCCIP双缺失乳腺癌细胞受照后,DNA双链断裂标志物γH2AX水平和焦点数量均低于BCCIP单缺失细胞;下调53BP1表达时,受照BCCIP阴性乳腺癌细胞的同源重组修复效率得到明显恢复,并且细胞辐射抗性得到明显增强.综上所述,53BP1缺失通过解除对同源重组修复的抑制,增加了BCCIP阴性乳腺癌细胞DNA双链断裂的修复效率,从而提高了细胞的辐射抗性.研究结果为阐明BCCIP/53BP1通过调控同源重组修复途径影响BCCIP阴性乳腺癌细胞辐射敏感性的作用机制,揭示三阴性乳腺癌放疗抗性的分子机制,以及发现新的放疗增敏靶点,提供了理论依据.

SCOPE:Lactoferrin (Lf) possess a protective potential to liver, but whether it can prevent alcoholic liver injury (ALI) remains unclear.METHODS AND RESULTS:Four groups of male C57BL/6J mice are fed with different diets, namely, AIN-93G diet for control (CON) and ethanol (EtOH) groups, and AIN-93G diet with 0.4% and 4% casein replaced by Lf for low-dose Lf (LLf) and high-dose Lf (HLf) groups, respectively. ALI is induced by giving 20% ethanol ad libitum combined with four "binges". Lf can remarkably decrease EtOH-induced mortality. Lf promotes aldehyde dehydrogenase-2 (ALDH2) expression and suppressing cytochrome P450 2E1 (CYP2E1) overexpression, resulting in the reduced hepatic superoxide and inflammation levels, which ultimately leads to the hepatic injury alleviation. However, HLf increases acetyl-CoA carboxylase and fatty acid synthase protein levels, which suggests that excessive intake may weaken the beneficial effects of Lf. Moreover, LLf increases the relative abundances of Akkermansia and Lactobacillus. Additionally, the study shows that Lf likely exerts action in its digestive product forms rather than intact Lf molecular in normal condition.CONCLUSION:LLf can ameliorate ALI, which is associated with the regulation of hepatic alcohol metabolism and the modulation of gut microbiota. However, excessive Lf intake may result in a diminished benefit.

为推进我国生物医学实验室安全管理体系的完善,以美国罗格斯肿瘤研究所为例,详细介绍了该研究所面向生物医学实验室实施的一系列安全管理措施,包括实验室准入制度及安全培训、实验室安全防护措施以及实验室应急预案.结合美国实验室成熟的安全管理经验,对国内高校生物医学实验室安全管理和应急预案的完善提出若干建议,包括建立准入制度并制定多样的培训计划、提供全面的实验安全提示、完善实验室的应急预案、优化实验室安全管理体系等,以促进实验人员有效安全操作和实验室的长效安全运行.

Rationale: Iron-saturated Lf (Holo-Lactoferrin, Holo-Lf) exhibits a superior anticancer property than low iron-saturated Lf (Apo-Lf). Ferroptosis is an iron-dependent cell death characterized by the accumulation of lipid peroxidation products and lethal reactive oxygen species (ROS). Radiotherapy also exerts its therapeutic effect through ROS. Methods: The effect of different iron-saturated Lf on ferroptosis and radiotherapy were tested on triple-negative breast cancer (TNBC) cell line MDA-MB-231 and non-TNBC cell line MCF-7. Results: Holo-Lf significantly increased the total iron content, promoted ROS generation, increased lipid peroxidation end product, malondialdehyde (MDA), and enhanced ferroptosis of MDA-MB-231 cells. By contrast, Apo-Lf upregulated SLC7a11 expression, increased GSH generation and inhibited ferroptosis of MDA-MB-231 cells. However, non-TNBC MCF-7 cells were resistant to Holo-Lf-induced ferroptosis because MCF-7 cells have a higher redox balance capacity than MDA-MB-231 cells. More importantly, Holo-Lf downregulated HIF-1α expression, ameliorated the hypoxia microenvironment in subcutaneous MDA-MB-231 tumors, and promoted radiation-induced DNA damage to hypoxic MDA-MB-231 cells. Finally, the efficacy of radiotherapy to MDA-MB-231 tumors was enhanced by Holo-Lf. Conclusion: Holo-Lf could induce ferroptosis in MDA-MB-231 cells and sensitize MDA-MB-231 tumors to radiotherapy.

目的 探讨PM2.5致人支气管上皮(human bronchial epithelial,HBE)细胞的毒性作用及可能机制.方法 探讨200μg/ml PM2.5混悬液染毒不同时段(0、1、3、6、12、24 h)对HBE细胞存活率和磷酸化核转录因子κB(nuclear factor kappa-B,NF-κB)p65蛋白表达水平的影响;检测PM2.5染毒不同时段后稳定转染了NF-κB反应元件调控的荧光素酶报告基因质粒的HBE细胞(HBE/NF-κB细胞)的荧光素酶活力;测定PM2.5染毒3 h后HBE细胞活性氧自由基(ROS)、细胞上清液中白细胞介素6(IL-6)和白细胞介素8(IL-8)的水平以及NF-κB信号通路相关基因的差异表达.结果 PM2.5混悬液染毒不同时段均能降低细胞存活率,24 h时降低趋势最明显,差异有统计学意义(P<0.05),仅为对照组的76.72％.在HBE/NF-κB细胞中,除PM2.5混悬液染毒12 h组外,其他各组均可诱导荧光素酶活力明显增加,差异有统计学意义(P<0.05).除PM2.5混悬液染毒12 h组外,其他各组HBE细胞磷酸化NF-κB p65蛋白水平均呈升高趋势,其中染毒3 h组变化最明显,差异有统计学意义(P<0.05),此变化与HBE/NF-κB细胞荧光素酶活力变化趋势基本一致.PM2.5染毒3 h后,细胞内ROS和细胞上清液中IL-6和IL-8水平均明显增加,差异有统计学意义(P<0.05),且PM2.5染毒组共有12个NF-κB信号通路相关差异基因表达,其中上调的基因有9个,下调的基因有3个.结论 HBE/NF-κB细胞可初步用于PM2.5致细胞炎症反应的快速评估,PM2.5暴露可诱导HBE细胞产生氧化应激与炎症反应,且可能与NF-κB信号通路改变有关.