Cancer remains a leading cause of global mortality, necessitating the development of advanced therapeutic strategies with enhanced efficacy and reduced systemic toxicity. Among promising bioactive agents, lactoferrin (LF)—a multifunctional iron-binding glycoprotein abundantly found in mammalian milk and exocrine secretions—has garnered significant interest for its potent and multifaceted anti-cancer properties. This review provides a comprehensive analysis of the current understanding of LF’s role in oncology, encompassing its structural biology, diverse mechanisms of action, and groundbreaking advancements in its application through nano-engineering. LF exerts anti-tumor effects through multiple pathways, including extracellular action, intracellular action, and immune regulation. It demonstrates a remarkable affinity for cancer cell membranes, binding to overexpressed anionic components such as glycosaminoglycans and sialic acids, as well as to specific receptors including the low-density lipoprotein receptor-related protein-1 (LRP-1). This selective binding facilitates targeted uptake. Upon internalization, LF orchestrates a direct assault by inducing cell-cycle arrest in phases such as G0/G1 or S phase through the modulation of key regulators including cyclins, CDKs, and p53. Furthermore, it promotes programmed cell death via apoptotic pathways, involving caspase activation and downregulation of anti-apoptotic proteins such as survivin. A more recently elucidated mechanism is the induction of ferroptosis, an iron-dependent form of cell death characterized by overwhelming lipid peroxidation. Beyond direct cytotoxicity, LF acts as a potent immunomodulator. It enhances natural killer (NK) cell activity, modulates T-lymphocyte populations, and crucially reprograms tumor-associated macrophages (TAMs) from a pro-tumor M2 state to an anti-tumor M1 state, thereby reversing the immunosuppressive tumor microenvironment (TME). The translation of LF’s potential has been significantly accelerated by nanotechnology. The inherent biocompatibility and natural tumor-targeting capabilities of LF make it an ideal platform for sophisticated drug-delivery systems. This review details various fabrication strategies for LF-based nanoparticles (NPs), including self-assembly, sol-in-oil emulsion, and electrostatic nanocomplexes, among others. Research demonstrates that nano-formulations not only protect LF from degradation but also enhance its bioactivity and anti-cancer potency. More importantly, LF NPs serve as versatile carriers for a wide array of therapeutic agents, including conventional chemotherapeutics, natural compounds, and imaging agents. These engineered systems enable synergistic therapy and facilitate site-specific delivery. Notably, the ability of LF to bind to receptors on the blood-brain barrier (BBB) has been leveraged to develop nano-systems for glioblastoma treatment. Other innovative designs utilize LF to modulate the TME—for instance, by alleviating tumor hypoxia to sensitize cells to radiotherapy and chemotherapy. Despite compelling pre-clinical evidence, the clinical translation of LF and its nano-formulations remains nascent. While early-phase trials have established a favorable safety profile for recombinant human LF, larger Phase III studies have yielded mixed results, underscoring the complexity of its action in humans. Key challenges include enhancing drug targeting, optimizing loading efficiency, ensuring batch-to-batch reproducibility, and achieving deep tumor penetration. Future research must focus on the rational design of next-generation LF-NPs. This entails developing standardized manufacturing protocols, engineering “smart” stimuli-responsive systems for targeted drug release in the TME, and constructing multi-targeting platforms. A concerted interdisciplinary effort is paramount to bridge the gap between bench and bedside. In conclusion, LF, particularly in its nano-engineered forms, represents a highly promising and versatile agent in the oncological arsenal, holding immense potential for precise and effective cancer therapy.

Cancer remains a leading cause of global mortality, necessitating the development of advanced therapeutic strategies with enhanced efficacy and reduced systemic toxicity. Among promising bioactive agents, lactoferrin (LF)—a multifunctional iron-binding glycoprotein abundantly found in mammalian milk and exocrine secretions—has garnered significant interest for its potent and multifaceted anti-cancer properties. This review provides a comprehensive analysis of the current understanding of LF’s role in oncology, encompassing its structural biology, diverse mechanisms of action, and groundbreaking advancements in its application through nano-engineering. LF exerts anti-tumor effects through multiple pathways, including extracellular action, intracellular action, and immune regulation. It demonstrates a remarkable affinity for cancer cell membranes, binding to overexpressed anionic components such as glycosaminoglycans and sialic acids, as well as to specific receptors including the low-density lipoprotein receptor-related protein-1 (LRP-1). This selective binding facilitates targeted uptake. Upon internalization, LF orchestrates a direct assault by inducing cell-cycle arrest in phases such as G0/G1 or S phase through the modulation of key regulators including cyclins, CDKs, and p53. Furthermore, it promotes programmed cell death via apoptotic pathways, involving caspase activation and downregulation of anti-apoptotic proteins such as survivin. A more recently elucidated mechanism is the induction of ferroptosis, an iron-dependent form of cell death characterized by overwhelming lipid peroxidation. Beyond direct cytotoxicity, LF acts as a potent immunomodulator. It enhances natural killer (NK) cell activity, modulates T-lymphocyte populations, and crucially reprograms tumor-associated macrophages (TAMs) from a pro-tumor M2 state to an anti-tumor M1 state, thereby reversing the immunosuppressive tumor microenvironment (TME). The translation of LF’s potential has been significantly accelerated by nanotechnology. The inherent biocompatibility and natural tumor-targeting capabilities of LF make it an ideal platform for sophisticated drug-delivery systems. This review details various fabrication strategies for LF-based nanoparticles (NPs), including self-assembly, sol-in-oil emulsion, and electrostatic nanocomplexes, among others. Research demonstrates that nano-formulations not only protect LF from degradation but also enhance its bioactivity and anti-cancer potency. More importantly, LF NPs serve as versatile carriers for a wide array of therapeutic agents, including conventional chemotherapeutics, natural compounds, and imaging agents. These engineered systems enable synergistic therapy and facilitate site-specific delivery. Notably, the ability of LF to bind to receptors on the blood-brain barrier (BBB) has been leveraged to develop nano-systems for glioblastoma treatment. Other innovative designs utilize LF to modulate the TME—for instance, by alleviating tumor hypoxia to sensitize cells to radiotherapy and chemotherapy. Despite compelling pre-clinical evidence, the clinical translation of LF and its nano-formulations remains nascent. While early-phase trials have established a favorable safety profile for recombinant human LF, larger Phase III studies have yielded mixed results, underscoring the complexity of its action in humans. Key challenges include enhancing drug targeting, optimizing loading efficiency, ensuring batch-to-batch reproducibility, and achieving deep tumor penetration. Future research must focus on the rational design of next-generation LF-NPs. This entails developing standardized manufacturing protocols, engineering “smart” stimuli-responsive systems for targeted drug release in the TME, and constructing multi-targeting platforms. A concerted interdisciplinary effort is paramount to bridge the gap between bench and bedside. In conclusion, LF, particularly in its nano-engineered forms, represents a highly promising and versatile agent in the oncological arsenal, holding immense potential for precise and effective cancer therapy.

In order to explore effective ways to reduce non-suicidal self-injury (NSSI) among female adolescents, a total of 45 female adolescent patients with NSSI in West China Hospital of Sichuan University and Guizhou Second Provincial People's Hospital from June 2021 to June 2024 were selected randomly that divided into groups A, B and C, with 15 cases in each group. Group A was treated with repeated transcranial magnetic stimulation (rTMS) and bipolar depression triple therapy, and group B was treated with bipolar depression triple therapy to compare the effectiveness and safety. Group C received bipolar depression triple therapy combined with sham stimulation which only produced stimulating sounds but no stimulating magnetic field as a control in the study. After treatment, the Hamilton Anxiety Score (HAMA), Hamilton Depression Score (HAMD) and Nurses' Global Assessment of Suicide Risk (NGASR) in group A were significantly lower than those in group B and C ( P < 0.01). rTMS combined with bipolar depression triple therapy has a definite effect on reducing NSSI in female adolescents, which can reduce the incidence rate of short-term NSSI behavior in patients.
Humans ; Female ; Adolescent ; Self-Injurious Behavior/prevention & control* ; Transcranial Magnetic Stimulation/methods* ; Bipolar Disorder/therapy* ; Combined Modality Therapy ; Treatment Outcome

Loss of protein homeostasis is a hallmark of cellular senescence, and ribosome pausing plays a crucial role in the collapse of proteostasis. However, our understanding of ribosome pausing in senescent cells remains limited. In this study, we utilized ribosome profiling and G-quadruplex RNA immunoprecipitation sequencing techniques to explore the impact of RNA G-quadruplex (rG4) on the translation efficiency in senescent cells. Our results revealed a reduction in the translation efficiency of rG4-rich genes in senescent cells and demonstrated that rG4 structures within coding sequence can impede translation both in vivo and in vitro. Moreover, we observed a significant increase in the abundance of rG4 structures in senescent cells, and the stabilization of the rG4 structures further exacerbated cellular senescence. Mechanistically, the RNA helicase DHX9 functions as a key regulator of rG4 abundance, and its reduced expression in senescent cells contributing to increased ribosome pausing. Additionally, we also observed an increased abundance of rG4, an imbalance in protein homeostasis, and reduced DHX9 expression in aged mice. In summary, our findings reveal a novel biological role for rG4 and DHX9 in the regulation of translation and proteostasis, which may have implications for delaying cellular senescence and the aging process.
G-Quadruplexes ; Cellular Senescence ; Ribosomes/genetics* ; Humans ; Animals ; Mice ; DEAD-box RNA Helicases/genetics* ; Protein Biosynthesis ; RNA/chemistry* ; Neoplasm Proteins

Objective To investigate the expression of NOP2/Sun RNA methyltransferase family member 2(NSUN2)and protein arginine methyltransferase 5(PRMT5)in retinoblastoma(Rb)tissue and their correlation with the survival prognosis of Rb patients.Methods From February 2019 to February 2021,84 patients with Rb(Rb group)were selected from Beijing Anzhen Hospital Affiliated to Capital Medical University Nanchong Hospital,and 50 normal retinal tissues were used as control group.Real-time fluorescence quantitative PCR(qRT-PCR)was used to detect the levels of NSUN2 mRNA and PRMT5 mRNA in retinal tissues.Kaplan-Meier curve was used to analyze the effect of NSUN2 mRNA and PRMT5 mRNA on the prognosis of Rb patients.COX regression analysis was used to analyze the factors affecting the prognosis of Rb.Results The expression of NSUN2 mRNA(3.11±0.42)and PRMT5 mRNA(2.84±0.39)in Rb cancer tissues were higher than that in the control group(0.80±0.23,0.76±0.20),and the differences were statistically significant(t=35.935,35.033,all P<0.001).The expression of NSUN2 mRNA and PRMT5 mRNA in Rb cancer tissues with tumor diameter≥20mm,undifferentiated and ⅡRC stage D～E were higher than that in tumor diameter<20mm,differentiated tissues and ⅡRC stage A～C cancer tissues,and the differences were statistically significant(t=18.297,141.770,16.693;18.663,139.144,39.947,均P<0.001).The 3-year progression-free survival rate in the high expression group of NSUN2 mRNA was lower than that in the low expression group(60.00%vs 88.64%).The 3-year progression-free survival rate in the high expression group of PRMT5 mRNA was lower than that in the low expression group(56.10%vs 93.02%)(Log rank χ2=13.440,19.501,all P<0.001).Undifferentiated type,ⅡRC stage D-E stage,NSUN2 mRNA high,PRMT5 mRNA high were risk factors affecting the prognosis of Rb patients(Waldχ2=5.923～7.161,all P<0.001).Conclusion The expression of NSUN2 mRNA and PRMT5 mRNA in Rb tissues is increased,which is related to the maximum diameter of tumor,pathological classification and ⅡRC stage,and can be used as a tumor marker to evaluate the survival prognosis of Rb.

Objective:To analyze the predictive value of platelet parameters and prognostic nutritional index(PNI)in activity of ulcerative colitis(UC).Methods:This retrospective study included 158 UC patients from the Department of anorectal medicine of our hospital from January 2020 to June 2022.Mayo total score and Truelove-Witts score were used to evaluate clinical activity.Patients with Mayo score>2 was defined as clinically active UC,and patients with Mayo score≤2 was defined as clinically remission.The histological activity was evaluated by Riley score.Evaluation of endoscopic activity of UC patients by Mayo endoscopic score.Results:Among the 158 patients included in the analysis,111 were in remission phase and the remaining 47 were in clinical active phase.Compared with the remission group,the levels of albumin,lymphocytes,and PNI in the clinically active group reduced significantly(P<0.05),while the levels of CRP,fecal calprotectin,neutrophils,white blood cells,NPR,and NLR increased significantly(P<0.05).Fecal calprotectin,CRP,NPR,NLR were significantly positively correlated with Mayo endoscopic score,Riley score,Truelove Witts score,and Mayo total score(P<0.05),while PNI was significantly negatively correlated with Mayo endoscopic score,Truelove Witts score,and Mayo total score(P<0.05).The ROC curve analysis results showed that fecal calprotectin and NPR had similar performance in predicting clinical activity in UC patients(AUC=0.868,0.850),followed by PNI(AUC=0.770)and NLR(AUC=0.756);Fecal calprotectin had the highest performance in predicting endoscopic activity in UC patients(AUC=0.840),followed by NPR(AUC=0.731),NLR(AUC=0.677),and PNI(AUC=0.671).Conclusions:NPR has demonstrated sufficient diagnostic utility in identifying UC patients with clinical and endoscopic activity,and is comparable in diagnostic performance to the fecal biomarker calprotectin.However,PNI has lower performance as a monitoring tool for UC disease activity.

Objective To investigate the expression of NOP2/Sun RNA methyltransferase family member 2(NSUN2)and protein arginine methyltransferase 5(PRMT5)in retinoblastoma(Rb)tissue and their correlation with the survival prognosis of Rb patients.Methods From February 2019 to February 2021,84 patients with Rb(Rb group)were selected from Beijing Anzhen Hospital Affiliated to Capital Medical University Nanchong Hospital,and 50 normal retinal tissues were used as control group.Real-time fluorescence quantitative PCR(qRT-PCR)was used to detect the levels of NSUN2 mRNA and PRMT5 mRNA in retinal tissues.Kaplan-Meier curve was used to analyze the effect of NSUN2 mRNA and PRMT5 mRNA on the prognosis of Rb patients.COX regression analysis was used to analyze the factors affecting the prognosis of Rb.Results The expression of NSUN2 mRNA(3.11±0.42)and PRMT5 mRNA(2.84±0.39)in Rb cancer tissues were higher than that in the control group(0.80±0.23,0.76±0.20),and the differences were statistically significant(t=35.935,35.033,all P<0.001).The expression of NSUN2 mRNA and PRMT5 mRNA in Rb cancer tissues with tumor diameter≥20mm,undifferentiated and ⅡRC stage D～E were higher than that in tumor diameter<20mm,differentiated tissues and ⅡRC stage A～C cancer tissues,and the differences were statistically significant(t=18.297,141.770,16.693;18.663,139.144,39.947,均P<0.001).The 3-year progression-free survival rate in the high expression group of NSUN2 mRNA was lower than that in the low expression group(60.00%vs 88.64%).The 3-year progression-free survival rate in the high expression group of PRMT5 mRNA was lower than that in the low expression group(56.10%vs 93.02%)(Log rank χ2=13.440,19.501,all P<0.001).Undifferentiated type,ⅡRC stage D-E stage,NSUN2 mRNA high,PRMT5 mRNA high were risk factors affecting the prognosis of Rb patients(Waldχ2=5.923～7.161,all P<0.001).Conclusion The expression of NSUN2 mRNA and PRMT5 mRNA in Rb tissues is increased,which is related to the maximum diameter of tumor,pathological classification and ⅡRC stage,and can be used as a tumor marker to evaluate the survival prognosis of Rb.

Objective:To analyze the immune reconstitution after BTKi treatment in patients with chronic lymphocytic leukemia(CLL).Methods:The clinical and laboratorial data of 59 CLL patients admitted from January 2017 to March 2022 in Fujian Medical University Union Hospital were collected and analyzed retrospectively.Results:The median age of 59 CLL patients was 60.5(36-78).After one year of BTKi treatment,the CLL clones(CD5+/CD19+)of 51 cases(86.4％)were significantly reduced,in which the number of cloned-B cells decreased significantly from(46±6.1)× 109/L to(2.3±0.4)× 109/L(P=0.0013).But there was no significant change in the number of non-cloned B cells(CD19+minus CD5+/CD19+).After BTKi treatment,IgA increased significantly from(0.75±0.09)g/L to(1.31±0.1)g/L(P＜0.001),while IgG and IgM decreased from(8.1±0.2)g/L and(0.52±0.6)g/L to(7.1±0.1)g/L and(0.47±0.1)g/L,respectively(P＜0.001,P=0.002).BTKi treatment resulted in a significant change in T cell subpopulation of CLL patients,which manifested as both a decrease in total number of T cells from(2.1±0.1)× 109/L to(1.6±0.4)× 109/L and NK/T cells from(0.11±0.1)× 109/L to(0.07±0.01)× 109/L(P=0.042,P=0.038),both an increase in number of CD4+cells from(0.15±6.1)× 109/L to(0.19±0.4)× 109/L and CD8+cells from(0.27±0.01)× 109/L to(0.41±0.08)× 109/L(both P＜0.001).BTKi treatment also up-regulated the expression of interleukin(IL)-2 while down-regulated IL-4 and interferon(IFN)-γ.However,the expression of IL-6,IL-10,and tumor necrosis factor(TNF)-α did not change significantly.BTKi treatment could also restored the diversity of TCR and BCR in CLL patients,especially obviously in those patients with complete remission(CR)than those with partial remission(PR).Before and after BTKi treatment,Shannon index of TCR in patients with CR was 0.02±0.008 and 0.14±0.001(P＜0.001),while in patients with PR was 0.01±0.03 and 0.05±0.02(P＞0.05),respectively.Shannon index of BCR in patients with CR was 0.19±0.003 and 0.33±0.15(P＜0.001),while in patients with PR was 0.15±0.009 and 0.23±0.18(P＜0.05),respectively.Conclusions:BTKi treatment can shrink the clone size in CLL patients,promote the expression of IgA,increase the number of functional T cells,and regulate the secretion of cytokines such as IL-2,IL-4,and IFN-γ.BTKi also promote the recovery of diversity of TCR and BCR.BTKi treatment contributes to the reconstitution of immune function in CLL patients.

Objective To explore the effect of collaborative mode of adopting infection prevention and control(IPC)and antimicrobial stewardship(AMS)by medical institutions on reducing bacterial resistance.Methods Healthcare-associated infection(HAI)management and antimicrobial-related indicators,as well as multidrug-resis-tant organism(MDRO)detection rates of all hospitalized patients in a hospital from January 1,2015 to December 31,2022 were collected.The effectiveness of collaborative mode of IPC and AMS was evaluated.Results Compared with 2015-2016,the incidence of MDRO HAI in 2021-2022 decreased from 0.22％to 0.16％(P＜0.05),anti-microbial use density in hospitalized patients decreased from 48.48 to 42.17,antimicrobial use rate decreased from 49.45％to 45.21％(P＜0.05).The use rate of prophylactic antimicrobial agents in class Ⅰ incision surgery de-creased from 48.62％to 33.13％(P＜0.05).Compared with 2017-2018,pathogen detection rate before antimi-crobial therapy increased from 60.73％to 72.18％in 2021-2022(P＜0.05).Compared with 2015-2016,except the detection rate of vancomycin-resistant Enterococcus faecalis slightly increased in 2021-2022,detection rates of other common MDRO decreased,especially methicillin-resistant Staphylococcus aureus,carbapenem-resistant Acine-tobacter baumannii,carbapenem-resistant Pseudomonas aeruginosa,broad-spectrum β-lactamase-producing Kleb-siella pneumoniae,broad-spectrum β-lactamase-producing Escherichia coli and fluoroquinolone-resistant Escherichia coli,differences were all statistically significant(all P＜0.05).Conclusion The collaborative mode of IPC and AMS can effectively promote the rational use of antimicrobial agents,decrease the occurrence and transmission of MDRO,and decrease bacterial resistance.

Objective Based on U.S.Food and Drug Administration Adverse Event Reporting System(FAERS)database,the signal mining of tizanidine adverse drug events(ADEs)was conducted to explore the occurrence characteristics of ADE,hoping to provide references for the safe clinical application of tizanidine.Methods The reporting odds ratio(ROR)and medicines and healthcare products regulatory agency methods(MHRA)were used to analyse the ADE of tizanidine using FAERS registration data from the first quarter of 2004 to the second quarter of 2022.After valid signals were obtained,the MedDRA was used for translation and system organ classification.Results A total of 7 135 reports of tizanidine ADE were obtained,including 1 732 patients,1 304 ADE types were involved.According to the results of 2 ADE signal mining methods,at the preferred term(PT)level,177 signals were detected.There were 32 PT signals not included in the drug instructions,including potassium wasting nephropathy,cardio-respiratory arrest,and foetal growth restriction etc.In 1 732 patients,the number of ADE cases of female was 2.37 times that in male(1 057 vs.446),and the age group between 40 and 64 accounted for a large proportion(36.03％).The highest proportion(32.79％)reported by consumers.The system organ class involved mainly included various neurological diseases and psychosis.The median time to onset of tizanidine-related ADEs was 75 d(interquartile range:28-223 d),but it was necessary to be vigilant that ADE may still occur 1 year after starting the drug(13.38％).Conclusion This study aims to suggest that clinical application of tizanidin-related ADE should be paid full attention to the occurrence of ADE such as potassium-wasting nephropathy and suicidally completed,as well as key populations such as women and patients of 40-64 years old.