p21 (encoded by the CDKN1A gene) is a critical cell cycle regulatory protein endowed with versatile biological functions. In various sex hormone-related cancers, p21 exhibits a paradoxical dual role, capable of both inhibiting tumorigenesis and promoting cancer progression, exerting dual, often opposing, effects on cellular fate that are dictated by the specific context. The clinical targeting of p21 remains elusive, largely due to its functionally pleiotropic and context-dependent nature within intricate regulatory networks. During the initial, hormone-dependent phase of cancers like breast and prostate cancer, p21 expression and activity are largely governed by the transcriptional programs of estrogen or androgen receptor signaling. This hormonal regulation contributes to the control of tumor cell proliferation and underpins the initial efficacy of endocrine therapies. In contrast, as these diseases advance to late stages or evolve into non-hormone-dependent subtypes—exemplified by castration-resistant prostate cancer (CRPC) and specific forms of triple-negative breast cancer (TNBC)—these conventional hormonal control mechanisms often become dysfunctional or are entirely bypassed. This fundamental transition creates a critical therapeutic void, highlighting the urgent need to identify and exploit alternative molecular pathways to effectively target p21’s function. Promising strategies may include the precise modulation of its upstream transcriptional regulators, downstream effector proteins, or the intersecting parallel signaling networks that critically influence its activity. This review provides a systematic synthesis of the intricate and interconnected mechanisms that underpin the dual effects of p21 in sex hormone-related tumors. These mechanisms are categorized into three core, interrelated functional domains. (1) cell cycle regulation: p21 executes its canonical tumor-suppressive role by binding to and inhibiting cyclin-dependent kinases (CDKs) and by directly interacting with proliferating cell nuclear antigen (PCNA), thereby inducing cell cycle arrest, predominantly at the G1/S checkpoint; (2) apoptosis modulation: p21 exerts a highly context-dependent influence on programmed cell death, functioning either as a pro-apoptotic agent under severe genotoxic stress or as a pro-survival factor by inhibiting apoptosis through interactions with proteins like Bcl-2; (3) hormonal and signaling crosstalk: p21 is an integral node within broader cellular networks, engaging in direct physical interactions with hormone receptors(e.g., AR, ER) and participating in complex feedback loops with key oncogenic pathways, including PI3K/AKT, MAPK/ERK, and p53. Critically, the role of p21 is not static but highly dynamic. It can undergo a functional switch from tumor-suppressive to tumor-promoting in response to therapeutic pressures, metabolic alterations, or evolving tumor microenvironment cues. These adaptive shifts are frequently implicated in the development of therapy resistance and disease recurrence, particularly in advanced, hormone-resistant cancers. By synthesizing these insights, this review aims to establish a coherent theoretical framework to guide the future development of novel therapeutic strategies that target the p21 pathway. It underscores the necessity of moving beyond a simplistic, binary view of p21 and emphasizes the forthcoming challenges, such as the discovery of reliable biomarkers to predict its functional state and the rational design of context-specific pharmacological modulators to selectively harness its therapeutic potential.

ObjectiveTo clarify whether METTL14 mediates the core role of acupuncture at Neiguan (PC6) in promoting myelination and improving behavior in young autistic rats through gene intervention technology. MethodsThe ASD model was established by intraperitoneal injection of valproic acid (VPA) in pregnant rats. Male offspring were intracerebroventricularly injected with adenovirus-packaged METTL14 shRNA (sh-METTL14) or its control (sh-NC) on postnatal day 1, with a model group set as well. Subsequently, the juvenile rats were divided into model group, acupuncture group, acupuncture+sh-NC group, and acupuncture+sh-METTL14 group. The acupuncture group received acupuncture at Neiguan (PC6) from postnatal day 7, once daily for 21 consecutive days. Neurobehavioral changes were evaluated by behavioral tests; METTL14 knockdown efficiency and the expression of METTL14, METTL3, and PTEN were detected by quantitative real-time PCR (qRT-PCR) and Western blot (WB); PTEN m⁶A levels were measured by RNA immunoprecipitation-qPCR (RIP-qPCR); myelin ultrastructure, expression of myelin basic protein (MBP) and neurofascin 155 (NF155), and dendritic spine density were observed using transmission electron microscopy (TEM), enzyme-linked immunosorbent assay (ELISA), immunofluorescence, qRT-PCR, and primary neuron culture. ResultsBehaviorally, knockdown of METTL14 significantly counteracted the beneficial effects of acupuncture in improving self-grooming, open field exploration, three-chamber social interaction, and Morris water maze learning and memory (P<0.05, P<0.01). Compared with the acupuncture+sh-NC group, the acupuncture+sh-METTL14 group showed significantly decreased mRNA and protein expression of hippocampal METTL14 (P<0.01), and the upregulating effects of acupuncture on METTL3 and PTEN expression were reversed (P<0.01). Meanwhile, knockdown of METTL14 significantly inhibited the acupuncture-induced increase in PTEN m⁶A levels (P<0.01). Morphologically, knockdown of METTL14 attenuated the improvement of myelin structure by acupuncture, reversed the downregulation of MBP and upregulation of NF155 induced by acupuncture, and blocked the increase in dendritic spine density (P<0.05, P<0.01). ConclusionMETTL14 is a key molecule mediating the therapeutic effect of acupuncture at Neiguan. Acupuncture at Neiguan upregulates METTL14, thereby enhancing m⁶A methylation modification of PTEN mRNA to stabilize its expression, ultimately promoting myelin development and improving behavioral symptoms in ASD juvenile rats. This preliminarily reveals the modern biological connotation of “opening Xuanfu and dredging myelin”.

ObjectiveTo clarify whether METTL14 mediates the core role of acupuncture at Neiguan (PC6) in promoting myelination and improving behavior in young autistic rats through gene intervention technology. MethodsThe ASD model was established by intraperitoneal injection of valproic acid (VPA) in pregnant rats. Male offspring were intracerebroventricularly injected with adenovirus-packaged METTL14 shRNA (sh-METTL14) or its control (sh-NC) on postnatal day 1, with a model group set as well. Subsequently, the juvenile rats were divided into model group, acupuncture group, acupuncture+sh-NC group, and acupuncture+sh-METTL14 group. The acupuncture group received acupuncture at Neiguan (PC6) from postnatal day 7, once daily for 21 consecutive days. Neurobehavioral changes were evaluated by behavioral tests; METTL14 knockdown efficiency and the expression of METTL14, METTL3, and PTEN were detected by quantitative real-time PCR (qRT-PCR) and Western blot (WB); PTEN m⁶A levels were measured by RNA immunoprecipitation-qPCR (RIP-qPCR); myelin ultrastructure, expression of myelin basic protein (MBP) and neurofascin 155 (NF155), and dendritic spine density were observed using transmission electron microscopy (TEM), enzyme-linked immunosorbent assay (ELISA), immunofluorescence, qRT-PCR, and primary neuron culture. ResultsBehaviorally, knockdown of METTL14 significantly counteracted the beneficial effects of acupuncture in improving self-grooming, open field exploration, three-chamber social interaction, and Morris water maze learning and memory (P<0.05, P<0.01). Compared with the acupuncture+sh-NC group, the acupuncture+sh-METTL14 group showed significantly decreased mRNA and protein expression of hippocampal METTL14 (P<0.01), and the upregulating effects of acupuncture on METTL3 and PTEN expression were reversed (P<0.01). Meanwhile, knockdown of METTL14 significantly inhibited the acupuncture-induced increase in PTEN m⁶A levels (P<0.01). Morphologically, knockdown of METTL14 attenuated the improvement of myelin structure by acupuncture, reversed the downregulation of MBP and upregulation of NF155 induced by acupuncture, and blocked the increase in dendritic spine density (P<0.05, P<0.01). ConclusionMETTL14 is a key molecule mediating the therapeutic effect of acupuncture at Neiguan. Acupuncture at Neiguan upregulates METTL14, thereby enhancing m⁶A methylation modification of PTEN mRNA to stabilize its expression, ultimately promoting myelin development and improving behavioral symptoms in ASD juvenile rats. This preliminarily reveals the modern biological connotation of “opening Xuanfu and dredging myelin”.

[Objective] To analyse and predict the tendencies of using erythrocyte blood in Changsha based on the autoregressive integrated moving average (ARIMA) model, long short-term memory (LSTM) and ARIMA-LSTM combination model, so as to provide reliable basis for designing a feasible and effective blood inventory management strategy. [Methods] The data of erythrocyte usage from hospitals in Changsha between January 2012 and December 2023 were collected, and ARIMA model, LSTM model and ARIMA-LSTM combination model were established. The actual erythrocyte consumption from January to May 2024 were used to assess and verify the prediction effect of the models. The extrapolation prediction accuracy of the models were tested using two evaluation indicators: mean absolute percentage error (MAPE) and root mean square error (RMSE), and then the prediction performance of the model was compared. [Results] The RMSE of LSTM model, optimal model ARIMA(1,1,1)(1,1,1)12 and ARIMA-LSTM combination model were respectively 5 206.66, 3 096.43 and 2 745.75, and the MAPE were 18.78%,11.54% and 9.76% respectively, which indicated that the ARIMA-LSTM combination model was more accurate than the ARIMA model and LSTM model, and the prediction results was basically consistent with the actual situation. [Conclusion] The ARIMA-LSTM model can better predict the clinical erythrocyte consumption in Changsha in the short term.

OBJECTIVE: To investigate the therapeutic effect of the short-penis treatment apparatus and wide-band infrared therapy apparatus on penile dysplasia (PDP) in children and establish objective parameters for assessing the severity of PDP. METHODS: This study included 252 children received in the Department of pediatric urology of the First Affiliated Hospital of Xinjiang Medical University from January to December 2023, 102 with PDP (the PDP group) and the other 150 with normal penile development (the control group), those of the former group treated with the short-penis therapeutic apparatus and wide-band infrared therapy apparatus. Before and after 30 days of treatment, we measured the flaccid penile length (FPL), stretched penile length (SPL) and penile diameters (PD) of the children, and defined the penile dysplasia index as the FPL/SPL and FPL/PD ratios. RESULTS: The penile parameters exhibited statistically significant differences between the PDP and control groups, (FPL:［1.97±0.72］cm vs ［3.25±0.51］ cm, P<0.01; SPL:［3.80±0.81］cm vs ［5.21±0.79］cm,P<0.01).The FPL remarkably increased in the PDP group after treatment(［1.97±0.72］cm vs ［2.90±1.20］ cm, P<0.01). Both FPL and SPL were notably shorter in the PDP cases than in the controls, with the cutoff values of 0.57 and 2.09, sensitivities of 80.7% and 95.3%, and specificities of 69.6% and 82.4% for FPL/SPL and FPL/PD, respectively. CONCLUSION The short-penis therapeutic apparatus and wide-band infrared therapy apparatus can promote the growth and development of the penis in children. The ratio of FPL/PD can serve as an objective indicator to effectively describe the severity of penile developmental abnormalities.
Humans ; Male ; Penis/abnormalities* ; Child ; Penile Diseases/therapy* ; Child, Preschool ; Infant

Objective To investigate the association of endometrial thickness(EMT)with obstetric and neonatal outcomes of monoparous pregnancy in fresh cleavage embryos transfer.Methods A total of 1 845 patients of monoparous pregnancy after fresh cleavage embryos transfer cycles from Jan 2016 to Mar 2022 at Shanghai First Maternity and Infant Hospital,Tongji Universtiy were analyzed retrospectively.Patients were categorized into three groups by EMT on transferation day:≤8 mm(group A),8-14 mm(group B)and≥14 mm(group C).The primary outcomes were preterm birth(PTB),birth weight and birth weight z-score,small-for-gestation age,large-for-gestation age,very low birth weight,low birth weight and macrosomia.The second outcomes were pregnancy and perinatal complications.The relationship between EMT and adverse neonatal outcomes was estimated by Logistic regression analysis.Results The rate of ectopic pregnancy was increased significantly in group A.No significant differences were found among the three groups in gestation age,birth weight,birth weight z-score,PTB,small for gestation age,large for gestation age,low birth weight,very low birth weight and macrosomia.Compared with group B,the odds of adverse neonatal outcomes did not show significant differences before and after adjustment in both group A and group C by Logistic regression analysis.Conclusion Thinner EMT in fresh cleavage embryos transfer is associated with higher rate of ectopic pregnancy,while it is not independently associated with adverse perinatal outcomes.

AIM:This study aims to investigate the mechanism by which Qingfei-Jiedu-Huatan Formula(QJHF)regulates autophagy in alveolar macrophages through mTOR in the treatment of severe pneumonia(SP)in rats.METHODS:Sixty SPF-grade male rats were randomly assigned to six groups:control,model,QJHF,moxifloxacin(MOX),rapamycin(RAPA),and QJHF+RAPA,with ten rats in each group.An SP rat model was established using Klebsiella pneumoniae.After seven days of treatment,changes in IL-33 and IFN-γ levels in bronchoalveolar lavage fluid(BALF)were measured using ELISA.Histopathological alterations in lung tissue were assessed via HE staining,and the autophagy of alveolar macrophages was detected using immunofluorescence co-localization methods.The expression levels of mTOR,beclin-1,and LC3 mRNA in lung tissue were analyzed using qPCR,while Western blot was employed to assess the protein levels of p-mTOR/mTOR,beclin-1,and LC3-II/LC3-I.RESULTS:Compared to the control group,the model group exhibited a deteriorated condition,characterized by alveolar wall rupture and thickening,significant inflammatory cell infiltration in the alveolar cavity,and extensive lung tissue damage(P<0.01).Elevated levels of IL-33 and IFN-γ in BALF were also observed(P<0.01),along with increased colocalization of CD68 and LC3 in immunofluorescence analy-sis.The mTOR mRNA expression in lung tissue decreased(P<0.01),while LC3 and beclin-1 mRNA expressions in-creased(P<0.01).Additionally,the protein expression ratio of p-mTOR/mTOR decreased(P<0.01),whereas LC3-II/LC3-I and beclin-1 protein levels increased(P<0.01).In comparison to the model group,significant improvements were noted after treatment with QJHF and MOX(P<0.01),while RAPA treatment led to a worsening of these indicators(P<0.05).A slight improvement was observed with the QJHF combined with RAPA intervention,though this was not statisti-cally significant.No significant differences were found between the MOX and QJHF groups.However,the QJHF+RAPA group displayed notable improvements in various indicators compared to the RAPA group(P<0.05).CONCLUSION:The QJHF can mitigate the inflammatory response associated with severe pneumonia,potentially by activating mTOR phos-phorylation activity,which in turn inhibits excessive autophagy in alveolar macrophages.

This study was aimed at developing an in vitro fluorescent substrate assay for the activity of leucyl aminopeptid-ase(LAP)from Echinococcus multilocularis and comparing it with the chemical chromogenic substrate enzyme activity assay.Through the establishment of reaction conditions for the fluorescent substrate-based in vitro enzyme activity assay,we com-pared the differences between the fluorescent substrate L-Leucine-7-amido-4-methylocoumarin(Leu-AMC)and the chemical chromogenic substrate L-Leucine-4-nitroanilide(Leu-pNA)through molecular docking,inhibition rates,and precision measures.Molecular docking revealed that the fluorescent substrate Leu-AMC had higher affinity for the protein than the chemical chromogenic substrate Leu-pNA.Through analysis of the effects of varying reaction conditions on fluorescence intensi-ty,we optimized the fluorescent substrate enzyme activity assay to demonstrate favorable performance at a reaction temperature of 37℃,a pH of 9.0,a protein concentration of 800 nmol/L,and a reaction duration of 60 minutes.Leu-AMC exhibited significant and distinct responses at a 5 μmol/L substrate concentration,under varying substrate conditions.The fluo-rescent substrate assay demonstrated more significant intergroup differences than the chemical chromogenic substrate assay when various inhibitors were added.This study established a fluorescence-based enzyme activity assay for leucyl aminopeptidase from Echinococcus multilocularis by using Leu-AMC as the substrate;this method demonstrated a more significant intergroup difference and sensitivity than the chemical chromogenic substrate assay.

Objective To explore the abnormal expression of the MT-ND family in pan-cancers and its prognostic value.Methods Transcriptome expression and clinical data of 33 cancers were downloaded from the TCGA database,thereby analyzing the expression differences of the MT-ND family in tissuesof different types of cancers and normal tissues.The prognostic role of the MT-ND family in pan-cancers was explored by univariate Cox regression analysis and Kaplan-Meier survival analysis.Results The expression of the MT-ND family was upregulated in the kidney chromophobe,acute myeloid leukemia and thymoma,and downregulated in the remaining tumors.The expression of the MT-ND family was associated with the overall survival rate of different types of cancers.In addition,the MT-ND family were significantly correlated with the immune invasion subtypes,and were correlated with stromal cell invasion and tumor cell stemness to varying degrees.The expression of MT-ND4 was downregulated in brain lower grade glioma,which was a protective factor for prognosis;while the expression of MT-ND4 in thymoma was upregulated,which was a risk factor for prognosis.Conclusion Pan-cancer analysis has confirmed that the MT-ND family can predict the tumor prognosis,which provides new ideas and strategies for the precision treatment and prognostic management of cancer.

Objective:To compare the efficacy of Ilizarov ring external fixation and unilateral rail external fixation in the treatment of infected bone defects following surgery for tibial fractures.Methods:A retrospective cohort study was conducted to analyze the clinical data of 50 patients with infected bone defects after surgery for tibial fractures, who were admitted to the 940th Hospital of the Joint Logistics Support Force of the PLA from August 2019 to November 2021, including 37 males and 13 females, aged 19-59 years [(42.2±8.8)years]. After debridement and osteotomy, 28 patients were treated with Ilizarov ring external fixation (Ilizarov group) and 22 with unilateral rail external fixation (unilateral fixation group). All the patients in the two groups had previously undergone internal fixation with plates or Kirschner wires for tibial fracture before bone transport. Bone transport started at one week for three stages after successful infection control and osteotomy and was conducted. The following parameters were compared between the two groups: frame-wearing time and healing index after bone transport, self-rating anxiety scale (SAS) grade at 6 months after bone transport, Paley score and Association for the Study and Application of the Method of Ilizarov (ASAMI) score at the last follow-up, Hospital for Special Surgery (HSS) knee score and Baird-Jackson ankle score on admission, after external fixator removal and at the last follow-up, and incidence of postoperative complications.Results:All the patients were followed up for 28-36 months [(32.5±1.6)months]. There were no significant differences in frame-wearing time or healing index between the two groups after bone transport ( P>0.05). At 6 months after bone transport, the SAS grade in the unilateral fixation group (13 patients with mild anxiety, 8 with moderate anxiety, and 1 with severe anxiety) was better than that in the Ilizarov group (6 patients with mild anxiety, 19 with moderate anxiety, 3 with severe anxiety) ( P<0.01). No significant differences were found in the Paley score or ASAMI score between the two groups at the last follow-up ( P>0.05). There were no significant differences in HSS knee score or Baird-Jackson ankle score between the two groups on admission, after external fixator removal or at the last follow-up ( P>0.05). No significant differences were observed in the incidence of pin tract infection, poor healing, infection in the bone elongation area, or re-fracture between the two groups ( P>0.05). The incidence of postoperative axial deviation was 0 in the Ilizarov group, lower than 18% in the unilateral fixation group (4/22) ( P<0.05). Conclusion:Although Ilizarov ring external fixation and unilateral rail external fixation demonstrate comparable efficacy in the treatment of infected bone defects after surgery for tibial fractures, the former provides superior mechanical stability and postoperative axial deviation correction, while the latter offers advantages in reducing psychological burden and enhancing treatment tolerance.