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”.

Purpose: To characterize the patterns of demographic data, dermatologic diagnosis, and disposition regarding pediatric dermatological presentations in an emergency department (ED) at Armadale Health Service, a secondary outer metropolitan hospital in Perth, Western Australia. Methods: Retrospective cross-sectional study auditing pediatric dermatological presentations to the ED from December 2022 through November 2023. We analyzed the age group, sex, dermatologic diagnosis, Australasian Triage Scale, ED length of stay, and disposition. The age group comprised infants, preschoolers, schoolers, and adolescents. The diagnosis included anaphylaxis and angioneurotic edema (AAE), allergy-related and urticarial dermatitis (AUD), eczema and other dermatitis (EOD), infective dermatoses, and not elsewhere classified. Results: Of the 540 pediatric patients who presented to the ED with a dermatological complaint, 44.4% were girls with a median age of 4.5 years (interquartile range, 1.5-9.3) and a hospitalization rate of 7.6%. The dermatologic diagnoses consisted of AUD (34.3%), infective dermatoses (29.3%), EOD (23.3%), AAE (8.5%), and not elsewhere classified (4.6%). Most patients were triaged as an Australasian Triage Scale category 3-4, with a median ED length of stay of 2.3 hours (1.5-3.5 hours). Pairwise comparisons showed differences in the diagnoses between infants and preschoolers and between schoolers and adolescents for EOD and infective dermatoses (P < 0.001). The hospitalized patients showed a higher proportion of AAE, EOD, and infective dermatoses than those discharged (P < 0.001). Patients with AUD were hospitalized less (odds ratio, 0.06; 95% confidence interval, 0.12-0.30; compared with AAE). No dermatological emergencies, such as Stevens-Johnson syndrome, were identified. Conclusion Our findings underscore regional differences and support global efforts to reduce non-life-threatening pediatric dermatological presentations to the ED. This study may contribute to the ongoing discourse on effectively managing such presentations in EDs.

Background: s/Aims: Sarcomatoid hepatocellular carcinoma (HCC) is a rare histological subtype of HCC characterized by extremely poor prognosis; however, its molecular characterization has not been elucidated. Methods: In this study, we conducted an integrated multiomics study of whole-exome sequencing, RNA-seq, spatial transcriptome, and immunohistochemical analyses of 28 paired sarcomatoid tumor components and conventional HCC components from 10 patients with sarcomatoid HCC, in order to identify frequently altered genes, infer the tumor subclonal architectures, track the genomic evolution, and delineate the transcriptional characteristics of sarcomatoid HCCs. Results: Our results showed that the sarcomatoid HCCs had poor prognosis. The sarcomatoid tumor components and the conventional HCC components were derived from common ancestors, mostly accessing similar mutational processes. Clonal phylogenies demonstrated branched tumor evolution during sarcomatoid HCC development and progression. TP53 mutation commonly occurred at tumor initiation, whereas ARID2 mutation often occurred later. Transcriptome analyses revealed the epithelial–mesenchymal transition (EMT) and hypoxic phenotype in sarcomatoid tumor components, which were confirmed by immunohistochemical staining. Moreover, we identified ARID2 mutations in 70% (7/10) of patients with sarcomatoid HCC but only 1–5% of patients with non-sarcomatoid HCC. Biofunctional investigations revealed that inactivating mutation of ARID2 contributes to HCC growth and metastasis and induces EMT in a hypoxic microenvironment. Conclusions We offer a comprehensive description of the molecular basis for sarcomatoid HCC, and identify genomic alteration (ARID2 mutation) together with the tumor microenvironment (hypoxic microenvironment), that may contribute to the formation of the sarcomatoid tumor component through EMT, leading to sarcomatoid HCC development and progression.

Objective To explore the application value of wide awake local anesthesia no tourniquet(WALANT)technique in outpatient surgery for locking of metacarpophalangeal joint with extension lag.Methods The clinical data of 6 patients with locking of meta-carpophalangeal joint with extension lag in Danyang People's Hospital from January 2019 to October 2023 were retrospectively analyzed.The patients were received outpatient surgery under the WALLANT technique for release,and lidocaine mixed solution containing 1∶100 000 epinephrine was injected into the proximal midpoint of the volar projection of the metacarpophalangeal joint.The joint was exposed with a volar or dorsal finger web incision to determine the unrestricted structure,and the collateral ligament and paralateral collateral ligament with high tension were cut off.The intraoperative blood loss,postoperative incision healing and complications were recorded.Visual analogue scale(VAS)was used to evaluate the intraoperative pain,and the range of motion of metacarpophalangeal joint and total active movement(TAM)of finger joint were observed during postoperative follow-up.Results The incision of patients were healed successfully in the first phase after surgery,without wound necrosis.The anesthesia effects of patients were all satisfied and the operation was successfully completed.The VAS score was less than 3 points and there was only a small amount of bleeding during the operation.The recovery of joint flexion and extension movements could be observed during the operation,and the TAM score after the operation was 20 points.No significant change was found on the range of motion of metacarpophalangeal joint or TAM of finger joint between the injured finger and the corresponding healthy finger(P>0.05).Conclusion WALANT technique for locking of metacarpophalangeal joint with extension lag surgery has good anesthesia effect,less bleeding in the incision,and clear vision of the surgery.It can avoid vascular and nerve injuries,observe the recovery of joint activities during the operation and relieve pain of patients,which is conducive to outpatient surgery and saving medical and social resources at the same time.

Aim To investigate the effect of dihydro-myricetin(DMY)on Ang Ⅱ-induced cardiac hypertro-phy in mice and the underlying mechanisms.Methods Fifty mice were randomly divided into control group,Ang Ⅱ group,Ang Ⅱ+catopril 12.0 mg·kg-1·d-1 group,AngⅡ+DMY 100 mg·kg-1·d-1 group,and Ang Ⅱ+DMY 200 mg·kg-1·d-1 group,with 10 mice in each group.The control mice were given saline by gavage,the drug intervention group was given DMY,and the positive drug group was given captopril;the mice in all groups except the control group were in-jected subcutaneously with Ang Ⅱ 1.0mg·kg-1·d-1.After four weeks,heart weight/body weight(HW/BW)and left ventricular weight/body weight(LVW/BW)ratios were calculated.The mRNA ex-pression of the fetal genes atrial natriuretic factor(ANF),brain natriuretic peptide(BNP),β-myosin heavy chain(β-MHC),adenosine triphosphate 5β-subunit(ATP 5β)and uncoupling protein 2(UCP2)were monitored,and the morphological changes of car-diac tissue were observed.Secondly,the creatine ki-nase isoenzyme(CK-MB),lactate dehydrogenase(LDH),free fatty acids(FFA)and lactic acid in ser-um were investigated.Lastly,the expression of AMP-activated proteinkinase(AMPK),peroxisome prolifer-ator-activated receptor alpha(PPAR-α)and T-cell nu-clear factor cytoplasmic 4(NFATc4)protein expres-sion were also detected.The Ang Ⅱ-induced H9C2 cardiomyocyte hypertrophy model was established and treated with the AMPK inhibitor compound C.The mRNA of ANF,BNP,β-MHC and the protein expres-sion of AMPK/PPAR-α were analyzed.Results DMY intervention significantly reduced HW/BW and LVW/BW in mice,fetal genes ANF,BNP,β-MHC and UCP2 mRNA expression decreased,whereas ATP 5 β mRNA increased,and the degree of hypertrophy of cardiomyocytes was alleviated.In addition,the serum levels of CK-MB,LDH,FFA and lactic acid were re-duced in DMY treated groups.Finally,DMY upregu-lated the protein expression of P-AMPK,AMPK and PPAR-α,and downregulated protein expression of NFATc4.In the Ang Ⅱ-induced cardiomyocyte hyper-trophy model,DMY pretreatment reduced the mRNA expression of fetal genes(ANF,BNP,β-MHC).However,when AMPK was inhibited by compound C,the expression of these fetal genes rebounded,accom-panied by decreased protein levels of AMPK and PPAR-α.Conclusions DMY can improve Ang Ⅱ-in-duced myocardial hypertrophy in mice by ameliorating disorders of glycolipid metabolism and increasing ener-gy supply to cardiomyocytes,and its mechanism is re-lated to the activation of the AMPK/PPAR-α pathway and the inhibition of NFATc4 expression.

Objective To analyse the clinical efficacy and safety of acupuncture combined with intermittent catheterisation in treating postoperative urinary retention after radical surgery for cervical cancer,and provide reference for the clinical treatment of postoperative urinary retention.Methods A retrospective analysis was conducted based on the clinical data of patients who underwent radical hysterectomy for cervical cancer at Obstetrics and Gynecology Hospital,Fudan University,from Sept 2019 to Dec 2021 and subsequently developed urinary retention.The patients were treated with a combination of acupuncture and intermittent catheterization.We observed residual urine volume,duration of acupuncture treatment,and urinary tract infection status to evaluate the effectiveness and safety of the acupuncture combined with intermittent catheterization regimen.We examined the relationship between treatment duration and various factors such as age,pathological type,surgical-pathological staging,surgical method,pre-treatment catheter indwelling time,pre-treatment residual urine volume,presence or absence of postoperative radiotherapy and chemotherapy,pre-existing urinary tract infection,and whether ureteral stenting was performed,in order to analyze the factors affecting the treatment duration.Results A total of 156 patients were reviewed.After treatment,132 cases had a post-treatment residual urine volume<100 mL,7 cases had a volume of 100-200 mL,and 15 cases had a volume>200 mL.Two cases still had great difficulty in urination after treatment,resulting in an overall effectiveness rate of 89.1%.No significant adverse events occurred in the patients.The treatment duration ranged from 2 to 17 days,with an average treatment time of 6.2 days.The treatment duration was a correlated with the preoperative indwelling catheter duration,residual urine volume and postoperative radiotherapy.Conclusion Acupuncture combined with intermittent catheterisation in treating urinary retention after radical surgery for cervical cancer has good efficacy,short treatment time and no obvious adverse effects,and can be an option for treating postoperative urinary retention.

Objective:Based on outpatient and emergency visit data,this study employs a staged VaDE model to uncover the heterogeneity structure of residents'healthcare-seeking behaviors and reveal cross-district mobility patterns.Methods:Outpatient and emergency visit records of permanent residents in District A,Shanghai,in 2024 were used.Each individual visit served as the analytical unit.A staged VaDE approach was applied for nonlinear dimensionality reduction and clustering,followed by feature analysis with cross-district visit rates.Results:The proposed model outperformed K-Means and VAE+K-Means in clustering performance,identifying seven typical healthcare-seeking patterns with significant differences in cross-district rates,demographic characteristics,care structures,and disease profiles.Cluster 1 comprised elderly patients with severe conditions and high cross-district rates;Cluster 2,young and middle-aged cross-district commuters;Cluster 3,mild-case or maternity-oriented visits;Cluster 4,infrequent visits by middle-aged and elderly patients;and Clusters 5～7,local chronic disease or low-burden visits.Conclusion:The staged VaDE model demonstrates strong capability in characterizing behavioral heterogeneity and identifying key cross-district mobility types,providing evidence for refined healthcare service management and regional coordination.

Since 1973,the World Symposium on Pulmonary Hypertension(WSPH)has served as a pivotal platform for the advancing research in pulmonary hypertension(PH).At the 6th WSPH in 2018,the WSPH expert group refined the definitions related to cardiopulmonary physiology and right ventricular(RV)failure,thereby underscoring the critical role of RV dysfunction in the progression of PH.With ongoing advances in the field,RV failure associated with PH has received increasing attention and is now recognized as an important determinant of the prognosis of PH.The 7th WSPH,held in Barcelona,Spain,in 2024,presented the latest perspectives on the RV pathophysiology and its interaction with the pulmonary vasculature.The symposium emphasized new insights into the pathology of RV failure,RV phenotypes across different PH subgroups,and progress in therapeutic approaches targeting RV dysfunction.Additionally,the WSPH expert group delineated prospective research directions and identified unresolved issues.This article will review the RV function-related updates from the 7th WSPH and summarize recent findings,providing a systematic review of the evolution and breakthroughs in RV function research within the context of PH.