BACKGROUND: Hypertension is associated with an increased risk of calcific aortic valve stenosis (CAVS). However, the directionality of causation between blood pressure traits and aortic stenosis is unclear, as is the benefit of antihypertensive drugs for CAVS. METHODS: Using genome-wide association studies (GWAS) summary statistics, we performed bidirectional two-sample univariable mendelian randomization (UVMR) to assess the causal associations of systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure (PP) with CAVS. Multivariable mendelian randomization (MVMR) was conducted to evaluate the direct effect of hypertension on CAVS, adjusting for confounders. Drug target mendelian randomization (MR) and summary-level MR (SMR) were used to estimate the effects of 12 classes of antihypertensive drugs and their target genes on CAVS risk. Inverse variance weighting was the primary MR method, with sensitivity analyses to validate results. RESULTS: UVMR showed SBP, DBP, and PP have causal effects on CAVS, with no significant reverse causality. MVMR confirmed the causality between hypertension and CAVS after adjusting for confounders. Drug-target MR analyses indicated that calcium channel blockers (CCBs), loop diuretics, and thiazide diuretics via SBP lowering exerted protective effects on CAVS risk. SMR analysis showed that the CCBs target gene CACNA2D2 and ARBs target gene AGTR1 were positively associated with CAVS risk, while diuretics target genes SLC12A5 and SLC12A1 were negatively associated with aortic stenosis risk. CONCLUSIONS Hypertension has a causal relationship with CAVS. Managing SBP in hypertensive patients with CCBs may prevent CAVS. ARBs might exert protective effects on CAVS independent of blood pressure reduction. The relationship between diuretics and CAVS is complex, with opposite effects through different mechanisms.

T-cell acute lymphoblastic leukemia (T-ALL) is a highly aggressive hematologic malignancy with a poor prognosis, despite advancements in treatment. Many patients struggle with relapse or refractory disease. Investigating the role of the super-enhancer (SE) regulated gene ubiquitin-specific protease 20 (USP20) in T-ALL could enhance targeted therapies and improve clinical outcomes. Analysis of histone H3 lysine 27 acetylation (H3K27ac) chromatin immunoprecipitation sequencing (ChIP-seq) data from six T-ALL cell lines and seven pediatric samples identified USP20 as an SE-regulated driver gene. Utilizing the Cancer Cell Line Encyclopedia (CCLE) and BloodSpot databases, it was found that USP20 is specifically highly expressed in T-ALL. Knocking down USP20 with short hairpin RNA (shRNA) increased apoptosis and inhibited proliferation in T-ALL cells. In vivo studies showed that USP20 knockdown reduced tumor growth and improved survival. The USP20 inhibitor GSK2643943A demonstrated similar anti-tumor effects. Mass spectrometry, RNA-Seq, and immunoprecipitation revealed that USP20 interacted with hypoxia-inducible factor 1 subunit alpha (HIF1A) and stabilized it by deubiquitination. Cleavage under targets and tagmentation (CUT&Tag) results indicated that USP20 co-localized with HIF1A, jointly modulating target genes in T-ALL. This study identifies USP20 as a therapeutic target in T-ALL and suggests GSK2643943A as a potential treatment strategy.

Metachromatic leukodystrophy (MLD) is an inherited disease caused by a deficiency of the enzyme arylsulfatase A (ARSA). Lentivirus-modified autologous hematopoietic stem cell gene therapy (HSCGT) has recently been approved for clinical use in pre and early symptomatic children with MLD to increase ARSA activity. Unfortunately, this advanced therapy is not available for most patients with MLD who have progressed to more advanced symptomatic stages at diagnosis. Patients with late-onset juvenile MLD typically present with a slower neurological progression of symptoms and represent a significant burden to the economy and healthcare system, whereas those with early onset infantile MLD die within a few years of symptom onset. We conducted a pilot study to determine the safety and benefit of HSCGT in patients with postsymptomatic juvenile MLD and report preliminary results. The safety profile of HSCGT was favorable in this long-term follow-up over 9 years. The most common adverse events (AEs) within 2 months of HSCGT were related to busulfan conditioning, and all AEs resolved. No HSCGT-related AEs and no evidence of distorted hematopoietic differentiation during long-term follow-up for up to 9.6 years. Importantly, to date, patients have maintained remarkably improved ARSA activity with a stable disease state, including increased Functional Independence Measure (FIM) score and decreased magnetic resonance imaging (MRI) lesion score. This long-term follow-up pilot study suggests that HSCGT is safe and provides clinical benefit to patients with postsymptomatic juvenile MLD.
Humans ; Leukodystrophy, Metachromatic/genetics* ; Pilot Projects ; Genetic Therapy/methods* ; Hematopoietic Stem Cell Transplantation ; Male ; Follow-Up Studies ; Female ; Lentivirus/genetics* ; Child ; Child, Preschool ; Hematopoietic Stem Cells/metabolism* ; Cerebroside-Sulfatase/metabolism* ; Adolescent

Combined with elastic network model (ENM), the perturbation response scanning (PRS) has emerged as a robust technique for pinpointing allosteric interactions within proteins. Here, we proposed the PRS analysis of drug-target networks (DTNs), which could provide a promising avenue in network medicine. We demonstrated the utility of the method by introducing a deep learning and network perturbation-based framework, for drug repurposing of multiple sclerosis (MS). First, the MS comorbidity network was constructed by performing a random walk with restart algorithm based on shared genes between MS and other diseases as seed nodes. Then, based on topological analysis and functional annotation, the neurotransmission module was identified as the "therapeutic module" of MS. Further, perturbation scores of drugs on the module were calculated by constructing the DTN and introducing the PRS analysis, giving a list of repurposable drugs for MS. Mechanism of action analysis both at pathway and structural levels screened dihydroergocristine as a candidate drug of MS by targeting a serotonin receptor of serotonin 2B receptor (HTR2B). Finally, we established a cuprizone-induced chronic mouse model to evaluate the alteration of HTR2B in mouse brain regions and observed that HTR2B was significantly reduced in the cuprizone-induced mouse cortex. These findings proved that the network perturbation modeling is a promising avenue for drug repurposing of MS. As a useful systematic method, our approach can also be used to discover the new molecular mechanism and provide effective candidate drugs for other complex diseases.

Compounds isolated from Epimedium include the total flavonoids of Epimedium , icariin, and its metabolites (icaritin, icariside I, and icariside II), which have similar molecular structures. Modern pharmacological research and clinical practice have proved that Epimedium and its active components have a wide range of pharmacological effects, especially in improving sexual function, hormone regulation, anti-osteoporosis, immune function regulation, anti-oxidation, and anti-tumor activity. To date, we still need a comprehensive source of knowledge about the pharmacological effects of Epimedium and its bioactive compounds on the male reproductive system. However, their actions in other tissues have been reviewed in recent years. This review critically focuses on the Epimedium , its bioactive compounds, and the biochemical and molecular mechanisms that modulate vital pathways associated with the male reproductive system. Such intrinsic knowledge will significantly further studies on the Epimedium and its bioactive compounds that protect the male reproductive system and provide some guidances for clinical treatment of related male reproductive disorders.
Male ; Epimedium/chemistry* ; Humans ; Genitalia, Male/drug effects* ; Flavonoids/therapeutic use* ; Animals

OBJECTIVE: To investigate the clinical features and prognosis of central nervous system (CNS) invasion in peripheral T-cell lymphoma (PTCL) and construct a risk prediction model for CNS invasion. METHODS: Clinical data of 395 patients with PTCL diagnosed and treated in the First Affiliated Hospital of Zhengzhou University from 1st January 2013 to 31st December 2022 were analyzed retrospectively. RESULTS: The median follow-up time of 395 PTCL patients was 24(1-143) months. There were 13 patients diagnosed CNS invasion, and the incidence was 3.3%. The risk of CNS invasion varied according to pathological subtype. The incidence of CNS invasion in patients with anaplastic large cell lymphoma (ALCL) was significantly higher than in patients with angioimmunoblastic T-cell lymphoma (AITL) (P <0.05). The median overall survival was significantly shorter in patients with CNS invasion than in those without CNS involvement, with a median survival time of 2.4(0.6-127) months after diagnosis of CNS invasion. The results of univariate and multivariate analysis showed that more than 1 extranodal involvement (HR=4.486, 95%CI : 1.166-17.264, P =0.029), ALCL subtype (HR=9.022, 95%CI : 2.289-35.557, P =0.002) and ECOG PS >1 (HR=15.890, 95%CI : 4.409-57.262, P <0.001) were independent risk factors for CNS invasion in PTCL patients. Each of these risk factors was assigned a value of 1 point and a new prediction model was constructed. It could stratify the patients into three distinct groups: low-risk group (0-1 point), intermediate-risk group (2 points) and high-risk group (3 points). The 1-year cumulative incidence of CNS invasion in the high-risk group was as high as 50.0%. Further evaluation of the model showed good discrimination and accuracy, and the consistency index was 0.913 (95%CI : 0.843-0.984). CONCLUSION The new model shows a precise risk assessment for CNS invasion prediction, while its specificity and sensitivity need further data validation.
Humans ; Lymphoma, T-Cell, Peripheral/pathology* ; Prognosis ; Retrospective Studies ; Central Nervous System Neoplasms/pathology* ; Neoplasm Invasiveness ; Male ; Female ; Central Nervous System/pathology* ; Middle Aged ; Adult

Body weight abnormalities, including overweight, obesity, and underweight, have become a dual public health challenge in Chinese adults: overweight and obesity lead to a variety of chronic complications, while underweight increases the risks of malnutrition, sarcopenia, and organ dysfunction. To systematically address these issues, multidisciplinary experts in endocrinology, sports science, nutrition, and psychiatry from various regions have held multiple weight management seminars. Based on the latest epidemiological data and clinical evidence, they expanded the guideline to include assessment and intervention strategies for underweight, in addition to the core content of obesity management. This guideline outlines the etiological mechanisms, evaluation methods, and multidimensional management strategies for overweight and obesity, covering key areas such as diagnosis and assessment, medical nutrition therapy, exercise prescription, pharmacological intervention, and psychological support. It is intended to provide a scientific and standardized approach to weight management across the adult population, aiming to curb the rising prevalence of obesity, mitigate complications associated with abnormal body weight, and improve nutritional status and overall quality of life.

Objective:To analysis the safety and feasibility of laparoscopic total hysterectomy in patients with obliterated rectouterine pouch.Methods:A retrospective analysis was conducted on 197 patients who underwent laparoscopic total hysterectomy at Peking University First Hospital, from July 2022 to July 2024. According to intraoperative observations, 197 patients were categorized into two groups: 58 cases with completely obliterated rectouterine pouch (obliterated group) and 139 cases with non-obliterated pouch (control group). General clinical characteristics, perioperative outcomes and 3-month follow-up after surgery were compared between two groups.Results:(1) Baseline characteristics: the age of the obliterated group was (45.7±3.7) years, and the control group was (48.0±3.8) years ( P<0.001). Primary complaint: dysmenorrhea prevalence was 53.4% (31/58) in the obliterated group, and was 35.3% (49/139; P<0.05) in the control group. Surgical indications: the proportion of adenomyosis and ovarian endometrioma was 77.6% (45/58) in the obliterated group, and was 51.1% (71/139; P<0.001) in the control group. No significant differences in body mass index, pelvic surgical history, or preoperative medication between the two groups (all P>0.05). (2) Intraoperative outcomes: the obliterated group demonstrated significantly higher rates of surgical interventions compared to the control group. Superficial endometriosis resection was performed in 91.4% (53/58) of the obliterated group versus 33.8% (47/139) in the control group ( P<0.001). Deep infiltrating endometriosis excision was required in 82.8% (48/58) of the obliterated group, contrasting sharply with 10.1% (14/139) in the control group ( P<0.001). Ureterolysis procedures were similarly elevated in the obliterated group (77.6%, 45/58) compared to the control group (7.9%, 11/139; P<0.001). Operative metrics revealed substantial intergroup disparities: the obliterated group exhibited a median surgical duration of 149.0 minutes (interquartile range: 114.0, 180.0 minutes), significantly prolonged relative to the control group′s 91.0 minutes (77.0, 107.0 minutes; P<0.001). Estimated blood loss followed a parallel pattern, with median volumes of 50.0 ml (20.0, 100.0 ml) in the obliterated group versus 20.0 ml (10.0, 20.0 ml) in the control group ( P<0.001). (3) Postoperative outcomes: the uterine weight of the obliterated group was 200.0 g (132.5, 260.0 g), and the control group was 240.0 g (180.0, 336.0 g; P<0.05). Hospital stay was prolonged in the obliterated group compared with the control group [7.0 days (6.0, 8.3 days) vs 6.0 days (5.0, 7.0 days); P<0.001]. The incidences of postoperative fever in the obliterated group and the control group were 20.7% (12/58) vs 12.2% (17/139; P>0.05). The incidences of minor complications in the obliterated group and the control group were 3.4% (2/58) vs 0 (0/139; P>0.05). No major complications (intraoperative hemorrhage, transfusion, visceral injury, conversion to laparotomy, or thromboembolism) occurred. (4) Follow up at 3 months after surgery: three months postoperatively, all patients underwent outpatient follow-up visits, during which symptoms such as pain were alleviated. Gynecological ultrasound and pelvic examinations were performed, and the vaginal stump exhibited good healing. Conclusion:Laparoscopic total hysterectomy performed by experienced minimally invasive gynecological specialists is safe and feasible for patients with obliterated rectouterine pouch.

Objective:To discuss the prevalence of contraindications to progestogens in patients with endometriosis and adenomyosis.Methods:Women of childbearing age aged 15-49 years, except for menopausal and malignant tumors, were enrolled in Peking University First Hospital from April to August 2024 for laparoscopic or open surgery, regardless of whether they had used or would be using progestogen drugs. The patients were divided into two groups: the case group was patients with pathologically confirmed endometriosis and adenomyosis, and the control group was patients with other benign gynecological diseases. The patient′s medical history and clinical data were collected.Results:A total of 745 patients were enrolled, including 362 cases (48.6%, 362/745) in the case group, 383 cases (51.4%, 383/745) in the control group; 61 patients with contraindications to progestogens, including 32 cases (8.8%, 32/362) in the case group, and 29 cases (7.6%, 29/383) in the control group ( χ2=0.398, P>0.05). Among them, there were 33 cases of liver disease, all of which were liver tumor (hepatic hemangioma only), including 18 cases (5.0%, 18/362) in the case group and 15 cases (3.9%, 15/383) in the control group. There were 11 cases of sex hormone-dependent or related tumors (breast cancer only), including 4 cases (1.1%, 4/362) in the case group and 7 cases (1.8%, 7/383) in the control group. There were 10 cases of vascular disease, including 4 cases of diabetic vascular disease, including 2 cases (0.6%, 2/362) in the case group and 2 cases (0.5%, 2/383) in the control group. There were 3 cases of venous thrombosis, including 2 cases (0.6%, 2/362) in the case group and 1 case (0.3%, 1/383) in the control group. There were 3 cases of cardiovascular and cerebrovascular diseases, including 1 case in the case group (0.3%, 1/362) and 2 cases (0.5%, 2/383) in the control group. There were 7 cases of renal insufficiency, including 3 cases of chronic nephritis complicated with renal insufficiency [including 2 cases (0.6%, 2/362) in the case group and 1 case (0.3%, 1/383) in the control group]; two cases of membranous nephropathy complicated with renal insufficiency were in the case group (0.6%, 2/362); one case of diabetic nephropathy complicated with renal insufficiency was in the control group (0.3%, 1/383); one case of uremia was in the case group (0.3%, 1/362). There were no statistically significant differences between the two groups (all P>0.05). Conclusions:There is no difference in the contraindications of progestogens in patients with endometriosis and adenomyosis compared with patients with other gynecological benign diseases. Liver tumors are more common in both two groups.