Beijing Emergency Medical Center

Self-renewal and differentiation of spermatogonial stem cells (SSCs) are critical for sustaining spermatogenesis in adult mammals. However, SSCs are highly heterogeneous, comprising a complex array of subpopulations whose identities and dynamic transitions remain greatly underappreciated. Through in silico analysis, we identified IL1R2 as a surface marker specific to the SSC subpopulation. IL1R2 enables the specific sorting of functionally active SSCs in both human and mouse. Il1r2CreERT2/+ Rosa26mTmG/+ mice allowed us to pulse-label and trace the lineage of Il1r2-expressing cells. We confirmed that IL1R2+ SSCs support spermatogenesis via both self-renewal and differentiation. Following spermatogenic disruption, IL1R2+ SSCs are reactivated for proliferation via the PI3K-AKT-mTORC1 pathway to replenish the SSC pool. Importantly, we demonstrated that PI3K-AKT-mTORC1 agonists can effectively enhance the recovery of spermatogenesis upon disruption. These findings highlight a promising therapeutic strategy to mitigate chemotherapy-induced infertility.

Hepatocellular carcinoma (HCC) shows marked heterogeneity and varying metastatic potential, challenging prognosis and treatment. This study evaluated multitracer PET imaging with [18F]FDG, [18F]FLT, and [18F]ACE to differentiate HCCs by metastatic behavior and explored its prognostic relevance. Four human HCC cell lines with varying metastatic potential (HepG2, QGY7701, MHCC97-H, MHCC97-L) were assessed for in vitro tracer uptake, proliferation, and invasion. Subcutaneous and spontaneous metastasis models were established in nude mice. Tumor uptake of tracers was quantified via microPET/CT. mRNA expression of MMP9 and VEGFR-2 and survival were analyzed. Fisher's classifier was applied to compare single-, dual-, and triple-tracer datasets with cross-validation. Tracer uptake significantly differed among cell lines (p < 0.001). The triple-tracer model ([18F]FDG + [ 18F]FLT + [18F]ACE) yielded the lowest classification error rate (0.074) compared with dual tracers (0.085-0.362). In vivo, [18F]FDG uptake correlated with metastatic potential, MMP9 and VEGFR-2 expression (r = 0.770-0.830, p < 0.05), and inversely with survival (r = - 0.726, p = 0.005). There is a significant difference in FDG uptake values between high-metastatic and low-metastatic cell lines as well as in tumor model.[18F]FLT uptake showed moderate correlation with biomarkers but not with survival, while [18F]ACE had no significant discriminative value. A multiparameter (multitracer) classification model had superior ability to discriminate four HCC cell lines with different biological behavior compared with dual tracers or single tracer through in vitro cell uptake experiment. [1⁸F]FDG uptake can distinguish between tumor models with high and low metastatic potential, and [1⁸F]FDG uptake can predict the survival time in metastatic models. [18F]FDG uptake probably be noninvasive prognostic marker, reflecting tumor heterogeneity and correlating with survival and metastasis-related biomarkers. This approach may aid in clinical stratification and personalized management of HCC.

Given the narrow therapeutic window, high inter-individual variability, and inherent risks of Narrow Therapeutic Index Drugs (NTIDs), this study systematically analyzes global NTID regulatory policies to explore pathways for optimizing China's lifecycle management system. The ultimate goals are to ensure clinical medication safety and promote the healthy development of the generic drug industry. This research conducts a systematic comparative policy review and narrative synthesis of the current regulatory landscape of NTIDs in China, covering both pre-market and post-market stages. We systematically identified and screened regulatory documents, technical guidelines, and policy statements from major international jurisdictions, including the United States Food and Drug Administration (USFDA), the European Medicines Agency (EMA), Health Canada, and Japan's Pharmaceuticals and Medical Devices Agency (PMDA). The analysis focused on four core pillars: catalog status, bioequivalence (BE) requirements, generic substitution policies, and post-market risk monitoring. China's NTID regulatory system currently under development but has not yet formed a comprehensive, systematic, and dynamically updated framework. Globally, regulatory bodies generally impose stricter lifecycle controls, particularly by narrowing BE acceptance intervals (e.g., AUC to 90.00-111.11%) and requiring replicated study designs (e.g., USFDA). However, significant differences persist in catalog management methods (explicit lists in the US and Japan vs. implicit guidance in the EU), BE limits (e.g., Health Canada's AUC of 90.00-112.00%), and generic substitution policies (e.g., the USFDA's BX rating and state-level substitution restrictions). Deficiencies in China persist in areas such as official catalog establishment and the lack of a scientific, graded substitution system. China should draw on international experience to optimize its NTID regulatory system. Recommended actions include strengthening catalog management and technical standards, improving the regulatory policy framework, establishing a scientific, graded substitution system, prudently advancing volume-based procurement (VPB), and enhancing post-market safety monitoring and risk governance capabilities.

The HSK16149-201/301 trial demonstrated short-term efficacy of the GABA analog crisugabalin for diabetic neuropathic pain. In the current study, patients in both the crisugabalin and placebo control groups of the HSK16149-201/301 trial were invited to receive 80 mg/day crisugabalin for an additional 52 weeks. The primary end point was safety. The secondary end point was pain control as measured using the Short-Form McGill Pain Questionnaire (SF-MPQ). A total of 301 patients (mean age 59.7 years and males 58.1%) were enrolled. The rate of treatment-related adverse events (TRAEs) was 38.9% (117/301). The most frequent TRAEs were dizziness (27.2%), somnolence (8.3%), and peripheral edema (3.0%). The rate of Grade 3 or higher TRAEs was 1.7%. TRAEs led to dose reduction in 41 patients (13.6%), treatment interruption and discontinuation each in three patients (1.0%). At week 52, the mean difference in SF-MPQ pain rating index (PRI) and visual analog scale pain score from baseline was -2.5 (95% CI -2.9 to -2.0; paired t-test p < 0.0001) and -23.4 (95% CI -25.6 to -21.2; paired t-test p < 0.0001), respectively. The proportion of patients with SF-MPQ PPI score ≤ 1 increased by 19.0% over baseline (p < 0.0001). In summary, crisugabalin at 80 mg/day was well tolerated and demonstrated sustained analgesic activities. ClinicalTrials.gov identifier: NCT05890053.

In a recent JASN article, Zhang et al. elegantly integrated spatial single-cell transcriptomics with lipidomics to identify a Cyp7b1/27-hydroxycholesterol (27-HC) axis that primes proximal straight tubules for ferroptosis in ischemic AKI, corroborated by ANCA-associated vasculitis-Cyp7b1 rescue.1 This map of segment-specific injury biology is highly informative.2 We write with one focused, dataset-answerable question about the robustness of the ferroptosis signal in proximal straight tubules. In the article, ferroptosis is predominant in injured proximal straight tubules (PST) clusters, with high ACSL4 and HMOX1 and Cyp7b1 downregulation.1 Because ferroptosis gene modules often include HMOX1 and ACSL4—the very genes lying downstream or upstream of the proposed 27-HC/estrogen receptor alpha pathway—gene set composition could amplify the association.3 Within the public single-cell RNA sequencing (GSE267242) and spatial datasets accompanying the article, could the authors clarify whether the inverse association between Cyp7b1 expression and the ferroptosis module in PST-4/PST-5 and outer-stripe spots persists after (1) adjusting for the authors' published injury score (Supplemental Table 2), cell cycle phase, and mitochondrial read fraction and (2) recomputing the ferroptosis module excluding HMOX1 and ACSL4? A within-cluster linear/partial-correlation or regression, with effect sizes and confidence intervals, would address this.4 If the association remains materially unchanged, it would strengthen the inference that the Cyp7b1/27-HC–estrogen receptor alpha axis confers ferroptosis susceptibility beyond global injury/dedifferentiation.5 If it attenuates, readers would better understand how much of the signal reflects injury severity rather than pathway specificity. Either way, this sensitivity analysis is feasible with the published datasets and would sharpen the mechanistic message for the community. We congratulate the authors on this important contribution and look forward to their clarification.

This study aims to evaluate the efficacy and safety of Crisugabalin in patients with diabetic peripheral neuropathic pain (DPNP), with a focus on its rapid onset of action. All the analyses in this study were based on data from a phase 2/3 adaptive randomized clinical trial that enrolled 596 patients. Participants were categorized into four treatment groups according to the intervention received: Crisugabalin 40mg/day, Crisugabalin 80mg/day, placebo, and Pregabalin 300mg/day. The primary endpoint was the change in the average daily pain score (ADPS) over a 13-week treatment period. Secondary endpoints included changes in the Numeric Rating Scale (NRS) and the daily sleep interference score (DSIS) during the first two weeks of treatment. Both Crisugabalin treatment groups (40mg/day and 80mg/day) demonstrated statistically significant reductions in ADPS compared to the placebo group starting from week 1 and continuing through week 13 (P<0.05). Significant differences in pain relief for the Pregabalin group were observed only from week 6. Improvements in NRS and DSIS scores were also noted in both Crisugabalin groups, with statistically significant enhancements evident as early as day 2 of administration. Safety assessments indicated that Crisugabalin was well-tolerated, with a low incidence of serious adverse events and no significant increase in dropout rates among participants. The findings suggest that Crisugabalin offers effective pain relief with an acceptable safety profile, highlighting its rapid onset in patients with DPNP. Clinical trial registration number derived from our parent project, we have retained the original registration identifier: NCT04647773.

Accurately predicting the thermal contact resistances (TCRs) between phase change materials (PCMs) and base is crucial to the design and fabrication of compounded phase change materials (CPCMs). The heat transfer equations for TCRs based on enthalpy are derived and corresponding lattice Boltzmann (LB) evolution equations based on enthalpy (HLBM) for TCRs are obtained. HLBM model for TCRs on the contact interface is friendly and integrated with HLBM model for CPCMs in the computational domain. Therefore, we propose an integrated HLBM model with TCRs to investigate liquid–solid phase change heat transfer in CPCMs. We extend the distribution function of enthalpy for TCRs from the straight contact interface to the curved contact interface by the scheme borrowed from the curved boundary interpolation. The accuracy, robustness, and computational cost for the integrated HLBM model are evaluated in several cases. When TCRs are ignored, the accuracy of the integrated HLBM model is equivalent to that of LB evolution equations based on temperature (TLBM). The integrated HLBM model embodies stronger robustness than the TLBM model when the TCRs and Rayleigh numbers are larger. The integrated HLBM model begins to show advantages when the Ra number is larger for the phase change and heat transfer processes of CPCMs. The integrated HLBM model with TCRs offers another option for simulating the flow, heat transfer, and phase change processes of CPCMs.

IntroductionThis study aims to explore the risk factors in the progression of gestational diabetes mellitus (GDM) to type 2 diabetes mellitus (T2DM).Material and methodsRelevant studies were comprehensively searched from PubMed, Web of Science, Cochrane Library, and Embase up to March 12. Data extraction was performed. Differences in risk factors were presented as odds ratios (OR) and corresponding 95% confidence intervals (CI). The quality of the included studies was assessed through the Newcastle-Ottawa Scale and the Agency for Healthcare Research and Quality scale.ResultsThis meta-analysis encompassed 46 studies involving a total of 196,494 patients. The factors most strongly associated with the risk of developing T2DM following GDM were the use of progestin-only contraceptives (odds ratio [OR]: 2.12, 95% confidence interval [CI] = 1.00–4.45, P = 0.049), recurrence of GDM (OR: 2.63, 95% CI = 1.88–3.69, P &amp;lt; 0.001), insulin use during pregnancy (OR: 4.35, 95% CI = 3.17–5.96, P &amp;lt; 0.001), pre-pregnancy body mass index (BMI) (OR: 2.97, 95% CI = 2.16–4.07, P &amp;lt; 0.001), BMI after delivery (OR: 4.17, 95% CI = 2.58–6.74, P &amp;lt; 0.001), macrosomia (OR: 3.30, 95% CI = 1.45–7.49, P = 0.04), hypertension (OR: 5.19, 95% CI = 1.31–20.51, P = 0.019), and HbA1c levels (OR: 3.32, 95% CI = 1.81–6.11, P &amp;lt; 0.001). Additionally, age (OR: 1.71, 95% CI = 1.23–2.38, P = 0.001), family history of diabetes (OR: 1.47, 95% CI = 1.27–1.70, P &amp;lt; 0.001), BMI during pregnancy (OR: 1.06, 95% CI = 1.00–1.12, P = 0.056), fasting blood glucose (FBG) (OR: 1.58, 95% CI = 1.36–1.84, P &amp;lt; 0.001), 1-hour oral glucose tolerance test (OGTT) (OR: 1.38, 95% CI = 1.02–1.87, P = 0.037), and 2-hour OGTT (OR: 1.54, 95% CI = 1.28–1.58, P &amp;lt; 0.001) were identified as moderate-risk factors for the development of T2DM.ConclusionThe systematic review and meta-analysis identified several moderate- to high-risk factors associated with the progression of T2DM in individuals with a history of GDM. These risk factors include the use of progestin-only contraceptives, pre-pregnancy BMI, BMI after delivery, macrosomia, hypertension, persistently elevated levels of HbA1c, fasting blood glucose (FBG), 1-hour and 2-hour oral glucose tolerance tests (OGTT), age, and family history of diabetes. Our findings serve as evidence for the early prevention and clinical intervention of the progression from GDM to T2DM and offer valuable insights to guide healthcare professionals in formulating customized management and treatment strategies for female patients with diverse forms of GDM.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/, identifier CRD42024545200.