BACKGROUND: Temozolomide (TMZ) resistance is a significant challenge in treating glioblastoma (GBM). Collagen remodeling has been shown to be a critical factor for therapy resistance in other cancers. This study aimed to investigate the mechanism of TMZ chemoresistance by GBM cells reprogramming collagens. METHODS: Key extracellular matrix components, including collagens, were examined in paired primary and recurrent GBM samples as well as in TMZ-treated spontaneous and grafted GBM murine models. Human GBM cell lines (U251, TS667) and mouse primary GBM cells were used for in vitro studies. RNA-sequencing analysis, chromatin immunoprecipitation, immunoprecipitation-mass spectrometry, and co-immunoprecipitation assays were conducted to explore the mechanisms involved in collagen accumulation. A series of in vitro and in vivo experiments were designed to assess the role of the collagen regulators prolyl 4-hydroxylase subunit alpha 1 (P4HA1) and yes-associated protein (YAP) in sensitizing GBM cells to TMZ. RESULTS: This study revealed that TMZ exposure significantly elevated collagen type I (COL I) expression in both GBM patients and murine models. Collagen accumulation sustained GBM cell survival under TMZ-induced stress, contributing to enhanced TMZ resistance. Mechanistically, P4HA1 directly binded to and hydroxylated YAP, preventing ubiquitination-mediated YAP degradation. Stabilized YAP robustly drove collagen type I alpha 1 ( COL1A1) transcription, leading to increased collagen deposition. Disruption of the P4HA1-YAP axis effectively reduced COL I deposition, sensitized GBM cells to TMZ, and significantly improved mouse survival. CONCLUSION P4HA1 maintained YAP-mediated COL1A1 transcription, leading to collagen accumulation and promoting chemoresistance in GBM.
Temozolomide ; Humans ; Glioblastoma/drug therapy* ; Animals ; Mice ; Cell Line, Tumor ; Drug Resistance, Neoplasm/genetics* ; YAP-Signaling Proteins ; Hydroxylation ; Dacarbazine/pharmacology* ; Adaptor Proteins, Signal Transducing/metabolism* ; Transcription Factors/metabolism* ; Collagen/biosynthesis* ; Collagen Type I/metabolism* ; Prolyl Hydroxylases/metabolism* ; Antineoplastic Agents, Alkylating/therapeutic use*

OBJECTIVES: Urinary calculi are characterized by a high recurrence rate, and patients' adherence to self-management after discharge directly affects health outcomes. Traditional offline follow-up models often face problems such as poor compliance and uneven allocation of medical resources, making it difficult to meet individualized health management needs. Remote follow-up provides a novel solution to optimize long-term management, improve health literacy, and enhance clinical outcomes. This study aims to evaluate the effect of remote follow-up under an intelligent medical collaborative model on quality of life and health-promoting lifestyle in patients with urinary calculi, and to assess its short-term impact on clinical outcomes. METHODS: A total of 118 patients with urinary calculi admitted to a tertiary hospital in Hunan Province between August and November 2024 were recruited and randomly assigned to a control group (n=59) or an intervention group (n=59). The control group received routine departmental follow-up, while the intervention group underwent remote follow-up based on an intelligent medical collaborative model for one month. Assessments were conducted before discharge (T0), 15 days after discharge (T1), and one month after discharge (T2), using the Wisconsin Stone Quality of Life Questionnaire and the Health-Promoting Lifestyle Profile. At T2, the incidence of forgotten ureteral stents (FUS), ureteral stent-related complications, unplanned readmissions, and patient satisfaction were evaluated. RESULTS: No significant differences were observed between groups at T0 in baseline characteristics or outcome measures (all P>0.05). At T1 and T2, the intervention group had significantly higher health-related quality of life scores than the control group (P<0.05). Generalized estimating equation (GEE) analysis showed significant between-group effects (Wald's χ²=22.961, P<0.001), time effects (Wald's χ²=23.065, P<0.001), and interaction effects (Wald's χ²=6.930, P<0.05). Similarly, at T1 and T2, the intervention group scored significantly higher on health-promoting lifestyle than the control group (P<0.05), with significant between-group effects (Wald's χ²=22.936, P<0.001), time effects (Wald's χ²=10.694, P<0.001), and interaction effects (Wald's χ²=18.921, P<0.05). No significant differences were found between groups in the incidence of FUS, ureteral stent-related complications, or unplanned readmissions (all P>0.05). Patient satisfaction was significantly higher in the intervention group (t=4.089, P<0.001). CONCLUSIONS Remote follow-up under an intelligent medical collaborative model helps improve quality of life, promote health-oriented lifestyles, and enhance patient satisfaction among individuals with urinary calculi.
Humans ; Quality of Life ; Male ; Female ; Urinary Calculi/therapy* ; Health Promotion/methods* ; Middle Aged ; Adult ; Follow-Up Studies ; Treatment Outcome

Objective: To compare the clinical efficacy of anterior column reconstruction using single or double titanium mesh cage (TMC) after total en bloc spondylectomy (TES) of thoracic and lumbar spinal tumors. Methods: A retrospective cohort study was performed involving 39 patients with thoracic or lumbar spinal tumors. All patients underwent TES, followed by anterior reconstruction and screw-rod instrumentation via a posterior-only procedure. Twenty-two patients in group A were treated with a single TMC to reconstruct the anterior column, whereas 17 patients in group B were reconstructed with double TMCs. Results: The overall follow-up is 20.5 ± 4.6 months. There is no significant difference between the 2 groups regarding age, sex, body mass index, tumor location, operative time, and intraoperative blood loss. The time for TMC placement was significantly shortened in the double TMCs group (5.2 ± 1.3 minutes vs. 15.6 ± 3.3 minutes, p = 0.004). Additionally, postoperative neural complications were significantly reduced with double TMCs (5/22 vs. 0/17, p = 0.046). The kyphotic Cobb angle and mean intervertebral height were significantly corrected in both groups (p ≤ 0.001), without obvious loss of correction at the last follow-up in either group. The bone fusion rates for single TMC and double TMCs were 77.3% and 76.5%, respectively. Conclusion Using 2 smaller TMCs instead of a single large one eases the placement of TMC by shortening the time and avoiding nerve impingement. Anterior column reconstruction with double TMC is a clinically feasible, and safe alternative following TES for thoracic and lumbar tumors.

Objective: To compare the clinical efficacy of anterior column reconstruction using single or double titanium mesh cage (TMC) after total en bloc spondylectomy (TES) of thoracic and lumbar spinal tumors. Methods: A retrospective cohort study was performed involving 39 patients with thoracic or lumbar spinal tumors. All patients underwent TES, followed by anterior reconstruction and screw-rod instrumentation via a posterior-only procedure. Twenty-two patients in group A were treated with a single TMC to reconstruct the anterior column, whereas 17 patients in group B were reconstructed with double TMCs. Results: The overall follow-up is 20.5 ± 4.6 months. There is no significant difference between the 2 groups regarding age, sex, body mass index, tumor location, operative time, and intraoperative blood loss. The time for TMC placement was significantly shortened in the double TMCs group (5.2 ± 1.3 minutes vs. 15.6 ± 3.3 minutes, p = 0.004). Additionally, postoperative neural complications were significantly reduced with double TMCs (5/22 vs. 0/17, p = 0.046). The kyphotic Cobb angle and mean intervertebral height were significantly corrected in both groups (p ≤ 0.001), without obvious loss of correction at the last follow-up in either group. The bone fusion rates for single TMC and double TMCs were 77.3% and 76.5%, respectively. Conclusion Using 2 smaller TMCs instead of a single large one eases the placement of TMC by shortening the time and avoiding nerve impingement. Anterior column reconstruction with double TMC is a clinically feasible, and safe alternative following TES for thoracic and lumbar tumors.

Objective: To compare the clinical efficacy of anterior column reconstruction using single or double titanium mesh cage (TMC) after total en bloc spondylectomy (TES) of thoracic and lumbar spinal tumors. Methods: A retrospective cohort study was performed involving 39 patients with thoracic or lumbar spinal tumors. All patients underwent TES, followed by anterior reconstruction and screw-rod instrumentation via a posterior-only procedure. Twenty-two patients in group A were treated with a single TMC to reconstruct the anterior column, whereas 17 patients in group B were reconstructed with double TMCs. Results: The overall follow-up is 20.5 ± 4.6 months. There is no significant difference between the 2 groups regarding age, sex, body mass index, tumor location, operative time, and intraoperative blood loss. The time for TMC placement was significantly shortened in the double TMCs group (5.2 ± 1.3 minutes vs. 15.6 ± 3.3 minutes, p = 0.004). Additionally, postoperative neural complications were significantly reduced with double TMCs (5/22 vs. 0/17, p = 0.046). The kyphotic Cobb angle and mean intervertebral height were significantly corrected in both groups (p ≤ 0.001), without obvious loss of correction at the last follow-up in either group. The bone fusion rates for single TMC and double TMCs were 77.3% and 76.5%, respectively. Conclusion Using 2 smaller TMCs instead of a single large one eases the placement of TMC by shortening the time and avoiding nerve impingement. Anterior column reconstruction with double TMC is a clinically feasible, and safe alternative following TES for thoracic and lumbar tumors.

Objective: To compare the clinical efficacy of anterior column reconstruction using single or double titanium mesh cage (TMC) after total en bloc spondylectomy (TES) of thoracic and lumbar spinal tumors. Methods: A retrospective cohort study was performed involving 39 patients with thoracic or lumbar spinal tumors. All patients underwent TES, followed by anterior reconstruction and screw-rod instrumentation via a posterior-only procedure. Twenty-two patients in group A were treated with a single TMC to reconstruct the anterior column, whereas 17 patients in group B were reconstructed with double TMCs. Results: The overall follow-up is 20.5 ± 4.6 months. There is no significant difference between the 2 groups regarding age, sex, body mass index, tumor location, operative time, and intraoperative blood loss. The time for TMC placement was significantly shortened in the double TMCs group (5.2 ± 1.3 minutes vs. 15.6 ± 3.3 minutes, p = 0.004). Additionally, postoperative neural complications were significantly reduced with double TMCs (5/22 vs. 0/17, p = 0.046). The kyphotic Cobb angle and mean intervertebral height were significantly corrected in both groups (p ≤ 0.001), without obvious loss of correction at the last follow-up in either group. The bone fusion rates for single TMC and double TMCs were 77.3% and 76.5%, respectively. Conclusion Using 2 smaller TMCs instead of a single large one eases the placement of TMC by shortening the time and avoiding nerve impingement. Anterior column reconstruction with double TMC is a clinically feasible, and safe alternative following TES for thoracic and lumbar tumors.

Objective: To compare the clinical efficacy of anterior column reconstruction using single or double titanium mesh cage (TMC) after total en bloc spondylectomy (TES) of thoracic and lumbar spinal tumors. Methods: A retrospective cohort study was performed involving 39 patients with thoracic or lumbar spinal tumors. All patients underwent TES, followed by anterior reconstruction and screw-rod instrumentation via a posterior-only procedure. Twenty-two patients in group A were treated with a single TMC to reconstruct the anterior column, whereas 17 patients in group B were reconstructed with double TMCs. Results: The overall follow-up is 20.5 ± 4.6 months. There is no significant difference between the 2 groups regarding age, sex, body mass index, tumor location, operative time, and intraoperative blood loss. The time for TMC placement was significantly shortened in the double TMCs group (5.2 ± 1.3 minutes vs. 15.6 ± 3.3 minutes, p = 0.004). Additionally, postoperative neural complications were significantly reduced with double TMCs (5/22 vs. 0/17, p = 0.046). The kyphotic Cobb angle and mean intervertebral height were significantly corrected in both groups (p ≤ 0.001), without obvious loss of correction at the last follow-up in either group. The bone fusion rates for single TMC and double TMCs were 77.3% and 76.5%, respectively. Conclusion Using 2 smaller TMCs instead of a single large one eases the placement of TMC by shortening the time and avoiding nerve impingement. Anterior column reconstruction with double TMC is a clinically feasible, and safe alternative following TES for thoracic and lumbar tumors.

Objective:This study is to understand the hot spots and trends in the recruitment of clinical trial subjects in China over the past 20 years, explore the existing problems and countermeasures, and provide scientific ideas for domestic clinical trial institutions to effectively solve the problem of subject recruitment.Methods:Bibliometric analysis was used to study the relevant literature from three major domestic databases from 2001 to 2021, analyzing key indicators such as annual publication volume, journal distribution, institutional distribution, regional distribution, and high-frequency keyword co-occurrence.Results:A total of 162 articles were selected. The results showed that the overall publication volume in this field showed an upward trend, and the research institutions were diversified, with a concentration of medical and pharmaceutical institutions and universities. The current research hotspots in this field focused on quality and efficiency improvement of subject recruitment, with themes of subject protection, ethical review, regulation development, standardized management, etc.Conclusions:The research in this field has made significant progress, but the overall research level is still relatively weak. Therefore, it is suggested that the country should play a role in macro-regulation, on the one hand, starting with top-level design, promoting the construction of a standardized management system for subject recruitment, continuously strengthening subject protection, and enhancing the effectiveness of scientific recruitment. On the other hand, releasing the potential of grassroots institutions and giving full play to the volume advantage by promoting the sinking of advantageous resources. Meanwhile, great importance should be attached to the development of Phase I clinical trials, giving full play to the strong internal energy of traditional medicine and promoting the development of Chinese traditional medicine. These multi-measures should provide a theoretical basis for exploring the transformation of ′clinical research hospitals′, and promote the high-quality development of new drug research and development in China.

SIRT6 belongs to the conserved NAD⁺-dependent deacetylase superfamily and mediates multiple biological and pathological processes. Targeting SIRT6 by allosteric modulators represents a novel direction for therapeutics, which can overcome the selectivity problem caused by the structural similarity of orthosteric sites among deacetylases. Here, developing a reversed allosteric strategy AlloReverse, we identified a cryptic allosteric site, Pocket Z, which was only induced by the bi-directional allosteric signal triggered upon orthosteric binding of NAD⁺. Based on Pocket Z, we discovered an SIRT6 allosteric inhibitor named JYQ-42. JYQ-42 selectively targets SIRT6 among other histone deacetylases and effectively inhibits SIRT6 deacetylation, with an IC₅₀ of 2.33 μmol/L. JYQ-42 significantly suppresses SIRT6-mediated cancer cell migration and pro-inflammatory cytokine production. JYQ-42, to our knowledge, is the most potent and selective allosteric SIRT6 inhibitor. This study provides a novel strategy for allosteric drug design and will help in the challenging development of therapeutic agents that can selectively bind SIRT6.

【Objective】 To establish a method for detecting human immunoglobulin Fc function based on surface plasmon resonance technology. 【Methods】 Based on the characteristic that FcγRI can be binded to the Fc segment of IgG, the affinity constant of the sample was detected by surface plasmon resonance, and its Fc function was the KD ratio of the sample to the standard. The method was validated for specificity/specificity, precision and robustness. The method and the pharmacopoeia method were used to detect the Fc function of 30 human immunoglobulins, and the correlation and consistency of the detection results were analyzed. 【Results】 The method validation results showed that this method has strong specificity/specificity (t values were 0.15, 0.22, both P>0.05), good precision (CV value 5.37%~10.69%) and good robustness (CV value 10.06%). The detection results of this method and the pharmacopoeia method have high correlation (r=0.96, P<0.05) and high consistency (Bias-2.060, 95% Limits of Agreement-5.628~1.508). 【Conclusion】 A method for detecting human immunoglobulin Fc function based on surface plasmon resonance has been successfully established.