Development and validation of a novel nomogram for predicting long-term rebleeding risk among patients with hemorrhagic moyamoya disease: a 10-year multicenter retrospective cohort study.

OBJECTIVE: The aim of this study was to develop and validate a predictive nomogram model for long-term rebleeding events in patients with hemorrhagic moyamoya disease (HMMD). METHODS: In total, 554 patients with HMMD from the Fifth Medical Center of the Chinese PLA General Hospital (5-PLAGH cohort) were included and randomly divided into training (390 patients) and internal validation (164 patients) sets. An independent cohort from the First Medical Center and Eighth Medical Center of Chinese PLA General Hospital (the 1-PLAGH and 8-PLAGH cohort) was used for external validation (133 patients). Univariate Cox regression analysis and least absolute shrinkage and selection operator (LASSO) regression algorithm were used to identify significant factors associated with rebleeding, which were used to develop a nomogram for predicting 5- and 10-year rebleeding. RESULTS: Intraventricular hemorrhage was the most common type of cerebral hemorrhage (39.0% of patients in the 5-PLAGH cohort and 42.9% of the 1-PLAGH and 8-PLAGH cohort). During the mean ± SD follow-up period of 10.4 ± 2.9 years, 91 (16.4%) patients had rebleeding events in the 5-PLAGH cohort. The rebleeding rates were 12.3% (68 patients) at 5 years and 14.8% (82 patients) at 10 years. Rebleeding events were observed in 72 patients (14.3%) in the encephaloduroarteriosynangiosis (EDAS) surgery group, whereas 19 patients (37.3%) experienced rebleeding events in the conservative treatment group. This difference was statistically significant (p < 0.001). We selected 4 predictors (age at onset, number of episodes of bleeding, posterior circulation involvement, and EDAS surgery) for nomogram development. The concordance index (C-index) values of the nomograms of the training cohort, internal validation cohort, and the external validation cohort were 0.767 (95% CI 0.704-0.830), 0.814 (95% CI 0.694-0.934), and 0.718 (95% CI 0.661-0.775), respectively. The nomogram at 5 years exhibited a sensitivity of 48.1% and specificity of 87.5%. The positive and negative predictive values were 38.2% and 91.3%, respectively. The nomogram at 10 years exhibited a sensitivity of 47.1% and specificity of 89.1%. The positive and negative predictive values were 48.5% and 88.5%, respectively. CONCLUSIONS: EDAS may prevent rebleeding events and improve long-term clinical outcomes in patients with HMMD. The nomogram accurately predicted rebleeding events and assisted clinicians in identifying high-risk patients and devising individual treatments. Simultaneously, comprehensive and ongoing monitoring should be implemented for specific patients with HMMD throughout their entire lifespan.

Association between polymorphism in the MTHFR gene and encephaloduroarteriosynangiosis-induced collateral circulation formation.

OBJECTIVE: This study aimed to investigate whether high homocysteine (Hcy) levels associated with the MTHFR gene influence the formation of the collateral vascular network in patients with moyamoya disease (MMD) after encephaloduroarteriosynangiosis (EDAS) by influencing the number of endothelial progenitor cells (EPCs) in peripheral blood. METHODS: A total of 118 Chinese patients with bilateral primary MMD were prospectively included. Blood samples were collected from the anterior cubital vein before surgery, and MTHFR rs9651118 was genotyped using high-throughput mass spectrometry to determine the genotype of the test specimen. Serum Hcy and EPC levels were measured, the latter with flow cytometry. Digital subtraction angiography was performed 6 months after EDAS, and the formation of collateral circulation was evaluated using the Matsushima grade system. The correlations between MTHFR rs9651118 genotype, Hcy and EPC levels, and Matsushima grade were compared. RESULTS: Among the 118 patients, 53 had the TT genotype (wild type) of MTHFR rs9651118, 33 TC genotype (heterozygous mutation), and 32 CC genotype (homozygous mutation). The mean ± SD Hcy level was 13.4 ± 9.5 µmol/L in TT patients, 9.8 ± 3.2 µmol/L in TC patients, and 8.9 ± 2.9 µmol/L in CC patients (p < 0.001). The level of EPCs in the venous blood of TT patients was 0.039% ± 0.016%, that of TC patients 0.088% ± 0.061%, and that of CC patients 0.103% ± 0.062% (p < 0.001). When the rs9651118 gene locus was mutated, Matsushima grade was better (p < 0.001) but there was no difference between heterozygous and homozygous mutations. CONCLUSIONS: The results suggest that the MTHFR rs9651118 polymorphism is a good biomarker for collateral vascular network formation after EDAS in MMD patients.

Phosphorylation of IDH1 Facilitates Progestin Resistance in Endometrial Cancer.

The progestin regimen is one of the main therapeutic strategies for women with endometrial cancer who undergo conservative management. Although many patients respond well to initial therapy, progestin-refractory disease inevitably emerges, and the molecular basis underlying progestin resistance has not been comprehensively elucidated. Herein, they demonstrated progestin results in p38-dependent IDH1 Thr 77 phosphorylation (pT77-IDH1). pT77-IDH1 translocates into the nucleus and is recruited to chromatin through its interaction with OCT6. IDH1-produced α-ketoglutarate (αKG) then facilitates the activity of OCT6 to promote focal adhesion related target gene transcription to confer progestin resistance. Pharmacological inhibition of p38 or focal adhesion signaling sensitizes endometrial cancer cells to progestin in vivo. The study reveals p38-dependent pT77-IDH1 as a key mediator of progestin resistance and a promising target for improving the efficacy of progestin therapy.

Clinical and genetic factors associated with contralateral progression in unilateral moyamoya disease: Longitudinal and Cross-Sectional Study.

Objective: This study aimed to explore the long-term outcome of unilateral moyamoya disease and predict the clinical and genetic factors associated with contralateral progression in unilateral moyamoya disease. Methods: We retrospectively recruited unilateral moyamoya disease patients with available genetic data who underwent encephaloduroarteriosynangiosis (EDAS) surgery at our institution from January 2009 to November 2017. Long-term follow-up data, including clinical outcomes, angiographic features, and genetic information, were analyzed. Results: A total of 83 unilateral moyamoya disease patients with available genetic data were enrolled in our study. The mean duration of clinical follow-up was 7.9 ± 2.0 years. Among all patients, 19 patients demonstrated contralateral progression to bilateral disease. Heterozygous Ring Finger Protein 213 p.R4810K mutations occurred significantly more frequently in unilateral moyamoya disease patients with contralateral progression. Furthermore, patients with contralateral progression typically demonstrated an earlier age of onset than those with non-progressing unilateral moyamoya disease. In the contralateral progression group, posterior circulation involvement was observed in 11 (11/19, 57.9%) patients compared to 12 (12/64, 18.8%) in the non-contralateral progression group (P = 0.001). The time to peak of cerebral perfusion and neurological status showed significant postoperative improvement. Conclusion: Long-term follow-up revealed that the EDAS procedure might provide benefits for unilateral moyamoya disease patients. Ring Finger Protein 213 p.R4810K mutations, younger age, and posterior circulation involvement might predict the contralateral progression of unilateral moyamoya disease.

Risk Factors for Massive Cerebral Infarction in Pediatric Patients With Moyamoya Disease.

BACKGROUND: To explore the risk factors for preoperative massive cerebral infarction (MCI) in pediatric patients with moyamoya disease (MMD). METHODS: Pediatric patients with MMD treated between 2017 and 2022 were enrolled. Logistic regression analysis was performed to identify risk factors for MCI among the patients, and a nomogram was constructed to identify potential predictors of MCI. Receiver operating characteristic (ROC) curves and areas under the curves were calculated to determine the effects of different risk factors. RESULTS: This study included 308 pediatric patients with MMD, including 36 with MCI. The MCI group exhibited an earlier age of onset than the non-MCI group. Significant intergroup differences were observed in familial MMD history, postcirculation involvement, duration from diagnosis to initiation of treatment, Suzuki stage, magnetic resonance angiography (MRA) score, collateral circulation score, and RNF213 p.R4810K variations. Family history, higher MRA score, lower collateral circulation score, and RNF213 p.R4810K variations were substantial risk factors for MCI in pediatric patients with MMD. The nomogram demonstrated excellent discrimination and calibration capabilities. The integrated ROC model, which included all the abovementioned four variables, showed superior diagnostic precision with a sensitivity of 67.86%, specificity of 87.01%, and accuracy of 85.11%. CONCLUSIONS: This study showed that family history, elevated MRA score, reduced collateral circulation score, and RNF213 p.R4810K variations are risk factors for MCI in pediatric patients with MMD. The synthesized model including these variables demonstrated superior predictive efficacy; thus, it can facilitate early identification of at-risk patients and timely initiation of appropriate interventions.

TSLP enhances progestin response in endometrial cancer via androgen receptor signal pathway.

BACKGROUND: The enriched proteins within in vitro fertilisation (IVF)-generated human embryonic microenvironment could reverse progestin resistance in endometrial cancer (EC). METHODS: The expression of thymic stromal lymphopoietin (TSLP) in EC was evaluated by immunoblot and IHC analysis. Transcriptome sequencing screened out the downstream pathway regulated by TSLP. The role of TSLP, androgen receptor (AR) and KANK1 in regulating the sensitivity of EC to progestin was verified through a series of in vitro and in vivo experiments. RESULTS: TSLP facilitates the formation of a BMP4/BMP7 heterodimer, resulting in activation of Smad5, augmenting AR signalling. AR in turn sensitises EC cells to progestin via KANK1. Downregulation of TSLP, loss of AR and KANK1 in EC patients are associated with tumour malignant progress. Moreover, exogenous TSLP could rescue the anti-tumour effect of progestin on mouse in vivo xenograft tumour. CONCLUSIONS: Our findings suggest that TSLP enhances the sensitivity of EC to progestin through the BMP4/Smad5/AR/KANK1 axis, and provide a link between embryo development and cancer progress, paving the way for the establishment of novel strategy overcoming progestin resistance using embryo original factors.

Exploring the causal relationships and mediating factors between depression, anxiety, panic, and atrial fibrillation: A multivariable Mendelian randomization study.

BACKGROUND: Atrial fibrillation is a significant cardiovascular disease, and the increased risk of its occurrence may be influenced by mental disorders. Currently, the causal relationship between them remains controversial. Our aim is to ascertain the relationship between atrial fibrillation and mental disorders including depression, anxiety, and panic, as well as the risk factors mediating this relationship, through the judgment of genetic susceptibility. METHODS: We utilized the summarized statistics from nine large-scale genome-wide association studies (in European populations), including depression (PGC, N = 807,553), anxiety (FinnGen, N = 429,209), panic (PGC, N = 230,878), diabetes (UK Biobank, N = 655,666), smoking (IEU, 607,291), hypertension (UK biobank, N = 463,010), obstructive sleep apnea (IEU, N = 476,853), obesity (UK biobank, N = 463,010), and AF (IEU, N = 1,030,836). By applying bidirectional two-sample Mendelian randomization and multivariable Mendelian randomization to depression, anxiety, panic, and AF, we analyzed their causal relationships and the independent influence of specific risk factors. Furthermore, a two-step MR approach was used to assess the mediating effects of diabetes, smoking, hypertension, obstructive sleep apnea, and obesity. RESULTS: Results from the Two-Sample Mendelian Randomization Inverse Variance Weighted Random Effects Model show: the occurrence of genetically predicted depression is related to an increased risk of atrial fibrillation (AF) (OR: 1.073; [95 % CI: 1.005-1.146] P < 0.05), and panic is more significantly associated than depression (OR: 1.017; [95 % CI: 1.008-1.027] P < 0.001), while anxiety has no causal relationship with the occurrence of AF (OR: 1.023; [95 % CI: 0.960-1.092], P > 0.05), and AF is not significantly related to the occurrence of depression, anxiety, or panic (P > 0.05). After correcting for the other two risk factors using multivariable Mendelian randomization, depression remains significantly related to the occurrence of AF (ß: 0.075; 95 % CI: [0.006, 0.144], P < 0.05), while panic and anxiety are not related to the occurrence of AF. Among them, the risk factors for AF occurrence, hypertension and obesity, are mediators between depression and AF, with mediation proportions of 74.9 % and 14.3 %, respectively. The mediating effects of diabetes, smoking, and obstructive sleep apnea were found to be not statistically significant. The above results are robust after sensitivity analysis. CONCLUSION: Our results identified that the genetic susceptibility to depression is an independent risk factor for the occurrence of AF, and that hypertension and obesity can mediate this process. Panic also poses some risk to the onset of AF. This demonstrates that controlling hypertension and obesity for emotional management is of great importance in preventing the occurrence of AF.

Nomogram for Predicting Long-term Outcomes of Encephaloduroarteriosynangiosis in Toddlers with Moyamoya Disease: a Longitudinal and Cross-sectional Study.

We investigated the long-term outcomes of encephaloduroarteriosynangiosis (EDAS) for stroke prevention in toddlers with moyamoya disease (MMD) using nomogram. Between January 2005 and December 2018, 74 toddlers with MMD underwent surgery in the Fifth Medical Centre, Chinese PLA General Hospital, 69 were < 4 years of age and included in the analysis. The modified Rankin scale (mRS) during follow-up evaluated clinical outcomes. To measure the effectiveness of EDAS, the annual risk of symptomatic infarction within the operated brain hemispheres was calculated. The event-free survival rate was determined using Kaplan-Meier curves. A nomogram generated using multivariate logistic regression analysis identified potential predictors associated with unfavorable outcomes. Additionally, discrimination, calibration, and clinical utility were assessed. A favorable clinical outcome was observed in 81.2% of the patients. The operated hemispheres showed an annual risk of 0.87% of symptomatic infarction and 0.23% of hemorrhage. Moreover, the 10-year event-free survival rates were 92.8% and 97.0% for symptomatic infarction and hemorrhage. Multivariate logistic analysis indicated that onset with infarction, initial mRS ≥ 3, and perioperative adverse events had significant and independent associations with unfavorable outcomes. However, an age at diagnosis of ≥ 2 years showed an association with favorable outcomes. Using these four factors, our model attained a concordance index of 0.912 (95% confidence interval, 0.842-0.982), well-fitted calibration curve, and cutoff value of 0.212 for predicting unfavorable outcomes. EDAS may prevent recurrent stroke and improve overall long-term clinical outcomes in toddlers with MMD. The developed nomogram accurately predicted unfavorable outcomes and assisted surgeons in patient evaluation.

Neurobehavioral effects of general anesthesia and cochlear implantation on hearing-impaired infants: A prospective observational cohort study.

INTRODUCTION: The potential adverse effects of prolonged exposure to anesthetics in pediatric patients with severe-to-profound sensorineural hearing loss remain unclear. This study aimed to examine whether early bilateral cochlear implantation involving long-duration anesthetic exposure caused greater developmental impairment than that with unilateral cochlear implantation. METHODS: This prospective observational study included normally developing infants with bilateral severe-to-profound sensorineural hearing loss aged 6 months to 2 years who were candidates for unilateral/bilateral cochlear implantation surgery. Baseline (T0), 6-month (T1), and 1-year (T2) Gesell Scale scores were measured. The outcomes included fine motor, adaptability, gross motor, language, and social skills scale 6 and 12 months postoperatively. RESULT: The 90 enrolled children with bilateral severe-to-profound sensorineural hearing loss (unilateral n = 43; bilateral n = 47) had a younger bilateral group (11.00 ± 3.66 vs. 15.63 ± 6.99 months, p < .001). Anesthesia duration was longer in the bilateral group (271.57 ± 36.09 vs. 148.81 ± 25.60 min, p < .001). Gross motor, fine motor, adaptability, and language scores improved in both groups, and no significant between-group differences occurred in the fine motor scale at T1 and T2. Language developmental quotients improved significantly in the bilateral group compared with the unilateral group at T1 (mean differences: 25.07 ± 4.37 vs. 10.88 ± 4.61, p < .001) and T2 (mean differences: 34.98 ± 5.94 vs. 15.28 ± 6.55, p < .001). Stepwise regression revealed that gross motor, adaptability, language, and social skill developmental quotients at T1 were positively correlated with those at T0. Gross motor, fine motor, and social skill developmental quotients at T2 were negatively correlated with age at operation. Language developmental quotients were positively correlated with T0 values (p < .001) and in the bilateral group (p < .001) at T1 and T2. CONCLUSIONS: When evaluating young children with bilateral severe-to-profound sensorineural hearing loss, despite longer exposures to general anesthesia, bilateral cochlear implantations were associated with more improvement in language scores and no differences in other skills compared with those with only unilateral implantation.

Outcomes and cost-effectiveness comparisons of progestin-primed ovarian stimulation, GnRH antagonist protocol, and luteal phase stimulation for fertility preservation.

OBJECTIVE: To compare the clinical outcomes and cost-effectiveness of progestin-primed ovarian stimulation (PPOS) and the gonadotropin-releasing hormone-antagonist (GnRH-A) protocol in fertility preservation (FP) in cancer patients. The stimulation option when patients were in the luteal phase was also explored. METHODS: This retrospective study analyzed clinical data from 163 patients who underwent FP. The number of retrieved oocytes and vitrified oocytes/embryos, total dose of gonadotropin, duration of stimulation, number of injections, and cost were compared among the PPOS, GnRH-A, and luteal phase stimulation (LPS) groups. RESULTS: No significant differences were noted in the numbers of retrieved oocytes and vitrified oocytes/embryos among the three groups. In the multiple regression model, age (P = 0.02) and antral follicle count (AFC) (P < 0.001), but not the controlled ovarian stimulation (COS) protocols (P = 0.586), were associated with the number of retrieved oocytes. The number of injections and the cost were all significantly lower in the PPOS and LPS groups than in the GnRH-A group(P < 0.001). CONCLUSION: PPOS had similar clinical results but was superior medically and economically to GnRH-A. For patients in the luteal phase, LPS was an optional protocol with similar outcomes and costs to PPOS.

Risk Factors for Preoperative Cerebral Infarction in Infants with Moyamoya Disease.

There have been few reports on the risk factors for preoperative cerebral infarction in childhood moyamoya disease (MMD) in infants under 4 years. The aim of this retrospective study is to identify clinical and radiological risk factors for preoperative cerebral infarction in infants under 4 years old with MMD, and the optimal timing for EDAS was also considered. We retrospectively analyzed the risk factors for preoperative cerebral infarction, confirmed by magnetic resonance angiography (MRA), in pediatric patients aged ˂4 years who underwent encephaloduroarteriosynangiosis between April 2005 and July 2022. The clinical and radiological outcomes were determined by two independent reviewers. In addition, potential risk factors for preoperative cerebral infarction, including infarctions at diagnosis and while awaiting surgery, were analyzed using a univariate model and multivariate logistic regression to identify independent predictors of preoperative cerebral infarction. A total of 160 hemispheres from 83 patients aged <4 years with MMD were included in this study. The mean age of all surgical hemispheres at diagnosis was 2.17±0.831 years (range 0.380-3.81 years). In the multivariate logistic regression model, we included all variables with P<0.1 in the univariate analysis. The multivariate logistic regression analysis indicated that preoperative MRA grade (odds ratio [OR], 2.05 [95% confidence interval [CI], 1.3-3.25], P=0. 002), and age at diagnosis (OR, 0.61 [95% CI, 0.4-0.92], P=0. 018) were predictive factors of infarction at diagnosis. The analysis further indicated that the onset of infarction (OR, 0.01 [95% CI, 0-0.08], P<0.001), preoperative MRA grade (OR, 1.7 [95% CI, 1.03-2.8], P=0.037), and duration from diagnosis to surgery (Diag-Op) (OR, 1.25 [95% CI, 1.11-1.41], P<0.001) were predictive factors for infarction while awaiting surgery. Moreover, the regression analysis indicated that family history (OR, 8.88 [95% CI, 0.91-86.83], P=0.06), preoperative MRA grade (OR, 8.72 [95% CI, 3.44-22.07], P<0.001), age at diagnosis (OR, 0.36 [95% CI, 0.14-0.91], P=0.031), and Diag-Op (OR, 1.38 [95% CI, 1.14-1.67], P=0.001) were predictive factors for total infarction. Therefore, during the entire treatment process, careful observation, adequate risk factor management, and optimal operation time are required to prevent preoperative cerebral infarction, particularly in pediatric patients with a family history, higher preoperative MRA grade, duration from diagnosis to operation longer than 3.53 months, and aged ˂3 years at diagnosis.

Surgical outcomes following encephaloduroarteriosynangiosis in moyamoya disease associated with hyperhomocysteinemia.

INTRODUCTION: This study investigated the effect of indirect revascularization surgery in adult patients with moyamoya disease (MMD) complicated with hyperhomocysteinemia (HHcy), and the effect of HHcy on the progression of adult MMD. METHODS: A retrospective case-control study was conducted in patients with MMD, with or without HHcy (n = 123). Postoperative collateral angiogenesis was evaluated using the Matsushima grading system and disease progression using the Suzuki staging system. Cerebral blood flow was evaluated before and after surgery using dynamic susceptibility contrast magnetic resonance imaging (DSC-MRI) and neurological function prognosis using the improved Rankin score (mRS). Univariate and multivariate logistic regression analyses were performed to determine risk factors for the clinical outcomes. RESULTS: There was no significant difference in the Suzuki stage composition ratios between the HHcy group and the non-HHcy group before and after surgery. Non-HHcy patients were more likely to grow new collateral circulating vessels after encephaloduroarteriosynangiosis (EDAS). Moreover, postoperative DSC-MRI indicated that the time to peak significantly improved. CONCLUSIONS: HHcy level may be a specific predictor of adverse clinical outcomes after EDAS in patients with MMD and a risk factor for poor collateral circulation and poor prognosis. Patients with MMD complicated with HHcy need to strictly control homocysteine levels before EDAS surgery.

In this retrospective study, we found that patients with MMD complicated by HHcy had poor collateral angiogenesis after EDAS, faster disease progression, and worse clinical outcomes.

The incidence of cytomegalovirus and BK polyomavirus infections in kidney transplant patients receiving mTOR inhibitors: A systematic review and meta-analysis.

Cytomegalovirus (CMV) and BK polyomavirus (BKPyV) infections after kidney transplant have become increasingly prevalent. Based on previous studies, the mammalian target of rapamycin (mTOR) inhibitors seem like attractive alternatives with antiviral activity. The objective of this systematic review and meta-analysis was to investigate the incidence of CMV and BKPyV infections in kidney transplantation recipients receiving mTOR inhibitors. This meta-analysis included three comparisons of immunosuppressant regimens commonly used after kidney transplantation: Comparison 1: mTOR inhibitors versus calcineurin inhibitors (CNI); Comparison 2: mTOR inhibitors versus antimetabolites (AM); and Comparison 3: mTOR inhibitors plus a reduced-dose of CNI versus AM plus a standard-dose of CNI. The group containing mTOR inhibitors was the study group and the remaining one was the control group. The incidence of CMV or BKPyV infection defined by positive culture, serology, or polymerase chain reaction testing was the primary outcome. A total of 61 studies involving 13,609 patients were included. As compared with the control group, a significantly decreased risk of CMV and BKPyV infections favoring the mTOR inhibitors-based group was shown in comparisons 1, 2, and 3 (p < 0.05). Compared with the control group in all three comparisons, mTOR inhibitors made no difference in regard to death and graft loss (p > 0.05). Compared with CNI, the incidence of biopsy-proven acute rejection (BPAR) and anemia was higher with mTOR inhibitors (p < 0.05). In comparisons 2 and 3, the risk of new-onset diabetes mellitus (NODM) was higher with mTOR inhibitors (p < 0.05). Early introduction of mTOR inhibitors reduced more CMV infections in comparisons 1 and 2 (p < 0.05). The mTOR inhibitor-based regimen is an attractive alternative with lower risk of CMV and BKPyV infections in kidney transplant recipients. The combination regimen is more appropriate and acceptable than the mTOR-inhibitor monotherapy-based regimen. Early introduction of mTOR inhibitors is recommended, although it is worth noting that attention should be paid to wound healing when mTOR inhibitors are introduced early.

High expression of PCOLCE gene indicate poor prognosis in patients and are associated with immune infiltration in glioma.

The procollagen C-protease enhancer (PCOLCE) has been identified to influence tumor growth and metastasis in multiple cancers. However, the relationship between PCOLCE activity and the progression of gliomas remains largely unknown. Glioma RNA-seq data were derived from the Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas databases for analysis. Kaplan-Meier survival curve, clinical characterization correlation, univariate and multivariate Cox, and receiver operating characteristic curve analyses were performed to assess the prognostic role of PCOLCE. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and Gene Set Enrichment Analysis were used to determine the functions or pathways associated with PCOLCE. The ESTIMATE and CIBERSORT algorithms, Spearman's rank correlation analysis, and Tumor Immune Estimation Resource (TIMER) databases were used to explore the relationship between PCOLCE and immune infiltration. Correlation analysis between PCOLCE, related genes, and immune cell markers was conducted using the TIMER database. Immunophenoscore assays were performed to determine differential PCOLCE expression levels in glioma. The sensitivity of multi-drugs were determined to explore potential chemotherapeutic agents in between PCOLCE. Compared to normal brain tissue, PCOLCE expression was increased in glioma and correlated with shorter overall survival (OS). Furthermore, significant differences were observed in the immune scores and immune cell infiltration levels. PCOLCE is positively associated with immune checkpoints and many immune markers. Additionally, PCOLCE expression was higher in gliomas with higher IPS Z-scores in CGGA. High expression of PCOLCE increased sensitivity to multiple chemotherapy agents in CGGA (P < 0.001), and TCGA. These results suggest that PCOLCE significantly influences the prognosis of patients with glioma, can serve as an independent prognostic factor, and is related to tumor immunity. PCOLCE may be a novel immune-related target for treating gliomas. Additionally, analysis of chemosensitivity in gliomas with high PCOLCE expression may provide a promising direction for drug development.

Natural course and risk factors of moyamoya disease with unruptured intracranial aneurysm.

Background and objective: The natural course and risk factors of moyamoya disease (MMD) associated with unruptured intracranial aneurysms involving stenosed parental arteries are scarcely studied. This study aimed to elucidate the natural course of MMD and its associated risk factors in patients with MMD with unruptured aneurysms. Methods: Between September 2006 and October 2021, patients with MMD with intracranial aneurysms at our center were examined. The natural course, clinical features, radiological features, and follow-up outcomes after revascularization were analyzed. Results: This study included 42 patients with MMD with intracranial aneurysms (42 aneurysms). The age distribution of MMD cases ranged from 6 to 69 years, with four children (9.5%) and 38 adults (90.5%). A total of 17 male and 25 female subjects were included (male-to-female ratio: 1:1.47). The first symptom was cerebral ischemia in 28 cases, and cerebral hemorrhage occurred in 14 cases. There were 35 trunk aneurysms and seven peripheral aneurysms. There were 34 small aneurysms (<5 mm) and eight medium aneurysms (5-15 mm). During the average clinical follow-up period of 37.90 ± 32.53 months, there was no rupture or bleeding from aneurysms. Twenty-seven of these patients underwent a cerebral angiography review, in which it was found that one aneurysm had enlarged, 16 had remained unchanged, and 10 had shrunk or disappeared. A correlation exists between the reduction or disappearance of aneurysms and the progression of the Suzuki stages of MMD (P = 0.015). Nineteen patients underwent EDAS on the aneurysm side, and nine aneurysms disappeared, while eight patients did not undergo EDAS on the aneurysm side and one aneurysm disappeared. Conclusion: The risk of rupture and hemorrhage of unruptured intracranial aneurysms is low when the parent artery already has stenotic lesions, thus, direct intervention may not be necessary for such aneurysms. The progression of the Suzuki stage of moyamoya disease may play a role in the shrinkage or disappearance of the aneurysms, thereby decreasing the risk of rupture and hemorrhage. Encephaloduroarteriosynangiosis (EDAS) surgery may also help promote atrophy or even the disappearance of the aneurysm, thus reducing the risk of further rupture and bleeding.

Simultaneous Bilateral Cochlear Implantation in Very Young Children Improves Adaptability and Social Skills: A Prospective Cohort Study.

OBJECTIVES: To investigate the value of using the Gesell Development Diagnosis Scale (GDDS) to predict developmental outcomes in very young children who undergo simultaneous bilateral cochlear implantation. DESIGN: In this prospective cohort study, a repeated-measures investigation was conducted in a tertiary referral hospital. A total of 62 children receiving simultaneous bilateral cochlear implantations were enrolled from April 2017 to August 2018. They were divided into 2 groups depending on the operative age: "Infants" group (6 to 12 months, N = 38) or "Children" group (12 to 36 months, N = 24). Data on the surgical outcomes, auditory development, speech production, and developmental indicators were collected until 2 years after the initial fitting. The primary outcome measure was the GDDS, a neuropsychological development examination. Secondary outcomes included the following: complication rate, aided pure-tone average, Infant-Toddler Meaningful Auditory Integration Scale, Categories of Auditory Performance-II, Meaningful Use of Speech Scale, Speech Intelligibility Rating, and the LittlEARS Auditory Questionnaire. RESULTS: The mean ages at implantation in infants and children groups were 9.2 ± 1.17 and 16.6 ± 3.60 months, respectively. Significant differences were found in the social skills ( p = 0.001) and adaptability ( p = 0.031) domains of GDDS. The younger the age of bilateral cochlear implants surgery, the higher developmental quotient of language, social skills, and adaptability the child could achieve after 2 years. The complication rates in the infants and children groups were 0% versus 2.1% ( p = 0.57). There was no surgical complication in the infants group. In the children group, 1 case with enlarged vestibular aqueduct and Mondini malformation had a receiver-implant misplacement on the right side (2%, 1/48). In the two groups, auditory performance and speech production had improved similarly. In the infants group, social skills developmental quotient at baseline had a significant positive relationship with Meaningful Use of Speech Scale after 2 years. CONCLUSIONS: Simultaneous bilateral cochlear implantation in younger children improves adaptability and social skills. GDDS is a sensitive tool of evaluating short-term effect of bilateral cochlear implants in neuropsychological development and constitutes a reliable predictor of speech production for the very younger pediatric cochlear implant users.

CDK7/GRP78 signaling axis contributes to tumor growth and metastasis in osteosarcoma.

Osteosarcoma derives from primitive bone-forming mesenchymal cells and is the most common primary bone malignancy. Therapeutic targeting of osteosarcoma has been unsuccessful; therefore, identifying novel osteosarcoma pathogenesis could offer new therapeutic options. CDK7 is a subunit within the general transcription factor TFIIH. We aim to explore the new mechanism by which CDK7 regulates osteosarcoma and our studies may provide new theoretical support for the use of CDK7 inhibitors in the treatment of osteosarcoma. Here, we investigate the molecular mechanism underlying the association between CDK7 and GRP78 in osteosarcoma. Specifically, we find that an E3 ubiquitin ligase TRIM21 binds and targets GRP78 for ubiquitination and degradation, whereas CDK7 phosphorylates GRP78 at T69 to inhibit TRIM21 recruitment, leading to GRP78 stabilization. Notably, a CDK7-specific inhibitor, THZ1, blunts osteosarcoma growth and metastasis. Combination treatment with CDK7 and GRP78 inhibitors yield additive effects on osteosarcoma growth and progression inhibition. Thus, simultaneous suppression of CDK7 and GRP78 activity represents a potential new approach for the treatment of osteosarcoma. In conclusion, the discovery of this previously unknown CDK7/GRP78 signaling axis provides the molecular basis and the rationale to target human osteosarcoma.

GFAT1-linked TAB1 glutamylation sustains p38 MAPK activation and promotes lung cancer cell survival under glucose starvation.

Reprogrammed cell metabolism is deemed as one of the hallmarks of cancer. Hexosamine biosynthesis pathway (HBP) acts as an "energy sensor" in cells to regulate metabolic fluxes. Glutamine-fructose-6-phosphate amidotransferase 1 (GFAT1), the rate-limiting enzyme of HBP, is broadly found with elevated expression in human cancers though its exact and concrete role in tumorigenesis still remains unknown and needs further investigation. P38 mitogen-activated protein kinase (MAPK) is an important component of stress-signaling pathway and plays a critical role in cell fate decision, whereas the underlying mechanism of its activation under nutrient stress also remains elusive. In this study, we show that glucose deprivation induces the interaction of GFAT1 with transforming growth factor ß-activated kinase 1 binding protein 1 (TAB1) in a TAB1 S438 phosphorylation-dependent manner. Subsequently, the binding of GFAT1 to TAB1 facilitates TTLL5-GFAT1-TAB1 complex formation, and the metabolic activity of GFAT1 for glutamate production further contributes to TTLL5-mediated TAB1 glutamylation. In consequence, TAB1 glutamylation promotes the recruitment of p38α MAPK and thus drives p38 MAPK activation. Physiologically, GFAT1-TAB1-p38 signaling promotes autophagy occurrence and thus protects tumor cell survival under glucose deficiency. Clinical analysis indicates that both GFAT1 and TAB1 S438 phosphorylation levels correlate with the poor prognosis of lung adenocarcinoma patients. These findings altogether uncover an unidentified mechanism underlying p38 MAPK signaling regulation by metabolic enzyme upon nutrient stress and provide theoretical rationality of targeting GFAT1 for cancer treatment.

Brusatol sensitizes endometrial hyperplasia and cancer to progestin by suppressing NRF2-TET1-AKR1C1-mediated progestin metabolism.

Progestin resistance is the main obstacle for the conservative therapy to maintain fertility in women with endometrial cancer. Brusatol was identified as an inhibitor of the NRF2 pathway; however, its impact on progestin resistance and the underlying mechanism remains unclear. Here, we found that brusatol sensitized endometrial cancer to progestin by suppressing NRF2-TET1-AKR1C1-mediated progestin metabolism. Brusatol transcriptionally suppressed AKR1C1 via modifying the hydroxymethylation status in its promoter region through TET1 inhibition. Suppression of AKR1C1 by brusatol resulted in decreased progesterone catabolism and maintained potent progesterone to inhibit endometrial cancer growth. This inhibition pattern has also been found in the established xenograft mouse and organoid models. Aberrant overexpression of AKR1C1 was found in paired endometrial hyperplasia and cancer samples from the same individuals with progestin resistance, whereas attenuated or loss of AKR1C1 was observed in post-treatment samples with well progestin response as compared with paired pre-treatment tissues. Our findings suggest that AKR1C1 expression pattern may serve as an important biomarker of progestin resistance in endometrial cancer.

Pectolinarigenin acts as a potential anti-osteosarcoma agent via mediating SHP-1/JAK2/STAT3 signaling.

Signal transducer and activator of transcription 3 (STAT3) plays essential roles in cancer progression and has been considered as a promising target for cancer therapy. Here, we used a dual luciferase assay to identify that pectolinarigenin inhibited STAT3 transcriptional activity. Further, results showed pectolinarigenin inhibited constitutive and IL6 induced STAT3 signaling, diminished the accumulation of STAT3 in the nucleus, dimerization and blocked STAT3 DNA binding activity. Mechanism investigations indicated that pectolinarigenin disturbed the STAT3/DNMT1/HDAC1 complex formation in the promoter region of SHP-1, which reversely mediates STAT3 signaling, leading to the upregulation of SHP-1 expression in osteosarcoma. We also found pectolinarigenin significantly suppressed osteosarcoma growth, induced apoptosis. In addition, pectolinarigenin blocked tumor cells migration, invasion and reserved EMT phenotype. In spontaneous tibial injection and patient-derived xenograft models of osteosarcoma, we identified administration (i.p.) of pectolinarigenin (20 mg/kg/2 days and 50 mg/kg/2 days) blocked STAT3 activation and disturbed tumor growth and metastasis with superior pharmacodynamic properties. Taken together, our findings demonstrate that pectolinarigenin may be a candidate for osteosarcoma intervention linked to its STAT3 signaling inhibitory activity.