In In recent years, small-molecule targeted protein degraders inducing protein degradation have been developing rapidly. These molecules are attracting substantial interest from researchers since they can overcome such limitations of traditional small-molecule inhibitors as their inapplicability to ‘undruggable’ targets and tendency to induce drug resistance. Compared with other targeted protein degraders, small-molecule hydrophobic tags (HyTs) may have a smaller number of hydrogen bond donors/acceptors, smaller molecular weights, and better pharmacokinetic profiles, thus attracting extensive attention from researchers. This review focuses on the possible mechanisms and popular types of HyTs, with special attention to the potential application value of adamantane, a typical hydrophobic tag, in the fields of cancer and neurodegeneration. In general, there are still some problems like fewer types of hydrophobic tags and insufficient research on degradation mechanisms, which still need to be further explored. This review is expected to provide researchers working in the fields of small-molecule targeted protein degraders with some valuable reference.

BACKGROUND: China bears the biggest atrial fibrillation (AF) burden in the world. However, little is known about the incidence and predictors of AF. This study aimed to investigate the current incidence of AF and its electrocardiographic (ECG) predictors in general community individuals aged over 60 years in China. METHODS: This was a prospective cohort study, recruiting subjects who were aged over 60 years and underwent annual health checkups from April to July 2015 in four community health centers in Songjiang District, Shanghai, China. The subjects were then followed up from 2015 to 2019 annually. Data on sociodemographic characteristics, medical history, and the resting 12-lead ECG were collected. Kaplan-Meier curve was used for showing the trends in AF incidence and calculating the predictors of AF. Associations of ECG abnormalities and AF incidence were examined using Cox proportional hazard models. RESULTS: This study recruited 18,738 subjects, and 351 (1.87%) developed AF. The overall incidence rate of AF was 5.2/1000 person-years during an observation period of 67,704 person-years. Multivariable Cox regression analysis indicated age (hazard ratio [HR], 1.07; 95% confidence interval [CI]: 1.06-1.09; P < 0.001), male (HR, 1.30; 95% CI: 1.05-1.62; P = 0.018), a history of hypertension (HR, 1.55; 95% CI: 1.23-1.95; P < 0.001), a history of cardiac diseases (HR, 3.23; 95% CI: 2.34-4.45; P < 0.001), atrial premature complex (APC) (HR, 2.82; 95% CI: 2.17-3.68; P < 0.001), atrial flutter (HR, 18.68; 95% CI: 7.37-47.31; P < 0.001), junctional premature complex (JPC) (HR, 3.57; 95% CI: 1.59-8.02; P = 0.002), junctional rhythm (HR, 18.24; 95% CI: 5.83-57.07; P < 0.001), ventricular premature complex (VPC) (HR, 1.76; 95% CI: 1.13-2.75, P = 0.012), short PR interval (HR, 5.49; 95% CI: 1.36-22.19; P = 0.017), right atrial enlargement (HR, 6.22; 95% CI: 1.54-25.14; P = 0.010), and pacing rhythm (HR, 3.99; 95% CI: 1.57-10.14; P = 0.004) were independently associated with the incidence of AF. CONCLUSIONS The present incidence of AF was 5.2/1000 person-years in the studied population aged over 60 years in China. Among various ECG abnormalities, only APC, atrial flutter, JPC, junctional rhythm, short PR interval, VPC, right atrial enlargement, and pacing rhythm were independently associated with AF incidence.
Humans ; Male ; Middle Aged ; Aged ; Atrial Fibrillation/epidemiology* ; Prospective Studies ; Incidence ; Atrial Flutter/complications* ; Risk Factors ; China/epidemiology* ; Electrocardiography

Glioblastoma multiforme (GBM), a highly malignant and heterogeneous brain tumor, contains various types of tumor and non-tumor cells. Whether GBM cells can trans-differentiate into non-neural cell types, including mural cells or endothelial cells (ECs), to support tumor growth and invasion remains controversial. Here we generated two genetic GBM models de novo in immunocompetent mouse brains, mimicking essential pathological and molecular features of human GBMs. Lineage-tracing and transplantation studies demonstrated that, although blood vessels in GBM brains underwent drastic remodeling, evidence of trans-differentiation of GBM cells into vascular cells was barely detected. Intriguingly, GBM cells could promiscuously express markers for mural cells during gliomagenesis. Furthermore, single-cell RNA sequencing showed that patterns of copy number variations (CNVs) of mural cells and ECs were distinct from those of GBM cells, indicating discrete origins of GBM cells and vascular components. Importantly, single-cell CNV analysis of human GBM specimens also suggested that GBM cells and vascular cells are likely separate lineages. Rather than expansion owing to trans-differentiation, vascular cell expanded by proliferation during tumorigenesis. Therefore, cross-lineage trans-differentiation of GBM cells is very unlikely to occur during gliomagenesis. Our findings advance understanding of cell lineage dynamics during gliomagenesis, and have implications for targeted treatment of GBMs.
Mice ; Animals ; Humans ; Glioblastoma/pathology* ; Endothelial Cells/pathology* ; DNA Copy Number Variations ; Brain/metabolism* ; Brain Neoplasms/pathology*

Objective:To compare the clinical effects of percutaneous curved vertebroplasty (PCVP) and unilateral percutaneous kyphoplasty (PKP) in the treatment of osteoporotic vertebral compression fracture (OVCF).Methods:A retrospective cohort study was used to analyze the clinical data of 104 patients with single vertebral OVCF treated in Tianjin Hospital from September 2019 to September 2020, including 21 males and 83 females; aged 50-91 years [(70.3±7.7)years]. AO classification of the fracture was type A1 in 65 patients and type A2 in 39. The patients received PCVP (PCVP group, n=51) or unilateral PKP surgery (unilateral PKP group, n=53). The operation time, bone cement injection volume, intraoperative fluoroscopy frequency, effective dispersion times of bone cement and excellent rate of bone cement distribution were compared between the two groups. In evaluation of the therapeutic effects of the two groups, visual analogue scale (VAS) and Oswestry dysfunction index (ODI) were measured preoperatively and at postoperative 24 hours, 3 months and 6 months; Beck index was measured preoperatively and at postoperative 24 hours and 3 months. The rate of bone cement leakage and rate of refracture of adjacent vertebral bodies were compared between the two groups. Results:All patients were followed up for 6-8 months [(6.4±0.7)months]. The operation time, bone cement injection volume and intraoperative fluoroscopy frequency in PCVP group was (12.15±1.63)minutes, (2.13±0.28)ml and (24.74±1.71)times, shorter or less than (22.09±1.62)minutes, (5.30±0.52)ml and (30.09±1.86)times in unilateral PKP group (all P<0.01). The effective dispersion times of bone cement in PCVP group was (1.42±0.04)times, higher than (1.18±0.02)times in unilateral PKP group ( P<0.01). The excellent rate of bone cement distribution in PCVP group was 94%, higher than 70% in unilateral PKP group ( P<0.01). There were no significant differences in VAS, ODI and Beck index between the two groups before operation and at 24 hours and 3 months after operation (all P>0.05). VAS and ODI in PCVP group were (1.20±0.49)points and 16.52±5.22 at 6 months after operation, lower than (1.49±0.58)points and 20.16±5.16 in unilateral PKP group (all P<0.01). VAS and ODI in the two groups were significantly improved at 24 hours, 3 months and 6 months after operation when compared with those before operation (all P<0.05). Beck index in the two groups detected at 24 hours and 3 months after operation was improved from that before operation (all P<0.05). Unilateral PKP group showed Beck index was 0.75±0.07 at 3 months after operation, significantly lower than 0.79±0.07 at 24 hours after operation ( P<0.05), but there was no significant change in PCVP group ( P>0.05). The leakage rate of bone cement in PCVP group was 16% (8/51), lower than 47% (25/53) in unilateral PKP group ( P<0.01). There was no significant difference in the incidence of refracture of adjacent vertebral bodies between the two groups during follow-up ( P>0.05). Conclusion:For OVCF, PCVP is superior to unilateral PKP in terms of operation time, amount of bone cement injection, intraoperative fluoroscopy frequency, dispersion effect of bone cement in vertebral body, pain, function improvement, maintenance of injured vertebral height and incidence of bone cement leakage.

Objective:To retrospectively analyze the failure patterns and outcomes of patients with locally advanced hypopharyngeal squamous cell carcinoma (HPSCC) after undergoing induction chemotherapy (IC) followed by definitive radiotherapy.Methods:For patients with locally advanced HPSCC who were treated with IC and definitive radiotherapy from August 2008 to December 2019, their data were collected from the medical records system, and their clinical characteristics, failure patterns, and survival were retrospectively analyzed.Results:A total of 116 eligible patient with squamous cell carcinoma were included in this study. with a median age of 59 (39-79), and 3, 3, 60, and 50 of them had stage Ⅱ, Ⅲ, Ⅳ A, and Ⅳ B HPSCC, respectively. Among these patients, 81 received 1~2 cycles of IC, and 35 received 3-4 cycles of IC. After treatment with IC, 54, 13, and 49 patients received concurrent chemoradiotherapy, radiotherapy combined with targeted therapy, and radiotherapy alone, respectively. The median follow-up was 34.6 months (95% CI: 28.7-40.5 months). The 3-year local recurrence-free survival (LRFS), regional recurrence-free survival (RRFS), metastasis-free survival (MFS), progression-free survival (PFS), and overall survival (OS) of all the patients were 63.5%, 82.8%, 75.2%, 47.3%, and 43.1%, respectively. Median PFS and OS were 26.1 and 28.0 months, respectively. Treatment failure was reported in 59 patients, of whom 22, 5, 12, 10, 3, 6 and 1 experienced local, regional, distant only, local-regional, regional-distant, local-distant, and local-regional-distant failure, respectively. The objective response rate (CR+ PR) of patients after IC was 55.2% (64/116). The LRFS, RRFS, PFS, and OS of IC responders (CR+ PR) were better than those of IC non-responders (SD+ PD) ( χ2 = 12.52, 5.16, 13.19, 11.72, all P< 0.05). Conclusions:IC combined with radical radiotherapy has efficacy to a certain extent in the treatment of locally advanced HPSCC, and locoregional recurrence predominates the failure patterns. The prognosis of IC responders is significantly better than that of IC non-responders.

Objective:To evaluate the survival outcomes of radiotherapy in patients with newly-diagnosed metastatic head and neck squamous cell carcinoma (HNSCC) based on data from the Surveillance, Epidemiology and End Results (SEER) database.Methods:A total of 1226 patients newly-diagnosed with metastatic HNSCC between 2010 and 2015 were selected from the SEER database. There were 762 patients (62.1%) in the radiotherapy group and 464 patients (37.9%) in the non-radiotherapy group. Kaplan-Meier method was used to calculate the cancer-specific survival (CSS) and overall survival (OS). The effect of radiotherapy on survival was assessed by Cox multivariate regression and Propensity score-matched analyses (PSM). According to the results of multivariate analysis, the patients were further divided into low-, intermediate- and high-risk groups, and the effect of radiotherapy on survival was analyzed in different risk groups.Results:The median CSS and OS time of the whole group was 11.0 months and 10.0 months, respectively. For patients in the radiotherapy group and non-radiotherapy group, the median CSS time was 13.0 months and 6.0 months, and the median OS time was 12.0 months and 6.0 months, respectively. Multivariate analysis showed that age (CSS, P=0.045;OS, P=0.002), primary tumor site (CSS, P=0.021;OS, P<0.001), T stage (CSS, P=0.001;OS, P=0.002), N stage (CSS, P=0.002;OS, P<0.001), number of metastatic organs (CSS, P<0.001;OS, P<0.001), surgery (CSS, P<0.001;OS, P<0.001), radiotherapy (CSS, P<0.001;OS, P<0.001), and chemotherapy (CSS, P<0.001;OS, P<0.001)were the independent prognostic factors. After PSM, patients with and without radiotherapy in the low-,intermediate-,and high-risk groups, the 3-year CSS rates were 62.5% vs 23.5%( P=0.008), 22.4% vs 15.7%( P=0.001)and 10.5% vs 9.6%( P=0.203), respectively; the 3-year OS were 58.0% vs 20.8%( P=0.002), 19.8% vs 12.7%( P=0.001)and 7.0% vs 6.1%( P=0.166), respectively. Conclusion:Radiotherapy significantly improves CSS and OS in the low- and intermediate-risk groups, but patients in the high-risk group do not benefit from radiotherapy.

Objective:To observe heart rate circadian rhythm in patients with chronic kidney disease (CKD) stage 5 and to analyze the effects of parathyroidectomy (PTX) on heart rate circadian rhythm in severe secondary hyperparathyroidism (SHPT) patients.Methods:A cross-sectional observation was performed in 213 patients with CKD stage 5 and 96 controls, and the patients were divided into those with severe SHPT (PTX group, n=70) and without severe SHPT (non-PTX group, n=143). Forty-six PTX patients were followed up prospectively. The baseline data were compared among these groups. Holter electrocardiogram was performed for each participant. Non-dipping heart rate was defined as night/day heart rate ratio greater than 0.9. Multiple linear regression analysis was used to analyze the related factors of heart rate circadian rhythm in patients with CKD stage 5. Results:The 24-hour, daytime and nighttime mean heart rate in patients with CKD stage 5 were all higher than those in controls, especially in PTX group (all P<0.05). The night/day heart rate ratios of controls and CKD stage 5 patients were (0.81±0.08) and (0.91±0.08) respectively ( P<0.01). Correlation analysis showed 24-hour and daytime or nighttime mean heart rate in patients with CKD stage 5 were positively correlated with serum levels of phosphorus and ln(alkaline phosphatase), while nighttime mean heart rate and night/day heart rate ratio were positively related with serum intact parathyroid hormone level. After adjusting with postoperative follow-up period (median time: 10.9 months), 24-hour and nighttime mean heart rate, and night/day heart rate ratio in PTX patients all decreased significantly (all P<0.01). Conclusions:Heart rate is increased and circadian rhythm is abnormal in patients with CKD stage 5, which are related with mineral and bone disorder. PTX significantly decreases 24-hour and nighttime mean heart rate in severe SHPT patients, and improves the heart rate circadian rhythm.

Objective:To assess the efficacy and toxicity of chemoradiotherapy in the treatment of early stage extranodal nasal-type NK/T-cell lymphoma (ENKTCL).Methods:Retrospective review was conducted for 174 patients with pathological proved early stage ENKTCL who were treated in the Department of Radiation Oncology, Peking University Cancer Hospital & Institute. The Kaplan-Meier survival analysis was adopted to calculate the local-regional control (LRC), overall survival (OS), and progression free survival (PFS), and the Log-rank test COX regression model were applied to univariate and multivariate analyses.Results:The patients in this study included 102 and 72 patients diagnosed with Ann Arbor stage-Ⅰ and stage-Ⅱ, respectively. Among them, two patients received radiotherapy alone and 172 patients were treated with combined chemoradiotherapy. The overall response rate of all the patients was 94.2%, with a complete response (CR) rate of 87.9% (153). Furthermore, the rates of 5-year OS, PFS, and LRC were 87.3%, 83.1%, and 91.9%, respectively. The most common toxicities during the chemotherapy and radiotherapy included myelosuppression and oral mucositis, with grade ≥ 3 myelosuppression and grade ≥ 3 oral mucositis accounting for 62.1% and 10.9% of all patients, respectively. As shown by multivariate analysis, the adverse prognostic factors for OS included age > 60, B symptoms, and stage Ⅱ, while the adverse prognostic factors for PFS included age > 60 and stage Ⅱ. Meanwhile, the PFS rate was significantly improved by increasing the radiation dose (≥ 50 Gy vs.<50 Gy), and the 5-year PFS rates of the two groups were 83.5% and 76.5%, respectively [hazard ratio ( HR) 0.374; 95% CI, 0.169-0.826; P=0.015]. Conclusions:A good therapeutic effect can be achieved for early stage NK/T-cell lymphoma and the toxicities after combined chemoradiotherapy can be tolerated.

Objective:To investigate the predictive value of abnormal heart rate circadian rhythm for all-cause mortality in stage 5 chronic kidney disease (CKD 5) patients.Methods:The retrospective study was performed in CKD 5 patients enrolled from the First Affiliated Hospital of Nanjing Medical University (Jiangsu Province Hospital) and the Affiliated BenQ Hospital of Nanjing Medical University from February, 2011 to December, 2019. A total of 159 healthy volunteers were enrolled as the healthy control group during the same period. The circadian rhythm of heart rate was monitored by 24-hour Holter. Related indices (including 24-hour, daytime and nighttime mean heart rate, night/day heart rate ratio, 24-hour maximum heart rate, 24-hour minimum heart rate and difference between maximum and minimum of 24-hour heart rate) were calculated. Non-dipping heart rate was defined as night/day heart rate ratio greater than 0.9. Cox regression model was used to analyze the risk factors of all-cause mortality in CKD 5 patients. Kaplan-Meier survival curve and Log-rank test were used to compare the differences of cumulative mortality between high ratio group (night/day heart rate ratio>0.91) and low ratio group (night/day heart rate ratio≤0.91). The nonlinear relationship between night/day heart rate ratio and all-cause mortality was analyzed by restricted cubic spline plot. Time-dependent receiver operating characteristic (ROC) curve was used to analyze the predictive value of night/day heart rate ratio for all-cause mortality in CKD 5 patients.Results:A total of 159 healthy volunteers and 221 CKD 5 patients were included in this study. There were 123 males (55.66%) and the age was (52.72±13.13) years old in CKD 5 patients. The total median follow-up time was 50.0 months. Compared with controls, 24-hour, nighttime mean heart rate, 24-hour minimum heart rate in CKD 5 patients were increased (all P<0.05), furthermore, the night/day heart rate ratio was higher [(0.91±0.09) vs (0.81±0.08), P<0.001], showing "non-dipping heart rate". However, the 24-hour maximum heart rate and the difference between maximum and minimum of 24-hour heart rate in CKD 5 patients were lower than controls (both P<0.05). Multivariate Cox regression analysis showed that the increased night/day heart rate ratio (per 0.1 increase, HR=1.557, 95% CI 1.073-2.258, P=0.020) was an independent influencing factor for all-cause mortality in CKD 5 patients. Kaplan-Meier survival curve analysis showed that the cumulative mortality of the high ratio group was significantly increased than that of the low ratio group (Log-rank test χ 2=7.232, P=0.007). From the restricted cubic spline plot, there was a linear effect between night/day heart rate ratio and all-cause mortality ( P=0.141), and when night/day heart rate ratio was above 0.91, the risk of all-cause mortality was significantly increased in CKD 5 patients. According to time-dependent ROC curve, the accuracy of night/day heart rate ratio in predicting all-cause mortality was 70.90% even when the survival time was up to 70.0 months. Conclusions:The circadian rhythm of heart rate in CKD 5 patients displays "non-dipping" state. High night/day heart rate ratio is an independent influencing factor for all-cause mortality in CKD 5 patients.

Objective:To explore overall survival(OS) and prognostic factors of brainstem gliomas (BSG) after intensity modulated radiotherapy (IMRT) by a retrospective single-center analysis.Methods:A total of twenty-one patients with BSG were collected in the Department of Radiation Oncology, Peking University Cancer Hospital from January 2012 to September 2019. All patients underwent IMRT. OS and potential prognostic factors were analyzed, including gender, age, operation type, imaging classification, tumor location, WHO grade, chemotherapy, radiotherapy pattern, time interval between morbidity and the first treatment, and radiation dose.Results:Eighteen of twenty-one patients were followed up more than 3 months. The median follow-up time was 15.5 (5.3-25.6) months. The median overall survival (mOS) was 20 (14.1-25.8) months. The 1 and 2-year OS rates were 86.2% and 34.5% respectively. Operation type, imaging classification, tumor location, WHO grade and radiotherapy pattern were the prognosis factors ( χ2=4.829-20.261, P<0.05). Conclusions:Patients with maximal safe surgical resection, focal endogenesis / exogenesis, tumor located in mesencephalon, low-grade gliomas and/or received postoperative radiotherapy have a better prognosis. It has certain reference value for guiding the clinical practice.