The new generation of artificial intelligence technology,represented by deep learning,has emerged as a crucial driving force in the advancement of new drug research and development.This article creatively proposes a workflow named"Molecular Factory"for the design and optimization of drug molecules based on artificial intelligence technology.This workflow integrates intelligent molecular generation models,high-performance molecular docking algorithms,and accurate protein-ligand binding affinity prediction methods.It has been integrated as a core module into DrugFlow,a one-stop drug design software platform,providing a comprehensive set of mature solutions for the discovery and optimization of lead compounds.Utilizing the"Molecular Factory"module,we conducted the research of second-generation inhibitors against Menin that can combat drug resistance.Through the integration of computational and experimental approaches,we rapidly identified multiple promising compounds.Among them,compound RG-10 exhibited the IC50 values of 9.681 nmol/L,233.2 nmol/L,and 40.09 nmol/L against the wild-type Menin,M327I mutant,and T349M mutant,respectively.Compared to the positive reference molecule SNDX-5613,which has entered Phase Ⅱ clinical trials,RG-10 demonstrated significantly enhanced inhibitory activity against the M327I and T349M mutants.These findings fully demonstrate the unique advantages of the"Molecular Factory"technology in practical drug design and development scenarios.It can rapidly and efficiently generate high-quality active molecules targeting specific protein structures,holding significant value and profound implications for advancing new drug discovery.

Background::Carotid intima-media thickness (IMT) and diameter, stiffness, and wave reflections, are independent and important clinical biomarkers and risk predictors for cardiovascular diseases. The purpose of the present study was to establish nationwide reference values of carotid properties for healthy Chinese adults and to explore potential clinical determinants.Methods::A total of 3053 healthy Han Chinese adults (1922 women) aged 18-79 years were enrolled at 28 collaborating tertiary centers throughout China between April 2021 and July 2022. The real-time tracking of common carotid artery walls was achieved by the radio frequency (RF) ultrasound system. The IMT, diameter, compliance coefficient, β stiffness, local pulse wave velocity (PWV), local systolic blood pressure, augmented pressure (AP), and augmentation index (AIx) were then automatically measured and reported. Data were stratified by age groups and sex. The relationships between age and carotid property parameters were analyzed by Jonckheere-Terpstra test and simple linear regressions. The major clinical determinants of carotid properties were identified by Pearson’s correlation, multiple linear regression, and analyses of covariance.Results::All the parameters of carotid properties demonstrated significantly age-related trajectories. Women showed thinner IMT, smaller carotid diameter, larger AP, and AIx than men. The β stiffness and PWV were significantly higher in men than women before forties, but the differences reversed after that. The increase rate of carotid IMT (5.5 μm/year in women and 5.8 μm/year in men) and diameter (0.03 mm/year in both men and women) were similar between men and women. For the stiffness and wave reflections, women showed significantly larger age-related variations than men as demonstrated by steeper regression slopes (all P for age by sex interaction <0.05). The blood pressures, body mass index (BMI), and triglyceride levels were identified as major clinical determinants of carotid properties with adjustment of age and sex. Conclusions::The age- and sex-specific reference values of carotid properties measured by RF ultrasound for healthy Chinese adults were established. The blood pressures, BMI, and triglyceride levels should be considered for clinical application of corresponding reference values.

Objective To understand the epidemic characteristics of heart failure in Guangzhou, and to provide a basis for the prevention and control of heart failure. Methods The information of patients hospitalized for heart failure in Guangzhou from January 1, 2017 to December 31, 2021 was collected, and t test, rank sum test, and χ² test were used to analyze the differences of central tendency and composition ratio. Results From 2017 to 2021, there were 6 823 hospitalized patients with heart failure in Guangzhou, with 8,716 hospitalizations and 849 deaths. The average age of hospitalization was 78.50 ±10.48 years old. Male patients were younger than female patients (P<0.001), and females died 3.86 years later than males on average (P<0.001). The number of hospitalizations for males (4 251 person times, accounting for 48.77%) was less than that for females (4 465 person times, accounting for 51.23%), and the number of hospitalizations for urban registered residence (7 346 person times, accounting for 84.28%) was much more than that for rural registered residence (1 370 person times, accounting for 15.72%). The number of hospitalizations in the fourth quarter was the largest. The combined rates of coronary heart disease, hypertension, type 2 diabetes, chronic obstructive pulmonary disease and hyperlipidemia were 58.65%, 69.52%, 34.92%, 10.69% and 10.23% respectively. There were differences in age, registered residence, residential area and complications among patients with acute and chronic heart failure (P<0.05). Conclusion The mortality of patients with heart failure in Guangzhou is high, and the distribution characteristics of acute and chronic heart failure is different. Corresponding preventive measures should be taken for different groups to reduce the disease burden and improve the quality of life.

Objective:To evaluate the prognostic value of pretreatment systemic immune-inflammation index (SII) and lactate dehydrogenase (LDH) in non-metastatic nasopharyngeal carcinoma (NPC).Methods:We retrospectively collected the data of 839 patients with non-metastatic NPC from National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital and Sun Yat-sen University Cancer Center between January 2007 and October 2015. All patients received intensity modulated radiation based treatment. Optimal cutoff value of SII and LDH were determined by X-title software. The association between SII, LDH and clinical prognosis of non-metastatic NPC patients were analyzed. Kaplan-Meier method was used for survival analysis, and Log rank test was used for comparison of survival rates between groups. Propensity score matching (PSM) analysis was carried out to minimize the effects of confounding factors. The risk stratification model of prognosis by combining N stage, SII and LDH was constructed to compare the prognosis of patients in high risk group, middle risk group and low risk group, and the receiver operating characteristic (ROC) curve analysis was used to evaluate its prognostic value.Results:The optimal cutoff value of SII is 447.2×10 9/L for predicting the 5-year overall survival (OS) of NPC patients, and the best cutoff value of LDH is 198.9 U/L. The proportion of patients with stage T3-4 and stage III-IVB in high SII group was higher than that in low SII group ( P<0.001). Multivariate Cox regression analysis showed that N stage, SII and LDH were independent factors of OS, progression-free survival (PFS) and distant metastasis-free survival (DMFS) of NPC patients (N stage, HR=1.705, 95% CI: 1.247-2.332; HR=1.755, 95% CI: 1.342-2.295; HR=2.161, 95% CI: 1.515-3.082. SII, HR=1.525, 95% CI: 1.097-2.119; HR=1.518, 95% CI: 1.150-2.004; HR=1.837, 95% CI: 1.272-2.653. LDH, HR=2.041, 95% CI: 1.403-2.968; HR=1.725, 95% CI: 1.233-2.414; HR=2.492, 95% CI: 1.690-3.672, respectively). After PSM, SII was still an independent prognostic factor of OS, PFS and DMFS in NPC patients ( HR=1.52, 95% CI: 1.09-2.12; HR=1.52, 95% CI: 1.15-2.00; HR=1.82, 95% CI: 1.26-2.63, respectively). Combined with N 2-3 stage, SII (>447.2×10 9/L), and LDH (>198.9 U/L), patients were divided into high-(3 risk factors), intermediate- (2 risk factors) and low-risk (0-1 risk factors) groups. The 5-year OS rates of patients in low-, intermediate- and high-risk groups were 86.1%, 79.8% and 41.2% respectively, the 5-year PFS rates were 80.7%, 70.2% and 33.9% respectively, and the 5-year DMFS rates were 88.9%, 79.2% and 47.5% respectively. There were significant differences in OS, PFS and DMFS among these three groups ( P<0.001). Distant metastasis was the main failure pattern in low-, intermediate- and high-risk groups, and the highest rate of distant metastasis was 83.3% (15/31) in high-risk group. ROC curve of the risk stratification model for predicting 5-year OS of NPC patients is 0.610, which is higher than TNM stage (0.609), SII (0.574) and LDH (0.558). Conclusions:Pretreatment SII and LDH are significantly correlated with the prognosis of patients with non-metastatic NPC. The combination of SII, LDH and N stage can stratify the prognostic risk of NPC patients. The risk stratification model can enhance the accuracy of prognosis.

Objective:To evaluate the prognostic value of pretreatment systemic immune-inflammation index (SII) and lactate dehydrogenase (LDH) in non-metastatic nasopharyngeal carcinoma (NPC).Methods:We retrospectively collected the data of 839 patients with non-metastatic NPC from National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital and Sun Yat-sen University Cancer Center between January 2007 and October 2015. All patients received intensity modulated radiation based treatment. Optimal cutoff value of SII and LDH were determined by X-title software. The association between SII, LDH and clinical prognosis of non-metastatic NPC patients were analyzed. Kaplan-Meier method was used for survival analysis, and Log rank test was used for comparison of survival rates between groups. Propensity score matching (PSM) analysis was carried out to minimize the effects of confounding factors. The risk stratification model of prognosis by combining N stage, SII and LDH was constructed to compare the prognosis of patients in high risk group, middle risk group and low risk group, and the receiver operating characteristic (ROC) curve analysis was used to evaluate its prognostic value.Results:The optimal cutoff value of SII is 447.2×10 9/L for predicting the 5-year overall survival (OS) of NPC patients, and the best cutoff value of LDH is 198.9 U/L. The proportion of patients with stage T3-4 and stage III-IVB in high SII group was higher than that in low SII group ( P<0.001). Multivariate Cox regression analysis showed that N stage, SII and LDH were independent factors of OS, progression-free survival (PFS) and distant metastasis-free survival (DMFS) of NPC patients (N stage, HR=1.705, 95% CI: 1.247-2.332; HR=1.755, 95% CI: 1.342-2.295; HR=2.161, 95% CI: 1.515-3.082. SII, HR=1.525, 95% CI: 1.097-2.119; HR=1.518, 95% CI: 1.150-2.004; HR=1.837, 95% CI: 1.272-2.653. LDH, HR=2.041, 95% CI: 1.403-2.968; HR=1.725, 95% CI: 1.233-2.414; HR=2.492, 95% CI: 1.690-3.672, respectively). After PSM, SII was still an independent prognostic factor of OS, PFS and DMFS in NPC patients ( HR=1.52, 95% CI: 1.09-2.12; HR=1.52, 95% CI: 1.15-2.00; HR=1.82, 95% CI: 1.26-2.63, respectively). Combined with N 2-3 stage, SII (>447.2×10 9/L), and LDH (>198.9 U/L), patients were divided into high-(3 risk factors), intermediate- (2 risk factors) and low-risk (0-1 risk factors) groups. The 5-year OS rates of patients in low-, intermediate- and high-risk groups were 86.1%, 79.8% and 41.2% respectively, the 5-year PFS rates were 80.7%, 70.2% and 33.9% respectively, and the 5-year DMFS rates were 88.9%, 79.2% and 47.5% respectively. There were significant differences in OS, PFS and DMFS among these three groups ( P<0.001). Distant metastasis was the main failure pattern in low-, intermediate- and high-risk groups, and the highest rate of distant metastasis was 83.3% (15/31) in high-risk group. ROC curve of the risk stratification model for predicting 5-year OS of NPC patients is 0.610, which is higher than TNM stage (0.609), SII (0.574) and LDH (0.558). Conclusions:Pretreatment SII and LDH are significantly correlated with the prognosis of patients with non-metastatic NPC. The combination of SII, LDH and N stage can stratify the prognostic risk of NPC patients. The risk stratification model can enhance the accuracy of prognosis.

Objective:To identify the population who can obtain clinical benefit from concurrent chemoradiotherapy through the survival analysis during concurrent chemoradiotherapy in different subgroups.Methods:All data from a phase Ⅲ randomized controlled clinical trial were collected to compare the efficacy between preoperative concurrent chemoradiotherapy and preoperative radiotherapy from 2002 to 2012 in Cancer Hospital of the Chinese Academy of Medical Sciences. A total of 222 patients received radiation therapy with a median dose of 69.96 Gy (27.56-76.00 Gy). The cisplatin chemotherapy regimen was adopted and the median dose was 250 mg (100-570 mg). In total, 98 patients received intensity-modulated radiotherapy (IMRT). The survival analysis was conducted with Kaplan- Meier method and univariate analysis was performed with log-rank test. The multivariate prognostic analysis was conducted with Cox’s regression model. Results:The median follow-up time was 59 months (7-139 months). Among them, 104 patients were assigned in the chemoradiotherapy group and 118 patients in the radiotherapy alone group. The local and regional recurrence rates did not significantly differ between two groups (both P>0.05), while chemoradiotherapy tended to decrease the distant metastasis rate compared with the radiotherapy alone (14.4% vs. 24.6, P=0.058). Univariate analysis showed that concurrent chemoradiotherapy significantly increased the local recurrence-free survival in the early N stage subgroup ( P=0.009), and there was an increasing trend in patients aged≤55 years and female patients ( P=0.052, 0.066). The distant metastasis-free survival was significantly improved in T 4( P=0.048), N 3( P=0.005), non-IMRT treatment ( P=0.001) and hypopharyngeal carcinoma ( P=0.004) subgroups, there was an increasing trend in male ( P=0.064), high-and moderate-grade squamous cell carcinoma ( P=0.076) and non-surgical treatment subgroups ( P=0.063). Multivariate analyses showed that concurrent chemoradiotherapy significantly prolonged the progression-free survival and overall survival in patients aged≤55 years ( P=0.017 and 0.039), women ( P=0.041 and 0.039), high-and moderate-grade squamous cell carcinoma ( P=0.006 and 0.022), N 3 stage ( P=0.001 and 0.017), non-surgical treatment ( P=0.007 and 0.033) and non-IMRT treatment subgroups ( P=0.030 and 0.024), and it significantly increased the progression-free survival in patients with hypopharyngeal carcinoma ( P=0.022). Conclusion:Concurrent chemoradiotherapy can be actively delivered for young age, female, high-and moderate-grade squamous cell carcinoma, N 3 stage, non-surgical treatment and non-IMRT treatment patients.

Objective: To investigate the pattern of lymph node metastasis (LNM) in patients with locally advanced (T₃, T₄) laryngeal squamous cell carcinoma (LALSC) and provide reference for the delineation of clinical target volume. Methods: Clinical data of 272 patients with LALSC treated in our hospital from 2000 to 2017 were retrospectively analyzed. All patients underwent bilateral neck dissection (at least level Ⅱ-Ⅳ). The LNM ratio of each node level was calculated. The risk factors of LNM were identified by univariate and multivariate logistic regression analyses. Results: LNM was found in 156 of 272 patients (57.1%). According to the location of primary lesions, all patients were divided into group A (n=72; unilateral without midline involvement), group B (n=86; unilateral with midline involvement) and group C (n=114; giant or central). In group A, the LNM ratio at ipsilateral level Ⅱ, Ⅲ and Ⅳ was 36.3%, 26.4% and 6.9%, whereas 13.9%, 8.3% and 1.4% at the contralateral level, respectively. In group B, the LNM ratio at ipsilateral level Ⅱ, Ⅲ and IV was 1.9%, 29.1% and 11.6%, whereas 18.6%, 14.0% and 1.2% at the contralateral level, respectively. In group C, the LNM ratio at the left neck level Ⅱ, Ⅲ and Ⅳ was 24.6%, 23.7% and 2.6%, whereas 21.9%, 26.3% and 6.1% at the right neck, respectively. Bilateral LNM ratio did not significantly differ between group A and group B/C (15.3%, 25.0%, P=0.093). Ipsilateral level Ⅲ metastasis (OR=2.929, 95%CI 1.041-8.245, P=0.042) and clinical N stage (OR=0.082, 95%CI 0.018-0.373, P=0.001) were associated with contralateral LNM. Ipsilateral level Ⅱ(P=0.043) or Ⅲ(P=0.009) metastasis were risk factors of the ipsilateral level Ⅳ metastasis. Conclusions Neck levels Ⅱ and Ⅲ are the high-risk LNM regions, whereaslevels Ⅳ and V are the low-risk areas. Ipsilateral level Ⅱ or Ⅲ metastases are the risk factors of ipsilateral level Ⅳ and contralateral cervical LNM. Contralateral neck LNM rarely occurs in cN₀ stage patients.

Background: Carbohydrate antigen 72-4 (CA72-4) is generally recognized as a tumor marker of digestive system. However, elevated serum CA72-4 level is also evident in many benign diseases and healthy subjects, and its sensitivity in diagnosing malignant tumor is quite poor. Aims: To reassess the value of CA72-4 in tumor screening and diagnosis. Methods: Three cohorts were established in this study. Inpatients who underwent a serum CA72-4 measurement and had a definite final diagnosis were included into Cohort 1 (retrospective study). Inpatients with elevated serum CA72-4 level who had not been diagnosed as malignant tumor before admission were included into Cohort 2 (retrospective study). Individuals who underwent a serum CA72-4 measurement and willing to take a follow-up for at least 2 years were included into Cohort 3 (prospective study). Malignancies had been preliminarily excluded in all individuals in Cohort 3 before enrollment. Results: Among the 2 173 patients recruited in Cohort 1, the prevalence of positive serum CA72-4 was significantly higher in patients with malignancies than those without (16.4% vs. 7.4%, P<0.05). The sensitivity and specificity of CA72-4 for diagnosis of malignant tumor were 36.5% and 76.2%, respectively, at the cut-off value (2.955 U/mL) identified by ROC curve analysis. Among the 1 807 patients recruited in Cohort 2, most of the participants (76.5%) did not have malignancies. Serum CA72-4 level was associated with the histological classification, tumor differentiation and TNM staging of malignancies (P<0.05). Among the 376 individuals who underwent a follow-up for no less than 2 years in Cohort 3, elevated serum CA72-4 level did not increase the risk of malignant tumor (OR=1.268, 95% CI: 0.283-5.687). Conclusions: CA72-4 is not a sensitive marker for tumor screening, its value as an item in physical examination should be re-evaluated. In patients who had positive serum CA72-4 and malignant tumor was ruled out in initial examination, the necessity of long-term follow-up of serum CA72-4 needs to be discussed.

Objective:To compare the effects of comprehensive treatment with different combinations of radiotherapy, chemotherapy and surgery on the survival of patients with locally advanced head and neck squamous cell carcinoma (LA-HNSCC).Methods:From September 2002 to May 2012, 222 patients were enrolled in a randomized controlled clinical trial to compare the clinical efficacy between preoperative radiotherapy and preoperative concurrent chemoradiotherapy. The chemotherapy was performed at the beginning of the radiotherapy, with cisplatin 30 mg/m 2 every week. Conventional radiotherapy or intensity-modulated radiotherapy (IMRT) was adopted. Clinical efficacy was evaluated during radiotherapy to 50 Gy in all patients. Whether surgery or original treatment regime was given was determined according to the clinical efficacy. The survival of different therapeutic methods was analyzed by Kaplan- Meier method. Results:The median follow-up time was 59 months (7-139 months). All patients were divided into four groups: radiotherapy group (R group, n=84), concurrent chemo-radiotherapy group (R+ C group, n=67), preoperative radiotherapy group (R+ S group, n=34) and preoperative concurrent chemoradiotherapy group (R+ C+ S group, n=37). The 5-year overall survival rates were 32%, 44%, 51%, and 52%, respectively (R+ C+ S group vs. R group, P=0.047). The 5-year progression-free survival rates were 34%, 48%, 49%, and 61%, respectively (R+ C Group vs. R group, P=0.081; R+ C+ S group vs. R group, P=0.035). The 5-yeal distant metastasis-free survival rates were 70%, 85%, 65%, and 73%, respectively (R+ C group vs. R+ S group, P=0.064; R+ C group vs. R+ S group, P=0.016). Conclusions:Compared with radiotherapy alone, comprehensive treatment with different combinations can improve the long-term survival of LA-HNSCC patients. Radiotherapy combined with chemotherapy has a tendency to improve the distant metastasis-free survival rate, The optimal comprehensive treatment modality that improves the overall survival of LA-HNSCC patients remains to be explored.

Objective:To analyze the incidence and high-risk factors of lymph node metastasis in the retropharyngeal region of hypopharyngeal squamous cell carcinoma based on magnetic resonance imaging (MRI), aiming to guide the delineation of clinical target area.Methods:Clinical data of patients who were pathologically diagnosed with hypopharyngeal carcinoma from January 2012 to September 2018 in our center were retrospectively analyzed. All patients received head and neck MRI before treatment. The diagnosis of lymph node metastasis and the delineation of primary gross target volume (GTV p) and lymph nodes target volume (GTV nd) were determined by all the radiation oncologists in head and neck group through twice weekly general round discussion. The cut-off points of GTV p and GTV nd were defined by establishing the receiver operating characteristic curve. All patients were divided into the high GTV p, low GTV p and high GTV nd and low GTV nd groups. Chi-square test was used for univariate analysis and logistic regression was utilized for multivariate analysis to analyze the high-risk factors of patients with retropharyngeal lymph node metastasis. Results:A total of 326 patients were included in this study, 295 of whom were diagnosed with cervical lymph node metastasis, accounting for 90.5%. The most common involved area was Level Ⅱ a, followed by Level Ⅲ, Level Ⅱ b, Level IV, Level Ⅶ a (retropharyngeal), Level V a, and Level V b. The incidence of retropharyngeal lymph node metastasis was 21.5%, and the incidence was 53.1% in patients with primary tumor located in the posterior pharyngeal wall. Univariate and multivariate analyses showed that patients with tumor originated from the posterior pharyngeal wall ( P=0.002), bilateral cervical lymph node metastasis ( P=0.020), larger GTV p (greater than 47 cm 3, P=0.003), and larger GTV nd (greater than 22 cm 3, P=0.023) were significantly associated with the occurrence of retropharyngeal lymph node metastasis. Conclusions:The incidence of retropharyngeal lymph node metastasis is high in hypopharyngeal carcinoma, especially in patients with primary tumors in the posterior pharyngeal wall, bilateral cervical lymph node metastasis and larger primary burden. Therefore, for patients with these risk factors, it is highly recommended that the clinical target area should be delineated to include the retropharyngeal lymph node drainage area.