Lysine-Specific Demethylase 1 Inhibitors: A Comprehensive Review Utilizing Computer-Aided Drug Design Technologies.

Lysine-specific demethylase 1 (LSD1/KDM1A) has emerged as a promising therapeutic target for treating various cancers (such as breast cancer, liver cancer, etc.) and other diseases (blood diseases, cardiovascular diseases, etc.), owing to its observed overexpression, thereby presenting significant opportunities in drug development. Since its discovery in 2004, extensive research has been conducted on LSD1 inhibitors, with notable contributions from computational approaches. This review systematically summarizes LSD1 inhibitors investigated through computer-aided drug design (CADD) technologies since 2010, showcasing a diverse range of chemical scaffolds, including phenelzine derivatives, tranylcypromine (abbreviated as TCP or 2-PCPA) derivatives, nitrogen-containing heterocyclic (pyridine, pyrimidine, azole, thieno[3,2-b]pyrrole, indole, quinoline and benzoxazole) derivatives, natural products (including sanguinarine, phenolic compounds and resveratrol derivatives, flavonoids and other natural products) and others (including thiourea compounds, Fenoldopam and Raloxifene, (4-cyanophenyl)glycine derivatives, propargylamine and benzohydrazide derivatives and inhibitors discovered through AI techniques). Computational techniques, such as virtual screening, molecular docking and 3D-QSAR models, have played a pivotal role in elucidating the interactions between these inhibitors and LSD1. Moreover, the integration of cutting-edge technologies such as artificial intelligence holds promise in facilitating the discovery of novel LSD1 inhibitors. The comprehensive insights presented in this review aim to provide valuable information for advancing further research on LSD1 inhibitors.

Comparison of long-term bowel symptoms after laparoscopic radical hysterectomy versus abdominal radical hysterectomy in patients with cervical cancer.

INTRODUCTION AND HYPOTHESIS: The objective of this study was to compare the long-term bowel symptoms between laparoscopic radical hysterectomy (LRH) and abdominal radical hysterectomy (ARH) in patients with cervical cancer. METHODS: A total of 207 patients who underwent radical hysterectomy (79 underwent LRH and 128 underwent ARH) at Peking University First Hospital from January 2010 to August 2020 were enrolled and their bowel symptoms were investigated using the Colorectal Anal Distress Inventory-8 (CRADI-8) of the Pelvic Floor Distress Inventory-20. The prevalence and severity of bowel symptoms were compared in the LRH and ARH groups, and multivariate analysis was performed to determine the factors associated with bowel symptoms. RESULTS: There was no difference in the CRADI-8 scores between the two groups. However, the prevalence of straining at stool was significantly higher in the ARH group than in the LRH group (19.5% versus 1.3%, p<0.001), and the score was significantly higher in the ARH group than in the LRH group too (0.4 versus 0, p<0.001). The prevalence of incomplete defecation was significantly higher in the ARH group than in the LRH group (13.3% versus 3.8%, p=0.029), and the ARH group also had a significantly higher score than the LRH group (0.3 versus 0.1, p=0.028). Multivariate analysis showed that ARH and postoperative interval were independent risk factors for the development of straining at stool. CONCLUSIONS: Patients with cervical cancer who underwent ARH may be more likely to develop symptoms related to constipation than those who underwent LRH. This finding has to be interpreted with caution owing to the study design.

Assessment of long-term sexual function of cervical cancer survivors after treatment: A cross-sectional study.

OBJECTIVES: This study aimed to investigate the long-term sexual function of patients with cervical cancer who underwent treatment and to explore influential factors. METHODS: This retrospective cross-sectional study was conducted at Peking University First Hospital in (Beijing, China). A total of 207 patients, who were diagnosed with Stage IA-IIA cervical cancer and had undergone surgical treatment (some patients had also been treated with adjuvant radiotherapy and chemotherapy) between January 2010 and August 2020, completed questionnaires via telephone. The median time since diagnosis was 54 (range, 13-138) months. Sexual function was assessed using the validated short form of Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire (PISQ-12). The multivariate logistic regression analysis was performed to determine factors influencing sexual function after treatment. RESULTS: The mean preoperative PISQ-12 score was 39.42 ± 3.922, and the mean postoperative PISQ-12 score was 32.60 ± 6.592, indicating a significant decrease in postoperative PISQ-12 score compared with preoperation (p < 0.001). In total, 49.8% of the patients had sexual dysfunction after treatment. According to the results of the multivariate logistic regression analysis, longer follow-up (months), ovariectomy, lack of hormone replacement therapy after ovariectomy and adjuvant radiotherapy were significantly associated with sexual dysfunction after treatment (p < 0.05). There was no significant correlation among surgical method, tumor stage, adjuvant chemotherapy, and sexual dysfunction after treatment. CONCLUSIONS: The sexual function of cervical cancer survivors significantly decreased after treatment, which was related to the length of follow-up, ovariectomy, and adjuvant radiotherapy. Hormone replacement therapy after ovariectomy can help patients to improve their sexual function.

Demethylase FTO-mediated m6A modification of SIK1 modulates placental cytotrophoblast syncytialization in type 2 diabetes mellitus.

Type 2 diabetes mellitus (T2DM) represents a common complication during pregnancy that affects fetoplacental development. We demonstrated the existence of impaired trophoblast syncytialization under hyperglycemic conditions. However, the exact mechanism remains unknown. RNA N6-methyladenosine (m6A) is an emerging regulatory mechanism of mRNA and participates in various biological processes. We described the global m6A modification pattern in T2DM placenta by the combined analysis of methylated RNA immunoprecipitation sequencing (MeRIP-Seq) and RNA sequencing (RNA-Seq). Both the m6A modification and expression of SIK1, which is critical for syncytialization, were significantly decreased in trophoblast exposed to hyperglycemic conditions. In addition, the m6A demethylase fat mass and obesity-associated protein (FTO) affects the expression and mRNA stability of SIK1 by binding to its 3'-untranslated region (UTR) m6A site. This work reveals that the FTO-m6A-SIK1 axis plays critical roles in regulating syncytialization in the placenta.

Predicting Natural Evolution in the RBD Region of the Spike Glycoprotein of SARS-CoV-2 by Machine Learning.

Machine learning (ML) is a key focus in predicting protein mutations and aiding directed evolution. Research on potential virus variants is crucial for vaccine development. In this study, the machine learning software PyPEF was employed to conduct mutation analysis within the receptor-binding domain (RBD) of the Spike glycoprotein of SARS-CoV-2. Over 48,960,000 variants were predicted. Eight prospective variants that could surface in the future underwent modeling and molecular dynamics simulations. The study forecasts that the latest variant, ISOY2P5O1, may potentially emerge around 17 November 2023, with an approximate window of uncertainty of ±22 days. The ISOY8P5O2 variant displayed an increased binding capacity in the dry assay, with a total predicted binding energy of -110.306 kcal/mol. This represents an 8.25% enhancement in total binding energy compared to the original SARS-CoV-2 strain discovered in Wuhan (-101.892 kcal/mol). Reverse research confirmed the structural significance of mutation sites using ML models, particularly in the context of protein folding. The study validated regression methods (SVR, RF, and PLS) with different data structures. This study investigates the effectiveness of the "ML-Guided Design Correctly Predicts Combinatorial Effects Strategy" compared to the "ML-Guided Design Correctly Predicts Natural Evolution Prediction Strategy". To enhance machine learning, we created a timestamping algorithm and two auxiliary programs using advanced techniques to rapidly process extensive data, surpassing batch sequencing capabilities. This study not only advances machine learning in guiding protein evolution but also holds potential for forecasting future viruses and vaccine development.

Predictors of posttraumatic growth of the family members of neurosurgical intensive care unit patients: A cross-sectional study.

OBJECTIVES: Confronted with the potentially traumatic experience of a patients intensive care unit hospitalisation, family members may show positive changes associated with growth in addition to negative impact. This study aimed to identify the level of posttraumatic growth of the family members of neurosurgical intensive care unit patients and to explore its relation to positive personality characteristics, such as gratitude, resilience and hope. DESIGN AND SETTING: A cross-sectional study involving 340 family members of patients admitted to the neurosurgical intensive care unit at a general tertiary hospital in Shanghai, China. METHODS: Before the patients' hospital discharge, the participants completed questionnaires, assessing posttraumatic growth (PTG Inventory), social support (Social Support Rating Scale), resilience (Chinese version of the Connor-Davidson Resilience Scale), hope (Herth Hope Index) and gratitude (Gratitude Questionnaire Six-Item Form). RESULTS: The mean total posttraumatic growth score was 73.38 (14.02). Hope, gratitude, resilience and social support showed a positive correlation with the posttraumatic growth Inventory scores. There were significant differences in the posttraumatic growth scores of the family members of neurosurgical intensive care patients with respect to their different religious beliefs, payment methods, family relationship quality and presence of chronic diseases among family members. Multiple linear regression analysis showed that gratitude, resilience and social support were independent predictors of the posttraumatic growth Inventory score. CONCLUSION: Family members may experience some degree of posttraumatic growth during hospitalisation of patients in the neurosurgical intensive care units. Gratitude, social support and resilience are predictive factors for posttraumatic growth.

Effect of ERAS Combined with Comfortable Nursing on Quality of Life and Complications in Femoral Neck Fractures of the Aged People.

OBJECTIVE: To explore the effect of enhanced recovery after surgery (ERAS) combined with comfortable nursing on the quality of life and complications of elderly patients with femoral neck fracture (FNF). METHODS: From May 2019 to May 2020, 80 senile FNF patients who admitted to our hospital were treated by total hip arthroplasty (THA). All patients were randomly divided upon admission into a control group (CG) with usual care and a study group (RG) with ERAS combined with comfort care of 40 patients each. The postoperative efficacy was assessed by Harris score of hip joint function, and the psychology was evaluated by self-rating anxiety scale (SAS). The SF-36 score of quality of life, the time of catheter removal, the time of getting out of bed, the hospital stays, the satisfaction of nursing, and the Barthel score of self-care ability were compared between the two groups before and after nursing, and the incidence of postoperative complications was also evaluated. RESULTS: Compared with the CG, the SF-36 score of quality of life and Barthel score of self-care ability in the RG were dramatically higher, while the SAS score of anxiety was dramatically lower. Besides, the time of catheter removal, the time of getting out of bed, and the hospital stays in the RG were dramatically lower (P < 0.05). Furthermore, the nursing satisfaction and postoperative efficacy of patients in the RG were obviously higher (both P < 0.05), while the incidence of complications in the RG was obviously lower (P < 0.05). CONCLUSION: ERAS combined with comfortable nursing can improve the hip joint function, quality of life, and self-care ability scores of senile FNF patients; relieve the anxiety in patients; and reduce the incidence of postoperative complications, which is valuable to be applied extensively.