A novel SIK2 inhibitor SIC-19 exhibits synthetic lethality with PARP inhibitors in ovarian cancer.

PURPOSE: Ovarian cancer patients with HR proficiency (HRP) have had limited benefits from PARP inhibitor treatment, highlighting the need for improved therapeutic strategies. In this study, we developed a novel SIK2 inhibitor, SIC-19, and investigated its potential to enhance the sensitivity and expand the clinical utility of PARP inhibitors in ovarian cancer. METHODS: The SIK2 protein was modeled using a Molecular Operating Environment (MOE), and the most favorable model was selected based on a GBVI/WSA dG scoring function. The Chembridge Compound Library was screened, and the top 20 candidate compounds were tested for their interaction with SIK2 and downstream substrates, AKT-pS473 and MYLK-pS343. SIC-19 emerged as the most promising drug candidate and was further evaluated using multiple assays. RESULTS: SIC-19 exhibited selective and potent inhibition of SIK2, leading to its degradation through the ubiquitination pathway. The IC50 of SIC-19 correlated inversely with endogenous SIK2 expression in ovarian cancer cell lines. Treatment with SIC-19 significantly inhibited cancer cell growth and sensitized cells to PARP inhibitors in vitro, as well as in ovarian cancer organoids and xenograft models. Mechanistically, SIK2 knockdown and SIC-19 treatment reduced RAD50 phosphorylation at Ser635, prevented nuclear translocation of RAD50, disrupted nuclear filament assembly, and impaired DNA homologous recombination repair, ultimately inducing apoptosis. These findings highlight the crucial role of SIK2 in the DNA HR repair pathway and demonstrate the significant PARP inhibitor sensitization achieved by SIC-19 in ovarian cancer. CONCLUSIONS: SIC-19, a novel SIK2 inhibitor, effectively inhibits tumor cell growth in ovarian cancer by interfering with RAD50-mediated DNA HR repair. Furthermore, SIC-19 enhances the efficacy of PARP inhibitors, providing a promising therapeutic strategy to improve outcomes for ovarian cancer patients.

Adverse outcomes in subsequent pregnancies in women with history of recurrent spontaneous abortion: A meta-analysis.

OBJECTIVE: This study aimed to investigate the association between a history of recurrent spontaneous abortion (RSA) and adverse outcomes in women with spontaneous conception. METHODS: A search strategy from the inception to March 3, 2023 was run in PubMed, Embase, Cochrane Library, and Web of Science databases. The odds ratio (OR), and the 95% confidence interval (CI) or point estimation were used as the evaluation indexes. Each outcome measure tested was assessed for heterogeneity using the Cochran Q test. Sensitivity analyses were performed to test the credibility of the meta-analysis results. RESULTS: Fifteen studies involving 1 475 389 pregnant women were included. A history of RSA was associated with gestational diabetes (OR: 2.21, 95% CI: 1.70-2.87, p < 0.001), preeclampsia (OR: 2.06, 95% CI: 1.49-2.86, p < 0.001), placenta previa (OR: 1.82, 95% CI: 1.09-3.02, p = 0.021), placental abruption (OR: 1.67, 95% CI: 1.36-2.06, p < 0.001), miscarriage (OR: 6.37, 95% CI: 3.83-10.57, p < 0.001), preterm birth (OR: 1.80, 95% CI: 1.36-2.37, p < 0.001), cesarean section (OR: 1.47, 95% CI: (1.13-1.91, p = 0.004), perinatal death (OR: 2.24, 95% CI: 1.39-3.60, p = 0.001), and neonatal intensive care unit admission (OR: 1.39, 95% CI: 1.01-1.92, p = 0.047). However, the associations of a history of RSA with gestational hypertension, small for gestational age, fetal anomalies, fetal growth restriction, and postpartum hemorrhage were not observed. CONCLUSION: This meta-analysis indicates a history of RSA was associated with increased risks of several adverse outcomes in pregnant women with spontaneous conception.

[Zuogui Pills and Yougui Pills in differential treatment of diminished ovarian reserve based on metabolomics].

Based on the metabolomics, this paper systematically analyzed the metabolic substance basis of Zuogui Pills and Yougui Pills in syndrome differentiation and treatment of diminished ovarian reserve(DOR), so as to provide a scientific basis for the traditional Chinese medicine(TCM) syndrome differentiation and treatment of DOR. Patients with DOR of kidney-Yin deficiency syndrome were collected from outpatient department of hospitals and treated with Zuogui Pills for 12 weeks. And kidney-Yang deficiency syndrome were treated with Yougui Pills for 12 weeks. Based on the non-targeted metabolomic research techniques, the potential biomarkers of Zuogui Pills and Yougui Pills in the treatment of DOR with kidney-Yin deficiency and kidney-Yang deficiency, respectively, were screened out, and metabolic pathways of biomarkers were analyzed. The pregnancy rate, basic serum hormone levels [basal follicle-stimulating hormone(bFSH), basal-luteinizing hormone(bLH), basal-estradiol(bE_2), and anti-Müllerian hormone(AMH)], TCM syndrome type score, and Kupperman score were recorded and statistically analyzed after treatment. The results showed that 23 patients with DOR of kidney-Yin deficiency syndrome and 25 patients of kidney-Yang deficiency syndrome were collected. Twenty-six differential metabolites, including L-carnitine, acetyl-CoA, coenzyme A, and coenzyme Q_(10)(CoQ10), were mapped to 12 metabolic pathways in patients with kidney-Yin deficiency treated with Zuogui Pills. Twenty-two differential metabolites, such as adipoyl-CoA, L-lysine, lysine arginine, and α-tocopherol, were mapped to 11 metabolic pathways in patients with kidney-Yang deficiency. After treatment, bFSH and bLH of patients with DOR were significantly lower than those before treatment(P<0.05). Although the comparison of bE_2 and AMH had no significant differences, there was a improvement trend. The TCM syndrome type score and Kupperman score of patients with DOR after TCM treatment were significantly lower than those before treatment(P<0.05).

An Analysis of the Clinical Medication Rules of Traditional Chinese Medicine for Polycystic Ovary Syndrome Based on Data Mining.

Objective: The aim of the present study is to investigate the rules and characteristics of the clinical administration of traditional Chinese medicine (TCM) in the treatment of polycystic ovary syndrome (PCOS) using data mining methods. Method: Medical cases of well-known contemporary TCM doctors treating PCOS were collected from the China National Knowledge Infrastructure, Chinese Biomedical Literature Service System, Wanfang, Chinese Scientific Journals Database, and PubMed; the data were then characterized, and a standardized database of medical cases was built. This database was used to (1) count the frequency of syndrome types and the herbs used in medical cases by data mining methods and (2) analyze drug association rules and systematic clustering methods. Results: A total of 330 papers were included, involving 382 patients and a total of 1,427 consultations. The most common syndrome type was kidney deficiency; sputum stasis was the core pathological product and causative factor. A total of 364 herbs were used. Among them, 22 herbs were used >300 times, including Danggui (Angelicae Sinensis Radix), Tusizi (Semen Cuscutae), Fuling (Poria), Xiangfu (Nutgrass Galingale Rhizome), and Baizhu (Atractylodis Macrocephalae Rhizoma). Additionally, 22 binomial associations were obtained from the analysis of association rules; five clustering formulae were obtained via the analysis of high-frequency drug clusters; and 27 core combinations were obtained by k-means clustering of formula. Conclusion: In the treatment of PCOS, TCM is primarily employed as a combination approach involving tonifying the kidneys, strengthening the spleen, eliminating damp and dissolving phlegm, activating blood circulation, and resolving blood stasis. The core prescription is primarily a compound intervention based on the Cangfu Daotan pill, Liuwei Dihuang pill, and Taohong Siwu decoction.

Facile fabrication of a biodegradable multi-hollow iron phosphate nanoplatform for tumor-specific nanocatalytic therapy and chemotherapy.

In this study, a type of biodegradable multi-hollow iron phosphate (FeP) with excellent Fenton reaction ability and doxorubicin (DOX) loading capacity is synthesized in one-pot. This hollow FeP with complex interior not only affords high drug loading efficiency, but also obviates DOX leakage in normal tissues. In order to inhibit the formation of inert Fe(OH)x and endow the nanoplatform with a highly hydrophilic surface, PEG was anchored to it with a dopamine linkage, which formed an Fe chelating complex. DOX-loaded FeP modified with PEG could be disintegrated when responding to the lysosomal acid environment, releasing both ferric and ferrous ions as well as DOX. Therefore, apart from chemotherapy with DOX, the continuously generated iron ions catalyze a fast Fenton reaction with the innate H2O2 in tumor cells and produce abundant highly toxic hydroxyl radicals for nanocatalytic tumor therapy. Taken together, we believe that this nanoplatform will significantly advance the fields of both Fe-based nanomaterials and nanocatalytic tumor therapy.

ThinPrep cytologic test combined with HPV typing to evaluate the degree of cervical diseases and the relationship between HPV typing and the pathological results of patients with atypical squamous cells of undetermined significance: a diagnostic test.

Background: Persistent infection with high-risk human papilloma virus (HPV) is the main cause of cervical cancer. Cervical precancerous lesions last for long and are reversible. Thus, the effective way to prevent cervical cancer is to make a timely diagnosis and administer treatment in the precancerous stage. This study sought to explore the evaluation of cervical cytology by a ThinPrep cytologic test (TCT) combined with HPV typing in patients with cervical diseases, and the relationship between HPV typing and the pathological results of patients with atypical squamous cells of undetermined significance (ASCUS). Methods: The medical records of 414 patients who received outpatient treatment at the Suzhou Hospital of Traditional Chinese Medicine from February 2020 to February 2022. The pathological results of all cases were followed-up, and data on patients' age, menopause, pregnancy status, birth status, HPV typing, and HPV infection status were collected and statistically analyzed. The positive predictive value, negative predictive value, sensitivity, and specificity of the 2 detection methods were calculated. The factors associated with ASCUS pathological results were analyzed by logistic regression. Results: Among the 414 patients, 230 had positive vaginal tissue biopsy results, taking this as the gold standard, the diagnostic value of TCT and HPV were examined and compared. HPV typing had a slightly higher sensitivity and positive predictive value than TCT; however, the 2 methods combined had the highest sensitivity and positive predictive value. The univariate analysis showed that the age, HPV infection, and HPV typing in the group of chronic cervicitis differed significantly from the group of cervical intraepithelial neoplasia (CIN) II+/cervical carcinoma (P<0.05). The logistic regression analysis showed that HPV infection, being HPV-16 positive, and being HPV-18 positive were risk factors of ASCUS disease (P<0.05). Conclusions: Compared to individual detection methods, TCT combined with HPV typing had a higher detection rate and screening accuracy for cervical diseases, and had the highest sensitivity and positive predictive value. HPV infection, being HPV-16 positive, and being HPV-18 positive are risk factors for ASCUS lesions. HPV typing detection can improve the accuracy of ASCUS shunt diagnosis and provide a reliable basis for the establishment of ASCUS shunt management.

Genetic polymorphisms in DNA repair genes and their association with risk of cervical cancer: A systematic review and meta-analysis.

BACKGROUND: There have been a large number of epidemiologic studies regarding the association between genetic polymorphisms in DNA repair genes and onset of cervical cancer. However, results are inconsistent. METHODS: Articles published before June 2021 and regarding genetic polymorphisms in DNA repair genes and cervical cancer were searched in following databases: PubMed, Web of Science, Google Scholar, and CNKI. With at least three articles for each polymorphism, we made meta-analysis to compute multivariate odds ratios (ORs) and their 95% confidence intervals (CIs). RESULTS: The present study showed significant associations between XRCC1 Arg399Gln polymorphisms and risk of cervical cancer in Asian, whereas no significant association between them were showed in Caucasian (Asian: GA vs. GG: OR = 1.27, 95%CI 1.06-1.52; AA vs. GG: OR = 1.91, 95%CI 1.29-2.83; GA + AA vs. GG: OR = 1.36, 95%CI 1.12-1.65; AA vs. GG + GA: OR = 1.66, 95%CI 1.17-2.37; Caucasian: GA vs. GG: OR = 1.08, 95%CI 0.83-1.41; AA vs. GG: OR = 2.18, 95%CI 0.75-6.31; GA + AA vs. GG: OR = 1.23, 95%CI 0.85-1.78; AA vs. GG + GA: OR = 1.70, 95%CI 0.69-4.18). In addition, there were significant associations between ERCC2 rs13181 polymorphisms and risk of cervical cancer in Asian (AC vs AA: OR = 0.53, 95%CI 0.37-0.75, I2 = 0.0%, p value of Q test = 0.847; AC + CC vs AA: OR = 0.50, 95%CI 0.36-0.70, I2 = 0.0%, p value of Q test = 0.856). CONCLUSIONS: The meta-analysis showed that there were significant associations between XRCC1 Arg399Gln and ERCC2 rs13181 polymorphisms and risk of cervical cancer.

Pressure-driven accumulation of Mn-doped mesoporous silica nanoparticles containing 5-aza-2-deoxycytidine and docetaxel at tumours with a dry cupping device.

Drug delivery with the help of nanoparticles could transport more payloads to tumour site. Owing to their limited accumulation and penetration in the tumour tissues, to increase delivery efficiency is currently still required for applying nanomedicine to treat tumour. Here, we initially report a pressure-driven accumulation of drug-loaded nanoparticles to tumours for efficient tumour therapy with a dry cupping device. The mesoporous Mn-doped silica based nanoparticles delivering 5-aza-2-deoxycytidine and docetaxel were prepared, characterised and used as a model nanomedicine to investigate the potential of dry cupping treatment. For this system, the Mn doping not only endowed the mesoporous silica nanoparticles biodegradability, but also made it much easier to bind a tumour targeting group, which is a G-quadruplex-forming aptamer AS1411. On tumour-bearing mice, the in vivo results demonstrated that the dry cupping treatment could substantially improve the distribution of nanomedicines at tumour site, resulting in enhanced treatment efficacy. Overall, this method enables the therapeutical nanoparticles accumulate to tumour through increasing the blood perfusion as well as altering the biological barrier, which opened up possibilities for the development of pressure-driven nanomedicine accumulation at tumour site.

LINC00665 promotes Ovarian Cancer progression through regulating the miRNA-34a-5p/E2F3 axis.

Objective: To clarify the role of LINC00665 in ovarian cancer (OC) progression and the possible mechanism. Methods: LINC00665 levels in OC tissues and cell lines were detected by qRT-PCR. The correlation between LINC00665 and clinicopathologic characteristics of OC patients was assessed. Biological functions of OC cell phenotypes influenced by LINC00665 were examined by CCK-8, colony formation and Transwell assay. Dual-luciferase reporter assay and RIP assay were conducted to verify the interaction between LINC00665 and its downstream target. Results: LINC00665 was upregulated in OC and linked to poor prognosis. Knockdown of LINC00665 blocked malignant proliferative, migratory and invasive functions of OC cells. By competitively binding miRNA-34a-5p, LINC00665 abolished the inhibitory effect of miR-34a-3p on its downstream gene E2F3, thus promoting OC progression. Conclusion: LINC00665/miRNA-34a-5p/E2F3 axis is involved in OC progression, providing novel insights into the clinical treatment of OC.