I2/CF3CO2Ag-mediated iodolactonization of various allenoic acids to access versatile 6- to 9-membered ring vinylic iodolactones.

Medium-sized lactones are important structural units, but their synthesis remains a great challenge. Herein, we report I2/CF3CO2Ag-mediated iodolactonization of allenoic acids to synthesize various 6- to 9-membered ring vinylic iodolactones in 16-89% yield. This protocol not only develops a new cyclization strategy of allenoic acids, but also provides highly functionalized medium-sized lactones containing alkene and halogen groups.

Qualitative and quantitative simulation of best management practices (BMPs) for contaminated megasite remediation using the SiteWise™ tool.

Remediation activities, particularly in megasites, may induce substantial secondary environmental impacts that must be addressed for green and sustainable remediation (GSR) practices. Only limited studies are available quantitatively assessing the environmental footprint and environmental benefits of implementing Best Management Practices (BMPs) in megasite remediation. This study used the SiteWise™ tool, a quantitative environmental footprint assessment for scenario simulation and benefit quantification of BMPs, on a contaminated megasite in Hebei Province, China. We observed a considerable environmental footprint and energy from the remediation. Taking the final implementation alternative (Alt 1) as an example, which is characterized by combining multiple remediation techniques, the greenhouse gas (GHG) emissions reached 113,474 t, the energy used was 2,082,841 million metric British thermal units (MMBTU), and other air pollutant emissions (NOx, SOx, and PM10) amounted to 856 t. Further BMP analyses highlighted the benefits of substituting the conventional solidification/stabilization agent with willow woodchip-based biochar, which could reduce GHG emissions by 50,806 t and energy used by 926,648 MMBTU. The overall environmental benefits of implementing all applicable BMPs in the remediation were significant, with a 66.85%, 50.15%, and 56.05% reduction in GHG emissions, energy used, and other air pollutants, respectively. Our study provides insights into quantifying the environmental footprint and exploring emission reduction pathways for contaminated megasite remediation. It also offers a feasible path for quantifying the environmental benefits of BMPs, promoting the development of GSR of contaminated sites.

Gefitinib, an effective treatment option for patients with pulmonary enteric adenocarcinoma harboring compound EGFR L858R and A871G mutation.

Pulmonary enteric adenocarcinoma (PEAC) is a rare lung adenocarcinoma with morphological and immunohistochemical similarities to colorectal adenocarcinoma and intestinal differentiation. PEAC belongs to the group of non-small-cell lung carcinoma (NSCLC) and is defined as having a more than 50% intestinal differentiation component. We report a postoperative (T4N2M0 stage IIIb) PEAC patient with EGFR L858R + A871G combined mutation. Following surgery, the patient underwent treatment with the first-generation EGFR-TKI, gefitinib, and achieved an impressive 5-year progression-free survival (PFS). This suggests that gefitinib may serve as an effective treatment option for PEAC patients with EGFR L858R + A871G compound mutations.

MiR-214-3p suppresses cervical cancer cell metastasis by downregulating THBS2.

Cervical cancer (CC) is the most common human gynecological malignancy worldwide. Recently, accumulating evidences revealed the critical functions of miRNAs in the occurrence and development of cervical cancer. In our study, we aimed to demonstrate the function of miR-214-3p in regulating cell metastasis in cervical cancer. We showed low expression of miR-214-3p in cervical cancer cells and demonstrated downregulation of miR-214-3p promoted cervical cancer metastasis. Furthermore, THBS2 was identified as a novel target of miR-214-3p in cervical cancer cells. miR-214-3p suppressed THBS2 expression by directly targeting 3'UTR of THBS2, resulting in the inhibition of cell viability, invasion and migration. Taken together, the results implied inhibited effects of miR-214-3p on cervical cancer and provided new insight into potential ways for cervical cancer diagnosis and treatment.

Identification of N1 methyladenosine-related biomarker predicting overall survival outcomes and experimental verification in ovarian cancer.

AIM: This study aimed to construct a N1-methyladenosine (m1A)-related biomarker model for predicting the prognosis of ovarian cancer (OVCA). METHODS: OVCA samples were clustered into two subtypes using the Non-Negative Matrix Factorization (NMF) algorithm, including TCGA (n = 374) as the training set and GSE26712 (n = 185) as the external validation set. Hub genes, which were screened to construct a risk model, and nomogram to predict the overall survival of OVCA were explored and validated through various bioinformatic analysis and quantitative real-time PCR. RESULTS: Following bootstrap correction, the C-index of nomogram was 0.62515, showing reliable performance. The functions of DEGs in the high- and low-risk groups were mainly enriched in immune response, immune regulation, and immune-related diseases. The immune cells relevant to the expression of hub genes were explored, for example, Natural Killer (NK) cells, T cells, activated dendritic cells (aDC). CONCLUSIONS: AADAC, CD38, CACNA1C, and ATP1A3 might be used as m1A-related biomarkers for OVCA, and the nomogram labeled with m1A for the first time had excellent performance for predicting overall survival in OVCA.

Effects of miR-202-5p silencing PIK3CA gene expression on proliferation, invasion, and epithelial-mesenchymal transition of cervical cancer SiHa cells through inhibiting PI3K/Akt/mTOR signaling pathway activation.

To explore the mechanism of miR-202-5p targeting the expression of PIK3CA and mediating the activation of PI3K/Akt/mTOR signaling pathway on the proliferation, invasion, and epithelial-mesenchymal transition (EMT) of cervical cancer. The objects of study were 105 cases of cervical cancer and their corresponding normal tissues. qRT-PCR was used to detect the expression of miR-202-5p and PIK3CA in adjacent normal tissue and cervical cancer tissue. Dual luciferase reporter assay was used to verify the targeting relationship between miR-202-5p and PIK3CA gene. Human cervical cancer cell lines HPV-16E6, SiHa, HeLa, and CaSki were purchased for our cell experiments. The expression levels of PIK3CA in the cells were detected by qRT-PCR. The cell line with higher expression levels was selected to complete the follow-up experiment. The cultured cells were transfected and divided into the miR-202-5p mimic NC group, miR-202-5p mimic group, miR-202-5p inhibitor NC group, miR-202-5p inhibitor group, siRNA-PIK3CA NC group, siRNA-PIK3CA group, miR-202-5p inhibitor NC + siRNA-PIK3CA NC group, miR-202-5p inhibitor + siRNA-PIK3CA NC group, and miR-202-5p inhibitor + siRNA-PIK3CA group. QRT-PCR was used to detect the expression of miR-202-5p. Western blot and qRT-PCR were applied to detect the mRNA and protein expression levels of related pathway proteins (PIK3CA, PI3K, PTEN, p-Akt1, and p-mTOR) and epithelial-mesenchymal transition-related factors (N-cadherin, E-cadherin, and vimentin). Cell proliferation was detected by plate colony formation assay. Transwell assay was used to detect the invasion ability of each group. When compared with the adjacent tissues, PIK3CA mRNA expression level was significantly increased and miR-202-5p expression level was significantly decreased in cervical cancer tissues (all P < 0.05). PIK3CA was a target gene of miR-202-5p. The mRNA expression level of PIK3CA in SiHa cervical cancer cells was significantly higher than that in CaSki, HeLa, and HPV-16E6 cells (all P < 0.05), and SiHa cervical cancer cells were selected to complete the follow-up experiments. When compared with the corresponding NC group, the expression of miR-202-5p in miR-202-5p mimic group was increased. In addition, the mRNA and protein expression levels of E-cadherin and PTEN in miR-202-5p mimic and siRNA-PIK3CA groups were increased, and the protein expression of p-Akt1 and p-mTOR was decreased, and also, the mRNA and protein expression levels of PIK3CA, PI3K, N-cadherin, and vimentin were decreased (all P < 0.05); in miR-202-5p inhibitor group, the expression levels of miR-202-5p, E-cadherin, and PTEN decreased, the protein expression of p-Akt1 and p-mTOR increased, and the mRNA and protein expression of PIK3CA, PI3K, N-cadherin, and vimentin increased in miR-202-5p inhibitor group (all P < 0.05); in miR-202-5p inhibitor + siRNA-PIK3CA group, the expression of miR-202-5p decreased (P < 0.05), but the mRNA and protein expression of PIK3CA, PI3K, p-Akt1, p-mTOR, N-cadherin, E-cadherin, and vimentin had no significant changes (all P > 0.05). When compared with the corresponding NC group, the number of cell clones in miR-202-5p mimic group and siRNA-PIK3CA group was decreased, and the invasion ability of miR-202-5p inhibitor group was increased, and the invasion ability was enhanced (all P < 0.05); miR-202-5p inhibitor + siRNA-PIK3CA group showed no significant change in the number of cell clones and the rate of invasion (P > 0.05). In conclusion, the overexpression of miR-202-5p can suppress PIK3CA gene expression and the activation of PI3K/Akt/mTOR signaling pathway to suppress the proliferation, invasion, and EMT of cervical cancer.

Observation on the Clinical Effect of Apatinib Combined with Chemotherapy in the Treatment of Advanced Non-Small Cell Lung Cancer.

OBJECTIVES: To evaluate the clinical effect of apatinib combined with chemotherapy in the treatment of advanced non-small cell lung cancer (NSCLC). METHODS: Eighty patients with advanced NSCLC treated in Hebei General Hospital from January 2017 to July 2020 were randomly divided into two groups: the experimental group and the control group, each with 40 cases. Patients in the control group were treated with conventional paclitaxel combined with cisplatin chemotherapy, while patients in the experimental group were treated with apatinib mesylate tablets based on the treatment of the control group. After treatment, tumor efficacy evaluation was conducted on all patients every two cycles, and the therapeutic effect, adverse drug reactions, improvement of quality-of-life scores prior to and after treatment, and changes of indicators such as tumor markers carcinoembryonic antigen (CEA) and carbohydrate antigen 153(CA153) were compared and analyzed between the two groups. RESULTS: The total effective rate of the experimental group was 67.5%, which was significantly better than the 45% of the control group (p=0.04); The incidence of adverse drug reactions in the experimental group was 25%, while that in the control group was 37.5%, with no significant difference (p=0.23); Moreover, the improvement rate of quality of life scores in the experimental group was significantly higher than that in the control group (p=0.03), and the levels of CEA and CA153 in the experimental group were significantly lower after treatment than those in the control group, with a statistically significant difference (p=0.01). CONCLUSION: Apatinib combined with conventional chemotherapy is effective in the treatment of advanced non-small cell lung cancer, the quality of life can be significantly improved, tumor markers can be significantly reduced, and adverse reactions will not be significantly increased.

Comparison of 3 Treatment Methods for Distal Tibial Fractures: A Network Meta-Analysis.

BACKGROUND The choice of optimal internal fixation device for distal tibial fractures remains controversial. The purpose of our study was to evaluate the effectiveness and safety of open reduction and internal fixation, minimally invasive percutaneous osteosynthesis, and intramedullary nailing of distal tibial fractures in adults using network meta-analysis of data from clinical trials. MATERIAL AND METHODS The studies were abstracted from MEDLINE, EMBASE, CNKI, and the Cochrane Central Register of Controlled Trials. Randomized controlled trials meeting inclusion and exclusion criteria were selected. Statistical analyses were conducted using Stata software, version 13.0 (Stata Corporation, College Station, Texas, USA). RESULTS Eleven randomized controlled trials were included. The total number of participants was 710 and the studies were published between 2005 and 2017. There were no significant differences in rates of delayed union, nonunion, or malunion among the various treatments (all p>0.05). The intramedullary nailing group had a lower incidence of wound complications than did the open reduction and internal fixation group and minimally invasive percutaneous osteosynthesis technique group. The SUCRA probabilities were 28.6% for ORIF, 98.4% for IMN, and 22.9% for MIPPO. CONCLUSIONS Given the superior results for intramedullary nailing in terms of wound complications, we recommend this procedure for treatment of distal tibial fractures. More RCTs focused on distal tibial fractures are needed to support the current evidence.

Protective effect of a novel Rho kinase inhibitor WAR-5 in experimental autoimmune encephalomyelitis by modulating inflammatory response and neurotrophic factors.

The Rho-kinase (ROCK) inhibitor Fasudil has proven beneficial in experimental autoimmune encephalomyelitis (EAE). Given the small safety window of Fasudil, we are looking for novel ROCK inhibitors, which have similar or stronger effect on EAE with greater safety. In this study, we report that WAR-5, a Y-27632 derivative, alleviates the clinical symptoms, attenuates myelin damage and reduces CNS inflammatory responses in EAE C57BL/6 mice at an extent similar to Fasudil, while exhibits less vasodilator and adverse reaction in vivo. WAR-5 inhibits ROCK activity, and selectively suppresses the expression of ROCK II in spleen, brain and spinal cord of EAE mice, especially in spinal cord, accompanied by decreased expression of Nogo. WAR-5 also regulates the imbalance of Th1/Th17 T cells and regulatory T cells, inhibits inflammatory microenvironment induced with NF-κB-IL-1ß pathway. Importantly, WAR-5 converts M1 toward M2 microglia/macrophages that are positively correlated with BDNF and NT-3 production. Taken together, WAR-5 exhibits therapeutic potential in EAE by more selectively inhibits ROCK II, with a greater safety than Fasudil, and is worthy of further clinical study to clarify its clinical value.

Lipoic acid protects dopaminergic neurons in LPS-induced Parkinson's disease model.

Parkinson's disease (PD) is a chronic neurodegenerative disease of the central nervous system (CNS), characterized by a loss of dopaminergic neurons, which is thought to be caused by both genetic and environmental factors. Recent findings suggest that neuroinflammation may be a pathogenic factor in the onset and progression of sporadic PD. Here we explore the potential therapeutic effect of lipoic acid (LA) on a lipolysaccharide (LPS)-induced inflammatory PD model. Our results for the first time showed that LA administration improved motor dysfunction, protected dopaminergic neurons loss, and decreased α-synuclein accumulation in the substantia nigra (SN) area of brain. Further, LA inhibited the activation of nuclear factor-κB (NF-κB) and expression of pro-inflammatory molecules in M1 microglia. Taken together, these results suggest that LA may exert a profound neuroprotective effect and is thus a promising anti-neuroinflammatory and anti-oxidative agent for halting the progression of PD. Interventions aimed at either blocking microglia-derived inflammatory mediators or modulating the polarization of microglia may be potentially useful therapies that are worth further investigation.

[Effect of Buyang Huanwu Decoction on mRNA Expressions of Aorta Rho Kinase and NF-κB p65 in Atherosclerosis Model Rats].

OBJECTIVE: To observe the effect of Buyang Huanwu Decoction (BYHWD), a representative formula of qi benefiting blood activating method on aorta Rho associated coiled-coil forming protein serine/threonine kinase (Rhokinase, ROCK) and nuclear transcription factor kappa B (NF-κB) p65 mRNA expressions and levels of blood lipids in atherosclerosis (AS) model rats. METHODS: The AS rat model was prepared by vitamin D3 and high fat diet. Totally 60 rats were randomly divided into 6 groups, i.e., the normal control group, the model group, the low dose BYHWD group (10 g/kg), the high dose BYHWD group (20 g/kg), the Simvastatin control group (0.6 mg/kg), and the BYHWD prevention group (10 g/kg), 10 in each group. After successful modeling all medication was intervened for 28 days. Expression levels oxidized low density lipoprotein (ox-LDL) were detected by ELISA. Levels of TG, TC, LDL-C, HDL-C were determined by enzyme method. Pathological changes of aortic tissue were observed under light microscope. mRNA expressions of Rho kinase and NF-κB p65 in aorta were detected by real time (RT) PCR. RESULTS: High fat diet and peritoneal injection of vitamin D3 could induce AS rat model. Typical atheromatous plaque formed in aorta of AS model rats. Compared with the normal control group, levels of TC, TG, LDL-C, and ox-LDL significantly increased in the model group, but the HDL-C level decreased (P < 0.01). Compared with the model group, levels of TC, TG, LDL-C, and ox-LDL all decreased, but HDL-C increased in low and high dose BYHWD groups, the Simvastatin control group, and the BYHWD prevention group (P < 0.05, P < 0.01). Compared with the low dose BYHWD group, above-mentioned indices were more obviously lowered in the high dose BYHWD group, the Simvastatin control group, and the BYHWD prevention group (P < 0.05). Compared with the normal control group, mRNA expression levels of Rho kinase and NF-κB p65 significantly increased in the model group (P < 0.01). Compared with the model group, mRNA expressions of Rho kinase and NF-κB p65 obviously decreased in low and high dose BYHWD groups, the Simvastatin control group, and the BYHWD prevention group (P < 0.01). Compared with the low dose BYHWD group, the two indicators were more obviously lowered in the high dose BYHWD group, the Simvastatin control group, and the BYHWD prevention group (P < 0.05). But there was no statistical difference in blood lipids levels, mRNA expression levels of Rho kinase or NF-κB p65 among the high dose BYHWD group, the Simvastatin control group, and the BYHWD prevention group (P >0. 05). CONCLUSIONS: BYHWD could down-regulate mRNA expression levels of Rho kinase and NF-κB p65, lower levels of blood lipids, and fight against AS. Suppressing Rho kinase pathway might be one of its mechanisms.

Heterochronous multiple primary prostate cancer and lymphoma: A case report.

BACKGROUND: Multiple primary malignant tumors (MPMTs) are rare type of cancer, especially when solid tumors are the first and lymphoma is the second primary malignancy. We report a patient with heterochronous MPMTs consisting of prostate cancer and rectal diffuse large B-cell lymphoma (DLBCL). CASE SUMMARY: We report a 77-year-old male patient diagnosed with prostate cancer who was treated with radiation therapy and one year of endocrine therapy with bicalutamide (50 mg per day) and an extended-release implant of goserelin (1/28 d). Seven years later, rectal DLBCL with lung metastases was found. CONCLUSION: Although rare, the possibility of prostate cancer combined with a double primary cancer of DLBCL can provide a deeper understanding.

USP7 promotes cervical cancer progression by stabilizing MTDH expression through deubiquitination.

BACKGROUND: Metadherin (MTDH) and ubiquitin specific protease 7 (USP7) have been identified to involve in the tumorigenesis of cervical cancer (CC). USP7 is one of the deubiquitinating enzymes. Here, this study aimed to explore whether USP7 affected CC progression via interacting with MTDH and regulating its stability via deubiquitination. METHODS: qRT-PCR and western blotting assays detected the levels of genes and proteins. Functional analysis was conducted using 5-ethynyl-2'-deoxyuridine (EdU), flow cytometry, transwell, and tube formation assays, respectively. Proteins between USP7 and MTDH were identified by co-immunoprecipitation assay. A mouse xenograft model was established for in vivo analysis. RESULTS: MTDH was highly expressed in CC tissues and cells, silencing of MTDH suppressed CC cell proliferation, migration, invasion, angiogenesis, and macrophage M2 polarization. Mechanistically, USP7 directly bound to MTDH, and maintained its stability by removing ubiquitination on MTDH. CC tissues and cells showed high USP7 expression, and USP7 knockdown also inhibited CC cell proliferation, migration, invasion, angiogenesis and macrophage M2 polarization, and these effects mediated by USP7 knockdown were reversed by MTDH overexpression. Moreover, USP7 knockdown impeded CC growth in vivo by regulating MTDH. CONCLUSION: Collectively, USP7 promoted CC cell proliferation, migration, invasion, angiogenesis, and macrophage M2 polarization in vitro, as well as tumor growth in vivo by regulating MTDH.

Optimal modalities and doses of mind-body exercise for depressive symptoms in adults: A systematic review of paired analyses, network analyses and dose-response meta-analyses.

The relative efficacy of various mind-body exercises in the treatment of depressive symptoms remains uncertain. We examined the optimal modalities (Tai Chi, qigong, yoga) and dose of mind-body exercise to improve depressive symptoms in adults. A systematic search of six electronic databases for randomized controlled trials on the relationship between exercise and depression was carried out, encompassing data from their inception up to November 2023. Pairwise analyses, network analyses and dose-response meta-analyses using random-effects models were performed to analyse the effect of exercise on depression. Forty studies were included. Results showed that Yoga [standardised mean difference (SMD) = -0.55; 95% confidence interval (CI): (-0.76, -0.35)] was the most effective form of exercise for improving depressive symptoms, followed by Qigong (SMD = -0.52; 95%CI: -0.92, -0.11) and Tai Chi exercise (SMD = -0.42; 95%CI: -0.71, -0.13). In addition, a non-linear dose-response relationship was found between overall mind-body exercise dose and depression levels and a significant response was observed after 260 METs-min. Our study examined the effectiveness of different types of mind-body exercise in improving depression and found that yoga may be the most effective adjunctive intervention. There was a non-linear dose-response relationship between total exercise and depression levels. However, caution should be exercised in interpreting and applying these results.

Synchronous Double Primary Tumors of Liver (Small Cell Neuroendocrine Carcinoma and Hepatocellular carcinoma): A Case Report.

This study presents a case of dual primary liver cancer involving small cell neuroendocrine carcinoma and hepatocellular carcinoma. The 58-year-old Chinese male patient, who has a medical history of viral hepatitis B, presented with right upper abdominal pain persisting for one month. Imaging studies indicated the presence of multiple liver masses in segments V and VII-VIII, as well as a mass in the left lung. Subsequent hepatic biopsy performed on both segments confirmed the presence of hepatocellular carcinoma in segment V and small cell neuroendocrine carcinoma in segment VII-VIII. After undergoing one cycle of chemotherapy, the lung mass exhibited a reduction in size, while the liver masses showed an inadequate response. Subsequently, the patient underwent Transcatheter Arterial Chemoembolization (TACE) and Hepatic Artery Infusion Chemotherapy (HIAC), resulting in partial remission (PR). However, the patient was diagnosed with brain metastasis and subsequently treated with Sorafenib and Tirelizumab, a Programmed Death 1 (PD-1) immune checkpoint inhibitor. The efficacy evaluation indicated stability, and no severe adverse effects were observed at the time of writing. The patient's survival time was 16 months.

Machine learning-driven source identification and ecological risk prediction of heavy metal pollution in cultivated soils.

To overcome challenges in assessing the impact of environmental factors on heavy metal accumulation in soil due to limited comprehensive data, our study in Yangxin County, Hubei Province, China, analyzed 577 soil samples in combination with extensive big data. We used machine learning techniques, the potential ecological risk index, and the bivariate local Moran's index (BLMI) to predict Cr, Pb, Cd, As, and Hg concentrations in cultivated soil to assess ecological risks and identify pollution sources. The random forest model was selected for its superior performance among various machine learning models, and results indicated that heavy metal accumulation was substantially influenced by environmental factors such as climate, elevation, industrial activities, soil properties, railways, and population. Our ecological risk assessment highlighted areas of concern, where Cd and Hg were identified as the primary threats. BLMI was used to analyze spatial clustering and autocorrelation patterns between ecological risk and environmental factors, pinpointing areas that require targeted interventions. Additionally, redundancy analysis revealed the dynamics of heavy metal transfer to crops. This detailed approach mapped the spatial distribution of heavy metals, highlighted the ecological risks, identified their sources, and provided essential data for effective land management and pollution mitigation.

The dominant role of extracellular polymeric substances produced by Achromobacter xylosoxidans BP1 in Cr(VI) microbial reduction.

Extracellular polymeric substances (EPS) have demonstrated significant benefits for reducing multivalent metal contamination. Using Achromobacter xylosoxidans BP1 isolated from a coal chemical site in China, this study elucidated the contribution of EPS production to Cr (VI) reduction and revealed its biological removal mechanism. BP1 grew at an optimum pH of 8 and the lowest inhibitory concentration of Cr(VI) was 300 mg/L. The spent medium completely removed Cr(VI), whereas resting cells were only able to remove 10.47 % and inactivated cells were nearly incapable of Cr(VI) removal. S-EPS and B-EPS reduced Cr(VI) by 98.59 % and 11.64 %, respectively. SEM-EDS analysis showed that the BP1 cells were stimulated to produce EPS under Cr stress. The XPS results showed that 29.63 % of Cr(VI) was enriched by intracellular bioaccumulation or biosorption and 70.37 % of Cr(VI) was reduced by extracellular enzymes to produce Cr(OH)3 and organic Cr(III) complexes. According to FTIR, EPS with -OH, COO-, and amide groups supplied binding sites and electrons for the reductive adsorption of Cr(VI). Genomic studies showed that BP1 primarily produces extracellular polysaccharides, metabolises sulphur and nitrogen, and reduces reactive oxygen species damage as a result of DNA repair proteases.

Corrigendum: The effect of gut microbiota dysbiosis on patients with preeclampsia.

[This corrects the article DOI: 10.3389/fcimb.2022.1022857.].

Causal association between lipid-lowering drugs and female reproductive endocrine diseases: a drug-targeted Mendelian randomization study.

Purpose: The relationship between dyslipidemia and female reproductive endocrine diseases has been increasingly studied. The use of lipid-lowering drugs in treating various related diseases, including coronary heart disease, may affect female reproductive endocrine diseases. Therefore, our study aims to investigate the effects of lipid-lowering drugs on female reproductive endocrine diseases and provide a basis for the appropriate selection of drugs. Methods: In this study, we focused on three drug targets of statins, namely HMG-CoA reductase (HMGCR) inhibitors, proprotein convertase kexin 9 (PCSK9) inhibitors, and Niemann-Pick C1-Like 1 (NPC1L1) inhibitors. To identify potential inhibitors for these targets, we collected single nucleotide polymorphisms (SNPs) associated with HMGCR, PCSK9, and NPC1L1 from published genome-wide association study statistics. Subsequently, we conducted a drug target Mendelian randomization (MR) analysis to investigate the effects of these inhibitors on reproductive endocrine diseases mediated by low-density lipoprotein cholesterol (LDL-C) levels. Alongside coronary heart disease as a positive control, our main outcomes of interest included the risk of polycystic ovary syndrome (PCOS), premature ovarian insufficiency (POI), premenstrual syndrome (PMS), abnormal uterine bleeding (including menorrhagia and oligomenorrhea), and infertility. Results: PCSK9 inhibitors significantly increased the risk of infertility in patients (OR [95%CI] = 1.14 [1.06, 1.23], p<0.05). In contrast, HMGCR inhibitors significantly reduced the risk of menorrhagia in female patients (OR [95%CI] = 0.85 [0.75, 0.97], p<0.05), but had no statistical impact on patients with oligomenorrhea. Conclusion: The findings suggest that PCSK9 inhibitors may significantly increase the risk of infertility in patients. On the other hand, HMGCR inhibitors could potentially offer protection against menorrhagia in women. However, no effects of lipid-lowering drugs have been observed on other reproductive endocrine disorders, such as PCOS, POF, PMS and oligomenorrhea.

Epithelioid hemangioendothelioma of the retroperitoneal giant type treated with Toripalimab: A case report.

Epithelioid hemangioendotheliomas (EHEs), low-grade malignant tumors of vascular endothelial cell origin, are characterized by vascular endothelial proliferation. In 2002, the World Health Organization classified EHEs as locally aggressive tumors with the potential to metastasize. Currently, the diagnosis of EHE is based on pathology, histological and immunohistochemical examinations. There are no standard treatment guidelines. We here report a 69-year-old man who presented with left-sided chest and abdominal pain for more than 2 months. Enhanced computed tomography of the thorax and abdomen in another hospital suggested a mass in the left adrenal region that was considered malignant. Positron emission tomography- computed tomography in our hospital suggested a large multi-loculated, hypermetabolic, cystic mass in the left adrenal region that was considered malignant. Accordingly, a puncture biopsy of the mass was performed and the diagnosis of EHE confirmed by pathological examination, including immunohistochemical staining. This patient was treated with the programmed death 1 (PD-1) immune checkpoint inhibitor toripalimab with long-term success. The best response was stable disease (SD) with a progression-free survival (PFS) of more than 13 months. The patient is still alive now. Because the sample size of previous studies was small, further studies are needed to determine the safety and efficacy of toripalimab in the treatment of EHE.