NR2F1 overexpression alleviates trophoblast cell dysfunction by inhibiting GDF15/MAPK axis in preeclampsia.

Abnormal functions of trophoblast cells are associated with the pathogenesis of preeclampsia (PE). Nuclear receptor subfamily 2 group F member 1 (NR2F1) acts as a transcriptionally regulator in many diseases, but its role in PE remains unknown. Hypoxia/reoxygenation (H/R)-stimulated HTR-8/SVneo cells were used to mimic PE injury in vitro. NR2F1 overexpression alleviated trophoblast apoptosis, as evidenced by the decreased number of TUNEL-positive cells and the downregulation of caspase 3 and caspase 9 expression in cells. NR2F1 overexpression increased the invasion and migration ability of HTR-8/SVneo cells, accompanied by increased protein levels of matrix metalloproteinase (MMP)-2 and MMP-9. mRNA-seq was applied to explore the underlying mechanism of NR2F1, identifying growth differentiation factor 15 (GDF15) as the possible downstream effector. Dual-luciferase reporter, ChIP-qPCR, and DNA pull-down assays confirmed that NR2F1 bound to the promoter of GDF15 and transcriptionally inhibited its expression. GDF15 overexpression increased apoptosis and decreased the ability of invasion and migration in HTR-8/SVneo cells expressing NR2F1. MAPK pathway was involved in the regulation of PE. Administration of p38 inhibitor, ERK inhibitor, and JNK inhibitor reversed the effect of simultaneous overexpression NR2F1 and GDF15 on trophoblast apoptosis, invasion, and migration. Our findings demonstrated that NR2F1 overexpression inhibited trophoblast apoptosis and promoted trophoblast invasion and migration. NR2F1 might negatively regulate GDF15 expression by binding to its promoter region, which further inhibited MAPK signaling pathway in PE. Our study highlights that NR2F1 might sever as a potential target in PE.

Anlotinib plus Sintilimab achieved in an antitumor effect of complete remission in a patient with advanced hepatocellular carcinoma: a case report.

Systemic therapies-based combination treatments have been developed rapidly in patients with advanced hepatocellular carcinoma (HCC). However, there are still a few patients not applicable to any recommended therapies, making it considerable to try new therapeutic options. Among them, anlotinib, a new oral tyrosine kinase inhibitor, is being widely used for many advanced malignancies. We present the first case of the antitumor effect of complete remission by anlotinib combined with an anti-programmed cell death protein 1 antibody, sintilimab, in a patient with advanced HCC. In April 2020, a 51-year-old male patient was diagnosed with large HCC and underwent hepatectomy with R0 resection. Two months later, he was admitted to our hospital because of a tumor relapse with multiple liver and lung metastases. After the failure of comprehensive treatment containing sorafenib, camrelizumab and transhepatic arterial chemotherapy and embolization, 2 months after tumor relapse, the patient started to receive anlotinib and sintilimab. The multiple tumor nodules were remarkable repressed both in the liver and lung. Six months after anlotinib plus sintilimab treatment, there were no residual tumors, and the alpha-fetoprotein level was decreased from 2310.9 mg/L to normal. Also, the patient continued to receive anlotinib to date. In subsequent follow-up visits until now, there was no sign of recurrence found on imaging. Anlotinib is a promising alternative for patients insensitive to the first-line targeted drugs. More clinical studies should be conducted to further broaden the clinical indications of anlotinib and immunotherapy in patients with HCC.

Exploring the significance of tumor volume in endometrial cancer: Clinical pathological features, prognosis, and adjuvant therapies.

To assist clinicians in formulating treatment strategies for endometrial cancer (EC), this retrospective study explores the relationship between tumor volume and clinical pathological features, as well as prognosis, in patients undergoing staging surgery. Preoperative pelvic MRI examinations were conducted on 234 histologically confirmed EC patients. The ITK-SNAP software was employed to manually delineate the region of interest in the MRI images and calculate the tumor volume (MRI-TV). The analysis focused on investigating the relationship between MRI-TV and the clinical pathological features and prognosis of EC patients. Larger MRI-TV was found to be associated with various adverse prognostic factors (G3, deep myometrial invasion, cervical stromal invasion, lymphovascular space invasion, lymph node metastasis, advanced international federation of gynecology and obstetrics staging, and receipt of adjuvant therapy). The receiver operating characteristic curve indicated that MRI-TV ≥ 8 cm3 predicted deep myometrial invasion, and MRI-TV ≥ 12 cm3 predicted lymph node metastasis. Penalized spline (P-spline) regression analysis identified 14 cm3 of MRI-TV as the optimal prognostic cutoff value. MRI-TV ≥ 14 cm3 was an independent prognostic factor for overall survival and disease-free survival. For patients with MRI-TV ≥ 14 cm3, the disease-free survival rate with adjuvant therapy was superior to that of the sole staging surgery group. This study demonstrates a significant correlation between MRI-TV and clinical pathological features and prognosis in EC. For patients with MRI-TV ≥ 14 cm3, staging surgery followed by adjuvant therapy was superior to sole staging surgery.

Pre-treatment systemic immune-inflammation index as a non-invasive biomarker for predicting clinical outcomes in patients with renal cell carcinoma: a meta-analysis of 20 studies.

INTRODUCTION: To systematically assess the predictive significance of systemic immune-inflammation index (SII) in renal cell carcinoma (RCC). METHODS: Relevant studies published before November 2022 were retrieved from public databases. Hazard ratio (HR), standardised mean difference (SMD) and relative risk (RR) were calculated to estimate associations of SII with prognosis, treatment responses and clinicopathological features. RESULTS: Twenty studies involving 6887 patients were eligible. The meta-analysis results revealed a high SII level was associated with worse overall survival (HR: 1.45, p < 0.001), progression-free survival (HR: 1.63, p = 0.001), cancer-specific survival (HR: 1.86, p < 0.001), lower overall response rate (RR: 0.62, p = 0.003), disease control rate (RR: 0.69, p = 0.002), larger tumour size (SMD: 0.39, p = 0.001), poorer IMDC risk (RR: 7.09, p < 0.001), higher Fuhrman grade (RR: 1.54, p = 0.004), tumour stage (RR: 1.67, p = 0.045), the presence of distant metastasis (brain: RR, 2.04, p = 0.001; bone: RR, 1.33, p = 0.024) and tumour necrosis (RR: 1.57, p = 0.031). Subgroup analysis showed SII predicted OS and PFS for non-Asian, but CSS for both Asian and non-Asian populations. CONCLUSION: Pre-treatment SII may be a promising predictor of clinical outcomes for RCC patients.

Effect and mechanism of microRNA-515-5p in proliferation and apoptosis of trophoblast cells in preeclampsia via manipulating histone deacetylase 2.

Preeclampsia (PE) refers to a pregnancy-specific disease that begins with the placenta. Differentially expressed microRNAs (miRs) are a feature of PE. This study tried to elicit the functional mechanism of miR-515-5p in trophoblast cell behaviors in PE. First, HTR-8/SVneo cells were transfected with miR-515-5p mimic or miR-515-5p inhibitor. Then, relative expression levels of miR-515-5p and histone deacetylase 2 (HDAC2) in HTR-8/SVneo cells were determined by reverse transcription-quantitative polymerase chain reaction. The potential binding site of miR-515-5p and HDAC2 was predicted on Targetscan and their binding relationship was verified via dual-luciferase assay. Proliferation, apoptosis, invasion, and migration of HTR-8/SVneo cells were assessed via cell counting kit-8, flow cytometry, Transwell, and wound healing assays, respectively. Protein levels of Cleaved caspase-3, Bcl-2, and Bax were determined via Western blot. Overexpressed miR-515-5p impeded proliferation and stimulated apoptosis of HTR-8/SVneo cells, and decreased levels of Cleaved caspase-3 and Bax and elevated Bcl-2, whilst opposite results were observed after miR-515-5p inhibition. miR-515-5p targeted HDAC2. Knockdown of HDAC2 annulled the promotional action of miR-515-5p inhibition on proliferative, invasive, and migratory abilities and its antiapoptotic action on HTR-8/SVneo cells. In brief, miR-515-5p affected the proliferation, apoptosis, invasion, and migration of HTR-8/SVneo cells by targeting HDAC2.

Organoid Models for Precision Cancer Immunotherapy.

Cancer immunotherapy is exploited for the treatment of disease by modulating the immune system. Since the conventional in vivo animal and 2D in vitro models insufficiently recapitulate the complex tumor immune microenvironment (TIME) of the original tumor. In addition, due to the involvement of the immune system in cancer immunotherapy, more physiomimetic cancer models, such as patient-derived organoids (PDOs), are required to evaluate the efficacy of immunotherapy agents. On the other hand, the dynamic interactions between the neoplastic cells and non-neoplastic host components in the TIME can promote carcinogenesis, tumor metastasis, cancer progression, and drug resistance of cancer cells. Indeed, tumor organoid models can properly recapitulate the TIME by preserving endogenous stromal components including various immune cells, or by adding exogenous immune cells, cancer-associated fibroblasts (CAFs), vasculature, and other components. Therefore, organoid culture platforms could model immunotherapy responses and facilitate the immunotherapy preclinical testing. Here, we discuss the various organoid culture approaches for the modeling of TIME and the applications of complex tumor organoids in testing cancer immunotherapeutics and personalized cancer immunotherapy.

A Scoping Review of Drug Epidemic Models.

The phenomenon of drug epidemics has been a global issue in the past decades, causing enormous damages to the physical and mental health of drug users and social well-being. Despite great efforts to curb drug epidemics at the governmental or social level, the total number of drug users has still been on the rise in recent years, along with illicit production and trafficking around the world. Inspired by dynamical epidemic models of infectious disease, a flourishment of promising results has been observed in the exploration of drug epidemic models. In this review, we aim to provide a scoping review of all existing drug epidemic modeling studies, and it has been shown that most studies focused on analyses of theoretical behaviors of the model systems, lacking emphasis on practical applications in real settings. We found that the drug epidemic models were characterized by a longer time scale, no incubation period, no significant prevention vaccines interfered, and population specificity. This review could assist policymakers and public health workers in gaining deeper insights into modeling tools, and help modelers improve their works, thus narrowing gaps between mathematical epidemiology and public health studies.

HSPA8 Is Identified as a Novel Regulator of Hypertensive Disorders in Pregnancy by Modulating the ß-Arrestin1/A1AR Axis.

Heat shock protein alpha 8 (HSPA8) was found to be downregulated in the placentas of patients with hypertensive disorders in pregnancy (HDP). We aim to explore the underlying role and mechanism of HSPA8 in HDP progression. Herein, HSPA8 mRNA expression in placentas and peripheral blood of patients with HDP and normal pregnant controls was measured with RT-qPCR. We found that HSPA8 expression was downregulated in placentas and peripheral blood of patients with HDP. HTR8/SVneo human trophoblast cells were transfected with pcDNA-HSPA8 or si-HSPA8. HSPA8 overexpression promoted cell proliferation, migration, and MMP-2 and MMP-9 protein levels, and inhibited apoptosis, while HSPA8 silencing showed the opposite results. Co-immunoprecipitation assay validated the binding between HSPA8 and ß-arrestin1, as well as ß-arrestin1 and A1AR proteins. HSPA8 bound with ß-arrestin1 protein and promoted ß-arrestin1 expression. ß-arrestin1 bound with A1AR protein and inhibited A1AR expression. Then, HTR8/SVneo cells were transfected with pcDNA-HSPA8 alone or together with si-ß-arrestin1, as well as transfected with pcDNA-ß-arrestin1 alone or together with pcDNA-A1AR. ß-arrestin1 silencing reversed the effects of HSPA8 overexpression on HTR8/SVneo cell functions. ß-arrestin1 overexpression promoted cell proliferation migration, and MMP-2 and MMP-9 protein levels, and inhibited apoptosis, while these effects were reversed by A1AR overexpression. Lentivirus HSPA8 overexpression vector (Lv-HSPA8) was injected into a preeclampsia (PE) rat model, which attenuated blood pressure and fetal detrimental changes in PE rats. In conclusion, HSPA8 promoted proliferation and migration and inhibited apoptosis in trophoblast cells, and attenuated the symptoms of PE rats by modulating the ß-arrestin1/A1AR axis. Our study provided a novel theoretical evidence and potential strategy for HDP treatment.

Prognostic value of lactate dehydrogenase for melanoma patients receiving anti-PD-1/PD-L1 therapy: A meta-analysis.

BACKGROUND: Several studies indicate the level of pretreatment lactate dehydrogenase (LDH) may be associated with the prognosis of patients receiving immune checkpoint inhibitors targeting programmed death receptor-1 (PD-1)/programmed death ligand 1 (PD-L1) which had been reported to dramatically improve the survival of patients with advanced or metastatic melanoma; however, no consensus has been reached because the presence of controversial conclusions. This study was to perform a meta-analysis to comprehensively explore the prognostic values of LDH for melanoma patients receiving anti-PD1/PD-L1 monotherapy. METHODS: A systematic electronic search in the databases of PubMed, EMBASE and the Cochrane library was performed to identify all related articles up to April, 2020. The pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were obtained to assess the prognostic values of pretreatment LDH in blood for overall survival (OS) and progression-free survival (PFS). RESULTS: A total of 22 eligible studies involving 2745 patients were included. Of them, 19 studies with 20 results assessed the OS and the pooled analysis showed that an elevated pretreatment LDH level was significantly associated with a worse OS (HR = 2.44; 95% CI: 1.95-3.04, P < .001). Thirteen studies reported PFS and meta-analysis also revealed that a higher pretreatment LDH level predicted a significantly shorter PFS (HR, 1.61; 95% CI, 1.34-1.92; P < .001). Although heterogeneity existed among these studies, the same results were acquired in subgroup analyses based on sample size, country, study design, cut-off of LDH, type of PD-1/PD-L1 inhibitors and statistics for HRs (all HRs > 1 and P < .05). CONCLUSION: This meta-analysis suggests LDH may serve as a potential biomarker to identify patients who can benefit from anti-PD-1/PD-L1 and then schedule treatments.

The diagnosis and management of rare cystic liver metastases from nasopharyngeal carcinoma: A case report.

RATIONAL: Nasopharyngeal carcinoma (NPC) with cystic liver metastases is so rarely observed that there are only three cases reported in the published literature. PATIENT CONCERNS: We present a case of NPC that received complete response after chemotherapy and definitive radiotherapy, but a liver cystic lesion was revealed on abdominal sonogram three months after the initial therapy. The cystic liver lesion initially resembled a simple liver cyst with fast growth, and then evolved into an abscess-like mass after a short term. Though abscess drainage was performed, and the mass shrank significantly, but it returned to previous size two months later. DIAGNOSES: Surgical resection was administrated both for diagnosis and treatment, and eventually the lesion was histologically demonstrated to be a liver metastasis. Eight months after the partial hepatectomy, cystic liver metastases recurred on computed tomography (CT) scan. INTERVENTIONS: Though palliative systematic chemotherapy including paclitaxel, cisplatin, gemcitabine, navobine and anti-epidemal growth factor receptor (anti-EGFR) molecular-targeted therapy were performed, the cystic metastases still gradually progressed. Then Transcatheter Hepatic Artery Chemoembolization (TACE) was administrated for five times, and all the lesions were obviously decreased in size. OUTCOMES: After TACE treatment, the liver metastases maintained stable for six months, but lung metastases were noted. Finally, the patient died of liver failure. LESSONS: The rare cystic appearance may be a special form which exists for liver metastases of NPC, indicating poor prognosis. Oncologists need to enhance the recognition and diagnosis level of this type of metastases. Intense follow-up and early diagnosis are important. While emphasizing the importance of local therapy and personal principles for liver metastases, TACE may be a preferred method for unresectable cystic liver metastases from NPC.