Adipose tissue development significantly influences meat quality and economic traits in beef cattle. In this study, we identified a novel circular RNA derived from two exons (exons 3 and exons 9) of the NID2 gene, designated as circNID2, which exhibits high structural stability and marked upregulation during bovine adipocyte differentiation. Functional assays demonstrated that circNID2 suppresses the proliferation and apoptosis of bovine preadipocytes while robustly promoting adipogenic differentiation and lipid accumulation. Although containing several putative open reading frames, circNID2 lacks protein-coding potential. Mechanistically, circNID2 functions as a competing endogenous RNA by sponging miR-339a, thereby relieving the post-transcriptional repression of its downstream target, Neuronatin (NNAT). Functional rescue experiments further validated that circNID2 partially neutralizes the regulatory effects of miR-339a on preadipocyte proliferation, apoptosis, and differentiation. Collectively, these findings demonstrate that circNID2 regulates bovine preadipocyte function through the newly established circNID2/miR-339a/NNAT axis. This study provides novel insights into the post-transcriptional mechanisms governing mammalian adipogenesis and highlights circNID2 as a potential molecular target for improving fat deposition traits in cattle.

Microplastics (MPs) are emerging as a novel pollutant, raising significant concerns regarding their adverse effects on human health. Furthermore, MPs are susceptible to light-induced aging in the environment, which alters their physical characteristics and potentially alters their toxic effects. While previous studies have documented the retention of MPs in the placenta, the specific impacts of MPs, particularly aged MPs, on placental function remain poorly understood. In the current study, we utilized 1 µm polystyrene microplastics (PS-MPs), a widely used model for MPs, to evaluate the effects of photoaged MPs on the placenta. Following oral administration of PS-MPs beginning on embryonic day 3.5 (E3.5), we observed impaired fetal growth and damage to the placental labyrinth chorionic layer in the treated pregnant mice by embryonic day 13.5 (E13.5). The photoaged PS-MPs were generated by exposure to simulated lighting for 7 or 14 days, resulting in alterations to their physical properties. Notably, enhanced cytotoxicity in trophoblast cells was observed for photoaged PS-MPs compared to pristine PS-MPs. Mechanistically, the altered physical properties of PS-MPs, along with elevated lipid peroxidation, may contribute to the increased cytotoxicity of the photoaged MPs. Our findings provide new insights into the detrimental effects and underlying mechanisms of both MPs and, in particular, aged MPs on the placenta and embryonic development. These insights are crucial for assessing the risks posed by MPs to human pregnancy.

5522 Background: Enlonstobart is a PD-1 inhibitor that has demonstrated durable anti-tumor activity and acceptable safety in patients with PD-L1 positive recurrent/metastatic cervical cancer in a multicenter, single-arm, open-label, phase II study. At primary cutoff date (May 27, 2023), the overall survival (OS) was not reached. Here, we report results from a pre-planned further follow-up (August 20, 2024). Methods: Eligible patients were ≥18 years old with PD-L1-positive (combined positive score ≥ 1) cervical cancer who had progression during or after or intolerance to the first-line platinum-based therapy. A total of 107 patients received enlonstobart 240 mg every two weeks for up to 24 months or until disease progression, intolerable toxicities, or other study discontinuation criteria were met. At the updated cutoff date, analyses of progression-free survival (PFS) and OS in the full analysis set (FAS), which consisted of all patients who had received at least one dose of enlonstobart treatment, and the per protocol set (PPS), which consisted of all patients in the FAS who had at least one available postbaseline tumor assessment were conducted. Results: At the cutoff date of August 20 2024, the median follow-up time was 15.84 months (range 0.4 ~ 35.6 months). In FAS, the median PFS was 3.06 (95 % CI 2.23–6.90) months. The median OS was 19.38 (95 % CI 14.95–25.40) months and the estimated OS rate was 68.14 % (95 %CI 58.20–76.19) at 12 months, 50.78 % (95 % CI 40.46–60.20) at 18 months, and 42.84 % (95 % CI 32.76–52.53) at 24 months. In PPS, the median PFS was 3.81 (95 % CI 2.63–7.49) months. The median OS was 21.26 (95 % CI 15.44–27.66) months and the estimated OS rate was 71.53 % (95 %CI 61.48–79.40) at 12 months, 53.32 % (95 % CI 42.64–62.87) at 18 months, and 44.98 % (95 % CI 34.50–54.89) at 24 months. Conclusions: Enlonstobart monotherapy showed a promising survival in patients with PD-L1 positive recurrent/metastatic cervical cancer, whose disease experienced progression after first-line platinum-based therapy. Clinical trial information: NCT04886700 .

BACKGROUNDS:Gastric cancer-associated mesenchymal stem cells (GC-MSCs) as integral components of the tumor microenvironment potentiate gastric cancer growth and metastasis. SALL4 is aberrantly upregulated in gastric cancer and pivotal for malignant progression. Whether GC-MSCs is responsible for SALL4 upregulation and the underlying mechanisms remains elusive. METHODS:Cancer growth and metastasis capacities were assessed by cell colony formation assay, transwell assay, and epithelial-mesenchymal transition protein detection in vitro as well as subcutaneous xenograft and peritoneal metastasis models in vivo. SALL4 was measured by qPCR, western blot and immunohistochemistry staining. Gain- and loss-functional analysis were performed for miRNA and target gene. β-catenin signaling was assessed by immunofluorescence staining and Top/FopFlash luciferase assay. Transcriptional regulation was conducted using chemicals, luciferase reporter and ChIP assay. Clinical tissues and TCGA-STAD database were included for expression profile, correlation and clinical relevance analysis. RESULTS:GC-MSCs promoted gastric cancer growth and metastasis along with elevation of SALL4 and miR-4669 in cancer cells and tissues. Overexpression of miR-4669 mimicked GC-MSC effects, while miR-4669 knockdown eliminated their oncogenic roles. TIMP3 was identified as a target of miR-4669 and mediated its functions. TIMP3 overexpression counteracted GC-MSC-induced cancer progression and SALL4 expression. GC-MSCs activated SALL4 transcription through the miR-4669/TIMP3/β-catenin pathway. The regulatory axis was aberrantly expressed in gastric cancer tissues, correlated with each other in certain cancer tissues and associated with lymph node metastasis. CONCLUSIONS:GC-MSCs transcriptionally upregulate SALL4 to facilitate gastric cancer cell growth and metastasis via miR-4669/TIMP3/β-catenin pathway, highlighting the crucial role of GC-MSCs in the aberrant upregulation of SALL4.

Purpose:To develop and validate computed tomography (CT)-based intratumoral and peritumoral radiomics signatures for preoperative prediction of lymph node metastasis (LNM) in patients with ovarian cancer (OC). Methods:Patients with pathological diagnosis of OC were retrospectively included. Intratumoral and peritumoral radiomics features were extracted from contrast-enhanced CT images. Intratumoral and peritumoral radiomics features were extracted from contrast-enhanced CT images. Intratumoral, peritumoral, and combined radiomics signatures were constructed, and their radiomics scores were calculated. Univariate and multivariate logistic regression analyses were performed to identify predictors of clinical outcomes. A radiomics nomogram was developed by incorporating the combined radiomics signature with clinical risk factors. The prediction efficiency of the various models was evaluated using the accuracy value, the area under the receiver-operating characteristic curve (AUC) and decision curve analysis (DCA). Results:Two hundred and seventy-three patients with OC were enrolled and randomly divided into a training cohort (n=190) and a test cohort (n=83) in a 7:3 ratio. The intratumoral, peritumoral, and combined radiomics signatures were constructed using 18, 11, and 17 radiomics features, respectively. The combined radiomics signature showed the best prediction ability, with accuracy of 0.783 and an AUC of 0.860 (95% confidence interval 0.779-0.941). The DCA results showed that the combined radiomics signature had better clinical application than the clinical model and the radiomics nomogram. Conclusions:A CT-based combined radiomics signature incorporating intratumoral and peritumoral radiomics features can predict LNM in patients with OC before surgery.

e17566 Background: Neutropenia is the most common hematological toxicity of myelosuppressive chemotherapy. To observe the efficacy and safety of efbemalenograstim alfa in the prevention of absolute neutrophil count (ANC) reduction after chemotherapy in Ovarian cancer(OC) and Cervical cancer(CC) patients at risk of platinum-containing chemotherapy with risk factors in febrile neutropenia (FN). Methods: This study was a single-arm, multicenter clinical trial(NCT06251947). A total of 83 patients would be enrolled, including 55 patients with primary epithelial OC (including fallopian tube cancer and primary peritoneal cancer) and 28 patients with primary or recurrent/metastatic CC in the first-line setting. All patients were scheduled to receive 3-6 cycles of chemotherapy regimen (Paclitaxel + Carboplatin/Cisplatin ± Bevacizumab). Efbemalenograstim alfa should be administered subcutaneously, 20mg per injection, within 24-48 hours after the completion of each chemotherapy cycle. The primary endpoint was the duration of grade 3 (ANC<1×10 9 /L) or 4 (ANC<0.5×10 9 /L) neutropenia in cycle 1. The safety was evaluated. Results: As of 23 December 2024, 53 patients were enrolled (Age: 56.0, 48.5-62.5), including 45 patients with OC and 8 patients with CC. The number of patients with complete data for at least one cycle of AE was 52 (OC:44, CC:8). In the OC patient cohort, the incidence of grade 3-4 neutropenia was 15.56% (7/45) with an initial duration of 1.86 days. The duration of initial grade 3-4 neutropenia in the 2 CC patients was 2.50 days. Of the 43 patients with complete blood count (CBC) data, 22 patients (CC: 3, OC: 19) reached ANC nadir on day 7 of the first cycle. Of the 37 OC patients with complete blood count data, 11 patients who reached a low on day 3 of the first cycle had a neutrophil count of 3.67 (2.97-4.95) and 19 patients who reached a low on day 7 of the first cycle had a neutrophil count of 2.76 (1.39-8.00). Treatment-related adverse events (TRAEs) in this study were predominantly grade 1 and 2, included anaemia, nausea, vomiting, thrombocytopenia and leucopenia. Grade 3 and 4 adverse reactions included thrombocytopenia, anaemia and leucopenia. In addition, no discontinuations due to TRAEs or deaths were reported during the study period. Conclusions: A single fixed dose of 20 mg of efbemalenograstim alfa was proved to be safe and effective in reducing chemotherapy-induced neutropenia and its complications in patients who received Chemotherapy. Efbemalenograstim alfa provides an alternative for patients with chemotherapy-induced neutropenia. Clinical trial information: NCT06251947 .

Rationale:Endometrial stromal sarcoma is an extremely rare mesenchymal neoplasm occurring in the extrauterine. Retroperitoneal endometrial stromal sarcoma with multiple pulmonary metastases, in particular, is extremely rare.Patient concerns:Forty-seven-year-old woman (gravida 3, para 2), was referred to our institution with complaints of fever.Diagnoses:Ultrasound and computed tomographic imaging of the abdomen identified the presence of masses in the pelvic region. Additionally, computed tomographic scans and X-ray evaluations of the thorax detected dispersed masses in both the lungs and pelvic area. Histopathological analysis of the pelvic region indicated the presence of low-grade endometrial stromal sarcoma. A computed tomography-guided pneumocentesis was conducted to further characterize the pulmonary lesions, confirming the diagnosis of low-grade endometrial stromal sarcoma.Interventions:The patient underwent tumor resection, subsequent treatment with Medroxyprogesterone acetate for 6 months, received microwave ablation for multiple lung metastases, PARP1 inhibitor for 4 courses, and has been undergoing chemotherapy (epirubicin/ifosfamide) up to the present time.Outcomes:Partial remission was obtained after the above treatment and this patient is now still alive maintaining for 3 years.Lessons:The identification and management of this disease remain a significant challenge due to its low prevalence. Further research involving a larger number of cases is necessary to ensure consistency in diagnosis and to establish effective treatment guidelines.

Recurrence and metastasis are the major issues for papillary thyroid cancer (PTC). Current morphological and molecular classification systems are not satisfied for PTC diagnosis due to lacking variant-specific morphological criteria and high signal-to-noise in mutation-based diagnosis, respectively. Importantly, intratumor heterogeneity is largely lost in current molecular classification system, which can be resolved by single cell RNA sequencing (scRNA-seq). However, scRNA-seq loses spatial information and morphological features. Herein, scRNA-seq is integrated and spatially-resolved transcriptomics (SRT) to elaborate the mechanisms underlying the spatial heterogeneity, malignancy and metastasis of PTCs by associating transcriptome and local morphology. This results demonstrated that PTC cells evolved with multiple routes, driven by the enhanced aerobic metabolism and the suppressed mRNA translation and protein synthesis and the involvement of cell-cell interaction. Two curated malignant and metastatic footprints can discriminate PTC cells from normal thyrocytes. Ferroptosis resistance contributed to PTC evolution. This results will advance the knowledge of intratumor spatial heterogeneity and evolution of PTCs at spatial and single-cell levels, and propose better diagnostic strategy.

Maternal anemia has been identified as a contributing factor to adverse reproductive outcomes associated with cadmium (Cd) exposure, a common heavy metal. Our recent findings suggest that inhibited erythroid differentiation and enucleation also play significant roles in the direct embryonic toxicity resulting from maternal Cd exposure. However, the effects of Cd exposure on lipid metabolism remodeling, which is essential for physiological erythropoiesis, remain poorly understood. In the present study, pregnant mice were administered low doses of CdCl2 via oral exposure from early to late gestation to mitigate Cd-induced maternal anemia. Compared to vehicle-treated controls, embryos from Cd-treated mice exhibited a slight decrease in weight, though without signs of atrophy. Consistent with our previous observations, fetal livers from Cd-exposed embryos demonstrated a dose-dependent inhibition of erythroid differentiation, as confirmed by ex vivo analysis. Notably, an intrinsic decrease in lipid peroxidation during erythroid differentiation was observed in the bone marrow and fetal livers of vehicle-treated mice, attributed to diminished lipid content. In contrast, this decrease in lipid peroxidation was absent in fetal liver erythroblasts from Cd-treated mice, where an increase in lipid peroxidation was instead noted. These findings elucidate a potential mechanism, lipid peroxidation, underlying Cd-induced embryonic toxicity.

Epidemiological and experimental studies have demonstrated the association of spontaneous abortion or embryonic atrophy with heavy metals, including some well-known anemia inducers, such as cadmium (Cd). However, the direct adverse effect of Cd on embryos without inducing maternal anemia remains unclear. In this study, we treated mice with a low dose of Cd before and after mating to minimize Cd-induced maternal anemia. Although most embryos developed normally, embryonic atrophy was still observed in a small percentage of embryos from Cd-exposed pregnant mice. Compared to the embryos from the control pregnant mice, a complete blockage of erythroid differentiation was observed in the atrophic embryos but no obvious alteration of erythroid differentiation in the non-atrophic embryos, respectively. Moreover, our results suggested delayed enucleation of erythroblasts in these non-atrophic embryos. Mechanically, the inhibited iron transport from the placenta to the fetus together with the increased iron export in the fetal livers might contribute to embryonic atrophy and delayed enucleation of erythroblasts upon Cd exposure. Our data may provide new insights into the embryonic toxicity of low-dose Cd.

Cisplatin is widely used in chemotherapies in cervical cancer (CC). Nevertheless, drug resistance in cancer patients poses a major threat to efficacy of treatment. To explore the underlying modulatory mechanism of SOX21-AS1 in cisplatin resistance in CC cell and mice models, Gepia database was referred for SOX21-AS1 expression in cancer tissues and normal ones. Reverse transcription quantitative real-time polymerase chain reaction was used to measure the differential expression of SOX21-AS1 in parental Siha cells and cisplatin-resistant Siha/DDP cells. Luciferase reporter gene assays were conducted to verify putative bindings between SOX21-AS1 and miR-9-3p. Western blot method was employed to evaluate the changes in cleaved-caspase 7 protein expression. Cisplatin resistance was evaluated in each transfected group using cell counting kit 8 method after cells were exposed to cisplatin (0, 7.5, 15, 30, 60, 120, and 240 mu g/mL) for 24 hours. Flow cytometry method was used to measure the apoptosis rates. Cell migration and invasion were measured using Transwell assays. Immunofluorescence method was applied to observe epithelial to mesenchymal transition (EMT) markers, including E-cadherin, Snail, matrix metalloproteinase (MMP)3, and MMP9. Siha/DDP cell groups stably transfected with sh-NC and sh-SOX21-AS1 were injected through tail vein of Balb/C mice. Lung tissue sections were used for hematoxylin and eosin staining and immunohistochemistry analysis. SOX1-AS1 expression was higher in cancer tissues than normal ones and was also higher in Siha/DDP rather than Siha cells. SOX21-AS1 was targeted by miR-9-3p in CC cells. Downregulation of SOX21-AS1 or overexpression of miR-9-3p inhibited cisplatin resistance in Siha/DDP cells and reduced cell invasion and migration and attenuated EMT progression. In vivo, the SOX21-AS1 knockdown led to less severe lung metastasis. Downregulation of SOX21-AS1 alleviated cisplatin resistance in CC through EMT inhibition.

Endometriosis is a hormone-associated disease which has been considered as the precursor for certain types of ovarian cancer. In recent years, emerging evidence demonstrated potent roles of lncRNA in regulating cancer development. Since endometriosis shares several features with cancer, we investigated the possible involvement of cancer-related lncRNAs in endometriosis, including UCA1, GAS5 and PTENP1. By using massARRAY system, we investigated certain genetic variations in cancer-related lncRNAs that can change the thermo-stability, leading to up-regulation or down-regulation of those lncRNAs. Our data indicated three risk genetic haplotypes in UCA1 which can stabilize the RNA structure and increase the susceptibility of endometriosis. Of note, such alterations were found to be associated with long-term pain and infertility in patients. It has been known that UCA1 can function as a ceRNA to sponge and inhibit miRNAs, resulting in loss-of-control on downstream target genes. Gene network analyses revealed fatty acid metabolism and mitochondria beta-oxidation as the major pathways associated with altered UCA1 expression in endometriosis patients. Our study thus provides evidence to highlight functional/epigenetic roles of UCA1 in endometriosis development via regulating fatty acid metabolism in women.

Chemoresistance is one of the major obstacles that lead to poor prognosis in cervical cancer. linc00958 was reported to be an oncogene in cervical cancer. However, its role in mediating chemoresistance remains to be revealed. To explore the regulatory mechanisms of linc00958 in cisplatin-resistant cervical cancer cells and further validate in xenograft mice. Online bioinformatic tools were used to conduct the pre-investigation of linc00958/miR-185-5p/RSF-1 and predict the associations between RSF-1 and AKT1/GSK3β/VEGFA in cervical cancer. RT-qPCR measured the RNA expression levels of linc00958/miR-185-5p/RSF-1 in SiHa and SiHa/DDP. Cell survival rates were evaluated by CCK8 methods after cells were exposed to differential concentrations of DDP. Dual-luciferase reporter methods were used to measure luciferase activity. Western blot measured RSF-1 protein and phosphorylated changes of AKT1/GSK3β. Immunofluorescence was employed to observe VEGFA secretion in vitro. Tube formation was applied to evaluate the in-vitro changes of angiogenesis. The SiHa/DDP cells stably transfected with pLKO-sh-NC or pLKO-sh-linc00958 plasmids, were injected into mice, establishing xenograft models. The changes in mice weight and tumor volumes were recorded. H&E staining and Immunohistochemistry (IHC) method was further performed. linc00958 expression was higher in SiHa/DDP cells. High linc00958 expression was associated with low overall survival. In SiHa/DDP cells linc00958/miR-185-5p/RSF-1 axis inhibited the cellular resistance to cisplatin and suppressed VEGFA and the tube formation through AKT1/GSK3β/VEGFA pathway. The knockdown of linc00958 inhibited RSF-1 and Ki67, curbing tumor growth; it also inhibited VEGFA and CD34, decreasing angiogenesis in mice. linc00958/miR-185-5p/RSF-1 modulates cisplatin resistance and angiogenesis through AKT1/GSK3β/VEGFA pathway in cervical cancer.

HOTAIR is a well-known long non-coding RNA (lncRNA) involved in various cellular signaling, whereas its functional impacts on endometriosis development are still largely unknown. To this end, six potential functional single nucleotide polymorphisms (SNPs) in HOTAIR, with minor allele frequencies more than 10% in Han population and altered net energy of RNA structures larger than 0.5 kcal/mol, were selected for genotyping study. The study included 207 endometriosis patients and 200 healthy women. Genetic substitutions at rs1838169 and rs17720428 were frequently found in endometriosis patients, and rs1838169 showed statistical significance (p = 0.0174). The G-G (rs1838169-rs17720428) haplotype showed the most significant association with endometriosis (p < 0.0001) with enhanced HOTAIR stability, and patients who harbor such haplotype tended to show higher CA125. Data mining further revealed higher mRNA HOTAIR levels in the endometria of patients with severe endometriosis which consistently showed reduced HOXD10 and HOXA5 levels. HOTAIR knockdown with specific shRNAs down-regulated cell proliferation and migration with the induction of HOXD10 and HOXA5 expression in human ovarian clear cancer cells. Our study therefore provided evidence to indicate a prominent role of HOTAIR in promoting endometriosis, which could be used as a potential target for clinical applications.

In article number 2000383, Jinxiang Han, Yajun Liu, and co-workers review how heavy metals induce bone damages through anemia-independent and -related routes. Anemia-independent routes include bone cell dysregulation, bone formation inhibition and bone degradation enhancement, and Ca/P homeostasis disruption. Stress erythropoiesis, erythropoietin deficiency, and disordered iron homeostasis are involved in anemia-related routes.

Background Remodeling and spacing factor-1 (RSF-1) is an identified tumor biomarker that is overexpressed in a variety of human cancers, but its effect on radiotherapy remains unclear. In this study, we aimed to explore the effect of RSF-1 siRNA on sensitizing cervical cancer cells to radiation and its underlying mechanism. Methods The mRNA and protein expression of RSF-1 in tissue and cells were measured by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting. Cell counting kit-8 (CCK-8) and colony formation assay were used to examine cell proliferation. Flow cytometry was used to analyzed the cell cycle and cell apoptosis. DNA damage was examined by the comet assay. ATM, ATR, CHK1, CHK2, H2AX, γH2AX and phosphorylated ATM, ATR, CHK1 and CHK2 were detected by Western blotting. γH2AX foci were demonstrated by immunofluorescence staining. Results RSF-1 was upregulated in cervical cancer tissue and decreased after effective treatment. RSF-1 siRNA in combination with radiation suppressed cell viability, redistributed cell cycles and also induced cell apoptosis in HeLa and SiHa cell lines. Further, knockdown of RSF-1 induced DNA damage by attenuating DNA repair capability, thereby sensitizing cervical cancer cells to radiation. Conclusions These data demonstrate that RSF-1 siRNA enhanced the sensitivity of radiotherapy, and targeting RSF-1 may be a promising approach for the development of novel radiosensitizing agents for the treatment of cervical cancer.

Abstract Objective: Apatinib mesylate is a novel vascular endothelial growth factor receptor 2 (VEGFR-2) inhibitor, which has exhibited good safety and efficacy in several types of solid tumors. The present study aimed to assess the clinical efficacy and safety of apatinib combined with chemotherapy and concurrent chemo-brachytherapy (CCBT) in patients with recurrent and advanced cervical cancer. Methods: A total of 52 patients with first diagnosed recurrent or untreated International Federation of Gynecology and Obstetrics stage IVB cervical cancer admitted at Shandong Cancer Hospital and Institute between July 2016 and May 2018 were analyzed in the current randomized controlled trial. The patients were randomly divided into 2 groups: the apatinib-treated group and the control group. Patients with recurrent cervical cancer in the apatinib-treated group were administered apatinib and carboplatin-paclitaxel as first-line chemotherapy. Patients with advanced cervical cancer were administered apatinib in combination with CCBT. In control group, patients with recurrent cervical cancer were treated with chemotherapy alone while patients with advanced cervical cancer received CCBT. Results: The progression-free survival was significantly prolonged in apatinib group compared with control group (10.1 months; 95% confidence interval (CI), 8.42–11.79 vs 6.4 months; 95% CI, 3.88–8.92; P < .01; hazard ratio (HR), 0.44; 95% CI, 0.25–0.78; P < .01). The objective response rate in apatinib group was obviously higher than that in control group (64.3% vs 33.3%, P < .05). Proteinuria, hand–foot syndrome, mucositis, and hypertension in all Grades were statistically more common in apatinib group than in control group. Apatinib did not obviously aggravate other radiotherapy or chemotherapy side effects. Conclusion: Apatinib exhibited promising clinical efficacy in cervical cancer patients, resulting in an improved response rate and prolonged progression-free survival compared with the control group, and had manageable side effects. Our study revealed that apatinib combination therapy, adenocarcinoma, and bone metastasis

Mounting evidence is revealing that heavy metals can incur disordered bone homeostasis, leading to the development of degenerative bone diseases, including osteoporosis, osteoarthritis, degenerative disk disease, and osteomalacia. Meanwhile, heavy metal-induced anemia has been found to be intertwined with degenerative bone diseases. However, the relationship and interplay among these adverse outcomes remain elusive. Thus, it is of importance to shed light on the modes of action (MOAs) and adverse outcome pathways (AOPs) responsible for degenerative bone diseases and anemia under exposure to heavy metals. In the current Review, the epidemiological and experimental findings are recapitulated to interrogate the contributions of heavy metals to degenerative bone disease development which may be attributable dependently and independently to anemia. A few likely mechanisms are postulated for anemia-independent degenerative bone diseases, including dysregulated osteogenesis and osteoblastogenesis, imbalanced bone formation and resorption, and disturbed homeostasis of essential trace elements. By contrast, remodeled bone microarchitecture, inhibited erythropoietin production, and disordered iron homeostasis are speculated to account for anemia-associated degenerative bone disorders upon heavy metal exposure. Together, this Review aims to elaborate available literature to fill in the knowledge gaps in understanding the detrimental effects of heavy metals on bone cells and bone homeostasis through different perspectives.

Most multiple primary cancers(MPCs) are double primaries, while quadruple cancer is rare, especially breast cancer and triple genital cancer. Our work is the first report about ametachronous quadruple cancer in the reproductive system, including breast, ovary, fallopian tube and cervix. A54-year-old woman, who underwent modified radical mastectomy and right breast tumor resection 3 years ago, presented with abnormal vaginal discharge for 2 months, and she was subsequently diagnosed with stage IIA2 cervical squamous cell carcinoma. She then underwent radiotherapy and chemotherapy, as well as radical hysterectomy, bilateral salpingo-oophorectomy and bilateral pelvic lymphadenectomy. Postoperative pathological findings revealed that the patient had cervical, ovarian and tubal triple cancers with different histopathology for all lesions, also different from breast cancer, implying that these tumors had separate etiology and were not metastatic tumors. Our work might provide aseries of diagnostic, etiological and therapeutic strategies for MPC patients.

Objective To investigate the effects of siRNA interference with chromosomal space recombination factor 1 (Rsf-1/HBXAP) on the chemosensitivity of cervical adenocarcinoma cells, and provide experimental evidence for gene-targeted therapy of cervical adeno-carcinoma. Methods Human cervical adenocarcinoma HeLa cells were transfected with Rsf-1/HBXAP-specific small interfering RNA (siRNA). The Rsf-1/HBXAP mRNA expression in HeLa cells was detected by real-time quantitative polymerase chain reaction (qRT-PCR). The proliferation of HeLa cells was detected by CCK-8 assay. The clone formation of HeLa cells was detected by plate cloning assay. The apoptosis of HeLa cells was detected by flow cytometry. Results Rsf-1/HBXAP-specific siRNA-1 significantly inhibited the expression of the Rsf-1/HBXAP gene. The IC50 of paclitaxel against siRNA-1 in the Rsf-1/HBXAP and non-interfering groups was 7.24 nM [95% CI:(3.14, 18.60)] and 3.66 nM [95% CI: (1.65, 7.86)], respectively. Plate cloning experiments showed that siRNA-1 interference with Rsf-1/HBXAP gene improved the radiosensitivity. Flow cytometry results showed that siRNA-1 interference with Rsf-1/HBXAP gene accelerated the apoptosis of HeLa cells. Conclusion The down-regulation of Rsf-1/HBXAP gene expression may increase the sensitivity of cervical ad-enocarcinoma cells to chemoradiotherapy. It may become a potential target for the treatment of cervical adenocarcinoma.