Fenitrothion induces glucose metabolism disorders in rat liver BRL cells by inhibiting AMPKα and IRS1/PI3K/AKT signaling pathway.

Fenitrothion (FNT) is a common organophosphorus pesticide that is widely used in both agricultural and domestic pest control. FNT has been frequently detected in various environmental media, including the human body, and is a notable contaminant. Epidemiological investigations have recently shown the implications of exposure to FNT in the incidence of various metabolic diseases, such as diabetes mellitus in humans, indicating that FNT may be a potential endocrine disruptor. However, the effects of FNT exposure on glucose homeostasis and their underlying mechanisms in model organisms remain largely unknown, which may limit our understanding of the health risks of FNT. In this study, FNT (4 5, 90, 180, and 4 50 µM) exposure model of rat hepatocytes (Buffalo Rat Liver, BRL cells) was established to investigate the effects and potential mechanisms of its toxicity on glucose metabolism. Several key processes of glucose metabolism were detected in this study. The results showed significantly increased glucose levels in the culture medium and decreased glycogen content in the FNT-exposed BRL cells. The results of quantitative real-time PCR and enzymology showed the abnormal expression of genes and activity/content of glucose metabolic enzymes involved in glucose metabolism, which might promote gluconeogenesis and inhibit glucose uptake, glycolysis, and glycogenesis. Furthermore, gluconeogenesis and glycolytic were carried out in the mitochondrial membrane. The abnormal of mitochondrial membrane potential may be a potential mechanism underlying FNT-induced glucose metabolism disorder. In addition, the mRNA and protein expression implicated that FNT may disrupt glucose metabolism by inhibiting the AMPKα and IRS1/PI3K/AKT signaling pathways. In conclusion, results provide in vitro evidence that FNT can cause glucose metabolism disorder, which emphasizes the potential health risks of exposure to FNT in inducing diabetes mellitus.

The impact of Paclitaxel-based hyperthermic intraperitoneal chemotherapy in advanced high-grade serous ovarian cancer patients - interim analysis of safety and immediate efficacy of a randomized control trial (C-HOC trial).

OBJECTIVE: This study evaluates the potential superiority of combining paclitaxel-based hyperthermic intraperitoneal chemotherapy (HIPEC) with sequential intravenous neoadjuvant chemotherapy over intravenous neoadjuvant chemotherapy alone in Chinese patients with Federation of Gynecology and Obstetrics (FIGO) stage IIIC, IVA and IVB high-grade serous ovarian/fallopian tube carcinoma (HGSOC). This interim analysis focuses on the safety and immediate efficacy of both regimens to determine the feasibility of the planned trial (C-HOC Trial). METHODS: In a single-center, open-label, randomized control trial, FIGO stage IIIC, IVA, and IVB HGSOC patients (FAGOTTI score ≥ 8 during laparoscopic exploration) unsuitable for optimal cytoreduction in primary debulking surgery (PDS) were randomized 2:1 during laparoscopic exploration. The Experiment Group (HIPEC Group) received one cycle of intraperitoneal neoadjuvant laparoscopic hyperthermic intraperitoneal chemotherapy (paclitaxel) followed by three cycles of intravenous chemotherapy (paclitaxel plus carboplatin), while the Control Group received only three cycles of intravenous chemotherapy. Both groups subsequently underwent interval debulking surgery (IDS). The adverse effects of chemotherapy, postoperative complications, and pathological chemotherapy response scores (CRS) after IDS were compared. RESULTS: Among 65 enrolled patients, 39 HIPEC Group and 21 Control Group patients underwent IDS. Grade 3-4 chemotherapy-related adverse effects were primarily hematological with no significant differences between the two groups. The HIPEC Group exhibited a higher proportion of CRS 3 (20.5% vs. 4.8%; P = 0.000). R0 resection rates in IDS were 69.2% (HIPEC Group) and 66.7% (Control Group). R2 resection occurred in 2.6% (HIPEC Group) and 14.3% (Control Group) cases. No reoperations or postoperative deaths were reported, and complications were managed conservatively. CONCLUSIONS: Combining HIPEC with IV NACT in treating ovarian cancer demonstrated safety and feasibility, with no increased chemotherapy-related adverse effects or postoperative complications. HIPEC improved tumor response to neoadjuvant chemotherapy, potentially enhancing progression-free survival (PFS). However, the final overall survival results are pending, determining if HIPEC combined with IV NACT is superior to IV NACT alone.

Strong evidence supports the use of estradiol therapy for the treatment of vaginal inflammation: a two-way Mendelian randomization study.

OBJECTIVE: Nowadays, there has been limited Mendelian randomization (MR) research focusing on the causal relationship between estradiol and vaginitis. Therefore, this study conducted a two-way MR study to clarify the causal effect and related influencing factors between them. METHODS: All genetic datasets were obtained using publicly available summary statistics based on individuals of European ancestry from the IEU GWAS database. MR analysis was performed using MR-Egger, weighted median (WM) and inverse variance weighted (IVW) methods to assess the causal relationship between exposure and outcome and to validate the findings by comprehensively evaluating the effects of pleiotropic effects and outliers. RESULTS: MR analysis revealed no significant causal relationship between estradiol and vaginitis risk. There was a negative correlation between estradiol and age at menarche (IVW, OR: 0.9996, 95% CI: 0.9992-1.0000, P = 0.0295; WM, OR: 0.9995, 95% CI: 0.9993-0.9998, P = 0.0003), and there was a positive correlation between age at menarche and vaginitis (IVW, OR: 1.5108, 95% CI: 1.1474-2.0930, P = 0.0043; MR-Egger, OR: 2.5575, 95% CI: 1.7664-9.6580, P = 0.0013). Estradiol was negatively correlated with age at menopause (IVW, OR: 0.9872, 95% CI: 0.9786-0.9959, P = 0.0041). However, there was no causal relationship between age at menopause and vaginitis (P > 0.05). In addition, HPV E7 Type 16, HPV E7 Type 18, and Lactobacillus had no direct causal effects on estradiol and vaginitis (P > 0.05). Sensitivity analyses revealed no heterogeneity and horizontal pleiotropy. CONCLUSION: When estrogen levels drop, it will lead to a later age of menarche, and a later age of menarche may increase the risk of vaginitis, highlighting that the longer the female reproductive tract receives estrogen stimulation, the stronger the defense ability is formed, and the prevalence of vaginitis is reduced. In conclusion, this study indirectly supports an association between reduced level of estrogen or short time of estrogen stimulation and increased risk of vaginitis.

Assessing health risks from bioaccessible PM2.5-bound toxic metals in Nanchang metro: Implications for metro workers and emissions control.

High concentrations of PM2.5 with enriched levels of metallic constituents could significantly affect the health and comfort of metro employees. To avoid overestimating the exposure risks, we investigated the bioaccessibility of toxic metals (TMs) bound in PM2.5 from the Nanchang metro using Gamble's solution method, and qualitatively analyzed the impact of valence state and various sources on the bioaccessibility of TMs bound to PM2.5. The results showed that the bioaccessibility of the studied TMs ranged from 2.1% to 88.1%, with As, Ba, Co and Pb being the most bioaccessible and V, Fe and Cr being the less bioaccessible. The bioaccessibility of TMs in our subway PM2.5 samples varied based on their valence and species, showing higher valence states associated with increased bioaccessibility. Vehicle traffic, secondary aerosols and wheel/rail sources were found to be significantly and positively associated with the bioaccessibility of several TMs, implying a severe potential risk from these three sources. Although both non-carcinogenic and carcinogenic risks associated with total TMs were found to be high, only As and Cr(VI) posed a considerable carcinogenic risk to metro workers based on the bioaccessible fractions and were therefore priority pollutants. In addition, potential carcinogenic risk was found to be more severe in platform than that in ticket counter. The results indicate that considerable efforts are required to control and manage PM2.5 and the associated TMs in the Nanchang subway, particularly from traffic, wheel/rail and secondary sources, to protect the health of metro staff and the public.

Neurodevelopmental toxicity and molecular mechanism of environmental concentration of tetrabromobisphenol A bis (2- hydroxyethyl) ether exposure to sexually developing male SD rats.

Tetrabromobisphenol A bis (2- hydroxyethyl) ether (TBBPA-DHEE), as one of the main derivatives of Tetrabromobisphenol A, been attracted attention for its health risks. In this study, the neurotoxicity, mechanism, and susceptivity of TBBPA-DHEE exposure to sexually developing male rats were systematically studied. Neurobehavioral research showed that TBBPA-DHEE exposure could significantly affect the behavior, learning,and memory abilities of male-developing rats, and aggravate their depression. TBBPA-DHEE exposure could inhibit the secretion of neurotransmitters. Transcriptomics studies show that TBBPA-DHEE can significantly affect gene expression, and a total of 334 differentially expressed genes are enriched. GO function enrichment analysis shows that TBBPA-DHEE exposure can significantly affect the expression of genes related to synapses and cell components. KEGG function enrichment analysis shows that TBBPA-DHEE exposure can significantly affect the expression of signal pathways related to nerves, nerve development, and signal transduction. Susceptibility analysis showed that female rats were more susceptible to TBBPA-DHEE exposure than male rats. Therefore, TBBPA-DHEE exposure has neurodevelopmental toxicity to male developmental rats, and female developmental rats are more susceptible than male developmental rats. Its possible molecular mechanism is that TBBPA-DHEE may inhibit the secretion of neurotransmitters and affect signal pathways related to neurodevelopment and signal transduction.

Anlotinib Inhibits Ovarian Cancer and Enhances Cisplatinum Sensitivity via Suppressing NOTCH2 Expression and Stemness.

BACKGROUND/AIM: The prognosis of ovarian cancer (OC) patients is especially poor for patients with chemotherapy resistance. Anlotinib, a novel multi-targeted tyrosine kinase inhibitor, has shown encouraging clinical efficacy in several tumor types. The aim of the present study was to examine the inhibitory efficacy and mechanism of anlotinib on the proliferation and chemosensitivity of OC cells. MATERIALS AND METHODS: The inhibitory effects of Anlotinib on SKOV3 and OVCAR3 OC cells were examined using CCK-8 cell-viability, colony-formation, flow-cytometry, transwell-migration and sphere-formation assays. A xenograft mouse model was used for in vivo studies. RT-qPCR and western blotting were used to detect gene expression. RESULTS: Molecular targets of anlotinib were elevated in OC patient tumors. Anlotinib significantly inhibited ovarian cancer cell proliferation and migration in vitro. Anlotinib enhanced the sensitivity of ovarian cancer cells to cisplatinum both in vitro and in vivo. Anlotinib suppressed sphere formation and the stemness phenotype of OC cells by inhibiting NOTCH2 expression. CONCLUSION: Anlotinib inhibits ovarian cancer and enhances cisplatinum sensitivity, suggesting its future clinical promise.

Can surgery boost the survival benefit of chemoradiotherapy in T1b1-T2a1 stage cervical cancer with lymph node metastasis? A population-based study.

OBJECTIVE: This study aimed to determine whether surgery followed by adjuvant chemoradiotherapy has superior survival outcomes for node-positive patients with T1b1-T2a1 stage cervical cancer compared with those who undergo chemoradiation. METHODS: We investigated the Surveillance, Epidemiology, and End Results database for 12,701 patients diagnosed between 2000 and 2018. Patients were stratified according to different T stages and different treatment strategies. Surgery included radical hysterectomy (RH) or total hysterectomy (TH). Radiotherapy (RT) included adjuvant chemoradiation or chemoradiation alone. Cox analyses were performed to select the clinically important factors of survival outcomes. Survival analysis was used to compare those who received different treatment methods. RESULTS: A total of 12,701 International Federation of Gynecology and Obstetrics 2018 stage IIIC cervical cancer patients were identified. The risk of overall survival (OS) was significantly different between patients who received and did not receive chemoradiotherapy in the T categories. In the propensity-score matched dataset, early-T stage (T1b1 and T1b2) and node-positive patients in the "RH+RT" and "TH+RT" groups had better disease-specific survival (DSS) than those in the RT group. No difference in DSS was observed between the "surgery following RT" group and the RT group in locally advanced stage (T1b3 and T2a1, node positive) patients. Regarding T1b1-T2a1 node-positive patients, the RH+RT group had a similar survival outcome to that in the TH+RT group. CONCLUSION: We showed that surgery following RT benefits early-T stage (T1b1 and T1b2) cervical cancer patients with lymph node metastasis. For locally advanced stages (T1b3 and T2a1), surgery and RT had similar survival outcomes.

The value of hypersensitivity quantitative fecal immunochemical test in early colorectal cancer detection.

At present, both the incidence and mortality rates of colorectal cancer are on the rise, making early screening a crucial tool in reducing the fatality rate. Although colonoscopy is the recommended method according to the guidelines, compliance tends to be poor. The fecal immunochemical test (FIT), a new technology that uses latex immunoturbidimetry to detect fecal blood, offers high specificity and sensitivity. Additionally, it is low-cost, easy to operate, and less likely to be affected by food and drugs, thus improving the compliance rate for population screening. Compared to other screening techniques, FIT represents a safer and more accurate option. This article reviews the application of FIT in early colorectal cancer screening.

Dual role of PRDX1 in redox-regulation and tumorigenesis: Past and future.

Tumour cells often display an active metabolic profile, leading to the intracellular accumulation of reactive oxygen species. As a member of the peroxidase family, peroxiredoxin 1 (PRDX1) functions generally in protecting against cell damage caused by H2O2. Additionally, PRDX1 plays a role as a molecular chaperone in various malignant tumours, exhibiting either tumour-promoting or tumour-suppressing effects. Currently, PRDX1-targeting drugs have demonstrated in vitro anticancer effects, indicating the potential of PRDX1 as a molecular target. Here we discussed the diverse functions of PRDX1 in tumour biology and provided a comprehensive analysis of the therapeutic potential of targeting PRDX1 signalling across various types of cancer.

Comparison of the diagnostic value of [68 Ga]Ga-FAPI-04 PET/MR and [18F]FDG PET/CT in patients with T stage ≤ 2a2 uterine cervical cancer: a prospective study.

PURPOSE: To compare the diagnostic value of [68 Ga]Ga-FAPI-04 PET/MR and [18F]FDG PET/CT in patients with T stage ≤ 2a2 uterine cervical cancer patients. METHODS: Patients pathologically diagnosed with cervical cancer and with a T stage ≤ T2a2 were prospectively enrolled. All patients underwent whole-body [68 Ga]Ga-FAPI-04 PET/MR and [18F]FDG PET/CT within 2 weeks, and surgical treatment was performed within 10 days after PET. RESULTS: Twenty-five patients were enrolled. Twenty patients underwent radical hysterectomy, among which all of them underwent pelvic lymphadenectomy, and 10 patients underwent para-aortic lymphadenectomy. Three patients received merely laparoscopic lymphadenectomy without hysterectomy. Two patients with both [18F]FDG and [68 Ga]Ga-FAPI-04 lymph node high metabolism were staged as FIGO IIIC1r, and concurrent chemoradiation therapy (CCRT) was performed. [18F]FDG and [68 Ga]Ga-FAPI-04 had equivalent detection ability on primary tumors, with a positive detection rate of 96.0%. The accuracy of T staging using [18F]FDG and [68 Ga]Ga-FAPI-04 was relatively 50% and 55.0%. Elevated and underrated staging was due to misdiagnosis of either vaginal infiltration or tumor size. In terms of lymph node metastasis detection, the specificity of [68 Ga]Ga-FAPI-04 was 100% (95% CI, 84.6% ~ 100.0%), which was significantly higher than [18F]FDG (59.1% (95% CI, 36.4% ~ 79.3%)) (p = 0.004). CONCLUSION: [68 Ga]Ga-FAPI-04 PET/MR and [18F]FDG PET/CT demonstrated an equivalent detection ability on cervical cancer primary tumors. However, [68 Ga]Ga-FAPI-04 PET/MR's diagnostic value in lymph node metastasis was significantly higher than [18F]FDG PET/CT. [68 Ga]Ga-FAPI-04 PET/MR has the potential for more accurate treatment planning, thus clarifying fertility preservation indications for early-stage young patients.

Unraveling the challenges of intravenous leiomyomatosis: a retrospective analysis of 11 cases.

OBJECTIVE: This study provides a concise overview of diagnostic and treatment strategies for intravenous leiomyomatosis (IVL), a rare disease with nonspecific clinical manifestations, based on cases from a tertiary referral hospital in China. METHODS: We retrospectively analyzed 11 premenopausal patients with confirmed IVL between 2018 and 2022. Clinical data from Ultrasound, Enhanced CT, and MRI were studied, along with surgical details, postoperative pathology, and follow-up information. RESULTS: Premenopausal patients showed no disease-specific symptoms, with 90.9% having a history of gynecological or obstetric surgery, and 72.7% having prior uterine fibroids. Cardiac involvement was evident in two cases, with echocardiography detecting abnormal floating masses from the inferior vena cava. Pelvic ultrasound indicated leiomyoma in 90.9% of cases, with ≥ 50 mm size. Surgery was the primary treatment, and lesions above the internal iliac vein resulted in significantly higher intraoperative blood loss (median 1300 ml vs. 50 ml, p = 0.005) and longer hospital stays (median 10 days vs. 4 days, p = 0.026). Three patients with lesions above the inferior vena cava required combined surgery with cardiac specialists. Recurrence occurred in 2 out of 11 patients with incomplete lesion resection. CONCLUSIONS: IVL mainly affects premenopausal women with uterine masses, primarily in the pelvic cavity (Stage I). Pelvic ultrasound aids early screening, while Enhanced CT or MR assists in diagnosing and assessing venous lesions. Complete resection is crucial to prevent recurrence. Lesions invading the internal iliac vein and above pose higher risks during surgery. A multidisciplinary team approach is essential for patients with lesions above the inferior vena cava, with simultaneous surgery as a potential treatment option.

CRD-BP as a Tumor Marker of Colorectal Cancer.

The National Cancer Center published a comparative report on cancer data between China and the United States in the Chinese Medical Journal, which shows that colorectal cancer (CRC) ranks second in China and fourth in the United States. It is worth noting that since 2000, the case fatality rate of CRC in China has skyrocketed, while the United States has gradually declined. Finding tumor markers with high sensitivity and specificity is our primary goal to reduce the case fatality rate of CRC. Studies have shown that CRD-BP (Insulin-like growth factor 2 mRNA-binding protein 1) can affect a variety of signaling pathways, such as Wnt.nuclear factor KB (NF-κB), and Hedgehog, and has good biological effects as a therapeutic target for CRC. CRD-BP is expected to become a tumor marker with high sensitivity and specificity of CRC. This paper reviews the research on CRD-BP as a tumor marker of CRC.

Impact of peritoneal vaginoplasty combined with radical hysterectomy on the quality of sexual life for patients with early-stage cervical cancer: trial protocol for a multi-center superiority randomized controlled trial.

BACKGROUND: Radical hysterectomy (RH) is commonly used to treat early-stage cervical cancer in women of childbearing age and sexual dysfunction due to postoperative vaginal shortening is a major concern. The impact of intraoperative vaginoplasty on prognosis and quality of sexual life in patients with early-stage cervical cancer remains controversial and lacks high-level evidence. However, there are few reports on vaginoplasty after RH to lengthen vagina in patients. This prospective, multi-center, randomized controlled trial aims to explore the impact of peritoneal vaginoplasty with or without ovarian transposition after laparoscopic RH on sexual dysfunction in patients with early-stage cervical cancer. METHODS: Eligible patients will be randomly assigned (1:1) to receive peritoneal vaginoplasty or not. The primary evaluation indicators are female sexual function index (FSFI) and male sexual satisfaction scale. The secondary evaluation indicators include EORTC QLQ-CX24, 2-year overall survival (OS), 5-year OS, 2-year progression-free survival (PFS), 5-year PFS and surgery-related complications. The trial will enroll 368 patients from 6 hospitals in China over a 3-year period and follow up for 5 years. TRIAL REGISTRATION: Chinese Clinical Trial Registry Identifier: ChiCTR2000040610.

Case Report: The first report of PPP2R1A mutations in mesonephric-like adenocarcinoma of endometrial carcinoma.

We performed clinical treatment, histopathology, immunohistochemistry and molecular analyses. To compare with the published literature and have a reference overview. A 57-year-old woman and a 77-year-old woman presented with mesonephric-like adenocarcinoma of endometrium at an early clinical stage. The former had no deep myometrial infiltration and no regional lymph node involvement. The latter had deep myometrial infiltration, presence of LVSI and no regional lymph node involvement. Both of the tumor cells were positive for PAX8, GATA-3,CD-10,TTF-1,AE1/AEs,Ki67,P53 and P16 in immunohistochemical staining (IHC)Test. Primary tumors were examined for gene mutations by next generation sequencing. The former was identified KRAS mutation. The latter had KRAS,PIKCA and PPP2R1A mutations. To our knowledge, it is the first time that PPP2R1A(protein phosphatase 2,regulatory subunit A,α) mutation in MLA is reported in English literature.

Comparison of the survival outcomes of laparoscopic, abdominal and gasless laparoscopic radical hysterectomy for early-stage cervical cancer: trial protocol of a multicenter randomized controlled trial (LAGCC trial).

Background: Radical hysterectomy (RH) is considered a cornerstone in the treatment of early-stage cervical cancer. However, the debate surrounding the optimal surgical approach, whether minimally invasive or open surgery, remains controversial. The objective of this trial is to evaluate the survival outcomes of cervical cancer patients who undergo different surgical approaches. Methods: This study is designed as a prospective, multicenter, open, parallel, and randomized controlled trial. A total of 500 patients diagnosed with stage IA1 with LVSI, IA2, IB1, or IB2 (2018 FIGO) will be recruited. Recruitment of participants started in November 2020. The participants will be randomly assigned to one of three groups: conventional laparoscopic RH, gasless laparoscopic RH, or abdominal RH. The primary endpoint of this trial is the 2-year disease-free survival (DFS) rate. The secondary endpoints will include the 2-year overall survival (OS) rate, 5-year DFS/OS, recurrence rates, operation time, intraoperative blood loss, surgery-related complications, and impact on quality of life (QoL). Discussion: We expect this trial to provide compelling and high-quality evidence to guide the selection of the most appropriate surgical approach for early-stage cervical cancer. Clinical trial registration: Chinese Clinical Trial Register, identifier ChiCTR2000035515.

Development and validation of real-time recombinase polymerase amplification-based assays for detecting HPV16 and HPV18 DNA.

IMPORTANCE: HPV DNA screening is an effective approach for the prevention of cervical cancer. The novel real-time recombinase polymerase amplification-based HPV detection systems we developed constitute an improvement over the HPV detection methods currently used in clinical practice and should help to extend cervical cancer screening in the future, particularly in point-of-care test settings.

Characteristics of amino acid metabolism in colorectal cancer.

In recent years, metabolomics research has become a hot spot in the screening and treatment of cancer. It is a popular technique for the quantitative characterization of small molecular compounds in biological cells, tissues, organs or organisms. Further study of the tumor revealed that amino acid changes may occur early in the tumor. The rapid growth and metabolism required for survival result in tumors exhibiting an increased demand for amino acids. An abundant supply of amino acids is important for cancer to maintain its proliferative driving force. Changes in amino acid metabolism can be used to screen malignant tumors and improve therapeutic outcomes. Therefore, it is particularly important to study the characteristics of amino acid metabolism in colorectal cancer. This article reviews several specific amino acid metabolism characteristics in colorectal cancer.

Persistent immune injury induced by short-term decabromodiphenyl ether (BDE-209) exposure to female middle-aged Balb/c mice.

Decabromodiphenyl ether (BDE-209), widely used in various industries for its excellent flame-retardant performance, could be enriched in humans and is closely associated with immune impairment. In addition, immune system is gradually declined and becoming more sensitive to environmental pollutants in the ageing process. Therefore, the immunotoxicity of BDE-209 (4, 40, and 400 mg/kg/day) to middle-aged mice and its recovery and susceptibility was first to be comprehensively investigated in this study. The results showed that BDE-209 exposure could lead to oxidative injury to immune organs (spleen, thymus, and liver), impair humoral (immunoglobulins), cellular (lymphopoiesis), and non-specific immunity, and disturb the expressions of the genes related to Th1/Th2 balance (T helper cells) in the middle-aged mice. In addition, Integrated Biomarker Response (IBR) indicated that BDE-209-induced immune impairment was challenging to self-regulated, and even exacerbated after 21 days of recovery and oxidative injury in immune organs could be the main reason. Furthermore, factorial analysis showed that middle-aged mice exposed to BDE-209 suffered from greater immune impairment than adult mice, and the immune impairment in aged mice is more difficult to be self-repaired than that in adult mice. It can be seen that the aged tend to suffer from BDE-209-induced persistent immune impairment and health threats.