Proteomics reveals dynamic metabolic changes in human hematopoietic stem progenitor cells from fetal to adulthood.

BACKGROUND: Hematopoietic stem progenitor cells (HSPCs) undergo phenotypical and functional changes during their emergence and development. Although the molecular programs governing the development of human hematopoietic stem cells (HSCs) have been investigated broadly, the relationships between dynamic metabolic alterations and their functions remain poorly characterized. METHODS: In this study, we comprehensively described the proteomics of HSPCs in the human fetal liver (FL), umbilical cord blood (UCB), and adult bone marrow (aBM). The metabolic state of human HSPCs was assessed via a Seahorse assay, RT‒PCR, and flow cytometry-based metabolic-related analysis. To investigate whether perturbing glutathione metabolism affects reactive oxygen species (ROS) production, the metabolic state, and the expansion of human HSPCs, HSPCs were treated with buthionine sulfoximine (BSO), an inhibitor of glutathione synthetase, and N-acetyl-L-cysteine (NAC). RESULTS: We investigated the metabolomic landscape of human HSPCs from the fetal, perinatal, and adult developmental stages by in-depth quantitative proteomics and predicted a metabolic switch from the oxidative state to the glycolytic state during human HSPC development. Seahorse assays, mitochondrial activity, ROS level, glucose uptake, and protein synthesis rate analysis supported our findings. In addition, immune-related pathways and antigen presentation were upregulated in UCB or aBM HSPCs, indicating their functional maturation upon development. Glutathione-related metabolic perturbations resulted in distinct responses in human HSPCs and progenitors. Furthermore, the molecular and immunophenotypic differences between human HSPCs at different developmental stages were revealed at the protein level for the first time. CONCLUSION: The metabolic landscape of human HSPCs at three developmental stages (FL, UCB, and aBM), combined with proteomics and functional validations, substantially extends our understanding of HSC metabolic regulation. These findings provide valuable resources for understanding human HSC function and development during fetal and adult life.

A retrospective study of anlotinib in patients with persistent, recurrent or metastatic cervical and endometrial cancer.

Background: The prognosis of persistent, recurrent or metastatic cervical and endometrial cancer is poor. Anlotinib is a novel multitarget tyrosine kinase inhibitor (TKI). The efficacy and safety of anlotinib in patients with cervical and endometrial cancer need to be evaluated. Methods: We retrospectively analyzed the efficacy and safety of anlotinib in patients with persistent, recurrent or metastatic cervical and endometrial cancers between March 2020 and June 2023. The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were analyzed. Results: The overall ORR and DCR were 24.14% and 55.17% respectively. The ORR and DCR in patients with cervical cancer were 25.00% and 56.25%; the ORR and DCR in patients with endometrial cancer were 23.08% and 53.85%. The patients received anlotinib plus immunotherapy had significantly higher rate of clinical benefit than those receiving anlotinnb alone (P=0.04). The DCR was significantly higher in patients receiving anlotinib combined with immunotherapy (DCR: 75.00% vs. 30.76%) than those without immunotherapy. The overall median PFS and OS were 12.2 months [95% confidence interval (CI): 6.6-17.8] and 22.3 months (95% CI: 20.9-23.7), respectively. The patients receiving anlotinib plus immunotherapy had significantly longer OS than those without immunotherapy [not reached vs. 12.5 months; hazard ratio (HR): 0.32 (95% CI: 0.1-0.99); P=0.04]. The most common AEs was fatigue (41.4%). Conclusions: Anlotinib might be a promising agent for persistent, recurrent or metastatic cervical and endometrial cancers with good tolerability. Moreover, anlotinib combined with immunotherapy showed synergistic antitumor effect.

Clinical Value Analysis of Serum TK1, SCC-Ag, and MUC-1 in the Diagnosis and Prognosis Evaluation of Cervical Cancer.

Objective: This study aims to analyze the diagnostic and prognostic value of serum thymidine kinase (TK1), squamous cell carcinoma antigen (SCC-Ag), and mucin-1 (MUC-1) in cervical cancer. Methods: This retrospective study included 85 cervical cancer patients as the experimental group treated at our hospital's obstetrics and gynecology department from January 2016 to January 2019. The benign group also consisted of 85 patients with benign lesions treated during the same period, and the comparison group comprised 85 patients with healthy physical examinations at the same time. Results: Serum levels of TK1, SCC-Ag, and MUC-1 were significantly higher in the experimental group than in the benign group and higher in the benign group than in the comparison group (P < .05). Additionally, serum TK1, SCC-Ag, and MUC-1 were higher in the lymph node metastasis group, infiltration depth > 1/2 group, tumor diameter ≥ 4 cm group, and stage III-IV group compared to the non-lymph node metastasis group, infiltration depth ≤ 1/2 group, tumor diameter <4 cm group, and stage I-II group (P < .05). No significant differences in serum TK1, SCC-Ag, and MUC-1 among different pathological types and age groups (P > .05). Moreover, serum TK1, SCC-Ag, and MUC-1 levels were higher in the deceased group compared to the survivor group (P < .05). These markers were negatively correlated with survival time (r value = -0.524, -0.428, -0.516), indicating that as the severity of cervical cancer increased, serum TK1, SCC-Ag, and MUC-1 concentrations also increased. The levels of these markers were significantly higher in deceased patients compared to survivors. Conclusions: Serum levels of TK1, SCC-Ag, and MUC-1 show promise as biomarkers for cervical cancer diagnosis and prognosis. TK1 and SCC-Ag are elevated, while MUC-1 is decreased in cervical cancer patients. Further research is warranted to confirm these findings and explore additional biomarkers.

Honokiol alleviates radiation-induced premature ovarian failure via enhancing Nrf2.

BACKGROUND: The ovary is highly sensitive to radiation, and patients receiving radiotherapy are at significant risk of premature ovarian failure (POF). This study aimed to explore the radioprotective effect of honokiol (HKL) on ionizing radiation (IR)-induced POF. METHODS: Female C57BL/6 mice were administered intraperitoneally with vehicle or HKL once daily for 7 days. On day 7, the mice in the IR and HKL+IR groups were exposed to 3.2 Gy whole-body radiation for one hour after the intraperitoneal injection and sacrificed 12 or 72 h after radiation exposure. The gonadosomatic index (GSI) was calculated. Blood samples were collected for enzyme-linked immunosorbent assay (ELISA). Ovaries were harvested for histological examination, immunohistochemistry, immunofluorescence, TUNEL, western blot, and qPCR. The fertility assessment was evaluated by calculating live offspring number. RESULTS: The optimum dose of HKL against radiation was 10 mg/kg via intraperitoneal injection. POF was induced 72 h after irradiation with significantly downregulated proliferating cell nuclear antigen (PCNA). The numbers of primordial and preantral follicles decreased significantly after irradiation (p < .001), whereas the number of atretic follicles increased (p < .001). The serum levels of estradiol (E2 ) and anti-Müllerian hormone (AMH) decreased to 50% of the control group after irradiation (p < .05). Moreover, the GSI after irradiation was 27% lower than in the control group (p < .05). The number of offspring in the IR group dropped by 50% compared with the control group (p < .05). HKL pretreatment protected the animals' fertility, GSI, PCNA, serum levels of E2 and AMH, and the number of primordial and preantral follicles. Significant upregulation of apoptosis-related proteins such as Pho-P53, Bax, Cyto C, C-caspase-3, C-PARP, and pyroptosis-related proteins such as Pho-NF-κB p65, NLRP3, caspase-1, IL-1ß, and IL-18 was observed after irradiation, while the expression of Bcl-2 decreased. HKL pretreatment prevented these changes. After irradiation, malondialdehyde (MDA), Nrf2, and HO-1 were upregulated. HKL treatment activated the expression of Nrf2 and HO-1 and promoted the nucleus translocation of Nrf2. Furthermore, HKL did not affect ovarian reserves under physiological conditions. CONCLUSIONS: HKL ameliorated IR-induced POF by inhibiting apoptosis and pyroptosis by enhancing Nrf2 expression and translocation.

Efficacy and safety of oral gonadotropin-releasing hormone antagonists in moderate-to-severe endometriosis-associated pain: a systematic review and network meta-analysis.

PURPOSE: The aim of this NMA is to comprehensively analyze evidence of oral GnRH antagonist in the treatment of moderate-to-severe endometriosis-associated pain. METHODS: Literature searching was performed to select eligible studies published prior to April 2022 in PubMed, Cochrane, Embase and Web of Science. Randomized controlled trials involving patients who suffered from moderate-to-severe endometriosis-associated pain and treated with oral nonpeptide GnRH antagonists or placebo were included. RESULTS: Elagolix 400 mg and ASP1707 15 mg were most efficient in reducing pelvic pain, dysmenorrhea and dyspareunia. Relugolix 40 mg was best in reducing the analgesics use. The rates of any TEAEs and TEAEs-related discontinuation were highest in relugolix 40 mg and elagolix 250 mg, respectively, while rates of hot flush and headache were highest in relugolix 40 mg and elagolix 150 mg. Significantly decreased spinal BMD was observed in elagolix 250 mg. CONCLUSION: Oral GnRH antagonists were effective in endometriosis-associated pain in 12w, and most of the efficiency and safety outcomes were expressed in a dose-dependent manner, but linzagolix 75 mg was an exception.

The effects of vasopressin injection technique on ovarian reserve in laparoscopic cystectomy of bilateral ovarian endometrioma: a retrospective cohort study.

OBJECTIVE: To evaluate the effects of vasopressin injection technique (VIT) on ovarian reserve in laparoscopic cystectomy of bilateral ovarian endometrioma. MATERIAL AND METHODS: A total of 122 patients with bilateral ovarian endometrioma undergoing laparoscopic cystectomy were assigned to control or the VIT group. Coagulation-event count and blood loss were recorded. Levels of serum anti-Müllerian hormone (AMH) were assessed at 1 day pre-operation, 1 month, 3 months, and 6 months post-operation. The follicles in the tissue sections were counted, and the maximum thickness of cyst wall was measured. RESULTS: Coagulation-event count and blood loss in the VIT group were statistically less than those in control group (P<0.05). In both groups, AMH levels at pre-operation were the highest among different time-points (P<0.05); a remarkable decrease of AMH level was observed at 1 month post-operation, and the values were the lowest among different time-points (P<0.05). At 3 months post-operation, AMH levels gradually increased to approximately 60% of those at pre-operation (P<0.05); at 6 months post-operation, AMH levels were significantly higher than those at 3 months post-operation in VIT group (P<0.05). AMH levels in VIT group were significantly higher than those in control group at each time-point post-operation (P<0.05). The cyst walls in control group were statistically thicker than those in VIT group (P<0.05). Consistent with results of cyst wall thickness, numbers of total follicle loss, primordial and primary follicles in VIT group were less than those of control group (P<0.05). CONCLUSION: VIT effectively protected ovarian reserve in laparoscopic cystectomy of bilateral ovarian endometrioma.

Clinical analysis of uterine arterial interventional chemoembolization combined with radiotherapy in mid-advanced cervical cancer.

PURPOSE: To compare the efficacy and safety of uterine arterial interventional chemoembolization (UAIC) combined with radiotherapy and intravenous chemotherapy combined with radiotherapy in the treatment of mid-advanced cervical cancer. METHODS: The clinical data of 128 patients with mid-advanced cervical cancer were retrospectively analyzed. According to different treatment methods, the patients were divided into two groups. Docetaxel+nedaplatin UAIC combined with intensity-modulated radiotherapy was performed in UAIC group (n=64), while docetaxel+nedaplatin intravenous chemotherapy combined with intensity-modulated radiotherapy (IMRT) was performed in the control group (n=64). The short-term clinical efficacy and incidence of adverse reactions were compared between the two groups. The tumor recurrence and survival status were recorded during follow-up, and the progression-free survival (PFS) and overall survival (OS) were compared between the two groups. RESULTS: The short-term clinical response rate was 70.3% (45/64) and 48.4% (31/64), respectively, in the UAIC and the control group. In the functional scales of European Organization for Research and Treatment of Cancer-Quality of Life Questionnaire-Core 30 (EORTC-QLQ-C30), the scores of physical function, role function, cognitive function, emotional function and social function were higher in the UAIC group than in the control group, but only the emotional function score had a statistically significant difference. In the symptom scales, the scores of sleep disturbance, nausea and vomiting, pain and fatigue were obviously lower in the UAIC group than those in the control group. The general health score was 79.46±11.28 points and 78.17±13.49 points, respectively, in the UAIC and the control group. Follow-up results revealed that the 3-year OS was 70.3% (45/64) and 73.4% (47/64), and the 3-year PFS was 64.1% (41/64) and 65.6% (42/64), respectively, in the UAIC and the control group. Log-rank test showed that OS and PFS had no statistically significant differences between the two groups. CONCLUSIONS: UAIC combined with radiotherapy has better short-term clinical efficacy than intravenous chemotherapy combined with radiotherapy in the treatment of mid-advanced cervical cancer, with fewer adverse reactions and higher quality of life, but it had no significant effect on the long-term survival and tumor progression.

Response to first-line treatment predicts progression-free survival benefit of small-cell lung cancer patients treated with anlotinib.

BACKGROUND: Anlotinib significantly extended progression-free survival (PFS) and overall survival (OS) in small-cell lung cancer (SCLC) as third or later line treatment. METHODS: In this study, we retrospectively analyzed the efficacy and safety of anlotinib in the clinical practice and aimed to identify risk factors for predicting the clinical benefit of anlotinib in SCLC patients. 29 SCLC patients treated with anlotinib monotherapy or combination therapy as second or later line treatment were included. PFS, OS, objective response rate (ORR), disease control rate (DCR), and adverse events (AEs) were analyzed. RESULTS: In whole patients, the median PFS was 2.1 months (95% confidence interval (CI): 1.1-3.2 months); The ORR and DCR were 10.3% and 48.3%, respectively; The median OS was 7.2 months (95%CI: 3.2-11.2 months). Cox regression analysis demonstrated that response to first-line treatment was the independent risk factor for PFS. The ORR (20.0% vs. 0%) and DCR (53.3% vs. 42.9%) were promoted in patients treated with anlotinib combination therapy comparing to anlotinib monotherapy. The most common AEs were hoarseness, fatigue, decreased appetite, oral mucositis, and anemia. No treatment-related AEs graded 3 or more. CONCLUSION: Anlotinib is an effective option for SCLC patients with tolerable toxicity as second or later line treatment. Patients sensitive to first-line treatment had longer PFS when treated with anlotinib. Anloitnib combined with other therapy increased the efficacy without adding toxicity.

Comparison between radiofrequency ablation combined with mifepristone and radiofrequency ablation for large uterine fibroids.

OBJECTIVE: To evaluate the clinical outcomes of transvaginal ultrasound-guided (US-guided) radiofrequency ablation (RFA) combined with mifepristone for the treatment of large uterine fibroids. METHODS: Between June 2016 and December 2018, a total of 30 patients with symptomatic uterine fibroids (≥5cm) who underwent transvaginal US-guided RFA combined with mifepristone were included in this retrospective study. A matching cohort of 30 patients underwent transvaginal US-guided RFA without mifepristone as controls. The technical efficacy, complications and mid-term treatment effectiveness were assessed and compared with the controls. RESULTS: The mean volume of uterine fibroid was 168.3 ± 40.1 cm3. The mean ablation time was 23.5 ± 11.3 min in the combined treatment group, which was demonstrably less than that of the RFA group, which was 45.7 ± 6.8 min. The mean number of punctures was 2.2 ± 0.6 in the combined treatment group, which was significantly less than that of the RFA group. No major complications occurred. The mean percentages of regression of fibroid at 3 and 12 months after the course of the combined treatment were 73.3% and 90.1%, respectively, which were significantly more than those of the RFA group. Quality of life and symptom scores improved in both groups but to a greater extent in the combined treatment group. CONCLUSIONS: US-guided RFA combined with mifepristone might be a simple, safe and effective alternative for the treatment of large uterine fibroids.

Ultrasound-guided transvaginal radiofrequency ablation combined with levonorgestrel-releasing intrauterine system for symptomatic uterine adenomyosis treatment.

OBJECTIVE: To evaluate the clinical outcomes of transvaginal ultrasound-guided radiofrequency ablation (RFA) combined with a levonorgestrel-releasing intrauterine system (LNG-IUS) for the treatment of symptomatic uterine adenomyosis. METHODS: Patients with symptomatic uterine adenomyosis treated with ultrasound-guided RFA in combined with an LNG-IUS from January 2013 to January 2016 and followed up for 3 years after treatment were selected. Assessment endpoints included the uterine volume reduction rate, dysmenorrheal score, symptom severity score and adverse events. RESULTS: Among the 72 patients, 64 completed the 3-year follow-up evaluations after treatment. No LNG-IUS expulsion was reported. Dysmenorrhea and symptom severity scores statistically significantly declined after the combined treatment of RFA and LNG-IUS was administered. The uterine volume significantly decreased, and the average reduction rate was 55%. CONCLUSION: Ultrasound-guided RFA combined with an LNG-IUS might be a simple, safe and effective alternative for the treatment of symptomatic adenomyosis.

Retroperitoneal ectopic pregnancy: A case report and literature review.

Retroperitoneal ectopic pregnancy (REP) is a rare type of pregnancy with retroperitoneal implantation of the embryo. Herein, we report a case of a 29-year-old female with REP admitted in our department. Moreover, we review the literatures published previously reporting REP with the aim to improve the understanding of diagnosis and treatment of REP.

Inhibitory and protective effect of obovatol against uterine fibroid (leiomyoma) cells.

Uterine fibroids (UF) or leiomyomas can be presented in post-menopausal women. The present study was aimed to examine the inhibitory and protective (anti-proliferative and apoptotic) effect of the obovatol (OB) in human leiomyoma cells (HuLM). The cell proliferative activity was determined by MTT assay and inflammatory markers were measured. Followed by evaluating DNA fragmentation and apoptotic markers using the ELISA kit method. Also, the apoptosis regulatory proteins expressions were determined using the immunoblot technique. Treatment with increasing concentration of OB (25-200 µM) significantly lowered the cell proliferation rate as well as considerably reduced the values of various pro-inflammatory cytokines like IL-1ß, TNF-α, IL-6. Whereas, the levels of DNA fragmentation and apoptotic marker like caspase-3 and 9 were considerably elevated after co-culturing HuLM cells with OB. In addition, apoptosis regulatory proteins like Bcl2 and Bax were substantially down and up-regulated respectively, by OB in a dose-dependent fashion. The above data clearly showcase that OB possesses potent anti-proliferative (inhibitory) as well as apoptotic activity and may be recommended as a chemotherapeutic agent against UF and related conditions. However, further studies are required before recommended for treating UF subjects.

Ultrasound-guided transcervical radiofrequency ablation for symptomatic uterine adenomyosis.

OBJECTIVE: To retrospectively evaluate the midterm outcomes of transvaginal ultrasound-guided radiofrequency ablation (RFA) for the treatment of symptomatic uterine adenomyosis. METHODS: 87 patients with symptomatic uterine adenomyosis, who met the inclusion criteria, were enrolled in our study from January 2013 to October 2015. All of the patients underwent transvaginal ultrasound-guided RFA and were followed up for 12 months. Assessment end points included uterus volume reduction rate, lesion regression rate, dysmenorrhoeal score, symptom severity score (SSS) and adverse events. RESULTS: In all 87 patients, 81 patients fulfilled the follow-up evaluations post-ablation. The mean uterine volume reduction rate was 35.8% at 1 month, 40.8% at 6 months and 41.2% at 12 months post-ablation. Dysmenorrhoea and SSS statistically significantly declined. Reintervention rate was 18.5%. Two patients developed intrauterine adhesion after ablation. No serious complications including penetration or burn injuries of the nearby organs were observed. CONCLUSION: Ultrasound-guided RFA might be a safe and effective minimally invasive alternative in the treatment of symptomatic adenomyosis. Advances in knowledge: This is the first study to evaluate the efficacy and safety of ultrasound-guided RFA for the treatment of adenomyosis to our knowledge. This is also the first study to provide various changes of intrauterine cavity after this treatment.

[Effect of carbon dioxide pneumoperitoneum during laparoscopic surgery on morphology of peritoneum].

OBJECTIVE: To investigate the influence of carbon dioxide (CO2) pneumoperitoneum during laparoscopic surgery on morphology of peritoneum. METHODS: Forty patients with myoma of uterus or simple ovarian cyst excluding peritonitis were randomly divided into 2 equal groups to undergo laparoscopic surgery with CO2 pneumoperitoneum or laparotomy respectively. Specimens of parietal peritoneum were obtained at different time points, 0, 30, 90, and 120 min after the beginning of observation, i.e. e, insufflation or opening of the peritoneal cavity, to undergo transmission electron microscopy and scanning electron microscopy to observe the morphological changes of mesothelial cells. RESULTS: In the laparotomy group, up to the time point of 60 min, there was no marked change of mesothelial cells. Intercellular cleft were occasionally found since 90 min and became significant 120 min after. However, in the CO2 pneumoperitoneum group bulging up of mesothelial cells was evident immediately at the time of filling of CO2, intercellular spaces could be found 30 min later, 60 min later intercellular cleft deep to the underlying basement membrane could be seen and the basement membrane lost its continuity and became uncovered, and 120 min later such changes became more significant and a small amount of lymphocytes and macrophages were found in the intercellular clefts. CONCLUSION: Carbon dioxide pneumoperitoneum during laparoscopic surgery causes significant morphological changes in the peritoneum duration of insufflation dependently.