Ultrasound-Triggered Azo Free Radicals for Cervical Cancer Immunotherapy.

PD-1 blockade is a first-line treatment for recurrent/metastatic cervical cancer but benefits only a small number of patients due to low preexisting tumor immunogenicity. Using immunogenic cell death (ICD) inducers is a promising strategy for improving immunotherapy, but these compounds are limited by the hypoxic environment of solid tumors. To overcome this issue, the nanosensitizer AIBA@MSNs were designed based on sonodynamic therapy (SDT), which induces tumor cell death under hypoxic conditions through azo free radicals in a method of nonoxygen radicals. Mechanistically, the azo free radicals disrupt both the structure and function of tumor mitochondria by reversing the mitochondrial membrane potential and facilitating the collapse of electron transport chain complexes. More importantly, the AIBA@MSN-based SDT serves as an effective ICD inducer and improves the antitumor immune capacity. The combination of an AIBA@MSN-based SDT with a PD-1 blockade has the potential to improve response rates and provide protection against relapse. This study provides insights into the use of azo free radicals as a promising SDT strategy for cancer treatment and establishes a basic foundation for nonoxygen-dependent SDT-triggered immunotherapy in cervical cancer treatment.

USP14 promotes the proliferation of cervical cancer via upregulating ß-catenin.

In recent years, the ubiquitin-proteasome system (UPS) has become a hot spot in medical research in cervical cancer (CC) and has received extensive attention. Among them, ubiquitin-specific protease 14 (USP14) is involved in a wide variety of typical cell signaling pathways and is recognized to be involved in the progression of most known tumors. However, the expression and significance of USP14 in CC have not been directly studied. Through database analysis, we found that USP14 was overexpressed in CC, which influenced the FIGO stage and prognosis of CC patients, and it was positively correlated with the expression level of ß-catenin. In this study, USP14 promoted the G1-S phase transition of Hela and Siha cells and inhibited cell apoptosis, thereby promoting the proliferation, migration, and invasion of CC cells. In addition, USP14 also significantly promoted the growth of subcutaneous tumor in nude mice. We also found that overexpression of USP14 significantly upregulated ß-catenin expression and increased the activity of Wnt/ß-catenin signaling pathway. While knockdown of USP14 resulted in the opposite. These results suggest that USP14 may promote the proliferation of CC by up-regulating the expression of ß-catenin, contributing to a deeper understanding of the mechanisms of CC and providing a potential therapeutic target.

A long-term retrospective analysis of management of cervical cancer during pregnancy.

OBJECTIVE: This study aims to describe cervical cancer during pregnancy (CCP) and investigate factors associated with survival outcomes. METHODS: This retrospective matched study included CCP patients from May 2007 to August 2021 and matched non-pregnant cervical cancer patients (1:2) based on age (±5 years), year at diagnosis (±2 years), histological type and stage (2018 FIGO). The Kaplan-Meier method and multivariate Cox regression analyses were used to assess the impact of pregnancy and clinicopathologic factors on prognosis. RESULTS: Thirty-eight CCP patients (stage IA to IIIC) and 76 non-pregnant patients were included. Most CCP patients were diagnosed in the first (31.6%) or second (47.4%) trimester. CCP patients had a longer waiting time than non-pregnant patients. Pregnancy continued in 42.1% (continuation of pregnancy [COP] group) and was terminated in 57.9% (termination of pregnancy [TOP] group) of patients. Survival analysis showed no significant differences in recurrence-free survival (RFS) or overall survival (OS) between pregnant and non-pregnant patients or between the COP and TOP groups. At the end of the follow-up period (range 12-178 months), 23 children born to CCP patients exhibited normal development. CONCLUSION: Pregnancy does not impact cervical cancer prognosis. The oncologic outcomes of the TOP and COP groups were comparable. A pregnancy-preserving strategy could be considered for managing CCP patients.

Interactions of Indoleamine 2,3-dioxygenase-expressing LAMP3+ dendritic cells with CD4+ regulatory T cells and CD8+ exhausted T cells: synergistically remodeling of the immunosuppressive microenvironment in cervical cancer and therapeutic implications.

BACKGROUND: Cervical cancer (CC) is the fourth most common cancer in women worldwide. Although immunotherapy has been applied in clinical practice, its therapeutic efficacy remains far from satisfactory, necessitating further investigation of the mechanism of CC immune remodeling and exploration of novel treatment targets. This study aimed to investigate the mechanism of CC immune remodeling and explore potential therapeutic targets. METHODS: We conducted single-cell RNA sequencing on a total of 17 clinical specimens, including normal cervical tissues, high-grade squamous intraepithelial lesions, and CC tissues. To validate our findings, we conducted multicolor immunohistochemical staining of CC tissues and constructed a subcutaneous tumorigenesis model in C57BL/6 mice using murine CC cell lines (TC1) to evaluate the effectiveness of combination therapy involving indoleamine 2,3-dioxygenase 1 (IDO1) inhibition and immune checkpoint blockade (ICB). We used the unpaired two-tailed Student's t-test, Mann-Whitney test, or Kruskal-Wallis test to compare continuous data between two groups and one-way ANOVA with Tukey's post hoc test to compare data between multiple groups. RESULTS: Malignant cervical epithelial cells did not manifest noticeable signs of tumor escape, whereas lysosomal-associated membrane protein 3-positive (LAMP3+ ) dendritic cells (DCs) in a mature state with immunoregulatory roles were found to express IDO1 and affect tryptophan metabolism. These cells interacted with both tumor-reactive exhausted CD8+ T cells and CD4+ regulatory T cells, synergistically forming a vicious immunosuppressive cycle and mediating CC immune escape. Further validation through multicolor immunohistochemical staining showed co-localization of neoantigen-reactive T cells (CD3+ , CD4+ /CD8+ , and PD-1+ ) and LAMP3+ DCs (CD80+ and PD-L1+ ). Additionally, a combination of the IDO1 inhibitor with an ICB agent significantly reduced tumor volume in the mouse model of CC compared with an ICB agent alone. CONCLUSIONS: Our study suggested that a combination treatment consisting of targeting IDO1 and ICB agent could improve the therapeutic efficacy of current CC immunotherapies. Additionally, our results provided crucial insights for designing drugs and conducting future clinical trials for CC.

CKAP2 promotes cervical cancer progression by modulating the tumor microenvironment via NF-κB signaling.

This study aimed to investigate whether CKAP2 could promote cervical cancer (CC) progression by modulating the tumor microenvironment (TME) via NF-κB signaling. The communication between cervical cancer cells and the TME, including THP-1 and HUVECs, was tested. Gain- and loss-of-function assays were performed to elucidate the role of CKAP2 in cervical cancer progression. Western blot analysis was exploited to investigate the potential involved mechanism involved. Here, we reported that cervical cancer tissues were enriched with macrophages and microvessels. CKAP2 increased the tumor-promoting macrophage population. The overexpression of CKAP2 not only promoted endothelial cell viability and tube formation but also increased vascular permeability, and vice versa. Moreover, CKAP2 promoted cervical cancer progression via NF-κB signaling. This effect could be blocked by the NF-κB signaling inhibitor JSH-23. Our findings indicated that CKAP2 could promote cervical cancer progression by modulating the TME via NF-κB signaling.

A comparison of concurrent chemoradiotherapy and radical surgery in patients with specific locally advanced cervical cancer (stage IB3, IIA2, IIICr): trial protocol for a randomized controlled study (C-CRAL trial).

BACKGROUND: At present, clinical dilemma remains to be solved in terms of therapy-choices for specific locally advanced cervical cancer (LACC) patients: 1) Although concurrent chemoradiotherapy (CCRT) is recommended as the first choice for them, many patients, influenced by the Chinese culture, prefer to choose radical surgery (RS) as their primary treatment. The difference between the 2 therapies in improving patient prognosis is still unknown. 2) Laparoscopy has been questioned since the noted Laparoscopic Approach to Cervical Cancer trial. Nevertheless, clinical research on laparoscopic surgery under the strict tumor-free principle is still underway globally, therefore whether laparoscopic surgery can be used for specific LACC is also an urgent issue to be explored. METHODS: A multi-center, randomized controlled study is designed to investigate the effect of different treatment strategies on the prognosis and quality of life (QoL) in patients with specific locally LACC. A total of 402 patients will be enrolled over a period of 3 years. Eligible patients will be randomized (3:1) to either RS group or CCRT group. Patients assigned to RS group will be randomized (1:2) to the abdominal RS group or laparoscopic RS group. All patients will then be followed-up for 5 years. The primary end point is the 2-year progression-free survival (PFS). The secondary end points include 5-year PFS, 2-year overall survival (OS), 5-year OS, adverse events caused by RS or CCRT and QoL. TRIAL REGISTRATION: Chinese Clinical Trial Registry Identifier: ChiCTR2000041315.

Spatiotemporally deciphering the mysterious mechanism of persistent HPV-induced malignant transition and immune remodelling from HPV-infected normal cervix, precancer to cervical cancer: Integrating single-cell RNA-sequencing and spatial transcriptome.

BACKGROUND: The mechanism underlying cervical carcinogenesis that is mediated by persistent human papillomavirus (HPV) infection remains elusive. AIMS: Here, for the first time, we deciphered both the temporal transition and spatial distribution of cellular subsets during disease progression from normal cervix tissues to precursor lesions to cervical cancer. MATERIALS & METHODS: We generated scRNA-seq profiles and spatial transcriptomics data from nine patient samples, including two HPV-negative normal, two HPV-positive normal, two HPV-positive HSIL and three HPV-positive cancer samples. RESULTS: We not only identified three 'HPV-related epithelial clusters' that are unique to normal, high-grade squamous intraepithelial lesions (HSIL) and cervical cancer tissues but also discovered node genes that potentially regulate disease progression. Moreover, we observed the gradual transition of multiple immune cells that exhibited positive immune responses, followed by dysregulation and exhaustion, and ultimately established an immune-suppressive microenvironment during the malignant program. In addition, analysis of cellular interactions further verified that a 'homeostasis-balance-malignancy' change occurred within the cervical microenvironment during disease progression. DISCUSSION: We for the first time presented a spatiotemporal atlas that systematically described the cellular heterogeneity and spatial map along the four developmental steps of HPV-related cervical oncogenesis, including normal, HPV-positive normal, HSIL and cancer. We identified three unique HPV-related clusters, discovered critical node genes that determined the cell fate and uncovered the immune remodeling during disease escalation. CONCLUSION: Together, these findings provided novel possibilities for accurate diagnosis, precise treatment and prognosis evaluation of patients with precancer and cervical cancer.

Single-Cell Landscape Highlights Heterogenous Microenvironment, Novel Immune Reaction Patterns, Potential Biomarkers and Unique Therapeutic Strategies of Cervical Squamous Carcinoma, Human Papillomavirus-Associated (HPVA) and Non-HPVA Adenocarcinoma.

Cervical adenocarcinomas (ADCs), including human papillomavirus (HPV)-associated (HPVA) and non-HPVA (NHPVA), though exhibiting a more malignant phenotype and poorer prognosis, are treated identically to squamous cell carcinoma (SCC). This clinical dilemma requires a deeper investigation into their differences. Herein a transcriptomic atlas of SCC, HPVA, and NHPVA-ADC using single-cell RNA (scRNA) and T-cell receptor sequencing (TCR-seq) is presented. Regarding structural cells, the malignancy origin of epithelial cells, angiogenic tip cells and two subtypes of fibroblasts is revealed. The promalignant properties of the structural cells using organoids are further confirmed. Regarding immune cells, myeloid cells with multiple functions other than antigen presentation and exhausted T lymphocytes contribute to immunosuppression. From the perspective of HPV infection, not only is HPV-dependent and independent cervical cancer oncogenesis proposed but also three immune reaction patterns mediated by T cells (coordinated/inactive/imbalanced) are identified. Strikingly, diagnostic biomarkers to distinguish ADC from SCC are discovered and prognostic biomarkers with marker genes for malignant epithelial cells, tip cells, and SPP1/C1QC macrophages are generated. Importantly, the efficacy of anti-CD96 and anti-TIGIT, not inferior to anti-PD1, in animal experiments is confirmed and targeted therapies specifically for HPV-positive SCC, HPVA and NHPVA-ADC, providing essential clues for further clinical trials, are proposed.

Association of preoperative conization with recurrences after laparoscopic radical hysterectomy for FIGO 2018 stage IB1 cervical cancer.

OBJECTIVE: To evaluate association of preoperative conization with recurrences after laparoscopic radical hysterectomy (LRH) for FIGO 2018 stage IB1 cervical cancer. METHODS: This is a retrospective single-center study. Patients who underwent LRH for cervical cancer with squamous, adenosquamous and adenocarcinoma subtype from January 2014 to December 2018 were reviewed. All patients were restaged according to the 2018 FIGO staging system. Those who were in FIGO 2018 stage IB1 met the inclusion criteria. General characteristics and oncologic outcomes including recurrence-free survival (RFS) were analyzed. RESULTS: A total of 1273 patients were included in the analysis. 616 (48.4%) patients underwent preoperative biopsy, and 657 (51.6%) patients underwent conization. Residual disease was observed in 822 (64.6%) patients. During a median follow-up of 50.30 months, 30 (2.4%) patients experienced recurrence. The univariate analysis showed that patients who had larger tumor diameter, the presence of residual tumor at final pathology, and underwent adjuvant treatment had a significant higher risk of recurrence (P < 0.01). Conversely, patients who underwent conization were significantly less likely to experience recurrence (P = 0.001). In the multivariate analysis, the independent risk factor associated with an increased risk of recurrence was resident macroscopic tumor (HR: 38.4, 95% CI 4.20-351.64, P = 0.001). On the contrary, preoperative conization was associated with a significantly lower risk of recurrence (HR: 0.26; 95% CI 0.10-0.63, P = 0.003). The Kaplan-Meier curves showed patients who underwent conization had improved survival over those who underwent biopsy (5 year RFS: 98.6 vs 95.1%, P = 0.001). The 5 year RFS of patients with residual tumor was significantly different (R0: 99.2%, R1: 97.4%, R2: 93.6%, P < 0.001), especially the patients with residual macroscopic tumor after conization (R0: 99.5%, R1: 99.0%, R2:92.4%, P = 0.006). CONCLUSION: Preoperative conization and the absence of residual tumor at the time of surgery might play a protective role in patients with FIGO 2018 IB1 cervical cancer following LRH, which support the theory of the influence of intraoperative tumor spread during radical hysterectomy. Further prospective evidence is needed.

Intraoperative frozen pathology exam of Common iliac lymph nodes and Para-Aortic lymphadenectomy on the prognosis and quality of life for patients with IB2-IIA2 Cervical Cancer: trial protocol for a randomized controlled trial (C-PACC trial).

BACKGROUND: The impact of para-aortic lymphadenectomy (PALD) on prognosis and quality of life (QoL) for IB2-IIA2 cervical cancer patients remain controversial. And whether intraoperative frozen pathology exam on common iliac lymph nodes could help predict para-aortic lymph node (PALN) metastasis was unanswered with high-level evidence. METHODS: A multi-center, randomized controlled study is intended to investigate the effect of PALD on the prognosis and QoL in cervical cancer patients and to assess the value of intraoperative frozen pathological evaluation of common iliac nodes metastasis for the prediction of PALN metastasis. After choosing whether to receive intraoperative frozen pathological examination of bilateral common iliac lymph nodes, eligible patients will be randomly assigned (1:1) to receive PALD or not. The primary end point is 2-year progression-free survival (PFS). The secondary end points include 5-year PFS, 2-year overall survival (OS), 5-year OS, adverse events (AEs) caused by PALD, AEs caused by radiotherapy and QoL. A total of 728 patients will be enrolled from 8 hospitals in China within 3-year period and followed up for 5 years. TRIAL REGISTRATION: Chinese Clinical Trial Register Identifier: ChiCTR2000035668.

A novel Silva pattern-based model for precisely predicting recurrence in intermediate-risk cervical adenocarcinoma patients.

BACKGROUND: Considering the unique biological behavior of cervical adenocarcinoma (AC) compared to squamous cell carcinoma, we now lack a distinct method to assess prognosis for AC patients, especially for intermediate-risk patients. Thus, we sought to establish a Silva-based model to predict recurrence specific for the intermediate-risk AC patients and guide adjuvant therapy. METHODS: 345 AC patients were classified according to Silva pattern, their clinicopathological data and survival outcomes were assessed. Among them, 254 patients with only intermediate-risk factors were identified. The significant cutoff values of four factors (tumor size, lymphovascular space invasion (LVSI), depth of stromal invasion (DSI) and Silva pattern) were determined by univariate and multivariate Cox analyses. Subsequently, a series of four-, three- and two-factor Silva-based models were developed via various combinations of the above factors. RESULTS: (1) We confirmed the prognostic value of Silva pattern using a cohort of 345 AC patients. (2) We established Silva-based models with potential recurrence prediction value in 254 intermediate-risk AC patients, including 12 four-factor models, 30 three-factor models and 16 two-factor models. (3) Notably, the four-factor model, which includes any three of four intermediate-risk factors (Silva C, ≥ 3 cm, DSI > 2/3, and > mild LVSI), exhibited the best recurrence prediction performance and surpassed the Sedlis criteria. CONCLUSIONS: Our study established a Silva-based four-factor model specific for intermediate-risk AC patients, which has superior recurrence prediction performance than Sedlis criteria and may better guide postoperative adjuvant therapy.

Estrogen Regulates the Expression and Function of lncRNA-H19 in Ectopic Endometrium.

Background: Long noncoding RNAs (lncRNAs) are involved in the pathogenesis of endometriosis and can be regulated by estrogen. This study aimed to investigate the role of estrogen in regulating the expression and function of lncRNA-H19 in endometriosis. Methods: Endometrial stromal cells (ESCs) were isolated from ectopic, eutopic endometrium with endometriosis and control endometrium without endometriosis, and lncRNA-H19 expression was detected using real-time polymerase chain reaction (RT-PCR). Ectopic endometrial stromal cells (ecESCs) were treated with 17ß-estradiol at 10-8mol/L for 0, 12, 24 and 48 hours, and lncRNA-H19 expressions of cells were evaluated using RT-PCR. After ecESCs were treated with 17ß-estradiol for 48 hours, lncRNA-H19 expression was knocked down and cell proliferative and invasive abilities were compared. Results: The expression of lncRNA-H19 in ecESCs was significantly higher than that in eutopic endometrial stromal cells (euESCs) and control ESCs. After treated with 17ß-estradiol, ecESCshadupregulatedlncRNA-H19 expression with time-dependent manner. Cell proliferation and invasion increased when estrogen upregulated lncRNA-H19 expression in ecESCs, however, cell proliferation restored and cell invasion did not change when lncRNA-H19 was knocked down in ecESCs. Conclusion: The expression and function of lncRNA-H19 was regulated by estrogen in ecESCs, which probably contributed to the pathogenesis of endometriosis.

Cleavage of tropomodulin-3 by asparagine endopeptidase promotes cancer malignancy by actin remodeling and SND1/RhoA signaling.

BACKGROUND: Abnormal proliferation and migration of cells are hallmarks of cancer initiation and malignancy. Asparagine endopeptidase (AEP) has specific substrate cleavage ability and plays a pro-cancer role in a variety of cancers. However, the underlying mechanism of AEP in cancer proliferation and migration still remains unclear. METHODS: Co-immunoprecipitation and following mass spectrometry were used to identify the substrate of AEP. Western blotting was applied to measure the expression of proteins. Single cell/nuclear-sequences were done to detect the heterogeneous expression of Tmod3 in tumor tissues. CCK-8 assay, flow cytometry assays, colony formation assay, Transwell assay and scratch wound-healing assay were performed as cellular functional experiments. Mouse intracranial xenograft tumors were studied in in vivo experiments. RESULTS: Here we showed that AEP cleaved a ubiquitous cytoskeleton regulatory protein, tropomodulin-3 (Tmod3) at asparagine 157 (N157) and produced two functional truncations (tTmod3-N and tTmod3-C). Truncated Tmod3 was detected in diverse tumors and was found to be associated with poor prognosis of high-grade glioma. Functional studies showed that tTmod3-N and tTmod3-C enhanced cancer cell migration and proliferation, respectively. Animal models further revealed the tumor-promoting effects of AEP truncated Tmod3 in vivo. Mechanistically, tTmod3-N was enriched in the cell cortex and competitively inhibited the pointed-end capping effect of wild-type Tmod3 on filamentous actin (F-actin), leading to actin remodeling. tTmod3-C translocated to the nucleus, where it interacted with Staphylococcal Nuclease And Tudor Domain Containing 1 (SND1), facilitating the transcription of Ras Homolog Family Member A/Cyclin Dependent Kinases (RhoA/CDKs). CONCLUSION: The newly identified AEP-Tmod3 protease signaling axis is a novel "dual-regulation" mechanism of tumor cell proliferation and migration. Our work provides new clues to the underlying mechanisms of cancer proliferation and invasive progression and evidence for targeting AEP or Tmod3 for therapy.

Mitochondria-Targeted Mesoporous Organic Silica Nanoplatforms for Overcoming Cisplatin Resistance by Disturbing Mitochondrial Redox Homeostasis.

Cisplatin (also known as DDP) resistance is one of the biggest challenges in the treatment of ovarian cancer. Recent studies have found that mitochondrion, as a potential target of DDP, participates in drug-related apoptosis and resistance. Overexpressed glutathione (GSH) in resistant cells is involved in protecting mitochondria from DDP or DDP-induced ROS. In this work, triphenylphosphonium (TPP) modified disulfide bond-rich (S-S) mesoporous organic silica nanoplatforms (DMON) were developed to deliver DDP (TPP-DMON@DDP) to mitochondria for overcoming DDP resistance. TPP supported the migration of nanoplatforms to the mitochondria, with consequent depletion of mitochondrial GSH by the S-S bond of DMON, leading to mitochondria in redox dyshomeostasis. These treated cells seemed more susceptible to the DDP released from the nanoplatforms. Significantly increased ROS production, mitochondrial damage, and apoptosis were observed in TPP-DMON@DDP-treated cells. Overall, interference of mitochondrial redox homeostasis provides a new opportunity for improving DDP cytotoxicity against resistant cells.

Targeting CD96 overcomes PD-1 blockade resistance by enhancing CD8+ TIL function in cervical cancer.

BACKGROUND: Novel therapies are needed to treat recurrent and advanced cervical cancer (CC), as their prognosis remains very poor. Although therapies targeting the programmed cell death protein 1 (PD-1) pathway have been approved for CC, a large subset of patients exhibit innate resistance. Using checkpoint inhibitors in combination could enhance their efficacy. METHODS: Blood samples, tumor specimens, and peritumorous (PT) tissues were obtained from patients with CC. The inhibitory receptor expression and phenotypical analysis of CD8+ T cells in CC specimens were analyzed by flow cytometry. The ligands of CD96 expressed by tumor cells were measured by immunohistochemistry and immunofluorescence. Sensitivity to pembrolizumab was evaluated by an ex vivo treatment assay based on the single-cell culture of CC specimens. The efficacies of PD-1 and/or CD96 blockades were explored using an ex vivo treatment assay and an human papillomavirus-positive TC-1 xenograft mouse model in vivo. RESULTS: We found that CD96 expression was elevated on CD8+ tumor-infiltrating lymphocytes (TILs) from patients with CC who were insensitive to the PD-1 blockade. These CD96-expressing CD8+ TILs often coexpressed PD-1. The ratio of the CD96+CD8+/CD96-CD8+ T-cell gene signature from the scRNA-seq data was significantly associated with the poor survival of patients with cervical squamous cell carcinoma and endocervical adenocarcinoma. The costimulatory receptor CD226, which competes with CD96, was downregulated in tumors compared with blood and PT tissue. CD96 and T-cell immunoreceptor with Ig and ITIM domains (TIGIT) were upregulated on intratumoral CD8+ T cells. The CD226/CD96/TIGIT signaling ligands were widely expressed in CC tumor tissues. Phenotypical profiling showed that PD-1+CD96+CD8+ TILs exhibited a terminally exhausted effector phenotype with high levels of T-cell immunoglobulin mucin receptor 3 (TIM-3) and granzyme B (GZMB) and extremely low levels of proinflammatory cytokines and cytotoxic molecules. PD-1+CD96 cells exhibited a precursor exhausted phenotype with TCF-1 positivity. CD96 was further upregulated by CD8+ TILs on PD-1 blockade. Treatment with the CD96 blockade significantly enhanced the PD-1 blockade to blunt tumor growth and improve the function of CD8+ TILs in both mouse and CC specimen models. CONCLUSIONS: Our findings showed that CD96 and PD-1 cooperatively and negatively regulate the function of CD8+ TILs, and CD96 blockade has promise for use in combination with PD-1 blockade for the treatment of CC.

Reproductive and postsurgical outcomes of infertile women with deep infiltrating endometriosis.

BACKGROUND: This study aimed to summarize and analyze clinical characteristics and reproductive outcomes in postoperative deep infiltrating endometriosis (DIE). METHODS: This retrospective cohort study included 55 reproductive-aged patients who were diagnosed with DIE, wished to conceive and underwent resection surgery at the Obstetrics and Gynecology Hospital, Fudan University, from January 2009-June 2017. Those with any plausible infertility factor or abnormalities in the partner's semen analysis were excluded. Patient characteristics, preoperative symptoms, infertility history, intraoperative findings and reproductive outcomes were followed up and recorded. Risk factors for reproductive outcomes were identified for women who became pregnant versus those who did not by univariate logistic regression. Additionally, pre- and postoperative endometriosis health profile questionnaire-30 (EHP-30), Knowles-Eccersley-Scott Symptom questionnaire (KESS), Cox Menstrual Symptom Scale (CMSS) and Female Sexual Function Index (FSFI) scores were used to evaluate the effect of DIE surgery on quality of life. RESULTS: The average age was 30.22 ± 3.62 years, with no difference between the pregnancy and nonpregnancy groups. The average follow-up time was 26.57 ± 14.51 months. There were 34 pregnancies (61.82%): 24 (70.59%) conceived spontaneously and 10 (29.41%) by in vitro fertilization (IVF). Twenty-eight patients (82.35%) had term deliveries. The interval between operation and pregnancy was 10.33 ± 5.6 (1-26) months. Univariate analysis showed that a lower endometriosis fertility index (EFI) score (EFI < 8) was a risk factor for infertility (OR: 3.17 (1.15-10.14), p = .044). For patients with incomplete surgery, postoperative gonadotropin-releasing hormone agonist (GnRHa) administration improved the pregnancy rate (p < 0.05). Regarding quality of life, there was significant improvement (p < 0.05) in the postoperative EHP-30, KESS and CMSS scores compared with preoperative scores in both groups. Although there was no obvious difference in FSFI scores, significant improvement in dyspareunia was observed (p < 0.05). CONCLUSIONS: Overall, the postoperative pregnancy rate of DIE patients was 61.82%. Surgical management of DIE for patients with complaints of pain and with pregnancy intentions was feasible and effective. Long-term expectant treatment should not be advised for patients with lower EFI scores (EFI < 8), and postoperative IVF-ET may be a good choice. More cases should be enrolled for further study, and randomized studies are required.

Accumulation of dysfunctional tumor-infiltrating PD-1+ DCs links PD-1/PD-L1 blockade immunotherapeutic response in cervical cancer.

Various predictive biomarkers are needed to select candidates for optimal and individualized treatments. Tumor-infiltrating immune cells have gained increasing interest in cancer research for the prediction of therapeutic response and survival. However, the role of dendritic cells (DCs) in PD-1 blockade immunotherapy remains unclear. In this study, we identified a population of PD-1+ DCs in the tumor microenvironment (TME) of cervical cancer (CC). The accumulation of PD-1+ DCs in cervical tumors was correlated with advanced stages, elevated preoperative squamous cell carcinoma antigen levels and lymph-vascular space invasion. PD-1 expression was induced on activated tumor-associated DCs (TADCs) in vitro compared with their resting counterparts. This PD-1+ DC population was characterized by reduced secretion of cytokines (IL-12, TNF-α, and IL-1ß) and dysfunctional induction of T cell proliferation and cytotoxic reaction. PD-1 blockade significantly reinvigorated PD-1+ DCs to release IL-12, TNF-α, and IL-1ß compared with PD-1- DCs. TILs from samples with higher PD-1+ DC infiltration could be induced to achieve a greater killing effect of PD-1 blockade treatment. Our findings suggested a role for PD-1+ DCs in immune surveillance dysfunction and CC progression. PD-1+ DC density in the TME may serve as a diagnostic factor for predicting the optimal beneficiaries of PD-1/PD-L1 blockade immunotherapy in CC.

Assessment of ESGO Quality Indicators in Cervical Cancer Surgery: A Real-World Study in a High-Volume Chinese Hospital.

The ESGO developed a list of fifteen quality indicators for cervical cancer surgery in order to audit and improve clinical practice in 2020. However, data from the developing countries with high incidence rates of cervical cancer is still lacking. Therefore, we conducted a retrospective study of 7081 cases diagnosed as cervical cancer between 2014 and 2019 in a Chinese single center according to the quality indicators proposed by ESGO. A total of 5952 patients underwent radical procedures, with an average of 992.0 per year. All surgeries were performed or supervised by a certified gynecologic oncologist as surgical qualification grading system has been established. Compared with the low-volume group, patients in the high-volume group (≥15 cases/year) had a shorter hospital stay (P<0.001), more free surgical margins (P=0.031), and less complications (P<0.001), but the 5-year recurrence-free survival and overall survival rates were similar (P>0.05). Treatment was not planned at a multidisciplinary team meeting but with the consultation system. The required preoperative workup was incomplete in 19.7% of patients with pelvic MRI and 45.7% of patients with PET-CT. A total of 1459 (20.6%) patients experienced at least one complication after surgery. The CDC grade IIIb or higher complications occurred in 80 patients, accounting for 5.5% complications. The urological fistula rate within 30 postoperative days were 0.3%. After primary surgical treatment, 97.4% patients had clear vaginal and parametrial margins. After restaging FIGO 2009 to FIGO 2018 system, 14.7% patients with a stage T1b disease were T-upstaged. After a median follow-up of 42 months, recurrence occurred in 448 patients, and 82.1% patients recurred within 2 years. The 2-year RFS rate of patients with pT1b1N0 was 97.3% in 2009 FIGO staging system. Lymph node staging was performed in 99.0% patients with a stage T1 disease. After a primary surgical treatment for a stage pT1b1N0 disease, 28.3% patients received adjuvant chemoradiotherapy. Above all, most of quality indicators reached the targets, except four quality indicators. The quality indicators of ESGO should be popularized and applied in China to guarantee quality of surgery.

Artificial intelligence: A powerful paradigm for scientific research.

Artificial intelligence (AI) coupled with promising machine learning (ML) techniques well known from computer science is broadly affecting many aspects of various fields including science and technology, industry, and even our day-to-day life. The ML techniques have been developed to analyze high-throughput data with a view to obtaining useful insights, categorizing, predicting, and making evidence-based decisions in novel ways, which will promote the growth of novel applications and fuel the sustainable booming of AI. This paper undertakes a comprehensive survey on the development and application of AI in different aspects of fundamental sciences, including information science, mathematics, medical science, materials science, geoscience, life science, physics, and chemistry. The challenges that each discipline of science meets, and the potentials of AI techniques to handle these challenges, are discussed in detail. Moreover, we shed light on new research trends entailing the integration of AI into each scientific discipline. The aim of this paper is to provide a broad research guideline on fundamental sciences with potential infusion of AI, to help motivate researchers to deeply understand the state-of-the-art applications of AI-based fundamental sciences, and thereby to help promote the continuous development of these fundamental sciences.