Cadonilimab plus platinum-based chemotherapy with or without bevacizumab as first-line treatment for persistent, recurrent, or metastatic cervical cancer (COMPASSION-16): a randomised, double-blind, placebo-controlled phase 3 trial in China.

BACKGROUND: Cadonilimab is a bispecific antibody targeting PD-1 and CTLA-4, which has shown substantial clinical benefits in advanced cervical cancer. In the COMPASSION-16 trial, we aimed to evaluate the addition of cadonilimab to first-line standard chemotherapy in persistent, recurrent, or metastatic cervical cancer. METHODS: In this randomised, double-blind, multicentre, placebo-controlled phase 3 trial, women aged 18-75 years across 59 clinical sites in China with previously untreated persistent, recurrent, or metastatic cervical cancer were randomly assigned (1:1) to receive cadonilimab (10 mg/kg) or placebo plus platinum-based chemotherapy with or without bevacizumab every 3 weeks for six cycles, followed by maintenance therapy every 3 weeks for up to 2 years. Randomisation was performed centrally through an interactive web-response system. Stratification factors were the use of bevacizumab (yes or no) and previous concurrent chemoradiotherapy (yes or no). The dual primary outcomes were progression-free survival as assessed by blinded independent central review and overall survival in the full analysis set. This study is registered with ClinicalTrials.gov, NCT04982237; the study has completed enrolment and is ongoing for treatment and follow-up. FINDINGS: 445 eligible women were enrolled between Sept 11, 2021, and June 23, 2022. Median progression-free survival was 12·7 months (95% CI 11·6-16·1) in the cadonilimab group and 8·1 months (7·7-9·6) in the placebo group (hazard ratio 0·62 [95% CI 0·49-0·80], p<0·0001); median overall survival was not reached (27·0 months to not estimable) versus 22·8 months (17·6-29·0), respectively (hazard ratio 0·64 [0·48-0·86], p=0·0011). The most common grade 3 or higher adverse events were decreased neutrophil count, decreased white blood cell count, and anaemia. INTERPRETATION: The addition of cadonilimab to first-line standard chemotherapy significantly improved progression-free survival and overall survival with a manageable safety profile in participants with persistent, recurrent, or metastatic cervical cancer. The data support the use of cadonilimab plus chemotherapy as an efficacious first-line therapy in persistent, recurrent, or metastatic cervical cancer. FUNDING: Akeso Biopharma.

Comparative effects of different treatments based on the levonorgestrel intrauterine system in endometrial carcinoma and endometrial hyperplasia patients: a network meta-analysis.

OBJECTIVE: Levonorgestrel intrauterine system (LNG-IUS) has been widely used in patients with endometrial carcinoma (EC), endometrial hyperplasia without atypical (EH), and atypical endometrial hyperplasia (AEH). The purpose of our Network meta-analysis (NMA) is to evaluate the efficacy of the treatments based on the LNG-IUS in patients with EC and EH with or without atypical. METHODS: We examined PubMed, EMBASE, Web of Science and the Cochrane Library up to 22 April 2024 to determine studies reporting treatment outcomes in EC and EH patients receiving LNG-IUS therapy, LNG-IUS + metformin (MET), oral progestins (OP), etc. We used EndNote 9 to select studies, Jadad scale and NOS scale to assess quality, stata(16.0) and R (4.3.1) to analysis the data. RESULTS: Overall, 28 studies involving 3752 patients were included in our NMA. As for EH patients, LNG-IUS (RR 1.21; 95% CrI [1.11, 1.34]) and LNG-IUS + MET (RR 323.57; 95% CrI [1.61, 214,223,188.1])] significantly increased CR rate in comparison with OP. Based on SUCRA, LNG-IUS + OP was the best treatment to improve CR(SUCRA = 67.2%) in patients with EC, whereas LNG-IUS + MET was superior in increasing CR (SUCRA = 99.8%) than any other treatments for EH patients. Besides, the ranking based on SUCRA illustrated that LNG-IUS alone was the best choice to raise CR rates (SUCRA = 76.7%) for AEH patients. In head-to-head meta-analysis, OP has a higher progression rate (RR 4, 95% CI 1.89-8.46, p = 0.062; I2 = 71.3%), a higher nausea rate (RR 1.93, 95% CI 1.24-3.01, p = 0.187; I2 = 40.4%) than LNG-IUS in patients with EH. In contrast, LNG-IUS had a irregular vaginal bleeding rates (RR 0.76, 95% CI 0.64-0.90, p = 0.034; I2 = 77.7%) than OP in EH patients. In addition, as for AEH patients, OP has a higher persistence rate (RR 4.31, 95% CI 1.43-13.00, p = 0.93; I2 = 0.0%) than LNG-IUS. CONCLUSION: According to the NMA, LNG-IUS related studies are feasible for conservative therapy in patients with EC and EH with or without atypical. Therefore, concerning the curative effect, we recommend LNG-IUS-based treatments as the best conservative therapy for EC and EH patients. However, future studies require large sample sizes and more outcomes to further evaluate the differences of treatment selections based on LNG-IUS.

Senaparib as first-line maintenance therapy in advanced ovarian cancer: a randomized phase 3 trial.

Poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors as maintenance therapy after first-line chemotherapy have improved progression-free survival in women with advanced ovarian cancer; however, not all PARP inhibitors can provide benefit for a biomarker-unselected population. Senaparib is a PARP inhibitor that demonstrated antitumor activity in patients with solid tumors, including ovarian cancer, in phase 1 studies. The multicenter, double-blind, phase 3 trial FLAMES randomized (2:1) 404 females with advanced ovarian cancer (International Federation of Gynecology and Obstetrics stage III-IV) and response to first-line platinum-based chemotherapy to senaparib 100 mg (n = 271) or placebo (n = 133) orally once daily for up to 2 years. The primary endpoint was progression-free survival assessed by blinded independent central review. At the prespecified interim analysis, the median progression-free survival was not reached with senaparib and was 13.6 months with placebo (hazard ratio 0.43, 95% confidence interval 0.32-0.58; P < 0.0001). The benefit with senaparib over placebo was consistent in the subgroups defined by BRCA1 and BRCA2 mutation or homologous recombination status. Grade ≥3 treatment-emergent adverse events occurred in 179 (66%) and 27 (20%) patients, respectively. Senaparib significantly improved progression-free survival versus placebo in patients with advanced ovarian cancer after response to first-line platinum-based chemotherapy, irrespective of BRCA1 and BRCA2 mutation status and with consistent benefits observed between homologous recombination subgroups, and was well tolerated. These results support senaparib as a maintenance treatment for patients with advanced ovarian cancer after a response to first-line chemotherapy. ClinicalTrials.gov identifier: NCT04169997 .

Exploratory biomarker analysis in the phase III L-MOCA study of olaparib maintenance therapy in patients with platinum-sensitive relapsed ovarian cancer.

BACKGROUND: The prospective phase III multi-centre L-MOCA trial (NCT03534453) has demonstrated the encouraging efficacy and manageable safety profile of olaparib maintenance therapy in the Asian (mainly Chinese) patients with platinum-sensitive relapsed ovarian cancer (PSROC). In this study, we report the preplanned exploratory biomarker analysis of the L-MOCA trial, which investigated the effects of homologous recombination deficiency (HRD) and programmed cell death ligand 1 (PD-L1) expression on olaparib efficacy. METHODS: HRD status was determined using the ACTHRD assay, an enrichment-based targeted next-generation sequencing assay. PD-L1 expression was assessed by SP263 immunohistochemistry assay. PD-L1 expression positivity was defined by the PD-L1 expression on ≥ 1% of immune cells. Kaplan-Meier method was utilised to analyse progression-free survival (PFS). RESULTS: This exploratory biomarker analysis included 225 patients and tested HRD status [N = 190; positive, N = 125 (65.8%)], PD-L1 expression [N = 196; positive, N = 56 (28.6%)], and BRCA1/2 mutation status (N = 219). The HRD-positive patients displayed greater median PFS than the HRD-negative patients [17.9 months (95% CI: 14.5-22.1) versus 9.2 months (95% CI: 7.5-13.8)]. PD-L1 was predominantly expressed on immune cells. Positive PD-L1 expression on immune cells was associated with shortened median PFS in the patients with germline BRCA1/2 mutations [14.5 months (95% CI: 7.4-18.2) versus 22.2 months (95% CI: 18.3-NA)]. Conversely, positive PD-L1 expression on immune cells was associated with prolonged median PFS in the patients with wild-type BRCA1/2 [20.9 months (95% CI: 13.9-NA) versus 8.3 months (95% CI: 6.7-13.8)]. CONCLUSIONS: HRD remained an effective biomarker for enhanced olaparib efficacy in the Asian patients with PSROC. Positive PD-L1 expression was associated with decreased olaparib efficacy in the patients with germline BRCA1/2 mutations but associated with improved olaparib efficacy in the patients with wild-type BRCA1/2. TRIAL REGISTRATION: NCT03534453. Registered at May 23, 2018.

Genome editing mRNA nanotherapies inhibit cervical cancer progression and regulate the immunosuppressive microenvironment for adoptive T-cell therapy.

CRISPR/Cas9-based genome editing is promising for therapy of cervical cancer by precisely targeting human papillomavirus (HPV). To develop CRISPR/Cas9-based genome editing nanotherapies, a pH-responsive hybrid nonviral nanovector was constructed for co-delivering Cas9 mRNA and guide RNAs (gRNAs) targeting E6 or E7 oncogenes. The pH-responsive nanovector was fabricated using an acetalated cyclic oligosaccharide (ACD), in combination with low molecular weight polyethyleneimine. Thus obtained hybrid ACD nanoparticles (defined as ACD NP) showed efficient loading for both Cas9 mRNA and E6 or E7 gRNA, giving rise to two pH-responsive genome editing nanotherapies E6/ACD NP and E7/ACD NP, respectively. Cellularly, ACD NP exhibited high transfection but low cytotoxicity in HeLa cervical carcinoma cells. Also, efficient genome editing of target genes was achieved in HeLa cells, with minimal off-target effects. In mice bearing HeLa xenografts, treatment with E6/ACD NP or E7/ACD NP afforded effective editing of target oncogenes and considerable antitumor activities. More importantly, treatment with E6/ACD NP or E7/ACD NP notably promoted CD8+ T cell survival by reversing the immunosuppressive microenvironment, thereby leading to synergistic antitumor effects by combination therapy using the gene editing nanotherapies and adoptive T-cell transfer. Consequently, our pH-responsive genome editing nanotherapies deserve further development for the treatment of HPV-associated cervical cancer, and they can also serve as promising nanotherapies to improve efficacies of other immune therapies against different advanced cancers by regulating the immunosuppressive tumor microenvironment.

The efficacy of ureteroscopic triage in increasing the cure rate of the first-line treatment for a ureterovaginal fistula resulting from radical hysterectomy.

Study objective: To explore the effect of pretreatment with ureteroscopic triage for iatrogenic ureterovaginal fistula (UVF) resulting from radical hysterectomy. Design: A retrospective cohort study. Setting: Department of gynecology at a tertiary medical center. Patients: Women diagnosed with UVF secondary to radical hysterectomy at our center between April 2008 to June 2018. Interventions: The patients were divided into two groups according to whether pretreatment with ureteroscopic triage was performed. Those in the non-triage group underwent retrograde placement of a double-J stent immediately following diagnosis as the first-line therapy. Patients in the triage group were first evaluated under ureteroscopy, their ureteral injuries were then classified into different grades and then underwent different treatments as the first-line therapy, including stent placement or reconstruction surgeries. The cure rate of the first-line therapy and the timeliness of the implementation of adjuvant radiotherapy were subsequently analyzed. Measurements and main results: Ninety-eight UVF patients were included. The demographics, ECOG status, stage of cervical cancer (FIGO 2009), types and onset time of symptoms were not different between the two groups. There were 54 patients in the nontriage group, with an overall first-line cure rate of 70.4% and a timely implementation rate of adjuvant radiotherapy of 38.5%. There were 44 patients in the evaluation group, with an overall first-line cure rate of 93.2% and a timely implementation rate of adjuvant radiotherapy of 90.0%. The differences were statistically significant (p < 0.001). Conclusion: Ureteroscopic triage of ureteral injuries can guide the selection of the optimal first-line therapy for patients with UVF secondary to radical hysterectomy, increase the cure rate and ensure the timely implementation of adjuvant radiotherapy.

Non-mechanical self-alignment system for free-space optical communications based on a cascaded liquid crystal optical antenna.

Free-space optical (FSO) communication has attracted extensive attention in recent years. To maintain a reliable FSO link, two main issues need to be addressed: beam drift and vibration. In this paper, we demonstrate a non-mechanical self-alignment system based on a cascaded liquid crystal optical antenna, in which a frequency decoupled hybrid integration Kalman filter (FDHI-KF) method is proposed to achieve predictive beam drift tracking and vibration mitigation. By leveraging the integrated control on our lab-made liquid crystal phase modulation devices, and implementing the adaptive algorithm on a heterogeneous field programmable gate array (FPGA), this system is capable of realizing precise self-alignment without any moving parts. Experiments are conducted to verify its performance in practical applications. We envision it to set a benchmark for future liquid crystal non-mechanical beam-steering systems in FSO communications.

SNP and DNA methylation analyses of a monozygotic twins discordant for complete endocardial cushion defect: a case report.

The exact cause of complete endocardial cushion defect (ECD) is still unknown. This report describes a unique pair of monozygotic twins (MZ twins) discordant for ECD. The chromosome karyotyping analysis revealed normal karyotype of 46, XY, 16qh+ and mat in both MZ twins. A genome-wide analysis of DNA using the Affymetrix SNP 6.0 revealed identical genotyping of single nucleotide polymorphisms (SNPs) and copy number variations (CNVs). An extensive methylation assay was carried out by NimbleGen 3 × 720 K CpG Island Plus RefSeq Promoter Arrays to analyze the potential epigenetic differences. The DNA methylation profiles of the affected twin seemed increased compared with that of the unaffected twin. However, further validation of Notch1 promoter hypermethylation and six top-ranked differentially methylated CpG sites by sodium bisulfate modification and methylation-specific PCR, failed to reveal consistent methylation differences between the twins. Other relevant factors, such as heritability and penetrance of the condition that place the MZ twins near to a threshold for ECD or variations in local epigenetic events in the twins' heart tissues, are probably responsible for the phenotypic discordance.

Learning curve for laparoendoscopic single-site radical hysterectomy using the "chopstick" technique: a retrospective cohort study.

Background: Laparoendoscopic single-site surgery (LESS), as a promising minimally invasive surgery, is confronted with the obstacle of the "chopstick effect" which limits its further application. The "chopstick" technique is characterized by the usage of instruments of parallel and equal length, and in operations relying on double-fulcrum and unique surgeon position can play a key role in overcoming the above disadvantage effect. This study sought to explore the learning curve for the use of the novel "chopstick" technique in laparoendoscopic single-site radical hysterectomy (LESS-RH) and evaluate the technique's practicability. Methods: Consecutive cervical cancer patients who underwent LESS-RH with the "chopstick" technique by a surgeon with rich experience in laparoscopy from November 2016 to September 2018 were included in the study. The learning curve of his surgeries with the "chopstick" technique was evaluated using the cumulative summation (CUSUM) method by analyzing operation time (OT) which was the surrogate indicator of surgical ability. The patients were divided into Phase I and Phase II based on the learning curve peak, whose demographic and perioperative characteristics, such as tumor Federation International of Gynecology and Obstetrics (FIGO) stage and histology, operation time, blood loss, and complications were collected and analyzed. Results: The mean OT was 231.5 min (range, 115-355 min). The division of the learning curve based on OT occurred after the first 15 cases were finished, dividing Phase I and Phase II. The mean OT for Phase I (259 min) was significantly longer than that of Phase II (219 min) (P=0.02). Only 1 intraoperative complication occurred in Phase I, and none occurred in Phase II. Major postoperative complications occurred more frequently in Phase I (N=3) than in Phase II (N=0). No significant differences were observed in terms of lymph nodes, blood loss, or pathological features. Conclusions: The "chopstick" technique may help surgeons obtain stable LESS surgical performance through a relatively short learning curve, even in some complex surgeries, such as radical hysterectomy.

Neoadjuvant chemotherapy for patients with international federation of gynecology and obstetrics stages IB3 and IIA2 cervical cancer: a multicenter prospective trial.

BACKGROUND: Preoperative neoadjuvant chemotherapy (NACT) has been widely used in developing countries for the treatment of patients with International Federation of Gynecology and Obstetrics (FIGO) stages IB3 and IIA2 cervical cancer. However, the effectiveness of NACT and treatment options for NACT-insensitive patients have been concerning. This study will assess prognostic differences between NACT and primary surgery treatment (PST), determine factors associated with prognosis, and explore better adjuvant treatment modalities for NACT-insensitive patients. METHODS: This study analyzed clinical characteristics, pathological characteristics, treatment options, and follow-up information of 774 patients with FIGO stages IB3 and IIA2 cervical cancer from 28 centers from January 2016 to October 2019 who participated in a multicenter, prospective, randomized controlled trial. RESULTS: For patients undergoing NACT, the 5-year OS and PFS rate was 85.8 and 80.5% respectively. They were similar in the PST group. There was no significant difference in OS and PFS between clinical response (CR)/partial response (PR) groups and stable disease (SD)/progressive disease (PD) groups. Apart from deep cervical invasion (p = 0.046) affecting OS for patients undergoing NACT, no other clinical and pathological factors were associated with OS. 97.8% of NACT-insensitive patients opted for surgery. If these patients did not have intermediate- or high-risk factors, whether they had undergone postoperative adjuvant therapy was irrelevant to their prognosis, whereas for patients with intermediate- or high-risk factors, adjuvant chemotherapy resulted in better PFS (chemotherapy vs. no therapy, p < 0.001; chemotherapy vs. radiotherapy, p = 0.019) and OS (chemotherapy vs. no therapy, p < 0.001; chemotherapy vs. radiotherapy, p = 0.002). CONCLUSIONS: NACT could be a choice for patients with FIGO stages IB3 and IIA2 cervical cancer. The main risk factor influencing prognosis in the NACT group is deep cervical invasion. After systematic treatment, insensitivity to NACT does not indicate a poorer prognosis. For NACT-insensitive patients, Chinese prefer surgery. Postoperative adjuvant therapy in patients with no intermediate- or high-risk factors does not improve prognosis, and chemotherapy in patients with intermediate- and high-risk factors is more effective than radiation therapy and other treatments. TRIAL REGISTRATION: The study was prospectively registered on ClinicalTrials.gov (NCT03308591); date of registration: 12/10/2017.

Human papillomavirus integration perspective in small cell cervical carcinoma.

Small cell cervical carcinoma (SCCC) is a rare but aggressive malignancy. Here, we report human papillomavirus features and genomic landscape in SCCC via high-throughput HPV captured sequencing, whole-genome sequencing, whole-transcriptome sequencing, and OncoScan microarrays. HPV18 infections and integrations are commonly detected. Besides MYC family genes (37.9%), we identify SOX (8.4%), NR4A (6.3%), ANKRD (7.4%), and CEA (3.2%) family genes as HPV-integrated hotspots. We construct the genomic local haplotype around HPV-integrated sites, and find tandem duplications and amplified HPV long control regions (LCR). We propose three prominent HPV integration patterns: duplicating oncogenes (MYCN, MYC, and NR4A2), forming fusions (FGFR3-TACC3 and ANKRD12-NDUFV2), and activating genes (MYC) via the cis-regulations of viral LCRs. Moreover, focal CNA amplification peaks harbor canonical cancer genes including the HPV-integrated hotspots within MYC family, SOX2, and others. Our findings may provide potential molecular criteria for the accurate diagnosis and efficacious therapies for this lethal disease.

microRNA-324-3p suppresses the aggressive ovarian cancer by targeting WNK2/RAS pathway.

Ovarian cancer (OC) has the highest mortality rate among gynecological cancers, which progresses owing to dysregulated microRNAs (miRNAs) expression. Our study attempts to reveal the mechanism by which decreased miR-324-3p expression suppresses OC proliferation. Quantitative real-time PCR, western blotting, in situ hybridization, and immunohistochemistry were performed to estimate miR-324-3p and WNK2 expression levels in OC cells and tissues. Cell Counting Kit-8, colony formation, EdU, and transwell assays were performed to analyze the influence of miR-324-3p and WNK2 on the proliferation and invasion ability of OC cells. Subsequently, xenograft models were established to examine the effects of WNK2 on OC cell proliferation in vivo, and databases and luciferase reporter assays were used to test the relationship between miR-324-3p and WNK2 expression. Then, we showed that miR-324-3p expression is decreased in OC cells and tissues, indicating its inhibitory effect on OC cell proliferation. Quantitative real-time PCR and luciferase reporter assays demonstrated that miR-324-3p inhibited WNK2 expression by directly binding to its 3' untranslated region. WNK2, an upregulated kinase, promotes the proliferation and invasion of OC cells by activating the RAS pathway. Moreover, WNK2 can partly reverse the inhibitory effects of miR-324-3p on OC cell proliferation. Hence, we demonstrate that miR-324-3p suppressed ovarian cancer progression by targeting the WNK2/RAS pathway. Our study provides theoretical evidence for the clinical application potential of miR-324-3p.

Fast, closed-loop iterative system-on-chip of deflection efficiency enhancement for a liquid crystal optical phased array.

To implement a liquid crystal optical phased array (LC-OPA) on a practical free-space laser communication terminal, there are two essential parameters: insertion loss and the closed-loop bandwidth required to meet the dynamic linking condition of the acquisition-tracking-pointing sub-system. Real-time hardware platforms and deflection efficiency optimization algorithms have been suggested since the invention of LC-OPA. In this paper, the so-called ZYNQ platform, a field-programmable-gate-array-based heterogeneous system-on-chip (SoC), is utilized to keep real-time response and accelerate data generation, such as beam steering, beamforming, beam enhancement, etc. In addition, a novel, to the best of our knowledge, optimization algorithm is proposed on the concept of dimension reduction of the number of objective variables. After deploying on this heterogeneous SoC platform, numerical simulations and experimental results both verify that, compared to the conventional PC-based system, the integrated SoC platform offers 15.8 times faster iterative speed, a rapid convergence rate, and excellent robustness, yet with less usage of power, physical size, and monetary cost. The efficiency enhancement process costs only a few seconds at any angle, laying the foundation for practical in-line applications.

Co-culture induces expression of female primordial germ cell-specific genes in human Wharton's jelly-derived mesenchymal stem cells.

OBJECTIVE: To detect mRNA and protein expression of meiosis-specific genes in human umbilical cord mesenchymal stem cells (hUMSCs) in an in vitro co-culture microenvironment with mouse primordial germ cells (PGCs), and to further explore the effective potential of hUMSCs to differentiate into PGCs. METHODS: HUMSCs were obtained from human Wharton's jelly fragments by adherent culture. PGCs were derived from 12.5 days post-coitum (dpc) BalbC mice. Then hUMSCs were co-cultured with PGCs in Matrigel, inside or outside of a culture chamber, respectively. The changes in morphology and cytogenetic characteristics were observed. SCP3 and DDX4 expression in hUMSCs were detected and analyzed using immunofluorescence staining. Oct-4, Stra8, Zp3 and Dmc1 gene expressions in PGCs, hUMSCs, and hUMSCs after co-culture with PGCs were analyzed by real time reverse transcription-polymerase chain reaction. RESULTS: Both hUMSCs and PGCs expressed Oct-4 at different degrees. After co-culture with PGCs, hUMSCs became rounded and showed AKP activity. HUMSCs suspension-cultured in Matrigel or adherent cultured with cell chamber significantly expressed Stra8, DMC1, SCP3 and DDX4 genes. CONCLUSION: HUMSCs can be induced to express PGC-specific genes Stra8 and DMC1, spermatogonium/oogonium-specific genes SCP3 and DDX4 that predict directed differentiation potential into early germ cells at a molecular level.

Tandem CAR-T cells targeting FOLR1 and MSLN enhance the antitumor effects in ovarian cancer.

Given the heterogeneity of solid tumors, single-target CAR-T cell therapy often leads to recurrence, especially in ovarian cancer (OV). Here, we constructed a Tandem-CAR targeting two antigens with secretory activity (IL-12) to improve the effects of CAR-T cell therapy. Twenty coexpressed upregulated genes were identified from the GEO database, and we found FOLR1 (folate receptor 1) and MSLN (mesothelin) were specifically and highly expressed in cancer tissues and only 11.25% of samples were negative for both antigens. We observed an increased proliferation rate for these three CAR-T cells, and Tandem CAR-T cells could efficiently lyse antigen-positive OV cells in vitro and secrete higher levels of cytokines than single-target CAR-T cells. More importantly, in vivo experiments indicated that Tandem CAR-T cells markedly decreased tumor volume, exhibited enhanced antitumor activity, and prolonged mouse survival. Furthermore, the infiltration and persistence of T cells in the Tandem-CAR group were higher than those in the MSLN-CAR and Control-T groups but comparable to those in the FOLR1-CAR group. Collectively, this study demonstrated that Tandem CAR-T cells secreting IL-12 could enhance immunotherapeutic effects by reducing tumor antigen escape and increasing T cell functionality, which could be a promising therapeutic strategy for OV and other solid tumors.

Study on the effect and mechanism of NFKBIA on cervical cancer progress in vitro and in vivo.

AIM: NFKBIA is frequently encountered. However, its expression and relevance of the proliferation, invasion, and migration in human cervical cancer (CC) remain unclear. The role and novel mechanism of NFKBIA in CC progression were investigated in this study. METHODS: We analyzed the expression of NFKBIA in CC and adjacent normal tissues and explored the proliferation, migration, and invasion of HeLa cells by treating with either wild-type NFKBIA plasmid or NFKBIA siRNA. Effect of NFKBIA on the epithelial-mesenchymal transition (EMT) and the ß-catenin-mediated transcription of target genes were evaluated subsequently. RESULTS: NFKBIA expression was lower in CC tissues than that of adjacent tissues. An obvious dysregulation of NFKBIA overexpression was revealed in CC cell proliferation, invasion, and migration, which differed from the effect of knockdown NFKBIA. NFKBIA overexpression facilitated the expression of both phosphorylated ß-catenin and E-cadherin protein. It inhibited the expression of vimentin, TWIST, as well as downstream targets of ß-catenin including c-MYC, TCF-4 and MMP14. Conversely, NFKBIA silencing elevated the expression of c-MYC, TCF-4, and MMP14, and promoted the EMT in HeLa cells. Both endogenous and exogenous NFKBIA interacted with ß-catenin. Moreover, ß-catenin overexpression stemmed effects of NFKBIA on the proliferation, migration, and invasion of HeLa cells. By overexpressing NFKBIA in vivo, the volume and size of tumors were notably decreased, while no obvious alteration was found in mice body weight. CONCLUSION: By inhibiting ß-catenin-mediated transcription, NFKBIA functioning as a tumor suppressor might be introduced as a novel anti-metastatic agent for the treatment of targeted CC.

Short-term ambient nitrogen dioxide exposure is associated with increased risk of spontaneous abortion: A hospital-based study.

There are increasing concerns with regard to spontaneous abortion (SAB), the loss of pregnancy without external intervention before 20 weeks of gestation, among reproductive-aged women. To date, limited evidence is available concerning the association between SAB and air pollutants, especially in developing countries. Daily baseline outpatient data for SAB from January 1, 2014, to December 31, 2018 (1826 days) were obtained in Chongqing, a metropolis of southwest China. The over-dispersed Poisson generalized additive model with control of meteorological conditions and day of week was used to estimate the short-term effects of ambient air pollution on the daily number of SAB outpatients. A total of 42,334 SAB outpatient visits for SAB were recorded. No statistically significant association was observed between SAB and CO, PM2.5, PM10, O3, and SO2. The positive association only appeared for NO2: positive associations between SAB and NO2 were observed in both single-day models (lag 0, lag 1, lag 3, and lag 4) and cumulative exposure models (lag 01, lag 03, and lag 05) and the most significant effects were observed at lag 05 (3.289%; 95% CI: 1.568%, 5.011%). Moreover, the women with higher ages (30-39 and > 39) were more sensitive than those with lower ages (18-29), and the effect estimates were more evident in cool seasons. Collectively, our results suggested that short-term NO2 exposure was associated with higher risk of SAB, especially in elder women and cool seasons, which may contribute to further understand the role of air pollution on SAB and other adverse obstetric outcomes.

Transcriptome-based stemness indices analysis reveals platinum-based chemo-theraputic response indicators in advanced-stage serous ovarian cancer.

Serous ovarian cancer (SOC) is a main histological subtype of ovarian cancer, in which cancer stem cells (CSC) are responsible for its chemoresistance. However, the underlying modulation mechanisms of chemoresistance led by cancer stemness are still undefined. We aimed to investigate potential drug-response indicators among stemness-associated biomarkers in advanced SOC samples. The mRNA expression-based stemness index (mRNAsi) of The Cancer Genome Atlas (TCGA) was evaluated and corrected by tumor purity. Weighted gene co-expression network analysis (WGCNA) was utilized to explore the gene modules and key genes involved in stemness characteristics. We found that mRNAsi and corrected mRNAsi scores were both greater in tumors of Grade 3 and 4 than that of Grade 1 and 2. Forty-two key genes were obtained from the most significant mRNAsi-related gene module. Functional annotation revealed that these key genes were mainly involved in the mitotic division. Thirteen potential platinum-response indicators were selected from the genes enriched to platinum-response associated pathways. Among them, we identified 11 genes with prognostic value of progression-free survival (PFS) in advanced SOC patients treated with platinum and 7 prognostic genes in patients treated with a combination of platinum and taxol. The expressions of the 13 key genes were also validated between platinum-resistant and -sensitive SOC samples of advanced stages in two Gene Expression Omnibus (GEO) datasets. The results revealed that CDC20 was a potential platinum-sensitivity indicator in advanced SOC. These findings may provide a new insight for chemotherapies in advanced SOC patients clinically.

Clinical significance and prognostic value of C-reactive protein/albumin ratio in gastric cancer.

PURPOSE: This study was aimed to evaluate the clinical significance and prognostic value of CRP/albumin ratio (CAR) in patients with gastric cancer. METHODS: The data of 205 gastric cancer patients who underwent surgery was analyzed retrospectively. The association of CAR with the clinical features and prognostic value in gastric cancer was analyzed. The data of this study was combined with previous studies to further determine the prognostic value of CAR in patients with gastric cancer using a meta-analysis method. RESULTS: Cox analysis revealed that preoperative CAR was an independent prognosis indicator in patients with gastric cancer. High expression of CAR indicated a shorter survival time than in those with lower expression. CAR has a higher prognostic value in the 1-, 3-, and 5-year overall survival in patients with gastric cancer. CAR showed significant difference regarding the gastric cancer patients' age, M stage, and clinical stage. The discriminate value of CAR in M stage of gastric cancer was high (area under the curve, 0.809). A meta-analysis combining previous data and our data showed that preoperative CAR demonstrated a significant association with the overall survival of patients with gastric cancer. CONCLUSION: This study demonstrated that preoperative CAR could serve as an important prognostic indicator in patients with gastric cancer.

An assessment of the analytical performance of non-invasive prenatal testing (NIPT) in detecting sex chromosome aneuploidies: 34,717-patient sample in a single prenatal diagnosis Centre in China.

OBJECTIVE: The present study aimed to evaluate the efficacy of a non-invasive prenatal test (NIPT) in the detection of the sex chromosome aneuploidies (SCAs) at our prenatal diagnosis centre. METHODS: Among a cohort of 34,717 pregnancies, maternal plasma samples from our prenatal diagnosis centre were subject to analysis of SCAs using NIPT detection. Pregnant women with NIPT positive results of SCAs were recommended to undergo an invasive prenatal diagnosis (i.e. karyotyping and fluorescence in situ hybridization) to validate the prediction value of NIPT. RESULTS: From 34,717 clinical pregnancies, 229 (0.66%) pregnancies were identified with SCAs. Of these, 78 (34.1%) cases were positive for 45,X and 151 (65.9%) cases comprised a sex chromosome trisomy. Of the 229 positive NIPT results, 193 (84.3%) cases had accepted an invasive diagnosis involving karyotyping analysis of the amniotic fluid, which confirmed 67 cases (34.7%) as true positive, as well as 126 cases (65.3%) as false positive. The positive predictive values were 23.07%, 50%, 36% and 27.27% respectively. The remaining 36 (15.7%) cases declined a prenatal diagnosis. The termination rates of 45,X, 47,XXY, 47,XXX and 47,XYY were 20.5%,46%,12.9% and 11.5% respectively. CONCLUSIONS: NIPT demonstrated a lower accuracy in predicting monosomy X than sex chromosome trisomies. After invasive testing, the fetal chromosome with 45,X and 47,XXY were terminated more often than those with 47,XXX, 47,XYY. Because NIPT is a screening test, false positive/negative cases exist, and pre- and post-test counselling is essential for informing patients about the benefits and limitations of the test. Confirmatory testing of abnormal results is recommended prenatally or after birth, and the importance of confirmatory testing and benefits of early diagnosis should be addressed.