Investigator

Jing Li

Director · Hinova Pharmaceuticals Inc., Translational Medicine and Cell Biology

JLJing Li
Papers(12)
Real-world data from …The Contribution and …Heterogeneous cellula…Mitochondrial and Cyt…Factors affecting car…Safety of fertility-s…Calculating the dose …A phase I dose-findin…Gastrointestinal even…Efficacy of neoadjuva…Prognostic value of p…And-1 Coordinates wit…
Collaborators(10)
Junpeng FanKatherine T. LiLarry H. MatherlyLi-juan WangLi MaLisa PolinLi ZhangMathew SchneiderMd. Junayed NayeenMiao-fang Wu
Institutions(8)
First Affiliated Hosp…Huazhong University O…University Of Califor…The Barbara Ann Karma…Sun Yat Sen UniversityYantaishan HospitalPeking Union Medical …Johns Hopkins Univers…

Papers

Mitochondrial and Cytosolic One-Carbon Metabolism Is a Targetable Metabolic Vulnerability in Cisplatin-Resistant Ovarian Cancer

Abstract One-carbon (C1) metabolism is compartmentalized between the cytosol and mitochondria with the mitochondrial C1 pathway as the major source of glycine and C1 units for cellular biosynthesis. Expression of mitochondrial C1 genes including SLC25A32, serine hydroxymethyl transferase (SHMT) 2, 5,10-methylene tetrahydrofolate dehydrogenase 2, and 5,10-methylene tetrahydrofolate dehydrogenase 1-like was significantly elevated in primary epithelial ovarian cancer (EOC) specimens compared with normal ovaries. 5-Substituted pyrrolo[3,2-d]pyrimidine antifolates (AGF347, AGF359, AGF362) inhibited proliferation of cisplatin-sensitive (A2780, CaOV3, IGROV1) and cisplatin-resistant (A2780-E80, SKOV3) EOC cells. In SKOV3 and A2780-E80 cells, colony formation was inhibited. AGF347 induced apoptosis in SKOV3 cells. In IGROV1 cells, AGF347 was transported by folate receptor (FR) α. AGF347 was also transported into IGROV1 and SKOV3 cells by the proton-coupled folate transporter (SLC46A1) and the reduced folate carrier (SLC19A1). AGF347 accumulated to high levels in the cytosol and mitochondria of SKOV3 cells. By targeted metabolomics with [2,3,3–2H]L-serine, AGF347, AGF359, and AGF362 inhibited SHMT2 in the mitochondria. In the cytosol, SHMT1 and de novo purine biosynthesis (i.e., glycinamide ribonucleotide formyltransferase, 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase) were targeted; AGF359 also inhibited thymidylate synthase. Antifolate treatments of SKOV3 cells depleted cellular glycine, mitochondrial NADH and glutathione, and showed synergistic in vitro inhibition toward SKOV3 and A2780-E80 cells when combined with cisplatin. In vivo studies with subcutaneous SKOV3 EOC xenografts in SCID mice confirmed significant antitumor efficacy of AGF347. Collectively, our studies demonstrate a unique metabolic vulnerability in EOC involving mitochondrial and cytosolic C1 metabolism, which offers a promising new platform for therapy.

Factors affecting caregivers’ HPV vaccination decisions for adolescent girls: A secondary analysis of a Chinese RCT

Background Despite the HPV vaccine’s effectiveness against cervical cancer, uptake among adolescent girls in China remains low, with caregivers playing a crucial role in vaccination decisions. This study investigates factors influencing caregivers’ action to vaccinate their adolescent daughters. Methods Pay-it-forward is a novel model that motivates participants in adopting healthy behaviors and making community contributions. In this study, it offers an individual a free shot of HPV vaccine and then asks whether they would like to donate to support another person to get the same vaccination. This study was embedded in a two-arm randomized controlled trial in China. Potential associated factors were identified based on Anderson’s Health Service Utilization Behavioral Model and analyzed through univariate and multivariate binary logistic regression. Caregivers’ information, knowledge, attitudes, vaccine confidence, hesitancy, and willingness to vaccinate were collected through online questionnaires. The endpoint was the receipt of the first dose HPV vaccine following an intervention or no intervention (pay-it-forward vs. standard-of-care), which was obtained from an electronic vaccination registry system. Results Among 321 caregivers, 25.9% of their daughters received the HPV vaccine, with 34.2% in the pay-it-forward group and 17.5% in the standard-of-care group. Daughters of caregivers who were previously unaware of the HPV vaccine were three times more likely to be vaccinated (OR=3.01,95%CI:1.27–7.14). Caregivers who did not intend to delay vaccination had daughters with eight times higher vaccination uptake (OR=8.26,95%CI:4.36–15.67). Participation in the “pay-it-forward” intervention increased vaccination rates by more than twofold (OR=2.22,95%CI:1.19–4.15). Daughters of unemployed or retired caregivers had nearly four times higher vaccination rates compared to those whose caregivers were employed (OR=3.97,95%CI:1.81–8.72). Prior refusal of the vaccine by caregivers was associated with an 80% reduction in vaccination uptake among daughters (OR=0.23,95%CI:0.06–0.81). Conclusion The pay-it-forward intervention, caregivers’ knowledge, intention to delay vaccination, occupation, and prior vaccine refusal significantly influence HPV vaccine uptake among adolescent girls in China. Tailored health education, financial support, and community involvement are essential to encourage HPV vaccination among adolescent girls in China.

Safety of fertility-sparing surgery in young women with stage I endometrioid epithelial and mucinous ovarian cancer: A population-based analysis

The aim of this study was to assess the safety of fertility-sparing surgery (FSS) in stage I endometrioid epithelial cancer (EEOC) and mucinous ovarian cancer (MOC). A retrospective case‒controlled study was conducted using the Surveillance, Epidemiology, and End Results (SEER) database, focusing on stage I EEOC and MOC between 2000 and 2016. The effects of FSS on overall survival (OS) were compared using log-rank tests. Univariate and multivariate Cox analyses were performed to control for confounders. The study identified 970 patients with FIGO stage I EEOC and 810 with stage I MOC. Of these patients, 116 (12.0%) EEOC and 268 (33.1%) MOC patients underwent fertility-sparing surgery. The results showed that patients with G3 EEOC had a worse 5-year OS than patients with G1 EEOC (96.1% vs. 90.1%, p = 0.020). IC stage MOC patients had a worse prognosis than IA and IB stage patients (94.9% vs. 88.7%, p = 0.001). FSS did not significantly affect the 5-year OS of patients with EEOC (94.8% vs. 95.4%, p = 0.687) or MOC (95.9% vs. 92.3%, p = 0.071). Further subgroup analysis according to tumor stage and histological grade did not show a worse OS with FSS in stage I EEOC or MOC patients, even with high-risk types such as G3 histology and IC phase. In a multivariable analysis, the application of FSS was not associated with inferior OS in EEOC or MOC. FSS for patients with stage I EEOC or MOC does not lead to worse outcomes than radical surgery, making it a viable option for young patients with early-stage disease wishing to preserve fertility.

Calculating the dose of cisplatin that is actually utilized in hyperthermic intraperitoneal chemotherapy among ovarian cancer patients

Abstract Background Hyperthermic intraperitoneal chemotherapy (HIPEC) is an important treatment for ovarian cancer. A certain portion of cisplatin exits the body via the perfusate at the end of HIPEC, so full-dose utilization cannot be achieved. Herein, we sought to explore how much cisplatin is actually utilized and its prognostic influence. Methods Cisplatin (70 mg/m2) was given at 43 °C for 90 min. The actually utilized dose (AD) of cisplatin was calculated using the following formula: AD (mg) = total dose (TD) (mg)-losing dose (LD) (mg); LD = volume (ml) of the perfusate (VPretained) that was retained in the HIPEC treatment system at the end of HIPEC * concentration of cisplatin in the perfusate (mg/ml). Result Sixty-two ovarian cancer patients were included. The median TD, median LD and median AD were 95 mg, 20.7 mg and 75.8 mg, respectively. The utility rate of cisplatin (AD/TD ratio) was 79.2%. On simple linear regression analysis, the TD and VPretained were found to significantly predict the AD. Based on these two factors, multiple linear regression analysis was conducted, and a significant regression equation was formulated [F (2, 59) = 71.419, P < 0.0001]: predicted AD (mg) = 30.079 + 0.667 TD (mg) – 0.010 VPretained (ml) (adjusted R2 = 0.698). In Cox regression analysis, AD was not noted to be associated with progression free survival or overall survival. Conclusion For ovarian cancer patients who receive cisplatin for HIPEC at 43 °C, the AD of cisplatin can be predicted using a regression equation and it has no prognostic impact.

A phase I dose-finding trial of hyperthermic intraperitoneal docetaxel combined with cisplatin in patients with advanced-stage ovarian cancer

To identify the maximum tolerated dose (MTD) of docetaxel combined with a fixed dose of cisplatin (75 mg/m²) delivered as hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with ovarian cancer. In this phase I trial, a time-to-event Bayesian optimal interval design was used. Docetaxel was given at a starting dose of 60 mg/m² and was increased in 5 mg/m² increments until the MTD was determined or the maximum dose level of 75 mg/m² was reached. The dose-limiting toxicity (DLT) rate was set at 25%, with a total sample size of 30 patients. HIPEC was delivered immediately following debulking surgery at a target temperature of 43°C for 90 minutes. From August 2022 to November 2022, 30 patients were enrolled. Among the patients who received a dose of docetaxel ≤65 mg/m², no DLT was reported. DLTs were observed in one patient who received 70 mg/m² docetaxel (grade 3 anaemia) and in three patients who received 75 mg/m² docetaxel (one case of grade 3 anaemia, one case of grade 3 hepatic impairment and one case of grade 4 thrombocytopenia). Patients treated with docetaxel 75 mg/m² in combination with cisplatin 75 mg/m² had an estimated DLT rate of 25%, which was the closest to the target DLT rate and was therefore chosen as the MTD. Docetaxel, in combination with a fixed dose of cisplatin (75 mg/m²), can be used safely at intraperitoneal doses of 75 mg/m² in ovarian cancer patients who received HIPEC (43°C, 90 minutes) following debulking surgery. ClinicalTrials.gov Identifier: NCT05410483.

Gastrointestinal events with PARP inhibitors in cancer patients: A meta‐analysis of phase II/III randomized controlled trials

PARP inhibitors are currently one of the most promising PARP targeted drugs for patients with certain types of cancer. Gastrointestinal (GI) events are common adverse events for all PARP inhibitors. We conducted this meta-analysis of randomized controlled trials (RCTs) to fully investigate the incidence and the relative risk of GI events in cancer patients receiving PARP inhibitors. Randomized controlled trials in cancer patients treated with PARP inhibitors were retrieved, and the systematic evaluation was conducted. Embase and PubMed/Medline were searched for articles published till July 2020. Twenty-nine RCTs and 9529 patients were included. The present meta-analysis suggests that the use of PARP inhibitors significantly increases the risk of developing all-grade nausea (RR, 1.46; 95% CI, 1.29-1.66; p < .00001), vomiting (RR, 1.39; 95% CI, 1.17-1.64; p = .0001), diarrhoea (RR, 1.14; 95% CI, 1.06-1.23; p = .0003) and decreased appetite (RR, 1.24; 95% CI, 1.14-1.36; p < .00001), but not for constipation. And the use of these agents significantly increased the risk of high-grade nausea (RR, 1.99; 95% CI, 1.44-2.74; p < .0001), vomiting (RR, 1.54; 95% CI, 1.11-2.14; p = .01) and decreased appetite (RR, 2.03; 95% CI, 1.22-3.40; p = .007), except for diarrhoea and constipation. Nausea was the most common GI event for these agents. Patients receiving veliparib were associated with a relatively lower risk of all-grade nausea and vomiting. Patients with ovarian cancer tend to have a higher risk of all-grade nausea and vomiting than those with non-ovarian cancer. The risk of all-grade nausea and vomiting tended to be higher when PARP inhibitors treatment was longer. PARP inhibitors were associated with a significant increased risk of GI events. Clinicians should be aware of these risks and perform regular monitoring.

Efficacy of neoadjuvant hyperthermic intraperitoneal chemotherapy in advanced high-grade serous ovarian cancer (the NHIPEC trial): study protocol for a randomised controlled trial

Background Neoadjuvant chemotherapy (NACT) is an important treatment option for patients with ovarian cancer. Although intravenous NACT can improve optimal resection rates and decrease surgical morbidity and mortality, these advantages do not translate into a survival benefit. Ovarian carcinoma is mainly confined to the peritoneal cavity, which makes it a potential target for hyperthermic intraperitoneal chemotherapy (HIPEC). Our previous study showed that HIPEC could be used in the neoadjuvant setting, which was named neoadjuvant HIPEC (NHIPEC). Since hyperthermia is an excellent chemosensitiser, we hypothesised that the combination of NHIPEC and intravenous NACT could show superior efficacy to intravenous NACT alone. Methods This study is a single-centre, open-label, randomised (1:1 allocation ratio) phase 2 trial. A total of 80 patients will be randomly assigned into an experimental group (NHIPEC+intravenous NACT) or a control group (intravenous NACT). Patients in the experimental group will receive NHIPEC following laparoscopic evaluation, and four tubes will be placed via the laparoscopic ports, which will be used to administer NHIPEC. Then, perfusion with docetaxel (60–75 mg/m 2 ) will be performed (43°C for 60 min, Day 0) followed by cisplatin (75 mg/m 2 , Day 1) infusion (43°C for 60 min) 24 hours later. After NHIPEC, two cycles of intravenous NACT will be given. Patients in the control group will receive three cycles of intravenous NACT. The primary endpoint is the proportion of patients who achieve a Chemotherapy Response Score (CRS) of 3 according to the CRS system. The secondary endpoints include progression-free survival, overall survival and the rates of complete resection and NHIPEC-related adverse events. Ethics approval and dissemination This study was approved by the Ethics Committee of Sun Yat-sen Memorial Hospital (approval number: 2020-ky-050). Results will be submitted to peer-reviewed journals and presented at national and international conferences. Trial registration number ChiCTR2000038173.

Prognostic value of preoperative soluble interleukin 2 receptor α as a novel immune biomarker in epithelial ovarian cancer

Epithelial ovarian cancer (EOC) is regarded as the deadliest gynecological cancer, and the demand for novel noninvasive prognostic biomarkers remains significant. This study aimed to investigate the prognostic value of preoperative blood biomarkers in EOC patients. In total, 73 patients who had undergone ovarian mass resection were enrolled. Serum concentration of biomarkers, including soluble interleukin 2 receptor α (sIL-2R), was measured 1-2 weeks before surgery. Independent prognostic factors for progression-free survival (PFS) were investigated with multivariate Cox regression analysis. A prognostic model was subsequently developed and evaluated by discrimination, calibration and clinical net benefit. Furthermore, transcriptome data of 376 EOC cases from The Cancer Genome Atlas (TCGA) were analyzed with ESTIMATE, CIBERSORT and Maftools algorithm to evaluate the correlation of IL2RA expression with tumor immune microenvironment and immunotherapeutic response. High sIL-2R concentration was found to be the only significant prognostic blood biomarker for PFS by multivariate Cox regression analysis in our center. A prognostic nomogram was developed with satisfactory discrimination, calibration and clinical net benefit. In addition, higher IL2RA expression was significantly associated with higher immune scores, activated CD4 sIL-2R is a potential prognostic immune biomarker for EOC patients, and a comprehensive prognostic model comprising sIL-2R with satisfactory discrimination and clinical appliance was developed. Therefore, we recommend routine sIL-2R testing in EOC patients.

And-1 Coordinates with the FANCM Complex to Regulate Fanconi Anemia Signaling and Cisplatin Resistance

Abstract The Fanconi anemia (FA) pathway is essential for repairing DNA interstrand crosslinks (ICL). ICLs induce stalled DNA replication forks and trigger activation of the FA pathway by promoting recruitment of the FANCM/FAAP24/MHF complex to ICL sites. Given that stalled replication forks are proximal to ICL sites, fork-associated proteins may coordinate with FA factors to rapidly sense ICLs for activation of FA signaling. Here we report that And-1, a replisome protein, is critical for activation of the FA pathway by sensing ICL-stalled forks and recruiting the FANCM/FAAP24 complex to ICLs. In response to ICLs, And-1 rapidly accumulated at ICL-stalled forks in a manner dependent on ataxia telangiectasia and Rad3-related protein–induced phosphorylation at T826. And-1 phosphorylation triggered an intramolecular change that promoted the interaction of And-1 with FANCM/FAAP24, resulting in recruitment of the FANCM/FAAP24 complex to ICLs. Furthermore, p-T826 And-1 was elevated in cisplatin-resistant ovarian cancer cells, and activated And-1 contributed to cisplatin resistance. Collectively, these studies elucidate a mechanism by which And-1 regulates FA signaling and identify And-1 as a potential target for developing therapeutic approaches to treat platinum-resistant ovarian cancer. Significance: This work shows that phosphorylation of And-1 by ATR activates Fanconi anemia signaling at interstrand crosslink–stalled replication forks by recruiting the FANCM/FAAP24 complex, revealing And-1 as a potential therapeutic target in cancer.

An Internet-Based Education Program for Human Papillomavirus Vaccination Among Female College Students in Mainland China: Application of the Information-Motivation-Behavioral Skills Model in a Cluster Randomized Trial

Background Patients diagnosed with cervical cancer in the last 2 decades were mainly young females. Human papillomavirus (HPV) vaccination is the most radical way to prevent HPV infection and cervical cancer. However, most female college students in mainland China have not yet been vaccinated, and their relevant knowledge is limited. Theory-based education delivered via the internet is a potentially accessible and useful way to promote HPV vaccination among this population. Objective This 3-month follow-up study intended to identify the feasibility and efficacy of an information-motivation-behavioral skills (IMB) model–based online intervention for promoting awareness and willingness regarding HPV vaccination among female college students. Methods A 7-day online HPV education program for female college students in mainland China was developed using a cluster randomized trial design. Recruitment and questionnaire surveys were performed online without face-to-face contact. SPSS 23.0 was used for statistical analysis. The chi-square test and t test were used to compare differences in qualitative and continuous variables between intervention and control groups. The generalized estimating equation was used to test the effectiveness of the intervention with a consideration of the time factor. Results Among 3867 participants, 102 had been vaccinated against HPV before the study (vaccination rate of 2.6%). A total of 3484 participants were followed up after the baseline survey, with no statistical difference in the loss rate between the intervention and control groups during the intervention and follow-up periods. At different follow-up time points, HPV-related knowledge, and the motivation, behavioral skills, and willingness regarding HPV vaccination were higher in the intervention group than in the control group. HPV-related knowledge was statistically different between the 2 groups, while the motivation, behavioral skills, and willingness regarding HPV vaccination only showed statistical differences right after the intervention, reaching a peak right after the intervention and then gradually reducing over time. Furthermore, there was no statistical difference in the HPV vaccination rate between the 2 groups. Conclusions IMB model–based online education could be a promising way to increase the HPV vaccination rate and reduce the burden of HPV infection and cervical cancer among high-risk female college students in China. Trial Registration Chinese Clinical Trial Registry ChiCTR1900025476; http://www.chictr.org.cn/showprojen.aspx? proj=42672 International Registered Report Identifier (IRRID) RR2-DOI:10.1186/s12889-019-7903-x

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

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

Feasibility and Acceptability of Pay-it-forward in Increasing Uptake of HPV Vaccination among 15- to 18-Year-Old Girls in China: Pilot RCT Results

Abstract China has a low human papillomavirus (HPV) vaccination rate due to limited public funding and mistrust in domestic vaccines. This pilot study aimed to evaluate the feasibility, acceptability, and preliminary effectiveness of an innovative pay-it-forward strategy to improve HPV vaccine uptake among adolescent girls. Conducted at a community health center in Western China (January 4–February 18, 2022), the study recruited 100 adolescent girls (ages 15–18 years) with no prior HPV vaccination. Participants were randomly assigned to either the standard-of-care arm (self-paid vaccines, n = 50) or the pay-it-forward arm (subsidized vaccines, handwritten postcards, and the opportunity to donate and/or write postcards, n = 50). Feasibility was assessed through recruitment, retention, and questionnaire completion rates. Acceptability and feasibility were measured using a standard scale. Preliminary effectiveness was evaluated by first-dose vaccination rate. Of 109 screened participants, 100 were eligible to participate (91.7%). The retention rate was 100% in both arms. The questionnaire completion rate was 98% (49/50) in the pay-it-forward arm and 82% (41/50) in the standard-of-care arm. Most participants self-reported that the strategy was feasible (97.6%, 41/42) and acceptable (90.5%, 38/42). Ninety-seven percent (97/100) of participants made vaccination appointments. The first-dose HPV vaccine uptake rate was 98% (49/50) in the pay-it-forward arm and 82% (41/50) in the standard-of-care arm (P &amp;lt; 0.05). No serious adverse events were identified. The pay-it-forward strategy was feasible and acceptable and showed preliminary effectiveness in increasing HPV vaccination uptake. Further refinement and population-based recruitment are needed to better reflect local contexts and enhance the generalizability of the formal trial. Prevention Relevance: The results of this pilot study demonstrate that the pay-it-forward strategy is both feasible and acceptable in increasing HPV vaccine uptake among 15- to 18-year-old girls. The future use of this strategy holds promise as an effective approach to enhance HPV vaccination rates that will eventually lead to a reduction in cervical cancer incidence.

14Works
15Papers
66Collaborators
1Trials
Uterine Cervical NeoplasmsOvarian NeoplasmsBiomarkers, TumorNeoplasm Recurrence, LocalAdenocarcinoma, MucinousPrognosisNeoplasm StagingCarcinoma, Ovarian Epithelial

Positions

2021–

Director

Hinova Pharmaceuticals Inc. · Translational Medicine and Cell Biology

2017–

Postdoctoral Researcher

George Washington University · Biochemistry and Molecular Medicine

Country

US

Keywords
DNA repairtranslational cancer research
Links & IDs
0000-0003-3029-0806

Scopus: 56412051900