Sintilimab combined with bevacizumab in relapsed or persistent ovarian clear cell carcinoma (INOVA): a multicentre, single-arm, phase 2 trial.

BACKGROUND: Ovarian clear cell carcinoma rarely responds to second-line chemotherapy, the recommended treatment for relapsed epithelial ovarian cancer. Here, we report the activity and safety of sintilimab in combination with bevacizumab in patients with relapsed or persistent ovarian clear cell carcinoma. METHODS: In the prospective, multicentre, single-arm, phase 2 INOVA trial, patients aged 18-75 years with histologically confirmed relapsed or persistent ovarian clear cell carcinoma were enrolled from eight tertiary hospitals in China. Eligible patients had an Eastern Cooperative Oncology Group performance status score of 0-2 and previous exposure to at least one cycle of platinum-containing chemotherapy. Enrolled patients received sintilimab (200 mg) and bevacizumab (15 mg/kg) intravenously every 3 weeks until disease progression. The primary endpoint was objective response rate assessed by independent central review based on Response Evaluation Criteria in Solid Tumours version 1.1. Eligible enrolled patients who received at least one cycle of treatment and had at least one tumour response assessment following the baseline assessment per protocol were included in the activity analysis. Patients who received at least one dose of study drug were included in the safety analysis. The study is registered with ClinicalTrials.gov (NCT04735861) and is ongoing. FINDINGS: Between April 8, 2021, and July 3, 2023, 51 patients were screened and 41 patients received at least one dose of sintilimab in combination with bevacizumab. Response evaluation was completed in 37 patients. Objective responses were observed in 15 patients (objective response rate 40·5%; 95% CI 24·8-57·9), of which five (14%) were complete responses and ten (27%) were partial responses. At data cutoff (Jan 29, 2024), the median follow-up was 16·9 months (IQR 7·5-23·4). Three (7%) patients developed grade 3 treatment-related adverse events including one patient with proteinuria, one patient with myocarditis, and one patient with rash. No treatment-related adverse events of worse than grade 3 severity were recorded. Treatment-related serious adverse events occurred in two (5%) patients including one patient with immune-related myocarditis and another with hypertension and renal dysfunction. No treatment-related deaths occurred. INTERPRETATION: Sintilimab in combination with bevacizumab showed promising anti-tumour activity and manageable safety in patients with relapsed or persistent ovarian clear cell carcinoma. Larger, randomised trials are warranted to compare this low-toxicity, chemotherapy-free combinatorial regimen with standard chemotherapy. FUNDING: National Key Technology Research and Development Program of China, National Natural Science Foundation of China, Beijing Xisike Clinical Oncology Research Foundation, and Innovent Biologics. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Endocytic recycling in plants: pathways and regulation.

Endocytic recycling is an intracellular trafficking pathway that returns endocytosed molecules to the plasma membrane via the recycling endosome. This pathway plays a crucial role in remodelling plasma membrane composition and is thus essential for cellular homeostasis. In plants, endocytic recycling regulates the localization and abundance of receptors, transporters, and channels at the plasma membrane that are involved in many aspects of plant growth and development. Despite its importance, the recycling endosome and the underlying sorting mechanisms for cargo recycling in plants remain understudied in comparison to the endocytic recycling pathways in animals. In this review, we focus on the cumulative evidence suggesting the existence of endosomes decorated by regulators that contribute to recycling in plant cells. We summarize the chemical inhibitors used for analysing cargo recycling and discuss recent advances in our understanding of how endocytic recycling participates in various plant cellular and physiological events.

Interleukin-2 promotes pegylated interferon alpha for hepatitis B surface antigen loss: A retrospective pragmatic clinical study at the Fourth Affiliated Hospital of Zhejiang University Medical College.

Background and Aims: Interleukin-2 (IL-2) can be used as an adjuvant therapy when pegylated interferon alpha (Peg-IFN-α) does not effectively promote hepatitis B surface antigen (HBsAg) loss, but the relevant timing, kinetic patterns, and prognostic associations of this intervention are unclear. Methods: A total of 115 patients with chronic hepatitis B (CHB) treated at our institution between October 2018 and March 2021 were included in this retrospective analysis. They were divided into two kinetic patterns by using K-medoids cluster analysis. Profile and prognostic associations were statistically analyzed between the two patterns. Results: After baseline standardization, before the intervention, the relative HBsAg level showed a continuously increasing trend, but after the intervention, it showed a continuously decreasing trend. Based on the relative change in the HBsAg level, two kinetic patterns, namely, a fluctuation platform pattern and a stepwise growth pattern, were identified by using K-medoids cluster analysis for all 115 patients before IL-2 intervention. Profile analysis showed that there were statistically significant differences between the two patterns before IL-2 intervention (p < 0.05), but their profiles showed the same trend after 2 weeks of IL-2 intervention. Prognostic association analysis showed that CD8+ T cells, alanine transaminase (ALT), age, natural killer (NK) cells, neutrophils, and course of treatment before IL-2 intervention were the six main indicators affecting the relative decrease in the HBsAg level. Conclusion: For CHB patients who have received continuous Peg-IFN-α treatment, IL-2 intervention should be given as early as possible when the HBsAg level has not decreased for four consecutive weeks or a fluctuation platform pattern is observed. After the intervention, a downward relative change in the HBsAg level can be maintained over 4 weeks. CD8+ T cells, ALT, NK cells, and neutrophils are baseline indicators closely related to the prognosis of this intervention.

Corrigendum: Long Non-Coding RNAs in the Tumor Immune Microenvironment: Biological Properties and Therapeutic Potential.

[This corrects the article DOI: 10.3389/fimmu.2021.697083.].

Targeting DNA Repair Response Promotes Immunotherapy in Ovarian Cancer: Rationale and Clinical Application.

Immune checkpoint inhibitors (ICI) have emerged as a powerful oncologic treatment modality for patients with different solid tumors. Unfortunately, the efficacy of ICI monotherapy in ovarian cancer is limited, and combination therapy provides a new opportunity for immunotherapy in ovarian cancer. DNA damage repair (DDR) pathways play central roles in the maintenance of genomic integrity and promote the progression of cancer. A deficiency in DDR genes can cause different degrees of DNA damage that enhance local antigen release, resulting in systemic antitumor immune responses. Thus, the combination of DDR inhibitors with ICI represents an attractive therapeutic strategy with the potential to improve the clinical outcomes of patients with ovarian cancer. In this review, we provide an overview of the interconnectivity between DDR pathway deficiency and immune response, summarize available clinical trials on the combination therapy in ovarian cancer, and discuss the potential predictive biomarkers that can be utilized to guide the use of combination therapy.

Long Non-Coding RNAs in the Tumor Immune Microenvironment: Biological Properties and Therapeutic Potential.

Cancer immunotherapy (CIT) is considered a revolutionary advance in the fight against cancer. The complexity of the immune microenvironment determines the success or failure of CIT. Long non-coding RNA (lncRNA) is an extremely versatile molecule that can interact with RNA, DNA, or proteins to promote or inhibit the expression of protein-coding genes. LncRNAs are expressed in many different types of immune cells and regulate both innate and adaptive immunity. Recent studies have shown that the discovery of lncRNAs provides a novel perspective for studying the regulation of the tumor immune microenvironment (TIME). Tumor cells and the associated microenvironment can change to escape recognition and elimination by the immune system. LncRNA induces the formation of an immunosuppressive microenvironment through related pathways, thereby controlling the escape of tumors from immune surveillance and promoting the development of metastasis and drug resistance. Using lncRNA as a therapeutic target provides a strategy for studying and improving the efficacy of immunotherapy.

Clinical Efficacy and Safety of Apatinib for the Treatment of Patients with Metastatic, Recurrent Cervical Cancer after Failure of Radiotherapy and First-Line Chemotherapy: A Prospective Study.

PURPOSE: As a small-molecule tyrosine kinase inhibitor of vascular endothelial growth factor receptor 2 (VEGFR2), apatinib has shown a survival benefit in multiple solid tumors. This study aims to evaluate the efficacy and safety of apatinib in patients with metastatic, recurrent cervical cancer after failure of radiotherapy and first-line chemotherapy. METHODS: A total of 42 patients between June 2018 and March 2019 were involved in this study. All patients orally received apatinib once daily in a 4-week cycle until disease progression or adverse events that prohibit further therapy. The primary endpoint was progression-free survival (PFS), the secondary endpoints were overall survival (OS), objective response rate (ORR), disease control rate (DCR), health-related quality of life (HRQoL) and adverse events. RESULTS: During a median follow-up of 13 months, 8 patients achieved a partial response and 24 cases achieved stable disease. None of them reported a complete response. The ORR and DCR were 19.0 and 76.2%, respectively. The median PFS was 6.0 months (95% CI 4.9-7.1), and the median OS was 12.0 months (95% CI 10.1-13.9). The global health score/HRQoL improved significantly following 3-cycle treatment (50.4 ± 12.5 vs. 60.1 ± 11.8; p < 0.01). The most frequent grade 3-4 adverse events were hand-foot syndrome, hypertension and fatigue. CONCLUSION: Apatinib should be an effective and tolerable treatment option for patients with metastatic, recurrent cervical cancer after failure of radiotherapy and first-line chemotherapy.

Effects of low doses of UV-B radiation supplementation on tuber quality in purple potato (Solanum tuberosum L.).

UV-B is an important environmental factor that differentially affects plant growth and secondary metabolites. However, our knowledge regarding the physiological and biochemical changes in under-ground plant organs responded to UV-B treatment remains limited. In this study, we investigated potato plant (Solanum tuberosum L.) and tuber responses to short-term supplemental UV-B exposure performed during tuber development. Our results indicated that the supplemental UV-B radiation with relative low dose had no obvious adverse impact on plant growth or tuber production. Nutritional composition analyses of tubers revealed that the contents of starch, soluble sugars, and proteins were significantly increased under lower UV-B radiation relative to controls. Similarly, low dose of UV-B treatment promoted the health-promoting compounds, including anthocyanin, phenols, and flavonoids in tubers. Moreover, higher activities of antioxidant enzymes were significantly induced in tubers in response to lower UV-B radiation. These findings suggest that short-term UV-B radiation supplementation at relative low doses can improve the tuber quality in potato plants.

Irradiation with low-dose gamma ray enhances tolerance to heat stress in Arabidopsis seedlings.

Gamma irradiation at low doses can stimulate the tolerance to environmental stress in plants. However, the knowledge regarding the mechanisms underlying the enhanced tolerance induced by low-dose gamma irradiation is far from fully understood. In this study, to investigate the physiological and molecular mechanisms of heat stress alleviated by low-dose gamma irradiation, the Arabidopsis seeds were exposed to a range of doses before subjected to heat treatment. Our results showed that 50-Gy gamma irradiation maximally promoted seedling growth in response to heat stress. The production rate of superoxide radical and contents of hydrogen peroxide and malondialdehyde in the seedlings irradiated with 50-Gy dose under heat stress were significantly lower than those of controls. The activities of antioxidant enzymes, glutathione (GSH) content and proline level in the gamma-irradiated seedlings were significantly increased compared with the controls. Furthermore, transcriptional expression analysis of selected genes revealed that some components related to heat tolerance were stimulated by low-dose gamma irradiation under heat shock. Our results suggest that low-dose gamma irradiation can modulate the physiological responses as well as gene expression related to heat tolerance, thus alleviating the stress damage in Arabidopsis seedlings.

Effects of low-energy N(+)-beam implantation on root growth in Arabidopsis seedlings.

The effects of ion implantation on the morphology changes and biological responses of plants are dependent on implantation doses. Previous studies mainly focus on the application of ion-beam technology in genetic mutation. Our knowledge regarding the mechanism underlying the plant growth inhibition induced by ion implantation remains limited. In this study, we explore the responses of root growth to low-energy N(+)-beam implantation using implanted Arabidopsis seeds. Our results showed that the root and root tip length were obviously reduced by implantation with large doses of low-energy N(+) beam. The analysis of confocal images showed that ion implantation reduced the cell viability and cell division activity in root meristem. The production rate of superoxide radical (O2(•-)) and contents of hydrogen peroxide (H2O2) in roots under ion implantation were markedly higher than those of controls. Transcriptional expression analysis of selected genes revealed that Arabidopsis RBOH genes associated with reactive oxygen species (ROS) production were significantly up-regulated in roots in response to ion implantation. The activities of antioxidant enzymes were also induced by ion implantation. Moreover, ROS scavenging obviously enhanced cell viability and cell division in response to ion implantation and alleviated the root growth inhibition of the implanted seedlings. Our results suggest that the overproduction of ROS induced by ion implantation is involved in the inhibitory effect of low-energy ion beam on root growth by affecting the cell viability and cell division of root meristem in Arabidopsis seedlings.

Pretreatment with low-dose gamma irradiation enhances tolerance to the stress of cadmium and lead in Arabidopsis thaliana seedlings.

Heavy metals are important environmental pollutants with negative impact on plant growth and development. To investigate the physiological and molecular mechanisms of heavy metal stress mitigated by low-dose gamma irradiation, the dry seeds of Arabidopsis thaliana were exposed to a Cobalt-60 gamma source at doses ranging from 25 to 150Gy before being subjected to 75µM CdCl2 or 500µM Pb(NO3)2. Then, the growth parameters, and physiological and molecular changes were determined in response to gamma irradiation. Our results showed that 50-Gy gamma irradiation gave maximal beneficial effects on the germination index and root length in response to cadmium/lead stress in Arabidopsis seedlings. The hydrogen peroxide and malondialdehyde contents in seedlings irradiated with 50-Gy gamma rays under stress were significantly lower than those of controls. The antioxidant enzyme activities and proline levels in the irradiated seedlings were significantly increased compared with the controls. Furthermore, a transcriptional expression analysis of selected genes revealed that some components of heavy metal detoxification were stimulated by low-dose gamma irradiation under cadmium/lead stress. Our results suggest that low-dose gamma irradiation alleviates heavy metal stress, probably by modulating the physiological responses and gene expression levels related to heavy metal resistance in Arabidopsis seedlings.

ROS and ABA signaling are involved in the growth stimulation induced by low-dose gamma irradiation in Arabidopsis seedling.

It has been well established that gamma rays at low doses have stimulatory effects on plant growth and development. However, our knowledge regarding the molecular mechanism underlying the growth stimulation remains limited. In this study, we report the role of reactive oxygen species (ROS) and abscisic acid (ABA) in the growth stimulation using irradiated Arabidopsis seeds. The results indicated that 50 Gy gamma irradiation presented maximal beneficial effects on germination index, root length, and fresh weight. The contents of hydrogen peroxide (H2O2) and activities of antioxidant enzymes under gamma irradiation were markedly higher than those of controls. ROS scavenging significantly suppressed the growth of the irradiated plants. Furthermore, endogenous ABA was induced under low-dose gamma irradiation. The growth stimulation and elevated H2O2 level were affected in the irradiated ABA-deficient mutant aba2-1 compared with the mutant control. Transcriptional expression analysis of selected genes revealed that several genes for ABA biosynthesis were upregulated, and the genes for ABA catabolic pathway and transport were differentially regulated in response to low-dose gamma irradiation. Our results suggest that ROS and ABA signaling play an essential role in the stimulatory effects of low-dose gamma irradiation and that ROS, as secondary molecules, mediate ABA signal transduction under irradiation in response to stress factors during plant growth.

Temporal trends of copper-bearing intrauterine device discontinuation: a population-based birth-cohort study of contraceptive use among rural married women in China.

Copper-bearing intrauterine device (IUD) insertion for long-term contraceptive use is high in China, but there has been evidence that first-year discontinuation rate of copper-bearing IUD has also increased rapidly in recent years especially among rural married women. To investigate long-term use of copper-bearing IUD, the authors examined the 7-year temporal trends of copper-bearing IUD discontinuation in a population-based birth-cohort study among 720 rural married women in China, from 2004 to 2012. Women requesting contraception were followed-up twice per year after the insertion of IUD. The gross cumulative life table discontinuation rates were calculated for each of the main reasons for discontinuation as well as for all reasons combined. By the end of 7 years, 384 discontinuations were observed. With a stepped-up trend, the gross cumulative life table rate for discontinuation increased from 10.06 (95% confidence interval = 7.86-12.27) per 100 women by the first year to 52.69 (95% confidence interval = 48.94-56.44) per 100 women by the end of 7 years, which increased rapidly in the first 2 years after copper-bearing IUD insertion, flattened out gradually in the following 2 years, then increased again in the last 3 years. Among reported method failure, expulsion and side effects were the main reasons for discontinuation of the copper-bearing IUD but not pregnancy. Personal reasons, such as renewal by personal will had influenced copper-bearing IUD use since the second year and should not be neglected. Based on this study, the temporal trends of copper-bearing IUD discontinuation was in a stepped-up trend in 7 years after insertion. Both reported method failure (expulsion and side effect) and personal reason had effect on the discontinuation of copper-bearing IUD, but pregnancy was no more the most important reason affecting the use of copper-bearing IUD.

Physiological and molecular characterization of the enhanced salt tolerance induced by low-dose gamma irradiation in Arabidopsis seedlings.

It has been established that gamma rays at low doses stimulate the tolerance to salt stress in plants. However, our knowledge regarding the molecular mechanism underlying the enhanced salt tolerance remains limited. In this study, we found that 50-Gy gamma irradiation presented maximal beneficial effects on germination index and root length in response to salt stress in Arabidopsis seedlings. The contents of H2O2 and MDA in irradiated seedlings under salt stress were significantly lower than those of controls. The activities of antioxidant enzymes and proline levels in the irradiated seedlings were markedly increased compared with the controls. Furthermore, transcriptional expression analysis of selected genes revealed that some components of salt stress signaling pathways were stimulated by low-dose gamma irradiation under salt stress. Our results suggest that gamma irradiation at low doses alleviates the salt stress probably by modulating the physiological responses as well as stimulating the stress signal transduction in Arabidopsis seedlings.